Sigma-1 receptor ligands and uses thereof

Abstract

The present invention relates to the medical field, more particularly to compounds that are sigma-1 receptor agonists and their use for the treatment of central nervous system disorders, including cognitive or neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. TIFF2023507508000017.tif88170

Description

[Technical Field]

[0001] The present invention relates to the medical field, more particularly to compounds that are sigma-1 receptor agonists and their use for the treatment of central nervous system disorders, including cognitive or neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. [Background technology]

[0002] Two sigma receptor subtypes have been identified based on their pharmacological profiles.

[0003] The sigma-1 receptor is a membrane-bound protein found throughout the body and widely expressed in the central nervous system, neurons, astrocytes, oligodendrocytes, and microglia. It is a single polypeptide transmembrane protein containing 223 amino acids. As a single 25 kD polypeptide and chaperone protein, it is highly expressed in the mitochondrial-associated endoplasmic reticulum (ER) membrane and plasma membrane. Its identified partner proteins include glucose-related protein 78 / binding immunoglobulin protein (BiP) and inositol-1,4,5 triphosphate (IP3) receptor. The sigma-1 receptor is a ligand-gated chaperone protein that binds and is activated / inactivated by various classes of pharmacological compounds, including dextrorotatory isomers of benzomorphans such as (+)-pentazocine and (+)-SKF-10,047. Although certain endogenous ligands that interact with sigma-1 receptors, such as neurosteroids, neuropeptides, cholinergic, or trace amines, have been identified, the existence of high-affinity endogenous sigma-1 receptor ligands remains unknown. Activation of sigma-1 receptors by agonists has several cellular consequences, but primarily leads to amplification of calcium exchange between the ER and mitochondria by interacting with IP3 receptors on the ER membrane, and to induction of ER stress pathways by interacting with ER stress sensors such as BiP or IRE-1.

[0004] Sigma-1 receptor agonists have been reported to have antidepressant effects in some animal models.For example, selective sigma-1 receptor agonists (+)-pentazocine, (+)-SKF-10,047, igmesine, OPC14523, DTG or SA4503 reduce the freezing behavior in fear conditioning stress test or the immobility time in forced swimming test, or are active in tail suspension test (Matsuno et al., Eur J Pharmacol 312:267-71, 1996; Tottori et al., Neuropharmacology 2001 41:976-88; Urani et al., J Pharmacol Exp Ther 298:1269-79, 2001).

[0005] Sigma-1 receptor agonists have also been reported to play a role in cell survival (Wang et al., Exp Cell Res 312:1439-46, 2006; Hayashi and Su, Cell 131:596-610, 2007; Jiang et al., Invest Ophthalmol Vis Sci 47:5576-82, 2006). Sigma-1 receptor ligands have been reported to be neuroprotective. The Sigma-1 receptor ligand opipramol has been reported to protect against ischemia in gerbils. In addition, other Sigma ligands, including BMY-14802, caramiphen, and haloperidol, have exhibited properties consistent with protective effects in in vivo models (Pontecorvo et al., Brain Res Bull 26:461-5, 1991). Several sigma ligands have been reported to inhibit ischemia-induced glutamate release from hippocampal slices in vitro (Lobner et al., Neurosci Lett 1 17:169-74, 1990). The sigma-1 receptor agonist (+)-pentazocine has also been reported to protect retinal cells from stress (Dun et al., Invest Ophthalmol Vis Sci 48:4785-94, 2007; Smith et al., Invest Ophthalmol Vis Sci 49:4154-61, 2008).

[0006] Of particular note is the utility of sigma-1 receptor agonists with low sigma-2 receptor affinity in treating neuronal damage, such as that resulting from ischemic brain / focal ischemia. Sigma-1 receptor agonists may also be useful in improving cognitive dysfunction, such as that exhibited with neurotransmitter dysfunction (e.g., acetylcholine), as well as age-related cognitive and anxiety-related dysfunction (including pregnancy stress resulting in learning deficits in the offspring).

[0007] Sigma-1 receptor agonists are effective antiamnesic compounds. This has been demonstrated in several pharmacological and pathological models of learning and memory dysfunction in rodents. In particular, sigma-1 receptor agonists are routinely tested in vivo against scopolamine-induced learning deficits, a model of muscarinic acetylcholine receptor (mAChR) blockade. For example, the sigma-1 receptor agonist LS-1-137 (Malik et al., Br J Pharmacol 172:2519-31, 2015), the sigma-1 positive modulator E1R (Zvejniece et al., Br J Pharmacol 171:761-71, 2014) or OZP002 (Maurice et al., Pharmacol Res 144:315-30, 2019), or the mixed mAChR / σ1 agonists ANAVEX1-41 or ANAVEX2-73 (bularcamesin), two diphenyl-3-furanmethanamine derivatives (Espallergues et al., Br J Pharmacol 152:267-79, 2017; Villard et al., Neuropsychopharmacology 34:1552-66, 2009) was recently characterized as an antiamnesic agent for scopolamine-induced learning impairment. The efficacy of sigma-1 receptor agonists as symptomatic drugs in cognition has been described not only in cholinergic amnesia models (e.g., scopolamine, mecamylamine, p-chloroamphetamine, forebrain lesions) but also in glutamatergic models of learning deficits. Using learning impairment induced by the noncompetitive NMDA receptor antagonist dizocilpine (MK-081), it has been demonstrated that the positive modulation exerted by sigma-1 receptors in NMDA neurotransmission has behavioral consequences, as suggested in vitro or in vivo using extracellular recordings of NMDA-induced firing of pyramidal neurons in the CA3 hippocampal region.The efficacy of sigma-1 receptor agonists in alleviating dizocilpine-induced learning impairment also points to the potential utility of these drugs in treating schizophrenia-associated cognitive deficits, particularly since the hypoglutamatergy model has been deemed highly valid for mimicking the negative symptoms of schizophrenia (Meltzer et al., Int J Neuropsychopharmacol 16:2181-94, 2013). Interestingly, sigma-1 receptor ligands tested in both the scopolamine and dizocilpine models showed similar active dose ranges in vivo. Thus, activation of sigma-1 receptors appears to similarly modulate the activity of two neurotransmitter systems involved in memory processes in limbic and cortical structures: the cholinergic and, particularly, the glutamatergic systems. Sigma-1 receptor agonists enhance NMDA-induced firing in the hippocampus at very low doses. (+)-SKF-10,047 (also known as arazosin), PRE084, and (+)-pentazocine increased the expression of the NR2A and NR2B subunits of the NMDA receptor and PSD95 (also known as SAP-90) in the rat hippocampus. Sigma-1 receptor agonist treatment resulted in increased interaction between the NR2 subunit and the Sigma-1 receptor, promoting transport of the NMDA receptor to the cell surface. Sigma-1 receptors are small-conductance Ca receptors. 2+ activation K +It interacts with NMDA receptors through modulation of electrical current (SK channels). At the behavioral level, 2-month-old male sigma-1 KO mice showed signs of anxiety in procedures including the open field, passive avoidance, and elevated plus maze, as well as an enhanced response to stress in the forced swim test. Thus, in male animals, sigma-1 receptor ablation increased stress and anxiety responses, but left memory responses unchanged. However, female sigma-1 KO mice showed memory alterations in spontaneous alternation and water maze learning paradigms, and this phenotype increased with age. Notably, both 2- and 14-month-old female sigma-1 KO mice showed reduced plasma levels of 17β-estradiol, and hormone replacement treatment reversed memory deficits in both young and aged mice (Chevallier et al., J Psychopharmacol 25:960-75, 2011). This suggests that sigma-1 receptor ablation has developmental effects during steroidal tonus.

