Novel heterocyclic compounds as MGLUR7 modulators

Abstract

The present invention relates to novel heterocyclic compounds. The present invention also relates to compounds that are modulators of metabotropic glutamate receptors (mGluRs), preferably metabotropic glutamate receptor subtype 7 ("mGluR7"). The present invention also relates to pharmaceutical combinations comprising such compounds, and their use for treating or preventing disorders associated with glutamate dysfunction or disorders in which metabotropic glutamate receptors, preferably the mGluR7 subtype of metabotropic glutamate receptors, are involved.

Description

SUMMARY OF THE INVENTION

[0002] The present invention relates to novel heterocyclic compounds. The present invention also relates to compounds that are modulators of metabotropic glutamate receptors (mGluRs), preferably metabotropic glutamate receptor subtype 7 ("mGluR7"). The present invention also relates to pharmaceutical compositions comprising such compounds, methods for preparing such compounds and compositions, and the use of such compounds and compositions for preventing or treating disorders associated with glutamate dysfunction or disorders in which metabotropic glutamate receptors, preferably the mGluR7 subtype of metabotropic glutamate receptors, are involved. Background of the Invention

[0004] Glutamate is the major amino acid neurotransmitter in the mammalian central nervous system (CNS) and plays an important role in several physiological functions, such as learning and memory, sensory perception, the development of synaptic plasticity, and motor control. In addition, glutamate is at the center of several neurological and psychiatric diseases in which there is an imbalance in glutamatergic neurotransmission.

[0005] Glutamate mediates synaptic neurotransmission through the activation of mGluR, which belongs to the class C G protein-coupled receptor (GPCR), which has a regulatory effect that helps fine-tune synaptic efficacy (Schoepp et al., Neuropharmacology (1999), 38: 1431). In particular, mGluR receptor subtype 7 (mGluR7) is widely distributed in the brain and has the highest degree of evolutionary conservation among all mGluR receptor species (Flor et al., Neuropharmacol. (1997), 36: 153). More importantly, mGluR7 has the lowest affinity for glutamate, remains inactive during normal neurotransmission states, and only becomes active under severe pathophysiological conditions or during excessive glutamate release (Ferraguti and Shigemoto, Cell Tissue Res. (2006), 326: 483). MGluR7 is thought to act as a tonic disruptor, inhibiting further glutamate release while simultaneously influencing the release of other neurotransmitters (eg, GABA) and preventing glutamate excitotoxicity in many pathological conditions involving the CNS and sensory disorders.

[0006] In particular, mGluR7 modulators, preferably antagonists, inverse agonists and negative allosteric modulators (NAMs), have been reported to have therapeutic potential for neurological, psychiatric, mood disorders, as well as pain and otic disorders based on experimental studies in laboratory animals believed to be relevant to clinical syndromes.

[0007] Isoxazolopyridinone derivatives, including MMPIP (6-(4-methoxyphenyl)-5-methyl-3-(4-pyridyl)-isoxazolo[4,5-c]pyridin-4(5H)-one hydrochloride), have been described as mGluR7 NAMs (Nakamura et al., Bioorg. Med. Chem. Lett. (2010), 20:726; Suzuki et al., J. Pharmacol. Exp. Ther. (2007), 323:147) and exhibit context-dependent pharmacology, partially to fully antagonizing mGluR7 in vitro and in vivo (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).

[0008] Tetrahydrobenzoxazole derivatives, including (+)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenzo[d]oxazol-4(5H)-one (ADX71743) and its racemic form, have been described as mGluR7 NAMs or inverse agonists and have been shown to have 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).

[0009] Chromenone derivatives, including 7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one (XAP044), are described as weak mGluR7 allosteric antagonists that bind to the extracellular domain of the receptor. XAP044 exhibits anxiolytic, antidepressant, antistress, and antipsychotic activities (Gee et al., J. Biol. Chem. (2014), 289:10975).

[0010] Combined expression of mGluR7 in brain regions and pharmacological modulation of mGluR7 in genetically modified mice and wild-type animals have revealed the important role of mGluR7 in many CNS diseases, including depression, schizophrenia, anxiety, obsessive-compulsive disorder and related symptoms (reviewed by et al., Curr. Neuropharmacol. (2016), 14(5):504), especially in acute and chronic stress-related diseases (reviewed by Peterlik et al., Curr Neuropharmacol. (2016), 14(5):514). In addition, mGluR7 represents a new therapeutic approach for the treatment of psychostimulant (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 inhibit pain responses, reduce anxiety- and depression-like behaviors, and improve cognitive performance in a mouse model of neuropathic pain (Pallazzo et al., Pain (2015), 156(6):1060).

[0011] mGluR7 has also been shown to be expressed in peripheral tissues such as the colonic mucosa and stomach (Julio-Pepper et al., Pharmacol. Rev. (2011), 63:35), suggesting its potential role in treating pathologies such as visceral pain, stress-related gastrointestinal dysfunction such as diarrhea or constipation in irritable bowel syndrome (IBS), or other related conditions.

[0012] In addition, mGluR7 is expressed in hair cells and spiral ganglion neurons of the inner ear along the vestibular system (Friedman et al. (2008) WO2008 / 131439) (Zhou et al., Int J Mol. Sci. (2013) 14(11):22857; Horii et al., Exp. Brain Res. (2001) 139(2):188), suggesting a potential role in treating pathologies 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.

[0013] It has been shown that mGluR7 is expressed in the synaptic terminals of certain cone bipolar cells in the retina ( et al., (1996) J. Neurosci., 16(15):4749-4756), suggesting that mGluR7 modulators have potential use in the acute and chronic treatment of glaucoma and other visual disorders.

[0014] Finally, a number of genome-wide human studies have also demonstrated the association of GRM7, the gene encoding mGluR7, with severe diseases such as age-related hearing loss (ARHL; presbycusis), as 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 most 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, as reported by Lu et al. (BMCMed. Genet. (2018), 19(1):4); tinnitus, as reported by Haider et al. (Front. Aging Neurosci. (2017), 9:346); schizophrenia, as reported by Niu et al. (Neurosci. Lett. (2015), 604:109); attention deficit hyperactivity disorder (ADHD), as reported by Elia et al. (Nat. Genet. (2011), 44:78); major depressive disorder, as reported by Li et al. (Eur. Neuropsychopharmacol. (2015), doi:10.1016 / j.euroneuro.2015.05.004) bipolar disorder, as reported by Kandaswamy et al. (Am. J. Med. Genet. B. Neuropsychiatr. Genet. (2015), 165B(4):365); alcohol addiction (Vadasz et al., Genomics (2007), 90(6):690); and autism spectrum disorders, including autism (Liu et al., Am. J. Med. Genet. B. Neuropsychiatr. Genet. (2015), 168B(4):258).

[0015] Together, these pharmacological and genetic data strongly support the potential of mGluR7 modulators for the treatment of a variety of diseases and related symptoms, including psychiatric, neurological, neurodevelopmental, otic, pain, visual, and gastrointestinal disorders.

[0016] It is an object of the present invention to provide compounds which are active at mGluRs, preferably at mGluR7.

[0017] Another object of the present invention is to provide a pharmaceutical composition comprising the compound.

[0018] Another object of the present invention is to provide such compounds and / or pharmaceutical compositions for use in treating diseases associated with mGluR, preferably mGluR7. SUMMARY OF THE INVENTION

[0020] The present invention relates to compounds of formula (I),

[0021]

[0022] in:

[0023] G is selected from N or CR 7 ,

[0024] E is selected from N or CR 8 ,

[0025] The condition is that at least one of G or E is N

[0026] Y is CR 9 ,

[0027] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 and R 9 are the same or different and are each independently selected from 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)2NR 10 R 11 、-NR 10 R 11 、-NR 10 C(=O)R 11 、-NR 10C(=O)OR 11 、-NR 10 S(O)2R 11 , an optionally substituted group selected from: -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl or -(C1-C6)cyanoalkyl,

[0028] Any two groups R 1 and R 2 、R 3 and R 4 , and R 5 and R 6 Can form oxo (=O) together,

[0029] where R 10 and R 11 are the same or different and are each independently selected from hydrogen, an optionally substituted group selected from: -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)cyanoalkyl, -(C3-C7)cycloalkyl or -(C1-C6)alkylene-(C3-C7)cycloalkyl,

[0030] wherein, optionally, selected from R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 9 、R 10 and R 11 Any two groups of 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,

[0031] n is an integer selected from 0 or 1,

[0032] Ar 1 is optionally substituted aryl or heteroaryl,

[0033] Ar 2 is optionally substituted aryl or heteroaryl,

[0034] and its N-oxide forms, pharmaceutically acceptable salts and solvates, or their optical isomers, racemates, diastereomers, enantiomers or tautomers.

[0035] Surprisingly, the compounds of general formula (I) show metabotropic glutamate receptor activity.

[0036] Preferably, in the compound of formula (I), Ar1 represents an aryl or heteroaryl group selected from:

[0037]

[0038] wherein m is the number of substituents A on the ring, which is an integer equal to 0, 1, 2, 3, 4 or 5.

[0039] Preferably, in the compound of formula (I), Ar 2 represents an aryl or heteroaryl group selected from:

[0040]

[0041] wherein p is the number of substituents B on the ring, which is an integer equal to 0, 1, 2, 3, 4 or 5. It will be understood that when Ar2 is bicyclic, B may be on either ring.

[0042] A and B, as described above, are the same or different and are each independently selected from hydrogen, halogen, -CN, -NO2, -OH, -NH2, -CF3, an optionally substituted group selected from: -(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 、-NR13 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)-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 , -(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 or -(C1-C6)alkylene-NR 13 -C(=NR 14 )-NR 15 R 16 ;

[0043] where R 13 、R 14 、R 15 and R 16 each independently selected from hydrogen, optionally substituted -(C1-C6)haloalkyl, -(C1-C6)alkyl, -(C1-C6)cyanoalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, heteroaryl, aryl, heterocycle, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-heterocycle and -(C1-C6)alkylene-aryl;

[0044] wherein, optionally, selected from R 13 、R 14 、R 15 or R 16 Any two groups of may be taken together to form a 3- to 10-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, cyano, nitro, hydroxy, amino, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl)2;

[0045] wherein any two groups A and any two groups B may be combined with intervening atoms to form a 3 to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the following: halogen, -CN, hydroxyl, amino, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0046] Preferably, in the compounds of formula (I), the substituents A are identical or different and are each independently selected from hydrogen, halogen, -CN, -CF3, -OH, -NH2, an optionally substituted group selected from: -(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)2NR13 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 ;

[0047] where R 13 、R 14 and R 15 each independently selected from hydrogen, optionally substituted -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, heteroaryl, aryl, heterocycle, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-heterocycle and -(C1-C6)alkylene-aryl;

[0048] Wherein, optionally, the substituent on A is selected from R 13 、R 14 or R 15 Any two groups of may be taken together to form a 3- to 10-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -NO2, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl)2;

[0049] wherein any two groups A may be combined with intervening atoms to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0050] Preferably, in the compound of formula (I), the substituents A are identical or different and are each independently selected from hydrogen, halogen, -CN, -CF3, -OH, an optionally substituted group selected from: -(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 ,

[0051] where R 13 and R 14 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;

[0052] Wherein, optionally, the group R on the substituent A 13 and R 14 Together they may form a 3- to 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl)2;

[0053] wherein any two groups A may be combined with intervening atoms to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0054] Preferably, in the compounds of formula (I), the substituents A are identical or different and are each independently selected from hydrogen, halogen, -CN, -CF3, -OH, an optionally substituted group selected from: -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C1-C6)alkylene-heterocycle, heterocycle, -O-(C1-C6)alkyl, O-(C1-C3)alkyl-(C3-C7)cycloalkyl, -(C1-C6)alkylene-OR 13 、-O-(C2-C6)alkylene-OR 13 、-NR 13 R 14 、-(C1-C6)alkylene-NR 13 R 14 or -NR13 C(=O)-R 14 ;

[0055] where R 13 and R 14 Each is independently selected from hydrogen, optionally substituted -(C1-C3)alkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl;

[0056] Wherein, optionally, the group R on the substituent A 13 and R 14 Together they may form a 3- to 6-membered carbocyclic or heterocyclic ring, wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl)2;

[0057] wherein any two groups A may be combined with intervening atoms to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0058] Preferably, in the compounds of formula (I), the substituents A are identical or different and are each independently selected from hydrogen, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxy (-OH), cyclopropyloxy, methoxymethyl, hydroxymethyl, 2-methoxyethoxy, 2-hydroxyethoxy, trifluoromethyl, chlorine, fluorine, cyano, dimethylamino, azetidinyl, pyrrolidinyl, morpholino, morpholinomethyl, acetamido.

[0059] Preferably, in the compound of formula (I), the substituents B are identical or different and are each independently selected from hydrogen, halogen, -CN, -CF3, an optionally substituted group selected from: -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C1-C6)alkylene-heterocycle, -(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 、-(C1-C6)alkylene-NR 13 R14 、-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)-OR15 、-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 ;

[0060] where R 13 、R 14 and R 15 each independently selected from hydrogen, optionally substituted -(C1-C6)haloalkyl, -(C1-C6)alkyl, -(C1-C6)cyanoalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, heteroaryl, aryl, heterocycle, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-heterocycle and -(C1-C6)alkylene-aryl;

[0061] Wherein, optionally, the substituent B is selected from R 13 、R 14 or R 15 Any two groups of may be taken together to form a 3- to 10-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -NO2, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl)2;

[0062] wherein any two groups B may be combined with intervening atoms to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0063] Preferably, in the compound of formula (I), the substituents B are identical or different and are each independently selected from hydrogen, halogen, -CF3, -CN, an optionally substituted group selected from: -(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 ;

[0064] where R 13 and R 14 each independently selected from hydrogen, optionally substituted -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, heteroaryl, aryl, heterocycle, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-heterocycle and -(C1-C6)alkylene-aryl;

[0065] Wherein, optionally, the substituent B is selected from R 13 and R 14 Any two groups of may be taken together to form a 3- to 10-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl)2;

[0066] wherein any two groups B may be combined with intervening atoms to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0067] Preferably, in the compounds of formula (I), the substituents B are identical or different and are each independently selected from hydrogen, halogen, -CF3, an optionally substituted group selected from: -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, heterocycle, -O-(C1-C6)alkyl, -O-(C3-C7)cycloalkyl, -O-(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C1-C6)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 ;

[0068] where R 13 and R 14 are each independently selected from hydrogen, optionally substituted -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl,

[0069] Wherein, optionally, the group R on the substituent B 13 and R 14 Together they may form a 3- to 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl)2;

[0070] wherein any two groups B may be combined with intervening atoms to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1C6)alkyl)2.

[0071] Preferably, in the compounds of formula (I), the substituents B are identical or different and are each independently selected from methyl, ethyl, cyclopropyl, methoxy, ethoxy, isopropoxy, cyclopropyloxy, cyclopentyloxy, benzyloxy, cyclopropylmethoxy, methoxymethyl, 1-hydroxyethyl, 2-methoxyethoxy, 3-methoxypropoxy, trifluoromethyl, chlorine, fluorine, dimethylamino, pyrrolidinyl, acetyl.

[0072] Preferably, in the compound of formula (I),

[0073] m is an integer equal to 0, 1 or 2; and / or

[0074] p is an integer equal to 1, 2 or 3.

[0075] Preferably, in the compound of formula (I), Ar 1 represents an aryl or heteroaryl group selected from:

[0076]

[0077] wherein A is as defined above;

[0078] wherein m is the number of substituents A on the ring, which is an integer equal to 0, 1, 2, 3 or 4.

[0079] Preferably, in the compound of formula (I), Ar 1 represents an aryl or heteroaryl group selected from:

[0080] 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, 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 yl, 5-fluoropyrimidin-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-methoxyethoxy)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, 5-methoxypyrazin-2-yl.

[0081] Preferably, in the compound of formula (I), Ar 2 represents an aryl or heteroaryl group selected from:

[0082]

[0083] wherein B and p are as defined above.

[0084] Preferably, in the compound of formula (I), Ar 2 represents an aryl or heteroaryl group selected from:

[0085]

[0086] wherein B and p are as defined above.

[0087] Preferably, in the compound of formula (I), Ar 2 represents an aryl or heteroaryl group selected from:

[0088]

[0089] wherein B and p are as defined above.

[0090] Preferably, in the compound of formula (I), Ar 2 represents an aryl or heteroaryl group selected from:

[0091] 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-cyclopropyloxy-2-methylphenyl, 5-cyclopropyloxy-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-(pyrrolidone)- phenyl, 3-(dimethylamino)-2-methylphenyl, 5-methoxy-2,4-dimethylphenyl, 3-cyclopropylphenyl, 3-(methoxymethyl)phenyl, 3-(dimethylamino)phenyl, (1-hydroxyethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-cyclopropyloxyphenyl, 5-methoxy-2-(trifluoromethyl)phenyl, 3-(cyclopentyloxy)phenyl, 2,6-difluoro-3-methoxyphenyl, 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-cyclopropyloxyphenyl, 1-cyclopropylindolin-4-yl, 1-cyclopropyl-1H-indol-4-yl.

[0092] Preferably, in the compound of formula (I), R 1 、R 2 、R 3 、R 4 、R 5 and R 6 are the same or different and are each independently selected from hydrogen, halogen, -OR 10 、-NR 10 R 11 , optionally substituted -(C1-C3)alkyl, R 10 and R 11 As defined before;

[0093] Any two groups R 1 and R 2 、R 3 and R 4 and R 5 and R6 Can form oxo together;

[0094] wherein, optionally, selected from R 1 、R 2 、R 3 、R 4 、R 5 and R 6 Any two groups of may be taken together to form an optionally substituted 3- to 10-membered non-aromatic carbocyclic or heterocyclic ring.

[0095] Preferably, in the compound of formula (I), R 1 、R 2 、R 3 、R 4 、R 5 and R 6 It's hydrogen.

[0096] Preferably, in the compound of formula (I), R 7 and R 8 Selected from hydrogen, halogen, -CN, -OR 10 、-NR 10 R 11 , -CF3, optionally substituted -(C1-C3)alkyl, wherein R 10 and R 11 are the same or different and are each independently selected from hydrogen, -(C1-C3)alkyl or -(C3-C7)cycloalkyl, R 10 and R 11 As defined before;

[0097] Wherein, optionally, two groups R 10 and R 11 Together they may form an optionally substituted 3- to 10-membered non-aromatic carbocyclic or heterocyclic ring.

[0098] Preferably, in the compound of formula (I), R 7 and R 8 It's hydrogen.

[0099] Preferably, in the compound of formula (I), R 9 Selected from hydrogen, halogen, -CN, -OR 10 、-NR 10 R 11 , -CF3, -optionally substituted-(C1-C3)alkyl, wherein R 10 and R 11 are the same or different and are each independently selected from hydrogen or -(C1-C3)alkyl,

[0100] Wherein, optionally, two groups R 10 and R 11Together they may form an optionally substituted 3- to 10-membered non-aromatic carbocyclic or heterocyclic ring.

[0101] Preferably, in the compound of formula (I), R 9 It's hydrogen.

[0102] Preferably, in the compounds of formula (I) according to the present invention, only one of G or E is N.

[0103] In a first preferred aspect of formula (I), the present invention provides a compound of formula (II):

[0104]

[0105] Among them, 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 the compound of formula (I),

[0106] and its N-oxide forms, pharmaceutically acceptable salts and solvates, or their optical isomers, racemates, diastereomers, enantiomers or tautomers.

[0107] Preferably, in the compound of formula (II):

[0108] -Ar 1 represents an aryl or heteroaryl group selected from:

[0109]

[0110] in:

[0111] -m is the number of substituents A on the ring, which is an integer equal to 0, 1, 2, 3 or 4,

[0112] -A is the same or different and is each independently selected from hydrogen, halogen, -CN, -CF3, -OH, -NH2, an optionally substituted group, the optionally substituted group being selected from: -(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-OR14 、-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 ;

[0113] -R 13 、R 14 and R 15 each independently selected from hydrogen, optionally substituted -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, heteroaryl, aryl, heterocycle, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-heterocycle and -(C1-C6)alkylene-aryl;

[0114] - wherein, optionally, the substituents on the group A are selected from R 13 、R 14 or R 15 Any two groups of may be taken together to form a 3- to 10-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -NO2, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl)2;

[0115] - wherein any two groups A can be combined with intervening atoms to form a 3- to 10-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl);

[0116] and / or

[0117] -Ar2 represents an aryl or heteroaryl group selected from:

[0118]

[0119] in

[0120] -p is the number of substituents B on the ring, which is an integer equal to 0, 1, 2, 3, 4 or 5,

[0121] -B are the same or different and are each independently selected from hydrogen, halogen, -CN, -CF3, an optionally substituted group, the optionally substituted group being selected from: -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C1-C6)alkylene-heterocycle, -(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 、-(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-R14 、-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)-OR13 、-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 ;

[0122] -R 13 、R 14 and R 15each independently selected from hydrogen, optionally substituted -(C1-C6)haloalkyl, -(C1-C6)alkyl, -(C1-C6)cyanoalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, heteroaryl, aryl, heterocycle, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-heterocycle and -(C1-C6)alkylene-aryl;

[0123] - wherein, optionally, the substituent B is selected from R 13 、R 14 or R 15 Any two groups of may be taken together to form a 3- to 10-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -NO2, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl)2;

[0124] - wherein any two groups B can be combined with intervening atoms to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0125] Preferably, in the compound of formula (II):

[0126] -A is the same or different and is each independently selected from hydrogen, halogen, -CN, -CF3, -OH, an optionally substituted group, the optionally substituted group being selected from: -(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 、-NR13 C(=O)-R 14 、-C(=O)-NR 13 R 14 、S(=O)2NR 13 R 14 or -NR 13 -S(=O)2R 14 ,

[0127] -R 13 、R 14 and R 15 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;

[0128] - wherein, optionally, the group R on the substituent A 13 、R 14 and R 15 Together they may form a 3- to 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl)2;

[0129] - wherein any two groups A may be combined with intervening atoms to form a 3- to 10-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl); and / or

[0130] -B are the same or different and are each independently selected from hydrogen, halogen, -CF3, -CN, an optionally substituted group, the optionally substituted group being selected from: -(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)-R13 、-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 ;

[0131] -R 13 and R 14 each independently selected from hydrogen, optionally substituted -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, heteroaryl, aryl, heterocycle, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-heterocycle and -(C1-C6)alkylene-aryl;

[0132] - wherein, optionally, the substituent B is selected from R 13 and R 14 Any two groups of may be taken together to form a 3- to 10-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl)2;

[0133] - wherein any two groups B may be combined with intervening atoms to form a 3- to 10-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl); and / or

[0134] -Only one of G or E is N.

[0135] In a second preferred aspect of formula (I), the present invention provides a compound of formula (III):

[0136]

[0137] Among them, G, E, Ar 1 、Ar 2 、R 1 、R 2 、R 3 、R 4 and R 9As defined above for the compound of formula (I),

[0138] and its N-oxide forms, pharmaceutically acceptable salts and solvates, or their optical isomers, racemates, diastereomers, enantiomers or tautomers.

[0139] Preferably, in the compound of formula (III),

[0140] -A is the same or different and is each independently selected from hydrogen, halogen, -CN, -CF3, -OH, an optionally substituted group, the optionally substituted group being selected from: -(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 ,

[0141] -R 13 and R 14 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;

[0142] - wherein, optionally, the group R on the substituent A 13 and R 14Together they may form a 3- to 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl)2;

[0143] - wherein any two groups A may be combined with intervening atoms to form a 3- to 10-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl); and / or

[0144] -B are the same or different and are each independently selected from hydrogen, halogen, -CF3, -CN, an optionally substituted group, the optionally substituted group being selected from: -(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 ;

[0145] -R 13 and R 14 each independently selected from hydrogen, optionally substituted -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, heteroaryl, aryl, heterocycle, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-heterocycle and -(C1-C6)alkylene-aryl;

[0146] - wherein, optionally, the substituent B is selected from R 13 and R 14 Any two groups of may be taken together to form a 3- to 10-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl)2;

[0147] - wherein any two groups B may be combined with intervening atoms to form a 3- to 10-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl); and / or

[0148] -Only one of G or E is N.

[0149] Preferably, in the compound of formula (III), G is nitrogen and E is CR 8 , where R 8 As defined above.

[0150] Preferably, in the compound of formula (III), G is nitrogen and E is CH.

[0151] The present invention also relates to the compounds according to the invention as described herein, either as a racemic mixture or as one or both of the individual optical isomers.

[0152] Particularly preferred compounds according to the present invention include the following compounds (list of preferred compounds), as well as their N-oxide forms, their pharmaceutically acceptable salts and solvates, or their optical isomers, racemates, diastereomers, enantiomers or tautomers:

[0153] 6-(2,4-Dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one,

[0154] 6-(3-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0155] 6-(4-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0156] (+)-6-(2,4-Dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one

[0157] (-)-6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one,

[0158] 6-(2,4-dimethylphenyl)-2-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one,

[0159] 2-(4-chloropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0160] 2-(3-chloropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0161] 2-(6-fluoropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0162] 6-(2,4-dimethylphenyl)-2-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0163] 6-(2,4-dimethylphenyl)-2-(4-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0164] 6-(2,4-dimethylphenyl)-2-(3-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0165] 6-(2,4-dimethylphenyl)-2-(6-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0166] 6-(2,4-dimethylphenyl)-2-(5-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0167] 6-(2,4-dimethylphenyl)-2-(4-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0168] 6-(2,4-dimethylphenyl)-2-(3-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0169] 6-(2,4-dimethylphenyl)-2-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0170] 6-(2,4-dimethylphenyl)-2-(5-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0171] 6-(2,4-dimethylphenyl)-2-(4-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0172] 6-(2,4-dimethylphenyl)-2-(3-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0173] 6-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)-2-cyanopyridine,

[0174] 6-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)nicotinonitrile,

[0175] 2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)isonicotinonitrile,

[0176] 2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)nicotinonitrile,

[0177] 6-(2,4-dimethylphenyl)-2-(5-hydroxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0178] 6-(2,4-dimethylphenyl)-2-(4-hydroxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0179] 6-(2,4-dimethylphenyl)-2-(5-(methoxymethyl)pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0180] 6-(2,4-dimethylphenyl)-2-(pyridin-3-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0181] 6-(2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0182] 6-(2,4-dimethylphenyl)-2-(pyrazin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0183] 6-(2,4-dimethylphenyl)-2-(pyrimidin-5-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0184] 6-(2,4-dimethylphenyl)-2-(thiazol-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0185] 6-(2,4-dimethylphenyl)-2-(thiazol-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0186] 6-(2,4-dimethylphenyl)-2-(1-methyl-1H-imidazol-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0187] 6-(2,4-dimethylphenyl)-2-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0188] 6-(2,4-dimethylphenyl)-2-(4,6-dimethylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0189] 2-(4-cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0190] 2-(5-hydroxypyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0191] 2-(5-(Hydroxymethyl)pyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0192] 6-(3-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0193] 6-(3-methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0194] 6-(3-methoxy-2-methylphenyl)-2-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0195] 2-(5-chloropyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0196] 6-(3-methoxy-2-methylphenyl)-2-(5-methoxypyrazin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0197] 2-(5-hydroxypyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0198] 6-(3-methoxy-2-methylphenyl)-2-(4-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0199] 6-(5-methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0200] 6-(5-methoxy-2-methylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0201] 2-(5-chloropyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0202] 6-(2,4-dimethylphenyl)-2-(pyridin-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0203] 2-(5-chloropyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one,

[0204] 6-(2,4-dimethylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0205] 6-(2,4-dimethylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0206] 6-(2,4-dimethylphenyl)-2-(5-fluoropyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0207] 6-(2,4-dimethylphenyl)-2-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0208] 6-(2,4-dimethylphenyl)-2-(4-methoxy-5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0209] 6-(2,4-dimethylphenyl)-2-(5-(morpholinomethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0210] 6-(2-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0211] 6-(3-(dimethylamino)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0212] 6-(3-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0213] 6-(5-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0214] 2-(Pyridin-2-yl)-6-(o-tolyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0215] 6-(3-cyclopropylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0216] 6-(3-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0217] 6-(3-(1-hydroxyethyl)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0218] 6-(3-cyclopropyloxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0219] 6-(2-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0220] 6-(2-methoxy-3-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0221] 6-(1-methylindolin-4-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0222] 6-(2-methoxy-4-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0223] 6-(2-methoxy-3-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0224] 6-(2-chloro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0225] 6-(5-methoxy-2-(trifluoromethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0226] 6-(2-Fluoro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0227] 6-(2-chloro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0228] 6-(2-methoxy-5-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0229] 6-(2-methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0230] 6-(1-methylindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0231] 6-(2-Fluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0232] 6-(5-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0233] 6-(2,5-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0234] 6-(2,3-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0235] 6-(3-(Methoxymethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0236] 6-(5-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0237] 6-(3-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0238] 6-(3-(cyclopentyloxy)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0239] 6-(4-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0240] 6-(1,5-dimethyl-1H-indazol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0241] 6- 2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0242] 6-(2,6-difluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0243] 6-(2-chloro-3-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0244] 6-(1-cyclopropyldihydroindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0245] 6-(3-cyclopropyloxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0246] 6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0247] 6-(2-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0248] 6-(3-(dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0249] 6-(5-methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0250] 6-(4-chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0251] 6-(4-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0252] 6-(3-(3-methoxypropoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0253] 6-(3-ethoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0254] 6-(3-(cyclopropylmethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0255] 6-(3-Isopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0256] 6-(3-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0257] 6-(3-(2-methoxyethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0258] 6-(3-(Benzyloxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0259] 2-(5-cyclopropylpyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0260] 2-(5-cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0261] 2-(5-cyclopropylpyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0262] 2-(5-cyclopropylpyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0263] 6-(3-methoxy-2-methylphenyl)-2-(5-(pyrrolidin-1-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0264] 6-(3-methoxy-2-methylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0265] 6-(2,4-dimethylphenyl)-2-(5-morpholinopyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0266] 6-(2,4-dimethylphenyl)-2-(5-morpholinopyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0267] 6-(2,4-dimethylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0268] 2-(5-(azetidin-1-yl)pyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0269] N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide,

[0270] 6-(3-methoxy-2-methylphenyl)-2-(5-(2-methoxyethoxy)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0271] (2-(5-(2-hydroxyethoxy)-pyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0272] 6-(3-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0273] 6-(2,4-dimethylphenyl)-2-(pyridin-2-yl)-2,5,6,7-tetrahydro-1H-cyclopenta[d]-pyridazin-1-one,

[0274] 7-(2,4-dimethylphenyl)-3-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one,

[0275] 6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0276] 2-(5-cyclopropylpyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0277] 2-(5-bromopyrimidin-2-yl)-6-(3-cyclopropyloxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0278] N-(2-(6-(3-cyclopropyloxy-2-methylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide,

[0279] (-)-6-(3-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0280] (+)-6-(3-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0281] (-)-6-(2-chloro-3-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0282] (+)-6-(2-chloro-3-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0283] (-)-6-(3-cyclopropyloxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0284] (+)-6-(3-cyclopropyloxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0285] (-)-6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0286] (+)-6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0287] (-)-N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide,

[0288] (+)-N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide,

[0289] (+)-6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0290] (-)-6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one.

