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 (mGluR), preferably metabotropic glutamate receptor subtype 7 ("mGluR7"). The invention also relates to pharmaceutical combinations comprising such compounds and their use for the treatment or prevention of disorders associated with glutamate dysfunction or in which metabotropic glutamate receptors, preferably the mGluR7 subtype of metabotropic glutamate receptors, are involved. # imgabs0 #

Description

[0001] This application is a divisional application. The application number of the original application is 201880062779.6, the filing date is September 26, 2018, the priority date is September 26, 2017, and the invention title is "Novel Heterocyclic Compounds as mGluR7 Modulators". Summary of the Invention

[0003] The present invention relates to novel heterocyclic compounds. The present invention also relates to compounds as 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 the compounds and compositions, and the use of the compounds and compositions for preventing or treating disorders associated with abnormal glutamate function or disorders involving metabotropic glutamate receptors, preferably the mGluR7 subtype of metabotropic glutamate receptors. Background of the Invention

[0005] Glutamate is the major amino acid neurotransmitter in the mammalian central nervous system (CNS) and plays important roles in several physiological functions such as learning and memory, sensory perception, development of synaptic plasticity, and motor control. In addition, glutamate is central to several neurological and psychiatric diseases in which there is an imbalance in glutamatergic neurotransmission.

[0006] Glutamate mediates synaptic neurotransmission through the activation of mGluRs, which belong to class C G protein-coupled receptors (GPCRs) and have a regulatory role in fine-tuning synaptic efficacy (Schoepp et al., Neuropharmacology (1999), 38:1431). In particular, the mGluR receptor subtype 7 (mGluR7) is widely distributed in the brain and has the highest degree of evolutionary conservation among all mGluR receptors across species (Flor et al., Neuropharmacol. (1997), 36:153). More importantly, mGluR7 has the lowest affinity for glutamate and remains inactive during normal neurotransmission states, becoming active only under severe pathophysiological conditions or during excessive glutamate release (Ferraguti and Shigemoto, Cell Tissue Res. (2006), 326:483). mGluR7 is thought to play a tonic break role, inhibiting further glutamate release while affecting the release of other neurotransmitters (e.g., GABA) and preventing glutamate excitotoxicity in many pathological conditions involving the CNS and sensory disorders.

[0007] Specifically, based on experimental studies in laboratory animals thought to be relevant to clinical syndromes, mGluR7 modulators, preferably antagonists, inverse agonists, and negative allosteric modulators (NAMs), have been reported to have potential for treating neurology, psychiatry, mood disorders, as well as pain and ear disorders.

[0008] Isoxazolopyridone 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 background-dependent pharmacology, which partially to fully antagonizes 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).

[0009] Tetrahydrobenzoxazole derivatives, including (+)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenz[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).

[0010] Chromenone derivatives, including 7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one (XAP044), have been described as weak mGluR7 allosteric antagonists that bind to the extracellular domain of the receptor. XAP044 has shown anxiolytic, antidepressant, antistress, and antipsychotic activities (Gee et al., J. Biol. Chem. (2014), 289:10975).

[0011] Co-expression of mGluR7 in brain regions and pharmacological modulation of mGluR7 in genetically modified mice and wild-type animals have revealed important roles 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 disorders (reviewed by Peterlik et al., Curr Neuropharmacol. (2016), 14(5):514). In addition, mGluR7 represents a novel 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). Moreover, the mGluR7 NAM MMPIP and the allosteric antagonist XAP44 have been shown to inhibit pain responses, reduce anxiety and depressive-like behaviors and improve cognitive performance in a mouse model of neuropathic pain (Pallazzo et al., Pain (2015), 156(6):1060).

[0012] It has also been shown that mGluR7 is 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 the treatment of pathologies such as visceral pain, stress-related gastrointestinal dysfunctions such as diarrhea or constipation in irritable bowel syndrome (IBS) or other related disorders.

[0013] 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 the treatment of pathologies related to the inner ear and the 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.

[0014] It has been shown that mGluR7 is expressed at the synaptic terminals of certain cone bipolar cells in the retina ( et al., (1996) J. Neurosci., 16(15):4749-4756), which suggests potential uses of mGluR7 modulators in the acute and chronic treatment of glaucoma and other visual disorders.

[0015] Finally, numerous genome-wide human studies have also confirmed 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 more recently by Haider et al. (Front. Aging Neurosci. (2017), 9:346) and Matyas et al. (Pathol. Oncol. Res. (2018), doi:10.1007 / s12253-018-0388-6); noise-induced hearing loss, as reported by Lu et al. (BMC Med. 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-related 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).

[0016] In summary, 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, ear, pain, visual, and gastrointestinal disorders.

[0017] An object of the present invention is to provide a compound having activity against mGluR, preferably against mGluR7.

[0018] Another object of the present invention is to provide a pharmaceutical composition comprising the compound.

[0019] Another object of the present invention is to provide such a compound and / or pharmaceutical composition for treating a disease associated with mGluR, preferably mGluR7. Summary of the Invention

[0021] The present invention relates to a compound of formula (I),

[0022]

[0023] wherein:

[0024] G is selected from N or CR 7 ,

[0025] E is selected from N or CR 8 ,

[0026] provided that at least one of G or E is N

[0027] Y is CR 9 ,

[0028] 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 10 C(=O)OR11 、 -NR 10 S(O)2R 11 、 An optionally substituted group, where the optionally substituted group is selected from: -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl or -(C1-C6)cyanoalkyl,

[0029] Any two groups R 1 and R 2 、 R 3 and R 4 、 and R 5 and R 6 may together form oxo(=O),

[0030] wherein R 10 and R 11 are the same or different and are each independently selected from hydrogen, an optionally substituted group, where the optionally substituted group is selected from: -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)cyanoalkyl, -(C3-C7)cycloalkyl or -(C1-C6)alkylene-(C3-C7)cycloalkyl,

[0031] wherein, optionally, any two groups selected from R 1 、 R 2 、 R 3 、 R 4 、 R 5 、 R 6 、 R 9 、 R 10 and R 11 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,

[0032] n is an integer selected from 0 or 1,

[0033] Ar 1 is an optionally substituted aryl or heteroaryl,

[0034] Ar 2 is an optionally substituted aryl or heteroaryl,

[0035] and its N-oxide form, its pharmaceutically acceptable salts and solvates, or their optical isomers, racemates, diastereoisomers, enantiomers or tautomers.

[0036] Surprisingly, the compounds of formula (I) exhibit metabotropic glutamate receptor activity.

[0037] Preferably, in the compounds of formula (I), Ar1 represents an aryl or heteroaryl group selected from:

[0038]

[0039] where m is the number of ring substituents A, which is an integer equal to 0, 1, 2, 3, 4, or 5.

[0040] Preferably, in the compound of formula (I), Ar 2 represents an aryl or heteroaryl group selected from:

[0041]

[0042] where p is the number of ring substituents B, which is an integer equal to 0, 1, 2, 3, 4, or 5. It should be understood that when Ar2 is bicyclic, B can be on either of the two rings.

[0043] A and B, as described above, are the same or different and are each independently selected from hydrogen, halogen, -CN, -NO2, -OH, -NH2, -CF3, optionally substituted groups 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)alkenyl-OR 13 、-(C2-C6)alkynyl-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)alkenyl-NR 13 R 14 、-(C2-C6)alkynyl-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 、-O-C(=O)-NR 13 R 14 、-(C1-C6)alkylene-O-C(=O)-NR 13 R 14 、-O-(C2-C6)alkylene-O-C(=O)-NR 13 R 14 、-NR 13 -(C2-C6)alkylene-O-C(=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 ;

[0044] wherein R 13 、R 14 、R 15 and R 16 are 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;

[0045] Wherein, optionally, selected from R 13 、R 14 、R 15 or R 16 Any two groups can together form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; each ring is optionally further substituted with 1 to 5 groups independently selected from the following: halogen, cyano, nitro, hydroxy, amino, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2;

[0046] Wherein any two groups A and any two groups B can combine with an inserted atom to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; each ring is optionally further substituted with 1 to 5 groups independently selected from the following: halogen, -CN, hydroxy, amino, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0047] Preferably, in the compounds of formula (I), the substituents A are the same or different and are each independently selected from hydrogen, halogen, -CN, -CF3, -OH, -NH2, optionally substituted groups 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-R13 、 -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)-R14 or -NR 13 -C(=O)-OR 14 ;

[0048] wherein R 13 , R 14 and R 15 are 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;

[0049] wherein, optionally, any two groups selected from R 13 , R 14 or R 15 on substituent A may together form a 3- to 10-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; where each ring is optionally further substituted with 1 to 5 groups independently selected from the following: halogen, -CN, -NO2, -OH, -NH2, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl)2;

[0050] where any two groups A may combine with an intervening atom to form a 3- to 10-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring; where each ring is optionally further substituted with 1 to 5 groups independently selected from the following: halogen, -CN, -OH, -NH2, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl)2.

[0051] Preferably, in the compounds of formula (I), the substituents A are the same or different and are each independently selected from hydrogen, halogen, -CN, -CF3, -OH, optionally substituted groups 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 14R 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 ,

[0052] wherein 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;

[0053] wherein, optionally, the groups R 13 and R 14 on substituent A may together form a 3- to 6-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted by 1 to 5 groups independently selected from the following: halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2;

[0054] wherein any two groups A may combine with an intervening atom to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted by 1 to 5 groups independently selected from the following: halogen, -CN, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0055] Preferably, in the compounds of formula (I), the substituents A are the same or different and are each independently selected from hydrogen, halogen, -CN, -CF3, -OH, optionally substituted groups 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 -NR 13 C(=O)-R 14 ;

[0056] wherein 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;

[0057] wherein, optionally, the groups R 13 and R 14 on substituent A may together form a 3- to 6-membered carbocyclic or heterocyclic ring, wherein each ring is optionally further substituted by 1 to 5 groups independently selected from: halogen, -CN, -OH, -NH2, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2;

[0058] wherein any two groups A may combine with an intervening atom to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted by 1 to 5 groups independently selected from: halogen, -CN, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0059] Preferably, in the compounds of formula (I), the substituents A are the same or different and are each independently selected from hydrogen, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxy (-OH), cyclopropoxy, methoxymethyl, hydroxymethyl, 2-methoxyethoxy, 2-hydroxyethoxy, trifluoromethyl, chlorine, fluorine, cyano, dimethylamino, azetidinyl, pyrrolidinyl, morpholino, morpholinomethyl, acetamido.

[0060] Preferably, in the compounds of formula (I), the substituents B are the same or different and are each independently selected from hydrogen, halogen, -CN, -CF3, optionally substituted groups 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-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 、 -(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)-NR13 R 14 、 -(C1-C6) alkylene - C(=O) - NR 13 R 14 、 -O-(C1-C6) alkylene - C(=O) - NR 13 R 14 、 -NR 13 -(C1-C6) alkylene - C(=O) - NR 14 R 15 、 -NR 13 C(=O) - R 14 、 -(C1-C6) alkylene - NR 13 C(=O) - R 14 、 -O-(C2-C6) alkylene - NR 13 C(=O) - R 14 、 -NR 13 -(C2-C6) alkylene - NR 14 C(=O) - R 15 、 -C(=O) - R 13 、 -(C1-C6) alkylene - C(=O) - R 13 、 -O-(C1-C6) alkylene - C(=O) - R 13 、 -NR 13 -(C1-C6) alkylene - C(=O) - R 14 、 -C(=O) - OR 13 、 -(C1-C6) alkylene - C(=O) - OR 13 、 -O-(C1-C6) alkylene - C(=O) - OR 13 、 -NR 13 -(C1-C6) alkylene - C(=O) - OR 14 、 -OC(=O) - R 13 、 -(C1-C6) alkylene - OC(=O) - R 13 、 -O-(C2-C6) alkylene - OC(=O) - R 13 、 -NR 13 -(C2-C6) alkylene - OC(=O) - R 14 、 -(C1-C6) alkylene - NR 13 -C(=O) - NR 14 R 15 、 -NR 13 -C(=O) - OR 14 、 -(C1-C6) alkylene - NR 13 -C(=O) - OR 14 、 -O-(C2-C6) alkylene - NR 13-C(=O)-OR 14 、-NR 13 -(C2-C6)alkylene-NR 14 -C(=O)-OR 15 、-O-C(=O)-NR 13 R 14 、-(C1-C6)alkylene-O-C(=O)-NR 13 R 14 、-O-(C2-C6)alkylene-O-C(=O)-NR 13 R 14 、-NR 13 -(C2-C6)alkylene-O-C(=O)-NR 14 R 15 、-C(=O)-(C1-C6)alkylene-NR 13 R 14 、-C(=O)-(C1-C6)alkylene-OR 13 ;

[0061] wherein R 13 、R 14 and R 15 are 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;

[0062] wherein, optionally, any two groups on substituent B selected from R 13 、R 14 or R 15 can together form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted by 1 to 5 groups independently selected from the following: halogen, -CN, -NO2, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2;

[0063] wherein any two groups B can combine with inserted atoms to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted by 1 to 5 groups independently selected from the following: halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0064] Preferably, in the compound of formula (I), the substituents B are the same 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 ;

[0065] wherein 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, heteroaryl, aryl, heterocycle, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-heterocycle and -(C1-C6)alkylene-aryl;

[0066] wherein, optionally, any two groups selected from R 13 and R 14 on the substituent B may together form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted by 1 to 5 groups independently selected from the following: halogen, CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2;

[0067] Any two of the groups B may combine with the inserted atom to form a 3- to 10-membered carbon ring, heterocyclic ring, aryl ring or heteroaryl ring; each ring is optionally further substituted with 1 to 5 groups independently selected from the following: halogen, -CN, -OH, -NH2, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

[0068] Preferably, in the compounds of formula (I), the substituents B are the same 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, heterocyclic ring, -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 ;

[0069] wherein 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,

[0070] wherein, optionally, the groups R 13 and R 14 on the substituent B may together form a 3- to 6-membered carbon ring, heterocyclic ring, aryl ring or heteroaryl ring; each ring is optionally further substituted with 1 to 5 groups independently selected from the following: halogen, -CN, -OH, -NH2, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2;

[0071] Any two of the groups B may combine with the inserted atom to form a 3- to 10-membered carbon ring, heterocyclic ring, aryl ring or heteroaryl ring; each ring is optionally further substituted with 1 to 5 groups independently selected from the following: halogen, -CN, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1C6)alkyl)2.

[0072] Preferably, in the compound of formula (I), the substituents B are the same or different and each independently selected from methyl, ethyl, cyclopropyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclopentyloxy, benzyloxy, cyclopropylmethoxy, methoxymethyl, 1-hydroxyethyl, 2-methoxyethoxy, 3-methoxypropoxy, trifluoromethyl, chlorine, fluorine, dimethylamino, pyrrolidinyl, acetyl.

[0073] Preferably, in the compound of formula (I),

[0074] m is an integer equal to 0, 1 or 2; and / or

[0075] p is an integer equal to 1, 2 or 3.

[0076] Preferably, in the compound of formula (I), Ar 1 represents aryl or heteroaryl, selected from:

[0077]

[0078] wherein A is as defined above;

[0079] wherein m is the number of ring substituents A, which is an integer equal to 0, 1, 2, 3 or 4.

[0080] Preferably, in the compound of formula (I), Ar 1 represents aryl or heteroaryl, selected from:

[0081] 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, 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.

[0082] Preferably, in the compound of formula (I), Ar 2 represents aryl or heteroaryl, which is selected from:

[0083]

[0084] wherein B and p are as defined above.

[0085] Preferably, in the compound of formula (I), Ar 2 represents aryl or heteroaryl, which is selected from:

[0086]

[0087] wherein B and p are as defined above.

[0088] Preferably, in the compound of formula (I), Ar 2 represents aryl or heteroaryl, which is selected from:

[0089]

[0090] wherein B and p are as defined above.

[0091] Preferably, in the compound of formula (I), Ar 2 represents an aryl or heteroaryl group selected from:

[0092] 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-cyclopropoxyphenyl, 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-methyldihydroindol-4-yl, 1,5-dimethyl-1H-indazol-4-yl; 2-chloro-3-cyclopropoxyphenyl, 1-cyclopropyldihydroindol-4-yl, 1-cyclopropyl-1H-indol-4-yl.

[0093] 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 each independently selected from hydrogen, halogen, -OR 10 , -NR 10 R 11 , optionally substituted -(C1-C3)alkyl, R 10 and R 11 as previously defined;

[0094] wherein any two groups R 1 and R 2 , R 3 and R 4 and R 5 and R6 may together form an oxo;

[0095] wherein, optionally, any two groups selected from R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may together form an optionally substituted 3- to 10-membered non-aromatic carbocyclic or heterocyclic ring.

[0096] Preferably, in the compound of formula (I), R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are hydrogen.

[0097] Preferably, in the compound of formula (I), R 7 and R 8 are selected from hydrogen, halogen, -CN, -OR 10 , -NR 10 R 11 , -CF3, an 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 previously defined;

[0098] wherein, optionally, two groups R 10 and R 11 may together form an optionally substituted 3- to 10-membered non-aromatic carbocyclic or heterocyclic ring.

[0099] Preferably, in the compound of formula (I), R 7 and R 8 are hydrogen.

[0100] Preferably, in the compound of formula (I), R 9 is selected from hydrogen, halogen, -CN, -OR 10 , -NR 10 R 11 , -CF3, - an 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,

[0101] wherein, optionally, two groups R 10 and R 11may together form an optionally substituted 3- to 10-membered non-aromatic carbocyclic or heterocyclic ring.

[0102] Preferably, in the compounds of formula (I), R 9 is hydrogen.

[0103] Preferably, in the compounds of formula (I) according to the invention, only one of G or E is N.

[0104] In a first preferred aspect of formula (I), the present invention provides compounds of formula (II):

[0105]

[0106] wherein 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),

[0107] and their N-oxide forms, their pharmaceutically acceptable salts and solvates, or their optical isomers, racemates, diastereoisomers, enantiomers or tautomers.

[0108] Preferably, in the compounds of formula (II):

[0109] -Ar 1 represents aryl or heteroaryl, selected from:

[0110]

[0111] wherein:

[0112] -m is the number of ring substituents A, which is an integer equal to 0, 1, 2, 3 or 4,

[0113] -A are the same 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-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 ;

[0114] -wherein R 13 、R 14 and R 15 are 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;

[0115] -wherein, optionally, any two groups selected from R 13 、R 14 or R 15 on substituent A may together form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; where each ring is optionally further substituted by 1 to 5 groups independently selected from: halogen, -CN, -NO2, -OH, -NH2, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2;

[0116] -where any two groups A may combine with inserted atoms to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; where each ring is optionally further substituted by 1 to 5 groups independently selected from: halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2;

[0117] and / or

[0118] -Ar 2 represents an aryl or heteroaryl group selected from:

[0119]

[0120] wherein

[0121] -p is the number of ring substituents B, which is an integer equal to 0, 1, 2, 3, 4 or 5,

[0122] -B are the same 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 R 14 、-O-(C2-C6)alkylene-NR 13 R 14 、-NR 13 -(C2-C6)alkylene-NR 14 R 15 、-SR 13 、-(C1-C6)alkylene-SR 13 、-O-(C2-C6)alkylene-SR 13 、-NR 13 -(C2-C6)alkylene-SR 14 、-S(=O)-R 13 、-(C1-C6)alkylene-S(=O)-R 13 、-O-(C1-C6)alkylene-S(=O)-R 13 、-NR 13 -(C1-C6)alkylene-S(=O)-R 14 、-S(=O)2-R 13 、-(C1-C6)alkylene-S(=O)2-R 13 、-O-(C1-C6)alkylene-S(=O)2-R 13 、-NR 13-(C1-C6) alkylene - S(=O)2 - R 14 、-S(=O)2NR 13 R 14 、-(C1-C6) alkylene - S(=O)2NR 13 R 14 、-O-(C1-C6) alkylene - S(=O)2NR 13 R 14 、-NR 13 -(C1-C6) alkylene - S(=O)2NR 14 R 15 、-NR 13 -S(=O)2R 14 、-(C1-C6) alkylene - NR 13 -S(=O)2R 14 、-O-(C2-C6) alkylene - NR 13 -S(=O)2R 14 、-NR 13 -(C2-C6) alkylene - NR 14 -S(=O)2R 15 、-C(=O)-NR 13 R 14 、-(C1-C6) alkylene - C(=O)-NR 13 R 14 、-O-(C1-C6) alkylene - C(=O)-NR 13 R 14 、-NR 13 -(C1-C6) alkylene - C(=O)-NR 14 R 15 、-NR 13 C(=O)-R 14 、-(C1-C6) alkylene - NR 13 C(=O)-R 14 、-O-(C2-C6) alkylene - NR 13 C(=O)-R 14 、-NR 13 -(C2-C6) alkylene - NR 14 C(=O)-R 15 、-C(=O)-R 13 、-(C1-C6) alkylene - C(=O)-R 13 、-O-(C1-C6) alkylene - C(=O)-R 13 、-NR 13 -(C1-C6) alkylene - C(=O)-R 14 、-C(=O)-OR 13, -(C1-C6) alkylene - C(=O) - OR 13 , -O-(C1-C6) alkylene - C(=O) - OR 13 , -NR 13 -(C1-C6) alkylene - C(=O) - OR 14 , -OC(=O) - R 13 , -(C1-C6) alkylene - OC(=O) - R 13 , -O-(C2-C6) alkylene - OC(=O) - R 13 , -NR 13 -(C2-C6) alkylene - OC(=O) - R 14 , -(C1-C6) alkylene - NR 13 -C(=O) - NR 14 R 15 , -NR 13 -C(=O) - OR 14 , -(C1-C6) alkylene - NR 13 -C(=O) - OR 14 , -O-(C2-C6) alkylene - NR 13 -C(=O) - OR 14 , -NR 13 -(C2-C6) alkylene - NR 14 -C(=O) - OR 15 , -O-C(=O) - NR 13 R 14 , -(C1-C6) alkylene - O-C(=O) - NR 13 R 14 , -O-(C2-C6) alkylene - O-C(=O) - NR 13 R 14 , -NR 13 -(C2-C6) alkylene - O-C(=O) - NR 14 R 15 , -C(=O)-(C1-C6) alkylene - NR 13 R 14 , -C(=O)-(C1-C6) alkylene - OR 13 ;

[0123] - where 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;

[0124] - wherein, optionally, substituents on B selected from R 13 、R 14 or R 15 any two groups of which may together form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; each ring being optionally further substituted by 1 to 5 groups independently selected from the following: halogen, -CN, -NO2, -OH, -NH2, -(C1-C6) alkyl 、 -O-(C1-C6) alkyl and -N-((C1-C6) alkyl)2;

[0125] - any two groups B may combine with an intervening atom to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; each ring being optionally further substituted by 1 to 5 groups independently selected from the following: halogen, -CN, -OH, -NH2, -(C1-C6) alkyl, -O-(C1-C6) alkyl and -N-((C1-C6) alkyl)2.

[0126] Preferably, in the compounds of formula (II):

[0127] - A are the same or different and 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 R14 、-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 ,

[0128] -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;

[0129] - 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 by 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;

[0130] - 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; and / or

[0131] -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 ;

[0132] - wherein 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, heteroaryl, aryl, heterocycle, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-heterocycle and -(C1-C6)alkylene-aryl;

[0133] - wherein, optionally, any two groups on substituent B selected from R 13 and R 14 may together form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted by 1 to 5 groups independently selected from: halogen, CN, -OH, -NH2, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2;

[0134] - wherein any two groups B may combine with inserted atoms to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted by 1 to 5 groups independently selected from: halogen, -CN, -OH, -NH2, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2; and / or

[0135] - only one of G or E is N.

[0136] In a second preferred aspect of formula (I), the present invention provides a compound of formula (III):

[0137]

[0138] wherein G, E, Ar 1 , Ar 2 , R 1, R 2 , R 3 , R 4 and R 9 as defined above for the compounds of formula (I),

[0139] and their N-oxide forms, pharmaceutically acceptable salts and solvates, or their optical isomers, racemates, diastereoisomers, enantiomers or tautomers.

[0140] Preferably, in the compounds of formula (III),

[0141] -A is the same or different and 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 ,

[0142] -wherein 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;

[0143] -wherein, optionally, the groups R 13 and R14 can together form a 3- to 6-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; where each ring is optionally further substituted with 1 to 5 groups independently selected from the following: halogen, -CN, -OH, -NH2, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2;

[0144] -where any two groups A can combine with the inserted atom to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; where each ring is optionally further substituted with 1 to 5 groups independently selected from the following: halogen, -CN, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2; and / or

[0145] -B is the same or different and is 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 ;

[0146] -where R 13 and R 14Each 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;

[0147] - wherein, optionally, the substituents on B are selected from R 13 and R 14 Any two groups of which may together form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted by 1 to 5 groups independently selected from the following: halogen, CN, -OH, -NH2, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2;

[0148] - Any two groups B may combine with an inserted atom to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted by 1 to 5 groups independently selected from the following: halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2; and / or

[0149] - Only one of G or E is N.

[0150] Preferably, in the compounds of formula (III), G is nitrogen and E is CR 8 , wherein R 8 is as defined above.

[0151] Preferably, in the compounds of formula (III), G is nitrogen and E is CH.

[0152] The present invention also relates to the compounds according to the present invention as described herein, which are in the form of a racemic mixture or one or both forms of the individual optical isomers.

[0153] Particularly preferred compounds according to the present invention include the following compounds (preferred compound list), and their N-oxide forms, their pharmaceutically acceptable salts and solvates, or their optical isomers, racemates, diastereoisomers, enantiomers or tautomers:

[0154] 6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one,

[0155] 6-(3-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0156] 6-(4-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

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

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

[0159] 6-(2,4-Dimethylphenyl)-2-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one,

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

[0161] 2-(3-Chloropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

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

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

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

[0165] 6-(2,4-Dimethylphenyl)-2-(3-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

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

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

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

[0169] 6-(2,4-Dimethylphenyl)-2-(3-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

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

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

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

[0173] 6-(2,4-Dimethylphenyl)-2-(3-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

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

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

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

[0177] 2-(6-(2,4-Dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)nicotinonitrile,

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

[0179] 6-(2,4-Dimethylphenyl)-2-(4-hydroxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

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

[0181] 6-(2,4-Dimethylphenyl)-2-(pyridin-3-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0182] 6-(2,4-Dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0183] 6-(2,4-Dimethylphenyl)-2-(pyrazin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0184] 6-(2,4-Dimethylphenyl)-2-(pyrimidin-5-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

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

[0186] 6-(2,4-Dimethylphenyl)-2-(thiazol-4-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0187] 6-(2,4-Dimethylphenyl)-2-(1-methyl-1H-imidazol-4-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0188] 6-(2,4-Dimethylphenyl)-2-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0189] 6-(2,4-Dimethylphenyl)-2-(4,6-dimethylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0190] 2-(4-Cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0191] 2-(5-Hydroxypyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0192] 2-(5-(Hydroxymethyl)pyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0193] 6-(3-Methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0194] 6-(3-Methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0195] 6-(3-Methoxy-2-methylphenyl)-2-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

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

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

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

[0199] 6-(3-Methoxy-2-methylphenyl)-2-(4-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

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

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

[0202] 2-(5-Chloropyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0203] 6-(2,4-Dimethylphenyl)-2-(pyridin-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0204] 2-(5-Chloropyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one,

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

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

[0207] 6-(2,4-Dimethylphenyl)-2-(5-fluoropyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0208] 6-(2,4-Dimethylphenyl)-2-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0209] 6-(2,4-Dimethylphenyl)-2-(4-methoxy-5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0210] 6-(2,4-Dimethylphenyl)-2-(5-(morpholinomethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0211] 6-(2-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0212] 6-(3-(Dimethylamino)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0213] 6-(3-Methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0214] 6-(5-Methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0215] 2-(Pyridin-2-yl)-6-(o-tolyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0216] 6-(3-Cyclopropylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0217] 6-(3-Methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0218] 6-(3-(1-Hydroxyethyl)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0219] 6-(3-Cyclopropoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0220] 6-(2-Methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0221] 6-(2-Methoxy-3-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0222] 6-(1-Methyldihydroindol-4-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0223] 6-(2-Methoxy-4-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

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

[0225] 6-(2-Chloro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0226] 6-(5-Methoxy-2-(trifluoromethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

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

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

[0229] 6-(2-Methoxy-5-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0230] 6-(2-Methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0231] 6-(1-Methyldihydroindol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

[0232] 6-(2-Fluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,

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

[0234] 6-(2,5-Dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0235] 6-(2,3-Dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0236] 6-(3-(Methoxymethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0237] 6-(5-Cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0238] 6-(3-Cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0239] 6-(3-(Cyclopentyloxy)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0240] 6-(4-Methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0241] 6-(1,5-Dimethyl-1H-indazol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0242] 6- -yl-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0243] 6-(2,6-Difluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0244] 6-(2-Chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0245] 6-(1-Cyclopropyldihydroindol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0246] 6-(3-Cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0247] 6-(2-Chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[0248] 6-(2-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0249] 6-(3-(Dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0250] 6-(5-Methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

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

[0252] 6-(4-Acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

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

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

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

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

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

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

[0259] 6-(3-(Benzyloxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0260] 2-(5-Cyclopropylpyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

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

[0262] 2-(5-Cyclopropylpyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0263] 2-(5-Cyclopropylpyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0264] 6-(3-Methoxy-2-methylphenyl)-2-(5-(pyrrolidin-1-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0265] 6-(3-Methoxy-2-methylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

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

[0267] 6-(2,4-Dimethylphenyl)-2-(5-morpholinopyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0268] 6-(2,4-Dimethylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

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

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

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

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

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

[0277] 2-(5-Bromopyrimidin-2-yl)-6-(3-cyclopropoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

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

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

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

[0281] (-)-6-(2-Chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

[0282] (+)-6-(2-Chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0298]

[0299] wherein 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 formulae (I), (II) and (III).

[0300] The disclosed compounds also include all pharmaceutically acceptable isotopic variants wherein at least one atom is replaced with an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes suitable for inclusion in the disclosed compounds include, but are not limited to, isotopes of hydrogen 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. The use of isotopic variants (e.g., deuterium, 2 H) can provide certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. Additionally, certain isotopic variants of the disclosed compounds can incorporate radioactive isotopes (e.g., tritium, 3 H or 14C), which can be used for drug and / or substrate tissue distribution studies. Using positron-emitting isotopes such as 11 C, 18 F, 15 O and 13 N substitution, it can be used for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotope-labeled compounds of formulas (I) to (III) are generally used as radiolabeled tracers for imaging studies, which are prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the attached examples, using appropriate isotope-labeled reagents instead of the previously used unlabeled reagents.

[0301] If there are tautomeric forms, the name of the tautomeric form depicted by the structure is generated. However, it should be clear that other undescribed tautomeric forms are also included within the scope of the present invention.

[0302] Definition of Terms

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

[0304] In the context of the present invention, it should be understood that the definitions given for each substituent of the compound of formula (I) apply to the corresponding substituents in the compounds of formulas (II) to (III).

[0305] Furthermore, it should be understood that each definition of a substituent can be directly combined and there is no ambiguity with the definition of another substituent.

[0306] To avoid 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 the subscript is the integer 0 (zero), the group referred to by the subscript indicates the absence of the group, i.e., there is a direct bond between the groups.

[0309] In the case where the subscript is the integer 0 (zero) and the group referred to by the subscript is an alkyl group, this indicates that the group is a hydrogen atom.

[0310] In this specification, unless otherwise specified, the term "bond" refers to a saturated covalent bond. When two or more bonds are adjacent to each other, they are assumed to be equivalent to one bond. For example, in the group -V-W-, 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-chain alkyl groups, and can 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 can be methyl, ethyl, n-propyl and isopropyl.