[0008] Therefore, sigma-1 receptor agonists are promising symptomatic drugs in rodent models of cognitive alterations associated with pathological aging and neurodegenerative diseases. First, igmesine and PRE-084 improved learning ability in senescence-accelerated mice (SAMP / 8) at low mg / kg doses (Maurice et al., Brain Res 733:219-30, 1996). Second, these compounds also alleviated memory deficits induced by amyloid toxicity in pharmacological models of Alzheimer's disease (AD). (+)-Pentazocine, PRE-084, ctamesine, dimemorfan, ANAVEX1-41, buralcamesine, OZP002, and sigma-1 receptor-binding neuroactive steroids inhibit oligomerized Aβ, which produces neurotoxicity closely related to AD pathology. 25-35Direct intracerebroventricular injection of the peptide attenuated learning deficits in mice (Meunier et al., Br J Pharmacol. 149: 998-1012, 2006; Villard et al., J Psychopharmacol 25: 1101-17, 2011; Maurice et al., Pharmacol Res 144: 315-30, 2019). All sigma-1 receptor agonists or positive modulators attenuated Aβ activity in spatial and non-spatial tasks involving short- and long-term memory. 25-35 These drugs alleviated induced learning impairments. These effects were blocked by BD1047, haloperidol, BMY-14,802, and progesterone, all putative sigma-1 receptor antagonists. Notably, while they blocked the effects of sigma-1 receptor agonists, the antagonists alone did not alter behavior (positively or negatively) in these models. Therefore, sigma-1 receptor agonists are promising agents for treating AD symptoms at active doses similar to or lower than those of the reference drugs donepezil, rivastigmine, galantamine, and memantine (Meunier et al., Br J Pharmacol 149: 998-1012, 2006).

[0009] Finally, bralcamesine, a mixed muscarinic and sigma-1 drug, successfully completed a phase 2 clinical trial in AD. The drug stabilized ADAS-ADL scores and limited MMSE score decline in patients after 3 years of treatment in patients with the highest drug bioavailability (Hample et al., CTAD Abstracts, 2018). [Prior art documents] [Patent documents]

[0010] [Patent Document 1] WO2010133528 [Patent Document 2] WO2010131147 [Patent Document 3] WO2009013335

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[0011] [Non-licensed document 1] Matsunoら, Eur J Pharmacol 312:267~71, 1996 [Non-licensed document 2] Tottoriら、Neuropharmacology 2001 41:976~88 [Non-licensed document 3] Uraniら, J Pharmacol Exp Ther 298:1269~79, 2001

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[0012] Therefore, there is currently a strong need for the development of new sigma-1 receptor agonists for the treatment of cognitive disorders associated with psychiatric pathologies, neurodegenerative diseases such as Alzheimer's, Huntington's and Parkinson's diseases, amyotrophic lateral sclerosis (ALS) or multiple sclerosis, and genetic diseases associated with MAM (mitochondria-associated membrane) dysfunction. The present invention seeks to meet this and other needs. Compounds according to the present invention have been found to have affinity for the sigma-1 receptor. [Means for solving the problem]

[0013] In this respect, the present invention provides a compound having the following formula (I):

[0014] [ka]

[0015] [In the formula, R1 and R2 are independently H, aryl (C1-C6) alkyl groups, aryl groups, cycloalkyl groups, a heterocyclic group, or SR (where R is alkyl, aryl, or aralkyl) represents wherein one of R1 and R2 is H and the other of R1 and R2 is different from H; X and Y are, respectively, CH and N, or N and CR4, or CH and CR4 Either wherein R4 represents H or (C1-C4) alkyl; n is 0, 1 or 2, m is 0 or 1, and m' is 0 or 1; R3 is a group selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (C1-C6)alkoxy and aryl(C1-C6)alkyl, (C1-C6)alkyl, OH, halogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (C1-C6)alkoxy, -C(O)R, -CHOHR, C(O)2R, C(O)NRR', -CONHOR, -CONHSO2R, -NRR', -N(R)C(O)R', -N(R)NR'R'', -N(R)C(O)2R', -N(R)C(O)NR'R'', -N(R)S(O)2R', -SR, -S(O)R, -S(O)2R, -S(O)NR-R', and -S(O)NR-R', where R, R', and R'' are independently H, (C1-C6)alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, (C1-C6)alkylcycloalkyl, (C1-C6)alkylaryl, (C1-C6)alkylheterocycloalkyl, or (C1-C6)alkylheteroaryl; or a group selected from the group consisting of OH, —C(O)R, —CHOHR, C(O)R, C(O)NRR′, —CONHOR, —CONHSOR, —NRR′, —N(R)C(O)R′, —N(R)NR′R″, —N(R)C(O)R′, —N(R)C(O)NR′R″, —N(R)S(O)R′, —SR, —S(O)R, —S(O)R, —S(O)NRR′ and S(O)NRR′, where R, R′ and R″ are independently H, (C1-C6)alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, (C1-C6)alkylcycloalkyl, (C1-C6)alkylaryl, (C1-C6)alkylheterocycloalkyl or (C1-C6)alkylheteroaryl; represents R5 represents H or OH; Each R6 independently represents H or a (C1-C6) alkyl group. It relates to an isomer, a solvate or any pharmaceutical salt thereof.

[0016] The present invention also relates to a compound as defined above for use as a medicine.

[0017] The present invention further relates to a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable support.

[0018] Another object of the present invention is a compound or pharmaceutical composition as defined above for use in the treatment of a disorder modulated by the sigma-1 receptor, including a cognitive or neurodegenerative disorder. In certain embodiments, the disorder is selected from the group consisting of: (1) neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, (2) cognitive and memory alterations such as pathological aging, ischemic amnesia, schizophrenia-related cognitive deficits, and depression, (3) developmental cognitive disorders such as autism-related disorders and mental retardation-related disorders, and (4) genetic diseases associated with MAM dysfunction. DETAILED DESCRIPTION OF THE INVENTION

[0019] definition According to the present invention, the following terms have the following meanings: Terms referred to herein with prefixes such as C1-C3, C1-C6, or C2-C6 can also be used with lower numbers of carbon atoms, such as C1-C2, C1-C5, or C2-C5. For example, when the term C1-C3 is used, it means that the corresponding hydrocarbon chain can contain from 1 to 3 carbon atoms, particularly 1, 2, or 3 carbon atoms. For example, when the term C1-C6 is used, it means that the corresponding hydrocarbon chain can contain from 1 to 6 carbon atoms, particularly 1, 2, 3, 4, 5, or 6 carbon atoms. For example, when the term C2-C6 is used, it means that the corresponding hydrocarbon chain can contain from 2 to 6 carbon atoms, particularly 2, 3, 4, 5, or 6 carbon atoms.

[0020] The term "alkyl" refers to a saturated straight-chain or branched-chain aliphatic group. The term "(C1-C3) alkyl" more specifically refers to methyl, ethyl, propyl, or isopropyl. The term "(C1-C6) alkyl" more specifically refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, or hexyl. In preferred embodiments, "alkyl" is methyl, ethyl, or propyl, more preferably methyl or ethyl. Alkyl groups include halogenated alkyl groups, such as perhalogenated alkyls (e.g., -CF3).

[0021] The term "alkenyl" refers to an unsaturated, straight-chain or branched-chain aliphatic group containing at least one carbon-carbon double bond. The term "(C2-C6)alkenyl" more specifically refers to ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, prenyl, or hexenyl. In a preferred embodiment, "alkenyl" is isobutenyl. "Isobutenyl" refers to a 2-methylprop-1-en-1-yl group.

