Heterocyclic compounds

Abstract

Compounds having activity against mGluRs, preferably the mGluR7, are provided.SOLUTION: A compound of formula (I): SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to novel heterocyclic compounds. The present invention is also directed to compounds that are modulators of metabotropic glutamate receptors (mGluRs), preferably modulators of metabotropic glutamate receptor subtype 7 ("mGluR7"). The present invention is also directed to pharmaceutical compositions containing such compounds, methods for preparing such compounds and compositions, and the use of such compounds and compositions for the prevention or treatment of disorders associated with glutamate dysfunction or disorders involving metabotropic glutamate receptors, preferably disorders involving the mGluR7 subtype of metabotropic glutamate receptor. [Background technology]

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

[0003] Glutamate regulates synaptic neurotransmission through activation of mGluRs. Class C G-protein coupled receptors (GPCRs), to which mGluRs belong, play a regulatory role, contributing to the fine-tuning of synaptic efficacy (Schoepp et al. Neuropharmacology (1999), 38:1431). In particular, mGlu receptor subtype 7 (mGluR7) is widely distributed in the brain and exhibits the highest degree of evolutionary conservation among all mGlu receptor species (Flor et al. Neuropharmacol. (1997), 36:153). More importantly, mGluR7 has the lowest affinity for glutamate and is inactive under normal neurotransmission conditions, becoming active only under severe pathophysiological conditions or excessive glutamate release (Ferraguti and Shigemoto, Cell Tissue Res. (2006), 326:483). MGluR7 is thought to act as a tonic break, inhibiting further release of glutamate by affecting the release of other neurotransmitters (e.g., GABA), preventing glutamate excitotoxicity, which is involved in many pathologies of CNS and sensory disorders.

[0004] Specifically, modulators of mGluR7, preferably antagonists, inverse agonists, and negative allosteric modulators (NAMs), have been reported to be potential therapeutic approaches for neurological, psychiatric, and mood disorders, as well as pain and hearing impairment, which are thought to be associated with clinical syndromes based on experimental studies using laboratory animals.

[0005] Isoxazolopyridinone derivatives, such as MMPIP (6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one hydrochloride), have been reported to be mGluR7 NAMs (Nakamura et al., Bioorg. Med. Chem. Lett. (2010), 20:726; Suzuki et al., J. Pharmacol. Exp. Ther. (2007), 323:147), and have shown partial to complete antagonism of mGluR7 in vivo and in vitro, demonstrating context-dependent pharmacology (Niswender et al., Mol. Pharmacol. (2010), 77:459; Hikichi et al., Eur. J. Pharmacol. (2010), 10, 106). MMPIP also exerts inverse agonist activity due to the constitutive activity of mGluR7 (Cieslik et al., Front. Mol. Neurosci., 20 September 2018, doi:10.3389 / fnmol.2018.00316).

[0006] Tetrahydrobenzoxazole derivatives, such as (+)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenzo[d]oxazol-4(5H)-one (ADX71743) and its racemic form, are mGluR7 NAMs or inverse agonists and have been reported to exhibit anxiolytic and antipsychotic activities (Kalinichev et al., J. Pharmacol. Exp. Ther. (2013), 344:624; Cieslik et al., Front. Mol. Neurosci., 20 September 2018, doi:10.3389 / fnmol.2018.00316).

[0007] Chromenone derivatives, such as 7-hydroxy-3-(4-indophenoxy)-4H-chromen-4-one (XAP044), are reported to be weak mGluR7 allosteric antagonists that bind to the extracellular domain of the receptor. XAP044 has been shown to have anxiolytic, antidepressant, antistress, and antipsychotic activities (Gee et al., J. Biol. Chem. (2014), 289:10975).

[0008] Combinatorial expression of mGluR7 in brain regions using genetically engineered and wild-type mice, as well as pharmacological manipulation of mGluR7, are revealing its important role in many CNS disorders, including depression, schizophrenia, anxiety, obsessive-compulsive disorder, and related conditions (reviewed by Pallazo et al., Curr. Neuropharmacol. (2016), 14(5): 504), and especially acute and chronic stress-related disorders (reviewed by Peterlik et al., Curr. Neuropharmacol. (2016), 14(5): 514). Furthermore, mGluR7 has also provided a novel therapeutic tool for the treatment of psychostimulant drug (i.e., nicotine and cocaine) dependence (Li and Markou, CNS Neurol. Disord. Drug Targets (2015), 14(6):738; Li et al., Neuropharmacology (2013), 66:12). Furthermore, the mGluR7 NAM MMPIP and the allosteric antagonist XAP44 have been shown to suppress pain responses, alleviate anxiety- and depression-like behaviors, and improve cognitive performance in mouse models of neuropathic pain (Pallazzo et al., Pain (2015), 156(6):1060).

[0009] Furthermore, mGluR7 has been reported to be expressed in peripheral tissues such as the colonic mucosa and stomach (Julio-Pepper et al., Pharmacol. Rev. (2011), 63:35), suggesting that it may also be effective in treating pathologies such as visceral pain and stress-related gastrointestinal dysfunction, such as diarrhea or constipation in irritable bowel syndrome (IBS) and other related disorders.

[0010] Furthermore, mGluR7 has been reported to be expressed in hair cells and spiral ganglion neurons of the inner ear (Friedman et al. (2008) WO2008 / 131439), as well as within the vestibular system (Zhou et al., Int J Mol. Sci. (2013) 14(11):22857; Horii et al., Exp. Brain Res. (2001) 139(2):188), suggesting that it may be effective in treating conditions related to the inner ear and auditory nervous system, such as age-related hearing loss (presbycusis), noise-induced hearing loss, acute and chronic hearing loss, tinnitus, Meniere's disease, and vestibular disorders.

[0011] mGluR7 has been shown to be expressed at the synaptic terminals of certain cone bipolar cells in the retina (Brandstatter et al., (1996) J. Neurosci., 16(15):4749-4756), suggesting that mGluR7 modulators may also be effective in the acute and chronic treatment of glaucoma and other visual disorders.

[0012] Finally, multiple genome-wide human studies have also demonstrated an association between GRM7, the gene encoding mGluR7, and severe disease. For example, age-related hearing loss (ARHL) / presbycusis has been reported by Friedman et al. (Hum. Mol. Genet. (2009), 18:785), Van Laer et al. (Eur. J. Hum. Genet. (2010), 18:685), Newman et al. (Hear. Res. (2012), 294:125), Luo et al. (Plos One (2013), 8(10):e77153), and more recently by Haider et al. (Front. Aging Neurosci. (2017), 9:346) and Matyas et al. (Pathol. Oncol. Res. (2018), doi: 10.1007 / s12253-018-0388-6). Noise-induced hearing loss has been reported by Lu et al. (BMC Med. Genet. (2018), 19(1):4). Tinnitus has been reported by Haider et al. (Front. Aging Neurosci. (2017), 9:346). Schizophrenia has been reported by Niu et al. (Neurosci. Lett. (2015), 604:109). Attention-Deficit Hyperactivity Disorder (ADHD) has been reported by Elia et al. (Nat. Genet. (2011), 44:78). Major depressive disorder has been reported by Li et al. (Eur. Neuropsychopharmacol. (2015), doi: 10.1016 / j.euroneuro.2015.05.004).Bipolar disorder has been reported by Kandaswamy et al. (Am. J. Med. Genet. B. Neuropsychiatr. Genet. (2015), 165B(4):365). Alcohol-related dependence has been reported by Vadasz et al. (Genomics (2007), 90(6):690). Autism spectrum disorders, e.g., autism, have been reported by Liu et al. (Am. J. Med. Genet. B. Neuropsychiatr. Genet. (2015), 168B(4):258).

[0013] Taken together, these pharmacological and genetic data strongly support the potential efficacy of mGluR7 modulators for the treatment of a wide range of diseases and related conditions, spanning psychiatric, neurological, and neurodevelopmental disorders, otalgia, pain, visual disorders, and gastrointestinal disorders. Summary of the Invention [Problem to be solved by the invention]

[0014] One object of the present invention is to provide compounds that have activity against mGluRs, preferably mGluR7.

[0015] Another object of the present invention is to provide pharmaceutical compositions containing such compounds.

[0016] Another object of the present invention is to provide such compounds and / or pharmaceutical compositions for treating mGluR-related disorders, preferably mGluR7-related disorders. [Means for solving the problem]

[0017] The present invention relates to a compound of formula (I): [ka] (where, G is N or CR 7is selected from E is N or CR 8 is selected from However, at least one of G and E is N. Y is CR 9 and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 may be the same or different, and each independently represents hydrogen, halogen, —CN, —CF3, —C(═O)R 10 , -C(=O)OR 10 , -C(=O)NR 10 R 11 , -OR 10 , -OC(=O)R 10 , -OC(=O)NR 10 R 11 , -SR 10 , -S(O)R 10 , -S(O)2R 10 , -S(O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(=O)R 11 , -NR 10 C(=O)OR 11 , -NR 10 S(O)2R 11 and an optionally substituted radical selected from -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, or -(C1-C6)cyanoalkyl, Any two radicals R 1 and R 2 , R 3 and R 4 , and R 5 and R 6 may together form an oxo (=O), where R 10 and R11 may be the same or different and are each independently selected from hydrogen and an optionally substituted radical selected from -(C-C)alkyl, -(C-C)haloalkyl, -(C-C)cyanoalkyl, -(C-C)cycloalkyl or -(C-C)alkylene-(C-C)cycloalkyl; where optionally R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 10 and R 11 any two radicals selected from may together form an optionally substituted 3- to 10-membered non-aromatic carbocyclic or heterocyclic ring or an optionally substituted 5- to 10-membered aromatic heterocyclic ring; n is an integer selected from 0 or 1; Ar 1 is an optionally substituted aryl or heteroaryl; Ar 2 is an optionally substituted aryl or heteroaryl; and the N-oxide forms thereof, pharmaceutically acceptable salts and solvates thereof, or optical isomers, racemates, diastereoisomers, enantiomers or tautomers thereof.

[0018] Surprisingly, compounds of general formula (I) exhibit metabotropic glutamate receptor activity.

[0019] Preferably, in the compound of formula (I), Ar 1 teeth, [ka] where m is the number of A substituents on the ring and is an integer equal to 0, 1, 2, 3, 4, or 5. represents an aryl or heteroaryl selected from:

[0020] Preferably, in the compound of formula (I), Ar 2 teeth, [ka] where p is the number of B substituents on the ring and is an integer equal to 0, 1, 2, 3, 4, or 5. It is to be understood that when Ar2 is a bicyclic ring, B may be present in either ring.

[0021] A and B, as described above, may be the same or different and each independently represent hydrogen, halogen, -CN, -NO2, -OH, -NH2, -CF3, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C3-C8)cycloalkenyl, -(C1-C6)cyanoalkyl, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-aryl, -(C1-C6)alkylene-heterocycle, aryl, heteroaryl, heterocycle, -OR 13 , -(C1-C6) alkylene-OR 13 , -O-(C2-C6) alkylene-OR 13 、 -NR 13 (C2-C6) alkylene-OR 14 , -(C2-C6)alkenylene-OR 13 , -(C2-C6)alkynylene-OR 13 , -NR 13 R 14 , -(C1-C6) alkylene-NR 13 R 14 , -O-(C2-C6) alkylene-NR 13 R 14 , -NR 13 -(C2-C6) alkylene-NR 14 R 15 , -(C2-C6)alkenylene-NR 13 R 14 , -(C2-C6)alkynylene-NR 13 R 14 , -SR13 , -(C1-C6) alkylene-SR 13 , -O-(C2-C6) alkylene-SR 13 , -NR 13 -(C2-C6) alkylene-SR 14 , -S(=O)-R 13 , -(C1-C6) alkylene-S(=O)-R 13 , -O-(C1-C6) alkylene-S(=O)-R 13 , -NR 13 -(C1-C6)alkylene-S(=O)-R 14 , -S(=O)2-R 13 , -(C1-C6) alkylene-S(=O)2-R 13 , -O-(C1-C6) alkylene-S(=O)2-R 13 , -NR 13 -(C1-C6)alkylene-S(=O)2-R 14 , -S(=O)2NR 13 R 14 , -(C1-C6) alkylene-S(=O)2NR 13 R 14 , -O-(C1-C6) alkylene-S(=O)2NR 13 R 14 , -NR 13 -(C1-C6)alkylene-S(=O)2NR 14 R 15 , -NR 13 -S(=O)2R 14 , -(C1-C6) alkylene-NR 13 -S(=O)2R 14 , -O-(C2-C6) alkylene-NR 13 -S(=O)2R 14 , -NR 13 -(C2-C6) alkylene-NR 14 -S(=O)2R 15 , -C(=O)-NR 13 R 14 , -(C1-C6) alkylene-C(=O)-NR 13 R 14 , -O-(C1-C6) alkylene-C(=O)-NR 13 R 14 , -NR 13-(C1-C6)alkylene-C(=O)-NR 14 R 15 , -NR 13 C(=O)-R 14 , -(C1-C6) alkylene-NR 13 C(=O)-R 14 , -O-(C2-C6) alkylene-NR 13 C(=O)-R 14 , -NR 13 -(C2-C6) alkylene-NR 14 C(=O)-R 15 , -C(=O)-R 13 , -(C1-C6) alkylene-C(=O)-R 13 , -O-(C1-C6) alkylene-C(=O)-R 13 , -NR 13 -(C1-C6)alkylene-C(=O)-R 14 , -C(=O)-OR 13 , -(C1-C6) alkylene-C(=O)-OR 13 , -O-(C1-C6) alkylene-C(=O)-OR 13 , -NR 13 -(C1-C6)alkylene-C(=O)-OR 14 , -OC(=O)-R 13 , -(C1-C6) alkylene-OC(=O)-R 13 , -O-(C2-C6) alkylene-OC(=O)-R 13 , -NR 13 -(C2-C6) alkylene-OC(=O)-R 14 , -NR 13 -C(=O)-NR 14 R 15 , -(C1-C6) alkylene-NR 13 -C(=O)-NR 14 R 15 , -O-(C2-C6) alkylene-NR 13 -C(=O)-NR 14 R 15 , -NR 13 -(C2-C6) alkylene-NR 14 -C(=O)-NR 15 R 16 , -NR 13 -C(=O)-OR14 , -(C1-C6) alkylene-NR 13 -C(=O)-OR 14 , -O-(C2-C6) alkylene-NR 13 -C(=O)-OR 14 , -NR 13 -(C2-C6) alkylene-NR 14 -C(=O)-OR 15 , -OC(=O)-NR 13 R 14 , -(C1-C6) alkylene-OC(=O)-NR 13 R 14 , -O-(C2-C6) alkylene-OC(=O)-NR 13 R 14 , -NR 13 -(C2-C6) alkylene-OC(=O)-NR 14 R 15 , -C(=O)-(C1-C6)alkylene-NR 13 R 14 , -(C1-C6)alkylene-C(=O)-(C1-C6)alkylene-NR 13 R 14 , -C(=O)-(C1-C6)alkylene-OR 13 , -(C1-C6)alkylene-C(=O)-(C1-C6)alkylene-OR 13 , -NR 13 -C(=S)-NR 14 R 15 , -(C1-C6) alkylene-NR 13 -C(=S)-NR 14 R 15 , -NR 13 -C(=NR 14 )-NR 15 R 16又は -(C1-C6) alkylene-NR 13 -C(=NR 14 )-NR 15 R 16 an optionally substituted radical selected from the group:

[0022] where R 13 , R 14 , R 15 and R16 are each independently selected from hydrogen, optionally substituted —(C-C)haloalkyl, —(C-C)alkyl, —(C-C)cyanoalkyl, —(C-C)cycloalkyl, —(C-C)alkylene-(C-C)cycloalkyl, heteroaryl, aryl, heterocycle, —(C-C)alkylene-heteroaryl, —(C-C)alkylene-heterocycle, and —(C-C)alkylene-aryl.

[0023] where, optionally, R 13 , R 14 , R 15 or R 16 Any two radicals selected from may together form a 3-10 membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally selected from halogen, cyano, nitro, hydroxyl, amino, -(C1-C6) alkyl, 、 It may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0024] wherein any two radicals A and any two radicals B, together with the intervening atoms, may form a 3- to 10-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring, wherein each ring is optionally selected from the group consisting of halogen, -CN, hydroxyl, amino, -(C1-C6) alkyl, -C1-C6-alkyl ... 、 It may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0025] Preferably, in the compound of formula (I), the substituents A may be the same or different and each independently represent hydrogen, halogen, -CN, -CF, -OH, -NH, -(C-C)alkyl, -(C-C)haloalkyl, -(C-C)cycloalkyl, -(C-C)alkylene-(C-C)cycloalkyl, -(C-C)alkylene-heterocycle, heterocycle, aryl, heteroaryl, -OR 13, -(C1-C6) alkylene-OR 13 , -O-(C2-C6) alkylene-OR 13 、 -NR 13 (C2-C6) alkylene-OR 14 , -NR 13 R 14 , -(C1-C6) alkylene-NR 13 R 14 , -O-(C2-C6) alkylene-NR 13 R 14 , -NR 13 -(C2-C6) alkylene-NR 14 R 15 , -SR 13 , -(C1-C6) alkylene-SR 13 , -O-(C2-C6) alkylene-SR 13 , -NR 13 -(C2-C6) alkylene-SR 14 , -S(=O)-R 13 , -S(=O)2-R 13 , -S(=O)2NR 13 R 14 , -(C1-C6) alkylene-S(=O)2NR 13 R 14 , -NR 13 -S(=O)2R 14 , -(C1-C6) alkylene-NR 13 -S(=O)2R 14 , -O-(C2-C6) alkylene-NR 13 -S(=O)2R 14 , -NR 13 -(C2-C6) alkylene-NR 14 -S(=O)2R 15 , -C(=O)-NR 13 R 14 , -(C1-C6) alkylene-C(=O)-NR 13 R 14 , -O-(C1-C6) alkylene-C(=O)-NR 13 R 14 , -NR 13 -(C1-C6)alkylene-C(=O)-NR 14 R 15 , -NR 13 C(=O)-R14 , -(C1-C6) alkylene-NR 13 C(=O)-R 14 , -O-(C2-C6) alkylene-NR 13 C(=O)-R 14 , -NR 13 -(C2-C6) alkylene-NR 14 C(=O)-R 15 , -C(=O)-R 13 , -C(=O)-OR 13 , -(C1-C6) alkylene-C(=O)-OR 13 , -O-(C1-C6) alkylene-C(=O)-OR 13 , -NR 13 -(C1-C6)alkylene-C(=O)-OR 14 , -OC(=O)-R 13 , -(C1-C6) alkylene-OC(=O)-R 13 , -O-(C2-C6) alkylene-OC(=O)-R 13 , -NR 13 -(C2-C6) alkylene-OC(=O)-R 14 or -NR 13 -C(=O)-OR 14 an optionally substituted radical selected from the group:

[0026] where R 13 , R 14 and R 15 are each independently selected from hydrogen, optionally substituted —(C-C)alkyl, —(C-C)cycloalkyl, —(C-C)alkylene-(C-C)cycloalkyl, heteroaryl, aryl, heterocycle, —(C-C)alkylene-heteroaryl, —(C-C)alkylene-heterocycle, and —(C-C)alkylene-aryl.

[0027] wherein optionally R on the substituent A 13 , R 14 or R 15Any two radicals selected from may together form a 3-10 membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally selected from halogen, -CN, -NO2, -OH, -NH2, -(C1-C6)alkyl. 、 It may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0028] wherein any two radicals A together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring, wherein each ring is optionally selected from the group consisting of halogen, -CN, -OH, -NH, -(C1-C6) alkyl, -C1-C6 ... 、 It may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0029] Preferably, in the compound of formula (I), the substituents A may be the same or different and each independently represent hydrogen, halogen, -CN, -CF, -OH, -(C-C)alkyl, -(C-C)haloalkyl, -(C-C)cycloalkyl, -(C-C)alkylene-(C-C)cycloalkyl, -(C-C)alkylene-heterocycle, heterocycle, -OR 13 , -(C1-C6) alkylene-OR 13 , -O-(C2-C6) alkylene-OR 13 、 -NR 13 (C2-C6) alkylene-OR 14 , -O(C2-C6) alkylene-NR 13 R 14 , -NR 13 -(C2-C6) alkylene-NR 14 R 15 , -NR 13 R 14 , -(C1-C6) alkylene-NR 13 R 14 , -NR 13 C(=O)-R 14 , -C(=O)-NR 13 R14 , S(=O)2NR 13 R 14 or -NR 13 -S(=O)2R 14 an optionally substituted radical selected from the group:

[0030] where R 13 and R 14 are each independently selected from hydrogen, optionally substituted —(C1-C3)alkyl, —(C3-C7)cycloalkyl, —(C1-C6)alkylene-(C3-C7)cycloalkyl, heterocycle, and —(C1-C6)alkylene-heterocycle.

[0031] wherein optionally a radical R on the substituent A 13 and R 14 may together form a 3- to 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring, wherein each ring is optionally selected from the group consisting of halogen, —CN, —OH, —NH, —(C1-C6)alkyl, 、 It may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0032] wherein any two radicals A together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, each of which may optionally be selected from the group consisting of halogen, -CN, -(C1-C6)alkyl, -C1-C6- ... 、 It may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0033] Preferably, in the compound of formula (I), the substituents A may be the same or different and each independently represent hydrogen, halogen, -CN, -CF, -OH, -(C-C)alkyl, -(C-C)haloalkyl, -(C-C)cycloalkyl, -(C-C)alkylene-(C-C)cycloalkyl, -(C-C)alkylene-heterocycle, heterocycle, -O-(C-C)alkyl, O-(C-C)alkyl-(C-C)cycloalkyl, -(C-C)alkylene-OR 13 , -O-(C2-C6) alkylene-OR 13 、 -NR 13 R 14 , -(C1-C6) alkylene-NR 13 R 14 or -NR 13 C(=O)-R 14 an optionally substituted radical selected from the group:

[0034] where R 13 and R 14 are each independently selected from hydrogen, optionally substituted —(C1-C3)alkyl, —(C3-C7)cycloalkyl, and —(C1-C6)alkylene-(C3-C7)cycloalkyl.

[0035] wherein optionally a radical R on the substituent A 13 and R 14 may together form a 3- to 6-membered carbocyclic or heterocyclic ring, where each ring is optionally selected from the group consisting of halogen, -CN, -OH, -NH, -(C-C) alkyl, 、 It may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0036] wherein any two radicals A together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, each of which may optionally be selected from the group consisting of halogen, -CN, -(C1-C6)alkyl, -C1-C6- ... 、It may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0037] Preferably, in the compound of formula (I), the substituents A, which may be the same or different, are each independently selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxy (—OH), cyclopropoxy, methoxymethyl, hydroxymethyl, 2-methoxyethoxy, 2-hydroxyethoxy, trifluoromethyl, chloro, fluoro, cyano, dimethylamino, azetidinyl, pyrrolidinyl, morpholino, morpholinomethyl, and acetamido.

[0038] Preferably, in the compound of formula (I), the substituents B may be the same or different and each independently represent hydrogen, halogen, -CN, -CF, -(C-C)alkyl, -(C-C)haloalkyl, -(C-C)cycloalkyl, -(C-C)alkylene-(C-C)cycloalkyl, -(C-C)alkylene-heterocycle, -(C-C)alkylene-aryl, heterocycle, -OR 13 , -(C1-C6) alkylene-OR 13 , -O-(C2-C6) alkylene-OR 13 、 -NR 13 (C2-C6) alkylene-OR 14 , -NR 13 R 14 , -(C1-C6) alkylene-NR 13 R 14 , -O-(C2-C6) alkylene-NR 13 R 14 , -NR 13 -(C2-C6) alkylene-NR 14 R 15 , -SR 13 , -(C1-C6) alkylene-SR 13 , -O-(C2-C6) alkylene-SR 13 , -NR 13 -(C2-C6) alkylene-SR 14 , -S(=O)-R13 , -(C1-C6) alkylene-S(=O)-R 13 , -O-(C1-C6) alkylene-S(=O)-R 13 , -NR 13 -(C1-C6)alkylene-S(=O)-R 14 , -S(=O)2-R 13 , -(C1-C6) alkylene-S(=O)2-R 13 , -O-(C1-C6) alkylene-S(=O)2-R 13 , -NR 13 -(C1-C6)alkylene-S(=O)2-R 14 , -S(=O)2NR 13 R 14 , -(C1-C6) alkylene-S(=O)2NR 13 R 14 , -O-(C1-C6) alkylene-S(=O)2NR 13 R 14 , -NR 13 -(C1-C6)alkylene-S(=O)2NR 14 R 15 , -NR 13 -S(=O)2R 14 , -(C1-C6) alkylene-NR 13 -S(=O)2R 14 , -O-(C2-C6) alkylene-NR 13 -S(=O)2R 14 , -NR 13 -(C2-C6) alkylene-NR 14 -S(=O)2R 15 , -C(=O)-NR 13 R 14 , -(C1-C6) alkylene-C(=O)-NR 13 R 14 , -O-(C1-C6) alkylene-C(=O)-NR 13 R 14 , -NR 13 -(C1-C6)alkylene-C(=O)-NR 14 R 15 , -NR 13 C(=O)-R 14 , -(C1-C6) alkylene-NR 13 C(=O)-R 14, -O-(C2-C6) alkylene-NR 13 C(=O)-R 14 , -NR 13 -(C2-C6) alkylene-NR 14 C(=O)-R 15 , -C(=O)-R 13 , -(C1-C6) alkylene-C(=O)-R 13 , -O-(C1-C6) alkylene-C(=O)-R 13 , -NR 13 -(C1-C6)alkylene-C(=O)-R 14 , -C(=O)-OR 13 , -(C1-C6) alkylene-C(=O)-OR 13 , -O-(C1-C6) alkylene-C(=O)-OR 13 , -NR 13 -(C1-C6)alkylene-C(=O)-OR 14 , -OC(=O)-R 13 , -(C1-C6) alkylene-OC(=O)-R 13 , -O-(C2-C6) alkylene-OC(=O)-R 13 , -NR 13 -(C2-C6) alkylene-OC(=O)-R 14 , -(C1-C6) alkylene-NR 13 -C(=O)-NR 14 R 15 , -NR 13 -C(=O)-OR 14 , -(C1-C6) alkylene-NR 13 -C(=O)-OR 14 , -O-(C2-C6) alkylene-NR 13 -C(=O)-OR 14 , -NR 13 -(C2-C6) alkylene-NR 14 -C(=O)-OR 15 , -OC(=O)-NR 13 R 14 , -(C1-C6) alkylene-OC(=O)-NR 13 R 14 , -O-(C2-C6) alkylene-OC(=O)-NR 13 R 14 , -NR 13-(C2-C6) alkylene-OC(=O)-NR 14 R 15 , -C(=O)-(C1-C6)alkylene-NR 13 R 14 , -C(=O)-(C1-C6)alkylene-OR 13 an optionally substituted radical selected from the group:

[0039] where R 13 , R 14 and R 15 are each independently selected from hydrogen, optionally substituted —(C-C)haloalkyl, —(C-C)alkyl, —(C-C)cyanoalkyl, —(C-C)cycloalkyl, —(C-C)alkylene-(C-C)cycloalkyl, heteroaryl, aryl, heterocycle, —(C-C)alkylene-heteroaryl, —(C-C)alkylene-heterocycle, and —(C-C)alkylene-aryl.

[0040] wherein optionally R on the substituent B 13 , R 14 or R 15 Any two radicals selected from may together form a 3-10 membered carbocyclic, heterocyclic, aryl or heteroaryl ring, where each ring is optionally selected from halogen, -CN, -NO2, -OH, -NH2, -(C1-C6)alkyl. 、 It may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0041] wherein any two radicals B together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally selected from the group consisting of halogen, -CN, -OH, -NH, -(C1-C6) alkyl, -C1-C6 ... 、 It may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0042] Preferably, in the compound of formula (I), the substituents B may be the same or different and each independently represent hydrogen, halogen, -CF, -CN, -(C-C)alkyl, -(C-C)haloalkyl, -(C-C)cycloalkyl, -(C-C)alkylene-(C-C)cycloalkyl, -(C-C)alkylene-aryl, heterocycle, -OR 13 , -(C1-C6) alkylene-OR 13 , -O-(C2-C6) alkylene-OR 13 、 -NR 13 (C2-C6) alkylene-OR 14 , -NR 13 R 14 , -SR 13 , -(C1-C6) alkylene-SR 13 , -S(=O)-R 13 , -S(=O)2-R 13 , -NR 13 C(=O)-R 14 , -C(=O)-NR 13 R 14 , -C(=O)-OR 13 , -OC(=O)-R 13 , -C(=O)-(C1-C6)alkylene-OR 13 or -C(=O)-R 13 an optionally substituted radical selected from the group:

[0043] where R 13 and R 14 are each independently selected from hydrogen, optionally substituted —(C-C)alkyl, —(C-C)cycloalkyl, —(C-C)alkylene-(C-C)cycloalkyl, heteroaryl, aryl, heterocycle, —(C-C)alkylene-heteroaryl, —(C-C)alkylene-heterocycle, and —(C-C)alkylene-aryl.

[0044] wherein optionally R on the substituent B 13 and R 14Any two radicals selected from may together form a 3-10 membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally selected from halogen, CN, -OH, -NH, -(C-C) alkyl. 、 It may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0045] wherein any two radicals B together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally selected from the group consisting of halogen, -CN, -OH, -NH, -(C1-C6) alkyl, -C1-C6 ... 、 It may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0046] Preferably, in the compound of formula (I), the substituents B may be the same or different and each independently represent hydrogen, halogen, -CF, -(C-C)alkyl, -(C-C)haloalkyl, -(C-C)cycloalkyl, -(C-C)alkylene-(C-C)cycloalkyl, heterocycle, -O-(C-C)alkyl, -O-(C-C)cycloalkyl, -O-(C-C)alkylene-(C-C)cycloalkyl, -(C-C)alkylene-OR 13 , -O-(C1-C6)alkylene-aryl, -O-(C2-C6)alkylene-O-(C1-C6)alkyl, -NR 13 R 14 or -C(=O)-R 13 an optionally substituted radical selected from the group:

[0047] where R 13 and R 14 are each independently selected from hydrogen, optionally substituted —(C1-C6)alkyl, —(C3-C7)cycloalkyl, and —(C1-C6)alkylene-(C3-C7)cycloalkyl.

[0048] wherein optionally a radical R on the substituent B 13 and R 14 may together form a 3- to 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring, wherein each ring is optionally selected from the group consisting of halogen, —CN, —OH, —NH, —(C1-C6)alkyl, 、 It may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0049] wherein any two radicals B together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, each ring optionally containing halogen, —CN, —(C1-C6)alkyl, 、 It may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1C6)alkyl)2.

[0050] Preferably, in the compound of formula (I), the substituents B may be the same or different and are each independently selected from the group consisting of methyl, ethyl, cyclopropyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclopentyloxy, benzyloxy, cyclopropylmethoxy, methoxymethyl, 1-hydroxyethyl, 2-methoxyethoxy, 3-methoxypropoxy, trifluoromethyl, chloro, fluoro, dimethylamino, pyrrolidinyl, and acetyl.

[0051] Preferably, in the compound of formula (I), m is an integer equal to 0, 1 or 2, and / or p is an integer equal to 1, 2, or 3.

[0052] Preferably, in the compound of formula (I), Ar 1 teeth, [ka] (where, A is as defined above, m is the number of substituents A on the ring and represents an integer equal to 0, 1, 2, 3, or 4. represents an aryl or heteroaryl selected from:

[0053] Preferably, in the compound of formula (I), Ar 1 pyridin-2-yl, 3-chloropyridin-2-yl, 4-chloropyridin-2-yl, 5-chloropyridin-2-yl, 3-fluoropyridin-2-yl, 4-fluoropyridin-2-yl, 5-fluoropyridin-2-yl, 6-fluoropyridin-2-yl, 3-methoxypyridin-2-yl, 4-methoxypyridin-2-yl, 5-methoxypyridin-2-yl, 6-methoxypyridin-2-yl, 3-methylpyridin-2-yl yl, 5-methylpyridin-2-yl, 4-methylpyridin-2-yl, 6-methylpyridin-2-yl, 5-cyclopropylpyridin-2-yl, 5-hydroxypyridin-2-yl, 5-(methoxymethyl)pyridin-2-yl, 5-(hydroxymethyl)pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyrimidin-2-yl, pyrimidin-5-yl, 5-chloropyrimidin-2-yl, 5-fluoropyridin-2 ... pyrimidin-2-yl, 5-methylpyrimidin-2-yl, 4-cyclopropylpyrimidin-2-yl, 5-cyclopropylpyrimidin-2-yl, 4,6-dimethylpyrimidin-2-yl, 5-(trifluoromethyl)pyrimidin-2-yl, 5-(morpholinomethyl)pyrimidin-2-yl, 4-methoxypyrimidin-2-yl, 5-methoxypyrimidin-2-yl, 4-methoxy-5-methylpyrimidin-2-yl, 5-(2-methoxy)pyrimidin-2-yl and represents an aryl or heteroaryl selected from the group consisting of 5-(ethoxy)pyrimidin-2-yl, 5-hydroxypyrimidin-2-yl, 5-(azetidin-1-yl)pyrimidin-2-yl, 5-(pyrrolidin-1-yl)pyrimidin-2-yl, 4-morpholinopyrimidin-2-yl, 5-morpholinopyrimidin-2-yl, thiazol-2-yl, thiazol-4-yl, 1-methyl-1H-imidazol-4-yl, and 5-methoxypyrazin-2-yl.

[0054] Preferably, in the compound of formula (I), Ar 2 teeth, [ka] (wherein B and p are as defined above.) represents an aryl or heteroaryl selected from:

[0055] Preferably, in the compound of formula (I), Ar 2 teeth, [ka] (wherein B and p are as defined above.) represents an aryl or heteroaryl selected from:

[0056] Preferably, in the compound of formula (I), Ar 2 teeth, [ka] (wherein B and p are as defined above.) represents an aryl or heteroaryl selected from:

[0057] Preferably, in the compound of formula (I), Ar 2are 2-methylphenyl, 2,4-dimethylphenyl, 2,4,6-trimethylphenyl, 3-methoxy-2-methylphenyl, 4-methoxy-2-methylphenyl, 5-methoxy-2-methylphenyl, 2-methoxy-3-methylphenyl, 3-methoxy-4-methylphenyl, 2-methoxy-4-methylphenyl, 2-methoxy-5-methylphenyl, 3-ethoxy-2-methylphenyl, 3-isopropoxy-2-methylphenyl, 3-cyclopropoxy-2-methylphenyl, 5-cyclopropoxy-2-methylphenyl, 3-(benzyloxy)-2-methylphenyl, 3-(3-methoxypropoxy)-2-methylphenyl, 3-(2-methoxyethoxy)-2-methylphenyl, 3-acetyl-2-methylphenyl, 4-acetyl-2-methylphenyl, 4-chloro-2-methylphenyl, 2-methyl-5-(pyrrolidin-1-yl)phenyl, 3-(dimethylamino)-2 2-chloro-3-methoxyphenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 1-methylindolin-4-yl, 1,5-dimethyl-1H-indazol-4-yl, 2-chloro-3-cyclopropoxyphenyl, 1-cyclopropylindolin-4-yl, 1-cyclopropyl-1H-indol-4-yl, or 1-cyclopropyl-1H-indol-4-yl.

[0058] Preferably, in the compounds of formula (I), R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may be the same or different, and each independently represents hydrogen, halogen, -OR 10 , -NR10 R 11 , optionally substituted -(C1-C3) alkyl, wherein R 10 and R 11 is as defined above, where any two radicals R 1 and R 2 , R 3 and R 4 , and R 5 and R 6 may together form oxo, where optionally R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Any two radicals selected from may be taken together to form an optionally substituted 3- to 10-membered non-aromatic carbocyclic or heterocyclic ring.

[0059] Preferably, in the compounds of formula (I), R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is hydrogen.

[0060] Preferably, in the compounds of formula (I), R 7 and R 8 But hydrogen, halogen, -CN, -OR 10 , -NR 10 R 11 , —CF3, and optionally substituted —(C1-C3)alkyl, wherein R 10 and R 11 may be the same or different and are each independently selected from hydrogen, -(C1-C3) alkyl, or -(C3-C7) cycloalkyl, where R 10 and R 11 is as defined above, wherein, optionally, the two radicals R 10 and R 11 may be taken together to form an optionally substituted 3- to 10-membered non-aromatic carbocyclic or heterocyclic ring.

[0061] Preferably, in the compounds of formula (I), R 7 and R 8 is hydrogen.

[0062] Preferably, in the compounds of formula (I), R 9 is hydrogen, halogen, -CN, -OR 10 , -NR 10 R 11 , —CF3, and optionally substituted —(C1-C3)alkyl, wherein R 10 and R 11 may be the same or different and are each independently selected from hydrogen or -(C1-C3) alkyl, wherein optionally, the two radicals R 10 and R 11 may be taken together to form an optionally substituted 3- to 10-membered non-aromatic carbocyclic or heterocyclic ring.

[0063] Preferably, in the compounds of formula (I), R 9 is hydrogen.

[0064] Preferably, only one of G or E is N in the compounds of formula (I) according to the present invention.

[0065] In a first preferred aspect of formula (I), the present invention provides a compound according to formula (II): [ka] (where G, E, Ar 1 , Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Y are as defined above for compounds of formula (I), and N-oxide forms thereof, pharmaceutically acceptable salts and solvates thereof, or optical isomers, racemates, diastereoisomers, enantiomers, or tautomers thereof.