[0312] In this specification, unless otherwise specified, the term "alkylene" includes straight-chain and branched-chain difunctional saturated hydrocarbon groups, and can 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 specified, the term "cycloalkyl" refers to an optionally substituted carbocyclic ring without heteroatoms, including mono-, bi- and tricyclic unsaturated carbocyclic rings. Cycloalkyl includes fused ring systems and spiro-fused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, fluorenyl and 1,2,3,4-tetrahydronaphthalene, etc. The term "(C3-C7)cycloalkyl" can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0314] In this specification, unless otherwise specified, the term "cycloalkenyl" refers to an optionally substituted carbocyclic ring without heteroatoms, including mono-, di- 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 can be, but is not limited to, cyclopentenyl and cyclohexenyl.

[0315] In this specification, unless otherwise specified, the term "alkenyl" includes straight-chain and branched-chain 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 can 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-chain 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 can 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-chain and branched alkynyl. The term "(C2-C6) alkynyl" has 2 to 6 carbon atoms and one or two triple bonds, and may 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, isopentynylene, 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 this specification, unless otherwise specified, 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 contains 1 to 3 heteroatoms, preferably selected from N, O, or S. Examples of "heteroaryl" may be, but are not limited to, thienyl, pyridyl, thiazolyl, isothiazolyl, furyl, pyrrolyl, triazolyl, imidazolyl, triazinyl, oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolinone, oxazolone, thiazolone, tetrazolyl, thiadiazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, benzofuryl, benzothienyl, thionaphthyl, indolyl, isoindolyl, pyridone, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, imidazopyridyl, oxazopyridyl, thiazopyridyl, imidazopyridazinyl, oxazopyridazinyl, thiazopyridazinyl, cynnolyl, pteridinyl, furazanyl, benzotriazolyl, pyrazolopyridyl, and purinyl.

[0321] In this specification, unless otherwise specified, the terms "alkylene-aryl", "alkylene-heteroaryl" and "alkylene-cycloalkyl" respectively refer to substituents connected to an aryl, heteroaryl or cycloalkyl through an alkyl group. The term "(C1-C6)alkylene-aryl" includes aryl-(C1-C6)-alkyl 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, and examples of heteroaryl are the same as those described in the above definitions, such as 2-furanylmethyl, 3-furanylmethyl, 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, and examples of cycloalkyl are the same as those described in the above definitions, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, etc.

[0322] In this specification, unless otherwise specified, the term "carbocyclic ring" refers to an optionally substituted 5- to 10-membered monocyclic, bicyclic or tricyclic saturated or partially saturated ring system and fused ring system that does not contain heteroatoms. Such a fused ring system may include a partially or fully unsaturated ring such as a benzene ring to form a fused ring system such as a benzo-fused carbocyclic ring.

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

[0324] In this specification, unless otherwise specified, 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, furanyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazolidinyl, pyrazolinyl, triazolyl, morpholinyl, piperazinyl, piperidinyl, piperidinone, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinone, thiomorpholinyl, oxadiazolyl, thiadiazolyl, tetrazolyl, phenyl, cyclohexyl, cyclopentyl, cyclohexenyl and cyclopentenyl.

[0325] In this specification, unless otherwise specified, 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 these rings may be, but are not limited to, imidazolidinyl, pyrazolinyl, morpholinyl, piperazinyl, piperidinyl, piperidone, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, tetrahydrothiopyranyl, furyl, pyrrolyl, dihydropyrrolyl, isoxazolyl, isothiazolyl, isoindolinone, dihydropyrrolo[1,2-b]pyrazole, oxazolyl, oxazolidinone, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, tetrahydropyridyl, 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 otherwise specified, the term "halo" or "halogen" may be fluorine, chlorine, bromine, or iodine.

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

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

[0329] In this specification, unless otherwise specified, the term "optionally substituted" refers to a group further bearing one or more substituents, which may be (C1-C6)alkyl, hydroxy (-OH), (C1-C6)alkylene-OR, where 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 where R is (C1-C6)alkyl), sulfonamide (S(=O)2-NH2), an ester of the formula C(O)OR (where R is (C1-C6)alkyl), and sulfonyl (S(=O)-R) (where R is (C1-C6)alkyl).

[0330] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, excipients, compositions or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problem 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 preparation of its acid or base salts. 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, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., 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, etc. Other addition salts include ammonium salts such as tromethamine, glucosamine, epomamine, etc., and metal salts such as sodium, potassium, calcium, zinc or magnesium.

[0332] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, 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 both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts is given 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" refers to derivatives of the disclosed compounds in which the parent compound is modified by preparation of its solvates. In this specification, unless otherwise stated, the term "solvate" refers to a stoichiometrically variable complex formed by a solute (e.g., a compound of formula (I)) and a solvent. The present invention includes solid forms of the compound of formula (I) in any solvate form, including, for example, solvates with water, such as hydrates, or solvates with organic solvents such as methanol, ethanol or acetonitrile, which are referred to as methanolates, ethanolates or acetonitriles, respectively; or any polymorphic form. The solvent does not interfere with the biological activity of the solute.

[0334] Pharmaceutically acceptable prodrugs of the compounds useful in the present invention, particularly compounds of formula (I), are derivatives having a chemically or metabolically cleavable group and are converted by solvolysis or under physiological conditions into the compounds useful in the present invention that are pharmaceutically active in vivo. Prodrugs of the compounds useful in the present invention can be formed in a conventional manner with the functional groups of the compounds such as amino, hydroxy or carboxy groups. Prodrug derivatives generally offer the advantages of solubility, tissue compatibility or delayed release in mammals including humans (see Bundgaard, H., Design of Prodrugs, pages 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 compounds used in the present invention, particularly compounds of formula (I), have a carboxy group, ester derivatives prepared by reacting the carboxy group with a suitable alcohol or amide derivatives prepared by reacting the carboxy group with a suitable amine can be exemplified as prodrugs. Particularly preferred ester derivatives as prodrugs are methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester or isobutyl ester. When the compounds used in the present invention have a hydroxy group, acyloxy derivatives prepared by reacting the hydroxy group with a suitable acyl halide or a suitable acid anhydride are exemplified as prodrugs. When the compounds used in the present invention have an amino group, amide derivatives prepared by reacting the amino group with a suitable acyl halide or a suitable mixed acid anhydride are exemplified as prodrugs.

[0335] The compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof can be administered as the compound itself or can be formulated for administration as a medicament. Within the scope of the present invention are pharmaceutical compositions comprising one or more compounds of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof as an active ingredient. The pharmaceutical compositions can optionally comprise one or more pharmaceutically acceptable excipients such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives or antioxidants.

[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" means an amount of a compound / drug according to the present invention that effectively prevents or treats a pathological condition.

[0341] A therapeutically effective amount can be readily determined by the attending diagnosing physician (such as a person skilled in the art) using conventional techniques and by observing the results obtained in similar circumstances. In determining a therapeutically effective amount, the attending diagnosing physician takes into account a number of factors, including but not limited to: the species of the subject; its size, age, and general health; the specific disease involved; the degree or severity of the disease involvement; the response of the individual subject; the particular compound 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", i.e., compatible with the other ingredients of the composition and not harmful to its recipient.

[0343] "Pharmaceutically" or "pharmaceutically acceptable" means molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to animals or humans, 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 agents, and absorption delaying agents, etc. The use of such media and agents for the use of a pharmaceutically active substance is well known in the art. Except for any conventional media or agents that are incompatible with the active ingredient, their use in a therapeutic composition is contemplated. Supplementary active ingredients may also be incorporated into the composition as appropriate therapeutic combinations.

[0345] The composition can be in a variety of pharmaceutical forms for the purpose of administration. With respect to suitable compositions, all compositions commonly used for systemic or local administration can be enumerated.

[0346] The pharmaceutical composition of the present invention can be prepared by any method known in the pharmaceutical art, for example, using the methods described in Remington's Pharmaceutical Sciences by Gennaro et al. (18th edition, Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical preparations and their Manufacture). To prepare the pharmaceutical composition of the present invention, a therapeutically effective amount of a specific compound, optionally in salt form, as the active ingredient is combined with a pharmaceutically acceptable carrier or diluent in the form of a close mixture, and the carrier or diluent can take various forms according to the dosage form required for administration. These pharmaceutical compositions are preferably in unit dosage forms, especially suitable for oral, topical, rectal or transdermal administration, by parenteral injection, by administration to the middle ear or inner ear or by inhalation.

[0347] It is particularly advantageous to formulate the above-mentioned pharmaceutical composition into a unit dosage form for ease of administration and uniformity of dosage. As used herein, the unit dosage form refers to a physically discrete unit suitable as a unit dose, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect and the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, cachets, suppositories, injection solutions or suspensions, etc., teaspoonfuls, tablespoonfuls and their separated multiples.

[0348] Since the compounds of the present invention are compounds that can be orally administered, the pharmaceutical composition for oral administration containing the compound is particularly advantageous.

[0349] To improve the solubility and / or stability of the compounds of the present invention in the pharmaceutical composition, it may be advantageous to use α-, β- or γ-cyclodextrin or its derivatives, especially hydroxyalkyl-substituted cyclodextrins, such as 2-hydroxypropyl-cyclodextrin or sulfobutyl-cyclodextrin. In addition, co-solvents such as alcohols can improve the solubility and / or stability of the compounds of the present invention in the pharmaceutical composition.

[0350] The present invention also relates to a method for preparing the pharmaceutical composition of the present invention, which is characterized by closely mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of the compound of the present invention.

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

[0352] The present invention also relates to the use of the compounds of the present invention or the compositions of the present invention for the preparation of medicaments or drugs.

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

[0354] Accordingly, the present invention relates to the compounds of the present invention or the compositions of the present invention for modulating, preferably reducing or inhibiting or negatively regulating the activity of mGluR receptors, particularly mGluR7.

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

[0356] The present invention also relates to a method for modulating, preferably reducing or inhibiting or negatively regulating the activity of mGluR receptors, particularly mGluR7, the method comprising administering a therapeutically effective amount of the compounds of the present invention or the compositions of the present invention to a patient in need thereof.

[0357] According to the present invention, the term "patient" or "patient in need" refers to an animal or human suffering from or likely to suffer 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 entirely within the capabilities and knowledge of those skilled in the art. A veterinarian or a doctor in the art can readily identify those subjects in need of such treatment by using clinical trials, physical examinations, medical / family histories or biological and diagnostic tests.

[0359] The present invention also relates to the compounds of the present invention or the compositions of the present invention for treating diseases associated with abnormal glutamate function.

[0360] The present invention also relates to the use of the compounds of the present invention or the compositions of the present invention in the preparation of a medicament for treating diseases associated with abnormal glutamate function.

[0361] In particular, the present invention thus also relates to the compounds of the present invention or the compositions according to the present invention for preventing or treating disorders associated with abnormal glutamate function in mammals including humans.

[0362] The present invention also relates to a method for treating diseases associated with abnormal glutamate function, the method comprising administering a therapeutically effective amount of the compounds of the present invention or the compositions of the present invention to a patient in need thereof.

[0363] As used herein, the term "treatment" refers to all processes in which the progression of a disease may be slowed, interrupted, stopped or halted or symptoms alleviated, but does not necessarily imply complete elimination of all symptoms.

[0364] The present invention also relates to the compounds or compositions of the present invention for 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 disorder, mood disorder due to general medical condition, mania, manic-depressive disorder, seasonal affective disorder; muscle spasms and disorders related to muscle spasm states including tremors, epilepsy, convulsions, migraine; disorders selected from neurodegenerative diseases such as mild cognitive impairment, Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis; disorders selected from psychotic mental disorders such as schizophrenia, delusional disorder, schizoaffective disorder, schizotypal disorder, substance-induced psychotic disorder; personality disorders including obsessive-compulsive personality disorder, schizoid personality, schizotypal disorder, borderline personality disorder, avoidant personality disorder with anxiety; childhood disorders including attention deficit / hyperactivity disorder, mental retardation, Down syndrome, tic disorders, autism spectrum disorders (such as Rett syndrome or fragile X syndrome) and autism; ear disorders including inner ear diseases, disorders, injuries or conditions such as sensorineural hearing loss, age-related hearing impairment (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 disease, acute tinnitus, chronic tinnitus, central auditory processing disorder 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; eye disorders including ocular hypertension, glaucoma, normal tension glaucoma, neurodegenerative disease conditions of the retina and optic nerve, retinal dystrophy, age-related macular degeneration and eye 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, brain hypoxia, cerebral hemorrhage or intracranial hematoma.

[0365] In particular, the present invention relates to a compound of the invention or a composition of the invention for 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 (such as 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 typically first diagnosed in infancy, childhood or adolescence, including but not limited to attention deficit disorders such as attention-deficit / hyperactivity disorder (ADHD), mental retardation, learning disorders, autism spectrum disorders (such as 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 mental disorders; somatoform disorders; sleep disorders; disorders related to muscle spasms and muscle spasticity states, including tremors, epilepsy, convulsions, migraine and traumatic brain injury.

[0366] In particular, the present invention relates to a compound of the invention or a composition of the invention for preventing or treating certain neurodegenerative conditions 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 invention or a composition of the invention for 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 invention or a composition of the invention for 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 abnormal glutamate function according to the present invention.

[0371] As already mentioned above, the term "treatment" does not necessarily imply the complete elimination or prevention of all symptoms, but can also refer to symptomatic treatment or prophylactic intervention of any of the above-mentioned disorders. In particular, symptoms that can be treated or prevented include, but are not limited to, cognitive deficits, fear behavior, hypervigilance, aggressive behavior, hearing deficits, pain, especially 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 there are alternative names, taxonomies and classification systems for the disorders described herein, and these evolve with medical and scientific progress.

[0373] The invention also relates to the use of a compound according to the invention as a radiolabeled tracer for imaging metabotropic glutamate receptors, preferably mGluR7, in mammals including humans.

[0374] The invention also relates to a compound according to general formula (I), (II), (III) or a stereoisomeric form thereof or an N-oxide thereof or a pharmaceutically acceptable salt or solvate thereof, in particular a compound according to formula (I), (II), (III) or a stereoisomeric form thereof or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the invention, for the treatment or prevention, in particular the treatment, of disorders in mammals including humans, the treatment or prevention of which is affected or facilitated by the neuromodulatory action of a compound according to the invention on mGluR, in particular mGluR7.

[0375] The invention also relates to a compound of formula (I) for the treatment, prevention, amelioration, control or reduction of the risk of various neurological and psychiatric disorders in humans associated with abnormal glutamate function, the treatment or prevention of which is affected or facilitated by the neuromodulatory action of a compound of the invention on mGluR receptors, in particular mGluR7.

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

[0377] The present invention also relates to methods for treating, preventing, ameliorating, controlling or reducing the risk of various neurological and psychiatric disorders associated with abnormal glutamate function in humans, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of the compounds of the present invention (especially the 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 their stereoisomeric forms or their N-oxides or their pharmaceutically acceptable salts or solvates, especially compounds of formula (I), (II), (III) or their stereoisomeric forms or their pharmaceutically acceptable salts or solvates, which are used for treating or preventing, especially treating 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, especially compounds of (I), (II), (III) or their stereoisomeric forms or their pharmaceutically acceptable salts or solvates in the preparation of a medicament or pharmaceutical product for treating or preventing, especially treating any of the diseases mentioned above.

[0380] The compounds of the present invention can be administered to mammals, preferably humans, for treating or preventing any of the diseases mentioned above.

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

[0382] Those skilled in the art will recognize that the therapeutically effective amount of the compounds of the present invention is an amount sufficient to modulate, inhibit or reduce the activity of mGluR, especially mGluR7, and this amount varies 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 the compound administered as a therapeutic agent for treating a disease will be determined by the attending physician according to the specific circumstances, in which the modulation, inhibition or reduction of mGluR activity, preferably mGluR7 activity, is beneficial.

[0383] Typically, a suitable dose is one that results in a compound concentration in the range of 0.5 nM to 200 μM, more typically 5 nM to 50 μM. To obtain these therapeutic concentrations, a patient in need of treatment may be administered an effective therapeutic daily dose of from about 0.01 mg / kg to about 50 mg / kg body weight, preferably from about 0.01 mg / kg to about 25 mg / kg body weight, more preferably from about 0.01 mg / kg to about 10 mg / kg body weight, more preferably from about 0.01 mg / kg to about 2.5 mg / kg body weight, even more preferably from about 0.05 mg / kg to about 1 mg / kg body weight, and more preferably from about 0.1 to about 0.5 mg / kg body weight. The amount of the compound according to the invention (also referred to herein as the active ingredient) required to achieve a therapeutic effect will of course vary on a case-by-case basis, depending on the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated. The treatment method may also include administering the active ingredient in a regimen of one to four intakes per day. In these treatment methods, the compounds of the invention are preferably formulated prior to hospitalization. As described below, suitable pharmaceutical formulations are prepared by known methods using well-known and readily available ingredients.

[0384] Combination Therapy

[0385] The compounds of the invention may be combined with one or more other medicaments for treating, preventing, controlling, ameliorating the above-mentioned diseases or disorders for which the compounds of the invention or the other medicaments may be useful or reducing the risk of the above-mentioned diseases or disorders, wherein the combination of the medicaments together is safer or more effective than either medicament alone. In another aspect, the invention relates to combination therapies, wherein the active compounds of the invention are administered together with another active compound. Such a combination may be a fixed-dose combination (the active ingredients to be combined are the subject of the same pharmaceutical formulation) or a free-dose combination (the active ingredients are in separate pharmaceutical formulations). Accordingly, another aspect of the invention relates to a combination of each active compound of the invention, preferably at least one active compound of the invention, with another active compound, said another active compound modulating a receptor or an enzyme in such a way that the efficacy and / or safety of the active compound of the invention is increased and / or the undesired side effects are reduced. The different medicaments of such a combination or product may be combined in a single formulation together with a pharmaceutically acceptable carrier or diluent, or they may each be present in separate formulations together with a pharmaceutically acceptable carrier or diluent.

[0386] Because modulators of mGluR, preferably mGluR7, that include the compounds of the present invention modulate the response of mGluR, preferably mGluR7, to endogenous glutamate and / or mGluR7 agonists and / or Group III agonists, it is understood that the present invention extends to the treatment of diseases associated with abnormal glutamate function by administering a combination of an effective amount of an mGluR7 modulator that includes the compounds of the present invention with an mGluR7 agonist and / or a Group III mGluR agonist.

[0387] The compounds of the present invention can also be used in combination with psychotherapy for the treatment, prevention, control, amelioration of a disease or disorder or reduction of the risk of a disease or disorder for which the compounds of the present invention can be useful.

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

[0389] The present invention also relates to a kit, which comprises:

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

[0391] - at least one other compound that modulates mGluR activity, preferably a compound that inhibits or reduces mGluR activity, preferably the mGluR is mGluR7, or a pharmaceutical composition comprising at least one compound that modulates mGluR activity, preferably a compound that inhibits or reduces mGluR activity, 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 depend on the particular compound of the present invention used, the particular disorder being treated, the severity of the disorder being treated, the age, weight, sex, degree of the disorder and general physical condition of the particular patient, and other medications the individual may be taking. In addition, it is obvious that the effective daily dosage can be decreased or increased depending on the response of the subject being treated and / or the evaluation of the physician prescribing the compounds of the present 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 compounds of the present invention that can be combined with a carrier substance 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 compounds of the present invention may preferably contain from 0.1 mg to about 1000 mg of the active compound. Preferred unit doses are from 1 mg to about 500 mg. More preferred unit doses are from 1 mg to about 300 mg. Even more preferred unit doses are from 1 mg to about 100 mg.

[0396] Such unit doses may be administered more than once a day, for example 2, 3, 4, 5, or 6 times a day, but preferably 1 or 2 times a day, such 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. Preferred doses are from 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, gender, and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs previously administered; and the severity of the particular disease being treated, which are well known to those skilled in the art.

[0397] A typical dose may be a 1 mg to about 100 mg tablet, or 1 mg to about 300 mg, taken once or multiple times a day, or an immediate release capsule or tablet taken once a day and containing a proportionately higher amount of the active ingredient. Delayed release effects can be obtained through capsule materials that dissolve at different pH values, through capsules or gel formulations that release slowly by osmotic pressure, or by any other known controlled release method.

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

[0399] Preparation of Compounds

[0400] A. Synthetic Methods

[0401] The compounds of the present invention, in particular the compounds of formulas (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 procedures. In all of the procedures described below, it should be understood that, in accordance with the general principles of organic chemistry, protecting groups for sensitive or reactive groups are used when necessary. The protecting groups are manipulated according to standard methods (T.W. Green and P.G.M. Wuts, 1991, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc.). These groups are then removed by methods readily apparent to those skilled in the art at a convenient stage of the synthesis.

[0402] The compounds of the present invention may be represented 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 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 give 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, resolution can be carried out by fractional crystallization as the salt of an optically active acid from various solvents or by other methods known in the literature.

[0403] Resolution of the final product, intermediate or starting material can be carried out by any suitable method known in the art (E.L. Eliel, S.H. Wilen and L.N. Mander, 1984, Stereochemistry of Organic Compounds, Wiley-Interscience).

[0404] wherein Ar 1 or Ar 2 Many heterocyclic compounds of formulas (I) to (III) in which Ar is a heteroaryl or heterocyclic group can be prepared using synthetic routes well known in the art (A.R. Katrizky and C.W. Rees, 1984, Comprehensive Heterocyclic Chemistry, Pergamon Press).

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

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

[0407] wherein R 9 The compounds of formulas (I), (II) and (III) in which R is hydrogen can be obtained according to Scheme 1 below:

[0408]

[0409] The cyclohexanone intermediate 1 is commercially available or can be synthesized by a variety of methods described in the literature by a person skilled in the art of organic chemistry.

[0410] The secondary alcohol intermediate 2 can be obtained by nucleophilic addition of an organometallic Ar 2 -M reagent (M = Li or MgX), which can be prepared, for example, from the corresponding appropriately substituted aromatic ring by metal-halide exchange using, for example, nBuLi or iPrMgCl, in an inert atmosphere such as, for example, a nitrogen atmosphere, 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, for example with pure TFA or in the presence of DCM, at room temperature or under reflux to form intermediate 3 (step ii).

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

[0413] The ketone intermediate 4 can be further reacted with POCl3 in the presence of DMF to give the chlorocarbonyl intermediate 5 (step iv), which is involved in 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 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 the 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 a person skilled in the art of organic chemistry) 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 formulas (I), (II) and (III), in which Y is CH and R 4 , R 8 and R 9 is hydrogen.

[0415] Alternatively, according to Method B in Process 1, intermediate 6 can react 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, and reacting at an appropriate temperature (Step vii) to obtain intermediate 7. Intermediate 7 reacts 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, and in a solvent such as toluene to carry out a cross-coupling reaction, or 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, and carrying out a copper-mediated coupling reaction at a suitable temperature (Step viii) to obtain the final compounds of formula (I), (II), and (III), where Y is CH, and R 4 、R 8 and R 9 are hydrogen.

[0416] Alternatively, intermediate 7 can use boric 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, and carrying out a Chan-Lam coupling reaction at a suitable temperature (Step ix) to obtain the final compounds of formula (I), (II), and (III), where Y is CH, and R 4 、R 8 and R 9 are hydrogen.

[0417] Alternatively, according to Method C in Process 1, lactone intermediate 6 can be converted to ester intermediate 8 as follows: using an aqueous solution of NaOH, followed by a halo-alkyl reagent such as ethyl iodide, in the presence of DMF, and alkylating at a suitable temperature (Step x). Then, as described in Methods A and B, intermediate 8 can be carried out according to Step xi, followed by Step viii or ix, or according to Step xii, in a 1- or 2-step sequence to obtain the final compounds of formula (I), (II), and (III), where Y is CH, and R 4 and R 8 are hydrogen.

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

[0419]

[0420] The cyclic ketone - acetal intermediate 9 can react with POCl3 in the presence of DMF to give the chloro - carbonyl intermediate 10 (step i). The carbonylation coupling reaction of intermediate 10 is carried out as follows: 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 obtain the ester - aldehyde intermediate 11 (step ii). Intermediate 12 can be obtained as follows: intermediate 11 reacts 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), and then using 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, for a cross - coupling reaction, or 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 for a copper - mediated coupling reaction (step iv).

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

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

[0423] According to method A in Scheme 2, intermediate 15 can use a boronate Ar 1 -B(OR’)2 or boric acid Ar 1 -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 mixture of dioxane / H2O, at a suitable temperature for a Suzuki cross - coupling reaction to obtain intermediate 16 (step viii).

[0424] Alternatively, according to Method B in Process 2, Intermediate 15 can react with bis(pinacolato)diboron 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 obtain Intermediate 17 (Step x). Intermediate 17 can be cross-coupled 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 obtain Intermediate 16 (Step xi).

[0425] Finally, the 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 obtain the final compounds of formula (I), (II) and (III), where Y is CH, and R 2 and R 8 is hydrogen (Step ix).

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

[0427]

[0428] The cyclic enone Intermediate 18 is commercially available or can be synthesized by those skilled in the art of organic chemistry using various methods described in the literature. Using a boronic ester Ar 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 under an inert atmosphere, a cross-coupling reaction can be carried out to obtain Intermediate 19 (Step i). The ketone Intermediate 19 can react with POCl3 in the presence of DMF to obtain Intermediate 20 (Step ii), and it can be further carbonylated and coupled 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 obtain the ester-aldehyde Intermediate 21 (Step iii). Intermediate 21 can react with a reactive (hetero)aryl hydrazine Ar 1 -NH2-NH2 (which can be commercially available or prepared by those skilled in the art of organic chemistry) in the presence of a catalyst such as PTSA and a solvent such as toluene or EtOH, at a suitable temperature (Step iv) to obtain the final compounds of formula (I), (II) and (III), where Y is CH, and R 2 and R8 and R 9 is hydrogen.

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

[0430]

[0431] The cycloalkylidene ketone intermediate 18 can be commercially available or synthesized by a person skilled in the art of organic chemistry using a variety of methods described in the literature. By reacting the intermediate 18 with a suitably substituted aromatic halide Ar 2 -X (preferably Ar 2 -Br or Ar 2 -I) in a cross-coupling reaction in the presence of a transition metal catalyst such as Pd(dppf)Cl2, in a solvent such as Et3N or Na2CO3, in the presence of a solvent such as DMSO, at a suitable temperature (step i), the intermediate 31 can be prepared.

[0432] The cycloalkenyl ketone intermediate 31 can be converted to the corresponding keto-ester intermediate 34 through a two-step reaction sequence: (step ii) in the presence of a base such as LDA or NaH, in an aprotic solvent such as THF, at a controlled temperature such as -78 °C, using, for example, cyanoethyl carbonate or diethyl carbonate for α-carboxylation; then (step iii) in a hydrogen atmosphere, at a pressure such as 50 psi, at a suitable temperature, using a catalytic palladium such as Pd / C for double bond hydrogenolysis.

[0433] This 2-step sequence can be reversed, starting with the hydrogenolysis step (iii), followed by the α-carboxylation step (ii) using the above conditions, to obtain the keto-ester intermediate 34.

[0434] The keto-ester intermediate 34 can be reacted with formamidine in the presence of a base such as K2CO3 and a solvent such as EtOH at a suitable temperature to obtain the intermediate 35 (step iv).

[0435] The intermediate 35 can be subjected to the cross-coupling reaction described in Scheme 1, for example, 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, and reacted with an aromatic halide Ar 1 -X (preferably Ar 1 -Br), or a copper-mediated coupling reaction can be carried out 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 v) to obtain the final compounds of formula (I), (II) and (III), wherein R 2, R 7 and R 9 is hydrogen.

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

[0437]

[0438] Compounds of formula (I), (II) and (III) represented by Intermediate 49, wherein the substituent B on Ar 2 is methoxy, can be reacted with a dealkylating agent such as boron tribromide in a solvent such as DCM at an appropriate temperature (Step I) to give hydroxy intermediate 50. Then, the hydroxy functional group can 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 is substituted by an oxo group.

[0439] Wherein any compound of formula (I), (II) and (III) wherein Ar 1 is substituted by alkyl, aryl, heteroaryl, amino or alkoxy can be obtained according to the following Scheme 6:

[0440]

[0441] Intermediate 51, represented by Intermediate 7 in Scheme 1 or Intermediate 35 in Scheme 4 but not limited thereto, can be subjected to a cross-coupling reaction with a halo(hetero)aryl of 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 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 boric acid or a borate 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 an appropriate temperature (Step II) to give compounds of formula (I), (II) and (III) wherein Ar 1 bears alkyl, aryl or heteroaryl.

[0442] According to Method B, a similar halide intermediate 52 (wherein A is a halogen group) can be reacted with an amine R 1 R2 NH reacts 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 obtain the compounds of formulas (I), (II) and (III), wherein Ar 1 carries an amino group.

[0443] In addition, according to Method C, intermediate 52, wherein A is an -OH group, can react with an alkyl halide (such as R-I, 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 obtain the compounds of formulas (I), (II) and (III), wherein Ar 1 carries an alkoxy group.

[0444] Alternatively, the compounds of formulas (I), (II) and (III), wherein Ar 2 carries a carbonyl group, can be obtained according to the following Scheme 7:

[0445]

[0446] Intermediate 53, wherein X is Br, can undergo a cross-coupling reaction with tributylstannyl ethoxyvinyl in the presence of a catalyst / ligand system (such as Pd(PPh3)4), a base (such as t-BuOK), in a solvent (such as dioxane), at an appropriate temperature, and subsequently hydrolysis in an acidic medium such as aqueous HCl, in a solvent such as EtOH, to obtain intermediate 54. The reduction of the cyclic double bond in intermediate 54 can be carried out 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 obtain the final compounds of formulas (I), (II) and (III), wherein Y is CH, Ar 2 carries an acetyl group.

[0447] B. Experiments

[0448] Several methods for preparing the compounds of the present invention are illustrated in the following examples. Unless otherwise stated, all starting 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 are carried out at room temperature without an inert atmosphere.

[0452] Example 1: 6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one, prepared according to Process 1, Method A.

[0453]

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

[0455] According to Process 1, Step i: To a solution of 1-bromo-2,4-dimethyl-benzene (20.00 g, 108.07 mmol, 1.00 equiv) in THF (100 mL) under N2 atmosphere and cooled to -70 °C was added dropwise n-BuLi (2.5 M, 45.39 mL, 1.05 equiv). The reaction mixture was stirred at -70 °C for 2 h. Then a solution of 1,4-dioxaspiro[4.5]decan-8-one (17.72 g, 113.47 mmol, 1.05 equiv) in THF (100 mL) was added dropwise at -70 °C, and the reaction mixture was stirred at -70 °C for 2 h. The reaction mixture was quenched with water (300 mL) and extracted with EtOAc (200 mL x 2). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (PE:EtOAc 10 / 1 to 5 / 1). Intermediate 2a (24.00 g, 86.00 mmol, 79.57% yield) was obtained as a pale yellow solid.

[0456] 1 1H NMR (DMSO-d6; 400 MHz) δ 7.31 - 7.29 (m, 1H), 6.90 - 6.89 (m, 2H), 4.66 (s, 1H), 3.87 (s, 4H), 2.49 (s, 3H), 2.21 (s, 3H), 2.00 - 1.94 (m, 4H), 1.79 - 1.76 (m, 2H), 1.53 - 1.51 (m, 2H).

