Substituted quinazolinone derivatives and their use as positive allosteric modulators of mGluR4

Abstract

The present invention relates to novel quinazolinone derivatives of formula (I), as well as pharmaceutical compositions containing these compounds. The compounds of formula (I) provided herein can act as positive allosteric modulators of metabotropic glutamate receptor subtype 4 (mGluR4) and can therefore be used as therapeutic agents, particularly in the treatment or prevention of conditions associated with altered glutamatergic signaling and / or functions or conditions that may be affected by alterations in glutamate levels or signaling. TIFF2022511236000407.tif50170

Description

[Technical Field]

[0001] The present invention relates to novel quinazolinone derivatives of formula (I), as well as pharmaceutical compositions containing these compounds. The compounds of formula (I) provided herein can be used as therapeutic agents, particularly in the treatment or prevention of conditions associated with altered glutamatergic signaling and / or functions or conditions that may be affected by alterations in glutamate levels or signaling, as they can act as positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). [Background technology]

[0002] Glutamate is the major amino acid transmitter in the mammalian central nervous system (CNS). Glutamate plays a key role in numerous physiological functions, including sensory perception, synaptic plasticity, motor control, and the regulation of respiratory and cardiovascular function, as well as learning and memory. Furthermore, glutamate is central to several different neurological and psychiatric disorders in which an imbalance in glutamatergic neurotransmission is observed.

[0003] Glutamate mediates synaptic neurotransmission through activation of ionotropic glutamate receptor channels (iGluRs), i.e., NMDA, AMPA, and kainate receptors, which are involved in fast excitatory transmission (Nakanishi S et al. (1998) Brain Res. Rev. 26:230-235).

[0004] Furthermore, glutamate activates metabotropic glutamate receptors (mGluRs), which play a more regulatory role in fine-tuning synaptic efficacy. mGluRs are G protein-coupled receptors (GPCRs) with seven transmembrane domains and belong to GPCR family 3, along with calcium-sensing receptors, GABA receptors, and pheromone receptors. The mGluR family consists of eight members, which are classified into three groups according to sequence homology, pharmacological profile, and the nature of the intracellular signaling cascades activated: group I, including mGluR1 and mGluR5; group II, including mGluR2 and mGluR3; and group III, including mGluR4, mGluR6, mGluR7, and mGluR8 (Schoepp D et al. (1999) Neuropharmacology, 38:1431-1476).

[0005] Glutamate activates mGluRs through binding to the large extracellular amino-terminal domain of the receptor, referred to herein as the orthosteric binding site. This activation induces a conformational change in the receptor, which results in activation of G-proteins and intracellular signaling pathways.

[0006] In the central nervous system, mGluR4 receptors are most abundantly expressed in the cerebellar cortex, basal ganglia, sensory relay nuclei of the thalamus, and the hippocampus (Bradley SR et al. (1999) Journal of Comparative Neurology 407:33-46; Corti C et al. (2002) Neuroscience 1 10:403-420). The mGluR4 subtype is negatively coupled to adenylate cyclase via activation of Gi / o proteins, is expressed primarily in presynaptic terminals, and acts as an autoreceptor or heteroreceptor; activation of mGluR4 reduces transmitter release from presynaptic terminals (Corti C et al. (2002) Neuroscience 1 10:403-420; Millan C et al. (2002) Journal of Biological Chemistry 277:47796-47803; Valenti O et al. (2003) Journal of Neuroscience 23:7218-7226). In some brain tissues, such as the rodent cerebellar cortex, mGluR4 receptors can also couple to Gq proteins and the PLC effector system, also reducing glutamate synaptic transmission (Chardonnet S et al. (2017) Neuropharmacology 121:247-260).

[0007] Until the recent discovery of mGluR subtype selectivity within group III and the variable pocket involved in the adjacent glutamate binding site (Goudet C et al. (2012) FASEB J 26(4):1682-93; Selvam C et al. (2018) J Med Chem 61(5):1969-89), most orthosteric agonists for mGluR4 were not selective and therefore could activate other group III mGluRs (Schoepp D et al. (1999) Neuropharmacology 38:1431-1476). The group III orthosteric agonist L-AP4 (L-2-amino-4-phosphonobutyrate) can suppress motor dysfunction in animal models of Parkinson's disease (Valenti O et al. (2003) J. Neurosci. 23:7218-7226) and reduce excitotoxicity (Bruno V et al. (2000) J. Neurosci. 20:6413-6420), and these effects appear to be mediated through mGluR4 (Marino MJ et al. (2005) Curr. Topics Med. Chem. 5:885-895). In addition to L-AP4, another selective group III mGluR agonist, ACPT-1, has been shown to cause a dose- and structure-dependent reduction in haloperidol-induced catalepsy and a reduction in haloperidol-enhanced proenkephalin mRNA expression in the striatum (Konieczny J et al. (2007) Neuroscience 145:611-620). Furthermore, Lopez et al. (2007) J. Neuroscience 27:6701-6711 showed that bilateral injection of ACPT-1 or L-AP4 into the globus pallidus completely abolished the severe akinesia deficits caused by 6-hydroxydopamine lesions of nigrostriatal dopamine neurons in a reaction time task without affecting control performance. Furthermore, the abrogation of haloperidol-induced catalepsy by intrapallidal ACPT-1 was prevented by concomitant administration of the selective group III receptor antagonist (R5)-alpha-cyclopropyl-4-phosphonophenylglycine.These results suggest that among the mGluR subtypes, group III mGluRs, and in particular mGluR4, represent highly interesting novel drug targets for the treatment of Parkinson's disease (for review, see Conn PJ et al. (2005) Nature Review Neuroscience 6:787-798; more recently, Charvin D (2018) Neuropharmacology 135:308-315).

[0008] The common endpoint of Parkinson's disease (PD) pathology is the progressive degeneration of dopaminergic neurons located in the substantia nigra pars compacta (SNpc), which project into the striatum and release dopamine. PD symptoms typically appear when more than 60% of SNpc neurons have already been lost. This results in severe movement abnormalities, including resting tremor, rigidity and stiffness, gait and balance control dysfunction, and dementia, which dramatically deteriorate the quality of life of patients and their families.

[0009] Current treatments attempt to replace missing dopamine or mimic its effects by providing patients with the dopamine precursor L-DOPA, inhibitors of dopamine-degrading enzymes (MAO inhibitors), or direct dopamine receptor agonists for extended periods. While these treatments have proven relatively effective in managing the core symptoms of PD, their long-term administration is associated with severe side effects. Classical treatment of parkinsonism typically involves the use of levodopa in combination with carbidopa (SINEMET™) or benserazide (MADOPAR™). Dopamine agonists, such as bromocriptine (PARLODEL™), lisuride, and pergolide (CELANCE™), act directly on dopamine receptors and are also used to treat parkinsonism. These molecules have the same side effect profile as levodopa. For example, after several years of treatment, the efficacy of L-DOPA tends to decrease in intensity and stability, causing inconsistent on / off periods that require extended dosing intervals. Furthermore, long-term administration of high doses of L-DOPA is associated with the development of involuntary movements (dyskinesias). Despite various attempts to address this disorder, levodopa-induced dyskinesias affect nearly all levodopa-treated PD patients at some point during the course of the disease (Rascol O et al. (2015) Mov Disord 30(11):1451-1460). Therefore, and because 86% of PD patients are currently receiving levodopa treatment, there is an urgent clinical need to improve levodopa-induced dyskinesias (Hechtner MC et al. (2014) Park Relat Disord 20:969-74). The large dopamine supply in the brain is also associated with psychiatric abnormalities, including depression, psychotic symptoms, obsessive-compulsive behavior, and sleep abnormalities. Finally, no compounds for PD in the current pharmacopoeia have demonstrated neuroprotective activity to slow disease progression. Therefore, efforts are needed to develop new treatments for PD that target neurochemical systems downstream of dopamine itself to address these important unmet medical needs.

[0010] Dopamine control of movement in healthy subjects follows a complex pattern of interactions between neurochemical systems and brain structures, according to a model described over the past decade (Wichmann T and Delong MR, (2003) Adv Neurol 91:9-18). This model is currently being developed to provide a more detailed understanding of the operation of the basal ganglia (for reviews, see Kravitz AV et al. (2010) Nature 466:622-26; Cui G et al. (2013) Nature 494:238-42; Cazorla M et al. (2015) Mov Disord 30:895-903). The basal ganglia, primarily consisting of the substantia nigra (SN) and the striatal and thalamic complex, constitute the basis for these interactions. The internal segment of the globus pallidus (GPi) and the SN pars reticularis (SNpr) act as relays between cortical areas that directly control movement and the basal ganglia themselves. GPi and SNpr receive both direct inhibitory connections (direct pathway) and indirect excitatory inputs (indirect pathway) from the basal ganglia. Both pathways are regulated by dopamine with opposite valence, such that the direct pathway is stimulated while the indirect pathway is inhibited by dopamine. As a result, in affected brains, dopamine deficiency leads to dysregulation of the output activity of both the direct and indirect pathways. Specifically, the indirect pathway is overactivated, as reflected by increased GABA release into the external segment of the globus pallidus (GPe). As a result, glutamate release increases in the SN pars compacta (SNpc), GPi, and SNpr. This imbalance in neurotransmission in the direct and indirect pathways is thought to cause abnormalities in motor control and accelerated neurodegeneration of dopaminergic neurons. Dissecting these pathways has provided insight into the possibility of targeting neurochemical pathways downstream of dopamine to restore function in the PD brain without directly interfering with it. In particular, metabotropic glutamate receptors (mGluRs) have been shown to regulate neurotransmitter release at the presynaptic level.Specifically, mGluR4, which is predominantly expressed in distinct brain regions, has been demonstrated to suppress glutamate and GABA neurotransmission at the subthalamic nucleus (STN)-SNpc (Valenti O et al. (2005) J Pharmacol Exp Ther 313:1296-1304) and striatum-GPe (Valenti O et al. (2003) J Neurosci 23:7218-7226; Cuomo D et al. (2009) J Neurochem 109:1096-1105) synapses, respectively. mGluR4 is more abundant at striatopallidal than at striatonigral synapses, and its localization suggests its function as a presynaptic heteroreceptor on GABAergic neurons (Bradley SR et al. (1999) Journal of Comparative Neurology 407:33-46). Selective activation or positive modulation of mGluR4 may decrease GABA release at this synapse, thereby reducing indirect pathway output and reducing or eliminating Parkinson's disease symptoms. Furthermore, mGluR4 is also expressed presynaptically on corticostriatal glutamatergic terminals that target indirect pathway neurons (Bradley SR et al. (1999) J Comp Neurol 407:33-46). Activation of mGluR4 at this site is predicted to preferentially inhibit stimulation of the already highly active indirect pathway while maintaining excitation of the direct pathway, thereby normalizing basal ganglia output (Bennouar KE et al. (2013) Neuropharmacology 66:158-69; Gubellini P et al. (2014) Neuropharmacology 85:166-77; Iskhakova L et al. (2016) Brain Struct Funct 221(9):4589-99).

[0011] Furthermore, behavioral analyses confirmed the beneficial effects of mGluR4 stimulation in both chronic and acute rat models of PD motor symptoms. For example, the cataleptic behavior observed after haloperidol administration and reserpine-induced immobility were both abolished by positive allosteric modulators (PAMs), such as VU0155041 (Niswender CM et al. (2008) Mol Pharmacol 74:1345-1358; Niswender CM et al. (2016) ACS Chem Neurosci 7:1201-11; Le Poul E et al. (2012) J Pharmacol Exp Therapeut 343:167-77; Charvin D et al. (2017) J Med Chem 60(20):8515-37). These basic models mimic key features of the human disease: rigidity and akinesia, respectively. More advanced models of PD motor symptoms (such as unilateral or bilateral 6-OHDA in rats or the MitoPark mouse transgenic model) have also been used to demonstrate the efficacy of PAM-activating group III mGluRs, specifically mGluR4 (Dube A et al. (2014) J Neurol Sci 510(14):452-53; Niswender CM et al. (2016) ACS Chem Neurosci 7:1201-11; Le Poul E et al. (2012) J Pharmacol Exp Therapeut 343:167-77; Charvin D et al. (2017) J Med Chem 60(20):8515-37).

[0012] Finally, increased glutamate release is thought to be at least partially responsible for the degeneration of remaining dopaminergic neurons, thereby worsening their condition and reducing the efficacy of treatment. Thus, the mGluR4 positive allosteric modulator (PAM) PHCCC, which reduces glutamate release, also protects neurons from further degeneration in rats treated with the neurotoxin 6-hydroxydopamine (6-OHDA), which selectively destroys dopaminergic neurons (Vernon AC (2009) J Neurosci 29:12842-12844; Betts MJ et al. (2012) Br J Pharmacol 166:2317-30). Similar results were obtained with PHCCC in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Battaglia G et al. (2006) J Neurosci 26:722-29) or in NMDA-lesioned mice using the group III mGluR agonist (+)-4-phosphonophenylglycine PPG (Bruno V et al. (2000) J Neurosci 20:6413-20).

[0013] More recently, the mGluR4 PAM compounds of invention WO2017 / 032874 have been found to be highly effective in preventing and / or treating levodopa-induced dyskinesia (LID), as demonstrated in the MPTP monkey model. These results confirm the therapeutic potential of group III mGluR activators to reduce dyskinesia incidence, as previously published several years ago using another mGluR4 PAM compound, namely LuAF21934, in the 6-OHDA rat model of LID (Bennouar KE et al. (2013) Neuropharmacology 66:158-69).

[0014] Altogether, these results suggest that stimulation of mGluR4, and more generally of group III mGluRs, is likely to alleviate PD symptoms, including levodopa-induced dyskinesia, in patients and provide neuroprotection to remaining neurons.

[0015] An emerging avenue for developing selective compounds that act at mGluRs is to identify molecules that act via allosteric mechanisms and modulate the receptors by binding to sites distinct from the highly conserved orthosteric binding site.

[0016] Positive allosteric modulators of mGluRs have recently emerged as novel pharmacological entities that offer this attractive alternative. Molecules of this type have been found in mGluR1, mGluR2, mGluR3, mGluR4, mGluR5, mGluR7, and mGluR8 (Knoflach F et al. (2001) Proc. Natl. Acad. Sci. USA 98:13402-13407; Johnson MP et al. (2002) Neuropharmacology 43:799-808; O'Brien JA et al. (2003) Mol. Pharmacol. 64:731-740; Johnson MP et al. (2003) J. Med. Chem. 46:3189-3192; Marino MJ et al. (2003) Proc. Natl. Acad. Sci. USA 100:13668-13673; Mitsukawa K et al. (2005), Proc. Natl. Acad. Sci. USA, 102(51):18712-18717, Wilson J et al. (2005), Neuropharmacology, 49:278, Mutel V (2002), Expert Opin. Ther. Patents, 12:1-8, Kew JN (2004), Pharmacol. Ther., 104(3):233-244, Johnson M. et al. (2004), Biochem. Soc. Trans., 32:881-887, Ritzen A, Mathiesen, JM and Thomsen C (2005), Basic Clin. Pharmacol. Toxicol., 97:202–213, Schann S et al. (2010), J Med Chem, 53(24):8775-79).

[0017] Looking closely at group III mGluRs, examples of allosteric ligands have been described for most mGluR subtype 4 (mGluR4): PHCCC, MPEP, and SIB1893 (Maj M et al. (2003), Neuropharmacology, 45(7), 895-903; Mathiesen JM et al. (2003), Br. J. Pharmacol. 138(6), 1026-30) were the first to be described in 2003. More recently, more potent positive allosteric modulators have been reported by different universities and private companies in the literature (Niswender CM et al. (2008) Mol. Pharmacol. 74(5) 1345-58; Niswender CM et al. (2008) Bioorg. Med. Chem. Lett 18(20) 5626-30; Williams R et al. (2009) Bioorg. Med. Chem. Lett. 19(3) 962-6; Engers DW et al. (2009) J. Med. Chem. 52(14):4115-18; Le Poul E et al. (2012) J Pharmacol Exp Therapeut 343:167-77; Bennouar They have been reported in KE et al. (2013), Neuropharmacology, 66:158-69, Dube A et al. (2014), J Neurol Sci, 510(14):452-53, and in two patent publications (WO2009 / 010454 and WO2009 / 010455) describing a family of amides and heteroaromatic compounds, and also published in Charvin D et al. ((2017), J Med Chem, 60:8515-37).

[0018] Few allosteric ligands have been identified for other group III mGluR subtypes. AMN082 is an mGluR7-specific allosteric agonist that binds in the seven-transmembrane domain of the receptor, while XAP044 is an antagonist that binds in the large amino-terminal extracellular domain, but at a site distinct from glutamate itself (Mitsukawa K et al. (2005) PNAS 102(51):18712-17; Gee CE et al. (2014) J Biol Chem 289(16):10975-87). Another series of mGluR7 negative allosteric modulator (NAM) chemicals with undisclosed structures are currently being developed by Pragma Therapeutics for hearing loss and stress disorders. AZ12216052 is an mGluR8 PAM discovered by Astra Zeneca that has been shown to reduce measures of anxiety in several rodent models (Duvoisin et al. (2010) Behav Brain Res 212(2):168-73).

[0019] PHCCC (N-phenyl-7-(hydroxyimino)cyclopropa[6]chromene-1a-carboxamide), a positive allosteric modulator of mGluR4 that is not active at other mGluRs (Maj et al. (2003) Neuropharmacology 45:895-906), has been shown to be effective in animal models of Parkinson's disease and therefore may be useful in the treatment of Parkinson's disease and other movement disorders and dyskinesias (Marino et al. (2003) Proc. Nat. Acad. Sci. USA 100:13668-13673), as well as neurodegeneration in Parkinson's disease (Marino et al. (2005) Curr. Topics Med. Chem. 5:885-895; Valenti et al. (2005) J. Pharmacol. Exp. Ther., 313:1296-1304; Vernon et al. (2005), Eur. J. Neurosci., 22:1799-1806; Battaglia et al. (2006), J. Neurosci., 26:7222-7229) represent a potential novel therapeutic avenue. Since these seminal publications, other mGluR4 positive modulators, and more generally group III mGluR positive modulators, have shown promising results in animal models of Parkinson's disease and neurodegeneration (Conn J et al. (2005), Nat Rev. Neuroscience, 6(10), pp. 787-98; Vernon AC et al. (2007), J. Pharmacol. Exp. Then, 320(1), pp. 397-409; Lopez S et al. (2008), Neuropharmacology, 55(4), pp. 483-90; Vernon AC et al. (2008), Neuroreport, 19(4), pp. 475-8; Niswender CM et al. (2008), Mol. Pharmacol. 74(5), pp. 1345-58).Other subtypes of group III mGlu receptors, namely mGluR7 and mGluR8, have also been demonstrated to have potential neuroprotective activity (Wang WY et al. (2012) Neuroscience 205:167-77) and anti-Parkinson's disease activity (for reviews see Amalric M et al. (2013) Neuropharm 66:53-64; Amalric M (2015) Curr Opin Pharmacol 20:29-34; Gubellini P et al. (2017) The Receptors, Humana Press, pp. 33-57; Litim N et al. (2017) Neuropharm 115:166-179). Indeed, the mGluR7-specific allosteric agonist AMN082 has been shown to reverse haloperidol-induced catalepsy and akinesia in reserpine-treated rats (Greco B et al. (2010) J Pharmacol Exp Ther 332(3):1064-71; Broadstock M et al. (2012) British J of Pharmacol 165(4b):1034-45; Konieczny J and Lenda T (2013) Pharmacol Rep 65(5):1194-203). The involvement of the mGluR8 subtype was also tested using the specific agonist (S)-3,4-dicarboxyphenylglycine (DCPG), which was shown to reverse prolonged (three doses of reserpine or haloperidol given spaced over a period of 18–20 h before measurement) but not acute (a single dose of reserpine or haloperidol given 2 h before measurement) catalepsy and akinesia, indicating that activation of this subtype may be particularly important to restore promoter effects in cases of prolonged dopamine depletion (Johnson KA et al. (2013) Neuropharmacol 66:187–95).

[0020] PHCCCs have shown neuroprotection from beta-amyloid protein toxicity and NMDA toxicity in mixed cultures of mouse cortical neurons, thereby demonstrating the ability of mGluR4 positive modulators to protect against neurodegeneration in Alzheimer's disease or from ischemic or traumatic insults (Maj et al. (2003) Neuropharmacology 45:895-906). Other studies examine the potential use of group III mGluRs to treat Alzheimer's disease. Interesting data in this direction come from in vivo data using mGluR7 knockout mice, which showed that group III mGluR7 promotes short-term memory (Holscher C et al. (2004) Behav Brain Res 154(2):473-81).

[0021] The neuroprotective potential of the group III mGlu receptor agonist ACPT-I was recently demonstrated in an animal model of ischemic stroke using both in vitro and in vivo studies, revealing that group III mGluR activation can not only be neuroprotective against ischemic neuronal injury but also suppress post-ischemic dysfunction (Domin H et al. (2016) Neuropharmacology 102:276-94).

[0022] mGluR4 positive allosteric modulators, such as PHCCC or ADX88178, have also been shown to be active in animal models of anxiety (Stachowicz et al. (2004), Eur. J. Pharmacol., 498:153-156; Kalinichev M et al. (2014), J. Pharmacol Exp Ther, 350(3):495-505) and depression (Palucha A et al. (2004), Neuropharmacology 46(2), 151-9). Previously, the group III mGluR agonist ACPT-1 was shown to produce dose-dependent anticonflict effects after intrahippocampal administration and antidepressant-like effects after intracerebroventricular administration in rats (Tatarczynska et al. (2002), Pol. J. Pharmacol., 54(6):707-710). The antidepressant effect was enhanced when a combination of both PHCCC and ACPT-1 compounds was used (Klak K et al. (2006), Amino Acids 32(2), pp. 169-72). More recently, ACPT-1, when injected intraperitoneally, has also been shown to have tranquilizer-like effects in stress-induced hyperthermia, the elevated plus maze test in mice, and the Vogel conflict test in rats (Stachowicz et al. (2009), Neuropharmacology, 57(3): pp. 227-234). Activation of group III mGluR8 also suppresses anxiety-like behavior in rodent models, as demonstrated by treating animals with the mGluR8-specific agonist DCPG or the PAM AZ12216052 (Duvoisin et al. (2010) Behav Brain Res 212(2):168-73; for review, see Raber J and Duvoisin RM (2015) Expert Opin Investig Drugs 24(4):519-28).

[0023] Group III mGluR modulators have shown positive results in several animal models of schizophrenia (Paiucha-Poniewiera A et al. (2008) Neuropharmacology 55(4):517-24). Similarly, ADX88178, a brain-penetrant positive allosteric modulator of mGlu4 receptors, has been shown to be active in rodent models of obsessive-compulsive disorder (OCD), fear, and psychosis (Kalinichev M et al. (2014) J Pharmacol Exp Ther 350(3):495-505).

[0024] Furthermore, mGluR4 positive modulators have been shown to alleviate autism-like symptoms in rodent models of autism spectrum disorder (Becker JA et al. (2014) Neuropsychopharmacology 39(9):2049-2060), while activators of mGluR7, another subtype of group III mGlu receptor, are under investigation by Vanderbilt University as a treatment for Rett syndrome (Gogliotti RG et al. (2017) Sci Transl Med 9(403)).

[0025] Associations between epilepsy and mGluR4 transcription levels and / or genetic variants have recently been published (Parihar R et al. (2014) J Genet 93(1):193-197; Dammann F et al. (2018) Epilepsy Res 139:157-163), indicating that mGluR4 modulators may be useful as treatments for epilepsy.

[0026] The beta-chemokine RANTES is critically involved in neuroinflammation and has been implicated in the pathophysiology of multiple sclerosis. Activation of group III mGluRs by L-AP4 reduces the synthesis and release of RANTES in wild-type cultured astrocytes, whereas the ability of L-AP4 to inhibit RANTES is significantly reduced in astrocyte cultures from mGluR4 knockout mice (Besong et al. (2002) Journal of Neuroscience 22:5403-5411). Expression of mGluR4 in dendritic cells can affect the T17 / Treg balance (Hansen AM and Caspi RR (2010) Nat Med 16(8):856-8; Zhao G et al. (2017) Int Immunopharmacol 46:80-86). Activation of mGluR4 via the endogenous agonist cinnabarinic acid or the highly selective and potent PAM ADX88178 is protective in a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) (Fazio F et al. (2014) Neuropharmacology 81:237-43; Volpi C et al. (2016) Neuropharmacology 102:59-71). The underlying mechanism has recently been elucidated: activation of mGluR4 with ADX88178 attenuates LPS-induced inflammation in primary microglia, resulting in the suppression of the expression of proinflammatory markers TNFα, MHCII, and iNOS (Ponnazhagan R et al. (2016) J Neuroimmune Pharmacol 11(2):231-7). Altogether, these data suggest that positive allosteric modulators of mGluR4 may be effective treatments for neuroinflammatory disorders of the central nervous system, including multiple sclerosis and related disorders (for review, see Levite M, (2017) J Neural Transm, 124(7):775-98).

[0027] Two distinct variants of the mGluR4 receptor are expressed in taste tissues and can act as receptors for umami taste (Monastyrskaia et al. (1999) Br. J Pharmacol. 128:1027-1034; Toyono et al. (2002) Arch. Histol. Cytol. 65:91-96; Eschle BK. (2008) Neuroscience 155(2):522-9). Therefore, positive allosteric modulators of mGluR4 may be useful as taste enhancers, flavoring agents, flavor enhancers, or food additives.

[0028] There is anatomical evidence that the majority of vagal afferents innervating gastric muscles express group III mGluRs (mGluR4, mGluR6, mGluR7, and mGluR8) and actively transport receptors to their peripheral terminals (Page et al., 2005, Gastroenterology, 128:402-10). Recently, peripheral group III mGluR activation has been shown to inhibit the mechanosensitivity of vagal afferents in vitro, which in turn suppresses transient lower esophageal sphincter relaxation and gastroesophageal reflux in vivo (Young et al., 2008, Neuropharmacol, 54:965-975). Labeling for mGluR4 and mGluR8 is abundant in vagal afferents in the inferior ganglion, at their termination in the nucleus tractus solitarius, and in vagal motoneurons of the stomach. These data suggest that positive allosteric modulators of group III mGluRs may be effective treatments for gastroesophageal reflux disease (GERD), lower esophageal disorders, and gastrointestinal disorders.

[0029] Activation of mGluR4 receptors expressed in a- and F-cells in the islets of Langerhans inhibits glucagon secretion. Molecules that activate or enhance the agonist activity of these receptors may be effective treatments for hyperglycemia, a symptom of type 2 diabetes (Uehara et al. (2004) Diabetes 53:998-1006).

[0030] Furthermore, mGluR4 signaling is also a mechanism involved in the regulation of chronic pain (Goudet C et al. (2008) Pain 137(1) 112-24; Zhang HM et al. (2009) Neuroscience 158(2) 875-84; Zussy C et al. (2018) Mol Psychiatry 23(3):509-520; for review see Palazzo E et al. (2017) J Neurochem 141(4):507-519).

[0031] Finally, mGluR4 has been shown to be expressed in prostate cancer cell lines (Pessimissis N et al. (2009) Anticancer Res. 29(1) 371-377), colorectal cancer (Chang HJ et al. (2005) CIL Cancer Res. 11(9) 3288-95), or more recently in osteosarcoma (Yang et al. (2014) J Cancer Res Clin Oncol 140(3):419-426; Wang et al. (2016) Mol Cli Oncol 4(1):65-69), and its activation using PHCCC has been shown to inhibit the growth of medulloblastoma (Iacoveili L et al. (2006) J Neurosci. 26(32) 8388-97). Similarly, very recent data in neuroblastoma and glioma cell lines demonstrated that mGluR8 overexpression induced suppression of cell proliferation, increased apoptosis, and increased vulnerability to some cytotoxic agents (Jantas D et al. (2018) Cancer Lett 3835(18):30400-2). Class III mGluR modulators may therefore also be used in the treatment of cancer.

[0032] Further prior art documents relating to structurally related compounds are as follows: WO01 / 083456 covers fused heteroaryl derivatives.

[0033] WO02 / 028841 relates to reagents for labelling biomolecules with aldehyde or keto functions.

[0034] WO03 / 048152 is directed to inflammation modulating agents.

[0035] WO2004 / 024162 discloses 2-amino-4-quinazolinones as LXR nuclear receptor binding compounds.

[0036] WO2004 / 041755 describes quinazolinone compounds as calcilytics.

[0037] WO2004 / 065392 discloses certain substituted quinoline and quinazoline compounds as inhibitors of ALK5 kinase.

[0038] WO2004 / 078733 covers fused pyrimidines and pyridines and their use as ALK-5 receptor ligands.

[0039] WO2004 / 078733 relates to quinazolinones useful as modulators of ion channels.

[0040] WO2005 / 035526 relates to bicyclic compounds and their therapeutic uses.

[0041] WO2006 / 051290 is directed to pharmaceutical compositions.

[0042] WO2006 / 071095 discloses quinazoline derivatives for treating and preventing obesity.

[0043] WO2008 / 020302 describes heteroaromatic quinoline compounds.

[0044] WO2009 / 064388 covers human methionine aminopeptidase 1 inhibitors and methods of treating disorders.

[0045] WO2009 / 111943 relates to compounds and their use as estrogen-related receptor modulators.

[0046] WO2010 / 018458 is directed to phenol derivatives and methods of using same.

[0047] WO2010 / 056758 discloses quinazoline derivatives as kinase inhibitors.

[0048] WO2010 / 106436 describes certain anti-inflammatory agents.

[0049] WO2010 / 136475 covers substituted quinazolines as fungicides.

[0050] WO2011 / 011522 relates to potent small molecule inhibitors of autophagy and methods of using same.

[0051] WO2011 / 045258 is directed to fused azine derivatives for treating diseases associated with acetylcholine receptors.

[0052] WO2011 / 082337 discloses therapeutic compounds and related methods of use.

[0053] WO2011 / 104183 relates to bactericidal, in particular fungicidal, 2-(pyridin-2-yl)pyrimidines for use in agriculture or horticulture.

[0054] WO2012 / 028578 discloses substituted fused pyrimidinones and dihydropyrimidinones for increasing the tolerance of plants to abiotic stress, and for improving plant growth and / or increasing plant yield.

[0055] WO2013 / 003586 describes certain quinazoline derivatives as striatal enriched tyrosine phosphatase (STEP) inhibitors.

[0056] WO2015 / 015318 covers certain quinazolinones as bromodomain inhibitors.

[0057] WO2016 / 199943 is directed to heterocyclic compounds as BET family protein inhibitors.

[0058] CN103319408 describes compounds for preventing and treating cardiovascular disease.

[0059] Further prior art documents, including documents relating to mGluR4 PAM compounds, are as follows: EP2953532, WO2011 / 050305, WO2011 / 029104, WO2011 / 100607, WO2011 / 051478, WO2012 / 009001, WO2013 / 107862, WO2014 / 117920, WO2014 / 121883, WO2014 / 121885, WO2015 / 04 4075, WO2015 / 104271, WO2016 / 146600, WO2016 / 030444, WO2017 / 009275, US2018 / 057490, US2018 / 057491, US2018 / 021312, US2018 / 022744, US2018 / 022745 and US2018 / 022746.

[0060] The citation of any reference in this application is not an admission that the reference is prior art relevant to the present application. [Prior art documents] [Patent documents]

[0061] [Patent Document 1] WO2017 / 032874 [Patent Document 2] WO2009 / 010454 [Patent Document 3] WO2009 / 010455 [Patent Document 4] WO01 / 083456 [Patent Document 5] WO02 / 028841 [Patent Document 6] WO03 / 048152 [Patent Document 7] WO2004 / 024162 [Patent Document 8] WO2004 / 041755 [Patent Document 9] WO2004 / 065392 [Patent Document 10] WO2004 / 078733 [Patent Document 11] WO2005 / 035526 [Patent Document 12] WO2006 / 051290 [Patent Document 13] WO2006 / 071095 [Patent Document 14] WO2008 / 020302 [Patent Document 15] WO2009 / 064388 [Patent Document 16] WO2009 / 111943 [Patent Document 17] WO2010 / 018458 [Patent Document 18] WO2010 / 056758 [Patent Document 19] WO2010 / 106436 [Patent Document 20] WO2010 / 136475 [Patent Document 21] WO2011 / 011522 [Patent Document 22] WO2011 / 045258 [Patent Document 23] WO2011 / 082337 [Patent Document 24] WO2011 / 104183 [Patent Document 25] WO2012 / 028578 [Patent Document 26] WO2013 / 003586 [Patent Document 27] WO2015 / 015318 [Patent Document 28] WO2016 / 199943 [Patent Document 29] CN103319408 [Patent Document 30] EP2953532 [Patent Document 31] WO2011 / 050305 [Patent Document 32] WO2011 / 029104 [Patent Document 33] WO2011 / 100607 [Patent Document 34] WO2011 / 051478 [Patent Document 35] WO2012 / 009001 [Patent Document 36] WO2013 / 107862 [Patent Document 37] WO2014 / 117920 [Patent Document 38] WO2014 / 121883 [Patent Document 39] WO2014 / 121885 [Patent Document 40] WO2015 / 044075 [Patent Document 41] WO2015 / 104271 [Patent Document 42] WO2016 / 146600 [Patent Document 43] WO2016 / 030444 [Patent Document 44] WO2017 / 009275 [Patent Document 45] US2018 / 057490 [Patent Document 46] US2018 / 057491 [Patent Document 47] US2018 / 021312 [Patent Document 48] US2018 / 022744 [Patent Document 49] US2018 / 022745 [License 50] US2018 / 022746 [Patent Document 51] WO2004 / 39815 [Non-licensed literature]

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Summary of the Invention

[0063] The present invention provides novel compounds that exhibit highly potent positive allosteric modulator activity at mGluR4, which makes them particularly suitable as therapeutic agents. The present invention also provides compounds that are positive allosteric modulators of mGluR4 and that exhibit favorable pharmacokinetic properties.