[0066] Preferably, in the compound of formula (II): - Ar 1 teeth, [ka] represents an aryl or heteroaryl selected from (where: m is the number of substituents A on the ring and is an integer equal to 0, 1, 2, 3 or 4; - A may be the same or different and each independently represents hydrogen, halogen, -CN, -CF3, -OH, -NH2, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C1-C6)alkylene-heterocycle, heterocycle, aryl, heteroaryl, -OR 13 , -(C1-C6) alkylene-OR 13 , -O-(C2-C6) alkylene-OR 13 、 -NR 13 (C2-C6) alkylene-OR 14 , -NR 13 R 14 , -(C1-C6) alkylene-NR 13 R 14 , -O-(C2-C6) alkylene-NR 13 R 14 , -NR 13 -(C2-C6) alkylene-NR 14 R 15 , -SR 13 , -(C1-C6) alkylene-SR 13 , -O-(C2-C6) alkylene-SR 13 , -NR 13 -(C2-C6) alkylene-SR 14 , -S(=O)-R 13 , -S(=O)2-R 13, -S(=O)2NR 13 R 14 , -(C1-C6) alkylene-S(=O)2NR 13 R 14 , -NR 13 -S(=O)2R 14 , -(C1-C6) alkylene-NR 13 -S(=O)2R 14 , -O-(C2-C6) alkylene-NR 13 -S(=O)2R 14 , -NR 13 -(C2-C6) alkylene-NR 14 -S(=O)2R 15 , -C(=O)-NR 13 R 14 , -(C1-C6) alkylene-C(=O)-NR 13 R 14 , -O-(C1-C6) alkylene-C(=O)-NR 13 R 14 , -NR 13 -(C1-C6)alkylene-C(=O)-NR 14 R 15 , -NR 13 C(=O)-R 14 , -(C1-C6) alkylene-NR 13 C(=O)-R 14 , -O-(C2-C6) alkylene-NR 13 C(=O)-R 14 , -NR 13 -(C2-C6) alkylene-NR 14 C(=O)-R 15 , -C(=O)-R 13 , -C(=O)-OR 13 , -(C1-C6) alkylene-C(=O)-OR 13 , -O-(C1-C6) alkylene-C(=O)-OR 13 , -NR 13 -(C1-C6)alkylene-C(=O)-OR 14 , -OC(=O)-R 13 , -(C1-C6) alkylene-OC(=O)-R 13 , -O-(C2-C6) alkylene-OC(=O)-R 13 , -NR 13-(C2-C6) alkylene-OC(=O)-R 14 or -NR 13 -C(=O)-OR 14 an optionally substituted radical selected from the group consisting of: - where R 13 , R 14 and R 15 are each independently selected from hydrogen, optionally substituted —(C-C)alkyl, —(C-C)cycloalkyl, —(C-C)alkylene-(C-C)cycloalkyl, heteroaryl, aryl, heterocycle, —(C-C)alkylene-heteroaryl, —(C-C)alkylene-heterocycle, and —(C-C)alkylene-aryl; - optionally R on the substituent A 13 , R 14 or R 15 Any two radicals selected from may together form a 3-10 membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally selected from halogen, -CN, -NO2, -OH, -NH2, -(C1-C6)alkyl. 、 may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl); - wherein any two radicals A together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, each ring optionally containing halogen, -CN, -OH, -NH2, -(C1-C6)alkyl; 、 may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6) alkyl and -N-((C1-C6) alkyl), and / or - Ar 2 teeth, [ka] represents an aryl or heteroaryl selected from (where p is the number of B substituents on the ring and is an integer equal to 0, 1, 2, 3, 4 or 5; - B may be the same or different and each independently represents hydrogen, halogen, -CN, -CF, -(C-C)alkyl, -(C-C)haloalkyl, -(C-C)cycloalkyl, -(C-C)alkylene-(C-C)cycloalkyl, -(C-C)alkylene-heterocycle, -(C-C)alkylene-aryl, heterocycle, -OR 13 , -(C1-C6) alkylene-OR 13 , -O-(C2-C6) alkylene-OR 13 、 -NR 13 (C2-C6) alkylene-OR 14 , -NR 13 R 14 , -(C1-C6) alkylene-NR 13 R 14 , -O-(C2-C6) alkylene-NR 13 R 14 , -NR 13 -(C2-C6) alkylene-NR 14 R 15 , -SR 13 , -(C1-C6) alkylene-SR 13 , -O-(C2-C6) alkylene-SR 13 , -NR 13 -(C2-C6) alkylene-SR 14 , -S(=O)-R 13 , -(C1-C6) alkylene-S(=O)-R 13 , -O-(C1-C6) alkylene-S(=O)-R 13 , -NR 13 -(C1-C6)alkylene-S(=O)-R 14 , -S(=O)2-R 13 , -(C1-C6) alkylene-S(=O)2-R 13 , -O-(C1-C6) alkylene-S(=O)2-R 13 , -NR 13 -(C1-C6)alkylene-S(=O)2-R 14 , -S(=O)2NR 13 R 14, -(C1-C6) alkylene-S(=O)2NR 13 R 14 , -O-(C1-C6) alkylene-S(=O)2NR 13 R 14 , -NR 13 -(C1-C6)alkylene-S(=O)2NR 14 R 15 , -NR 13 -S(=O)2R 14 , -(C1-C6) alkylene-NR 13 -S(=O)2R 14 , -O-(C2-C6) alkylene-NR 13 -S(=O)2R 14 , -NR 13 -(C2-C6) alkylene-NR 14 -S(=O)2R 15 , -C(=O)-NR 13 R 14 , -(C1-C6) alkylene-C(=O)-NR 13 R 14 , -O-(C1-C6) alkylene-C(=O)-NR 13 R 14 , -NR 13 -(C1-C6)alkylene-C(=O)-NR 14 R 15 , -NR 13 C(=O)-R 14 , -(C1-C6) alkylene-NR 13 C(=O)-R 14 , -O-(C2-C6) alkylene-NR 13 C(=O)-R 14 , -NR 13 -(C2-C6) alkylene-NR 14 C(=O)-R 15 , -C(=O)-R 13 , -(C1-C6) alkylene-C(=O)-R 13 , -O-(C1-C6) alkylene-C(=O)-R 13 , -NR 13 -(C1-C6)alkylene-C(=O)-R 14 , -C(=O)-OR 13 , -(C1-C6) alkylene-C(=O)-OR 13, -O-(C1-C6) alkylene-C(=O)-OR 13 , -NR 13 -(C1-C6)alkylene-C(=O)-OR 14 , -OC(=O)-R 13 , -(C1-C6) alkylene-OC(=O)-R 13 , -O-(C2-C6) alkylene-OC(=O)-R 13 , -NR 13 -(C2-C6) alkylene-OC(=O)-R 14 , -(C1-C6) alkylene-NR 13 -C(=O)-NR 14 R 15 , -NR 13 -C(=O)-OR 14 , -(C1-C6) alkylene-NR 13 -C(=O)-OR 14 , -O-(C2-C6) alkylene-NR 13 -C(=O)-OR 14 , -NR 13 -(C2-C6) alkylene-NR 14 -C(=O)-OR 15 , -OC(=O)-NR 13 R 14 , -(C1-C6) alkylene-OC(=O)-NR 13 R 14 , -O-(C2-C6) alkylene-OC(=O)-NR 13 R 14 , -NR 13 -(C2-C6) alkylene-OC(=O)-NR 14 R 15 , -C(=O)-(C1-C6)alkylene-NR 13 R 14 , -C(=O)-(C1-C6)alkylene-OR 13 an optionally substituted radical selected from the group consisting of: - where R 13 , R 14 and R 15are each independently selected from hydrogen, optionally substituted —(C-C)haloalkyl, —(C-C)alkyl, —(C-C)cyanoalkyl, —(C-C)cycloalkyl, —(C-C)alkylene-(C-C)cycloalkyl, heteroaryl, aryl, heterocycle, —(C-C)alkylene-heteroaryl, —(C-C)alkylene-heterocycle, and —(C-C)alkylene-aryl; - optionally R on the substituent B 13 , R 14 or R 15 Any two radicals selected from may together form a 3-10 membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally selected from halogen, -CN, -NO2, -OH, -NH2, -(C1-C6)alkyl. 、 may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl); - wherein any two radicals B together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, each ring optionally containing halogen, -CN, -OH, -NH2, -(C1-C6)alkyl; 、 It may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0067] Preferably, in the compound of formula (II): - A may be the same or different and each independently represents hydrogen, halogen, -CN, -CF3, -OH, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C1-C6)alkylene-heterocycle, heterocycle, -OR 13 , -(C1-C6) alkylene-OR 13 , -O-(C2-C6) alkylene-OR 13 、 -NR 13(C2-C6) alkylene-OR 14 , -O(C2-C6) alkylene-NR 13 R 14 , -NR 13 -(C2-C6) alkylene-NR 14 R 15 , -NR 13 R 14 , -(C1-C6) alkylene-NR 13 R 14 , -NR 13 C(=O)-R 14 , -C(=O)-NR 13 R 14 , S(=O)2NR 13 R 14 or -NR 13 -S(=O)2R 14 and optionally substituted radicals selected from the group consisting of: - where R 13 , R 14 and R 15 are each independently selected from hydrogen, optionally substituted —(C-C)alkyl, —(C-C)cycloalkyl, —(C-C)alkylene-(C-C)cycloalkyl, heterocycle, and —(C-C)alkylene-heterocycle; where optionally a radical R on the substituent A 13 , R 14 and R 15 may together form a 3- to 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring, wherein each ring is optionally selected from the group consisting of halogen, —CN, —OH, —NH, —(C1-C6)alkyl, 、 may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl); - wherein any two radicals A together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, each ring optionally containing halogen, -CN, -(C1-C6)alkyl, 、may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl); and / or - B may be the same or different and each independently represents hydrogen, halogen, -CF3, -CN, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C1-C6)alkylene-aryl, heterocycle, -OR 13 , -(C1-C6) alkylene-OR 13 , -O-(C2-C6) alkylene-OR 13 、 -NR 13 (C2-C6) alkylene-OR 14 , -NR 13 R 14 , -SR 13 , -(C1-C6) alkylene-SR 13 , -S(=O)-R 13 , -S(=O)2-R 13 , -NR 13 C(=O)-R 14 , -C(=O)-NR 13 R 14 , -C(=O)-OR 13 , -OC(=O)-R 13 , -C(=O)-(C1-C6)alkylene-OR 13 or -C(=O)-R 13 an optionally substituted radical selected from the group - where R 13 and R 14 are each independently selected from hydrogen, optionally substituted —(C-C)alkyl, —(C-C)cycloalkyl, —(C-C)alkylene-(C-C)cycloalkyl, heteroaryl, aryl, heterocycle, —(C-C)alkylene-heteroaryl, —(C-C)alkylene-heterocycle, and —(C-C)alkylene-aryl; - optionally R on the substituent B 13 and R 14Any two radicals selected from may together form a 3-10 membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally selected from halogen, CN, -OH, -NH, -(C-C) alkyl. 、 may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl); - wherein any two radicals B together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, each ring optionally containing halogen, -CN, -OH, -NH2, -(C1-C6)alkyl; 、 and / or may be further substituted by 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2; - Only one of G or E is N.

[0068] In a second preferred aspect of formula (I), the present invention provides a compound according to formula (III): [ka] (where G, E, Ar 1 , Ar 2 , R 1 , R 2 , R 3 , R 4 and R 9 is as defined above for compounds of formula (I), and N-oxide forms thereof, pharmaceutically acceptable salts and solvates thereof, or optical isomers, racemates, diastereoisomers, enantiomers, or tautomers thereof.

[0069] Preferably, in the compound of formula (III), - A may be the same or different and each independently represents hydrogen, halogen, -CN, -CF3, -OH, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C1-C6)alkylene-heterocycle, heterocycle, -OR 13 , -(C1-C6) alkylene-OR 13 , -O-(C2-C6) alkylene-OR 13 、 -NR 13 (C2-C6) alkylene-OR 14 , -O(C2-C6) alkylene-NR 13 R 14 , -NR 13 -(C2-C6) alkylene-NR 14 R 15 , -NR 13 R 14 , -(C1-C6) alkylene-NR 13 R 14 , -NR 13 C(=O)-R 14 , -C(=O)-NR 13 R 14 , S(=O)2NR 13 R 14 or -NR 13 -S(=O)2R 14 an optionally substituted radical selected from the group - where R 13 and R 14 are each independently selected from hydrogen, optionally substituted —(C-C)alkyl, —(C-C)cycloalkyl, —(C-C)alkylene-(C-C)cycloalkyl, heterocycle, and —(C-C)alkylene-heterocycle; where optionally a radical R on the substituent A 13 and R 14 may together form a 3- to 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring, wherein each ring is optionally selected from the group consisting of halogen, —CN, —OH, —NH, —(C1-C6)alkyl, 、may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl); - wherein any two radicals A together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, each ring optionally containing halogen, -CN, -(C1-C6)alkyl, 、 and / or may be further substituted by 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2; - B may be the same or different and each independently represents hydrogen, halogen, -CF3, -CN, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C1-C6)alkylene-aryl, heterocycle, -OR 13 , -(C1-C6) alkylene-OR 13 , -O-(C2-C6) alkylene-OR 13 、 -NR 13 (C2-C6) alkylene-OR 14 , -NR 13 R 14 , -SR 13 , -(C1-C6) alkylene-SR 13 , -S(=O)-R 13 , -S(=O)2-R 13 , -NR 13 C(=O)-R 14 , -C(=O)-NR 13 R 14 , -C(=O)-OR 13 , -OC(=O)-R 13 , -C(=O)-(C1-C6)alkylene-OR 13 or -C(=O)-R 13 an optionally substituted radical selected from the group consisting of: - where R 13 and R 14are each independently selected from hydrogen, optionally substituted —(C-C)alkyl, —(C-C)cycloalkyl, —(C-C)alkylene-(C-C)cycloalkyl, heteroaryl, aryl, heterocycle, —(C-C)alkylene-heteroaryl, —(C-C)alkylene-heterocycle, and —(C-C)alkylene-aryl; - optionally R on the substituent B 13 and R 14 Any two radicals selected from may together form a 3-10 membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally selected from halogen, CN, -OH, -NH, -(C-C) alkyl. 、 may be further substituted with 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl); - wherein any two radicals B together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, each ring optionally containing halogen, -CN, -OH, -NH2, -(C1-C6)alkyl; 、 and / or may be further substituted by 1 to 5 radicals independently selected from -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2; - Only one of G or E is N.

[0070] Preferably, in the compound of formula (III), G is nitrogen and E is CR 8 (where R 8 is as defined above.

[0071] Preferably, in the compound of formula (III), G is nitrogen and E is CH.

[0072] The present invention also relates to the compounds according to the invention described herein in the form of a racemic mixture or in the form of one or both of the individual optical isomers.

[0073] Examples of particularly preferred compounds according to the present invention include the compounds in the following list (Preferred Compound List), as well as their N-oxide forms, pharmaceutically acceptable salts and solvates thereof, or optical isomers, racemates, diastereoisomers, enantiomers, or tautomers thereof: 6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one, 6-(3-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(4-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one, (-)-6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one, 6-(2,4-dimethylphenyl)-2-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one, 2-(4-chloropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(3-chloropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(6-fluoropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(4-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(3-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(6-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(4-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(3-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(4-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(3-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)picolinonitrile, 6-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)nicotinonitrile, 2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)isonicotinonitrile, 2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)nicotinonitrile, 6-(2,4-dimethylphenyl)-2-(5-hydroxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(4-hydroxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-(methoxymethyl)pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(pyridin-3-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(pyrazin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(pyrimidin-5-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(thiazol-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(thiazol-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(1-methyl-1H-imidazol-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(4,6-dimethylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(4-cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-hydroxypyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-(hydroxymethyl)pyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-methoxy-2-methylphenyl)-2-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-chloropyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-methoxy-2-methylphenyl)-2-(5-methoxypyrazin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-hydroxypyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-methoxy-2-methylphenyl)-2-(4-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-methoxy-2-methylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-chloropyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(pyridin-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-chloropyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-fluoropyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(4-methoxy-5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-(morpholinomethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(dimethylamino)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(pyridin-2-yl)-6-(o-tolyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-cyclopropylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(1-hydroxyethyl)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-cyclopropoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-methoxy-3-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(1-methylindolin-4-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-methoxy-4-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-methoxy-3-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-chloro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-methoxy-2-(trifluoromethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-fluoro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-chloro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-methoxy-5-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(1-methylindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-fluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,5-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,3-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(methoxymethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(cyclopentyloxy)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(4-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(1,5-dimethyl-1H-indazol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-mesityl-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,6-difluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(1-cyclopropylindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one 6-(2-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(4-chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(4-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(3-methoxypropoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-ethoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(cyclopropylmethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-isopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(2-methoxyethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(benzyloxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-cyclopropylpyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-cyclopropylpyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-cyclopropylpyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-methoxy-2-methylphenyl)-2-(5-(pyrrolidin-1-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-methoxy-2-methylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-morpholinopyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-morpholinopyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-(azetidin-1-yl)pyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide, 6-(3-methoxy-2-methylphenyl)-2-(5-(2-methoxyethoxy)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (2-(5-(2-hydroxyethoxy)-pyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(pyridin-2-yl)-2,5,6,7-tetrahydro-1H-cyclopenta[d]-pyridazin-1-one, 7-(2,4-dimethylphenyl)-3-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one, 6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-cyclopropylpyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one 2-(5-bromopyrimidin-2-yl)-6-(3-cyclopropoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, N-(2-(6-(3-cyclopropoxy-2-methylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide, (-)-6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (-)-6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (-)-6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (-)-6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (-)-N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide, (+)-N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide, (+)-6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (-)-6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-bromopyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-bromopyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-bromopyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-bromopyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-bromopyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, and 2-(5-Bromo-4-methoxypyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one.

[0074] The present invention also relates to compounds of the following formulae (IV), (V), (VI), (VII), (VIII) and (IX) as intermediates of the compounds of formulae (I), (II) and (III). [ka] where G, E, Ar 1 , Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Y are as defined above for compounds of formula (I), (II) and (III).

[0075] The disclosed compounds also include all pharmaceutically acceptable isotopic variations in which at least one atom is replaced with an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes suitable for inclusion in the disclosed compounds include, but are not limited to, isotopes of hydrogen, e.g., 2 H and 3 H; isotopes of carbon, e.g. 11 C. 13 C and 14 C; isotopes of nitrogen, e.g. 15 N; isotopes of oxygen, e.g. 17 O and 18 O; isotopes of phosphorus, e.g. 32 P and 33 P; isotopes of sulfur, e.g. 35S; isotopes of fluorine, e.g. 18 F; and isotopes of chlorine, e.g. 36 Cl, etc. Isotopic variations (e.g., deuterium, 2 The use of radioisotopes (e.g., tritium, HCl ... 3 H, or 14 C, etc.). 11 C. 18 F, 15 O and 13 Substitution with positron-emitting isotopes, such as N, is useful in positron emission topography (PET) studies to analyze substrate receptor occupancy. Isotopically labeled compounds of formulas (I) to (III) can generally be used as radiolabeled tracers for imaging analysis. Such isotopically labeled compounds can be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the Examples below, using an appropriate isotopically labeled reagent in place of the previously used non-labeled reagent.

[0076] For tautomeric forms, the name of the tautomeric form of the depicted structure is given, but it will be understood that other tautomeric forms not shown are also included within the scope of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0077] Definition of Terms Listed below are definitions of various terms used to describe the invention in this specification and the appended claims.

[0078] Naturally, the definitions given to the respective substituents of the compound of formula (I) in the present invention also apply to the corresponding substituents of the compounds of formulas (II) to (III).

[0079] It is also understood that each substituent definition can be directly and unambiguously linked to another substituent definition.

[0080] For the avoidance of doubt, it is to be understood that in this specification "(C1-C6)" means a carbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, and "(C0-C6)" means a carbon radical having 0, 1, 2, 3, 4, 5 or 6 carbon atoms.

[0081] As used herein, "C" means carbon atom, "N" means nitrogen atom, "O" means oxygen atom, and "S" means sulfur atom.

[0082] If the subscript is the integer 0 (zero), it indicates that the radical to which the subscript refers is absent, i.e., there is a direct bond between the radicals on both sides.

[0083] When the subscript is the integer 0 (zero) and the radical to which the subscript refers is an alkyl, it indicates that the radical is a hydrogen atom.

[0084] As used herein, unless otherwise specified, the term "bond" refers to a saturated covalent bond. When two or more bonds are adjacent to one another, they are considered to be equivalent to one bond. For example, in the radical -VW-, if both V and W are bonds, the radical represents a single bond.

[0085] As used herein, unless otherwise stated, the term "alkyl" includes both straight-chain and branched-chain alkyl radicals, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neopentyl, n-hexyl, i-hexyl, or t-hexyl, etc. The term "(C0-C3)alkyl" refers to an alkyl radical having 0, 1, 2, or 3 carbon atoms, such as methyl, ethyl, n-propyl, and i-propyl.

[0086] As used herein, unless otherwise specified, the term "alkylene" includes both straight-chain and branched-chain difunctional saturated hydrocarbon radicals, examples of which include methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, t-butylene, n-pentylene, i-pentylene, t-pentylene, neopentylene, n-hexylene, i-hexylene, or t-hexylene.

[0087] As used herein, unless otherwise specified, the term "cycloalkyl" refers to an optionally substituted carbocycle containing no heteroatoms and including mono-, bi-, or cyclic unsaturated carbocycles. Cycloalkyl includes fused and spiro-fused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, fluorenyl, and 1,2,3,4-tetrahydronaphthalene, and the like. The term "(C3-C7)cycloalkyl" may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0088] As used herein, unless otherwise specified, the term "cycloalkenyl" refers to an optionally substituted carbocycle containing no heteroatoms and including mono-, bi-, or cyclic unsaturated carbocycles. The term "(C2-C6)cycloalkenyl" refers to a cycloalkyl radical having 2 to 6 carbon atoms and 1 or 2 double bonds. Examples include, but are not limited to, cyclopentenyl and cyclohexenyl.

[0089] As used herein, unless otherwise specified, the term "alkenyl" includes both straight- and branched-chain alkenyl radicals. The term "(C2-C6)alkenyl" refers to an alkenyl radical having 2 to 6 carbon atoms and 1 or 2 double bonds. Examples include, but are not limited to, vinyl, allyl, propenyl, i-propenyl, butenyl, i-butenyl, crotyl, pentenyl, i-pentenyl, and hexenyl.

[0090] As used herein, unless otherwise specified, the term "alkenylene" includes both straight-chain and branched-chain disubstituted alkenyl radicals. The term "(C2-C6)alkenylene" refers to an alkenylene radical having 2 to 6 carbon atoms and 1 or 2 double bonds. Examples include, but are not limited to, vinylene, arylene, propenylene, i-propenylene, butenylene, i-butenylene, crotylene, pentenylene, i-pentenylene, hexenylene, and the like.

[0091] As used herein, unless otherwise specified, the term "alkynyl" includes both straight-chain and branched-chain alkynyl radicals. (C2-C6)alkynyl has 2 to 6 carbon atoms and 1 or 2 triple bonds. Examples include, but are not limited to, ethynyl, propargyl, butynyl, pentynyl, and hexynyl.

[0092] As used herein, unless otherwise specified, the term "alkynylene" includes both straight-chain and branched-chain disubstituted alkynylene radicals. The term (C2-C6)alkynylene has 2 to 6 carbon atoms and 1 or 2 triple bonds. Examples include, but are not limited to, ethynylene, propargylene, butynylene, pentynylene, i-pentynylene, and hexynylene.

[0093] The term "aryl" refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system containing at least one unsaturated 6- to 10-membered aromatic ring. Examples and suitable values ​​of the term "aryl" include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indyl, indenyl, and the like.

[0094] As used herein, unless otherwise specified, the term "heteroaryl" refers to an optionally substituted 5-10 membered monocyclic or bicyclic unsaturated aromatic ring system containing at least one heteroatom independently selected from N, O, or S. Heteroaryl preferably contains 1 to 3 heteroatoms, preferably selected from N, O, or S. Examples of "heteroaryl" include, but are not limited to, thynyl, pyridinyl, thiazolyl, isothiazolyl, furyl, pyrrolyl, triazolyl, imidazolyl, triazinyl, oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl, thiadiazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, tetrahydrotriazolopyridinyl, and tetrahydrotriazolopyrimidinyl. , benzofuryl, benzothiophenyl, thionaphthyl, indolyl, isoindolyl, pyrizonyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, imidazopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl, cinnolyl, pteridinyl, furazanyl, benzotriazolyl, pyrazolopyridinyl, and purinyl.

[0095] As used herein, unless otherwise specified, the terms "alkylene-aryl," "alkylene-heteroaryl," and "alkylene-cycloalkyl" refer to an aryl, heteroaryl, or cycloalkyl radical to which a substituent is attached via an alkyl radical, respectively. The term "(C-C)alkylene-aryl" refers to an aryl-(C-C)-alkyl radical, including, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylmethyl, and 2-naphthylmethyl. The term "(C-C)alkylene-heteroaryl" includes heteroaryl-(C-C)-alkyl radicals. Here, examples of heteroaryl are the same as those exemplified in the above definition, such as 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl, 1-imidazolylmethyl, 2-imidazolylmethyl, 3-imidazolylmethyl, 2-oxazolylmethyl, 3-oxazolylmethyl, 2-thiazolylmethyl, 3-thiazolylmethyl, 2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, 1-quinolylmethyl, etc. The term "-(C-C) alkylene-(C-C) cycloalkyl" includes a -(C-C)-cycloalkyl-(C-C)-alkyl radical. Here, examples of cycloalkyl are the same as those exemplified in the above definition, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, etc.

[0096] As used herein, unless otherwise specified, the term "carbocycle" refers to optionally substituted, heteroatom-free, 5- to 10-membered monocyclic, bicyclic, or tricyclic saturated or partially saturated ring systems and fused ring systems. Such fused ring systems may also include fused ring systems containing one partially or fully unsaturated ring (e.g., benzene, etc.), such as benzofused carbocycles.

[0097] As used herein, unless otherwise specified, the term "heterocycle" refers to a 5-10 membered monocyclic or bicyclic saturated or partially saturated ring system that may be optionally substituted and contains at least one heteroatom independently selected from N, O, and S. Such heterocycles preferably contain 1 to 3 heteroatoms, preferably selected from N, O, or S.

[0098] As used herein, unless otherwise specified, five- or six-membered rings containing one or more atoms independently selected from C, N, O, and S include saturated or unsaturated carbocyclic and heterocyclic rings, as well as aromatic and heteroaromatic rings. Examples of such rings include, but are not limited to, furyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazolidinyl, imidazolinyl, triazolyl, morpholinyl, piperazinyl, piperidyl, piperizonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinonyl, thiomorpholinyl, oxadiazolyl, thiadiazolyl, tetrazolyl, phenyl, cyclohexyl, cyclopentyl, cyclohexenyl, cyclopentenyl, and the like.

[0099] As used herein, unless otherwise specified, 3- to 10-membered rings containing one or more atoms independently selected from C, N, O, and S include saturated or unsaturated carbocyclic and heterocyclic rings, as well as aromatic and heteroaromatic rings. Examples of such rings include, but are not limited to, imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidyl, piperizonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, tetrahydrothiopyranyl, furyl, pyrrolyl, dihydropyrrolyl, isoxazolyl, isothiazolyl, isoindolinonyl, dihydropyrrolo[1,2-b]pyrazolyl, oxazolyl, oxazolidinonyl, pyrazinyl, pyrazolinyl, and pyrazolinyl. aryl, pyridazinyl, pyridinyl, tetrahydropyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, triazolyl, phenyl, cyclopropyl, aziridinyl, cyclobutyl, azetidinyl, oxadiazolyl, thiadiazolyl, tetrazolyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, and cyclooctenyl.

[0100] As used herein, unless otherwise stated, the term "halo" or "halogen" refers to, for example, fluorine, chlorine, bromine, or iodine.

[0101] As used herein, unless otherwise stated, the term "haloalkyl" means an alkyl radical, as defined above, substituted with one or more halo radicals. The term "(C1-C6)haloalkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and the like.

[0102] As used herein, unless otherwise stated, the term "cyanoalkyl" refers to an alkyl radical, as defined above, substituted with one or more cyano (CN) radicals.

[0103] As used herein, unless otherwise specified, the term "optionally substituted" refers to a radical further having one or more substituents, such as (C-C) alkyl, hydroxy (-OH), (C-C) alkylene-OR (where R is H or (C-C) alkyl), mercapto (-SH), aryl, heteroaryl, heterocyclic, (C-C) alkylene-aryl, (C-C) alkylene-heterocyclic, (C-C) alkylene-(C-C) cycloalkyl, (C-C) alkylene-heteroaryl, halogen, trifluoroalkyl (preferably trifluoromethyl), trifluoroalkoxy, and the like. Examples include cyano (preferably trifluoromethoxy), cyano (CN), cyanoalkyl (preferably cyanomethyl), nitro (NO), amino (NH), carboxyl (COH), carboxamide (CONH), carbamate (NH-C(=O)OR (where R is (C1-C6)alkyl), sulfonamide (S(=O)2-NH2), ester of formula C(O)OR (where R is (C1-C6)alkyl), and sulfonyl (S(=O)-R) (where R is (C1-C6)alkyl).

[0104] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, excipients, compositions, or dosage forms that are suitable, within the scope of sound medical judgment, for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other significant complications, etc., in accordance with a reasonable benefit-risk ratio.

[0105] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds modified by converting the parent compound into its acid or base salt. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, such as mono-, di-, or tri-salts thereof, as well as salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid, glucoronic acid, glutamic acid, benzoic acid, salicylic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, and lactic acid. Further addition salts include ammonium salts such as tromethamine, meglumine, and epolamine, and metal salts such as sodium, potassium, calcium, zinc, and magnesium.

[0106] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Such salts can generally be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, acetonitrile, and the like are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 20 th ed., Mack Publishing Company, Easton, PA, 2000, the disclosure of which is incorporated herein by reference.

[0107] As used herein, a "pharmaceutically acceptable solvate" refers to a derivative of a compound of the present disclosure, which is modified by converting the parent compound into its solvate. As used herein, unless otherwise specified, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (e.g., a compound of formula (I)) and a solvent. The present invention encompasses any solvated form of a compound of formula (I) in solid form. The present invention encompasses, for example, solvates with water (e.g., hydrates), or solvates with organic solvents such as methanol, ethanol, or acetonitrile (commonly known as methanolates, ethanolates, or acetonitriles, respectively), or any polymorphs thereof. Such solvents may not interfere with the biological activity of the solute.

[0108] Pharmaceutically acceptable prodrugs of compounds usable in the present invention, particularly compounds of Formula (I), are derivatives that have chemically or metabolically cleavable groups and are converted into pharmaceutically active compounds in vivo by solvolysis or under physiological conditions. Prodrugs of compounds usable in the present invention can be formed by conventional methods using functional groups of the compounds, such as amino, hydroxy, or carboxy groups. Prodrug derivative forms often offer advantages in terms of solubility, tissue compatibility, or delayed release in mammals, including humans (see Bundgaard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting parent acidic compounds with a suitable alcohol or amides prepared by reacting parent acidic compounds with a suitable amine. When the compound used in the present invention, particularly the compound of formula (I), has a carboxyl group, examples of prodrugs include ester derivatives prepared by reacting the carboxyl group with an appropriate alcohol, and amide derivatives prepared by reacting the carboxyl group with an appropriate amine. Particularly preferred ester derivatives as prodrugs include methyl esters, ethyl esters, n-propyl esters, i-propyl esters, n-butyl esters, and i-butyl esters. When the compound used in the present invention has a hydroxyl group, examples of prodrugs include acyloxy derivatives obtained by reacting the hydroxyl group with an appropriate acyl halide or an appropriate acid anhydride. When the compound used in the present invention has an amino group, examples of prodrugs include amide derivatives obtained by reacting the amino group with an appropriate acid halide or an appropriate mixed anhydride.

[0109] The compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered as a compound per se or formulated as a pharmaceutical. The present invention includes within its scope pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof as an active ingredient. Such pharmaceutical compositions may optionally contain one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, or antioxidants.

[0110] Such pharmaceutical compositions may contain one or more solubility enhancers, examples of which include poly(ethylene glycol), e.g., poly(ethylene glycol) having a molecular weight ranging from about 200 to about 5,000 Da, ethylene glycol, propylene glycol, nonionic surfactants, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate, phospholipids, lecithin, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, cyclodextrin, hydroxyethyl-3-cyclodextrin, hydroxypropyl-3-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dihydroxypropyl-3-cyclodextrin, Examples of the cyclodextrin include glucosyl-α-cyclodextrin, glucosyl-3-cyclodextrin, diglucosyl-3-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-3-cyclodextrin, maltosyl-Y-cyclodextrin, maltotriosyl-3-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-3-cyclodextrin, methyl-3-cyclodextrin, carboxyalkyl thioether, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and any combination thereof.

[0111] As used herein, unless otherwise specified, a particular compound may exist in one or more particular geometric, optical, enantiomeric, diastereomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms. Examples include, but are not limited to, cis and trans forms; E and Z forms; endo and exo forms; R-, S-, and meso forms; D and L forms; d and l forms; (+) and (−) forms; keto, enol, enolate forms; α and β forms; axial and equatorial forms; and combinations thereof. These are collectively referred to as "isomers" or "isomeric forms."

[0112] It should be noted that the term "isomer" specifically includes compounds with one or more isotopic substitutions. For example, H may be in any of its isotopic forms. Examples include, but are not limited to: 1 H, 2 H(D), 3 H(T), etc. C can also be any isotopic form thereof. Examples include, but are not limited to: 11 C. 12 C. 13 C. 14 C. O may also be any isotopic form thereof. Examples include, but are not limited to: 16 O. 18 O, etc. F may also be any isotopic form thereof. Examples include, but are not limited to: 19 F, 18 Examples include F.

[0113] The present invention also relates to compositions, preferably pharmaceutical compositions, comprising at least one compound according to the present invention. Preferably, such compositions contain a compound according to the present invention in a therapeutically effective amount. By "therapeutically effective amount" is meant an amount of a compound / drug according to the present invention effective to prevent or treat a pathological condition.

[0114] A therapeutically effective amount can be readily determined by the attending physician, as one skilled in the art, by using conventional techniques or by reference to results obtained under similar circumstances. In determining a therapeutically effective amount, the attending physician will consider various factors, including, but not limited to, the species, size, age, and general health of the subject, the specific disease involved, the extent or severity of the involvement of such disease, the response of the individual subject, the specific compound administered, the method of administration, the bioavailability inherent in the administered formulation, the selected dosing regimen, the presence or absence of concomitant medications, and other relevant circumstances.

[0115] The composition may further comprise a pharmaceutically acceptable excipient. Such carriers or diluents must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0116] "Pharmaceutically" or "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other unanticipated reactions when properly administered to an animal or human.

[0117] As used herein, "pharmaceutically acceptable excipient" includes any carrier, diluent, adjuvant, or vehicle, such as preservatives or antioxidants, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, and the like. Such media and agents used for pharmaceutical active substances are well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions as suitable therapeutic combinations.

[0118] The composition can be in various pharmaceutical forms for administration purposes. Suitable compositions include any composition normally used for systemic or local administration of drugs.

[0119] The pharmaceutical compositions of the present invention can be prepared by any method known in the pharmaceutical industry. See, for example, Gennaro et al., Remington's Pharmaceutical Sciences (18th ed., Mack Publishing Company, 1990, especially Part 8: Pharmaceutical Preparations and their Manufacture). To prepare the pharmaceutical compositions of the present invention, a therapeutically effective amount of a specific compound as the active ingredient, optionally in salt form, is intimately mixed with a pharmaceutically acceptable carrier or diluent. Such carriers or diluents can take a variety of forms depending on the variety of formulations suitable for the desired administration. These pharmaceutical compositions are preferably in unit dosage form, particularly suitable for oral, topical, rectal, or transdermal administration, parenteral injection, administration to the middle or inner ear, or inhalation.

[0120] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage forms. As used herein, unit dosage form refers to physically discrete units suitable for single administration, each containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect, in association with the necessary pharmaceutical carrier. Examples of such unit dosage forms include tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injection solutions or suspensions, etc., teaspoonfuls, tablespoons, and segregated multiples thereof.

[0121] Since the compounds according to the present invention are orally administrable compounds, pharmaceutical compositions for oral administration containing such compounds are particularly advantageous.

[0122] To enhance the solubility and / or stability of the compounds of the present invention in pharmaceutical compositions, it is advantageous to use α-, β-, or γ-cyclodextrin or derivatives thereof, in particular hydroxyalkyl-substituted cyclodextrins such as 2-hydroxypropylcyclodextrin or sulfobutylcyclodextrin, etc. Cosolvents such as alcohols can also improve the solubility and / or stability of the compounds of the present invention in pharmaceutical compositions.

[0123] The present invention also relates to a method for preparing a pharmaceutical composition according to the present invention, which comprises intimately admixing a therapeutically effective amount of a compound according to the present invention with a pharmaceutically acceptable carrier.

[0124] The present invention also relates to the use of such compounds as described above as medicines.

[0125] The present invention also relates to the use of a compound according to the invention or a composition according to the invention in the preparation of a pharmaceutical or medicament.

[0126] The inventors have surprisingly found that the above-mentioned compounds are modulators of mGlu receptors, preferably modulators of mGluR7, preferably antagonists of mGluR7.

[0127] The present invention therefore relates to a compound according to the invention or a composition according to the invention for use to modulate, preferably reduce, inhibit or negatively modulate, the activity of an mGlu receptor, in particular the activity of mGluR7.

[0128] The present invention also relates to the use of a compound according to the invention or a composition according to the invention in the preparation of a medicament for use in modulating, preferably reducing, inhibiting or negatively modulating the activity of an mGlu receptor, in particular the activity of mGluR7.

[0129] The present invention also relates to a method for modulating, preferably reducing, inhibiting or negatively modulating the activity of mGlu receptors, in particular the activity of mGluR7, which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to the invention or a composition according to the invention.

[0130] According to the present invention, the term "patient" or "patient in need thereof" refers to an animal or human suffering from or likely to suffer from a pathological condition whose etiology involves an active cysteine ​​protease. Preferably, the patient is a human.

[0131] Identifying subjects in need of treatment for the diseases and conditions described herein is well within the ability and knowledge of one of ordinary skill in the art. A veterinarian or physician, as skilled in the art, can readily identify subjects in need of such treatment by using clinical tests, physical examinations, medical / family history, or biological and diagnostic tests.

[0132] The present invention also relates to a compound according to the invention or a composition according to the invention for use in the treatment of a disease associated with glutamate dysfunction.

[0133] The present invention also relates to the use of a compound according to the invention or a composition according to the invention in the preparation of a medicament for treating a disease associated with glutamate dysfunction.

[0134] In particular, the present invention relates to a compound according to the invention or a composition according to the invention for use in the prevention or treatment of a disorder associated with glutamate dysfunction in a mammal, including a human.

[0135] The present invention also relates to a method for treating a disease associated with glutamate dysfunction, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to the present invention or a composition according to the present invention.

[0136] As used herein, the term "treatment" is intended to refer to any process that can result in slowing, interrupting, preventing or halting the progression of a disease, although it does not necessarily indicate complete elimination of all symptoms.

[0137] The present invention also relates to a method for treating anxiety disorders, such as agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, and post-traumatic stress disorder. mood disorders, such as bipolar disorder (I & II), cyclothymic disorder, depression, dysthymic disorder, major depressive disorder, drug-induced mood disorder, mood disorders due to general medical conditions, mania, manic-depressive disorder, seasonal affective disorder; muscle spasms and muscle spasticity-related disorders, such as tremors, epilepsy, convulsions, and migraines; neurodegenerative disorders, such as mild cognitive impairment, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis; mental disorders, such as schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder, and drug-induced psychosis; personality disorders, such as obsessive-compulsive personality disorder, schizoid disorder, and schizophrenia. idiopathic personality disorder, borderline personality disorder, anxious-avoidant personality disorder; childhood disorders such as attention deficit hyperactivity disorder, mental retardation, Down's syndrome, tic disorders, autism spectrum disorders (e.g., Rett syndrome or fragile X syndrome) and autism; hearing disorders such as inner ear diseases, disorders, impairments or conditions, such as sensorineural hearing loss, age-related hearing loss (presbycusis), Meniere's disease, sudden hearing loss, noise-induced hearing loss, drug-induced hearing loss, recessive hearing loss, cisplatin-induced hearing loss, aminoglycoside-induced hearing loss, otitis media, toxic hearing loss, autoimmune inner ear disease, acute tinnitus, chronic tinnitus, central auditory processing disorders, and vestibular disorders; gastrointestinal disorders such as diarrhea, constipation, gastroesophageal reflux disease reflux disease (GERD), lower esophageal sphincter disease or disorder, gastrointestinal motility disorder, colitis, Crohn's disease or irritable bowel syndrome (IBS); pain disorders, such as acute pain, chronic pain, severe pain, intractable pain, inflammatory pain, post-operative pain, headache, cancer pain, neuropathic pain, post-traumatic pain, and visceral pain; cognitive and mood disorders associated with the aforementioned disorders;The present invention relates to a compound of the present invention or a composition of the present invention for use in the prevention or treatment of ophthalmic diseases such as ocular hypertension, glaucoma, normal tension glaucoma, neurodegenerative conditions of the retina and optic nerve, retinal dystrophies, age-related macular degeneration, and eye conditions such as conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, inflammation and / or neurodegeneration; traumatic brain injury, stroke, ischemia, spinal cord injury, cerebral hypoxia, cerebral hemorrhage, or intracranial hematoma;

[0138] In particular, the present invention relates to the treatment of certain neurological and psychiatric disorders, such as anxiety disorders, including but not limited to phobias, generalized anxiety disorder (GAD), panic disorder, obsessive-compulsive disorder (OCD), acute and chronic stress-related disorders (e.g., post-traumatic stress disorder), and the like. mood disorders, including but not limited to major depressive disorder, depression and treatment-resistant depression, mania, bipolar disorder; amnesic and other cognitive disorders; disorders that are usually first diagnosed in infancy, childhood, or adolescence, including but not limited to attention deficit disorders, such as attention deficit hyperactivity disorder, mental retardation, learning disabilities, autism spectrum disorders (e.g., Rett syndrome or fragile X syndrome); substance-related disorders, including but not limited to alcohol dependence, alcohol abuse, drug dependence, and drug abuse; schizophrenia and other psychiatric disorders; somatoform disorders; sleep disorders; muscle spasms and muscle spasticity-related disorders, including tremors, epilepsy, convulsions, migraines; and traumatic brain injury.

[0139] In particular, the present invention relates to a compound of the present invention or a composition of the present invention for use in the prevention or treatment of certain neurodegenerative conditions or diseases, such as mild cognitive impairment, dementia, Alzheimer's disease, and Parkinson's disease.

[0140] In particular, the present invention relates to a compound of the present invention or a composition of the present invention for use in the prevention or treatment of certain pain conditions or disorders, such as acute pain, chronic pain, neuropathic pain, post-traumatic pain, and visceral pain.

[0141] In particular, the present invention relates to a compound of the present invention or a composition of the present invention for use in the prevention or treatment of hearing disorders such as age-related hearing loss (or presbycusis), noise-induced hearing loss, cisplatin-induced hearing loss, aminoglycoside-induced hearing loss, acute and chronic tinnitus, central auditory processing disorders, and vestibular disorders.

[0142] The present invention also relates to the compound according to the present invention or the composition according to the present invention for use in the prevention or treatment of anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, depression, bipolar disorder, schizophrenia, autism spectrum disorder, hearing impairment, pain, and the like.

[0143] All of the above-mentioned diseases are considered to fall under the category of diseases associated with glutamate dysfunction as defined in the present invention.

[0144] As already mentioned above, the term "treatment" does not necessarily indicate the complete elimination or prevention of all symptoms, but may refer to symptomatic treatment or preventative intervention for any of the above disorders. In particular, symptoms that may be treated or prevented include, but are not limited to, cognitive impairment, fearful behavior, hyperirritability, aggressive behavior, hearing impairment, pain, especially in anxiety disorders, acute stress disorder, chronic stress disorder, post-traumatic stress disorder, schizophrenia, ear disorders, and pain disorders.

[0145] Those skilled in the art will appreciate that alternative nomenclatures, nosologies, and classification systems exist for the disorders described herein, and these evolve with medical and scientific advances.

[0146] The present invention also relates to the use of the compounds according to the invention as radiolabelled tracers for imaging metabotropic glutamate receptors, preferably mGluR7, in mammals, such as humans.

[0147] The present invention also relates to the use of a compound according to general formula (I), (II), (III), or a stereoisomer thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, in particular a compound of formula (I), (II), (III), or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the present invention, for use in the treatment or prevention, in particular the treatment, of pathologies in mammals, including humans, which are modified or ameliorated by the neuromodulatory effect of the compounds according to the present invention on mGluRs, in particular mGluR7.

[0148] The present invention also relates to compounds according to formula (I) for use in the treatment, prevention, amelioration, suppression or reduction of the risk of disorders associated with various neurological and psychogenic glutamate dysfunction in mammals, including humans, the treatment or prevention of which is modified or ameliorated by the neuromodulatory effect of compounds according to formula (I) according to the present invention on mGlu receptors, particularly mGluR7.

[0149] The present invention also relates to a method for the treatment or prevention, in particular the treatment, of pathologies in mammals, including humans, which treatment or prevention is modified or ameliorated by the neuromodulatory action of the compounds according to formula (I) according to the present invention on mGlu receptors, in particular mGluR7, which method comprises administering to an individual in need thereof a therapeutically effective amount of a compound according to general formula (I), (II), (III), or a stereoisomer thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, in particular a compound of formula (I), (II), (III), or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the present invention.

[0150] The present invention also relates to a method for the treatment, prevention, amelioration, suppression or reduction of the risk of various neurological and psychosomatic glutamate dysfunction-associated disorders in humans, the treatment or prevention of which is modified or ameliorated by the neuromodulatory effect of the compounds according to formula (I) according to the present invention on mGlu receptors, particularly mGluR7.

[0151] The present invention also relates to compounds according to formula (I), (II), (III), or a stereoisomeric form thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, in particular to compounds of formula (I), (II), (III), or a stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, for the treatment or prevention, in particular the treatment, of any of the above-mentioned diseases.

[0152] The present invention also relates to the use of a compound according to formula (I), (II), (III), or a stereoisomer thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, in particular a compound according to formula (I), (II), (III), in the preparation of a medicament for the treatment or prevention, in particular the treatment, of any of the above-mentioned diseases. The present invention relates to the use of a compound, or a stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof.

[0153] The compounds of the present invention can be administered to mammals, preferably humans, for the treatment or prevention of any of the diseases mentioned above.

[0154] Therefore, the present invention also relates to a method for the prevention and / or treatment of any of the above-mentioned diseases, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to the invention.

[0155] As will be appreciated by those skilled in the art, a therapeutically effective amount of a compound of the present invention refers to an amount sufficient to modulate, inhibit, or reduce the activity of mGluRs, particularly mGluR7. Such amounts will vary depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient, etc. Generally, the amount of compound to be administered as a therapeutic agent to treat diseases in which modulation, inhibition, or reduction of mGluR activity, preferably mGluR7 activity, is beneficial, such as the disorders described herein, will be determined on a case-by-case basis by the attending physician.

[0156] Generally, an appropriate dose is one that results in a compound concentration in the range of 0.5 nM to 200 μM, more typically 5 nM to 50 μM. To achieve these therapeutic concentrations, a patient in need of treatment is administered an effective therapeutic daily dose of about 0.01 mg / kg to about 50 mg / kg body weight, preferably about 0.01 mg / kg to about 25 mg / kg body weight, more preferably about 0.01 mg / kg to about 10 mg / kg body weight, more preferably about 0.01 mg / kg to about 2.5 mg / kg body weight, even more preferably about 0.05 mg / kg to about 1 mg / kg body weight, and even more preferably about 0.1 to about 0.5 mg / kg body weight. Of course, the amount of the compound of the present invention (sometimes referred to herein as the active ingredient) required to achieve a therapeutic effect will vary on a case-by-case basis and will depend on the specific compound, route of administration, the age and condition of the recipient, and the specific disorder or disease being treated. The treatment method may also include administering the active ingredient in a dosage regimen of one to four times daily. In these treatment methods, the compound of the present invention is preferably prescribed before hospitalization. As described below, suitable pharmaceutical formulations can be prepared by known procedures using well-known and readily available ingredients.