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

[0458] According to Process 1, Step ii: A solution of intermediate 2a (10.00 g, 38.12 mmol, 1.00 equiv) in TFA (500.00 mL) was stirred at 15 °C for 1 hour, then the mixture was stirred and heated to 80 °C for 18 hours. The mixture was concentrated under vacuum. The residue was quenched with saturated NaHCO3 solution and the pH was adjusted to pH 7 - 8, and extracted with EtOAc (200 mL x 2). 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 (11.00 g, 54.92 mmol, 72.04% yield) was obtained as a pale yellow oil. 1 1H NMR (CDCl3; 400 MHz) δ 7.06 - 6.97 (m, 4H), 6.23 - 6.18 (m, 1H), 3.95 - 3.91 (m, 1H), 2.57 - 2.53 (m, 2H), 2.51 (s, 3H), 2.50 - 2.33 (m, 4H), 1.99 - 1.95 (m, 1H).

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

[0460] According to Process 1, Step iii: Under N2 atmosphere, Pd / C (2.00 g, 49.93 mmol, 1.00 equiv) was added to a solution of intermediate 3a (10.00 g, 49.93 mmol, 1.00 equiv) in EtOAc (100.00 mL). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 30 °C under H2 (50 psi) for 4 hours. The mixture was filtered and the filtrate was concentrated under vacuum. Crude product intermediate 4a (10.00 g, 49.43 mmol, 99.01% yield) was obtained and used directly in the next step as a brown solid. 1 1H NMR (CDCl3; 400 MHz) δ 7.12 - 7.02 (m, 3H), 3.25 - 3.22 (m, 1H), 2.57 - 2.53 (m, 4H), 2.41 (s, 3H), 2.33 (s, 3H), 2.16 - 2.15 (m, 2H), 1.96 - 1.94 (m, 2H).

[0461] Intermediate 5a: 2-Chloro-5-(2,4-dimethylphenyl)cyclohex-1-enecarbaldehyde

[0462] According to Process 1, Step iv: At 0 °C under a N2 atmosphere, POCl3 (6.82 g, 44.49 mmol, 3.00 equivalents) was added dropwise to a solution of intermediate 4a (13.01 g, 177.96 mmol, 12.00 equivalents) in CH2Cl2 (10 mL). After stirring at 10 °C for 1 hour, a solution of intermediate 1c (3.00 g, 14.83 mmol, 1.00 equivalent) in CH2Cl2 (40 mL) was added dropwise. The mixture was stirred at 50 °C for 4 hours. The mixture was quenched with saturated NaHCO3 solution and the pH was adjusted to pH 7 - 8, and extracted with CH2Cl2 (150 mL x 2). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column 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 1H NMR (400 MHz, CDCl3) δ 10.25 (s, 1H), 7.09 - 6.95 (m, 3H), 3.03 - 2.73 (m, 4H), 2.32 (d, J = 2.6 Hz, 6H), 2.23 - 2.06 (m, 1H), 2.05 - 1.90 (m, 2H).

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

[0464] According to Process 1, Step v: Under a N2 atmosphere, to a mixture of intermediate 5a (500.00 mg, 2.01 mmol, 1.00 equivalent), Pd(dppf)Cl2 (147.08 mg, 201.01 μmol, 0.10 equivalent), and Et3N (610.19 mg, 6.03 mmol, 3.00 equivalent) in MeOH (10.00 mL). The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred at 90 °C for 12 hours under a CO atmosphere (1 MPa). The mixture was filtered and the filtrate was concentrated in vacuo. Intermediate 6a (650.00 mg, crude) was obtained as a brown solid. 1 1H NMR: (400 MHz, CDCl3) δ 7.09 - 6.98 (m, 3H), 5.67 (s, 1H), 3.60 (s, 3H), 3.19 - 3.05 (m, 1H), 2.70 - 2.59 (m, 1H), 2.57 - 2.44 (m, 2H), 2.33 (s, 3H), 2.31 (s, 3H), 2.06 - 1.95 (m, 1H), 1.88 - 1.76 (m, 1H).

[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 pyridin-2-yl-hydrazine hydrochloride (160.28 mg, 1.47 mmol, 2.00 equivalents) 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 mL x 2). The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative-HPLC to give Example 1 (30.00 mg, 90.52 μmol, 6.16% yield), as a brown solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.67 (d, J = 4.0 Hz, 1H), 7.82 - 7.91 (m, 1H), 7.69 - 7.77 (m, 2H), 7.33 - 7.39 (m, 1H), 6.99 - 7.15 (m, 3H), 3.09 - 321 (m, 1H), 2.99 (d, J = 17.6 Hz, 1H), 2.76 - 2.86 (m, 1H), 2.59 - 2.75 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2.08 - 2.19 (m, 1H), 1.80 - 1.95 (m, 1H).

[0467] Example 2: 6-(3-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Process 1, Method A.

[0468]

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

[0470] According to Process 1, Steps i to v: Intermediate 6b was prepared starting from 1-bromo-3-methoxybenzene similar to intermediate 6a in Example 1, to give a brown liquid, with 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 Process 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), a yellow solid.( 1 1H-NMR (400 MHz, MeOD) δ 8.62 - 8.61 (m, 1H), 8.08 - 8.05 (m, 1H), 7.90 (s, 1H), 7.69 - 7.67 (m, 1H), 7.62 - 7.56 (m, 1H), 7.29 - 7.27 (m, 1H), 6.94 - 6.90 (m, 2H), 6.83 - 6.84 (1H), 3.07 - 2.86 (m, 4H), 2.68 - 2.57 (m, 1H), 1.99 - 1.96 (m, 1H), 1.96 - 1.93 (m, 1H).

[0473] Example 3: 6-(4-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Process 1, Method A.

[0474]

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

[0476] According to Process 1, Steps i to v: Intermediate 6c was prepared starting from 1-bromo-4-methoxybenzene similar to intermediate 6a in Example 1, to give a brown liquid with an overall yield of 14%. 1 1H NMR (MeOD; 400 MHz) δ 7.22 - 7.20 (m, 2H), 6.91 - 6.87 (m, 2H), 5.88 (s, 1H), 3.93 - 3.91 (m, 1H), 3.83 - 3.81 (m, 1H), 3.77 - 3.80 (m, 3H), 2.95 - 2.85 (m, 1H), 2.64 - 2.59 (m, 1H), 2.31 - 2.42 (m, 3H), 2.05 - 2.03 (m, 1H), 1.85 - 1.80 (m, 1H), 1.30 - 1.25 (m, 3H).

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

[0478] According to Process 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 1H-NMR (400 MHz, DMSO-d6) δ 8.61 - 8.60 (m, 1H), 8.04 - 8.00 (m, 1H), 7.59 - 7.56 (m, 2H), 7.30 - 7.23 (m, 2H), 6.93 - 6.90 (m, 2H), 3.70 (s, 3H), 2.92 - 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 (400 mg) constituting the racemic Example 1 were separated by preparative SFC to give (-)-6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one with 100% enantiomeric excess, Example 4 (72 mg, 18%), and (+)-6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one with 99% enantiomeric excess, Example 5 (59 mg, 15%), both as yellow solids.

[0482] Example 4:[[ID=1⑤]] 1 1H-NMR (400 MHz, CDCl3) δ 8.67 (br.s., 1H), 7.82 - 7.91 (m, 1H), 7.69 - 7.77 (m, 2H), 7.33 - 7.39 (m, 1H), 6.99 - 7.15 (m, 3H), 3.09 - 3.21 (m, 1H), 2.99 (d, J = 17.6 Hz, 1H), 2.76 - 2.86 (m, 1H), 2.59 - 2.75 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2.08 - 2.19 (m, 1H), 1.80 - 1.95 (m, 1H).

[0483] Example 5:1 H-NMR (400 MHz, CDCl3) δ 8.67 (br.s., 1H), 7.82 - 7.91 (m, 1H), 7.69 - 7.77 (m, 2H), 7.33 - 7.39 (m, 1H), 6.99 - 7.15 (m, 3H), 3.09 - 3.21 (m, 1H), 2.99 (d, J = 17.6 Hz, 1H), 2.76 - 2.86 (m, 1H), 2.59 - 2.75 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2.08 - 2.19 (m, 1H), 1.80 - 1.95 (m, 1H).

[0484] Example 6: 6-(2,4-Dimethylphenyl)-2-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one, prepared according to Process 1, Method B.

[0485]

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

[0487] According to Process 1, Step vii: To a solution of Intermediate 6a (1.2 g, 4.19 mmol, 1 equivalent) in EtOH (10 mL) and AcOH (1 mL) was added N2H4·H2O (427.66 mg, 8.37 mmol, 415.20 μL, 2.0 equivalents). The mixture was stirred at 80 °C for 3 hours and then cooled to 0 °C. The white solid formed was collected by filtration. Intermediate 7a (830 mg, 3.26 mmol, 77.96% yield) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 7.64 (s, 1H), 7.15 - 7.08 (m, 1H), 7.03 - 6.93 (m, 2H), 3.09 - 2.93 (m, 1H), 2.74 - 2.57 (m, 3H), 2.47 - 2.37 (m, 1H), 2.28 (s, 3H), 2.24 (s, 3H), 1.96 - 1.85 (m, 1H), 1.83 - 1.68 (m, 1H).

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

[0489] According to Process 1, Step viii: To a solution of intermediate 7a (100.00 mg, 353.87 μmol, 1.00 equiv) in DMF (5.00 mL) at 20 °C under N2 atmosphere 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), K3PO4 (187.79 mg, 884.68 μmol, 2.50 equiv). Then the mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was filtered, the filtrate was acidified to pH = 5 with 12 M aqueous HCl and filtered. The filtrate was purified by preparative-HPLC to give Example 6 (71.93 mg, 196.61 μmol, 55.56% yield) as a beige solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.62 (d, J = 2.3 Hz, 1H), 7.87 - 7.82 (m, 1H), 7.78 - 7.73 (m, 2H), 7.14 - 7.09 (m, 1H), 7.08 - 7.04 (m, 2H), 3.20 - 3.11 (m, 1H), 3.04 - 2.95 (m, 1H), 2.87 - 2.78 (m, 1H), 2.77 - 2.60 (m, 2H), 2.34 (s, 3H), 2.33 (s, 3H), 2.20 - 2.11 (m, 1H), 1.95 - 1.83 (m, 1H).

[0490] Example 7: 2-(4-chloropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Process 1, Method B.

[0491]

[0492] According to Process 1, Step viii: Example 7 was prepared starting from intermediate 7a (150.00 mg, 530.81 μmol) and 2-bromo-4-chloropyridine (306.45 mg, 1.59 mmol) as in Example 6 to give Example 7 (178.10 mg, 484.85 μmol, 91.34% yield) as a brown solid. 1H-NMR (400 MHz, CDCl3) δ 8.49 (d, J = 5.4 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.66 (s, 1H), 7.29 (dd, J = 1.8, 5.3 Hz, 1H), 7.05 - 7.00 (m, 1H), 6.99 - 6.94 (m, 2H), 3.12 - 3.02 (m, 1H), 2.96 - 2.86 (m, 1H), 2.80 - 2.69 (m, 1H), 2.67 - 2.53 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 2.10 - 2.02 (m, 1H), 1.86 - 1.74 (m, 1H).

[0493] Example 8: 2-(3-chloropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one was prepared according to Process 1, Method B.

[0494]

[0495] According to Process 1, Step viii: Example 8 was prepared starting from intermediate 7a (200.00 mg, 707.74 μmol) and 2-bromo-3-chloropyridine (408.59 mg, 2.12 mmol) as in Example 6, to give Example 8 (24.40 mg, 66.69 μmol, 9.42% yield), as an off-white solid. 1 H-NMR (400 MHz, CDCl3) δ 8.58 (dd, J = 1.6, 4.7 Hz, 1H), 7.95 (dd, J = 1.5, 8.0 Hz, 1H), 7.72 (s, 1H), 7.44 (dd, J = 4.6, 8.0 Hz, 1H), 7.16 - 7.11 (m, 1H), 7.10 - 7.04 (m, 2H), 3.17 (br s, 1H), 3.02 (br d, J = 19.6 Hz, 1H), 2.89 - 2.78 (m, 1H), 2.78 - 2.61 (m, 2H), 2.38 (s, 3H), 2.34 (s, 3H), 2.20 - 2.10 (m, 1H), 1.91 (br s, 1H).

[0496] Example 9: 6-(2,4-dimethylphenyl)-2-(6-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one was prepared according to Process 1, Method B.

[0497]

[0498] 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 Process 1, Step viii as in Example 6, to give Example 9 (32.00 mg, 91.59 μmol, 33% yield), as a yellow solid.( 1 1H-NMR (400 MHz, DMSO-d6) δ 8.23 - 8.21 (m, 1H), 7.88 (s, 1H), 7.61 - 7.59 (m, 1H), 7.36 - 7.34 (m, 1H), 7.16 - 7.13 (m, 1H), 7.02 - 7.00 (m, 2H).

[0499] Example 10: 6-(2,4-dimethylphenyl)-2-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, was prepared according to Process 1, Method B.

[0500]

[0501] 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 Process 1, Step viii as in Example 6, to give Example 10 (32.00 mg, 91.59 μmol, 23% yield), as a yellow solid.( 1 1H-NMR (400 MHz, DMSO-d6) δ 8.62 - 8.61 (m, 1H), 7.97 - 7.95 (m, 1H), 7.86 (s, 1H), 7.71 - 7.67 (m, 1H), 7.16 - 7.14 (m, 1H), 7.02 - 7.00 (m, 2H), 3.10 - 3.07 (m, 1H), 2.84 - 2.70 (m, 4H), 2.30 (s, 3H), 2.25 (s, 3H), 1.94 - 1.84 (m, 1H), 1.83 - 1.81 (m, 1H).

[0502] Example 11: 6-(2,4-dimethylphenyl)-2-(4-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, was prepared according to Process 1, Method B.

[0503]

[0504] According to Process 1, Step viii: Example 11 was prepared starting from intermediate 7a (60.00 mg, 235.91 μmol) and 2-bromo-4-fluoropyridine (103.79 mg, 589.78 μmol) according to Example 6, to give Example 11 (24.00 mg, 68.69 μmol, 29% yield), as a yellow solid. 1 1H-NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.88 (s, 1H), 7.66 - 7.61 (m, 1H), 7.53 - 7.51 (m, 1H), 7.16 - 7.14 (m, 1H), 7.03 - 7.00 (m, 2H), 3.08 - 3.01 (m, 1H), 2.84 - 2.58 (m, 4H), 2.30 (s, 3H), 2.25 (s, 3H), 1.94 - 1.84 (m, 1H), 1.83 - 1.81 (m, 1H).

[0505] Example 12: 6-(2,4-Dimethylphenyl)-2-(3-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, was prepared according to Process 1, Method B.

[0506]

[0507] According to Process 1, Step viii: Example 12 was prepared starting from intermediate 7a (90.00 mg, 353.87 μmol) and 2-bromo-3-fluoropyridine (186.83 mg, 1.06 mmol) according to Example 6, to give Example 12 (15.00 mg, 42.93 μmol, 12% yield), as a yellow solid. 1 1H-NMR (400 MHz, DMSO-d6) δ 8.50 - 8.48 (m, 1H), 8.06 - 8.01 (m, 1H), 7.92 (s, 1H), 7.72 - 7.70 (s, 1H), 7.17 - 7.14 (m, 1H), 7.02 - 7.00 (m, 2H), 3.11 - 3.05 (m, 1H), 2.86 - 2.68 (m, 4H), 2.34 (s, 3H), 2.27 (s, 3H), 1.94 - 1.83 (m, 2H).

[0508] Example 13: 6-(2,4-Dimethylphenyl)-2-(6-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, was prepared according to Process 1, Method B.

[0509]

[0510] According to Process 1, Step viii: Example 13 was prepared starting from intermediate 7a (70.00 mg, 275.23 μmol) and 2-bromo-4-methoxypyrimidine (129.37 mg, 688.08 μmol, 84.56 μL) according to Example 6, to obtain Example 13 (45.00 mg, 124.50 μmol, 45% yield), which is a yellow solid. 1 1H-NMR (400 MHz, DMSO-d6) δ 7.93 - 7.84 (m, 1H), 7.84 (s, 1H), 7.16 - 7.12 (m, 2H), 7.02 - 7.00 (m, 2H), 6.96 - 6.94 (m, 1H), 3.83 (s, 3H), 3.10 - 3.07 (m, 1H), 2.81 - 2.66 (m, 4H), 2.31 (s, 3H), 2.25 (s, 3H), 1.95 - 1.93 (m, 1H), 1.83 - 1.80 (m, 1H).

[0511] Example 14: 6-(2,4-dimethylphenyl)-2-(5-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, was prepared according to Process 1, Method B.

[0512]

[0513] According to Process 1, Step viii: Example 14 was prepared starting from intermediate 7a (70.00 mg, 275.23 μmol) and 2-bromo-5-methoxypyrimidine (129.37 mg, 688.08 μmol) according to Example 6, to obtain Example 14 (30.00 mg, 83.00 μmol, 30.16% yield), which is a yellow solid. 1 1H-NMR (400 MHz, DMSO-d6) δ 8.28 - 8.27 (m, 1H), 7.82 (s, 1H), 7.60 - 7.59 (m, 1H), 7.58 - 7.57 (m, 1H), 7.16 - 7.13 (m, 1H), 7.02 - 7.00 (m, 2H), 3.91 (s, 3H), 3.10 - 3.07 (m, 1H), 2.93 - 2.55 (m, 4H), 2.31 (s, 3H), 2.25 (s, 3H), 1.93 - 1.90 (m, 1H), 1.84 - 1.80 (m, 1H).

[0514] Example 15: 6-(2,4-dimethylphenyl)-2-(4-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, was prepared according to Process 1, Method B.

[0515]

[0516] According to Process 1, Step viii: Example 15 was prepared starting from intermediate 7a (70.00 mg, 275.23 μmol) and 2-bromo-4-methoxypyrimidine (129.37 mg, 688.08 μmol) according to Example 6, to obtain Example 15 (53.00 mg, 146.64 μmol, 53% yield), which is a yellow solid. 1 1H-NMR (400 MHz, DMSO-d6) δ 8.41 - 8.39 (m, 1H), 7.83 (s, 1H), 7.16 - 7.10 (m, 3H), 7.02 - 7.00 (m, 1H), 3.89 (s, 3H), 3.07 - 3.02 (m, 1H), 2.78 - 2.66 (m, 4H), 2.30 (s, 3H), 2.25 (s, 3H), 1.93 - 1.83 (m, 1H), 1.82 - 1.80 (m, 1H).

[0517] Example 16: 6-(2,4-dimethylphenyl)-2-(3-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, was prepared according to Process 1, Method B.

[0518]

[0519] According to Process 1, Step viii: Example 16 was prepared starting from intermediate 7a (90.00 mg, 353.87 μmol) and 2-bromo-3-methoxypyrimidine (166.34 mg, 884.68 μmol) according to Example 6, to obtain Example 16 (17.00 mg, 47.03 μmol, 13% yield), which is a yellow solid. 1 1H-NMR (400 MHz, DMSO-d6) δ 8.15 - 8.13 (m, 1H), 7.81 (s, 1H), 7.72 - 7.70 (m, 1H), 7.57 - 7.55 (m, 1H), 7.16 - 7.14 (m, 1H), 7.02 - 7.00 (m, 2H), 3.80 (s, 3H), 3.10 - 3.07 (m, 1H), 2.82 - 2.67 (m, 4H), 2.31 (s, 3H), 2.25 (s, 3H), 1.92 - 1.81 (m, 2H).

[0520] Example 17: 6-(2,4-dimethylphenyl)-2-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, was prepared according to Process 1, Method B.

[0521]

[0522] According to Process 1, Step viii: Example 17 was prepared starting from intermediate 7a (80.00 mg, 283.10 μmol) and 2-bromo-6-methylpyridine (146.10 mg, 849.30 μmol, 96.75 μL) according to Example 6, to obtain Example 17 (59.06 mg, 170.97 μmol, 60.39% yield), which is a beige solid. 1 1H-NMR (400 MHz, CDCl3) δ 7.81 - 7.69 (m, 2H), 7.45 (d, J = 7.9 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 7.12 - 7.08 (m, 1H), 7.07 - 7.02 (m, 2H), 3.19 - 3.08 (m, 1H), 3.03 - 2.92 (m, 1H), 2.86 - 2.76 (m, 1H), 2.73 - 2.59 (m, 5H), 2.35 (s, 3H), 2.32 (s, 3H), 2.12 (td, J = 2.9, 10.4 Hz, 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 Process 1, Method B.

[0524]

[0525] According to Process 1, Step viii: Example 18 was prepared starting from intermediate 7a (80.00 mg, 283.10 μmol) and 2-bromo-5-methylpyridine (146.10 mg, 849.30 μmol) according to Example 6, to obtain Example 18 (52.33 mg, 151.49 μmol, 53.51% yield), which is a beige solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.49 (d, J = 1.5 Hz, 1H), 7.73 (s, 1H), 7.71 - 7.66 (m, 1H), 7.64 - 7.60 (m, 1H), 7.14 - 7.10 (m, 1H), 7.08 - 7.04 (m, 2H), 3.21 - 3.09 (m, 1H), 3.06 - 2.94 (m, 1H), 2.87 - 2.77 (m, 1H), 2.76 - 2.60 (m, 2H), 2.43 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H), 2.19 - 2.09 (m, 1H), 1.96 - 1.81 (m, 1H).

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

[0527]

[0528] According to Process 1, Step viii: Example 19 was prepared starting from intermediate 7a (80.00 mg, 283.10 μmol) and 2-bromo-4-methylpyridine (146.10 mg, 849.30 μmol, 94.26 μL) as in Example 6, to give Example 19 (69.51 mg, 201.22 μmol, 71.08% yield), as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.53 (d, J = 5.1 Hz, 1H), 7.74 (s, 1H), 7.56 (s, 1H), 7.14 - 7.10 (m, 1H), 7.08 - 7.04 (m, 1H), 7.08 - 7.04 (m, 2H), 3.22 - 3.07 (m, 1H), 3.06 - 2.95 (m, 1H), 2.87 - 2.78 (m, 1H), 2.76 - 2.61 (m, 2H), 2.47 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H), 2.20 - 2.09 (m, 1H), 1.97 - 1.80 (m, 1H).

[0529] Example 20: 6-(2,4-Dimethylphenyl)-2-(3-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Process 1, Method B.

[0530]

[0531] According to Process 1, Step viii: Example 20 was prepared starting from intermediate 7a (80.00 mg, 283.10 μmol) and 2-bromo-3-methylpyridine (146.09 mg, 849.30 μmol) as in Example 6, to give Example 20 (8.60 mg, 24.75 μmol, 8.74% yield), as an off-white solid. 1H-NMR (400 MHz, CDCl3) δ 8.55 - 8.44 (m, 1H), 7.74 (d, J = 6.7 Hz, 1H), 7.71 (s, 1H), 7.36 (dd, J = 4.8, 7.7 Hz, 1H), 7.16 - 7.11 (m, 1H), 7.10 - 7.04 (m, 2H), 3.16 (br s, 1H), 3.07 - 2.94 (m, 1H), 2.88 - 2.78 (m, 1H), 2.77 - 2.61 (m, 2H), 2.38 (s, 3H), 2.36 - 2.33 (m, 1H), 2.34 (s, 3H), 2.27 (s, 3H), 2.20 - 2.09 (m, 1H), 1.98 - 1.83 (m, 1H).

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

[0533]

[0534] According to Process 1, Step viii: Example 21 was prepared starting from intermediate 7a (80.00 mg, 283.10 μmol) and 6-bromo-2-cyanopyridine (155.43 mg, 849.30 μmol) as in Example 6, to give Example 21 (53.43 mg, 146.31 μmol, 51.68% yield), as a white solid. 1 H-NMR (400 MHz, CDCl3) δ 8.05 - 7.99 (m, 2H), 7.81 - 7.75 (m, 2H), 7.13 - 7.10 (m, 1H), 7.08 - 7.05 (m, 2H), 3.21 - 3.11 (m, 1H), 2.99 (br dd, J = 5.3, 19.1 Hz, 1H), 2.89 - 2.80 (m, 1H), 2.78 - 2.59 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.20 - 2.11 (m, 1H), 1.96 - 1.82 (m, 1H).

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

[0536]

[0537] According to Process 1, Step viii: Example 22 was prepared starting from intermediate 7a (80.00 mg, 283.10 μmol) and 6-bromonicotinonitrile (155.43 mg, 849.30 μmol) according to Example 6, to give Example 22 (21.19 mg, 59.45 μmol, 21.00% yield), as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.03 (d, J = 2.3 Hz, 1H), 7.98 - 7.91 (m, 1H), 7.73 - 7.67 (m, 1H), 6.98 (d, J = 17.4 Hz, 3H), 3.13 - 3.01 (m, 1H), 2.97 - 2.85 (m, 1H), 2.79 - 2.70 (m, 1H), 2.68 - 2.52 (m, 2H), 2.27 (s, 3H), 2.25 (s, 3H), 2.11 - 2.02 (m, 1H), 1.87 - 1.74 (m, 1H).

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

[0539]

[0540] According to Process 1, Step viii: Example 23 was prepared starting from intermediate 7a (80.00 mg, 283.10 μmol) and 2-bromoisonicotinonitrile (17.27 mg, 94.37 μmol) according to Example 6, to give Example 23 (28.72 mg, 80.58 μmol, 28.46% yield), as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.85 (d, J = 4.4 Hz, 1H), 8.13 (s, 1H), 7.78 (s, 1H), 7.59 (dd, J = 1.3, 5.0 Hz, 1H), 7.16 - 7.03 (m, 3H), 3.22 - 3.12 (m, 1H), 3.06 - 2.96 (m, 1H), 2.89 - 2.80 (m, 1H), 2.79 - 2.62 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.21 - 2.12 (m, 1H), 1.98 - 1.83 (m, 1H).

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

[0542]

[0543] According to Process 1, Step viii: Example 24 was prepared starting from intermediate 7a (80.00 mg, 283.10 μmol) and 2-bromonicotinonitrile (155.43 mg, 849.30 μmol) according to Example 6, to give Example 24 (8.80 mg, 24.69 μmol, 8.72% yield), as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.88 (d, J = 5.0 Hz, 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.75 (s, 1H), 7.61 - 7.52 (m, 1H), 7.15 - 7.04 (m, 3H), 3.22 - 3.13 (m, 1H), 3.08 - 3.00 (m, 1H), 2.88 - 2.79 (m, 1H), 2.78 - 2.64 (m, 2H), 2.38 (s, 3H), 2.34 (s, 3H), 2.15 (br s, 1H), 1.99 - 1.83 (m, 1H).

[0544] Example 25: 6-(2,4-Dimethylphenyl)-2-(5-hydroxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, was prepared according to Process 1, Method B.

[0545]

[0546] According to Process 1, Step viii: Example 25 was prepared starting from intermediate 7a (100.00 mg, 353.87 μmol) and 6-bromo-3-hydroxypyridine (184.72 mg, 1.06 mmol) according to Example 6, to give Example 25 (42.10 mg, 115.12 μmol, 32.53% yield), as an off-white solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.24 (dd, J = 1.8, 4.8 Hz, 1H), 7.87 (dd, J = 1.6, 7.8 Hz, 1H), 7.19 (dd, J = 4.8, 7.8 Hz, 1H), 7.15 - 7.11 (m, 1H), 7.09 - 7.04 (m, 2H), 3.26 - 3.16 (m, 1H), 3.15 - 3.06 (m, 1H), 3.04 - 2.96 (m, 1H), 2.92 - 2.80 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.24 - 2.14 (m, 1H), 2.04 - 1.95 (m, 1H).

[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 CH2Cl2 (5.00 mL) was added BBr3 (693.11 mg, 2.77 mmol, 266.58 μL, 5.00 equiv). The mixture was stirred at 40 °C for 12 h, 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 Na2SO4, 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 1H-NMR (400 MHz, DMSO-d6) δ 8.26 (brd, J = 4.5 Hz, 1H), 7.81 (s, 1H), 7.15 (br d, J = 7.9 Hz, 1H), 7.05 - 6.96 (m, 2H), 6.86 (br s, 2H), 3.07 (br s, 1H), 2.85 - 2.59 (m, 3H), 2.58 - 2.53 (m, 1H), 2.31 (s, 3H), 2.25 (s, 3H), 1.93 (br s, 1H), 1.88 - 1.75 (m, 1H).

[0550] Example 27: 6-(2,4-Dimethylphenyl)-2-(5-(methoxymethyl)pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 1, Method B.

[0551]

[0552] According to Scheme 1, Step viii: Example 27 was prepared starting from Intermediate 7a (100.00 mg, 353.87 μmol) and 2-bromo-5-(methoxymethyl)pyridine (214.50 mg, 1.06 mmol) as in Example 6, to give Example 27 (56.21 mg, 149.71 μmol, 42.31% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.24 (dd, J = 1.8, 4.8 Hz, 1H), 7.87 (dd, J = 1.6, 7.8 Hz, 1H), 7.19 (dd, J = 4.8, 7.8 Hz, 1H), 7.15 - 7.11 (m, 1H), 7.09 - 7.04 (m, 2H), 3.26 - 3.16 (m, 1H), 3.15 - 3.06 (m, 1H), 3.04 - 2.96 (m, 1H), 2.92 - 2.80 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.24 - 2.14 (m, 1H), 2.04 - 1.95 (m, 1H).

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

[0554]

[0555] According to Process 1, Step viii: Example 28 was prepared starting from intermediate 7a (80.00 mg, 283.10 μmol) and 3-bromopyridine (134.19 mg, 849.30 μmol, 81.82 μL) as in Example 6, to give Example 28 (32.83 mg, 99.06 μmol, 34.99% yield), as a white solid. 1 H-NMR (400 MHz, CDCl3) δ 9.04 - 8.91 (m, 1H), 8.63 (br s, 1H), 8.09 (br d, J = 8.3 Hz, 1H), 7.73 (d, J = 1.9 Hz, 1H), 7.44 (br s, 1H), 7.18 - 7.01 (m, 3H), 3.16 (br s, 1H), 3.02 (br d, J = 19.2 Hz, 1H), 2.88 - 2.79 (m, 1H), 2.77 - 2.61 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.17 (br d, J = 13.1 Hz, 1H), 1.91 (br d, J = 11.8 Hz, 1H).

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

[0557]

[0558] According to Process 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 (400 MHz, CDCl3) δ 8.95 (d, J = 4.9 Hz, 2H), 7.71 (s, 1H), 7.44 (t, J = 4.8 Hz, 1H), 7.14 - 7.10 (m, 1H), 7.08 - 7.04 (m, 2H), 3.21 - 3.11 (m, 1H), 3.08 - 2.98 (m, 1H), 2.87 - 2.78 (m, 1H), 2.76 - 2.63 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.14 (br dd, J = 5.8, 13.5 Hz, 1H), 1.95 - 1.83 (m, 1H).

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

[0560]

[0561] According to Process 1, Step viii: Example 30 was prepared starting from intermediate 7a (80.00 mg, 283.10 μmol) and 2-bromopyrazine (135.02 mg, 849.30 μmol) according to Example 6, to give Example 30 (48.17 mg, 144.92 μmol, 51.19% yield), as an off-white solid. 1 H-NMR (400 MHz, CDCl3) δ 9.05 (d, J = 1.1 Hz, 1H), 8.60 - 8.50 (m, 1H), 7.69 (s, 1H), 7.05 - 7.01 (m, 1H), 7.00 - 6.94 (m, 2H), 3.13 - 3.02 (m, 1H), 3.13 - 3.02 (m, 1H), 2.98 - 2.87 (m, 1H), 2.80 - 2.71 (m, 1H), 2.69 - 2.54 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 2.12 - 2.02 (m, 1H), 1.88 - 1.74 (m, 1H).