[0022] The term "alkoxy" or "alkyloxy" corresponds to an alkyl group as defined above attached to the molecule by an -O- (ether) bond. (C1-C3)alkoxy includes methoxy, ethoxy, propyloxy, and isopropyloxy. (C1-C6)alkoxy includes methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy, pentyloxy, and hexyloxy. In a preferred embodiment, "alkoxy" or "alkyloxy" is methoxy.

[0023] The term "cycloalkyl" refers to a saturated or unsaturated (preferably at least one double carbon-carbon bond) mono-, bi-, or tricyclic alkyl group having between 3 and 20 carbon atoms (C 20) also referred to as cycloalkyl). This also includes fused, bridged, or spiro-connected cycloalkyl groups. The term "cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "cycloalkyl" can also refer to 5- to 10-membered bridged carbocyclyl, preferably bicyclo[2,2,2]octanyl, such as bicyclo[2,2,1]heptanyl, bicyclo[2,2,2]octanyl, or adamantyl. In preferred embodiments, "cycloalkyl" is cyclopropyl, cyclopentyl, or cyclohexyl.

[0024] The term "heterocycloalkyl" refers to a saturated or unsaturated (preferably at least one double carbon-carbon bond) cycloalkyl group as defined above, further containing at least one heteroatom or heteroatom group, such as a nitrogen, oxygen, or sulfur atom. This also includes fused, bridged, or spiro-connected heterocycloalkyl groups. Representative heterocycloalkyl groups include, but are not limited to, 3-dioxolane, benzo[1,3]dioxolyl, pyranyl, tetrahydropyranyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, azepanyl, 1,4-dioxanyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, morpholinyl, 1,4-dithianyl, pyrrolidinyl, quinolidinyl, oxozolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, dihydropyranyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, and tetrahydrothiophenyl. The term "heterocycloalkyl" can also refer to 5- to 10-membered bridged heterocyclyls, such as 7-oxabicyclo[2,2,1]heptanyl. In preferred embodiments, heterocycloalkyl is azepanyl, piperidinyl, pyrrolidinyl, or tetrahydropyranyl.

[0025] The term "aryl" refers to a mono- or bicyclic aromatic hydrocarbon having from 6 to 14 carbon atoms (C6-C6). 14) also referred to as aryl). For example, the term "aryl" includes phenyl or naphthyl. In a preferred embodiment, aryl is phenyl.

[0026] The term "heteroaryl," as used herein, refers to an aromatic mono- or polycyclic group containing between 5 and 14 atoms and including one or more heteroatoms or heteroatom groups, such as nitrogen (N), oxygen (O), or sulfur (S) atoms. Examples of such mono- and polycyclic heteroaryl groups include pyridinyl, thiazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, triazinyl, thianthrenyl, isobenzofuranyl, phenoxanthinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, indazolyl, propanol, phenoxanthinyl ... In a preferred embodiment, heteroaryl is pyridyl or imidazolyl.

[0027] The term "heterocycle" or "heterocyclic group" refers to a saturated or unsaturated, alicyclic or aromatic, mono- or polycyclic hydrocarbon containing one or more heteroatoms, such as oxygen (O), nitrogen (N), or sulfur (S), and optionally containing one or more oxo groups. Heterocycles include, but are not limited to, heteroaryl, heterocycloalkyl, and other heterocyclic derivatives, such as isoindolinyl, indolinyl, chromanyl, isochromanyl, phthalidyl, pyrrolidinonyl, imidazolidinonyl, chromenyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, xanthenyl, benzoxazolinyl, isatinyl, or dihydropyridyl. Preferably, the heterocycle is heteroaryl or heterocycloalkyl, more preferably piperidinyl, pyrrolidinyl, azepanyl, pyrrolyl, imidazolyl, or thiophenyl.

[0028] The term "nitrogen-containing heterocycle" or "nitrogen-containing heterocyclic group" refers to a heterocycle, as defined above, containing at least one nitrogen atom. Examples of nitrogen-containing heterocycles include, but are not limited to, piperidinyl, pyrrolidinyl, azepanyl, pyrrolyl, or imidazolyl, preferably piperidinyl.

[0029] The term "arylalkyl" or "aralkyl," as used herein, corresponds to an alkyl, as defined above, substituted with at least one aryl group, as defined above. More specifically, "aryl(C1-C6)alkyl" refers to a (C1-C6)alkyl, as defined above, substituted with at least one aryl group, as defined above. Examples of arylalkyl may be benzyl or phenylethyl (also called phenethyl).

[0030] The term "alkylcycloalkyl" as used herein corresponds to a cycloalkyl as defined above substituted by at least one alkyl group as defined above. More specifically, "(C1-C6) alkylcycloalkyl" refers to a cycloalkyl as defined above substituted by at least one (C1-C6) alkyl group as defined above.

[0031] The term "alkylheterocycloalkyl" as used herein corresponds to a heterocycloalkyl as defined above substituted by at least one alkyl group as defined above. More specifically, "(C1-C6) alkylheterocycloalkyl" refers to a heterocycloalkyl as defined above substituted by at least one (C1-C6) alkyl group as defined above.

[0032] The term "alkylaryl" as used herein corresponds to an aryl as defined above substituted with at least one alkyl group as defined above. More specifically, "(C1-C6) alkylaryl" refers to an aryl as defined above substituted with at least one (C1-C6) alkyl group as defined above.

[0033] The term "alkylheteroaryl" as used herein corresponds to heteroaryl as defined above substituted with at least one alkyl group as defined above. More specifically, "(C1-C6) alkylheteroaryl" refers to heteroaryl as defined above substituted with at least one (C1-C6) alkyl group as defined above.

[0034] The term "halogen" corresponds to a fluorine, chlorine, bromine or iodine atom, preferably fluorine, chlorine or bromine, more preferably chlorine or fluorine.

[0035] The phrase "substituted by at least" means that a group is substituted with one or several groups from the list.

[0036] It is understood that substitution by two or more substituents on a hydrocarbon chain, such as an alkyl or cycloalkyl chain, can occur on the same carbon and / or on different carbons. For example, the structure of an ethyl chain substituted by two given groups "A" and "B" can be represented by the structure of formula (II) or (III):

[0037] [ka]

[0038] Including but not limited to:

[0039] Unless otherwise specified, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups as defined above may be unsubstituted or substituted by at least one substituent, said at least one substituent being halogen, preferably fluorine and chlorine, CN, NO, SOH, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C(O)R, —C(O)R, —OH, —OR, —CHOHR, —C(O)NRR′, —CONHOR, —CONHSOR, —NRR′, —N(R)C is selected from the group consisting of: -(O)R', -N(R)NR'R'', -N(R)C(O)R', -N(R)C(O)NR'R'', -N(R)S(O)R', -SR, -S(O)R, -S(O)R, -S(O)R, -S(O)NRR', -S(O)NRR'; R, R', and R'' are independently H, (C1-C6)alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, (C1-C6)alkylcycloalkyl, (C1-C6)alkylaryl, (C1-C6)alkylheterocycloalkyl, or (C1-C6)alkylheteroaryl.

[0040] As used herein, the terms "treatment," "treat," or "treating" refer to any action intended to improve the well-being of a patient, including the cure, prevention, protection, and delay of disease. In certain embodiments, such terms refer to the amelioration or eradication of a disease or its associated symptoms. In other embodiments, the terms refer to minimizing the spread or worsening of a disease resulting from the administration of one or more therapeutic agents to a subject with such a disease.

[0041] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to animals, preferably mammals, and even more preferably humans, including adults, children, newborns, and prenatal humans. However, the term "subject" can also refer to non-human animals, particularly mammals such as dogs, cats, horses, cows, pigs, sheep, and non-human primates, among others.