[0064] The present invention therefore solves the problem of obtaining new and / or improved therapeutic agents for medical intervention in conditions associated with altered glutamatergic signaling and / or functions and conditions that may be affected by alterations in glutamate levels or signaling. [Means for solving the problem]

[0065] Thus, the present invention provides a compound of formula (I)

[0066] [ka]

[0067] or a pharmaceutically acceptable salt thereof.

[0068] The compounds of the present invention have been found to be potent positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4) and may therefore be advantageously used as therapeutic agents, particularly in the treatment or prevention of conditions associated with altered glutamatergic signaling and / or functions or conditions that may be affected by alterations in glutamate levels or signaling.

[0069] In accordance with the present invention, it has been surprisingly discovered that the lactam nitrogen ring atom contained in the quinazolinone ring of compounds of formula (I) must be unsubstituted for compounds that exhibit mGluR4 positive allosteric modulator (PAM) activity, as also shown in formula (I). This is demonstrated by a comparison of the mGluR4 PAM activity of compounds, as depicted in the following scheme:

[0070] [ka]

[0071] Compound 3 according to the present invention, in which the lactam nitrogen ring atom of the quinazolinone ring is unsubstituted, is a positive allosteric modulator (PAM) of mGluR4 with an EC50 of less than 1 μM.

[0072] In contrast, reference compound 38, an N-substituted analog of compound 3 bearing a methyl substituent at the lactam nitrogen ring atom of the quinazolinone ring, has no PAM activity at mGluR4 up to 100 μM.

[0073] The aromatic ring R contained in the compound of formula (I) 1 It has further been surprisingly discovered that, in order to exhibit mGluR4 PAM activity, a group needs to be linked to the residue of the compound (i.e., to the quinazolinone ring of Formula (I)) via a ring carbon atom and needs to contain a nitrogen ring atom in the ortho position, i.e., adjacent to the ring carbon atom linked to the residue of the compound of Formula (I) (i.e., to the quinazolinone ring of Formula (I)). This is demonstrated by a comparison of the mGluR4 PAM activity of compounds depicted in the following scheme:

[0074] [ka]

[0075] Aromatic ring (R 1an aromatic ring R having a nitrogen ring atom adjacent to the carbon ring atom connecting each of the quinazolinone rings to the residue of the compound (i.e., to the quinazolinone ring contained in each compound); 1 Compounds 15, 9 and 5 according to the invention containing a group are positive allosteric modulators (PAMs) of mGluR4 with an EC50 of less than 1 μM.

[0076] In contrast, aromatic rings R 1 that do not have a nitrogen ring atom at a specific position adjacent to the carbon ring atom that connects the aromatic ring to the residue of the respective compound 1 Reference compounds 20, 21 and 6 containing the group have no PAM activity at mGluR4 up to 100 μM.

[0077] The groups / variables in the compounds of formula (I) obtained according to the present invention, or in the pharmaceutically acceptable salts thereof, are as follows:

[0078] [ka]

[0079] It has the meaning of

[0080] R 1 is as follows:

[0081] [ka]

[0082] groups, each one of which may be selected from one or more R 11 group, optionally substituted.

[0083] Each R 11 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-aryl, -(C 0~3 alkylene)-heteroaryl, -(C 0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl, wherein said -(C 0~3 the aryl moiety in the -(C alkylene)-aryl; 0~3 the heteroaryl portion of the -(C alkylene)-heteroaryl; 0~3 The cycloalkyl moiety in the -(C alkylene)-cycloalkyl, 0~3 Each heterocycloalkyl moiety in the alkylene-heterocycloalkyl is one or more R 12 group, optionally substituted.

[0084] Each R 12 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), cycloalkyl, and heterocycloalkyl.

[0085] The ring atoms X1, X2, X3 and X4 in formula (I) have the following meanings: X1 is C(R X1 ) or N, and X2 is C(-LR X2 ) or N, and X3 is C(R X3 ) or N, and X4 is C(R X4 ) or N, and at least one of the ring atoms X1, X2, X3 and X4 is not N.

[0086] R X1 is hydrogen, C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-aryl, -(C 0~3 alkylene)-heteroaryl, -(C 0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl, wherein said -(C 0~3 the aryl moiety in the -(C alkylene)-aryl; 0~3 the heteroaryl portion of the -(C alkylene)-heteroaryl; 0~3 The cycloalkyl moiety in the -(C alkylene)-cycloalkyl, 0~3Each heterocycloalkyl moiety in the alkylene-heterocycloalkyl is one or more R X11 group, optionally substituted.

[0087] Each R X11 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), cycloalkyl, and heterocycloalkyl.

[0088] L is a covalent bond, C 1~10 Alkylene, C 2~10 Alkenylene and C 2~10 alkynylene, 1~10 Alkylene, 2~10 Alkenylene or the C 2~10One or more -CH2- units contained in the alkynylene may be -O-, -CO-, -C(=O)O-, -OC(=O)-, -NH-, -N(C 1~5 alkyl)-, -NH-CO-, -N(C 1~5 alkyl)-CO-, -CO-NH-, -CO-N(C 1~5 alkyl)-, -S-, -SO-, -SO2-, -SO2-NH-, -SO2-N(C 1~5 alkyl)-, -NH-SO2-, -N(C 1~5 alkyl)-SO2-, carbocyclylene, and heterocyclylene, wherein said carbocyclylene and said heterocyclylene are each independently selected from C 1~4 Alkyl, -OH, -O(C 1~4 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)(C 1~4 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl) and —CN, and 1~10 Alkylene, 2~10 Alkenylene and the C 2~10 Alkynylene is a halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 and optionally substituted with one or more groups independently selected from alkyl.

[0089] R X2 is C 2~10 Alkyl, carbocyclyl, heterocyclyl and -L 1 -R X21 wherein C is selected from 2~10The alkyl, the carbocyclyl, and the heterocyclyl each may be one or more R X22 group, optionally substituted.

[0090] L 1 is a covalent bond, C 1~10 Alkylene, C 2~10 Alkenylene and C 2~10 alkynylene, 1~10 Alkylene, 2~10 Alkenylene or the C 2~10 One or more -CH2- units contained in the alkynylene may be -O-, -CO-, -C(=O)O-, -OC(=O)-, -NH-, -N(C 1~5 alkyl)-, -NH-CO-, -N(C 1~5 alkyl)-CO-, -CO-NH-, -CO-N(C 1~5 alkyl)-, -S-, -SO-, -SO2-, -SO2-NH-, -SO2-N(C 1~5 alkyl)-, -NH-SO2- and -N(C 1~5 alkyl)-SO2-, and 1~10 Alkylene, 2~10 Alkenylene and the C 2~10 Alkynylene is a halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 and optionally substituted with one or more groups independently selected from alkyl.

[0091] R X21 is C 2~5 alkyl, carbocyclyl, and heterocyclyl, wherein said carbocyclyl and said heterocyclyl each comprise one or more R X22 group, optionally substituted.

[0092] Each R X22 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-aryl, -(C 0~3 alkylene)-heteroaryl, -(C 0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl, wherein said -(C 0~3 the aryl moiety in the -(C alkylene)-aryl; 0~3 the heteroaryl portion of the -(C alkylene)-heteroaryl; 0~3 The cycloalkyl moiety in the -(C alkylene)-cycloalkyl, 0~3 Each heterocycloalkyl moiety in the alkylene-heterocycloalkyl is one or more R X23 group, optionally substituted.

[0093] Each R X23 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), cycloalkyl, and heterocycloalkyl.

[0094] R X3 is hydrogen, C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-aryl, -(C 0~3 alkylene)-heteroaryl, -(C 0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl, wherein said -(C 0~3 the aryl moiety in the -(C alkylene)-aryl; 0~3the heteroaryl portion of the -(C alkylene)-heteroaryl; 0~3 The cycloalkyl moiety in the -(C alkylene)-cycloalkyl, 0~3 Each heterocycloalkyl moiety in the alkylene-heterocycloalkyl is one or more R X31 group, optionally substituted.

[0095] Each R X31 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), cycloalkyl, and heterocycloalkyl.

[0096] R X4 is hydrogen, C 1~5 Alkyl, C 2~5Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-aryl, -(C 0~3 alkylene)-heteroaryl, -(C 0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl, wherein said -(C 0~3 the aryl moiety in the -(C alkylene)-aryl; 0~3 the heteroaryl portion of the -(C alkylene)-heteroaryl; 0~3 The cycloalkyl moiety in the -(C alkylene)-cycloalkyl, 0~3 Each heterocycloalkyl moiety in the alkylene-heterocycloalkyl is one or more R X41 group, optionally substituted.

[0097] Each R X41 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), cycloalkyl, and heterocycloalkyl.

[0098] According to the present invention,

[0099] [ka]

[0100] are excluded from formula (I).

[0101] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient. Accordingly, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, or any of the foregoing, and a pharmaceutically acceptable excipient, for use as a medicament.

[0102] The present invention further relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, for use in the treatment or prevention of a condition associated with altered glutamatergic signaling and / or a function or condition that may be affected by alterations in glutamate levels or signaling.

[0103] Furthermore, the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a condition associated with altered glutamatergic signaling and / or a function or condition that may be affected by alterations in glutamate levels or signaling.

[0104] The present invention also relates to methods of treating or preventing conditions associated with altered glutamatergic signaling and / or functions or conditions that may be affected by alterations in glutamate levels or signaling, comprising administering to a subject (preferably a human) in need thereof a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing in combination with a pharmaceutically acceptable excipient. It is understood that a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is administered in accordance with the method.

[0105] Conditions to be treated or prevented in accordance with the present invention, i.e., conditions associated with altered glutamatergic signaling and / or functions or conditions that may be affected by altered glutamate levels or signaling, include, in particular, epilepsy, including neonatal, infantile, childhood and adult syndromes, partial (localization-related) and generalized epilepsies, with partial and generalized convulsive and non-convulsive seizures, with and without impaired consciousness, and status epilepticus; dementia of the Alzheimer's type (DAT), Alzheimer's disease, Pick's disease, vascular dementia, Lewy body disease. , metabolic dementia, toxic diseases and deficiencies (including alcoholism, hypothyroidism and vitamin B12 deficiency), dementia and related disorders including AIDS-dementia complex, Creutzfeldt-Jakob disease and atypical subacute spongiform encephalopathy; Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, hepatolenticular degeneration, chorea (including Huntington's disease and hemiballismus), athetosis, dystonia (including spasmodic torticollis, occupational movement disorder, Gilles de la Tourette's syndrome), tardive or drug-induced dyskinesia (levodopa-induced dyskinesia) motor neuron disease or amyotrophic lateral sclerosis (ALS); spinocerebellar degeneration, e.g. Friedreich's ataxia and other hereditary cerebellar ataxias, primarily spinal muscular atrophies, other neurodegenerative and / or genetic disorders of the nervous system, including hereditary neuropathies and phakopathies; peripheral nervous system, including trigeminal neuralgia, facial neuropathy, disorders of other cranial nerves, radiculo- and plexopathies, mononeuritis, e.g. carpal tunnel syndrome and sciatica, hereditary and idiopathic peripheral neuropathies, inflammatory and toxic neuropathies disorders; multiple sclerosis and other autoimmune diseases, including lupus (i.e. systemic lupus erythematosus) and psoriasis; infantile cerebral palsy (spastic), monoplegia, paraplegia or quadriplegia; hemiplegia and hemiparesis, flaccid or spastic, and other paralytic syndromes; cerebrovascular disorders, including subarachnoid hemorrhage, intracerebral hemorrhage, occlusion and stenosis of extracerebral arteries, occlusion of cerebral arteries including thrombosis and embolism, cerebral ischemia, stroke, transient ischemic attack, atherosclerosis, vascular dementia, aneurysm, cerebral damage due to cardiac bypass surgery and transplant; migraine, including classic migraine and variants, e.g. cluster headache; headache;neuromuscular disorders including myasthenia gravis, acute muscle spasms, myopathies including muscular dystrophies, myotonia and familial periodic paralysis; disorders of the eye and visual pathways including retinal disorders and visual abnormalities; intracranial trauma / injury and their sequelae; trauma / injury to the nerves and spinal cord and their sequelae; intoxication and toxic effects of non-medical substances; accidental intoxication with drugs, medical substances and biological products acting on the central, peripheral and autonomic nervous systems; neurological and psychiatric adverse effects of drugs, medical substances and biological substances; disorders of sphincter control and sexual function; social disorders, e.g. autism or autism spectrum disorder or fragile X syndrome; mental retardation, learning disabilities, motor skill disorders, communication disorders, pervasive developmental disorders, attention deficit and disruptive behavior disorders, feeding and eating disorders, TIC disorders, elimination disorders, and other disorders, usually minor Psychiatric disorders diagnosed in childhood, childhood, or adolescence; delirium and other cognitive disorders; substance-related disorders, including alcohol-related disorders, nicotine-related disorders, and disorders related to cocaine, opioids, cannabis, hallucinogens, and other drugs; schizophrenia and other psychiatric disorders; mood disorders, including depressive disorders and bipolar disorders; anxiety disorders, including panic disorders, phobias, obsessive-compulsive disorders, stress disorders, and generalized anxiety disorder; eating disorders, including anorexia and bulimia; sleep disorders, including sleep disorders (insomnia, hypersomnia, narcolepsy, breathing-related sleep disorders) and parasomnias; drug-induced movement disorders, including neuroleptic-induced parkinsonism and tardive dyskinesia; endocrine and metabolic disorders, including diabetes, endocrine disorders, and hypoglycemia; acute and chronic pain; nausea and vomiting; irritable bowel syndrome; or cancer.

[0106] Preferably, the conditions treated or prevented in accordance with the present invention are dementia and related disorders including dementia of the Alzheimer's type (DAT), Alzheimer's disease, Pick's disease, vascular dementia, Lewy body disease, metabolic dementia, toxic diseases and deficiencies (including alcoholism, hypothyroidism and vitamin B12 deficiency), AIDS-dementia complex, Creutzfeldt-Jakob disease and atypical subacute spongiform encephalopathy; Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, hepatolenticular degeneration, chorea (including Huntington's disease and hemiballismus), athetosis, dystonia (spastic Parkinsonism and movement disorders including torticollis, occupational dyskinesia, Gilles de la Tourette's syndrome, tardive or drug-induced dyskinesia (including levodopa-induced dyskinesia), tremor and myoclonus; social disorders such as autism or autism spectrum disorder, or fragile X syndrome; acute and chronic pain; anxiety disorders including panic disorder, phobias, obsessive-compulsive disorder, stress disorder, and generalized anxiety disorder; schizophrenia and other psychiatric disorders; mood disorders including depressive disorder and bipolar disorder; endocrine and metabolic disorders including diabetes, endocrine disorders, and hypoglycemia; or cancer. More preferably, the condition treated or prevented in accordance with the present invention is Parkinson's disease.

[0107] The present invention further provides a method for identifying a test agent that binds to metabotropic glutamate receptor 4 (mGluR4), or in other words, determining the ability of one or more test agents to bind to the receptor, comprising the steps of: (a) contacting mGluR4 with a labeled, preferably radioactively or fluorescently labeled, compound of the present invention (i.e., a compound of Formula (I), or a pharmaceutically acceptable salt thereof), under conditions that allow binding of the compound to mGluR4, thereby producing a bound, labeled compound; (b) detecting a signal corresponding to the amount of bound, labeled compound in the absence of the test agent; (c) contacting the bound, labeled compound with a test agent; (d) detecting a signal corresponding to the amount of bound, labeled compound in the presence of the test agent; and (e) comparing the signal detected in step (d) with the signal detected in step (b) to determine whether the test agent binds to mGluR4. As will be appreciated, a substantially unchanged signal detected in step (d) compared to 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 compounds of the present invention. A decreased or increased signal detected in step (d) compared to the signal detected in step (b) indicates that the test agent binds to the receptor. Thus, agents that bind to mGluR4 can be identified among the test agents used in the above method. It will further be appreciated that it is preferable to remove unbound labeled compound, for example, in a washing step, before performing steps (b) and (d).

[0108] The mGluR4 used in the above method may be a human form (see, for example, Flor PJ et al., Neuropharmacology. 1995, 34:149-155; Makoff A et al., Brain Res. Mol. Brain Res. 1996, 37:239-248; or Wu S et al., Brain Res. Mol. Brain Res. 1998, 53:88-97), such as the protein under accession number NP_000832, or a protein having at least 80% (preferably at least 90%, more preferably at least 95%, and even more preferably at least 99%) amino acid identity to said protein under accession number NP_000832, or, for example, a mouse or rat form (see, for example, Tanabe Y et al., Neuron. 1992, 8:169-179), or a non-human form thereof, including homologs thereof found in different species (e.g., different mammalian species), or a mutein of any of the foregoing, which mutein retains mGluR4 activity. The mutein is preferably obtained by substitution, insertion, addition, and / or deletion of one or more (e.g., 1 to 20, including 1 to 10 or 1 to 3) amino acid residues of the foregoing. The mGluR4 used in the above method can also be a functional fragment of any of the foregoing (including the muteins), i.e., a fragment that retains the mGluR4 activity of each of the foregoing, or, in other words, a fragment that has essentially the same biological activity as each of the foregoing (i.e., at least about 60% of the activity, preferably at least about 70% of the activity, more preferably at least about 80% of the activity, and even more preferably at least about 90% of the activity). Those skilled in the art will be readily in a position to determine whether mGluR4 activity is maintained using techniques known in the art, such as knockout and rescue experiments. Furthermore, the mGluR4 used in the above methods can also be a compound comprising any one or more of the foregoing (including, but not limited to, the protein under Accession No. NP_000832, a protein having at least 80% amino acid identity to said protein under Accession No. NP_000832, or a functional fragment thereof) that has maintained mGluR4 activity.Preferably, the mGluR4 used in the above method is human.

[0109] The present invention also relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as a positive allosteric modulator of mGluR4 (i.e., as an mGluR4 PAM) in research, particularly as a research tool compound. Accordingly, the present invention refers to the in vitro use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as an mGluR4 PAM, and particularly to the in vitro use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as a research tool compound acting as an mGluR4 PAM. The present invention also relates to methods for achieving positive allosteric modulation of mGluR4, particularly in vitro methods, comprising the application of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. The present invention further relates to a method for achieving positive allosteric modulation of mGluR4, comprising the step of applying a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a test sample (e.g., a biological sample) or a test animal (i.e., a non-human test animal). The present invention also refers to a method, particularly an in vitro method, for achieving positive allosteric modulation of mGluR4 in a sample (e.g., a biological sample), comprising applying a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the sample. The present invention further provides a method for achieving positive allosteric modulation of mGluR4, comprising contacting a test sample (e.g., a biological sample) or a test animal (i.e., a non-human test animal) with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. The mGluR4 is preferably human mGluR4. The terms "sample," "test sample," and "biological sample" include, but are not limited to, cells, cell cultures, or cellular or subcellular extracts; biopsies obtained from animals (e.g., humans), or extracts thereof; or blood, serum, plasma, saliva, urine, feces, or some other bodily fluid, or extracts thereof.It should be understood that the term "in vitro" is used in the context of this specification to mean "outside a living human or animal body", which in particular includes experiments performed on cells, cell or subcellular extracts, and / or biological molecules in an artificial environment, e.g., an aqueous solution or medium, which may be provided in, for example, a flask, a test tube, a Petri dish, a microtiter plate. DETAILED DESCRIPTION OF THE INVENTION

[0110] The compounds of formula (I) obtained according to the present invention

[0111] [ka]

[0112] or a pharmaceutically acceptable salt thereof is described in more detail below.

[0113] R 1 is as follows:

[0114] [ka]

[0115] groups, each one of which may be selected from one or more (e.g., 1, 2, or 3) R 11 group, optionally substituted.

[0116] R 1 Examples of R are those disclosed in the Examples section, which are included in any of the specific compounds of the invention. 1 The group includes any of the groups.

[0117] Preferably, R 1 is as follows:

[0118] [ka]

[0119] groups, each one of which may be selected from one or more R 11 group, optionally substituted; Or R 1 is the base

[0120] [ka]

[0121] which is a group consisting of one or more R 11A group, optionally substituted.

[0122] More preferably, R 1 is as follows:

[0123] [ka]

[0124] groups, each one of which is selected from one or more R 11 group, optionally substituted.

[0125] Even more preferably, R 1 is as follows:

[0126] [ka]

[0127] groups, each one of which is selected from one or more R 11 group, optionally substituted.

[0128] Even more preferably, R 1 is as follows:

[0129] [ka]

[0130] groups, each one of which is selected from one or more R 11 group, optionally substituted.

[0131] Even more preferably, R 1 is as follows:

[0132] [ka]

[0133] groups, each one of which is selected from one or more R 11 group, optionally substituted.

[0134] Even more preferably, R 1 is the base

[0135] [ka]

[0136] and the groups depicted above are each selected from one or more R 11 group, optionally substituted.

[0137] Each R 11 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-aryl, -(C 0~3 alkylene)-heteroaryl, -(C0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl; Said -(C 0~3 the aryl moiety in the -(C alkylene)-aryl; 0~3 the heteroaryl portion of the -(C alkylene)-heteroaryl; 0~3 The cycloalkyl moiety in the -(C alkylene)-cycloalkyl, 0~3 Each heterocycloalkyl portion of the alkylene-heterocycloalkyl is selected from one or more (e.g., 1, 2, or 3) R 12 group, optionally substituted; Furthermore, each R 12 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5alkyl), cycloalkyl, and heterocycloalkyl.

[0138] Preferably, each R 11 is C 1~5 Alkyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl) and -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl).

[0139] More preferably, each R 11 is C 1~5 Alkyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl) and -(C 0~3 alkylene)-CN.

[0140] Even more preferably, each R 11 is C 1~5 Alkyl (e.g., methyl or ethyl), —OH, —O(C 1~5 alkyl) (e.g., methoxy or ethoxy), halogen (e.g., —F or —Cl), C 1~5haloalkyl (e.g., -CF3), -O-(C 1~5 haloalkyl) (e.g., —OCF3) and —CN.

[0141] Each R 11A is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-heteroaryl, -(C 0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl; Said -(C 0~3 the heteroaryl portion of the -(C alkylene)-heteroaryl; 0~3 The cycloalkyl moiety in the -(C alkylene)-cycloalkyl, 0~3 Each heterocycloalkyl portion of the alkylene-heterocycloalkyl is selected from one or more (e.g., 1, 2, or 3) R 12 group, optionally substituted; Furthermore, each R 12 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), cycloalkyl, and heterocycloalkyl.

[0142] Preferably, each R 11A is C 1~5 Alkyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl) and -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl).

[0143] More preferably, each R 11A is C 1~5 Alkyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl) and -(C 0~3 alkylene)-CN.

[0144] Even more preferably, each R 11A is C 1~5 Alkyl (e.g., methyl or ethyl), —OH, —O(C 1~5 alkyl) (e.g., methoxy or ethoxy), halogen (e.g., —F or —Cl), C 1~5 haloalkyl (e.g., -CF3), -O-(C 1~5 haloalkyl) (e.g., —OCF3) and —CN.

[0145] As explained above, R 1 is the structure

[0146] [ka]

[0147] and the pyridin-2-yl group may be a pyridin-2-yl group having one or more R 11 group, optionally substituted.

[0148] In this case, the pyridin-2-yl group is

[0149] [ka]

[0150] and each one of the groups depicted above is preferably a substituted pyridin-2-yl group selected from any one of the groups 11The group is optionally further substituted.

[0151] More preferably, the pyridin-2-yl group is

[0152] [ka]

[0153] and each one of the groups depicted above is selected from one or more R 11 It is optionally further substituted with a group (eg, one group).

[0154] Even more preferably, the pyridin-2-yl group is

[0155] [ka]

[0156] is a trifluoromethyl- or methyl-substituted pyridin-2-yl group selected from any one of the groups

[0157] Therefore, R 1 is as follows:

[0158] [ka]

[0159] It is particularly preferred that each one of the groups depicted above is selected from one or more R 11 groups (and the groups depicted above are preferably substituted with any of the R 11 (not further substituted with a group). Even more preferably, R 1 teeth,

[0160] [ka]

[0161] and the groups depicted above are each selected from one or more R 11 group, optionally substituted.

[0162] Most preferably, R 1 teeth,

[0163] [ka]

[0164] is.

[0165] The ring atoms X1, X2, X3 and X4 in formula (I) have the following meanings: X1 is C(R X1 ) or N, and X2 is C(-LR X2 ) or N, and X3 is C(R X3 ) or N, and X4 is C(R X4 ) or N, and at least one of the ring atoms X1, X2, X3 and X4 is not N.

[0166] Preferably, X1 is C(R X1 ) or N, and X2 is C(-LR X2 ) and X3 is C(R X3 ) or N, and X4 is C(R X4 ) or N.

[0167] More preferably, X1 is C(R X1 ) or N, and X2 is C(-LR X2 ) and X3 is C(R X3 ) or N, and X4 is C(R X4 )

[0168] Even more preferably, X1 is C(R X1 ) or N, and X2 is C(-LR X2 ) and X3 is C(R X3 ) or N, and X4 is C(RX4 ) and one of X1 and X3 is N or neither is N (i.e., at least one of X1 and X3 is not N).

[0169] Even more preferably, X1 is C(R X1 ) or N, and X2 is C(-LR X2 ) and X3 is C(R X3 ) and X4 is C(R X4 )

[0170] Even more preferably, X1 is C(R X1 ) and X2 is C(-LR X2 ) and X3 is C(R X3 ) and X4 is C(R X4 )

[0171] Thus, according to the above definitions of X1, X2, X3 and X4, the compound of formula (I) is

[0172] [ka]

[0173] It is particularly preferred that the compound of formula (I) has the structure

[0174] [ka]

[0175] It is even more preferable that the polymer has the structure:

[0176] R X1 is hydrogen, C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-aryl, -(C 0~3 alkylene)-heteroaryl, -(C 0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl; Said -(C 0~3 the aryl moiety in the -(C alkylene)-aryl; 0~3 the heteroaryl portion of the -(C alkylene)-heteroaryl; 0~3 The cycloalkyl moiety in the -(C alkylene)-cycloalkyl, 0~3 Each heterocycloalkyl portion of the alkylene-heterocycloalkyl is selected from one or more (e.g., 1, 2, or 3) R X11 group, optionally substituted; Furthermore, each R X11 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), cycloalkyl, and heterocycloalkyl.

[0177] Preferably, R X1 is hydrogen, C 1~5 Alkyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl) and -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl).

[0178] More preferably, R X1 is hydrogen, C 1~5 Alkyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl) and -(C 0~3 alkylene)-CN.

[0179] Even more preferably, R X1is hydrogen, C 1~5 Alkyl, -OH, -O(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl) and —CN.

[0180] Even more preferably, R X1 is hydrogen.

[0181] L is a covalent bond, C 1~10 Alkylene, C 2~10 Alkenylene and C 2~10 alkynylene, Said C 1~10 Alkylene, 2~10 Alkenylene or the C 2~10 One or more (for example, one or two) -CH2- units contained in the alkynylene may be -O-, -CO-, -C(=O)O-, -OC(=O)-, -NH-, -N(C 1~5 alkyl)-, -NH-CO-, -N(C 1~5 alkyl)-CO-, -CO-NH-, -CO-N(C 1~5 alkyl)-, -S-, -SO-, -SO2-, -SO2-NH-, -SO2-N(C 1~5 alkyl)-, -NH-SO2-, -N(C 1~5 alkyl)-SO2-, carbocyclylene (e.g., cycloalkylene or arylene), and heterocyclylene (e.g., heterocycloalkylene or heteroarylene), wherein said carbocyclylene (or said cycloalkylene or arylene) and said heterocyclylene (or said heterocycloalkylene or heteroarylene) are each independently selected from C 1~4 Alkyl, -OH, -O(C 1~4 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~4 alkyl), -N(C 1~4Alkyl)(C 1~4 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 optionally substituted with one or more groups independently selected from -(alkyl), -(haloalkyl), and -CN; Furthermore, the above C 1~10 Alkylene, 2~10 Alkenylene and the C 2~10 Alkynylene is a halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 alkyl).

[0182] X2 is C(-LR X2 ) and when L is a covalent bond, R X2 It is understood that the groups are attached directly to the corresponding ring carbon atoms of the quinazolinone ring of the compound of formula (I), as illustrated below.

[0183] [ka]

[0184] Preferably, L is a covalent bond or C 1~10 is alkylene, Said C 1~10 One or two -CH2- units contained in the alkylene are -O-, -CO-, -C(=O)O-, -OC(=O)-, -NH-, -N(C 1~5 alkyl)-, -NH-CO-, -N(C 1~5 alkyl)-CO-, -CO-NH-, -CO-N(C 1~5 alkyl)-, -S-, -SO-, -SO2-, -SO2-NH-, -SO2-N(C 1~5alkyl)-, -NH-SO2-, -N(C 1~5 and optionally substituted by a group independently selected from the group consisting of alkyl)-SO2-, cycloalkylene, arylene, heterocycloalkylene, and heteroarylene, wherein the cycloalkylene, arylene, heterocycloalkylene, and heteroarylene are each selected from the group consisting of C 1~4 Alkyl, -OH, -O(C 1~4 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)(C 1~4 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 optionally substituted with one or more (e.g., 1, 2, or 3) groups independently selected from —(alkyl), —(haloalkyl), and —CN; Furthermore, the above C 1~10 Alkylene is halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 alkyl).

[0185] More preferably, L is a covalent bond or C 1~8 is alkylene, Said C 1~8 One -CH2- unit contained in alkylene can be -O-, -CO-, -NH- and -N(C 1~5 optionally substituted by a group selected from Furthermore, the above C 1~8 Alkylene is halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 alkyl).

[0186] Even more preferably, L is a covalent bond, C 1~5 alkylene (e.g., -CH2-, -CH2CH2- or -CH2CH2CH2-), -O-, -O-(C 1~5 alkylene)-(e.g., -O-CH2-, -O-CH2CH2-, -O-CH2CH2CH2- or -O-CH2CH2CH2CH2-), -CO-, -(C 1~5 alkylene)-CO- (e.g., -CH2-CO-), -NH-, -NH-(C 1~5 alkylene)-, -N(C 1~5 alkyl)- and -N(C 1~5 alkyl)-(C 1~5 alkylene)-, Said C 1~5 alkylene, or the —O—(C 1~5 alkylene)-, the -NH-(C 1~5 alkylene)- and the -N(C 1~5 alkyl)-(C 1~5 C contained in either 1~5 The alkylene portion is halogen, -CF3, -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 and optionally substituted with one or more groups independently selected from alkyl.

[0187] Even more preferably, L is a covalent bond, C 1~5 alkylene (e.g., -CH2-, -CH2CH2- or -CH2CH2CH2-), -O-, -O-(C 1~5alkylene)-(for example, -O-CH2-, -O-CH2CH2-, -O-CH2CH2CH2- or -O-CH2CH2CH2CH2-), -NH-, -NH-(C 1~5 alkylene)-, -N(C 1~5 alkyl)- and -N(C 1~5 alkyl)-(C 1~5 alkylene)-, Said C 1~5 alkylene, or the —O—(C 1~5 alkylene)-, the -NH-(C 1~5 alkylene)- and the -N(C 1~5 alkyl)-(C 1~5 C contained in either 1~5 The alkylene portion is halogen, -CF3, -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 and optionally substituted with one or more groups independently selected from alkyl.

[0188] Even more preferably, L is a covalent bond, C 1~5 Alkylene (e.g., -CH2-, -CH2CH2- or -CH2CH2CH2-), -O- and -O-(C 1~5 alkylene)-(for example, —O—CH—, —O—CHCH—, —O—CHCH— or —O—CHCHCH—).

[0189] R X2 is C 2~10 alkyl, carbocyclyl (e.g., cycloalkyl or aryl), heterocyclyl (e.g., heterocycloalkyl or heteroaryl), and -L 1 -R X21 wherein C is selected from 2~10 The alkyl, the carbocyclyl, and the heterocyclyl each may have one or more (e.g., 1, 2, or 3) R X22 group, optionally substituted.