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

[0563]

[0564] According to Process 1, Step viii: Example 31 was prepared starting from intermediate 7a (80.00 mg, 283.10 μmol) and 5-bromopyrimidine (135.02 mg, 849.30 μmol) according to Example 6, to obtain Example 31 (24.80 mg, 74.61 μmol, 26.35% yield), which is a brown solid. 1 1H-NMR (400 MHz, CDCl3) δ 9.23 (s, 2H), 9.19 (s, 1H), 7.74 (s, 1H), 7.12 - 7.08 (m, 1H), 7.08 - 7.03 (m, 2H), 3.20 - 3.10 (m, 1H), 3.06 - 2.95 (m, 1H), 2.87 - 2.77 (m, 1H), 2.76 - 2.60 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2.21 - 2.11 (m, 1H), 1.95 - 1.82 (m, 1H).

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

[0566]

[0567] According to Process 1, Step viii: Example 32 was prepared starting from intermediate 7a (120.00 mg, 471.83 μmol) and 2-bromothiazole (116.08 mg, 707.75 μmol, 63.78 μL) according to Example 6, to obtain Example 32 (12.00 mg, 34.51 μmol, 8.76% yield), which is a yellow solid. 1 1H-NMR (400 MHz, CDCl3) δ 1.84 - 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, 5.08 Hz, 1H) 3.12 - 3.20 (m, 1H) 7.05 (br d, J = 5.77 Hz, 2H) 7.07 - 7.12 (m, 1H) 7.30 (d, J = 3.39 Hz, 1H) 7.81 (d, J = 3.39 Hz, 1H) 7.90 (s, 1H).

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

[0569]

[0570] According to Process 1, Step viii: Example 33 was prepared starting from intermediate 7a (80.00 mg, 314.55 μmol) and 4-bromothiazole (77.39 mg, 471.83 μmol, 42.52 μL) as in Example 6, to give Example 33 (8.00 mg, 23.44 μmol, 7.45% yield), as an off-white solid. 1 1H-NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.65 (s, 2H), 7.14 (d, J = 8.4 Hz, 1H), 7.06 - 6.96 (m, 2H), 3.82 (s, 3H), 3.23 - 3.11 (m, 1H), 2.97 - 2.82 (m, 2H), 2.81 - 2.71 (m, 1H), 2.70 - 2.57 (m, 1H), 2.36 (s, 3H), 2.29 (s, 3H), 2.14 - 2.04 (m, 1H), 1.98 - 1.83 (m, 1H).

[0571] Example 34: 6-(2,4-dimethylphenyl)-2-(1-methyl-1H-imidazol-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Process 1, Method B.

[0572]

[0573] According to Process 1, Step viii: Example 34 was prepared starting from intermediate 7a (100.00 mg, 353.87 μmol) and 4-bromo-1-methyl-1H-imidazole (113.95 mg, 707.74 μmol) as in Example 6, to give Example 34 (10.61 mg, 31.72 μmol, 8.97% yield), as a white solid. 1 1H-NMR (400 MHz, MeOD) δ 7.89 (s, 1H), 7.65 (s, 2H), 7.14 (d, J = 8.4 Hz, 1H), 7.06 - 6.96 (m, 2H), 3.82 (s, 3H), 3.23 - 3.11 (m, 1H), 2.97 - 2.82 (m, 2H), 2.81 - 2.71 (m, 1H), 2.70 - 2.57 (m, 1H), 2.36 (s, 3H), 2.29 (s, 3H), 2.14 - 2.04 (m, 1H), 1.98 - 1.83 (m, 1H)

[0574] Example 35: 6-(2,4-dimethylphenyl)-2-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 1, Method B.

[0575]

[0576] According to Process 1, Step viii: Example 35 was prepared starting from Intermediate 7a (0.2 g, 786.39 μmol) and 2-chloro-4-methoxypyrimidine (136.42 mg, 943.67 μmol) as in Example 6, to give Example 35 (0.118 g, 323.05 μmol, 41.08% yield), as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.74 (s, 1H), 7.15 - 7.00 (m, 3H), 6.87 (d, J = 5.6 Hz, 1H), 4.06 (s, 3H), 3.21 - 3.10 (m, 1H), 3.09 - 3.01 (m, 1H), 2.88 - 2.79 (m, 1H), 2.77 - 2.61 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2.18 - 2.10 (m, 1H), 1.95 - 1.81 (m, 1H).

[0577] Example 36: 6-(2,4-dimethylphenyl)-2-(4,6-dimethylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 1, Method B.

[0578]

[0579] According to Process 1, Step viii: Example 36 was prepared starting from Intermediate 7a (0.2 g, 786.39 μmol) and 2-chloro-4,6-dimethylpyrimidine (168.19 mg, 1.18 mmol) as in Example 6, to give Example 36 (0.034 g, 89.61 μmol, 11.40% yield), as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.15 (s, 1H), 7.12 - 7.07 (m, 1H), 7.06 - 7.02 (m, 2H), 3.18 - 3.07 (m, 1H), 2.98 - 2.90 (m, 1H), 2.85 - 2.76 (m, 1H), 2.74 - 2.65 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.16 - 2.05 (m, 1H), 1.92 - 1.78 (m, 1H).

[0580] Example 37: 2-(4-Cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Process 1, Method B.

[0581]

[0582] According to Process 1, Step viii: Example 37 was prepared starting from intermediate 7a (0.2 g, 786.39 μmol) and 2-chloro-4-cyclopropylpyrimidine (145.89 mg, 943.67 μmol) as in Example 6, to give Example 37 (0.029 g, 77.86 μmol, 9.90% yield), as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.64 (d, J = 4.4 Hz, 1H), 7.65 (s, 1H), 7.18 (d, J = 4.8 Hz, 1H), 7.13 - 7.07 (m, 1H), 7.06 - 6.97 (m, 2H), 3.14 - 3.11 (m, 1H), 3.04 - 2.92 (m, 1H), 2.84 - 2.74 (m, 1H), 2.69 - 2.63 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.15 - 2.08 (m, 2H), 1.92 - 1.85 (m, 1H), 1.28 - 1.12 (m, 4H).

[0583] Example 38: 2-(5-Hydroxypyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Process 1, Method B.

[0584]

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

[0586] According to Process 1, Steps i to v: Intermediate 6d was prepared starting from 1-bromo-3-methoxy-2-methylbenzene similar to intermediate 6a in Example 1, and obtained in an overall yield of 15%, as a brown liquid. 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 Process 1, Step vii: Intermediate 7b was prepared starting from Intermediate 6d (21.30 g, 73.87 mmol) similar to Intermediate 7a in Example 6, to give 15.30 g of Intermediate 7b (56.60 mmol, 76.62% yield), as a white solid. 1 HNMR (400 MHz, DMSO-d6) δ 12.76 (br s, 1H), 7.65 (s, 1H), 7.10 - 7.18 (m, 1H), 6.84 (t, J = 8.72 Hz, 2H), 3.77 (s, 3H), 3.10 (br s, 1H), 2.55 - 2.75 (m, 3H), 2.35 - 2.47 (m, 1H), 2.15 (s, 3H), 1.90 (br s, 1H), 1.76 (dq, J = 4.89, 11.84 Hz, 1H).

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

[0590] According to Process 1, Step viii: Example 38 was prepared starting from Intermediate 7b (150.00 mg, 554.88 μmol) and 6-bromo-3-hydroxypyridine (115.86 mg, 665.85 μmol) according to Example 6, to give Example 38 (72.80 mg, 200.12 μmol, 36.07% yield), as a white solid. 1 H-NMR (400 MHz, DMSO-d6) δ 10.40 (br s, 1H), 8.04 - 8.10 (m, 1H), 7.80 (s, 1H), 7.29 - 7.36 (m, 2H), 7.14 - 7.21 (m, 1H), 6.89 (d, J = 7.65 Hz, 1H), 6.85 (d, J = 8.16 Hz, 1H), 3.78 (s, 3H), 3.09 - 3.21 (m, 1H), 2.62 - 2.82 (m, 3H), 2.52 - 2.59 (m, 1H), 2.17 (s, 3H), 1.89 - 2.01 (m, 1H), 1.74 - 1.87 (m, 1H).

[0591] Example 39: 2-(5-(Hydroxymethyl)pyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Process 1, Method B.

[0592]

[0593] According to Process 1, Step viii: Example 39 was prepared starting from intermediate 7b (150.00 mg, 554.88 μmol) and (6-bromopyridin-3-yl)methanol (125.19 mg, 665.86 μmol) according to Example 6, to give Example 39 (81.97 mg, 216.96 μmol, 39.10% yield), as a white solid. 1 H-NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 1.63 Hz, 1H), 7.92 (dd, J = 2.20, 8.09 Hz, 1H), 7.84 (s, 1H), 7.52 (d, J = 8.16 Hz, 1H), 7.18 (t, J = 7.97 Hz, 1H), 6.89 (d, J = 7.78 Hz, 1H), 6.85 (d, J = 8.16 Hz, 1H), 5.45 (t, J = 5.71 Hz, 1H), 4.62 (d, J = 5.52 Hz, 2H), 3.78 (s, 3H), 3.12 - 3.22 (m, 1H), 2.64 - 2.86 (m, 3H), 2.55 (br d, J = 9.66 Hz, 1H), 2.18 (s, 3H), 1.94 (br s, 1H), 1.78 - 1.89 (m, 1H).

[0594] Example 40: 6-(3-Methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, was prepared according to Process 1, Method B.

[0595]

[0596] According to Process 1, Step viii: Example 40 was prepared starting from intermediate 7b (150.00 mg, 554.88 μmol) and 5-bromopyrimidine (105.86 mg, 665.86 μmol) according to Example 6, to give Example 40 (45.56 mg, 128.81 μmol, 23.21% yield), as a brown solid. 1 H-NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 4.89 Hz, 2H), 7.85 (s, 1H), 7.71 (t, J = 4.89 Hz, 1H), 7.14 - 7.21 (m, 1H), 6.87 (dd, J = 7.97, 17.63 Hz, 2H), 3.78 (s, 3H), 3.14 - 3.24 (m, 1H), 2.78 - 2.87 (m, 1H), 2.66 - 2.77 (m, 2H), 2.56 (br d, J = 10.04 Hz, 1H), 2.18 (s, 3H), 1.94 (br s, 1H), 1.78 - 1.91 (m, 1H).

[0597] Example 41: 6-(3-Methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 1, Method B.

[0598]

[0599] According to Process 1, Step viii: Example 41 was prepared starting from intermediate 7b (150.00 mg, 554.88 μmol) and 2-bromo-5-methylpyrimidine (116.51 mg, 665.86 μmol) as in Example 6, to give Example 41 (75.16 mg, 206.05 μmol, 37.13% yield), as a white solid. 1 1H-NMR (400 MHz, DMSO-d6) δ 8.84 (s, 2H), 7.83 (s, 1H), 7.14 - 7.23 (m, 1H), 6.87 (dd, J = 7.91, 16.69 Hz, 2H), 3.78 (s, 3H), 3.13 - 3.23 (m, 1H), 2.64 - 2.87 (m, 3H), 2.52 - 2.60 (m, 1H), 2.38 (s, 3H), 2.18 (s, 3H), 1.94 (br s, 1H), 1.75 - 1.90 (m, 1H).

[0600] Example 42: 6-(3-Methoxy-2-methylphenyl)-2-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 1, Method B.

[0601]

[0602] According to Process 1, Step viii: Example 42 was prepared starting from intermediate 7b (150.00 mg, 554.88 μmol) and 2-bromo-4-methoxypyrimidine (125.85 mg, 665.85 μmol) as in Example 6, to give Example 42 (97.29 mg, 256.84 μmol, 46.29% yield), as a red solid. 1H-NMR(400MHz, DMSO-d6) δ 8.69 (d, J = 5.77 Hz, 1H), 7.83 (s, 1H), 7.18 (t, J = 7.97 Hz, 1H), 7.13 (d, J = 5.90 Hz, 1H), 6.89 (d, J = 7.65 Hz, 1H), 6.85 (d, J = 8.16 Hz, 1H), 3.93 (s, 3H), 3.78 (s, 3H), 3.13 - 3.24 (m, 1H), 2.64 - 2.86 (m, 3H), 2.56 (br d, J = 9.41 Hz, 1H), 2.18 (s, 3H), 1.94 (br s, 1H), 1.78 - 1.90 (m, 1H).

[0603] Example 43: 2-(5-Chloropyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 1, Method B.

[0604]

[0605] According to Process 1, Step viii: Example 43 was prepared starting from intermediate 7b (150.00 mg, 554.88 μmol) and 2-bromo-5-chloropyrimidine (128.80 mg, 665.86 μmol) as in Example 6, to give Example 43 (98.84 mg, 257.92 μmol, 46.48% yield), as a white solid. 1 H-NMR(400MHz, DMSO-d6)) δ 9.16 (s, 2H), 7.87 (s, 1H), 7.15 - 7.20 (m, 1H), 6.89 (d, J = 7.65 Hz, 1H), 6.85 (d, J = 8.03 Hz, 1H), 3.78 (s, 3H), 3.12 - 3.24 (m, 1H), 2.78 - 2.86 (m, 1H), 2.65 - 2.76 (m, 2H), 2.53 - 2.61 (m, 1H), 2.18 (s, 3H), 1.91 - 2.00 (m, 1H), 1.76 - 1.90 (m, 1H).

[0606] Example 44: 6-(3-Methoxy-2-methylphenyl)-2-(5-methoxypyrazin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 1, Method B.

[0607]

[0608] According to Process 1, Step viii: Example 44 was prepared starting from intermediate 7b (150.00 mg, 554.88 μmol) and 2-bromo-5-methoxypyrazine (125.85 mg, 665.86 μmol) according to Example 6, to give Example 44 (111.11 mg, 290.09 μmol, 52.28% yield), as a white solid. 1 1H-NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 1.25 Hz, 1H), 8.35 (d, J = 1.25 Hz, 1H), 7.89 (s, 1H), 7.14 - 7.22 (m, 1H), 6.89 (d, J = 7.65 Hz, 1H), 6.85 (d, J = 8.16 Hz, 1H), 3.99 (s, 3H), 3.78 (s, 3H), 3.10 - 3.22 (m, 1H), 2.64 - 2.86 (m, 3H), 2.56 (br d, J = 9.41 Hz, 1H), 2.18 (s, 3H), 1.94 (br s, 1H), 1.78 - 1.89 (m, 1H).

[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 Process 1, Method B.

[0610]

[0611] According to Process 1, Step viii: Example 45 was prepared starting from intermediate 7b (450 mg, 1.66 mmol) and 2-bromo-5-hydroxypyrimidine (349.55 mg, 2.00 mmol) according to Example 6, to give Example 45 (520 mg, 1.43 mmol, 85.72% yield), as a brown solid. 1 1H-NMR (400 MHz, DMSO-d6) δ 8.43 (s, 2H), 7.79 (s, 1H), 7.14 - 7.21 (m, 1H), 6.89 (d, J = 7.78 Hz, 1H), 6.85 (d, J = 8.28 Hz, 1H), 3.76 - 3.81 (m, 3H), 3.11 - 3.25 (m, 1H), 2.67 - 2.84 (m, 3H), 2.55 - 2.60 (m, 1H), 2.18 (s, 3H), 1.93 (br s, 1H), 1.76 - 1.89 (m, 1H).

[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 Process 1, Method B.

[0613]

[0614] According to Process 1, Step viii: Example 46 was prepared starting from intermediate 7b (70 mg, 258.95 μmol) and 4-(2-bromopyrimidin-4-yl)morpholine (75.85 mg, 310.74 μmol) according to Example 6, to obtain Example 46 (32.49 mg, 74.12 μmol, 28.62% yield), as an off-white solid. 1 1H-NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 6.15 Hz, 1H), 7.77 (s, 1H), 7.15 - 7.21 (m, 1H), 6.96 (d, J = 6.27 Hz, 1H), 6.89 (d, J = 7.78 Hz, 1H), 6.85 (d, J = 8.16 Hz, 1H), 3.79 (s, 3H), 3.67 (br d, J = 5.02 Hz, 4H), 3.62 (br d, J = 4.77 Hz, 4H), 3.17 (brt, J = 8.97 Hz, 1H), 2.62 - 2.83 (m, 3H), 2.52 - 2.59 (m, 1H), 2.18 (s, 3H), 1.93 (br s, 1H), 1.83 (dq, J = 4.83, 11.90 Hz, 1H).

[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 Process 1, Method B.

[0616]

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

[0618] According to Process 1, Steps i to v: Intermediate 6e was prepared starting from 2-bromo-4-methoxy-1-methylbenzene, similar to intermediate 6a in Example 1, and obtained in an overall yield of 9.3%, as a yellow solid. 1 1H NMR: (CDCl3, 400 MHz) δ 7.02 (d, J = 8.4 Hz, 1H), 6.70 - 6.61 (m, 2H), 5.58 (s, 1H), 3.71 (s, 3H), 3.51 (s, 3H), 3.05 - 2.90 (m, 1H), 2.47 - 2.36 (m, 2H), 2.31 - 2.14 (m, 5H), 1.94 - 1.86 (m, 1H), 1.75 - 1.62 (m, 1H).

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

[0620] According to Process 1, Step vii: Intermediate 7c was prepared starting from Intermediate 6e (1.30 g, 4.51 mmol) similar to Intermediate 7a in Example 6, to give Intermediate 7c (0.4 g, 1.48 mmol, 32.82% yield), as a white solid. 1 HNMR: (CDCl3, 400 MHz) δ 7.55 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.73 - 6.68 (m, 2H), 3.78 (s, 3H), 3.12 - 3.08 (m, 1H), 2.93 - 2.91 (m, 1H), 2.74 - 2.71 (m, 1H), 2.65 - 2.58 (m, 2H), 2.28 (s, 3H), 2.13 - 2.09 (m, 1H), 1.90 - 1.69 (m, 1H).

[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 Process 1, Step viii: Example 47 was prepared starting from Intermediate 7c (0.1 g, 369.92 μmol) and 2-chloro-5-methylpyrimidine (142.67 mg, 1.11 mmol) according to Example 6, to give Example 47 (0.005 g, 13.80 μmol, 3.73% yield), as a yellow solid. 1 H-NMR (400 MHz, CDCl3) δ 8.75 (s, 2H), 7.70 (s, 1H), 7.12 (br d, J = 8.4 Hz, 1H), 6.77 (s, 1H), 6.72 (m, d, J = 8.4 Hz, 1H), 3.80 (s, 3H), 3.17 - 2.96 (m, 2H), 2.87 - 2.76 (m, 1H), 2.71 - 2.65 (m, 2H), 2.43 (s, 3H), 2.31 (s, 3H), 2.15 - 2.11 (m, 1H), 1.90 - 1.85 (m, 1H).

[0623] Example 48: 6-(5-methoxy-2-methylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Process 1, Method B.

[0624]

[0625] According to Process 1, Step viii: Example 48 was prepared starting from Intermediate 7c (0.1 g, 369.92 μmol) and 2-chloro-5-methoxypyrimidine (160.43 mg, 1.11 mmol) according to Example 6, to give Example 48 (0.003 g, 7.93 μmol, 2.14% yield), as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.46 (s, 2H), 7.59 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.73 - 6.64 (m, 2H), 3.93 (s, 3H), 3.73 (s, 3H), 3.04 - 2.97 (m, 2H), 2.71 - 2.46 (m, 3H), 2.23 (s, 3H), 2.08 (m, 1H), 1.80 (m, 1H).

[0626] Example 49: 2-(5-chloropyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, was prepared according to Process 1, Method B.

[0627]

[0628] According to Process 1, Step viii: Example 49 was prepared starting from Intermediate 7c (0.1 g, 369.92 μmol) and 2-bromo-5-chloropyrimidine (214.66 mg, 1.11 mmol) according to Example 6, to give Example 49 (0.011 g, 28.73 μmol, 7.77% yield), as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.85 (s, 2H), 7.69 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.76 (s, 1H), 6.72 (dd, J = 8.0, 2.4 Hz, 1H), 3.80 (s, 3H), 3.18 - 3.08 (m, 1H), 3.07 - 2.97 (m, 1H), 2.86 - 2.76 (m, 1H), 2.71 - 2.65 (m, 2H), 2.31 (s, 3H), 2.15 (m, 1H), 1.88 - 1.81 (m, 1H).

[0629] Example 50: 6-(2,4-dimethylphenyl)-2-(pyridin-4-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, was prepared according to Process 1, Method B.

[0630]

[0631] According to Process 1, Step ix: To a mixture of intermediate 7a (150.00 mg, 530.81 μmol, 1.00 equivalent), 4-pyridylboronic acid (130.49 mg, 1.06 mmol, 2.00 equivalents) in dioxane (5.00 mL) was added DMAP (194.55 mg, 1.59 mmol, 3.00 equivalents), pyridine (41.99 mg, 530.81 μmol, 42.84 μL, 1.00 equivalent) and Cu(OAc)2 (96.41 mg, 530.81 μmol, 1.00 equivalent). The mixture was heated to 90 °C and stirred for 12 h. The resulting mixture was filtered, and the filtrate was acidified to pH = 5 with 12 M HCl and filtered. The resulting solution was purified by preparative HPLC to give Example 50 (8.98 mg, 26.01 μmol, 4.90% yield) as a yellow solid. 1 1H-NMR (400 MHz, DMSO-d6) δ 8.76 (brs, 2H), 7.97 (s, 1H), 7.78 (br s, 2H), 7.15 (d, J = 8.5 Hz, 1H), 7.04 - 6.98 (m, 2H), 3.13 - 3.01 (m, 1H), 2.86 - 2.73 (m, 2H), 2.71 - 2.64 (m, 1H), 2.63 - 2.55 (m, 1H), 2.30 (s, 3H), 2.25 (s, 3H), 2.00 - 1.91 (m, 1H), 1.88 - 1.75 (m, 1H).

[0632] Example 51: 2-(5-Chloropyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 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 (6g, 22.03 mmol, 1 equiv) in MeOH (100 mL) was added to NaOH (2.64 g, 66.09 mmol, 3 equiv) in H2O (40 mL), and then the mixture was stirred at 20 °C for 24 h. The organic solvent was removed under reduced pressure. The residue was acidified to pH = 3 by adding 2N HCl at 20 °C, and 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 pale yellow oil. 1 HNMR (400 MHz, CDCl3) δ 7.16 - 6.93 (m, 3H), 6.03 (s, 1H), 3.20 - 3.01 (m, 1H), 2.79 - 2.64 (m, 1H), 2.56 - 2.42 (m, 2H), 2.36 - 2.31 (m, 7H), 2.04 - 1.96 (m, 1H), 1.90 - 1.73 (m, 1H).

[0636] Intermediate 8a: Ethyl 5-formyl-2',4'-dimethyl-1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-carboxylate

[0637] According to Scheme 1, Step x: TMG (1.34 g, 11.61 mmol, 1.46 mL, 1.5 equiv) was added to a solution of intermediate 6a’ (2 g, 7.74 mmol, 1 equiv) in DMF (20 mL) at 20 °C. After addition, the mixture was stirred at this temperature for half an hour at 20 °C. Ethyl iodide (3.02 g, 19.36 mmol, 1.55 mL, 2.5 equiv) was added, and the resulting mixture was immediately heated at 45 °C for 14 h. The solvent was removed under reduced pressure. The residue was dissolved in water (20 mL), then the pH was adjusted to 4 with 4N HCl, and extracted with EtOAc (15 mL x 3). The combined organic layers were 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] 11H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 7.13 - 6.94 (m, 3H), 4.34 (q, J = 7.2 Hz, 2H), 3.00 - 2.88 (m, 1H), 2.83 - 2.71 (m, 2H), 2.70 - 2.57 (m, 1H), 2.31 (s, 6H), 2.25 - 2.13 (m, 1H), 1.99 (m, 1H), 1.87 - 1.72 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H).

[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: 2-Hydrazinyl-5-chloropyrimidine (105.15 mg, 367.19 μmol, 1 equiv) was added in one portion to a mixture of intermediate 8a (53.08 mg, 367.19 μmol, 1 equiv) in EtOH (10 mL) and AcOH (5 mL) at 20 °C. The mixture was stirred at 100 °C for 12 h. The mixture was filtered and concentrated in vacuo. The residue was purified by preparative-HPLC to give Example 51 (0.009 g, 24.53 μmol, 6.68% yield) as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.86 (s, 2H), 7.69 (s, 1H), 7.16 - 6.99 (m, 3H), 3.14 (m, 1H), 3.01 (m, 1H), 2.86 - 2.77 (m, 1H), 2.75 - 2.60 (m, 2H), 2.35 (s, 3H), 2.33 (s, 3H), 2.12 (m, 1H), 1.93 - 1.82 (m, 1H).

[0641] Example 52: 6-(2,4-Dimethylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(NH)-one, prepared according to Scheme 1, Method C.

[0642]

[0643] According to Scheme 1, step xii: Example 52 was prepared starting from intermediate 8a (105.15 mg, 367.19 μmol) and 2-hydrazinyl-5-methylpyrimidine (45.58 mg, 367.19 μmol) as in Example 51 to give Example 52 (0.023 g, 66.39 μmol, 18.08% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.74 (s, 2H), 7.68 (s, 1H), 7.16 - 6.99 (m, 3H), 3.14 (m, 1H), 3.06 - 2.96 (m, 1H), 2.86 - 2.76 (m, 1H), 2.69 (m, 2H), 2.43 (s, 3H), 2.36 (s, 3H), 2.32 (s, 3H), 2.16 - 2.08 (m, 1H), 1.93 - 1.81 (m, 1H).

[0644] Example 53: 6-(2,4-Dimethylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Process 1, Method C.

[0645]

[0646] According to Process 1, Step xii: Example 53 was prepared as in Example 51 starting from intermediate 8a (105.15 mg, 367.19 μmol) and 2-hydrazinyl-5-methoxypyrimidine (51.46 mg, 367.19 μmol), to give Example 53 (0.059 g, 161.16 μmol, 43.89% yield), as a white solid. 1 H-NMR (400 MHz, CDCl3) δ 8.53 (s, 2H), 7.67 (s, 1H), 7.15 - 6.97 (m, 3H), 4.00 (s, 3H), 3.14 (br s, 1H), 2.99 (m, 1H), 2.85 - 2.76 (m, 1H), 2.74 - 2.59 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.12 (m, 1H), 1.87 (m, 1H).

[0647] Example 54: 6-(2,4-Dimethylphenyl)-2-(5-fluoropyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Process 1, Method C.

[0648]

[0649] According to Process 1, Step xii: Example 54 was prepared as in Example 51 starting from intermediate 8a (105.15 mg, 367.19 μmol) and 5-fluoro-2-hydrazinylpyrimidine (47.04 mg, 367.19 μmol), to give 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-tetrahydrophtalazin-1(2H)-one, prepared according to Process 1, Method C.

[0651]

[0652] According to Process 1, Step xii: Example 55 was prepared starting from Intermediate 8a (105.15 mg, 367.19 μmol) and 2-hydrazinyl-5-(trifluoromethyl)pyrimidine (65.40 mg, 367.19 μmol) as in Example 51, to give 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),3.07 - 2.97(m,1H),2.87 - 2.78(m,1H),2.36(s,3H),2.33(s,3H),2.14(m,1H),1.95 - 1.83(m,1H).

[0653] Example 56: 6-(2,4-Dimethylphenyl)-2-(4-methoxy-5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 1, Method C.

[0654]

[0655] Intermediate 56’: 2-(5-Bromo-4-methoxypyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[0656] According to Process 1, Step xii: Intermediate 56’ was prepared starting from Intermediate 8a (392.32 mg, 1.37 mmol) and 5-bromo-2-hydrazinyl-4-methoxypyrimidine (0.3 g, 1.37 mmol) according to Example 51, to give Intermediate 56’ (0.17 g, 385.21 μmol, 28.12% yield), as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.66 (s, 1H), 7.14 - 6.99 (m, 3H), 4.13 (s, 3H), 3.20 - 3.08 (m, 1H), 3.04 - 2.94 (m, 1H), 2.85 - 2.75 (m, 1H), 2.75 - 2.65 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.19 - 2.09 (m, 1H), 1.92 - 1.85 (m, 1H).

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

[0658] At 20 °C under N2, Pd(dppf)Cl2 (16.58 mg, 22.66 μmol, 0.1 equiv) and K2CO3 (93.95 mg, 679.78 μmol, 3 equiv) were added in one portion 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). The mixture was stirred at 100 °C for 12 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative-HPLC to give Example 56 (0.044 g, 116.27 μmol, 51.31% yield), as a white solid. 1 H-NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.66 (s, 1H), 7.14 - 6.99 (m, 3H), 4.13 (s, 3H), 3.20 - 3.08 (m, 1H), 3.04 - 2.94 (m, 1H), 2.85 - 2.75 (m, 1H), 2.75 - 2.65 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.19 - 2.09 (m, 1H), 1.92 - 1.85 (m, 1H).

[0659] Example 57: 6-(2,4-Dimethylphenyl)-2-(5-(morpholinomethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 1, Method C.

[0660]

[0661] According to Process 1, Step xii: Example 57 was prepared starting from intermediate 8a (105.15 mg, 367.19 μmol) and 4-((2-hydrazinylpyrimidin-5-yl)methyl)morpholine (76.83 mg, 367.19 μmol) as in Example 51, to give Example 57 (0.023 g, 53.30 μmol, 14.52% yield), as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.87 (s, 2H), 7.69 (s, 1H), 7.17 - 6.98 (m, 3H), 3.78 - 3.70 (m, 4H), 3.60 (s, 2H), 3.15 (m, 1H), 3.01 (m, 1H), 2.87 - 2.76 (m, 1H), 2.70 (m, 1H), 2.75 - 2.61 (m, 1H), 2.51 (m, 4H), 2.36 (s, 3H), 2.32 (s, 3H), 2.11 (m, 1H), 1.95 - 1.81 (m, 1H).

[0662] Example 58: 6-(2-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, was prepared according to Process 2, Method A.

[0663]

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

[0665] According to Process 2, Step i: POCl3 (490.66 g, 3.20 mol, 297.37 mL, 2.50 equivalents) was added dropwise to a solution of DMF (187.11 g, 2.56 mol, 196.96 mL, 2.00 equivalents) in CH2Cl2 (2.00 L) at 0 °C. The mixture was stirred at 0 °C for 2 h. Then 1,4-dioxaspiro[4.5]dec-8-one (200.00 g, 1.28 mol, 1.00 equivalent) in CH2Cl2 (500.00 mL) was 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 saturated aqueous NaHCO3 (2 L) and maintained at pH > 7 by adding solid NaHCO3, and extracted with CH2Cl2 (5 L x 2). The CH2Cl2 phase was concentrated. The resulting residue was purified by column chromatography (PE / EtOAc = 20 / 1). Intermediate 56a (120.00 g, 506.34 mmol, 39.56% yield) was obtained as a yellow oil. 11H NMR (400 MHz, CDCl3) δ 10.19 - 10.10 (m, 1H), 4.05 - 3.94 (m, 4H), 2.91 - 2.75 (m, 2H), 2.57 - 2.42 (m, 2H), 1.99 - 1.83 (m, 2H).

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

[0667] According to Process 2, Step ii: To a solution of Intermediate 10 (122.00 g, 514.78 mmol, 1.00 equivalent) in MeOH (800.00 mL) and DMA (400.00 mL), add Pd(OAc)2 (17.34 g, 77.22 mmol, 0.15 equivalent), DPPF (42.81 g, 77.22 mmol, 0.15 equivalent) and AcONa (84.45 g, 1.03 mol, 2.00 equivalents). Stir the reaction mixture at 80 °C under CO (50 Psi) for 12 h. Filter the reaction mixture, concentrate the filtrate, and pour the residue into water (2000 mL x 2), and extract with ethyl acetate (2000 mL x 3). Wash the combined organic layers with saturated brine (1000 ml x 3), and then concentrate under reduced pressure. Purify the residue by column chromatography (PE:EtOAc = 20:1 to 3:1). Obtain Intermediate 11 (78.50 g, 329.64 mmol, 64.04% yield), as a yellow oil. 1 1H NMR (400 MHz, CDCl3) δ 5.61 (d, J = 1.1 Hz, 1H), 4.03 - 3.99 (m, 4H), 3.53 (s, 3H), 2.62 - 2.53 (m, 1H), 2.49 - 2.40 (m, 3H), 1.85 (t, J = 6.3 Hz, 2H).