[0157] Combination therapy The compounds of the present invention may be used in combination with one or more other drugs to treat, prevent, control, ameliorate, or reduce the risk of a disease or condition for which the compounds of the present invention or other drugs may be useful, if the combination is safer or more effective than either drug alone. In another aspect, the present invention relates to combination therapies in which an active compound of the present invention is administered with another active compound. Such combinations may be fixed-dose combinations (i.e., the combined active ingredients are in the same pharmaceutical formulation) or flexible-dose combinations (i.e., the combined active ingredients are in different pharmaceutical formulations). Thus, a further aspect of the present invention refers to the combination of each active compound of the present invention, preferably at least one active compound of the present invention, with another active compound that modulates a receptor or enzyme to improve the efficacy and / or safety of the active compound of the present invention and / or reduce undesirable side effects. The different drugs in such combinations or products may be combined in a single formulation with pharmaceutically acceptable carriers or diluents, or may be formulated in separate formulations with pharmaceutically acceptable carriers or diluents.

[0158] Modulators of mGluRs, preferably mGluR7 modulators, including the compounds of the present invention, modulate the response of mGluRs, preferably mGluR7, to endogenous glutamate and / or mGluR7 agonists and / or Group III agonists. Accordingly, the present invention extends to the treatment of disorders associated with glutamate dysfunction by administering an effective amount of a modulator of mGluR7, including the compounds of the present invention, in combination with an mGluR7 agonist and / or a Group III mGluR agonist.

[0159] Compounds of the present invention may also be used in combination with psychotherapy in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions in which compounds of the present invention may have utility.

[0160] The present invention also relates to pharmaceutical compositions according to the present invention, further comprising another compound, that modulate, preferably inhibit or reduce, the activity of an mGluR, wherein the mGluR is preferably mGluR7.

[0161] The present invention also provides - at least one compound according to the invention or a pharmaceutical composition comprising at least one compound according to the invention, - at least one other compound that modulates the activity of mGluRs (preferably mGluR7), preferably inhibits or reduces the activity of mGluRs, or a pharmaceutical composition comprising at least one compound that modulates the activity of mGluRs (preferably mGluR7), preferably inhibits or reduces the activity of mGluRs; The present invention also relates to a kit comprising:

[0162] dose As is well known to those skilled in the art, the exact dose (or therapeutically effective amount, as that term is used herein) and frequency of administration will depend on the type of compound of the invention being used, the type of condition being treated, the severity of the condition being treated, the age, weight, sex, extent of the disease, and general health of the patient being treated, as well as other medications the subject may be taking, etc. It will also be appreciated that the effective daily dose may be lowered or increased depending on the response of the subject and / or the evaluation of the physician prescribing the compound of the invention.

[0163] The pharmaceutical composition contains, depending on the mode of administration, 0.05 to 99% by mass, preferably 0.1 to 70% by mass, more preferably 0.1 to 50% by mass of the active ingredient, and 1 to 99.95% by mass, preferably 30 to 99.9% by mass, more preferably 50 to 99.9% by mass of a pharmaceutically acceptable carrier. All percentages herein are based on the total mass of the composition.

[0164] The amount of a compound of the present invention that can be combined with a carrier material to produce a single dose will vary depending on the disease being treated, the mammalian species being treated, the particular mode of administration, etc. However, as a general guideline, a suitable unit dose of a compound of the present invention preferably contains, for example, 0.1 mg to about 1000 mg of active compound. A preferred unit dose is 1 mg to about 500 mg. A more preferred unit dose is 1 mg to about 300 mg. An even more preferred unit dose is 1 mg to about 100 mg.

[0165] Such a unit dose can be administered two or more times daily, for example, two, three, four, five, or six times daily, preferably once or twice daily. For a 70 kg adult, the total dose can be adjusted so that the single dose is in the range of 0.001 to about 15 mg per kg of body weight. A preferred single dose is 0.01 to about 1.5 mg per kg of body weight. Such treatment can be continued for weeks or months, or even years. However, the specific dose level for an individual patient will, of course, vary depending on a variety of factors, including, but not limited to, the activity of the specific compound used, the age, weight, general health, sex, diet, etc., of the individual being treated, the time and route of administration, excretion rate, other drugs previously administered to the subject, and the severity of the particular disease for which the subject is being treated.

[0166] Typical dosages include a tablet of 1 mg to about 100 mg or 1 mg to about 300 mg taken once a day or multiple times a day, or a sustained-release capsule or tablet containing a relatively high concentration of the active ingredient taken once a day. The sustained-release effect can be achieved by using multiple capsule materials with different dissolving pH values, capsule or gel formulations with an osmotic sustained-release effect, or other known controlled-release means.

[0167] It may be necessary to use dosages outside these ranges in some cases, as will be apparent to those skilled in the art. It should also be noted that a clinician or treating physician will know how and when to initiate, interrupt, adjust, or terminate treatment depending on an individual patient's response. [Example]

[0168] Preparation of compounds

[0169] A. Method of synthesis The compounds of the present invention, particularly those of formulae (I), (II), and (III), can be prepared by methods known to those skilled in the art of organic synthesis or by using the following synthetic schemes. In all schemes described below, it is understood that protecting groups for sensitive or reactive groups are used where necessary in accordance with general principles of organic chemistry. Protecting groups can be manipulated according to standard methods (TW Green and PGM Wuts, 1991, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc.). These groups are subsequently removed at an appropriate stage of the synthesis by methods well known to those skilled in the art.

[0170] The compounds of the present invention may be mixtures of enantiomers, which may be resolved into R- and S-enantiomers. For example, if a specific enantiomer is desired, it can be separated from a racemic mixture, e.g., using chiral chromatographic techniques. Alternatively, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, and the resulting diastereomeric mixture separated. The auxiliary can then be cleaved to give the desired pure enantiomer. Alternatively, for molecules containing basic functionalities, such as amino or acidic functionalities, such as carboxyl, resolution can be achieved by fractional crystallization as optically active acid salts using various solvents, or by other methods known in the literature.

[0171] Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art (EL Eliel, SH Wilen and LN Mander, 1984, Stereochemistry of Organic Compounds, Wiley-Interscience).

[0172] Among the compounds of formulae (I) to (III), Ar 1 or Ar 2 Many of the heterocyclic compounds in which is a heteroaromatic or heterocyclic group can be prepared using synthetic routes well known in the art (AR Katrizky and CW Rees, 1984, Comprehensive Heterocyclic Chemistry, Pergamon Press).

[0173] The synthesis of mGluR modulators disclosed in this invention was prepared using the following synthetic schemes. Specific conditions for carrying out these reactions are provided in the Examples below. The synthetic schemes set forth below are illustrative approaches to the compounds of the invention, but these routes should not be construed as the only possible synthetic routes to the compounds of the invention.

[0174] The compounds of formulae (I) to (III) can be converted into their pure enantiomers (+) and (-) by, for example, using chiral separation.

[0175] R 9 Compounds of formula (I), (II) and (III) in which is hydrogen can be obtained according to Scheme 1 below. [ka]

[0176] The cyclic ketone intermediate 1 is commercially available or can be synthesized by one skilled in the art of organic chemistry using several methods described in the literature.

[0177] The secondary alcohol intermediate 2 can be prepared by, for example, the organometallic reagent Ar 2 The organometallic reagents can be obtained by nucleophilic addition of -M (M = Li or MgX) from the corresponding appropriately substituted aromatic rings by metal halide exchange, e.g., using nBuLi or iPrMgCl, under an inert atmosphere, e.g., nitrogen, at a controlled temperature, e.g., -78 °C, in an aprotic solvent, e.g., dry THF (step i).

[0178] Intermediate 2 can be further dehydrated under acidic conditions, such as TFA, or in the presence of DCM at room temperature or under reflux to form intermediate 3 (step ii).

[0179] The cycloalkenyl ketone intermediate 3 can be converted to the corresponding cycloalkyl ketone intermediate 4 (step iii) by hydrogenolysis using, for example, a palladium catalyst such as Pd / C under a hydrogen atmosphere at a pressure such as 50 psi and a temperature such as 30°C.

[0180] The ketone intermediate 4 is further reacted with POCl in the presence of DMF to provide the chlorocarbonyl intermediate 5 (Step iv), which can be subjected to a carbonylative coupling reaction using a CO-releasing reagent such as carbon monoxide, a base such as EtN or AcONa, a transition metal catalyst such as Pd(dppf)Cl, or a catalyst such as Pd(OAc) in combination with a ligand such as dppf in a solvent such as MeOH at a suitable temperature to provide the lactone intermediate 6 (Step v).

[0181] According to Scheme 1, Method A, intermediate 6 is reacted with an aryl or heteroaryl hydrazine Ar 1 -NH2-NH2. 1 -NH-NH may be commercially available or can be prepared by one skilled in the art of organic chemistry in the presence of a catalyst such as PTSA in a solvent such as toluene or EtOH at an appropriate temperature (step ix). 4 , R8 , and R 9 is hydrogen.

[0182] Alternatively, according to Method B in Scheme 1, intermediate 6 can be converted to hydrazine NH by using AcOH in the presence of a solvent such as EtOH under acidic conditions and at a suitable temperature, or by using PTSA in the presence of a solvent such as toluene. 2 NH 2 (step vii) to provide intermediate 7. This intermediate 7 can be reacted with a (hetero)aromatic halide Ar 1 -X (preferably Ar 1 -Br) at a suitable temperature, for example, in the presence of a catalyst / ligand system such as Pd2(dba)3 / xantphos, a base such as t-BuOK, and a solvent such as toluene, or by copper-mediated coupling using CuI and a ligand such as DMEDA or a cyclic diamine ligand in the presence of a base such as K3PO4, and a solvent such as DMF or a mixed solvent such as DMF / dioxane (step viii), to give the desired product when Y is CH and R 4 , R 8 , and R 9 is hydrogen.

[0183] Alternatively, intermediate 7 can be reacted with a boronic acid or ester Ar 1 -B(OR')2 with a catalyst such as Cu(OAc)2 in the presence of a base such as pyridine in a solvent such as CH2Cl2 at a suitable temperature (step ix) to give a compound in which Y is CH and R 4 , R 8 , and R 9 Final compounds of formula (I), (II) and (III) can be obtained in which is hydrogen.

[0184] Alternatively, according to Scheme 1, Method C, lactone intermediate 6 can be converted to ester intermediate 8 using aqueous NaOH, followed by alkylation with a haloalkyl reagent (such as ethyl iodide) in the presence of DMF at a suitable temperature (Step x). This intermediate 8 can then be subjected to Step xi followed by Steps viii or ix, or Step xii, as described in Steps A and B, to afford intermediates 8 in a one or two step sequence where Y is CH and R 4 and R 8 Final compounds of formula (I), (II) and (III) can be obtained in which is hydrogen.

[0185] R 9 Compounds of formula (I), (II) and (III) in which is hydrogen can be obtained according to Scheme 2 below. [ka]

[0186] The cyclic ketoacetal intermediate 9 is reacted with POCl in the presence of DMF to generate the chlorocarbonyl intermediate 10 (Step i). This intermediate 10 is then subjected to a carbonylative coupling reaction using a CO-releasing agent, such as a CO-releasing agent, in the presence of a base such as EtN or AcONa, in the presence of a transition metal catalyst such as Pd(dppf)Cl, or in combination with a catalyst such as Pd(OAc) and a ligand such as dppf, in a solvent such as MeOH at a suitable temperature to give the ester-aldehyde intermediate 11 (Step ii). The synthesis of intermediate 12 can be achieved by reacting intermediate 11 with hydrazine NHNH under acidic conditions at a suitable temperature using AcOH in the presence of a solvent such as EtOH or PTSA in the presence of a solvent such as toluene (Step iii), followed by the addition of an aromatic halide, Ar, in a solvent such as toluene at a suitable temperature. 1 -X (preferably Ar 1-Br) in the presence of a catalyst / ligand system such as Pd2(dba)3 / xantphos and a base such as t-BuOK, or copper-mediated coupling using CuI and a ligand such as DMEDA or a cyclic diamine ligand in the presence of a base such as K3PO4 and a solvent such as DMF or a mixture of solvents such as DMF / dioxane (step iv).

[0187] Alternatively, intermediate 11 can be reacted with arylhydrazine Ar in the presence of a catalyst such as PTSA and a solvent such as toluene or EtOH. 1 Reaction with -NH2-NH2 (either commercially available or can be prepared by one skilled in the art of organic chemistry) at an appropriate temperature may provide intermediate 13 directly (step v).

[0188] Treatment of intermediate 13 under acidic conditions using TFA or HCl solution in the presence of a solvent such as acetonitrile or DCM at a suitable temperature provides intermediate 14 (Step vi). Reaction of ketone intermediate 14 with TfO in the presence of a base such as EtN and a solvent such as DCM at a suitable temperature provides the key triflate intermediate 15 (Step vii).

[0189] According to Scheme 2, Method A, intermediate 15 can be converted to a boronic ester Ar in the presence of a catalyst / ligand system and a base such as Pd(PPh), NaCO, or KCO in a solvent such as THF or a dioxane / HO mixture at a suitable temperature. 1 -B(OR')2 or boronic acid Ar 1 Suzuki cross-coupling reaction with -B(OH)2 provides intermediate 16 (step viii).

[0190] Alternatively, according to Method B of Scheme 2, intermediate 15 can be reacted with a bis-spinacol-diborane ester in the presence of a base such as Na2CO3 or K2CO3 and a catalyst system such as Pd(dppf)Cl2 in a solvent such as dioxane at a suitable temperature to provide intermediate 17 (step x). Intermediate 17 can be reacted with an aromatic halide, Ar, in the presence of a base such as Na2CO3 and a catalyst / ligand system such as Pd(dppf)Cl2 in a solvent such as dioxane-HO at a suitable temperature to provide intermediate 17. 2 -X (preferably Ar 2 —Br) to generate intermediate 16 (step xi).

[0191] Finally, intermediate 16 can be hydrogenolyzed using palladium hydroxide in the presence of ammonium formate in a solvent such as EtOH at a suitable temperature to reduce the cyclic double bond, ultimately affording compounds of formula (I), (II) and (III) (where Y is CH and R 2 and R 8 is hydrogen.) is provided (step ix).

[0192] The compounds of formula (I), (II) and (III) can be obtained according to Scheme 3 below. [ka]

[0193] The cyclic enone intermediate 18 can be obtained commercially or can be synthesized by one skilled in the art using several methods described in the literature. This intermediate 18 can be prepared by reacting the cyclic enone intermediate 18 with the boronate ester Ar in the presence of a catalyst / ligand system such as Rh(COD)Cl, a base such as KOX, and a solvent such as dioxane / HO under an inert atmosphere at a suitable temperature. 1 -B(OR')2 or boronic acid Ar 1A cross-coupling reaction using -B(OH)2 provides intermediate 19 (step i). The ketone intermediate 19 is reacted with POCl3 in the presence of DMF to generate intermediate 20 (step ii). Intermediate 20 is then subjected to a carbonylative coupling reaction using a CO-releasing agent such as carbon monoxide in the presence of a base such as ET3N or AcONa and a transition metal catalyst such as Pd(dppf)Cl2 in a solvent such as EtOH at a suitable temperature to provide the ester-aldehyde intermediate 21 (step iii). Intermediate 21 is then reacted with (hetero)arylhydrazine Ar in the presence of a catalyst such as PTSA and a solvent such as toluene or EtOH at a suitable temperature to provide the ester-aldehyde intermediate 21. 1 -NH-NH (which may be commercially available or may be prepared by one skilled in the art of organic chemistry) (step iv) to finally give compounds of formula (I), (II) and (III) (where Y is CH and R 2 , R 8 and R 9 is hydrogen.) is provided.

[0194] Compounds of formula (I), (II) and (III) (wherein R 9 is hydrogen.) can be obtained according to Scheme 4 below. [ka]

[0195] The cycloalkylene ketone intermediate 18 can be commercially available or can be synthesized by one skilled in the art using several methods described in the literature. Intermediate 18 can be prepared by reacting intermediate 18 with an appropriately substituted aromatic halide, Ar, in the presence of a transition metal catalyst such as Pd(dppf)Cl, in a solvent such as EtN or NaCO, or in the presence of DMSO at a suitable temperature. 2 -X (preferably Ar 2 -Br or Ar 2 -I) to prepare intermediate 31 (step i).

[0196] The cycloalkenyl ketone intermediate 31 can be converted to the corresponding ketoester intermediate 34 by a two-step reaction sequence: (step ii) α-carboxylation using, for example, cyanoethyl carbonate or diethyl carbonate in the presence of a base such as LDA or NaH in an aprotic solvent such as THF at a controlled temperature such as −78° C., followed by (step iii) hydrogenolysis of the double bond in the presence of a catalytic palladium, for example, Pd / C, under a hydrogen atmosphere at a pressure such as 50 psi at an appropriate temperature.

[0197] This two-step sequence can also be carried out starting with hydrogenolysis step (iii) followed by α-carboxylation step (ii) using the conditions previously described to provide ketoester intermediate 34.

[0198] Ketoester intermediate 34 can be reacted with formamidine in the presence of a base such as K2CO3 and a solvent such as EtOH at a suitable temperature to provide intermediate 35 (step iv).

[0199] Intermediate 35 can be prepared by a cross-coupling reaction such as that described in Scheme 1, for example, by coupling an aromatic halide, Ar, to a methyl group in the presence of a catalyst / ligand system such as Pd2(dba)3 / Xantphos, a base such as t-BuOK, and a solvent such as toluene. 1 -X (preferably Ar 1 -Br) or by copper mediated coupling reaction using ligands such as CuI, DMEDA or cyclic diamine ligands in the presence of a base such as KPO in a solvent such as DMF or a mixed solvent such as DMF / dioxane at an appropriate temperature (step v), to give the final compounds of formula (I), (II) and (III) (wherein R 2 , R 7 and R 9 is hydrogen.) is provided.

[0200] Ar 2 Compounds of formula (I), (II) or (III) in which is substituted with an OR group can be obtained according to Scheme 5 below. [ka]

[0201] Compounds of formula (I), (II) and (III) represented by intermediate 49 (wherein Ar 2 where substituent B is a methoxy group. Reaction of (step i) with a dealkylating agent such as boron tribromide in a solvent such as DCM at a suitable temperature provides hydroxy intermediate 50. This hydroxy functionality can be decomposed into an alkyl halide (e.g., R 2- I, R 2- Br or R 2 -Cl) to give compounds of formula (I), (II) and (III), 2 is substituted with an oxo group.

[0202] Ar 1 Compounds of formula (I), (II) or (III) in which is substituted by an alkyl, aryl, heteroaryl, amino or alkoxy radical can be obtained according to Scheme 6 below. [ka]

[0203] Intermediate 51 (represented by, but not limited to, intermediate 7 in Scheme 1 or 35 in Scheme 4) can be converted to a compound of formula A-Ar in the presence of a catalyst / ligand system (e.g., Pd2(dba)3 / Xantphos) in a base (e.g., t-BuOK) and a solvent (e.g., toluene) at a suitable temperature. 1Cross-coupling with a halo(hetero)aryl of -X provides intermediate 51 (step i). According to Method A, intermediate 52, where A is a halide radical Cl, Br, or I, can be further reacted with a boronic acid or boronic ester in the presence of a catalyst / ligand system such as Pd(dppf)Cl or RuPhos, in the presence of a base such as KOAc or CsCO, in a solvent such as dioxane or dioxane-HO at a suitable temperature (step ii) to give Ar 1 Compounds of formula (I), (II), and (III) are provided wherein is an alkyl, aryl, or heteroaryl radical.

[0204] According to Method B, the same halide intermediate 52, where A is a halide radical, can be reacted with an amine R in the presence or absence of a catalyst / ligand system such as Pd(dppf)Cl or RuPhos, in the presence of a base such as NaCO or CsCO, in a solvent such as dioxane, at a suitable temperature. 1 R 2 NH (step iii) to give Ar 1 Compounds of formula (I), (II) and (III) are provided in which R 1 has an amino group.

[0205] Further, according to Method C, intermediate 52 (A is an -OH radical) can be reacted with an alkyl halide (such as R—I, R—Br, or R—Cl) in a solvent such as DMS in the presence of a base such as CsCO at a suitable temperature (step iv) to give Ar 1 Compounds of formula (I), (II) and (III) are provided wherein:

[0206] Or, Ar 2 The compounds of formulae (I), (II) and (III) having a carboxyl group can be obtained by the following scheme 7. [ka]

[0207] Intermediate 53, where X is Br, can be subjected to a cross-coupling reaction using tributyltin ethoxyvinyl in the presence of a catalyst / ligand system (e.g., Pd(PPh3)4) and a base (e.g., t-BuOK) in a solvent (e.g., dioxane) at a suitable temperature, followed by hydrolysis in an acidic medium such as aqueous HCl in a solvent such as EtOH to provide intermediate 54. Reduction of the cyclic double bond of intermediate 54 (step ii) in the presence of palladium on charcoal in the presence of ammonium formate or the like in a solvent such as EtOH at a suitable temperature finally affords intermediate 54, where Y is CH and Ar 2 Compounds of formula (I), (II) and (III) are provided in which R 1 has an acetyl group.

[0208] B. Experimental Section Illustrative methods for preparing the compounds of this invention are described in the following examples. Unless otherwise specified, all starting materials were obtained from commercial suppliers and used without purification. Specifically, the following abbreviations may be used in the examples and throughout the specification:

[0209] [Table 1]

[0210] All temperatures are in degrees Celsius unless otherwise noted. All reactions were conducted under an inert atmosphere at room temperature unless otherwise noted.

[0211] Example 1: 6-(2,4-Dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one was prepared according to Scheme 1, Method A. [ka]

[0212] Intermediate 2a: 8-(2,4-dimethyl-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol According to Scheme 1, Step i, a solution of 1-bromo-2,4-dimethyl-benzene (20.00 g, 108.07 mmol, 1.00 eq) in THF (100 mL) was cooled to -70 °C under a N atmosphere, and n-BuLi (2.5 M, 45.39 mL, 1.05 eq) was added dropwise. The reaction mixture was stirred at -70 °C for 2 h. Subsequently, a solution of 1,4-dioxa-spiro[4.5]decan-8-one (17.72 g, 113.47 mmol, 1.05 eq) in THF (100 mL) was added dropwise at -70 °C, and the reaction mixture was stirred at -70 °C for 2 h. The reaction mixture was quenched with water (300 mL) and extracted with EtOAc (200 mL × 2). The organic layer was dried over NaSO and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (PE: EtOAc = 10 / 1 to 5 / 1) to give Intermediate 2a (24.00 g, 86.00 mmol, 79.57% yield) as a pale yellow solid.

[0213] 1 H NMR (DMSO-d6; 400MHz) δ 7.31-7.29 (m, 1H), 6.90-6.89 (m, 2H), 4.66 (s, 1H), 3.87 (s, 4H), 2.49 (s, 3H), 2.21 (s, 3H), 2.00-1.94 (m, 4H), 1.79-1.76 (m, 2H), 1.53-1.51 (m, 2H).

[0214] Intermediate 3a: 4-(2,4-dimethyl-phenyl)-cyclohex-3-enone According to Scheme 1, step ii, a solution of intermediate 2a (10.00 g, 38.12 mmol, 1.00 eq) in TFA (500.00 mL) was stirred at 15 °C for 1 h, followed by stirring and heating the mixture at 80 °C for 18 h. The mixture was concentrated in vacuo. The residue was quenched with saturated NaHCO solution, the pH was adjusted to pH 7-8, and extracted with EtOAc (200 mL × 2). The organic layer was dried over NaSO and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE: EtOAc = 10 / 1 to 5 / 1). Intermediate 3a (11.00 g, 54.92 mmol, 72.04% yield) was obtained as a pale yellow oil.

[0215] 1 H NMR (CDCl3; 400MHz) δ 7.06-6.97 (m, 4H), 6.23-6.18 (m, 1H), 3.95-3.91 (m, 1H), 2.57-2.53 (m, 2H), 2.51 (s, 3H), 2.50-2.33 (m, 4H), 1.99-1.95 (m, 1H).

[0216] Intermediate 4a: 4-(2,4-dimethylphenyl)cyclohexan-1-one According to Scheme 1, Step iii, to a solution of intermediate 3a (10.00 g, 49.93 mmol, 1.00 eq) in EtOAc (100.00 mL) under a N atmosphere was added Pd / C (2.00 g, 49.93 mmol, 1.00 eq). The suspension was degassed in vacuo and purged with H for several hours. The mixture was stirred under H (50 psi) at 30 °C for 4 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. Crude intermediate 4a (10.00 g, 49.43 mmol, 99.01% yield) was obtained as a brown solid and used directly in the next step.

[0217] 1H NMR (CDCl3; 400MHz) δ 7.12-7.02 (m, 3H), 3.25-3.22 (m, 1H), 2.57-2.53 (m, 4H), 2.41 (s, 3H), 2.33 (s, 3H), 2.16-2.15 (m, 2H), 1.96-1.94 (m, 2H).

[0218] Intermediate 5a: 2-chloro-5-(2,4-dimethyl-phenyl)-cyclohex-1-enecarbaldehyde According to Scheme 1, Step iv, to a solution of intermediate 4a (13.01 g, 177.96 mmol, 12.00 eq) in CHCl (10 mL) was added POCl (6.82 g, 44.49 mmol, 3.00 eq) dropwise at 0 °C under a N atmosphere. After stirring at 10 °C for 1 h, a solution of intermediate 1c (3.00 g, 14.83 mmol, 1.00 eq) in CHCl (40 mL) was added dropwise. The mixture was stirred at 50 °C for 4 h. The mixture was quenched with saturated NaHCO solution, the pH was adjusted to pH 7–8, and extracted with CHCl (150 mL × 2). The organic layer was dried over NaSO and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE / EtOAc=10 / 1) to give intermediate 5a (1.70 g, 6.83 mmol, 46.06% yield) as a yellow oil.

[0219] 1 H NMR (400MHz, CDCl3) δ 10.25 (s, 1H), 7.09-6.95 (m, 3H), 3.03-2.73 (m, 4H), 2.32 (d, J = 2.6 Hz, 6H), 2.23-2.06 (m, 1H), 2.05-1.90 (m, 2H).

[0220] Intermediate 6a: 5-(2,4-dimethylphenyl)-3-methoxy-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one According to Scheme 1, Step v, intermediate 5a (500.00 mg, 2.01 mmol, 1.00 eq), Pd(dppf)Cl (147.08 mg, 201.01 μmol, 0.10 eq), and EtN (610.19 mg, 6.03 mmol, 3.00 eq) were mixed in MeOH (10.00 mL) under a N atmosphere. The suspension was degassed under vacuum and purged with CO for several hours. The mixture was stirred at 90 °C under a CO atmosphere (1 MPa) for 12 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. Intermediate 6a (650.00 mg, crude) was obtained as a brown solid.

[0221] 1 H NMR: (400MHz, CDCl3) δ 7.09-6.98 (m, 3H), 5.67 (s, 1H), 3.60 (s, 3H), 3.19-3.05 (m, 1H), 2.70-2.59 (m, 1H), 2.57-2.44 (m, 2H), 2.33 (s, 3H), 2.31 (s, 3H), 2.06-1.95 (m, 1H), 1.88-1.76 (m, 1H).

[0222] Example 1: 6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one According to Scheme 1, Method A, Step vi, a mixture of Intermediate 6a (200.00 mg, 734.38 μmol, 1.00 eq) and pyridin-2-yl-hydrazine hydrochloride (160.28 mg, 1.47 mmol, 2.00 eq) in toluene (10.00 mL) was stirred and heated at 110° C. for 8 h. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and water (100 mL) and extracted with EtOAc (100 mL×2). The organic layer was dried over NaSO and concentrated in vacuo. The crude product was purified by preparative HPLC to give Example 1 (30.00 mg, 90.52 μmol, 6.16% yield) as a brown solid.

[0223] 1H-NMR (400 MHz, CDCl3) δ 8.67 (d, J = 4.0 Hz, 1H), 7.82 - 7.91 (m, 1H), 7.69 - 7.77 (m, 2H), 7.33 - 7.39 (m, 1H), 6.99 - 7.15 (m, 3H), 3.09 - 321 (m, 1H), 2.99 (d, J = 17.6 Hz, 1H), 2.76 - 2.86 (m, 1H), 2.59 - 2.75 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2.08 - 2.19 (m, 1H), 1.80 - 1.95 (m, 1H).

[0224] Example 2: (6-(3-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method A. [ka]

[0225] Intermediate 6b: 3-Methoxy-5-(3-methoxyphenyl)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one Following Scheme 1, steps i-v, intermediate 6b was prepared in the same manner as intermediate 6a in Example 1, starting from 1-bromo-3-methoxybenzene, and was obtained as a brown liquid in 19% overall yield. m / z (M+H) + = 275.1.

[0226] Example 2: 6-(3-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 1, Method A, Step vi, Example 2 was prepared according to Example 1 starting from Intermediate 6b (800.00 mg, 832.35 μmol) using pyridin-2-yl-hydrazine hydrochloride (181.77 mg, 1.25 mmol) to obtain a yellow solid (8.20 mg, 24.60 μmol).

[0227] 1 H-NMR (400 MHz, MeOD) δ 8.62-8.61 (m, 1H), 8.08-8.05 (m, 1H), 7.90(s,1H), 7.69-7.67(m,1H),7.62-7.56(m,1H),7.29-7.27(m,1H), 6.94-6.90(m, 2H). 6.83-6.84(1H), 3.07-2.86 (m, 4H), 2.68-2.57 (m, 1H), 1.99-1.96 (m, 1H), 1.96-1.93 (m, 1H).

[0228] Example 3: 6-(4-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method A. [ka]

[0229] Intermediate 6c: 3-Methoxy-5-(4-methoxyphenyl)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one According to Scheme 1, steps i-v, intermediate 6c was prepared similarly to intermediate 6a in Example 1 starting from 1-bromo-4-methoxybenzene and obtained as a brown liquid in 14% overall yield.

[0230] 1 H NMR (MeOD; 400MHz) δ 7.22-7.20 (m, 2H), 6.91-6.87(m, 2H), 5.88 (s, 1H), 3.93-3.91 (m, 1H), 3.83-3.81(m,1H), 3.77-3.80 (m, 3H), 2.95-2.85 (m, 1H), 2.64-2.59 (m, 1H), 2.31-2.42 (m, 3H), 2.05-2.03 (m, 1H), 1.85- 1.80 (m,1H), 1.30-1.25 (m, 3H).

[0231] Example 3: 6-(4-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 1, Method A, Step vi, Example 3 was prepared according to Example 1 starting from Intermediate 6c (200.00 mg, 693.63 μmol) and pyridin-2-yl-hydrazine hydrochloride (201.97 mg, 1.39 mmol) to afford Example 3 as a green solid (26.00 mg, 77.99 μmol).

[0232] 1 H-NMR (400 MHz, DMSO-d6) δ 8.61-8.60 (m, 1H), 8.04-8.00(m,1H), 7.59-7.56(m, 2H), 7.30-7.23(m,2H), 6.93-6.90(m,2H), 3.70 (s, 3H), 292-2.73 (m, 5H), 2.05-2.02 (m, 1H), 1.85-1.82(m, 1H),1.81-1.78 (m, 1H).

[0233] Example 4: (-)-6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one and Example 5: (+)-6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one [ka]

[0234] The constituent enantiomers of racemic Example 1 (400 mg) were separated by preparative SFC to give (-)6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one Example 4 (72 mg, 18%) in 100% enantiomeric excess and (+)6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one Example 5 (59 mg, 15%) in 99% enantiomeric excess, both as yellow solids.

[0235] Example 4: 1 H-NMR (400 MHz, CDCl3) δ 8.67 (br.s., 1H), 7.82 - 7.91 (m, 1H), 7.69 - 7.77 (m, 2H), 7.33 - 7.39 (m, 1H), 6.99 - 7.15 (m, 3H), 3.09 - 321 (m, 1H), 2.99 (d, J = 17.6 Hz, 1H), 2.76 - 2.86 (m, 1H), 2.59 - 2.75 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2.08 - 2.19 (m, 1H), 1.80 - 1.95 (m, 1H).

[0236] Example 5: 1 H-NMR (400 MHz, CDCl3) δ 8.67 (br.s., 1H), 7.82 - 7.91 (m, 1H), 7.69 - 7.77 (m, 2H), 7.33 - 7.39 (m, 1H), 6.99 - 7.15 (m, 3H), 3.09 - 321 (m, 1H), 2.99 (d, J = 17.6 Hz, 1H), 2.76 - 2.86 (m, 1H), 2.59 - 2.75 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2.08 - 2.19 (m, 1H), 1.80 - 1.95 (m, 1H).

[0237] Example 6: 6-(2,4-Dimethylphenyl)-2-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0238] Intermediate 7a: 6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 1, step vii, to a solution of intermediate 6a (1.2 g, 4.19 mmol, 1 eq) in EtOH (10 mL) and AcOH (1 mL) was added N2H4.HO (427.66 mg, 8.37 mmol, 415.20 μL, 2.0 eq). The mixture was stirred at 80 °C for 3 h and then cooled to 0 °C. The formed white solid was collected after filtration. Intermediate 7a (830 mg, 3.26 mmol, 77.96% yield) was obtained as a white solid.

[0239] 1 H NMR (400MHz, DMSO-d6) δ 12.74 (s, 1H), 7.64 (s, 1H), 7.15-7.08 (m, 1H), 7.03-6.93 (m, 2H), 3.09-2.93 (m, 1H), 2.74-2.57 (m, 3H), 2.47-2.37 (m, 1H), 2.28 (s, 3H), 2.24 (s, 3H), 1.96-1.85 (m, 1H), 1.83-1.68 (m, 1H).

[0240] Example 6: 6-(2,4-dimethylphenyl)-2-(6-chloropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 1, Step viii, to a solution of intermediate 7a (100.00 mg, 353.87 μmol, 1.00 eq) in DMF (5.00 mL) was added 5-chloro-2-bromopyridine (204.30 mg, 1.06 mmol, 3.00 eq), DMEDA (18.72 mg, 212.32 μmol, 22.82 μL, 0.60 eq), CuI (33.70 mg, 176.94 μmol, 0.50 eq), and KPO (187.79 mg, 884.68 μmol, 2.50 eq) at 20 °C under a N atmosphere. The mixture was then heated to 110 °C and stirred for 12 h. The reaction was filtered, and the filtrate was acidified to pH = 5 with 12 M aqueous HCl and filtered. The filtrate was purified by preparative HPLC to give Example 6 (71.93 mg, 196.61 μmol, 55.56% yield) as a gray-yellow solid.

[0241] 1 H-NMR (400 MHz, CDCl3) δ 8.62 (d, J=2.3 Hz, 1H), 7.87 - 7.82 (m, 1H), 7.78 - 7.73 (m, 2H), 7.14 - 7.09 (m, 1H), 7.08 - 7.04 (m, 2H), 3.20 - 3.11 (m, 1H), 3.04 - 2.95 (m, 1H), 2.87 - 2.78 (m, 1H), 2.77 - 2.60 (m, 2H), 2.34 (s, 3H), 2.33 (s, 3H), 2.20 - 2.11 (m, 1H), 1.95 - 1.83 (m, 1H).

[0242] Example 7: 2-(4-chloropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0243] According to Scheme 1, step viii, Example 7 was prepared according to Example 6 starting from Intermediate 7a (150.00 mg, 530.81 μmol) and 2-bromo-4-chloropyridine (306.45 mg, 1.59 mmol) to afford Example 7 (178.10 mg, 484.85 μmol, 91.34% yield) as a brown solid.

[0244] 1 H-NMR (400 MHz, CDCl3) δ 8.49 (d, J=5.4 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.66 (s, 1H), 7.29 (dd, J=1.8, 5.3 Hz, 1H), 7.05 - 7.00 (m, 1H), 6.99 - 6.94 (m, 2H), 3.12 - 3.02 (m, 1H), 2.96 - 2.86 (m, 1H), 2.80 - 2.69 (m, 1H), 2.67 - 2.53 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 2.10 - 2.02 (m, 1H), 1.86 - 1.74 (m, 1H).

[0245] Example 8: 2-(3-chloropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0246] According to Scheme 1, step viii, Example 8 was prepared according to Example 6 starting from Intermediate 7a (200.00 mg, 707.74 μmol) and 2-bromo-3-chloropyridine (408.59 mg, 2.12 mmol) to afford Example 8 (24.40 mg, 66.69 μmol, 9.42% yield) as a gray-yellow solid.

[0247] 1H-NMR (400 MHz, CDCl3) δ 8.58 (dd, J=1.6, 4.7 Hz, 1H), 7.95 (dd, J=1.5, 8.0 Hz, 1H), 7.72 (s, 1H), 7.44 (dd, J=4.6, 8.0 Hz, 1H), 7.16 - 7.11 (m, 1H), 7.10 - 7.04 (m, 2H), 3.17 (br s, 1H), 3.02 (br d, J=19.6 Hz, 1H), 2.89 - 2.78 (m, 1H), 2.78 - 2.61 (m, 2H), 2.38 (s, 3H), 2.34 (s, 3H), 2.20 - 2.10 (m, 1H), 1.91 (br s, 1H).

[0248] Example 9: 6-(2,4-dimethylphenyl)-2-(6-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0249] According to Scheme 1, step viii, Example 9 was prepared according to Example 6 starting from Intermediate 7a (70.00 mg, 275.23 μmol) and 2-bromo-6-fluoropyridine (145.31 mg, 825.69 μmol) to afford Example 9 (32.00 mg, 91.59 μmol, 33% yield) as a yellow solid.

[0250] 1 H-NMR (400 MHz, DMSO-d6) δ 8.23-8.21 (m, 1H), 7.88 (s,1H), 7.61-7.59 (m,1H), 7.36-7.34 (m,1H), 7.16-7.13 (m,1H), 7.02-7.00(m,2H).

[0251] Example 10: 6-(2,4-dimethylphenyl)-2-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0252] According to Scheme 1, step viii, Example 10 was prepared according to Example 6 starting from Intermediate 7a (70.00 mg, 275.23 μmol) and 2-bromo-5-fluoropyridine (145.31 mg, 825.69 μmol) to afford Example 10 (32.00 mg, 91.59 μmol, 23% yield) as a yellow solid.

[0253] 1 H-NMR (400 MHz, DMSO-d6) δ 8.62-8.61 (m, 1H), 7.97-7.95 (m,1H), 7.86 (s,1H), 7.71-7.67 (m,1H), 7.16-7.14 (m,1H), 7.02-7.00 (m,2H), 3.10-3.07 (m,1H), 2.84-2.70 (m,4H), 2,30 (s,3H), 2.25 (s,3H), 1.94-1.84 (m,1H), 1.83-1.81 (m,1H).

[0254] Example 11: 6-(2,4-dimethylphenyl)-2-(4-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0255] According to Scheme 1, step viii, Example 11 was prepared according to Example 6 starting from Intermediate 7a (60.00 mg, 235.91 μmol) and 2-bromo-4-fluoropyridine (103.79 mg, 589.78 μmol) to afford Example 11 (24.00 mg, 68.69 μmol, 29% yield) as a yellow solid.

[0256] 1 H-NMR (400 MHz, DMSO-d6) δ 8.66 (s,1H), 7.88 (s,1H), 7.66-7.61 (m,1H), 7.53-7.51 (m,1H), 7.16-7.14 (m,1H), 7.03-7.00 (m,2H), 3.08-3.01 (m,1H), 2.84-2.58 (m,4H), 2.30 (s,3H), 2.25 (s,3H), 1.94-1.84 (m,1H), 1.83-1.81 (m,1H).

[0257] Example 12: 6-(2,4-dimethylphenyl)-2-(3-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0258] According to Scheme 1, step viii, Example 12 was prepared according to Example 6 starting from Intermediate 7a (90.00 mg, 353.87 μmol) and 2-bromo-3-fluoropyridine (186.83 mg, 1.06 mmol) to afford Example 12 (15.00 mg, 42.93 μmol, 12% yield) as a yellow solid.

[0259] 1H-NMR (400 MHz, DMSO-d6) δ 8.50-8.48 (m,1H), 8.06-8.01 (m,1H), 7.92 (s,1H), 7.72-7.70(s, 1H), 7.17-7.14 (m,1H), 7.02-7.00 (m,2H), 3.11-3.05 (m,1H), 2.86-2.68 (m,4H), 2.34 (s,3H), 2.27 (s,3H), 1.94-1.83 (m,2H).

[0260] Example 13: 6-(2,4-Dimethylphenyl)-2-(6-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0261] According to Scheme 1, step viii, Example 13 was prepared according to Example 6 starting from Intermediate 7a (70.00 mg, 275.23 μmol) and 2-bromo-4-methoxypyrimidine (129.37 mg, 688.08 μmol, 84.56 μL) to afford Example 13 (45.00 mg, 124.50 μmol, 45% yield) as a yellow solid.

[0262] 1 H-NMR (400 MHz, DMSO-d6) δ 7.93-7.84 (m,1H), 7.84 (s,1H), 7.16-7.12(m, 2H), 7.02-7.00(m,2H), 6.96-6.94 (m,1H), 3.83 (s,3H), 3.10-3.07 (m,1H), 2.81-2.66 (m,4H), 2.31 (s,3H), 2.25 (s,3H), 1.95-1.93 (m,1H), 1.83-1.80 (m,1H).

[0263] Example 14: 6-(2,4-Dimethylphenyl)-2-(5-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0264] According to Scheme 1, step viii, Example 14 was prepared according to Example 6 starting from Intermediate 7a (70.00 mg, 275.23 μmol) and 2-bromo-5-methoxypyrimidine (129.37 mg, 688.08 μmol) to afford Example 14 (30.00 mg, 83.00 μmol, 30.16% yield) as a yellow solid.

[0265] 1 H-NMR (400 MHz, DMSO-d6) δ 8.28-8.27 (m,1H), 7.82 (s,1H), 7.60-7.59(m,1H), 7.58-7.57 (m,1H), 7.16-7.13 (m,1H), 7.02-7.00 (m,2H), 3.91 (s,3H), 3.10-3.07 (m,1H), 2.93-2.55 (m,4H), 2.31 (s,3H), 2.25 (s,3H), 1.93-1.90 (m,1H), 1.84-1.80 (m,1H).

[0266] Example 15: 6-(2,4-dimethylphenyl)-2-(4-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0267] According to Scheme 1, step viii, Example 15 was prepared according to Example 6 starting from Intermediate 7a (70.00 mg, 275.23 μmol) and 2-bromo-4-methoxypyrimidine (129.37 mg, 688.08 μmol) to afford Example 15 (53.00 mg, 146.64 μmol, 53% yield) as a yellow solid.

[0268] 1 H-NMR (400 MHz, DMSO-d6) δ 8.41-8.39 (m,1H), 7.83 (s,1H), 7.16-7.10 (m,3H), 7.02-7.00 (m,1H), 3.89 (s,3H), 3.07-3.02 (m,1H), 2.78-2.66 (m,4H), 2.30 (s,3H), 2.25 (s,3H), 1.93-1.83 (m,1H), 1.82-1.80 (m,1H).