[0190] For example, R X2 is C 2~10 may be selected from alkyl, carbocyclyl (e.g., cycloalkyl or aryl), heterocycloalkyl, and heteroaryl, wherein said heterocycloalkyl is a monocyclic heterocycloalkyl or a spiro-cyclic heterocycloalkyl; 2~10 The alkyl, the carbocyclyl, the heterocycloalkyl, and the heteroaryl each may have one or more (e.g., 1, 2, or 3) R X22 group, optionally substituted.

[0191] Preferably, R X2 is C 2~10 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl; 2~10 The alkyl, the cycloalkyl, the aryl, the heterocycloalkyl, and the heteroaryl each may have one or more (e.g., 1, 2, or 3) R X22 The heterocycloalkyl may be, for example, a monocyclic heterocycloalkyl or a spiro-cyclic heterocycloalkyl.

[0192] More preferably, R X2 is selected from cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, and said cycloalkyl, said aryl, said heterocycloalkyl, and said heteroaryl each contain one or more (e.g., 1, 2, or 3) R X22 group, optionally substituted.

[0193] Even more preferably, R X2is azetidinyl (e.g., azetidin-3-yl), oxetanyl (e.g., oxetan-3-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl or pyrrolidin-3-yl), oxopyrrolidinyl (e.g., 2-oxo-pyrrolidin-1-yl or 5-oxo-pyrrolidin-3-yl), tetrahydrofuranyl (e.g., tetrahydrofuran-3-yl), piperidinyl (e.g., piperidin-1-yl, piperidin-3-yl or piperidin-4-yl), oxopiperidinyl (e.g., 2-oxo- piperidin-4-yl or 6-oxo-piperidin-3-yl), piperazinyl (e.g., piperazin-1-yl), oxopiperazinyl (e.g., 3-oxo-piperazin-1-yl), morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), dioxidethiomorpholinyl (e.g., 1,1-dioxidethiomorpholin-4-yl), tetrahydropyranyl (e.g., tetrahydropyran-4-yl), oxazepanyl (e.g., [1,4]oxazepan -4-yl), 2-oxa-6-aza-spiro[3.3]heptanyl (e.g., 2-oxa-6-aza-spiro[3.3]heptan-6-yl), 2-oxa-7-aza-spiro[3.5]nonyl (e.g., 2-oxa-7-aza-spiro[3.5]non-7-yl), 6-oxa-2-aza-spiro[3.4]octyl (e.g., 6-oxa-2-aza-spiro[3.4]oct-2-yl), 3-oxa-9-aza-spiro[5.5]undecyl (e.g., 3-oxa-9-aza-spiro[5.5]undeca -9-yl), 7-oxa-2-aza-spiro[4.5]decyl (e.g., 7-oxa-2-aza-spiro[4.5]dec-2-yl), 8-oxa-2-aza-spiro[4.5]decyl (e.g., 8-oxa-2-aza-spiro[4.5]dec-2-yl), 3-oxa-8-aza-bicyclo[3.2.1]octyl (e.g., 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl), 8-oxa-3-aza-bicyclo[3.2.1]octyl (e.g., 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl), phenyl, oxazolyl (e.g., oxazol-4-yl), pyridinyl (e.g., pyridin-3-yl or pyridin-4-yl), pyrazinyl (e.g., pyrazin-2-yl) and pyrimidinyl (e.g., pyrimidin-5-yl), wherein each one of the foregoing cyclic groups is selected from one or more R. X22 group, optionally substituted.

[0194] Even more preferably, R X2 is azetidinyl (e.g., azetidin-3-yl), oxetanyl (e.g., oxetan-3-yl), pyrrolidinyl (e.g., pyrrolidin-3-yl), oxopyrrolidinyl (e.g., 2-oxo-pyrrolidin-1-yl), tetrahydrofuranyl (e.g., tetrahydrofuran-3-yl), piperidinyl (e.g., piperidin-3-yl or piperidin-4-yl), oxo piperidinyl (e.g., 6-oxo-piperidin-3-yl), piperazinyl (e.g., piperazin-1-yl), morpholinyl (e.g., morpholin-4-yl), tetrahydropyranyl (e.g., tetrahydropyran-4-yl), 2-oxa-7-aza-spiro[3.5]nonyl (e.g., 2-oxa-7-aza-spiro[3.5]non-7-yl), 6-oxa-2-aza- Pyro[3.4]octyl (e.g., 6-oxa-2-aza-spiro[3.4]oct-2-yl), 3-oxa-9-aza-spiro[5.5]undecyl (e.g., 3-oxa-9-aza-spiro[5.5]undec-9-yl), 7-oxa-2-aza-spiro[4.5]decyl (e.g., 7-oxa-2-aza-spiro[4.5]dec-2-yl), 8-oxa-2-aza-spiro [4.5]decyl (e.g., 8-oxa-2-aza-spiro[4.5]dec-2-yl), phenyl, oxazolyl (e.g., oxazol-4-yl), pyridinyl (e.g., pyridin-3-yl or pyridin-4-yl), pyrazinyl (e.g., pyrazin-2-yl), and pyrimidinyl (e.g., pyrimidin-5-yl), each one of the foregoing cyclic groups being selected from one or more R X22 group, optionally substituted.

[0195] L1 is a covalent bond, C 1~10 Alkylene, C 2~10 Alkenylene and C 2~10 alkynylene, 1~10 Alkylene, 2~10 Alkenylene or the C 2~10 One or more (for example, one or two) -CH2- units contained in the alkynylene may be -O-, -CO-, -C(=O)O-, -OC(=O)-, -NH-, -N(C 1~5 alkyl)-, -NH-CO-, -N(C 1~5 alkyl)-CO-, -CO-NH-, -CO-N(C 1~5 alkyl)-, -S-, -SO-, -SO2-, -SO2-NH-, -SO2-N(C 1~5 alkyl)-, -NH-SO2- and -N(C 1~5 alkyl)-SO2-, and 1~10 Alkylene, 2~10 Alkenylene and the C 2~10 Alkynylene is a halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 alkyl).

[0196] Preferably, L 1 is a covalent bond or C 1~10 alkylene, 1~10 One or two -CH2- units contained in the alkylene are -O-, -CO-, -C(=O)O-, -OC(=O)-, -NH-, -N(C 1~5 alkyl)-, -NH-CO-, -N(C 1~5 alkyl)-CO-, -CO-NH-, -CO-N(C 1~5alkyl)-, -S-, -SO-, -SO2-, -SO2-NH-, -SO2-N(C 1~5 alkyl)-, -NH-SO2- and -N(C 1~5 alkyl)-SO2-, and 1~10 Alkylene is halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 alkyl).

[0197] More preferably, L 1 is a covalent bond or C 1~8 alkylene, 1~8 One -CH2- unit contained in alkylene can be -O-, -CO-, -NH- and -N(C 1~5 and optionally substituted by a group selected from the group consisting of C 1~8 Alkylene is halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 alkyl).

[0198] Even more preferably, L 1 is a covalent bond, C 1~5 alkylene (e.g., -CH2-, -CH2CH2- or -CH2CH2CH2-), -O-, -O-(C 1~5alkylene)-(for example, -O-CH2-, -O-CH2CH2-, -O-CH2CH2CH2- or -O-CH2CH2CH2CH2-), -NH-, -NH-(C 1~5 alkylene)-, -N(C 1~5 alkyl)- and -N(C 1~5 alkyl)-(C 1~5 alkylene)-, wherein C 1~5 alkylene, or the —O—(C 1~5 alkylene)-, the -NH-(C 1~5 alkylene)- and the -N(C 1~5 alkyl)-(C 1~5 C contained in either 1~5 The alkylene portion is halogen, -CF3, -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 and optionally substituted with one or more groups independently selected from alkyl.

[0199] Even more preferably, L 1 is a covalent bond, C 1~5 alkylene (e.g., -CH2-, -CH2CH2- or -CH2CH2CH2-), -O- and -O-(C 1~5 alkylene)-(for example, —O—CH—, —O—CHCH—, —O—CHCH— or —O—CHCHCH—).

[0200] R X21 is C 2~5 selected from alkyl, carbocyclyl (e.g., cycloalkyl or aryl), and heterocyclyl (e.g., heterocycloalkyl or heteroaryl), wherein said carbocyclyl and said heterocyclyl each have one or more (e.g., 1, 2, or 3) R X22 group, optionally substituted.

[0201] Preferably, RX21 is C 2~5 selected from alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, wherein said cycloalkyl, said aryl, said heterocycloalkyl, and said heteroaryl each have one or more (e.g., 1, 2, or 3) R X22 group, optionally substituted.

[0202] Each R X22 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-aryl, -(C 0~3 alkylene)-heteroaryl, -(C 0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl; Said -(C 0~3 the aryl moiety in the -(C alkylene)-aryl; 0~3 the heteroaryl portion of the -(C alkylene)-heteroaryl; 0~3 The cycloalkyl moiety in the -(C alkylene)-cycloalkyl, 0~3 Each heterocycloalkyl portion of the alkylene-heterocycloalkyl is selected from one or more (e.g., 1, 2, or 3) R X23 group, optionally substituted, Furthermore, each R X23 is C 1~5 Alkyl, C2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), cycloalkyl, and heterocycloalkyl.

[0203] Preferably, each R X22 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-aryl, -(C 0~3 alkylene)-heteroaryl, -(C 0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl.

[0204] More preferably, each R X22 is C 1~5 Alkyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl) and -(C 0~3 alkylene)-CN.

[0205] Even more preferably, each R X22 is C 1~5 Alkyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C1~5 haloalkyl) and —CN.

[0206] -LR X2 Examples of -LR are included in specific compounds of the invention disclosed in the Examples section. X2 The group includes any of the groups.

[0207] L and R X2 According to the above definition, -LR in the compound of formula (I) X2 The group is -R X2 Or -(C 1~8 alkylene)-R X2 It is particularly preferable that 1~8 One -CH2- unit contained in alkylene can be -O-, -CO-, -NH- and -N(C 1~5 alkyl)-, wherein said C 1~8 Alkylene is halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 alkyl), and further comprising one or more (e.g., 1, 2, or 3) groups independently selected from R X2 is selected from cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, and said cycloalkyl, said aryl, said heterocycloalkyl, and said heteroaryl each contain one or more (e.g., 1, 2, or 3) R X22 group, optionally substituted.

[0208] More preferably, -LR X2 The group is -R X2 , -(C 1~5 alkylene)-R X2 , -OR X2 and -O-(C 1~5 alkylene)-RX2 Selected from R X2 is selected from cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, and said cycloalkyl, said aryl, said heterocycloalkyl, and said heteroaryl each contain one or more (e.g., 1, 2, or 3) R X22 group, optionally substituted.

[0209] -LR X2 In the above definition of the group, R X2 is azetidinyl (e.g., azetidin-3-yl), oxetanyl (e.g., oxetan-3-yl), pyrrolidinyl (e.g., pyrrolidin-3-yl), oxopyrrolidinyl (e.g., 2-oxo-pyrrolidin-1-yl), tetrahydrofuranyl (e.g., tetrahydrofuran-3-yl), piperidinyl (e.g., piperidin-3-yl or piperidin-4-yl), oxopiperidinyl, dinyl (e.g., 6-oxo-piperidin-3-yl), piperazinyl (e.g., piperazin-1-yl), morpholinyl (e.g., morpholin-4-yl), tetrahydropyranyl (e.g., tetrahydropyran-4-yl), 2-oxa-7-aza-spiro[3.5]nonyl (e.g., 2-oxa-7-aza-spiro[3.5]non-7-yl), 6-oxa-2-aza-spiro[3.4 ]octyl (e.g., 6-oxa-2-aza-spiro[3.4]oct-2-yl), 3-oxa-9-aza-spiro[5.5]undecyl (e.g., 3-oxa-9-aza-spiro[5.5]undec-9-yl), 7-oxa-2-aza-spiro[4.5]decyl (e.g., 7-oxa-2-aza-spiro[4.5]dec-2-yl), 8-oxa-2-aza-spiro[4.5]decyl ( For example, 8-oxa-2-aza-spiro[4.5]dec-2-yl), phenyl, oxazolyl (e.g., oxazol-4-yl), pyridinyl (e.g., pyridin-3-yl or pyridin-4-yl), pyrazinyl (e.g., pyrazin-2-yl) and pyrimidinyl (e.g., pyrimidin-5-yl), wherein each one of the foregoing cyclic groups is selected from one or more R X22 group, optionally substituted.

[0210] -LR X2 is as follows:

[0211] [ka]

[0212] and the cyclic moiety in each of the above depicted groups is selected from one or more (e.g., one or two) R X22 The group is optionally further substituted.

[0213] Even more preferably, -LR X2 is as follows:

[0214] [ka]

[0215] The cyclic moiety in each of the groups depicted above may be selected from one or more (e.g., one or two) R X22 The group is optionally further substituted.

[0216] Even more preferably, -LR X2 is as follows:

[0217] [ka]

[0218] The cyclic moiety in each of the groups depicted above may be selected from one or more (e.g., one or two) R X22 The group is optionally further substituted.

[0219] Most preferably, -LR X2 teeth,

[0220] [ka]

[0221] and the cyclic moiety in the group depicted above can be one or more (e.g., one or two) R X22 The group is optionally further substituted.

[0222] R X3 is hydrogen, C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-aryl, -(C 0~3 alkylene)-heteroaryl, -(C 0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl; Said -(C 0~3 the aryl moiety in the -(C alkylene)-aryl; 0~3 the heteroaryl portion of the -(C alkylene)-heteroaryl; 0~3 The cycloalkyl moiety in the -(C alkylene)-cycloalkyl, 0~3 Each heterocycloalkyl portion of the alkylene-heterocycloalkyl is selected from one or more (e.g., 1, 2, or 3) R X31 group, optionally substituted, Furthermore, each R X31 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), cycloalkyl, and heterocycloalkyl.

[0223] The aforementioned -(C 0~3 The heterocycloalkyl moiety in an alkylene)-heterocycloalkyl group can be, for example, a monocyclic heterocycloalkyl or a spiro-cyclic heterocycloalkyl.

[0224] Preferably, R X3 is hydrogen, C 1~5 Alkyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl) and -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl).

[0225] More preferably, R X3 is hydrogen, C 1~5Alkyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl) and -(C 0~3 alkylene)-CN.

[0226] Even more preferably, R X3 is hydrogen, C 1~5 Alkyl (e.g., methyl or ethyl), —OH, —O(C 1~5 alkyl) (e.g., methoxy or ethoxy), halogen (e.g., —F or —Cl) and C 1~5 haloalkyl (e.g., —CF3).

[0227] Even more preferably, R X3 is selected from hydrogen, —OH and —OCH3. X3 is particularly preferably hydrogen.

[0228] R X4 is hydrogen, C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-aryl, -(C 0~3 alkylene)-heteroaryl, -(C 0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl; Said -(C 0~3 the aryl moiety in the -(C alkylene)-aryl; 0~3 the heteroaryl portion of the -(C alkylene)-heteroaryl; 0~3 The cycloalkyl moiety in the -(C alkylene)-cycloalkyl, 0~3 Each heterocycloalkyl portion of the alkylene-heterocycloalkyl is selected from one or more (e.g., 1, 2, or 3) R X41 group, optionally substituted, Furthermore, each R X41 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), cycloalkyl, and heterocycloalkyl.

[0229] Preferably, R X4 is hydrogen, C 1~5 Alkyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; The aryl, the heteroaryl, the cycloalkyl, and the heterocycloalkyl are each selected from the group consisting of C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 and optionally substituted with one or more (e.g., 1, 2, or 3) groups independently selected from alkyl, cycloalkyl, and heterocycloalkyl.

[0230] More preferably, R X4 is hydrogen, C 1~5 Alkyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, cycloalkyl, and heterocycloalkyl.

[0231] Even more preferably, R X4 is hydrogen, C 1~5 alkyl (e.g., methyl or ethyl), -OC 1~5 alkyl (e.g., methoxy or ethoxy), halogen (e.g., —F or —Cl), C 1~5 Haloalkyl (e.g., -CF3) and C 3~7 cycloalkyl (eg, cyclopropyl).

[0232] Even more preferably, R X4 is selected from hydrogen, methyl, —OCH3, halogen (e.g., —F or —Cl), and cyclopropyl. For example, R X4 can be methyl, —OCH 3 , halogen, or cyclopropyl.

[0233] Even more preferably, R X4 is selected from hydrogen, methyl, halogen (e.g., —F or —Cl), and cyclopropyl. X4 is particularly preferably selected from methyl, —F and —Cl.

[0234] Even more preferably, R X4 is methyl.

[0235] According to the present invention,

[0236] [ka]

[0237] are excluded from formula (I).

[0238] Therefore, the compounds depicted above, as well as pharmaceutically acceptable salts thereof, are excluded from the present invention.

[0239] below

[0240] [ka]

[0241] are further preferably excluded from the present invention.

[0242] It is particularly preferred that the compound of formula (I) according to the invention is one of the specific compounds of formula (I) further described below in the Examples section of this specification, either in non-salt form (e.g., free base / acid form) or as a pharmaceutically acceptable salt of the respective compound.

[0243] Thus, the compound of formula (I) 6-(3-pyridin-4-yl-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 2-Isoquinolin-3-yl-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 2-pyridin-2-yl-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one; 2-(4-Methoxy-pyridin-2-yl)-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one; 2-(5-fluoro-pyridin-2-yl)-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-(5-trifluoromethyl-pyridin-3-yl)-3H-quinazolin-4-one; 6-[3-(4-pyridyl)propoxy]-2-[5-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one; 2-(4-methyl-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-(6-methyl-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-(5-methylpyrazin-2-yl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-(4-chloro-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-(4-ethyl-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 6-[3-(4-pyridyl)propoxy]-2-[6-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one; 2-(4-Bromo-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-(4-cyclopropyl-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-(2-methyl-oxazol-4-yl)-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one; 6-(2-pyridin-3-yl-ethoxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(4-Bromo-benzyloxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; Tert-butyl 3-(4-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-quinazolin-6-yl)oxyazetidine-1-carboxylate; 6-(azetidin-3-yloxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 6-(1-pyrimidin-4-yl-azetidin-3-yloxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 3-(4-hydroxy-2-thieno[2,3-c]pyridin-5-yl-quinazolin-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester; 6-(azetidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(1-propionyl-azetidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(piperidin-4-yloxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(1-propionyl-piperidin-4-yloxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(2-morpholin-4-yl-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 6-(2-Methoxy-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 6-(2-morpholin-4-yl-ethoxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(2-Methoxy-ethoxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(3-pyridin-3-yl-propoxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 4-(4-oxo-2-pyridin-2-yl-3,4-dihydro-quinazolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester; 6-(piperidin-4-yloxy)-2-pyridin-2-yl-3H-quinazolin-4-one; 6-(1-acetyl-piperidin-4-yloxy)-2-pyridin-2-yl-3H-quinazolin-4-one; 4-[4-oxo-2-(4-trifluoromethyl-pyridin-2-yl)-3,4-dihydro-quinazolin-6-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester; 6-(piperidin-4-ylmethoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 6-(1-acetyl-piperidin-4-ylmethoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; tert-Butyl 4-[(4-oxo-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-6-yl)oxymethyl]piperidine-1-carboxylate; 6-(4-piperidylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(1-acetyl-piperidin-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(1-propionyl-piperidin-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 3-(4-oxo-2-thieno[2,3-c]pyridin-5-yl-3,4-dihydro-quinazolin-6-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester; 6-(pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(1-acetyl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 4-[4-oxo-2-(4-trifluoromethyl-pyridin-2-yl)-3,4-dihydro-quinazolin-6-yl]-piperazine-1-carboxylic acid tert-butyl ester; 6-Piperazin-1-yl-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 6-(4-propionyl-piperazin-1-yl)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 4-(4-oxo-2-thieno[2,3-c]pyridin-5-yl-3,4-dihydro-quinazolin-6-yl)-piperidine-1-carboxylic acid tert-butyl ester; 6-piperidin-4-yl-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(1-acetyl-piperidin-4-yl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-[2-(tetrahydro-pyran-4-yl)-ethoxy]-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 6-[3-(3-fluoro-pyridin-4-yl)-propoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-[3-(4-methanesulfonyl-phenyl)-propoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(3-pyrazin-2-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-[3-(3-methoxy-pyridin-4-yl)-propoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-[3-(2-methyl-pyridin-4-yl)-propoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(3-oxazol-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-pyrido[3,2-d]pyrimidin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-pyrido[3,2-d]pyrimidin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-pyrido[2,3-d]pyrimidin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-pyrido[3,4-d]pyrimidin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-7-trifluoromethyl-3H-quinazolin-4-one; 5-chloro-6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-chloro-6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Cyclopropyl-6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-ethyl-6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Fluoro-6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(tetrahydro-pyran-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(2-oxetan-3-yl-ethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-[2-(tetrahydro-furan-3-yl)-ethoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-[2-(tetrahydro-pyran-4-yl)-ethoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(tetrahydro-furan-3-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; R-8-methyl-6-(tetrahydro-furan-3-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; S-8-methyl-6-(tetrahydro-furan-3-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(1-methyl-6-oxo-piperidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; R-8-methyl-6-((1-methyl-6-oxopiperidin-3-yl)oxy)-2-(thieno[2,3-c]pyridin-5-yl)quinazolin-4(3H)-one; S-8-methyl-6-((1-methyl-6-oxopiperidin-3-yl)oxy)-2-(thieno[2,3-c]pyridin-5-yl)quinazolin-4(3H)-one; 8-methyl-6-(1-propionyl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; R-8-methyl-6-(1-propionyl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; S-8-methyl-6-(1-propionyl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(1-oxetan-3-yl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; R-8-methyl-6-(1-oxetan-3-yl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; S-8-methyl-6-(1-oxetan-3-yl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-[2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-ethoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(piperidin-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(1-oxetan-3-yl-piperidin-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(1-propionyl-piperidin-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(1-methanesulfonyl-piperidin-4-ylmethoxy)-8-methyl-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(2-oxa-7-aza-spiro[3.5]non-7-yl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(6-oxa-2-aza-spiro[3.4]oct-2-yl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(3-oxa-9-aza-spiro[5.5]undec-9-yl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(7-oxa-2-aza-spiro[4.5]dec-2-yl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(8-oxa-2-aza-spiro[4.5]dec-2-yl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(2-hydroxy-2-methyl-propylamino)-8-methyl-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(2-piperidin-3-yl-ethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-[2-(1-acetyl-piperidin-3-yl)-ethoxy]-8-methyl-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-[2-(4-acetyl-piperazin-1-yl)-ethoxy]-8-methyl-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 3-(8-methyl-4-oxo-2-thieno[2,3-c]pyridin-5-yl-3,4-dihydro-quinazolin-6-yl)-propionaldehyde; 8-methyl-6-(3-morpholin-4-yl-propyl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(2-morpholin-4-yl-ethyl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(3-pyridin-4-yl-propoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 8-methyl-6-(tetrahydro-furan-3-ylmethoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 8-methyl-6-(1-propionyl-azetidin-3-yloxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 8-methyl-6-(1-oxetan-3-yl-piperidin-4-yloxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 8-methyl-6-(3-oxa-9-aza-spiro[5.5]undec-9-yl)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 8-methyl-6-(3-pyridin-4-yl-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-methyl-2-pyrrolo[1,2-c]pyrimidin-3-yl-6-(tetrahydro-furan-3-ylmethoxy)-3H-quinazolin-4-one; 8-methyl-6-(3-oxa-9-aza-spiro[5.5]undec-9-yl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-methyl-6-(1-oxetan-3-yl-piperidin-4-yloxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-methyl-6-[1-(tetrahydro-pyran-4-yl)-ethoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; R-8-methyl-6-[1-(tetrahydro-pyran-4-yl)-ethoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; S-8-methyl-6-[1-(tetrahydro-pyran-4-yl)-ethoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-[1-(tetrahydro-pyran-4-yl)-ethoxy]-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; R-8-methyl-6-[1-(tetrahydro-pyran-4-yl)-ethoxy]-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; S-8-methyl-6-[1-(tetrahydro-pyran-4-yl)-ethoxy]-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 6-[(3-fluorotetrahydrofuran-3-yl)methoxy]-8-methyl-2-[4-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one; 8-methyl-6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2-thieno[2,3-c]pyridin-5-yl-3-(2-trimethylsilylethoxymethyl)pyrido[3,2-d]pyrimidin-4-one; 8-methyl-6-(morpholinomethyl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(morpholinomethyl)-2-[4-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one; 8-methyl-6-(1-propanoylazetidin-3-yl)oxy-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(2-morpholinoethyl)-2-[4-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one; 8-methyl-6-[(1-methyl-6-oxo-3-piperidyl)oxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-methyl-6-(morpholinomethyl)-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 8-methyl-6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 8-methyl-6-(2-[1,4]oxazepan-4-yl-ethyl)-2-thieno[2,3-b]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(2-[1,4]oxazepan-4-yl-ethyl)-2-thieno[3,2-b]pyridin-6-yl-3H-quinazolin-4-one; 8-methyl-6-(2-morpholin-4-yl-ethyl)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-methyl-6-(2-morpholin-4-yl-ethyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-methyl-6-(morpholinomethyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-methyl-6-(2-morpholino-2-oxoethyl)-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 8-methyl-6-(2-morpholino-2-oxo-ethyl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(2-piperidin-1-yl-ethyl)-2-thieno[2,3-b]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(1-methyl-6-oxo-piperidin-3-yloxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-Methyl-6-(1-methyl-2-oxo-piperidin-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one 8-methyl-6-(1-piperidylmethyl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(2-morpholino-2-oxo-ethyl)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-methyl-6-[(4-methylpiperazin-1-yl)methyl]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(pyrrolidin-1-ylmethyl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(2-morpholino-2-oxo-ethyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-methyl-6-(morpholine-4-carbonyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-methyl-6-(1-methyl-6-oxo-piperidin-3-yloxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 8-methyl-2-thieno[2,3-c]pyridin-5-yl-6-(thiomorpholinomethyl)-3H-quinazolin-4-one; 8-methyl-6-[2-(1,4-oxazepan-4-yl)-2-oxo-ethyl]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(pyrrolidin-1-ylmethyl)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-methyl-6-(1-methyl-5-oxo-pyrrolidin-3-yl)oxy-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-methyl-6-[(3R)-1-methyl-5-oxo-pyrrolidin-3-yl]oxy-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-methyl-6-[(3S)-1-methyl-5-oxo-pyrrolidin-3-yl]oxy-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; Benzyl 3-[(8-methyl-4-oxo-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-6-yl)oxy]pyrrolidine-1-carboxylate; Benzyl (3S)-3-[(8-methyl-4-oxo-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-6-yl)oxy]pyrrolidine-1-carboxylate; benzyl (3R)-3-[(8-methyl-4-oxo-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-6-yl)oxy]pyrrolidine-1-carboxylate; 8-methyl-6-[2-(4-methyl-3-oxo-piperazin-1-yl)ethyl]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-[2-(4-methyl-3-oxo-piperazin-1-yl)ethyl]-2-[4-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one; 8-methyl-6-[2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-[2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl]-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-methyl-6-[(4-methyl-3-oxo-piperazin-1-yl)methyl]-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(2-((2-methoxyethyl)(methyl)amino)ethyl)-8-methyl-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 6-(2-(1,1-dioxidothiomorpholino)ethyl)-8-methyl-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 6-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]-8-methyl-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(((2-methoxyethyl)(methyl)amino)methyl)-8-methyl-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 6-[(4-methoxy-1-piperidyl)methyl]-8-methyl-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-[(2,2-dimethylmorpholin-4-yl)methyl]-8-methyl-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-chloro-6-(2-morpholinoethyl)-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 8-methyl-6-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; N,N-Dimethyl-1-((8-methyl-4-oxo-2-(thieno[3,2-c]pyridin-6-yl)-3,4-dihydroquinazolin-6-yl)methyl)piperidine-4-carboxamide; 6-((4-(methoxymethyl)piperidin-1-yl)methyl)-8-methyl-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 8-Methoxy-6-(2-morpholinoethyl)-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 8-Bromo-6-(2-morpholinoethyl)-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 6-(2-(2,2-dimethylmorpholino)ethyl)-8-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 8-methyl-6-((4-methyl-3-oxopiperazin-1-yl)methyl)-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 6-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)ethyl)-8-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 6-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)ethyl)-8-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 6-(2-(4-hydroxypiperidin-1-yl)ethyl)-8-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 6-(2-(4,4-difluoropiperidin-1-yl)ethyl)-8-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 6-(2-(4-methoxypiperidin-1-yl)ethyl)-8-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 8-methyl-6-(2-morpholinoethyl)-2-(4-(trifluoromethyl)pyridin-2-yl)pyrido[3,2-d]pyrimidin-4(3H)-one; and a pharmaceutically acceptable salt of any one of the foregoing compounds.

[0244] The present invention also relates to each of the intermediates further described below in the Examples section of this specification, including any one of these intermediates in non-salt form or in the form of a salt (e.g., a pharmaceutically acceptable salt) of the respective compound. Such intermediates may be used in particular in the synthesis of compounds of formula (I).

[0245] Various methods for preparing compounds of formula (I) will be readily apparent to those skilled in the art of synthetic chemistry. For example, compounds of formula (I) can be prepared as described below, and in particular, they can be prepared according to or analogous to the synthetic routes described in the Examples section.

[0246] [ka]

[0247] -LR X2 In the case of =-OR, compounds of formula (I) can be prepared from the corresponding anthranilic amide of formula (A) and a carboxylic acid under peptide coupling conditions, typically using BOP (benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate) as a coupling reagent, followed by a cyclization step under basic conditions at elevated temperature (Valeur et al. (2009), Chem. Soc. Rev., 38:606-631). Anthranilic acids of formula (A) can be prepared by reduction of the corresponding nitro derivatives of formula (B). Typical conditions are the use of palladium on carbon and hydrogen, or the use of metals such as iron (Orlandi et al. (2018), Org. Process Res. Dev., 22:430-445). The -OR chain can be introduced from a fluorinated derivative of formula (C) and an alcohol by nucleophilic aromatic substitution. Typical conditions are the use of base at elevated temperatures (Bunnett et al. (1951), Chem. Rev., 49:273-412). -LRX2 The group can be introduced directly from the corresponding alcohol, or the -OR chain can be modified to then form the -LR X2 For example, a deprotection step and / or further functionalization can be performed. Finally, the anthranilic amide of formula (C) can be obtained from the corresponding anthranilic acid of formula (D) in the presence of ammonia under peptide coupling conditions, typically using BOP as the coupling reagent.

[0248] [ka]

[0249] Alternatively, -LR X2 = -OR, compounds of formula (I) can be prepared from compounds of formula (F) and alcohols by nucleophilic substitution or cross-coupling reactions, such as Ullmann-type reactions (Altman et al. (2008), J. Org. Chem., 73:284-286) or Pallad-catalyzed coupling reactions (Bruno et al. (2013), Org. Lett., 15:2876-2879), or by photoredox-nickel-catalyzed CO coupling reactions (Terrett et al. (2015), Nature, 524:330). -LR X2 The group can be introduced directly from the corresponding alcohol, or the -OR chain can be modified to then form the -LR X2 For example, a deprotection step and / or further functionalization can be performed.

[0250] Alternatively, -LR X2 In the case of =-OR, compounds of formula (I) can be prepared from compounds of formula (E) by Mitsunobu reaction with alcohols or by nucleophilic substitution from halide or pseudohalide derivatives (Swamy et al. (2009) Chem. Rev. 109:2551-265). X2 The group can be introduced directly from the corresponding alcohol or halide or pseudohalide, or the -OR chain can be modified to then form an -LR X2For example, a deprotection step and / or further functionalization can be performed.

[0251] -LR X2 In the case of =-N-RR', compounds of formula (I) can be prepared from compounds of formula (F) derived from amines via the Buchwald-Hartwig reaction (Heravi et al. (2018), J. Organomet. Chem., 861:17). -LR X2 The group can be introduced directly from the corresponding amine, or the -N-RR' chain can be modified to then form -LR X2 For example, a deprotection step and / or further functionalization can be performed.

[0252] -LR X2 In the case of -CR = -CRR'R'', or -CR = R'R'', or C≡R, compounds of formula (I) can be prepared from compounds of formula (F) derived from organometallic reagents, for example by Suzuki (Maluenda et al. (2015), Molecules, 20:7528) or Negishi (Haas et al. (2016), ACS Catal., 6:1540) coupling, or by palladium-catalyzed aminocarbonylation reaction (Wannberg et al. (2003), J. Org. Chem., 14:5750). X2 The group can be introduced directly from the corresponding organometallic reagent, or the -CRR'R'' or -CR=R'R'' or C≡R chain can be modified to then form -LR X2 For example, hydroboration and / or deprotection and / or further functionalization can be carried out.

[0253] Compounds of formula (F) can be prepared from the corresponding anthranilamide of formula (G) and a carboxylic acid under peptide coupling conditions, typically using BOP as a coupling reagent, followed by cyclization under basic conditions and heat.