[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) was added N2H4.H2O (33.68 g, 659.28 mmol, 32.70 mL, 2.00 equivalents). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated and adjusted to pH = 7 with saturated aqueous NaHCO3. Then it was extracted with CH2Cl2 (30.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Intermediate 12 (66.00 g, 316.99 mmol, 96.16% yield) was obtained as a yellow solid.

[0670] 1 H NMR (400 MHz, DMSO-d6) δ 7.58 (s, 1H), 3.93 (s, 4H), 2.72 (s, 2H), 2.54 (br t, J = 6.7 Hz, 2H), 1.80 (t, J = 6.7 Hz, 2H).

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

[0672] According to Process 2, Step v: To a solution of Intermediate 12 (40.00 g, 192.11 mmol, 1.00 equivalent) and 2-bromopyridine (36.42 g, 230.53 mmol, 21.94 mL, 1.20 equivalents) in dioxane (500.00 mL) were added CuI (7.32 g, 38.42 mmol, 0.20 equivalent), (1S,2S)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (5.47 g, 38.42 mmol, 0.20 equivalent) and K3PO4 (101.95 g, 480.28 mmol, 2.50 equivalents). The mixture was stirred at 100 °C for 12 h. 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 layers were dried over Na2SO4, filtered, and concentrated. The residue was recrystallized from MTBE (100 mL) at 20 °C. Intermediate 13a (56.00 g, crude) was obtained as a grey solid. 11H NMR (400 MHz, CDCl3) δ 8.67 (br s, 1H), 7.92 - 7.79 (m, 1H), 7.68 (br s, 2H), 7.35 (br s, 1H), 4.04 (s, 4H), 2.87 (br t, J = 6.0 Hz, 2H), 2.81 (s, 2H), 1.94 (br t, J = 6.5 Hz, 2H).

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

[0674] According to Process 2, Step vi: To a solution of Intermediate 13a (25.00 g, 87.63 mmol, 1.00 equivalent) in CH2Cl2 (250.00 mL) and TFA (75.00 mL) was added H2O (3.16 g, 175.26 mmol, 3.16 mL, 2.00 equivalents). The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into saturated aqueous NaHCO3 (500.0 mL), and extracted with CH2Cl2 (500.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, CH2Cl2:EtOAc = 1:2 to 0:1). Intermediate 14a (8.80 g, 33.20 mmol, 37.88% yield) was obtained as a yellow solid. 1 1H NMR (400 MHz, CDCl3) δ 8.67 (dd, J = 1.1, 4.9 Hz, 1H), 7.89 (dt, J = 1.9, 7.7 Hz, 1H), 7.75 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.39 (ddd, J = 0.9, 4.9, 7.4 Hz, 1H), 3.46 (s, 2H), 3.16 (t, J = 7.0 Hz, 2H), 2.67 (t, J = 7.0 Hz, 2H).

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

[0676] According to Process 2, Step vii: To a solution of intermediate 14a (5.00 g, 18.86 mmol, 1.00 equiv) in CH2Cl2 (50.00 mL) at 0 °C was added Et3N (2.29 g, 22.63 mmol, 3.14 mL, 1.20 equiv) and Tf2O (5.85 g, 20.75 mmol, 3.42 mL, 1.10 equiv). The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, 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 1H NMR (400 MHz, CDCl3) δ 8.68 - 8.63 (m, 1H), 7.88 (dt, J = 1.9, 7.8 Hz, 1H), 7.78 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.38 (ddd, J = 0.9, 4.9, 7.4 Hz, 1H), 6.36 (t, J = 1.4 Hz, 1H), 3.18 - 3.10 (m, 2H), 2.84 - 2.75 (m, 2H).

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

[0678] According to Process 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(PPh3)4 (119.73 mg, 103.61 μmol, 0.20 equiv), and Na2CO3 (2 M, 1.17 mL, 4.50 equiv) in THF (4.00 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 70 °C under a N2 atmosphere for 3 h. The mixture was added to water (20 mL), extracted with AcOEt (20 mL x 3), the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (PE:EtOAc = 0:1) to give intermediate 16a (190.00 mg, crude) as a yellow oil.

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

[0680] According to Process 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 a N2 atmosphere for 2 h. The mixture was filtered, concentrated under reduced pressure, and purified by preparative-HPLC to give Example 58 (27.59 mg, 82.68 μmol, 29.15% yield) as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.68 (dd, J = 1.1, 4.8 Hz, 1H), 7.88 (dt, J = 1.9, 7.8 Hz, 1H), 7.78 - 7.72 (m, 2H), 7.37 (ddd, J = 0.9, 4.9, 7.3 Hz, 1H), 7.28 - 7.25 (m, 1H), 7.21 (dd, J = 1.5, 7.5 Hz, 1H), 7.02 - 6.97 (m, 1H), 6.94 (d, J = 8.3 Hz, 1H), 3.88 (s, 3H), 3.45 - 3.31 (m, 1H), 3.05 - 2.88 (m, 2H), 2.75 - 2.60 (m, 2H), 2.22 - 2.13 (m, 1H), 2.05 - 1.89 (m, 1H).

[0681] Example 59: 6-(3-(Dimethylamino)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Process 2, Method A.

[0682]

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

[0684] According to Process 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 as 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] Example 59: Prepared starting from Intermediate 16b (160.00 mg, 427.40 μmol) according to the same method as described in Example 58 in Process 2, to give Example 59 (15.47 mg, 43.85 μmol, 10.26% yield), as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.69 (dd, J = 1.1, 4.8 Hz, 1H), 7.89 (dt, J = 1.9, 7.8 Hz, 1H), 7.78 - 7.73 (m, 2H), 7.38 (ddd, J = 1.0, 4.9, 7.4 Hz, 1H), 7.26 (t, J = 8.1 Hz, 1H), 6.70 - 6.63 (m, 3H), 3.05 - 2.98 (m, 1H), 3.05 - 2.98 (m, 7H), 2.96 - 2.86 (m, 2H), 2.84 - 2.75 (m, 1H), 2.72 - 2.59 (m, 1H), 2.30 - 2.21 (m, 1H), 1.98 - 1.85 (m, 1H).

[0687] Example 60: 6-(3-Methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Process 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 Process 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] Example 60: 6-(5-Methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared starting from intermediate 16c (170.00 mg, 492.20 μmol) according to the same method as described in Example 58, to give Example 60 (24.35 mg, 69.95 μmol, 14.21% yield), as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.69 (dd, J = 1.1, 4.8 Hz, 1H), 7.89 (dt, J = 1.9, 7.8 Hz, 1H), 7.79 - 7.71 (m, 2H), 7.38 (ddd, J = 0.9, 4.9, 7.4 Hz, 1H), 7.26 - 7.18 (m, 1H), 6.91 - 6.78 (m, 2H), 3.87 (s, 3H), 3.31 - 3.18 (m, 1H), 3.06 - 2.94 (m, 1H), 2.89 - 2.79 (m, 1H), 2.78 - 2.63 (m, 2H), 2.27 (s, 3H), 2.20 - 2.12 (m, 1H), 1.98 - 1.85 (m, 1H).

[0693] Example 61: 6-(5-Methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Process 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 Process 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 as 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 Process 2, Step ix: Example 61 was prepared starting from intermediate 16d (200.00 mg, 579.06 μmol) according to the same method as described in Example 58, to give Example 61 (19.01 mg, 52.64 μmol, 9.09% yield), as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.69 (dd, J = 1.1, 4.8 Hz, 1H), 7.89 (dt, J = 1.9, 7.8 Hz, 1H), 7.77 - 7.73 (m, 2H), 7.38 (ddd, J = 1.0, 4.9, 7.4 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 2.6 Hz, 1H), 6.74 (dd, J = 2.6, 8.3 Hz, 1H), 3.82 (s, 3H), 3.20 - 3.10 (m, 1H), 3.08 - 2.99 (m, 1H), 2.88 - 2.80 (m, 1H), 2.75 - 2.62 (m, 2H), 2.33 (s, 3H), 2.22 - 2.13 (m, 1H), 1.95 - 1.83 (m, 1H).

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

[0700]

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

[0702] According to Process 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 as 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 Process 2, Step ix: Example 62 was prepared starting from Intermediate 16e (70.00 mg, 210.86 μmol) according to the same method as described for Example 58, to give Example 62 (12.55 mg, 39.07 μmol, 18.53% yield), as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.59 (dd, J = 1.1, 4.8 Hz, 1H), 7.80 (dt, J = 1.9, 7.7 Hz, 1H), 7.70 - 7.62 (m, 2H), 7.29 (ddd, J = 0.9, 4.9, 7.5 Hz, 1H), 7.17 - 7.07 (m, 4H), 3.16 - 3.05 (m, 1H), 2.98 - 2.86 (m, 1H), 2.81 - 2.71 (m, 1H), 2.69 - 2.53 (m, 2H), 2.32 (s, 3H), 2.13 - 2.03 (m, 1H), 1.89 - 1.76 (m, 1H).

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

[0706]

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

[0708] According to Process 2, Step viii: Intermediate 16f was prepared in the same manner as described for Intermediate 16a in Example 58 starting from Intermediate 15a (100.00 mg, 243.23 μmol) and (3-cyclopropylphenyl)boronic acid pinacol ester (89.07 mg, 364.85 μmol), giving 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 Process 2, Step ix: Example 63 was prepared in the same manner as described for Example 58 starting from Intermediate 16f (10.00 mg, 21.38 μmol), giving Example 63 (4.63 mg, 13.48 μmol, 63.06% yield), as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.68 (br d, J = 3.8 Hz, 1H), 7.94 - 7.84 (m, 1H), 7.79 - 7.71 (m, 2H), 7.42 - 7.34 (m, 1H), 7.31 - 7.23 (m, 2H), 7.09 - 7.01 (m, 2H), 6.97 (br d, J = 7.4 Hz, 1H), 3.05 - 2.84 (m, 3H), 2.82 - 2.60 (m, 2H), 2.24 (br d, J = 8.9 Hz, 1H), 1.98 - 1.83 (m, 2H), 1.06 - 0.95 (m, 2H), 0.74 (q, J = 4.9 Hz, 2H).

[0711] Example 64: 6-(3-Methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Process 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 Process 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 Process 2, Step ix: Example 64 was prepared starting from Intermediate 16g (130.00 mg, 299.60 μmol) according to the same method as described for Example 58, to give Example 64 (31.00 mg, 89.23 μmol, 29.78% yield), as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.62 - 8.56 (m, 1H), 7.83 - 7.76 (m, 1H), 7.68 - 7.62 (m, 2H), 7.32 - 7.25 (m, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 6.66 (s, 1H), 3.79 (s, 3H), 2.96 - 2.76 (m, 3H), 2.74 - 2.49 (m, 2H), 2.21 - 2.10 (m, 4H), 1.88 - 1.73 (m, 1H).

[0717] Example 65: 6-(3-(1-Hydroxyethyl)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Process 2, Method A.

[0718]

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

[0720] According to Process 2, Step viii: Intermediate 16h was prepared in the same manner as described for Intermediate 16a in Example 58 starting from Intermediate 15a (100.00 mg, 243.23 μmol) and (3-acetylphenyl)boronic acid (59.82 mg, 364.85 μmol), 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 Process 2, Step ix: Example 65 was prepared in the same manner as described for Example 58 starting from Intermediate 16h (70.00 mg, 156.97 μmol), to give Example 65 (4.05 mg, 11.54 μmol, 4.31% yield), as a white solid. 11H-NMR (400 MHz, CDCl3) δ 8.68 (broad d, J = 3.9 Hz, 1H), 7.93 - 7.85 (m, 1H), 7.79 - 7.70 (m, 2H), 7.41 - 7.35 (m, 2H), 7.32 (broad d, J = 7.9 Hz, 2H), 7.21 (broad d, J = 7.5 Hz, 1H), 4.95 (q, J = 6.3 Hz, 1H), 3.06 - 2.96 (m, 2H), 2.95 - 2.86 (m, 1H), 2.84 - 2.74 (m, 1H), 2.73 - 2.61 (m, 1H), 2.26 (broad d, J = 9.0 Hz, 1H), 1.98 - 1.88 (m, 1H), 1.88 - 1.77 (m, 1H), 1.55 (d, J = 6.5 Hz, 3H).

[0723] Example 66: 6-(3-Cyclopropoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 2, Method A.

[0724]

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

[0726] According to Process 2, Step viii: Intermediate 16i was prepared in the same manner as described for Intermediate 16a in Example 58 starting from Intermediate 15a (100.00 mg, 243.23 μmol) and (3-cyclopropoxyphenyl)boronic acid pinacol ester (96.85 mg, 364.84 μmol), 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-Cyclopropoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[0728] According to Process 2, Step ix: Example 66 was prepared in the same manner as described for Example 58 starting from Intermediate 16i (40.00 mg, 59.32 μmol), to give Example 66 (8.54 mg, 23.74 μmol, 40.01% yield) as a white solid. 1H-NMR(400MHz,CDCl3)δ8.68(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(br d,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, prepared according to Process 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 Process 2, Step viii: Intermediate 16j was prepared in the same manner as described for Intermediate 16a in Example 58 starting from Intermediate 15a (200.00 mg, 519.68 μmol) and (2-methoxy-4-methylphenyl)boronic acid (129.38 mg, 779.52 μmol) 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 Process 2, Step ix: Example 67 was prepared in the same manner as described for Example 58 starting from Intermediate 16j (180.00 mg, 521.15 μmol) 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-tetrahydrophtalazin-1(2H)-one, prepared according to Process 2, Method A.

[0736]

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

[0738] According to Process 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-tetrahydrophtalazin-1(2H)-one

[0740] According to Process 2, Step ix: Example 68 was prepared starting from Intermediate 16k (190.00 mg, 550.10 μmol) according to the same method as 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) δ 8.43(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-Methyldihydroindol-4-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Process 2, Method A.

[0742]

[0743] Intermediate 16l: 6-(1-Methyldihydroindol-4-yl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0744] According to Process 2, Step viii: Intermediate 16l was prepared starting from Intermediate 15a (0.2 g, 535.75 μmol) and (1-methyldihydroindol-4-yl)boronic acid pinacol ester (138.84 mg, 535.75 μmol) according to the same method as described for Intermediate 16a in Example 58, to give Intermediate 16l (0.15 g, crude), as a yellow solid. m / z (M + H) + = 357.3; 1 HNMR (MeOD, 400 MHz) δ 8.60(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-Methyldihydroindol-4-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0746] Example 69: Prepared starting from Intermediate 16l (0.15 g, 420.85 μmol) according to the same method as described in Example 58, to give Example 69 (55 mg, 151.30 μmol, 35.95% yield), as a white solid. 1 1H-NMR (400 MHz, DMSO-d6) δ 8.67 (br d, J = 3.6 Hz, 1H), 7.87 (td, J = 7.8, 2.0 Hz, 1H), 7.71 - 7.78 (m, 2H), 7.36 (dd, J = 6.4, 5.0 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 6.58 (d, J = 7.8 Hz, 1H), 6.42 (d, J = 7.8 Hz, 1H), 3.29 - 3.41 (m, 2H), 2.89 - 3.11 (m, 4H), 2.75 - 2.88 (m, 5H), 2.53 - 2.72 (m, 1H), 2.17 (m, 1H), 1.80 - 1.98 (m, 1H).

[0747] Example 70: 6-(2-Methoxy-4-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 2, Method A.

[0748]

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

[0750] According to Process 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 1H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 4.8 Hz, 2H), 7.63 (s, 1H), 7.40 (t, J = 4.8 Hz, 1H), 4.05 (s, 4H), 2.91 (br t, J = 6.7 Hz, 2H), 2.81 (s, 2H), 1.94 (t, J = 6.7 Hz, 2H).

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

[0752] According to Process 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 (400 MHz, DMSO-d6) δ 9.04 (d, J = 4.8 Hz, 2H), 7.88 (s, 1H), 7.79 (d, J = 6.4 Hz, 1H), 3.55 (s, 2H), 2.95 (br t, J = 6.9 Hz, 2H), 2.56 (t, J = 7.0 Hz, 2H).

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

[0754] According to Process 2, Step vii: Intermediate 15b was prepared starting from Intermediate 14b (3.50 g, 14.45 mmol) according to the same method 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 (400 MHz, MeOD) δ 9.03 - 8.94 (m, 2H), 8.03 - 7.92 (m, 1H), 7.70 - 7.59 (m, 1H), 6.66 (t, J = 1.4 Hz, 1H), 3.15 - 3.05 (m, 2H), 2.92 - 2.83 (m, 2H).

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

[0756] According to Process 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 as 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] Example 70: 6-(2-Methoxy-3-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared starting from intermediate 16m (177.00 mg, 511.00 μmol) according to the same method as described in Example 58, to give Example 70 (23.80 mg, 62.85 μmol, 12.30% yield), as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 9.02 (s, 1H), 7.85 (s, 1H), 7.72 (t, J = 4.89 Hz, 1H), 7.12 - 7.18 (m, 1H), 6.88 (d, J = 3.39 Hz, 1H), 6.86 (d, J = 3.89 Hz, 1H), 4.43 - 4.71 (m, 1H), 3.12 - 3.22 (m, 1H), 2.66 - 2.86 (m, 3H), 2.56 (br d, J = 9.91 Hz, 1H), 2.18 (s, 3H), 1.91 - 2.00 (m, 1H), 1.79 - 1.90 (m, 1H), 1.28 (d, J = 6.02 Hz, 6H).

[0759] Example 71: 6-(2-Methoxy-3-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared according to Process 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 Process 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 Process 2, Step ix: Example 71 was prepared starting from intermediate 16n (180.00 mg, 519.66 μmol) according to the same method as described in Example 58, to give Example 71 (13.00 mg, 37.31 μmol, 7.18% yield), as a white solid.1 H-NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 9.02 (s, 1H), 7.86 (s, 1H), 7.72 (t, J = 4.89 Hz, 1H), 7.12 - 7.20 (m, 1H), 6.90 (d, J = 7.65 Hz, 1H), 6.86 (d, J = 8.03 Hz, 1H), 4.09 (dd, J = 3.89, 5.40 Hz, 2H), 3.66 - 3.74 (m, 2H), 3.12 - 3.23 (m, 1H), 2.65 - 2.88 (m, 3H), 2.57 (br d, J = 8.28 Hz, 1H), 2.20 (s, 3H), 1.95 (br s, 1H), 1.78 - 1.90 (m, 1H).

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

[0766]

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

[0768] According to Process 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-tetrahydrophtalazin-1(2H)-one

[0770] According to Process 2, Step ix: Example 72 was prepared starting from Intermediate 16o (190.00 mg, 517.99 μmol) according to the same method as 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) δ 9.03(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-tetrahydrophtalazin-1(2H)-one, prepared according to Process 2, Method A

[0772]

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

[0774] According to Process 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-tetrahydrophtalazin-1(2H)-one

[0776] According to Process 2, Step ix: Example 73 was prepared starting from Intermediate 16p (72.00 mg, 179.84 μmol) according to the same method as described for Example 58, to give Example 73 (8.30 mg, 19.84 μmol, 11.03% yield), as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.94 (d, J = 4.8 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 2.5 Hz, 1H), 6.72 (dd, J = 2.6, 8.3 Hz, 1H), 3.81 (s, 3H), 3.19 - 2.99 (m, 2H), 2.88 - 2.78 (m, 1H), 2.75 - 2.61 (m, 2H), 2.32 (s, 3H), 2.21 - 2.10 (m, 1H), 1.94 - 1.81 (m, 1H)

[0777] Example 74: 6-(2-Fluoro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 2, Method A.

[0778]

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

[0780] According to Process 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-tetrahydrophtalazin-1(2H)-one

[0782] According to Process 2, Step ix: Example 74 was prepared starting from Intermediate 16q (60.00 mg, 171.26 μmol) according to the same method as described for Example 58, to give Example 74 (7.70 mg, 21.66 μmol, 12.65% yield), as a white solid. 11H-NMR (400 MHz, CDCl3) δ 8.94 (d, J = 4.9 Hz, 2H), 7.70 (s, 1H), 7.43 (t, J = 4.8 Hz, 1H), 7.10 (d, J = 7.7 Hz, 1H), 7.04 - 6.97 (m, 2H), 3.20 - 3.10 (m, 1H), 3.04 (br dd, J = 5.1, 19.4 Hz, 1H), 2.86 - 2.61 (m, 3H), 2.34 (s, 6H), 2.18 - 2.09 (m, 1H), 1.95 - 1.83 (m, 1H).

[0783] Example 75: 6-(2-Chloro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 2, Method A.

[0784]

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

[0786] According to Process 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-tetrahydrophtalazin-1(2H)-one

[0788] According to Process 2, Step ix: Example 75 was prepared starting from Intermediate 16r (160.00 mg, 436.21 μmol) according to the same method as described for Example 58, to give Example 75 (5.80 mg, 15.65 μmol, 3.59% yield), as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.94 (d, J = 4.9 Hz, 2H), 7.71 (s, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 2.9 Hz, 1H), 6.76 (dd, J = 2.9, 8.7 Hz, 1H), 3.82 (s, 3H), 3.48 - 3.37 (m, 1H), 3.08 - 2.93 (m, 2H), 2.76 - 2.57 (m, 2H), 2.25 - 2.16 (m, 1H), 1.97 - 1.84 (m, 1H).

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

[0790]

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

[0792] According to Process 2, Step viii: Intermediate 16s was prepared in the same manner as described for Intermediate 16a starting from Intermediate 15b (200.00 mg, 480.91 μmol) and (5-methoxy-2-methylphenyl)boronic acid (119.73 mg, 721.37 μmol), giving 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-tetrahydrophtalazin-1(2H)-one

[0794] According to Process 2, Step ix: Example 76 was prepared in the same manner as described for Example 58 starting from Intermediate 16s (120.00 mg, 346.44 μmol), giving Example 76 (15.00 mg, 54.38 μmol, 15.70% yield), as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.94 (d, J = 4.8 Hz, 2H), 7.69 (s, 1H), 7.41 (t, J = 4.9 Hz, 1H), 7.07 - 6.98 (m, 2H), 6.81 (d, J = 8.3 Hz, 1H), 3.83 (s, 3H), 3.39 - 3.26 (m, 1H), 3.06 - 2.85 (m, 2H), 2.73 - 2.59 (m, 2H), 2.31 (s, 3H), 2.14 (br dd, J = 3.5, 13.3 Hz, 1H), 1.99 - 1.87 (m, 1H).

[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 Process 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 Process 2, Step viii: Intermediate 16t was prepared starting from Intermediate 15b (250.00 mg, 500.95 μmol) and (2-Methyl-5-(pyrrolidin-1-yl)phenyl)boronic acid pinacol ester (334.07 mg, 751.43 μmol) according to the same method as described for Intermediate 16a in Example 58, to give Intermediate 16t (110.00 mg, crude), as a yellow solid. m / z (M + H) + = 386.2.

[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 Process 2, Step ix: Example 77 was prepared starting from Intermediate 16t (110.00 mg, 285.37 μmol) according to the same method as described for Example 58, to give Example 77 (9.84 mg, 24.20 μmol, 8.48% yield), as a yellow solid. 11H-NMR (400 MHz, CDCl3) δ 8.94 (d, J = 4.8 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.09 - 7.03 (m, 1H), 6.46 - 6.40 (m, 2H), 3.31 - 3.25 (m, 4H), 3.18 - 3.01 (m, 2H), 2.87 - 2.62 (m, 3H), 2.28 (s, 3H), 2.21 - 2.14 (m, 1H), 2.01 (td, J = 3.3, 6.6 Hz, 4H), 1.95 - 1.84 (m, 1H).

[0801] Example 78: 6-(1-Methyldihydroindol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Scheme 2, Method A.

[0802]

[0803] Intermediate 16u: 6-(1-Methyldihydroindol-4-yl)-2-(pyrimidin-2-yl)-7,8-dihydrophtalazin-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-methyldihydroindol-4-yl)boronic acid pinacol ester (241.60 mg, 751.41 μmol) according to the same method as 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-tetrahydrophtalazin-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 method as described for Example 58, to give Example 78 (26.79 mg, 71.41 μmol, 18.23% yield), as a yellow solid. 11H-NMR (400 MHz, CDCl3) δ 8.94 (d, J = 4.9 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J = 4.9 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.92 (dd, J = 2.5, 8.3 Hz, 1H), 6.86 (d, J = 2.5 Hz, 1H), 3.79 - 3.66 (m, 1H), 3.19 - 3.09 (m, 1H), 3.08 - 2.98 (m, 1H), 2.87 - 2.78 (m, 1H), 2.74 - 2.61 (m, 2H), 2.32 (s, 3H), 2.19 - 2.10 (m, 1H), 1.93 - 1.79 (m, 1H), 0.79 - 0.76 (m, 4H).

[0807] Example 79: 6-(2-Fluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 2, Method A.

[0808]

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

[0810] According to Process 2, Step viii: Intermediate 16v was prepared in the same manner as described for Intermediate 16a in Example 58 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), 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-tetrahydrophtalazin-1(2H)-one

[0812] According to Process 2, Step ix: Example 79 was prepared in the same manner as described for Example 58 starting from Intermediate 16v (140.00 mg, 399.60 μmol), to give Example 79 (9.04 mg, 25.45 μmol, 6.37% yield), as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.94 (d, J = 4.9 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.31 - 7.27 (m, 1H), 7.00 (dd, J = 1.7, 8.2 Hz, 1H), 6.93 (t, J = 1.9 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 3.79 - 3.70 (m, 1H), 3.05 - 2.85 (m, 3H), 2.80 - 2.60 (m, 2H), 2.29 - 2.17 (m, 1H), 1.95 - 1.81 (m, 1H), 0.83 - 0.77 (m, 4H).

[0813] Example 80: 6-(5-Methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 2, Method A.

[0814]

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

[0816] According to Process 2, Step viii: Intermediate 16w was prepared in the same manner as described for Intermediate 16a starting from Intermediate 15b (250.00 mg, 500.94 μmol) and (5-methoxy-2-methylphenyl)boronic acid (124.72 mg, 751.41 μmol), giving 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-tetrahydrophtalazin-1(2H)-one

[0818] According to Process 2, Step ix: Example 80 was prepared in the same manner as described for Example 58 starting from Intermediate 16w (110.00 mg, 317.57 μmol), giving 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=4.99,10.42,17.25Hz,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(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-tetrahydrophtalazin-1(2H)-one, prepared according to Process 2, Method A.

[0820]

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

[0822] According to Process 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-tetrahydrophtalazin-1(2H)-one

[0824] According to Process 2, Step ix: Example 81 was prepared starting from Intermediate 16x (75.00 mg, 227.01 μmol) according to the same method as 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-tetrahydrophtalazin-1(2H)-one, prepared according to Process 2, Method A.

[0826]

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

[0828] According to Process 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-tetrahydrophtalazin-1(2H)-one

[0830] According to Process 2, Step ix: Example 82 was prepared starting from Intermediate 16y (100.00 mg, 302.68 μmol) according to the same method as described for Example 58, to give Example 82 (4.78 mg, 13.70 μmol, 4.53% yield), as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 8.61 (s, 2H), 7.81 (s, 1H), 7.14 - 7.22 (m, 1H), 6.88 (dd, J = 7.91, 16.81 Hz, 2H), 3.75 - 3.82 (m, 7H), 3.34 (br s, 4H), 3.12 - 3.22 (m, 1H), 2.76 - 2.86 (m, 1H), 2.63 - 2.75 (m, 2H), 2.56 (br s, 1H), 2.18 (s, 3H), 1.94 (br s, 1H), 1.77 - 1.90 (m, 1H).

[0831] Example 83: 6-(3-(Methoxymethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 2, Method A.

[0832]

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

[0834] According to Process 2, Step viii: Intermediate 16z was prepared in the same manner as described for Intermediate 16a starting from Intermediate 15b (590 mg, 1.18 mmol) and (3-(methoxymethyl)phenyl)boronic acid (196.23 mg, 1.18 mmol), giving 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-tetrahydrophtalazin-1(2H)-one

[0836] According to Process 2, Step ix: Example 83 was prepared in the same manner as described for Example 58 starting from Intermediate 16z (260 mg, 750.62 μmol), giving Example 83 (24.91 mg, 70.28 μmol, 9.36% yield), as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 8.72 (s, 2H), 7.82 (s, 1H), 7.14 - 7.21 (m, 1H), 6.89 (d, J = 7.65 Hz, 1H), 6.85 (d, J = 8.16 Hz, 1H), 5.03 (t, J = 5.46 Hz, 1H), 4.24 - 4.31 (m, 2H), 3.75 - 3.80 (m, 5H), 3.13 - 3.22 (m, 1H), 2.67 - 2.86 (m, 3H), 2.55 (br d, J = 9.79 Hz, 1H), 2.18 (s, 3H), 1.93 (br s, 1H), 1.78 - 1.89 (m, 1H).

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

[0838]

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

[0840] According to Process 2, Step viii: Intermediate 16aa was prepared starting from Intermediate 15b (200 mg, 523.65 μmol) and (5-cyclopropoxy-2-methylphenyl)boronic acid pinacol ester (244.71 mg, 785.47 μmol) according to the 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-Cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[0842] According to Process 2, Step ix: Example 84 was prepared starting from Intermediate 16aa (210 mg, 563.88 μmol) according to the same method as 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) δ 8.35 (d, J = 6.15 Hz, 1H), 7.77 (s, 1H), 7.15 - 7.21 (m, 1H), 6.96 (d, J = 6.27 Hz, 1H), 6.89 (d, J = 7.78 Hz, 1H), 6.85 (d, J = 8.16 Hz, 1H), 3.79 (s, 3H), 3.67 (br d, J = 5.02 Hz, 4H), 3.62 (br d, J = 4.77 Hz, 4H), 3.17 (br t, J = 8.97 Hz, 1H), 2.62 - 2.83 (m, 3H), 2.52 - 2.59 (m, 1H), 2.18 (s, 3H), 1.93 (br s, 1H), 1.83 (dq, J = 4.83, 11.90 Hz, 1H).

[0843] Example 85: 6-(3-Cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 2, Method A.

[0844]

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

[0846] According to Process 2, Step viii: Intermediate 16ab was prepared starting from Intermediate 15b (200 mg, 523.65 μmol) and (3-cyclopropoxyphenyl)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-Cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[0848] According to Process 2, Step ix: Example 85 was prepared starting from Intermediate 16ab (170 mg, 474.34 μmol) according to the same method as described for Example 58, to give Example 85 (12.36 mg, 33.03 μmol, 6.96% yield), as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.93 (d, J = 4.8 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J = 4.9 Hz, 1H), 7.27 - 7.22 (m, 1H), 6.82 (d, J = 7.8 Hz, 1H), 6.80 - 6.76 (m, 2H), 4.78 (qd, J = 2.9, 5.7 Hz, 1H), 3.03 - 2.84 (m, 3H), 2.80 - 2.71 (m, 1H), 2.71 - 2.60 (m, 1H), 2.26 - 2.16 (m, 1H), 1.96 - 1.78 (m, 7H), 1.68 - 1.59 (m, 2H).

[0849] Example 86: 6-(3-(Cyclopentyloxy)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Scheme 2, Method A.