[0291] 2-(5-bromopyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0292] 2-(5-bromopyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0293] 2-(5-bromopyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0294] 2-(5-bromopyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0295] 2-(5-bromopyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one and

[0296] 2-(5-bromo-4-methoxypyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one.

[0297] The present invention also relates to compounds of the following formulae (IV), (V), (VI), (VII), (VIII) and (IX) as intermediates for compounds of formulae (I), (II) and (III)

[0298]

[0299] Among them, 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 the compounds of formula (I), (II) and (III).

[0300] The disclosed compounds also include all pharmaceutically acceptable isotopic variations in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of suitable isotopes for inclusion in the disclosed compounds include, but are not limited to, isotopes of hydrogen, such as 2 H and 3 H; isotopes of carbon, such as 11 C. 13 C and 14 C; isotopes of nitrogen, such as 15 N; isotopes of oxygen, such as 17 O and 18 O; isotopes of phosphorus, such as 32 P and 33 P; isotopes of sulfur, such as 35 S; isotopes of fluorine, such as 18 F; and isotopes of chlorine, such as 36 Cl. Isotopic variants (e.g. deuterium, 2 The use of H) may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In addition, certain isotopic variations of the disclosed compounds may incorporate radioactive isotopes (e.g., tritium, 3 H or 14 C), which can be used for drug and / or substrate tissue distribution studies. 11 C. 18 F. 15 O and 13N substitution can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I) to (III) are generally useful as radiolabeled tracers for imaging studies and are prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously used.

[0301] If tautomeric forms exist, the name of the tautomeric form depicted in the structure will be generated. However, it will be understood that other tautomeric forms not described are also included within the scope of the present invention.

[0302] Definition of terms

[0303] Listed below are definitions of various terms used to describe the present invention in the specification and claims.

[0304] In the context of the present invention, it is to be understood that the definitions given for the individual substituents in the compounds of formula (I) apply to the corresponding substituents in the compounds of formulae (II) to (III).

[0305] Furthermore, it is to be understood that each definition of a substituent is directly combinable and unambiguous with the definition of another substituent.

[0306] For the avoidance of doubt, it should be understood that in this specification, "(C1-C6)" refers to a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. "(C0-C6)" refers to a carbon group having 0, 1, 2, 3, 4, 5 or 6 carbon atoms.

[0307] In this specification, "C" represents a carbon atom, "N" represents a nitrogen atom, "O" represents an oxygen atom, and "S" represents a sulfur atom.

[0308] In the case where a subscript is the integer 0 (zero), the group to which the subscript refers indicates that the group is not present, ie, there is a direct bond between the groups.

[0309] Where a subscript is the integer 0 (zero) and the group to which the subscript refers is an alkyl group, this means that the group is a hydrogen atom.

[0310] In this specification, unless otherwise indicated, the term "bond" refers to a saturated covalent bond. When two or more bonds are adjacent to each other, they are assumed to be equal to one bond. For example, in the group -VW-, where both V and W can be bonds, the group represents a single bond.

[0311] In this specification, unless otherwise specified, the term "alkyl" includes straight-chain and branched alkyl groups and may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, isohexyl or tert-hexyl. The term "(C0-C3)alkyl" refers to an alkyl group having 0, 1, 2 or 3 carbon atoms and may be methyl, ethyl, n-propyl and isopropyl.

[0312] In this specification, unless otherwise stated, the term "alkylene" includes straight and branched difunctional saturated hydrocarbon groups and may be methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene, isopentylene, tert-pentylene, neopentylene, n-hexylene, isohexylene or tert-hexylene.

[0313] In this specification, unless otherwise indicated, the term "cycloalkyl" refers to an optionally substituted carbocyclic ring containing no heteroatoms, including mono-, bi-, and tricyclic unsaturated carbocyclic rings. Cycloalkyl groups include fused ring systems and spiro-fused ring systems. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, fluorenyl, and 1,2,3,4-tetrahydronaphthalene. The term "(C3-C7)cycloalkyl" may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0314] In this specification, unless otherwise indicated, the term "cycloalkenyl" refers to an optionally substituted carbocyclic ring containing no heteroatoms, including mono-, bi- and tricyclic unsaturated carbocyclic rings. The term "(C2-C6)cycloalkenyl" refers to a cycloalkyl group having 2 to 6 carbon atoms and one or two double bonds, and may be, but is not limited to, cyclopentenyl and cyclohexenyl.

[0315] In this specification, unless otherwise specified, the term "alkenyl" includes straight-chain and branched alkenyl groups. The term "(C2-C6)alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms and one or two double bonds, and may be, but is not limited to, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, crotyl, pentenyl, isopentenyl, and hexenyl.

[0316] In this specification, unless otherwise specified, the term "alkenylene" includes straight-chain and branched disubstituted alkenyl groups. The term "(C2-C6)alkenylene" refers to an alkenylene group having 2 to 6 carbon atoms and one or two double bonds, and may be, but is not limited to, vinylene, allylene, propenylene, isopropenylene, butenylene, isobutenylene, butenylene, pentenylene, isopentenylene, and hexenylene.

[0317] In this specification, unless otherwise specified, the term "alkynyl" includes straight and branched chain alkynyl groups. The term (C2-C6)alkynyl has 2-6 carbon atoms and one or two triple bonds, and can be, but is not limited to, ethynyl, propargyl, butynyl, pentynyl and hexynyl.

[0318] In this specification, unless otherwise specified, the term "alkynylene" includes straight-chain and branched disubstituted alkynylene. The term (C2-C6)alkynylene has 2 to 6 carbon atoms and one or two triple bonds, and may be, but is not limited to, ethynylene, propynylene, butynylene, pentynylene, isopentenylene, and hexynylene.

[0319] 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" are, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indolyl, indenyl, and the like.

[0320] In the present specification, unless otherwise stated, the term "heteroaryl" refers to an optionally substituted 5- to 10-membered monocyclic or bicyclic unsaturated aromatic ring system containing at least one heteroatom independently selected from N, O or S. Preferably, the heteroaryl group contains 1 to 3 heteroatoms, preferably selected from N, O or S. Examples of "heteroaryl" can be, but are not limited to, thienyl, pyridyl, thiazolyl, isothiazolyl, furanyl, pyrrolyl, triazolyl, imidazolyl, triazinyl, oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolinyl, oxazolonyl, thiazolonyl, tetrazolyl, thiadiazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, tetrahydrotriazolopyridinyl, tetrahydrotriazolopyrimidinyl, benzofuranyl, , benzothiophenyl, thionaphthyl, indolyl, isoindolyl, pyridonyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, imidazopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl, cynnolyl, pteridinyl, furazanyl, benzotriazolyl, pyrazolopyridinyl and purinyl.

[0321] In this specification, unless otherwise indicated, the terms "alkylene-aryl", "alkylene-heteroaryl" and "alkylene-cycloalkyl" refer to substituents attached to an aryl, heteroaryl or cycloalkyl group, respectively, through an alkyl group. The term "(C1-C6)alkylene-aryl" includes aryl-(C1-C6)-alkyl groups such as benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylmethyl and 2-naphthylmethyl. The term "(C1-C6)alkylene-heteroaryl" includes heteroaryl-(C1-C6)-alkyl, wherein examples of heteroaryl are the same as those described 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-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 1-quinolylmethyl, etc. The term "-(C1-C6)alkylene-(C3-C7)cycloalkyl" includes -(C3-C7)-cycloalkyl-(C1-C6)-alkyl, wherein examples of cycloalkyl are the same as those described in the above definition, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, etc.

[0322] In this specification, unless otherwise indicated, the term "carbocycle" refers to an optionally substituted 5- to 10-membered monocyclic, bicyclic or tricyclic saturated or partially saturated ring system and fused ring system containing no heteroatoms. Such fused ring systems may include a partially or fully unsaturated ring, such as a benzene ring, to form a fused ring system, such as a benzo-fused carbocycle.

[0323] In this specification, unless otherwise stated, the term "heterocycle" refers to an optionally substituted 5- to 10-membered monocyclic or bicyclic saturated or partially saturated ring system containing at least one heteroatom independently selected from N, O and S. Preferably, the heterocycle contains 1 to 3 heteroatoms, preferably selected from N, O or S.

[0324] In this specification, unless otherwise indicated, 5- or 6-membered rings containing one or more atoms independently selected from C, N, O and S include aromatic and heteroaromatic rings, as well as carbocyclic and heterocyclic rings, which may be saturated or unsaturated. Examples of these rings may be, but are not limited to, furyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazolidinyl, pyrazolinyl, triazolyl, morpholinyl, piperazinyl, piperidinyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinoneyl, thiomorpholinyl, oxadiazolyl, thiadiazolyl, tetrazolyl, phenyl, cyclohexyl, cyclopentyl, cyclohexenyl and cyclopentenyl.

[0325] In this specification, unless otherwise stated, 3- to 10-membered rings containing one or more atoms independently selected from C, N, O and S include aromatic and heteroaromatic rings, as well as carbocyclic and heterocyclic rings, which may be saturated or unsaturated. Examples of such rings can be, but are not limited to, imidazolidinyl, pyrazolinyl, morpholinyl, piperazinyl, piperidinyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, tetrahydrothiopyranyl, furanyl, pyrrolyl, dihydropyrrolyl, isoxazolyl, isothiazolyl, isoindolinonyl, dihydropyrrolo[1,2-b]pyrazolyl, oxazolyl, oxazolidinonyl, pyrazinyl, pyrazolyl, 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.

[0326] In this specification, unless stated otherwise, the term "halo" or "halogen" may be fluoro, chloro, bromo or iodo.

[0327] In this specification, unless otherwise indicated, the term "haloalkyl" refers to an alkyl group as defined above that is substituted with one or more halogen groups. The term "(C1-C6)haloalkyl" may include, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, etc.

[0328] In this specification, unless stated otherwise, the term "cyanoalkyl" refers to an alkyl group as defined above substituted by one or more cyano (CN) groups.

[0329] In the present specification, unless otherwise specified, the term "optionally substituted" refers to a group further carrying one or more substituents, which may be (C1-C6) alkyl, hydroxy (-OH), (C1-C6) alkylene-OR, wherein R is H or (C1-C6) alkyl, mercapto (-SH), aryl, heteroaryl, heterocycle, (C1-C6) alkylene-aryl, (C1-C6) alkylene-heterocycle, (C1-C6) alkylene-(C3-C7) cycloalkyl, (C1-C6) alkylene-heteroaryl, halogen, trifluoroalkyl (preferably trifluoromethyl), trifluoroalkoxy (preferably trifluoromethoxy), cyano (CN), cyanoalkyl (preferably cyanomethyl), nitro (NO2), amino (NH2), carboxyl (CO2H), formamide (CONH2), carbamate (NH-C(=O)OR (wherein R is (C1-C6) alkyl), sulfonamide (S(=O)2-NH2), ester of formula C(O)OR (wherein R is (C1-C6) alkyl) and sulfonyl (S(=O)-R) (wherein R is (C1-C6) alkyl) group.

[0330] As used herein, the expression "pharmaceutically acceptable" refers to those compounds, materials, excipients, compositions or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problematic complications, and are commensurate with a reasonable benefit / risk ratio.

[0331] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by preparing an acid or base salt thereof. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, these conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, including their mono-, di-, or tri-salts; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid, glucuronic acid, glutamic acid, benzoic acid, salicylic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, lactic acid, and the like. Other addition salts include ammonium salts such as tromethamine, meglumine, epolamine, and the like, and metal salts such as sodium, potassium, calcium, zinc, or magnesium.

[0332] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing alkaline or acidic moieties by conventional chemical methods. Typically, these salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water or in an organic solvent or in a mixture of the two. Typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts is found in Remington's Pharmaceutical Sciences, 20th edition, Mack Publishing Company, Easton, PA, 2000, the disclosure of which is incorporated herein by reference.

[0333] As used herein, "pharmaceutically acceptable solvates" refer to derivatives of the disclosed compounds in which the parent compound is modified by preparing its solvate. In this specification, unless otherwise indicated, 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 includes solid forms of compounds of Formula (I) in the form of any solvate, including, for example, solvates with water, such as hydrates, or solvates with organic solvents such as methanol, ethanol, or acetonitrile, referred to as methanolates, ethanolates, or acetonitrile, respectively; or any polymorphic form. The solvent may not interfere with the biological activity of the solute.

[0334] The pharmaceutically acceptable prodrugs that can be used for the compounds of the present invention, particularly compounds of formula (I) are derivatives with chemical or metabolic cleavable groups, and are transformed into compounds for use in the present invention that are pharmaceutically active in vivo by solvolysis or under physiological conditions. Prodrugs that can be used for the compounds of the present invention can be formed in a conventional manner with functional groups such as amino, hydroxyl or carboxyl groups of the compounds. Prodrug derivative forms generally provide advantages 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 the parent acidic compound with a suitable alcohol, or amides prepared by reacting the parent acidic compound with a suitable amine. When the compound used in the present invention, particularly compounds of formula (I) have a carboxyl group, ester derivatives prepared by reacting the carboxyl group with a suitable alcohol or amide derivatives prepared by reacting the carboxyl group with a suitable amine can be exemplified as prodrugs. Particularly preferred ester derivatives as prodrugs are methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl. When the compound used in the present invention has a hydroxyl group, an acyloxy derivative prepared by reacting the hydroxyl group with a suitable acyl halide or a suitable acid anhydride is exemplified as a prodrug. When the compound used in the present invention has an amino group, an amide derivative prepared by reacting the amino group with a suitable acyl halide or a suitable mixed acid anhydride is exemplified as a prodrug.

[0335] Formula (I) compound or its pharmaceutically acceptable salt, solvate or prodrug can be used as compound itself or can be formulated into medicine and be administered. Within the scope of the present invention is to comprise one or more formula (I) compounds or its pharmaceutically acceptable salt, solvate or prodrug as pharmaceutical composition of active ingredient. Pharmaceutical composition can optionally comprise one or more pharmaceutically acceptable excipients, such as carrier, diluent, filler, disintegrant, lubricant, adhesive, colorant, pigment, stabilizer, preservative or antioxidant.

[0336] The pharmaceutical composition may also include one or more solubilizing agents, such as poly(ethylene glycol), including poly(ethylene glycol) having a molecular weight of about 200 to about 5,000 Da, ethylene glycol, propylene glycol, nonionic surfactants, tyloxapol, polysorbate 80, polyethylene glycol-15-hydroxystearate, phospholipids, lecithin, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, cyclodextrin, hydroxyethyl-3-cyclodextrin, hydroxypropyl-3-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dihydroxypropyl -3-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-3-cyclodextrin, diglucosyl-3-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-3-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-3-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-3-cyclodextrin, methyl-3-cyclodextrin, carboxyalkyl sulfide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

[0337] In this specification, unless otherwise indicated, certain compounds may exist in one or more specific geometric, optical, enantiomeric, diastereomeric, epimeric, stereoisomeric, tautomeric, conformational or anomeric forms, including but 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- and enolate- forms; α- and β- forms; axial and equatorial forms; and combinations thereof, collectively referred to as "isomers" or "isomeric forms."

[0338] Note that the term "isomer" specifically includes compounds having one or more isotopic substitutions. For example, H may be in any isotopic form, including but not limited to 1 H. 2 H(D) and 3 H(T); C can be in any isotopic form, including but not limited to 11 C. 12 C. 13 C. 14 C; O can be in any isotopic form, including but not limited to 16 O and 18 O; etc. F may be in any isotopic form, including but not limited to 19 F and 18 F; etc.

[0339] The present invention also relates to a composition, preferably a pharmaceutical composition, comprising at least one compound according to the invention. Preferably, the compound according to the invention is contained in the composition in a therapeutically effective amount.

[0340] "Therapeutically effective amount" refers to an amount of a compound / drug according to the present invention that is effective in preventing or treating a pathological condition.

[0341] A therapeutically effective amount can be readily determined by an attending diagnostician (e.g., one skilled in the art) using routine techniques and observing results obtained under similar circumstances. In determining a therapeutically effective amount, the attending diagnostician considers many factors, including, but not limited to: the species of the subject; its size, age, and general health; the specific disease involved; the extent or severity of the disease; the response of the individual subject; the specific compound being administered; the mode of administration; the bioavailability characteristics of the administered formulation; the dosage regimen selected; the use of concomitant medications; and other relevant circumstances.

[0342] The composition may further comprise a pharmaceutically acceptable excipient. The carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0343] "Pharmaceutically" or "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered to an animal or a human, as appropriate.

[0344] As used herein, "pharmaceutically acceptable excipient" includes any carrier, diluent, adjuvant, or vehicle, such as preservatives or antioxidants, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Any conventional media or agents that are incompatible with the active ingredient are contemplated for use in therapeutic compositions. Supplementary active ingredients may also be incorporated into the compositions as appropriate therapeutic combinations.

[0345] The composition may be in various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemic or local administration.

[0346] The pharmaceutical compositions of the present invention can be prepared by any method known in the pharmaceutical field, for example, using methods such as those described in Remington's Pharmaceutical Sciences (18th edition, Mack Publishing Company, 1990, see in particular Section 8: Pharmaceutical preparations and their Manufacture) by people such as Gennaro. In order to prepare the pharmaceutical compositions of the present invention, a therapeutically effective amount of a particular compound as an active ingredient, optionally in the form of a salt, is combined in the form of an intimate mixture with a pharmaceutically acceptable carrier or diluent, which can take a variety of forms depending on the form of the formulation required for administration. These pharmaceutical compositions are ideally in unit dosage form, particularly suitable for oral, topical, rectal or transdermal administration, by parenteral injection, by administration through the middle ear or inner ear, or by inhalation.

[0347] It is particularly advantageous to formulate the pharmaceutical compositions described above into unit dosage forms for ease of administration and uniformity of dosage. As used herein, unit dosage forms refer to physically discrete units suitable for use as unit doses, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect, together with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions, etc., teaspoonfuls, tablespoonfuls, and isolated polyploids thereof.

[0348] Since the compound of the present invention is an orally administrable compound, a pharmaceutical composition for oral administration comprising the compound is particularly advantageous.

[0349] In order to improve the solubility and / or stability of the compounds of the present invention in pharmaceutical compositions, it may be advantageous to use α-, β- or γ-cyclodextrin or derivatives thereof, particularly hydroxyalkyl-substituted cyclodextrins, such as 2-hydroxypropyl-cyclodextrin or sulfobutyl-cyclodextrin. In addition, cosolvents such as alcohols may improve the solubility and / or stability of the compounds of the present invention in pharmaceutical compositions.

[0350] The present invention also relates to a process for preparing the pharmaceutical composition of the present invention, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound of the present invention.

[0351] The present invention relates to the use of the above compounds as medicines.

[0352] The present invention also relates to the use of the compound of the present invention or the composition of the present invention for preparing a medicine or a drug.

[0353] The present inventors surprisingly found that the above compounds are modulators of mGluR receptors, preferably antagonists of mGluR7, more preferably antagonists of mGluR7.

[0354] Therefore, the present invention relates to a compound according to the invention or a composition according to the invention for use in modulating, preferably reducing or inhibiting or downregulating the activity of mGluR receptors, in particular mGluR7.

[0355] The present invention also relates to the use of the compound or composition of the present invention for the preparation of a medicament for modulating, preferably reducing or inhibiting or negatively modulating the activity of mGluR receptors, in particular mGluR7.

[0356] The present invention also relates to a method of modulating, preferably reducing or inhibiting or downregulating the activity of mGluR receptors, in particular mGluR7, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a composition of the present invention.

[0357] According to the present invention, the term "patient" or "patient in need thereof" refers to an animal or human being suffering from or at risk of suffering from a pathological condition involving active cysteine ​​proteases in its pathogenesis. Preferably, the patient is a human.

[0358] The identification of those subjects in need of treatment for the diseases and conditions described herein is well within the ability and knowledge of those skilled in the art. A veterinarian or physician in the art can readily identify those subjects in need of such treatment using clinical trials, physical examinations, medical / family history, or biological and diagnostic tests.

[0359] The present invention further relates to a compound according to the invention or a composition according to the invention for use in the treatment of diseases which are associated with glutamate dysfunction.

[0360] The present invention also relates to use of the compound or composition of the present invention in preparing a medicament for treating diseases associated with glutamate dysfunction.

[0361] In particular, the present invention therefore also relates to a compound according to the invention or a composition according to the invention for use in preventing or treating disorders associated with glutamate dysfunction in mammals, including humans.

[0362] The present invention also relates to a method for treating diseases associated with glutamate dysfunction, which method comprises administering a therapeutically effective amount of a compound according to the present invention or a composition according to the present invention to a patient in need thereof.

[0363] As used herein, the term "treatment" refers to all procedures which may slow, interrupt, arrest or stop the progression of a disease or alleviate symptoms, but does not necessarily mean complete elimination of all symptoms.

[0364] The present invention also relates to a compound of the present invention or a composition of the present invention for use in preventing or treating anxiety disorders, such as agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), social phobia, other phobias; mood disorders, including bipolar disorder (I & II), cyclothymic disorder, depression, dysthymic disorder, major depressive disorder, substance-induced mood disorders, mood disorders due to general medical conditions, mania, manic-depressive disorder, seasonal affective disorder; muscle spasticity and disorders associated with muscle spasticity, including tremor, epilepsy, convulsions, migraine; selected from the group consisting of disorders selected from the group consisting of: a degenerative disorder such as mild cognitive impairment, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis; a disorder selected from the group consisting of psychotic disorders such as schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder; personality disorders including obsessive-compulsive personality disorder, schizotypal personality disorder, schizotypal disorder, borderline personality disorder, anxious-avoidant personality disorder; childhood disorders including attention-deficit / hyperactivity disorder, mental retardation, Down syndrome, tic disorder, autism spectrum disorder (e.g., Rett syndrome or fragile X syndrome), and autism; ear disorders including including inner ear diseases, disorders, injuries 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, hidden hearing loss, cisplatin-induced hearing loss, aminoglycoside-induced hearing loss, otitis media, ototoxicity, autoimmune inner ear diseases, acute tinnitus, chronic tinnitus, central auditory processing disorders and vestibular disorders; gastrointestinal disorders, including diarrhea, constipation, gastroesophageal reflux disease (GERD), lower esophageal sphincter disease or disorder, gastrointestinal motility disorders, colitis, Crohn's disease or irritable bowel syndrome (IBS); pain Conditions, including acute pain, chronic pain, severe pain, intractable pain, inflammatory pain, postoperative pain, headache, cancer pain, neuropathic pain, post-traumatic pain, and visceral pain; cognitive deficits and mood disorders associated with the above disorders and conditions; ocular disorders, including ocular hypertension, glaucoma, normal-tension glaucoma, neurodegenerative disease conditions of the retina and optic nerve, retinal dystrophies, age-related macular degeneration, and ocular conditions such as conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, inflammation, and / or neurodegeneration; disorders caused by traumatic brain injury, stroke, hemorrhagic stroke, ischemia, spinal cord injury, cerebral hypoxia, cerebral hemorrhage, or intracranial hematoma.

[0365] In particular, the present invention relates to compounds of the present invention or compositions of the present invention for use in preventing or treating 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 (PTSD); mood disorders, including but not limited to major depressive disorder, depression and treatment-resistant depression, mania, bipolar disorder; amnesia and other cognitive disorders; disorders that are typically 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 psychotic disorders; somatoform disorders; sleep disorders; disorders associated with muscle spasms and spasticity, including tremors, epilepsy, convulsions, migraines and traumatic brain injury.

[0366] In particular, the present invention relates to a compound of the present invention or a composition of the present invention for use in preventing or treating certain neurodegenerative disorders or diseases, such as mild cognitive impairment, dementia, Alzheimer's disease and Parkinson's disease.

[0367] In particular, the present invention relates to a compound of the present invention or a composition of the present invention for use in preventing or treating certain pain conditions or diseases, such as acute pain, chronic pain, neuropathic pain, post-traumatic pain and visceral pain.

[0368] In particular, the present invention relates to a compound of the present invention or a composition of the present invention for use in preventing or treating ear disorders, including 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.

[0369] The present invention also relates to the use of a compound according to the invention or a composition according to the invention for preventing or treating anxiety disorders, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, depression, bipolar disorder, schizophrenia, autism spectrum disorders, ear diseases and pain.

[0370] All of the above diseases are considered to be diseases associated with glutamate dysfunction according to the present invention.

[0371] As already mentioned above, the term "treatment" does not necessarily mean the complete elimination or prevention of all symptoms, but can also refer to the symptomatic treatment or preventive intervention of any of the above-mentioned conditions. In particular, the symptoms that can be treated or prevented include, but are not limited to, cognitive deficits, fearful behavior, hypervigilance, aggressive behavior, hearing impairment, pain, in particular anxiety disorders, acute stress disorder, chronic stress disorder, post-traumatic stress disorder, schizophrenia, ear diseases and pain disorders.

[0372] Those skilled in the art will recognize that alternative nomenclatures, nosologies, and classification systems exist for the disorders described herein and that these evolve with medical and scientific progress.

[0373] The present invention further relates to the use of the compounds according to the invention as radiolabeled tracers for imaging metabotropic glutamate receptors, preferably mGluR7, in mammals including humans.

[0374] The present invention also relates to compounds according to the general formula (I), (II), (III) or their stereoisomeric forms or their N-oxides or their pharmaceutically acceptable salts or solvates, in particular compounds of the formula (I), (II), (III) or their stereoisomeric forms or their pharmaceutically acceptable salts or solvates, or pharmaceutical compositions according to the invention, for use in the treatment or prevention, in particular of disorders in mammals including humans, the treatment or prevention of which is influenced or promoted by the neuromodulatory effects of the compounds according to the invention on mGluR, in particular mGluR7.