[0042] The terms "amount," "quantity," and "dose" are used interchangeably herein and can refer to the absolute quantification of a molecule.

[0043] As used herein, the terms "active ingredient," "active ingredient," and "active pharmaceutical ingredient" are equivalent and refer to an ingredient of a pharmaceutical composition that has a therapeutic effect.

[0044] As used herein, the term "therapeutic effect" refers to an effect induced by an active ingredient or a pharmaceutical composition according to the present invention that is capable of preventing or delaying the onset of a disease, such as a neurodegenerative or cognitive disease, or curing the disease or attenuating its effects.

[0045] As used herein, the term "effective amount" refers to an amount of an active ingredient or pharmaceutical composition that prevents, eliminates, or reduces the adverse effects of a disease. It is clear that the amount to be administered can be adapted by those skilled in the art according to the subject to be treated, the nature of the disease, etc. In particular, the dosage and regimen of administration can be a function of the nature, stage, and severity of the disease to be treated, as well as the weight, age, and general health of the subject to be treated, and the judgment of the physician.

[0046] As used herein, the term "excipient or pharmaceutically acceptable carrier" refers to any ingredient, other than the active ingredient, present in a pharmaceutical composition. The addition may be aimed at imparting a particular consistency or other physical or taste characteristics to the final product. The excipient or pharmaceutically acceptable carrier must be free from any interaction, especially chemical interaction, with the active ingredient.

[0047] compound The object of the present invention is, inter alia, to provide a compound or a pharmaceutically acceptable salt thereof for use in the treatment of disorders modulated by sigma receptors, such as cognitive or neurodegenerative disorders, said compound having formula (I) as shown below:

[0048] [ka]

[0049] (R1 and R2 are independently H, aryl (C1-C6) alkyl groups, aryl groups, cycloalkyl groups, a heterocyclic group, preferably a nitrogen-containing heterocyclic group, or SR (where R is an alkyl, aryl, or aralkyl group) represents wherein one of R1 and R2 is H and the other of R1 and R2 is different from H; X and Y are, respectively, CH and N, or N and CR4, or CH and CR4 Either wherein R4 represents H or (C1-C4) alkyl; n is 0, 1 or 2, m is 0 or 1, and m' is 0 or 1; R3 is a group selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (C1-C6)alkoxy and aryl(C1-C6)alkyl, (C1-C6)alkyl, OH, halogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (C1-C6)alkoxy, -C(O)R, -CHOHR, C(O)R, C(O)NRR', -CONHOR, -CONHSOR, -NRR', -N(R)C(O)R', -N(R)NR'R'', -N(R)C(O)R', -N(R)C(O)NR'R'', -N(R)S(O)R', -SR, -S(O)R, -S(O)R , -S(O)NRR', and -S(O)NRR', where R, R', and R'' are independently H, (C1-C6)alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, (C1-C6)alkylcycloalkyl, (C1-C6)alkylaryl, (C1-C6)alkylheterocycloalkyl, or (C1-C6)alkylheteroaryl; or a group selected from the group consisting of OH, —C(O)R, —CHOHR, C(O)R, C(O)NRR′, —CONHOR, —CONHSOR, —NRR′, —N(R)C(O)R′, —N(R)NR′R″, —N(R)C(O)R′, —N(R)C(O)NR′R″, —N(R)S(O)R′, —SR, —S(O)R, —S(O)R, —S(O)NRR′ and —S(O)NRR′, wherein R, R′ and R″ are independently H, (C1-C6)alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, (C1-C6)alkylcycloalkyl, (C1-C6)alkylaryl, (C1-C6)alkylheterocycloalkyl or (C1-C6)alkylheteroaryl; represents R5 represents H or OH; Each R6 independently represents H or a (C1-C6) alkyl group. isomers, solvates or any pharmaceutical salts thereof.

[0050] In certain embodiments, compounds of the present invention are those in which R1 and R2 are independently: H, aryl (C1-C6) alkyl groups, aryl groups, cycloalkyl groups, a heterocyclic group, preferably a nitrogen-containing heterocyclic group, or SR (where R is an alkyl, aryl, or aralkyl group) represents wherein one of R1 and R2 is H and the other of R1 and R2 is different from H; the group is optionally substituted with at least one -OH, halogen, (C1-C6) alkyl or (C1-C6) alkyloxy; It is of formula (I).

[0051] In certain embodiments, compounds of the present invention are those in which R1 is: aryl (C1-C6) alkyl groups, aryl groups, cycloalkyl groups, a heterocyclic group, preferably a nitrogen-containing heterocyclic group, or SR (where R is alkyl, aryl, or aralkyl) represents R2 is H, It is of formula (I).

[0052] In another particular embodiment, the compounds of the present invention are those in which R1 and R2 are independently: H, aryl (C1-C6) alkyl groups such as benzyl or phenethyl; an aryl group such as phenyl, or heterocyclic groups, preferably nitrogen-containing heterocyclic groups such as piperidinyl, pyrrolidinyl, azepanyl, pyrrolyl or imidazolyl; represents wherein one of R1 and R2 is H and the other of R1 and R2 is different from H; the group is optionally substituted with at least one -OH, halogen, (C1-C6) alkyl or (C1-C6) alkyloxy group; It is of formula (I).

[0053] In a preferred embodiment, the compounds of the present invention are those in which R1 is aryl(C1-C6)alkyl groups such as benzyl or phenethyl, preferably phenethyl; an aryl group such as phenyl, or heterocyclic groups, preferably nitrogen-containing heterocyclic groups such as piperidinyl, pyrrolidinyl, azepanyl, pyrrolyl or imidazolyl; represents R2 represents H, It is of formula (I).

[0054] In a more preferred embodiment, the compounds of the present invention are those in which R1 is aryl(C1-C6)alkyl groups such as benzyl or phenethyl, preferably phenethyl, or Aryl groups such as phenyl represents R2 represents H, It is of formula (I).

[0055] According to a particular embodiment, when R1 or R2 represents a nitrogen-containing heterocycle, said group is preferably linked to the rest of the molecule by a nitrogen atom of said nitrogen-containing heterocycle.

[0056] Preferably, R1 is aryl, such as phenyl.

[0057] Preferably, R2 is H.

[0058] In more particular embodiments, R2 is H and R1 is phenyl optionally substituted by one or more groups selected from the group consisting of halogen, preferably fluorine or chlorine, alkyl, including alkyl groups (such as CF3) substituted by one or more halogen atoms, cycloalkyl, -OH, or (C1-C6)alkoxy, such as methoxy, as defined above.

[0059] In another particular embodiment, R represents H, R2 is aryls such as phenyl; aryl (C1-C6) alkyl groups such as benzyl or phenethyl, or Heterocyclic groups, preferably nitrogen-containing heterocyclic groups such as piperidinyl represents Preferably, R2 represents aryl, such as phenyl.