[0850]

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

[0852] According to Scheme 2, Step viii: Intermediate 16ac was prepared in the same manner as described for Intermediate 16a starting from Intermediate 15b (300 mg, 785.48 μmol) and (3-(cyclopentyloxy)phenyl)boronic acid pinacol ester (425.50 mg, 1.18 mmol), giving 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-tetrahydrophtalazin-1(2H)-one

[0854] According to Scheme 2, Step ix: Example 86 was prepared in the same manner as described for Example 58 starting from Intermediate 16ac (240 mg, 621.04 μmol), giving Example 86 (29.15 mg, 73.01 μmol, 11.76% yield), as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.93 (d, J = 4.8 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J = 4.9 Hz, 1H), 7.27 - 7.22 (m, 1H), 6.82 (d, J = 7.8 Hz, 1H), 6.80 - 6.76 (m, 2H), 4.78 (qd, J = 2.9, 5.7 Hz, 1H), 3.03 - 2.84 (m, 3H), 2.80 - 2.71 (m, 1H), 2.71 - 2.60 (m, 1H), 2.26 - 2.16 (m, 1H), 1.96 - 1.78 (m, 7H), 1.68 - 1.59 (m, 2H).

[0855] Example 87: 6-(4-Methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 2, Method A.

[0856]

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

[0858] According to Process 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) by 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, 400 MHz) δ 9.02 (d, J = 4.8 Hz, 2H), 8.00 (s, 1H), 7.71 (t, J = 4.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 8.4, 2.4 Hz, 1H), 6.40 (s, 1H), 3.75 (s, 3H), 2.75 - 2.85 (m, 2H), 2.60 - 2.70 (m, 2H), 2.36 (s, 3H).

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

[0860] Example 87: 6-(1,5-Dimethyl-1H-indazol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one was prepared starting from intermediate 16ad (0.15 g, 433.05 μmol) according to the same method as described in Example 58, to give Example 87 (42 mg, 120.55 μmol, 27.84% yield), as a white solid. 1 1H-NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 4.8 Hz, 2H), 7.85 (s, 1H), 7.71 (t, J = 4.8 Hz, 1H), 7.13 - 7.23 (m, 1H), 6.77 (br d, J = 2.8 Hz, 2H), 3.72 (s, 3H), 3.07 (m, 1H), 2.57 - 2.85 (m, 4H), 2.32 (s, 3H), 1.78 - 1.99 (m, 2H).

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

[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 Process 2, Step ix: Example 88 was prepared starting from intermediate 16ae (51.39 mg, 138.73 μmol) according to the same method as described in Example 58, to give Example 88 (4 mg, 10.74 μmol, 7.74% yield), as a pale yellow solid. 1H-NMR(400 MHz, DMSO-d6) δ 9.03 (d, J = 4.8 Hz, 3H), 8.24 (s, 1H), 7.85 (s, 1H), 7.68 - 7.76 (m, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.01 (s, 3H), 3.19 (m, 1H), 3.12 - 3.12 (m, 1H), 2.73 - 2.94 (m, 4H), 2.44 (s, 3H), 1.99 (m, 2H).

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

[0868]

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

[0870] According to Scheme 2, Step viii: Intermediate 16af was prepared from intermediate 15b (200.00 mg, 534.34 μmol) and boronic acid (87.64 mg, 534.34 μmol) starting by the same method as described for intermediate 16a, to give intermediate 16af (0.15 g, 435.53 μmol, 81.51% yield), as a yellow solid. m / z (M + H)+ = 345.3; 1 1H NMR (DMSO-d6, 400 MHz) δ 9.03 (d, J = 4.8 Hz, 2H), 7.99 (s, 1H), 7.71 (t, J = 4.8 Hz, 1H), 6.92 (s, 2H), 6.26 (s, 1H), 2.78 - 2.91 (m, 2H), 2.52 - 2.56 (m, 2H), 2.24 (s, 3H), 2.20 (s, 6H).

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

[0872] According to Scheme 2, Step ix: Example 89 was prepared from intermediate 16af (150.00 mg, 435.53 μmol) starting by the same method as described for Example 58, to give Example 89 (8 mg, 22.61 μmol, 5.19% yield), as a white solid. 1H-NMR(400 MHz, DMSO-d6) δ 9.01 (d, J = 4.8 Hz, 2H), 7.81 (s, 1H), 7.67 - 7.73 (m, 1H), 6.81 (s, 2H), 3.28 - 3.30 (m, 1H), 2.95 - 3.08 (m, 1H), 2.64 - 2.84 (m, 2H), 2.32 (s, 6H), 2.18 (s, 3H), 1.89 (m, 2H).

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

[0874]

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

[0876] According to Process 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, 400 MHz) δ 9.03 (d, J = 4.8 Hz, 2H), 8.04 (s, 1H), 7.72 (t, J = 4.8 Hz, 1H), 7.06 - 7.34 (m, 2H), 6.71 (s, 1H), 3.86 (s, 3H), 2.76 - 2.89 (m, 2H), 2.62 - 2.73 (m, 2H).

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

[0878] According to Process 2, Step ix: Example 90 was prepared starting from Intermediate 16ag (0.15 g, 407.24 μmol) according to the same method as 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) δ 9.02 (d, J = 4.8 Hz, 2H), 7.83 (s, 1H), 7.71 (t, J = 4.8 Hz, 1H), 6.99 - 7.19 (m, 3H), 3.83 (s, 3H), 3.36 - 3.43 (m, 1H), 2.71 - 3.04 (m, 4H), 1.97 - 2.18 (m, 3H).

[0879] Example 91: 6-(2-Chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 2, Method A

[0880]

[0881] Intermediate 16ah: 6-(2-Chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophtalazin-1(2H)-one

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

[0883] ) δ 8.94 (d, J = 4.8 Hz, 2H), 7.79 (s, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.29 - 7.24 (m, 2H), 6.91 (dd, J = 1.6, 7.6 Hz, 1H), 6.35 (t, J = 1.6 Hz, 1H), 3.84 (tt, J = 3.2, 5.9 Hz, 1H), 3.08 - 2.98 (m, 2H), 2.84 - 2.72 (m, 2H), 0.92 - 0.82 (m, 4H).

[0884] Example 91: 6-(2-Chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydro-phtalazin-1(2H)-one

[0885] According to Process 2, Step ix: Example 91 was prepared in the same manner as described for Example 58 starting from Intermediate 16ah (1.20 g, 2.88 mmol), to give Example 91 (517 mg, 1.26 mmol, 43.9% yield), as a white solid. 11H-NMR (400 MHz, CDCl3) δ 8.93 (d, J = 4.8 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.26 - 7.22 (m, 2H), 6.95 - 6.86 (m, 1H), 3.83 (tt, J = 3.0, 5.8 Hz, 1H), 3.58 - 3.47 (m, 1H), 3.04 - 2.92 (m, 2H), 2.82 - 2.57 (m, 2H), 2.24 - 2.14 (m, 1H), 1.99 - 1.86 (m, 1H), 0.93 - 0.80 (m, 4H).

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

[0887]

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

[0889] According to Process 2, Step viii: Intermediate 16ai was prepared starting from Intermediate 15b (2.00 g, 5.34 mmol) and (1-cyclopropyldihydroindol-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), a yellow solid. m / z (M+H) + = 384.0

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

[0891] According to Process 2, Step ix: Example 92 was prepared starting from Intermediate 16ai (1.70 g, 4.43 mmol) according to a similar method as described for Example 58, to give Example 92 (230 mg, 549.19 μmol, 35.10% yield), as a pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ 8.94 (d, J = 4.8 Hz, 1H), 8.97 - 8.90 (m, 1H), 7.69 (s, 1H), 7.42 (t, J = 5.0 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 3.46 - 3.39 (m, 2H), 3.06 - 2.89 (m, 4H), 2.85 - 2.59 (m, 3H), 2.19 - 2.11 (m, 2H), 1.95 - 1.83 (m, 1H), 0.73 - 0.63 (m, 4H).

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

[0893]

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

[0895] According to Process 2, Step viii: Intermediate 16aj was prepared starting from Intermediate 15c (3.00 g, 7.49 mmol) and (3-cyclopropoxy-2-methylphenyl)boronic acid pinacol ester (2.25 g, 7.49 mmol) 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 (400 MHz, CDCl3) δ 8.74 (s, 2H), 7.75 (s, 1H), 7.25 - 7.16 (m, 2H), 6.81 (dd, J = 1.8, 7.0 Hz, 1H), 6.23 (s, 1H), 3.80 - 3.73 (m, 1H), 3.03 - 2.94 (m, 2H), 2.72 - 2.63 (m, 2H), 2.43 (s, 3H), 2.18 (s, 3H), 0.85 - 0.73 (m, 4H).

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

[0897] Example 93: Prepared starting from intermediate 16aj (1.20 g, 3.02 mmol) according to the same method as described in Example 58 in Process 2, to give Example 93 (500 mg, 1.27 mmol, 42.1% yield), as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.74 (s, 2H), 7.68 (s, 1H), 7.24 - 7.13 (m, 2H), 6.86 (d, J = 6.5 Hz, 1H), 3.78 - 3.71 (m, 1H), 3.26 - 3.17 (m, 1H), 3.04 - 2.95 (m, 1H), 2.86 - 2.76 (m, 1H), 2.75 - 2.60 (m, 2H), 2.43 (s, 3H), 2.19 (s, 3H), 2.17 - 2.09 (m, 1H), 1.95 - 1.82 (m, 1H), 0.82 - 0.76 (m, 4H).

[0898] Example 94: 6-(2-Chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Process 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 Process 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 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 2H), 7.83 - 7.74 (m, 1H), 7.33 - 7.21 (m, 1H), 7.04 - 6.81 (m, 2H), 6.36 (s, 1H), 4.10 - 3.89 (m, 3H), 3.18 - 2.96 (m, 2H), 2.88 - 2.73 (m, 2H), 2.44 (s, 3H).

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

[0903] Example 94 was prepared starting from Intermediate 16ak (600 mg, 1.54 mmol) according to the same method as described in Example 58 in Process 2, to give Example 94 (230 mg, 588 μmol, 38.2% yield, 97.8% purity), as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.73 (s, 2H), 7.69 (s, 1H), 7.26 - 7.23 (m, 1H), 6.88 (dd, J = 4.4, 8.0 Hz, 2H), 3.93 (s, 3H), 3.61 - 3.49 (m, 1H), 3.02 - 2.92 (m, 2H), 2.82 - 2.58 (m, 2H), 2.43 (s, 3H), 2.19 (td, J = 2.8, 10.0 Hz, 1H), 1.98 - 1.85 (m, 1H).

[0904] Example 95: 6-(2-Chloro-4-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, was prepared according to Process 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 Process 2, Step x: At 25 °C under N2, Pin2B2 (1.02 g, 4.01 mmol, 1.5 equiv) was added in one portion to a solution of Intermediate 15b (1 g, 2.67 mmol, 1 equiv), Pd(dppf)Cl2 (97.74 mg, 133.58 μmol, 0.05 equiv) and KOAc (524.41 mg, 5.34 mmol, 2 equiv) in dioxane (20 mL). The mixture was stirred at 100 °C for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (PE:EtOAc = 1:1) to give Intermediate 17a (0.85 g, 2.41 mmol, 90.33% yield), as a yellow solid.

[0908] m / z (M+H) + = 353.3; 1 1H NMR (CDCl3, 400 MHz) δ 8.92 (d, J = 4.8 Hz, 2H), 7.77 (s, 1H),

[0909] 7.41 (t, J = 4.8 Hz, 1H), 6.99 (s, 1H), 2.74 - 2.89 (t, J = 8.8 Hz, 2H), 2.46 - 2.61 (t, J = 8.8 Hz, 2H), 1.32 (s, 12H).

[0910] Intermediate 16al: 6-(2-chloro-4-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophtalazin-1(2H)-one

[0911] According to Process 2, Step xi: At 20 °C under N2, to a mixture of Intermediate 17a (247.04 mg, 1.20 mmol, 64.34 μL, 1.5 equiv) and 1-bromo-2-chloro-4-methylbenzene (0.3 g, 801.51 μmol, 1 equiv) in dioxane (10 mL) was added all at once Na2CO3 (339.80 mg, 3.21 mmol, 4 equiv) and Pd(dppf)Cl2·CH2Cl2 (65.45 mg, 80.15 μmol, 0.1 equiv) in H2O (1 mL). The mixture was stirred at 100 °C for 12 h. The mixture was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EtOAc = 0:1, 1:0) to give Intermediate 16al (0.15 g, 427.59 μmol, 53.35% yield), as a yellow solid. 1 1H NMR (400 MHz, CDCl3) δ 9.07 - 9.03 (m, 3H), 8.04 (s, 1H), 7.76 - 7.68 (m, 2H), 7.40 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.57 (s, 1H), 2.87 - 2.79 (m, 2H), 2.77 - 2.67 (m, 2H), 2.35 (s, 3H).

[0912] Example 95: 6-(2-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[0913] According to Process 2, Step ix: Example 95 was prepared starting from Intermediate 16al (0.15 g, 427.59 μmol) according to the same method as described for Example 58, to give Example 95 (0.018 g, 51.02 μmol, 11.93% yield), as a white solid. 11H-NMR (400 MHz, CDCl3) δ 8.94 (d, J = 4.0 Hz, 2H), 7.71 (s, 1H), 7.42 (t, J = 4.4 Hz, 1H), 7.25 (s, 1H), 7.17 - 7.12 (m, 1H), 7.12 - 7.06 (m, 1H), 3.52 - 3.39 (m, 1H), 3.04 - 2.92 (m, 2H), 2.76 - 2.58 (m, 2H), 2.34 (s, 3H), 2.22 - 2.05 (m, 2H), 1.97 - 1.85 (m, 1H).

[0914] Example 96: 6-(3-(Dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 2, Method B.

[0915]

[0916] Intermediate 16am: 6-(3-(Dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophtalazin-1(2H)-one

[0917] According to Process 2, Step xi: Intermediate 16am was prepared starting from Intermediate 17a (0.2 g, 567.87 μmol) and 3-bromo-N,N,2-trimethylaniline (121.58 mg, 567.87 μmol) according to the same method as described for Intermediate 16al, to give Intermediate 16am (0.15 g, 417.33 μmol, 73.49% yield), as a yellow solid. m / z (M+H) + = 360.3; 1 1H NMR (CDCl3, 400 MHz) δ 8.94 (d, J = 4.9 Hz, 3H), 7.78 (s, 1H), 7.44 - 7.40 (m, 2H), 7.20 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.26 (s, 1H), 2.96 - 3.07 (m, 2H), 2.66 - 2.76 (m, 8H), 2.35 (s, 3H).

[0918] Example 96: 6-(3-(Dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-j5,6,7,8-tetrahydrophtalazin-1(2H)-one

[0919] Example 96 was prepared starting from intermediate 16am (0.15 g, 417.33 μmol) according to the same method as described for Example 58 in Process 2, to give Example 96 (14 mg, 34.93 μmol, 8.37% yield), as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.94 (d, J = 4.8 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.28 (m, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 3.16 (m, 1H), 2.97 - 2.92 (m, 1H), 2.91 - 2.75 (m, 7H), 2.65 - 2.59 (m, 2H), 2.35 (s, 3H), 2.08 2.06 (m, 1H), 1.86 - 1.81 (m, 1H).

[0920] Example 97: 6-(5-Methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, was prepared according to Process 2, Method B.

[0921]

[0922] Intermediate 16an: 6-(5-Methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophtalazin-1(2H)-one

[0923] According to Process 2, Step xi: Intermediate 16an was prepared starting from intermediate 17a (0.3 g, 851.80 μmol) and 1-bromo-5-methoxy-2,4-dimethylbenzene (183.21 mg, 851.80 μmol) according to the same method as described for intermediate 16al, to give intermediate 16an (0.2 g, 554.93 μmol, 65.15% yield), as a yellow solid. m / z (M+H) + = 361.3; 1 1H NMR (CDCl3, 400 MHz) δ 9.03 (d, J = 4.8 Hz, 2H), 8.01 (s, 1H), 7.71 (t, J = 4.8 Hz, 1H), 7.04 (s, 1H), 6.80 (s, 1H), 6.44 (s, 1H), 3.79 (s, 3H), 2.76 - 2.89 (m, 2H), 2.61 - 2.73 (m, 2H), 2.26 (s, 3H), 2.14 (s, 3H).

[0924] Example 97: 6-(5-Methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0925] According to Process 2, Step ix: Example 97 was prepared starting from Intermediate 16nj (0.2 g, 554.93 μmol) according to the same method as described for Example 58, to give Example 97 (8 mg, 22.07 μmol, 3.98% yield), as a white solid. 1 1H-NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 4.4 Hz, 2H), 7.86 (s, 1H), 7.71 (t, J = 4.4 Hz, 1H), 6.93 (s, 1H), 6.83 (s, 1H), 3.77 (s, 3H), 3.07 (m, 1H), 2.72 - 2.88 (m, 4H), 2.23 (s, 3H), 2.09 (s, 3H), 1.78 - 2.01 (m, 2H).

[0926] Example 98 6-(4-Chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, was prepared according to Process 2, Method B.

[0927]

[0928] Intermediate 16ao: 6-(4-Chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

[0929] According to Process 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 as 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.

[0930] Example 98: 6-(4-Chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0931] According to Process 2, Step ix: Example 98 was prepared starting from Intermediate 16ao (120 mg, 342.07 μmol) according to the same method as described for Example 58, to give Example 98 (13 mg, 36.85 μmol, 10.77% yield), as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 4.8 Hz, 2H), 7.85 (s, 1H), 7.71 (t, J = 4.8 Hz, 1H), 7.22 - 7.34 (m, 3H), 3.14 (m, 1H), 2.65 - 2.89 (m, 4H), 2.36 (s, 2H), 1.81 - 2.01 (m, 2H).

[0932] Example 99: 6-(4-Acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 2, Method B.

[0933]

[0934] Intermediate 16ap: 6-(4-Acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophtalazin-1(2H)-one

[0935] According to Process 2, Step xi: Intermediate 16ap was prepared starting from Intermediate 17a (0.3 g, 851.80 μmol) and 1-(4-bromo-3-methylphenyl)ethan-1-one (181.49 mg, 851.80 μmol) according to the same method as described for Intermediate 16al, to give Intermediate 16ap (0.18 g, 502.24 μmol, 58.96% yield), as a yellow solid. m / z (M + H) + = 359.2; 1 HNMR (DMSO-d6, 400 MHz) δ 9.03 (d, J = 4.8 Hz, 2H), 8.03 (s, 1H), 7.88 (s, 1H), 7.83 (br d, J = 8.0 Hz, 1H), 7.72 (t, J = 4.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 6.52 (s, 1H), 2.80 - 2.89 (m, 2H), 2.66 - 2.75 (m, 2H), 2.59 (s, 3H), 2.44 (s, 3H).

[0936] Example 99: 6-(4-Acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[0937] According to Process 2, Step ix: Example 99 was prepared starting from Intermediate 16ap (150.00 mg, 418.53 μmol) according to the same method as described for Example 58, to give Example 99 (22 mg, 61.04 μmol, 14.58% yield), as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 4.8 Hz, 2H), 7.85 (s, 1H), 7.76 - 7.83 (m, 2H), 7.71 (t, J = 4.8 Hz, 1H), 7.43 (br d, J = 8.0 Hz, 1H), 3.16 - 3.27 (m, 1H), 2.65 - 2.93 (m, 4H), 2.55 (s, 3H), 2.43 (s, 3H), 1.83 - 2.03 (m, 2H).

[0938] Example 100: 6-(3-(3-Methoxypropoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Scheme 5.

[0939]

[0940] Intermediate 50: 6-(3-Hydroxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0941] According to Scheme 5, Step i: At 0 °C under N2, BBr3 (8.99 g, 35.90 mmol, 3.46 mL, 5.00 equivalents) was added dropwise to a solution of Compound Example 40 (2.50 g, 7.18 mmol, 1.00 equivalent) in CH2Cl2 (30.00 mL). The mixture was stirred at 0 °C for 1.5 hours. At 0 °C, the mixture was poured into H2O (80 mL). The pH of the aqueous phase was adjusted to about 6 - 7 by adding solid K2CO3. A large amount of precipitate formed. The mixture was filtered, and the combined aqueous phase was extracted with CH2Cl2 (60 mL x 5), filtered, and concentrated in vacuo. The filter cake was dissolved in CH2Cl2 / MeOH (1 / 10, 100 mL) and stirred for 1 hour. The mixture was filtered. All the organic phases were combined and dried in vacuo. Intermediate 50 (2.60 g, 5.99 mmol, 83.39% yield) was obtained as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 9.01 (s, 1H), 7.85 (s, 1H), 7.71 (t, J = 4.89 Hz, 1H), 6.88 - 6.95 (m, 1H), 6.63 - 6.69 (m, 1H), 6.60 (d, J = 7.65 Hz, 1H), 3.07 - 3.15 (m, 1H), 2.66 - 2.85 (m, 3H), 2.56 (br s, 1H), 2.13 (s, 3H), 1.91 - 1.99 (m, 1H), 1.74 - 1.86 (m, 1H).

[0942] Example 100: (6-(3-(3-methoxypropoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one

[0943] According to Process 5, Step ii: At 25 °C under N2, Cs2CO3 (116.93 mg, 358.89 μmol, 1.5 equivalents) was added in one portion to a mixture of Intermediate 50 (80 mg, 239.26 μmol, 1 equivalent) and 1-bromo-3-methoxypropane (73.22 mg, 478.52 μmol, 38.27 μL, 2 equivalents) in DMF (2 mL). The mixture was stirred at 100 °C for 12 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and purified by preparative-HPLC to obtain Example 100 (25 mg, 61.50 μmol, 25.71% yield), as a white solid. 1 1H-NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 4.8 Hz, 2H), 7.85 (s, 1H), 7.71 (t, J = 4.8 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.80 - 6.93 (m, 2H), 4.00 (t, J = 6.2 Hz, 2H), 3.51 (t, J = 6.2 Hz, 2H), 3.26 (s, 3H), 3.16 - 3.19 (m, 1H), 2.58 - 2.87 (m, 4H), 2.19 (s, 3H), 1.76 - 2.02 (m, 4H).

[0944] Example 101: 6-(3-ethoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Process 5.

[0945]

[0946] According to Process 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 as described for Example 100, to obtain Intermediate Example 101 (25 mg, 68.98 μmol, 28.83% yield), as a white solid. 1H-NMR(400MHz, DMSO-d6) δ 9.02 (d, J = 4.8 Hz, 2H), 7.84 (s, 1H), 7.71 (br t, J = 4.8 Hz, 1H), 7.15 (br t, J = 7.8 Hz, 1H), 7.07 - 7.26 (m, 1H), 6.85 (br dd, J = 19.0, 7.8 Hz, 2H), 4.01 (q, J = 6.8 Hz, 2H), 3.16 - 3.18 (m, 1H), 2.56 - 2.93 (m, 4H), 2.19 (s, 3H), 1.75 - 2.03 (m, 2H), 1.36 (br t, J = 6.8 Hz, 3H).

[0947] Example 102: 6-(3-(Cyclopropylmethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Scheme 5.

[0948]

[0949] According to Scheme 5, step ii: Example 102 was prepared in the same manner as described for Example 100 starting from intermediate 50 (150.00 mg, 345.43 μmol) and (bromomethyl)cyclopropane (233.16 mg, 1.73 mmol), to give intermediate Example 102 ((58.63 mg, 150.78 μmol, 43.65% yield), as a white solid. 1 H-NMR(400MHz, DMSO-d6) δ 9.03 (s, 1H), 9.02 (s, 1H), 7.85 (s, 1H), 7.71 (t, J = 4.83 Hz, 1H), 7.10 - 7.17 (m, 1H), 6.88 (d, J = 7.65 Hz, 1H), 6.81 (d, J = 8.16 Hz, 1H), 3.82 (d, J = 6.65 Hz, 2H), 3.12 - 3.23 (m, 1H), 2.65 - 2.87 (m, 3H), 2.52 - 2.62 (m, 1H), 2.21 (s, 3H), 1.94 (br s, 1H), 1.76 - 1.89 (m, 1H), 1.19 - 1.30 (m, 1H), 0.52 - 0.61 (m, 2H), 0.29 - 0.37 (m, 2H).

[0950] Example 103: 6-(3-Isopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Scheme 5.

[0951]

[0952] According to Process 5, Step ii: Intermediate 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 as described for Example 100, to give Intermediate Example 103 (71.78 mg, 190.68 μmol, 46.00% yield), as a white solid. 1 1H-NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 9.02 (s, 1H), 7.85 (s, 1H), 7.72 (t, J = 4.89 Hz, 1H), 7.12 - 7.18 (m, 1H), 6.88 (d, J = 3.39 Hz, 1H), 6.86 (d, J = 3.89 Hz, 1H), 4.43 - 4.71 (m, 1H), 3.12 - 3.22 (m, 1H), 2.66 - 2.86 (m, 3H), 2.56 (br d, J = 9.91 Hz, 1H), 2.18 (s, 3H), 1.91 - 2.00 (m, 1H), 1.79 - 1.90 (m, 1H), 1.28 (d, J = 6.02 Hz, 6H).

[0953] Example 104: 6-(3-Cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 5

[0954]

[0955] According to Process 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 (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 9.02 (s, 1H), 7.85 (s, 1H), 7.71 (t, J = 4.89 Hz, 1H), 7.16 (t, J = 7.91 Hz, 1H), 6.90 (d, J = 7.53 Hz, 1H), 6.85 (d, J = 8.16 Hz, 1H), 6.08 (tdd, J = 4.99, 10.42, 17.25 Hz, 1H), 5.43 (dd, J = 1.76, 17.32 Hz, 1H), 5.26 (dd, J = 1.69, 10.60 Hz, 1H), 4.56 (d, J = 4.89 Hz, 2H), 3.12 - 3.24 (m, 1H), 2.65 - 2.87 (m, 3H), 2.56 (br d, J = 8.53 Hz, 1H), 2.22 (s, 3H), 1.95 (br s, 1H), 1.79 - 1.91 (m, 1H).

[0956] Example 105: 6-(3-(2-Methoxyethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Scheme 5

[0957]

[0958] According to Scheme 5, step ii: Example 105 was prepared in the same manner as described for Example 100 starting from intermediate 50 (200.00 mg, 460.57 μmol) and 1-bromo-2-methoxyethane (320.07 mg, 2.30 mmol), giving intermediate Example 105 (41.81 mg, 106.54 μmol, 23.13% yield), as a white solid. 1 H-NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 9.02 (s, 1H), 7.86 (s, 1H), 7.72 (t, J = 4.89 Hz, 1H), 7.12 - 7.20 (m, 1H), 6.90 (d, J = 7.65 Hz, 1H), 6.86 (d, J = 8.03 Hz, 1H), 4.09 (dd, J = 3.89, 5.40 Hz, 2H), 3.66 - 3.74 (m, 2H), 3.12 - 3.23 (m, 1H), 2.65 - 2.88 (m, 3H), 2.57 (br d, J = 8.28 Hz, 1H), 2.20 (s, 3H), 1.95 (br s, 1H), 1.78 - 1.90 (m, 1H).

[0959] Example 106: 6-(3-(Benzyloxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Scheme 5.

[0960]

[0961] 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 1H-NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 9.01 (s, 1H), 7.85 (s, 1H), 7.71 (t, J = 4.83 Hz, 1H), 7.45 - 7.51 (m, 2H), 7.41 (t, J = 7.40 Hz, 2H), 7.30 - 7.35 (m, 1H), 7.13 - 7.19 (m, 1H), 6.94 (d, J = 8.16 Hz, 1H), 6.91 (d, J = 7.78 Hz, 1H), 5.11 (s, 2H), 3.13 - 3.25 (m, 1H), 2.65 - 2.88 (m, 3H), 2.56 (br d, J = 9.41 Hz, 1H), 2.24 (s, 3H), 1.95 (br s, 1H), 1.77 - 1.90 (m, 1H).

[0962] Example 107: 2-(5-Cyclopropylpyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Scheme 6, Method A.

[0963]

[0964] Intermediate 52a: 2-(5-Bromopyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[0965] According to Process 6, Step i: At 25 °C under N2, CuI (35.23 mg, 184.96 μmol, 0.5 equiv), K3PO4 (196.31 mg, 924.81 μmol, 2.5 equiv) and DMEDA (16.30 mg, 184.96 μmol, 0.5 equiv) were added in one portion to a mixture of intermediate 7c (0.1 g, 369.92 μmol, 1 equiv) and 2,5-dibromopyrimidine (263.99 mg, 1.11 mmol, 3 equiv) in dioxane (20 mL). 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: (CDCl 3, 400 MHz) H) δ 8.88 (s, 2H), 7.61 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.75 - 6.58 (m, 2H), 3.73 (s, 3H), 3.07 - 2.85 (m, 2H), 2.75 - 2.65 (m, 1H), 2.61 - 2.57 (m, 2H), 2.23 (s, 3H), 2.08 - 2.05 (m, 1H), 1.81 - 1.76 (m, 1H).

[0966] Example 107 2-(5-Cyclopropylpyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one According to Process 6, Step ii: At 25 °C under N2, Pd(dppf)Cl2 (17.12 mg, 23.40 μmol, 0.05 equiv) and K2CO3 (77.61 mg, 0.56 mmol, 3.0 equiv) were added in one portion to a mixture of intermediate 52a (0.2 g, 468.06 μmol, 1 equiv) and cyclopropylboronic acid (78.25 mg, 0.94 mmol, 5 equiv) in dioxane (20 mL). The mixture was stirred at 25 °C for 5 min, then heated to 110 °C and stirred for 12 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was pre-purified by column chromatography followed by preparative HPLC to give Example 107 (0.053 g, 136.44 μmol, 29.15% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.77 (s, 2H), 7.84 (s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 6.73 (dd, J = 2.4, 8.4 Hz, 1H), 3.78 (s, 3H), 3.11 (m, 1H), 2.80 - 2.52 (m, 4H), 2.28 (s, 3H), 2.09 - 2.06 (m, 1H), 1.93 - 1.84 (m, 3H), 1.14 - 1.14 (m, 2H), 1.00 - 0.97 (m, 2H).

[0967] Example 108: 2-(5-Cyclopropylpyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 6, Method A.

[0968]

[0969] Intermediate 52b: 2-(5-Bromopyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

[0970] 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 as described for Intermediate 52a, to give Intermediate 52b (0.7 g, 1.71 mmol, 86.78% yield), as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 7.98 (dd, J = 8.4, 2.0 Hz, 1H), 7.80 - 7.66 (m, 2H), 7.18 - 6.95 (m, 3H), 3.14 (m, 1H), 3.06 - 2.93 (m, 1H), 2.86 - 2.76 (m, 1H), 2.76 - 2.61 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.14 (m, H), 1.96 - 1.78 (m, 1H).

[0971] Example 108 2-(5-Cyclopropylpyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one According to Scheme 6, Step ii: Example 108 was prepared starting from intermediate 52b (0.2,487.44 μmol) and cyclopropylboronic acid (209.35 mg, 2.44 mmol) according to the same method as described for intermediate Example 107, to give Example 108 (0.08 g, 213.20 μmol, 43.74% yield), as a white solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.63 (s, 2H), 7.69 (s, 1H), 7.17 - 6.97 (m, 3H), 3.14 (m, 1H), 3.00 (m, 1H), 2.86 - 2.76 (m, 1H), 2.75 - 2.59 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.12 (m, 1H), 2.03 - 1.95 (m, 1H), 1.98 (m, 1H), 1.93 - 1.77 (m, 1H), 1.25 - 1.10 (m, 2H), 0.88 (m, 2H).

[0972] Example 109: 2-(5-Cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Scheme 6, Method A.

[0973]

[0974] Intermediate 52c: 2-(5-Bromopyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[0975] 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 as described for intermediate 52a, to give intermediate 52c (1.2 g, 2.92 mmol, 74.20% yield), as a pale yellow solid. 1 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 2H), 7.69 (s, 1H), 7.14 - 6.99 (m, 3H), 3.26 - 3.09 (m, 1H), 3.00 (m, 1H), 2.86 - 2.75 (m, 1H), 2.75 - 2.59 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.12 (m, 1H), 1.93 - 1.79 (m, 1H).