[0375] The present invention also relates to compounds of formula (I), which are used for treating, preventing, improving, controlling or reducing the risk of various neurological and psychiatric disorders associated with glutamate dysfunction in humans, wherein the treatment or prevention of said diseases is affected or promoted by the neuromodulatory effect of the compounds of the present invention on mGluR receptors, especially mGluR7.

[0376] The present invention also relates to a method for treating or preventing, in particular treating, disorders in mammals including humans, the treatment or prevention of which is influenced or promoted by the neuromodulatory effect of the compounds of the present invention on mGluR, in particular mGluR7, comprising administering to a human in need thereof a therapeutically effective amount of a compound of the general formula (I), (II), (III) or its stereoisomeric form or its N-oxide or its pharmaceutically acceptable salt or solvate, in particular a compound of the formula (I), (II), (III) or its stereoisomeric form or its pharmaceutically acceptable salt or solvate, or a pharmaceutical composition according to the present invention.

[0377] The present invention also relates to methods for treating, preventing, ameliorating, controlling or reducing the risk of various neurological and psychiatric disorders in humans associated with glutamate dysfunction, the treatment or prevention of which is affected or facilitated by the neuromodulatory effects of the compounds of the present invention (especially compounds according to formula (I)) on mGluR receptors, especially mGluR7.

[0378] The present invention also relates to compounds according to formula (I), (II), (III), or stereoisomeric forms thereof, or N-oxides thereof, or pharmaceutically acceptable salts or solvates thereof, in particular compounds according to formula (I), (II), (III) or stereoisomeric forms thereof, or pharmaceutically acceptable salts or solvates thereof, for use in the treatment or prevention, in particular the treatment of any of the diseases mentioned above.

[0379] The present invention also relates to the use of compounds according to formula (I), (II), (III) or their stereoisomeric forms or their N-oxides or their pharmaceutically acceptable salts or solvates, in particular the use of compounds according to formula (I), (II), (III) or their stereoisomeric forms or their pharmaceutically acceptable salts or solvates in the preparation of medicaments or pharmaceutical products for the treatment or prevention, in particular the treatment, of any of the diseases mentioned above.

[0380] 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.

[0381] Therefore, the present invention also relates to a method for preventing and / or treating any of the diseases mentioned above, which comprises administering a therapeutically effective amount of a compound according to the present invention to a patient in need thereof.

[0382] Those skilled in the art will recognize that a therapeutically effective amount of a compound of the invention is an amount sufficient to modulate, inhibit or reduce mGluR activity, particularly mGluR7 activity, and that this amount will vary depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient. Generally, the amount of compound administered as a therapeutic agent for the disease in which modulation, inhibition or reduction of mGluR activity, preferably mGluR7 activity, is beneficial will be determined by the attending physician on a case-by-case basis.

[0383] Typically, a suitable dosage is one that results in a compound concentration in the range of 0.5nM to 200μM, more typically 5nM to 50μM. In order to obtain these therapeutic concentrations, patients in need of treatment may be administered an effective therapeutic daily dose of about 0.01mg / kg to about 50mg / kg body weight, preferably about 0.01mg / kg to about 25mg / kg body weight, more preferably about 0.01mg / kg to about 10mg / kg body weight, more preferably about 0.01mg / kg to about 2.5mg / kg body weight, even more preferably about 0.05mg / kg to about 1mg / kg body weight, more preferably about 0.1 to about 0.5mg / kg body weight. The amount of the compound according to the present invention (also referred to herein as active ingredient) required for achieving the therapeutic effect will of course vary based on each case, with specific compound, route of administration, recipient's age and condition, and the specific illness or disease being treated. Therapeutic methods can also include administering the active ingredient in a regimen of one to four intakes per day. In these therapeutic methods, the compound of the present invention is preferably prepared before admission. As described below, suitable pharmaceutical preparations are prepared by known methods using well-known and readily available ingredients.

[0384] Combination therapy

[0385] The compound of the present invention can be used in combination with one or more other drugs for treating, preventing, controlling, improving the above-mentioned diseases or conditions to which the compound of the present invention or other drugs may be useful, or reducing the above-mentioned diseases or conditions risk, wherein the combination of drugs together is safer or more effective than any one drug alone. In another aspect, the present invention relates to combination therapy, wherein the active compound of the present invention is administered together with another active compound. This combination can be a fixed dose combination (the active ingredients to be combined are the subject of the same pharmaceutical preparation) or a free dose combination (the active ingredient is in a separate pharmaceutical preparation). Therefore, another aspect of the present invention relates to each active compound of the present invention, preferably at least one active compound of the present invention, in combination with another active compound, wherein the other active compound regulates a receptor or enzyme in a manner that increases the efficacy and / or safety of the active compound of the present invention and / or reduces undesirable side effects. The different drugs of this combination or product can be combined in a single formulation together with a pharmaceutically acceptable carrier or diluent, or they can each be present in a separate formulation together with a pharmaceutically acceptable carrier or diluent.

[0386] Because modulators of mGluRs, preferably mGluR7, including compounds of the present invention, modulate the response of mGluRs, preferably mGluR7, to endogenous glutamate and / or mGluR7 agonists and / or Group III agonists, it will be understood that the present invention extends to the treatment of diseases associated with glutamate dysfunction by administering an effective amount of a mGluR7 modulator, including compounds of the present invention, in combination with an mGluR7 agonist and / or Group III mGluR agonist.

[0387] The compounds of the present invention may also be used in combination with psychotherapy to treat, prevent, control, ameliorate, or reduce the risk of a disease or condition for which the compounds of the present invention may have utility.

[0388] The present invention also relates to a pharmaceutical composition according to the invention, further comprising another compound that modulates the activity of a mGluR, preferably a compound that inhibits or reduces the activity of a mGluR, preferably the mGluR is mGluR7.

[0389] The present invention also relates to a kit comprising:

[0390] at least one compound according to the invention or a pharmaceutical composition comprising at least one compound according to the invention; and

[0391] at least one further compound that modulates, preferably inhibits or reduces the activity of a mGluR, preferably the mGluR is mGluR7, or a pharmaceutical composition comprising at least one compound that modulates, preferably inhibits or reduces the activity of a mGluR, preferably the mGluR is mGluR7.

[0392] dose

[0393] As is well known to those skilled in the art, the precise dosage (or therapeutically effective amount as referred to herein) and frequency of administration will depend on the specific compound of the invention used, the specific condition being treated, the severity of the condition being treated, the age, weight, sex, extent of the condition and general physical condition of the specific patient, and other medications that the individual may be taking. Furthermore, it will be apparent that the effective daily dose may be lowered or increased depending on the response of the subject being treated and / or on the evaluation of the physician prescribing the compounds of the invention.

[0394] Depending on the mode of administration, the pharmaceutical composition will contain 0.05 to 99% by weight, preferably 0.1 to 70% by weight, more preferably 0.1 to 50% by weight of the active ingredient, and 1 to 99.95% by weight, preferably 30 to 99.9% by weight, more preferably 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

[0395] The amount of the compound of the present invention that can be combined with the carrier material to produce a single dosage form will vary depending on the disease being treated, the mammalian species, and the specific mode of administration. However, as a general guide, a suitable unit dose of the compound of the present invention may, for example, preferably contain 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.

[0396] Such a unit dose may be administered more than once per day, for example 2, 3, 4, 5 or 6 times per day, but preferably 1 or 2 times per day, so that the total dose for a 70 kg adult is in the range of 0.001 to about 15 mg per kg of subject body weight per administration. A preferred dose is 0.01 to about 1.5 mg per kg of subject body weight per administration, and such treatment may be extended for several weeks or months, and in some cases, for several years. However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors, including the activity of the specific compound used; the age, weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have been previously administered; and the severity of the specific disease being treated, as is well known to those skilled in the art.

[0397] A typical dosage may be a 1 mg to about 100 mg tablet, or 1 mg to about 300 mg, taken once a day or multiple times a day, or a single-release capsule or tablet taken once a day and containing a proportionally higher amount of the active ingredient. Extended release may be achieved by capsule materials that dissolve at different pH values, by capsule or gel formulations that release slowly by osmotic pressure, or by any other known controlled release method.

[0398] In some cases, it may be necessary to use dosages outside of these ranges, as will be apparent to those skilled in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to initiate, interrupt, adjust or terminate treatment in conjunction with individual patient response.

[0399] Preparation of compounds

[0400] A. Synthesis Method

[0401] Compounds of the present invention, particularly compounds of formula (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 processes. In all processes described below, it should be understood that, according to the general principles of organic chemistry, protecting groups for sensitive or reactive groups may be used when necessary. Protecting groups are operated according to standard methods (TW Green and PGM Wuts, 1991, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc.). These groups are then removed at a convenient stage of the synthesis using methods readily apparent to those skilled in the art.

[0402] The compounds of the present invention may be expressed as mixtures of enantiomers, which can be resolved into their respective R- or S-enantiomers. For example, if a specific enantiomer is desired, it can be obtained by separation from the racemic mixture using chiral chromatographic techniques, or prepared by asymmetric synthesis or by derivatization with a chiral auxiliary and separation of the resulting diastereomeric mixture. The auxiliary group can then be cleaved to obtain the desired pure enantiomer. Alternatively, when the molecule contains a basic functional group such as an amino functional group or an acidic functional group such as a carboxyl functional group, it can be resolved by fractional crystallization from various solvents as an optically active acid salt or by other methods known in the literature.

[0403] Resolution of final products, intermediates or starting materials can be carried out by any suitable method known in the art (ELE Liel, SH Wilen and LN Mander, 1984, Stereochemistry of Organic Compounds, Wiley-Interscience).

[0404] Among them, Ar 1 or Ar 2 Many heterocyclic compounds of formulae (I) to (III) that are heteroaryl or heterocyclic can be prepared using synthetic routes well known in the art (AR Katrizky and CR Rees, 1984, Comprehensive Heterocyclic Chemistry, Pergamon Press).

[0405] The synthesis of mGluR modulators disclosed in the present invention has been prepared using the following synthetic schemes. The specific conditions for implementing these reactions are provided in the Examples. The synthetic schemes described below show exemplary methods for the compounds of this invention, but these approaches should not be considered as the only possible synthetic routes for the compounds of this invention.

[0406] Compounds of formula (I) to (III) can be converted into their pure enantiomeric forms (+) and (-) using, for example, chiral separation.

[0407] where R 9 Compounds of formula (I), (II) and (III) wherein H is hydrogen can be obtained according to the following Scheme 1:

[0408]

[0409] Cyclic ketone intermediate 1 is commercially available or can be synthesized by one skilled in the art of organic chemistry using a variety of methods described in the literature.

[0410] The secondary alcohol intermediate 2 can be synthesized by organometallic Ar 2 -M reagents (M = Li or MgX) which can be obtained, for example, by metal-halide exchange from the corresponding appropriately substituted aromatic ring using, for example, nBuLi or iPrMgCl, under an inert atmosphere such as, for example, nitrogen, at a controlled temperature such as, for example, -78°C in an aprotic solvent such as, for example, dry THF (step i).

[0411] Intermediate 2 can be further dehydrated under acidic conditions, such as neat TFA or in the presence of DCM, at room temperature or under reflux to form intermediate 3 (step ii).

[0412] Cycloalkenyl ketone intermediate 3 can be converted to the corresponding cycloalkyl ketone intermediate 4 by hydrogenolysis using catalytic palladium such as Pd / C under a hydrogen atmosphere at a pressure of, for example, 50 psi at, for example, 30° C. (step iii).

[0413] Ketone intermediate 4 can be further reacted with POCl3 in the presence of DMF to give chlorocarbonyl intermediate 5 (step iv), which is subjected to carbonylation coupling reaction using a CO-releasing reagent 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, or using a combination of a catalyst such as Pd(OAc)2 and a ligand such as dppf, in a solvent such as MeOH at a suitable temperature to give lactone intermediate 6 (step v).

[0414] According to Method A in Scheme 1, intermediate 6 can be reacted with an aryl or heteroaryl hydrazine Ar 1 -NH2-NH2 (which can be commercially available or prepared by one skilled in the art of organic chemistry) is reacted in the presence of a catalyst such as PTSA and a solvent such as toluene or EtOH at a suitable temperature (step ix) to give the final compounds of formula (I), (II) and (III), wherein Y is CH, R 4 、R 8 and R 9 It's hydrogen.

[0415] Alternatively, according to method B in Scheme 1, intermediate 6 can be reacted with hydrazine NH2NH2 under acidic conditions using AcOH in the presence of a solvent such as EtOH, or using PTSA in the presence of a solvent such as toluene at an appropriate temperature (step vii) to give intermediate 7. Intermediate 7 is reacted with (hetero)aromatic halide Ar 1 -X (preferably Ar 1 -Br) in the presence of a catalyst / ligand system such as Pd2(dba)3 / Xantphos, a base such as t-BuOK, in a solvent such as toluene, or a copper-mediated coupling reaction using CuI, a ligand such as DMEDA or in 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 at a suitable temperature (step viii) to give the final compounds of formula (I), (II) and (III), wherein Y is CH, and R 4 、R 8 and R 9 It's hydrogen.

[0416] Alternatively, intermediate 7 can be prepared using a boronic acid or ester Ar 1 -B(OR')2, in the presence of a catalyst such as Cu(OAc)2, a base such as pyridine, in a solvent such as CH2Cl2, at a suitable temperature, a Chan-Lam coupling reaction (step ix) is carried out to give the final compounds of formula (I), (II) and (III), wherein Y is CH, and R 4 、R 8 and R 9 It's hydrogen.

[0417] Alternatively, according to method C in Scheme 1, lactone intermediate 6 can be converted to ester intermediate 8 by alkylation using aqueous NaOH followed by a halo-alkyl reagent such as ethyl iodide in the presence of DMF at a suitable temperature (step x). Intermediate 8 can then be processed in a 1- or 2-step sequence according to step xi, followed by steps viii or ix, or according to step xii, as described in methods A and B to provide the final compounds of formula (I), (II) and (III), wherein Y is CH and R 4 and R 8 It's hydrogen.

[0418] where R 9 Compounds of formula (I), (II) and (III) where H is hydrogen can also be obtained according to the following Scheme 2:

[0419]

[0420] Cyclic ketone-acetal intermediate 9 can be reacted with POCl3 in the presence of DMF to give chlorocarbonyl intermediate 10 (step i). Intermediate 10 is subjected to a carbonylation coupling reaction using a CO-releasing reagent 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, or a combination of a catalyst such as Pd(OAc)2 and a ligand such as dppf, in a solvent such as MeOH at a suitable temperature to give ester-aldehyde intermediate 11 (step ii). Intermediate 12 can be obtained by reacting intermediate 11 with hydrazine NH2NH2 under acidic conditions using AcOH in the presence of a solvent such as EtOH, or using PTSA in the presence of a solvent such as toluene at a suitable temperature (step iii), followed by reaction with an aromatic halide Ar 1 -X (preferably Ar 1 -Br), in the presence of a catalyst / ligand system such as Pd2(dba)3 / Xantphos, a base such as t-BuOK, in a solvent such as toluene, or a copper-mediated coupling reaction using CuI, a ligand such as DMEDA or in 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 at a suitable temperature (step iv).

[0421] Alternatively, intermediate 11 can be reacted with an arylhydrazine Ar 1 -NH2-NH2 (which can be commercially available or prepared by one skilled in the art of organic chemistry) reacts in the presence of a catalyst such as PTSA and a solvent such as toluene or EtOH at a suitable temperature to directly give intermediate 13 (step v).

[0422] Intermediate 13 can be treated with TFA or aqueous HCl under acidic conditions in the presence of solvents such as acetonitrile or DCM at an appropriate temperature to provide intermediate 14 (step vi). Ketone intermediate 14 can be reacted with Tf2O in the presence of a base such as Et3N and a solvent such as DCM at an appropriate temperature to provide the key triflate intermediate 15 (step vii).

[0423] According to Method A in Scheme 2, intermediate 15 can be prepared using a boronate ester Ar 1 -B(OR')2 or boric acid Ar 1 Suzuki cross-coupling of -B(OH)2 in the presence of a catalyst / ligand system such as Pd(PPh3)4, a base such as Na2CO3 or K2CO3, in a solvent such as THF or a dioxane / H2O mixture at a suitable temperature affords intermediate 16 (step viii).

[0424] Alternatively, according to method B in Scheme 2, intermediate 15 can be reacted with a bispinacol-diborane ester in the presence of a base such as Na2CO3 or K2CO3 and a catalytic system such as Pd(dppf)Cl2 in a solvent such as dioxane at a suitable temperature to give intermediate 17 (step x). Intermediate 17 can be reacted with an aromatic halide Ar 2 -X (preferably Ar 2 -Br), in the presence of a catalyst / ligand system such as Pd(dppf)Cl2, a base such as Na2CO3, in a solvent such as dioxane-H2O, at a suitable temperature to give intermediate 16 (step xi).

[0425] Finally, reduction of the cyclic double bond in intermediate 16 can be carried out by hydrogenolysis, for example using palladium hydroxide in the presence of ammonium formate in a solvent such as EtOH at a suitable temperature to afford the final compounds of formula (I), (II) and (III), wherein YCH, and R 2 and R 8 is hydrogen (step ix).

[0426] Compounds of formula (I), (II) and (III) can also be obtained according to the following Scheme 3:

[0427]

[0428] Cyclic enone intermediate 18 is commercially available or can be synthesized by one skilled in the art of organic chemistry using a variety of methods described in the literature. 1 -B(OR')2 or boric acid Ar 1 -B(OH)2, in the presence of a catalyst / ligand system such as Rh(COD)Cl2, a base such as KOH, in a solvent such as dioxane / H2O, at a suitable temperature and inert atmosphere, a cross-coupling reaction can be carried out to give intermediate 19 (step i). Ketone intermediate 19 can be reacted with POCl3 in the presence of DMF to give intermediate 20 (step ii), which can be further subjected to a carbonylation 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 give ester-aldehyde intermediate 21 (step iii). Intermediate 21 can be reacted with a (hetero)arylhydrazine Ar 1 -NH2-NH2 (which can be commercially available or prepared by one skilled in the art of organic chemistry) is reacted in the presence of a catalyst such as PTSA and a solvent such as toluene or EtOH at a suitable temperature (step iv) to give the final compounds of formula (I), (II) and (III), wherein Y is CH and R 2 、R8 and R 9 It's hydrogen.

[0429] where R 9 Compounds of formula (I), (II) and (III) where R is hydrogen can also be obtained according to the following Scheme 4:

[0430]

[0431] Cycloalkylene ketone intermediates 18 can be commercially available or synthesized by one skilled in the art of organic chemistry using a variety of methods described in the literature. Intermediate 18 is reacted 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 at a suitable temperature (step i). 2 -X (preferably Ar 2 -Br or Ar 2 -I) Cross-coupling reaction can produce intermediate 31.

[0432] The cycloalkenyl ketone intermediate 31 can be converted to the corresponding keto-ester intermediate 34 via 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, for example, −78° C.; followed by (step iii) double bond hydrogenolysis using catalytic palladium such as Pd / C under a hydrogen atmosphere at a pressure such as 50 psi at an appropriate temperature.

[0433] This two-step sequence can be reversed, starting with a hydrogenolysis step (iii) followed by an α-carboxylation step (ii) using the conditions described above to provide the ketoester intermediate 34.

[0434] Ketoester intermediate 34 can be reacted with formamidine in the presence of a base such as K 2 CO 3 and a solvent such as EtOH at a suitable temperature to give intermediate 35 (step iv).

[0435] Intermediate 35 can be subjected to the cross-coupling reaction described in Scheme 1, for example, with an aromatic halide Ar in the presence of a catalyst / ligand system such as Pd2(dba)3 / Xantphos, a base such as t-BuOK, in a solvent such as toluene. 1 -X (preferably Ar 1 -Br) reaction, or copper-mediated coupling reaction (step v) using CuI, ligands such as DMEDA or in 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 at a suitable temperature to obtain the final compounds of formula (I), (II) and (III), wherein R 2、R 7 and R 9 It's hydrogen.

[0436] Ar 2 Any compound of formula (I), (II) or (III) substituted with an OR group can be obtained according to the following Scheme 5:

[0437]

[0438] The compounds of formula (I), (II) and (III) represented by intermediate 49, wherein Ar 2 The substituent B on the hydroxyl group is a methoxy group and can be reacted with a dealkylating agent such as boron tribromide in a solvent such as DCM at a suitable temperature (step I) to give the hydroxyl intermediate 50. The hydroxyl function can then be reacted with an alkylating agent such as an alkyl halide (e.g., R 2 -I, R 2 -Br or R 2 -Cl) in the presence of a base such as Cs2CO3, in a solvent such as DMF, at an appropriate temperature (step II) to give compounds of formula (I), (II) and (III), wherein Ar 2 Substituted with an oxo group.

[0439] Among them, Ar 1 Any compound of formula (I), (II) and (III) substituted with an alkyl, aryl, heteroaryl, amino or alkoxy group can be obtained according to the following Scheme 6:

[0440]

[0441] Intermediate 51 represented by but not limited to intermediate 7 in Scheme 1 or intermediate 35 in Scheme 4 can be prepared using the formula A-Ar 1 -X, in the presence of a catalyst / ligand system (e.g., Pd2(dba)3 / Xantphos), a base (e.g., t-BuOK), in a solvent (e.g., toluene), at a suitable temperature, a cross-coupling reaction is carried out to give intermediate 51 (step i). According to method A, intermediate 52, wherein A is a halogen group Cl, Br, or I, can be further reacted with a boronic acid or a boronate ester in the presence of a catalyst / ligand system such as Pd(dppf)Cl2 or RuPhos, a base such as KOAc or Cs2CO3, in a solvent such as dioxane or dioxane-H2O, at a suitable temperature (step II) to give compounds of formula (I), (II), and (III), wherein Ar 1 With an alkyl, aryl or heteroaryl group.

[0442] According to Method B, similar halide intermediates 52 (where A is a halogen group) can be reacted with amines R 1 R2 NH is reacted in the presence or absence of a catalyst / ligand system such as Pd(dppf)Cl2 or RuPhos, a base such as Na2CO3 or Cs2CO, in a solvent such as dioxane at a suitable temperature (step III) to give compounds of formula (I), (II) and (III), wherein Ar 1 With amino group.

[0443] Alternatively, according to method C, intermediate 52, wherein A is a -OH group, can be reacted with an alkyl halide (such as RI, R-Br or R-Cl) in the presence of a base such as Cs2CO3 in a solvent such as DMF at an appropriate temperature (step iv) to give compounds of formula (I), (II) and (III), wherein Ar 1 With alkoxy group.

[0444] Alternatively, where Ar 2 Compounds of formula (I), (II) and (III) having a carbonyl group can be obtained according to the following scheme 7:

[0445]

[0446] Intermediates 53 wherein X is Br can be cross-coupled using tributyltinethoxyvinyl in the presence of a catalyst / ligand system (e.g., Pd(PPh3)4, a base (e.g., t-BuOK) in a solvent (e.g., dioxane) at an appropriate temperature, followed by hydrolysis in an acidic medium such as aqueous HCl in a solvent such as EtOH to afford intermediates 54. Reduction of the cyclic double bond in intermediates 54 can be achieved by hydrogenolysis using, for example, palladium on carbon in the presence of ammonium formate in a solvent such as EtOH at an appropriate temperature (step ii) to afford the final compounds of formula (I), (II), and (III) wherein Y is CH, Ar 2 With acetyl group.

[0447] B. Experiment

[0448] Several methods for preparing the compounds of the present invention are described in the following examples. Unless otherwise indicated, all raw materials are obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification.

[0449]

[0450]

[0451] Unless otherwise stated, all temperatures are expressed in °C (degrees Celsius). Unless otherwise stated, all reactions were carried out at room temperature without inert atmosphere.

[0452] 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.

[0453]

[0454] Intermediate 2a: 8-(2,4-dimethyl-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol

[0455] According to process 1, step i: n-BuLi (2.5M, 45.39mL, 1.05 equivalents) was added dropwise to a solution of 1-bromo-2,4-dimethyl-benzene (20.00g, 108.07mmol, 1.00 equivalents) in THF (100mL) under N2 atmosphere and cooled to -70°C. The reaction mixture was stirred at -70°C for 2 hours. A solution of 1,4-dioxa-spiro[4.5]decane-8-one (17.72g, 113.47mmol, 1.05 equivalents) in THF (100mL) was then added dropwise at -70°C, and the reaction mixture was stirred at -70°C for 2 hours. The reaction mixture was quenched with water (300mL) and extracted with EtOAc (200mLx2). The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by flash column chromatography on silica gel (PE:EtOAc 10 / 1 to 5 / 1) to afford Intermediate 2a (24.00 g, 86.00 mmol, 79.57% yield) as a light yellow solid.

[0456] 1 H NMR (DMSO-d6; 400MHz) δ7.31-7.29(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).

[0457] Intermediate 3a: 4-(2,4-dimethyl-phenyl)-cyclohex-3-enone

[0458] According to process 1, step ii: the solution of intermediate 2a (10.00g, 38.12mmol, 1.00 equivalent) in TFA (500.00mL) was stirred at 15 ℃ for 1 hour, then the mixed solution was stirred, and heated to 80 ℃ for 18 hours. The mixed solution was concentrated under vacuum. The residue was quenched with saturated NaHCO solution, and the pH was adjusted to pH 7-8, extracted with EtOAc (200mLx2). The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE:EtOAc 10 / 1 to 5 / 1). Intermediate 3a (11.00g, 54.92mmol, 72.04% yield) was obtained as a light yellow oil. 1 HNMR (CDCl3; 400MHz) δ7.06-6.97(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).

[0459] Intermediate 4a: 4-(2,4-dimethylphenyl)cyclohexan-1-one

[0460] According to process 1, step iii: under N2 atmosphere, to the solution of intermediate 3a (10.00g, 49.93mmol, 1.00 equivalent) in EtOAc (100.00mL), add Pd / C (2.00g, 49.93mmol, 1.00 equivalent). The suspension is degassed under vacuum and purified several times with H2. The mixed solution is stirred at 30°C for 4 hours under H2 (50psi). The mixed solution is filtered, and the filtrate is concentrated under vacuum. Obtain crude product intermediate 4a (10.00g, 49.43mmol, 99.01% yield), and directly used in the next step as a brown solid. 1 H NMR (CDCl3; 400MHz) δ7.12-7.02(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).

[0461] Intermediate 5a: 2-chloro-5-(2,4-dimethyl-phenyl)-cyclohex-1-enecarbaldehyde

[0462] According to process 1, step iv: at 0 ℃ under N2 atmosphere to intermediate 4a (13.01g, 177.96mmol, 12.00 equivalents) in CH2Cl2 (10mL) in solution was added dropwise POCl3 (6.82g, 44.49mmol, 3.00 equivalents). After stirring at 10 ℃ for 1 hour, a solution of intermediate 1c (3.00g, 14.83mmol, 1.00 equivalents) in CH2Cl2 (40mL) was added dropwise. The mixed solution was stirred at 50 ℃ for 4 hours. The mixed solution was quenched with saturated NaHCO3 solution, and the pH was adjusted to pH 7-8, extracted with CH2Cl2 (150mLx2). The organic layer was dried over Na2SO4 and concentrated under vacuum. 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. 1 H NMR (400MHz, CDCl3) δ10.25 (s, 1H), 7.09-6.95 (m, 3H), 3.03-2.73 (m, 4H), 2.32 (d, J = 2.6Hz, 6H), 2.23-2.06 (m, 1H), 2.05-1.90 (m, 2H).

[0463] Intermediate 6a: 5-(2,4-dimethylphenyl)-3-methoxy-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

[0464] According to Scheme 1, step v: Under N2 atmosphere, intermediate 5a (500.00 mg, 2.01 mmol, 1.00 equiv), Pd(dppf)Cl2 (147.08 mg, 201.01 μmol, 0.10 equiv), Et3N (610.19 mg, 6.03 mmol, 3.00 equiv) in MeOH (10.00 mL) were added. The suspension was degassed under vacuum and purged with CO2 several times. The mixture was stirred at 90 ° C under a CO2 atmosphere (1 MPa) for 12 hours. The mixture was filtered and the filtrate was concentrated under vacuum. Intermediate 6a (650.00 mg, crude product) was obtained as a brown solid. 1 H NMR: (400MHz, CDCl3) δ7.09-6.98(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).