[0269] Example 16: 6-(2,4-Dimethylphenyl)-2-(3-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0270] According to Scheme 1, step viii, Example 16 was prepared according to Example 6 starting from Intermediate 7a (90.00 mg, 353.87 μmol) and 2-bromo-3-methoxypyrimidine (166.34 mg, 884.68 μmol) to afford Example 16 (17.00 mg, 47.03 μmol, 13% yield) as a yellow solid.

[0271] 1H-NMR (400 MHz, DMSO-d6) δ 8.15-8.13 (m,1H), 7.81 (s,1H), 7.72-7.70 (m,1H), 7.57-7.55 (m,1H), 7.16-7.14 (m,1H), 7.02-7.00 (m,2H), 3.80 (s,3H), 3.10-3.07(m,1H), 2.82-2.67 (m,4H), 2.31 (s,3H), 2.25 (s,3H), 1.92-1.81 (m,2H).

[0272] Example 17: 6-(2,4-Dimethylphenyl)-2-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0273] According to Scheme 1, step viii, Example 17 was prepared according to Example 6 starting from Intermediate 7a (80.00 mg, 283.10 μmol) and 2-bromo-6-methylpyridine (146.10 mg, 849.30 μmol, 96.75 μL) to afford Example 17 (59.06 mg, 170.97 μmol, 60.39% yield) as a gray-yellow solid.

[0274] 1 H-NMR (400 MHz, CDCl3) δ 7.81 - 7.69 (m, 2H), 7.45 (d, J=7.9 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 7.12 - 7.08 (m, 1H), 7.07 - 7.02 (m, 2H), 3.19 - 3.08 (m, 1H), 3.03 - 2.92 (m, 1H), 2.86 - 2.76 (m, 1H), 2.73 - 2.59 (m, 5H), 2.35 (s, 3H), 2.32 (s, 3H), 2.12 (td, J=2.9, 10.4Hz, 1H), 1.94 - 1.80 (m, 1H).

[0275] Example 18: 6-(2,4-Dimethylphenyl)-2-(5-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0276] According to Scheme 1, step viii, Example 18 was prepared according to Example 6 starting from Intermediate 7a (80.00 mg, 283.10 μmol) and 2-bromo-5-methylpyridine (146.10 mg, 849.30 μmol) to afford Example 18 (52.33 mg, 151.49 μmol, 53.51% yield) as a gray-yellow solid.

[0277] 1 H-NMR (400 MHz, CDCl3) δ 8.49 (d, J=1.5 Hz, 1H), 7.73 (s, 1H), 7.71 - 7.66 (m, 1H), 7.64 - 7.60 (m, 1H), 7.14 - 7.10 (m, 1H), 7.08 - 7.04 (m, 2H), 3.21 - 3.09 (m, 1H), 3.06 - 2.94 (m, 1H), 2.87 - 2.77 (m, 1H), 2.76 - 2.60 (m, 2H), 2.43 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H), 2.19 - 2.09 (m, 1H), 1.96 - 1.81 (m, 1H).

[0278] Example 19: 6-(2,4-dimethylphenyl)-2-(4-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0279] According to Scheme 1, step viii, Example 19 was prepared according to Example 6 starting from Intermediate 7a (80.00 mg, 283.10 μmol) and 2-bromo-4-methylpyridine (146.10 mg, 849.30 μmol, 94.26 μL) to afford Example 19 (69.51 mg, 201.22 μmol, 71.08% yield) as a white solid.

[0280] 1 H-NMR (400 MHz, CDCl3) δ 8.53 (d, J=5.1 Hz, 1H), 7.74 (s, 1H), 7.56 (s, 1H), 7.14 - 7.10 (m, 1H), 7.08 - 7.04 (m, 1H), 7.08 - 7.04 (m, 2H), 3.22 - 3.07 (m, 1H), 3.06 - 2.95 (m, 1H), 2.87 - 2.78 (m, 1H), 2.76 - 2.61 (m, 2H), 2.47 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H), 2.20 - 2.09 (m, 1H), 1.97 - 1.80 (m, 1H).

[0281] Example 20: 6-(2,4-dimethylphenyl)-2-(3-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0282] According to Scheme 1, step viii, Example 20 was prepared according to Example 6 starting from Intermediate 7a (80.00 mg, 283.10 μmol) and 2-bromo-3-methylpyridine (146.09 mg, 849.30 μmol) to afford Example 20 (8.60 mg, 24.75 μmol, 8.74% yield) as a gray-yellow solid.

[0283] 1H-NMR (400 MHz, CDCl3) δ 8.55 - 8.44 (m, 1H), 7.74 (d, J=6.7 Hz, 1H), 7.71 (s, 1H), 7.36 (dd, J=4.8, 7.7 Hz, 1H), 7.16 - 7.11 (m, 1H), 7.10 - 7.04 (m, 2H), 3.16 (br s, 1H), 3.07 - 2.94 (m, 1H), 2.88 - 2.78 (m, 1H), 2.77 - 2.61 (m, 2H), 2.38 (s, 3H), 2.36 - 2.33 (m, 1H), 2.34 (s, 3H), 2.27 (s, 3H), 2.20 - 2.09 (m, 1H), 1.98 - 1.83 (m, 1H).

[0284] Example 21: 6-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)picolinonitrile was prepared according to Scheme 1, Method B. [ka]

[0285] According to Scheme 1, step viii, Example 21 was prepared according to Example 6 starting from Intermediate 7a (80.00 mg, 283.10 μmol) and 6-bromopicolinonitrile (155.43 mg, 849.30 μmol) to afford Example 21 (53.43 mg, 146.31 μmol, 51.68% yield) as a white solid.

[0286] 1H-NMR (400 MHz, CDCl3) δ 8.05 - 7.99 (m, 2H), 7.81 - 7.75 (m, 2H), 7.13 - 7.10 (m, 1H), 7.08 - 7.05 (m, 2H), 3.21 - 3.11 (m, 1H), 2.99 (br dd, J=5.3, 19.1 Hz, 1H), 2.89 - 2.80 (m, 1H), 2.78 - 2.59 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.20 - 2.11 (m, 1H), 1.96 - 1.82 (m, 1H).

[0287] Example 22: 6-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)nicotinonitrile was prepared according to Scheme 1, Method B. [ka]

[0288] According to Scheme 1, step viii, Example 22 was prepared according to Example 6 starting from Intermediate 7a (80.00 mg, 283.10 μmol) and 6-bromonicotinonitrile (155.43 mg, 849.30 μmol) to afford Example 22 (21.19 mg, 59.45 μmol, 21.00% yield) as a white solid.

[0289] 1 H-NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.03 (d, J=2.3 Hz, 1H), 7.98 - 7.91 (m, 1H), 7.73 - 7.67 (m, 1H), 6.98 (d, J=17.4 Hz, 3H), 3.13 - 3.01 (m, 1H), 2.97 - 2.85 (m, 1H), 2.79 - 2.70 (m, 1H), 2.68 - 2.52 (m, 2H), 2.27 (s, 3H), 2.25 (s, 3H), 2.11 - 2.02 (m, 1H), 1.87 - 1.74 (m, 1H).

[0290] Example 23: 2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)isonicotinonitrile was prepared according to Scheme 1, Method B. [ka]

[0291] According to Scheme 1, step viii, Example 23 was prepared according to Example 6 starting from Intermediate 7a (80.00 mg, 283.10 μmol) and 2-bromoisonicotinonitrile (17.27 mg, 94.37 μmol) to afford Example 23 (28.72 mg, 80.58 μmol, 28.46% yield) as a white solid.

[0292] 1 H-NMR (400 MHz, CDCl3) δ 8.85 (d, J=4.4 Hz, 1H), 8.13 (s, 1H), 7.78 (s, 1H), 7.59 (dd, J=1.3, 5.0 Hz, 1H), 7.16 - 7.03 (m, 3H), 3.22 - 3.12 (m, 1H), 3.06 - 2.96 (m, 1H), 2.89 - 2.80 (m, 1H), 2.79 - 2.62 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.21 - 2.12 (m, 1H), 1.98 - 1.83 (m, 1H).

[0293] Example 24: 2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)nicotinonitrile was prepared according to Scheme 1, Method B. [ka]

[0294] According to Scheme 1, step viii, Example 24 was prepared according to Example 6 starting from Intermediate 7a (80.00 mg, 283.10 μmol) and 2-bromonicotinonitrile (155.43 mg, 849.30 μmol) to afford Example 24 (8.80 mg, 24.69 μmol, 8.72% yield) as a white solid.

[0295] 1 H-NMR (400 MHz, CDCl3) δ 8.88 (d, J=5.0 Hz, 1H), 8.20 (d, J=7.9 Hz, 1H), 7.75 (s, 1H), 7.61 - 7.52 (m, 1H), 7.15 - 7.04 (m, 3H), 3.22 - 3.13 (m, 1H), 3.08 - 3.00 (m, 1H), 2.88 - 2.79 (m, 1H), 2.78 - 2.64 (m, 2H), 2.38 (s, 3H), 2.34 (s, 3H), 2.15 (br s, 1H), 1.99 - 1.83 (m, 1H).

[0296] Example 25: 6-(2,4-dimethylphenyl)-2-(5-hydroxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0297] According to Scheme 1, step viii, Example 25 was prepared according to Example 6 starting from Intermediate 7a (100.00 mg, 353.87 μmol) and 6-bromo-3-hydroxypyridine (184.72 mg, 1.06 mmol) to afford Example 25 (42.10 mg, 115.12 μmol, 32.53% yield) as an off-white solid.

[0298] 1H-NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.24 (dd, J=1.8, 4.8 Hz, 1H), 7.87 (dd, J=1.6, 7.8 Hz, 1H), 7.19 (dd, J=4.8, 7.8 Hz, 1H), 7.15 - 7.11 (m, 1H), 7.09 - 7.04 (m, 2H), 3.26 - 3.16 (m, 1H), 3.15 - 3.06 (m, 1H), 3.04 - 2.96 (m, 1H), 2.92 - 2.80 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.24 - 2.14 (m, 1H), 2.04 - 1.95 (m, 1H).

[0299] Example 26: 6-(2,4-dimethylphenyl)-2-(4-hydroxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one [ka]

[0300] To a solution of compound Example 15 (200.00 mg, 553.34 μmol, 1.00 eq) in CHCl (5.00 mL) was added BBr (693.11 mg, 2.77 mmol, 266.58 μL, 5.00 eq). The mixture was stirred at 40°C for 12 hours, and the desired product was detected. The mixture was added to water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure, and the residue was purified by preparative TLC (PE: EtOAc = 0:1). Example 26 (130.00 mg, 370.46 μmol, 66.95% yield) was obtained as a white solid.

[0301] 1H-NMR (400 MHz, DMSO-d6) δ 8.26 (br d, J=4.5 Hz, 1H), 7.81 (s, 1H), 7.15 (br d, J=7.9 Hz, 1H), 7.05 - 6.96 (m, 2H), 6.86 (br s, 2H), 3.07 (br s, 1H), 2.85 - 2.59 (m, 3H), 2.58 - 2.53 (m, 1H), 2.31 (s, 3H), 2.25 (s, 3H), 1.93 (br s, 1H), 1.88 - 1.75 (m, 1H).

[0302] Example 27: 6-(2,4-dimethylphenyl)-2-(5-(methoxymethyl)pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0303] According to Scheme 1, step viii, Example 27 was prepared according to Example 6 starting from Intermediate 7a (100.00 mg, 353.87 μmol) and 2-bromo-5-(methoxymethyl)pyridine (214.50 mg, 1.06 mmol) to afford Example 27 (56.21 mg, 149.71 μmol, 42.31% yield) as a white solid.

[0304] 1H-NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.24 (dd, J=1.8, 4.8 Hz, 1H), 7.87 (dd, J=1.6, 7.8 Hz, 1H), 7.19 (dd, J=4.8, 7.8 Hz, 1H), 7.15 - 7.11 (m, 1H), 7.09 - 7.04 (m, 2H), 3.26 - 3.16 (m, 1H), 3.15 - 3.06 (m, 1H), 3.04 - 2.96 (m, 1H), 2.92 - 2.80 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.24 - 2.14 (m, 1H), 2.04 - 1.95 (m, 1H).

[0305] Example 28: 6-(2,4-dimethylphenyl)-2-(pyridin-3-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0306] According to Scheme 1, step viii, Example 28 was prepared according to Example 6 starting from Intermediate 7a (80.00 mg, 283.10 μmol) and 3-bromopyridine (134.19 mg, 849.30 μmol, 81.82 μL) to afford Example 28 (32.83 mg, 99.06 μmol, 34.99% yield) as a white solid.

[0307] 1H-NMR (400 MHz, CDCl3) δ 9.04 - 8.91 (m, 1H), 8.63 (br s, 1H), 8.09 (br d, J=8.3 Hz, 1H), 7.73 (d, J=1.9 Hz, 1H), 7.44 (br s, 1H), 7.18 - 7.01 (m, 3H), 3.16 (br s, 1H), 3.02 (br d, J=19.2 Hz, 1H), 2.88 - 2.79 (m, 1H), 2.77 - 2.61 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.17 (br d, J=13.1 Hz, 1H), 1.91 (br d, J=11.8 Hz, 1H).

[0308] Example 29: 6-(2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0309] According to Scheme 1, step viii, Example 29 was prepared according to Example 6 starting from Intermediate 7a (780 mg, 3.07 mmol) and 2-bromopyrimidine (585.11 mg, 3.68 mmol) to afford Example 29 (383.35 mg, 1.12 mmol, 36.48% yield) as a white solid.

[0310] 1H-NMR (400 MHz, CDCl3) δ 8.95 (d, J=4.9 Hz, 2H), 7.71 (s, 1H), 7.44 (t, J=4.8 Hz, 1H), 7.14 - 7.10 (m, 1H), 7.08 - 7.04 (m, 2H), 3.21 - 3.11 (m, 1H), 3.08 - 2.98 (m, 1H), 2.87 - 2.78 (m, 1H), 2.76 - 2.63 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.14 (br dd, J=5.8, 13.5 Hz, 1H), 1.95 - 1.83 (m, 1H).

[0311] Example 30: 6-(2,4-dimethylphenyl)-2-(pyrazin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0312] According to Scheme 1, step viii, Example 30 was prepared according to Example 6 starting from Intermediate 7a (80.00 mg, 283.10 μmol) and 2-bromopyrazine (135.02 mg, 849.30 μmol) to afford Example 30 (48.17 mg, 144.92 μmol, 51.19% yield) as a gray-yellow solid.

[0313] 1H-NMR (400 MHz, CDCl3) δ 9.05 (d, J=1.1 Hz, 1H), 8.60 - 8.50 (m, 1H), 7.69 (s, 1H), 7.05 - 7.01 (m, 1H), 7.00 - 6.94 (m, 2H), 3.13 - 3.02 (m, 1H), 3.13 - 3.02 (m, 1H), 2.98 - 2.87 (m, 1H), 2.80 - 2.71 (m, 1H), 2.69 - 2.54 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 2.12 - 2.02 (m, 1H), 1.88 - 1.74 (m, 1H).

[0314] Example 31: 6-(2,4-dimethylphenyl)-2-(pyrimidin-5-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0315] According to Scheme 1, step viii, Example 31 was prepared according to Example 6 starting from Intermediate 7a (80.00 mg, 283.10 μmol) and 5-bromopyrimidine (135.02 mg, 849.30 μmol) to afford Example 31 (24.80 mg, 74.61 μmol, 26.35% yield) as a brown solid.

[0316] 1 H-NMR (400 MHz, CDCl3) δ 9.23 (s, 2H), 9.19 (s, 1H), 7.74 (s, 1H), 7.12 - 7.08 (m, 1H), 7.08 - 7.03 (m, 2H), 3.20 - 3.10 (m, 1H), 3.06 - 2.95 (m, 1H), 2.87 - 2.77 (m, 1H), 2.76 - 2.60 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2.21 - 2.11 (m, 1H), 1.95 - 1.82 (m, 1H).

[0317] Example 32: 6-(2,4-dimethylphenyl)-2-(thiazol-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B [ka]

[0318] According to Scheme 1, step viii, Example 32 was prepared according to Example 6 starting from Intermediate 7a (120.00 mg, 471.83 μmol) and 2-bromothiazole (116.08 mg, 707.75 μmol, 63.78 μL) to afford Example 32 (12.00 mg, 34.51 μmol, 8.76% yield) as a yellow solid.

[0319] 1 H-NMR (400 MHz, CDCl3) δ 1.84 - 1.96 (m, 1 H) 2.12 - 2.21 (m, 1 H) 2.33 (s, 3 H) 2.36 (s, 3 H) 2.66 - 2.81 (m, 2 H) 2.82 - 2.92 (m, 1 H) 3.07 (br dd, J=19.89, 5.08 Hz, 1 H) 3.12 - 3.20 (m, 1 H) 7.05 (br d, J=5.77 Hz, 2 H) 7.07 - 7.12 (m, 1 H) 7.30 (d, J=3.39 Hz, 1 H) 7.81 (d, J=3.39Hz, 1H) 7.90 (s, 1 H).

[0320] Example 33: 6-(2,4-dimethylphenyl)-2-(thiazol-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0321] According to Scheme 1, step viii, Example 33 was prepared according to Example 6 starting from Intermediate 7a (80.00 mg, 314.55 μmol) and 4-bromothiazole (77.39 mg, 471.83 μmol, 42.52 μL) to afford Example 33 (8.00 mg, 23.44 μmol, 7.45% yield) as an off-white solid.

[0322] 1 H-NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.65 (s, 2H), 7.14 (d, J=8.4 Hz, 1H), 7.06 - 6.96 (m, 2H), 3.82 (s, 3H), 3.23 - 3.11 (m, 1H), 2.97 - 2.82 (m, 2H), 2.81 - 2.71 (m, 1H), 2.70 - 2.57 (m, 1H), 2.36 (s, 3H), 2.29 (s, 3H), 2.14 - 2.04 (m, 1H), 1.98 - 1.83 (m, 1H).

[0323] Example 34: 6-(2,4-dimethylphenyl)-2-(1-methyl-1H-imidazol-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0324] According to Scheme 1, step viii, Example 34 was prepared according to Example 6 starting from Intermediate 7a (100.00 mg, 353.87 μmol) and 4-bromo-1-methyl-1H-imidazole (113.95 mg, 707.74 μmol) to afford Example 34 (10.61 mg, 31.72 μmol, 8.97% yield) as a white solid.

[0325] 1H-NMR (400 MHz, MeOD) δ 7.89 (s, 1H), 7.65 (s, 2H), 7.14 (d, J=8.4 Hz, 1H), 7.06 - 6.96 (m, 2H), 3.82 (s, 3H), 3.23 - 3.11 (m, 1H), 2.97 - 2.82 (m, 2H), 2.81 - 2.71 (m, 1H), 2.70 - 2.57 (m, 1H), 2.36 (s, 3H), 2.29 (s, 3H), 2.14 - 2.04 (m, 1H), 1.98 - 1.83 (m, 1H)

[0326] Example 35: 6-(2,4-dimethylphenyl)-2-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0327] According to Scheme 1, step viii, Example 35 was prepared according to Example 6 starting from Intermediate 7a (0.2 g, 786.39 μmol) and 2-chloro-4-methoxypyrimidine (136.42 mg, 943.67 μmol) to afford Example 35 (0.118 g, 323.05 μmol, 41.08% yield) as a white solid.

[0328] 1 H-NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.74 (s, 1H), 7.15-7.00 (m, 3H), 6.87 (d, J = 5.6 Hz, 1H), 4.06 (s, 3H), 3.21-3.10 (m, 1H), 3.09-3.01 (m, 1H), 2.88-2.79 (m, 1H), 2.77-2.61 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2.18-2.10 (m, 1H), 1.95 - 1.81 (m, 1H).

[0329] Example 36: 6-(2,4-dimethylphenyl)-2-(4,6-dimethylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0330] According to Scheme 1, step viii, Example 36 was prepared according to Example 6 starting from Intermediate 7a (0.2 g, 786.39 μmol) and 2-chloro-4,6-dimethylpyrimidine (168.19 mg, 1.18 mmol) to afford Example 36 (0.034 g, 89.61 μmol, 11.40% yield) as a white solid.

[0331] 1 H-NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.15 (s, 1H), 7.12-7.07 (m, 1H), 7.06-7.02 (m, 2H), 3.18-3.07 (m, 1H), 2.98-2.90 (m, 1H), 2.85-2.76 (m, 1H), 2.74-2.65 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.16-2.05 (m, 1H), 1.92-1.78 (m, 1H).

[0332] Example 37: 2-(4-Cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0333] According to Scheme 1, step viii, Example 37 was prepared according to Example 6 starting from Intermediate 7a (0.2 g, 786.39 μmol) and 2-chloro-4-cyclopropylpyrimidine (145.89 mg, 943.67 μmol) to afford Example 37 (0.029 g, 77.86 μmol, 9.90% yield) as a white solid.

[0334] 1 H-NMR (400 MHz, CDCl3) δ 8.64 (d, J = 4.4 Hz, 1H), 7.65 (s, 1H), 7.18 (d, J = 4.8 Hz, 1H), 7.13-7.07 (m, 1H), 7.06-6.97 (m, 2H), 3.14-3.11 (m, 1H), 3.04-2.92 (m, 1H), 2.84-2.74 (m, 1H), 2.69-2.63 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.15-2.08 (m, 2H), 1.92-1.85 (m, 1H), 1.28-1.12 (m, 4H).

[0335] Example 38: 2-(5-Hydroxypyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0336] Intermediate 6d: 3-Methoxy-5-(3-methoxy-2-methylphenyl)-4,5,6,7-tetrahydroiso-benzofuran-1(3H)-one Following Scheme 1, steps i-v, intermediate 6d was prepared similarly to intermediate 6a in Example 1, starting from 1-bromo-3-methoxy-2-methylbenzene, and was obtained as a brown liquid in 15% overall yield. m / z (M+H) + = 289.1

[0337] Intermediate 7b: 6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one Intermediate 7b was prepared starting from intermediate 6d (21.30 g, 73.87 mmol) according to Scheme 1, step vii, in a similar manner to intermediate 7a in Example 6 to give intermediate 7b (15.30 g, 56.60 mmol, 76.62% yield) as a white solid.

[0338] 1 H NMR (400 MHz, DMSO-d6) δ 12.76 (br s, 1H), 7.65 (s, 1H), 7.10-7.18 (m, 1H), 6.84 (t, J=8.72 Hz, 2H), 3.77 (s, 3H), 3.10 (br s, 1H), 2.55-2.75 (m, 3H), 2.35-2.47 (m, 1H), 2.15 (s, 3H), 1.90 (br s, 1H), 1.76 (dq, J=4.89, 11.84 Hz, 1H).

[0339] Example 38: 2-(5-hydroxypyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 1, step viii, Example 38 was prepared according to Example 6 starting from Intermediate 7b (150.00 mg, 554.88 μmol) and 6-bromo-3-hydroxypyridine (115.86 mg, 665.85 μmol) to afford Example 38 (72.80 mg, 200.12 μmol, 36.07% yield) as a white solid.

[0340] 1H-NMR (400 MHz, DMSO-d6) δ 10.40 (br s, 1H), 8.04-8.10 (m, 1H), 7.80 (s, 1H), 7.29-7.36 (m, 2H), 7.14-7.21 (m, 1H), 6.89 (d, J=7.65 Hz, 1H), 6.85 (d, J=8.16 Hz, 1H), 3.78 (s, 3H), 3.09-3.21 (m, 1H), 2.62-2.82 (m, 3H), 2.52-2.59 (m, 1H), 2.17 (s, 3H), 1.89-2.01 (m, 1H), 1.74-1.87 (m, 1H).

[0341] Example 39: 2-(5-(hydroxymethyl)pyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0342] According to Scheme 1, step viii, Example 39 was prepared according to Example 6 starting from Intermediate 7b (150.00 mg, 554.88 μmol) and (6-bromopyridin-3-yl)methanol (125.19 mg, 665.86 μmol) to afford Example 39 (81.97 mg, 216.96 μmol, 39.10% yield) as a white solid.

[0343] 1H-NMR (400 MHz, DMSO-d6) δ 8.52 (d, J=1.63 Hz, 1H), 7.92 (dd, J=2.20, 8.09 Hz, 1H), 7.84 (s, 1H), 7.52 (d, J=8.16 Hz, 1H), 7.18 (t, J=7.97 Hz, 1H), 6.89 (d, J=7.78 Hz, 1H), 6.85 (d, J=8.16 Hz, 1H), 5.45 (t, J=5.71 Hz, 1H), 4.62 (d, J=5.52 Hz, 2H), 3.78 (s, 3H), 3.12-3.22 (m, 1H), 2.64-2.86 (m, 3H), 2.55 (br d, J=9.66 Hz, 1H), 2.18 (s, 3H), 1.94 (br s, 1H), 1.78-1.89 (m, 1H).

[0344] Example 40: 6-(3-Methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0345] According to Scheme 1, step viii, Example 40 was prepared according to Example 6 starting from Intermediate 7b (150.00 mg, 554.88 μmol) and 5-bromopyrimidine (105.86 mg, 665.86 μmol) to afford Example 40 (45.56 mg, 128.81 μmol, 23.21% yield) as a brown solid.

[0346] 1H-NMR (400 MHz, DMSO-d6) δ 9.02 (d, J=4.89 Hz, 2H), 7.85 (s, 1H), 7.71 (t, J=4.89 Hz, 1H), 7.14-7.21 (m, 1H), 6.87 (dd, J=7.97, 17.63 Hz, 2H), 3.78 (s, 3H), 3.14-3.24 (m, 1H), 2.78-2.87 (m, 1H), 2.66-2.77 (m, 2H), 2.56 (br d, J=10.04 Hz, 1H), 2.18 (s, 3H), 1.94 (br s, 1H), 1.78-1.91 (m, 1H).

[0347] Example 41: 6-(3-Methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0348] According to Scheme 1, step viii, Example 41 was prepared according to Example 6 starting from Intermediate 7b (150.00 mg, 554.88 μmol) and 2-bromo-5-methylpyrimidine (116.51 mg, 665.86 μmol) to afford Example 41 (75.16 mg, 206.05 μmol, 37.13% yield) as a white solid.

[0349] 1 H-NMR (400 MHz, DMSO-d6) δ 8.84 (s, 2H), 7.83 (s, 1H), 7.14-7.23 (m, 1H), 6.87 (dd, J=7.91, 16.69 Hz, 2H), 3.78 (s, 3H), 3.13-3.23 (m, 1H), 2.64-2.87 (m, 3H), 2.52-2.60 (m, 1H), 2.38 (s, 3H), 2.18 (s, 3H), 1.94 (br s, 1H), 1.75-1.90 (m, 1H).

[0350] Example 42: 6-(3-Methoxy-2-methylphenyl)-2-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0351] According to Scheme 1, step viii, Example 42 was prepared according to Example 6 starting from Intermediate 7b (150.00 mg, 554.88 μmol) and 2-bromo-4-methoxypyrimidine (125.85 mg, 665.85 μmol) to afford Example 42 (97.29 mg, 256.84 μmol, 46.29% yield) as a red solid.

[0352] 1 H-NMR (400 MHz, DMSO-d6) δ 8.69 (d, J=5.77 Hz, 1H), 7.83 (s, 1H), 7.18 (t, J=7.97 Hz, 1H), 7.13 (d, J=5.90 Hz, 1H), 6.89 (d, J=7.65 Hz, 1H), 6.85 (d, J=8.16 Hz, 1H), 3.93 (s, 3H), 3.78 (s, 3H), 3.13-3.24 (m, 1H), 2.64-2.86 (m, 3H), 2.56 (br d, J=9.41 Hz, 1H), 2.18 (s, 3H), 1.94 (br s, 1H), 1.78-1.90 (m, 1H).

[0353] Example 43: 2-(5-chloropyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0354] According to Scheme 1, step viii, Example 43 was prepared according to Example 6 starting from Intermediate 7b (150.00 mg, 554.88 μmol) and 2-bromo-5-chloropyrimidine (128.80 mg, 665.86 μmol) to afford Example 43 (98.84 mg, 257.92 μmol, 46.48% yield) as a white solid.

[0355] 1 H-NMR (400 MHz, DMSO-d6)) δ 9.16 (s, 2H), 7.87 (s, 1H), 7.15-7.20 (m, 1H), 6.89 (d, J=7.65 Hz, 1H), 6.85 (d, J=8.03 Hz, 1H), 3.78 (s, 3H), 3.12-3.24 (m, 1H), 2.78-2.86 (m, 1H), 2.65-2.76 (m, 2H), 2.53-2.61 (m, 1H), 2.18 (s, 3H), 1.91-2.00 (m, 1H), 1.76-1.90 (m, 1H).

[0356] Example 44: 6-(3-Methoxy-2-methylphenyl)-2-(5-methoxypyrazin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0357] According to Scheme 1, step viii, Example 44 was prepared according to Example 6 starting from Intermediate 7b (150.00 mg, 554.88 μmol) and 2-bromo-5-methoxypyrazine (125.85 mg, 665.86 μmol) to afford Example 44 (111.11 mg, 290.09 μmol, 52.28% yield) as a white solid.

[0358] 1H-NMR (400 MHz, DMSO-d6) δ 8.47 (d, J=1.25 Hz, 1H), 8.35 (d, J=1.25 Hz, 1H), 7.89 (s, 1H), 7.14-7.22 (m, 1H), 6.89 (d, J=7.65 Hz, 1H), 6.85 (d, J=8.16 Hz, 1H), 3.99 (s, 3H), 3.78 (s, 3H), 3.10-3.22 (m, 1H), 2.64-2.86 (m, 3H), 2.56 (br d, J=9.41 Hz, 1H), 2.18 (s, 3H), 1.94 (br s, 1H), 1.78-1.89 (m, 1H).

[0359] Example 45: 2-(5-Hydroxypyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0360] According to Scheme 1, step viii, Example 45 was prepared according to Example 6 starting from Intermediate 7b (450 mg, 1.66 mmol) and 2-bromo-5-hydroxypyrimidine (349.55 mg, 2.00 mmol) to afford Example 45 (520 mg, 1.43 mmol, 85.72% yield) as a brown solid.

[0361] 1 H-NMR (400 MHz, DMSO-d6) δ 8.43 (s, 2H), 7.79 (s, 1H), 7.14-7.21 (m, 1H), 6.89 (d, J=7.78 Hz, 1H), 6.85 (d, J=8.28 Hz, 1H), 3.76-3.81 (m, 3H), 3.11-3.25 (m, 1H), 2.67-2.84 (m, 3H), 2.55-2.60 (m, 1H), 2.18 (s, 3H), 1.93 (br s, 1H), 1.76-1.89 (m, 1H).

[0362] Example 46: 6-(3-Methoxy-2-methylphenyl)-2-(4-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0363] According to Scheme 1, step viii, Example 46 was prepared according to Example 6 starting from Intermediate 7b (70 mg, 258.95 μmol) and 4-(2-bromopyrimidin-4-yl)morpholine (75.85 mg, 310.74 μmol) to afford Example 46 (32.49 mg, 74.12 μmol, 28.62% yield) as an off-white solid.

[0364] 1 H-NMR (400 MHz, DMSO-d6) δ 8.35 (d, J=6.15 Hz, 1H), 7.77 (s, 1H), 7.15-7.21 (m, 1H), 6.96 (d, J=6.27 Hz, 1H), 6.89 (d, J=7.78 Hz, 1H), 6.85 (d, J=8.16 Hz, 1H), 3.79 (s, 3H), 3.67 (br d, J=5.02 Hz, 4H), 3.62 (br d, J=4.77 Hz, 4H), 3.17 (br t, J=8.97 Hz, 1H), 2.62-2.83 (m, 3H), 2.52-2.59 (m, 1H), 2.18 (s, 3H), 1.93 (br s, 1H), 1.83 (dq, J=4.83, 11.90 Hz, 1H).

[0365] Example 47: 6-(5-Methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0366] Intermediate 6e: 3-Methoxy-5-(5-methoxy-2-methylphenyl)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one According to Scheme 1, steps i-v, intermediate 6e was prepared similarly to intermediate 6a in Example 1 starting from 2-bromo-4-methoxy-1-methylbenzene in an overall yield of 9.3% as a yellow solid.

[0367] 1 H NMR: (CDCl3, 400 MHz) δ 7.02 (d, J = 8.4 Hz, 1H), 6.70-6.61 (m, 2H), 5.58 (s, 1H), 3.71 (s, 3H), 3.51 (s, 3H), 3.05-2.90 (m, 1H), 2.47-2.36 (m, 2H), 2.31-2.14 (m, 5H), 1.94-1.86 (m, 1H), 1.75-1.62 (m, 1H)

[0368] Intermediate 7c: 6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one Intermediate 7c was prepared starting from intermediate 6e (1.30 g, 4.51 mmol) according to Scheme 1, step vii, in a similar manner to intermediate 7a in Example 6 to give intermediate 7c (0.4 g, 1.48 mmol, 32.82% yield) as a white solid.

[0369] 1 H NMR: (CDCl3, 400 MHz) δ 7.55 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.73-6.68 (m, 2H), 3.78 (s, 3H), 3.12-3.08 (m, 1H), 2.93-2.91 (m, 1H), 2.74-2.71 (m, 1H), 2.65-2.58 (m, 2H), 2.28 (s, 3H), 2.13-2.09 (m, 1H), 1.90-1.69 (m, 1H).

[0370] Example 47: 6-(5-Methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one According to Scheme 1, step viii, Example 47 was prepared according to Example 6 starting from Intermediate 7c (0.1 g, 369.92 μmol) and 2-chloro-5-methylpyrimidine (142.67 mg, 1.11 mmol) to afford Example 47 (0.005 g, 13.80 μmol, 3.73% yield) as a yellow solid.

[0371] 1 H-NMR (400 MHz, CDCl3) δ 8.75 (s, 2H), 7.70 (s, 1H), 7.12 (br d, J = 8.4 Hz, 1H), 6.77 (s, 1H), 6.72 (m, d, J = 8.4 Hz, 1H), 3.80 (s, 3H), 3.17-2.96 (m, 2H), 2.87-2.76 (m, 1H), 2.71-2.65 (m, 2H), 2.43 (s, 3H), 2.31 (s, 3H), 2.15-2.11 (m, 1H), 1.90-1.85 (m,1H).

[0372] Example 48: 6-(5-Methoxy-2-methylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0373] According to Scheme 1, step viii, Example 48 was prepared according to Example 6 starting from Intermediate 7c (0.1 g, 369.92 μmol) and 2-chloro-5-methoxypyrimidine (160.43 mg, 1.11 mmol) to afford Example 48 (0.003 g, 7.93 μmol, 2.14% yield) as a white solid.

[0374] 1H-NMR (400 MHz, CDCl3) δ 8.46 (s, 2H), 7.59 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.73-6.64 (m, 2H), 3.93 (s, 3H), 3.73 (s, 3H), 3.04-2.97 (m, 2H), 2.71-2.46 (m, 3H), 2.23 (s, 3H), 2.08 (m, 1H), 1.80 (m, 1H).

[0375] Example 49: 2-(5-chloropyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0376] According to Scheme 1, step viii, Example 49 was prepared according to Example 6 starting from Intermediate 7c (0.1 g, 369.92 μmol) and 2-bromo-5-chloropyrimidine (214.66 mg, 1.11 mmol) to afford Example 49 (0.011 g, 28.73 μmol, 7.77% yield) as a white solid.

[0377] 1 H-NMR (400 MHz, CDCl3) δ 8.85 (s, 2H), 7.69 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.76 (s, 1H), 6.72 (dd, J = 8.0, 2.4 Hz, 1H), 3.80 (s, 3H), 3.18-3.08 (m, 1H), 3.07-2.97 (m, 1H), 2.86-2.76 (m, 1H), 2.71-2.65 (m, 2H), 2.31 (s, 3H), 2.15 (m, 1H), 1.88-1.81 (m, 1H).

[0378] Example 50: 6-(2,4-dimethylphenyl)-2-(pyridin-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0379] According to Scheme 1, Step ix, to a mixture of Intermediate 7a (150.00 mg, 530.81 μmol, 1.00 eq) and 4-pyridylboronic acid (130.49 mg, 1.06 mmol, 2.00 eq) in dioxane (5.00 mL) was added DMAP (194.55 mg, 1.59 mmol, 3.00 eq), pyridine (41.99 mg, 530.81 μmol, 42.84 μL, 1.00 eq), and Cu(OAc) (96.41 mg, 530.81 μmol, 1.00 eq). The mixture was heated to 90° C. and stirred for 12 hours. The reaction mixture was filtered, and the filtrate was acidified to pH 5 with 12 M HCl and filtered. The resulting solution was purified by preparative HPLC to give Example 50 (8.98 mg, 26.01 μmol, 4.90% yield) as a yellow solid.

[0380] 1 H-NMR (400 MHz, DMSO-d6) δ 8.76 (br s, 2H), 7.97 (s, 1H), 7.78 (br s, 2H), 7.15 (d, J=8.5 Hz, 1H), 7.04 - 6.98 (m, 2H), 3.13 - 3.01 (m, 1H), 2.86 - 2.73 (m, 2H), 2.71 - 2.64 (m, 1H), 2.63 - 2.55 (m, 1H), 2.30 (s, 3H), 2.25 (s, 3H), 2.00 - 1.91 (m, 1H), 1.88 - 1.75 (m, 1H).

[0381] Example 51: 2-(5-chloropyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method C. [ka]

[0382] Intermediate 6a': 5-Formyl-2',4'-dimethyl-1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid To a solution of intermediate 6a (6 g, 22.03 mmol, 1 eq) in MeOH (100 mL), a solution of NaOH (2.64 g, 66.09 mmol, 3 eq) in HO (40 mL) was added and stirred at 20 °C for 24 h. The organic solvent was removed under reduced pressure. The residue was acidified to pH = 3 with 2 N HCl at 20 °C and extracted with EtOAc (30 mL × 3). The combined organic layer was washed with brine to pH = 7, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 50 / 1, 1 / 1) to give intermediate 6a' (2 g, 7.74 mmol, 35.14% yield) as a pale yellow oil.

[0383] 1 H NMR (400MHz, CDCl3) δ 7.16-6.93 (m, 3H), 6.03 (s, 1H), 3.20-3.01 (m, 1H), 2.79-2.64 (m, 1H), 2.56-2.42 (m, 2H), 2.36-2.31 (m, 7H), 2.04-1.96 (m, 1H), 1.90-1.73 (m, 1H).

[0384] Intermediate 8a: Ethyl 5-formyl-2',4'-dimethyl-1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-carboxylate According to Scheme 1, step x, to a solution of intermediate 6a' (2 g, 7.74 mmol, 1 eq) in DMF (20 mL) was added TMG (1.34 g, 11.61 mmol, 1.46 mL, 1.5 eq) at 20 °C. The mixture was then stirred at this temperature for 30 min. Ethyl iodide (3.02 g, 19.36 mmol, 1.55 mL, 2.5 eq) was added at 20 °C, and the resulting mixture was heated at 45 °C for 14 h without delay. The solvent was removed under reduced pressure. The residue was dissolved in water (20 mL), adjusted to pH = 4 with 4 N HCl, and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with water (10 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc=20 / 1, 1 / 1) to give intermediate 8a (1.8 g, 6.29 mmol, 81.18% yield) as a yellow oil.

[0385] 1 H NMR (400MHz, CDCl3) δ10.08(s, 1H), 7.13-6.94(m, 3H), 4.34(q, J = 7.2 Hz, 2H), 3.00-2.88(m, 1H), 2.83-2.71(m, 2H), 2.70-2.57(m, 1H), 2.31(s, 6H), 2.25-2.13(m, 1H), 1.99(m, 1H), 1.87-1.72(m, 1H), 1.38(t, J = 7.2 Hz, 3H).

[0386] Example 51: (2-(5-chloropyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one According to Scheme 1, Step xii, to a mixture of intermediate 8a (53.08 mg, 367.19 μmol, 1 eq) in EtOH (10 mL) and AcOH (5 mL) at 20° C. was added 2-hydrazinyl-5-chloropyrimidine (105.15 mg, 367.19 μmol, 1 eq) in one portion. The mixture was stirred at 100° C. for 12 hours. The mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give Example 51 (0.009 g, 24.53 μmol, 6.68% yield) as a white solid.

[0387] 1 H-NMR (400 MHz, CDCl3) δ 8.86 (s, 2H), 7.69 (s, 1H), 7.16 - 6.99 (m, 3H), 3.14 (m, 1H), 3.01 (m, 1H), 2.86 - 2.77 (m, 1H), 2.75 - 2.60 (m, 2H), 2.35 (s, 3H), 2.33 (s, 3H), 2.12 (m, 1H), 1.93 - 1.82 (m, 1H).

[0388] Example 52: 6-(2,4-dimethylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method C. [ka]

[0389] According to Scheme 1, step xii, Example 52 was prepared according to Example 51 starting from Intermediate 8a (105.15 mg, 367.19 μmol) and 2-hydrazinyl-5-methylpyrimidine (45.58 mg, 367.19 μmol) to afford Example 52 (0.023 g, 66.39 μmol, 18.08% yield) as a white solid.

[0390] 1 H-NMR (400 MHz, CDCl3) δ 8.74 (s, 2H), 7.68 (s, 1H), 7.16-6.99 (m, 3H), 3.14 (m, 1H), 3.06-2.96 (m, 1H), 2.86-2.76 (m, 1H), 2.69 (m, 2H), 2.43 (s, 3H), 2.36 (s, 3H), 2.32 (s, 3H), 2.16-2.08 (m, 1H), 1.93-1.81 (m, 1H).

[0391] Example 53: 6-(2,4-dimethylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method C. [ka]

[0392] According to Scheme 1, step xii, Example 53 was prepared according to Example 51 starting from Intermediate 8a (105.15 mg, 367.19 μmol) and 2-hydrazinyl-5-methoxypyrimidine (51.46 mg, 367.19 μmol) to afford Example 53 (0.059 g, 161.16 μmol, 43.89% yield) as a white solid.

[0393] 1 H-NMR (400 MHz, CDCl3) δ 8.53 (s, 2H), 7.67 (s, 1H), 7.15 - 6.97 (m, 3H), 4.00 (s, 3H), 3.14 (br s, 1H), 2.99 (m, 1H), 2.85 - 2.76 (m, 1H), 2.74-2.59 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.12 (m, 1H), 1.87 (m, 1H).

[0394] Example 54: 6-(2,4-dimethylphenyl)-2-(5-fluoropyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method C. [ka]

[0395] According to Scheme 1, step xii, Example 54 was prepared according to Example 51 starting from Intermediate 8a (105.15 mg, 367.19 μmol) and 5-fluoro-2-hydrazinylpyrimidine (47.04 mg, 367.19 μmol) to afford Example 54 (0.077 g, 217.32 μmol, 59.18% yield) as a white solid.