[0060] In another particular embodiment, when R or R represent aryl, such as phenyl, said aryl may be unsubstituted or a halogen, preferably fluorine or chlorine, alkyl optionally substituted with at least one halogen, preferably fluorine, more preferably the alkyl group is —CF3, -OH, and -OR (R is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably alkyl, more preferably methyl or CF3) may be substituted with at least one substituent selected from:

[0061] In certain embodiments, R3 is H, (C1-C6) alkyl groups such as methyl or ethyl; (C2-C6) alkenyl groups such as isobutenyl, cycloalkyl groups such as cyclopropyl, cyclopentyl, cyclohexyl or cyclohexenyl, aryl groups such as phenyl, heterocycloalkyl groups such as tetrahydropyranyl; Heteroaryl groups such as pyridyl or imidazolyl And, the above groups optionally substituted by at least one (C1-C6)alkyl, OH, halogen (e.g., fluorine, chlorine), aryl (e.g., phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, (C1-C6)alkoxy, -C(O)R, -N(R)C(O)R' (where R and R' are independently H, (C1-C6)alkyl, cycloalkyl, aryl (such as phenyl optionally substituted by halogen, preferably fluorine), heterocycloalkyl, heteroaryl, (C1-C6)alkylcycloalkyl, (C1-C6)alkylaryl, (C1-C6)alkylheterocycloalkyl or (C1-C6)alkylheteroaryl); preferably the above groups optionally substituted by at least one OH, halogen (e.g., chlorine), alkoxy (e.g., methoxy), -N(R)C(O)R' (where R and R' are H or (C1-C6)alkyl (e.g., methyl)); or a group selected from -CHOHR, -C(O)R, -C(O)R, where R is H, (C1-C6)alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, (C1-C6)alkylcycloalkyl, (C1-C6)alkylaryl, (C1-C6)alkylheterocycloalkyl or (C1-C6)alkylheteroaryl, and R is preferably aryl (e.g. phenyl) optionally substituted by halogen (e.g. fluorine); Represents.

[0062] In another particular embodiment, R3 is aryl, such as phenyl; heterocycloalkyl, such as tetrahydropyranyl, and - (C1-C6) alkyl, such as methyl, optionally substituted with OH is selected from the group consisting of:

[0063] In a preferred embodiment, R3 is Cyclopentyl, cyclohexyl, cyclopropyl, Pyridyl, imidazolyl, phenyl optionally substituted by halogen, such as chlorine or fluorine, or by OH, Benzyl, tetrahydropyranyl, -C(O)R group (wherein R is (C1-C6) alkyl, preferably methyl), -CHOHR groups, where R is aryl, preferably phenyl, optionally substituted by fluorine, -C(O)R groups, where R is aryl, preferably phenyl, optionally substituted by fluorine, optionally substituted with one or two substituents, each of which is Phenyl, · OH, Methoxy, -NHC(O)R' group (R' is (C1-C6) alkyl, preferably methyl), methyl, independently selected from the group consisting of Ethyl, and Isobutenyl is selected from the group consisting of:

[0064] In a more preferred embodiment, R3 is phenyl.

[0065] In certain embodiments, X and Y are each CH and N, or N and CR4 (R4 is H or (C1-C4) alkyl, preferably H) Either:

[0066] In a preferred embodiment, X and Y are N and CR4, respectively, where R4 is H or (C1-C4) alkyl, preferably R4 is H or methyl, more preferably R4 is H.

[0067] In a preferred embodiment, R5 is H.

[0068] In certain embodiments, (each) R6 is independently H or methyl.

[0069] It is understood that: - if n is 0, R6 is absent; - when n is 1, one R6 is present and the compound of formula (I) has the following structure:

[0070] [ka]

[0071] [wherein R1, R2, R3, R5, X, Y, m, and m' are as defined above, and R6 is H or a (C1-C6) alkyl group] is represented by - when n is 2, two R6 are present and the compound of formula (I) has the following structure:

[0072] [ka]

[0073] wherein R1, R2, R3, R5, X, Y, m, and m' are as defined above, and each R6 is independently H or a (C1-C6) alkyl group. is expressed by

[0074] In a preferred embodiment, R6 is H (each R6 when n is 2).

[0075] In a preferred embodiment, R5 and (each) R6 are H.

[0076] In certain embodiments, m is 0.

[0077] In another particular embodiment, m' is 1.

[0078] In another particular embodiment, m is 0 and m' is 1.

[0079] Preferably, n is 0 or 1, and more preferably, n is 1.

[0080] In certain embodiments, the compounds of the present invention have the following features: n is 1, and / or m is 0, and / or m' is 1, and / or R1 represents an aryl group, and / or R2 is H, and / or R3, a group selected from H, aryl (e.g., phenyl), (C1-C6)alkyl (e.g., methyl, ethyl), (C2-C6)alkenyl (e.g., isobutenyl), cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), heterocycloalkyl (e.g., tetrahydropyranyl), heteroaryl (e.g., pyridyl, imidazolyl), (C1-C6)alkoxy (e.g., methoxy), aryl(C1-C6)alkyl (e.g., benzyl), the above groups optionally substituted by one or two (C1-C6)alkyl, OH, halogen (e.g., fluorine, chlorine), aryl (e.g., phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, (C1-C6)alkoxy, —C(O)R, —N(R)C(O)R′, where R and R′ are independently H, (C1-C6)alkyl, cycloalkyl, aryl (such as phenyl optionally substituted by halogen, preferably fluorine), heterocycloalkyl, heteroaryl, (C1-C6)alkylcycloalkyl, (C1-C6)alkylaryl, (C1-C6)alkylheterocycloalkyl or (C1-C6)alkylheteroaryl; or A group selected from the group consisting of -CHOHR, -C(O)R, -C(O)R, where R is H, (C1-C6)alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, (C1-C6)alkylcycloalkyl, (C1-C6)alkylaryl, (C1-C6)alkylheterocycloalkyl or (C1-C6)alkylheteroaryl. represents and / or R5 is H, and / or Each R6 is H and preferably all of the following are satisfied:

[0081] In certain embodiments, R1 is Aryl (C1-C6) alkyl groups such as phenethyl, aryl groups, such as phenyl, optionally substituted by halogen (e.g., chlorine); Heterocyclic groups (preferably nitrogen-containing heterocyclic groups) such as piperidinyl is selected from the group consisting of R2 is H, R3 is aryl, such as phenyl; heterocycloalkyl, such as tetrahydropyranyl, and - (C1-C6) alkyl, such as methyl, optionally substituted with OH is selected from the group consisting of R5 is H or OH, preferably H; R6 is H or (C1-C6) alkyl such as methyl, preferably H; X and Y are, respectively, CH and N, or N and CR4 (R4 is H or (C1-C4) alkyl, preferably H), Preferably N and CH Either n is 0 or 1, preferably 1; m is 0 and m' is 1.

[0082] In certain embodiments, the aryl group is a phenyl group optionally substituted with at least one substituent, said at least one substituent being: a halogen, preferably fluorine or chlorine, alkyl optionally substituted with at least one halogen, preferably fluorine, preferably —CF3, -OH, and -OR, where R is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, preferably alkyl, and more preferably methyl. is selected from.

[0083] In a more particular embodiment, ⇒ R1 and R2 are independently H, Benzyl, phenethyl, phenyl groups optionally substituted by fluorine, chlorine, hydroxy, methoxy or -CF3, piperidinyl group, represents wherein one of R1 and R2 is H and the other of R1 and R2 is different from H; ⇒ X and Y are either CH and N, or N and CH, or CH and CH, respectively; ⇒ n is 0, 1 or 2, ⇒ m is 0 or 1, and m' is 0 or 1, ⇒ R3 is, H Cyclopentyl, cyclohexyl, cyclopropyl, Pyridyl, imidazolyl, phenyl optionally substituted by halogen, such as chlorine, or by OH, Benzyl, tetrahydropyranyl, -C(O)R group (wherein R is (C1-C6) alkyl, preferably methyl), -CHOHR groups, where R is aryl, preferably phenyl, optionally substituted by fluorine, -C(O)R groups, where R is aryl, preferably phenyl, optionally substituted by fluorine, optionally substituted with one or two substituents, each of which is Phenyl, · OH, Methoxy, -NHC(O)R group, where R is (C1-C6) alkyl, preferably methyl; methyl, independently selected from the group consisting of Ethyl, or Isobutenyl Represents.

[0084] As used herein, "a compound of the invention" means a compound as described above, or a pharmaceutically acceptable salt, any isomer or solvate form thereof.