[0465] Example 1: 6-(2,4-Dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one

[0466] According to process 1, method A, step vi: a mixture of intermediate 6a (200.00 mg, 734.38 μmol, 1.00 equivalent) and pyridine-2-yl-hydrazine hydrochloride (160.28 mg, 1.47 mmol, 2.00 equivalent) in toluene (10.00 mL) was stirred and heated to 110 ° C for 8 hours. The mixture was concentrated under vacuum. The residue was dissolved in EtOAc (100 mL) and water (100 mL) and extracted with EtOAc (100 mLx2). The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative-HPLC to obtain Example 1 (30.00 mg, 90.52 μmol, 6.16% yield) as a brown solid. 1 H-NMR (400MHz, CDCl3) δ8.67(d,J=4.0Hz,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=17.6Hz,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).

[0467] 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.

[0468]

[0469] Intermediate 6b: 3-methoxy-5-(3-methoxyphenyl)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

[0470] According to Scheme 1, steps i to v: Intermediate 6b was prepared similarly to Intermediate 6a in Example 1 starting from 1-bromo-3-methoxybenzene to give a brown liquid in an overall yield of 19%. m / z (M+H) + =275.1.

[0471] Example 2: 6-(3-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0472] According to Scheme 1, Method A, Step vi: Example 2 was prepared starting from Intermediate 6b (800.00 mg, 832.35 μmol) and pyridin-2-yl-hydrazine hydrochloride (181.77 mg, 1.25 mmol) as in Example 1 to give Example 2 (8.20 mg, 24.60 μmol) as a yellow solid. ( 1 H-NMR(400MHz,MeOD)δ8.62-8.61(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).

[0473] 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.

[0474]

[0475] Intermediate 6c: 3-methoxy-5-(4-methoxyphenyl)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

[0476] According to Scheme 1, steps i to v: Intermediate 6c was prepared starting from 1-bromo-4-methoxybenzene similarly to Intermediate 6a in Example 1 to give a brown liquid in an overall yield of 14%. 1 H NMR (MeOD; 400MHz) δ7.22-7.20(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).

[0477] Example 3: 6-(4-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0478] According to Scheme 1, Method A, Step vi: Example 3 was prepared starting from Intermediate 6c (200.00 mg, 693.63 μmol) and pyridin-2-yl-hydrazine hydrochloride (201.97 mg, 1.39 mmol) as in Example 1 to give Example 3 (26.00 mg, 77.99 μmol) as a green solid. ( 1 H-NMR (400MHz, DMSO-d6) δ8.61-8.60(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).

[0479] 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

[0480]

[0481] The enantiomers constituting racemic Example 1 (400 mg) were separated by preparative SFC to afford (-)6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one, Example 4 (72 mg, 18%) with an enantiomeric excess of 100%, and (+)6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one, Example 5 (59 mg, 15%) with an enantiomeric excess of 99%, both as yellow solids.

[0482] Embodiment 4: 1 H-NMR(400MHz, CDCl3)δ8.67(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 = 17.6Hz, 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).

[0483] Example 5:1 H-NMR(400MHz, CDCl3)δ8.67(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 = 17.6Hz, 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).

[0484] 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 and Method B.

[0485]

[0486] Intermediate 7a: 6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0487] 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.H2O (427.66 mg, 8.37 mmol, 415.20 μL, 2.0 eq). The mixture was stirred at 80°C for 3 hours and then cooled to 0°C. The resulting white solid was collected and filtered. Intermediate 7a (830 mg, 3.26 mmol, 77.96% yield) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ12.74(s,1H),7.64(s,1H),7.15-7.08(m,1H),7.03-6.93(m,2H),3.09-2.93(m,1 H),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).

[0488] Example 6: 6-(2,4-dimethylphenyl)-2-(6-chloropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0489] According to Scheme 1, step viii: To a solution of intermediate 7a (100.00 mg, 353.87 μmol, 1.00 equiv) in DMF (5.00 mL) was added 5-chloro-2-bromopyridine (204.30 mg, 1.06 mmol, 3.00 equiv), DMEDA (18.72 mg, 212.32 μmol, 22.82 μL, 0.60 equiv), CuI (33.70 mg, 176.94 μmol, 0.50 equiv), and K 3 PO 4 (187.79 mg, 884.68 μmol, 2.50 equiv) at 20° C. under N 2 atmosphere. The mixture was then heated to 110° C. and stirred for 12 hours. The reaction mixture was filtered, and the filtrate was acidified to pH=5 with 12 M HCl aqueous solution and filtered. The filtrate was purified by preparative-HPLC to afford Example 6 (71.93 mg, 196.61 μmol, 55.56% yield) as a beige solid. 1 H-NMR (400MHz, CDCl3) δ8.62 (d, J = 2.3Hz, 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).

[0490] 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 and Method B.

[0491]

[0492] 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 obtain Example 7 (178.10 mg, 484.85 μmol, 91.34% yield) as a brown solid. 1H-NMR (400MHz, CDCl3) δ8.49(d,J=5.4Hz,1H),7.75(d,J=1.6Hz,1H),7.66(s,1H),7.29(dd,J=1.8,5.3Hz,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).

[0493] 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 and Method B.

[0494]

[0495] 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 obtain Example 8 (24.40 mg, 66.69 μmol, 9.42% yield) as a beige solid. 1 H-NMR (400MHz, CDCl3) δ8.58 (dd, J=1.6, 4.7Hz, 1H), 7.95 (dd, J=1.5, 8.0Hz, 1H), 7.7 2(s,1H),7.44(dd,J=4.6,8.0Hz,1H),7.16-7.11(m,1H),7.10-7.04(m,2H),3.17(br s,1H),3.02(br d,J=19.6Hz,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).

[0496] 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 and Method B.

[0497]

[0498] According to Scheme 1, step viii: Example 9 was prepared starting from intermediate 7a (70.00 mg, 275.23 μmol) and 2-bromo-6-fluoropyridine (145.31 mg, 825.69 μmol) according to Example 6 to give Example 9 (32.00 mg, 91.59 μmol, 33% yield) as a yellow solid. ( 1 H-NMR (400MHz, DMSO-d6) δ8.23-8.21(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).

[0499] 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 and Method B.

[0500]

[0501] According to Scheme 1, step viii: Example 10 was prepared starting from intermediate 7a (70.00 mg, 275.23 μmol) and 2-bromo-5-fluoropyridine (145.31 mg, 825.69 μmol) according to Example 6 to give Example 10 (32.00 mg, 91.59 μmol, 23% yield) as a yellow solid. ( 1 H-NMR (400MHz, DMSO-d6) δ8.62-8.61(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).

[0502] 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 and Method B.

[0503]

[0504] 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 obtain Example 11 (24.00 mg, 68.69 μmol, 29% yield) as a yellow solid. 1 H-NMR(400MHz,DMSO-d6)δ8.66(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).

[0505] 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 and Method B.

[0506]

[0507] 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 obtain Example 12 (15.00 mg, 42.93 μmol, 12% yield) as a yellow solid. 1 H-NMR(400MHz,DMSO-d6)δ8.50-8.48(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).

[0508] 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 and Method B.

[0509]

[0510] 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 obtain Example 13 (45.00 mg, 124.50 μmol, 45% yield) as a yellow solid. 1 H-NMR(400MHz,DMSO-d6)δ7.93-7.84(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).

[0511] 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 and Method B.

[0512]

[0513] 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 obtain Example 14 (30.00 mg, 83.00 μmol, 30.16% yield) as a yellow solid. 1 H-NMR(400MHz,DMSO-d6)δ8.28-8.27(m,1H),7.82(s,1H),7.60-7.59(m,1H),7.58-7.57(m,1H),7.16-7.13(m,1H),7.02-7.0 0(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).

[0514] 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 and Method B.

[0515]

[0516] 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 obtain Example 15 (53.00 mg, 146.64 μmol, 53% yield) as a yellow solid. 1 H-NMR(400MHz,DMSO-d6)δ8.41-8.39(m,1H),7.83(s,1H),7.16-7.10(m,3H),7.02-7.00(m,1H),3.89(s,3 H),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).

[0517] 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 and Method B.

[0518]

[0519] 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 obtain Example 16 (17.00 mg, 47.03 μmol, 13% yield) as a yellow solid. 1 H-NMR(400MHz,DMSO-d6)δ8.15-8.13(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).

[0520] 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 and Method B.

[0521]

[0522] 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 obtain Example 17 (59.06 mg, 170.97 μmol, 60.39% yield) as a beige solid. 1 H-NMR (400MHz, CDCl3) δ7.81-7.69(m,2H),7.45(d,J=7.9Hz,1H),7.24(d,J=7.7Hz,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).

[0523] 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 and Method B.

[0524]

[0525] 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 obtain Example 18 (52.33 mg, 151.49 μmol, 53.51% yield) as a beige solid. 1 H-NMR (400MHz, CDCl3) δ8.49 (d, J = 1.5Hz, 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).

[0526] Example 19: 6-(2,4-dimethylphenyl)-2-(4-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 1, Method B

[0527]

[0528] 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 obtain Example 19 (69.51 mg, 201.22 μmol, 71.08% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ8.53(d,J=5.1Hz,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).

[0529] 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 and Method B.

[0530]

[0531] 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 obtain Example 20 (8.60 mg, 24.75 μmol, 8.74% yield) as a beige solid. 1H-NMR (400MHz, CDCl3) δ8.55-8.44(m,1H),7.74(d,J=6.7Hz,1H),7.71(s,1H ),7.36(dd,J=4.8,7.7Hz,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).

[0532] Example 21: 6-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)-2-cyanopyridine was prepared according to Scheme 1 and Method B.

[0533]

[0534] 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-bromo-2-cyanopyridine (155.43 mg, 849.30 μmol) to obtain Example 21 (53.43 mg, 146.31 μmol, 51.68% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ8.05-7.99(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=5.3,19.1Hz,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).

[0535] Example 22: 6-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)nicotinonitrile was prepared according to Scheme 1 and Method B.

[0536]

[0537] 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 give Example 22 (21.19 mg, 59.45 μmol, 21.00% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ8.86 (s, 1H), 8.03 (d, J = 2.3Hz, 1H), 7.98-7.91 (m, 1H), 7.73-7.67 (m, 1H), 6.98 (d, J = 17.4Hz, 3H), 3.13-3.0 1(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).

[0538] Example 23: 2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)isonicotinonitrile was prepared according to Scheme 1 and Method B.

[0539]

[0540] 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 give Example 23 (28.72 mg, 80.58 μmol, 28.46% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ8.85(d,J=4.4Hz,1H),8.13(s,1H),7.78(s,1H),7.59(dd,J=1.3,5.0Hz,1H),7.16-7.03(m,3H),3.22-3.1 2(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).

[0541] Example 24: 2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)nicotinonitrile, prepared according to Scheme 1, Method B.

[0542]

[0543] 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 give Example 24 (8.80 mg, 24.69 μmol, 8.72% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ8.88(d,J=5.0Hz,1H),8.20(d,J=7.9Hz,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).

[0544] 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 and Method B.

[0545]

[0546] 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 obtain Example 25 (42.10 mg, 115.12 μmol, 32.53% yield) as an off-white solid. 1 H-NMR (400MHz, CDCl3) δ8.74(s,1H),8.24(dd,J=1.8,4.8Hz,1H),7.87(dd,J=1.6,7.8Hz,1H),7.19(dd,J=4.8,7.8Hz,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).

[0547] Example 26: 6-(2,4-dimethylphenyl)-2-(4-hydroxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0548]

[0549] To a solution of compound Example 15 (200.00 mg, 553.34 μmol, 1.00 equiv) in CHCl (5.00 mL) was added BBr (693.11 mg, 2.77 mmol, 266.58 μL, 5.00 equiv). 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, 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. 1 H-NMR (400MHz, DMSO-d6) δ8.26(brd,J=4.5Hz,1H),7.81(s,1H),7.15(br d,J=7.9Hz,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).

[0550] 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 and Method B.

[0551]

[0552] 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 obtain Example 27 (56.21 mg, 149.71 μmol, 42.31% yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ8.74(s,1H),8.24(dd,J=1.8,4.8Hz,1H),7.87(dd,J=1.6,7.8Hz,1H),7.19(dd,J=4.8,7.8Hz,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).

[0553] Example 28: 6-(2,4-dimethylphenyl)-2-(pyridin-3-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1 and Method B.

[0554]

[0555] 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 obtain Example 28 (32.83 mg, 99.06 μmol, 34.99% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ9.04-8.91(m,1H),8.63(br s,1H),8.09(br d,J=8.3Hz,1H),7.73(d,J=1.9Hz,1H),7.44(br s,1H),7.18-7.01(m,3H),3.16(br s,1H),3.02(br d,J=19.2Hz,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=13.1Hz,1H),1.91(br d,J=11.8Hz,1H).

[0556] Example 29: 6-(2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 1, Method B.

[0557]

[0558] According to Scheme 1, step viii: Example 29 was prepared starting from intermediate 7a (780 mg, 3.07 mmol) and 2-bromopyrimidine (585.11 mg, 3.68 mmol) according to Example 6 to give Example 29 (383.35 mg, 1.12 mmol, 36.48% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ8.95(d,J=4.9Hz,2H),7.71(s,1H),7.44(t,J=4.8Hz,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=5.8,13.5Hz,1H),1.95-1.83(m,1H).

[0559] Example 30: 6-(2,4-dimethylphenyl)-2-(pyrazin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 1, Method B.

[0560]

[0561] 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 obtain Example 30 (48.17 mg, 144.92 μmol, 51.19% yield) as a beige solid. 1 H-NMR (400MHz, CDCl3) δ9.05 (d, J = 1.1Hz, 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).

[0562] Example 31: 6-(2,4-dimethylphenyl)-2-(pyrimidin-5-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 1, Method B.

[0563]

[0564] 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 obtain Example 31 (24.80 mg, 74.61 μmol, 26.35% yield) as a brown solid. 1 H-NMR (400MHz, CDCl3) δ9.23(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).

[0565] Example 32: 6-(2,4-dimethylphenyl)-2-(thiazol-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 1, Method B

[0566]

[0567] 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 obtain Example 32 (12.00 mg, 34.51 μmol, 8.76% yield) as a yellow solid. 1 H-NMR(400MHz, CDCl3)δ1.84-1.96(m,1H)2.12-2.21(m,1H)2.33(s,3H)2.36(s,3H)2.66-2.81(m,2H)2.82-2.92(m,1H)3.07(br dd,J=19.89,5.08Hz,1H)3.12-3.20(m,1H)7.05(br d,J=5.77Hz,2H)7.07-7.12(m,1H)7.30(d,J=3.39Hz,1H)7.81(d,J=3.39Hz,1H)7.90(s,1H).

[0568] Example 33: 6-(2,4-dimethylphenyl)-2-(thiazol-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 1 and Method B.

[0569]

[0570] According to Scheme 1, step viii: Example 33 was prepared according to Example 6 starting from intermediate 7a (80.00 mg, 314.55 umol) and 4-bromothiazole (77.39 mg, 471.83 μmol, 42.52 μL) to obtain Example 33 (8.00 mg, 23.44 μmol, 7.45% yield) as an off-white solid. 1 H-NMR (400MHz, CDCl3) δ7.89 (s, 1H), 7.65 (s, 2H), 7.14 (d, J = 8.4Hz, 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).

[0571] 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 and Method B.

[0572]

[0573] 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-imidazolide (113.95 mg, 707.74 μmol) to obtain Example 34 (10.61 mg, 31.72 μmol, 8.97% yield) as a white solid. 1 H-NMR (400MHz, MeOD) δ7.89 (s, 1H), 7.65 (s, 2H), 7.14 (d, J = 8.4Hz, 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)

[0574] 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 and Method B.

[0575]

[0576] 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 obtain Example 35 (0.118 g, 323.05 μmol, 41.08% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ8.60 (s, 1H), 7.74 (s, 1H), 7.15-7.00 (m, 3H), 6.87 (d, J = 5.6Hz, 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).

[0577] 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 and Method B.

[0578]

[0579] 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 obtain Example 36 (0.034 g, 89.61 μmol, 11.40% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ7.69(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).

[0580] 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 and Method B.

[0581]

[0582] 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 obtain Example 37 (0.029 g, 77.86 μmol, 9.90% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ8.64(d,J=4.4Hz,1H),7.65(s,1H),7.18(d,J=4.8Hz,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).

[0583] 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 and Method B.

[0584]

[0585] Intermediate 6d: 3-methoxy-5-(3-methoxy-2-methylphenyl)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

[0586] According to Scheme 1, steps i to v: Intermediate 6d was prepared similarly to Intermediate 6a in Example 1 starting from 1-bromo-3-methoxy-2-methylbenzene and obtained as a brown liquid in an overall yield of 15%. m / z (M+H) + =289.1.

[0587] Intermediate 7b: 6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0588] According to Scheme 1, step vii: Intermediate 7b was prepared similarly to Intermediate 7a in Example 6 starting from Intermediate 6d (21.30 g, 73.87 mmol) to give Intermediate 7b (15.30 g, 56.60 mmol, 76.62% yield) as a white solid. 1 HNMR(400MHz,DMSO-d6)δ12.76(br s,1H),7.65(s,1H),7.10-7.18(m,1H),6.84(t,J=8.72Hz,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=4.89,11.84Hz,1H).

[0589] Example 38: 2-(5-hydroxypyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0590] 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 obtain Example 38 (72.80 mg, 200.12 μmol, 36.07% yield) as a white solid. 1 H-NMR(400MHz,DMSO-d6)δ10.40(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=7.65Hz,1H),6.85(d,J=8.16Hz,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).

[0591] 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.

[0592]

[0593] 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 obtain Example 39 (81.97 mg, 216.96 μmol, 39.10% yield) as a white solid. 1 H-NMR (400MHz, DMSO-d6) δ8.52(d,J=1.63Hz,1H),7.92(dd,J=2.20,8.09Hz,1H),7.84(s,1H),7.52(d,J=8.16Hz,1H),7.18(t,J=7.97Hz,1H),6.89( d,J=7.78Hz,1H),6.85(d,J=8.16Hz,1H),5.45(t,J=5.71Hz,1H),4.62(d, J=5.52Hz,2H),3.78(s,3H),3.12-3.22(m,1H),2.64-2.86(m,3H),2.55(br d,J=9.66Hz,1H),2.18(s,3H),1.94(br s,1H),1.78-1.89(m,1H).

[0594] 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.

[0595]

[0596] 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 obtain Example 40 (45.56 mg, 128.81 μmol, 23.21% yield) as a brown solid. 1 H-NMR (400MHz, DMSO-d6) δ9.02(d,J=4.89Hz,2H),7.85(s,1H),7.71(t,J=4.89Hz,1H),7.14-7.21(m,1H),6. 87(dd,J=7.97,17.63Hz,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=10.04Hz,1H),2.18(s,3H),1.94(br s,1H),1.78-1.91(m,1H).

[0597] 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 and Method B.

[0598]

[0599] 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 obtain Example 41 (75.16 mg, 206.05 μmol, 37.13% yield) as a white solid. 1 H-NMR(400MHz,DMSO-d6)δ8.84(s,2H),7.83(s,1H),7.14-7.23(m,1H),6.87(dd,J=7.91,16.69Hz,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).

[0600] 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.

[0601]

[0602] 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 obtain Example 42 (97.29 mg, 256.84 μmol, 46.29% yield) as a red solid. 1H-NMR (400MHz, DMSO-d6) δ8.69(d,J=5.77Hz,1H),7.83(s,1H),7.18(t,J=7.97Hz,1H),7.13(d,J=5.90Hz,1H),6.89 (d,J=7.65Hz,1H),6.85(d,J=8.16Hz,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=9.41Hz,1H),2.18(s,3H),1.94(br s,1H),1.78-1.90(m,1H).

[0603] 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 and Method B.

[0604]

[0605] 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 obtain Example 43 (98.84 mg, 257.92 μmol, 46.48% yield) as a white solid. 1 H-NMR (400MHz, DMSO-d6)) δ9.16(s,2H),7.87(s,1H),7.15-7.20(m,1H),6.89(d,J=7.65Hz,1H),6.85(d,J=8.03Hz,1H),3.78(s,3 H),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).

[0606] 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 and Method B.

[0607]

[0608] 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 obtain Example 44 (111.11 mg, 290.09 μmol, 52.28% yield) as a white solid. 1 H-NMR (400MHz, DMSO-d6) δ8.47(d,J=1.25Hz,1H),8.35(d,J=1.25Hz,1H),7.89(s,1H),7.14-7.22(m,1H),6.89(d ,J=7.65Hz,1H),6.85(d,J=8.16Hz,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=9.41Hz,1H),2.18(s,3H),1.94(br s,1H),1.78-1.89(m,1H).

[0609] 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 and Method B.

[0610]

[0611] 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 obtain Example 45 (520 mg, 1.43 mmol, 85.72% yield) as a brown solid. 1 H-NMR (400MHz, DMSO-d6) δ8.43 (s, 2H), 7.79 (s, 1H), 7.14-7.21 (m, 1H), 6.89 (d, J = 7.78Hz, 1H), 6.85 (d, J = 8. 28Hz,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).

[0612] 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.

[0613]

[0614] 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 obtain Example 46 (32.49 mg, 74.12 μmol, 28.62% yield) as an off-white solid. 1 H-NMR(400MHz,DMSO-d6)δ8.35(d,J=6.15Hz,1H),7.77(s,1H),7.15-7.21(m,1H),6.96 (d,J=6.27Hz,1H),6.89(d,J=7.78Hz,1H),6.85(d,J=8.16Hz,1H),3.79(s,3H),3.67(br d,J=5.02Hz,4H),3.62(br d,J=4.77Hz,4H),3.17(brt,J=8.97Hz,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, 11.90Hz, 1H).

[0615] 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 and Method B.

[0616]

[0617] Intermediate 6e: 3-methoxy-5-(5-methoxy-2-methylphenyl)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

[0618] According to Scheme 1 steps i to v: Intermediate 6e was prepared analogously to intermediate 6a in Example 1 starting from 2-bromo-4-methoxy-1-methylbenzene and obtained in 9.3% overall yield as a yellow solid. 1 H NMR: (CDCl3, 400MHz) δ7.02 (d, J = 8.4Hz, 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).

[0619] Intermediate 7c: 6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0620] According to Scheme 1, step vii: Intermediate 7c was prepared similarly to intermediate 7a in Example 6 starting from intermediate 6e (1.30 g, 4.51 mmol) to give intermediate 7c (0.4 g, 1.48 mmol, 32.82% yield) as a white solid. 1 HNMR: (CDCl3, 400MHz) δ7.55 (s, 1H), 7.09 (d, J = 8.0Hz, 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).

[0621] Example 47: 6-(5-methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one

[0622] 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 obtain Example 47 (0.005 g, 13.80 μmol, 3.73% yield) as a yellow solid. 1 H-NMR(400MHz, CDCl3)δ8.75(s,2H),7.70(s,1H),7.12(br d,J=8.4Hz,1H),6.77(s,1H),6.72(m,d,J=8.4Hz,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).

[0623] 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.

[0624]

[0625] 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 obtain Example 48 (0.003 g, 7.93 μmol, 2.14% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ8.46 (s, 2H), 7.59 (s, 1H), 7.04 (d, J = 8.4Hz, 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).

[0626] 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 and Method B.

[0627]

[0628] 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 obtain Example 49 (0.011 g, 28.73 μmol, 7.77% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ8.85(s,2H),7.69(s,1H),7.12(d,J=8.4Hz,1H),6.76(s,1H),6.72(dd,J=8.0,2.4Hz,1H),3.80(s,3 H),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).

[0629] 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.

[0630]

[0631] According to Scheme 1, step ix: To a mixture of intermediate 7a (150.00 mg, 530.81 μmol, 1.00 equiv) and 4-pyridylboronic acid (130.49 mg, 1.06 mmol, 2.00 equiv) in dioxane (5.00 mL) was added DMAP (194.55 mg, 1.59 mmol, 3.00 equiv), pyridine (41.99 mg, 530.81 μmol, 42.84 μL, 1.00 equiv) and Cu(OAc)2 (96.41 mg, 530.81 μmol, 1.00 equiv). The mixture was heated to 90°C and stirred for 12 hours. The resulting mixture was filtered, and the filtrate was acidified to pH = 5 with 12M HCl and filtered. The resulting solution was purified by preparative HPLC to afford Example 50 (8.98 mg, 26.01 μmol, 4.90% yield) as a yellow solid. 1 H-NMR(400MHz,DMSO-d6)δ8.76(brs,2H),7.97(s,1H),7.78(br s,2H),7.15(d,J=8.5Hz,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).

[0632] Example 51: 2-(5-chloropyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 1, Method C.

[0633]

[0634] Intermediate 6a': 5-Formyl-2',4'-dimethyl-1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid

[0635] A solution of intermediate 6a (6 g, 22.03 mmol, 1 eq) in MeOH (100 mL) was added to NaOH (2.64 g, 66.09 mmol, 3 eq) in H2O (40 mL), followed by stirring at 20°C for 24 hours. The organic solvent was removed under reduced pressure. The residue was acidified to pH = 3 by adding 2N HCl at 20°C, then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine to pH = 7, dried over Na2SO4, 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 light yellow oil. 1 H NMR (400MHz, CDCl3) δ7.16-6.93(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).

[0636] Intermediate 8a: 5-Formyl-2',4'-dimethyl-1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid ethyl ester

[0637] According to process 1, step x: TMG (1.34 g, 11.61 mmol, 1.46 mL, 1.5 equivalents) was added to a solution of intermediate 6a' (2 g, 7.74 mmol, 1 equivalent) in DMF (20 mL) at 20 ° C. After addition, the mixed solution was stirred at this temperature at 20 ° C for half an hour. Ethyl iodide (3.02 g, 19.36 mmol, 1.55 mL, 2.5 equivalents) was added and the resulting mixture was heated at 45 ° C for 14 hours immediately. The solvent was removed under reduced pressure. The residue was dissolved in water (20 mL), then adjusted to pH = 4 with 4N HCl, and extracted with EtOAc (15 mL x 3). The combined organic layer was washed with water (10 mL x 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.

[0638] 1H NMR (400MHz, CDCl3) δ10.08(s,1H),7.13-6.94(m,3H),4.34(q,J=7.2Hz,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=7.2Hz,3H).

[0639] Example 51: (2-(5-chloropyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one

[0640] 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) was added 2-hydrazino-5-chloropyrimidine (105.15 mg, 367.19 μmol, 1 eq) at 20 ° C. The mixture was stirred at 100 ° C for 12 hours. The mixture was filtered and concentrated under vacuum. The residue was purified by preparative HPLC to give Example 51 (0.009 g, 24.53 μmol, 6.68% yield) as a white solid. 1 H-NMR(400MHz, CDCl3)δ8.86(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).

[0641] 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.

[0642]

[0643] 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-hydrazino-5-methylpyrimidine (45.58 mg, 367.19 μmol) to obtain Example 52 (0.023 g, 66.39 μmol, 18.08% yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ8.74(s,2H),7.68(s,1H),7.16-6.99(m,3H),3.14(m,1H),3.06-2.96(m,1H),2.8 6-2.76(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).

[0644] 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.

[0645]

[0646] 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-hydrazino-5-methoxypyrimidine (51.46 mg, 367.19 μmol) to obtain Example 53 (0.059 g, 161.16 μmol, 43.89% yield) as a white solid. 1 H-NMR(400MHz, CDCl3)δ8.53(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).

[0647] 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.

[0648]

[0649] 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-hydrazinopyrimidine (47.04 mg, 367.19 μmol) to obtain Example 54 (0.077 g, 217.32 μmol, 59.18% yield) as a white solid. 1H-NMR(400MHz, CDCl3)δ8.77(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).

[0650] 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.

[0651]

[0652] 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-hydrazino-5-(trifluoromethyl)pyrimidine (65.40 mg, 367.19 μmol) to obtain Example 55 (0.023 g, 55.36 μmol, 15.08% yield) as a white solid. 1 H-NMR(400MHz, CDCl3)δ9.08(s,2H),7.65(s,1H),7.08-6.96(m,3H),3.21-3.10(m,1H),3.0 7-2.97(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).

[0653] 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.

[0654]

[0655] Intermediate 56': 2-(5-bromo-4-methoxypyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0656] 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-hydrazino-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. 1 H NMR(400MHz, CDCl3)δ8.71(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).