[0396] 1 H-NMR (400 MHz, CDCl3) δ 8.77 (s, 2H), 7.68 (s, 1H), 7.13-6.99 (m, 3H), 3.15 (m, 1H), 3.00 (m, 1H), 2.87-2.77 (m, 1H), 2.70 (m, 2H), 2.36 (s, 3H), 2.32 (s, 3H), 2.15-2.08 (m, 1H), 1.95-1.82 (m, 1H).

[0397] Example 55: 6-(2,4-dimethylphenyl)-2-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method C. [ka]

[0398] According to Scheme 1, step xii, Example 55 was prepared according to Example 51 starting from Intermediate 8a (105.15 mg, 367.19 μmol) and 2-hydrazinyl-5-(trifluoromethyl)pyrimidine (65.40 mg, 367.19 μmol) to afford Example 55 (0.023 g, 55.36 μmol, 15.08% yield) as a white solid.

[0399] 1H-NMR (400 MHz, CDCl3) δ 9.08 (s, 2H), 7.65 (s, 1H), 7.08-6.96 (m, 3H), 3.21-3.10 (m, 1H), 3.07-2.97 (m, 1H), 2.87- 2.78 (m, 1H), 2.36 (s, 3H), 2.33 (s, 3H), 2.14 (m, 1H), 1.95 - 1.83 (m, 1H).

[0400] Example 56: 6-(2,4-dimethylphenyl)-2-(4-methoxy-5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method C. [ka]

[0401] Intermediate 56': 2-(5-bromo-4-methoxypyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 1, step xii, intermediate 56′ was prepared according to Example 51 starting from intermediate 8a (392.32 mg, 1.37 mmol) and 5-bromo-2-hydrazinyl-4-methoxypyrimidine (0.3 g, 1.37 mmol) to give intermediate 56′ (0.17 g, 385.21 μmol, 28.12% yield) as a white solid.

[0402] 1 H NMR (400MHz, CDCl3) δ 8.71 (s, 1H), 7.66 (s, 1H), 7.14-6.99 (m, 3H), 4.13 (s, 3H), 3.20-3.08 (m, 1H), 3.04-2.94 (m, 1H), 2.85-2.75 (m, 1H), 2.75-2.65 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.19-2.09 (m, 1H), 1.92-1.85 (m,1H).

[0403] Example 56: 6-(2,4-dimethylphenyl)-2-(4-methoxy-5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one To a mixture of methylboronic acid (27.13 mg, 453.19 μmol) and Intermediate 56' (0.1 g, 226.59 μmol) in dioxane (10 mL) at 20 °C under N was added Pd(dppf)Cl (16.58 mg, 22.66 μmol, 0.1 eq) and KCO (93.95 mg, 679.78 μmol, 3 eq) in one portion. The mixture was stirred at 100 °C for 12 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give Example 56 (0.044 g, 116.27 μmol, 51.31% yield) as a white solid.

[0404] 1 H-NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.66 (s, 1H), 7.14-6.99 (m, 3H), 4.13 (s, 3H), 3.20-3.08 (m, 1H), 3.04-2.94 (m, 1H), 2.85-2.75 (m, 1H), 2.75-2.65 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.19-2.09 (m, 1H), 1.92-1.85 (m,1H).

[0405] Example 57: 6-(2,4-dimethylphenyl)-2-(5-(morpholinomethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method C. [ka]

[0406] According to Scheme 1, step xii, Example 57 was prepared according to Example 51 starting from Intermediate 8a (105.15 mg, 367.19 μmol) and 4-((2-hydrazinylpyrimidin-5-yl)methyl)morpholine (76.83 mg, 367.19 μmol) to afford Example 57 (0.023 g, 53.30 μmol, 14.52% yield) as a white solid.

[0407] 1 H-NMR (400 MHz, CDCl3) δ 8.87 (s, 2H), 7.69 (s, 1H), 7.17-6.98 (m, 3H), 3.78-3.70 (m, 4H), 3.60 (s, 2H), 3.15 (m, 1H), 3.01 (m, 1H), 2.87-2.76 (m, 1H), 2.70 (m, 1H), 2.75 - 2.61 (m, 1H), 2.51 (m, 4H), 2.36 (s, 3H), 2.32 (s, 3H), 2.11 (m, 1H), 1.95-1.81 (m, 1H).

[0408] Example 58: 6-(2-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0409] Intermediate 10: 8-Chloro-1,4-dioxaspiro[4.5]dec-7-ene-7-carbaldehyde According to Scheme 2, step i, a solution of DMF (187.11 g, 2.56 mol, 196.96 mL, 2.00 eq) in CH2Cl2 (2.00 L) was treated with POCl at 0 °C. 3(To this mixture was added dropwise 1,4-dioxaspiro[4.5]decan-8-one (490.66 g, 3.20 mol, 297.37 mL, 2.50 eq). The mixture was stirred at 0 °C for 2 h. Next, a solution of 1,4-dioxaspiro[4.5]decan-8-one (200.00 g, 1.28 mol, 1.00 eq) in CHCl (500.00 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was poured into saturated aqueous NaHCO (2 L), and solid NaHCO was added to maintain a pH > 7. The mixture was extracted with CHCl (5 L × 2), and the CHCl phase was concentrated. The resulting residue was purified by column chromatography (PE / EtOAc = 20 / 1). Intermediate 56a (120.00 g, 506.34 mmol, 39.56% yield) was obtained as a yellow oil.

[0410] 1 H NMR (400MHz, CDCl3) δ 10.19 - 10.10 (m, 1H), 4.05 - 3.94 (m, 4H), 2.91 - 2.75 (m, 2H), 2.57 - 2.42 (m, 2H), 1.99 - 1.83 (m, 2H).

[0411] Intermediate 11: Methyl 7-formyl-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate According to Scheme 2, Step ii, to a solution of intermediate 10 (122.00 g, 514.78 mmol, 1.00 eq) in MeOH (800.00 mL) and DMA (400.00 mL) was added Pd(OAc) (17.34 g, 77.22 mmol, 0.15 eq), DPPF (42.81 g, 77.22 mmol, 0.15 eq), and AcONa (84.45 g, 1.03 mol, 2.00 eq). The reaction mixture was stirred at 80 °C under CO (50 psi) for 12 h. The reaction mixture was filtered, the filtrate was concentrated, and the residue was poured into water (2000 mL × 2) and extracted with ethyl acetate (2000 mL × 3). The combined organic layers were washed with saturated brine (1000 mL × 3) and concentrated under reduced pressure. The residue was purified by column chromatography (PE: EtOAc = 20: 1 to 3: 1) to give Intermediate 11 (78.50 g, 329.64 mmol, 64.04% yield) as a yellow oil.

[0412] 1 H NMR (400MHz, CDCl3) δ 5.61 (d, J=1.1 Hz, 1H), 4.03 - 3.99 (m, 4H), 3.53 (s, 3H), 2.62 - 2.53 (m, 1H), 2.49 - 2.40 (m, 3H), 1.85 (t, J=6.3 Hz, 2H).

[0413] Intermediate 12: 7,8-Dihydro-2H-spiro[phthalazine-6,2'-[1,3]dioxolan]-1(5H)-one According to Scheme 2, step iii, to a solution of intermediate 11 (78.50 g, 329.64 mmol, 1.00 eq) in EtOH (750.00 mL) and AcOH (75.00 mL) was added N2H4.HO (33.68 g, 659.28 mmol, 32.70 mL, 2.00 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated and adjusted to pH = 7 with saturated aqueous NaHCO3 solution. It was then extracted with CHCl2 (30.00 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Intermediate 12 (66.00 g, 316.99 mmol, 96.16% yield) was obtained as a yellow solid.

[0414] 1 H NMR (400MHz, DMSO-d6) δ 7.58 (s, 1H), 3.93 (s, 4H), 2.72 (s, 2H), 2.54 (br t, J=6.7 Hz, 2H), 1.80 (t, J=6.7 Hz, 2H).

[0415] Intermediate 13a: 2-(pyridin-2-yl)-7,8-dihydro-2H-spiro[phthalazine-6,2'-[1,3]dioxolan]-1(5H)-one According to Scheme 2, step v, to a solution of intermediate 12 (40.00 g, 192.11 mmol, 1.00 eq) and 2-bromopyridine (36.42 g, 230.53 mmol, 21.94 mL, 1.20 eq) in dioxane (500.00 mL) was added CuI (7.32 g, 38.42 mmol, 0.20 eq), (1S,2S)-N 1 ,N 2- Dimethylcyclohexane-1,2-diamine (5.47 g, 38.42 mmol, 0.20 eq) and KPO (101.95 g, 480.28 mmol, 2.50 eq) were added. The mixture was stirred at 100 °C for 12 h. The reaction was filtered and concentrated. The filter cake was washed with CHCl (200 mL × 3). Water (2.0 L) was added to the residue, and it was extracted with CHCl (1.0 L × 3). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was recrystallized from MTBE (100 mL) at 20 °C. Intermediate 13a (56.00 g, crude) was obtained as a gray solid.

[0416] 1 H NMR (400MHz, CDCl3) δ 8.67 (br s, 1H), 7.92 - 7.79 (m, 1H), 7.68 (br s, 2H), 7.35 (br s, 1H), 4.04 (s, 4H), 2.87 (br t, J=6.0 Hz, 2H), 2.81 (s, 2H), 1.94 (br t, J=6.5 Hz, 2H).

[0417] Intermediate 14a: 2-(pyridin-2-yl)-7,8-dihydrophthalazine-1,6(2H,5H)-dione According to Scheme 2, Step vi, to a solution of intermediate 13a (25.00 g, 87.63 mmol, 1.00 eq) in CHCl (250.00 mL) and TFA (75.00 mL) was added HO (3.16 g, 175.26 mmol, 3.16 mL, 2.00 eq). The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into saturated aqueous NaHCO (500.0 mL) and extracted with CHCl (500.0 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO, CHCl: EtOAc = 1:2 to 0:1). Intermediate 14a (8.80 g, 33.20 mmol, 37.88% yield) was obtained as a yellow solid.

[0418] 1 H NMR (400MHz, CDCl3) δ 8.67 (dd, J=1.1, 4.9 Hz, 1H), 7.89 (dt, J=1.9, 7.7 Hz, 1H), 7.75 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.39 (ddd, J=0.9, 4.9, 7.4 Hz, 1H), 3.46 (s, 2H), 3.16 (t, J=7.0 Hz, 2H), 2.67 (t, J=7.0 Hz, 2H).

[0419] Intermediate 15a: 1-oxo-2-(pyridin-2-yl)-1,2,7,8-tetrahydrophthalazin-6-yl trifluoromethanesulfonate According to Scheme 2, Step vii, to a solution of intermediate 14a (5.00 g, 18.86 mmol, 1.00 eq) in CHCl (50.00 mL) at 0 °C, EtN (2.29 g, 22.63 mmol, 3.14 mL, 1.20 eq) and TfO (5.85 g, 20.75 mmol, 3.42 mL, 1.10 eq) were added. The reaction was stirred at 20 °C for 12 h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO, PE:EtOAc = 5:1 to 1:1). Intermediate 15a (4.40 g, 11.43 mmol, 60.62% yield) was obtained as a yellow solid.

[0420] 1 H NMR (400MHz, CDCl3) δ 8.68 - 8.63 (m, 1H), 7.88 (dt, J=1.9, 7.8 Hz, 1H), 7.78 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.38 (ddd, J=0.9, 4.9, 7.4 Hz, 1H), 6.36 (t, J=1.4 Hz, 1H), 3.18 - 3.10 (m, 2H), 2.84 - 2.75 (m, 2H).

[0421] Intermediate 16a: 6-(2-methoxyphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, Step viii, a mixture of intermediate 15a (200.00 mg, 518.07 μmol, 1.00 eq), (2-methoxyphenyl)-boronic acid (157.45 mg, 1.04 mmol, 2.00 eq), Pd(PPh3)4 (119.73 mg, 103.61 μmol, 0.20 eq), and Na2CO3 (2 M, 1.17 mL, 4.50 eq) in THF (4.00 mL) was degassed and purged with N2 for 3 h, and then the mixture was stirred under N2 atmosphere at 70 °C for 3 h. Water (20 mL) was added to the mixture, which was then extracted with AcOEt (20 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (PE: EtOAc = 0:1) to give intermediate 16a (190.00 mg, crude) as a yellow oil.

[0422] Example 58: 6-(2-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, a mixture of intermediate 16a (200.00 mg, 283.67 μmol, 1.00 eq), Pd(OH) (79.68 mg, 56.73 μmol, 10% purity, 0.20 eq), and ammonium formate (178.88 mg, 2.84 mmol, 10.00 eq) in EtOH (20.00 mL) was degassed and purged with N for 3 h, and then the mixture was stirred under N at 60° C. for 2 h. The mixture was filtered, concentrated under reduced pressure, and purified by preparative HPLC to give Example 58 (27.59 mg, 82.68 μmol, 29.15% yield) as a white solid.

[0423] 1 H-NMR (400 MHz, CDCl3) δ 8.68 (dd, J=1.1, 4.8 Hz, 1H), 7.88 (dt, J=1.9, 7.8 Hz, 1H), 7.78 - 7.72 (m, 2H), 7.37 (ddd, J=0.9, 4.9, 7.3 Hz, 1H), 7.28 - 7.25 (m, 1H), 7.21 (dd, J=1.5, 7.5 Hz, 1H), 7.02 - 6.97 (m, 1H), 6.94 (d, J=8.3 Hz, 1H), 3.88 (s, 3H), 3.45 - 3.31 (m, 1H), 3.05 - 2.88 (m, 2H), 2.75 - 2.60 (m, 2H), 2.22 - 2.13 (m, 1H), 2.05 - 1.89 (m, 1H).

[0424] Example 59: 6-(3-(dimethylamino)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0425] Intermediate 16b: 6-(3-(dimethylamino)phenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16b was prepared starting from intermediate 15a (200.00 mg, 486.46 μmol) and (3-(dimethylamino)phenyl)boronic acid (160.53 mg, 972.92 μmol) according to the method described for intermediate 16a in Example 58 to afford intermediate 16b (160.00 mg, 427.40 μmol, 87.86% yield) as a yellow oil.

[0426] Example 59: 6-(3-(dimethylamino)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 59 was prepared starting from Intermediate 16b (160.00 mg, 427.40 μmol) following the same method as described for example in 58 to afford Example 59 (15.47 mg, 43.85 μmol, 10.26% yield) as a white solid.

[0427] 1 H-NMR (400 MHz, CDCl3) δ 8.69 (dd, J=1.1, 4.8 Hz, 1H), 7.89 (dt, J=1.9, 7.8 Hz, 1H), 7.78 - 7.73 (m, 2H), 7.38 (ddd, J=1.0, 4.9, 7.4 Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 6.70 - 6.63 (m, 3H), 3.05 - 2.98 (m, 1H), 3.05 - 2.98 (m, 7H), 2.96 - 2.86 (m, 2H), 2.84 - 2.75 (m, 1H), 2.72 - 2.59 (m, 1H), 2.30 - 2.21 (m, 1H), 1.98 - 1.85 (m, 1H).

[0428] Example 60: 6-(3-Methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0429] Intermediate 16c: 6-(3-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16c was prepared starting from intermediate 15a (200.00 mg, 518.07 μmol) and (3-methoxy-2-methylphenyl)boronic acid (85.99 mg, 518.07 μmol) according to the method described for intermediate 16a in Example 58 to afford intermediate 16c (200.00 mg, 272.16 μmol, 52.53% yield) as a yellow oil.

[0430] Example 60: 6-(3-Methoxy-2-methylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 60 was prepared starting from intermediate 16c (170.00 mg, 492.20 μmol) following the same method as described for example in 58 to give Example 60 (24.35 mg, 69.95 μmol, 14.21% yield) as a white solid.

[0431] 1H-NMR (400 MHz, CDCl3) δ 8.69 (dd, J=1.1, 4.8 Hz, 1H), 7.89 (dt, J=1.9, 7.8 Hz, 1H), 7.79 - 7.71 (m, 2H), 7.38 (ddd, J=0.9, 4.9, 7.4 Hz, 1H), 7.26 - 7.18 (m, 1H), 6.91 - 6.78 (m, 2H), 3.87 (s, 3H), 3.31 - 3.18 (m, 1H), 3.06 - 2.94 (m, 1H), 2.89 - 2.79 (m, 1H), 2.78 - 2.63 (m, 2H), 2.27 (s, 3H), 2.20 - 2.12 (m, 1H), 1.98 - 1.85 (m, 1H).

[0432] Example 61: 6-(5-Methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0433] Intermediate 16d: 6-(5-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16d was prepared starting from intermediate 15a (227.51 mg, 589.32 μmol) and (5-methoxy-2-methylphenyl)boronic acid (97.82 mg, 589.32 μmol) according to the method described for intermediate 16a in Example 58 to afford intermediate 16d (200.00 mg, crude) as a yellow oil.

[0434] Example 61: 6-(5-Methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 61 was prepared starting from intermediate 16d (200.00 mg, 579.06 μmol) following the same method as described for example in 58 to give Example 61 (19.01 mg, 52.64 μmol, 9.09% yield) as a white solid.

[0435] 1 H-NMR (400 MHz, CDCl3) δ 8.69 (dd, J=1.1, 4.8 Hz, 1H), 7.89 (dt, J=1.9, 7.8 Hz, 1H), 7.77 - 7.73 (m, 2H), 7.38 (ddd, J=1.0, 4.9, 7.4 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 6.80 (d, J=2.6 Hz, 1H), 6.74 (dd, J=2.6, 8.3 Hz, 1H), 3.82 (s, 3H), 3.20 - 3.10 (m, 1H), 3.08 - 2.99 (m, 1H), 2.88 - 2.80 (m, 1H), 2.75 - 2.62 (m, 2H), 2.33 (s, 3H), 2.22 - 2.13 (m, 1H), 1.95 - 1.83 (m, 1H).

[0436] Example 62: 2-(Pyridin-2-yl)-6-(o-tolyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0437] Intermediate 16e: 2-(pyridin-2-yl)-6-(o-tolyl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16e was prepared starting from intermediate 15a (200.00 mg, 486.46 μmol) and o-tolylboronic acid (132.28 mg, 972.92 μmol) according to the method described for intermediate 16a in Example 58 to afford intermediate 16e (70.00 mg, 210.86 μmol, 43.35% yield) as a brown solid.

[0438] Example 62: 2-(pyridin-2-yl)-6-(o-tolyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 62 was prepared starting from intermediate 16e (70.00 mg, 210.86 μmol) following the same method as described for example in 58 to give Example 62 (12.55 mg, 39.07 μmol, 18.53% yield) as a white solid.

[0439] 1 H-NMR (400 MHz, CDCl3) δ 8.59 (dd, J=1.1, 4.8 Hz, 1H), 7.80 (dt, J=1.9, 7.7 Hz, 1H), 7.70 - 7.62 (m, 2H), 7.29 (ddd, J=0.9, 4.9, 7.5 Hz, 1H), 7.17 - 7.07 (m, 4H), 3.16 - 3.05 (m, 1H), 2.98 - 2.86 (m, 1H), 2.81 - 2.71 (m, 1H), 2.69 - 2.53 (m, 2H), 2.32 (s, 3H), 2.13 - 2.03 (m, 1H), 1.89 - 1.76 (m, 1H).

[0440] Example 63: 6-(3-Cyclopropylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0441] Intermediate 16f: 6-(3-cyclopropylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16f was prepared starting from intermediate 15a (100.00 mg, 243.23 μmol) and (3-cyclopropylphenyl)boronic acid pinacol ester (89.07 mg, 364.85 μmol) according to the method described for intermediate 16a in Example 58 to afford intermediate 16f (20.00 mg, 42.76 μmol, 17.58% yield) as a brown solid.

[0442] Example 63: 6-(3-cyclopropylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 63 was prepared starting from intermediate 16f (10.00 mg, 21.38 μmol) following the same method as described for example in 58 to give Example 63 (4.63 mg, 13.48 μmol, 63.06% yield) as a white solid.

[0443] 1 H-NMR (400 MHz, CDCl3) δ 8.68 (br d, J=3.8 Hz, 1H), 7.94 - 7.84 (m, 1H), 7.79 - 7.71 (m, 2H), 7.42 - 7.34 (m, 1H), 7.31 - 7.23 (m, 2H), 7.09 - 7.01 (m, 2H), 6.97 (br d, J=7.4 Hz, 1H), 3.05 - 2.84 (m, 3H), 2.82 - 2.60 (m, 2H), 2.24 (br d, J=8.9 Hz, 1H), 1.98 - 1.83 (m, 2H), 1.06 - 0.95 (m, 2H), 0.74 (q, J=4.9 Hz, 2H).

[0444] Example 64: 6-(3-Methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0445] Intermediate 16g: 6-(3-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, Step viii, intermediate 16g was prepared starting from intermediate 15a (200.00 mg, 518.07 μmol) and (3-methoxy-4-methylphenyl)boronic acid (171.98 mg, 1.04 mmol) according to the method described for intermediate 16a in Example 58 to give intermediate 16g (130.00 mg, 299.60 μmol, 57.83% yield) as a yellow solid. m / z (M+H) + = 346.1.

[0446] Example 64: 6-(3-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 64 was prepared following the same method as described for example in 58, starting from Intermediate 16g (130.00 mg, 299.60 μmol) to afford Example 64 (31.00 mg, 89.23 μmol, 29.78% yield) as a white solid.

[0447] 1 H-NMR (400 MHz, CDCl3) δ 8.62 - 8.56 (m, 1H), 7.83 - 7.76 (m, 1H), 7.68 - 7.62 (m, 2H), 7.32 - 7.25 (m, 1H), 7.04 (d, J=7.5 Hz, 1H), 6.69 (d, J=7.5 Hz, 1H), 6.66 (s, 1H), 3.79 (s, 3H), 2.96 - 2.76 (m, 3H), 2.74 - 2.49 (m, 2H), 2.21 - 2.10 (m, 4H), 1.88 - 1.73 (m, 1H).

[0448] Example 65: 6-(3-(1-hydroxyethyl)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0449] Intermediate 16h: 6-(3-acetylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, Step viii, intermediate 16h was prepared starting from intermediate 15a (100.00 mg, 243.23 μmol) and (3-acetylphenyl)boronic acid (59.82 mg, 364.85 μmol) according to the method described for intermediate 16a in Example 58 to give intermediate 16h (70.00 mg, 156.97 μmol, 64.54% yield) as an off-white solid. m / z (M+H) + = 344.1.

[0450] Example 65: 6-(3-(1-hydroxyethyl)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 65 was prepared starting from Intermediate 16h (70.00 mg, 156.97 μmol) following the same method as described for example in 58 to afford Example 65 (4.05 mg, 11.54 μmol, 4.31% yield) as a white solid.

[0451] 1H-NMR (400 MHz, CDCl3) δ 8.68 (br d, J=3.9 Hz, 1H), 7.93 - 7.85 (m, 1H), 7.79 - 7.70 (m, 2H), 7.41 - 7.35 (m, 2H), 7.32 (br d, J=7.9 Hz, 2H), 7.21 (br d, J=7.5 Hz, 1H), 4.95 (q, J=6.3 Hz, 1H), 3.06 - 2.96 (m, 2H), 2.95 - 2.86 (m, 1H), 2.84 - 2.74 (m, 1H), 2.73 - 2.61 (m, 1H), 2.26 (br d, J=9.0 Hz, 1H), 1.98 - 1.88 (m, 1H), 1.88 - 1.77 (m, 1H), 1.55 (d, J=6.5 Hz, 3H).

[0452] Example 66: 6-(3-Cyclopropoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0453] Intermediate 16i: 6-(3-cyclopropoxyphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, Step viii, intermediate 16i was prepared starting from intermediate 15a (100.00 mg, 243.23 μmol) and (3-cyclopropoxyphenyl)boronic acid pinacol ester (96.85 mg, 364.84 μmol) according to the method described for intermediate 16a in Example 58 to give intermediate 16i (80.00 mg, 118.63 μmol, 48.78% yield) as an off-white solid. m / z (M+H) + = 358.1.

[0454] Example 66: 6-(3-cyclopropoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 66 was prepared starting from intermediate 16i (40.00 mg, 59.32 μmol) following the same method as described for example in 58 to give Example 66 (8.54 mg, 23.74 μmol, 40.01% yield) as a white solid.

[0455] 1 H-NMR (400 MHz, CDCl3) δ 8.68 (br d, J=4.3 Hz, 1H), 7.89 (dt, J=1.6, 7.7 Hz, 1H), 7.78 - 7.72 (m, 2H), 7.38 (dd, J=5.0, 7.2 Hz, 1H), 7.34 - 7.29 (m, 1H), 7.01 (dd, J=2.0, 8.2 Hz, 1H), 6.94 (s, 1H), 6.90 (d, J=7.7 Hz, 1H), 3.82 - 3.71 (m, 1H), 3.03 - 2.86 (m, 3H), 2.82 - 2.59 (m, 2H), 2.25 (br d, J=13.2 Hz, 1H), 1.97 - 1.83 (m, 1H), 0.84 - 0.79 (m, 4H).

[0456] Example 67: 6-(2-Methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0457] Intermediate 16j: 6-(2-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, Step viii, intermediate 16j was prepared starting from intermediate 15a (200.00 mg, 519.68 μmol) and (2-methoxy-4-methylphenyl)boronic acid (129.38 mg, 779.52 μmol) according to the method described for intermediate 16a in Example 58 to give intermediate 16j (180.00 mg, crude) as a brown oil. m / z (M+H) + = 346.1.

[0458] Example 67: 6-(2-Methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 67 was prepared starting from intermediate 16j (180.00 mg, 521.15 μmol) following the same method as described for example in 58 to give Example 67 (24.94 mg, 71.64 μmol, 13.75% yield) as a white solid.

[0459] 1 H-NMR (400 MHz, CDCl3) δ 8.94 (d, J=4.8 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J=4.9 Hz, 1H), 7.08 (dt, J=1.4, 8.0 Hz, 1H), 6.93 - 6.87 (m, 1H), 6.81 (t, J=6.5 Hz, 1H), 3.92 (s, 3H), 3.41 - 3.28 (m, 1H), 3.04 - 2.88 (m, 2H), 2.81 - 2.63 (m, 2H), 2.24 - 2.14 (m, 1H), 2.02 - 1.91 (m, 1H).

[0460] Example 68: 6-(2-Methoxy-3-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0461] Intermediate 16k: 6-(2-methoxy-3-methylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, Step viii, intermediate 16k was prepared starting from intermediate 15a (200.00 mg, 519.68 μmol) and (2-methoxy-3-methylphenyl)boronic acid pinacol ester (214.90 mg, 779.51 μmol) according to the method described for intermediate 16a in Example 58 to give intermediate 16k (190.00 mg, crude) as a brown oil. m / z (M+H) + = 346.1.

[0462] Example 68: 6-(2-Methoxy-3-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 68 was prepared starting from intermediate 16k (190.00 mg, 550.10 μmol) following the same method as described for example 58 to afford Example 68 (16.44 mg, 46.80 μmol, 8.51% yield) as a white solid.

[0463] 1 H-NMR (400 MHz, DMSO-d6) δ 8.43 (s, 2H), 7.79 (s, 1H), 7.14-7.21 (m, 1H), 6.89 (d, J=7.78 Hz, 1H), 6.85 (d, J=8.28 Hz, 1H), 3.76-3.81 (m, 3H), 3.11-3.25 (m, 1H), 2.67-2.84 (m, 3H), 2.55-2.60 (m, 1H), 2.18 (s, 3H), 1.93 (br s, 1H), 1.76-1.89 (m, 1H).

[0464] Example 69: 6-(1-Methylindolin-4-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0465] Intermediate 16l: 6-(1-methylindolin-4-yl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, Step viii, intermediate 16l was prepared starting from intermediate 15a (0.2 g, 535.75 μmol) and (1-methylindolin-4-yl)boronic acid pinacol ester (138.84 mg, 535.75 μmol) according to the method described for intermediate 16a in Example 58 to give intermediate 16l (0.15 g, crude) as a yellow solid. m / z (M+H) + = 357.3

[0466] 1 H NMR (MeOD, 400 MHz) δ 8.60 (br d, J = 4.4 Hz, 1H), 7.94-8.08 (m, 2H), 7.67 (br d, J = 7.6 Hz, 1H), 7.46-7.56 (m, 1H), 7.13 (br t, J = 7.6 Hz, 1H), 6.77 (br d, J = 8.0 Hz, 1H), 6.47-6.59 (m, 2H), 3.04-3.14 (m, 2H), 2.87-2.97 (m, 2H), 2.79-2.86 (m, 2H), 2.76 (s, 3H).

[0467] Example 69: 6-(1-methylindolin-4-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 69 was prepared starting from intermediate 16l (0.15 g, 420.85 μmol) following the same method as described for example in 58 to give Example 69 (55 mg, 151.30 μmol, 35.95% yield) as a white solid.

[0468] 1H-NMR (400 MHz, DMSO-d6) δ 8.67 (br d, J = 3.6 Hz, 1H), 7.87 (td, J = 7.8, 2.0 Hz, 1H), 7.71-7.78 (m, 2H), 7.36 (dd, J = 6.4, 5.0 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 6.58 (d, J = 7.8 Hz, 1H), 6.42 (d, J = 7.8 Hz, 1H), 3.29-3.41 (m, 2H), 2.89-3.11 (m, 4H), 2.75-2.88 (m, 5H), 2.53-2.72 (m, 1H), 2.17 (m, 1H), 1.80-1.98 (m, 1H).

[0469] Example 70: 6-(2-Methoxy-4-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0470] Intermediate 13b: 2-(pyrimidin-2-yl)-7,8-dihydro-2H-spiro[phthalazine-6,2'-[1,3]dioxolan]-1(5H)-one According to Scheme 2, step iv, intermediate 13b was prepared starting from intermediate 12 (40.00 g, 192.11 mmol) and 2-bromopyrimidine (36.65 g, 230.53 mmol) according to the method described for intermediate 13a to give intermediate 13b (62.00 g, crude) as a gray solid.

[0471] 1 H NMR (400MHz, CDCl3) δ 8.92 (d, J=4.8 Hz, 2H), 7.63 (s, 1H), 7.40 (t, J=4.8 Hz, 1H), 4.05 (s, 4H), 2.91 (br t, J=6.7 Hz, 2H), 2.81 (s, 2H), 1.94 (t, J=6.7 Hz, 2H).

[0472] Intermediate 14b: 2-(pyrimidin-2-yl)-7,8-dihydrophthalazine-1,6(2H,5H)-dione According to Scheme 2, step vi, intermediate 14b was prepared starting from intermediate 13b (18.00 g, 62.87 mmol) following a similar method as described for intermediate 14a to afford intermediate 14b (7.60 g, 18.83 mmol, 29.95% yield) as a brown solid.

[0473] 1 H NMR (400MHz, DMSO-d6) δ 9.04 (d, J=4.8 Hz, 2H), 7.88 (s, 1H), 7.79 (d, J=6.4 Hz, 1H), 3.55 (s, 2H), 2.95 (br t, J=6.9 Hz, 2H), 2.56 (t, J=7.0 Hz, 2H).

[0474] Intermediate 15b: 1-oxo-2-(pyrimidin-2-yl)-1,2,7,8-tetrahydrophthalazin-6-yl trifluoromethanesulfonate According to Scheme 2, step vii, intermediate 15b was prepared starting from intermediate 14b (3.50 g, 14.45 mmol) following the method described for intermediate 15a to give intermediate 15b (4.30 g, 8.62 mmol, 59.63% yield) as a yellow solid.

[0475] 1 H NMR (400MHz, MeOD) δ 9.03 - 8.94 (m, 2H), 8.03 - 7.92 (m, 1H), 7.70 - 7.59 (m, 1H), 6.66 (t, J=1.4 Hz, 1H), 3.15 - 3.05 (m, 2H), 2.92 - 2.83 (m, 2H).

[0476] Intermediate 16m: 6-(2-methoxy-4-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, Step viii, intermediate 16m was prepared starting from intermediate 15b (200.00 mg, 480.91 μmol) and (2-methoxy-4-methylphenyl)boronic acid (119.73 mg, 721.37 μmol) according to the method described for intermediate 16a in Example 58 to give intermediate 16m (177.00 mg, crude) as a yellow oil. m / z (M+H) + = 347.1.

[0477] Example 70: 6-(2-Methoxy-4-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 70 was prepared starting from Intermediate 16m (177.00 mg, 511.00 μmol) following the same method as described for example in 58 to give Example 70 (23.80 mg, 62.85 μmol, 12.30% yield) as a white solid.

[0478] 1 H-NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 9.02 (s, 1H), 7.85 (s, 1H), 7.72 (t, J=4.89 Hz, 1H), 7.12-7.18 (m, 1H), 6.88 (d, J=3.39 Hz, 1H), 6.86 (d, J=3.89 Hz, 1H), 4.43-4.71 (m, 1H), 3.12-3.22 (m, 1H), 2.66-2.86 (m, 3H), 2.56 (br d, J=9.91 Hz, 1H), 2.18 (s, 3H), 1.91-2.00 (m, 1H), 1.79-1.90 (m, 1H), 1.28 (d, J=6.02 Hz, 6H).

[0479] Example 71: 6-(2-Methoxy-3-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0480] Intermediate 16n: 6-(2-methoxy-3-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16n was prepared starting from intermediate 15b (200.00 mg, 480.90 μmol) and (2-methoxy-3-methylphenyl)boronic acid pinacol ester (198.88 mg, 721.35 μmol) according to the method described for intermediate 16a. Intermediate 16n (180.00 mg, crude) was obtained as a brown oil. m / z (M+H) + = 347.1.

[0481] Example 71: 6-(2-Methoxy-3-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 71 was prepared starting from intermediate 16n (180.00 mg, 519.66 μmol) following the same method as described for example in 58 to give Example 71 (13.00 mg, 37.31 μmol, 7.18% yield) as a white solid.

[0482] 1 H-NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 9.02 (s, 1H), 7.86 (s, 1H), 7.72 (t, J=4.89 Hz, 1H), 7.12-7.20 (m, 1H), 6.90 (d, J=7.65 Hz, 1H), 6.86 (d, J=8.03 Hz, 1H), 4.09 (dd, J=3.89, 5.40 Hz, 2H), 3.66-3.74 (m, 2H), 3.12-3.23 (m, 1H), 2.65-2.88 (m, 3H), 2.57 (br d, J=8.28 Hz, 1H), 2.20 (s, 3H), 1.95 (br s, 1H), 1.78-1.90 (m, 1H).

[0483] Example 72: 6-(2-chloro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0484] Intermediate 16o: 6-(2-chloro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, Step viii, intermediate 16o was prepared following the method described for intermediate 16a, starting from intermediate 15b (200.00 mg, 480.91 μmol) and (2-chloro-3-methoxyphenyl)boronic acid pinacol ester (134.46 mg, 721.37 μmol), to give intermediate 16o (190.00 mg, crude) as a yellow oil. m / z (M+H) + = 367.0, 369.0.

[0485] Example 72: 6-(2-chloro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 72 was prepared starting from intermediate 16o (190.00 mg, 517.99 μmol) following the same method as described for example in 58 to give Example 72 (29.90 mg, 80.42 μmol, 15.53% yield) as a white solid.

[0486] 1H-NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 9.01 (s, 1H), 7.85 (s, 1H), 7.71 (t, J=4.83 Hz, 1H), 7.45-7.51 (m, 2H), 7.41 (t, J=7.40 Hz, 2H), 7.30-7.35 (m, 1H), 7.13-7.19 (m, 1H), 6.94 (d, J=8.16 Hz, 1H), 6.91 (d, J=7.78 Hz, 1H), 5.11 (s, 2H), 3.13-3.25 (m, 1H), 2.65-2.88 (m, 3H), 2.56 (br d, J=9.41 Hz, 1H), 2.24 (s, 3H), 1.95 (br s, 1H), 1.77-1.90 (m, 1H).

[0487] Example 73: 6-(5-Methoxy-2-(trifluoromethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0488] Intermediate 16p: 6-(5-methoxy-2-(trifluoromethyl)phenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16p was prepared following the method described for intermediate 16a, starting from intermediate 15b (200.00 mg, 480.91 μmol) and (5-methoxy-2-(trifluoromethyl)phenyl)boronic acid pinacol ester (242.14 mg, 721.37 μmol), to give intermediate 16p (72.00 mg, crude) as a yellow solid. m / z (M+H) + = 401.1.

[0489] Example 73: 6-(5-methoxy-2-(trifluoromethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 73 was prepared starting from intermediate 16p (72.00 mg, 179.84 μmol) following the same method as described for example in 58 to give Example 73 (8.30 mg, 19.84 μmol, 11.03% yield) as a white solid.

[0490] 1 H-NMR (400 MHz, CDCl3) δ 8.94 (d, J=4.8 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J=4.8 Hz, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.78 (d, J=2.5 Hz, 1H), 6.72 (dd, J=2.6, 8.3 Hz, 1H), 3.81 (s, 3H), 3.19 - 2.99 (m, 2H), 2.88 - 2.78 (m, 1H), 2.75 - 2.61 (m, 2H), 2.32 (s, 3H), 2.21 - 2.10 (m, 1H), 1.94 - 1.81 (m, 1H)

[0491] Example 74: 6-(2-Fluoro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0492] Intermediate 16q: 6-(2-fluoro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16q was prepared following the method described for intermediate 16a, starting from intermediate 15b (200.00 mg, 480.91 μmol) and (2-fluoro-5-methoxyphenyl)boronic acid pinacol ester (122.60 mg, 721.37 μmol), to give intermediate 16q (60.00 mg, crude) as a brown solid. m / z (M+H) + = 351.0.

[0493] Example 74: 6-(2-fluoro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 74 was prepared starting from intermediate 16q (60.00 mg, 171.26 μmol) following the same method as described for example in 58 to give Example 74 (7.70 mg, 21.66 μmol, 12.65% yield) as a white solid.

[0494] 1 H-NMR (400 MHz, CDCl3) δ 8.94 (d, J=4.9 Hz, 2H), 7.70 (s, 1H), 7.43 (t, J=4.8 Hz, 1H), 7.10 (d, J=7.7 Hz, 1H), 7.04 - 6.97 (m, 2H), 3.20 - 3.10 (m, 1H), 3.04 (br dd, J=5.1, 19.4 Hz, 1H), 2.86 - 2.61 (m, 3H), 2.34 (s, 6H), 2.18 - 2.09 (m, 1H), 1.95 - 1.83 (m, 1H).

[0495] Example 75: 6-(2-chloro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0496] Intermediate 16r: 6-(2-chloro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16r was prepared following the method described for intermediate 16a, starting from intermediate 15b (200.00 mg, 480.91 μmol) and (2-chloro-5-methoxyphenyl)boronic acid pinacol ester (193.72 mg, 721.37 μmol), to give intermediate 16r (160.00 mg, crude) as a brown solid. m / z (M+H) + = 367.0, 369.0.

[0497] Example 75: 6-(2-chloro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 75 was prepared starting from intermediate 16r (160.00 mg, 436.21 μmol) following the same method as described for example in 58 to give Example 75 (5.80 mg, 15.65 μmol, 3.59% yield) as a white solid.

[0498] 1 H-NMR (400 MHz, CDCl3) δ 8.94 (d, J=4.9 Hz, 2H), 7.71 (s, 1H), 7.42 (t, J=4.8 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 6.82 (d, J=2.9 Hz, 1H), 6.76 (dd, J=2.9, 8.7 Hz, 1H), 3.82 (s, 3H), 3.48 - 3.37 (m, 1H), 3.08 - 2.93 (m, 2H), 2.76 - 2.57 (m, 2H), 2.25 - 2.16 (m, 1H), 1.97 - 1.84 (m, 1H).

[0499] Example 76: 6-(2-Methoxy-5-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0500] Intermediate 16s: 6-(2-methoxy-5-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16s was prepared following the method described for intermediate 16a, starting from intermediate 15b (200.00 mg, 480.91 μmol) and (5-methoxy-2-methylphenyl)boronic acid (119.73 mg, 721.37 μmol), to give intermediate 16s (120.00 mg, crude) as a yellow solid. m / z (M+H) + = 347.1.

[0501] Example 76: 6-(2-Methoxy-5-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 76 was prepared starting from intermediate 16s (120.00 mg, 346.44 μmol) following the same method as described for example in 58 to give Example 76 (15.00 mg, 54.38 μmol, 15.70% yield) as a white solid.

[0502] 1 H-NMR (400 MHz, CDCl3) δ 8.94 (d, J=4.8 Hz, 2H), 7.69 (s, 1H), 7.41 (t, J=4.9 Hz, 1H), 7.07 - 6.98 (m, 2H), 6.81 (d, J=8.3 Hz, 1H), 3.83 (s, 3H), 3.39 - 3.26 (m, 1H), 3.06 - 2.85 (m, 2H), 2.73 - 2.59 (m, 2H), 2.31 (s, 3H), 2.14 (br dd, J=3.5, 13.3 Hz, 1H), 1.99 - 1.87 (m, 1H).

[0503] Example 77: 6-(2-methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0504] Intermediate 16t: 6-(2-methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, Step viii, intermediate 16t was prepared starting from intermediate 15b (250.00 mg, 500.95 μmol) and (2-methyl-5-(pyrrolidin-1-yl)phenyl)boronic acid pinacol ester (334.07 mg, 751.43 μmol) according to the method described for intermediate 16a in Example 58 to give intermediate 16t (110.00 mg, crude) as a yellow solid. m / z (M+H) + = 386.2.

[0505] Example 77: 6-(2-methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 77 was prepared starting from Intermediate 16t (110.00 mg, 285.37 μmol) following the same method as described for example in 58 to give Example 77 (9.84 mg, 24.20 μmol, 8.48% yield) as a yellow solid.

[0506] 1H-NMR (400 MHz, CDCl3) δ 8.94 (d, J=4.8 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J=4.8 Hz, 1H), 7.09 - 7.03 (m, 1H), 6.46 - 6.40 (m, 2H), 3.31 - 3.25 (m, 4H), 3.18 - 3.01 (m, 2H), 2.87 - 2.62 (m, 3H), 2.28 (s, 3H), 2.21 - 2.14 (m, 1H), 2.01 (td, J=3.3, 6.6 Hz, 4H), 1.95 - 1.84 (m, 1H).

[0507] Example 78: 6-(1-Methylindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0508] Intermediate 16u: 6-(1-methylindolin-4-yl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, Step viii, intermediate 16u was prepared starting from intermediate 15b (250.00 mg, 500.94 μmol) and (1-methylindolin-4-yl)boronic acid pinacol ester (241.60 mg, 751.41 μmol) according to the method described for intermediate 16a in Example 58 to afford intermediate 16u (140.00 mg, crude) as a yellow solid. m / z (M+H) + = 358.2.

[0509] Example 78: 6-(2-methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 78 was prepared starting from intermediate 16u (140.00 mg, 391.71 μmol) following the same method as described for example 58 to afford Example 78 (26.79 mg, 71.41 μmol, 18.23% yield) as a yellow solid.