[0254] [ka]

[0255] Anthranilamides of formula (G) can be prepared from the corresponding acids of formula (H) in the presence of ammonia under peptide coupling conditions, typically using BOP as the coupling reagent.

[0256] Alternatively, the anthranilamides of formula (G) can be prepared from the corresponding nitrile derivatives of formula (J) by hydration.

[0257] [ka]

[0258] -LR X2 In the case of =-CH2-CH2-NRR', compounds of formula (I) can be prepared from compounds of formula (K) by cyclization under basic heating conditions. Compounds of formula (K) can be prepared from nitrile derivatives of formula (M) by hydration and peptide coupling reaction with an acid, regardless of the order of steps. Typical hydration conditions are the use of a strong acid, such as hydrochloric acid or sulfuric acid, or a strong base, such as potassium carbonate; alternatively, milder conditions are the use of, for example, aqueous hydrogen peroxide and dimethyl sulfoxide in the presence of a base, such as potassium carbonate or sodium hydroxide. Peptide coupling reactions can be carried out in a variety of ways, for example, by activating the carboxylic acid using BOP, T3P (propylphosphonic anhydride), oxalyl chloride, or phosphorus oxychloride (Valeur et al. (2009), Chem. Soc. Rev., 38:606-631). By introducing an amine HNRR', compounds of formula (M) can be obtained by activation of an alcohol derivative of formula (O) to form a leaving group such as mesylate, tosylate, triflate or halide, followed by nucleophilic substitution. Typical conditions are the use of a base such as triethylamine or potassium carbonate. Compounds of formula (O) can be prepared by halogenation of compounds of formula (P), typically using N-bromosuccinimide or iodine as halogenating agents.

[0259] -R X4The group can be modified during the course of synthesis by electrophilic halogenation of a compound of formula (O) or (M) or by Pallad-catalyzed coupling, e.g., Suzuki coupling, with a compound of formula (O) or (M) to derive an alkyl group from the halogen (Maluenda et al. (2015), Molecules, 20:7528).

[0260] [ka]

[0261] -LR X2 In the case of =-CH2-C(O)-NRR', compounds of formula (I) can be prepared from an anthranilamide of formula (Q) and a carboxylic acid under peptide coupling conditions, typically using BOP as a coupling reagent, followed by a cyclization step under basic conditions at elevated temperatures (Valeur et al. (2009) Chem. Soc. Rev. 38:606-631). One possibility for synthesizing compounds of formula (Q) is by decarboxylation of compounds of formula (R), followed by reduction of the resulting nitro derivative and coupling of the amine NRR' with the amide, typically using BOP as a coupling reagent. Compounds of formula (R) can be prepared by nucleophilic aromatic substitution with fluorinated derivatives or formula (C) using dialkyl malonates in the presence of base at elevated temperatures.

[0262] Additionally, compounds of formula (I) may be further functionalized, for example by cross-coupling reactions, when X1, X3 and / or X4 = C-Hal, to provide other compounds of formula (I).

[0263] While carrying out all of the syntheses described above, the lactam NH bond may be temporarily protected, for example by an SEM protecting group.

[0264] -LR X2 and the various reactants used to introduce the starting materials are either commercially available or can be prepared by classical organic chemistry reactions as described in the examples.

[0265] The following definitions apply throughout the present specification and claims, unless otherwise indicated.

[0266] The term "hydrocarbon group" refers to a group consisting of carbon and hydrogen atoms.

[0267] As used herein, the term "alkyl" refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group which may be straight-chained or branched. Thus, an "alkyl" group does not contain any carbon-carbon double bonds or any carbon-carbon triple bonds. 1~5 "Alkyl" refers to an alkyl group having 1 to 5 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl). Unless otherwise defined, the term "alkyl" preferably refers to a C 1~4 It refers to alkyl, more preferably methyl or ethyl, even more preferably methyl.

[0268] As used herein, the term "alkenyl" refers to a monovalent unsaturated acyclic hydrocarbon group, which may be straight-chained or branched, and which contains one or more (e.g., one or two) carbon-carbon double bonds, but no carbon-carbon triple bonds. 2~5 The term "alkenyl" refers to an alkenyl group having 2 to 5 carbon atoms. Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, or prop-2-en-1-yl), butenyl, butadienyl (e.g., buta-1,3-dien-1-yl or buta-1,3-dien-2-yl), pentenyl, or pentadienyl (e.g., isoprenyl). Unless otherwise defined, the term "alkenyl" preferably refers to an alkenyl group having from 2 to 5 carbon atoms. 2~4 refers to alkenyl.

[0269] As used herein, the term "alkynyl" refers to a monovalent unsaturated acyclic hydrocarbon group, which may be straight-chained or branched, and which contains one or more (e.g., one or two) carbon-carbon triple bonds and, optionally, one or more (e.g., one or two) carbon-carbon double bonds. 2~5 The term "alkynyl" refers to an alkynyl group having from 2 to 5 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), or butynyl. Unless otherwise defined, the term "alkynyl" preferably refers to an alkynyl group having from 2 to 5 carbon atoms. 2~4 refers to alkynyl.

[0270] As used herein, the term "alkylene" refers to an alkanediyl group, i.e., a divalent saturated acyclic hydrocarbon group, which may be linear or branched. 1~5 "Alkylene" refers to an alkylene group having 1 to 5 carbon atoms; 0~3 The term "alkylene" refers to either a covalent bond (corresponding to the "C alkylene" alternative) or a C 1~3 indicates the presence of alkylene. Preferred exemplary alkylene groups are methylene (-CH-), ethylene (e.g., -CH-CH- or -CH(-CH)-), propylene (e.g., -CH-CH-CH-, -CH(-CH-CH)-, -CH-CH(-CH)- or -CH(-CH)-CH-), or butylene (e.g., -CH-CH-CH-CH-). Unless otherwise defined, the term "alkylene" preferably refers to a C 1~4 Alkylene (specifically, linear C 1~4 It refers to alkylene), more preferably methylene or ethylene.

[0271] As used herein, the term "alkenylene" refers to an alkenediyl group, i.e., a divalent unsaturated acyclic hydrocarbon group, which may be linear or branched and contains one or more (e.g., one or two) carbon-carbon double bonds but no carbon-carbon triple bonds. 2~8"Alkenylene" refers to an alkenylene group having from 2 to 8 carbon atoms. Unless otherwise defined, the term "alkenylene" preferably refers to an alkenylene group having from 2 to 8 carbon atoms. 2~4 Alkenylene (specifically, linear C 2~4 (including alkenylene).

[0272] As used herein, the term "alkynylene" refers to an alkynediyl group, i.e., a divalent unsaturated acyclic hydrocarbon group, which may be linear or branched and contains one or more (e.g., one or two) carbon-carbon triple bonds and, optionally, one or more (e.g., one or two) carbon-carbon double bonds. 2~8 "Alkynylene" refers to an alkynylene group having from 2 to 8 carbon atoms. Unless otherwise defined, the term "alkynylene" preferably refers to a C 2~4 Alkynylene (specifically, linear C 2~4 (including alkynylene).

[0273] As used herein, the term "carbocyclyl" refers to hydrocarbon ring groups, including monocyclic rings, as well as bridged, spiro, and / or fused ring systems (which may be composed of, for example, two or three rings), which ring groups may be saturated, partially unsaturated (i.e., unsaturated but not aromatic), or aromatic. Unless otherwise defined, "carbocyclyl" preferably refers to aryl, cycloalkyl, or cycloalkenyl.

[0274] As used herein, the term "carbocyclylene," as defined hereinabove, refers to a carbocyclyl group having two points of attachment, i.e., a divalent hydrocarbon ring group, including monocyclic rings, as well as bridged rings, spiro rings, and / or fused ring systems (which may, for example, be composed of two or three rings), which ring groups may be saturated, partially unsaturated (i.e., unsaturated but not aromatic), or aromatic. Unless otherwise defined, "carbocyclylene" preferably refers to arylene, cycloalkylene, or cycloalkenylene.

[0275] As used herein, the term "heterocyclyl" refers to ring groups including monocyclic rings, as well as bridged rings, spiro rings, and / or fused ring systems (which may be composed of, e.g., two or three rings), which contain one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) can be optionally oxidized, and one or more carbon ring atoms can be optionally oxidized (i.e., to form an oxo group), and further wherein the ring group can be saturated, partially unsaturated (i.e., unsaturated but not aromatic), or aromatic. For example, each heteroatom-containing ring within the ring group may contain 1 or 2 O atoms and / or 1 or 2 S atoms (which may be optionally oxidized) and / or 1, 2, 3, or 4 N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may be optionally oxidized) in the corresponding heteroatom-containing ring. Unless otherwise defined, "heterocyclyl" preferably refers to heteroaryl, heterocycloalkyl, or heterocycloalkenyl.

[0276] As used herein, the term "heterocyclylene," as defined herein above, refers to a heterocyclyl group having two points of attachment, i.e., a bivalent ring group including monocyclic rings, as well as bridged rings, spiro rings, and / or fused ring systems (which may, for example, be composed of two or three rings), wherein said ring group contains one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) can be optionally oxidized, and one or more carbon ring atoms can be optionally oxidized (i.e., to form an oxo group), and further wherein said ring group can be saturated, partially unsaturated (i.e., unsaturated but not aromatic), or aromatic. For example, each heteroatom-containing ring within the ring group may contain 1 or 2 O atoms and / or 1 or 2 S atoms (which may be optionally oxidized) and / or 1, 2, 3, or 4 N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may be optionally oxidized) in the corresponding heteroatom-containing ring. Unless otherwise defined, "heterocyclylene" preferably refers to heteroarylene, heterocycloalkylene, or heterocycloalkenylene.

[0277] As used herein, the term "aryl" refers to aromatic hydrocarbon ring groups, including monocyclic aromatic rings containing at least one aromatic ring (e.g., a ring system composed of two or three fused rings, at least one of which is aromatic, or a bridged ring system composed of two or three rings, at least one of which is aromatic), as well as bridged and / or fused ring systems. "Aryl" can refer to, for example, phenyl, naphthyl, diarylnyl (i.e., 1,2-dihydronaphthyl), tetralinyl (i.e., 1,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1H-indenyl), anthracenyl, phenanthrenyl, 9H-fluorenyl, or azulenyl. Unless otherwise defined, "aryl" preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, and even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl.

[0278] As used herein, the term "arylene" refers to a divalent aromatic hydrocarbon ring group, as defined herein above, including aryl groups, but having two points of attachment, i.e., monocyclic aromatic rings containing at least one aromatic ring, as well as bridged and / or fused ring systems (e.g., a ring system composed of two or three fused rings, at least one of which is aromatic, or a bridged ring system composed of two or three rings, at least one of which is aromatic). "Arylene" can refer, for example, to phenylene (e.g., phen-1,2-diyl, phen-1,3-diyl, or phen-1,4-diyl), naphthylene (e.g., naphthalene-1,2-diyl, naphthalene-1,3-diyl, naphthalene-1,4-diyl, naphthalene-1,5-diyl, naphthalene-1,6-diyl, naphthalene-1,7-diyl, naphthalene-2,3-diyl, naphthalene-2,5-diyl, naphthalene-2,6-diyl, naphthalene-2,7-diyl, or naphthalene-2,8-diyl), 1,2-dihydronaphthylene, 1,2,3,4-tetrahydronaphthylene, indanylene, indenylene, anthracenylene, phenanthrenylene, 9H-fluorenylene, or azulenylene. Unless otherwise defined, "arylene" preferably has from 6 to 14 ring atoms, more preferably from 6 to 10 ring atoms, and even more preferably refers to phenylene or naphthylene, and most preferably phenylene (especially phen-1,4-diyl).

[0279] As used herein, the term "heteroaryl" refers to aromatic ring groups, including monocyclic aromatic rings containing at least one aromatic ring, as well as bridged and / or fused ring systems (e.g., a ring system composed of two or three fused rings, at least one of which is aromatic, or a bridged ring system composed of two or three rings, at least one of which is aromatic), which contain one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) can be optionally oxidized, and further, one or more carbon ring atoms can be optionally oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring contained in the aromatic ring group may contain 1 or 2 O atoms and / or 1 or 2 S atoms (which may be optionally oxidized) and / or 1, 2, 3 or 4 N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may be optionally oxidized) in the corresponding heteroatom-containing ring. "Heteroaryl" includes, for example, thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-1-benzopyranyl or 4H-1-benzopyranyl), isochromenyl (e.g., 1H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 1H-pyrrolyl), imidazolyl, pyridinyl ... pyrazolyl, pyridyl (i.e., pyridinyl, e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g., 3H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [[1,10]phenanthrolinyl, [1,7]phenanthrolinyl or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (i.e., furazanyl) or 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, aryl or 1,3,4-thiadiazolyl), phenoxazinyl, pyrazolo[1,5-a]pyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidin-3-yl), 1,2-benzisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e., benzothienyl), triazolyl (e.g., 1H-1,2,3-triazolyl, 2H -1,2,3-triazolyl, 1H-1,2,4-triazolyl or 4H-1,2,4-triazolyl), benzotriazolyl, 1H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,3-c]pyridinyl or 1,3-dihydrofuro[3,4-c]pyridinyl). pyridinyl), imidazopyridinyl (e.g., imidazo[1,2-a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl, tetrahydrothienopyridinyl (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl, 1,3-benzodioxolyl, benzodioxanyl (e.g., 1,3-benzodioxanyl or 1,4-benzodioxanyl) or coumarinyl.Unless otherwise defined, the term "heteroaryl" preferably refers to a 5- to 14-membered (more preferably 5- to 10-membered) monocyclic ring or fused ring system containing one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized; even more preferably, "heteroaryl" refers to a 5- or 6-membered monocyclic ring containing one or more (e.g., 1, 2, or 3) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized.

[0280] As used herein, the term "heteroarylene," as defined herein above, refers to a divalent aromatic ring group, including heteroaryl groups having two points of attachment, i.e., monocyclic aromatic rings containing at least one aromatic ring, and bridged and / or fused ring systems (e.g., a ring system composed of two or three fused rings, at least one of which is aromatic, or a bridged ring system composed of two or three rings, at least one of which is aromatic), wherein the aromatic ring group contains one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) can be optionally oxidized, and further, one or more carbon ring atoms can be optionally oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring within the aromatic ring group can contain 1 or 2 O atoms and / or 1 or 2 S atoms (which can be optionally oxidized) and / or 1, 2, 3, or 4 N atoms (which can be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which can be optionally oxidized) in the corresponding heteroatom-containing ring. "Heteroarylene" includes, for example, thienylene (i.e., thiophenylene, e.g., thien-2,3-diyl, thien-2,4-diyl, or thien-2,5-diyl), benzo[b]thienylene, naphtho[2,3-b]thienylene, thianthrenylene, furylene (i.e., furanylene, e.g., furan-2,3-diyl, furan-2,4-diyl, or furan-2,5-diyl), benzofuranylene, isobenzofuranylene, chromanylene, benzo[b]thienylene, naphtho[2,3-b]thienylene, thianthrenylene, thienylene, benzo[b] ... ethylene, chromenylene, isochromenylene, chromonylene, xanthenylene, phenoxathiinylene, pyrrolylene, imidazolylene, pyrazolylene, pyridylene (i.e., pyridinylene), pyrazinylene, pyrimidinylene, pyridazinylene, indolylene, isoindolylene, indazolylene, indolizinylene, purinylene, quinolylene, isoquinolylene, phthalazinylene, naphthyridinylene, quinoxalinylene, cinnolinylene, butylene,Rizinylene, carbazolylene, β-carbolinylene, phenanthridinylene, acridinylene, perimidinylene, phenanthrolinylene, phenazinylene, thiazolylene (e.g., thiazole-2,4-diyl, thiazole-2,5-diyl, or thiazole-4,5-diyl), isothiazolylene (e.g., isothiazole-3,4-diyl, isothiazole-3,5-diyl, or isothiazole-4,5-diyl), phenothiazinylene, oxazolylene (e.g., oxazole-2,4-diyl, oxazole-2,5-diyl, or oxazolylene), 1,2,4-oxadiazole-3,5-diyl, 1,2,5-oxadiazole-3,4-diyl, or 1,3,4-oxadiazole-2,5-diyl), thiadiazole-3,5-diyl, 1,2,5-thiadiazole-3,4-diyl, or 1,3,4-thiadiazole-2,5-diyl), pheno Xazinylene, pyrazolo[1,5-a]pyrimidinylene, 1,2-benzisoxazolylene, benzothiazolylene, benzothiadiazolylene, benzoxazolylene, benzisoxazolylene, benzimidazolylene, benzo[b]thiophenylene (i.e., benzothienylene), triazolylene (e.g., 1H-1,2,3-triazolylene, 2H-1,2,3-triazolylene, 1H-1,2,4-triazolylene, or 4H-1,2,4-triazolylene), benzotriazolylene, 1H-tetrazolylene, 2H-tetrazolylene, triazolylene, diazinylene (e.g., 1,2,3-triazinylene, 1,2,4-triazinylene, or 1,3,5-triazinylene), furo[2,3-c]pyridinylene, dihydrofuropyridinylene (e.g., 2,3-dihydrofuro[2,3-c]pyridinylene or 1,3-dihydrofuro[3,4-c]pyridinylene), imidazopyridinylene (e.g., imidazo[1,2-a]pyridinylene or imidazo[3,2-a]pyridinylene), quinazolinylene, thienopyridinylene, tetrahydrothienopyridinylene (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinylene), dibenzofuranylene, 1,3-benzodioxolylene, benzodioxanylene (for example, 1,3-benzodioxanylene or 1,4-benzodioxanylene) or coumarinylene. Unless otherwise defined, the term "heteroarylene" refers to a divalent monocyclic ring or fused ring system, preferably 5- to 14-membered (more preferably 5- to 10-membered) ring containing one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, in which one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized; even more preferably, "heteroarylene" refers to a divalent 5- or 6-membered ring containing one or more (e.g., 1, 2, or 3) ring heteroatoms independently selected from O, S, and N, in which one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized. A "heteroarylene," including any of the specific heteroarylene groups described herein, may be attached through two carbon ring atoms, particularly through the two carbon ring atoms having the greatest distance from each other (in terms of the number of ring atoms separating them with the shortest possible connection), within one single ring or within the entire ring system of the corresponding heteroarylene.

[0281] As used herein, the term "cycloalkyl" refers to saturated hydrocarbon ring groups including monocyclic rings, as well as bridged rings, spiro rings, and / or fused ring systems (e.g., may be composed of two or three rings, e.g., a fused ring system composed of two or three fused rings). "Cycloalkyl" can refer to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl. Unless otherwise defined, "cycloalkyl" preferably refers to a C 3~11 It refers to cycloalkyl, more preferably C 3~7 Particularly preferred "cycloalkyls" are monocyclic saturated hydrocarbon rings having from 3 to 7 ring members.

[0282] As used herein, the term "cycloalkylene" refers to a cycloalkyl group, as defined herein above, having two points of attachment, i.e., a divalent saturated hydrocarbon ring group, including monocyclic rings, as well as bridged rings, spiro rings, and / or fused ring systems (e.g., which may be composed of two or three rings, e.g., a fused ring system composed of two or three fused rings). "Cycloalkylene" may refer to, for example, cyclopropylene (e.g., cyclopropane-1,1-diyl or cyclopropane-1,2-diyl), cyclobutylene (e.g., cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, or cyclobutane-1,3-diyl), cyclopentylene (e.g., cyclopentane-1,1-diyl, cyclopentane-1,2-diyl, or cyclopentane-1,3-diyl), cyclohexylene (e.g., cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl, or cyclohexane-1,4-diyl), cycloheptylene, decalinylene (i.e., decahydronaphthylene), or adamantylene. Unless otherwise defined, "cycloalkylene" preferably refers to a cycloalkylene having a C 3~11 It refers to cycloalkylene, more preferably C 3~7 Particularly preferred "cycloalkylenes" are divalent monocyclic saturated hydrocarbon rings having from 3 to 7 ring members.

[0283] As used herein, the term "heterocycloalkyl" refers to saturated ring groups, including monocyclic rings, bridged rings, spiro rings, and / or fused ring systems (e.g., which may be composed of two or three rings, e.g., a fused ring system composed of two or three fused rings), which contain one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) can be optionally oxidized, and further, one or more carbon ring atoms can be optionally oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring within the saturated ring group can contain 1 or 2 O atoms and / or 1 or 2 S atoms (which can be optionally oxidized) and / or 1, 2, 3, or 4 N atoms (which can be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which can be optionally oxidized) in the corresponding heteroatom-containing ring. "Heterocycloalkyl" includes, for example, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1,4-diazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazolidinyl, cyclohexane (cyclohexane), ... It may refer to zepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, thiiranyl, thietanyl, tetrahydrothiophenyl (i.e., thiolanyl), 1,3-dithiolanyl, thianyl, thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl. Unless otherwise defined, "heterocycloalkyl" refers to a saturated ring group, preferably having 3 to 11 members, that is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein the ring group contains one or more (e.g., 1, 2, 3, or 4) independently selected from O, S, and N. ), wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized; more preferably, "heterocycloalkyl" refers to a 5- to 7-membered saturated monocyclic ring group containing one or more (e.g., 1, 2, or 3) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized.

[0284] As used herein, the term "heterocycloalkylene," as defined hereinabove, refers to a heterocycloalkyl group having two points of attachment, i.e., a divalent saturated ring group including monocyclic rings, as well as bridged rings, spiro rings, and / or fused ring systems (e.g., which may be composed of two or three rings, e.g., a fused ring system composed of two or three fused rings), which ring group contains one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, the remaining ring atoms being carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) can be optionally oxidized, and further, one or more carbon ring atoms can be optionally oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring contained in said saturated ring group may contain 1 or 2 O atoms and / or 1 or 2 S atoms (which may be optionally oxidized) and / or 1, 2, 3 or 4 N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may be optionally oxidized) in the corresponding heteroatom-containing ring. Examples of "heterocycloalkylene" include aziridinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, piperazinylene, azepanylene, diazepanylene (e.g., 1,4-diazepanylene), oxazolidinylene, isoxazolidinylene, thiazolidinylene, isothiazolidinylene, morpholinylene, thiomorpholinylene, oxazepanylene, oxiranylene, oxetane, and cyclohexane.

[0033] Unless otherwise defined, "heterocycloalkylene" may refer to a 3- to 11-membered divalent saturated ring that is preferably a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings). "Heterocycloalkylene" refers to a 5- to 7-membered divalent saturated monocyclic ring group containing one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized; more preferably, "heterocycloalkylene" refers to a 5- to 7-membered divalent saturated monocyclic ring group containing one or more (e.g., 1, 2, or 3) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized.

[0285] As used herein, the term "cycloalkenyl" refers to unsaturated alicyclic (i.e., non-aromatic) hydrocarbon ring groups, including monocyclic rings, bridged rings, spiro rings, and / or fused ring systems (e.g., may be composed of two or three rings, e.g., a fused ring system composed of two or three fused rings), which contain one or more (e.g., one or two) carbon-carbon double bonds and no carbon-carbon triple bonds. "Cycloalkenyl" can refer, for example, to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl. Unless otherwise defined, "cycloalkenyl" preferably refers to a C 3~11 It refers to cycloalkenyl, more preferably C 3~7 Particularly preferred "cycloalkenyls" are monocyclic unsaturated alicyclic hydrocarbon rings having 3 to 7 ring members and containing one or more (e.g., 1 or 2, preferably 1) carbon-carbon double bonds.

[0286] As used herein, the term "cycloalkenylene" refers to a divalent unsaturated alicyclic (i.e., non-aromatic) hydrocarbon ring group, as defined herein above, including cycloalkenyl groups having two attachment points, monocyclic rings, and bridged rings, spiro rings, and / or fused ring systems (e.g., may be composed of two or three rings, e.g., a fused ring system composed of two or three fused rings), wherein the hydrocarbon ring group contains one or more (e.g., one or two) carbon-carbon double bonds and no carbon-carbon triple bonds. "Cycloalkenylene" can refer to, for example, cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, cyclohexadienylene, cycloheptenylene, or cycloheptadienylene. Unless otherwise defined, "cycloalkenylene" preferably refers to a C 3~11 It refers to cycloalkenylene, more preferably C 3~7 Particularly preferred "cycloalkenylene" refers to a divalent monocyclic unsaturated alicyclic hydrocarbon ring having 3 to 7 ring members and containing one or more (e.g., one or two, preferably one) carbon-carbon double bonds.

[0287] As used herein, the term "heterocycloalkenyl" refers to unsaturated alicyclic (i.e., non-aromatic) ring groups, including monocyclic rings, bridged rings, spiro rings, and / or fused ring systems (e.g., which may be composed of two or three rings, e.g., a fused ring system composed of two or three fused rings), which ring groups contain one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, the remaining ring atoms are carbon atoms, one or more S ring atoms (if present) and / or one or more N ring atoms (if present) can be optionally oxidized, one or more carbon ring atoms can be optionally oxidized (i.e., to form an oxo group), and further, which ring groups contain at least one double bond between adjacent ring atoms and no triple bonds between adjacent ring atoms. For example, each heteroatom-containing ring within the unsaturated alicyclic group can contain 1 or 2 O atoms and / or 1 or 2 S atoms (which may be optionally oxidized) and / or 1, 2, 3, or 4 N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may be optionally oxidized) in the corresponding heteroatom-containing ring. "Heterocycloalkenyl" includes, for example, imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-1H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridinyl), dihydropyridinyl (e.g., 1,2-dihydropyridinyl or 2,3-dihydropyridinyl), pyranyl (e.g., 2H-pyranyl or 4H- pyranyl), thiopyranyl (e.g., 2H-thiopyranyl or 4H-thiopyranyl), dihydropyranyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazinyl, dihydroisoindolyl, octahydroquinolinyl (e.g., 1,2,3,4,4a,5,6,7-octahydroquinolinyl) or octahydroisoquinolinyl (e.g., 1,2,3,4,5,6,7,8-octahydroisoquinolinyl).Unless otherwise defined, "heterocycloalkenyl" refers to an unsaturated alicyclic ring group, preferably a 3- to 11-membered ring, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), which ring group contains one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, one or more carbon ring atoms are optionally oxidized, and the ring group has at least one double bond between adjacent ring atoms. and does not contain any triple bonds between adjacent ring atoms, more preferably, "heterocycloalkenyl" refers to a 5- to 7-membered monocyclic unsaturated non-aromatic ring group containing one or more (e.g., 1, 2, or 3) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized, said ring group containing at least one double bond between adjacent ring atoms and no triple bonds between adjacent ring atoms.

[0288]

[0023] As used herein, the term "heterocycloalkenylene," as defined herein above, refers to a divalent unsaturated alicyclic (i.e., non-aromatic) ring group, as defined hereinabove, having two points of attachment, including monocyclic rings and bridged rings, spiro rings, and / or fused ring systems (e.g., which may be composed of two or three rings, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) can be optionally oxidized, and wherein one or more carbon ring atoms can be optionally oxidized (i.e., to form an oxo group), and further wherein said ring group contains at least one double bond between adjacent ring atoms and no triple bonds between adjacent ring atoms. For example, each heteroatom-containing ring within the unsaturated alicyclic group can contain 1 or 2 O atoms and / or 1 or 2 S atoms (which can be optionally oxidized) and / or 1, 2, 3, or 4 N atoms (which can be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which can be optionally oxidized) in the corresponding heteroatom-containing ring. "Heterocycloalkenylene" can refer, for example, to imidazolinylene, tetrahydropyridinylene, dihydropyridinylene, pyranylene, thiopyranylene, dihydropyranylene, dihydrofuranylene, dihydropyrazolylene, dihydropyrazinylene, dihydroisoindolylene, octahydroquinolinylene, or octahydroisoquinolinylene. Unless otherwise defined, "heterocycloalkenylene" refers to a divalent unsaturated alicyclic ring group, preferably 3 to 11 membered, that is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), that contains one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized, and wherein the ring The group contains at least one double bond between adjacent ring atoms and no triple bonds between adjacent ring atoms, more preferably, "heterocycloalkenylene" refers to a 5- to 7-membered divalent monocyclic unsaturated non-aromatic ring group containing one or more (e.g., 1, 2, or 3) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized, said ring group containing at least one double bond between adjacent ring atoms and no triple bonds between adjacent ring atoms.

[0289] As used herein, the term "halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br) or iodo (-I).

[0290] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms independently selected from fluoro, chloro, bromo, and iodo, preferably all fluoro atoms. It is understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, therefore, determined by the number of carbon atoms included in the alkyl portion of the haloalkyl group. "Haloalkyl" can refer to, for example, -CF, -CHF, -CHF, -CF-CH, -CH-CF, -CH-CHF, -CH-CF-CH, -CH-CF-CF, or -CH(CF). A particularly preferred "haloalkyl" group is -CF.

[0291] As used herein, the terms "optional," "optionally," and "may" indicate that the indicated feature may or may not be present. Whenever the terms "optional," "optionally," or "may" are used, the present invention specifically relates to both possibilities, i.e., the presence of the corresponding feature or the absence of the corresponding feature. For example, the phrase "X is optionally substituted with Y" (or "X may be substituted with Y") means that X is substituted with Y or is unsubstituted. Similarly, when a component of a composition is designated as "optional," the present invention specifically relates to both possibilities, i.e., the presence of the corresponding component (contained in the composition) or the absence of the corresponding component in the composition.

[0292] Herein, various groups are referred to as "optionally substituted." Generally, these groups may have one or more substituents, for example, 1, 2, 3, or 4 substituents. It is understood that the maximum number of substituents is limited by the number of attachment sites available on the substituted moiety. Unless otherwise defined, "optionally substituted" groups referred to herein preferably have two or fewer substituents, and in particular may have only one substituent. Furthermore, unless otherwise defined, it is preferred that there are no optional substituents, i.e., the corresponding group is unsubstituted.

[0293] Those skilled in the art will recognize that substituents contained in the compounds of the present invention may be attached to the remainder of the respective compound via several different positions of the corresponding specific substituent. Unless otherwise defined, preferred positions of attachment for various specific substituents are as illustrated in the Examples.

[0294] As used herein, unless clearly indicated otherwise or contradicted by context, the terms "a," "an," and "the" are used interchangeably with "one or more" and "at least one." Thus, for example, a composition comprising "a" compound of Formula (I) can be interpreted as referring to a composition comprising "one or more" compounds of Formula (I).

[0295] As used herein, the term "about" preferably refers to ±10% of the indicated numerical value, more preferably ±5% of the indicated numerical value, and particularly to the exact indicated numerical value.

[0296] As used herein, the term "comprising" (or "comprise," "comprises," "contain," "contains," or "containing") means "containing, among other things," i.e., "containing, among further optional elements," unless clearly indicated otherwise or contradicted by context. In addition, the term also includes the narrower meanings of "consisting essentially of" and "consisting of." For example, the term "A comprising B and C" means "A containing, among other things, B and C," and A may contain further optional elements (e.g., "A containing B, C, and D" may also be included), but the term also includes the meanings "A consisting essentially of B and C" and "A consisting of B and C" (i.e., A does not contain any other components besides B and C).

[0297] The scope of the present invention includes all pharmaceutically acceptable salt forms of the compounds of formula (I), which may be formed, for example, by protonation of an atom bearing a lone pair of electrons susceptible to protonation, e.g., an amino group, with an inorganic or organic acid, or as a salt of an acidic group (e.g., a carboxylic acid group) with a physiologically acceptable cation.

[0298] Exemplary base addition salts include, for example, alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkylamine salts such as N,N-dibenzylethylenediamine salts, benzathine salts, benethamine 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, lysine salts, or histidine salts.

[0299] Exemplary acid addition salts include, for example, mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate (e.g., sulfate or hydrogen sulfate), nitrate, phosphate (e.g., phosphate, hydrogen phosphate, or dihydrogen phosphate), carbonate, bicarbonate, perchlorate, borate, or thiocyanate; acetate, propionate, butyrate, valerate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycerin, glycerol, hydroxybenzoate ... Organic acid salts such as cholate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate or pivalate; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate or camphorsulfonate; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate.

[0300] Preferred pharmaceutically acceptable salts of the compound of formula (I) include hydrochloride, hydrobromide, mesylate, sulfate, tartrate, fumarate, acetate, citrate, and phosphate. A particularly preferred pharmaceutically acceptable salt of the compound of formula (I) is hydrochloride. Thus, the compound of formula (I), including any one of the specific compounds of formula (I) described herein, is preferably in the form of hydrochloride, hydrobromide, mesylate, sulfate, tartrate, fumarate, acetate, citrate, or phosphate, and the compound of formula (I) is particularly preferably in the form of hydrochloride.

[0301] It is understood that the present invention also relates to the non-salt forms of compounds of formula (I), including any one of the specific compounds described herein.

[0302] Furthermore, the scope of the present invention includes compounds of formula (I) in certain solvated forms, including, for example, solvates with water (i.e., as hydrates) or solvates with organic solvents such as methanol, ethanol, or acetonitrile (i.e., as methanolates, ethanolates, or acetonitriles). All physical forms, including either amorphous or crystalline forms (i.e., polymorphs) of compounds of formula (I), are also encompassed within the scope of the present invention. It should be understood that such solvates and physical forms of pharmaceutically acceptable salts of compounds of formula (I) are also encompassed by the present invention.