[0085] The term "isomer" refers to compounds that have the same molecular formula as identified herein but differ in the nature or the bonding sequence of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are designated "stereoisomers." Stereoisomers that are not mirror images of each other are designated "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are designated "enantiomers" or "optical isomers." "Stereoisomer" refers to racemates, enantiomers, and diastereoisomers.

[0086] Those skilled in the art will recognize that stereocenters exist in the compounds of the present invention. Any chiral center in the compounds of the present invention can be (R), (S), or racemic. Thus, the present invention includes all possible stereoisomers and geometric isomers of the compounds of formula (I), including not only racemates but also optically active isomers. According to a preferred embodiment, the compound of the present invention is of formula (II). When a compound of formula (I) is desired as a single enantiomer, it can be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting materials or any suitable intermediate. Resolution of the final product, intermediate, or starting material can be carried out by any suitable method known in the art. See, for example, Stereochemistry of Carbon Compounds, by EL Eliel (Mcgraw Hill, 1962) and Tables of Resolving Agents, by SH Wilen.

[0087] Those skilled in the art of organic chemistry will recognize that many organic compounds can form complexes with solvents in which they are reacted or in which they are precipitated or crystallized. These complexes are known as "solvates." For example, complexes with water are known as "hydrates." Solvates of compounds of formula (I) or (II) are within the scope of the present invention.

[0088] Those skilled in the art of organic chemistry will also recognize that many organic compounds can exist in more than one crystalline form. For example, the crystalline form can vary from solvate to solvate. Thus, all crystalline forms of the compounds of the present invention or pharmaceutically acceptable solvates thereof are within the scope of the present invention.

[0089] The term "pharmaceutically acceptable salts" or "pharmaceutical salts" of the compounds of the present invention includes conventional salts and quaternary ammonium salts formed from pharmaceutically acceptable inorganic or organic acids or bases. More specific examples of suitable acid salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid, citric acid, palmoic acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, stearic acid, tannic acid, and the like. More specific examples of suitable base salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine salts.

[0090] For example, preferred salt forms include hydrochloride salts.

[0091] In certain embodiments, the compound of formula (I) is 2-(1-benzylpiperidin-4-yl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-(1-benzylpiperidin-4-yl)-5-phenylpyridazin-3(2H)-one hydrochloride; 4-phenyl-2-[1-(2-phenylethyl)piperidin-4-yl]-2,3-dihydropyridazin-3-one hydrochloride; 2-[1-(cyclopropylmethyl)piperidin-4-yl]-4-phenyl-2,3-dihydropyridazin-3-one hydrochloride; 2-[1-(cyclopentylmethyl)piperidin-4-yl]-4-phenyl-2,3-dihydropyridazin-3-one hydrochloride; 2-(1-benzylazepan-4-yl)-4-phenyl-2,3-dihydropyridazin-3-one hydrochloride; 2-((1-benzylpiperidin-4-yl)methyl)-6-methyl-4-phenylpyridazin-3(2H)-one; 2-((1-benzylpiperidin-4-yl)methyl)-5-phenylpyridazin-3(2H)-one hydrochloride; 2-[(1-benzylpiperidin-3-yl)methyl]-4-phenyl-2,3-dihydropyridazin-3-one hydrochloride; 2-((1-phenethylpiperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 4-phenyl-2-((1-propylpiperidin-4-yl)methyl)pyridazin-3(2H)-one hydrochloride; 2-((1-(4-chlorobenzyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 4-phenyl-2-((1-(pyridin-4-ylmethyl)piperidin-4-yl)methyl)pyridazin-3(2H)-one hydrochloride; 4-phenyl-2-((1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)methyl)pyridazin-3(2H)-one hydrochloride; 2-{[1-(1H-imidazol-5-ylmethyl)piperidin-4-yl]methyl}-4-phenyl-2,3-dihydropyridazin-3-one hydrochloride; 4-phenyl-2-((1-((tetrahydro-2H-pyran-3-yl)methyl)piperidin-4-yl)methyl)pyridazin-3(2H)-one hydrochloride; 2-((1-(4-hydroxybenzyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-((1-(2-methoxyethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-((1-(2-methoxy-1-phenylethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; N-(2-{4-[(6-oxo-5-phenyl-1,6-dihydropyridazin-1-yl)methyl]piperidin-1-yl}ethyl)acetamide hydrochloride; 2-((1-(2-(4-fluorophenyl)-2-hydroxyethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-((1-(2-hydroxy-2-phenylethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-(2-(1-benzylpiperidin-4-yl)ethyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-(2-(1-benzylpiperidin-4-yl)ethyl)-5-phenylpyridazin-3(2H)-one hydrochloride; 2-(1-(1-benzylpiperidin-4-yl)ethyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-((1-benzyl-4-hydroxypiperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-(1-benzylpiperidin-4-yl)-4-(4-methoxyphenyl)pyridazin-3(2H)-one hydrochloride; 2-(1-benzylpiperidin-4-yl)-4-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazin-3-one hydrochloride; 2-(1-benzylpiperidin-4-yl)-4-[4-(chlorophenyl]-2,3-dihydropyridazin-3-one hydrochloride; 2-[(1-benzylpiperidin-4-yl)methyl]-4-(2-chlorophenyl)-2,3-dihydropyridazin-3-one hydrochloride; 2-[(1-benzylpiperidin-4-yl)methyl]-4-(4-hydroxyphenyl)-2,3-dihydropyridazin-3-one hydrochloride; 2-((1-benzylpiperidin-4-yl)methyl)-4-(4-fluorophenyl)pyridazin-3(2H)-one hydrochloride; 2-((1-benzylpiperidin-4-yl)methyl)-4-phenethylpyridazin-3(2H)-one, 2-(1-benzylpiperidin-4-yl)-4-(2-phenylethyl)-2,3-dihydropyridazin-3-one hydrochloride; 2-(1-benzylpiperidin-4-yl)-4-(piperidin-1-yl)-2,3-dihydropyridazin-3-one hydrochloride; 2-[(1-benzylpiperidin-4-yl)methyl]-4-(piperidin-1-yl)-2,3-dihydropyridazin-3-one hydrochloride; 2-((1-benzylpiperidin-4-yl)methyl)-4-morpholinopyridazin-3(2H)-one hydrochloride; 2-((1-benzylpiperidin-4-yl)methyl)-4-(4-phenylpiperazin-1-yl)pyridazin-3(2H)-one hydrochloride; 2-((1-benzylpiperidin-4-yl)methyl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)pyridazin-3(2H)-one hydrochloride; 3-(1-benzylpiperidin-4-yl)-5-phenylpyrimidin-4(3H)-one hydrochloride; 1-(1-benzylpiperidin-4-yl)-3-phenyl-1,2-dihydropyridin-2-one hydrochloride; 3-((1-benzylpiperidin-4-yl)methyl)-5-phenylpyrimidin-4(3H)-one; and 1-[(1-benzylpiperidin-4-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one hydrochloride is selected from the group consisting of:

[0092] Preferably, the compound is 2-(1-benzylpiperidin-4-yl)-4-phenylpyridazin-3(2H)-one hydrochloride; 3-(1-benzylpiperidin-4-yl)-5-phenylpyrimidin-4(3H)-one hydrochloride; 2-((1-benzylpiperidin-4-yl)methyl)-4-phenethylpyridazin-3(2H)-one; 2-[(1-benzylpiperidin-4-yl)methyl]-4-(piperidin-1-yl)-2,3-dihydropyridazin-3-one hydrochloride; 2-((1-benzyl-4-hydroxypiperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 4-phenyl-2-((1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)methyl)pyridazin-3(2H)-one hydrochloride; 2-(1-(1-benzylpiperidin-4-yl)ethyl)-4-phenylpyridazin-3(2H)-one hydrochloride; and 2-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride is selected from the group consisting of:

[0093] The compounds of the present invention can be prepared by several methods, in particular as illustrated in the examples. The starting products are commercial products or products prepared from commercial compounds or compounds known to those skilled in the art according to known syntheses.