[0657] Example 56: 6-(2,4-dimethylphenyl)-2-(4-methoxy-5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0658] 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 N2 was added Pd(dppf)Cl2 (16.58 mg, 22.66 μmol, 0.1 eq) and K2CO3 (93.95 mg, 679.78 μmol, 3 eq) in one portion. The mixture was stirred at 100°C for 12 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford Example 56 (0.044 g, 116.27 μmol, 51.31% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ8.71(s,1H),7.66(s,1H),7.14-6.99(m,3H),4.13(s,3H),3.20-3.08(m,1H),3.04-2.9 4(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).

[0659] 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.

[0660]

[0661] 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-hydrazinopyrimidin-5-yl)methyl)morpholine (76.83 mg, 367.19 μmol) to obtain Example 57 (0.023 g, 53.30 μmol, 14.52% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ8.87(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).

[0662] 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.

[0663]

[0664] Intermediate 10: 8-chloro-1,4-dioxaspiro[4.5]dec-7-ene-7-carbaldehyde

[0665] According to Scheme 2, step i: POCl3 (490.66 g, 3.20 mol, 297.37 mL, 2.50 equiv) was added dropwise to a solution of DMF (187.11 g, 2.56 mol, 196.96 mL, 2.00 equiv) in CHCl (2.00 L) at 0°C. The mixture was stirred at 0°C for 2 h. 1,4-dioxaspiro[4.5]decane-8-one (200.00 g, 1.28 mol, 1.00 equiv) in CHCl (500.00 mL) was then added dropwise to the mixture at 0°C. The reaction mixture was stirred at 0°C for 2 h. The reaction mixture was poured into a saturated aqueous NaHCO3 solution (2 L) and maintained at pH>7 by adding solid NaHCO3. The mixture was extracted with CHCl (5 L x 2) and the CHCl phase was concentrated. The resulting residue was purified by column chromatography (PE / EtOAc=20 / 1) to afford Intermediate 56a (120.00 g, 506.34 mmol, 39.56% yield) as a yellow oil. 1H NMR (400MHz, CDCl3) δ10.19-10.10(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).

[0666] Intermediate 11: methyl 7-formyl-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate

[0667] According to Scheme 2, step ii: To a solution of intermediate 10 (122.00 g, 514.78 mmol, 1.00 equiv) in MeOH (800.00 mL) and DMA (400.00 mL) was added Pd(OAc)2 (17.34 g, 77.22 mmol, 0.15 equiv), DPPF (42.81 g, 77.22 mmol, 0.15 equiv) and AcONa (84.45 g, 1.03 mol, 2.00 equiv). 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 x 2) and extracted with ethyl acetate (2000 mL x 3). The combined organic layers were washed with saturated brine (1000 ml x 3) and then concentrated under reduced pressure. The residue was purified by column chromatography (PE:EtOAc=20:1 to 3:1) to afford Intermediate 11 (78.50 g, 329.64 mmol, 64.04% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ5.61 (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 = 6.3Hz, 2H).

[0668] Intermediate 12: 7,8-dihydro-2H-spiro[phthalazine-6,2'-[1,3]dioxolane]-1(5H)-one

[0669] According to process 2, step iii: to a solution of intermediate 11 (78.50 g, 329.64 mmol, 1.00 equivalent) in EtOH (750.00 mL) and AcOH (75.00 mL), N2H4.H2O (33.68 g, 659.28 mmol, 32.70 mL, 2.00 equivalent) was added. The mixed solution was stirred at 80 ° C for 12 hours. The reaction mixture was concentrated and adjusted to pH = 7 with a saturated NaHCO3 aqueous solution. It was then extracted with CH2Cl2 (30.00 mLx3). 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.

[0670] 1 H NMR (400MHz, DMSO-d6) δ7.58 (s, 1H), 3.93 (s, 4H), 2.72 (s, 2H), 2.54 (br t, J = 6.7Hz, 2H), 1.80 (t, J = 6.7Hz, 2H).

[0671] Intermediate 13a: 2-(pyridin-2-yl)-7,8-dihydro-2H-spiro[phthalazine-6,2'-[1,3]dioxolane]-1(5H)-one

[0672] According to Scheme 2, step v: To a solution of intermediate 12 (40.00 g, 192.11 mmol, 1.00 equiv) and 2-bromopyridine (36.42 g, 230.53 mmol, 21.94 mL, 1.20 equiv) in dioxane (500.00 mL) were added CuI (7.32 g, 38.42 mmol, 0.20 equiv), (1S,2S)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (5.47 g, 38.42 mmol, 0.20 equiv) and K3PO4 (101.95 g, 480.28 mmol, 2.50 equiv). The mixture was stirred at 100 ° C for 12 hours. The reaction mixture was filtered and concentrated. The filter cake was washed with CH2Cl2 (200 mL x 3). The residue was added to water (2.0 L) and extracted with CH2Cl2 (1.0 L x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was recrystallized from MTBE (100 mL) at 20 ° C. Intermediate 13a (56.00 g, crude product) was obtained as a gray solid. 1H NMR (400MHz, CDCl3) δ8.67(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=6.0Hz,2H),2.81(s,2H),1.94(br t,J=6.5Hz,2H).

[0673] Intermediate 14a: 2-(pyridin-2-yl)-7,8-dihydrophthalazine-1,6(2H,5H)-dione

[0674] According to Scheme 2, step vi: To a solution of intermediate 13a (25.00 g, 87.63 mmol, 1.00 equiv) in CHCl (250.00 mL) and TFA (75.00 mL) was added HO (3.16 g, 175.26 mmol, 3.16 mL, 2.00 equiv). The mixture was stirred at 20°C for 12 hours. The reaction mixture was poured into a saturated aqueous NaHCO solution (500.0 mL) and extracted with CHCl (500.0 mL x 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. 1 H NMR (400MHz, CDCl3) δ8.67(dd,J=1.1,4.9Hz,1H),7.89(dt,J=1.9,7.7Hz,1H),7.75(s,1H),7.70(d,J=8 .0Hz,1H),7.39(ddd,J=0.9,4.9,7.4Hz,1H),3.46(s,2H),3.16(t,J=7.0Hz,2H),2.67(t,J=7.0Hz,2H).

[0675] Intermediate 15a: 1-oxo-2-(pyridin-2-yl)-1,2,7,8-tetrahydrophthalazin-6-yl trifluoromethanesulfonate

[0676] According to Scheme 2, step vii: To a solution of intermediate 14a (5.00 g, 18.86 mmol, 1.00 equiv) in CHCl (50.00 mL) was added EtN (2.29 g, 22.63 mmol, 3.14 mL, 1.20 equiv) and TfO (5.85 g, 20.75 mmol, 3.42 mL, 1.10 equiv) at 0°C. The reaction mixture was stirred at 20°C for 12 hours. 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. 1 H NMR (400MHz, CDCl3) δ8.68-8.63(m,1H),7.88(dt,J=1.9,7.8Hz,1H),7.78(s,1H),7.69(d,J=8.0Hz, 1H), 7.38 (ddd, J=0.9, 4.9, 7.4Hz, 1H), 6.36 (t, J=1.4Hz, 1H), 3.18-3.10 (m, 2H), 2.84-2.75 (m, 2H).

[0677] Intermediate 16a: 6-(2-methoxyphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0678] According to Scheme 2, step viii: A mixture of intermediate 15a (200.00 mg, 518.07 μmol, 1.00 equiv), (2-methoxyphenyl)-boronic acid (157.45 mg, 1.04 mmol, 2.00 equiv), Pd(PPh 3 ) 4 (119.73 mg, 103.61 μmol, 0.20 equiv), and Na 2 CO 3 (2 M, 1.17 mL, 4.50 equiv) in THF (4.00 mL) was degassed and purged with N 2 three times, and then the mixture was stirred at 70° C. under N 2 atmosphere for 3 hours. The mixture was added to water (20 mL), extracted with AcOEt (20 mL×3), and the organic layer was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-TLC (PE:EtOAc=0:1) to give Intermediate 16a (190.00 mg, crude) as a yellow oil.

[0679] Example 58: 6-(2-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0680] According to Scheme 2, Step ix: A mixture of intermediate 16a (200.00 mg, 283.67 μmol, 1.00 equiv), Pd(OH)2 (79.68 mg, 56.73 μmol, 10% purity, 0.20 equiv) and ammonium formate (178.88 mg, 2.84 mmol, 10.00 equiv) in EtOH (20.00 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 60°C under N2 atmosphere for 2 hours. 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. 1 H-NMR (400MHz, CDCl3) δ8.68 (dd, J=1.1, 4.8Hz, 1H), 7.88 (dt, J=1.9, 7.8Hz, 1H), 7 .78-7.72(m,2H),7.37(ddd,J=0.9,4.9,7.3Hz,1H),7.28-7.25(m,1H),7.21(dd,J= 1.5,7.5Hz,1H),7.02-6.97(m,1H),6.94(d,J=8.3Hz,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).

[0681] 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.

[0682]

[0683] Intermediate 16b: 6-(3-(dimethylamino)phenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0684] 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 same method described for intermediate 16a in Example 58 to give intermediate 16b (160.00 mg, 427.40 μmol, 87.86% yield) as a yellow oil.

[0685] Example 59: 6-(3-(dimethylamino)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0686] According to Scheme 2, Step ix: Example 59 was prepared starting from Intermediate 16b (160.00 mg, 427.40 μmol) according to the same procedure described for Example 58 to give Example 59 (15.47 mg, 43.85 μmol, 10.26% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ8.69 (dd, J=1.1, 4.8Hz, 1H), 7.89 (dt, J=1.9, 7.8Hz, 1 H),7.78-7.73(m,2H),7.38(ddd,J=1.0,4.9,7.4Hz,1H),7.26(t,J=8.1Hz,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).

[0687] 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.

[0688]

[0689] Intermediate 16c: 6-(3-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0690] According to Scheme 2, step viii: Intermediate 16c was prepared according to the same method as described for intermediate 16a in Example 58, starting from intermediate 15a (200.00 mg, 518.07 μmol) and (3-methoxy-2-methylphenyl)boronic acid (85.99 mg, 518.07 μmol) to give intermediate 16c (200.00 mg, 272.16 μmol, 52.53% yield) as a yellow oil.

[0691] Example 60: 6-(3-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0692] According to Scheme 2, Step ix: Example 60 was prepared starting from Intermediate 16c (170.00 mg, 492.20 μmol) according to the same method described for Example 58 to give Example 60 (24.35 mg, 69.95 μmol, 14.21% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ8.69 (dd, J=1.1, 4.8Hz, 1H), 7.89 (dt, J=1.9, 7.8Hz, 1 H),7.79-7.71(m,2H),7.38(ddd,J=0.9,4.9,7.4Hz,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).

[0693] 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.

[0694]

[0695] Intermediate 16d: 6-(5-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0696] 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 same method described for intermediate 16a in Example 58 to give intermediate 16d (200.00 mg, crude) as a yellow oil.

[0697] Example 61: 6-(5-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0698] According to Scheme 2, Step ix: Example 61 was prepared starting from Intermediate 16d (200.00 mg, 579.06 μmol) according to the same method described for Example 58 to give Example 61 (19.01 mg, 52.64 μmol, 9.09% yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ8.69 (dd, J=1.1, 4.8Hz, 1H), 7.89 (dt, J=1.9, 7.8Hz, 1H), 7.77- 7.73(m,2H),7.38(ddd,J=1.0,4.9,7.4Hz,1H),7.15(d,J=8.3Hz,1H),6.80(d,J=2.6Hz ,1H),6.74(dd,J=2.6,8.3Hz,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).

[0699] Example 62: 2-(pyridin-2-yl)-6-(o-tolyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 2, Method A

[0700]

[0701] Intermediate 16e: 2-(pyridin-2-yl)-6-(o-tolyl)-7,8-dihydrophthalazin-1(2H)-one

[0702] 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 same method described for intermediate 16a in Example 58 to give intermediate 16e (70.00 mg, 210.86 μmol, 43.35% yield) as a brown solid.

[0703] Example 62: 2-(Pyridin-2-yl)-6-(o-tolyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0704] According to Scheme 2, Step ix: Example 62 was prepared starting from Intermediate 16e (70.00 mg, 210.86 μmol) according to the same method described for Example 58 to give Example 62 (12.55 mg, 39.07 μmol, 18.53% yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ8.59(dd,J=1.1,4.8Hz,1H),7.80(dt,J=1.9,7.7Hz,1H),7.70-7.62(m,2H),7.29(ddd,J=0.9,4.9,7.5Hz,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).

[0705] Example 63: 6-(3-cyclopropylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 2, Method A

[0706]

[0707] Intermediate 16f: 6-(3-cyclopropylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0708] 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 same method described for intermediate 16a in Example 58 to give intermediate 16f (20.00 mg, 42.76 μmol, 17.58% yield) as a brown solid.

[0709] Example 63: 6-(3-cyclopropylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0710] According to Scheme 2, Step ix: Example 63 was prepared starting from Intermediate 16f (10.00 mg, 21.38 μmol) according to the same method described for Example 58 to give Example 63 (4.63 mg, 13.48 μmol, 63.06% yield) as a white solid. 1H-NMR(400MHz,CDCl3)δ8.68(br d,J=3.8Hz,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=7.4Hz,1H),3.05-2.84(m,3H),2.82-2.60(m,2H),2.24(br d,J=8.9Hz,1H),1.98-1.83(m,2H),1.06-0.95(m,2H),0.74(q,J=4.9Hz,2H).

[0711] 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.

[0712]

[0713] Intermediate 16g: 6-(3-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0714] 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 same method as 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.

[0715] Example 64: 6-(3-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0716] According to Scheme 2, Step ix: Example 64 was prepared starting from Intermediate 16g (130.00 mg, 299.60 μmol) according to the same method described for Example 58 to give Example 64 (31.00 mg, 89.23 μmol, 29.78% yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ8.62-8.56(m,1H),7.83-7.76(m,1H),7.68-7.62(m,2H),7.32-7.25(m,1H),7.04(d,J=7.5Hz,1H),6 .69(d,J=7.5Hz,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).

[0717] 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.

[0718]

[0719] Intermediate 16h: 6-(3-acetylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0720] 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 same 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.

[0721] Example 65: 6-(3-(1-hydroxyethyl)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0722] According to Scheme 2, Step ix: Example 65 was prepared starting from Intermediate 16h (70.00 mg, 156.97 μmol) according to the same method described for Example 58 to give Example 65 (4.05 mg, 11.54 μmol, 4.31% yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ8.68(br d,J=3.9Hz,1H),7.93-7.85(m,1H),7.79-7.70(m,2H),7.41-7.35(m,2H),7.32(br d,J=7.9Hz,2H),7.21(br d,J=7.5Hz,1H),4.95(q,J=6.3Hz,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=9.0Hz,1H),1.98-1.88(m,1H),1.88-1.77(m,1H),1.55(d,J=6.5Hz,3H).

[0723] Example 66: 6-(3-cyclopropyloxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A.

[0724]

[0725] Intermediate 16i: 6-(3-cyclopropyloxyphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0726] According to Scheme 2, step viii: Intermediate 16i was prepared starting from Intermediate 15a (100.00 mg, 243.23 μmol) and (3-cyclopropyloxyphenyl)boronic acid pinacol ester (96.85 mg, 364.84 μmol) according to the same 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.

[0727] Example 66: 6-(3-cyclopropyloxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0728] According to Scheme 2, Step ix: Example 66 was prepared starting from intermediate 16i (40.00 mg, 59.32 μmol) according to the same method described for Example 58 to give Example 66 (8.54 mg, 23.74 μmol, 40.01% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.68 (br d,J=4.3Hz,1H),7.89(dt,J=1.6,7.7Hz,1H),7.78-7.72(m,2H),7.38(dd, J=5.0,7.2Hz,1H),7.34-7.29(m,1H),7.01(dd,J=2.0,8.2Hz,1H),6.94(s, 1H), 6.90 (d, J = 7.7Hz, 1H), 3.82-3.71 (m, 1H), 3.03-2.86 (m, 3H), 2.82-2. 59(m,2H),2.25(brd,J=13.2Hz,1H),1.97-1.83(m,1H),0.84-0.79(m,4H).

[0729] 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.

[0730]

[0731] Intermediate 16j: 6-(2-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0732] 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 same 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.

[0733] Example 67: 6-(2-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0734] According to Scheme 2, Step ix: Example 67 was prepared starting from Intermediate 16j (180.00 mg, 521.15 μmol) according to the same method described for Example 58 to give Example 67 (24.94 mg, 71.64 μmol, 13.75% yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ8.94(d,J=4.8Hz,2H),7.70(s,1H),7.42(t,J=4.9Hz,1H),7.08(dt,J=1.4,8.0Hz,1H),6.93-6.87(m,1H), 6.81(t,J=6.5Hz,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).

[0735] 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.

[0736]

[0737] Intermediate 16k: 6-(2-methoxy-3-methylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0738] 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 same method as 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.

[0739] Example 68: 6-(2-methoxy-3-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0740] According to Scheme 2, Step ix: Example 68 was prepared starting from Intermediate 16k (190.00 mg, 550.10 μmol) according to the same procedure described for Example 58 to give Example 68 (16.44 mg, 46.80 μmol, 8.51% yield) as a white solid. 1H-NMR (400MHz, DMSO-d6) δ8.43 (s, 2H), 7.79 (s, 1H), 7.14-7.21 (m, 1H), 6.89 (d, J = 7.78Hz, 1H), 6.85 (d, J = 8. 28Hz,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).

[0741] 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.

[0742]

[0743] Intermediate 161: 6-(1-methylindolin-4-yl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0744] According to Scheme 2, step viii: Intermediate 161 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 same method described for Intermediate 16a in Example 58 to give Intermediate 161 (0.15 g, crude) as a yellow solid. m / z (M+H) + =357.3; 1 HNMR (MeOD, 400MHz) δ8.60 (br d, J=4.4Hz, 1H), 7.94-8.08 (m, 2H), 7.67 (br d, J=7.6Hz, 1H), 7.46-7.56 (m, 1H), 7.13 (br t, J=7.6Hz, 1H), 6.77 (br d,J=8.0Hz,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).

[0745] Example 69: 6-(1-methylindolin-4-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0746] According to Scheme 2, Step ix: Example 69 was prepared starting from Intermediate 161 (0.15 g, 420.85 μmol) according to the same method described for Example 58 to give Example 69 (55 mg, 151.30 μmol, 35.95% yield) as a white solid. 1 H-NMR(400MHz,DMSO-d6)δ8.67(br d,J=3.6Hz,1H),7.87(td,J=7.8,2.0Hz,1H),7.71-7.78(m,2H),7.36(dd,J=6.4,5.0Hz,1H),7.13(t,J=7.8Hz,1H),6.58(d,J=7.8Hz,1 H), 6.42 (d, J = 7.8Hz, 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).

[0747] 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.

[0748]

[0749] Intermediate 13b: 2-(pyrimidin-2-yl)-7,8-dihydro-2H-spiro[phthalazin-6,2'-[1,3]dioxolane]-1(5H)-one

[0750] 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 same method as described for intermediate 13a to give intermediate 13b (62.00 g, crude) as a grey solid. 1 H NMR (400MHz, CDCl3) δ8.92(d,J=4.8Hz,2H),7.63(s,1H),7.40(t,J=4.8Hz,1H),4.05(s,4H),2.91(br t,J=6.7Hz,2H),2.81(s,2H),1.94(t,J=6.7Hz,2H).

[0751] Intermediate 14b: 2-(pyrimidin-2-yl)-7,8-dihydrophthalazine-1,6(2H,5H)-dione

[0752] According to Scheme 2, step vi: Intermediate 14b was prepared starting from intermediate 13b (18.00 g, 62.87 mmol) according to a similar method as described for intermediate 14a to give intermediate 14b (7.60 g, 18.83 mmol, 29.95% yield) as a brown solid. 1 H NMR (400MHz, DMSO-d6) δ9.04(d,J=4.8Hz,2H),7.88(s,1H),7.79(d,J=6.4Hz,1H),3.55(s,2H),2.95(br t,J=6.9Hz,2H),2.56(t,J=7.0Hz,2H).

[0753] Intermediate 15b: 1-oxo-2-(pyrimidin-2-yl)-1,2,7,8-tetrahydrophthalazin-6-yl trifluoromethanesulfonate

[0754] According to Scheme 2, step vii: Intermediate 15b was prepared starting from intermediate 14b (3.50 g, 14.45 mmol) according to the same procedure as described for intermediate 15a to give intermediate 15b (4.30 g, 8.62 mmol, 59.63% yield) as a yellow solid. 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 = 1.4Hz, 1H), 3.15-3.05 (m, 2H), 2.92-2.83 (m, 2H).

[0755] Intermediate 16m: 6-(2-methoxy-4-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0756] 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 same 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.

[0757] Example 70: 6-(2-methoxy-4-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0758] According to Scheme 2, Step ix: Example 70 was prepared starting from Intermediate 16m (177.00 mg, 511.00 μmol) according to the same method described for Example 58 to give Example 70 (23.80 mg, 62.85 μmol, 12.30% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ9.03 (s, 1H), 9.02 (s, 1H), 7.85 (s, 1H), 7.72 (t, J = 4.89Hz, 1H), 7.12-7.18 (m, 1H), 6.8 8(d,J=3.39Hz,1H),6.86(d,J=3.89Hz,1H),4.43-4.71(m,1H),3.12-3.22(m,1H),2.66-2.86(m,3H),2.56(br d,J=9.91Hz,1H),2.18(s,3H),1.91-2.00(m,1H),1.79-1.90(m,1H),1.28(d,J=6.02Hz,6H).

[0759] 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.

[0760]

[0761] Intermediate 16n: 6-(2-methoxy-3-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0762] 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 same method as described for Intermediate 16a to give Intermediate 16n (180.00 mg, crude) as a brown oil. m / z (M+H) + =347.1.

[0763] Example 71: 6-(2-methoxy-3-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0764] According to Scheme 2, Step ix: Example 71 was prepared starting from Intermediate 16n (180.00 mg, 519.66 μmol) according to the same method described for Example 58 to give Example 71 (13.00 mg, 37.31 μmol, 7.18% yield) as a white solid.1 H-NMR (400MHz, CDCl3) δ9.04 (s, 1H), 9.02 (s, 1H), 7.86 (s, 1H), 7.72 (t, J = 4.89Hz, 1H), 7.12-7.20 (m, 1H), 6.90 (d, J = 7.65Hz, 1H),6.86(d,J=8.03Hz,1H),4.09(dd,J=3.89,5.40Hz,2H),3.66-3.74(m,2H),3.12-3.23(m,1H),2.65-2.88(m,3H),2.57(br d,J=8.28Hz,1H),2.20(s,3H),1.95(br s,1H),1.78-1.90(m,1H).

[0765] Example 72: 6-(2-chloro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 2, Method A

[0766]

[0767] Intermediate 16o: 6-(2-chloro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0768] According to Scheme 2, step viii: Intermediate 16o was prepared 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) according to the same method as described for Intermediate 16a to give Intermediate 16o (190.00 mg, crude) as a yellow oil. m / z (M+H) + =367.0,369.0.

[0769] Example 72: 6-(2-chloro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0770] According to Scheme 2, step ix: Example 72 was prepared starting from intermediate 16o (190.00 mg, 517.99 μmol) according to the same method described for Example 58 to give Example 72 (29.90 mg, 80.42 μmol, 15.53% yield) as a white solid. 1H-NMR (400MHz, DMSO-d6) δ9.03(s,1H),9.01(s,1H),7.85(s,1H),7.71(t,J=4.83Hz,1H),7.45-7.51(m,2H),7.41(t,J=7.40Hz,2H),7.30- 7.35(m,1H),7.13-7.19(m,1H),6.94(d,J=8.16Hz,1H),6.91(d,J=7.78Hz,1H),5.11(s,2H),3.13-3.25(m,1H),2.65-2.88(m,3H),2.56(br d,J=9.41Hz,1H),2.24(s,3H),1.95(br s,1H),1.77-1.90(m,1H).

[0771] Example 73: 6-(5-methoxy-2-(trifluoromethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 2, Method A

[0772]

[0773] Intermediate 16p: 6-(5-methoxy-2-(trifluoromethyl)phenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0774] According to Scheme 2, step viii: Intermediate 16p was prepared 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) according to the same method as described for Intermediate 16a to give Intermediate 16p (72.00 mg, crude) as a yellow solid. m / z (M+H) + =401.1.

[0775] Example 73: 6-(5-methoxy-2-(trifluoromethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0776] According to Scheme 2, Step ix: Example 73 was prepared starting from Intermediate 16p (72.00 mg, 179.84 μmol) according to the same method described for Example 58 to give Example 73 (8.30 mg, 19.84 μmol, 11.03% yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ8.94(d,J=4.8Hz,2H),7.70(s,1H),7.42(t,J=4.8Hz,1H),7.13(d,J=8.3Hz,1H),6.78(d,J=2.5Hz,1H),6.72(dd,J =2.6,8.3Hz,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)

[0777] 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.

[0778]

[0779] Intermediate 16q: 6-(2-fluoro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0780] According to Scheme 2, step viii: Intermediate 16q was prepared 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) according to the same method as described for Intermediate 16a to give Intermediate 16q (60.00 mg, crude) as a brown solid. m / z (M+H) + =351.0.

[0781] Example 74: 6-(2-Fluoro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0782] According to Scheme 2, Step ix: Example 74 was prepared starting from Intermediate 16q (60.00 mg, 171.26 μmol) according to the same method described for Example 58 to give Example 74 (7.70 mg, 21.66 μmol, 12.65% yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ8.94(d,J=4.9Hz,2H),7.70(s,1H),7.43(t,J=4.8Hz,1H),7.10(d,J=7.7Hz,1H),7.04-6.97(m,2H),3.20-3.10(m,1H),3.04(br dd,J=5.1,19.4Hz,1H),2.86-2.61(m,3H),2.34(s,6H),2.18-2.09(m,1H),1.95-1.83(m,1H).

[0783] 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.

[0784]

[0785] Intermediate 16r: 6-(2-chloro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0786] According to Scheme 2, step viii: Intermediate 16r was prepared 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) according to the same method as described for Intermediate 16a to give Intermediate 16r (160.00 mg, crude) as a brown solid. m / z (M+H) + =367.0,369.0.

[0787] Example 75: 6-(2-chloro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0788] According to Scheme 2, Step ix: Example 75 was prepared starting from Intermediate 16r (160.00 mg, 436.21 μmol) according to the same method described for Example 58 to give Example 75 (5.80 mg, 15.65 μmol, 3.59% yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ8.94(d,J=4.9Hz,2H),7.71(s,1H),7.42(t,J=4.8Hz,1H),7.32(d,J=8.8Hz,1H),6.82(d,J=2.9Hz,1H),6.76 (dd,J=2.9,8.7Hz,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).

[0789] Example 76: 6-(2-methoxy-5-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 2, Method A

[0790]

[0791] Intermediate 16s: 6-(2-methoxy-5-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0792] According to Scheme 2, step viii: Intermediate 16s was prepared starting from Intermediate 15b (200.00 mg, 480.91 μmol) and (5-methoxy-2-methylphenyl)boronic acid (119.73 mg, 721.37 μmol) according to the same method as described for Intermediate 16a to give Intermediate 16s (120.00 mg, crude) as a yellow solid. m / z (M+H) + =347.1.

[0793] Example 76: 6-(2-methoxy-5-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0794] According to Scheme 2, Step ix: Example 76 was prepared starting from Intermediate 16s (120.00 mg, 346.44 μmol) according to the same procedure described for Example 58 to give Example 76 (15.00 mg, 54.38 μmol, 15.70% yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ8.94(d,J=4.8Hz,2H),7.69(s,1H),7.41(t,J=4.9Hz,1H),7.07-6.98(m,2H),6.81( d,J=8.3Hz,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=3.5,13.3Hz,1H),1.99-1.87(m,1H).

[0795] Example 77: 6-(2-methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 2, Method A

[0796]

[0797] Intermediate 16t: 6-(2-methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0798] According to Scheme 2, step viii: Intermediate 16t was prepared by the same method as described for Intermediate 16a in Example 58 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) to give Intermediate 16t (110.00 mg, crude) as a yellow solid. m / z (M+H) + =386.2.

[0799] Example 77: 6-(2-methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0800] According to Scheme 2, Step ix: Example 77 was prepared starting from Intermediate 16t (110.00 mg, 285.37 μmol) according to the same method described for Example 58 to give Example 77 (9.84 mg, 24.20 μmol, 8.48% yield) as a yellow solid. 1H-NMR (400MHz, CDCl3) δ8.94(d,J=4.8Hz,2H),7.70(s,1H),7.42(t,J=4.8Hz,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=3.3,6.6Hz,4H),1.95-1.84(m,1H).