[0303] Furthermore, compounds of formula (I) may exist in various isomeric, particularly stereoisomers (including, for example, geometric isomers (or cis / trans isomers), enantiomers, atropisomers and diastereoisomers), or tautomeric, particularly prototropic tautomers, forms. All such isomers of compounds of formula (I), in admixture or in pure or substantially pure form, are contemplated as part of the present invention.

[0304] With respect to stereoisomers, the present invention encompasses isolated optical isomers of the compounds according to the invention as well as any mixtures thereof (particularly including racemic mixtures / racemates). Racemates can be resolved by physical methods, such as fractional crystallization, separation or crystallization of diastereoisomeric derivatives or separation by chiral column chromatography. Individual optical isomers can be obtained from the racemate via salt formation with an optically active acid followed by crystallization.

[0305] The present invention further encompasses certain tautomers (e.g., keto / enol tautomers or lactam / lactim tautomers) of the compounds presented herein, and in particular the following compounds of formula (I):

[0306] [ka]

[0307] This includes tautomers of the formula:

[0308] The scope of the present invention also includes compounds of formula (I) where one or more atoms are replaced by a specific isotope of the corresponding atom.

[0309] For example, the present invention provides compounds in which one or more hydrogen atoms (or, for example, all hydrogen atoms) have been replaced by deuterium atoms (i.e., 2 H, also referred to as "D"), encompasses compounds of formula (I). Accordingly, the present invention also encompasses compounds of formula (I) that are enriched with deuterium. Naturally occurring hydrogen is approximately 99.98 mol% hydrogen-1 ( 1 H) and about 0.0156 mol% deuterium ( 2 The deuterium content at one or more hydrogen positions in a compound of formula (I) can be increased using deuteration techniques known in the art. For example, a compound or reactant of formula (I), or a precursor used in the synthesis of a compound of formula (I), can be subjected to an H / D exchange reaction using, for example, heavy water (DO). Further suitable deuteration techniques are described in Atzrodt J et al., Bioorg Med Chem, 20(18), pp. 5658-5667, 2012; William JS et al., Journal of Labeled Compounds and Radiopharmaceuticals, 53(11-12), pp. 635-644, 2010; and Modvig A et al., J Org Chem, 79, pp. 5861-5868, 2014. The deuterium content can be determined, for example, using mass spectrometry or NMR spectroscopy. Unless otherwise indicated, it is preferred that the compounds of formula (I) are not deuterium enriched. Thus, in the compounds of formula (I), naturally occurring hydrogen atoms or 1 The presence of H hydrogen atoms is preferred.

[0310] The present invention relates to a method for producing a positron-emitting isotope of one or more atoms, e.g., 18 F, 11 C. 13 N, 15 O.76 Br, 77 Br, 120 I and / or 124 The present invention also encompasses compounds of formula (I) in which one or more fluorine atoms (or, for example, all fluorine atoms) are replaced by: I. Such compounds may be used as tracers, trackers, or imaging probes in positron emission tomography (PET). The present invention therefore provides compounds of formula (I) in which: (i) one or more fluorine atoms (or, for example, all fluorine atoms) are: 18 (ii) a compound of formula (I) wherein one or more carbon atoms (or, for example, all carbon atoms) are replaced by a F atom; 11 (iii) compounds of formula (I) in which one or more nitrogen atoms (or, for example, all nitrogen atoms) are replaced by 13 (iv) compounds of formula (I) wherein one or more oxygen atoms (or, for example, all oxygen atoms) are replaced by an N atom; 15 (v) a compound of formula (I) in which one or more bromine atoms (or, for example, all bromine atoms) are replaced by an O atom; 76 (vi) compounds of formula (I) in which one or more bromine atoms (or, for example, all bromine atoms) are replaced by 77 (vii) a compound of formula (I) in which one or more iodine atoms (or, for example, all iodine atoms) are replaced by a Br atom; 120 and (viii) compounds of formula (I) wherein one or more iodine atoms (or, for example, all iodine atoms) are replaced by 124 This includes compounds of formula (I) where R is replaced by an I atom.

[0311] In general, it is preferred that no atoms in the compounds of formula (I) are replaced by any specific isotope.

[0312] The compounds of formula (I) may also be used in the form of pharmaceutically acceptable prodrugs, i.e., derivatives of the compounds of formula (I) that have chemically or metabolically cleavable groups and that become pharmaceutically active compounds of formula (I) in vivo by solvolysis or under physiological conditions. Prodrugs of the compounds of the present invention can be formed by conventional means using functional groups of the compounds, such as amino, hydroxy, or carboxy groups. Prodrug forms often offer advantages in terms of solubility, tissue compatibility, or delayed release in mammals (see Bundgaard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include, for example, acid derivatives such as esters prepared by reacting the acidic parent compound with a suitable alcohol, or amides prepared by reacting the acidic parent compound with a suitable amine. When the compound of the present invention has a carboxyl group, examples of the prodrug include 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. Particularly preferred ester derivatives as prodrugs are methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester, morpholinoethyl ester, N,N-diethylglycolamide ester, and α-acetoxyethyl ester. When the compound of the present invention has a hydroxyl group, examples of the prodrug include an acyloxy derivative prepared by reacting the hydroxyl group with a suitable acid halide or a suitable acid anhydride. Particularly preferred acyloxy derivatives as prodrugs include -OC(=O)-CH3, -OC(=O)-C2H5, -OC(=O)-(tert-Bu), -OC(=O)-C 15 H 31, -OC(=O)-(m-COONa-Ph), -OC(=O)-CH2CH2COONa, -O(C=O)-CH(NH2)CH3, or -OC(=O)-CH2-N(CH3)2. When the compound of the present invention has an amino group, examples of the prodrug include amide derivatives prepared by reacting the amino group with a suitable acid halide or a suitable mixed anhydride. Particularly preferred amide derivatives as prodrugs are -NHC(=O)-(CH2)2OCH3 or -NHC(=O)-CH(NH2)CH3.

[0313] The compounds obtained according to the present invention, i.e., compounds of formula (I) and / or pharmaceutically acceptable salts thereof, may be administered as the compounds themselves or may be formulated as medicaments. The medicaments / pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants and / or solubility enhancers.

[0314] The pharmaceutical compositions may contain one or more solubility enhancers, for example, poly(ethylene glycol)s including poly(ethylene glycol)s having a molecular weight ranging from about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, non-ionic surfactants, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate (e.g., Kolliphor® HS 15, CAS 10144-1014), hydroxybenzoates (e.g., hydroxybenzoates ... 70142-34-6), phospholipids, lecithin, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, glucosyl-α-cyclodextrin, The cyclodextrin may include glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

[0315] Pharmaceutical compositions can be formulated by techniques known to those skilled in the art, such as those published in "Remington: The Science and Practice of Pharmacy," Pharmaceutical Press, 22nd Edition. Pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, e.g., intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardiac, rectal, nasal, topical, aerosol, or vaginal administration. Oral dosage forms include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, liquids, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, gums, chewable tablets, and effervescent tablets. Parenteral dosage forms include liquids, 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 ovulae. Dosage forms for nasal administration can be administered via inhalation and insufflation, for example, with a metered inhaler. Dosage forms for topical administration include creams, gels, ointments, salves, patches, and transdermal delivery systems.

[0316] The compounds of the present invention, or the pharmaceutical compositions described above comprising the compounds of the present invention, may be administered to a subject by any convenient route of administration, whether systemic / peripheral or to the desired site of action, including, but not limited to, one or more of oral (e.g., as a tablet, capsule, or as an ingestible liquid), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using infusion or injection techniques, including, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal, and also, e.g., by implantation of a depot, e.g., subcutaneous or intramuscular), pulmonary (e.g., via the mouth or nose, e.g., using an aerosol, e.g., by inhalation or insufflation therapy), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (including intravitreal or intracameral), rectal, or vaginal administration.

[0317] When the compound or pharmaceutical composition is administered parenterally, examples of such administration include one or more of intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracardiac, intracranial, intramuscular, or subcutaneous administration of the compound or pharmaceutical composition, and / or administration by use of injection techniques. For parenteral administration, the compound is 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 solution should be suitably buffered (preferably to a pH of 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.

[0318] The compounds or pharmaceutical compositions may also be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions which may contain flavorings or colorants for immediate, delayed, modified, sustained, pulsed or controlled release applications.

[0319] Tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen 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, lubricants such as magnesium stearate, stearic acid, glyceryl behenate, and talc may be included. Solid compositions of a similar type may also be used as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, or high molecular weight polyethylene glycols. In aqueous suspensions and / or elixirs, the agent may be combined with various sweetening or flavoring agents, coloring or pigments, emulsifying and / or suspending agents, and diluents, such as water, ethanol, propylene glycol, and glycerin, as well as combinations thereof.

[0320] Alternatively, the compounds or pharmaceutical compositions may be administered in the form of a suppository or pessary, or may be applied topically in the form of a gel, hydrogel, lotion, liquid, cream, ointment or powder. The compounds of the invention may also be administered dermally or transdermally, for example, by the use of a skin patch.

[0321] The compound or pharmaceutical composition can also be administered via a sustained-release system. Suitable examples of sustained-release compositions include semipermeable polymer matrices in the form of shaped articles, such as films or microcapsules. Sustained-release matrices include, for example, polylactide, copolymers of L-glutamic acid and gamma-ethyl-L-glutamic acid, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly-D-(-)-3-hydroxybutyric acid. Sustained-release pharmaceutical compositions also include liposome-encapsulated compounds. The present invention therefore also relates to liposomes containing the compounds of the present invention.

[0322] The compound or pharmaceutical composition can also be administered by pulmonary, rectal or ocular route.For ophthalmic use, they can be formulated as a micronized suspension in isotonic pH-adjusted sterile saline, or preferably as a solution in isotonic pH-adjusted sterile saline, optionally combined with a preservative, such as benzalkonium chloride.Alternatively, they can be formulated in an ointment such as petrolatum.

[0323] It is also contemplated to prepare dry powder formulations of compounds of formula (I) for pulmonary administration, particularly inhalation. Such dry powders can be prepared by spray drying under conditions that result in a substantially amorphous, glassy, ​​or substantially crystalline bioactive powder. Thus, dry powders of compounds of the present invention can be made following an emulsification / spray drying process.

[0324] For topical application to the skin, the compounds or pharmaceutical compositions can be formulated, for example, in a suitable ointment containing the active compound suspended or dissolved in a mixture of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax, and water. Alternatively, they can be formulated, for example, in a suitable lotion or cream suspended or dissolved in a mixture of one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol, and water.

[0325] The present invention therefore relates to the compounds or pharmaceutical compositions provided herein, and the corresponding compounds or pharmaceutical compositions should be administered by any one of the following routes: oral; topical route, including transdermal, intranasal, ocular, buccal or sublingual; parenteral route, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, intraurethral or intracranial; pulmonary route, including inhalation or insufflation therapy; gastrointestinal; intrauterine; intraocular; subcutaneous; ophthalmic route, including intravitreal or intracameral; rectal; or vaginal.Preferred administration routes are oral or parenteral administration, and oral administration is particularly preferred.Therefore, it is particularly preferred that the compounds or pharmaceutical compositions of the present invention should be administered orally (particularly by oral ingestion or swallowing).

[0326] Typically, a physician will determine the actual dosage that will be most suitable for an individual subject. The specific dose level and frequency of administration for any particular individual subject may vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and length of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the specific condition, and the individual subject being treated.

[0327] A suggested, but further non-limiting, dosage of the compound according to the present invention for oral administration to humans (approximately 70 kg body weight) can be 0.05 to 2000 mg of active ingredient per unit dose, preferably 0.1 mg to 1000 mg. The unit dose can be administered, for example, 1 to 3 times per day. The unit dose can be administered 1 to 7 times per week, for example, 1 or less times per day. It is recognized that it may be necessary to vary the dosage on a daily basis depending on the age and weight of the patient / subject and the severity of the condition being treated. The exact dosage and route of administration are ultimately at the discretion of the attending physician or veterinarian.

[0328] A compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered as a monotherapy (e.g., without a concomitant administration of an additional therapeutic agent, or without a concomitant administration of an additional therapeutic agent for the same disease being treated or prevented with the compound of formula (I). However, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, may also be administered in combination with one or more additional therapeutic agents. When a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used in combination with a second therapeutic agent active against the same disease or condition, the dose of each compound may differ from that when the corresponding compound is used alone, in particular, a lower dose of each compound may be used. The combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, with one or more additional therapeutic agents may involve simultaneous / concurrent administration (as a single pharmaceutical formulation or separate pharmaceutical formulations) of the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agents, or sequential / separate administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agents. When administration is sequential, the compound of formula (I) according to the present invention, or a pharmaceutically acceptable salt thereof, or the one or more additional therapeutic agents may be administered first. When administration is simultaneous, the one or more additional therapeutic agents may be included in the same pharmaceutical formulation as the compound of formula (I), or a pharmaceutically acceptable salt thereof, or they may be administered in two or more different (separate) pharmaceutical formulations.

[0329] Preferably, the one or more additional therapeutic agents administered in combination with the compounds of the invention are selected from levodopa, levodopa with a selective extracerebral decarboxylase inhibitor, carbidopa, entacapone, COMT inhibitors, dopamine agonists, dopamine receptor agonists, apomorphine, anticholinergics, cholinergic agonists, neuroleptic butyrophenones, neuroleptic diphenylbutylpiperidines, neuroleptic heterocyclic dibenzazepines, neuroleptic indolones, neuroleptic phenothiazines, neuroleptic thioxanthenes, NMDA receptor antagonists, MAO-B inhibitors, mGluR3 PAMs or agonists, mGluR4 PAMs or agonists, mGluR5 antagonists, and A2A antagonists.

[0330] In particular, in the treatment or prevention of Parkinson's disease, the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I), or a pharmaceutically acceptable salt thereof, may also be administered in combination with one or more additional anti-Parkinson's agents, such as, for example, levodopa, melevodopa, etilevodopa, droxidopa, aprindole, apomorphine, bromocriptine, cabergoline, ciladopa, dihydroergocriptine, lisuride, pardoprunox, pergolide, piribedil, pramipexole, ropinirole, rotigotine, ladostigil, lazabemide, mofegiline, pargyline, rasagiline, selegiline, entacapone, nitecapone, tolcapone, benserazide, carbidopa, methyldopa, benzatrol, benzotriazide ... The antiparkinsonian agent may be selected from benzodiazepine, biperiden, bornaprine, chlorphenoxamine, cyclimine, dexetimide, dimenhydrinate, diphenhydramine, ethanautine, ethybenzatropine, mazaticol, methixene, orphenadrine, phenglutarimide, piroheptine, procyclidine, profenamine, trihexyphenidyl, tropatepine, amantadine, budipine, memantine, methylxanthines, rimantadine, UWA-101, and pharmaceutically acceptable salts of any of these agents. Preferred antiparkinsonian agents include levodopa, carbidopa, and / or biperiden, especially levodopa.

[0331] In the treatment or prevention of Parkinson's disease, the combined administration of a compound or pharmaceutical composition of the present invention with one or more additional anti-Parkinson's agents can be achieved, for example, by simultaneous / concomitant administration (either as a single pharmaceutical formulation or as separate pharmaceutical formulations) or by sequential / separate administration.

[0332] The subject or patient treated according to the present invention may be an animal (e.g., a non-human animal). Preferably, the subject / patient is a mammal. More preferably, the subject / patient is a human (e.g., a male or female human) or a non-human mammal (e.g., a guinea pig, hamster, rat, mouse, rabbit, dog, cat, horse, monkey, ape, marmoset, baboon, gorilla, chimpanzee, orangutan, gibbon, sheep, cow, or pig). Most preferably, the subject / patient treated according to the present invention is a human.

[0333] As used herein, the term "treatment" of a condition, disorder, or disease is well known in the art. "Treatment" of a condition, disorder, or disease implies that the condition, disorder, or disease is suspected or diagnosed in a patient / subject. A patient / subject suspected of suffering from a condition, disorder, or disease typically exhibits particular clinical and / or pathological symptoms that one of skill in the art would consider likely to be attributable to a particular pathological condition (i.e., diagnosing the condition, disorder, or disease).

[0334] "Treatment" of a condition, disorder, or disease may, for example, result in a halt in the progression of the condition, disorder, or disease (e.g., no worsening of symptoms is observed) or a slowing in the progression of the condition, disorder, or disease (in cases where the halt in progression is only transient). "Treatment" of a condition, disorder, or disease may also result in a partial response (e.g., improvement of symptoms) or a complete response (e.g., disappearance of symptoms) in a subject / patient afflicted with the condition, disorder, or disease. Thus, "treatment" of a condition, disorder, or disease may also refer to an alleviation of the condition, disorder, or disease, which may result in, for example, a halt in the progression of the condition, disorder, or disease or a slowing in the progression of the condition, disorder, or disease. Such a partial or complete response may be followed by a relapse. It should be understood that a subject / patient may receive a wide range of responses to treatment (e.g., the exemplary responses described herein above). Treatment of a condition, disorder, or disease may include, inter alia, curative treatment (preferably resulting in a complete response, ultimately leading to cure of the condition, disorder, or disease) and palliative treatment (including the alleviation of symptoms).

[0335] As used herein, the term "prevention" of a condition, disorder, or disease is also well known in the art. For example, a patient / subject suspected of being susceptible to a condition, disorder, or disease would particularly benefit from prevention of the condition, disorder, or disease. A subject / patient may have a susceptibility or predisposition to a condition, disorder, or disease, including, but not limited to, a genetic predisposition. Such predisposition may be determined by standard methods or assays using, for example, genetic markers or phenotypic indicators. It should be understood that the condition, disorder, or disease prevented in accordance with the present invention has not been or cannot be diagnosed in the patient / subject (e.g., the patient / subject does not exhibit any clinical or pathological symptoms). Thus, the term "prevention" includes the use of a compound of the present invention before certain clinical and / or pathological symptoms have been or can be diagnosed or determined by the attending physician.

[0336] It is to be understood that the present invention specifically relates to each and every combination of features and embodiments described herein, including any general and / or preferred feature / embodiment combination. In particular, the present invention specifically relates to each combination of meanings (including general and / or preferred meanings) of the various groups and variables contained in formula (I).

[0337] Several documents are cited herein, including patents, patent applications, and scientific literature. The disclosures of these documents, although not believed to be relevant to the patentability of this invention, are incorporated herein by reference in their entirety. More specifically, all documents referred to are incorporated by reference to the same extent as if each individual document were specifically and individually indicated to be incorporated by reference.

[0338] Reference in this specification to any of the prior publications (or information derived therefrom) is not, and should not be taken as, an acknowledgement or understanding or any form of suggestion that the corresponding prior publication (or information derived therefrom) forms part of the common general knowledge in the art to which this specification relates.

[0339] The present invention relates in particular to the following items: 1. Formula (I)

[0340] [ka]

[0341] (In the formula, R 1 is as follows:

[0342] [ka]

[0343] groups, each one of which may be selected from one or more R 11 group, optionally substituted; Each R 11 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-aryl, -(C 0~3 alkylene)-heteroaryl, -(C 0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl, wherein said -(C 0~3 the aryl moiety in the -(C alkylene)-aryl; 0~3 the heteroaryl portion of the -(C alkylene)-heteroaryl; 0~3 The cycloalkyl moiety in the -(C alkylene)-cycloalkyl, 0~3 Each heterocycloalkyl moiety in the alkylene-heterocycloalkyl is one or more R 12 group, optionally substituted; Each R 12 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), cycloalkyl, and heterocycloalkyl; X1 is C(R X1 ) or N, X2 is C(-LR X2 ) or N, X3 is C(R X3 ) or N, X4 is C(R X4 ) or N, at least one of the ring atoms X1, X2, X3 and X4 is not N; R X1 is hydrogen, C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-aryl, -(C 0~3 alkylene)-heteroaryl, -(C 0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl, wherein said -(C 0~3 the aryl moiety in the -(C alkylene)-aryl; 0~3the heteroaryl portion of the -(C alkylene)-heteroaryl; 0~3 The cycloalkyl moiety in the -(C alkylene)-cycloalkyl, 0~3 Each heterocycloalkyl moiety in the alkylene-heterocycloalkyl is one or more R X11 group, optionally substituted; Each R X11 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), cycloalkyl, and heterocycloalkyl; L is a covalent bond, C 1~10 Alkylene, C 2~10 Alkenylene and C 2~10 alkynylene, 1~10 Alkylene,2~10 Alkenylene or the C 2~10 One or more -CH2- units contained in the alkynylene may be -O-, -CO-, -C(=O)O-, -OC(=O)-, -NH-, -N(C 1~5 alkyl)-, -NH-CO-, -N(C 1~5 alkyl)-CO-, -CO-NH-, -CO-N(C 1~5 alkyl)-, -S-, -SO-, -SO2-, -SO2-NH-, -SO2-N(C 1~5 alkyl)-, -NH-SO2-, -N(C 1~5 alkyl)-SO2-, carbocyclylene, and heterocyclylene, wherein said carbocyclylene and said heterocyclylene are each independently selected from C 1~4 Alkyl, -OH, -O(C 1~4 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)(C 1~4 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl) and —CN, and 1~10 Alkylene, 2~10 Alkenylene and the C 2~10 Alkynylene is a halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 alkyl), R X2 is C 2~10 Alkyl, carbocyclyl, heterocyclyl and -L 1 -R X21 wherein C is selected from2~10 The alkyl, the carbocyclyl, and the heterocyclyl each may be one or more R X22 group, optionally substituted; L 1 is a covalent bond, C 1~10 Alkylene, C 2~10 Alkenylene and C 2~10 alkynylene, 1~10 Alkylene, 2~10 Alkenylene or the C 2~10 One or more -CH2- units contained in the alkynylene may be -O-, -CO-, -C(=O)O-, -OC(=O)-, -NH-, -N(C 1~5 alkyl)-, -NH-CO-, -N(C 1~5 alkyl)-CO-, -CO-NH-, -CO-N(C 1~5 alkyl)-, -S-, -SO-, -SO2-, -SO2-NH-, -SO2-N(C 1~5 alkyl)-, -NH-SO2- and -N(C 1~5 alkyl)-SO2-, and 1~10 Alkylene, 2~10 Alkenylene and the C 2~10 Alkynylene is a halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 alkyl), R X21 is C 2~5 alkyl, carbocyclyl, and heterocyclyl, wherein said carbocyclyl and said heterocyclyl each comprise one or more R X22 group, optionally substituted; Each R X22 is C 1~5 Alkyl, C2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-aryl, -(C 0~3 alkylene)-heteroaryl, -(C 0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl, wherein said -(C 0~3 the aryl moiety in the -(C alkylene)-aryl; 0~3 the heteroaryl portion of the -(C alkylene)-heteroaryl; 0~3 The cycloalkyl moiety in the -(C alkylene)-cycloalkyl, 0~3 Each heterocycloalkyl moiety in the alkylene-heterocycloalkyl is one or more R X23 group, optionally substituted; Each R X23 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), cycloalkyl, and heterocycloalkyl; R X3 is hydrogen, C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-aryl, -(C 0~3 alkylene)-heteroaryl, -(C 0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl, wherein said -(C 0~3 the aryl moiety in the -(C alkylene)-aryl; 0~3 the heteroaryl portion of the -(C alkylene)-heteroaryl; 0~3 The cycloalkyl moiety in the -(C alkylene)-cycloalkyl, 0~3Each heterocycloalkyl moiety in the alkylene-heterocycloalkyl is one or more R X31 group, optionally substituted; Each R X31 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), cycloalkyl, and heterocycloalkyl; R X4 is hydrogen, C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-aryl, -(C 0~3 alkylene)-heteroaryl, -(C 0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl, wherein said -(C 0~3 the aryl moiety in the -(C alkylene)-aryl; 0~3 the heteroaryl portion of the -(C alkylene)-heteroaryl; 0~3 The cycloalkyl moiety in the -(C alkylene)-cycloalkyl, 0~3 Each heterocycloalkyl moiety in the alkylene-heterocycloalkyl is one or more R X41 group, optionally substituted; Each R X41 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), cycloalkyl, and heterocycloalkyl; However, the following

[0344] [ka]

[0345] is excluded from formula (I), or a pharmaceutically acceptable salt thereof. 2. R 1 But,

[0346] [ka]

[0347] wherein each one of the groups depicted above is selected from one or more R 11 group, optionally substituted; or R 1 But,

[0348] [ka]

[0349] groups, each one of which is selected from one or more R 11 2. The compound of item 1, optionally further substituted with a group.

[0350] 3. R 1 But,

[0351] [ka]

[0352] groups, each one of which is selected from one or more R 11 2. The compound of item 1, optionally substituted with a group.

[0353] 4. R 1 But,

[0354] [ka]

[0355] groups, each one of which is selected from one or more R 11 group, optionally substituted; R 1 But,

[0356] [ka]

[0357] and the groups depicted above are preferably one or more R 11 2. The compound of item 1, optionally substituted with a group.

[0358] 5. Each R 11 But C 1~5 Alkyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl) and -(C 0~3 The compound of any one of items 1 to 4, independently selected from:

[0359] 6. X2 is C(-LR X2 6. The compound of any one of items 1 to 5, wherein

[0360] 7. X1 is C(R X1 ) and X2 is C(-LR X2 ) and X3 is C(R X3 ) and X4 is C(R X4 6. The compound of any one of items 1 to 5, wherein

[0361] 8. R X1 But hydrogen, C 1~5 Alkyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl) and -(C 0~3 8. The compound of any one of items 1 to 7, wherein the compound is selected from:

[0362] 9. L is a covalent bond, C 1~5 Alkylene, -O-, -O-(C 1~5alkylene)-, -NH-, -NH-(C 1~5 alkylene)-, -N(C 1~5 alkyl)- and -N(C 1~5 alkyl)-(C 1~5 alkylene)-, wherein said —O—(C 1~5 alkylene)-, the -NH-(C 1~5 alkylene)- and the -N(C 1~5 alkyl)-(C 1~5 alkylene)- 1~5 Alkylene or C 1~5 The alkylene portion is halogen, -CF3, -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 9. The compound of any one of items 1 to 8, optionally substituted with one or more groups independently selected from:

[0363] 10. L is a covalent bond, C 1~5 Alkylene, —O— and —O—(C 1~5 9. The compound of any one of items 1 to 8, selected from:

[0364] 11. R X2 is selected from cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, and said cycloalkyl, said aryl, said heterocycloalkyl, and said heteroaryl each comprise one or more R X22 11. The compound of any one of items 1 to 10, optionally substituted with a group.

[0365] 12. -LR X2 The group is -R X2 , -(C 1~5 alkylene)-R X2 , -OR X2 and -O-(C 1~5 alkylene)-R X2 Selected from R X2is selected from cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, and said cycloalkyl, said aryl, said heterocycloalkyl, and said heteroaryl each comprise one or more R X22 9. The compound of any one of items 1 to 8, optionally substituted with a group.

[0366] 13. R X2 is selected from azetidinyl, oxetanyl, pyrrolidinyl, oxopyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxopiperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, 2-oxa-7-aza-spiro[3.5]nonyl, 6-oxa-2-aza-spiro[3.4]octyl, 3-oxa-9-aza-spiro[5.5]undecyl, 7-oxa-2-aza-spiro[4.5]decyl, 8-oxa-2-aza-spiro[4.5]decyl, phenyl, oxazolyl, pyridinyl, pyrazinyl, and pyrimidinyl, and each one of the foregoing cyclic groups may be selected from one or more R X22 13. The compound of any one of items 1 to 12, optionally substituted with a group.

[0367] 14. R X3 But hydrogen, C 1~5 Alkyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl) and -(C0~3 14. The compound of any one of items 1 to 13, wherein the compound is selected from:

[0368] 15. R X4 But hydrogen, C 1~5 Alkyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 15. The compound of any one of items 1 to 14, wherein the compound is selected from alkylene)-CN, cycloalkyl, and heterocycloalkyl.

[0369] 16. R X4 is selected from hydrogen, methyl, —OCH 3 , halogen and cyclopropyl.

[0370] 17. R X4 is selected from methyl, —OCH 3 , halogen and cyclopropyl.