[0510] 1 H-NMR (400 MHz, CDCl3) δ 8.94 (d, J=4.9 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J=4.9 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.92 (dd, J=2.5, 8.3 Hz, 1H), 6.86 (d, J=2.5 Hz, 1H), 3.79 - 3.66 (m, 1H), 3.19 - 3.09 (m, 1H), 3.08 - 2.98 (m, 1H), 2.87 - 2.78 (m, 1H), 2.74 - 2.61 (m, 2H), 2.32 (s, 3H), 2.19 - 2.10 (m, 1H), 1.93 - 1.79 (m, 1H), 0.79 - 0.76 (m, 4H).

[0511] Example 79: 6-(2-Fluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0512] Intermediate 16v: 6-(2-fluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, Step viii, intermediate 16v was prepared starting from intermediate 15b (250.00 mg, 500.95 μmol) and (2-fluoro-3-methoxyphenyl)boronic acid pinacol ester (189.43 mg, 751.42 μmol) according to the method described for intermediate 16a in Example 58 to give intermediate 16v (140.00 mg, crude) as a yellow solid. m / z (M+H) + = 351.0.

[0513] Example 79: 6-(2-fluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 79 was prepared starting from Intermediate 16v (140.00 mg, 399.60 μmol) following the same method as described for example in 58 to afford Example 79 (9.04 mg, 25.45 μmol, 6.37% yield) as a white solid.

[0514] 1 H-NMR (400 MHz, CDCl3) δ 8.94 (d, J=4.9 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J=4.8 Hz, 1H), 7.31 - 7.27 (m, 1H), 7.00 (dd, J=1.7, 8.2 Hz, 1H), 6.93 (t, J=1.9 Hz, 1H), 6.88 (d, J=7.7 Hz, 1H), 3.79 - 3.70 (m, 1H), 3.05 - 2.85 (m, 3H), 2.80 - 2.60 (m, 2H), 2.29 - 2.17 (m, 1H), 1.95 - 1.81 (m, 1H), 0.83 - 0.77 (m, 4H).

[0515] Example 80: 6-(5-Methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0516] Intermediate 16w: 6-(5-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16w was prepared following the method described for intermediate 16a, starting from intermediate 15b (250.00 mg, 500.94 μmol) and (5-methoxy-2-methylphenyl)boronic acid (124.72 mg, 751.41 μmol), to give intermediate 16w (110.00 mg, crude) as a brown solid. m / z (M+H) + = 347.1

[0517] Example 80: 6-(5-Methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 80 was prepared starting from intermediate 16w (110.00 mg, 317.57 μmol) following the same method as described for example in 58 to give Example 80 (23.99 mg, 68.58 μmol, 21.60% yield) as a white solid.

[0518] 1H-NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 9.02 (s, 1H), 7.85 (s, 1H), 7.71 (t, J=4.89 Hz, 1H), 7.16 (t, J=7.91 Hz, 1H), 6.90 (d, J=7.53 Hz, 1H), 6.85 (d, J=8.16 Hz, 1H), 6.08 (tdd, J=4.99, 10.42, 17.25 Hz, 1H), 5.43 (dd, J=1.76, 17.32 Hz, 1H), 5.26 (dd, J=1.69, 10.60 Hz, 1H), 4.56 (d, J=4.89 Hz, 2H), 3.12-3.24 (m, 1H), 2.65-2.87 (m, 3H), 2.56 (br d, J=8.53 Hz, 1H), 2.22 (s, 3H), 1.95 (br s, 1H), 1.79-1.91 (m, 1H).

[0519] Example 81: 6-(2,5-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0520] Intermediate 16x: 6-(2,5-dimethylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16x was prepared following the method described for intermediate 16a, starting from intermediate 15b (250.00 mg, 500.94 μmol) and (2,5-dimethylphenyl)boronic acid (112.70 mg, 751.41 μmol), to give intermediate 16x (75.00 mg, crude) as a yellow solid. m / z (M+H) + = 331.2.

[0521] Example 81: 6-(2,5-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 81 was prepared starting from intermediate 16x (75.00 mg, 227.01 μmol) following the same method as described for example in 58 to give Example 81 (16.9 mg, 50.69 μmol, 22.33% yield) as a white solid.

[0522] 1 H-NMR (400 MHz, CDCl3) δ 8.18 (s, 2H), 7.78 (s, 1H), 7.14-7.21 (m, 1H), 6.89 (d, J=7.91 Hz, 1H), 6.85 (d, J=8.03 Hz, 1H), 3.78 (s, 3H), 3.27-3.34 (m, 4H), 3.13-3.22 (m, 1H), 2.65-2.83 (m, 3H), 2.52-2.58 (m, 1H), 2.18 (s, 3H), 1.91-2.05 (m, 5H), 1.77-1.89 (m, 1H).

[0523] Example 82: 6-(2,3-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0524] Intermediate 16y: 6-(2,3-dimethylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16y was prepared following the method described for intermediate 16a, starting from intermediate 15b (250.00 mg, 500.94 μmol) and (2,3-dimethylphenyl)boronic acid (112.70 mg, 751.41 μmol), to give intermediate 16y (100.00 mg, crude) as a yellow solid. m / z (M+H) += 331.2.

[0525] Example 82: 6-(2,3-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 82 was prepared starting from intermediate 16y (100.00 mg, 302.68 μmol) following the same method as described for example in 58 to give Example 82 (4.78 mg, 13.70 μmol, 4.53% yield) as a yellow solid.

[0526] 1 H-NMR (400 MHz, DMSO-d6) δ 8.61 (s, 2H), 7.81 (s, 1H), 7.14-7.22 (m, 1H), 6.88 (dd, J=7.91, 16.81 Hz, 2H), 3.75-3.82 (m, 7H), 3.34 (br s, 4H), 3.12-3.22 (m, 1H), 2.76-2.86 (m, 1H), 2.63-2.75 (m, 2H), 2.56 (br s, 1H), 2.18 (s, 3H), 1.94 (br s, 1H), 1.77-1.90 (m, 1H).

[0527] Example 83: 6-(3-(methoxymethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0528] Intermediate 16z: 6-(3-(methoxymethyl)phenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16z was prepared following the method described for intermediate 16a, starting from intermediate 15b (590 mg, 1.18 mmol) and (3-(methoxymethyl)phenyl)boronic acid (196.23 mg, 1.18 mmol), to give intermediate 16z (280 mg, crude) as a yellow solid. m / z (M+H) + = 347.1.

[0529] Example 83: 6-(3-(methoxymethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 83 was prepared starting from intermediate 16z (260 mg, 750.62 μmol) following the same method as described for example in 58 to give Example 83 (24.91 mg, 70.28 μmol, 9.36% yield) as a white solid.

[0530] 1 H-NMR (400 MHz, DMSO-d6) δ 8.72 (s, 2H), 7.82 (s, 1H), 7.14-7.21 (m, 1H), 6.89 (d, J=7.65 Hz, 1H), 6.85 (d, J=8.16 Hz, 1H), 5.03 (t, J=5.46 Hz, 1H), 4.24-4.31 (m, 2H), 3.75-3.80 (m, 5H), 3.13-3.22 (m, 1H), 2.67-2.86 (m, 3H), 2.55 (br d, J=9.79 Hz, 1H), 2.18 (s, 3H), 1.93 (br s, 1H), 1.78-1.89 (m, 1H).

[0531] Example 84: 6-(5-Cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0532] Intermediate 16aa: 6-(5-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16aa was prepared starting from intermediate 15b (200 mg, 523.65 μmol) and (5-cyclopropoxy-2-methylphenyl)boronic acid pinacol ester (244.71 mg, 785.47 μmol) according to the method described for intermediate 16a to give intermediate 16aa (210 mg, crude) as a yellow solid. m / z (M+H) + = 373.2.

[0533] Example 84: 6-(5-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 84 was prepared starting from intermediate 16aa (210 mg, 563.88 μmol) following the same method as described for example in 58 to give Example 84 (13.78 mg, 36.77 μmol, 6.52% yield) as a white solid.

[0534] 1 H-NMR (400 MHz, DMSO-d6) δ 8.35 (d, J=6.15 Hz, 1H), 7.77 (s, 1H), 7.15-7.21 (m, 1H), 6.96 (d, J=6.27 Hz, 1H), 6.89 (d, J=7.78 Hz, 1H), 6.85 (d, J=8.16 Hz, 1H), 3.79 (s, 3H), 3.67 (br d, J=5.02 Hz, 4H), 3.62 (br d, J=4.77 Hz, 4H), 3.17 (br t, J=8.97 Hz, 1H), 2.62-2.83 (m, 3H), 2.52-2.59 (m, 1H), 2.18 (s, 3H), 1.93 (br s, 1H), 1.83 (dq, J=4.83, 11.90 Hz, 1H).

[0535] Example 85: 6-(3-Cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0536] Intermediate 16ab: 6-(3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16ab was prepared following the method described for intermediate 16a, starting from intermediate 15b (200 mg, 523.65 μmol) and (3-cyclopropoxyphenyl)boronic acid pinacol ester (241.24 mg, 785.48 μmol), to give intermediate 16ab (170 mg, crude) as a yellow solid. m / z (M+H) + = 359.2.

[0537] Example 85: 6-(3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 85 was prepared starting from intermediate 16ab (170 mg, 474.34 μmol) following the same method as described for example in 58 to give Example 85 (12.36 mg, 33.03 μmol, 6.96% yield) as a white solid.

[0538] 1H-NMR (400 MHz, CDCl3) δ 8.93 (d, J=4.8 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J=4.9 Hz, 1H), 7.27 - 7.22 (m, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.80 - 6.76 (m, 2H), 4.78 (qd, J=2.9, 5.7 Hz, 1H), 3.03 - 2.84 (m, 3H), 2.80 - 2.71 (m, 1H), 2.71 - 2.60 (m, 1H), 2.26 - 2.16 (m, 1H), 1.96 - 1.78 (m, 7H), 1.68 - 1.59 (m, 2H).

[0539] Example 86: 6-(3-(cyclopentyloxy)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0540] Intermediate 16ac: 6-(3-(cyclopentyloxy)phenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16ac was prepared following the method described for intermediate 16a, starting from intermediate 15b (300 mg, 785.48 μmol) and (3-(cyclopentyloxy)phenyl)boronic acid pinacol ester (425.50 mg, 1.18 mmol), to give intermediate 16ac (240 mg, crude) as a yellow solid. m / z (M+H) + = 387.1.

[0541] Example 86: 6-(3-(cyclopentyloxy)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 86 was prepared starting from intermediate 16ac (240 mg, 621.04 μmol) following the same method as described for example in 58 to give Example 86 (29.15 mg, 73.01 μmol, 11.76% yield) as a white solid.

[0542] 1 H-NMR (400 MHz, CDCl3) δ 8.93 (d, J=4.8 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J=4.9 Hz, 1H), 7.27 - 7.22 (m, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.80 - 6.76 (m, 2H), 4.78 (qd, J=2.9, 5.7 Hz, 1H), 3.03 - 2.84 (m, 3H), 2.80 - 2.71 (m, 1H), 2.71 - 2.60 (m, 1H), 2.26 - 2.16 (m, 1H), 1.96 - 1.78 (m, 7H), 1.68 - 1.59 (m, 2H).

[0543] Example 87: 6-(4-Methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0544] Intermediate 16ad: 6-(4-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16ad was prepared following the method described for intermediate 16a, starting from intermediate 15b (0.3 g, 801.51 μmol) and (4-methoxy-2-methylphenyl)boronic acid (133.04 mg, 801.51 μmol), to give intermediate 16ad (0.2 g, crude) as a yellow solid. m / z (M+H) + =347.1

[0545] 1 H NMR (DMSO-d6, 400 MHz) δ 9.02 (d, J = 4.8 Hz, 2H), 8.00 (s, 1H), 7.71 (t, J = 4.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 8.4, 2.4 Hz, 1H), 6.40 (s, 1H), 3.75 (s, 3H), 2.75-2.85 (m, 2H), 2.60-2.70 (m, 2H), 2.36 (s, 3H).

[0546] Example 87: 6-(4-Methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 87 was prepared starting from intermediate 16ad (0.15 g, 433.05 μmol) following the same method as described for example in 58 to give Example 87 (42 mg, 120.55 μmol, 27.84% yield) as a white solid.

[0547] 1 H-NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 4.8 Hz, 2H), 7.85 (s, 1H), 7.71 (t, J = 4.8 Hz, 1H), 7.13-7.23 (m, 1H), 6.77 (br d, J = 2.8 Hz, 2H), 3.72 (s, 3H), 3.07 (m, 1H), 2.57-2.85 (m, 4H), 2.32 (s, 3H), 1.78-1.99 (m, 2H).

[0548] Example 88: 6-(1,5-Dimethyl-1H-indazol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0549] Intermediate 16ae: 6-(1,5-dimethyl-1H-indazol-4-yl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16ae was prepared according to the method described for intermediate 16a using intermediate 15b (0.2 g, 534.34 μmol) and (1,5-dimethyl-1H-indazol-4-yl)boronic acid pinacol ester (145.42 mg, 534.34 μmol) to give intermediate 16ae (50 mg, 134.99 μmol, 25.26% yield) as a yellow solid. m / z (M+H) + = 371.2.

[0550] Example 88: 6-(1,5-dimethyl-1H-indazol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 88 was prepared starting from intermediate 16ae (51.39 mg, 138.73 μmol) following the same method as described for example for 58 to afford Example 88 (4 mg, 10.74 μmol, 7.74% yield) as a light yellow solid.

[0551] 1 H-NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 4.8 Hz, 3H), 8.24 (s, 1H), 7.85 (s, 1H), 7.68-7.76 (m, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.01 (s, 3H), 3.19 (m, 1H), 3.12-3.12 (m, 1H), 2.73-2.94 (m, 4H), 2.44 (s, 3H), 1.99 (m, 2H).

[0552] Example 89: 6-Mesityl-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0553] Intermediate 16af: 6-mesityl-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16af was prepared starting from intermediate 15b (200.00 mg, 534.34 μmol) and mesitylboronic acid (87.64 mg, 534.34 μmol) according to the method described for intermediate 16a to give intermediate 16af (0.15 g, 435.53 μmol, 81.51% yield) as a yellow solid. m / z (M+H)+ = 345.3;

[0554] 1 H NMR (DMSO-d6, 400 MHz) δ 9.03 (d, J = 4.8 Hz, 2H), 7.99 (s, 1H), 7.71 (t, J = 4.8 Hz, 1H), 6.92 (s, 2H), 6.26 (s, 1H), 2.78-2.91 (m, 2H), 2.52-2.56 (m, 2H), 2.24 (s, 3H), 2.20 (s, 6H).

[0555] Example 89: 6-Mesityl-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 89 was prepared starting from intermediate 16af (150.00 mg, 435.53 μmol) following the same method as described for example in 58 to give Example 89 (8 mg, 22.61 μmol, 5.19% yield) as a white solid.

[0556] 1H-NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 4.8 Hz, 2H), 7.81 (s, 1H), 7.67-7.73 (m, 1H), 6.81 (s, 2H), 3.28-3.30 (m, 1H), 2.95-3.08 (m, 1H), 2.64-2.84 (m, 2H), 2.32 (s, 6H), 2.18 (s, 3H), 1.89 (m, 2H).

[0557] Example 90: 6-(2,6-Difluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0558] Intermediate 16ag: 6-(2,6-difluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16ag was prepared starting from intermediate 15b (0.2 g, 534.34 μmol) and (2,6-difluoro-3-methoxyphenyl)boronic acid (100.42 mg, 534.34 μmol) according to the method described for intermediate 16a to give intermediate 16ag (0.15 g, 407.24 μmol, 76.21% yield) as a yellow solid. m / z (M+H) + = 369.1

[0559] 1 H NMR (DMSO-d6, 400 MHz) δ 9.03 (d, J = 4.8 Hz, 2H), 8.04 (s, 1H), 7.72 (t, J = 4.8 Hz, 1H), 7.06-7.34 (m, 2H), 6.71 (s, 1H), 3.86 (s, 3H), 2.76-2.89 (m, 2H), 2.62-2.73 (m, 2H).

[0560] Example 90: 6-(2,6-difluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 90 was prepared starting from intermediate 16ag (0.15 g, 407.24 μmol) following the same method as described for example in 58 to give Example 90 (60 mg, 162.01 μmol, 39.78% yield) as a white solid.

[0561] 1 H-NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 4.8 Hz, 2H), 7.83 (s, 1H), 7.71 (t, J = 4.8 Hz, 1H), 6.99-7.19 (m, 3H), 3.83 (s, 3H), 3.36-3.43 (m, 1H), 2.71-3.04 (m, 4H), 1.97-2.18 (m, 3H).

[0562] Example 91: 6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0563] Intermediate 16ah: 6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16ah was prepared starting from intermediate 15b (2.50 g, 6.68 mmol) and (2-chloro-3-cyclopropoxyphenyl)boronic acid pinacol ester (1.83 g, 6.21 mmol) following the method described for intermediate 16a to give intermediate 16ah (1.60 g, 3.84 mmol, 57.4% yield) as a yellow solid.

[0564] 1H NMR (400MHz, CDCl3) δ 8.94 (d, J = 4.8 Hz, 2H), 7.79 (s, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.29 - 7.24 (m, 2H), 6.91 (dd, J = 1.6, 7.6 Hz, 1H), 6.35 (t, J = 1.6 Hz, 1H), 3.84 (tt, J = 3.2, 5.9 Hz, 1H), 3.08 - 2.98 (m, 2H), 2.84 - 2.72 (m, 2H), 0.92 - 0.82 (m, 4H).

[0565] Example 91: 6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one According to Scheme 2, step ix, Example 91 was prepared starting from intermediate 16ah (1.20 g, 2.88 mmol) following the same method as described for example in 58 to give Example 91 (517 mg, 1.26 mmol, 43.9% yield) as a white solid.

[0566] 1 H-NMR (400 MHz, CDCl3) δ 8.93 (d, J = 4.8 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.26 - 7.22 (m, 2H), 6.95 - 6.86 (m, 1H), 3.83 (tt, J = 3.0, 5.8 Hz, 1H), 3.58 - 3.47 (m, 1H), 3.04 - 2.92 (m, 2H), 2.82 - 2.57 (m, 2H), 2.24 - 2.14 (m, 1H), 1.99 - 1.86 (m, 1H), 0.93 - 0.80 (m, 4H).

[0567] Example 92: 6-(1-Cyclopropylindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0568] Intermediate 16ai: 6-(1-cyclopropylindolin-4-yl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16ai was prepared starting from intermediate 15b (2.00 g, 5.34 mmol) and 1-cyclopropylindolin-4-yl)boronic acid pinacol ester (1.50 g, 5.26 mmol) according to the method described for intermediate 16a to give intermediate 16ai (1.70 g, 4.43 mmol, 83.0% yield) as a yellow solid. m / z (M+H) + = 384.0

[0569] Example 92: 6-(1-cyclopropylindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 92 was prepared starting from intermediate 16ai (1.70 g, 4.43 mmol) following a similar procedure to, for example, 58, to afford Example 92 (230 mg, 549.19 μmol, 35.10% yield) as a pale yellow solid.

[0570] 1H-NMR (400 MHz, CDCl3) δ 8.94 (d, J = 4.8 Hz, 1H), 8.97 - 8.90 (m, 1H), 7.69 (s, 1H), 7.42 (t, J = 5.0 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 3.46 - 3.39 (m, 2H), 3.06 - 2.89 (m, 4H), 2.85 - 2.59 (m, 3H), 2.19 - 2.11 (m, 2H), 1.95 - 1.83 (m, 1H), 0.73 - 0.63 (m, 4H).

[0571] Example 93: 6-(3-Cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0572] Intermediate 16aj: 6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16aj was prepared starting from intermediate 15c (3.00 g, 7.49 mmol) and (3-cyclopropoxy-2-methylphenyl)boronic acid pinacol ester (2.25 g, 7.49 mmol) following the method described for intermediate 16a to give intermediate 16aj (2.10 g, 5.28 mmol, 70.5% yield) as a yellow solid.

[0573] 1H NMR (400MHz, CDCl3) δ 8.74 (s, 2H), 7.75 (s, 1H), 7.25 - 7.16 (m, 2H), 6.81 (dd, J = 1.8, 7.0 Hz, 1H), 6.23 (s, 1H), 3.80 - 3.73 (m, 1H), 3.03 - 2.94 (m, 2H), 2.72 - 2.63 (m, 2H), 2.43 (s, 3H), 2.18 (s, 3H), 0.85 - 0.73 (m, 4H).

[0574] Example 93: 6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 93 was prepared starting from intermediate 16aj (1.20 g, 3.02 mmol) following the same method as described for example in 58 to give Example 93 (500 mg, 1.27 mmol, 42.1% yield) as a white solid.

[0575] 1 H-NMR (400 MHz, CDCl3) δ 8.74 (s, 2H), 7.68 (s, 1H), 7.24 - 7.13 (m, 2H), 6.86 (d, J = 6.5 Hz, 1H), 3.78 - 3.71 (m, 1H), 3.26 - 3.17 (m, 1H), 3.04 - 2.95 (m, 1H), 2.86 - 2.76 (m, 1H), 2.75 - 2.60 (m, 2H), 2.43 (s, 3H), 2.19 (s, 3H), 2.17 - 2.09 (m, 1H), 1.95 - 1.82 (m, 1H), 0.82 - 0.76 (m, 4H).

[0576] Example 94: 6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A. [ka]

[0577] Intermediate 16ak: 6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16ak was prepared starting from intermediate 15c (3.00 g, 7.49 mmol) and (2-chloro-3-methoxyphenyl)boronic acid pinacol ester (1.40 g, 7.49 mmol) following the method described for intermediate 16a to give intermediate 16ak (2.40 g, 6.15 mmol, 82.1% yield, 97.6% purity) as a yellow solid.

[0578] 1 H NMR (400MHz, CDCl3) δ 8.75 (s, 2H), 7.83 - 7.74 (m, 1H), 7.33 - 7.21 (m, 1H), 7.04 - 6.81 (m, 2H), 6.36 (s, 1H), 4.10 - 3.89 (m, 3H), 3.18 - 2.96 (m, 2H), 2.88 - 2.73 (m, 2H), 2.44 (s, 3H).

[0579] Example 94: 6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 94 was prepared starting from intermediate 16ak (600 mg, 1.54 mmol) following the same method as described for example in 58 to give Example 94 (230 mg, 588 μmol, 38.2% yield, 97.8% purity) as a white solid.

[0580] 1H-NMR (400 MHz, CDCl3) δ 8.73 (s, 2H), 7.69 (s, 1H), 7.26 - 7.23 (m, 1H), 6.88 (dd, J = 4.4, 8.0 Hz, 2H), 3.93 (s, 3H), 3.61 - 3.49 (m, 1H), 3.02 - 2.92 (m, 2H), 2.82 - 2.58 (m, 2H), 2.43 (s, 3H), 2.19 (td, J = 2.8, 10.0 Hz, 1H), 1.98 - 1.85 (m, 1H).

[0581] Example 95: 6-(2-chloro-4-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method B. [ka]

[0582] Intermediate 17a: 2-(pyrimidin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step x, to a solution of intermediate 15b (1 g, 2.67 mmol, 1 eq), Pd(dppf)Cl2 (97.74 mg, 133.58 μmol, 0.05 eq), and KOAc (524.41 mg, 5.34 mmol, 2 eq) in dioxane (20 mL) at 25 °C under N2, Pin2B2 (1.02 g, 4.01 mmol, 1.5 eq) was added in one portion. The mixture was stirred at 100 °C for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 1:1) to give intermediate 17a (0.85 g, 2.41 mmol, 90.33% yield) as a yellow solid. m / z (M+H) + = 353.3

[0583] 1H NMR (CDCl3, 400 MHz) δ 8.92 (d, J = 4.8 Hz, 2H), 7.77 (s, 1H), 7.41 (t, J = 4.8 Hz, 1H), 6.99 (s, 1H), 2.74-2.89 (t, J = 8.8 Hz, 2H), 2.46-2.61 (t, J = 8.8 Hz, 2H), 1.32 (s, 12H).

[0584] Intermediate 16al: 6-(2-chloro-4-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, Step xi, to a mixture of intermediate 17a (247.04 mg, 1.20 mmol, 64.34 μL, 1.5 eq) and 1-bromo-2-chloro-4-methylbenzene (0.3 g, 801.51 μmol, 1 eq) in dioxane (10 mL) was added a solution of NaCO (339.80 mg, 3.21 mmol, 4 eq) in HO (1 mL) and Pd(dppf)Cl.CHCl (65.45 mg, 80.15 μmol, 0.1 eq) in one portion at 20 °C under N. The mixture was stirred at 100 °C for 12 h. The mixture was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EtOAc = 0:1, 1:0) to give intermediate 16al (0.15 g, 427.59 μmol, 53.35% yield) as a yellow solid.

[0585] 1 H NMR (400MHz, CDCl3) δ 9.07-9.03 (m, 3H), 8.04 (s, 1H), 7.76-7.68 (m, 2H), 7.40 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.57 (s, 1H), 2.87-2.79 (m, 2H), 2.77-2.67 (m, 2H), 2.35 (s, 3H).

[0586] Example 95: 6-(2-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 95 was prepared starting from intermediate 16al (0.15 g, 427.59 μmol) following the same method as described for example in 58 to give Example 95 (0.018 g, 51.02 μmol, 11.93% yield) as a white solid.

[0587] 1 H-NMR (400 MHz, CDCl3) δ 8.94 (d, J = 4.0 Hz, 2H), 7.71 (s, 1H), 7.42 (t, J = 4.4 Hz, 1H), 7.25 (s, 1H), 7.17-7.12 (m, 1H), 7.12-7.06 (m, 1H), 3.52-3.39 (m, 1H), 3.04-2.92 (m, 2H), 2.76-2.58 (m, 2H), 2.34 (s, 3H), 2.22-2.05 (m, 2H), 1.97-1.85 (m, 1H).

[0588] Example 96: 6-(3-(dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method B. [ka]

[0589] Intermediate 16am: 6-(3-(dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step xi, intermediate 16am was prepared starting from intermediate 17a (0.2 g, 567.87 μmol) and 3-bromo-N,N,2-trimethylaniline (121.58 mg, 567.87 μmol) according to the same method as described for intermediate 16al to give intermediate 16am (0.15 g, 417.33 μmol, 73.49% yield) as a yellow solid. m / z (M+H) + = 360.3

[0590] 1 H NMR (CDCl3, 400 MHz) δ 8.94 (d, J = 4.9 Hz, 3H), 7.78 (s, 1H), 7.44-7.40 (m, 2H), 7.20 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.26 (s, 1H), 2.96-3.07 (m, 2H), 2.66-2.76 (m, 8H), 2.35 (s, 3H).

[0591] Example 96: 6-(3-(dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 96 was prepared starting from intermediate 16am (0.15 g, 417.33 μmol) following the same method as described for example in 58 to give Example 96 (14 mg, 34.93 μmol, 8.37% yield) as a white solid.

[0592] 1H-NMR (400 MHz, CDCl3) δ 8.94 (d, J = 4.8 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.28 (m, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 3.16 (m, 1H), 2.97-2.92 (m, 1H), 2.91-2.75 (m, 7H), 2.65-2.59 (m, 2H), 2.35 (s, 3H), 2.082.06 (m, 1H), 1.86-1.81 (m, 1H).

[0593] Example 97: 6-(5-Methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method B. [ka]

[0594] Intermediate 16an: 6-(5-methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step xi, intermediate 16an was prepared starting from intermediate 17a (0.3 g, 851.80 μmol) and 1-bromo-5-methoxy-2,4-dimethylbenzene (183.21 mg, 851.80 μmol) according to the same method as described for intermediate 16al to give intermediate 16an (0.2 g, 554.93 μmol, 65.15% yield) as a yellow solid. m / z (M+H) + = 361.3

[0595] 1H NMR (CDCl3, 400 MHz) δ 9.03 (d, J = 4.8 Hz, 2H), 8.01 (s, 1H), 7.71 (t, J = 4.8 Hz, 1H), 7.04 (s, 1H), 6.80 (s, 1H), 6.44 (s, 1H), 3.79 (s, 3H), 2.76-2.89 (m, 2H), 2.61-2.73 (m, 2H), 2.26 (s, 3H), 2.14 (s, 3H).

[0596] Example 97: 6-(5-methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 97 was prepared starting from intermediate 16nj (0.2 g, 554.93 μmol) following the same method as described for example in 58 to give Example 97 (8 mg, 22.07 μmol, 3.98% yield) as a white solid.

[0597] 1 H-NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 4.4 Hz, 2H), 7.86 (s, 1H), 7.71 (t, J = 4.4 Hz, 1H), 6.93 (s, 1H), 6.83 (s, 1H), 3.77 (s, 3H), 3.07 (m, 1H), 2.72-2.88 (m, 4H), 2.23 (s, 3H), 2.09 (s, 3H), 1.78-2.01 (m, 2H).

[0598] Example 98: 6-(4-chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method B. [ka]

[0599] Intermediate 16ao: 6-(4-chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step viii, intermediate 16ao was prepared starting from intermediate 15b (0.3 g, 801.51 μmol) and (4-chloro-2-methylphenyl)boronic acid (136.58 mg, 801.51 μmol) according to the method described for intermediate 16a in Example 58 to give intermediate 16ao (0.15 g, 427.59 μmol, 53.35% yield) as a yellow solid. m / z (M+H) + = 351.1.

[0600] Example 98: 6-(4-chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 98 was prepared starting from intermediate 16ao (120 mg, 342.07 μmol) following the same method as described for example 58 to give Example 98 (13 mg, 36.85 μmol, 10.77% yield) as a white solid.

[0601] 1 H-NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 4.8 Hz, 2H), 7.85 (s, 1H), 7.71 (t, J = 4.8 Hz, 1H), 7.22-7.34 (m, 3H), 3.14 (m, 1H), 2.65-2.89 (m, 4H), 2.36 (s, 2H), 1.81-2.01 (m, 2H).

[0602] Example 99: 6-(4-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method B. [ka]

[0603] Intermediate 16ap: 6-(4-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 2, step xi, intermediate 16ap was prepared starting from intermediate 17a (0.3 g, 851.80 μmol) and 1-(4-bromo-3-methylphenyl)ethan-1-one (181.49 mg, 851.80 μmol) according to the same method as described for intermediate 16al to give intermediate 16ap (0.18 g, 502.24 μmol, 58.96% yield) as a yellow solid. m / z (M+H) + = 359.2

[0604] 1 H NMR (DMSO-d6, 400 MHz) δ 9.03 (d, J = 4.8 Hz, 2H), 8.03 (s, 1H), 7.88 (s, 1H), 7.83 (br d, J = 8.0 Hz, 1H), 7.72 (t, J = 4.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 6.52 (s, 1H), 2.80-2.89 (m, 2H), 2.66-2.75 (m, 2H), 2.59 (s, 3H), 2.44 (s, 3H).

[0605] Example 99: 6-(4-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, step ix, Example 99 was prepared starting from intermediate 16ap (150.00 mg, 418.53 μmol) following the same method as described for example in 58 to give Example 99 (22 mg, 61.04 μmol, 14.58% yield) as a white solid.

[0606] 1H-NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 4.8 Hz, 2H), 7.85 (s, 1H), 7.76-7.83 (m, 2H), 7.71 (t, J = 4.8 Hz, 1H), 7.43 (br d, J = 8.0 Hz, 1H), 3.16-3.27 (m, 1H), 2.65-2.93 (m, 4H), 2.55 (s, 3H), 2.43 (s, 3H), 1.83-2.03 (m, 2H).

[0607] Example 100: 6-(3-(3-methoxypropoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 5. [ka]

[0608] Intermediate 50: 6-(3-hydroxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one According to Scheme 5, Step i, to a solution of compound Example 40 (2.50 g, 7.18 mmol, 1.00 eq) in CHCl (30.00 mL) was added BBr (8.99 g, 35.90 mmol, 3.46 mL, 5.00 eq) dropwise at 0 °C under N. The mixture was stirred at 0 °C for 1.5 h. The mixture was poured into HO (80 mL) at 0 °C. The pH of the aqueous phase was adjusted to approximately 6-7 by adding solid KCO. A large amount of precipitate formed. The mixture was filtered, and the combined aqueous phases were extracted with CHCl (60 mL × 5), filtered, and concentrated in vacuo. The filter cake was dissolved in CHCl / MeOH (1 / 10, 100 mL) and stirred for 1 h. The mixture was filtered. All organic phases were combined and dried under vacuum. Intermediate 50 (2.60 g, 5.99 mmol, 83.39% yield) was obtained as a brown solid.

[0609] 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 9.01 (s, 1H), 7.85 (s, 1H), 7.71 (t, J=4.89 Hz, 1H), 6.88-6.95 (m, 1H), 6.63-6.69 (m, 1H), 6.60 (d, J=7.65 Hz, 1H), 3.07-3.15 (m, 1H), 2.66-2.85 (m, 3H), 2.56 (s, 1H), 2.13 (s, 3H), 1.91-1.99 (m, 1H), 1.74-1.86 (m, 1H).

[0610] Example 100: (6-(3-(3-methoxypropoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one According to Scheme 5, step ii, to a mixture of intermediate 50 (80 mg, 239.26 μmol, 1 eq) and 1-bromo-3-methoxypropane (73.22 mg, 478.52 μmol, 38.27 μL, 2 eq) in DMF (2 mL) was added CsCO (116.93 mg, 358.89 μmol, 1.5 eq) in one portion at 25 °C under N. The mixture was stirred at 100 °C for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by preparative HPLC to give Example 100 (25 mg, 61.50 μmol, 25.71% yield) as a white solid.

[0611] 1 H-NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 4.8 Hz, 2H), 7.85 (s, 1H), 7.71 (t, J = 4.8 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.80-6.93 (m, 2H), 4.00 (t, J = 6.2 Hz, 2H), 3.51 (t, J = 6.2 Hz, 2H), 3.26 (s, 3H), 3.16-3.19 (m, 1H), 2.58-2.87 (m, 4H), 2.19 (s, 3H), 1.76-2.02 (m, 4H).

[0612] Example 101: 6-(3-ethoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 5. [ka]

[0613] According to Scheme 5, step ii, Example 101 was prepared following the same method as described for example for 100, starting from Intermediate 50 (80 mg, 239.26 μmol) and iodoethane (74.63 mg, 478.51 μmol) to afford Intermediate Example 101 (25 mg, 68.98 μmol, 28.83% yield) as a white solid.

[0614] 1 H-NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 4.8 Hz, 2H), 7.84 (s, 1H), 7.71 (br t, J = 4.8 Hz, 1H), 7.15 (br t, J = 7.8 Hz, 1H), 7.07-7.26 (m, 1H), 6.85 (br dd, J=19.0, 7.8 Hz, 2H), 4.01 (q, J = 6.8 Hz, 2H), 3.16-3.18 (m, 1H), 2.56-2.93 (m, 4H), 2.19 (s, 3H), 1.75-2.03 (m, 2H), 1.36 (br t, J=6.8 Hz, 3H).

[0615] Example 102: 6-(3-(cyclopropylmethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 5. [ka]

[0616] According to Scheme 5, step ii, Example 102 was prepared following the same method as described for example for 100, starting from Intermediate 50 (150.00 mg, 345.43 μmol) and (bromomethyl)cyclopropane (233.16 mg, 1.73 mmol) to afford Intermediate Example 102 (58.63 mg, 150.78 μmol, 43.65% yield) as a white solid.

[0617] 1 H-NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 9.02 (s, 1H), 7.85 (s, 1H), 7.71 (t, J=4.83 Hz, 1H), 7.10-7.17 (m, 1H), 6.88 (d, J=7.65 Hz, 1H), 6.81 (d, J=8.16 Hz, 1H), 3.82 (d, J=6.65 Hz, 2H), 3.12-3.23 (m, 1H), 2.65-2.87 (m, 3H), 2.52-2.62 (m, 1H), 2.21 (s, 3H), 1.94 (br s, 1H), 1.76-1.89 (m, 1H), 1.19-1.30 (m, 1H), 0.52-0.61 (m, 2H), 0.29-0.37 (m, 2H).

[0618] Example 103: 6-(3-Isopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 5. [ka]

[0619] According to Scheme 5, step ii, Example 103 was prepared following the same method as described for example for 100, starting from Intermediate 50 (180.00 mg, 414.51 μmol) and 2-bromopropane (352.31 mg, 2.07 mmol) to afford Intermediate Example 103 (71.78 mg, 190.68 μmol, 46.00% yield) as a white solid.

[0620] 1 H-NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 9.02 (s, 1H), 7.85 (s, 1H), 7.72 (t, J=4.89 Hz, 1H), 7.12-7.18 (m, 1H), 6.88 (d, J=3.39 Hz, 1H), 6.86 (d, J=3.89 Hz, 1H), 4.43-4.71 (m, 1H), 3.12-3.22 (m, 1H), 2.66-2.86 (m, 3H), 2.56 (br d, J=9.91 Hz, 1H), 2.18 (s, 3H), 1.91-2.00 (m, 1H), 1.79-1.90 (m, 1H), 1.28 (d, J=6.02 Hz, 6H).

[0621] Example 104: 6-(3-Cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 5. [ka]

[0622] According to Scheme 5, step ii, Example 104 was prepared following the same method as described for example for 100, starting from Intermediate 50 (150 mg, 345.42 μmol) and 2-bromocyclopropane (417.88 mg, 3.45 mmol) to afford Intermediate Example 104 (19.84 mg, 51.56 μmol, 14.93% yield) as a white solid.

[0623] 1H-NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 9.02 (s, 1H), 7.85 (s, 1H), 7.71 (t, J=4.89 Hz, 1H), 7.16 (t, J=7.91 Hz, 1H), 6.90 (d, J=7.53 Hz, 1H), 6.85 (d, J=8.16 Hz, 1H), 6.08 (tdd, J=4.99, 10.42, 17.25 Hz, 1H), 5.43 (dd, J=1.76, 17.32 Hz, 1H), 5.26 (dd, J=1.69, 10.60 Hz, 1H), 4.56 (d, J=4.89 Hz, 2H), 3.12-3.24 (m, 1H), 2.65-2.87 (m, 3H), 2.56 (br d, J=8.53 Hz, 1H), 2.22 (s, 3H), 1.95 (br s, 1H), 1.79-1.91 (m, 1H).

[0624] Example 105: 6-(3-(2-methoxyethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 5. [ka]

[0625] According to Scheme 5, step ii, Example 105 was prepared following the same method as described for example for 100, starting from Intermediate 50 (200.00 mg, 460.57 μmol) and 1-bromo-2-methoxyethane (320.07 mg, 2.30 mmol) to afford Intermediate Example 105 (41.81 mg, 106.54 μmol, 23.13% yield) as a white solid.

[0626] 1H-NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 9.02 (s, 1H), 7.86 (s, 1H), 7.72 (t, J=4.89 Hz, 1H), 7.12-7.20 (m, 1H), 6.90 (d, J=7.65 Hz, 1H), 6.86 (d, J=8.03 Hz, 1H), 4.09 (dd, J=3.89, 5.40 Hz, 2H), 3.66-3.74 (m, 2H), 3.12-3.23 (m, 1H), 2.65-2.88 (m, 3H), 2.57 (br d, J=8.28 Hz, 1H), 2.20 (s, 3H), 1.95 (br s, 1H), 1.78-1.90 (m, 1H).

[0627] Example 106: 6-(3-(benzyloxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 5. [ka]

[0628] According to Scheme 5, step ii, Example 106 was prepared following the same method as described for example for 100, starting from Intermediate 50 (180.00 mg, 414.51 μmol) and (bromomethyl)benzene (212.68 mg, 1.24 mmol) to afford Intermediate Example 106 (61.03 mg, 143.77 μmol, 34.68% yield) as a white solid.

[0629] 1H-NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 9.01 (s, 1H), 7.85 (s, 1H), 7.71 (t, J=4.83 Hz, 1H), 7.45-7.51 (m, 2H), 7.41 (t, J=7.40 Hz, 2H), 7.30-7.35 (m, 1H), 7.13-7.19 (m, 1H), 6.94 (d, J=8.16 Hz, 1H), 6.91 (d, J=7.78 Hz, 1H), 5.11 (s, 2H), 3.13-3.25 (m, 1H), 2.65-2.88 (m, 3H), 2.56 (br d, J=9.41 Hz, 1H), 2.24 (s, 3H), 1.95 (br s, 1H), 1.77-1.90 (m, 1H).

[0630] Example 107: 2-(5-cyclopropylpyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 6, Method A. [ka]

[0631] Intermediate 52a: 2-(5-bromopyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 6, Step i, to a mixture of intermediate 7c (0.1 g, 369.92 μmol, 1 eq) and 2,5-dibromopyrimidine (263.99 mg, 1.11 mmol, 3 eq) in dioxane (20 mL) at 25 °C under N was added CuI (35.23 mg, 184.96 μmol, 0.5 eq), KPO (196.31 mg, 924.81 μmol, 2.5 eq), and DMEDA (16.30 mg, 184.96 μmol, 0.5 eq) in one portion. The mixture was stirred at 25 °C for 5 min, then heated to 110 °C and stirred for 12 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (PE: EtOAc = 15 / 1 to 1 / 1) to give intermediate 52a (0.08 g, 187.22 μmol, 50.61% yield) as a yellow solid.

[0632] 1 H NMR: (CDCl 3, 400 MHz) H) δ 8.88 (s, 2H), 7.61 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.75-6.58 (m, 2H), 3.73 (s, 3H), 3.07-2.85 (m, 2H), 2.75-2.65 (m, 1H), 2.61-2.57 (m, 2H), 2.23 (s, 3H), 2.08-2.05 (m, 1H), 1.81-1.76 (m, 1H).

[0633] Example 107: 2-(5-cyclopropylpyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 6, Step ii, to a mixture of intermediate 52a (0.2 g, 468.06 μmol, 1 eq) and cyclopropylboronic acid (78.25 mg, 0.94 mmol, 5 eq) in dioxane (20 mL) at 25 °C under N was added Pd(dppf)Cl (17.12 mg, 23.40 μmol, 0.05 eq) and KCO (77.61 mg, 0.56 mmol, 3.0 eq) in one portion. The mixture was stirred at 25 °C for 5 min, then heated to 110 °C and stirred for 12 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was pre-purified by column chromatography followed by preparative HPLC to give Example 107 (0.053 g, 136.44 μmol, 29.15% yield) as a white solid.

[0634] 1 H-NMR (400 MHz, CDCl3) δ 8.77 (s, 2H), 7.84 (s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 6.73 (dd, J = 2.4, 8.4 Hz, 1H), 3.78 (s, 3H), 3.11 (m, 1H), 2.80-2.52 (m, 4H), 2.28 (s, 3H), 2.09-2.06 (m, 1H), 1.93-1.84 (m, 3H), 1.14-1.14 (m, 2H), 1.00-0.97 (m, 2H).