[0801] 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.

[0802]

[0803] Intermediate 16u: 6-(1-methylindolin-4-yl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0804] 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 same method described for Intermediate 16a in Example 58 to give Intermediate 16u (140.00 mg, crude) as a yellow solid. m / z (M+H) + =358.2.

[0805] Example 78: 6-(2-methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0806] According to Scheme 2, Step ix: Example 78 was prepared starting from Intermediate 16u (140.00 mg, 391.71 μmol) according to the same procedure described for Example 58 to give Example 78 (26.79 mg, 71.41 μmol, 18.23% yield) as a yellow solid. 1H-NMR (400MHz, CDCl3) δ8.94(d,J=4.9Hz,2H),7.70(s,1H),7.42(t,J=4.9Hz,1H ),7.13(d,J=8.4Hz,1H),6.92(dd,J=2.5,8.3Hz,1H),6.86(d,J=2.5Hz,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).

[0807] 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.

[0808]

[0809] Intermediate 16v: 6-(2-fluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0810] 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 same method as 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.

[0811] Example 79: 6-(2-Fluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0812] According to Scheme 2, Step ix: Example 79 was prepared starting from Intermediate 16v (140.00 mg, 399.60 μmol) according to the same method described for Example 58 to give Example 79 (9.04 mg, 25.45 μmol, 6.37% yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ8.94(d,J=4.9Hz,2H),7.70(s,1H),7.42(t,J=4.8Hz,1H),7.31-7.27(m,1H),7.00(dd,J=1.7,8.2Hz,1H),6.93(t,J=1.9 Hz,1H),6.88(d,J=7.7Hz,1H),3.79-3.70(m,1H),3.05-2.85(m,3H),2.8 0-2.60(m,2H),2.29-2.17(m,1H),1.95-1.81(m,1H),0.83-0.77(m,4H).

[0813] 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.

[0814]

[0815] Intermediate 16w: 6-(5-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0816] According to Scheme 2, step viii: Intermediate 16w was prepared starting from Intermediate 15b (250.00 mg, 500.94 μmol) and (5-methoxy-2-methylphenyl)boronic acid (124.72 mg, 751.41 μmol) according to the same method as described for Intermediate 16a to give Intermediate 16w (110.00 mg, crude) as a brown solid. m / z (M+H) + =347.1

[0817] Example 80: 6-(5-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0818] According to Scheme 2, Step ix: Example 80 was prepared starting from Intermediate 16w (110.00 mg, 317.57 μmol) according to the same method described for Example 58 to give Example 80 (23.99 mg, 68.58 μmol, 21.60% yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ9.03 (s, 1H), 9.02 (s, 1H), 7.85 (s, 1H), 7.71 (t, J = 4.89Hz, 1H), 7.16 ( t,J=7.91Hz,1H),6.90(d,J=7.53Hz,1H),6.85(d,J=8.16Hz,1H),6.08(tdd,J=4.99,10.42,1 7.25Hz,1H),5.43(dd,J=1.76,17.32Hz,1H),5.26(dd,J=1.69,10.60Hz,1H),4.56(d,J=4.89 Hz,2H),3.12-3.24(m,1H),2.65-2.87(m,3H),2.56(brd,J=8.53Hz,1H),2.22(s,3H),1.95(br s,1H),1.79-1.91(m,1H).

[0819] Example 81: 6-(2,5-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 2, Method A.

[0820]

[0821] Intermediate 16x: 6-(2,5-dimethylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0822] According to Scheme 2, step viii: Intermediate 16x was prepared starting from Intermediate 15b (250.00 mg, 500.94 μmol) and (2,5-dimethylphenyl)boronic acid (112.70 mg, 751.41 μmol) according to the same method as described for Intermediate 16a to give Intermediate 16x (75.00 mg, crude) as a yellow solid. m / z (M+H) + =331.2.

[0823] Example 81: 6-(2,5-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0824] According to Scheme 2, Step ix: Example 81 was prepared starting from Intermediate 16x (75.00 mg, 227.01 μmol) according to the same method described for Example 58 to give Example 81 (16.9 mg, 50.69 μmol, 22.33% yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ8.18(s,2H),7.78(s,1H),7.14-7.21(m,1H),6.89(d,J=7.91Hz,1H),6.85(d,J=8.03Hz,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).

[0825] 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.

[0826]

[0827] Intermediate 16y: 6-(2,3-dimethylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0828] According to Scheme 2, step viii: Intermediate 16y was prepared starting from Intermediate 15b (250.00 mg, 500.94 μmol) and (2,3-dimethylphenyl)boronic acid (112.70 mg, 751.41 μmol) according to the same method as described for Intermediate 16a to give Intermediate 16y (100.00 mg, crude) as a yellow solid. m / z (M+H) + =331.2.

[0829] Example 82: 6-(2,3-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0830] According to Scheme 2, step ix: Example 82 was prepared starting from intermediate 16y (100.00 mg, 302.68 μmol) according to the same procedure described for Example 58 to give Example 82 (4.78 mg, 13.70 μmol, 4.53% yield) as a yellow solid. 1H-NMR (400MHz, DMSO-d6) δ8.61(s,2H),7.81(s,1H),7.14-7.22(m,1H),6.88(dd,J=7.91,16.81Hz,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).

[0831] 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.

[0832]

[0833] Intermediate 16z: 6-(3-(methoxymethyl)phenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0834] According to Scheme 2, step viii: Intermediate 16z was prepared starting from Intermediate 15b (590 mg, 1.18 mmol) and (3-(methoxymethyl)phenyl)boronic acid (196.23 mg, 1.18 mmol) according to the same method as described for Intermediate 16a to give Intermediate 16z (280 mg, crude) as a yellow solid. m / z (M+H) + =347.1.

[0835] Example 83: 6-(3-(Methoxymethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0836] According to Scheme 2, Step ix: Example 83 was prepared starting from Intermediate 16z (260 mg, 750.62 μmol) according to the same method described for Example 58 to give Example 83 (24.91 mg, 70.28 μmol, 9.36% yield) as a white solid. 1H-NMR (400MHz, DMSO-d6) δ8.72(s,2H),7.82(s,1H),7.14-7.21(m,1H),6.89(d,J=7.65Hz,1H),6.85(d,J=8.16Hz ,1H),5.03(t,J=5.46Hz,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=9.79Hz,1H),2.18(s,3H),1.93(br s,1H),1.78-1.89(m,1H).

[0837] Example 84: 6-(5-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 2, Method A

[0838]

[0839] Intermediate 16aa: 6-(5-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0840] According to Scheme 2, step viii: Intermediate 16aa was prepared starting from Intermediate 15b (200 mg, 523.65 μmol) and (5-cyclopropyloxy-2-methylphenyl)boronic acid pinacol ester (244.71 mg, 785.47 μmol) according to the same method as described for Intermediate 16a to give Intermediate 16aa (210 mg, crude) as a yellow solid. m / z (M+H) + =373.2.

[0841] Example 84: 6-(5-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0842] According to Scheme 2, Step ix: Example 84 was prepared starting from intermediate 16aa (210 mg, 563.88 μmol) according to the same procedure described for Example 58 to give Example 84 (13.78 mg, 36.77 μmol, 6.52% yield) as a white solid. 1H-NMR(400MHz,DMSO-d6)δ8.35(d,J=6.15Hz,1H),7.77(s,1H),7.15-7.21(m,1H),6.96 (d,J=6.27Hz,1H),6.89(d,J=7.78Hz,1H),6.85(d,J=8.16Hz,1H),3.79(s,3H),3.67(br d,J=5.02Hz,4H),3.62(br d,J=4.77Hz,4H),3.17(br t,J=8.97Hz,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, 11.90Hz, 1H).

[0843] Example 85: 6-(3-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A.

[0844]

[0845] Intermediate 16ab: 6-(3-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0846] According to Scheme 2, step viii: Intermediate 16ab was prepared starting from Intermediate 15b (200 mg, 523.65 μmol) and (3-cyclopropyloxyphenyl)boronic acid pinacol ester (241.24 mg, 785.48 μmol) according to the same method as described for Intermediate 16a to give Intermediate 16ab (170 mg, crude) as a yellow solid. m / z (M+H) + =359.2.

[0847] Example 85: 6-(3-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0848] According to Scheme 2, step ix: Example 85 was prepared starting from intermediate 16ab (170 mg, 474.34 μmol) according to the same method described for Example 58 to give Example 85 (12.36 mg, 33.03 μmol, 6.96% yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ8.93(d,J=4.8Hz,2H),7.70(s,1H),7.42(t,J=4.9Hz,1H),7.27-7.22(m,1H),6.82(d,J=7.8Hz,1H),6.80-6.76(m,2H), 4.78(qd,J=2.9,5.7Hz,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).

[0849] 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.

[0850]

[0851] Intermediate 16ac: 6-(3-(cyclopentyloxy)phenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0852] According to Scheme 2, step viii: Intermediate 16ac was prepared starting from Intermediate 15b (300 mg, 785.48 μmol) and (3-(cyclopentyloxy)phenyl)boronic acid pinacol ester (425.50 mg, 1.18 mmol) according to the same method as described for Intermediate 16a to give Intermediate 16ac (240 mg, crude) as a yellow solid. m / z (M+H) + =387.1.

[0853] Example 86: 6-(3-(Cyclopentyloxy)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0854] According to Scheme 2, Step ix: Example 86 was prepared starting from intermediate 16ac (240 mg, 621.04 μmol) according to the same procedure described for Example 58 to give Example 86 (29.15 mg, 73.01 μmol, 11.76% yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ8.93(d,J=4.8Hz,2H),7.70(s,1H),7.42(t,J=4.9Hz,1H),7.27-7.22(m,1H),6.82(d,J=7.8Hz,1H),6.80-6.76(m,2H), 4.78(qd,J=2.9,5.7Hz,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).

[0855] 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.

[0856]

[0857] Intermediate 16ad: 6-(4-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0858] According to Scheme 2, step viii: Intermediate 16ad was prepared starting from Intermediate 15b (0.3 g, 801.51 μmol) and (4-methoxy-2-methylphenyl)boronic acid (133.04 mg, 801.51 μmol) according to the same method as described for Intermediate 16a to give Intermediate 16ad (0.2 g, crude) as a yellow solid. m / z (M+H) + =347.1; 1 H NMR(DMSO-d6,400MHz)δ9.02(d,J=4.8Hz,2H),8.00(s,1H),7.71(t,J=4.8Hz,1H),7.21(d,J=8.4Hz,1H),6.86(d,J=2 .4Hz,1H),6.81(dd,J=8.4,2.4Hz,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).

[0859] Example 87: 6-(4-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0860] According to Scheme 2, Step ix: Example 87 was prepared starting from intermediate 16ad (0.15 g, 433.05 μmol) according to the same method described for Example 58 to give Example 87 (42 mg, 120.55 μmol, 27.84% yield) as a white solid. 1 H-NMR (400MHz, DMSO-d6) δ9.02(d,J=4.8Hz,2H),7.85(s,1H),7.71(t,J=4.8Hz,1H),7.13-7.23(m,1H),6.77(br d,J=2.8Hz,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).

[0861] 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.

[0862]

[0863] Intermediate 16ae: 6-(1,5-dimethyl-1H-indazol-4-yl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0864] According to Scheme 2, step viii: Intermediate 16ae was prepared 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) according to the same method as described for Intermediate 16a to give Intermediate 16ae (50 mg, 134.99 μmol, 25.26% yield) as a yellow solid. m / z (M+H) + =371.2.

[0865] Example 88: 6-(1,5-dimethyl-1H-indazol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0866] According to Scheme 2, step ix: Example 88 was prepared starting from intermediate 16ae (51.39 mg, 138.73 μmol) according to the same method described for Example 58 to give Example 88 (4 mg, 10.74 μmol, 7.74% yield) as a light yellow solid. 1H-NMR (400MHz, DMSO-d6) δ9.03(d,J=4.8Hz,3H),8.24(s,1H),7.85(s,1H),7.68-7.76(m,1H),7.41(d,J=8.4Hz,1H ),7.23(d,J=8.4Hz,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).

[0867] Example 89:6- 1-Hydroxy-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Scheme 2, Method A.

[0868]

[0869] Intermediate 16af:6- 2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0870] According to Scheme 2, step viii: Intermediate 16af was prepared from Intermediate 15b (200.00 mg, 534.34 μmol) and Starting from boronic acid (87.64 mg, 534.34 μmol), intermediate 16af (0.15 g, 435.53 μmol, 81.51% yield) was obtained as a yellow solid. m / z (M+H) + = 345.3; 1 H NMR(DMSO-d6,400MHz)δ9.03(d,J=4.8Hz,2H),7.99(s,1H),7.71(t,J=4.8Hz,1H),6.9 2(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).

[0871] Example 89:6- 2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0872] According to Scheme 2, step ix: Example 89 was prepared starting from intermediate 16af (150.00 mg, 435.53 μmol) according to the same method described for Example 58 to give Example 89 (8 mg, 22.61 μmol, 5.19% yield) as a white solid. 1H-NMR(400MHz,DMSO-d6)δ9.01(d,J=4.8Hz,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).

[0873] Example 90: 6-(2,6-difluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 2, Method A

[0874]

[0875] Intermediate 16ag: 6-(2,6-difluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0876] 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 same method as 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; 1 H NMR(DMSO-d6,400MHz)δ9.03(d,J=4.8Hz,2H),8.04(s,1H),7.72(t,J=4.8Hz,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).

[0877] Example 90: 6-(2,6-difluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0878] According to Scheme 2, Step ix: Example 90 was prepared starting from intermediate 16ag (0.15 g, 407.24 μmol) according to the same method described for Example 58 to give Example 90 (60 mg, 162.01 μmol, 39.78% yield) as a white solid. 1H-NMR (400MHz, DMSO-d6) δ9.02(d,J=4.8Hz,2H),7.83(s,1H),7.71(t,J=4.8Hz,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).

[0879] Example 91: 6-(2-chloro-3-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 2, Method A

[0880]

[0881] Intermediate 16ah: 6-(2-chloro-3-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0882] According to Scheme 2, step viii: Intermediate 16ah was prepared starting from intermediate 15b (2.50 g, 6.68 mmol) and (2-chloro-3-cyclopropyloxyphenyl)boronic acid pinacol ester (1.83 g, 6.21 mmol) according to the same procedure as described for intermediate 16a to give intermediate 16ah (1.60 g, 3.84 mmol, 57.4% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3

[0883] )δ8.94(d,J=4.8Hz,2H),7.79(s,1H),7.42(t,J=4.8Hz,1H),7.35-7.30(m,1H),7.29-7.24(m,2H),6.91(dd,J=1.6,7. 6Hz,1H),6.35(t,J=1.6Hz,1H),3.84(tt,J=3.2,5.9Hz,1H),3.08-2.98(m,2H),2.84-2.72(m,2H),0.92-0.82(m,4H).

[0884] Example 91: 6-(2-chloro-3-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one

[0885] According to Scheme 2, Step ix: Example 91 was prepared starting from intermediate 16ah (1.20 g, 2.88 mmol) according to the same procedure described for Example 58 to give Example 91 (517 mg, 1.26 mmol, 43.9% yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ8.93(d,J=4.8Hz,2H),7.70(s,1H),7.42(t,J=4.8Hz,1H),7.26-7.22(m,2H),6.95-6.86(m,1H),3.83(tt,J =3.0,5.8Hz,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).

[0886] Example 92: 6-(1-cyclopropyldihydroindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 2, Method A

[0887]

[0888] Intermediate 16ai: 6-(1-cyclopropyldihydroindolin-4-yl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0889] According to Scheme 2, step viii: Intermediate 16ai was prepared starting from Intermediate 15b (2.00 g, 5.34 mmol) and 1-cyclopropyldihydroindolin-4-yl)boronic acid pinacol ester (1.50 g, 5.26 mmol) according to the same method as 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

[0890] Example 92: 6-(1-cyclopropyldihydroindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0891] According to Scheme 2, Step ix: Example 92 was prepared starting from intermediate 16ai (1.70 g, 4.43 mmol) according to a method similar to that described for Example 58 to give Example 92 (230 mg, 549.19 μmol, 35.10% yield) as a light yellow solid. 1H-NMR (400MHz, CDCl3) δ8.94(d,J=4.8Hz,1H),8.97-8.90(m,1H),7.69(s,1H),7.42(t,J=5.0Hz,1H),7.13(t,J=7.6Hz,1H),6.77(d,J=7.6Hz, 1H),6.61(d,J=7.6Hz,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).

[0892] Example 93: 6-(3-cyclopropyloxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 2, Method A

[0893]

[0894] Intermediate 16aj: 6-(3-cyclopropyloxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0895] According to Scheme 2, step viii: Intermediate 16aj was prepared starting from intermediate 15c (3.00 g, 7.49 mmol) and (3-cyclopropyloxy-2-methylphenyl)boronic acid pinacol ester (2.25 g, 7.49 mmol) according to the same method as described for intermediate 16a to give intermediate 16aj (2.10 g, 5.28 mmol, 70.5% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.74(s,2H),7.75(s,1H),7.25-7.16(m,2H),6.81(dd,J=1.8,7.0Hz,1H),6.23(s,1 H),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).

[0896] Example 93: 6-(3-cyclopropyloxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0897] According to Scheme 2, Step ix: Example 93 was prepared starting from Intermediate 16aj (1.20 g, 3.02 mmol) according to the same procedure described for Example 58 to give Example 93 (500 mg, 1.27 mmol, 42.1% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ8.74(s,2H),7.68(s,1H),7.24-7.13(m,2H),6.86(d,J=6.5Hz,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).

[0898] Example 94: 6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 2, Method A

[0899]

[0900] Intermediate 16ak: 6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0901] 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) according to the same method as described for intermediate 16a to give intermediate 16ak (2.40 g, 6.15 mmol, 82.1% yield, 97.6% purity) as a yellow solid. 1 H NMR(400MHz, CDCl3)δ8.75(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).

[0902] Example 94: 6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0903] According to Scheme 2, Step ix: Example 94 was prepared starting from intermediate 16ak (600 mg, 1.54 mmol) according to the same method described for Example 58 to give Example 94 (230 mg, 588 μmol, 38.2% yield, 97.8% purity) as a white solid. 1 H-NMR (400MHz, CDCl3) δ8.73 (s, 2H), 7.69 (s, 1H), 7.26-7.23 (m, 1H), 6.88 (dd, J = 4.4, 8.0Hz, 2H), 3.93 (s, 3H), 3.6 1-3.49(m,1H),3.02-2.92(m,2H),2.82-2.58(m,2H),2.43(s,3H),2.19(td,J=2.8,10.0Hz,1H),1.98-1.85(m,1H).

[0904] Example 95: 6-(2-chloro-4-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 2, Method B.

[0905]

[0906] Intermediate 17a: 2-(pyrimidin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0907] 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) was added Pin2B2 (1.02 g, 4.01 mmol, 1.5 eq) in one portion at 25°C under N2. The mixture was stirred at 100°C for 12 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography (PE:EtOAc=1:1) to obtain intermediate 17a (0.85 g, 2.41 mmol, 90.33% yield) as a yellow solid.

[0908] m / z(M+H) + =353.3; 1H NMR(CDCl3,400MHz)δ8.92(d,J=4.8Hz,2H),7.77(s,1H),7.41(t,J=4.8Hz,1H),6. 99(s,1H),2.74-2.89(t,J=8.8Hz,2H),2.46-2.61(t,J=8.8Hz,2H),1.32(s,12H).

[0909] Intermediate 16a1: 6-(2-chloro-4-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0910] 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 NaCO (339.80 mg, 3.21 mmol, 4 eq) and Pd(dppf)Cl.CHCl (65.45 mg, 80.15 μmol, 0.1 eq) in HO (1 mL) at 20° C. under N2. The mixture was stirred at 100° C. for 12 h. The mixture was filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EtOAc=0:1, 1:0) to give intermediate 16a1 (0.15 g, 427.59 μmol, 53.35% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ9.07-9.03(m,3H),8.04(s,1H),7.76-7.68(m,2H),7.40(s,1H),7.34(d,J=8 .0Hz,1H),7.24(d,J=8.0Hz,1H),6.57(s,1H),2.87-2.79(m,2H),2.77-2.67(m,2H),2.35(s,3H).

[0911] Example 95: 6-(2-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0912] According to Scheme 2, Step ix: Example 95 was prepared starting from intermediate 16a1 (0.15 g, 427.59 μmol) according to the same method described for Example 58 to give Example 95 (0.018 g, 51.02 μmol, 11.93% yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ8.94(d,J=4.0Hz,2H),7.71(s,1H),7.42(t,J=4.4Hz,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).

[0913] 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.

[0914]

[0915] Intermediate 16am: 6-(3-(dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0916] 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 16a1 to give Intermediate 16am (0.15 g, 417.33 μmol, 73.49% yield) as a yellow solid. m / z (M+H) + =360.3; 1 H NMR(CDCl3,400MHz)δ8.94(d,J=4.9Hz,3H),7.78(s,1H),7.44-7.40(m,2H),7.20(t,J=8.0Hz,1H),7.06 (d,J=8.0Hz,1H),6.90(d,J=7.6Hz,1H),6.26(s,1H),2.96-3.07(m,2H),2.66-2.76(m,8H),2.35(s,3H).

[0917] Example 96: 6-(3-(Dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0918] According to Scheme 2, Step ix: Example 96 was prepared starting from intermediate 16am (0.15 g, 417.33 μmol) according to the same method described for Example 58 to give Example 96 (14 mg, 34.93 μmol, 8.37% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ8.94(d,J=4.8Hz,2H),7.70(s,1H),7.42(t,J=4.8Hz,1H),7.28(m,1H),7.02(d,J=8.0Hz,1H),6.98(d,J=8 .0Hz,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).

[0919] 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.

[0920]

[0921] Intermediate 16an: 6-(5-methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0922] According to Scheme 2, step xi: Intermediate 16an was prepared 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 16a1 to give Intermediate 16an (0.2 g, 554.93 μmol, 65.15% yield) as a yellow solid. m / z (M+H) + =361.3; 1 H NMR(CDCl3,400MHz)δ9.03(d,J=4.8Hz,2H),8.01(s,1H),7.71(t,J=4.8Hz,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).

[0923] Example 97: 6-(5-methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0924] According to Scheme 2, Step ix: Example 97 was prepared starting from intermediate 16nj (0.2 g, 554.93 μmol) according to the same method described for Example 58 to give Example 97 (8 mg, 22.07 μmol, 3.98% yield) as a white solid. 1 H-NMR (400MHz, DMSO-d6) δ9.02(d,J=4.4Hz,2H),7.86(s,1H),7.71(t,J=4.4Hz,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).

[0925] 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.

[0926]

[0927] Intermediate 16ao: 6-(4-chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0928] 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 same 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.

[0929] Example 98: 6-(4-chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0930] According to Scheme 2, step ix: Example 98 was prepared starting from intermediate 16ao (120 mg, 342.07 μmol) according to the same method described for Example 58 to give Example 98 (13 mg, 36.85 μmol, 10.77% yield) as a white solid. 1H-NMR(400MHz,DMSO-d6)δ9.02(d,J=4.8Hz,2H),7.85(s,1H),7.71(t,J=4.8Hz,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).

[0931] Example 99: 6-(4-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 2, Method B.

[0932]

[0933] Intermediate 16ap: 6-(4-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0934] 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 16a1 to give Intermediate 16ap (0.18 g, 502.24 μmol, 58.96% yield) as a yellow solid. m / z (M+H) + =359.2; 1 HNMR(DMSO-d6,400MHz)δ9.03(d,J=4.8Hz,2H),8.03(s,1H),7.88(s,1H),7.83(br d,J=8.0Hz,1H),7.72(t,J=4.8Hz,1H),7.41(d,J=8.0Hz,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).

[0935] Example 99: 6-(4-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0936] According to Scheme 2, Step ix: Example 99 was prepared starting from intermediate 16ap (150.00 mg, 418.53 μmol) according to the same method described for Example 58 to give Example 99 (22 mg, 61.04 μmol, 14.58% yield) as a white solid. 1H-NMR (400MHz, DMSO-d6) δ9.02(d,J=4.8Hz,2H),7.85(s,1H),7.76-7.83(m,2H),7.71(t,J=4.8Hz,1H),7.43(br d,J=8.0Hz,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).

[0937] Example 100: 6-(3-(3-methoxypropoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 5.

[0938]

[0939] Intermediate 50: 6-(3-hydroxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one

[0940] According to process 5, step i: at 0 ℃ under N2, to a solution of compound Example 40 (2.50 g, 7.18 mmol, 1.00 equiv) in CH2Cl2 (30.00 mL) was added dropwise BBr3 (8.99 g, 35.90 mmol, 3.46 mL, 5.00 equiv). The mixture was stirred at 0 ℃ for 1.5 hours. At 0 ℃, the mixture was poured into H2O (80 mL). The pH of the aqueous phase was adjusted to about 6-7 by adding K2CO3 solid. A large amount of precipitate formed. The mixture was filtered, and the combined aqueous phases were extracted with CH2Cl2 (60 mL x 5), filtered, and concentrated under vacuum. The filter cake was dissolved with CH2Cl2 / MeOH (1 / 10, 100 mL) and stirred for 1 hour. 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. 1 H NMR(400MHz,DMSO-d6)δ9.03(s,1H),9.01(s,1H),7.85(s,1H),7.71(t,J=4.89Hz,1H),6.88-6.95 (m,1H),6.63-6.69(m,1H),6.60(d,J=7.65Hz,1H),3.07-3.15(m,1H),2.66-2.85(m,3H),2.56(br s,1H),2.13(s,3H),1.91-1.99(m,1H),1.74-1.86(m,1H).

[0941] Example 100: (6-(3-(3-methoxypropoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one

[0942] 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) at 25°C under N2. The mixture was stirred at 100°C for 12 hours. 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. 1 H-NMR (400MHz, DMSO-d6) δ9.02(d,J=4.8Hz,2H),7.85(s,1H),7.71(t,J=4.8Hz,1H),7.15(t,J=8.0Hz,1H),6.80-6.93(m,2H),4 .00(t,J=6.2Hz,2H),3.51(t,J=6.2Hz,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).

[0943] Example 101: 6-(3-ethoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 5.

[0944]

[0945] According to Scheme 5, step ii: Example 101 was prepared starting from intermediate 50 (80 mg, 239.26 μmol) and iodoethane (74.63 mg, 478.51 μmol) according to the same method described for Example 100 to give intermediate Example 101 (25 mg, 68.98 μmol, 28.83% yield) as a white solid. 1H-NMR (400MHz, DMSO-d6) δ9.02(d,J=4.8Hz,2H),7.84(s,1H),7.71(br t,J=4.8Hz,1H),7.15(br t,J=7.8Hz,1H),7.07-7.26(m,1H),6.85(br dd,J=19.0,7.8Hz,2H),4.01(q,J=6.8Hz,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=6.8Hz,3H).

[0946] Example 102: 6-(3-(cyclopropylmethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 5.

[0947]

[0948] According to Scheme 5, step ii: Example 102 was prepared starting from intermediate 50 (150.00 mg, 345.43 μmol) and (bromomethyl)cyclopropane (233.16 mg, 1.73 mmol) according to the same method described for Example 100 to give intermediate Example 102 ((58.63 mg, 150.78 μmol, 43.65% yield) as a white solid. 1 H-NMR (400MHz, DMSO-d6) δ9.03(s,1H),9.02(s,1H),7.85(s,1H),7.71(t,J=4.83Hz,1H),7.10-7.17(m,1H),6.88(d,J=7.65Hz,1 H),6.81(d,J=8.16Hz,1H),3.82(d,J=6.65Hz,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).

[0949] Example 103: 6-(3-Isopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 5.

[0950]

[0951] According to Scheme 5, step ii: Example 103 was prepared starting from intermediate 50 (180.00 mg, 414.51 μmol) and 2-bromopropane (352.31 mg, 2.07 mmol) according to the same method described for Example 100 to give intermediate Example 103 (71.78 mg, 190.68 μmol, 46.00% yield) as a white solid. 1 H-NMR (400MHz, DMSO-d6) δ9.03 (s, 1H), 9.02 (s, 1H), 7.85 (s, 1H), 7.72 (t, J = 4.89Hz, 1H), 7.12-7.18 (m, 1H), 6. 88(d,J=3.39Hz,1H),6.86(d,J=3.89Hz,1H),4.43-4.71(m,1H),3.12-3.22(m,1H),2.66-2.86(m,3H),2.56(br d,J=9.91Hz,1H),2.18(s,3H),1.91-2.00(m,1H),1.79-1.90(m,1H),1.28(d,J=6.02Hz,6H).