[0371] 18. 6-(3-pyridin-4-yl-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 2-Isoquinolin-3-yl-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 2-pyridin-2-yl-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one; 2-(4-Methoxy-pyridin-2-yl)-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one; 2-(5-fluoro-pyridin-2-yl)-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-(5-trifluoromethyl-pyridin-3-yl)-3H-quinazolin-4-one; 6-[3-(4-pyridyl)propoxy]-2-[5-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one; 2-(4-methyl-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-(6-methyl-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-(5-methylpyrazin-2-yl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-(4-chloro-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-(4-ethyl-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 6-[3-(4-pyridyl)propoxy]-2-[6-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one; 2-(4-Bromo-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-(4-cyclopropyl-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-(2-methyl-oxazol-4-yl)-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one; 6-(2-pyridin-3-yl-ethoxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(4-Bromo-benzyloxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; Tert-butyl 3-(4-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-quinazolin-6-yl)oxyazetidine-1-carboxylate; 6-(azetidin-3-yloxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 6-(1-pyrimidin-4-yl-azetidin-3-yloxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 3-(4-hydroxy-2-thieno[2,3-c]pyridin-5-yl-quinazolin-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester; 6-(azetidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(1-propionyl-azetidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(piperidin-4-yloxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(1-propionyl-piperidin-4-yloxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(2-morpholin-4-yl-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 6-(2-Methoxy-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 6-(2-morpholin-4-yl-ethoxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(2-Methoxy-ethoxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(3-pyridin-3-yl-propoxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 4-(4-oxo-2-pyridin-2-yl-3,4-dihydro-quinazolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester; 6-(piperidin-4-yloxy)-2-pyridin-2-yl-3H-quinazolin-4-one; 6-(1-acetyl-piperidin-4-yloxy)-2-pyridin-2-yl-3H-quinazolin-4-one; 4-[4-oxo-2-(4-trifluoromethyl-pyridin-2-yl)-3,4-dihydro-quinazolin-6-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester; 6-(piperidin-4-ylmethoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 6-(1-acetyl-piperidin-4-ylmethoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; tert-Butyl 4-[(4-oxo-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-6-yl)oxymethyl]piperidine-1-carboxylate; 6-(4-piperidylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(1-acetyl-piperidin-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(1-propionyl-piperidin-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 3-(4-oxo-2-thieno[2,3-c]pyridin-5-yl-3,4-dihydro-quinazolin-6-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester; 6-(pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(1-acetyl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 4-[4-oxo-2-(4-trifluoromethyl-pyridin-2-yl)-3,4-dihydro-quinazolin-6-yl]-piperazine-1-carboxylic acid tert-butyl ester; 6-Piperazin-1-yl-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 6-(4-propionyl-piperazin-1-yl)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 4-(4-oxo-2-thieno[2,3-c]pyridin-5-yl-3,4-dihydro-quinazolin-6-yl)-piperidine-1-carboxylic acid tert-butyl ester; 6-piperidin-4-yl-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(1-acetyl-piperidin-4-yl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-[2-(tetrahydro-pyran-4-yl)-ethoxy]-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 6-[3-(3-fluoro-pyridin-4-yl)-propoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-[3-(4-methanesulfonyl-phenyl)-propoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(3-pyrazin-2-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-[3-(3-methoxy-pyridin-4-yl)-propoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-[3-(2-methyl-pyridin-4-yl)-propoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(3-oxazol-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-pyrido[3,2-d]pyrimidin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-pyrido[3,2-d]pyrimidin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-pyrido[2,3-d]pyrimidin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-pyrido[3,4-d]pyrimidin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-7-trifluoromethyl-3H-quinazolin-4-one; 5-chloro-6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-chloro-6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Cyclopropyl-6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-ethyl-6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Fluoro-6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(tetrahydro-pyran-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(2-oxetan-3-yl-ethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-[2-(tetrahydro-furan-3-yl)-ethoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-[2-(tetrahydro-pyran-4-yl)-ethoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(tetrahydro-furan-3-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; R-8-methyl-6-(tetrahydro-furan-3-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; S-8-methyl-6-(tetrahydro-furan-3-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(1-methyl-6-oxo-piperidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; R-8-methyl-6-((1-methyl-6-oxopiperidin-3-yl)oxy)-2-(thieno[2,3-c]pyridin-5-yl)quinazolin-4(3H)-one; S-8-methyl-6-((1-methyl-6-oxopiperidin-3-yl)oxy)-2-(thieno[2,3-c]pyridin-5-yl)quinazolin-4(3H)-one; 8-methyl-6-(1-propionyl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; R-8-methyl-6-(1-propionyl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; S-8-methyl-6-(1-propionyl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(1-oxetan-3-yl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; R-8-methyl-6-(1-oxetan-3-yl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; S-8-methyl-6-(1-oxetan-3-yl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-[2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-ethoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(piperidin-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(1-oxetan-3-yl-piperidin-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(1-propionyl-piperidin-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(1-methanesulfonyl-piperidin-4-ylmethoxy)-8-methyl-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(2-oxa-7-aza-spiro[3.5]non-7-yl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(6-oxa-2-aza-spiro[3.4]oct-2-yl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(3-oxa-9-aza-spiro[5.5]undec-9-yl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(7-oxa-2-aza-spiro[4.5]dec-2-yl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(8-oxa-2-aza-spiro[4.5]dec-2-yl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(2-hydroxy-2-methyl-propylamino)-8-methyl-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(2-piperidin-3-yl-ethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-[2-(1-acetyl-piperidin-3-yl)-ethoxy]-8-methyl-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-[2-(4-acetyl-piperazin-1-yl)-ethoxy]-8-methyl-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 3-(8-methyl-4-oxo-2-thieno[2,3-c]pyridin-5-yl-3,4-dihydro-quinazolin-6-yl)-propionaldehyde; 8-methyl-6-(3-morpholin-4-yl-propyl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(2-morpholin-4-yl-ethyl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(3-pyridin-4-yl-propoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 8-methyl-6-(tetrahydro-furan-3-ylmethoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 8-methyl-6-(1-propionyl-azetidin-3-yloxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 8-methyl-6-(1-oxetan-3-yl-piperidin-4-yloxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 8-methyl-6-(3-oxa-9-aza-spiro[5.5]undec-9-yl)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 8-methyl-6-(3-pyridin-4-yl-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-methyl-2-pyrrolo[1,2-c]pyrimidin-3-yl-6-(tetrahydro-furan-3-ylmethoxy)-3H-quinazolin-4-one; 8-methyl-6-(3-oxa-9-aza-spiro[5.5]undec-9-yl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-methyl-6-(1-oxetan-3-yl-piperidin-4-yloxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-methyl-6-[1-(tetrahydro-pyran-4-yl)-ethoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; R-8-methyl-6-[1-(tetrahydro-pyran-4-yl)-ethoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; S-8-methyl-6-[1-(tetrahydro-pyran-4-yl)-ethoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-[1-(tetrahydro-pyran-4-yl)-ethoxy]-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; R-8-methyl-6-[1-(tetrahydro-pyran-4-yl)-ethoxy]-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; S-8-methyl-6-[1-(tetrahydro-pyran-4-yl)-ethoxy]-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 6-[(3-fluorotetrahydrofuran-3-yl)methoxy]-8-methyl-2-[4-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one; 8-methyl-6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2-thieno[2,3-c]pyridin-5-yl-3-(2-trimethylsilylethoxymethyl)pyrido[3,2-d]pyrimidin-4-one; 8-methyl-6-(morpholinomethyl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(morpholinomethyl)-2-[4-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one; 8-methyl-6-(1-propanoylazetidin-3-yl)oxy-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(2-morpholinoethyl)-2-[4-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one; 8-methyl-6-[(1-methyl-6-oxo-3-piperidyl)oxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-methyl-6-(morpholinomethyl)-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 8-methyl-6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 8-methyl-6-(2-[1,4]oxazepan-4-yl-ethyl)-2-thieno[2,3-b]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(2-[1,4]oxazepan-4-yl-ethyl)-2-thieno[3,2-b]pyridin-6-yl-3H-quinazolin-4-one; 8-methyl-6-(2-morpholin-4-yl-ethyl)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-methyl-6-(2-morpholin-4-yl-ethyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-methyl-6-(morpholinomethyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-methyl-6-(2-morpholino-2-oxoethyl)-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 8-methyl-6-(2-morpholino-2-oxo-ethyl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(2-piperidin-1-yl-ethyl)-2-thieno[2,3-b]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(1-methyl-6-oxo-piperidin-3-yloxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-Methyl-6-(1-methyl-2-oxo-piperidin-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one 8-methyl-6-(1-piperidylmethyl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(2-morpholino-2-oxo-ethyl)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-methyl-6-[(4-methylpiperazin-1-yl)methyl]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(pyrrolidin-1-ylmethyl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(2-morpholino-2-oxo-ethyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-methyl-6-(morpholine-4-carbonyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-methyl-6-(1-methyl-6-oxo-piperidin-3-yloxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 8-methyl-2-thieno[2,3-c]pyridin-5-yl-6-(thiomorpholinomethyl)-3H-quinazolin-4-one; 8-methyl-6-[2-(1,4-oxazepan-4-yl)-2-oxo-ethyl]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-(pyrrolidin-1-ylmethyl)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-methyl-6-(1-methyl-5-oxo-pyrrolidin-3-yl)oxy-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-methyl-6-[(3R)-1-methyl-5-oxo-pyrrolidin-3-yl]oxy-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-methyl-6-[(3S)-1-methyl-5-oxo-pyrrolidin-3-yl]oxy-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; Benzyl 3-[(8-methyl-4-oxo-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-6-yl)oxy]pyrrolidine-1-carboxylate; Benzyl (3S)-3-[(8-methyl-4-oxo-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-6-yl)oxy]pyrrolidine-1-carboxylate; benzyl (3R)-3-[(8-methyl-4-oxo-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-6-yl)oxy]pyrrolidine-1-carboxylate; 8-methyl-6-[2-(4-methyl-3-oxo-piperazin-1-yl)ethyl]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-[2-(4-methyl-3-oxo-piperazin-1-yl)ethyl]-2-[4-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one; 8-methyl-6-[2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-methyl-6-[2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl]-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-methyl-6-[(4-methyl-3-oxo-piperazin-1-yl)methyl]-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(2-((2-methoxyethyl)(methyl)amino)ethyl)-8-methyl-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 6-(2-(1,1-dioxidothiomorpholino)ethyl)-8-methyl-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 6-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]-8-methyl-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(((2-methoxyethyl)(methyl)amino)methyl)-8-methyl-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 6-[(4-methoxy-1-piperidyl)methyl]-8-methyl-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-[(2,2-dimethylmorpholin-4-yl)methyl]-8-methyl-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-chloro-6-(2-morpholinoethyl)-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 8-methyl-6-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; N,N-Dimethyl-1-((8-methyl-4-oxo-2-(thieno[3,2-c]pyridin-6-yl)-3,4-dihydroquinazolin-6-yl)methyl)piperidine-4-carboxamide; 6-((4-(methoxymethyl)piperidin-1-yl)methyl)-8-methyl-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 8-Methoxy-6-(2-morpholinoethyl)-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 8-Bromo-6-(2-morpholinoethyl)-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 6-(2-(2,2-dimethylmorpholino)ethyl)-8-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 8-methyl-6-((4-methyl-3-oxopiperazin-1-yl)methyl)-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 6-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)ethyl)-8-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 6-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)ethyl)-8-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 6-(2-(4-hydroxypiperidin-1-yl)ethyl)-8-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 6-(2-(4,4-difluoropiperidin-1-yl)ethyl)-8-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 6-(2-(4-methoxypiperidin-1-yl)ethyl)-8-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 8-methyl-6-(2-morpholinoethyl)-2-(4-(trifluoromethyl)pyridin-2-yl)pyrido[3,2-d]pyrimidin-4(3H)-one; and a pharmaceutically acceptable salt of any one of the foregoing compounds.

[0372] 19. A pharmaceutical composition comprising a compound according to any one of items 1 to 18 and a pharmaceutically acceptable excipient.

[0373] 20. A compound of any one of items 1 to 18 for use as a medicine.

[0374] 21. A compound of any one of items 1 to 18 or a pharmaceutical composition of item 19 for use in the treatment or prevention of a condition associated with altered glutamatergic signaling and / or a function or condition that may be affected by alterations in glutamate levels or signaling.

[0375] 22. Use of a compound of any one of items 1 to 18 in the preparation of a medicament for treating or preventing a condition associated with altered glutamatergic signaling and / or a function or condition that may be affected by alterations in glutamate levels or signaling.

[0376] 23. A method for treating or preventing a condition associated with altered glutamatergic signaling and / or a function or condition that may be affected by alterations in glutamate levels or signaling, comprising administering a compound of item 1 to a subject in need thereof.

[0377] 24. The condition to be treated or prevented is epilepsy; dementia and related disorders including Alzheimer's disease, Alzheimer's disease, Pick's disease, vascular dementia, Lewy body disease, metabolic dementia, toxic and deficiency diseases, AIDS-dementia complex, Creutzfeldt-Jakob disease, and atypical subacute spongiform encephalopathy; Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, hepatolenticular degeneration, chorea, Huntington's disease, hemiballismus, athetosis, dystonia, spasmodic torticollis, occupational movement disorder, Gilles de la Tourette's syndrome, late-onset or drug-induced Parkinsonism and movement disorders, including levodopa-induced dyskinesia, levodopa-induced dyskinesia, tremor and myoclonus; motor neuron disease or amyotrophic lateral sclerosis; neurodegenerative and / or genetic disorders of the nervous system, including spinocerebellar degeneration, Friedreich's ataxia and other hereditary cerebellar ataxias, primarily spinal muscular atrophies, hereditary neuropathies and phakopathies; trigeminal neuralgia, facial neuropathy, disorders of other cranial nerves, nerve root and plexopathies, mononeuritis, carpal tunnel syndrome, sciatica, hereditary and idiopathic peripheral neuropathies, inflammatory and toxic neuropathies Disorders of the peripheral nervous system, including rheumatoid arthropathy; multiple sclerosis and other autoimmune diseases, including systemic lupus erythematosus and psoriasis; infantile cerebral palsy; hemiplegia, hemiparesis and other paralytic syndromes; cerebrovascular disorders, including subarachnoid hemorrhage, intracerebral hemorrhage, occlusion and stenosis of extracerebral arteries, cerebral artery occlusion, including thrombosis and embolism, cerebral ischemia, stroke, transient ischemic attack, atherosclerosis, vascular dementia, aneurysm, cerebral damage due to cardiac bypass surgery and transplant; migraine, including deforming migraine, including classic migraine and cluster headache; headache; myasthenia gravis, acute muscle spasms, muscular dystrophy neuromuscular disorders, including myopathies, myotonia and familial periodic paralysis, including cerebrovascular diseases; disorders of the eye and visual pathways, including retinal disorders and visual abnormalities; intracranial trauma / injury and their sequelae; trauma / injury to the nerves and spinal cord and their sequelae; intoxication and toxic effects of non-medical substances; accidental intoxication with drugs, medical substances and biological products acting on the central, peripheral and autonomic nervous systems; neurological and psychiatric adverse effects of drugs, medical substances and biological substances; disorders of sphincter control and sexual function; social disorders, including autism or autism spectrum disorder or fragile X syndrome;Psychiatric disorders including mental retardation, learning disabilities, motor skill disorders, communication disorders, pervasive developmental disorders, attention deficit and disruptive behavior disorders, feeding and eating disorders, TIC disorders, and elimination disorders; delirium and other cognitive disorders; substance-related disorders including alcohol-related disorders, nicotine-related disorders, and disorders related to cocaine, opioids, cannabis, hallucinogens, and other drugs; schizophrenia and other psychiatric disorders; mood disorders including depressive disorders and bipolar disorders; anxiety disorders including panic disorders, phobias, obsessive-compulsive disorders, stress disorders, and generalized anxiety disorder; anorexia and overeating 22. The compound for use according to item 21, or the pharmaceutical composition for use according to item 21, or the use of item 22, or the method of item 23, selected from any one of the following: eating disorders including sleep disorders, including insomnia, insomnia, hypersomnia, narcolepsy, breathing-related sleep disorders and parasomnias; drug-induced movement disorders including neuroleptic-induced parkinsonism and tardive dyskinesia; endocrine and metabolic diseases including diabetes, endocrine gland disorders, hypoglycemia; acute and chronic pain; nausea and vomiting; irritable bowel syndrome; and cancer.

[0378] 25. The condition to be treated or prevented is dementia and related disorders, including Alzheimer's disease, Pick's disease, vascular dementia, Lewy body disease, metabolic dementia, toxic and deficiency diseases, AIDS-dementia complex, Creutzfeldt-Jakob disease, and atypical subacute spongiform encephalopathy; Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, hepatolenticular degeneration, chorea, Huntington's disease, hemiballismus, athetosis, dystonia, spasmodic torticollis, occupational movement disorder, Gilles de la Tourette's syndrome, tardive or drug-induced dyskinesia, levodopa-induced dyskinesia, tremor. and myoclonus; social disorders including autism or autism spectrum disorder, or fragile X syndrome; acute and chronic pain; anxiety disorders including panic disorder, phobias, obsessive-compulsive disorder, stress disorders, and generalized anxiety disorder; schizophrenia and other psychiatric disorders; mood disorders including depressive disorders and bipolar disorders; endocrine and metabolic disorders including diabetes, endocrine disorders, and hypoglycemia; and cancer.

[0379] 26. A compound of any one of items 1 to 18 or a pharmaceutical composition of item 19 for use in the treatment or prevention of Parkinson's disease.

[0380] 27. Use of a compound of any one of items 1 to 28 in the preparation of a medicament for treating or preventing Parkinson's disease.

[0381] 28. A method for treating or preventing Parkinson's disease, comprising administering a compound of item 1 to a subject in need thereof.

[0382] 29. A compound for use according to any one of items 20, 21 or 24 to 26, or a pharmaceutical composition for use according to items 21 or 24 to 26, or the use of item 22, 24, 25 or 27, or the method of item 23, wherein the compound or pharmaceutical composition or medicament is administered orally.

[0383] 30. A compound for use according to any one of items 20, 21, 24 to 26 or 29, or a pharmaceutical composition for use according to any one of items 21, 24 to 26 or 29, or the use of any one of items 22, 24, 25, 27 or 29, wherein said compound or said pharmaceutical composition or said medicament is administered to a human subject.

[0384] 31. The method of item 23, wherein the subject is a human.

[0385] 32. A method for identifying a test agent that binds to metabotropic glutamate receptor 4 (mGluR4), comprising: (a) contacting mGluR4 with a radioactively or fluorescently labeled compound according to any one of items 1 to 18 under conditions that allow binding of the compound to mGluR4, thereby producing a bound, labeled compound; (b) detecting a signal corresponding to the amount of bound labeled compound in the absence of the test agent; (c) contacting the bound labeled compound with a test agent; (d) detecting a signal corresponding to the amount of bound labeled compound in the presence of the test agent; and (e) comparing the signal detected in step (d) with the signal detected in step (b) to determine whether the test agent binds to mGluR4. A method comprising:

[0386] 33. Use of a compound as defined in any one of items 1 to 18 as a positive allosteric modulator of mGluR4 in vitro.

[0387] The invention is also illustrated by the following exemplary figures. [Brief explanation of the drawings]

[0388] [Figure 1]The anticataleptic effects of exemplary compounds of formula (I) were measured in vivo in a mouse haloperidol-induced catalepsy model (see Section III of the Examples). The figure shows the average latency time spent in the bar in each group of animals, measured between 135 and 270 minutes after haloperidol injection. The anticataleptic effects of the compounds were compared with those of the vehicle-treated group using ANOVA followed by Dunnett's test. Compounds 81, 100, 114, 119, 143, and 144, orally administered at 1 mg / kg 60 minutes after haloperidol injection, showed significant anticataleptic effects (adjusted P values ​​less than 0.0001, 0.0065, 0.0066, 0.0307, ​​0.0176, and 0.0115, respectively).

[0389] The present invention is now described by reference to the following examples, which are illustrative only and should not be construed as limiting the scope of the invention.

[0390] The compounds described in the Examples section below are defined by their chemical formula and their corresponding chemical name. In cases where there is a discrepancy between a chemical formula designated herein and its corresponding chemical name, the present invention relates to both the compound defined by the chemical formula and the compound defined by the chemical name, and particularly to the compound defined by the chemical formula. [Example]

[0391] General Experimental Procedures All reagents were of commercial grade and used without further purification. Commercially available anhydrous solvents were used when necessary. Most reactions were carried out under an inert atmosphere (argon). Column chromatography was generally carried out on a Biotage Isolera Four instrument using Biotage KP-Sil cartridges. Thin-layer chromatography was carried out using pre-coated silica gel F-254 plates.

[0392] 1H NMR spectra were recorded on a Bruker AMX-400 spectrometer. Proton chemical shifts are listed relative to residual CDCl (7.26 ppm), DMSO (2.50 ppm), or DO (4.78 ppm). Splitting patterns were designated as s (singlet), d (doublet), dd (doublet-doublet), t (triplet), tt (triplet-triplet), td (triplet-doublet), q (quartet), quint (quintet), sex (sextuplet), sept (septuplet), m (multiplet), or b (broad).

[0393] The HPLC system was a Waters platform equipped with a 2767 sample manager, a 2525 pump, and a photodiode array detector (190-400 nm). The HPLC was coupled to a Waters Acquity QDa detector. All mass spectra were full scan experiments (mass range 110-850 amu). Mass spectra were acquired using electrospray ionization. The column used was an XSelect CSH C in analytical mode. 18 3.5 μM (4.6 × 50 mm) and XSelect CSH prep C in preparative mode 18 The column diameter was 5 μM (19 × 100 mm). The mobile phase in both cases consisted of an appropriate gradient A and B. A was water with 0.1% formic acid, and B was acetonitrile with 0.1% formic acid. The flow rate was 1 mL per minute in analytical mode and 25 mL per minute in preparative mode. All HPLC / MS runs were performed at room temperature. The UPLC system was a Waters Aquity platform equipped with a photodiode array detector (190-400 nm). The column used was an Acquity CSH C 18The column diameter was 1.7 μM (2.1 × 30 mm). The mobile phase consisted of gradients A and B. A was water with 0.025% TFA, and B was acetonitrile with 0.025% TFA. The flow rate was 0.8 mL per minute. All analyses were performed at 55 °C. The UPLC was coupled to a Waters SQD2 platform. All mass spectra were full scan experiments (mass range 100-800 amu). Mass spectra were acquired using electrospray ionization.

[0394] Melting points were determined on a Barnstead Electrothermal 9100 and are uncorrected.

[0395] I. Synthesis of Selected Compounds of the Invention The following compounds were synthesized and characterized as summarized below.

[0396] Pyrrolo[1,2-c]pyrimidine-3-carboxylic acid, thieno[3,2-c]pyridine-6-carboxylic acid and thieno[2,3-c]pyridine-5-carboxylic acid were prepared according to the conditions described in the literature (J. Org. Chem., 1999, 64, 7788-7801; J. Med. Chem., 2006, 49, 4425-4436; and WO2004 / 39815).

[0397] Example 1 Synthesis of Compound 1 (6-(3-pyridin-4-yl-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one)

[0398] [ka]

[0399] Process 1 Under an inert atmosphere, a solution of 5-fluoro-2-nitrobenzoic acid (2.50 g, 13.5 mmol), ammonia (0.5 M in dioxane, 54.0 mL, 27.0 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (8.90 g, 20.3 mmol), and diisopropylethylamine (6.10 mL, 35.1 mmol) in aqueous dichloromethane (68.0 mL) was stirred at room temperature for 16 hours. The mixture was then poured into a saturated aqueous solution of ammonium chloride (250 mL) and extracted with dichloromethane (2 × 200 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, and concentrated in vacuo. The crude dark solid was purified by flash column chromatography on silica gel using cyclohexane / ethyl acetate as eluent to give 5-fluoro-2-nitrobenzamide (2.40 g, 13.0 mmol, 96%) as a brown solid.

[0400] [ka]

[0401] M / Z (M+H) + = 185.2.

[0402] Process 2 To a suspension of sodium hydride (60% suspension in oil, 0.84 g, 21.7 mmol) in anhydrous DMF (15.0 mL) was added dropwise a solution of 4-pyridinepropanol (1.49 g, 10.8 mmol) in DMF (15.0 mL) at 0 °C under an inert atmosphere. After 5 min, a solution of 5-fluoro-2-nitrobenzamide (2.00 g, 10.8 mmol) in DMF (15.0 mL) was added dropwise at 0 °C under vigorous stirring. The resulting reddish mixture was stirred at room temperature for 1 h, then diluted with water (100 mL) and extracted with ethyl acetate (3 × 300 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, and concentrated in vacuo. The crude dark oil was purified by flash column chromatography on silica gel using dichloromethane / methanol as eluent to give 2-nitro-5-(3-pyridin-4-yl-propoxy)-benzamide (2.05 g, 63%) as an orange oil.

[0403] [ka]

[0404] 1 7.14 (dd, J 9.0, 2.8 Hz, 1H, Ar); 7.28 (d, J 5.8 Hz, 2H, Ar); 7.64 (bs, 1H, NH); 8.02 (bs, 1H, NH); 8.04 (d, J 9.0 Hz, 1H, Ar); 8.47 (d, J 5.8 Hz, 2H, Ar). M / Z (M+H) + = 302.1.

[0405] Process 3 To a solution of 2-nitro-5-(3-pyridin-4-yl-propoxy)-benzamide (2.05 g, 6.80 mmol) in methanol (23.0 mL) and DMF (8.0 mL) was added 10% palladium on charcoal (1.45 g). The suspension was placed under hydrogen gas at atmospheric pressure and stirred at room temperature for 2 hours. The mixture was then filtered through a pad of Celite. The methanol was removed in vacuo to give an orange solution, which was partitioned between water (50 mL) and ethyl acetate (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, and concentrated in vacuo. The crude oil was purified by flash column chromatography on silica gel using dichloromethane / methanol as eluent to give 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide (0.96 g, 3.54 mmol, 52%) as a yellow solid.

[0406] [ka]

[0407] 1 H-NMR (400 MHz, DMSO): 1.99 (m, 2H, CH2); 2.75 (t, J 7.6 Hz, 2H, CH2); 3.89 (t, J 6.6 Hz, 2H, CH2-O); 6.12 (bs, 2H, NH2); 6.63 (d, J 8.9 Hz, 1H, Ar); 6.84 (dd, J 8.9, 2.8 Hz, 1H, Ar); 7.05 (bs, 1H, NH); 7.12 (d, J 2.8 Hz, 1H, Ar); 7.26 (d, J 5.9 Hz, 2H, Ar); 7.67 (bs, 1H, NH); 8.46 (d, J 5.9 Hz, 2H, Ar). M / Z (M+H) + = 272.2.

[0408] Process 4 A suspension of 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide (100 mg, 0.37 mmol), pyrrolo[1,2-c]pyrimidine-3-carboxylic acid (70 mg, 0.41 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (245 mg, 0.56 mmol), and diisopropylethylamine (0.20 mL, 1.11 mmol) in anhydrous DMF (1.0 mL) was stirred at 70 °C for 4 h. The mixture was then poured into ice water (10 mL) to give a gray precipitate, which was collected by filtration and triturated with dichloromethane (2 × 2 mL). The gray solid was suspended in a mixture of sodium hydroxide (5% in water, 0.5 mL) and ethanol (0.5 mL) and heated under reflux for 1 h. The ethanol was removed under vacuum, and the resulting solution was poured into a saturated aqueous solution of ammonium chloride (5.0 mL). A brown precipitate formed, which was collected by filtration and rinsed several times with water (3.0 mL). The solid was then dried overnight under high vacuum in the presence of P2O5 at 50 °C to give compound 1 (60 mg, 41%) as a brown powder.

[0409] [ka]

[0410] 1H-NMR (400 MHz, DMSO): 2.12 (m, 2H, CH2); 2.82 (t, J 7.6 Hz, 2H, CH2); 4.12 (t, J 6.4 Hz, 2H, CH2-O); 6.85 (d, J 3.4 Hz, 1H, Ar); 7.06 (t, J 7.30 (d, J 5.6 Hz, 2H, Ar); 7.48 (dd, J 8.8, 2.9 Hz, 1H, Ar); 7.52 (d, J 2.9 Hz, 1H, Ar); 7.69 (d, J 8.8 Hz, 1H, Ar); 7.89 (s, 1H, Ar); 8.48 (m, 3H, Ar); 9.33 (s, 1H, Ar); No NH signal observed. M / Z (M+H) + = 398.1. MP = 202-206℃.

[0411] Compound 2 (2-Isoquinolin-3-yl-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one hydrochloride)

[0412] [ka]

[0413] Compound 2 was prepared according to the procedure of Example 1, Step 4, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and isoquinoline-3-carboxylic acid. The HCl salt was obtained by adding excess HCl (2N in EtO) to a solution of the free base in dichloromethane followed by filtration. Compound 2 was obtained as a white solid in 92% yield. 13.26 (t, J 7.6 Hz, 2H, CH2); 4.28 (t, J 6.4 Hz, 2H, CH2-O); 7.55 (dd, J 8.9, 2.8 Hz, 1H, Ar); 7.96 (d, J 8.9 Hz, 1H, Ar); 7.97 (d, J 7.3 Hz, 1H, Ar); 8.05 (t, J 7.3 Hz, 1H, Ar); 8.09 (d, J 6.5 Hz, 2H, Ar); 8.25 (d, J 8.2 Hz, 1H, Ar); 8.36 (d, J 8.2 Hz, 1H, Ar); 8.78 (d, J 6.5 Hz, 2H, Ar); 9.04 (s, 1H, Ar); 9.58 (s, 1H, Ar); NH signal absent; HCl salt signal absent. M / Z (M+H) + = 409.2. MP > 250℃.

[0414] Compound 3 (6-(3-pyridin-4-yl-propoxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one hydrochloride)

[0415] [ka]

[0416] Compound 3 was prepared according to the procedure of Example 1, Step 4, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and thieno[3,2-c]pyridine-6-carboxylic acid. The HCl salt was obtained by adding excess HCl (2N in EtO) to a solution of the free base in dichloromethane and methanol, followed by filtration. Compound 3 was obtained as a yellow solid in 93% yield. 1H-NMR (400 MHz, DMSO): 2.17 (m, 2H, CH2); 3.06 (t, J 7.6 Hz, 2H, CH2); 4.13 (t, J 6.4 Hz, 2H, CH2-O); 7.38 (dd, J 9.0, 3.0 Hz, 1H, Ar); (d, J 3.0 Hz, 1H, Ar); 7.70 (m, 2H, Ar); 7.96 (d, J 6.6 Hz, 2H, Ar); 8.06 (d, J 5.5 Hz, 1H, Ar); 8.77 (d, J 6.6 Hz, 2H, Ar); 9.08 (s, 1H, Ar); 9.24 (s, 1H, Ar); NH signal not observed; No HCl salt signal was observed. M / Z (M+H) + = 415.2. MP > 250℃.

[0417] Compound 4 (6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-6-yl-3H-quinazolin-4-one hydrochloride)

[0418] [ka]

[0419] Compound 4 was prepared according to the procedure of Example 1, Step 4, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and thieno[2,3-c]pyridine-6-carboxylic acid. The HCl salt was obtained by adding excess HCl (2N in EtO) to a solution of the free base in methanol, followed by filtration. Compound 4 was obtained as a yellow solid in 73% yield. 1H-NMR (400 MHz, DMSO): 2.24 (m, 2H, CH2); 3.13 (t, J 7.6 Hz, 2H, CH2); 4.20 (t, J 6.4 Hz, 2H, CH2-O); 7.44 (dd, J 9.0, 2.9 Hz, 1H, Ar); 7.78 (d, J 9.0 Hz, 1H, Ar); 7.81 (d, J 5.2 Hz, 1H, Ar); 8.04 (d, J 6.7 Hz, 2H, Ar); 8.31 (d, J 5.2 Hz, 1H, Ar); 8.85 (d, J 6.7 Hz, 2H, Ar); 8.95 (s, 1H, Ar); 9.47 (s, 1H, Ar); NH signal not observed; HCl salt signal not observed. M / Z (M+H) + = 415.1. MP > 250℃.

[0420] Compound 5 (2-pyridin-2-yl-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one hydrochloride)

[0421] [ka]

[0422] Compound 5 was prepared according to the procedure of Example 1, Step 4, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and picolinic acid. The HCl salt was obtained by adding 1 equivalent of HCl (2N in EtO) to a solution of the free base in dichloromethane followed by filtration. Compound 5 was obtained as a yellow solid in 84% yield. 1H-NMR (400 MHz, DMSO): 2.23 (m, 2H, CH2); 3.13 (t, J 7.6 Hz, 2H, CH2); 4.19 (t, J 6.4 Hz, 2H, CH2-O); 7.43 (dd, J 9.0, 2.9 Hz, 1H, Ar); 7.66 (m, 1H, Ar); 7.77 (d, J 9.0 Hz, 1H, Ar); 8.03 (d, J 6.6 Hz, 2H, Ar); 8.08 (t, J 7.7 Hz, 1H, Ar); 8.43 (d, J 7.7 Hz, 1H, Ar); 8.76 (d, J 4.5 Hz, 1H, Ar); 8.85 (d, J 6.6 Hz, 2H, Ar); NH signal absent; HCl salt signal absent. M / Z (M+H) + = 359.2. MP > 250℃.

[0423] Reference compound 6 (2-pyridin-3-yl-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one hydrochloride)

[0424] [ka]

[0425] Compound 6 (reference) was prepared according to the procedure of Example 1, Step 4, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and nicotinic acid. The HCl salt was obtained by adding excess HCl (2N in EtO) to a solution of the free base in dichloromethane, followed by filtration. Compound 6 was obtained as a white solid in 60% yield. 1H-NMR (400 MHz, DMSO): 2.24 (m, 2H, CH2); 3.12 (t, J 7.6 Hz, 2H, CH2); 4.20 (t, J 6.4 Hz, 2H, CH2-O); 7.44 (dd, J 9.0, 2.9 Hz, 1H, Ar); (d, J 2.9 Hz, 1H, Ar); 7.77 (d, J 9.0 Hz, 1H, Ar); 7.91 (dd, J 8.1, 5.3 Hz, 1H, Ar); 8.04 (d, J 6.5 Hz, 2H, Ar); 8.46 (m, 3H, Ar); 8.92 (d, J 5.3 Hz, 1H, Ar); 9.41 (s, 1H, Ar); NH signal not observed; HCl salt signal not observed. M / Z (M+H) + = 359.2. MP > 250℃.

[0426] Compound 7 (2-(4-methoxy-pyridin-2-yl)-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one hydrochloride)

[0427] [ka]

[0428] Compound 7 was prepared according to the procedure of Example 1, Step 4, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and 4-methoxypicolinic acid. The HCl salt was obtained by adding excess HCl (2N in EtO) to a solution of the free base in dichloromethane followed by filtration. Compound 7 was obtained as a white solid in 86% yield. 1H-NMR (400 MHz, DMSO): 2.23 (m, 2H, CH2); 3.12 (t, J 7.6 Hz, 2H, CH2); 4.01 (s, 3H, CH3-O); 4.20 (t, J 6.4 Hz, 2H, CH2-O); 7.29 (m, 1H, Ar); 7.44 (dd, J 8.8, 2.9 Hz, 1H, Ar); 7.56 (d, J 2.9 Hz, 1H, Ar); 7.78 (d, J 8.8 Hz, 1H, Ar); 8.03 (m, 3H, Ar); 8.60 (d, J 5.8 Hz, 1H, Ar); 8.84 (d, J 6.5 Hz, 2H, Ar); NH signal not observed; No HCl salt signal was observed. M / Z (M+H) + = 389.1. MP > 250℃.

[0429] Compound 8 (2-(5-fluoro-pyridin-2-yl)-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one hydrochloride)

[0430] [ka]

[0431] Compound 8 was prepared according to the procedure of Example 1, Step 4, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and 5-fluoropicolinic acid. The crude product was purified by flash column chromatography on silica gel using dichloromethane / methanol as eluent. The HCl salt was obtained by adding excess HCl (2N in EtO) to a solution of the free base in dichloromethane followed by filtration. Compound 8 was obtained as a yellow solid in 42% yield. 13.11 (t, J 7.6 Hz, 2H, CH2); 4.19 (t, J 6.4 Hz, 2H, CH2-O); 7.43 (dd, J 8.8, 3.0 Hz, 1H, Ar); 7.75 (d, J 8.8 Hz, 1H, Ar); 8.00 (m, 3H, Ar); 8.48 (dd, J 8.8, 4.5 Hz, 1H, Ar); 8.75 (d, J 2.8 Hz, 1H, Ar); 8.83 (d, J 6.7 Hz, 2H, Ar); NH signal not observed; No HCl salt signal was observed. M / Z (M+H) + = 377.1. MP > 250℃.

[0432] Compound 9 (6-(3-pyridin-4-yl-propoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one hydrochloride)

[0433] [ka]

[0434] Compound 9 was prepared according to the procedure of Example 1, Step 4, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and 4-trifluoromethylpicolinic acid. The HCl salt was obtained by adding excess HCl (2N in EtO) to a solution of the free base in dichloromethane followed by filtration. Compound 9 was obtained as a white solid in 69% yield. 1H-NMR (400 MHz, DMSO): 2.23 (m, 2H, CH2); 3.11 (t, J 7.6 Hz, 2H, CH2); 4.20 (t, J 6.4 Hz, 2H, CH2-O); 7.46 (dd, J 8.9, 3.0 Hz, 1H, Ar); 7.57 (d, J 3.0 Hz, 1H, Ar); 7.84 (d, J 8.9 Hz, 1H, Ar); 7.99 (d, J 6.5 Hz, 2H, Ar); 8.04 (d, J 5.1 Hz, 1H, Ar); 8.61 (s, 1H, Ar); 8.82 (d, J 6.5 Hz, 2H, Ar); 9.03 (d, J 5.1 Hz, 1H, Ar); 12.10 (bs, 1H, NH); no HCl salt signal observed. M / Z (M+H) + = 427.1. MP = 239-245℃.