[0635] Example 108: 2-(5-Cyclopropylpyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 6, Method A. [ka]

[0636] Intermediate 52b: 2-(5-bromopyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 6, step i, intermediate 52b was prepared starting from intermediate 7a (0.5 g, 1.97 mmol) and 2,5-dibromopyridine (558.87 mg, 2.36 mmol) following the same method as described for intermediate 52a to give intermediate 52b (0.7 g, 1.71 mmol, 86.78% yield) as a pale yellow solid.

[0637] 1 H NMR (400MHz, CDCl3) δ 8.72 (s, 1H), 7.98 (dd, J = 8.4, 2.0 Hz, 1H), 7.80-7.66 (m, 2H), 7.18-6.95 (m, 3H), 3.14 (m, 1H), 3.06-2.93 (m, 1H), 2.86-2.76 (m, 1H), 2.76-2.61 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.14 (m, H), 1.96-1.78 (m, 1H).

[0638] Example 108: 2-(5-cyclopropylpyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 6, step ii, Example 108 was prepared starting from Intermediate 52b (0.2, 487.44 μmol) and cyclopropylboronic acid (209.35 mg, 2.44 mmol) following the same method as described for Intermediate Example 107 to afford Example 108 (0.08 g, 213.20 μmol, 43.74% yield) as a white solid.

[0639] 1H-NMR (400 MHz, CDCl3) δ 8.63 (s, 2H), 7.69 (s, 1H), 7.17-6.97 (m, 3H), 3.14 (m, 1H), 3.00 (m, 1H), 2.86-2.76 (m, 1H), 2.75-2.59 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.12 (m, 1H), 2.03-1.95 (m, 1H), 1.98 (m, 1H), 1.93-1.77 (m, 1H), 1.25-1.10 (m, 2H), 0.88 (m, 2H).

[0640] Example 109: 2-(5-Cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 6, Method A. [ka]

[0641] Intermediate 52c: 2-(5-bromopyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 6, step i, intermediate 52c was prepared according to the same method as described for intermediate 52a, starting from intermediate 7a (1 g, 3.93 mmol) and 2,5-dibromopyrimidine (1.12 g, 4.72 mmol) to give intermediate 52c (1.2 g, 2.92 mmol, 74.20% yield) as a pale yellow solid.

[0642] 1 H NMR (400MHz, CDCl3) δ 8.95 (s, 2H), 7.69 (s, 1H), 7.14-6.99 (m, 3H), 3.26-3.09 (m, 1H), 3.00 (m, 1H), 2.86-2.75 (m, 1H), 2.75-2.59 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.12 (m, 1H), 1.93-1.79 (m, 1H).

[0643] Example 109: 2-(5-cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 6, step ii, Example 109 was prepared according to the same method as described for Intermediate Example 107, starting from Intermediate 52c (200.48 mg, 487.44 μmol) and cyclopropylboronic acid (209.35 mg, 2.44 mmol) to afford Example 109 (0.124 g, 329.59 μmol, 67.62% yield) as a pale yellow solid.

[0644] 1 H-NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.71 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 2.0, 8.4 Hz, 1H), 7.13-7.07 (m, 1H), 7.06-7.00 (m, 2H), 3.19-3.09 (m, 1H), 3.04-2.92 (m, 1H), 2.85-2.76 (m, 1H), 2.74-2.58 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.15-2.10 (m, 1H), 2.03-1.94 (m, 1H), 1.93-1.81 (m, 1H), 1.13-1.05 (m, 2H), 0.82-0.74 (m, 2H).

[0645] Example 110: 2-(5-Cyclopropylpyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 6, Method A. [ka]

[0646] Intermediate 52d: 2-(5-bromopyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 6, step i, intermediate 52d was prepared according to the same method as described for intermediate 52a, starting from intermediate 7b (1 g, 3.70 mmol) and 2,5-dibromopyridine (2.63 g, 11.10 mmol) to give intermediate 52d (1.2 g, 2.81 mmol, 76.09% yield) as a yellow solid.

[0647] 1 H NMR (DMSO-d6, 400MHz) δ 8.76 (m, 1H), 8.28 (dd, J = 2.0, 8.4 Hz, 1H), 7.95 (m, 1H), 7.63 (br s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.00-6.85 (m, 2H), 3.79 (s, 3H), 3.17 (m, 1H), 2.87-2.65 (m, 4H), 2.25 (m, 1H), 2.18 (s, 3H), 1.88-1.81 (m, 1H).

[0648] Example 110: 2-(5-cyclopropylpyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 6, step ii, Example 110 was prepared according to the same method as described for Intermediate Example 107, starting from Intermediate 52d (0.3 g, 703.72 μmol) and cyclopropylboronic acid (302.24 mg, 3.52 mmol) to afford Example 110 (0.09 g, 232.27 μmol, 33.01% yield) as a yellow solid.

[0649] 1H-NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.83 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 3.79 (s, 3H), 3.15 (m, 1H), 2.87-2.65 (m, 4H), 2.34 (m, 1H), 2.18 (s, 3H), 2.05 (m, 1H), 1.85 (m, 1H), 1.08-1.05 (m, 2H), 0.83 (m, 2H).

[0650] Example 111: 6-(3-Methoxy-2-methylphenyl)-2-(5-(pyrrolidin-1-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 6, Method B. [ka]

[0651] According to Scheme 6, Step iii, a mixture of Example 43 (180 mg, 470.17 μmol, 1 eq) and pyrrolidine (66.88 mg, 940.33 μmol, 78.49 μL, 2 eq) in dioxane (5 mL) was added at 20 °C under N2 with RUPHOS precatalyst (36.52 mg, 47.02 μmol, 0.1 eq) and Cs2CO3 (382.97 mg, 1.18 mmol, 2.5 eq). The mixture was stirred at 100 °C for 12 h. The mixture was poured into HO (15 mL). The aqueous phase was filtered and extracted with CHCl2 (20 mL × 2). The combined organic phases were concentrated in vacuo and combined with the filter cake, and the crude product was purified by preparative HPLC. Example 111 (0.98 mg, 2.21 μmol, 0.5% yield) was obtained as a white solid.

[0652] 1H-NMR (400 MHz, DMSO-d6) δ 8.18 (s, 2H), 7.78 (s, 1H), 7.14-7.21 (m, 1H), 6.89 (d, J=7.91 Hz, 1H), 6.85 (d, J=8.03 Hz, 1H), 3.78 (s, 3H), 3.27-3.34 (m, 4H), 3.13-3.22 (m, 1H), 2.65-2.83 (m, 3H), 2.52-2.58 (m, 1H), 2.18 (s, 3H), 1.91-2.05 (m, 5H), 1.77-1.89 (m, 1H).

[0653] Example 112: (6-(3-Methoxy-2-methylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 6, Method B. [ka]

[0654] According to Scheme 6, step iii, Example 112 was prepared following the same method as described for example 111, starting from Example 43 (150 mg, 391.81 μmol) and morpholine (68.27 mg, 783.61 μmol, 68.96 μL) to afford Example 112 (37.27 mg, 83.31 μmol, 21.26% yield) as a white solid.

[0655] 1 H-NMR (400 MHz, DMSO-d6) δ 8.61 (s, 2H), 7.81 (s, 1H), 7.14-7.22 (m, 1H), 6.88 (dd, J=7.91, 16.81 Hz, 2H), 3.75-3.82 (m, 7H), 3.34 (br s, 4H), 3.12-3.22 (m, 1H), 2.76-2.86 (m, 1H), 2.63-2.75 (m, 2H), 2.56 (br s, 1H), 2.18 (s, 3H), 1.94 (br s, 1H), 1.77-1.90 (m, 1H).

[0656] Example 113: 6-(3-Methoxy-2-methylphenyl)-2-(5-morpholinopyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 6, Method B. [ka]

[0657] According to Scheme 6, step iii, Example 113 was prepared following the same method as described in, for example, 111, starting from intermediate 52d (0.2 g, 469.15 μmol) and morpholine (81.74 mg, 938.29 μmol, 82.57 μL) to afford Example 113 (0.092 g, 212.71 μmol, 45.34% yield) as a yellow solid.

[0658] 1 H-NMR (400 MHz, CDCl3) δ 8.45 (br s, 1H), 8.03 (br s, 1H), 7.81 (br s, 1H), 7.59 (br s, 1H), 7.23 (br t, J = 7.8 Hz, 1H), 6.95-6.81 (m, 2H), 3.94 (m, 4H), 3.88 (s, 3H), 3.37 (br s, 4H), 3.25 (br s, 1H), 2.99 (m, 1H), 2.92-2.82 (m, 1H), 2.81-2.65 (m, 3H), 2.27 (s, 3H), 2.16 (br s, 1H), 1.93-1.90 (m, 1H).

[0659] Example 114: 6-(2,4-dimethylphenyl)-2-(5-morpholinopyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 6, Method B. [ka]

[0660] According to Scheme 6, step iii, Example 114 was prepared following the same method as described in, for example, 111, starting from Intermediate 52b (0.15 g, 365.58 μmol) and morpholine (63.70 mg, 731.16 μmol, 64.34 μL) to afford Example 114 (0.029 g, 66.14 μmol, 18.09% yield) as a pale yellow solid.

[0661] 1 H-NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 8.02-7.90 (m, 1H), 7.78 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.13-7.01 (m, 3H), 3.97-3.87 (m, 4H), 3.40-3.29 (m, 4H), 3.20-3.08 (m, 1H), 2.98 (m, 1H), 2.89-2.78 (m, 1H), 2.71 (m, 2H), 2.35 (s, 3H), 2.33 (s, 3H), 2.15-2.10 (m, 1H), 1.95-1.82 (m, 1H).

[0662] Example 115: 6-(2,4-dimethylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 6, Method B. [ka]

[0663] According to Scheme 6, step iii, Example 115 was prepared following the same method as described in, for example, 111, starting from Intermediate 52c (0.15 g, 364.70 μmol) and morpholine (63.55 mg, 729.40 μmol, 64.19 μL) to afford Example 115 (0.053 g, 126.95 μmol, 34.81% yield) as a pale yellow solid.

[0664] 1H-NMR (400 MHz, CDCl3) δ 8.48 (s, 2H), 7.69 (s, 1H), 7.13-6.99 (m, 3H), 3.97-3.88 (m, 4H), 3.38-3.28 (m, 4H), 3.20-3.08 (m, 1H), 2.99 (m, 1H), 2.88-2.75 (m, 1H), 2.70 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.17-2.05 (m, 1H), 1.95-1.80 (m, 1H).

[0665] Example 116: 2-(5-(azetidin-1-yl)pyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 6, Method B. [ka]

[0666] According to Scheme 6, step iii, Example 116 was prepared following the same method as described in, for example, 111, starting from intermediate 52c (0.15, 364.70 μmol) and azetidine (136.48 mg, 1.46 mmol, 161.32 μL) to afford Example 116 (0.004 g, 9.81 μmol, 2.69% yield) as a pale yellow solid.

[0667] 1 H-NMR (400 MHz, CDCl3) δ 8.01 (s, 2H), 7.65 (s, 1H), 7.17-6.99 (m, 3H), 4.08 (t, J = 7.2 Hz, 4H), 3.12 (m, 1H), 3.02-2.95 (m, 1H), 2.83-2.75 (m, 1H), 2.70-2.62 (m, 2H), 2.62-2.52 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.12-2.06 (m, 1H), 1.92-1.80 (m, 1H).

[0668] Example 117: N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide was prepared according to Scheme 6, Method B. [ka]

[0669] According to Scheme 6, Step iii, to a mixture of intermediate 52c (0.1 g, 243.13 μmol, 1 eq) and acetamide (28.72 mg, 486.27 μmol, 2 eq) in dioxane at 25° C. under N2, (1S,2S)-N,N-dimethylcyclohexane-1,2-diamine (6.92 mg, 48.63 μmol, 0.2 eq), CuI (9.24 mg, 48.63 μmol, 0.2 eq), and K3PO4 (129 mg, 607.82 μmol, 2.5 eq) were added in one portion. The mixture was stirred at 25° C. for 5 minutes, then heated to 100° C. and stirred for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was further purified by preparative HPLC to give Example 117 (0.021 g, 53.92 μmol, 22.18% yield) as a white solid.

[0670] 1 H-NMR (400 MHz, CDCl3) δ 8.93 (s, 2H), 8.58 (s, 1H), 7.66 (s, 1H), 7.03-6.97 (m, 3H), 3.12-3.06 (m, 1H), 2.98-2.88 (m, 1H), 2.82-2.72 (m, 1H), 2.72-2.61 (m, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 2.15 (s, 3H), 2.12-2.05 (m, 1H), 1.88-1.82 (m, 1H).

[0671] Example 118: 6-(3-Methoxy-2-methylphenyl)-2-(5-(2-methoxyethoxy)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 6, Method C. [ka]

[0672] According to Scheme 6, step iv, a solution of compound Example 45 (150 mg, 411.64 μmol, 1 eq) in DMA (3 mL) was treated with CsCO 3( To the resulting mixture was added 1-bromo-2-methoxyethane (268.24 mg, 823.28 μmol, 2 eq) and 1-bromo-2-methoxyethane (572.14 mg, 4.12 mmol, 386.58 μL, 10 eq). The mixture was stirred at 20° C. for 12 hours. The pH of the mixture was adjusted to 7 by adding HCl (6N). The mixture was filtered. The filtrate was concentrated to give the crude product. The crude product was purified by preparative HPLC to give Example 118 (79.75 mg, 186.50 μmol, 45.31% yield) as a white solid.

[0673] 1 H-NMR (400 MHz, CDCl3) δ 8.75 (s, 2H), 7.70 (s, 1H), 7.12 (br d, J = 8.4 Hz, 1H), 6.77 (s, 1H), 6.72 (m, d, J = 8.4 Hz, 1H), 3.80 (s, 3H), 3.17-2.96 (m, 2H), 2.87-2.76 (m, 1H), 2.71-2.65 (m, 2H), 2.43 (s, 3H), 2.31 (s, 3H), 2.15-2.11 (m, 1H), 1.90-1.85 (m,1H).

[0674] Example 119: 2-(5-(2-hydroxyethoxy)pyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 6, Method C. [ka]

[0675] According to Scheme 6, step iv, Example 119 was prepared following the same method as described for example 118, starting from Example 45 (150 mg, 411.64 μmol) and 2-bromoethan-1-ol (514.40 mg, 4.12 mmol) to afford Example 119 (45.04 mg, 107.73 μmol, 26.17% yield) as a white solid.

[0676] 1 H-NMR (400 MHz, CDCl3) δ 8.46 (s, 2H), 7.59 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.73-6.64 (m, 2H), 3.93 (s, 3H), 3.73 (s, 3H), 3.04-2.97 (m, 2H), 2.71-2.46 (m, 3H), 2.23 (s, 3H), 2.08 (m, 1H), 1.80 (m, 1H).

[0677] Example 120: 6-(3-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 7. [ka]

[0678] Intermediate 53: 6-(3-bromo-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 2, Step viii, to a mixture of intermediate 15b (2 g, 5.68 mmol, 1 eq) and 1,3-dibromo-2-methylbenzene (1.42 g, 5.68 mmol, 72.57 μL, 1 eq) in dioxane (30 mL) and HO (2 mL) was added Pd(dppf)Cl (207.76 mg, 283.93 μmol, 0.05 eq) and NaCO (1.81 g, 17.04 mmol, 3 eq) in one portion at 25 °C under N. The mixture was stirred at 90 °C for 12 h. The residue was poured into ice water (w / w = 1 / 1) (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give Intermediate 53 (1.4 g, 3.54 mmol, 62.37% yield) as a yellow solid.

[0679] 1 H NMR (CDCl3, 400 MHz) δ 8.92 (d, J = 4.8 Hz, 2H), 7.75 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 4.8 Hz, 1H), 7.11-7.06 (m, 2H), 6.24 (s, 1H), 3.00 (t, J = 9.6 Hz, 2H), 2.64 (t, J = 9.6 Hz, 2H), 2.42 (s, 3H).

[0680] Intermediate 54: 6-(3-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one According to Scheme 7, Step i, to a mixture of intermediate 53 (0.2 g, 506.01 μmol, 1 eq) and tributyl(1-ethoxyvinyl)stannane (365.49 mg, 1.01 mmol, 341.58 μL, 2 eq) in dioxane (20 mL) at 25 °C under N was added Pd(PPh3)2Cl2 (17.76 mg, 25.30 μmol, 0.05 eq) in one portion. The mixture was stirred at 100 °C for 3 h. HCl (3 M; 20 mL) was added to the reaction, which was stirred at 25 °C for 30 min and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc = 0 / 1) to give intermediate 54 (0.15 g, crude) as a yellow solid.

[0681] 1 H NMR (DMSO-d6, 400 MHz) δ 9.01 (d, J = 4.8 Hz, 2H), 7.99 (s, 1H), 7.65-7.75 (m, 1H), 7.36 (s, 1H), 6.42 (s, 1H), 2.78-2.87 (m, 2H), 2.60-2.68 (m, 2H), 2.56 (s, 3H), 2.36 (s, 3H).

[0682] Example 120: 6-(3-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 7, step ii, to a mixture of intermediate 54 (150.00 mg, 418.53 μmol, 1 eq) and ammonium formate (131.96 mg, 2.09 mmol, 5 eq) in EtOH (30 mL) under N was added Pd / C (0.3 g, 5% purity). The mixture was stirred at 25° C. for 16 h. The mixture was filtered and concentrated under reduced pressure, and the resulting residue was purified by PREP-HPLC to give Example 120 (4 mg, 10.86 μmol, 2.60% yield) as a white solid.

[0683] (DMSO-d6) δ 9.02 (d, J = 4.8 Hz, 2H), 7.85 (s, 1H), 7.71 (br t, J = 4.8 Hz, 1H), 7.48 (m, 2H), 7.29-7.36 (m, 1H), 3.27 (m, 1H), 2.65-2.95 (m, 4H), 2.54 (s, 3H), 2.35 (s, 3H), 1.88-2.03 (m, 2H).

[0684] Example 121: 6-(2,4-dimethylphenyl)-2-(pyridin-2-yl)-2,5,6,7-tetrahydro-1H-cyclopenta[d]-pyridazin-1-one was prepared according to Scheme 3. [ka]

[0685] Intermediate 19: 3-(2,4-dimethylphenyl)cyclopentan-1-one According to Scheme 3, step i, to a mixture of Rh(COD)Cl (180.17 mg, 0.37 mmol) in dioxane (20 mL) and HO (4 mL) was added KOH (4.10 g, 73.08 mmol). The resulting mixture was stirred at 20 °C under N for 0.5 h. Next, to this mixture was added dropwise a solution of cyclopent-2-en-1-one (6.00 g, 73.08 mmol) and (2,4-dimethylphenyl)boronic acid (21.92 g, 146.16 mmol) in dioxane (20 mL) at 20 °C. The resulting mixture was stirred at 20 °C for 1.5 h. LCMS confirmed the desired product. The reaction mixture was diluted with 200 mL of ethyl acetate and washed with water (60 mL × 3). The organic phase was then dried over anhydrous NaSO and evaporated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1) to give Intermediate 19 (11.00 g, 80% yield) as a yellow liquid.

[0686] 1H NMR (CDCl3; 400MHz) δ 7.17- 7.10(m, 1H), 7.07-7.02 (m, 2H), 3.67-3.54 (m, 1H), 2.70-2.60 (m, 1H), 2.55-2.45(m, 1H), 2.43-2.39 (m, 1H), 2.381 (s, 3H), 2.37-2.35 (m,1H), 2.34 (s, 3H ), 2.31-2.26 (m,1H), 2.10-1.96 (m,1H).

[0687] Intermediate 20: 2-chloro-4-(2,4-dimethylphenyl)cyclopent-1-ene-1-carbaldehyde According to Scheme 3, step ii, to a mixture of DMF (7.76 g, 106.24 mmol, 8.2 mL) in CHCl (100 mL) was added POCl (13.03 g, 84.99 mmol, 7.9 mL) at −20 °C. The mixture was then stirred at 0 °C for 1 h. To this mixture was then added a solution of Intermediate 19 (10.00 g, 53.12 mmol) in CHCl (20 mL) at −20 °C. The reaction was stirred at 0 °C for 2 h. The reaction was then stirred at 25 °C for 12 h. LCMS confirmed the reaction was complete. The reaction was quenched to 0 °C with water (100 mL). The mixture was then extracted with CHCl (100 mL × 3). The combined organic layers were dried over anhydrous NaSO and filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography (PE: EtOAc = 10:1). 2-Chloro-4-(2,4-dimethylphenyl)cyclopent-1-ene-1-carbaldehyde 20 and its regioisomer 2-chloro-5-(2,4-dimethylphenyl)cyclopent-1-ene-1-carbaldehyde 20′ (3.00 g, 24% yield) were obtained as yellow oils and used in the next step.

[0688] Intermediate 21: Ethyl 4-(2,4-dimethylphenyl)-2-formylcyclopent-1-ene-1-carboxylate To a mixture of intermediates 20 and 20' (1.5 g, 6.39 mmol) and EtN (1.29 g, 12.78 mmol, 1.77 mL) in EtOH (40 mL) was added Pd(dppf)Cl (467.61 mg, 0.64 mmol) under N protection at 25 °C. The suspension was degassed in vacuo and purged with CO for several hours. The mixture was stirred under CO (3 MPa) at 120 °C for 12 hours. The reaction mixture was then concentrated. A crude mixture of intermediate 21 and its regioisomer 21' (1.5 g, crude) was obtained as a black solid and used in the next step.

[0689] Example 121: 6-(2,4-dimethylphenyl)-2-(pyridin-2-yl)-2,5,6,7-tetrahydro-1H-cyclopenta[d]-pyridazin-1-one To a mixture of intermediate 21 and its regioisomer 21' (3.00 g, 11.02 mmol) and 2-pyridylhydrazine (2.41 g, 16.53 mmol HCl) in toluene (100 mL) at 25 °C under N was added TsOH (1.90 g, 11.02 mmol). The mixture was stirred at 120 °C for 48 h. The reaction mixture was concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 3:1), and the resulting crude product was further purified by preparative HPLC. Example 121 (180 mg, 5% yield) was obtained as a yellow oil.

[0690] 1 H-NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.10-7.96 (m, 2H), 7.90-7.80 (m, 1H), 7.55-7.45 (m,1H), 7.13 (d, J = 7.6Hz, 1H), 7.07-6.99 (m, 2H), 4.10-3.99 (m, 1H), 3.50-3.37 (m, 2H), 3.06-3.01 (m, 2H), 2.38 (s, 3H), 2.33 (s, 3H).

[0691] Example 122: 7-(2,4-dimethylphenyl)-3-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one was prepared according to Scheme 4. [ka]

[0692] Intermediate 31: 2',4'-dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4H)-one According to Scheme 4, Step i, a solution of cyclohex-2-en-1-one (3.50 g, 36.41 mmol, 1.00 eq), 1-indo-2,4-dimethylbenzene (10.81 g, 46.60 mmol, 1.28 eq), Na2CO3 (6.04 g, 72.82 mmol, 2.00 eq), Pd(PPh3)2Cl2 (2.56 g, 3.64 mmol, 0.10 eq), and XPhos (2.08 g, 4.37 mmol, 0.12 eq) in DMSO (100.00 mL) was stirred at 100 °C under a N2 atmosphere for 2 h. The desired product was confirmed by LCMS, and the reaction was completed. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with H2O (40 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE: EtOAc = 5:1) to give Intermediate 31 (1.60 g, 7.99 mmol, 22% yield) as a brown liquid.

[0693] 1 H NMR (CDCl3; 400MHz) δ 7.19-6.94 (m, 3H), 5.92-5.90 (m, 1H), 2.53-2.50 (m, 2H), 2.45-2.40 (m, 2H), 2.26 (s, 3H), 2.21 (s, 3H), 2.09-2.05 (m, 2H).

[0694] Intermediate 33: Ethyl 2',4'-dimethyl-5-oxo-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carboxylate According to Scheme 4, Step iii, to a solution of intermediate 31 (2.40 g, 11.98 mmol, 1.00 eq) in THF (60.00 mL) was added LDA (2 M, 8.99 mL, 1.50 eq) dropwise at −78° C. The resulting mixture was stirred at −78° C. for 1 hour. Ethyl cyanoacetate (1.66 g, 16.77 mmol, 1.65 mL, 1.40 eq) was added dropwise to the reaction mixture at −78° C. and stirred for 4 hours. The reaction mixture was quenched with aqueous NH4Cl (20 mL) and extracted with 150 mL of ethyl acetate. The combined organic layers were washed with 100 mL of HO, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE:EtOAc = 5:1). Intermediate 33 (2.10 g, 7.71 mmol, 64.37% yield) was obtained as a yellow oil.

[0695] 1 H NMR (CDCl3; 400MHz) δ 7.04-7.04 (m, 3H), 6.09-6.05 (m, 1H), 4.25-4.3 (m, 2H), 2.73-2.53 (m, 4H), 2.35 (s, 3H), 2.30 (s, 3H) 1.66-1.60 (m, 3H).

[0696] Intermediate 34: Ethyl 4-(2,4-dimethylphenyl)-2-oxocyclohexane-1-carboxylate According to Scheme 4, step ii, a solution of intermediate 33 (1.40 g, 5.14 mmol, 1.00 eq) in MeOH (20.00 mL) was added to Pd / C (500 mg, 10% purity) under a N atmosphere. The suspension was degassed under vacuum and purged with H for several hours. The mixture was stirred under H (50 psi) at 20 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (PE: EtOAc = 10:1). Intermediate 34 (500.00 mg, 1.82 mmol, 35.40% yield) was obtained as a yellow oil.

[0697] Intermediate 35: 7-(2,4-dimethylphenyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one According to Scheme 4, step iv, a mixture of intermediate 34 (200 mg, 729.00 μmol, 1.00 eq), KCO (403.02 mg, 2.92 mmol, 4.00 eq), and formamide (113.84 mg, 1.09 mmol, 1.50 eq) in EtOH (8.00 mL) was stirred at 90 °C for 3 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (100 mL). This solution was washed with H0 (40 mL × 3). The organic phase was dried over anhydrous NaSO, filtered, and concentrated in vacuo. Intermediate 35 (120.00 mg, 471.83 μmol, 65% yield) was obtained as a pale yellow solid.

[0698] 1 H NMR (DMSO-d6; 400MHz) δ 12.30 (s, 1H), 7.99 (s, 1H), 7.17-7.11 (m, 1H), 6.97-6.99 (m, 1H), 3.11-3.08 (m, 1H), 2.68-2.39 (m, 4H), 2.28 (s, 3H), 2.24 (s, 3H), 1.86-1.84(m, 2H), 1.75-1.1.72 (m, 2H).

[0699] Example 122: 7-(2,4-dimethylphenyl)-3-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one According to Scheme 4, Step v, a mixture of intermediate 35 (100.00 mg, 393.19 μmol, 1.00 eq), 2-bromopyridine (80.76 mg, 511.15 μmol, 1.30 eq), CuI (7.49 mg, 39.32 μmol, 0.10 eq), 1,10-penanthroline (14.17 mg, 78.64 μmol, 0.20 eq), and KOH (44.12 mg, 786.38 μmol, 2.00 eq) in DMF (4.00 mL) was stirred at 100 °C for 12 h under a N atmosphere. The reaction mixture was diluted with 100 mL of ethyl acetate and washed with water (30 mL × 3). The organic phase was dried over NaSO and evaporated in vacuo. The crude product was purified by preparative HPLC (with formic acid). Example 122 (45.00 mg, 135.78 μmol, 34.53% yield) was obtained as a yellow solid.

[0700] 1 H-NMR (400 MHz, DMSO-d6) δ 8.66-8.65 (m, 1H), 8.48 (s, 1H), 8.06-8.04 (m, 1H), 7.77-7.75 (m, 1H), 7.59-7.55 (m, 1H), 7.18-7.15 (m, 1H), 7.02-6.99 (m, 1H), 3.16-3.14 (m, 1H), 2.75-2.66 (m, 4H), 2.30 (s, 3H), 2.25 (s, 3H),1.94-1.921 (m, 1H), 1.83-1.81 (m, 2H).

[0701] Example 124: 6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one [ka]

[0702] To a mixture of Example 92 (50.0 mg, 130 μmol, 1.00 eq) in DCM (2.00 mL) at 25 °C, MnO (113 mg, 1.30 mmol, 10.0 eq) was added. The mixture was stirred at 25 °C for 23 h. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography (SiO, PE / EtOAc = 1 / 1 to 0:1, Rf = 0.48) to give Example 124 (37.0 mg, 94.7 μmol) as a green solid.

[0703] 1 H-NMR (400 MHz, CDCl3) δ 8.94 (d, J=4.8 Hz, 2H), 7.71 (s, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.42 (t, J=4.8 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H), 7.18 (d, J=3.4 Hz, 1H), 6.99 (d, J=7.4 Hz, 1H), 6.50 (d, J=3.4 Hz, 1H), 3.48 - 3.33 (m, 2H), 3.07 - 2.87 (m, 3H), 2.80 - 2.66 (m, 1H), 2.37 - 2.28 (m, 1H), 2.14 - 2.06 (m, 1H), 1.11 - 1.02 (m, 4H).

[0704] Example 125: 2-(5-Cyclopropylpyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 6, Method A. [ka]

[0705] Intermediate 52e: 2-(5-bromopyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 6, step i, intermediate 52e was prepared according to the same method as described for intermediate 52a, starting from intermediate 7b (500 mg, 1.85 mmol) and 2,5-dibromopyridine (527.98 mg, 2.22 mmol) to give intermediate 52e (0.5 g, 1.01 mmol, 54.41% yield) as a red solid. m / z (M+H) + = 427.0, 429.0.

[0706] Example 125: 2-(5-cyclopropylpyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 6, step ii, Example 125 was prepared following the same method as described for example in 107, starting from intermediate 52e (180 mg, 421.26 μmol) and cyclopropylboronic acid (72.37 mg, 842.51 μmol) to afford Example 125 (14.61 mg, 37.35 μmol, 8.87% yield) as a light pink solid.

[0707] 1 H-NMR (400 MHz, DMSO-d6) δ 8.76 (s, 2H), 7.83 (s, 1H), 7.18 (t, J=7.97 Hz, 1H), 6.90 (d, J=7.65 Hz, 1H), 6.86 (d, J=8.16 Hz, 1H), 3.79 (s, 3H), 3.13-3.24 (m, 1H), 2.64-2.85 (m, 3H), 2.57 (br s, 1H), 2.18 (s, 3H), 2.04-2.12 (m, 1H), 1.94 (br s, 1H), 1.78-1.90 (m, 1H), 1.08-1.18 (m, 2H), 0.90-1.01 (m, 2H).

[0708] Example 126: 2-(5-Bromopyrimidin-2-yl)-6-(3-cyclopropoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1, Method B. [ka]

[0709] Intermediate 6f: 5-(3-cyclopropoxy-2-methylphenyl)-3-methoxy-4,5,6,7-tetrahydroisobenzo-furan-1(3H)-one Following Scheme 1, steps i-v, intermediate 6f was prepared similarly to intermediate 6a in Example 1, starting from 1-bromo-3-cyclopropoxy-2-methylbenzene, and was obtained as a colorless oil in 6% overall yield. m / z (M+H) + = 315.3.

[0710] Intermediate 7d: 6-(3-cyclopropoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 1, step vii, intermediate 7b was prepared starting from intermediate 6f (1.77 g, 5.60 mmol) in a similar manner to intermediate 7a in Example 6 to give intermediate 7d (1.52 g, 4.56 mmol, 81.5% yield) as a light yellow solid.

[0711] 1 H NMR (400 MHz, DMSO-d6) δ 10.73 (br s, 1H), 7.56 (s, 1H), 7.22 - 7.11 (m, 2H), 6.84 (d, J=7.4 Hz, 1H), 3.77 - 3.70 (m, 1H), 3.22 - 3.11 (m, 1H), 2.99 - 2.88 (m, 1H), 2.81 - 2.71 (m, 1H), 2.71 - 2.54 (m, 2H), 2.18 (s, 3H), 2.15 - 2.08 (m, 1H), 1.92 - 1.80 (m, 1H), 0.82 - 0.77 (m, 4H).

[0712] Example 126: 2-(5-bromopyrimidin-2-yl)-6-(3-cyclopropoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one According to Scheme 1, step viii, Example 126 was prepared according to Example 6 starting from Intermediate 7d (1.00 g, 3.00 mmol) and 2,5-dibromopyrimidine (856 mg, 3.60 mmol) to afford Example 126 (0.74 g, 1.52 mmol, 50.7% yield) as a red solid.

[0713] 1 H NMR (400 MHz, CDCl3) δ 8.95 (s, 2H), 7.69 (s, 1H), 7.24 - 7.14 (m, 2H), 6.85 (d, J=7.6 Hz, 1H), 3.77 - 3.70 (m, 1H), 3.20 (br s, 1H), 3.00 (br d, J=16.3 Hz, 1H), 2.86 - 2.78 (m, 1H), 2.70 (br dd, J=9.2, 16.8 Hz, 2H), 2.20 - 2.18 (m, 3H), 2.13 (br s, 1H), 1.94 - 1.85 (m, 1H), 0.82 - 0.77 (m, 4H).

[0714] Example 127: N-(2-(6-(3-cyclopropoxy-2-methylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide was prepared according to Scheme 6, Method B. [ka]

[0715] According to Scheme 6, step iii, Example 127 was prepared according to Example 117 starting from Example 126 (0.85 g, 1.88 mmol) and acetamide (222 mg, 3.75 mmol) to afford Example 127 (242 mg, 558.61 μmol, 29.79% yield) as a light yellow solid.

[0716] 1H NMR (400 MHz, CDCl3) δ 9.07 - 9.00 (m, 1H), 8.97 (s, 2H), 7.76 (s, 1H), 7.24 - 7.15 (m, 2H), 6.86 (br d, J=7.4 Hz, 1H), 3.75 (br s, 1H), 3.25 (br s, 1H), 3.00 (br d, J=19.4 Hz, 1H), 2.92 - 2.82 (m, 1H), 2.82 - 2.64 (m, 2H), 2.20 (s, 6H), 2.17 - 2.13 (m, 1H), 1.93 (br d, J=7.2 Hz, 1H), 0.80 (br s, 4H).

[0717] Example 128: (-)-6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one and Example 129: (+)-6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one [ka]

[0718] The constituent enantiomers of racemic Example 104 (483 mg) were separated by preparative SFC to give (-)-6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one Example 128 (188 mg, 39%) in 100% enantiomeric excess and (+)-6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one Example 129 (199 mg, 41%) in 99.9% enantiomeric excess, both as white solids.

[0719] Example 128: 1H-NMR (400 MHz, CDCl3) δ 8.94 (d, J = 4.4 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.28 - 7.15 (m, 2H), 6.85 (d, J = 7.6 Hz, 1H), 3.75 (tt, J = 6.0, 3.2 Hz, 1H), 3.25-3.17 (m, 1H), 3.05 - 2.95 (m, 1H), 2.87 - 2.76 (m, 1H), 2.75 - 2.60 (m, 2H), 2.20 - 2.10 (m, 1H), 1.95 - 1.83 (m, 1H), 0.85 - 0.75 (m, 4H).

[0720] Example 129: 1 H-NMR (400 MHz, CDCl3) δ 8.94 (d, J = 4.4 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.25 - 7.15 (m, 2H), 6.86 (d, J = 7.6 Hz, 1H), 3.75 (tt, J = 6.0, 3.2 Hz, 1H), 3.25-3.17 (m, 1H), 3.05 - 2.95 (m, 1H), 2.83 - 2.76 (m, 1H), 2.75 - 2.60 (m, 2H), 2.20 - 2.07 (m, 1H), 1.95 - 1.82 (m, 1H), 0.85 - 0.75 (m, 4H).

[0721] Example 130: (-)-6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one and Example 131: (+)-6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one [ka]

[0722] The constituent enantiomers of racemic Example 91 (505 mg) were separated by preparative SFC to give (-)-6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one Example 130 (187 mg, 37%) in 99.6% enantiomeric excess, and (+)-6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one Example 131 (187 mg, 37%) in 99.9% enantiomeric excess, both as white solids.

[0723] Example 130: 1 H-NMR (400 MHz, CDCl3) δ 8.93 (d, J = 4.4 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.26 - 7.23 (m, 2H), 6.92 - 6.87 (m, 1H), 3.83 (tt, J = 6.0, 3.2 Hz, 1H), 3.59 - 3.49 (m, 1H), 3.05 - 2.92 (m, 2H), 2.76 - 2.58 (m, 2H), 2.23 - 2.14 (m, 1H), 1.99 - 1.85 (m, 1H), 0.90 - 0.83 (m, 4H).

[0724] Example 131: 1 H-NMR (400 MHz, CDCl3) δ 8.93 (d, J=4.8 Hz, 2H), 7.70 (s, 1H), 7.45 - 7.39 (m, 1H), 7.26 - 7.23 (m, 2H), 6.94 - 6.86 (m, 1H), 3.83 (tt, 0.92 - 0.79 (m, 4H).

[0725] Example 132: (-)-6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one and Example 133: (+)-6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one [ka]

[0726] The constituent enantiomers of racemic Example 93 (488 mg) were separated by preparative SFC to give (-)-6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one Example 132 (232 mg, 48%) in 100% enantiomeric excess and (+)-6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one Example 133 (210 mg, 43%) in 100% enantiomeric excess, both as white solids.

[0727] Example 132: 1 H-NMR (400 MHz, CDCl3) δ 8.74 (s, 2H), 7.68 (s, 1H), 7.25 - 7.15 (m, 2H), 6.85 (d, J = 6.4 Hz, 1H), 3.74 (tt, J = 6.0, 3.2 Hz, 1H), 3.26-3.17 (m, 1H), 3.05 - 2.95 (m, 1H), 2.85 - 2.77 (m, 1H), 2.75 - 2.60 (m, 2H), 2.43 (s, 3H), 2.18 - 2.10 (m, 1H), 1.95 - 1.83 (m, 1H), 0.85 - 0.78 (m, 4H).

[0728] Example 133: 1H-NMR (400 MHz, CDCl3) δ 8.74 (s, 2H), 7.68 (s, 1H), 7.23 - 7.15 (m, 2H), 6.85 (d, J = 6.4 Hz, 1H), 3.74 (tt, J = 6.0, 3.2 Hz, 1H), 3.25-3.16 (m, 1H), 3.05 - 2.95 (m, 1H), 2.85 - 2.77 (m, 1H), 2.75 - 2.60 (m, 2H), 2.43 (s, 3H), 2.18 - 2.07 (m, 1H), 1.95 - 1.83 (m, 1H), 0.83 - 0.76 (m, 4H).

[0729] Example 134: (-)-6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one and Example 135: (+)-6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one [ka]

[0730] The constituent enantiomers of racemic Example 94 (493 mg) were separated by preparative SFC to give (-)-6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one Example 134 (218 mg, 48%) in 100% enantiomeric excess and (+)-6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one Example 135 (215 mg, 43%) in 99.9% enantiomeric excess, both as white solids.

[0731] Example 134: 1H NMR (400MHz, CDCl3) δ 8.73 (s, 2H), 7.69 (s, 1H), 7.30 - 7.25 (m, 1H), 6.90 - 6.86 (m, 2H), 3.94 (s, 3H), 3.56 - 3.53 (m, 1H), 3.04 - 2.93 (m, 2H), 2.75 - 2.57 (m, 2H), 2.42 (s, 3H), 2.20 - 2.15 (m, 1H), 1.93 - 1.85 (m, 1H).

[0732] Example 135: 1 H NMR (400MHz, CDCl3) δ 8.73 (s, 2H), 7.69 (s, 1H), 7.27 - 7.22 (m, 1H), 6.90 - 6.86 (m, 2H), 3.93 (s, 3H), 3.56 - 3.53 (m, 1H), 3.04 - 2.93 (m, 2H), 2.75 - 2.57 (m, 2H), 2.42 (s, 3H), 2.23 - 2.15 (m, 1H), 1.93 - 1.85 (m, 1H).

[0733] Example 136: (-)-N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide and Example 137: (+)-N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide [ka]

[0734] The constituent enantiomers of racemic Example 117 (610 mg) were separated by preparative SFC to give (−)-N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide Example 136 (187 mg, 31%) in 99.4% enantiomeric excess, and (+)-N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide Example 137 (218 mg, 36%) in 100% enantiomeric excess, both as yellow solids.

[0735] Example 136: 1 H-NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 7.76 (s, 1H), 7.12-7.05(m, 3H), 3.17-2.70 (m, 5H), 2.37 (s, 3H), 2.33 (s, 3H), 2.22-2.18 (m, 4H), 1.97-1.90(m, 1H).

[0736] Example 137: 1 H-NMR (400 MHz, CDCl3) δ =8.90 (s, 1H), 7.76 (s, 1H), 7.04-6.97(m, 3H), 3.10-2.62 (m, 5H), 2.29 (s, 3H), 2.25 (s, 3H), 2.10-2.09 (m, 4H), 1.87-1.83(m, 1H).

[0737] Example 138: (+)-6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one and Example 139: (-)-6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one [ka]

[0738] The constituent enantiomers of racemic Example 124 (440 mg) were separated by preparative SFC to give (+)-6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one Example 138 (140 mg, 32%) in 99.5% enantiomeric excess, and (-)-6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one Example 139 (155 mg, 35%) in 98.9% enantiomeric excess, both as yellow solids.

[0739] Example 138: 1 H-NMR (400 MHz, CDCl3) δ 8.94 (d, J=4.9 Hz, 2H), 7.71 (s, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.42 (t, J=4.8 Hz, 1H), 7.24 (t, J=7.7 Hz, 1H), 7.18 (d, J=3.3 Hz, 1H), 6.99 (d, J=7.2 Hz, 1H), 6.50 (d, J=3.2 Hz, 1H), 3.42 - 3.37 (m, 2H), 3.04 - 2.96 (m, 3H), 2.93 - 2.73 (m, 1H), 2.32 (br d, J=11.7 Hz, 1H), 2.10 - 2.06 (m, 1H), 1.12 - 1.02 (m, 4H).

[0740] Example 139: 1H-NMR (400 MHz, CDCl3) δ 8.94 (d, J=4.9 Hz, 2H), 7.71 (s, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.42 (t, J=4.8 Hz, 1H), 7.24 (t, J=7.7 Hz, 1H), 7.18 (d, J=3.3 Hz, 1H), 6.99 (d, J=7.2 Hz, 1H), 6.50 (s, 1H), 3.50 - 3.38 (m, 2H), 3.03 - 2.93 (m, 3H), 2.88- 2.73 (m, 1H), 2.30 (br d, J=11.7 Hz, 1H), 2.09 - 2.03 (m, 1H), 1.10 - 1.04 (m, 4H).