[0952] Example 104: 6-(3-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 5

[0953]

[0954] According to Scheme 5, step ii: Example 104 was prepared starting from intermediate 50 (150 mg, 345.42 μmol) and 2-bromocyclopropane (417.88 mg, 3.45 mmol) according to the same method as described for Example 100 to give intermediate Example 104 (19.84 mg, 51.56 μmol, 14.93% yield) as a white solid. 1H-NMR(400MHz,DMSO-d6)δ9.03(s,1H),9.02(s,1H),7.85(s,1H),7.71(t,J=4.89Hz ,1H),7.16(t,J=7.91Hz,1H),6.90(d,J=7.53Hz,1H),6.85(d,J=8.16Hz,1H),6.08(t dd,J=4.99,10.42,17.25Hz,1H),5.43(dd,J=1.76,17.32Hz,1H),5.26(dd,J=1.69, 10.60Hz,1H),4.56(d,J=4.89Hz,2H),3.12-3.24(m,1H),2.65-2.87(m,3H),2.56(br d,J=8.53Hz,1H),2.22(s,3H),1.95(br s,1H),1.79-1.91(m,1H).

[0955] Example 105: 6-(3-(2-methoxyethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 5

[0956]

[0957] According to Scheme 5, step ii: Example 105 was prepared starting from intermediate 50 (200.00 mg, 460.57 μmol) and 1-bromo-2-methoxyethane (320.07 mg, 2.30 mmol) according to the same method described for Example 100 to give intermediate Example 105 (41.81 mg, 106.54 μmol, 23.13% yield) as a white solid. 1 H-NMR (400MHz, DMSO-d6) δ9.04(s,1H),9.02(s,1H),7.86(s,1H),7.72(t,J=4.89Hz,1H),7.12-7.20(m,1H),6.90(d,J=7.65Hz ,1H),6.86(d,J=8.03Hz,1H),4.09(dd,J=3.89,5.40Hz,2H),3.66-3.74(m,2H),3.12-3.23(m,1H),2.65-2.88(m,3H),2.57(br d,J=8.28Hz,1H),2.20(s,3H),1.95(br s,1H),1.78-1.90(m,1H).

[0958] Example 106: 6-(3-(Benzyloxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 5.

[0959]

[0960] According to Scheme 5, step ii: Example 106 was prepared starting from intermediate 50 (180.00 mg, 414.51 μmol) and (bromomethyl)benzene (212.68 mg, 1.24 mmol) according to the same method as described for Example 100 to give intermediate Example 106 (61.03 mg, 143.77 μmol, 34.68% yield) as a white solid. 1 H-NMR (400MHz, DMSO-d6) δ9.03(s,1H),9.01(s,1H),7.85(s,1H),7.71(t,J=4.83Hz,1H),7.45-7.51(m,2H),7.41(t,J=7.40Hz,2H),7.30- 7.35(m,1H),7.13-7.19(m,1H),6.94(d,J=8.16Hz,1H),6.91(d,J=7.78Hz,1H),5.11(s,2H),3.13-3.25(m,1H),2.65-2.88(m,3H),2.56(br d,J=9.41Hz,1H),2.24(s,3H),1.95(br s,1H),1.77-1.90(m,1H).

[0961] 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.

[0962]

[0963] Intermediate 52a: 2-(5-bromopyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0964] 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) was added CuI (35.23 mg, 184.96 μmol, 0.5 eq), K 3 PO 4 (196.31 mg, 924.81 μmol, 2.5 eq) and DMEDA (16.30 mg, 184.96 μmol, 0.5 eq) at 25° C. under N 2 . 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. 1 H NMR: (CDCl3,400MHz)H)δ8.88(s,2H),7.61(s,1H),7.05(d,J=8.4Hz,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).

[0965] 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) was added Pd(dppf)Cl2 (17.12 mg, 23.40 μmol, 0.05 eq) and K2CO3 (77.61 mg, 0.56 mmol, 3.0 eq) in one portion at 25°C under N2. 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 μιηοΐ, 29.15% yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ8.77(s,2H),7.84(s,1H),7.11(d,J=8.4Hz,1H),6.84(d,J=2.4Hz,1H),6.73(dd,J=2.4,8.4Hz,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).

[0966] 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.

[0967]

[0968] Intermediate 52b: 2-(5-bromopyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0969] 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) according to the same method described for intermediate 52a to give intermediate 52b (0.7 g, 1.71 mmol, 86.78% yield) as a light yellow solid. 1 H NMR(400MHz, CDCl3)δ8.72(s,1H),7.98(dd,J=8.4,2.0Hz,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).

[0970] 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 according to the same method described for intermediate Example 107 starting from intermediate 52b (0.2, 487.44 μmol) and cyclopropylboronic acid (209.35 mg, 2.44 mmol) to give Example 108 (0.08 g, 213.20 μmol, 43.74% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ8.63(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).

[0971] 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.

[0972]

[0973] Intermediate 52c: 2-(5-bromopyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0974] According to Scheme 6, step i: Intermediate 52c was prepared starting from intermediate 7a (1 g, 3.93 mmol) and 2,5-dibromopyrimidine (1.12 g, 4.72 mmol) according to the same method described for intermediate 52a to give intermediate 52c (1.2 g, 2.92 mmol, 74.20% yield) as a light yellow solid. 1 H NMR(400MHz, CDCl3)δ8.95(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).

[0975] 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 give Example 109 (0.124 g, 329.59 μmol, 67.62% yield) as a light yellow solid. 1 H-NMR (400MHz, CDCl3) δ8.44(s,1H),7.71(s,1H),7.59(d,J=8.4Hz,1H),7.46(dd,J =2.0,8.4Hz,1H),7.13-7.07(m,1H),7.06-7.00(m,2H),3.19-3.09(m,1H),3.04-2.9 2(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).

[0976] 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.

[0977]

[0978] Intermediate 52d: 2-(5-bromopyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0979] According to Scheme 6, step i: Intermediate 52d was prepared starting from intermediate 7b (1 g, 3.70 mmol) and 2,5-dibromopyridine (2.63 g, 11.10 mmol) according to the same method described for intermediate 52a to give intermediate 52d (1.2 g, 2.81 mmol, 76.09% yield) as a yellow solid. 1H NMR(DMSO-d6,400MHz)δ8.76(m,1H),8.28(dd,J=2.0,8.4Hz,1H),7.95(m,1H),7.63(br s,1H),7.18(t,J=8.0Hz,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).

[0980] 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 starting from intermediate 52d (0.3 g, 703.72 μmol) and cyclopropylboronic acid (302.24 mg, 3.52 mmol) according to the same method described for intermediate Example 107 to give Example 110 (0.09 g, 232.27 μmol, 33.01% yield) as a yellow solid. 1 H-NMR (400MHz, DMSO-d6) δ8.41(s,1H),7.83(s,1H),7.61(d,J=8.4Hz,1H),7.42(d,J=8.4Hz,1H),7.19(t,J=8.0Hz,1H),6.90(d,J=8.0Hz,1H),6.85 (d,J=8.0Hz,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).

[0981] Example 111: 6-(3-methoxy-2-methylphenyl)-2-(5-(pyrrolidin-1-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 6, Method B.

[0982]

[0983] According to Scheme 6, step iii: To 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) at 20° C. under N 2 was added RUPHOS precatalyst (36.52 mg, 47.02 μmol, 0.1 eq) and Cs 2 CO 3 (382.97 mg, 1.18 mmol, 2.5 eq). The mixture was stirred at 100° C. for 12 hours. The mixture was poured into H 2 O (15 mL). The aqueous phase was filtered and extracted with CH 2 Cl 2 (20 mL x 2). The combined organic phases were concentrated under vacuum and mixed with the filter cake to give the crude product, which was purified by preparative HPLC. Example 111 (0.98 mg, 2.21 μmol, 0.5% yield) was obtained as a white solid. 1 H-NMR (400MHz, DMSO-d6) δ8.18(s,2H),7.78(s,1H),7.14-7.21(m,1H),6.89(d,J=7.91Hz,1H),6.85(d,J=8.03Hz,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).

[0984] 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.

[0985]

[0986] According to Scheme 6, step iii: Example 112 was prepared starting from Example 43 (150 mg, 391.81 μmol) and morpholine (68.27 mg, 783.61 μmol, 68.96 μL) according to the same method described for Example 111 to give Example 112 (37.27 mg, 83.31 μmol, 21.26% yield) as a white solid. 1H-NMR (400MHz, DMSO-d6) δ8.61(s,2H),7.81(s,1H),7.14-7.22(m,1H),6.88(dd,J=7.91,16.81Hz,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).

[0987] Example 113: 6-(3-methoxy-2-methylphenyl)-2-(5-morpholinopyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 6, Method B.

[0988]

[0989] According to Scheme 6, step iii: Example 113 was prepared starting from intermediate 52d (0.2 g, 469.15 μmol) and morpholine (81.74 mg, 938.29 μmol, 82.57 μL) according to the same method described for Example 111 to give Example 113 (0.092 g, 212.71 μmol, 45.34% yield) as a yellow solid. 1 H-NMR (400MHz, CDCl3) δ8.45(br s,1H),8.03(br s,1H),7.81(br s,1H),7.59(br s,1H),7.23(br t,J=7.8Hz,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).

[0990] Example 114: 6-(2,4-dimethylphenyl)-2-(5-morpholinopyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 6, Method B.

[0991]

[0992] According to Scheme 6, step iii: Example 114 was prepared starting from intermediate 52b (0.15 g, 365.58 μmol) and morpholine (63.70 mg, 731.16 μmol, 64.34 μL) according to the same method described for Example 111 to give Example 114 (0.029 g, 66.14 μmol, 18.09% yield) as a light yellow solid. 1 H-NMR (400MHz, CDCl3) δ8.42 (s, 1H), 8.02-7.90 (m, 1H), 7.78 (s, 1H), 7.54 (d, J = 8.8Hz, 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).

[0993] Example 115: 6-(2,4-dimethylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 6, Method B

[0994]

[0995] According to Scheme 6, step iii: Example 115 was prepared starting from intermediate 52c (0.15 g, 364.70 μmol) and morpholine (63.55 mg, 729.40 μmol, 64.19 μL) according to the same method described for Example 111 to give Example 115 (0.053 g, 126.95 μmol, 34.81% yield) as a light yellow solid. 1 H-NMR (400MHz, CDCl3) δ8.48(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).

[0996] Example 116: 2-(5-(azetidin-1-yl)pyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 6, Method B.

[0997]

[0998] According to Scheme 6, step iii: Example 116 was prepared starting from intermediate 52c (0.15, 364.70 μmol) and azetidine (136.48 mg, 1.46 mmol, 161.32 μL) according to the same method described for Example 111 to give Example 116 (0.004 g, 9.81 μmol, 2.69% yield) as a light yellow solid. 1 H-NMR (400MHz, CDCl3) δ8.01(s,2H),7.65(s,1H),7.17-6.99(m,3H),4.08(t,J=7.2Hz,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).

[0999] 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.

[1000]

[1001] 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 was added (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) in one portion at 25°C under N2. The mixture was stirred at 25°C for 5 min, then heated to 100°C and stirred for 12 h. 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. 1H-NMR (400MHz, CDCl3) δ8.93(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).

[1002] 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.

[1003]

[1004] According to process 6, step iv: to a solution of compound Example 45 (150 mg, 411.64 μmol, 1 equivalent) in DMA (3 mL) was added Cs2CO3 (268.24 mg, 823.28 μmol, 2 equivalents) and 1-bromo-2-methoxyethane (572.14 mg, 4.12 mmol, 386.58 μL, 10 equivalents). 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 obtain a crude product. The crude product was purified by preparative-HPLC to obtain Example 118 (79.75 mg, 186.50 μmol, 45.31% yield) as a white solid. 1 H-NMR(400MHz, CDCl3)δ8.75(s,2H),7.70(s,1H),7.12(br d,J=8.4Hz,1H),6.77(s,1H),6.72(m,d,J=8.4Hz,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).

[1005] 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.

[1006]

[1007] According to Scheme 6, step iv: Example 119 was prepared starting from Example 45 (150 mg, 411.64 μmol) and 2-bromoethan-1-ol (514.40 mg, 4.12 mmol) according to the same method as described for Example 118 to give Example 119 (45.04 mg, 107.73 μmol, 26.17% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ8.46 (s, 2H), 7.59 (s, 1H), 7.04 (d, J = 8.4Hz, 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).

[1008] Example 120: 6-(3-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 7.

[1009]

[1010] Intermediate 53: 6-(3-bromo-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[1011] 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 H₂O (2 mL) was added Pd(dppf)Cl₂ (207.76 mg, 283.93 μmol, 0.05 eq) and Na₂CO₃ (1.81 g, 17.04 mmol, 3 eq) in one portion at 25°C under N₂. The mixture was stirred at 90°C for 12 hours. The residue was poured into ice water (w / w = 1 / 1) (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum to afford Intermediate 53 (1.4 g, 3.54 mmol, 62.37% yield) as a yellow solid. 1H NMR(CDCl3,400MHz)δ8.92(d,J=4.8Hz,2H),7.75(s,1H),7.54(d,J=7.6Hz,1H),7.40(t,J=4.8Hz ,1H),7.11-7.06(m,2H),6.24(s,1H),3.00(t,J=9.6Hz,2H),2.64(t,J=9.6Hz,2H),2.42(s,3H).

[1012] Intermediate 54: 6-(3-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[1013] 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) was added Pd(PPh ) Cl (17.76 mg, 25.30 μmol, 0.05 eq) at 25° C. under N . The mixture was stirred at 100° C. for 3 hours. HCl (3 M; 20 mL) was added to the reaction and stirred at 25° C. for 30 min and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc=0 / 1) to give intermediate 54 (0.15 g, crude product) as a yellow solid. 1 H NMR(DMSO-d6,400MHz)δ9.01(d,J=4.8Hz,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).

[1014] Example 120: 6-(3-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[1015] According to process 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) was added Pd / C (0.3 g, 5% purity) under N2. The mixture was stirred at 25 °C for 16 hours. The mixture was filtered, concentrated under reduced pressure, and the resulting residue was purified by preparative-HPLC to give Example 120 (4 mg, 10.86 μmol, 2.60% yield) as a white solid. (DMSO-d6)δ9.02(d,J=4.8Hz,2H),7.85(s,1H),7.71(br t,J=4.8Hz,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).

[1016] Example 121: 6-(2,4-dimethylphenyl)-2-(pyridin-2-yl)-2,5,6,7-tetrahydro-1H-cyclopenta[d]-pyridazin-1-one, prepared according to Scheme 3.

[1017]

[1018] Intermediate 19: 3-(2,4-dimethylphenyl)cyclopentan-1-one

[1019] According to process 3, step i: to a mixture of Rh(COD)Cl2 (180.17 mg, 0.37 mmol) in dioxane (20 mL) and H2O (4 mL) was added KOH (4.10 g, 73.08 mmol). The resulting mixture was stirred at 20°C under N2 for 0.5 hours. Then, a solution of cyclopent-2-ene-1-one (6.00 g, 73.08 mmol) and (2,4-dimethylphenyl)boronic acid (21.92 g, 146.16 mmol) in dioxane (20 mL) was added dropwise at 20°C. The resulting mixture was stirred at 20°C for 1.5 hours. LCMS showed the desired product. The reaction mixture was diluted with 200 mL of ethyl acetate and washed with water (60 mL x 3). The organic phase was then dried over anhydrous Na2SO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc=20:1) to obtain Intermediate 19 (11.00 g, 80% yield) as a yellow liquid. 1H NMR (CDCl3; 400MHz) δ7.17-7.10(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).

[1020] Intermediate 20: 2-chloro-4-(2,4-dimethylphenyl)cyclopent-1-ene-1-carbaldehyde

[1021] According to Scheme 3, step ii: POCl3 (13.03 g, 84.99 mmol, 7.9 mL) was added to a mixture of DMF (7.76 g, 106.24 mmol, 8.2 mL) in CHCl2 (100 mL) at -20°C. The mixture was then stirred at 0°C for 1 hour. A solution of Intermediate 19 (10.00 g, 53.12 mmol) in CHCl2 (20 mL) was then added to the mixture at -20°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was then stirred at 25°C for 12 hours. LCMS showed that the reaction mixture was complete. The reaction was quenched with water (100 mL) at 0°C. The mixture was then extracted with CHCl2 (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc=10:1). A mixture of 2-chloro-4-(2,4-dimethylphenyl)cyclopent-1-ene-1-carbaldehyde 20 and its positional isomer 2-chloro-5-(2,4-dimethylphenyl)cyclopent-1-ene-1-carbaldehyde 20' (3.00 g, 24% yield) was obtained as a yellow oil and used in the next step.

[1022] Intermediate 21: ethyl 4-(2,4-dimethylphenyl)-2-formylcyclopent-1-ene-1-carboxylate

[1023] 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) at 25°C under N protection. The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred at 120°C under CO (3 MPa) for 12 hours. The reaction mixture was then concentrated. A crude mixture of intermediate 21 and its positional isomer 21' (1.5 g, crude product) was obtained as a black solid and used in the next step.

[1024] Example 121: 6-(2,4-dimethylphenyl)-2-(pyridin-2-yl)-2,5,6,7-tetrahydro-1H-cyclopenta[d]-pyridazin-1-one

[1025] To a mixture of intermediate 21 and its positional isomer 21' (3.00 g, 11.02 mmol) and 2-pyridylhydrazine (2.41 g, 16.53 mmol HCl) in toluene (100 mL) was added TsOH (1.90 g, 11.02 mmol) at 25 ° C under N2. The mixture was stirred at 120 ° C for 48 hours. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc=3:1) to obtain a crude product, which was further purified by preparative-HPLC. Example 121 (180 mg, 5% yield) was obtained as a yellow oil. 1 H-NMR (400MHz, CDCl3) δ8.75(s,1H),8.10-7.96(m,2H),7.90-7.80(m,1H),7.55-7.45(m,1H),7.13(d,J=7.6H z,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).

[1026] Example 122: 7-(2,4-dimethylphenyl)-3-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one, prepared according to Scheme 4.

[1027] Intermediate 31: 2',4'-dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4H)-one

[1028] According to Scheme 4, step i: A solution of cyclohex-2-en-1-one (3.50 g, 36.41 mmol, 1.00 equiv), 1-iodo-2,4-dimethylbenzene (10.81 g, 46.60 mmol, 1.28 equiv), Na2CO3 (6.04 g, 72.82 mmol, 2.00 equiv), Pd(PPh3)2Cl2 (2.56 g, 3.64 mmol, 0.10 equiv), and XPhos (2.08 g, 4.37 mmol, 0.12 equiv) in DMSO (100.00 mL) was stirred at 100 ° C under N2 atmosphere for 2 hours. LCMS showed the desired product, and the reaction was complete. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with H2O (40 mL x 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 afford Intermediate 31 (1.60 g, 7.99 mmol, 22% yield) as a brown liquid. 1 H NMR (CDCl3; 400MHz) δ7.19-6.94(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).

[1029] Intermediate 33: 2',4'-dimethyl-5-oxo-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid ethyl ester

[1030] According to Scheme 4, step iii: LDA (2M, 8.99 mL, 1.50 eq) was added dropwise to a solution of intermediate 31 (2.40 g, 11.98 mmol, 1.00 eq) in THF (60.00 mL) 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 solution (20 mL) and extracted with 150 mL of ethyl acetate. The combined organic layers were washed with 100 mL of H2O, 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. 1H NMR (CDCl3; 400MHz) δ7.04-7.04(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).

[1031] Intermediate 34: 4-(2,4-dimethylphenyl)-2-oxocyclohexane-1-carboxylic acid ethyl ester

[1032] According to process 4, step ii: Pd / C (500 mg, 10% purity) was added to a solution of intermediate 33 (1.40 g, 5.14 mmol, 1.00 equivalent) in MeOH (20.00 mL) under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 20 ° C under H2 (50 psi) 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.

[1033] Intermediate 35: 7-(2,4-dimethylphenyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one

[1034] According to Scheme 4, step iv: A mixture of intermediate 34 (200 mg, 729.00 μmol, 1.00 equiv), K2CO3 (403.02 mg, 2.92 mmol, 4.00 equiv) and formimidamide (113.84 mg, 1.09 mmol, 1.50 equiv) in EtOH (8.00 mL) was stirred at 90 ° C for 3 hours. The reaction mixture was concentrated and the residue was diluted with ethyl acetate (100 ml). The solution was washed with H2O (40 mL x 3). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Intermediate 35 (120.00 mg, 471.83 μmol, 65% yield) was obtained as a light yellow solid. 1 H NMR (DMSO-d6; 400MHz) δ12.30(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).

[1035] Example 122: 7-(2,4-dimethylphenyl)-3-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one

[1036] According to process 4, step v: a mixture of intermediate 35 (100.00 mg, 393.19 μmol, 1.00 equiv), 2-bromopyridine (80.76 mg, 511.15 μmol, 1.30 equiv), CuI (7.49 mg, 39.32 μmol, 0.10 equiv), 1,10-phenanthroline (14.17 mg, 78.64 μmol, 0.20 equiv) and KOH (44.12 mg, 786.38 μmol, 2.00 equiv) in DMF (4.00 mL) was stirred at 100 ° C under N2 atmosphere for 12 hours. The reaction mixture was diluted with 100 mL of ethyl acetate and washed with water (30 mL x 3). The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude product was purified by preparative HPLC (formic acid as an additive). Example 122 (45.00 mg, 135.78 μmol, 34.53% yield) was obtained as a yellow solid. 1 H-NMR(400MHz,DMSO-d6)δ8.66-8.65(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).

[1037] Example 124: 6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[1038]

[1039] To a mixture of Example 92 (50.0 mg, 130 μmol, 1.00 equiv) in DCM (2.00 mL) was added MnO2 (113 mg, 1.30 mmol, 10.0 equiv) at 25°C. The mixture was stirred at 25°C for 23 h. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography (SiO2, PE / EtOAc = 1 / 1 to 0:1, Rf = 0.48) to afford Example 124 (37.0 mg, 94.7 μmol) as a green solid. 1H-NMR (400MHz, CDCl3) δ8.94(d,J=4.8Hz,2H),7.71(s,1H),7.51(d,J=8.2Hz, 1H),7.42(t,J=4.8Hz,1H),7.24(t,J=7.8Hz,1H),7.18(d,J=3.4Hz,1H),6.99 (d,J=7.4Hz,1H),6.50(d,J=3.4Hz,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).

[1040] Example 125: 2-(5-cyclopropylpyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 6, Method A

[1041]

[1042] Intermediate 52e: 2-(5-bromopyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[1043] According to Scheme 6, step i: Intermediate 52e was prepared starting from Intermediate 7b (500 mg, 1.85 mmol) and 2,5-dibromopyridine (527.98 mg, 2.22 mmol) according to the same method as described for Intermediate 52a 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.

[1044] 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 starting from intermediate 52e (180 mg, 421.26 μmol) and cyclopropylboronic acid (72.37 mg, 842.51 μmol) according to the same method described for Example 107 to give Example 125 (14.61 mg, 37.35 μmol, 8.87% yield) as a light pink solid. 1H-NMR (400MHz, DMSO-d6) δ8.76(s,2H),7.83(s,1H),7.18(t,J=7.97Hz,1H),6.90(d,J=7.65 Hz,1H),6.86(d,J=8.16Hz,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).

[1045] Example 126: 2-(5-bromopyrimidin-2-yl)-6-(3-cyclopropyloxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 1, Method B

[1046]

[1047] Intermediate 6f: 5-(3-cyclopropyloxy-2-methylphenyl)-3-methoxy-4,5,6,7-tetrahydroisobenzo-furan-1(3H)-one was prepared according to Scheme 1, steps i to v: Intermediate 6f was prepared similarly to Intermediate 6a in Example 1 starting from 1-bromo-3-cyclopropyloxy-2-methylbenzene and obtained as a colorless oil in an overall yield of 6%. m / z (M+H) + =315.3.

[1048] Intermediate 7d: 6-(3-cyclopropyloxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[1049] According to Scheme 1, step vii: Intermediate 7b was prepared similarly to intermediate 7a in Example 6 starting from intermediate 6f (1.77 g, 5.60 mmol) to give intermediate 7d (1.52 g, 4.56 mmol, 81.5% yield) as a light yellow solid. 1 HNMR(400MHz,DMSO-d6)δ10.73(br s,1H),7.56(s,1H),7.22-7.11(m,2H),6.84(d,J=7.4Hz,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).

[1050] Example 126: 2-(5-bromopyrimidin-2-yl)-6-(3-cyclopropyloxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[1051] 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 give Example 126 (0.74 g, 1.52 mmol, 50.7% yield) as a red solid. 1 H NMR (400MHz, CDCl3) δ8.95(s,2H),7.69(s,1H),7.24-7.14(m,2H),6.85(d,J=7.6Hz,1H),3.77-3.70(m,1H),3.20(br s,1H),3.00(br d,J=16.3Hz,1H),2.86-2.78(m,1H),2.70(br dd,J=9.2,16.8Hz,2H),2.20-2.18(m,3H),2.13(br s,1H),1.94-1.85(m,1H),0.82-0.77(m,4H).

[1052] Example 127: N-(2-(6-(3-cyclopropyloxy-2-methylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide, prepared according to Scheme 6, Method B

[1053]

[1054] 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 give Example 127 (242 mg, 558.61 μmol, 29.79% yield) as a light yellow solid. 1H NMR (400MHz, CDCl3) δ9.07-9.00(m,1H),8.97(s,2H),7.76(s,1H),7.24-7.15(m,2H),6.86(br d,J=7.4Hz,1H),3.75(br s,1H),3.25(br s,1H),3.00(br d,J=19.4Hz,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(brd,J=7.2Hz,1H),0.80(br s,4H).

[1055] Example 128: (-)-6-(3-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one and Example 129: (+)-6-(3-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[1056]

[1057] The enantiomers constituting racemic Example 104 (483 mg) were separated by preparative SFC to afford (-)-6-(3-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, Example 128 (188 mg, 39%) with an enantiomeric excess of 100%, and (+)-6-(3-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, Example 129 (199 mg, 41%) with an enantiomeric excess of 99.9% as white solids.

[1058] Example 128: 1 H-NMR (400MHz, CDCl3) δ8.94(d,J=4.4Hz,2H),7.70(s,1H),7.42(t,J=4.8Hz,1H),7.28-7.15(m,2H),6.85(d,J=7.6Hz,1H),3.75(tt,J=6.0,3. 2Hz,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).

[1059] Example 129:1 H-NMR (400MHz, CDCl3) δ8.94(d,J=4.4Hz,2H),7.70(s,1H),7.42(t,J=4.8Hz,1H),7.25-7.15(m,2H),6.86(d,J=7.6Hz,1H),3.75(tt,J=6.0,3. 2Hz,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).

[1060] Example 130: (-)-6-(2-chloro-3-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one and Example 131: (+)-6-(2-chloro-3-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[1061]

[1062] The enantiomers constituting racemic Example 91 (505 mg) were separated by preparative SFC to afford (-)-6-(2-chloro-3-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, Example 130 (187 mg, 37%) with an enantiomeric excess of 99.6%, and (+)-6-(2-chloro-3-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, Example 131 (187 mg, 37%) with an enantiomeric excess of 99.9%, both as white solids.

[1063] Example 130: 1 H-NMR (400MHz, CDCl3) δ8.93(d,J=4.4Hz,2H),7.70(s,1H),7.42(t,J=4.8Hz,1H),7.26-7.23(m,2H),6.92-6.87(m,1H),3.83(tt,J =6.0,3.2Hz,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).

[1064] Example 131: 1H-NMR (400MHz, CDCl3) δ8.93(d,J=4.8Hz,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,J=3 .2,6.0Hz,1H),3.63-3.45(m,1H),3.04-2.91(m,2H),2.77-2.57(m,2H),2.23-2.13(m,1H),1.99-1.85(m,1H),0.92-0.79(m,4H).

[1065] Example 132: (-)-6-(3-cyclopropyloxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one and Example 133: (+)-6-(3-cyclopropyloxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[1066]

[1067] The enantiomers constituting racemic Example 93 (488 mg) were separated by preparative SFC to afford (-)-6-(3-cyclopropyloxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, Example 132 (232 mg, 48%) with an enantiomeric excess of 100%, and (+)-6-(3-cyclopropyloxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, Example 133 (210 mg, 43%) with an enantiomeric excess of 100%, both as white solids.