[0094] Therapeutic Uses of the Compounds The present invention relates to a pharmaceutical or veterinary composition comprising a compound according to the present invention. Preferably, the pharmaceutical composition further comprises a pharmaceutically or veterinarily acceptable carrier (or "adjuvant") or additive. The present invention further relates to a method for treating a disease in a subject, wherein a therapeutically effective amount of a compound according to the present invention is administered to said subject in need thereof. The present invention relates to the use of a compound according to the present invention as a medicament. The present invention also relates to the use of a compound according to the present invention for the manufacture of a medicament.

[0095] Additionally, the present invention relates to a method for treating a disorder modulated by sigma-1 receptors (e.g., a cognitive or neurodegenerative disorder) in a subject, wherein a therapeutically effective amount of a compound according to the present invention is administered to said subject suffering from a disorder modulated by sigma-1 receptors (e.g., a cognitive or neurodegenerative disorder).

[0096] The present invention also relates to the use of a compound according to the invention for the manufacture of a medicament for the treatment of a disorder modulated by the sigma-1 receptor (e.g. a cognitive or neurodegenerative disorder).The present invention relates to a compound according to the invention for use in the treatment of a disorder modulated by the sigma-1 receptor (e.g. a cognitive disorder).

[0097] In certain embodiments of the present invention, the disorder modulated by the sigma-1 receptor is selected from the group consisting of: (1) neurodegenerative diseases, including but not limited to Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis; (2) cognitive and memory alterations, including but not limited to pathological aging, ischemic amnesia, schizophrenia-associated cognitive deficits, and depression; (3) developmental cognitive disorders, including but not limited to autism-associated disorders and mental retardation-associated disorders; and (4) genetic diseases associated with MAM dysfunction.

[0098] Pharmaceutical Composition The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention, the compositions further comprising at least one pharmaceutically acceptable carrier (or "adjuvant") or excipient.

[0099] The present invention also relates to a pharmaceutical composition of the present invention for use in the treatment of a disease. The present invention also relates to the use of a pharmaceutical composition according to the present invention for the manufacture of a medicament for treating a disease in a subject. The present invention further relates to a method for treating a disease in a subject, wherein a therapeutically effective amount of a pharmaceutical composition according to the present invention is administered to said subject suffering from said disease.

[0100] Preferably, the disease is a disorder modulated by sigma-1 receptor. More preferably, the disease is selected from the group consisting of: (1) neurodegenerative diseases, including but not limited to Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis; (2) cognitive and memory alterations, including but not limited to pathological aging, ischemic amnesia, schizophrenia-related cognitive deficits, and depression; (3) developmental cognitive disorders, including but not limited to autism-related disorders and mental retardation-related disorders; and (4) genetic diseases associated with MAM dysfunction.

[0101] Subjects, Regimen and Administration The subject according to the present invention is an animal, preferably a mammal, and even more preferably a human. However, the term "subject" can also refer to non-human animals, particularly mammals such as dogs, cats, horses, cows, pigs, sheep, donkeys, rabbits, ferrets, gerbils, hamsters, chinchillas, rats, mice, guinea pigs, and non-human primates, among others, in need of treatment.

[0102] A human subject according to the present invention may be a human in the prenatal stage, a newborn, a child, an infant, an adolescent or an adult, in particular an adult at least 40 years of age, preferably an adult at least 50 years of age.

[0103] In a preferred embodiment, the subject has been diagnosed with a disease. Preferably, the subject has been diagnosed with a disease modulated by the sigma-1 receptor.

[0104] Methods for diagnosing these diseases are well known to those skilled in the art.

[0105] The compounds according to the present invention or the pharmaceutical compositions according to the present invention may be administered by any conventional route of administration, in particular by topical, enteral, oral, parenteral, intranasal, intravenous, intraarterial, intramuscular, intratumoral, subcutaneous or intraocular administration.

[0106] In particular, the compounds according to the invention or pharmaceutical compositions according to the invention may be formulated for topical, enteral, oral, parenteral, intranasal, intravenous, intraarterial, intramuscular, subcutaneous or intraocular administration, and the like.

[0107] Preferably, the compounds according to the present invention or the pharmaceutical compositions according to the present invention are administered by enteral or parenteral administration routes. When administered parenterally, the compounds according to the present invention or the pharmaceutical compositions according to the present invention are preferably administered by intravenous administration route. When administered enterally, the compounds according to the present invention or the pharmaceutical compositions according to the present invention are preferably administered by oral administration route.

[0108] Pharmaceutical compositions containing the molecules are formulated according to standard pharmaceutical practice known to those skilled in the art (Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York).

[0109] For oral administration, the compositions can be formulated into conventional oral dosage forms, such as tablets, capsules, powders, granules, and liquid preparations such as syrups, elixirs, and concentrated drops. Non-toxic solid carriers or excipients can be used, including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. Compressed tablets also require binders, which are agents that impart cohesive qualities to powdered materials. For example, starch, gelatin, sugars such as lactose or dextrose, and natural or synthetic gums can be used as binders. Tablets also require disintegrants to facilitate tablet breakage. Disintegrants include starch, clay, cellulose, algin, gums, and crosslinked polymers. Furthermore, tablets also contain lubricants and glidants to prevent adhesion of tablet materials to the surface during the manufacturing process and to improve the flow characteristics of powdered materials during manufacturing. Colloidal silicon dioxide is most commonly used as a glidant, and compounds such as talc or stearic acid are most commonly used as lubricants.

[0110] For transdermal administration, the composition may be formulated in ointment, cream, or gel form, and appropriate penetrants or detergents such as dimethyl sulfoxide, dimethylacetamide, and dimethylformamide may be used to facilitate penetration.

[0111] For transmucosal administration, nasal sprays, rectal or vaginal suppositories can be used. The active compound can be incorporated into any known suppository base by methods known in the art. Examples of such bases include cocoa butter, polyethylene glycol (carbowax), polyethylene sorbitan monostearate, and mixtures thereof with other suitable materials for modifying the melting point or dissolution rate.

[0112] Pharmaceutical compositions according to the present invention may be formulated to release the active drug substantially immediately upon administration or at any predetermined time or period after administration.

[0113] Preferably, treatment with a compound according to the invention or a pharmaceutical composition according to the invention is initiated within one year, preferably within 6, 5, 4, 3, 2 or 1 month after diagnosis of the disease.

[0114] The compounds according to the invention or the pharmaceutical compositions according to the invention may be administered as a single dose or, preferably, in multiple doses.

[0115] Preferably, the treatment is administered periodically, preferably daily to monthly, more preferably daily to every two weeks, more preferably daily to weekly, and even more preferably daily. In certain embodiments, the treatment is administered several times a day, such as two or three times a day.

[0116] The duration of treatment with the compound according to the invention or the pharmaceutical composition according to the invention is preferably for one week, more preferably between one week and one or more years. Alternatively, treatment may continue as long as the disease persists.

[0117] The amount of the compound according to the invention or of the pharmaceutical composition according to the invention to be administered must be determined by standard procedures well known to those skilled in the art. To determine the appropriate dosage, the physiological data of the patient (e.g., age, size, and weight) and the route of administration must be taken into account so that a therapeutically effective amount is administered to the patient.