[0435] Compound 10 (6-[3-(4-pyridyl)propoxy]-2-[5-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one hydrochloride)

[0436] [ka]

[0437] Compound 10 was prepared according to the procedure of Example 1, Step 4, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and 5-trifluoromethylpicolinic acid. The HCl salt was obtained by adding excess HCl in MeOH to a solution of the free base in MeOH, followed by concentration to dryness and trituration in EtO. Compound 10 was obtained as a yellow solid in 45% yield. 1H-NMR (400 MHz, DMSO): 2.22 (tt, J 7.3, 6.1 Hz, 2H, CH2); 3.08 (t, J 7.3 Hz, 2H, CH2); 4.20 (t, J 6.1 Hz, 2H, CH2-O); 7.46 (dd, J 8.8, 3.0 Hz; 1H, Ar); 7.57 (d, J 3.0 Hz, 1H, Ar); 7.79 (d, J 8.8 Hz, 1H, Ar); 7.94 (d, J 6.6 Hz, 2H, Ar); 8.47 (dd, J 8.5, 1.8 Hz, 1H Ar); 8.59 (d, J 8.5 Hz, 1H, Ar); 8.79 (d, J 6.6 Hz, 2H, Ar); 9.11-9.12 (m, 1H, Ar); 12.06 (bs, 1H, NH). No HCl salt signal observed. M / Z (M+H) + = 427.4. MP > 250℃.

[0438] Compound 11 (2-(4-methyl-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one dihydrochloride)

[0439] [ka]

[0440] Compound 11 was prepared according to the procedure of Example 1, Step 4, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and 4-methylpyridine-2-carboxylic acid. The HCl salt was obtained by adding excess HCl in MeOH to a solution of the free base in MeOH and dichloromethane, followed by concentration to dryness and trituration in EtO. Compound 11 was obtained as a yellow solid in 51% yield. 1H-NMR (400 MHz, DMSO): 2.23 (tt, J 7.1, 5.9 Hz, 2H, CH2); 2.47 (s, 3H, CH3); 3.11 (t, J 7.1 Hz, 2H, CH2); 4.19 (t, J 5.9 Hz, 2H, CH2-O); 7.43 (dd, J 8.8, 2.3 Hz; 1H, Ar); 7.48 (d, J 4.5 Hz, 1H, Ar); 7.55 (d, J 2.3 Hz, 1H, Ar); 7.76 (d, J 8.8 Hz, 1H, Ar); 8.01 (d, J 6.2 Hz, 2H Ar); 8.23 (s, 1H, Ar); 8.60 (d, J 4.5 Hz, 1H, Ar); 9.83 (d, J 6.2 Hz, 2H, Ar). No NH signal; no HCl salt signal. M / Z (M+H) + = 373.3. MP = 175-250℃.

[0441] Compound 12 (2-(6-methyl-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one dihydrochloride)

[0442] [ka]

[0443] Compound 12 was prepared according to the procedure of Example 1, Step 4, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and 6-methylpyridine-2-carboxylic acid. The HCl salt was obtained by adding excess HCl in MeOH to a solution of the free base in MeOH and dichloromethane, followed by concentration to dryness and trituration in EtO. Compound 12 was obtained as a yellow solid in 34% yield. 1H-NMR (400 MHz, DMSO): 2.27 (tt, J 7.5, 6.2 Hz, 2H, CH2); 2.62 (s, 3H, CH3); 3.11 (t, J 7.5 Hz, 2H, CH2); 4.19 (t, J 6.2 Hz, 2H, CH2-O); 7.42 (dd, J 8.8, 2.9 Hz, 1H, Ar); 7.50 (d, J 7.7 Hz, 1H, Ar); 7.56 (d, J 2.9 Hz, 1H, Ar); 7.76 (d, J 8.8 Hz, 1H Ar); 7.95 (t, J 7.7 Hz, 1H Ar); 8.02 (d, J 6.6 Hz, 2H, Ar); 8.22 (d, J 7.7 Hz, 1H, Ar); 8.83 (d, J 6.6 Hz, 2H, Ar). No NH or HCl salt signals were observed. M / Z (M+H) + = 373.3. MP > 250℃.

[0444] Compound 13 (2-(5-methylpyrazin-2-yl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one dihydrochloride)

[0445] [ka]

[0446] Compound 13 was prepared according to the procedure of Example 1, Step 4, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and 5-methylpyrazine-2-carboxylic acid. The HCl salt was obtained by adding excess HCl in MeOH to a solution of the free base in MeOH and dichloromethane, followed by concentration to dryness and trituration in EtO. Compound 13 was obtained as a yellow solid in 18% yield. 1H-NMR (400 MHz, DMSO): 2.15 (tt, J 7.5, 6.2 Hz, 2H, CH2-O); 2.56 (s, 3H, CH3); 3.02 (t, J 7.5Hz, 2H, CH2); 4.12 (t, J 6.2 Hz, 2H, CH2-O); 7.37 (dd, J 8.9, 2.9 Hz, 1H, Ar); 7.49 (d, J 2.9 Hz, 1H, Ar); 7.71 (d, J 8.9 Hz, 1H, Ar); 7.88 (d, J 5.6 Hz, 2H, Ar); 8.63 (s, 1H, Ar); 8.73 (d, J 5.6 Hz, 2H, Ar); 9.34 (s, 1H, Ar); 12.00 (bs, 1H, NH). No HCl salt signal observed. M / Z (M+H) + = 374.3. MP > 250℃.

[0447] Compound 14 (2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one hydrochloride)

[0448] [ka]

[0449] Compound 14 was prepared according to the procedure of Example 1, Step 4, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and 5-chloro-4-(trifluoromethyl)pyridine-2-carboxylic acid. The HCl salt was obtained by adding excess HCl (1.25 M in MeOH) to a solution of the free base in MeOH and dichloromethane, followed by concentration to dryness and trituration in EtO. Compound 14 was obtained as a yellow solid in 47% yield. 1H-NMR (400 MHz, MeOD): 2.35 (tt, J 7.8, 5.9 Hz, 2H, CH2); 3.24 (t, J 7.8 Hz, 2H, CH2); 4.24 (t, J 5.9 Hz, 2H, CH2-O); 7.46 (dd, J 8.9, 2.9 Hz, 1H Ar); 7.64 (d, J 2.9 Hz, 1H, Ar); 7.84 (d, J 8.9 Hz, 1H, Ar); 8.05 (d, J 6.4 Hz, 2H, Ar); 8.75 (d, J 6.4 Hz, 2H, Ar); 8.80 (s, 1H, Ar); 8.97 (s, 1H, Ar). No NH or HCl salt signals were observed. M / Z (M+H) + = 461.2. MP =134-250℃.

[0450] Compound 15 (2-(4-chloro-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one hydrochloride)

[0451] [ka]

[0452] Compound 15 was prepared according to the procedure of Example 1, Step 4, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and lithium 4-chloropyridine-2-carboxylate, using 3 equivalents of benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate. The HCl salt was obtained by adding excess HCl in EtO to a solution of the free base in dichloromethane, followed by filtration. Compound 15 was obtained as a yellow solid in 68% yield. 1H-NMR (400 MHz, DMSO): 2.22 (tt, J 7.2, 6.2 Hz, 2H, CH2); 3.09 (t, J 7.2 Hz, 2H, CH2); 4.19 (t, J 6.2 Hz, 2H, CH2-O); 7.45 (dd, J 8.8, 3.0 Hz; 1H, Ar); 7.56 (d, J 3.0 Hz, 1H, Ar); 7.77-7.80 (m, 2H, Ar); 7.96 (d, J 6.2 Hz, 2H, Ar); 8.41 (d, J 2.0 Hz, 1H Ar); 8.72 (d, J 5.3 Hz, 1H, Ar); 8.80 (d, J 6.2 Hz, 2H, Ar). No NH or HCl salt signals were observed. M / Z (M+H) + = 393.3. MP = 232-241℃.

[0453] Lithium 4-chloropyridine-2-carboxylate was prepared as follows:

[0454] [ka]

[0455] To a suspension of methyl 4-chloropyridine-2-carboxylate (50 mg, 0.29 mmol) in THF (0.5 mL) and water (0.5 mL) was added LiOH (14 mg, 0.58 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated to dryness to give the product (quantitative yield). 1 H-NMR (400 MHz, DMSO): 7.53 (dd, J 5.4, 2.3 Hz; 1H, Ar); 7.92 (dd, J 2.3, 0.5 Hz; 1H, Ar); 8.43 (dd, J 5.4, 0.5 Hz; 1H, Ar).

[0456] Compound 16 (2-(4-ethyl-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one dihydrochloride)

[0457] [ka]

[0458] Compound 16 was prepared according to the procedure for compound 15, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and lithium 4-ethylpyridine-2-carboxylate. The HCl salt was obtained by adding excess HCl in EtO to a solution of the free base in dichloromethane, followed by concentration to dryness. Compound 16 was obtained as a brown solid in 38% yield. 1 H-NMR (400 MHz, DMSO): 1.33 (t, J 7.4 Hz, 3H, CH3); 2.29 (tt, J 7.7, 6.2 Hz, 2H, CH2); 2.85 (q, J 7.4 Hz, 2H, CH2); 3.18 (t, J 7.7 Hz, 2H, CH2); 4.25 (t, J 6.2 Hz, 2H, CH2-O); 7.49-7.51 (m; 1H, Ar); 7.54-7.62 (m, 2H, Ar); 7.83-7.85 (m, 1H, Ar); 8.09 (d, J 6.3 Hz, 2H, Ar); 8.35 (bs, 1H Ar); 8.68-8.70 (m, 1H, Ar); 8.90 (d, J 5.4 Hz, 2H, Ar). No NH or HCl salt signals were observed. M / Z (M+H) + = 387.3.

[0459] Lithium 4-ethylpyridine-2-carboxylate was prepared as follows:

[0460] [ka]

[0461] To a suspension of methyl 4-ethylpyridine-2-carboxylate (88 mg, 0.53 mmol) in THF (0.8 mL) and water (0.8 mL) was added LiOH (26 mg, 1.07 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated to dryness to give the product (quantitative yield). 1 H-NMR (400 MHz, DMSO): 1.20 (t, J 7.5 Hz, 3H, CH3); 2.67 (m, 2H, CH2); 7.28 (bs, 1H, Ar); 7.84 (bs, 1H, Ar); 8.31 (bs ,1H, Ar).

[0462] Compound 17 (6-[3-(4-pyridyl)propoxy]-2-[6-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one hydrochloride)

[0463] [ka]

[0464] Compound 17 was prepared according to the procedure of Example 1, Step 4, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and 6-(trifluoromethyl)pyridine-2-carboxylic acid. The HCl salt was obtained by adding excess HCl in MeOH to a solution of the free base in MeOH and dichloromethane, followed by concentration to dryness and trituration in EtO. Compound 17 was obtained as a yellow solid in 81% yield. 13.08 (t, J 7.5 Hz, 2H, CH2); 4.20 (t, J 6.2 Hz, 2H, CH2-O); ); 7.45 (dd, J 8.8, 3.0 Hz; 1H, Ar); 7.58 (d, J 3.0 Hz, 1H, Ar); 7.78 (d, J 8.8 Hz, 1H, Ar); 7.95 (d, J 6.7 Hz, 2H, Ar); 8.14 (d, J 7.8 Hz, 1H, Ar); 8.35 (t, J 7.8 Hz, 1H, Ar); 8.64 (d, J 7.8 Hz, 1H, Ar); 8.79 (d, J 6.7 Hz, 2H, Ar); 11.94 (bs, 1H, NH). No HCl salt signal observed. M / Z (M+H) + = 427.3. MP = 238-250℃.

[0465] Compound 18 (2-(4-bromo-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one)

[0466] [ka]

[0467] Compound 18 was prepared starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and 4-bromopyridine-2-carboxylic acid according to the procedure of Example 1, Step 4. Compound 18 was obtained as a beige solid in 88% yield. 1H-NMR (400 MHz, DMSO): 2.10 (tt, J 7.5, 6.3 Hz, 2H, CH2); 2.81 (t, J 7.5 Hz, 2H, CH2); 4.04 (t, J 6.3 Hz, 2H, CH2-O); 7.15 (dd, J 8.8, 3.0 Hz; 1H, Ar); 7.29 (dd, J 5.9 Hz, 2H, Ar); 7.43 (d, J 3.0 Hz, 1H, Ar); 7.53 (d, J 8.8 Hz, 1H, Ar); 7.64 (dd, J 5.3, 2.0 Hz, 1H Ar); 8.46 (d, J 5.9 Hz, 2H, Ar); 8.51 (d, J 5.3 Hz, 1H, Ar); 8.59 (d, J 2.0 Hz, 1H, Ar). No NH signal was observed. M / Z (M[ 81 Br]+H) + = 439.1. MP > 250℃.

[0468] Compound 19 (2-(4-cyclopropyl-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one dihydrochloride)

[0469] [ka]

[0470] Compound 19 was prepared according to the procedure for compound 15, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and lithium 4-cyclopropylpyridine-2-carboxylate. The HCl salt was obtained by adding excess HCl in EtO to a solution of the free base in dichloromethane, followed by filtration. Compound 19 was obtained as a green solid in 70% yield. 1H-NMR (400 MHz, DMSO): 0.88-1.00 (m, 2H, CH2); 1.17-1.21 (m, 2H, CH2); 2.12-2.26 (m, 3H, CH2+ CH); 3.10 (t, J 7.2 Hz, 2H, CH2); 4.18 (t, J 6.1 Hz, 2H, CH2-O); 7.28-7.59 (m, 3H, Ar); 7.73-7.83 (m, 1H, Ar); 7.97-8.05 (m, 2H, Ar); 8.09-8.18 (m, 1H, Ar); 8.50-8.60 (m, 1H, Ar); 8.78-8.88 (m, 2H, Ar). No NH or HCl salt signals were observed. M / Z (M+H) + = 399.3. MP = 110-156℃.

[0471] Lithium 4-cyclopropylpyridine-2-carboxylate was prepared as follows:

[0472] [ka]

[0473] To a suspension of methyl 4-cyclopropylpyridine-2-carboxylate (131 mg, 0.69 mmol) in THF (1.2 mL) and water (1.2 mL) was added LiOH (34 mg, 1.43 mmol), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated to dryness to give the product (142 mg, quantitative yield). 1 H-NMR (400 MHz, DMSO): 0.81 (s, 2H, CH2); 1.08 (s, 2H, CH2); 1.99 (s, 1H, CH); 7.14 (bs, 1H, Ar); 7.56 (bs, 1H, Ar); 8.22 (bs, 1H, Ar).

[0474] Methyl 4-cyclopropylpyridine-2-carboxylate was prepared as follows:

[0475] [ka]

[0476] Under an inert atmosphere, methyl 4-bromopyridine-2-carboxylate (150 mg, 0.69 mmol) was dissolved in dry dioxane (5 mL). Copper iodide (26 mg, 0.14 mmol) and PdCl(dppf).CHCl (56 mg, 0.07 mmol) were added, followed by cyclopropylzinc bromide (0.5 M in THF, 4.0 mL, 2.08 mmol). The reaction mixture was then stirred at 80 °C for 2 h. The mixture was then partitioned between water and ethyl acetate, extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to give methyl 4-cyclopropylpyridine-2-carboxylate (quantitative yield) as a red oil. 1 H-NMR (400 MHz, DMSO): 0.85 (tt, J 4.5, 6.7 Hz, 2H, CH2); 1.11 (m, 2H, CH2); 2.07 (m, 1H, CH); 3.86 (s, 3H, CH3); 7.32 (dd, J 1.7, 5.1 Hz, 1H, Ar); 7.75 (d, J 1.7 Hz, 1H Ar); 8.50 (d, 5.1 Hz, 1H, Ar).

[0477] Reference compound 20 (2-(3-chlorophenyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one hydrochloride)

[0478] [ka]

[0479] Compound 20 (reference) was prepared according to the procedure of Example 1, Step 4, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and 3-chlorobenzoic acid. The product was purified by column chromatography on silica gel using dichloromethane / methanol as eluent. The HCl salt was obtained by adding excess HCl (1.25 M in EtO) to a solution of the free base in dichloromethane followed by filtration. Compound 20 was obtained as a white solid in 5% yield. 1 3.11 (t, J 7.6 Hz, 2H, CH2); 4.18 (t, J 6.2 Hz, 2H, CH2-O); 7.41 (dd, J 2.9, 8.8 Hz, 1H, Ar); (d, J 2.9 Hz, 1H, Ar); 7.58 (t, 7.9 Hz, 1H, Ar); 7.65 (qd, J 1.1, 8.0 H, 1H, Ar); 7.72 (d, J 8.8 Hz, 1H, Ar); 7.99 (d, J 6.4 Hz, 2H, Ar); 8.13 (td, J 1.3, 7.8 Hz, 1H, Ar); 8.23 (t, J 1.8 Hz, 1H, Ar); 8.82 (d, J 6.6 Hz, 2H, Ar); 12.58 (bs, 1H, NH); no HCl salt signal observed. M / Z (M+H) + = 392. MP > 250℃.

[0480] Reference compound 21 (6-[3-(4-pyridyl)propoxy]-2-[3-(trifluoromethyl)phenyl]-3H-quinazolin-4-one hydrochloride)

[0481] [ka]

[0482] Compound 21 (reference) was prepared according to the procedure of Example 1, Step 4, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and 3-(trifluoromethyl)benzoic acid. The product was purified by column chromatography on silica gel using dichloromethane / methanol as eluent. The HCl salt was obtained by adding excess HCl (1.25 M in EtO) to a solution of the free base in dichloromethane followed by filtration. Compound 21 was obtained as a white solid in 15% yield. 1 H-NMR (400 MHz, DMSO): 2.23 (q, J 6.9 Hz, 2H, CH2); 3.11 (t, J 7.6 Hz, 2H, CH2); 4.18 (t, J 6.2 Hz, 2H, CH2-O); 7.42 (dd, J 3.0, 8.9 Hz, 1H, 7.54 (d, J 3.0 Hz, 1H, Ar); 7.75 (d, J 8.9 Hz, 1H, Ar); 7.79 (t, J 7.9 Hz, 1H, Ar); 7.94 (d, J 7.8 Hz, 1H, Ar); 8.02 (d, J 6.6 Hz, 2H, Ar); 8.47 (d, J 8.1 Hz, 1H, Ar); 8.52 (s, 1H, Ar); 8.83 (d, J 6.7 Hz, 2H, Ar); 12.73 (bs, 1H, NH); no HCl salt signal observed. M / Z (M+H) + = 426. MP > 250℃.

[0483] Compound 22 (2-(2-methyl-oxazol-4-yl)-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one hydrochloride)

[0484] [ka]

[0485] Compound 22 was prepared according to the procedure of Example 1, Step 4, starting from 2-amino-5-(3-pyridin-4-yl-propoxy)-benzamide and 2-methyloxazole-4-carboxylic acid. The HCl salt was obtained by adding excess HCl (2N in EtO) to a solution of the free base in MeOH followed by concentration. Compound 22 was obtained as a yellow solid in 83% yield. 1 H-NMR (400 MHz, DMSO): 2.22 (m, 2H, CH2); 2.54 (s, 3H, CH3); 3.10 (t, J 7.6 Hz, 2H, CH2); 4.17 (t, J 6.4 Hz, 2H, CH2-O); 7.40 (dd, J 8.9, 2.9 Hz, 1H, Ar); 7.51 (d, J 2.9 Hz, 1H, Ar); 7.68 (d, J 8.9 Hz, 1H, Ar); 8.03 (d, J 6.7 Hz, 2H, Ar); 8.84 (m, 3H, Ar); NH signal absent; HCl salt signal absent. M / Z (M+H) + = 363.1. MP > 250℃.

[0486] Example 2 Synthesis of Compound 23 (6-(2-pyridin-3-yl-ethoxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one hydrochloride)

[0487] [ka]

[0488] Step 1: 2-Nitro-5-(2-pyridin-3-yl-ethoxy)-benzamide was prepared starting from 2-nitro-5-fluorobenzamide and 2-pyridin-3-yl-ethanol according to the procedure in Example 1, Step 2. It was obtained as a white powder in 31% yield.

[0489] [ka]

[0490] 1 H-NMR (400 MHz, CDCl3): 3.11 (t, J 6.6 Hz, 2H, CH2); 4.40 (t, J 6.6 Hz, 2H, CH2-O); 7.07 (d, J 2.7 Hz, 1H, Ar); 7.15 (dd, J 9.0, 2.7 Hz, 1H, Ar); 7.35 (dd, J 7.8, 4.8 Hz, 1H, Ar); 7.64 (bs, 1H, NH); 7.78 (d, J 7.8 Hz, 1H, Ar); 8.01 (bs, 1H, NH); 8.03 (d, J 9.0 Hz, 1H, Ar); 8.45 (dd, J 4.8, 1.7 Hz, 1H, Ar); 8.56 (d, J 1.7 Hz, 1H, Ar). M / Z (M+H) + = 288.1.

[0491] Step 2: 2-Amino-5-(2-pyridin-3-yl-ethoxy)-benzamide was prepared according to the procedure of Example 1, Step 3 and isolated in 86% yield as a beige solid.

[0492] [ka]

[0493] 16.83 (dd, J 7.04 (bs, 1H, NH); 7.11 (d, J 2.9 Hz, 1H, Ar); 7.35 (dd, J 7.7, 4.8 Hz, 1H, Ar); 7.71 (bs, 1H, NH); 7.74 (d, J 7.7 Hz, 1H, Ar); 8.44 (dd, J 4.8, 1.7 Hz, 1H, Ar); 8.54 (d, J 1.7 Hz, 1H, Ar). M / Z (M+H) + = 258.1.

[0494] Step 3: Compound 23 was prepared according to the procedure of Example 1, Step 4, starting from 2-amino-5-(2-pyridin-3-yl-ethoxy)-benzamide and thieno[3,2-c]pyridine-6-carboxylic acid. The HCl salt was obtained by adding excess HCl (2N in EtO) to a solution of the free base in MeOH followed by concentration. Compound 23 was obtained as a yellow solid in 80% yield.

[0495] [ka]

[0496] 1H-NMR (400 MHz, DMSO): 3.49 (t, J 6.0 Hz, 2H, CH2); 4.54 (t, J 6.0 Hz, 2H, CH2-O); 7.57 (dd, J 9.0, 2.9 Hz, 1H, Ar); 7.75 (d, J 2.9 Hz, 1H, Ar); 7.87 (d, J 5.4 Hz, 1H, Ar); 7.94 (d, J 9.0 Hz, 1H, Ar); 8.13 (dd, J 8.1, 5.7 Hz, 1H, Ar); 8.19 (d, J 5.4 Hz, 1H, Ar); 8.76 (d, J 8.1 Hz, 1H, Ar); 8.81 (d, J 5.7 Hz, 1H, Ar); 8.97 (s, 1H, Ar); 9.20 (s, 1H, Ar); 9.43 (s, 1H, Ar); no NH signal; no HCl salt signal. M / Z (M+H) + = 401.0. MP > 250℃.

[0497] Example 3 Synthesis of Compound 24 (6-(4-bromo-benzyloxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one)

[0498] [ka]

[0499] Step 1: 2-Nitro-5-(4-bromo-benzyloxy)benzamide was prepared starting from 2-nitro-5-fluorobenzamide and 4-bromobenzyl alcohol according to the procedure in Example 1, Step 2. It was obtained as a yellow solid in 63% yield.

[0500] [ka]

[0501] M / Z (M[ 79 Br]+H) += 351.0.

[0502] Step 2: 2-Amino-5-(4-bromo-benzyloxy)benzamide was prepared according to the procedure of Example 1, Step 3 and isolated in 55% yield as a pale yellow solid.

[0503] [ka]

[0504] M / Z (M[ 79 Br]+H) + = 321.0.

[0505] Step 3: Compound 24 was prepared starting from 2-amino-5-(4-bromo-benzyloxy)benzamide and thieno[3,2-c]pyridine-6-carboxylic acid according to the procedure of Example 1, Step 4. Compound 24 was obtained as a beige solid in 69% yield.

[0506] [ka]

[0507] 1 H-NMR (400 MHz, DMSO): 5.16 (s, 2H, CH2-O); 7.24 (dd, J 8.8, 2.9 Hz, 1H, Ar); 7.47 (d, J 8.5 Hz, 2H, Ar); 7.53 (d, J 2.9 Hz, 1H, Ar); 8.8 Hz, 1H, Ar); 7.61 (d, J 8.5 Hz, 2H, Ar); 7.67 (d, J 5.4 Hz, 1H, Ar); 7.91 (d, J 5.4 Hz, 1H, Ar); 9.05 (s, 1H, Ar); 9.18 (s, 1H, Ar); No NH signal was observed. M / Z (M[ 79 Br]+H) + = 364.0. MP > 250℃.

[0508] Example 4 Synthesis of Compound 25 (tert-butyl 3-(4-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-quinazolin-6-yl)oxyazetidine-1-carboxylate), Compound 26 (6-(azetidin-3-yloxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one hydrochloride), and Compound 27 (6-(1-pyrimidin-4-yl-azetidin-3-yloxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one)

[0509] [ka]

[0510] Step 1: 3-(4-Nitro-3-carbamoyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester was prepared starting from 2-nitro-5-fluorobenzamide and 1-boc-3-hydroxyazetidine according to the procedure in Example 1, Step 2. It was obtained as a yellow oil in 94% yield.

[0511] [ka]

[0512] M / Z (M+Na) + = 360.1.

[0513] Step 2: 3-(4-Amino-3-carbamoyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester was prepared according to the procedure of Example 1, Step 3 and isolated in 94% yield as a pale yellow solid which was taken on crude to the next step.

[0514] [ka]

[0515] 1 H-NMR (400 MHz, DMSO): 1.38 (s, 9H, tert-butyl); 3.76 (m, 2H, 2 CH); 4.24 (m, 2H, 2 CH); 4.87 (m, 1H, CH); 6.21 (bs, 2H, NH2); 6.65 (d, J 8.8 6.78 (dd, J 8.8, 2.8 Hz, 1H, Ar); 6.97 (d, J 2.8 Hz, 1H, Ar); 7.08 (bs, 1H, NH); 7.74 (bs, 1H, NH). + = 330.1.

[0516] Step 3: 3-(4-Hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-quinazolin-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester 25 was prepared according to the procedure of Example 1, Step 4, starting from 3-(4-amino-3-carbamoyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester and pyrrolo[1,2-c]pyrimidine-3-carboxylic acid. It was obtained as a green solid in 50% yield.

[0517] [ka]

[0518] 1H-NMR (400 MHz, DMSO): 1.45 (s, 9H, tert-butyl); 3.91 (m, 2H, 2 CH); 4.40 (m, 2H, 2 CH); 5.21 (m, 1H, CH); 6.90 (d, J 3.8 Hz, 1H, Ar); 7.11 (dd, J 3.8, 2.7 Hz, 1H, Ar); 7.38 (d, J 2.9 Hz, 1H, Ar); 7.47 (dd, J 8.8, 2.9 Hz, 1H, Ar); 7.76 (d, J 8.8 Hz, 1H, Ar); 7.94 (d, J 2.7 Hz, 1H, Ar); 8.54 (s, 1H, Ar); 9.37 (s, 1H, 11.11 (bs, 1H, NH). M / Z (M+H) + = 434.1. MP > 250℃.

[0519] Step 4: To a solution of 3-(4-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-quinazolin-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester 25 (135 mg, 0.31 mmol) in dichloromethane (2.0 mL) was added dropwise a solution of HCl (2N in EtO, 1.55 mL) at 0 °C. After stirring the reaction mixture at room temperature for 2 h, the dark precipitate was collected by filtration, triturated with dichloromethane, and dried under vacuum. 6-(azetidin-3-yloxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-quinazolin-4-ol hydrochloride 26 (148 mg, quantitative yield) was obtained with a purity of 70% (UV by LC / MS) and was carried on crude to the next step without purification.

[0520] [ka]

[0521] M / Z (M+H) + = 334.1.

[0522] Step 5: Under an inert atmosphere, a suspension of 6-(azetidin-3-yloxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-quinazolin-4-ol hydrochloride 26 (148 mg, 0.40 mmol), 4-bromopyrimidine hydrochloride (156 mg, 0.80 mmol), and diisopropylethylamine (0.30 mL, 1.60 mmol) in ethanol (2.2 mL) was stirred at room temperature for 20 h. The solvent was removed in vacuo, and the crude dark oil was purified by flash column chromatography on silica gel using dichloromethane / methanol as eluent to give compound 27 (30 mg, 18%) as a yellow solid.

[0523] [ka]

[0524] 1 H-NMR (400 MHz, DMSO): 4.10 (m, 2H, 2 CH); 4.58 (m, 2H, 2 CH); 5.39 (m, 1H, CH); 6.50 (d, J 5.9 Hz, 1H, Ar); 6.86 (d, J 6.7 Hz, 1H, Ar); 7.06 (m, 1H, Ar); 7.48 (m, 2H, Ar); 7.75 (d, J 8.2 Hz, 1H, Ar); 7.89 (s, 1H, Ar); 8.20 (d, J 5.9 Hz, 1H, Ar); 8.51 (m, 2H, Ar); 9.31 (s, 1H, Ar); 11.16 (bs, 1H, NH). M / Z (M+H) + = 412.1. MP > 250℃.

[0525] Example 5 Synthesis of Compound 28 (3-(4-hydroxy-2-thieno[2,3-c]pyridin-5-yl-quinazolin-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester), Compound 29 (6-(azetidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-quinazolin-4-ol 2,2,2-trifluoroacetate), and Compound 30 (6-(1-propionyl-azetidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one)

[0526] [ka]

[0527] Step 1: 3-(4-Hydroxy-2-thieno[2,3-c]pyridin-5-yl-quinazolin-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester 28 was prepared according to the procedure of Example 1, Step 4, starting from 3-(4-amino-3-carbamoyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (440 mg, 0.94 mmol) and thieno[2,3-c]pyridine-5-carboxylic acid (252 mg, 1.41 mmol). It was obtained as a white solid (430 mg, quantitative yield).

[0528] [ka]

[0529] M / Z (M+H) + = 451.0.

[0530] Step 2: To a solution of 3-(4-hydroxy-2-thieno[2,3-c]pyridin-5-yl-quinazolin-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester 28 (430 mg, 0.95 mmol) in dichloromethane (5.0 mL) was added TFA (750 μL, 9.60 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness in vacuo. Trituration with diethyl ether afforded 6-(azetidin-1-ium-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-quinazolin-4-ol 2,2,2-trifluoroacetate 29 (quantitative yield) as a yellow solid.

[0531] [ka]

[0532] M / Z (M+H) + = 350.9.

[0533] Step 3: To a mixture of 6-(azetidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-quinazolin-4-ol 2,2,2-trifluoroacetate 29 (200 mg, 0.43 mmol) and triethylamine (180 μL, 1.29 mmol) in DMF (4.5 mL) was added dropwise propionyl chloride (40 μL, 0.43 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 h and then poured into ice water (20 mL). The resulting beige precipitate was collected by filtration and purified by column chromatography on silica gel using dichloromethane / methanol as eluent to give compound 30 (69 mg, 39%) as a white solid.

[0534] [ka]

[0535] 1H-NMR (400 MHz, DMSO): 0.97 (t, J 7.5 Hz, 3H, ethyl); 2.12 (q, J 7.5 Hz, 2H, ethyl); 3.86 (m, 1H, CH); 4.14 (m, 1H, CH); 4.34 (m, 1H, CH); (m,1H, CH); 5.23 (m, 1H, CH); 7.40 (d, J 2.9 Hz, 1H, Ar); 7.48 (dd, J 8.8, 2.9 Hz, 1H, Ar); 7.80 (m, 2H, Ar); 8.27 (d, J 5.4 Hz, 1H, Ar); 8.93 (s, 1H, Ar); 9.43 (s, 1H, Ar); 11.81 (s, 1H, NH). M / Z (M+H) + = 406.9. MP > 250℃.

[0536] Example 6 Synthesis of Compound 31 (6-(piperidin-4-yloxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one) and Compound 32 (6-(1-propionyl-piperidin-4-yloxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one)

[0537] [ka]

[0538] Step 1: 5-(1-acetyl-piperidin-4-yloxy)-2-nitro-benzamide was prepared starting from 2-nitro-5-fluorobenzamide and 1-acetyl-4-hydroxypiperidine according to the procedure in Example 1, Step 2. It was obtained as a yellow oil in 33% yield.

[0539] [ka]

[0540] M / Z (M+H) += 308.1.

[0541] Step 2: 5-(1-Acetyl-piperidin-4-yloxy)-2-amino-benzamide was prepared according to the procedure in Example 2, Step 3 and isolated in 85% yield as a yellow solid, which was used in the next step without purification.