[1068] Example 132: 1 H-NMR (400MHz, CDCl3) δ8.74(s,2H),7.68(s,1H),7.25-7.15(m,2H),6.85(d,J=6.4Hz,1H),3.74(tt,J=6.0,3.2Hz,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).

[1069] Example 133: 1H-NMR (400MHz, CDCl3) δ8.74(s,2H),7.68(s,1H),7.23-7.15(m,2H),6.85(d,J=6.4Hz,1H),3.74(tt,J=6.0,3.2Hz,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).

[1070] 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

[1071]

[1072] The enantiomers constituting racemic Example 94 (493 mg) were separated by preparative SFC to afford (-)-6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, Example 134 (218 mg, 48%) with an enantiomeric excess of 100%, and (+)-6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, Example 135 (215 mg, 43%) with an enantiomeric excess of 99.9%, both as white solids.

[1073] Example 134: 1 H NMR(400MHz, CDCl3)δ8.73(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).

[1074] Example 135: 1H NMR(400MHz, CDCl3)δ8.73(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).

[1075] 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

[1076]

[1077] The enantiomers constituting racemic Example 117 (610 mg) were separated by preparative SFC to afford (-)-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%) with an enantiomeric excess of 99.4% 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%) with an enantiomeric excess of 100% as yellow solids.

[1078] Example 136: 1 H-NMR(400MHz, CDCl3)δ8.99(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).

[1079] Example 137: 1 H-NMR (400MHz, 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).

[1080] 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

[1081]

[1082] The enantiomers constituting racemic Example 124 (440 mg) were separated by preparative SFC to afford (+)-6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, Example 138 (140 mg, 32%) with an enantiomeric excess of 99.5%, 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%) with an enantiomeric excess of 98.9%, both as yellow solids.

[1083] Example 138: 1 H-NMR (400MHz, CDCl3) δ8.94(d,J=4.9Hz,2H),7.71(s,1H),7.52(d,J=8.2Hz,1H),7.42(t,J=4.8Hz,1H),7.24(t,J=7.7Hz,1H),7. 18(d,J=3.3Hz,1H),6.99(d,J=7.2Hz,1H),6.50(d,J=3.2Hz,1H),3.42-3.37(m,2H),3.04-2.96(m,3H),2.93-2.73(m,1H),2.32(br d,J=11.7Hz,1H),2.10-2.06(m,1H),1.12-1.02(m,4H).

[1084] Example 139: 1H-NMR (400MHz, CDCl3) δ8.94(d,J=4.9Hz,2H),7.71(s,1H),7.52(d,J=8.2Hz,1H),7.42(t,J=4.8Hz,1H),7.24(t,J=7.7Hz,1H ),7.18(d,J=3.3Hz,1H),6.99(d,J=7.2Hz,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=11.7Hz,1H),2.09-2.03(m,1H),1.10-1.04(m,4H).

[1085] C. Analysis

[1086] Melting point:

[1087] Values ​​are peak values ​​and are obtained within the experimental uncertainty typically associated with this analytical method. For many compounds, melting points were determined in open capillaries on a YRT-3 apparatus. Melting points were measured using a temperature gradient of 1.5°C / minute. 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.

[1088] DSC conditions

[1089] instrument: NETZSCH DSC214 Crucible Pan Al, with hole cover Protective airflow <![CDATA[N2 60mL / min]]> Purify airflow <![CDATA[N2 40mL / min <!-- 96 -->]]> Gradient ratio: 50℃to350℃;10℃ / min

[1090] LCMS method:

[1091] High performance liquid chromatography (HPLC) is measured using LC pump, diode array or UV detector. The flow from chromatographic column is introduced into a mass spectrometer (MS) configured with an atmospheric pressure ion source. It is within the knowledge of those skilled in the art to set tuning parameters to obtain the ion of the nominal monoisotopic molecular weight (MW) and / or the accurate mass monoisotopic molecular weight of the compound being allowed to be identified. Data acquisition is carried out with applicable software. Using ES MS detector, both positive ionization mode and negative ionization mode are collected.

[1092] Compounds can be described by their molecular ions corresponding to [M+H] (protonated molecules) and / or [MH] (deprotonated molecules). For molecules with multiple isotopic patterns (Br, Cl), the reported value is that obtained for the lowest isotopic mass. All results are obtained with the usual experimental uncertainties associated with the methods used.

[1093] NMR:

[1094] 1 H NMR spectra were recorded on a Varian 400 MHz spectrometer. Chemical shifts are expressed in parts per million (ppm, delta units). Splitting patterns describe the apparent multiplicity and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or br (broad).

[1095] SFC-MS:

[1096] Preparative chiral separations were performed using a preparative instrument equipped with a Waters 2998 PDA detector. The specific method used is described below and the results are reported in Table 1.

[1097]

[1098]

[1099] Optical rotation:

[1100] Optical rotations were measured on a Rudolph AUTOPOL V polarimeter using a sodium lamp (589 nm) in methanol or chloroform as solvent at a concentration of 10 mg / mL at a temperature of 20° C. The sign of the rotation (+ or -) is given in Table 1 and is reported in degrees.

[1101] Table 1. Analytical data of individual optical isomers

[1102]

[1103] In vitro pharmacology

[1104] 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 glutamate or an mGluR7 agonist such as L-AP4.

[1105] The methods described below are suitable for characterizing these compounds, in particular the compounds of formula (I).

[1106] Inositol monophosphate production test (IP1 test):

[1107] Membrane preparation and protocol:

[1108] HEK293 cells were transiently transfected with mGluR7 by electroporation and seeded in polyornithine-coated 96-well plates at a density of 150,000 cells / well. To monitor receptor activity by measuring the production of inositol monophosphate (IP1), mGluR7 was transfected with a chimeric Gq / Gi protein (Gqtop) and co-transfected with EAAC1 (glutamate transporter) to avoid the influence of extracellular glutamate. Cells were cultured in Dulbecco's modified Eagle's medium (DMEM, Invitrogen, Cergy Pontoise, France) supplemented with 10% fetal bovine serum (FBS). The culture medium was changed with Glutamax™ (Invitrogen, Cergy Pontoise, France) to reduce the extracellular glutamate concentration 3 hours before stimulation.

[1109] HTRF-based assays from CisBio Bioassays allow for the measurement of different cell signaling pathways, particularly those that allow for the determination of the production of the second messenger inositol phosphate (IP). IP1 production was determined using the IP-One HTRF kit (CisBio BioAnalassay), a competitive immunoassay using cryptate-labeled anti-IP1 antibodies and d2-labeled IP, according to the manufacturer's recommendations. All points were performed in triplicate.

[1110] Data Analysis

[1111] Data were analyzed using Prism 6 software (GraphPad Software, San Diego, CA). Typically, in each experiment, a four-parameter concentration-response curve equation was used to fit the data, and the potency (IC 50 ) is estimated as logarithm (log IC 50 ). Data were calculated as a percentage of the control mGluR7 agonist L-AP4 response, which was defined as the response to addition of EC 80 -equivalent concentrations of L-AP4.

[1112] result:

[1113] Table 2 below shows the average IC values ​​obtained from at least two independent experiments. 50 .

[1114] Table 2 .Pharmacological activities of the compounds of the present invention.

[1115]

[1116]

[1117] Table 2 - continued

[1118]

[1119] *Table Notes:

[1120] (+):1μM <IC 50 <30 μM

[1121] (++):500nM <IC 50 <1 μM

[1122] (+++):IC 50 <500nM

[1123] In vivo pharmacology

[1124] The compounds of formula (I), (II) and (III) are antagonists or negative allosteric modulators of mGluR7 and can exert in vivo pharmacological activity in disease models associated with glutamate dysfunction.

[1125] Pharmacological models suitable for characterizing the efficacy of such compounds in various indications may be, but are not limited to, the animal models described below. One skilled in the art will recognize that alternative models of the conditions described herein exist and can be used, and that these models evolve with medical and scientific progress.

[1126] Elevated plus maze (EPM) model of anxiety in rodents: This test can be performed as described by Pellow et al. (Neurosci Methods (1985), 149) and File et al. (Psychopharmacol. (1993), 491). The apparatus consists of a gray PVC cross-shaped maze elevated from the floor. It has two opposing open arms and two opposing closed arms of the same size, but with walls. The center square formed by the arms is open. The apparatus is placed in a dimly lit room. Sixty minutes after the second stress period, each animal is placed in the center square of the plus maze, facing the closed arm. They are then allowed to explore the maze freely during a 5-minute test. The maze is cleaned with water between each animal to avoid odor traces left by the animals. During the EPM test, the following parameters are measured: time spent in the open arms (TO), time spent in the closed arms (TC), number of entries into the open arms (EO), and number of entries into the closed arms (EC). Two parameters were calculated: Time Ratio (% time spent in the open arms) = TO / TO + TC; Entry Ratio (% entries into the open arms) = EO / EO + EC. Entry was defined as all four paws in the arms. Compounds of Formula (I), (II), and (III) were administered 30 minutes to 2 hours prior to the EPM test (depending on their pharmacokinetic properties).

[1127] Fear Conditioning Model of Post-Traumatic Stress Disorder in Rats:

[1128] The experiment can be carried out in a compartment of an active avoidance cage (or shuttle box), which has a grid floor controlled by a personal computer and can transmit foot shocks. The test should be carried out in 2 stages (conditioning and testing) at intervals of 24 hours. Phase 1 (called conditioning) consists of the background white noise (63dB) produced in the compartment during the entire experiment. The conditioning period lasts for 5 minutes and 30 seconds. Rats are placed in the compartment and adapted for 2 minutes, then given four 1-second foot shocks (0.5mA) at intervals of 60 seconds between the shocks. Thirty seconds after the last shock, rats are removed from the chamber and then put back in their cages. Phase 2 (testing) is carried out 24 hours after conditioning. Rats are put back in the compartment and their freezing behavior (freezing behavior) is recorded for 5 minutes. The total time spent by rat freezing behavior, the start time of each attack of freezing during 5 minutes of testing, and the duration are experimental parameters. Compounds of formula (I), (II) and (III) may be administered 30 minutes to 2 hours prior to the test session (depending on their pharmacokinetic properties).

[1129] Novel object recognition test for cognitive deficits in mice: The experiment can be performed according to Nilsson et al. (2007) with minor modifications (Wozniak et al., 2016). After a 2-day familiarization period (10 minutes / day), a training trial is performed in which the mice are allowed to explore two identical objects for 5 minutes. Approximately 1 hour later, a trial is performed in which one of the familiar objects is replaced by a novel object. The animals are then allowed to explore the objects for 5 minutes. The compounds of formula (I), (II) and (III) can be administered 30 minutes to 2 hours (depending on their pharmacokinetic properties) before MK-801 (0.3 mg / kg), which is administered 30 minutes before the training trial. Exploration (i.e., sniffing or touching) of the familiar (T) is measured by a trained observer. 熟悉 ) or new objects (T 新 ) and then calculate the recognition index of each mouse [(T 新 –T 熟悉 ) / (T 新 +T 熟悉 )]x 100.

[1130] Prepulse inhibition (PPI) test for rodent schizophrenia: the method can be carried out according to Czyrak et al. (2003). On the day before the experiment, animals were subjected to a single startle phase consisting of two trials, during which they were each presented 20 times. During the first trial, a 120dB, 40ms pulse was presented, and in the second trial, a 75dB, 20ms prepulse was performed before the pulse. On the same day of the experiment, animals were familiarized with background white noise (65dB) for 5 minutes (which lasted throughout the test), and then the startle phase was performed as described above. The startle response amplitude was defined as the maximum force detected during the recording window and the difference (threshold value was set to 10g) between the force measured before the stimulation was about to begin. For each animal, amplitude was averaged for each type of trial. PPI was calculated by dividing the difference between the amplitude of pulse (P) and prepulse+pulse (PP+P) by the amplitude of the individual pulse [([P-(PP+P)] / P)x100]. Compounds of formula (I), (II) and (III) can be administered 30 minutes to 2 hours (depending on their pharmacokinetic properties) before MK-801 (0.3 mg / kg), which is administered 30 minutes before the familiarization phase.

[1131] Noise-induced hearing loss model in mice:

[1132] Groups of 3-4 month old CBA / CaJ mice undergo baseline testing (auditory brainstem response (ABR) audiogram, distortion product otoacoustic emissions (DPOAE)) and are subsequently exposed to loud noise consisting of an 8-16 kHz noise octave band at 110 to 120 dB sound pressure level (SPL) (preferably 110 dB SPL) over a period of 30 minutes to 2 hours (preferably 45 minutes). This noise injury regimen has consistently been shown to produce a threshold shift of 25-35 dB in CBA mice (Kujawa and Liberman, 2009). Compounds of formula (I), (II) and (III) can be administered 30 minutes to 2 hours (depending on their pharmacokinetic properties) before and / or after noise exposure. Hearing function is measured at different time points, for example, 24 hours, 2 weeks and 4 weeks after acoustic trauma. The experimental groups are compared to the control group by measuring, for example, ABR thresholds or ABR threshold shifts.

[1133] Colorectal distension test for visceral pain in rats. This method can be performed according to Moloney et al. (Neurobiol of Stress (2015), 28). Animals are fasted overnight (16 hours) and anesthetized with isoflurane on the day of testing. A 6 cm latex balloon is inserted into the colorectal cavity, 1 cm from the anus. Animals are allowed to recover for 20 minutes before colorectal distension begins. The paradigm used is a phasic distension from 0 mmHg to 80 mmHg over 8 minutes using a computer-driven electronic barostat. The parameters measured are the threshold pressure (mmHg) that induces visually recognizable visceral pain behavior and the total number of pain behaviors. Postures defined as visceral pain behaviors are abdominal retraction and / or abdominal withdrawal reflex. Compounds of formula (I), (II) and (III) can be administered 30 minutes to 2 hours (depending on their pharmacokinetic properties) before colorectal distension (T0). Ten minutes later (T10), animals undergo the balloon insertion procedure and are allowed to recover until T30. Visceral pain behavior was assessed at T30, and animals were euthanized immediately thereafter. [1...

Claims

1. Compound of formula (I): in: G is selected from N or CR 7 , E is selected from N or CR 8 , The condition is that only one of G or E is N, Y is CR 9 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 The same or different are independently selected from hydrogen, halogen, -CN, -CF3, -OR 10 、-NR 10 R 11 , and -(C1-C6)alkyl, Where R 10 and R 11 are the same or different and are each independently selected from hydrogen and -(C1-C6)alkyl, n is an integer selected from 0 or 1, Ar 1 is a heteroaryl group selected from: wherein m is the number of substituents A on the ring, which is an integer equal to 0, 1 or 2, wherein the substituents A are identical or different and are each independently selected from hydrogen, halogen, -CN, -CF3, -OH and the optionally substituted following groups: -(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 , 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; Ar 2 is an aryl or heteroaryl group selected from: wherein p is the number of substituents B on the ring, which is an integer equal to 0, 1, 2 or 3, Wherein the substituents B are the same or different and are each independently selected from hydrogen, halogen, -CF3, -CN and the following groups which are optionally substituted: -(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 , where R 13 and R 14 each independently selected from hydrogen, optionally substituted -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, heteroaryl, aryl, heterocycle, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-heterocycle and -(C1-C6)alkylene-aryl; wherein the term "optionally substituted" means optionally substituted by one or more groups selected from (C1-C6)alkyl, -OH, (C1-C6)alkylene-OH, (C1-C6)alkylene-O(C1-C6)alkyl, -SH, aryl, heteroaryl, heterocycle, (C1-C6)alkylene-aryl, (C1-C6)alkylene-heterocycle, (C1-C6)alkylene-(C3-C7)cycloalkyl, (C1-C6)alkylene-heteroaryl, halogen, trifluoroalkyl, trifluoroalkoxy, cyano, cyanoalkyl, -NH2, -CO2H, -CONH2-, -NH-C(=O)O-(C1-C6)alkyl, -S(=O)2-NH2, -C(O)O-(C1-C6)alkyl and -S(=O)-(C1-C6)alkyl; in, The term "aryl" refers to a 6- to 10-membered monocyclic or bicyclic hydrocarbon ring system containing at least one unsaturated aromatic ring; Wherein, the term "heteroaryl" refers to a 5- to 10-membered monocyclic or bicyclic unsaturated aromatic ring system containing at least one heteroatom independently selected from N, O or S; Wherein, the term "heterocycle" refers to a 5- to 10-membered monocyclic or bicyclic saturated or partially saturated ring system containing at least one heteroatom independently selected from N, O and S; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 of formula (II): or a pharmaceutically acceptable salt thereof, The groups in formula (II) have the same meanings as defined in claim 1.

3. A compound according to claim 1 of formula (III): or a pharmaceutically acceptable salt thereof, The groups in formula (III) have the same meanings as defined in claim 1.

4. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: -A is the same or different and is independently selected from hydrogen, halogen, -CN, -CF3, -OH and the following groups which are optionally substituted: -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C1-C6)alkylene-heterocycle, heterocycle, -O-(C1-C3)alkyl, -O-(C1-C3)alkylene-(C3-C7)cycloalkyl, -(C1-C6)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 ;and -R 13 and R 14 Each is independently selected from hydrogen, optionally substituted -(C1-C3)alkyl, -(C3-C7)cycloalkyl, or -(C1-C6)alkylene-(C3-C7)cycloalkyl.

5. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: -B are the same or different and are each independently selected from hydrogen, halogen, -CF3 and the following groups which are optionally substituted: -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, heterocycle, -O-(C1-C6)alkyl, -O-(C3-C7)cycloalkyl, -O-(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C1-C6)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 ;and -R 13 and R 14 Each is independently selected from hydrogen, optionally substituted -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl.

6. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein: -R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are each independently selected from hydrogen, halogen, -OR 10 、-NR 10 R 11 , and -(C1-C3)alkyl.

7. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein: -R 7 and R 8 Selected from hydrogen, halogen, -CN, -OR 10 、-NR 10 R 11 , -CF3, and -(C1-C3)alkyl, where R 10 and R 11 are the same or different and are each independently selected from hydrogen and -(C1-C3)alkyl.

8. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein: -R 9 Selected from hydrogen, halogen, -CN, -OR 10 、-NR 10 R 11 , -CF3 and -(C1-C3)alkyl, where R 10 and R 11 are the same or different and are each independently selected from hydrogen and -(C1-C3)alkyl.

9. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 1 To R 6 It's hydrogen.

10. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 It's hydrogen.

11. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R 9 It's hydrogen.

12. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein: A is the same or different and is each independently selected from hydrogen, methyl, ethyl, cyclopropyl, methoxy, ethoxy, -OH, cyclopropyloxy, methoxymethyl, hydroxymethyl, 2-methoxyethoxy, 2-hydroxyethoxy, trifluoromethyl, chlorine, fluorine, cyano, dimethylamino, azetidinyl, pyrrolidinyl, morpholino, morpholinomethyl, acetamido; and / or B is the same or different and is each independently selected from methyl, ethyl, cyclopropyl, methoxy, ethoxy, isopropoxy, cyclopropyloxy, cyclopentyloxy, benzyloxy, cyclopropylmethoxy, methoxymethyl, 1-hydroxyethyl, 2-methoxyethoxy, 3-methoxypropoxy, trifluoromethyl, chlorine, fluorine, dimethylamino, pyrrolidinyl, and acetyl.

13. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein: Ar 1 represents an aryl or heteroaryl group selected from the group consisting of 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, 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-chloro pyrimidin-2-yl, 5-fluoropyrimidin-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-methoxyethoxy)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, 5-methoxypyrazin-2-yl; and / or Ar 2 represents an aryl or heteroaryl group selected from the group consisting of 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-methylphenyl, 5-methoxy-2,4-dimethylphenyl, 3-cyclopropylphenyl, 3-(methoxymethyl)phenyl, 3-(dimethylamino)phenyl, (1-hydroxyethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-cyclopropyloxyphenyl, 5-methoxy-2-(trifluoromethyl)phenyl, 3-(cyclopentyloxy)phenyl, 2,6-difluoro-3-methoxyphenyl, 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-cyclopropyloxyphenyl, 1-cyclopropylindolin-4-yl, 1-cyclopropyl-1H-indol-4-yl.

14. A compound selected from: 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)-2-cyanopyridine, 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-cyclopropyloxyphenyl)-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-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-cyclopropyloxyphenyl)-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- 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-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(1-cyclopropyldihydroindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-cyclopropyloxy-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-cyclopropyloxy-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-cyclopropyloxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, N-(2-(6-(3-cyclopropyloxy-2-methylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide, (-)-6-(3-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(3-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (-)-6-(2-chloro-3-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(2-chloro-3-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (-)-6-(3-cyclopropyloxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(3-cyclopropyloxy-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 a pharmaceutically acceptable salt thereof.

15. A compound according to claim 1, selected from: 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)-2-cyanopyridine, 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-cyclopropyloxyphenyl)-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-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-cyclopropyloxyphenyl)-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- 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-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(1-cyclopropyldihydroindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-cyclopropyloxy-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-cyclopropyloxy-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, or a pharmaceutically acceptable salt thereof.

16. A compound according to claim 1, selected from: 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-cyclopropyloxyphenyl)-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-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-cyclopropyloxyphenyl)-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- 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-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(1-cyclopropyldihydroindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-cyclopropyloxy-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-cyclopropyloxy-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, and 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, or a pharmaceutically acceptable salt thereof.

17. A compound according to claim 1, selected from: 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-cyclopropyloxyphenyl)-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-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-cyclopropyloxyphenyl)-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- 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-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(1-cyclopropyldihydroindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-cyclopropyloxy-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-cyclopropyloxy-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-cyclopropyloxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, N-(2-(6-(3-cyclopropyloxy-2-methylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide, (-)-6-(3-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(3-cyclopropyloxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (-)-6-(2-chloro-3-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(2-chloro-3-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (-)-6-(3-cyclopropyloxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(3-cyclopropyloxy-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 a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

19. A method for preparing a pharmaceutical composition according to claim 18, characterized in that A pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

20. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for reducing or inhibiting or negatively regulating the activity of a metabotropic glutamate receptor, which is mGluR7.

21. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disorder associated with mGluR7.

22. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disorder associated with mGluR7, the disorder being selected from: anxiety disorders; disorders associated with muscle spasms and spasticity; neurodegenerative diseases; psychotic disorders; personality disorders; childhood disorders; ear disorders; gastrointestinal disorders; pain disorders; cognitive deficits and mood disorders associated with the above disorders and conditions; eye disorders; disorders caused by traumatic brain injury, stroke, ischemia, spinal cord injury, cerebral hypoxia, cerebral hemorrhage or intracranial hematoma.

23. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disorder associated with mGluR7 selected from the group consisting of mood disorders and hemorrhagic stroke.

24. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of a disorder associated with mGluR7, the disorder being selected from the group consisting of agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), social phobia, bipolar disorder, cyclothymic disorder, depression, dysthymic disorder, substance-induced mood disorder, mania, seasonal affective disorder, tremor, epilepsy, convulsions, migraine, mild cognitive impairment, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, delusional disorder, schizoaffective disorder, substance-induced psychosis, Psychotic disorders, obsessive-compulsive personality disorder, schizophrenic personality disorder, borderline personality disorder, anxious avoidant personality disorder, attention-deficit / hyperactivity disorder, mental retardation, Down syndrome, tic disorder, autism spectrum disorder, autism, inner ear diseases, diarrhea, constipation, gastroesophageal reflux disease (GERD), lower esophageal sphincter disease, gastrointestinal motility disease, colitis, Crohn's disease, irritable bowel syndrome (IBS), acute pain, chronic pain, severe pain, intractable pain, inflammatory pain, postoperative pain, headache, cancer pain, neuropathic pain, post-traumatic pain, visceral pain, intraocular hypertension, glaucoma, neurodegenerative conditions of the retina and optic nerve, retinal dystrophy and age-related macular degeneration.

25. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disorder associated with mGluR7 selected from the group consisting of major depressive disorder, manic depression, schizophreniform disorder and normal-tension glaucoma.

26. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disorder associated with mGluR7 selected from the group consisting of schizotypal disorder and schizotypal disorder.

27. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of a disorder associated with mGluR7 selected from the group consisting of bipolar disorder type I, bipolar disorder type II, Rett syndrome, fragile X syndrome, sensorineural hearing loss, age-related hearing impairment, Meniere's disease, sudden hearing loss, noise-induced hearing loss, drug-induced hearing loss, hidden hearing loss, cisplatin-induced hearing loss, aminoglycoside-induced hearing loss, otitis media, ototoxicity, autoimmune inner ear disease, acute tinnitus, chronic tinnitus, central auditory processing disorder and vestibular disorders and eye disorders.

28. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disorder associated with mGluR7 selected from the group consisting of presbycusis, keratoconjunctivitis sicca and vernal conjunctivitis.

29. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disorder associated with mGluR7, which disorder is conjunctivitis.

30. The use according to claim 22, wherein the ocular disorder is selected from inflammation and / or neurodegeneration.

31. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of a disorder associated with mGluR7 selected from the group consisting of: anxiety disorders; mood disorders; disorders associated with muscle spasms and spasticity; neurodegenerative diseases.

32. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of a disorder associated with mGluR7 selected from the group consisting of agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), social phobia, bipolar disorder, cyclothymic disorder, dysthymic disorder, major depressive disorder, substance-induced mood disorder, mania, manic-depressive disorder or seasonal affective disorder, tremor, epilepsy, convulsions or migraine, mild cognitive impairment, Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis.

33. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disorder associated with mGluR7, which disorder is depression.

34. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disorder associated with mGluR7 selected from the group consisting of bipolar disorder type I and bipolar disorder type II.

35. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of a disorder associated with mGluR7 selected from the group consisting of: psychotic disorders; personality disorders; childhood disorders; and ear disorders.

36. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disorder associated with mGluR7 selected from the group consisting of schizophrenia, delusional disorder, schizoaffective disorder, substance-induced psychotic disorder, obsessive-compulsive personality disorder, schizotypal personality, borderline personality disorder, anxious-avoidant personality disorder, attention-deficit / hyperactivity disorder, mental retardation, Down syndrome, tic disorder, autistic spectrum disorder, autism, and inner ear disease.

37. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disorder associated with mGluR7, which disorder is a schizophreniform disorder.

38. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of a disorder associated with mGluR7 selected from the group consisting of: Rett syndrome or fragile X syndrome, sensorineural hearing loss, age-related hearing impairment, Meniere's disease, sudden hearing loss, noise-induced hearing loss, drug-induced hearing loss, hidden hearing loss, cisplatin-induced hearing loss, aminoglycoside-induced hearing loss, otitis media, ototoxicity, autoimmune inner ear disease, acute tinnitus, chronic tinnitus, central auditory processing disorder and vestibular disorder.

39. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disorder associated with mGluR7, which disorder is presbycusis.

40. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disorder associated with mGluR7, the disorder being selected from: gastrointestinal disorders; pain disorders; cognitive deficits and mood disorders associated with the above disorders and disorders; eye disorders; disorders caused by traumatic brain injury, stroke, ischemia, spinal cord injury, cerebral hypoxia, cerebral hemorrhage or intracranial hematoma.

41. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disorder associated with mGluR7, which disorder is hemorrhagic stroke.

42. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention or treatment of a disorder associated with mGluR7 selected from the group consisting of diarrhea, constipation, gastroesophageal reflux disease (GERD), lower esophageal sphincter disease or disorder, gastrointestinal motility disease, colitis, Crohn's disease or irritable bowel syndrome (IBS), acute pain, chronic pain, severe pain, intractable pain, inflammatory pain, postoperative pain, headache, cancer pain, neuropathic pain, post-traumatic pain and visceral pain, intraocular hypertension, glaucoma, neurodegenerative disease conditions of the retina and optic nerve, retinal dystrophy, age-related macular degeneration.

43. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disorder associated with mGluR7, which disorder is normal-tension glaucoma.

44. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of a disorder associated with mGluR7, which disorder is an ocular disorder.

45. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of a disorder associated with mGluR7 selected from the group consisting of: keratoconjunctivitis sicca and vernal conjunctivitis.

46. ​​Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for the preparation of a radiolabelled tracer for imaging a metabotropic glutamate receptor in a mammal including a human, wherein the metabotropic glutamate receptor is mGluR7.

47. A compound of formula (IV), (V) or (VI) as an intermediate of a compound of formula (I), (II) or (III), wherein G, E, Ar 1 ,Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n and Y are as defined in any one of claims 1 to 13

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