[0741] C.Analysis Department Melting point: Values ​​are peak values ​​and are obtained with the experimental error normally associated with this analytical method. For many compounds, melting points were determined on a YRT-3 apparatus using open capillary tubes. Melting points were measured with a temperature gradient of 1.5°C / min. The maximum temperature was 270°C. Melting points were read from a digital display. For some compounds, a DSC method was used according to the following conditions:

[0742] [Table 2]

[0743] LCMS method: High-performance liquid chromatography (HPLC) measurements were performed using an LC pump, diode array, or UV detector. The flow from the column was directed to a mass spectrometer (MS) configured with an atmospheric pressure ion source. By appropriately setting tuning parameters, it is within the knowledge of one skilled in the art to obtain ions that allow identification of the apparent monoisotopic molecular weight (MW) and / or the exact mass monoisotopic molecular weight of a compound. Data collection was performed using appropriate software. An ES MS detector was used, and data was acquired in both positive and negative ionization modes.

[0744] Compounds can be described using molecular ions corresponding to [M+H] (protonated molecule) and / or [MH] (deprotonated molecule). For molecules with multiple isotopic patterns (Br, Cl), the reported value is that obtained at the lowest isotopic mass. All results are subject to experimental error normally associated with the method used.

[0745] NMR: 1 H NMR spectra were recorded on a Varian 400 MHz spectrometer. Chemical shifts are expressed in parts per million (ppm, δ units). Splitting patterns indicate apparent multiplicity and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or br (broad line).

[0746] SFC-MS: Preparative chiral separations were performed using a Waters 2998 PDA detector equipped with a preparative instrument. The specific methods used are described below, and the results are shown in Table 1.

[0747] [Table 3]

[0748] Optical rotation: Optical rotations were measured using a Rudolph AUTOPOL V polarimeter at 20°C using a sodium lamp (589 nm) at a concentration of 10 mg / mL and methanol or chloroform as the solvent. The sign (+ or -) and degree (°) of rotation are shown in Table 1.

[0749] [Table 4]

[0750] In vitro pharmacology The compounds of formula (I), (II) and (III) are antagonists or negative allosteric modulators of mGluR7 because they reduce or inhibit the mGluR7 response induced by mGluR7 agonists such as glutamate or L-AP4.

[0751] Suitable methods for the characterization of such compounds, more particularly compounds according to formula (I), are described below.

[0752] Inositol monophosphate synthesis assay (IP1 assay): Membrane preparation and protocol: HEK293 cells were transiently transfected with mGluR7 by electroporation and seeded at a density of 150,000 cells / well in polyornithine-coated 96-well plates. To enable monitoring of receptor activity by measuring inositol monophosphate (IP1) production, mGluR7 was transfected with a chimeric Gq / Gi protein (Gqtop). To avoid the influence of extracellular glutamate, mGluR7 was cotransfected with the glutamate transporter EAAC1. Cells were cultured in Dulbecco's modified Eagle's medium (DMEM; Invitrogen, Cergy-Pontoise, France) supplemented with 10% fetal bovine serum (FBS). Glutamax® was used. TM The medium was replaced with 100 mL of 1000 mM Tris-HCl (pH 7.5) (Invitrogen, Cergy Pontoise, France) to reduce extracellular glutamate concentrations 3 hours before stimulation.

[0753] CisBio Bioassays' HTRF-based assays can measure various cell signaling pathways and, based on the results, determine the production of the second messenger inositol phosphate (IP). IP production was determined using the IP-One HTRF kit (CisBio Bioassays), a competitive immunoassay using cryptate-labeled anti-IP1 antibody and d2-labeled IP, according to the manufacturer's instructions. Each point was performed in triplicate.

[0754] Data analysis Data were analyzed using Prism 6 software (GraphPad Software, San Diego, CA). In principle, data were fitted using a four-parameter concentration-response curve equation for each experiment. Potency (IC 50 ) is the logarithm (logIC 50 ) Data w...

Claims

1. Compounds of formula (I): 【Chemistry 1】 (where, G is N or CR ７ is selected from E is N or CR ８ is selected from provided that at least one of G and E is N; Y is CR ９ and R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ and R ９ may be the same or different, and each independently represents hydrogen, halogen, —CN, —CF ３ -C(=O)R １０ , -C(=O)OR １０ , —C(═O)NR １０ R １１ , -OR １０ , —OC(═O)R １０ , -OC(=O)NR １０ R １１ , -SR １０ , -S(O)R １０ , -S(O) ２ R １０ , -S(O) ２ NR １０ R １１ , -NR １０ R １１ , -NR １０ C(=O)R １１ , -NR １０ C(=O)OR １１ , -NR １０ S (O) ２ R １１ , and -(C １ -C ６ ) alkyl, -(C １ -C ６ ) haloalkyl, —(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl, or —(C １ -C ６ ) an optionally substituted radical selected from cyanoalkyl; where any two radicals R １ and R ２ , R ３ and R ４ , and R ５ and R ６ may together form an oxo (=O), Here, R １０ and R １１ may be the same or different, and each independently represents hydrogen and -(C １ -C ６ ) alkyl, -(C １ -C ６ ) haloalkyl, —(C １ -C ６ ) cyanoalkyl, —(C ３ -C ７ ) cycloalkyl or -(C １ -C ６ ) alkylene-(C ３ -C ７ ) an optionally substituted radical selected from cycloalkyl; where optionally R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ９ , R １０ and R １１ any two radicals selected from may together form an optionally substituted 3- to 10-membered non-aromatic carbocyclic or heterocyclic ring or a 5- to 10-membered aromatic heterocyclic ring; n is an integer selected from 0 or 1; Ar １ is an optionally substituted aryl or heteroaryl; Ar ２ is an optionally substituted aryl or heteroaryl; or the N-oxide forms thereof, pharmaceutically acceptable salts and solvates thereof, or optical isomers, racemates, diastereoisomers, enantiomers, or tautomers thereof.

2. - Ar １ teeth, 【Chemistry 2】 where m is the number of A substituents on the ring and is an integer equal to 0, 1, 2, 3, 4, or 5. and / or represents an aryl or heteroaryl selected from - Ar ２ teeth, 【Transformation 3】 where p is the number of B substituents on the ring and is an integer equal to 0, 1, 2, 3, 4, or 5. represents an aryl or heteroaryl selected from (wherein A and B may be the same or different, and each independently represents hydrogen, halogen, —CN, —NO ２ , —OH, —NH ２ , -CF ３ , and -(C １ -C ６ ) alkyl, -(C １ -C ６ ) haloalkyl, —(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl, -(C ３ -C ８ ) cycloalkenyl, -(C １ -C ６ ) cyanoalkyl, —(C １ -C ６ ) alkylene-heteroaryl, -(C １ -C ６ ) alkylene-aryl, -(C １ -C ６ ) alkylene-heterocycle, aryl, heteroaryl, heterocycle, -OR １３ , -(C １ -C ６ ) alkylene-OR １３ , —O—(C ２ -C ６ ) alkylene-OR １３ 、 -NR １３ (C ２ -C ６ ) alkylene-OR １４ , -(C ２ -C ６ ) alkenylene-OR １３ , -(C ２ -C ６ ) alkynylene-OR １３ , -NR １３ R １４ , -(C １ -C ６ ) alkylene-NR １３ R １４ , —O—(C ２ -C ６ ) alkylene-NR １３ R １４ , -NR １３ -(C ２ -C ６ ) alkylene-NR １４ R １５ , -(C ２ -C ６ ) Alkenylene-NR １３ R １４ , -(C ２ -C ６ ) Alkynylene-NR １３ R １４ , -SR １３ , -(C １ -C ６ ) alkylene-SR １３ , —O—(C ２ -C ６ ) alkylene-SR １３ , -NR １３ -(C ２ -C ６ ) alkylene-SR １４ , -S(=O)-R １３ , -(C １ -C ６ ) alkylene-S(=O)-R １３ , —O—(C １ -C ６ ) alkylene-S(=O)-R １３ , -NR １３ -(C １ -C ６ ) alkylene-S(=O)-R １４ , -S(=O) ２ -R １３ , -(C １ -C ６ ) alkylene-S(=O) ２ -R １３ , —O—(C １ -C ６ ) alkylene-S(=O) ２ -R １３ , -NR １３ -(C １ -C ６ ) alkylene-S(=O) ２ -R １４ , -S(=O) ２ NR １３ R １４ , -(C １ -C ６ ) alkylene-S(=O) ２ NR １３ R １４ , —O—(C １ -C ６ ) alkylene-S(=O) ２ NR １３ R １４ , -NR １３ -(C １ -C ６ ) alkylene-S(=O) ２ NR １４ R １５ , -NR １３ -S(=O) ２ R １４ , -(C １ -C ６ ) alkylene-NR １３ -S(=O) ２ R １４ , —O—(C ２ -C ６ ) alkylene-NR １３ -S(=O) ２ R １４ , -NR １３ -(C ２ -C ６ ) alkylene-NR １４ -S(=O) ２ R １５ , -C(=O)-NR １３ R １４ , -(C １ -C ６ ) alkylene-C(═O)-NR １３ R １４ , —O—(C １ -C ６ ) alkylene-C(═O)-NR １３ R １４ , -NR １３ -(C １ -C ６ ) alkylene-C(═O)-NR １４ R １５ , -NR １３ C(=O)-R １４ , -(C １ -C ６ ) alkylene-NR １３ C(=O)-R １４ , —O—(C ２ -C ６ ) alkylene-NR １３ C(=O)-R １４ , -NR １３ -(C ２ -C ６ ) alkylene-NR １４ C(=O)-R １５ , —C(═O)—R １３ , -(C １ -C ６ ) alkylene-C(=O)-R １３ , —O—(C １ -C ６ ) alkylene-C(=O)-R １３ , -NR １３ -(C １ -C ６ ) alkylene-C(=O)-R １４ , -C(=O)-OR １３ , -(C １ -C ６ ) alkylene-C(=O)-OR １３ , —O—(C １ -C ６ ) alkylene-C(=O)-OR １３ , -NR １３ -(C １ -C ６ ) alkylene-C(=O)-OR １４ , -OC(=O)-R １３ , -(C １ -C ６ ) alkylene-OC(=O)-R １３ , —O—(C ２ -C ６ ) alkylene-OC(=O)-R １３ , -NR １３ -(C ２ -C ６ ) alkylene-OC(=O)-R １４ , -NR １３ —C(═O)—NR １４ R １５ , -(C １ -C ６ ) alkylene-NR １３ —C(═O)—NR １４ R １５ , —O—(C ２ -C ６ ) alkylene-NR １３ —C(═O)—NR １４ R １５ , -NR １３ -(C ２ -C ６ ) alkylene-NR １４ —C(═O)—NR １５ R １６ , -NR １３ -C(=O)-OR １４ , -(C １ -C ６ ) alkylene-NR １３ -C(=O)-OR １４ , —O—(C ２ -C ６ ) alkylene-NR １３ -C(=O)-OR １４ , -NR １３ -(C ２ -C ６ ) alkylene-NR １４ -C(=O)-OR １５ , -OC(=O)-NR １３ R １４ , -(C １ -C ６ ) alkylene-O-C(=O)-NR １３ R １４ , —O—(C ２ -C ６ ) alkylene-O-C(=O)-NR １３ R １４ , -NR １３ -(C ２ -C ６ ) alkylene-O-C(=O)-NR １４ R １５ , -C(=O)-(C １ -C ６ ) alkylene-NR １３ R １４ , -(C １ -C ６ ) alkylene-C(=O)-(C １ -C ６ ) alkylene-NR １３ R １４ , -C(=O)-(C １ -C ６ ) alkylene-OR １３ , -(C １ -C ６ ) alkylene-C(=O)-(C １ -C ６ ) alkylene-OR １３ , -NR １３ -C(=S)-NR １４ R １５ , -(C １ -C ６ ) alkylene-NR １３ -C(=S)-NR １４ R １５ , -NR １３ -C(=NR １４ )-NR １５ R １６又は -(C １ -C ６ ) alkylene-NR １３ -C(=NR １４ )-NR １５ R １６ an optionally substituted radical selected from the group selected from the group consisting of: Here, R １３ , R １４ , R １５ and R １６ are each independently hydrogen, optionally substituted -(C １ -C ６ ) haloalkyl, —(C １ -C ６ ) alkyl, -(C １ -C ６ ) cyanoalkyl, —(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl, heteroaryl, aryl, heterocycle, -(C １ -C ６ ) alkylene-heteroaryl, -(C １ -C ６ ) alkylene-heterocycle, and -(C １ -C ６ ) alkylene-aryl; where optionally R １３ , R １４ , R １５ or R １６ Any two radicals selected from may together form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally selected from halogen, cyano, nitro, hydroxyl, amino, -(C １ -C ６ ) alkyl 、 -O-(C １ -C ６ ) alkyl, and —N—((C １ -C ６ ) alkyl) ２ and optionally further substituted by 1 to 5 radicals independently selected from wherein any two radicals A and any two radicals B together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring optionally contains halogen, —CN, hydroxyl, amino, —(C １ -C ６ ) alkyl 、 -O-(C １ -C ６ ) alkyl, and —N—((C １ -C ６ ) alkyl) ２ may be further substituted with 1 to 5 radicals independently selected from The compound of claim 1.

3. Formula (II): 【Chemistry 4】 (where - Ar １ teeth, 【Transformation 5】 represents an aryl or heteroaryl selected from where: m is the number of substituents A on the ring and is an integer equal to 0, 1, 2, 3 or 4, - A may be the same or different, and each independently represents hydrogen, halogen, -CN, or -CF ３ , —OH, —NH ２ , and -(C １ -C ６ ) alkyl, -(C １ -C ６ ) haloalkyl, —(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-heterocycle, heterocycle, aryl, heteroaryl, -OR １３ , -(C １ -C ６ ) alkylene-OR １３ , —O—(C ２ -C ６ ) alkylene-OR １３ 、 -NR １３ (C ２ -C ６ ) alkylene-OR １４ , -NR １３ R １４ , -(C １ -C ６ ) alkylene-NR １３ R １４ , —O—(C ２ -C ６ ) alkylene-NR １３ R １４ , -NR １３ -(C ２ -C ６ ) alkylene-NR １４ R １５ , -SR １３ , -(C １ -C ６ ) alkylene-SR １３ , —O—(C ２ -C ６ ) alkylene-SR １３ , -NR １３ -(C ２ -C ６ ) alkylene-SR １４ , -S(=O)-R １３ , -S(=O) ２ -R １３ , -S(=O) ２ NR １３ R １４ , -(C １ -C ６ ) alkylene-S(=O) ２ NR １３ R １４ , -NR １３ -S(=O) ２ R １４ , -(C １ -C ６ ) alkylene-NR １３ -S(=O) ２ R １４ , —O—(C ２ -C ６ ) alkylene-NR １３ -S(=O) ２ R １４ , -NR １３ -(C ２ -C ６ ) alkylene-NR １４ -S(=O) ２ R １５ , -C(=O)-NR １３ R １４ , -(C １ -C ６ ) alkylene-C(═O)-NR １３ R １４ , —O—(C １ -C ６ ) alkylene-C(═O)-NR １３ R １４ , -NR １３ -(C １ -C ６ ) alkylene-C(═O)-NR １４ R １５ , -NR １３ C(=O)-R １４ , -(C １ -C ６ ) alkylene-NR １３ C(=O)-R １４ , —O—(C ２ -C ６ ) alkylene-NR １３ C(=O)-R １４ , -NR １３ -(C ２ -C ６ ) alkylene-NR １４ C(=O)-R １５ , —C(═O)—R １３ , -C(=O)-OR １３ , -(C １ -C ６ ) alkylene-C(=O)-OR １３ , —O—(C １ -C ６ ) alkylene-C(=O)-OR １３ , -NR １３ -(C １ -C ６ ) alkylene-C(=O)-OR １４ , -OC(=O)-R １３ , -(C １ -C ６ ) alkylene-OC(=O)-R １３ , —O—(C ２ -C ６ ) alkylene-OC(=O)-R １３ , -NR １３ -(C ２ -C ６ ) alkylene-OC(=O)-R １４ , or -NR １３ -C(=O)-OR １４ an optionally substituted radical selected from the group - where R １３ , R １４ and R １５ are each independently hydrogen, optionally substituted -(C １ -C ６ ) alkyl, -(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl, heteroaryl, aryl, heterocycle, -(C １ -C ６ ) alkylene-heteroaryl, -(C １ -C ６ ) alkylene-heterocycle, and -(C １ -C ６ ) alkylene-aryl; where optionally R on the substituent A １３ , R １４ or R １５ Any two radicals selected from may together form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally substituted with halogen, —CN, —NO ２ , —OH, —NH ２ , -(C １ -C ６ ) alkyl 、 -O-(C １ -C ６ ) alkyl, and —N—((C １ -C ６ ) alkyl) ２ and optionally further substituted by 1 to 5 radicals independently selected from - wherein any two radicals A together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, each ring optionally containing halogen, -CN, -OH, -NH ２ , -(C １ -C ６ ) alkyl 、 -O-(C １ -C ６ ) alkyl, and —N—((C １ -C ６ ) alkyl) ２ and optionally further substituted by 1 to 5 radicals independently selected from and / or - Ar ２ teeth, 【Transformation 6】 represents an aryl or heteroaryl selected from where p is the number of substituents B on the ring and is an integer equal to 0, 1, 2, 3, 4 or 5, - B may be the same or different, and each independently represents hydrogen, halogen, -CN, or -CF ３ , and -(C １ -C ６ ) alkyl, -(C １ -C ６ ) haloalkyl, —(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-heterocycle, -(C1-C6) alkylene-aryl, heterocycle, -OR １３ , -(C １ -C ６ ) alkylene-OR １３ , —O—(C ２ -C ６ ) alkylene-OR １３ 、 -NR １３ (C ２ -C ６ ) alkylene-OR １４ , -NR １３ R １４ , -(C １ -C ６ ) alkylene-NR １３ R １４ , —O—(C ２ -C ６ ) alkylene-NR １３ R １４ , -NR １３ -(C ２ -C ６ ) alkylene-NR １４ R １５ , -SR １３ , -(C １ -C ６ ) alkylene-SR １３ , —O—(C ２ -C ６ ) alkylene-SR １３ , -NR １３ -(C ２ -C ６ ) alkylene-SR １４ , -S(=O)-R １３ , -(C １ -C ６ ) alkylene-S(=O)-R １３ , —O—(C １ -C ６ ) alkylene-S(=O)-R １３ , -NR １３ -(C １ -C ６ ) alkylene-S(=O)-R １４ , -S(=O) ２ -R １３ , -(C １ -C ６ ) alkylene-S(=O) ２ -R １３ , —O—(C １ -C ６ ) alkylene-S(=O) ２ -R １３ , -NR １３ -(C １ -C ６ ) alkylene-S(=O) ２ -R １４ , -S(=O) ２ NR １３ R １４ , -(C １ -C ６ ) alkylene-S(=O) ２ NR １３ R １４ , —O—(C １ -C ６ ) alkylene-S(=O) ２ NR １３ R １４ , -NR １３ -(C １ -C ６ ) alkylene-S(=O) ２ NR １４ R １５ , -NR １３ -S(=O) ２ R １４ , -(C １ -C ６ ) alkylene-NR １３ -S(=O) ２ R １４ , —O—(C ２ -C ６ ) alkylene-NR １３ -S(=O) ２ R １４ , -NR １３ -(C ２ -C ６ ) alkylene-NR １４ -S(=O) ２ R １５ , -C(=O)-NR １３ R １４ , -(C １ -C ６ ) alkylene-C(═O)-NR １３ R １４ , —O—(C １ -C ６ ) alkylene-C(═O)-NR １３ R １４ , -NR １３ -(C １ -C ６ ) alkylene-C(═O)-NR １４ R １５ , -NR １３ C(=O)-R １４ , -(C １ -C ６ ) alkylene-NR １３ C(=O)-R １４ , —O—(C ２ -C ６ ) alkylene-NR １３ C(=O)-R １４ , -NR １３ -(C ２ -C ６ ) alkylene-NR １４ C(=O)-R １５ , —C(═O)—R １３ , -(C １ -C ６ ) alkylene-C(=O)-R １３ , —O—(C １ -C ６ ) alkylene-C(=O)-R １３ , -NR １３ -(C １ -C ６ ) alkylene-C(=O)-R １４ , -C(=O)-OR １３ , -(C １ -C ６ ) alkylene-C(=O)-OR １３ , —O—(C １ -C ６ ) alkylene-C(=O)-OR １３ , -NR １３ -(C １ -C ６ ) alkylene-C(=O)-OR １４ , -OC(=O)-R １３ , -(C １ -C ６ ) alkylene-OC(=O)-R １３ , —O—(C ２ -C ６ ) alkylene-OC(=O)-R １３ , -NR １３ -(C ２ -C ６ ) alkylene-OC(=O)-R １４ , -(C １ -C ６ ) alkylene-NR １３ —C(═O)—NR １４ R １５ , -NR １３ -C(=O)-OR １４ , -(C １ -C ６ ) alkylene-NR １３ -C(=O)-OR １４ , —O—(C ２ -C ６ ) alkylene-NR １３ -C(=O)-OR １４ , -NR １３ -(C ２ -C ６ ) alkylene-NR １４ -C(=O)-OR １５ , -OC(=O)-NR １３ R １４ , -(C １ -C ６ ) alkylene-O-C(=O)-NR １３ R １４ , —O—(C ２ -C ６ ) alkylene-O-C(=O)-NR １３ R １４ , -NR １３ -(C ２ -C ６ ) alkylene-O-C(=O)-NR １４ R １５ , -C(=O)-(C １ -C ６ ) alkylene-NR １３ R １４ , -C(=O)-(C １ -C ６ ) alkylene-OR １３ an optionally substituted radical selected from the group - where R １３ , R １４ and R １５ are each independently hydrogen, optionally substituted -(C １ -C ６ ) haloalkyl, —(C １ -C ６ ) alkyl, -(C １ -C ６ ) cyanoalkyl, —(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl, heteroaryl, aryl, heterocycle, -(C １ -C ６ ) alkylene-heteroaryl, -(C １ -C ６ ) alkylene-heterocycle, and -(C １ -C ６ ) alkylene-aryl; where optionally R on the substituent B １３ , R １４ or R １５ Any two radicals selected from may together form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally substituted with halogen, —CN, —NO ２ , —OH, —NH ２ , -(C １ -C ６ ) alkyl 、 -O-(C １ -C ６ ) alkyl, and —N—((C １ -C ６ ) alkyl) ２ and optionally further substituted by 1 to 5 radicals independently selected from - wherein any two radicals B together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, each ring optionally containing halogen, -CN, -OH, -NH ２ , -(C １ -C ６ ) alkyl 、 -O-(C １ -C ６ ) alkyl, and —N—((C １ -C ６ ) alkyl) ２ It may be further substituted with 1 to 5 radicals independently selected from:

3. The compound according to claim 1 or 2, wherein

4. - A may be the same or different, and each independently represents hydrogen, halogen, -CN, or -CF ３ , —OH, and —(C １ -C ６ ) alkyl, -(C １ -C ６ ) haloalkyl, —(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-heterocycle, heterocycle, -OR １３ , -(C １ -C ６ ) alkylene-OR １３ , —O—(C ２ -C ６ ) alkylene-OR １３ 、 -NR １３ (C ２ -C ６ ) alkylene-OR １４ , -O(C ２ -C ６ ) alkylene-NR １３ R １４ , -NR １３ -(C ２ -C ６ ) alkylene-NR １４ R １５ , -NR １３ R １４ , -(C １ -C ６ ) alkylene-NR １３ R １４ , -NR １３ C(=O)-R １４ , -C(=O)-NR １３ R １４ , S(=O) ２ NR １３ R １４ or -NR １３ -S(=O) ２ R １４ an optionally substituted radical selected from the group - where R １３ and R １４ are each independently hydrogen, optionally substituted -(C １ -C ３ ) alkyl, -(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl, heterocycle, and -(C １ -C ６ ) alkylene-heterocycle; where optionally a radical R on the substituent A １３ and R １４ may together form a 3- to 6-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally substituted with halogen, —CN, —OH, —NH ２ , -(C １ -C ６ ) alkyl 、 -O-(C １ -C ６ ) alkyl, and —N—((C １ -C ６ ) alkyl) ２ and optionally further substituted by 1 to 5 radicals independently selected from - where any two radicals A together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally selected from the group consisting of halogen, -CN, -(C １ -C ６ ) alkyl 、 -O-(C １ -C ６ ) alkyl, and —N—((C １ -C ６ ) alkyl) ２ and / or may be further substituted by 1 to 5 radicals independently selected from - B may be the same or different, and each independently represents hydrogen, halogen, or -CF ３ , -CN, and -(C １ -C ６ ) alkyl, -(C １ -C ６ ) haloalkyl, —(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-aryl, heterocycle, —OR １３ , -(C １ -C ６ ) alkylene-OR １３ , —O—(C ２ -C ６ ) alkylene-OR １３ 、 -NR １３ (C ２ -C ６ ) alkylene-OR １４ , -NR １３ R １４ , -SR １３ , -(C １ -C ６ ) alkylene-SR １３ , -S(=O)-R １３ , -S(=O) ２ -R １３ , -NR １３ C(=O)-R １４ , -C(=O)-NR １３ R １４ , -C(=O)-OR １３ , -OC(=O)-R １３ , -C(=O)-(C １ -C ６ ) alkylene-OR １３ or -C(=O)-R １３ an optionally substituted radical selected from the group - where R １３ and R １４ are each independently hydrogen, optionally substituted -(C １ -C ６ ) alkyl, -(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl, heteroaryl, aryl, heterocycle, -(C １ -C ６ ) alkylene-heteroaryl, -(C １ -C ６ ) alkylene-heterocycle, and -(C １ -C ６ ) alkylene-aryl; where optionally R on the substituent B １３ and R １４ Any two radicals selected from may together form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally substituted with halogen, CN, —OH, —NH ２ , -(C １ -C ６ ) alkyl 、 -O-(C １ -C ６ ) alkyl, and —N—((C １ -C ６ ) alkyl) ２ and optionally further substituted by 1 to 5 radicals independently selected from - wherein any two radicals B together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, each ring optionally containing halogen, -CN, -OH, -NH ２ , -(C １ -C ６ ) alkyl 、 -O-(C １ -C ６ ) alkyl, and —N—((C １ -C ６ ) alkyl) ２ and optionally further substituted by 1 to 5 radicals independently selected from and / or Only one of G or E is N; The compound according to any one of claims 1 to 3.

5. Formula (III): 【Transformation 7】 (where - A may be the same or different, and each independently represents hydrogen, halogen, -CN, or -CF ３ , and —OH, —(C １ -C ６ ) alkyl, -(C １ -C ６ ) haloalkyl, —(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-heterocycle, heterocycle, -OR １３ , -(C １ -C ６ ) alkylene-OR １３ , —O—(C ２ -C ６ ) alkylene-OR １３ 、 -NR １３ (C ２ -C ６ ) alkylene-OR １４ , -O(C ２ -C ６ ) alkylene-NR １３ R １４ , -NR １３ -(C ２ -C ６ ) alkylene-NR １４ R １５ , -NR １３ R １４ , -(C １ -C ６ ) alkylene-NR １３ R １４ , -NR １３ C(=O)-R １４ , -C(=O)-NR １３ R １４ , S(=O) ２ NR １３ R １４ or -NR １３ -S(=O) ２ R １４ an optionally substituted radical selected from the group - where R １３ and R １４ are each independently hydrogen, optionally substituted -(C １ -C ３ ) alkyl, -(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl, heterocycle, and -(C １ -C ６ ) alkylene-heterocycle; where optionally a radical R on the substituent A １３ and R １４ may together form a 3- to 6-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally substituted with halogen, —CN, —OH, —NH ２ , -(C １ -C ６ ) alkyl 、 -O-(C １ -C ６ ) alkyl, and —N—((C １ -C ６ ) alkyl) ２ and optionally further substituted by 1 to 5 radicals independently selected from - where any two radicals A together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally selected from the group consisting of halogen, -CN, -(C １ -C ６ ) alkyl 、 -O-(C １ -C ６ ) alkyl, and —N—((C １ -C ６ ) alkyl) ２ and / or may be further substituted by 1 to 5 radicals independently selected from - B may be the same or different, and each independently represents hydrogen, halogen, or -CF ３ , -CN, -(C １ -C ６ ) alkyl, -(C １ -C ６ ) haloalkyl, —(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-aryl, heterocycle, —OR １３ , -(C １ -C ６ ) alkylene-OR １３ , —O—(C ２ -C ６ ) alkylene-OR １３ 、 -NR １３ (C ２ -C ６ ) alkylene-OR １４ , -NR １３ R １４ , -SR １３ , -(C １ -C ６ ) alkylene-SR １３ , -S(=O)-R １３ , -S(=O) ２ -R １３ , -NR １３ C(=O)-R １４ , -C(=O)-NR １３ R １４ , -C(=O)-OR １３ , -OC(=O)-R １３ , -C(=O)-(C １ -C ６ ) alkylene-OR １３ or -C(=O)-R １３ an optionally substituted radical selected from the group - where R １３ and R １４ are each independently hydrogen, optionally substituted -(C １ -C ６ ) alkyl, -(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl, heteroaryl, aryl, heterocycle, -(C １ -C ６ ) alkylene-heteroaryl, -(C １ -C ６ ) alkylene-heterocycle, and -(C １ -C ６ ) alkylene-aryl; where optionally R on the substituent B １３ and R １４ Any two radicals selected from may together form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally substituted with halogen, CN, —OH, —NH ２ , -(C １ -C ６ ) alkyl 、 -O-(C １ -C ６ ) alkyl, and —N—((C １ -C ６ ) alkyl) ２ and optionally further substituted by 1 to 5 radicals independently selected from - wherein any two radicals B together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, each ring optionally containing halogen, -CN, -OH, -NH ２ , -(C １ -C ６ ) alkyl 、 -O-(C １ -C ６ ) alkyl, and —N—((C １ -C ６ ) alkyl) ２ and / or may be further substituted by 1 to 5 radicals independently selected from Only one of G or E is N.) 3. The compound according to claim 1 or 2, wherein

6. - A may be the same or different, and each independently represents hydrogen, halogen, -CN, or -CF ３ , —OH, and —(C １ -C ６ ) alkyl, -(C １ -C ６ ) haloalkyl, —(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-heterocycle, heterocycle, —O—(C １ -C ６ ) alkyl, O—(C １ -C ３ ) alkyl-(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-OR １３ , —O—(C ２ -C ６ ) alkylene-OR １３ 、 -NR １３ R １４ , -(C １ -C ６ ) alkylene-NR １３ R １４ or -NR １３ C(=O)-R １４ an optionally substituted radical selected from the group -R １３ and R １４ are each independently hydrogen, optionally substituted -(C １ -C ３ ) alkyl, -(C ３ -C ７ ) cycloalkyl, or —(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl; optionally a radical R on the substituent A １３ and R １４ may together form a 3- to 6-membered carbocyclic or heterocyclic ring, wherein each ring is optionally substituted with a halogen, —CN, —OH, —NH ２ , -(C １ -C ６ ) alkyl 、 -O-(C １ -C ６ ) alkyl, and —N—((C １ -C ６ ) alkyl) ２ and optionally further substituted by 1 to 5 radicals independently selected from Any two radicals A together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally selected from the group consisting of halogen, —CN, —(C １ -C ６ ) alkyl 、 -O-(C １ -C ６ ) alkyl, and —N—((C １ -C ６ ) alkyl) ２ may be further substituted by 1 to 5 radicals independently selected from 、 The compound according to any one of claims 2 to 5.

7. - B may be the same or different, and each independently represents hydrogen, halogen, or -CF ３ , and -(C １ -C ６ ) alkyl, -(C １ -C ６ ) haloalkyl, —(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl, heterocycle, —O—(C １ -C ６ ) alkyl, —O—(C ３ -C ７ ) cycloalkyl, —O—(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-OR １３ , —O—(C １ -C ６ ) alkylene-aryl, —O—(C ２ -C ６ ) alkylene-O-(C １ -C ６ ) alkyl, —NR １３ R １４ or -C(=O)-R １３ an optionally substituted radical selected from the group -R １３ and R １４ are each independently hydrogen, optionally substituted -(C １ -C ６ ) alkyl, -(C ３ -C ７ ) cycloalkyl, -(C １ -C ６ ) alkylene-(C ３ -C ７ ) cycloalkyl; optionally a radical R on the substituent B １３ and R １４ may together form a 3- to 6-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally substituted with halogen, —CN, —OH, —NH ２ , -(C １ -C ６ ) alkyl 、 -O-(C １ -C ６ ) alkyl, and —N—((C １ -C ６ ) alkyl) ２ and optionally further substituted by 1 to 5 radicals independently selected from Any two radicals B together with the intervening atoms may form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally selected from the group consisting of halogen, —CN, —(C １ -C ６ ) alkyl 、 -O-(C １ -C ６ ) alkyl, and —N—((C １ C ６ ) alkyl) ２ and optionally further substituted by 1 to 5 radicals independently selected from The compound according to any one of claims 2 to 6.

8. - Ar １ teeth, 【Transformation 8】 and / or represents an aryl or heteroaryl selected from - Ar ２ teeth, 【Chemistry 9】 represents an aryl or heteroaryl selected from A compound according to any one of claims 1 to 7.

9. -R １ , R ２ , R ３ , R ４ , R ５ and R ６ may be the same or different, and each independently represents hydrogen, halogen, or —OR １０ , -NR １０ R １１ or optionally substituted -(C １ -C ３ ) alkyl; any two radicals R １ and R ２ , R ３ and R ４ , and R ５ and R ６ may together form oxo, optionally, R １ , R ２ , R ３ , R ４ , R ５ and R ６ any two radicals selected from may be taken together to form an optionally substituted 3- to 10-membered non-aromatic carbocyclic or heterocyclic ring; A compound according to any one of claims 1 to 8.

10. -R ７ and R ８ is hydrogen, halogen, -CN, -OR １０ , -NR １０ R １１ , -CF ３ or optionally substituted -(C １ -C ３ ) alkyl, wherein R １０ and R １１ may be the same or different, and each independently represents hydrogen, -(C １ -C ３ ) alkyl or -(C ３ -C ７ ) cycloalkyl; optionally, the two radicals R １０ and R １１ may together form an optionally substituted 3- to 10-membered non-aromatic carbocyclic or heterocyclic ring; A compound according to any one of claims 1 to 9.

11. -R ９ is hydrogen, halogen, -CN, -OR １０ , -NR １０ R １１ , -CF ３ or optionally substituted -(C １ -C ３ ) alkyl, wherein R １０ and R １１ may be the same or different, and each independently represents hydrogen or -(C １ -C ３ ) alkyl; optionally, the two radicals R １０ and R １１ may together form an optionally substituted 3- to 10-membered non-aromatic carbocyclic or heterocyclic ring; A compound according to any one of claims 1 to 10.

12. -R １ ~R ６ is hydrogen, -R ７ and R ８ is hydrogen, and / or -R ９ is hydrogen, A compound according to any one of claims 1 to 11.

13. 6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one, 6-(3-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(4-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one, (-)-6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one, 6-(2,4-dimethylphenyl)-2-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one, 2-(4-chloropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(3-chloropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(6-fluoropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(4-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(3-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(6-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(4-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(3-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(4-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(3-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)picolinonitrile, 6-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)nicotinonitrile, 2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)isonicotinonitrile, 2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)nicotinonitrile, 6-(2,4-dimethylphenyl)-2-(5-hydroxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(4-hydroxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-(methoxymethyl)pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(pyridin-3-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(pyrazin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(pyrimidin-5-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(thiazol-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(thiazol-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(1-methyl-1H-imidazol-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(4,6-dimethylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(4-cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-hydroxypyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-(hydroxymethyl)pyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-methoxy-2-methylphenyl)-2-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-chloropyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-methoxy-2-methylphenyl)-2-(5-methoxypyrazin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-hydroxypyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-methoxy-2-methylphenyl)-2-(4-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-methoxy-2-methylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-chloropyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(pyridin-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-chloropyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-fluoropyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(4-methoxy-5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-(morpholinomethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(dimethylamino)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(pyridin-2-yl)-6-(o-tolyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-cyclopropylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(1-hydroxyethyl)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-cyclopropoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-methoxy-3-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(1-methylindolin-4-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-methoxy-4-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-methoxy-3-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-chloro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-methoxy-2-(trifluoromethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-fluoro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-chloro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-methoxy-5-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(1-methylindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-fluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,5-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,3-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(methoxymethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(cyclopentyloxy)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(4-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(1,5-dimethyl-1H-indazol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-mesityl-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,6-difluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(1-cyclopropylindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one 6-(2-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(4-chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(4-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(3-methoxypropoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-ethoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(cyclopropylmethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-isopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(2-methoxyethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(benzyloxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-cyclopropylpyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-cyclopropylpyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-cyclopropylpyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-methoxy-2-methylphenyl)-2-(5-(pyrrolidin-1-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-methoxy-2-methylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-morpholinopyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-morpholinopyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-(azetidin-1-yl)pyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide, 6-(3-methoxy-2-methylphenyl)-2-(5-(2-methoxyethoxy)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (2-(5-(2-hydroxyethoxy)-pyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-dimethylphenyl)-2-(pyridin-2-yl)-2,5,6,7-tetrahydro-1H-cyclopenta[d]-pyridazin-1-one, 7-(2,4-dimethylphenyl)-3-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one, 6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-cyclopropylpyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-bromopyrimidin-2-yl)-6-(3-cyclopropoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, N-(2-(6-(3-cyclopropoxy-2-methylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide, (-)-6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (-)-6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (-)-6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (-)-6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (-)-N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide, (+)-N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide, (+)-6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (-)-6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-bromopyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-bromopyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-bromopyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-bromopyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-bromopyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, and 2-(5-bromo-4-methoxypyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one or its N-oxide form, pharmaceutically acceptable salts and solvates thereof, or optical isomers, racemates, diastereoisomers, enantiomers, or tautomers thereof, selected from:

14. A compound according to any one of claims 1 to 13 in the form of a racemic mixture or in the form of one or both of the individual optical isomers.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 14 and a pharmaceutically acceptable excipient.

16. 16. A pharmaceutical composition according to claim 15 for modulating, preferably reducing, inhibiting or negatively modulating, the activity of metabotropic glutamate receptors, in particular mGluR7.

17. 16. A pharmaceutical composition according to claim 15 for the prevention or treatment of disorders associated with glutamate dysfunction in a mammal, such as a human.

18. Anxiety disorders, such as agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, and post-traumatic stress disorder mood disorders, such as bipolar disorder (I & II), cyclothymic disorder, depression, dysthymic disorder, major depressive disorder, drug-induced mood disorder, mood disorders due to general medical conditions, mania, manic depression, seasonal affective disorder; muscle spasms and disorders associated with muscle spasms, such as tremors, epilepsy, convulsions, migraines; neurodegenerative disorders, such as mild cognitive impairment, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis; mental disorders, such as schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder, and drug-induced psychosis; personality disorders, such as obsessive-compulsive personality disorder, schizoid personality disorder, schizophrenia, and other disorders associated with muscle spasms, such as tremors, epilepsy, convulsions, and migraines; chyloid disorder, borderline personality disorder, anxious-avoidant personality disorder; childhood disorders such as attention deficit hyperactivity disorder, mental retardation, Down's syndrome, tic disorders, autism spectrum disorders (e.g., Rett syndrome or fragile X syndrome) and autism; hearing disorders such as inner ear diseases, disorders, impairments or conditions, such as sensorineural hearing loss, age-related hearing loss (presbycusis), Meniere's disease, sudden hearing loss, noise-induced hearing loss, drug-induced hearing loss, recessive hearing loss, cisplatin-induced hearing loss, aminoglycoside-induced hearing loss, otitis media, toxic hearing loss, autoimmune inner ear disease, acute tinnitus, chronic tinnitus, central auditory processing disorders, and vestibular disorders; gastrointestinal disorders such as diarrhea, constipation, gastroesophageal reflux disease gastrointestinal motility disorders, colitis, Crohn's disease or irritable bowel syndrome (IBS); pain disorders, such as acute pain, chronic pain, severe pain, intractable pain, inflammatory pain, post-operative pain, headache, cancer pain, neuropathic pain, post-traumatic pain, and visceral pain; cognitive and mood disorders associated with the aforementioned disorders;18. The pharmaceutical composition according to claim 15 or 17, for the prevention or treatment of disorders selected from ophthalmic diseases such as ocular hypertension, glaucoma, normal tension glaucoma, neurodegenerative conditions of the retina and optic nerve, retinal dystrophies, age-related macular degeneration, and eye conditions such as conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, inflammation and / or neurodegeneration; disorders resulting from traumatic brain injury, stroke, ischemia, spinal cord injury, cerebral hypoxia, cerebral hemorrhage or intracranial hematoma.

19. Anxiety disorders, such as agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, and post-traumatic stress disorder mood disorders, such as bipolar disorder (I & II), cyclothymic disorder, depression, dysthymic disorder, major depressive disorder, drug-induced mood disorder, mood disorders due to general medical conditions, mania, manic depression, seasonal affective disorder; muscle spasms and disorders associated with muscle spasms, such as tremors, epilepsy, convulsions, migraines; neurodegenerative disorders, such as mild cognitive impairment, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis; mental disorders, such as schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder, and drug-induced psychosis; personality disorders, such as obsessive-compulsive personality disorder, schizoid personality disorder, schizophrenia, and other disorders associated with muscle spasms, such as tremors, epilepsy, convulsions, and migraines; chyloid disorder, borderline personality disorder, anxious-avoidant personality disorder; childhood disorders such as attention deficit hyperactivity disorder, mental retardation, Down's syndrome, tic disorders, autism spectrum disorders (e.g., Rett syndrome or fragile X syndrome) and autism; hearing disorders such as inner ear diseases, disorders, impairments or conditions, such as sensorineural hearing loss, age-related hearing loss (presbycusis), Meniere's disease, sudden hearing loss, noise-induced hearing loss, drug-induced hearing loss, recessive hearing loss, cisplatin-induced hearing loss, aminoglycoside-induced hearing loss, otitis media, toxic hearing loss, autoimmune inner ear disease, acute tinnitus, chronic tinnitus, central auditory processing disorders, and vestibular disorders; gastrointestinal disorders such as diarrhea, constipation, gastroesophageal reflux disease gastrointestinal motility disorders, colitis, Crohn's disease or irritable bowel syndrome (IBS); pain disorders, such as acute pain, chronic pain, severe pain, intractable pain, inflammatory pain, post-operative pain, headache, cancer pain, neuropathic pain, post-traumatic pain, and visceral pain; cognitive and mood disorders associated with the aforementioned disorders;Use of a compound according to any one of claims 1 to 14 for the manufacture of a medicament for the prevention or treatment of disorders selected from ophthalmic diseases such as ocular hypertension, glaucoma, normal tension glaucoma, neurodegenerative conditions of the retina and optic nerve, retinal dystrophies, age-related macular degeneration, and eye conditions such as conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, inflammation and / or neurodegeneration; disorders resulting from traumatic brain injury, stroke, ischemia, spinal cord injury, cerebral hypoxia, cerebral hemorrhage or intracranial hematoma.

20. Use of a compound according to any one of claims 1 to 14 as a radiolabelled tracer for imaging metabotropic glutamate receptors, preferably mGluR7, in mammals, such as humans.

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