[0542] [ka]

[0543] M / Z (M+Na) + = 300.1.

[0544] Step 3: 6-(Piperidin-4-yloxy)-2-thieno[3,2-c]...

Claims

1. Formula (I) 【Chemistry 1】 [In the formula, R 1 is based on the following 【Chemistry 2】 and each one of the groups depicted above is selected from one or more R 11 group, optionally substituted; Or R 1 But, 【Chemistry 3】 which is one or more R 11A group, optionally substituted; Each R 11 But, C 1～5 Alkyl, -(C 0～3 alkylene)-OH, -(C 0～3 alkylene)-O(C 1～5 alkyl), -(C 0～3 alkylene)-SH, -(C 0～3 alkylene)-S(C 1～5 alkyl), -(C 0～3 (alkylene)-NH 2 , -(C 0～3 alkylene)-NH(C 1～5 alkyl), -(C 0～3 Alkylene)-N(C 1～5 Alkyl)(C 1～5 alkyl), -(C 0～3 Alkylene)-halogen, -(C 0～3 Alkylene)-(C 1～5 haloalkyl), -(C 0～3 alkylene)-O-(C 1～5 haloalkyl), -(C 0～3 alkylene)-CN, -(C 0～3 alkylene)-CHO, -(C 0～3 alkylene)-CO-(C 1～5 alkyl), -(C 0～3 alkylene)-COOH, -(C 0～3 alkylene)-CO-O-(C 1～5 alkyl), -(C 0～3 alkylene)-O-CO-(C 1～5 alkyl), -(C 0～3 (alkylene)-CO-NH 2 , -(C 0～3 alkylene)-CO-NH(C 1～5 alkyl), -(C 0～3 Alkylene)-CO-N(C 1～5 Alkyl)(C 1～5 alkyl), -(C 0～3 alkylene)-NH-CO-(C 1～5 alkyl), -(C 0～3 Alkylene)-N(C 1～5 Alkyl)-CO-(C 1～5 alkyl), -(C 0～3 (alkylene)-SO 2 -NH 2 , -(C 0～3 (alkylene)-SO 2 -NH(C 1～5 alkyl), -(C 0～3 (alkylene)-SO 2 -N(C 1～5 Alkyl)(C 1～5 alkyl), -(C 0～3 (alkylene)-NH-SO 2 -(C 1～5 Alkyl) and -(C 0～3 Alkylene)-N(C 1～5 Alkyl)-SO 2 -(C 1～5 alkyl), Each R 11A But, C 1～5 Alkyl, -(C 0～3 alkylene)-OH, -(C 0～3 alkylene)-O(C 1～5 alkyl), -(C 0～3 alkylene)-SH, -(C 0～3 alkylene)-S(C 1～5 alkyl), -(C 0～3 (alkylene)-NH 2 , -(C 0～3 alkylene)-NH(C 1～5 alkyl), -(C 0～3 Alkylene)-N(C 1～5 Alkyl)(C 1～5 alkyl), -(C 0～3 Alkylene)-halogen, -(C 0～3 Alkylene)-(C 1～5 haloalkyl), -(C 0～3 alkylene)-O-(C 1～5 haloalkyl), -(C 0～3 alkylene)-CN, -(C 0～3 alkylene)-CHO, -(C 0～3 alkylene)-CO-(C 1～5 alkyl), -(C 0～3 alkylene)-COOH, -(C 0～3 alkylene)-CO-O-(C 1～5 alkyl), -(C 0～3 alkylene)-O-CO-(C 1～5 alkyl), -(C 0～3 (alkylene)-CO-NH 2 , -(C 0～3 alkylene)-CO-NH(C 1～5 alkyl), -(C 0～3 Alkylene)-CO-N(C 1～5 Alkyl)(C 1～5 alkyl), -(C 0～3 alkylene)-NH-CO-(C 1～5 alkyl), -(C 0～3 Alkylene)-N(C 1～5 Alkyl)-CO-(C 1～5 alkyl), -(C 0～3 (alkylene)-SO 2 -NH 2 , -(C 0～3 (alkylene)-SO 2 -NH(C 1～5 alkyl), -(C 0～3 (alkylene)-SO 2 -N(C 1～5 Alkyl)(C 1～5 alkyl), -(C 0～3 (alkylene)-NH-SO 2 -(C 1～5 Alkyl) and -(C 0～3 Alkylene)-N(C 1～5 Alkyl)-SO 2 -(C 1～5 alkyl), X 1 is C(R X1 ) or N, X 2 is C(-LR X2 ) and X 3 is C(R X3 ) or N, X 4 is C(R X4 ) or N, R X1 But hydrogen, C 1～5 Alkyl, -OH, -O(C 1～5 Alkyl), halogen, C 1～5 Haloalkyl and -O-(C 1～5 haloalkyl); L is a covalent bond, C 1～10 Alkylene, C 2～10 Alkenylene and C 2～10 alkynylene, 1～10 Alkylene, 2～10 Alkenylene or the C 2～10 Alkynylene may contain one or more -CH 2 - The units are -O-, -CO-, -C(=O)O-, -OC(=O)-, -NH-, -N(C 1～5 Alkyl)-, -NH-CO-, -N(C 1～5 Alkyl)-CO-, -CO-NH-, -CO-N(C 1～5 Alkyl)-, -S-, -SO-, -SO 2 -, -SO 2 -NH-, -SO 2 -N(C 1～5 Alkyl)-, -NH-SO 2 -, -N(C 1～5 Alkyl)-SO 2 - and carbocyclylene, wherein the carbocyclylene is 1～4 Alkyl, -OH, -O(C 1～4 alkyl), -SH, -S(C 1～5 alkyl), -NH 2 , -NH(C 1～4 alkyl), -N(C 1～4 Alkyl)(C 1～4 Alkyl), halogen, C 1～5 Haloalkyl, -O-(C 1～5 haloalkyl) and -CN, and 1～10 Alkylene, 2～10 Alkenylene and the C 2～10 The alkynylene is halogen, C 1～5 Haloalkyl, -O-(C 1～5 haloalkyl), -CN, -OH, -O(C 1～5 alkyl), -SH, -S(C 1～5 alkyl), -NH 2 , -NH(C 1～5 Alkyl) and -N(C 1～5 Alkyl)(C 1～5 alkyl), R X2 But, C 2～10 Alkyl, carbocyclyl, heterocyclyl and -L 1 -R X21 C is selected from 2～10 The alkyl, the carbocyclyl and the heterocyclyl each may have one or more R X22 group, optionally substituted; L 1 is a covalent bond, C 1～10 Alkylene, C 2～10 Alkenylene and C 2～10 alkynylene, 1～10 Alkylene, 2～10 Alkenylene or the C 2～10 Alkynylene may contain one or more -CH 2 - The units are -O-, -CO-, -C(=O)O-, -OC(=O)-, -NH-, -N(C 1～5 Alkyl)-, -NH-CO-, -N(C 1～5 Alkyl)-CO-, -CO-NH-, -CO-N(C 1～5 Alkyl)-, -S-, -SO-, -SO 2 -, -SO 2 -NH-, -SO 2 -N(C 1～5 Alkyl)-, -NH-SO 2 - and -N(C 1～5 Alkyl)-SO 2 -, and further comprising a group independently selected from 1～10 Alkylene, 2～10 Alkenylene and the C 2～10 The alkynylene is halogen, C 1～5 Haloalkyl, -O-(C 1～5 haloalkyl), -CN, -OH, -O(C 1～5 alkyl), -SH, -S(C 1～5 alkyl), -NH 2 , -NH(C 1～5 Alkyl) and -N(C 1～5 Alkyl)(C 1～5 alkyl), R X21 But, C 2～5 alkyl, carbocyclyl and heterocyclyl, said carbocyclyl and said heterocyclyl each being selected from one or more R X22 group, optionally substituted; Each R X22 But, C 1～5 Alkyl, C 2～5 Alkenyl, C 2～5 Alkynyl, -(C 0～3 alkylene)-OH, -(C 0～3 alkylene)-O(C 1～5 alkyl), -(C 0～3 alkylene)-SH, -(C 0～3 alkylene)-S(C 1～5 alkyl), -(C 0～3 (alkylene)-NH 2 , -(C 0～3 alkylene)-NH(C 1～5 alkyl), -(C 0～3 Alkylene)-N(C 1～5 Alkyl)(C 1～5 alkyl), -(C 0～3 Alkylene)-halogen, -(C 0～3 Alkylene)-(C 1～5 haloalkyl), -(C 0～3 alkylene)-O-(C 1～5 haloalkyl), -(C 0～3 alkylene)-CN, -(C 0～3 alkylene)-CHO, -(C 0～3 alkylene)-CO-(C 1～5 alkyl), -(C 0～3 alkylene)-COOH, -(C 0～3 alkylene)-CO-O-(C 1～5 alkyl), -(C 0～3 alkylene)-O-CO-(C 1～5 alkyl), -(C 0～3 (alkylene)-CO-NH 2 , -(C 0～3 alkylene)-CO-NH(C 1～5 alkyl), -(C 0～3 Alkylene)-CO-N(C 1～5 Alkyl)(C 1～5 alkyl), -(C 0～3 alkylene)-NH-CO-(C 1～5 alkyl), -(C 0～3 Alkylene)-N(C 1～5 Alkyl)-CO-(C 1～5 alkyl), -(C 0～3 (alkylene)-SO 2 -NH 2 , -(C 0～3 (alkylene)-SO 2 -NH(C 1～5 alkyl), -(C 0～3 (alkylene)-SO 2 -N(C 1～5 Alkyl)(C 1～5 alkyl), -(C 0～3 (alkylene)-NH-SO 2 -(C 1～5 alkyl), -(C 0～3 Alkylene)-N(C 1～5 Alkyl)-SO 2 -(C 1～5 alkyl), -(C 0～3 alkylene)-SO-(C 1～5 alkyl), -(C 0～3 (alkylene)-SO 2 -(C 1～5 alkyl), -(C 0～3 alkylene)-aryl, -(C 0～3 alkylene)-heteroaryl, -(C 0～3 alkylene)-cycloalkyl and -(C 0～3 alkylene)-heterocycloalkyl, 0～3 The aryl portion of the -(C 0～3 the heteroaryl portion of the -(C 0～3 The cycloalkyl portion of the -(C 0～3 Each heterocycloalkyl moiety in the alkylene-heterocycloalkyl is one or more R X23 group, optionally substituted; Each R X23 But, C 1～5 Alkyl, C 2～5 Alkenyl, C 2～5 Alkynyl, -OH, -O(C 1～5 alkyl), -SH, -S(C 1～5 alkyl), -NH 2 , -NH(C 1～5 alkyl), -N(C 1～5 Alkyl)(C 1～5 Alkyl), halogen, C 1～5 Haloalkyl, -O-(C 1～5 haloalkyl), -CN, -CHO, -CO-(C 1～5 alkyl), -COOH, -CO-O-(C 1～5 alkyl), -O-CO-(C 1～5 alkyl), -CO-NH 2 , -CO-NH(C 1～5 alkyl), -CO-N(C 1～5 Alkyl)(C 1～5 alkyl), -NH-CO-(C 1～5 alkyl), -N(C 1～5 Alkyl)-CO-(C 1～5 Alkyl), -SO 2 -NH 2 , -SO 2 -NH(C 1～5 Alkyl), -SO 2 -N(C 1～5 Alkyl)(C 1～5 alkyl), -NH-SO 2 -(C 1～5 alkyl), -N(C 1～5 Alkyl)-SO 2 -(C 1～5 alkyl), -SO-(C 1～5 Alkyl), -SO 2 -(C 1～5 alkyl), cycloalkyl, and heterocycloalkyl; R X3 But hydrogen, C 1～5 Alkyl, -OH, -O(C 1～5 Alkyl), halogen, C 1～5 Haloalkyl and -O-(C 1～5 haloalkyl); R X4 But hydrogen, C 1～5 Alkyl, -OH, -O(C 1～5 Alkyl), halogen, C 1～5 Haloalkyl, -O-(C 1～5 haloalkyl) and cycloalkyl; -LR X2 The group is -OR X2 (In the formula, R X2 is aryl or heteroaryl, and the aryl and the heteroaryl each have one or more R X22 group, optionally substituted, each R 11A If exists, C 1～5 Alkyl, -(C 0～3 alkylene)-OH, -(C 0～3 alkylene)-O(C 1～5 alkyl), -(C 0～3 alkylene)-SH, -(C 0～3 alkylene)-S(C 1～5 alkyl), -(C 0～3 (alkylene)-NH 2 , -(C 0～3 alkylene)-NH(C 1～5 alkyl), -(C 0～3 Alkylene)-N(C 1～5 Alkyl)(C 1～5 alkyl), -(C 0～3 Alkylene)-halogen, -(C 0～3 Alkylene)-(C 1～5 haloalkyl), -(C 0～3 alkylene)-O-(C 1～5 haloalkyl), -(C 1～3 alkylene)-CN, -(C 0～3 alkylene)-CHO, -(C 0～3 alkylene)-CO-(C 1～5 alkyl), -(C 0～3 alkylene)-COOH, -(C 0～3 alkylene)-CO-O-(C 1～5 alkyl), -(C 0～3 alkylene)-O-CO-(C 1～5 alkyl), -(C 0～3 (alkylene)-CO-NH 2 , -(C 0～3 alkylene)-CO-NH(C 1～5 alkyl), -(C 0～3 Alkylene)-CO-N(C 1～5 Alkyl)(C 1～5 alkyl), -(C 0～3 alkylene)-NH-CO-(C 1～5 alkyl), -(C 0～3 Alkylene)-N(C 1～5 Alkyl)-CO-(C 1～5 alkyl), -(C 0～3 (alkylene)-SO 2 -NH 2 , -(C 0～3 (alkylene)-SO 2 -NH(C 1～5 alkyl), -(C 0～3 (alkylene)-SO 2 -N(C 1～5 Alkyl)(C 1～5 alkyl), -(C 0～3 (alkylene)-NH-SO 2 -(C 1～5 Alkyl) and -(C 0～3 Alkylene)-N(C 1～5 Alkyl)-SO 2 -(C 1～5 alkyl), However, the following 【Chemistry 4】 is excluded from formula (I), and 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof, with the further proviso that compounds of formula (I) are excluded.

2. R 1 But, 【Chemistry 6】 wherein each one of the groups depicted above is selected from one or more R 11 group, optionally substituted; Or R 1 But, 【Chemistry 7】 which is represented by one or more R 11A 2. The compound of claim 1, optionally substituted with a group.

3. Each R 11 and each R 11A But, C 1～5 Alkyl, -(C 0～3 alkylene)-OH, -(C 0～3 alkylene)-O(C 1～5 alkyl), -(C 0～3 alkylene)-SH, -(C 0～3 alkylene)-S(C 1～5 alkyl), -(C 0～3 (alkylene)-NH 2 , -(C 0～3 alkylene)-NH(C 1～5 alkyl), -(C 0～3 Alkylene)-N(C 1～5 Alkyl)(C 1～5 alkyl), -(C 0～3 Alkylene)-halogen, -(C 0～3 Alkylene)-(C 1～5 haloalkyl), -(C 0～3 alkylene)-O-(C 1～5 haloalkyl) and -(C 0～3 3. The compound according to claim 1 or 2, wherein each of the groups is independently selected from the group consisting of alkylene)-CN.

4. X 1 But, C(R X1 ) and X 2 But C(-LR X2 ) and X 3 But, C(R X3 ) and X 4 But, C(R X4 4. The compound according to claim 1, wherein

5. R X2 is selected from cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, each of which is selected from one or more R X22 5. The compound according to claim 1, optionally substituted with a group.

6. -LR X2 The group is -R X2 , -(C 1～5 Alkylene)-R X2 , -OR X2 and -O-(C 1～5 Alkylene)-R X2 Selected from R X2 is selected from cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, each of which is selected from one or more R X22 5. The compound according to claim 1, optionally substituted with a group.

7. R X2 is selected from azetidinyl, oxetanyl, pyrrolidinyl, oxopyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxopiperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, 2-oxa-7-aza-spiro[3.5]nonyl, 6-oxa-2-aza-spiro[3.4]octyl, 3-oxa-9-aza-spiro[5.5]undecyl, 7-oxa-2-aza-spiro[4.5]decyl, 8-oxa-2-aza-spiro[4.5]decyl, phenyl, oxazolyl, pyridinyl, pyrazinyl and pyrimidinyl, each one of the foregoing cyclic groups being selected from one or more R X22 7. The compound according to claim 1, optionally substituted with a group.

8. R X4 is hydrogen, methyl, -OCH 3 8. The compound according to claim 1 , wherein the aryl group is selected from halogen and cyclopropyl.

9. R X4 Methyl, -OCH 3 8. The compound according to claim 1 , wherein the aryl group is selected from halogen and cyclopropyl.

10. 6-(3-pyridin-4-yl-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 2-Isoquinolin-3-yl-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 2-Pyridin-2-yl-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one; 2-(4-Methoxy-pyridin-2-yl)-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one; 2-(5-fluoro-pyridin-2-yl)-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-(5-trifluoromethyl-pyridin-3-yl)-3H-quinazolin-4-one; 6-[3-(4-pyridyl)propoxy]-2-[5-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one; 2-(4-methyl-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-(6-methyl-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-(5-methylpyrazin-2-yl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-(4-chloro-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-(4-ethyl-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 6-[3-(4-pyridyl)propoxy]-2-[6-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one; 2-(4-Bromo-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-(4-cyclopropyl-2-pyridyl)-6-[3-(4-pyridyl)propoxy]-3H-quinazolin-4-one; 2-(2-Methyl-oxazol-4-yl)-6-(3-pyridin-4-yl-propoxy)-3H-quinazolin-4-one; 6-(2-pyridin-3-yl-ethoxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(4-Bromo-benzyloxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; Tert-Butyl 3-(4-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-quinazolin-6-yl)oxyazetidine-1-carboxylate; 6-(azetidin-3-yloxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 6-(1-pyrimidin-4-yl-azetidin-3-yloxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 3-(4-hydroxy-2-thieno[2,3-c]pyridin-5-yl-quinazolin-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester; 6-(azetidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(1-propionyl-azetidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(piperidin-4-yloxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(1-propionyl-piperidin-4-yloxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(2-morpholin-4-yl-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 6-(2-Methoxy-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 6-(2-morpholin-4-yl-ethoxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(2-Methoxy-ethoxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(3-pyridin-3-yl-propoxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 4-(4-oxo-2-pyridin-2-yl-3,4-dihydro-quinazolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester; 6-(piperidin-4-yloxy)-2-pyridin-2-yl-3H-quinazolin-4-one; 6-(1-acetyl-piperidin-4-yloxy)-2-pyridin-2-yl-3H-quinazolin-4-one; 4-[4-oxo-2-(4-trifluoromethyl-pyridin-2-yl)-3,4-dihydro-quinazolin-6-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester; 6-(piperidin-4-ylmethoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 6-(1-acetyl-piperidin-4-ylmethoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; tert-Butyl 4-[(4-oxo-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-6-yl)oxymethyl]piperidine-1-carboxylate; 6-(4-piperidylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(1-acetyl-piperidin-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(1-propionyl-piperidin-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 3-(4-oxo-2-thieno[2,3-c]pyridin-5-yl-3,4-dihydro-quinazolin-6-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester; 6-(pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(1-acetyl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 4-[4-oxo-2-(4-trifluoromethyl-pyridin-2-yl)-3,4-dihydro-quinazolin-6-yl]-piperazine-1-carboxylic acid tert-butyl ester; 6-Piperazin-1-yl-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 6-(4-propionyl-piperazin-1-yl)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 4-(4-oxo-2-thieno[2,3-c]pyridin-5-yl-3,4-dihydro-quinazolin-6-yl)-piperidine-1-carboxylic acid tert-butyl ester; 6-piperidin-4-yl-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(1-acetyl-piperidin-4-yl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-[2-(tetrahydro-pyran-4-yl)-ethoxy]-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 6-[3-(3-fluoro-pyridin-4-yl)-propoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-[3-(4-methanesulfonyl-phenyl)-propoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(3-pyrazin-2-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-[3-(3-methoxy-pyridin-4-yl)-propoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-[3-(2-methyl-pyridin-4-yl)-propoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(3-oxazol-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-pyrido[3,2-d]pyrimidin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-pyrido[3,2-d]pyrimidin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-pyrido[2,3-d]pyrimidin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-pyrido[3,4-d]pyrimidin-4-one; 6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-7-trifluoromethyl-3H-quinazolin-4-one; 5-Chloro-6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Chloro-6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Cyclopropyl-6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Ethyl-6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Fluoro-6-(3-pyridin-4-yl-propoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(tetrahydro-pyran-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(2-oxetan-3-yl-ethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-[2-(tetrahydro-furan-3-yl)-ethoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-[2-(tetrahydro-pyran-4-yl)-ethoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(tetrahydro-furan-3-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; R-8-Methyl-6-(tetrahydro-furan-3-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; S-8-Methyl-6-(tetrahydro-furan-3-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(1-methyl-6-oxo-piperidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; R-8-methyl-6-((1-methyl-6-oxopiperidin-3-yl)oxy)-2-(thieno[2,3-c]pyridin-5-yl)quinazolin-4(3H)-one; S-8-Methyl-6-((1-methyl-6-oxopiperidin-3-yl)oxy)-2-(thieno[2,3-c]pyridin-5-yl)quinazolin-4(3H)-one; 8-Methyl-6-(1-propionyl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; R-8-Methyl-6-(1-propionyl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; S-8-Methyl-6-(1-propionyl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(1-oxetan-3-yl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; R-8-methyl-6-(1-oxetan-3-yl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; S-8-Methyl-6-(1-oxetan-3-yl-pyrrolidin-3-yloxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-[2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-ethoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(piperidin-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(1-oxetan-3-yl-piperidin-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(1-propionyl-piperidin-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(1-methanesulfonyl-piperidin-4-ylmethoxy)-8-methyl-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(2-oxa-7-aza-spiro[3.5]non-7-yl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(6-oxa-2-aza-spiro[3.4]oct-2-yl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(3-oxa-9-aza-spiro[5.5]undec-9-yl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(7-oxa-2-aza-spiro[4.5]dec-2-yl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(8-oxa-2-aza-spiro[4.5]dec-2-yl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-(2-hydroxy-2-methyl-propylamino)-8-methyl-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(2-piperidin-3-yl-ethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-[2-(1-acetyl-piperidin-3-yl)-ethoxy]-8-methyl-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 6-[2-(4-acetyl-piperazin-1-yl)-ethoxy]-8-methyl-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 3-(8-methyl-4-oxo-2-thieno[2,3-c]pyridin-5-yl-3,4-dihydro-quinazolin-6-yl)-propionaldehyde; 8-Methyl-6-(3-morpholin-4-yl-propyl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(2-morpholin-4-yl-ethyl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(3-pyridin-4-yl-propoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 8-Methyl-6-(tetrahydro-furan-3-ylmethoxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 8-Methyl-6-(1-propionyl-azetidin-3-yloxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 8-Methyl-6-(1-oxetan-3-yl-piperidin-4-yloxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 8-Methyl-6-(3-oxa-9-aza-spiro[5.5]undec-9-yl)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 8-Methyl-6-(3-pyridin-4-yl-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-Methyl-2-pyrrolo[1,2-c]pyrimidin-3-yl-6-(tetrahydro-furan-3-ylmethoxy)-3H-quinazolin-4-one; 8-Methyl-6-(3-oxa-9-aza-spiro[5.5]undec-9-yl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-Methyl-6-(1-oxetan-3-yl-piperidin-4-yloxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-Methyl-6-[1-(tetrahydro-pyran-4-yl)-ethoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; R-8-Methyl-6-[1-(tetrahydro-pyran-4-yl)-ethoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; S-8-Methyl-6-[1-(tetrahydro-pyran-4-yl)-ethoxy]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-[1-(tetrahydro-pyran-4-yl)-ethoxy]-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; R-8-Methyl-6-[1-(tetrahydro-pyran-4-yl)-ethoxy]-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; S-8-Methyl-6-[1-(tetrahydro-pyran-4-yl)-ethoxy]-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 6-[(3-fluorotetrahydrofuran-3-yl)methoxy]-8-methyl-2-[4-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one; 8-Methyl-6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2-thieno[2,3-c]pyridin-5-yl-3-(2-trimethylsilylethoxymethyl)pyrido[3,2-d]pyrimidin-4-one; 8-Methyl-6-(morpholinomethyl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(morpholinomethyl)-2-[4-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one; 8-Methyl-6-(1-propanoylazetidin-3-yl)oxy-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(2-morpholinoethyl)-2-[4-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one; 8-Methyl-6-[(1-methyl-6-oxo-3-piperidyl)oxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-Methyl-6-(morpholinomethyl)-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 8-Methyl-6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 8-Methyl-6-(2-[1,4]oxazepan-4-yl-ethyl)-2-thieno[2,3-b]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(2-[1,4]oxazepan-4-yl-ethyl)-2-thieno[3,2-b]pyridin-6-yl-3H-quinazolin-4-one; 8-Methyl-6-(2-morpholin-4-yl-ethyl)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-Methyl-6-(2-morpholin-4-yl-ethyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-Methyl-6-(morpholinomethyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-Methyl-6-(2-morpholino-2-oxoethyl)-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 8-Methyl-6-(2-morpholino-2-oxo-ethyl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(2-piperidin-1-yl-ethyl)-2-thieno[2,3-b]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(1-methyl-6-oxo-piperidin-3-yloxy)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-Methyl-6-(1-methyl-2-oxo-piperidin-4-ylmethoxy)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one 8-Methyl-6-(1-piperidylmethyl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(2-morpholino-2-oxo-ethyl)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-Methyl-6-[(4-methylpiperazin-1-yl)methyl]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(pyrrolidin-1-ylmethyl)-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(2-morpholino-2-oxo-ethyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-Methyl-6-(morpholine-4-carbonyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-3H-quinazolin-4-one; 8-Methyl-6-(1-methyl-6-oxo-piperidin-3-yloxy)-2-(4-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one; 8-Methyl-2-thieno[2,3-c]pyridin-5-yl-6-(thiomorpholinomethyl)-3H-quinazolin-4-one; 8-Methyl-6-[2-(1,4-oxazepan-4-yl)-2-oxo-ethyl]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-(pyrrolidin-1-ylmethyl)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-Methyl-6-(1-methyl-5-oxo-pyrrolidin-3-yl)oxy-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-Methyl-6-[(3R)-1-methyl-5-oxo-pyrrolidin-3-yl]oxy-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-Methyl-6-[(3S)-1-methyl-5-oxo-pyrrolidin-3-yl]oxy-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; Benzyl 3-[(8-methyl-4-oxo-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-6-yl)oxy]pyrrolidine-1-carboxylate; Benzyl (3S)-3-[(8-methyl-4-oxo-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-6-yl)oxy]pyrrolidine-1-carboxylate; Benzyl (3R)-3-[(8-methyl-4-oxo-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-6-yl)oxy]pyrrolidine-1-carboxylate; 8-Methyl-6-[2-(4-methyl-3-oxo-piperazin-1-yl)ethyl]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-[2-(4-methyl-3-oxo-piperazin-1-yl)ethyl]-2-[4-(trifluoromethyl)-2-pyridyl]-3H-quinazolin-4-one; 8-Methyl-6-[2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl]-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one; 8-Methyl-6-[2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl]-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-Methyl-6-[(4-methyl-3-oxo-piperazin-1-yl)methyl]-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(2-((2-methoxyethyl)(methyl)amino)ethyl)-8-methyl-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 6-(2-(1,1-dioxidothiomorpholino)ethyl)-8-methyl-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 6-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-8-methyl-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-(((2-methoxyethyl)(methyl)amino)methyl)-8-methyl-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 6-[(4-Methoxy-1-piperidyl)methyl]-8-methyl-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 6-[(2,2-dimethylmorpholin-4-yl)methyl]-8-methyl-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; 8-Chloro-6-(2-morpholinoethyl)-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 8-Methyl-6-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-2-thieno[3,2-c]pyridin-6-yl-3H-quinazolin-4-one; N,N-Dimethyl-1-((8-methyl-4-oxo-2-(thieno[3,2-c]pyridin-6-yl)-3,4-dihydroquinazolin-6-yl)methyl)piperidine-4-carboxamide; 6-((4-(methoxymethyl)piperidin-1-yl)methyl)-8-methyl-2-(thieno[3,2-c]pyridin-6-yl)quinazolin-4(3H)-one; 8-Methoxy-6-(2-morpholinoethyl)-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 8-Bromo-6-(2-morpholinoethyl)-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 6-(2-(2,2-dimethylmorpholino)ethyl)-8-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 8-Methyl-6-((4-methyl-3-oxopiperazin-1-yl)methyl)-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 6-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)ethyl)-8-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 6-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)ethyl)-8-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 6-(2-(4-hydroxypiperidin-1-yl)ethyl)-8-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 6-(2-(4,4-difluoropiperidin-1-yl)ethyl)-8-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 6-(2-(4-methoxypiperidin-1-yl)ethyl)-8-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one; 8-Methyl-6-(2-morpholinoethyl)-2-(4-(trifluoromethyl)pyridin-2-yl)pyrido[3,2-d]pyrimidin-4(3H)-one; and a pharma- ceutically acceptable salt of any one of the preceding compounds.

11. 11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and a pharma- ceutically acceptable excipient.

12. 12. A pharmaceutical composition as described in claim 11 for use in the treatment or prevention of a condition associated with altered glutamatergic signaling and / or a function or condition that may be affected by alterations in glutamate levels or signaling.

13. Use of a compound according to any one of claims 1 to 10 in the preparation of a medicament for treating or preventing a condition associated with altered glutamatergic signalling and / or a function or condition that may be affected by alterations in glutamate levels or signalling.

14. The condition to be treated or prevented is dementia and related disorders, including Alzheimer's dementia, Alzheimer's disease, Pick's disease, vascular dementia, Lewy body disease, metabolic dementia, toxic diseases and deficiencies, AIDS-dementia complex, Creutzfeldt-Jakob disease and atypical subacute spongiform encephalopathy; Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, hepatolenticular degeneration, chorea, Huntington's disease, hemiballismus, athetosis, dystonia, spasmodic torticollis, occupational movement disorder, Gilles de la Tourette's syndrome, tardive or drug-induced dysplasia.

13. The pharmaceutical composition for use as defined in claim 12, wherein the therapeutic target is selected from any one of: parkinsonism and movement disorders including dyskinesia, levodopa-induced dyskinesia, tremor and myoclonus; social disorders including autism or autism spectrum disorder, or fragile X syndrome; acute and chronic pain; anxiety disorders including panic disorder, phobias, obsessive-compulsive disorder, stress disorder and generalized anxiety disorder; schizophrenia and other psychiatric disorders; mood disorders including depressive disorder and bipolar disorder; endocrine and metabolic disorders including diabetes, endocrine disorders and hypoglycemia; and cancer.

15. The condition to be treated or prevented is dementia and related disorders including Alzheimer's disease, Alzheimer's disease, Pick's disease, vascular dementia, Lewy body disease, metabolic dementia, toxic and deficiency diseases, AIDS-dementia complex, Creutzfeldt-Jakob disease and atypical subacute spongiform encephalopathy; Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, hepatolenticular degeneration, chorea, Huntington's disease, hemiballismus, athetosis, dystonia, spasmodic torticollis, occupational movement disorder, Gilles de la Tourette's syndrome, late-onset or drug-induced 14. The use according to claim 13, wherein the treatment is selected from any one of: parkinsonism and movement disorders including paroxysmal dyskinesia, levodopa-induced dyskinesia, tremor and myoclonus; social disorders including autism or autism spectrum disorder, or fragile X syndrome; acute and chronic pain; anxiety disorders including panic disorder, phobias, obsessive-compulsive disorder, stress disorder and generalized anxiety disorder; schizophrenia and other psychiatric disorders; mood disorders including depressive disorder and bipolar disorder; endocrine and metabolic disorders including diabetes, endocrine disorders and hypoglycemia; and cancer.

16. 12. A pharmaceutical composition according to claim 11 for use in the treatment or prevention of Parkinson's disease.

17. 13. Use of a compound according to any one of claims 1 to 10 in the preparation of a medicament for treating or preventing Parkinson's disease.

18. 1. A method for identifying a test agent that binds to metabotropic glutamate receptor 4 (mGluR4), comprising: (a) contacting mGluR4 with a radioactively or fluorescently labeled compound according to any one of claims 1 to 10 under conditions that allow binding of the compound to mGluR4, thereby producing a bound labeled compound; (b) detecting a signal corresponding to the amount of bound labeled compound in the absence of the test agent; (c) contacting the bound labeled compound with a test agent; (d) detecting a signal corresponding to the amount of bound labeled compound in the presence of the test agent; and (e) comparing the signal detected in step (d) with the signal detected in step (b) to determine whether the test agent binds to mGluR4. The method includes:

19. 13. Use of a compound according to any one of claims 1 to 10 as a positive allosteric modulator of mGluR4 in vitro.

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