[0976] Example 109 2-(5-Cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one According to Scheme 6, Step ii: Example 109 was prepared starting from Intermediate 52c (200.48 mg, 487.44 μmol) and cyclopropylboronic acid (209.35 mg, 2.44 mmol) according to the same method as described for Intermediate Example 107, to give Example 109 (0.124 g, 329.59 μmol, 67.62% yield), as a pale yellow solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.71 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 2.0, 8.4 Hz, 1H), 7.13 - 7.07 (m, 1H), 7.06 - 7.00 (m, 2H), 3.19 - 3.09 (m, 1H), 3.04 - 2.92 (m, 1H), 2.85 - 2.76 (m, 1H), 2.74 - 2.58 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.15 - 2.10 (m, 1H), 2.03 - 1.94 (m, 1H), 1.93 - 1.81 (m, 1H), 1.13 - 1.05 (m, 2H), 0.82 - 0.74 (m, 2H).

[0977] Example 110: 2-(5-Cyclopropylpyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Scheme 6, Method A.

[0978]

[0979] Intermediate 52d: 2-(5-Bromopyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[0980] 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 as described for Intermediate 52a, to give Intermediate 52d (1.2 g, 2.81 mmol, 76.09% yield), as a yellow solid. 11H NMR (DMSO-d6, 400 MHz) δ 8.76 (m, 1H), 8.28 (dd, J = 2.0, 8.4 Hz, 1H), 7.95 (m, 1H), 7.63 (br s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.00 - 6.85 (m, 2H), 3.79 (s, 3H), 3.17 (m, 1H), 2.87 - 2.65 (m, 4H), 2.25 (m, 1H), 2.18 (s, 3H), 1.88 - 1.81 (m, 1H).

[0981] 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 as described for Intermediate Example 107, to give Example 110 (0.09 g, 232.27 μmol, 33.01% yield), as a yellow solid. 1 1H-NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.83 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 3.79 (s, 3H), 3.15 (m, 1H), 2.87 - 2.65 (m, 4H), 2.34 (m, 1H), 2.18 (s, 3H), 2.05 (m, 1H), 1.85 (m, 1H), 1.08 - 1.05 (m, 2H), 0.83 (m, 2H).

[0982] Example 111: 6-(3-Methoxy-2-methylphenyl)-2-(5-(pyrrolidin-1-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, was prepared according to Scheme 6, Method B.

[0983]

[0984] According to Process 6, Step iii: At 20 °C under N2, to a mixture of Example 43 (180 mg, 470.17 μmol, 1 equiv) and pyrrolidine (66.88 mg, 940.33 μmol, 78.49 μL, 2 equiv) in dioxane (5 mL) was added RUPHOS precatalyst (36.52 mg, 47.02 μmol, 0.1 equiv) and Cs2CO3 (382.97 mg, 1.18 mmol, 2.5 equiv). The mixture was stirred at 100 °C for 12 h. The mixture was poured into H2O (15 mL). The aqueous phase was filtered and extracted with CH2Cl2 (20 mL x 2). The combined organic phases were concentrated in vacuo 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 1H-NMR (400 MHz, DMSO-d6) δ 8.18 (s, 2H), 7.78 (s, 1H), 7.14 - 7.21 (m, 1H), 6.89 (d, J = 7.91 Hz, 1H), 6.85 (d, J = 8.03 Hz, 1H), 3.78 (s, 3H), 3.27 - 3.34 (m, 4H), 3.13 - 3.22 (m, 1H), 2.65 - 2.83 (m, 3H), 2.52 - 2.58 (m, 1H), 2.18 (s, 3H), 1.91 - 2.05 (m, 5H), 1.77 - 1.89 (m, 1H).

[0985] Example 112: (6-(3-Methoxy-2-methylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, was prepared according to Process 6, Method B.

[0986]

[0987] According to Process 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 as 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) δ 8.61(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).

[0988] 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.

[0989]

[0990] According to Scheme 6, step iii: Example 113 was prepared in the same manner as described for Example 111 starting from intermediate 52d (0.2 g, 469.15 μmol) and morpholine (81.74 mg, 938.29 μmol, 82.57 μL), to give Example 113 (0.092 g, 212.71 μmol, 45.34% yield), as a yellow solid. 1 H-NMR(400MHz, CDCl3) δ 8.45(br s, 1H), 8.03(br s, 1H), 7.81(br s, 1H), 7.59(br s, 1H), 7.23(br t, J = 7.8Hz, 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).

[0991] 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.

[0992]

[0993] According to Process 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 as described for Example 111, to give Example 114 (0.029 g, 66.14 μmol, 18.09% yield), as a pale yellow solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 8.02 - 7.90 (m, 1H), 7.78 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.13 - 7.01 (m, 3H), 3.97 - 3.87 (m, 4H), 3.40 - 3.29 (m, 4H), 3.20 - 3.08 (m, 1H), 2.98 (m, 1H), 2.89 - 2.78 (m, 1H), 2.71 (m, 2H), 2.35 (s, 3H), 2.33 (s, 3H), 2.15 - 2.10 (m, 1H), 1.95 - 1.82 (m, 1H).

[0994] Example 115: 6-(2,4-Dimethylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Process 6, Method B

[0995]

[0996] According to Process 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 as described for Example 111, to give Example 115 (0.053 g, 126.95 μmol, 34.81% yield), as a pale yellow solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.48 (s, 2H), 7.69 (s, 1H), 7.13 - 6.99 (m, 3H), 3.97 - 3.88 (m, 4H), 3.38 - 3.28 (m, 4H), 3.20 - 3.08 (m, 1H), 2.99 (m, 1H), 2.88 - 2.75 (m, 1H), 2.70 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.17 - 2.05 (m, 1H), 1.95 - 1.80 (m, 1H).

[0997] Example 116: 2-(5-(azetidin-1-yl)pyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Scheme 6, Method B.

[0998]

[0999] 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 as described for Example 111, to give Example 116 (0.004 g, 9.81 μmol, 2.69% yield), as a pale yellow solid. 1 1H-NMR (400 MHz, CDCl3) δ 8.01 (s, 2H), 7.65 (s, 1H), 7.17 - 6.99 (m, 3H), 4.08 (t, J = 7.2 Hz, 4H), 3.12 (m, 1H), 3.02 - 2.95 (m, 1H), 2.83 - 2.75 (m, 1H), 2.70 - 2.62 (m, 2H), 2.62 - 2.52 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.12 - 2.06 (m, 1H), 1.92 - 1.80 (m, 1H).

[1000] Example 117: N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophtalazin-2(1H)-yl)pyrimidin-5-yl)acetamide, prepared according to Scheme 6, Method B.

[1001]

[1002] According to Scheme 6, Step iii: At 25 °C under N2, (1S,2S)-N,N-dimethylcyclohexane-1,2-diamine (6.92 mg, 48.63 μmol, 0.2 equiv), CuI (9.24 mg, 48.63 μmol, 0.2 equiv) and K3PO4 (129 mg, 607.82 μmol, 2.5 equiv) were added in one portion to a mixture of intermediate 52c (0.1 g, 243.13 μmol, 1 equiv) and acetamide (28.72 mg, 486.27 μmol, 2 equiv) in dioxane. 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 (400 MHz, CDCl3) δ 8.93 (s, 2H), 8.58 (s, 1H), 7.66 (s, 1H), 7.03 - 6.97 (m, 3H), 3.12 - 3.06 (m, 1H), 2.98 - 2.88 (m, 1H), 2.82 - 2.72 (m, 1H), 2.72 - 2.61 (m, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 2.15 (s, 3H), 2.12 - 2.05 (m, 1H), 1.88 - 1.82 (m, 1H).

[1003] Example 118: 6-(3-Methoxy-2-methylphenyl)-2-(5-(2-methoxyethoxy)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 6, Method C.

[1004]

[1005] According to Scheme 6, Step iv: To a solution of Compound Example 45 (150 mg, 411.64 μmol, 1 equiv) in DMA (3 mL) was added Cs2CO3 (268.24 mg, 823.28 μmol, 2 equiv) and 1-bromo-2-methoxyethane (572.14 mg, 4.12 mmol, 386.58 μL, 10 equiv). The mixture was stirred at 20 °C for 12 h. The pH of the mixture was adjusted to 7 by adding HCl (6N). The mixture was filtered. The filtrate was concentrated to give the crude product. The crude product was purified by preparative-HPLC to give Example 118 (79.75 mg, 186.50 μmol, 45.31% yield), as a white solid. 1 H-NMR (400 MHz, CDCl3) δ 8.75 (s, 2H), 7.70 (s, 1H), 7.12 (br d, J = 8.4 Hz, 1H), 6.77 (s, 1H), 6.72 (m, d, J = 8.4 Hz, 1H), 3.80 (s, 3H), 3.17 - 2.96 (m, 2H), 2.87 - 2.76 (m, 1H), 2.71 - 2.65 (m, 2H), 2.43 (s, 3H), 2.31 (s, 3H), 2.15 - 2.11 (m, 1H), 1.90 - 1.85 (m, 1H).

[1006] Example 119: 2-(5-(2-Hydroxyethoxy)pyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, prepared according to Scheme 6, Method C.

[1007]

[1008] According to Process 6, Step iv: Example 119 was prepared starting from Example 45 (150 mg, 411.64 μmol) and 2-bromoethanol (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 1H-NMR (400 MHz, CDCl3) δ 8.46 (s, 2H), 7.59 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.73 - 6.64 (m, 2H), 3.93 (s, 3H), 3.73 (s, 3H), 3.04 - 2.97 (m, 2H), 2.71 - 2.46 (m, 3H), 2.23 (s, 3H), 2.08 (m, 1H), 1.80 (m, 1H).

[1009] Example 120: 6-(3-Acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, was prepared according to Process 7.

[1010]

[1011] Intermediate 53: 6-(3-Bromo-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[1012] According to Process 2, Step viii: At 25 °C under N2, Pd(dppf)Cl2 (207.76 mg, 283.93 μmol, 0.05 equivalent) and Na2CO3 (1.81 g, 17.04 mmol, 3 equivalents) were added in one portion to a mixture of Intermediate 15b (2 g, 5.68 mmol, 1 equivalent) and 1,3-dibromo-2-methylbenzene (1.42 g, 5.68 mmol, 72.57 μL, 1 equivalent) in dioxane (30 mL) and H2O (2 mL). The mixture was stirred at 90 °C for 12 h. The residue was poured into ice water (w / w = 1 / 1) (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give Intermediate 53 (1.4 g, 3.54 mmol, 62.37% yield), as a yellow solid. 11H NMR (CDCl3, 400 MHz) δ 8.92 (d, J = 4.8 Hz, 2H), 7.75 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 4.8 Hz, 1H), 7.11 - 7.06 (m, 2H), 6.24 (s, 1H), 3.00 (t, J = 9.6 Hz, 2H), 2.64 (t, J = 9.6 Hz, 2H), 2.42 (s, 3H).

[1013] Intermediate 54: 6-(3-Acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophtalazin-1(2H)-one

[1014] According to Process 7, Step i: At 25 °C under N2, Pd(PPh3)2Cl2 (17.76 mg, 25.30 μmol, 0.05 equiv) was added in one portion to a mixture of Intermediate 53 (0.2 g, 506.01 μmol, 1 equiv) and tributyl(1-ethoxyvinyl)stannane (365.49 mg, 1.01 mmol, 341.58 μL, 2 equiv) in dioxane (20 mL). The mixture was stirred at 100 °C for 3 h. HCl (3 M; 20 mL) was added to the reaction, and the mixture was stirred at 25 °C for 30 min and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc = 0 / 1) to give Intermediate 54 (0.15 g, crude), as a yellow solid. 1 1H NMR (DMSO-d6, 400 MHz) δ 9.01 (d, J = 4.8 Hz, 2H), 7.99 (s, 1H), 7.65 - 7.75 (m, 1H), 7.36 (s, 1H), 6.42 (s, 1H), 2.78 - 2.87 (m, 2H), 2.60 - 2.68 (m, 2H), 2.56 (s, 3H), 2.36 (s, 3H).

[1015] Example 120: 6-(3-Acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[1016] According to Process 7, Step ii: Under N2, Pd / C (0.3 g, 5% purity) was added to a mixture of intermediate 54 (150.00 mg, 418.53 μmol, 1 equiv) and ammonium formate (131.96 mg, 2.09 mmol, 5 equiv) in EtOH (30 mL). The mixture was stirred at 25 °C for 16 h. 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) δ 9.02 (d, J = 4.8 Hz, 2H), 7.85 (s, 1H), 7.71 (br t, J = 4.8 Hz, 1H), 7.48 (m, 2H), 7.29 - 7.36 (m, 1H), 3.27 (m, 1H), 2.65 - 2.95 (m, 4H), 2.54 (s, 3H), 2.35 (s, 3H), 1.88 - 2.03 (m, 2H).

[1017] Example 121: 6-(2,4-Dimethylphenyl)-2-(pyridin-2-yl)-2,5,6,7-tetrahydro-1H-cyclopenta[d]-pyridazin-1-one, prepared according to Process 3.

[1018]

[1019] Intermediate 19: 3-(2,4-Dimethylphenyl)cyclopentan-1-one

[1020] According to Process 3, Step i: KOH (4.10 g, 73.08 mmol) was added to a mixture of Rh(COD)Cl2 (180.17 mg, 0.37 mmol) in dioxane (20 mL) and H2O (4 mL). The resulting mixture was stirred at 20 °C under N2 for 0.5 h. Then, a solution of cyclopent-2-en-1-one (6.00 g, 73.08 mmol) and (2,4-dimethylphenyl)boronic acid (21.92 g, 146.16 mmol) in dioxane (20 mL) was added dropwise to the resulting mixture at 20 °C. The resulting mixture was stirred at 20 °C for 1.5 h. LCMS showed the desired product. The reaction mixture was diluted with 200 mL of ethyl acetate and washed with water (60 mL x 3). Then the organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc = 20:1). Intermediate 19 (11.00 g, 80% yield) was obtained as a yellow liquid. 11H NMR (CDCl3; 400 MHz) δ 7.17 - 7.10 (m, 1H), 7.07 - 7.02 (m, 2H), 3.67 - 3.54 (m, 1H), 2.70 - 2.60 (m, 1H), 2.55 - 2.45 (m, 1H), 2.43 - 2.39 (m, 1H), 2.381 (s, 3H), 2.37 - 2.35 (m, 1H), 2.34 (s, 3H), 2.31 - 2.26 (m, 1H), 2.10 - 1.96 (m, 1H).

[1021] Intermediate 20: 2-Chloro-4-(2,4-dimethylphenyl)cyclopent-1-ene-1-carbaldehyde

[1022] According to Process 3, Step ii: At -20 °C, 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 CH2Cl2 (100 mL). The mixture was then stirred at 0 °C for 1 hour. Then, a solution of Intermediate 19 (10.00 g, 53.12 mmol) in CH2Cl2 (20 mL) was added to the mixture at -20 °C. The reaction mixture was stirred at 0 °C for 2 hours. Then, the reaction mixture was stirred at 25 °C for 12 hours. LCMS indicated that the reaction mixture was complete. The reaction was quenched with water (100 mL) at 0 °C. Then, the mixture was extracted with CH2Cl2 (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.

[1023] Intermediate 21: Ethyl 4-(2,4-dimethylphenyl)-2-formylcyclopent-1-ene-1-carboxylate

[1024] At 25 °C under N2 protection, Pd(dppf)Cl2 (467.61 mg, 0.64 mmol) was added to a mixture of intermediates 20 and 20' (1.5 g, 6.39 mmol) and Et3N (1.29 g, 12.78 mmol, 1.77 mL) in EtOH (40 mL). 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. Then the reaction mixture was concentrated. A crude mixture of intermediate 21 and its positional isomer 21' (1.5 g, crude) was obtained as a black solid and used in the next step.

[1025] Example 121: 6-(2,4-Dimethylphenyl)-2-(pyridin-2-yl)-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-1-one

[1026] At 25 °C under N2, TsOH (1.90 g, 11.02 mmol) was added 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). 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 1H-NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.10 - 7.96 (m, 2H), 7.90 - 7.80 (m, 1H), 7.55 - 7.45 (m, 1H), 7.13 (d, J = 7.6 Hz, 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).

[1027] Example 122: 7-(2,4-Dimethylphenyl)-3-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one, prepared according to Scheme 4.

[1028] Intermediate 31: 2',4'-Dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4H)-one

[1029] According to Process 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 a N2 atmosphere for 2 h. 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). Intermediate 31 (1.60 g, 7.99 mmol, 22% yield) was obtained as a brown liquid. 1 1H NMR (CDCl3; 400 MHz) δ 7.19 - 6.94 (m, 3H), 5.92 - 5.90 (m, 1H), 2.53 - 2.50 (m, 2H), 2.45 - 2.40 (m, 2H), 2.26 (s, 3H), 2.21 (s, 3H), 2.09 - 2.05 (m, 2H).

[1030] Intermediate 33: Ethyl 2',4'-dimethyl-5-oxo-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carboxylate

[1031] According to Process 4, Step iii: LDA (2 M, 8.99 mL, 1.50 equiv) was added dropwise to a solution of Intermediate 31 (2.40 g, 11.98 mmol, 1.00 equiv) in THF (60.00 mL) at -78 °C. The resulting mixture was stirred at -78 °C for 1 h. 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 h. The reaction mixture was quenched with an 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. 11H NMR (CDCl3; 400 MHz) δ 7.04 - 7.04 (m, 3H), 6.09 - 6.05 (m, 1H), 4.25 - 4.3 (m, 2H), 2.73 - 2.53 (m, 4H), 2.35 (s, 3H), 2.30 (s, 3H) 1.66 - 1.60 (m, 3H).

[1032] Intermediate 34: Ethyl 4-(2,4-dimethylphenyl)-2-oxocyclohexane-1-carboxylate

[1033] According to Process 4, Step ii: Under a N2 atmosphere, 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). 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 h. 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.

[1034] Intermediate 35: 7-(2,4-Dimethylphenyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one

[1035] According to Process 4, Step iv: A mixture of Intermediate 34 (200 mg, 729.00 μmol, 1.00 equivalent), K2CO3 (403.02 mg, 2.92 mmol, 4.00 equivalents), and formimidamide (113.84 mg, 1.09 mmol, 1.50 equivalents) in EtOH (8.00 mL) was stirred at 90 °C for 3 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (100 ml). The solution was washed with H2O (40 mL x 3). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Intermediate 35 (120.00 mg, 471.83 μmol, 65% yield) was obtained as a pale yellow solid. 1 1H NMR (DMSO-d6; 400 MHz) δ 12.30 (s, 1H), 7.99 (s, 1H), 7.17 - 7.11 (m, 1H), 6.97 - 6.99 (m, 1H), 3.11 - 3.08 (m, 1H), 2.68 - 2.39 (m, 4H), 2.28 (s, 3H), 2.24 (s, 3H), 1.86 - 1.84 (m, 2H), 1.75 - 1.1.72 (m, 2H).

[1036] Example 122: 7-(2,4-Dimethylphenyl)-3-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one

[1037] According to Process 4, Step v: A mixture of intermediate 35 (100.00 mg, 393.19 μmol, 1.00 equivalent), 2-bromopyridine (80.76 mg, 511.15 μmol, 1.30 equivalents), CuI (7.49 mg, 39.32 μmol, 0.10 equivalent), 1,10-phenanthroline (14.17 mg, 78.64 μmol, 0.20 equivalent) and KOH (44.12 mg, 786.38 μmol, 2.00 equivalents) in DMF (4.00 mL) was stirred at 100 °C under a N2 atmosphere for 12 h. 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 in vacuo. 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 1H-NMR (400 MHz, DMSO-d6) δ 8.66 - 8.65 (m, 1H), 8.48 (s, 1H), 8.06 - 8.04 (m, 1H), 7.77 - 7.75 (m, 1H), 7.59 - 7.55 (m, 1H), 7.18 - 7.15 (m, 1H), 7.02 - 6.99 (m, 1H), 3.16 - 3.14 (m, 1H), 2.75 - 2.66 (m, 4H), 2.30 (s, 3H), 2.25 (s, 3H), 1.94 - 1.921 (m, 1H), 1.83 - 1.81 (m, 2H).

[1038] Example 124: 6-(1-Cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[1039]

[1040] To a mixture of Example 92 (50.0 mg, 130 μmol, 1.00 equivalent) in DCM (2.00 mL) at 25 °C was added MnO2 (113 mg, 1.30 mmol, 10.0 equivalents). 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 give 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).

[1041] Example 125: 2-(5-Cyclopropylpyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Scheme 6, Method A

[1042]

[1043] Intermediate 52e: 2-(5-Bromopyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[1044] According to Scheme 6, Step i: Intermediate 52e was prepared in the same manner as described for Intermediate 52a starting from Intermediate 7b (500 mg, 1.85 mmol) and 2,5-dibromopyridine (527.98 mg, 2.22 mmol), to give Intermediate 52e (0.5 g, 1.01 mmol, 54.41% yield), as a red solid. m / z(M+H) + = 427.0, 429.0.

[1045] Example 125: 2-(5-Cyclopropylpyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one According to Scheme 6, Step ii: Example 125 was prepared in the same manner as described for Example 107 starting from Intermediate 52e (180 mg, 421.26 μmol) and cyclopropylboronic acid (72.37 mg, 842.51 μmol), to give Example 125 (14.61 mg, 37.35 μmol, 8.87% yield), as a light pink solid. 1H-NMR (400 MHz, DMSO-d6) δ 8.76 (s, 2H), 7.83 (s, 1H), 7.18 (t, J = 7.97 Hz, 1H), 6.90 (d, J = 7.65 Hz, 1H), 6.86 (d, J = 8.16 Hz, 1H), 3.79 (s, 3H), 3.13 - 3.24 (m, 1H), 2.64 - 2.85 (m, 3H), 2.57 (br s, 1H), 2.18 (s, 3H), 2.04 - 2.12 (m, 1H), 1.94 (br s, 1H), 1.78 - 1.90 (m, 1H), 1.08 - 1.18 (m, 2H), 0.90 - 1.01 (m, 2H).

[1046] Example 126: 2-(5-Bromopyrimidin-2-yl)-6-(3-cyclopropoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, prepared according to Process 1, Method B

[1047]

[1048] Intermediate 6f: 5-(3-Cyclopropoxy-2-methylphenyl)-3-methoxy-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one According to Process 1, Steps i to v: Intermediate 6f is prepared starting from 1-bromo-3-cyclopropoxy-2-methylbenzene similar to Intermediate 6a in Example 1, obtained in an overall yield of 6% as a colorless oil. m / z (M+H) + = 315.3.

[1049] Intermediate 7d: 6-(3-Cyclopropoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[1050] According to Process 1, Step vii: Intermediate 7b is prepared starting from Intermediate 6f (1.77 g, 5.60 mmol) similar to Intermediate 7a in Example 6, to give Intermediate 7d (1.52 g, 4.56 mmol, 81.5% yield) as a pale yellow solid. 1 HNMR (400 MHz, DMSO-d6) δ 10.73 (br s, 1H), 7.56 (s, 1H), 7.22 - 7.11 (m, 2H), 6.84 (d, J = 7.4 Hz, 1H), 3.77 - 3.70 (m, 1H), 3.22 - 3.11 (m, 1H), 2.99 - 2.88 (m, 1H), 2.81 - 2.71 (m, 1H), 2.71 - 2.54 (m, 2H), 2.18 (s, 3H), 2.15 - 2.08 (m, 1H), 1.92 - 1.80 (m, 1H), 0.82 - 0.77 (m, 4H).

[1051] Example 126: 2-(5-Bromopyrimidin-2-yl)-6-(3-cyclopropoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[1052] According to Process 1, Step viii: Example 126 was prepared starting from Intermediate 7d (1.00 g, 3.00 mmol) and 2,5-dibromopyrimidine (856 mg, 3.60 mmol) as in Example 6, to give Example 126 (0.74 g, 1.52 mmol, 50.7% yield), as a red solid. 1 H NMR (400 MHz, CDCl3) δ 8.95 (s, 2H), 7.69 (s, 1H), 7.24 - 7.14 (m, 2H), 6.85 (d, J = 7.6 Hz, 1H), 3.77 - 3.70 (m, 1H), 3.20 (br s, 1H), 3.00 (br d, J = 16.3 Hz, 1H), 2.86 - 2.78 (m, 1H), 2.70 (br dd, J = 9.2, 16.8 Hz, 2H), 2.20 - 2.18 (m, 3H), 2.13 (br s, 1H), 1.94 - 1.85 (m, 1H), 0.82 - 0.77 (m, 4H).

[1053] Example 127: N-(2-(6-(3-Cyclopropoxy-2-methylphenyl)-1-oxo-5,6,7,8-tetrahydrophtalazin-2(1H)-yl)pyrimidin-5-yl)acetamide, prepared according to Process 6, Method B

[1054]

[1055] According to Process 6, Step iii: Example 127 was prepared starting from Example 126 (0.85 g, 1.88 mmol) and acetamide (222 mg, 3.75 mmol) as in Example 117, to give Example 127 (242 mg, 558.61 μmol, 29.79% yield), as a pale yellow solid. 11H NMR (400 MHz, CDCl3) δ 9.07 - 9.00 (m, 1H), 8.97 (s, 2H), 7.76 (s, 1H), 7.24 - 7.15 (m, 2H), 6.86 (br d, J = 7.4 Hz, 1H), 3.75 (br s, 1H), 3.25 (br s, 1H), 3.00 (br d, J = 19.4 Hz, 1H), 2.92 - 2.82 (m, 1H), 2.82 - 2.64 (m, 2H), 2.20 (s, 6H), 2.17 - 2.13 (m, 1H), 1.93 (br d, J = 7.2 Hz, 1H), 0.80 (br s, 4H).

[1056] Example 128: (-)-6-(3-Cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one and Example 129: (+)-6-(3-Cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[1057]

[1058] The enantiomers constituting the racemic Example 104 (483 mg) were separated by preparative SFC to give (-)-6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, Example 128 (188 mg, 39%) with 100% enantiomeric excess, and (+)-6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, Example 129 (199 mg, 41%) with 99.9% enantiomeric excess, a white solid with 99.9% enantiomeric excess.

[1059] Example 128: 1 1H-NMR (400 MHz, CDCl3) δ 8.94 (d, J = 4.4 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.28 - 7.15 (m, 2H), 6.85 (d, J = 7.6 Hz, 1H), 3.75 (tt, J = 6.0, 3.2 Hz, 1H), 3.25 - 3.17 (m, 1H), 3.05 - 2.95 (m, 1H), 2.87 - 2.76 (m, 1H), 2.75 - 2.60 (m, 2H), 2.20 - 2.10 (m, 1H), 1.95 - 1.83 (m, 1H), 0.85 - 0.75 (m, 4H).

[1060] Example 129:1 H-NMR (400 MHz, CDCl3) δ 8.94 (d, J = 4.4 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.25 - 7.15 (m, 2H), 6.86 (d, J = 7.6 Hz, 1H), 3.75 (tt, J = 6.0, 3.2 Hz, 1H), 3.25 - 3.17 (m, 1H), 3.05 - 2.95 (m, 1H), 2.83 - 2.76 (m, 1H), 2.75 - 2.60 (m, 2H), 2.20 - 2.07 (m, 1H), 1.95 - 1.82 (m, 1H), 0.85 - 0.75 (m, 4H).

[1061] Example 130: (-)-6-(2-Chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one and Example 131: (+)-6-(2-Chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[1062]

[1063] The enantiomers constituting the racemic Example 91 (505 mg) were separated by preparative SFC to obtain (-)-6-(2-Chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, Example 130 (187 mg, 37%), with an enantiomeric excess of 99.6%, and (+)-6-(2-Chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, Example 131 (187 mg, 37%), with an enantiomeric excess of 99.9%, both as white solids.

[1064] Example 130: 1 H-NMR (400 MHz, CDCl3) δ 8.93 (d, J = 4.4 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.26 - 7.23 (m, 2H), 6.92 - 6.87 (m, 1H), 3.83 (tt, J = 6.0, 3.2 Hz, 1H), 3.59 - 3.49 (m, 1H), 3.05 - 2.92 (m, 2H), 2.76 - 2.58 (m, 2H), 2.23 - 2.14 (m, 1H), 1.99 - 1.85 (m, 1H), 0.90 - 0.83 (m, 4H).

[1065] Example 131: 11H-NMR (400 MHz, CDCl3) δ 8.93 (d, J = 4.8 Hz, 2H), 7.70 (s, 1H), 7.45 - 7.39 (m, 1H), 7.26 - 7.23 (m, 2H), 6.94 - 6.86 (m, 1H), 3.83 (tt, J = 3.2, 6.0 Hz, 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).

[1066] Example 132: (-)-6-(3-Cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one and Example 133: (+)-6-(3-Cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[1067]

[1068] The enantiomers constituting the racemic Example 93 (488 mg) were separated by preparative SFC to give (-)-6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, Example 132 (232 mg, 48%), with 100% enantiomeric excess, and (+)-6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, Example 133 (210 mg, 43%), with 100% enantiomeric excess, both as white solids.

[1069] Example 132: 1 1H-NMR (400 MHz, CDCl3) δ 8.74 (s, 2H), 7.68 (s, 1H), 7.25 - 7.15 (m, 2H), 6.85 (d, J = 6.4 Hz, 1H), 3.74 (tt, J = 6.0, 3.2 Hz, 1H), 3.26 - 3.17 (m, 1H), 3.05 - 2.95 (m, 1H), 2.85 - 2.77 (m, 1H), 2.75 - 2.60 (m, 2H), 2.43 (s, 3H), 2.18 - 2.10 (m, 1H), 1.95 - 1.83 (m, 1H), 0.85 - 0.78 (m, 4H).

[1070] Example 133: 1H-NMR (400 MHz, CDCl3) δ 8.74 (s, 2H), 7.68 (s, 1H), 7.23 - 7.15 (m, 2H), 6.85 (d, J = 6.4 Hz, 1H), 3.74 (tt, J = 6.0, 3.2 Hz, 1H), 3.25 - 3.16 (m, 1H), 3.05 - 2.95 (m, 1H), 2.85 - 2.77 (m, 1H), 2.75 - 2.60 (m, 2H), 2.43 (s, 3H), 2.18 - 2.07 (m, 1H), 1.95 - 1.83 (m, 1H), 0.83 - 0.76 (m, 4H).

[1071] 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

[1072]

[1073] The enantiomers constituting the racemic Example 94 (493 mg) were separated by preparative SFC to give (-)-6-(2-Chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, Example 134 (218 mg, 48%), 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.

[1074] Example 134: 1 H NMR (400 MHz, CDCl3) δ 8.73 (s, 2H), 7.69 (s, 1H), 7.30 - 7.25 (m, 1H), 6.90 - 6.86 (m, 2H), 3.94 (s, 3H), 3.56 - 3.53 (m, 1H), 3.04 - 2.93 (m, 2H), 2.75 - 2.57 (m, 2H), 2.42 (s, 3H), 2.20 - 2.15 (m, 1H), 1.93 - 1.85 (m, 1H).

[1075] Example 135: 11H NMR (400 MHz, CDCl3) δ 8.73 (s, 2H), 7.69 (s, 1H), 7.27 - 7.22 (m, 1H), 6.90 - 6.86 (m, 2H), 3.93 (s, 3H), 3.56 - 3.53 (m, 1H), 3.04 - 2.93 (m, 2H), 2.75 - 2.57 (m, 2H), 2.42 (s, 3H), 2.23 - 2.15 (m, 1H), 1.93 - 1.85 (m, 1H).

[1076] Example 136: (-)-N-(2-(6-(2,4-Dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophtalazin-2(1H)-yl)pyrimidin-5-yl)acetamide and Example 137: (+)-N-(2-(6-(2,4-Dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophtalazin-2(1H)-yl)pyrimidin-5-yl)acetamide

[1077]

[1078] The enantiomers constituting the racemic Example 117 (610 mg) were separated by preparative SFC to give Example 136 (-)-N-(2-(6-(2,4-Dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophtalazin-2(1H)-yl)pyrimidin-5-yl)acetamide (187 mg, 31%) with an enantiomeric excess of 99.4%, and Example 137 (+)-N-(2-(6-(2,4-Dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophtalazin-2(1H)-yl)pyrimidin-5-yl)acetamide (218 mg, 36%) with an enantiomeric excess of 100%, both as yellow solids.

[1079] Example 136: 1 1H-NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 7.76 (s, 1H), 7.12 - 7.05 (m, 3H), 3.17 - 2.70 (m, 5H), 2.37 (s, 3H), 2.33 (s, 3H), 2.22 - 2.18 (m, 4H), 1.97 - 1.90 (m, 1H).

[1080] Example 137: 1 1H-NMR (400 MHz, CDCl3) δ = 8.90 (s, 1H), 7.76 (s, 1H), 7.04 - 6.97 (m, 3H), 3.10 - 2.62 (m, 5H), 2.29 (s, 3H), 2.25 (s, 3H), 2.10 - 2.09 (m, 4H), 1.87 - 1.83 (m, 1H).

[1081] Example 138: (+)-6-(1-Cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one and Example 139: (-)-6-(1-Cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one

[1082]

[1083] The enantiomers constituting the racemic Example 124 (440 mg) were separated by preparative SFC to give (+)-6-(1-Cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-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-tetrahydrophtalazin-1(2H)-one, Example 139 (155 mg, 35%), with an enantiomeric excess of 98.9%, both as yellow solids.

[1084] Example 138: 1 1H-NMR (400 MHz, CDCl3) δ 8.94 (d, J = 4.9 Hz, 2H), 7.71 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.18 (d, J = 3.3 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.50 (d, J = 3.2 Hz, 1H), 3.42 - 3.37 (m, 2H), 3.04 - 2.96 (m, 3H), 2.93 - 2.73 (m, 1H), 2.32 (br d, J = 11.7 Hz, 1H), 2.10 - 2.06 (m, 1H), 1.12 - 1.02 (m, 4H).

[1085] Example 139: 1H-NMR (400 MHz, CDCl3) δ 8.94 (d, J = 4.9 Hz, 2H), 7.71 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.42 (t, J = 4.8 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.18 (d, J = 3.3 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.50 (s, 1H), 3.50 - 3.38 (m, 2H), 3.03 - 2.93 (m, 3H), 2.88 - 2.73 (m, 1H), 2.30 (br d, J = 11.7 Hz, 1H), 2.09 - 2.03 (m, 1H), 1.10 - 1.04 (m, 4H).

[1086] C. Analysis Part

[1087] Melting Point:

[1088] Values are peak values and are obtained within the experimental uncertainties normally associated with the analytical method. For many compounds, the melting point is determined in an open capillary on a YRT-3 apparatus. The melting point is measured with a temperature gradient of 1.5 °C / min. The maximum temperature is 270 °C. The melting point is read from a digital display. For some compounds, the DSC method is used according to the following conditions.

[1089] DSC Conditions

[1090] Instrument: NETZSCH DSC214 Crucible Pan Al, with perforated lid Protective Gas Flow <![CDATA[N2 60mL / min]]> Purified Gas Flow <![CDATA[N2 40mL / min]]> Gradient Ratio: 50°C to 350°C; 10°C / min

[1091] LCMS Method:

[1092] High performance liquid chromatography (HPLC) measurements are carried out using an LC pump, a diode array or a UV detector. The flow from the column is directed to a mass spectrometer (MS) equipped with an atmospheric pressure ionization source. It is within the knowledge of those skilled in the art to set the tuning parameters so as to obtain ions that permit the identification of the nominal monoisotopic molecular weight (MW) and / or the exact mass monoisotopic molecular weight of the compound. Data acquisition is carried out using suitable software. Using an ES MS detector, acquisition is carried out in both positive ionization mode and negative ionization mode.

[1093] Compounds can be described by their molecular ions corresponding to [M + H] (protonated molecule) and / or [M - H] (deprotonated molecule). For molecules having multiple isotope patterns (Br, Cl), the reported value is the value obtained for the lowest isotope mass. All results are obtained with the experimental uncertainties normally associated with the methods used.

[1094] NMR

[1095] 1 1H NMR spectra were recorded on a Varian 400 MHz spectrometer. Chemical shifts are expressed in parts per million (ppm, δ units). The splitting patterns describe the apparent multiplicity and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

[1096] SFC-MS

[1097] 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.

[1098]

[1099]

[1100] Optical Rotation

[1101] Optical rotations were measured at 20 °C on a Rudolph AUTOPOL V polarimeter using a sodium lamp (589 nm) at a concentration of 10 mg / mL in methanol or chloroform as the solvent. The sign of rotation (+ or -) is given in Table 1 and reported in degrees.

[1102] Table 1. Analytical data for the individual optical isomers

[1103]

[1104] In Vitro Pharmacology

[1105] The compounds of formula (I), (II) and (III) are antagonists or negative allosteric modulators of mGluR7 as they reduce or inhibit the mGluR7 responses induced by glutamate or mGluR7 agonists such as L-AP4.

[1106] The methods described below are applicable to the characterization of these compounds, especially the compounds of formula (I).

[1107] Inositol Monophosphate Production Assay (IP1 Assay):

[1108] Membrane preparation and protocol:

[1109] HEK293 cells were transiently transfected with mGluR7 by electroporation and seeded in poly-L-ornithine-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 also co-transfected wit...

Claims

1. A compound of formula (I): Wherein: G is selected from N or CR 7 , E is selected from N or CR 8 , Provided that at least 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 are the same or different and 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 10 C(=O)OR 11 , -NR 10 S(O)2R 11 or 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, Any two of the groups R 1 and R 2 、R 3 and R 4 、and R 5 and R 6 may together form oxo (=O), wherein R 10 and R 11 are the same or different and each independently selected from hydrogen or 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, Among them, Optionally, any two groups selected from R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 10 and R 11 may together form an optionally substituted 3- to 10-membered non-aromatic carbocyclic or heterocyclic ring or a 5- to 10-membered aromatic heterocyclic ring. n is an integer selected from 0 or 1, Ar 1 is an optionally substituted aryl or heteroaryl, Ar 2 is an optionally substituted aryl or heteroaryl, or its N-oxide form, its pharmaceutically acceptable salt or solvate, or their optical isomers, racemates, diastereoisomers, enantiomers or tautomers.

2. The compound according to claim 1, wherein: -Ar 1 represents aryl or heteroaryl, which is selected from: where m is the number of ring substituents A, which is an integer equal to 0, 1, 2, 3, 4 or 5, and / or -Ar 2 represents aryl or heteroaryl, which is selected from: where p is the number of ring substituents B, which is an integer equal to 0, 1, 2, 3, 4 or 5, wherein A and B are the same or different and each independently selected from hydrogen, halogen, -CN, -NO2, -OH, -NH2, -CF3, optionally substituted groups 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 、-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 、-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 、-O-C(=O)-NR 13 R 14 、-(C1-C6) alkylene-O-C(=O)-NR 13 R 14 、-O-(C2-C6) alkylene-O-C(=O)-NR 13 R 14 、-NR 13 -(C2-C6) alkylene-O-C(=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 ; wherein R 13 , R 14 , R 15 and R 16 are 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; Among them, Optionally, selected from R 13 , R 14 , R 15 or R 16 any two groups may together form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted by 1 to 5 groups independently selected from: halogen, cyano, nitro, hydroxy, amino, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2; Any two groups A and any two groups B can combine with the inserted atom to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; each ring is optionally further substituted by 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.

3. A compound according to claim 1 or 2 of formula (II): Wherein -Ar 1 represents aryl or heteroaryl, which is selected from: Wherein: - m is the number of ring substituents A, which is an integer equal to 0, 1, 2, 3 or 4, - A is the same or different and 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)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 ; - wherein R 13 , R 14 and R 15 are 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; - Among them, Optionally, any two groups selected from R 13 , R 14 or R 15 on substituent A may together form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted by 1 to 5 groups independently selected from the following: halogen, -CN, -NO2, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2; - wherein any two groups A can combine with an inserted atom to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted by 1 to 5 groups independently selected from: halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2; and / or -Ar 2 represents aryl or heteroaryl, which is selected from: Wherein - p is the number of ring substituents B, which is an integer equal to 0, 1, 2, 3, 4 or 5, -B is the same or different and is independently selected from hydrogen, halogen, -CN, -CF3, optionally substituted groups, and the optionally substituted groups are 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-R 14 、-S(=O)2NR 13 R 14 、-(C1-C6) alkylene-S(=O)2NR 13 R 14 、-O-(C1-C6) alkylene-S(=O)2NR 13 R 14 、-NR 13 -(C1-C6) alkylene-S(=O)2NR 14 R 15 、-NR 13 -S(=O)2R 14 、-(C1-C6) alkylene-NR 13 -S(=O)2R 14 、-O-(C2-C6) alkylene-NR 13 -S(=O)2R 14 、-NR 13 -(C2-C6) alkylene-NR 14 -S(=O)2R 15 、-C(=O)-NR 13 R 14 、-(C1-C6) alkylene-C(=O)-NR 13 R 14 、-O-(C1-C6) alkylene-C(=O)-NR 13 R 14 、-NR 13 -(C1-C6) alkylene -C(=O)-NR 14 R 15 、-NR 13 C(=O)-R 14 、-(C1-C6)alkylene-NR 13 C(=O)-R 14 、-O-(C2-C6)alkylene -NR 13 C(=O)-R 14 、-NR 13 -(C2-C6) alkylene-NR 14 C(=O)-R 15 、-C(=O)-R 13 、-(C1-C6) alkylene-C(=O)-R 13 、-O-(C1-C6) alkylene-C(=O)-R 13 、-NR 13 -(C1-C6) alkylene-C(=O)-R 14 、-C(=O)-OR 13 、-(C1-C6) alkylene -C(=O)-OR 13 、-O-(C1-C6) alkylene-C(=O)-OR 13 、-NR 13 -(C1-C6) alkylene-C(=O)-OR 14 、-OC(=O)-R 13 、-(C1-C6) alkylene-OC(=O)-R 13 、-O-(C2-C6) alkylene-OC(=O)-R 13 、-NR 13 -(C2-C6) alkylene-OC(=O)-R 14 、-(C1-C6) alkylene-NR 13 -C(=O)-NR 14 R 15 、-NR 13 -C(=O)-OR 14 、-(C1-C6) alkylene-NR 13 -C(=O)-OR 14 、-O-(C2-C6) alkylene-NR 13 -C(=O)-OR 14 、-NR 13 -(C2-C6) alkylene-NR 14 -C(=O)-OR 15 、-O-C(=O)-NR 13 R 14 、-(C1-C6) alkylene-O-C(=O)-NR 13 R 14 、-O-(C2-C6) alkylene-O-C(=O)-NR 13 R 14 、-NR 13 -(C2-C6) alkylene-O-C(=O)-NR 14 R 15 、-C(=O)-(C1-C6) alkylene-NR 13 R 14 、or -C(=O)-(C1-C6) alkylene-OR 13 ; - wherein R 13 , R 14 and R 15 are 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; - wherein, optionally, any two groups selected from R 13 , R 14 or R 15 on the substituent B may together form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted by 1 to 5 groups independently selected from the following: halogen, -CN, -NO2, -OH, -NH2, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2; - Any two of the groups B can combine with the inserted atom to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; each ring is optionally further substituted by 1 to 5 groups independently selected from the following: halogen, -CN, -OH, -NH2, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

4. The compound according to any one of claims 1 to 3, wherein: -A is the same or different and is independently selected from hydrogen, halogen, -CN, -CF3, -OH, an optionally substituted group, and the optionally substituted group is 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 ; - wherein 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; - Among them, Optionally, groups R on substituent A 13 and R 14 may together form a 3- to 6-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; where each ring is optionally further substituted with 1 to 5 groups independently selected from: halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2; -Any two of the groups A can combine with the inserted atom to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; each ring is optionally further substituted by 1 to 5 groups independently selected from the following: halogen, -CN, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2; and / or -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 ; - wherein 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, heteroaryl, aryl, heterocycle, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-heterocycle and -(C1-C6)alkylene-aryl; - wherein, optionally, any two groups selected from R 13 and R 14 on substituent B may together form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted by 1 to 5 groups independently selected from the following: halogen, CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2; - wherein any two groups B can combine with an inserted atom to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted by 1 to 5 groups independently selected from: halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2; and / or only one of G or E is N.

5. A compound according to claim 1 or 2 of formula (III): Wherein -A is the same or different and 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 ; - wherein 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; - Among them, Optionally, the groups R on substituent A 13 and R 14 may together form a 3- to 6-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; where each ring is optionally further substituted by 1 to 5 groups independently selected from: halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2; - Any two of the groups A can combine with the inserted atom to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; each ring is optionally further substituted by 1 to 5 groups independently selected from the following: halogen, -CN, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2; and / or -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 ; - wherein 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, heteroaryl, aryl, heterocycle, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-heterocycle and -(C1-C6)alkylene-aryl; - wherein, optionally, any two groups selected from R 13 and R 14 on substituent B may together form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted by 1 to 5 groups independently selected from: halogen, CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2; - wherein any two groups B can combine with an inserted atom to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted by 1 to 5 groups independently selected from: halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2; and / or only one of G or E is N.

6. The compound according to any one of claims 2 to 5, wherein: -A is the same or different and 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 -NR 13 C(=O)-R 14 ; -R 13 and R 14 each independently selected from hydrogen, optionally substituted -(C1-C3)alkyl, -(C3-C7)cycloalkyl, or -(C1-C6)alkylene-(C3-C7)cycloalkyl; - Optionally, the groups R on substituent A 13 and R 14 may together form a 3- to 6-membered carbocyclic or heterocyclic ring, each ring optionally further substituted by 1 to 5 groups independently selected from: halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl)2; and - Any two groups A can combine with an inserted atom to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; each ring is optionally further substituted by 1 to 5 groups independently selected from the following: halogen, -CN, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1-C6)alkyl)2.

7. The compound according to any one of claims 2 to 6, wherein: -B is the same or different and is independently selected from hydrogen, halogen, -CF3, optionally substituted groups, where the optionally substituted groups are 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 ; -R 13 and R 14 each independently selected from hydrogen, optionally substituted -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl; - Optionally, the group R on substituent B 13 and R 14 may together form a 3- to 6-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; wherein each ring is optionally further substituted by 1 to 5 groups independently selected from the following: halogen, -CN, -OH, -NH2, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl)2; - Any two groups B can combine with the inserted atom to form a 3- to 10-membered carbocyclic, heterocyclic, aryl or heteroaryl ring; each ring is optionally further substituted by 1 to 5 groups independently selected from the following: halogen, -CN, -(C1-C6)alkyl 、 -O-(C1-C6)alkyl and -N-((C1C6)alkyl)2.

8. The compound according to any one of claims 1 to 7, wherein: -Ar 1 represents aryl or heteroaryl, which is selected from:

9. The compound according to any one of claims 1 to 8, wherein: -Ar 2 represents aryl or heteroaryl, which is selected from:

10. The compound according to any one of claims 1 to 9, wherein: -R 1 、R 2 、R 3 、R 4 、R 5 and R 6 are the same or different and each independently selected from hydrogen, halogen, -OR 10 、-NR 10 R 11 、or optionally substituted -(C1-C3)alkyl, - Any two groups R 1 and R 2 、R 3 and R 4 as well as R 5 and R 6 may together form oxo, and - Optionally, selected from R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Any two groups may together form an optionally substituted 3- to 10-membered non-aromatic carbocyclic or heterocyclic ring.

11. The compound according to any one of claims 1 to 10, wherein: -R 7 and R 8 selected from hydrogen, halogen, -CN, -OR 10 , -NR 10 R 11 , -CF3, or optionally substituted -(C1-C3)alkyl, wherein R 10 and R 11 are the same or different and each independently selected from hydrogen, -(C1-C3)alkyl or -(C3-C7)cycloalkyl, and - Optionally, two groups R 10 and R 11 may together form an optionally substituted 3- to 10-membered non-aromatic carbocyclic or heterocyclic ring.

12. The compound according to any one of claims 1 to 11, wherein: -R 9 selected from hydrogen, halogen, -CN, -OR 10 , -NR 10 R 11 , -CF3, or - optionally substituted -(C1-C3) alkyl, where R 10 and R 11 are the same or different and are each independently selected from hydrogen or -(C1-C3) alkyl, and - Optionally, two groups R 10 and R 11 may together form an optionally substituted 3- to 10-membered non-aromatic carbocyclic or heterocyclic ring.

13. A compound according to any one of claims 1 to 12, wherein R 1 to R 6 is hydrogen.

14. A compound according to any one of claims 1 to 13, wherein R 7 and R 8 are hydrogen.

15. A compound according to any one of claims 1 to 14, wherein R 9 is hydrogen.

16. The compound according to claim 1, which is selected from: 6-(2,4-dimethylphenyl)-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-dimethylphenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one, (-)-6-(2,4-dimethylphenyl)-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-tetrahydrophtalazin-1(2H)-one, 6-(3-Methoxy-2-methylphenyl)-2-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 2-(5-Chloropyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Methoxy-2-methylphenyl)-2-(5-methoxypyrazin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 2-(5-Hydroxypyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Methoxy-2-methylphenyl)-2-(4-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(5-Methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(5-Methoxy-2-methylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 2-(5-Chloropyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(pyridin-4-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 2-(5-Chloropyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydro-phtalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-fluoropyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(4-methoxy-5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-(morpholinomethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(Dimethylamino)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-Methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(Pyridin-2-yl)-6-(o-tolyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-Cyclopropylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-Methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(1-Hydroxyethyl)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-Cyclopropoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-Methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-Methoxy-3-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(1-Methyldihydroindol-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-Methyldihydroindol-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-tetrahydrophtalazin-1(2H)-one, 6-(2,5-Dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2,3-Dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(Methoxymethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(5-Cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(Cyclopentyloxy)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(4-Methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(1,5-Dimethyl-1H-indazol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6- 6 - (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-tetrahydrophtalazin-1(2H)-one, 6-(2-Chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(1-Cyclopropyldihydroindol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one 6-(2-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(Dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(5-Methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(4-Chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(4-Acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(3-Methoxypropoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Ethoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(Cyclopropylmethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Isopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(2-Methoxyethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(Benzyloxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 2-(5-Cyclopropylpyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 2-(5-Cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 2-(5-Cyclopropylpyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 2-(5-Cyclopropylpyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Methoxy-2-methylphenyl)-2-(5-(pyrrolidin-1-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Methoxy-2-methylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-morpholinopyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-morpholinopyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 2-(5-(Azetidin-1-yl)pyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, N-(2-(6-(2,4-Dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophtalazin-2(1H)-yl)pyrimidin-5-yl)acetamide, 6-(3-Methoxy-2-methylphenyl)-2-(5-(2-methoxyethoxy)pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, (2-(5-(2-Hydroxyethoxy)-pyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-Acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(pyridin-2-yl)-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-1-one, 7-(2,4-Dimethylphenyl)-3-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one, 6-(1-Cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-Cyclopropylpyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(5-Bromopyrimidin-2-yl)-6-(3-cyclopropoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, N-(2-(6-(3-Cyclopropoxy-2-methylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide, (-)-6-(3-Cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(3-Cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (-)-6-(2-Chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(2-Chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (-)-6-(3-Cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(3-Cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (-)-6-(2-Chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (+)-6-(2-Chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (-)-N-(2-(6-(2,4-Dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide, (+)-N-(2-(6-(2,4-Dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide, (+)-6-(1-Cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, (-)-6-(1-Cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 2-(5-Bromopyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 2-(5-Bromopyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 2-(5-Bromopyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 2-(5-Bromopyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 2-(5-Bromopyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, and 2-(5-Bromo-4-methoxypyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one; or an N-oxide form thereof, a pharmaceutically acceptable salt or solvate thereof, or an optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof.

17. The compound according to claim 1, selected from: 6-(2,4-Dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phtalazin-1-one, 6-(3-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(4-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, (+)-6-(2,4-Dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phtalazin-1-one, (-)-6-(2,4-Dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phtalazin-1-one, 6-(2,4-Dimethylphenyl)-2-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydro-phtalazin-1(2H)-one, 2-(4-Chloropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 2-(3-Chloropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 2-(6-Fluoropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-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-tetrahydrophthalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-fluoropyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(4-methoxy-5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-(morpholinomethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(Dimethylamino)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-Methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-Methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(Pyridin-2-yl)-6-(o-tolyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-Cyclopropylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-Methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(1-Hydroxyethyl)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-Cyclopropoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-Methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-Methoxy-3-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(1-Methyldihydroindol-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-tetrahydrophtalazin-1(2H)-one, 6-(2-Methoxy-3-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Chloro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(5-Methoxy-2-(trifluoromethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Fluoro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Chloro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Methoxy-5-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(1-Methyldihydroindol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Fluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(5-Methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2,5-Dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2,3-Dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(Methoxymethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(5-Cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(Cyclopentyloxy)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(4-Methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(1,5-Dimethyl-1H-indazol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6- 6-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2,6-Difluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(1-Cyclopropyldihydroindol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one 6-(2-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(Dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(5-Methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(4-Chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(4-Acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(3-Methoxypropoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Ethoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(Cyclopropylmethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Isopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(2-Methoxyethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(Benzyloxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 2-(5-Cyclopropylpyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, or its N-oxide form, its pharmaceutically acceptable salts or solvates, or their optical isomers, racemates, diastereoisomers, enantiomers or tautomers.

18. The compound according to claim 1, selected from: 6-(2,4-Dimethylphenyl)-2-(pyridin-3-yl)-5,6,7,8-tetrahydrophtalazin-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-tetrahydrophthalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-fluoropyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(4-methoxy-5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-(morpholinomethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(Dimethylamino)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-Methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-Methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(Pyridin-2-yl)-6-(o-tolyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-Cyclopropylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-Methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(1-Hydroxyethyl)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-Cyclopropoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-Methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-Methoxy-3-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(1-Methyldihydroindol-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-Methyldihydroindol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-Fluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-Methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,5-Dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,3-Dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(Methoxymethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-Cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-Cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(Cyclopentyloxy)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(4-Methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(1,5-Dimethyl-1H-indazol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6- 6-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2,6-Difluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(1-Cyclopropyldihydroindol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one 6-(2-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(Dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(5-Methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(4-Chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(4-Acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(3-Methoxypropoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Ethoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(Cyclopropylmethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Isopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(2-Methoxyethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, and 6-(3-(Benzyloxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 2-(5-Cyclopropylpyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, or its N-oxide form, its pharmaceutically acceptable salts or solvates, or their optical isomers, racemates, diastereoisomers, enantiomers or tautomers.

19. The compound according to claim 1, which is 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-tetrahydrophthalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-fluoropyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(4-methoxy-5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2,4-Dimethylphenyl)-2-(5-(morpholinomethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(2-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(Dimethylamino)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-Methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(5-Methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 2-(Pyridin-2-yl)-6-(o-tolyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-Cyclopropylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-Methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-(1-Hydroxyethyl)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6-(3-Cyclopropoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Methoxy-3-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(1-Methyldihydroindol-4-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Methoxy-4-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Methoxy-3-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Chloro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(5-Methoxy-2-(trifluoromethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Fluoro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Chloro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Methoxy-5-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(1-Methyldihydroindol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Fluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(5-Methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2,5-Dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2,3-Dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(Methoxymethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(5-Cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(Cyclopentyloxy)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(4-Methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(1,5-Dimethyl-1H-indazol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6- 6-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2,6-Difluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(1-Cyclopropyldihydroindol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(2-Chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one 6-(2-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(Dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(5-Methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(4-Chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(4-Acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(3-Methoxypropoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Ethoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(Cyclopropylmethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Isopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-Cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one, 6-(3-(2-Methoxyethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-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-cyclopentadieno[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-tetrahydrophtalazin-1(2H)-one 2-(5-Bromopyrimidin-2-yl)-6-(3-cyclopropoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one N-(2-(6-(3-Cyclopropoxy-2-methylphenyl)-1-oxo-5,6,7,8-tetrahydrophtalazin-2(1H)-yl)pyrimidin-5-yl)acetamide (-)-6-(3-Cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one (+)-6-(3-Cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one (-)-6-(2-Chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one (+)-6-(2-Chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one (-)-6-(3-Cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one (+)-6-(3-Cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one (-)-6-(2-Chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one (+)-6-(2-Chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one (-)-N-(2-(6-(2,4-Dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophtalazin-2(1H)-yl)pyrimidin-5-yl)acetamide (+)-N-(2-(6-(2,4-Dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophtalazin-2(1H)-yl)pyrimidin-5-yl)acetamide (+)-6-(1-Cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one (-)-6-(1-Cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one 2-(5-Bromopyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one 2-(5-Bromopyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-1(2H)-one 2-(5-Bromopyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophtalazin-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 an N-oxide form, a pharmaceutically acceptable salt or solvate thereof, or an optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof.

20. A compound according to any one of claims 1 to 19, which is in the form of a racemic mixture or in the form of one or both of the individual optical isomers.

21. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 20 and a pharmaceutically acceptable excipient.

22. A compound according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21 for use as a medicament.

23. A method for preparing the pharmaceutical composition according to claim 21, characterized in that A pharmaceutically acceptable carrier is intimately admixed with a therapeutically effective amount of a compound according to any one of claims 1 to 20.

24. A compound or composition for use according to claim 22 for modulating, preferably reducing or inhibiting or negatively regulating the activity of a metabotropic glutamate receptor, in particular mGluR7.

25. A compound or composition for use according to either claim 22 or 24 for preventing or treating in a mammal, including a human, a disorder associated with abnormal glutamate function.

26. A compound or composition for use according to any one of claims 22, 24, and 25, for 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, major depressive disorder, dysthymic disorder, major depressive disorder, substance-induced mood disorder, mood disorder due to a general medical condition, mania, manic-depressive disorder, seasonal affective disorder; disorders related to muscle spasms and spastic states, including tremors, epilepsy, convulsions, migraines; disorders selected from neurodegenerative diseases such as mild cognitive impairment, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis; disorders selected from psychotic mental disorders such as schizophrenia, delusional disorder, schizoaffective disorder, schizotypal disorder, substance-induced psychotic disorder; personality disorders, including obsessive-compulsive personality disorder, schizoid personality, schizotypal disorder, borderline personality disorder, avoidant personality disorder with anxiety; childhood disorders, including attention deficit / hyperactivity disorder, mental retardation, Down syndrome, tic disorders, autism spectrum disorders (such as Rett syndrome or fragile X syndrome) and autism; ear disorders, including inner ear diseases, disorders, injuries or conditions such as sensorineural hearing loss, age-related hearing impairment (presbycusis), Meniere's disease, sudden hearing loss, noise-induced hearing loss, drug-induced hearing loss, occult 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; 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; eye disorders, including elevated intraocular pressure, glaucoma, normal-tension glaucoma, neurodegenerative disease conditions of the retina and optic nerve, retinal dystrophy, age-related macular degeneration, and eye 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, brain hypoxia, cerebral hemorrhage, or intracranial hematoma.

27. Use of a compound according to any one of claims 1 to 20 for the preparation of a medicament for modulating the activity of metabotropic glutamate receptors.

28. Use of a compound according to any one of claims 1 to 20 for the preparation of a medicament for reducing or inhibiting or negatively regulating the activity of metabotropic glutamate receptors.

29. Use according to claim 27 or 28, wherein the metabotropic glutamate receptor is mGluR7.

30. A compound according to any one of claims 1 to 20 for use in the preparation of a medicament for preventing or treating in mammals including humans a disorder associated with abnormal glutamate function.

31. Use of a compound according to any one of claims 1 to 20 for the preparation of a medicament for preventing or treating a disorder selected from: anxiety disorders such as agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), social phobia or other phobias; mood disorders including bipolar disorder (I&II), cyclothymic disorder, depression, dysthymic disorder, major depressive disorder, substance-induced mood disorder, mood disorder due to a general medical condition, mania, manic-depressive disorder or seasonal affective disorder; disorders related to myoclonus and spastic states including tremors, epilepsy, convulsions or migraines; disorders selected from neurodegenerative diseases such as mild cognitive impairment, Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis; disorders selected from psychotic mental disorders such as schizophrenia, delusional disorder, schizoaffective disorder, schizotypal disorder, substance-induced psychotic disorder; personality disorders including obsessive-compulsive personality disorder, schizoid personality, schizotypal disorder, borderline personality disorder, avoidant personality disorder with anxiety; childhood disorders including attention deficit / hyperactivity disorder, mental retardation, Down syndrome, tic disorders, autism spectrum disorders (such as Rett syndrome or fragile X syndrome) and autism; ear disorders including inner ear diseases, disorders, injuries or conditions such as sensorineural hearing loss, age-related hearing impairment (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 disease, acute tinnitus, chronic tinnitus, central auditory processing disorder 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; eye disorders including ocular hypertension, glaucoma, normal tension glaucoma, neurodegenerative disease conditions of the retina and optic nerve, retinitis pigmentosa, age-related macular degeneration and eye 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, brain hypoxia, cerebral hemorrhage or intracranial hematoma.

32. Use of a compound according to any one of claims 1 to 20 for the preparation of a medicament for preventing or treating a disorder selected from: anxiety disorders such as agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), social phobia or other phobias; mood disorders including bipolar disorder (I&II), cyclothymic disorder, depression, dysthymic disorder, major depressive disorder, substance-induced mood disorder, mood disorder due to a general medical condition, mania, manic-depressive disorder or seasonal affective disorder; disorders related to muscle spasms and spasticity including tremors, epilepsy, convulsions or migraine; and disorders selected from neurodegenerative diseases such as 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 20 for the preparation of a medicament for preventing or treating a disorder selected from: psychotic mental disorders such as schizophrenia, delusional disorder, schizoaffective disorder, schizotypal disorder, substance-induced psychotic disorder; personality disorders including obsessive-compulsive personality disorder, schizoid personality, schizotypal disorder, borderline personality disorder, avoidant personality disorder with anxiety; childhood disorders including attention deficit / hyperactivity disorder, mental retardation, Down syndrome, tic disorders, autism spectrum disorders (such as Rett syndrome or fragile X syndrome) and autism; and ear disorders including inner ear diseases, disorders, injuries or conditions such as sensorineural hearing loss, age-related hearing impairment (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 disease, acute tinnitus, chronic tinnitus, central auditory processing disorder and vestibular disorders.

34. Use of a compound according to any one of claims 1 to 20 for the preparation of a medicament for preventing or treating a disorder selected from: 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 related to the above disorders and conditions; eye disorders including elevated intraocular pressure, glaucoma, normal-tension glaucoma, neurodegenerative disease conditions of the retina and optic nerve, retinitis pigmentosa, age-related macular degeneration and eye 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, brain hypoxia, cerebral hemorrhage or intracranial hematoma. Use of a compound according to any one of claims 1 to 20 as a radiolabeled tracer for imaging metabotropic glutamate receptors, preferably mGluR7, in mammals including humans.

36. Compounds of formula (IV), (V), (VI), (VII), (VIII) or (IX) which are intermediates of the compounds 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 and Y are as defined in any one of claims 1 to 15.

37. A compound as defined in claim 36, which is a compound of formula (IV), (V), (VI).

38. A compound as defined in claim 36, which is a compound of formula (VII), (VIII) or (IX).

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