[0118] In a preferred embodiment, the total compound dose for each administration of a compound according to the invention or of a pharmaceutical composition according to the invention is comprised between 0.00001 and 1 g, preferably between 0.01 and 10 mg.

[0119] The form of the pharmaceutical composition, the route of administration and the dosage of the compound according to the present invention or of the pharmaceutical composition according to the present invention can be adjusted by those skilled in the art according to the type and severity of the disease and the patient, in particular their age, weight, sex and general physical condition.

[0120] The present invention is also described in further detail in the following examples, which are not intended to limit the scope of the invention as defined by the appended claims. [Example]

[0121] The following synthetic methods and schemes illustrate general procedures by which the compounds of the present invention can be prepared. Starting materials were obtained from commercial sources or prepared using methods known to those skilled in the art. For example, the compounds of the present invention can be prepared according to or in analogy with the synthetic routes detailed in the Examples section. In particular, compounds of general formula (I) and their pharmaceutically acceptable salts can be synthesized according to the methods described in the following schemes, where X represents a halogen and R represents any group at the corresponding position in general formula (I). Although the numbering of the R groups in the following schemes differs from the group designations in general formula (I), it will be understood that these schemes illustrate the preparation of compounds of formula (I), and therefore, these R groups are defined according to the groups corresponding to the same positions of bonds in general formula (I). Purification of intermediates and final products was carried out via normal or reverse phase chromatography using a Dionex Ultimate 300 with the following parameters: flow rate of 0.5 mL / min, column temperature: 30°C, solvent system: A (MeOH) and B (0.05% TFA in HO), t=0 to 1 min: 50 to 60% B, then t=1 min to t=10 min: 60 to 100% B and t=10 min to t=15 min: 100% B.

[0122] A. Preparation of Compounds According to the Invention General synthetic methods and examples derived from pyridazin-3(2H)-ones The preparation of compounds of formula (I) can be carried out using conventional methods and along various synthetic routes (see Scheme 1). 4 or 5-halogenopyridazinones of general formula A, which are commercially available or as described above, can be prepared by the following methods: 1、2Starting from (I), Suzuki-Miyaura cross-coupling reaction with arylboronic acids in the presence of tetrakis(triphenylphosphine)palladium afforded the corresponding 4- or 5-arylpyridazinone derivatives (intermediate B). N-Alkylation of intermediate B with an appropriate tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (or azepane-1-carboxylate) derivative of general formula C in an inert solvent such as 2-butanone or DMF afforded intermediate D. The base used can be sodium hydride or alkaline sodium bicarbonate. Deprotection of the protected BOC group and subsequent reductive amination with an appropriate aldehyde in the presence of NaBHCN afforded examples of the present invention (see Examples A.1, A.2, and A.5). Direct alkylation of the deprotected piperidine intermediate with an appropriate halogenoalkyl derivative can be carried out by methods well known in the art, as illustrated in Scheme 1 (Example A.3). Alkylation could also be carried out with bromomethyl ketone derivatives, and the resulting ketones were finally converted to secondary alcohols by treatment with sodium borohydride (Example A.4). All final compounds were isolated as hydrochloride salts, prepared by standard methods from the corresponding bases. 1 X = 4-Cl, Chin. E., Li. J., Lui. AS-T.; Talamas, FX, WO2010133528; X =4-Br, Aciro. C. et al., WO2010131147 2 X= 5-Cl, Lizos. D., Weiler. S., Stiefl. NJ, WO2009013335; X= 5-I, Becknell, NC et al., Bioorg. Med. Chem., 2012, 20(12), 3880~3886.

[0123] Scheme 1: General synthetic method for the preparation of 2-substituted-N-substituted-piperidin-4-yl-4 or (5)-phenylpyridazin-3(2H)-ones.

[0124] [ka]

[0125] Conditions: a) K2CO3, Pd(PPh3)4, Ar-PhB(OH)2, toluene, EtOH, HO, 120°C, 16 hours; b) n=0, K2CO3, 2-butanone, 85°C, 24 hours; c) n=1, NaH, DMF, 110°C, 18 hours; d) TFA, DCM, 25°C, 45 minutes; e) R3-CHO, NaBH3CN; DIEA, MeOH, 25°C, 18 hours; f) K2CO3, DMF or MeCN, 80°C, 18 hours; g) MeOH, NaBH4, 25°C, 6.5 hours.

[0126] Example A.1 2-(1-benzylpiperidin-4-yl)-4-phenylpyridazin-3(2H)-one hydrochloride (Compound 1). Step 1: tert-Butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate, intermediate C (m'=m=0, n=0). To a stirred solution of tert-butyl 4-hydroxy-1-piperidinecarboxylate (1.28 g, 5.1 mmol) and EtN (1.43 mL, 10.22 mmol) in DCM (35 mL) at room temperature was added dropwise methanesulfonyl chloride (0.44 mL, 5.62 mmol). The reaction mixture was stirred at room temperature for 4 hours and washed successively with 0.1 N aqueous HCl, HO, and brine. The organic layer was dried over NaSO and concentrated in vacuo to afford tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate as a pale orange solid (yield 1.4 g). 1 H NMR (400 MHz, CDCl3) : δ 4.85 - 4.93 (m, 1 H), 3.66 - 3.75 (m, 2 H), 3.25 - 3.35 (m, 2 H), 3.04 (s, 3 H), 1.92 - 2.01 (m, 2 H), 1.77 - 1.86 (m, 2 H), 1.46 (s, 9 H). 13C NMR (101 MHz, CDCl3): δ 154.7, 80.1, 67.8, 40.5, 34.3, 28.5.

[0127] Step 2: tert-Butyl 4-(6-oxo-5-phenylpyridazin-1(6H)-yl)piperidine-1-carboxylate D (m′=m=0, n=0) A 50 ml flask (under oven-dried argon) was charged with 4-phenyl-2,3-dihydropyridazin-3-one (200 mg, 1.16 mmol, 1.0 equiv., preparation see Example A.2), N-Boc-4-(2-((methylsulfonyl)oxy)ethyl)piperidine (487 mg, 1.74 mmol, 1.5 equiv.), and KCO (241.6 mg, 1.74 mmol, 1.5 equiv.). 2-Butanone (10 ml) was added, and the mixture was heated at 85 °C for 48 h (HPLC monitoring: complete conversion). The mixture was quenched with HO (150 ml) and extracted with EtOAc (3 × 40 ml). The combined organic layers were washed with brine (2 × 50 ml), dried over NaSO, filtered, and evaporated to dryness. The resulting residue was purified by silica gel flash chromatography using EtOAc / heptane:1:2 as eluent to afford the title compound as a white solid (260 mg, 63%). 1 H NMR (400 MHz, CDCl3): δ 7.85 (d, 1H, J = 4.0 Hz), 7.76 (m, 2H), 7.42 (m, 3H), 7.24 (d, 1H, J = 4.0 Hz), 5.15 (m, 1H), 4.26 (bs, 2H), 2.88 (m, 2H), 2.00-1.86 (m, 4H), 1.46 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 160.0, 154.9, 139.6, 136.4, 134.3, 129.7, 128.9, 129.6, 127.3, 79.8, 55.7, 43.4, 30.5, 28.7.

[0128] Step 3: 4-phenyl-2-(piperidin-4-yl)pyridazin-3(2H)-one 2,2,2-trifluoroacetate To an ice-cold solution of tert-butyl 4-(6-oxo-5-phenylpyridazin-1(6H)-yl)piperidine-1-carboxylate (260 mg, 0.73 mmol, 1 equiv.) in DCM (5 mL) was added TFA (2 mL), and the resulting mixture was stirred for 1 h. The crude reaction was concentrated in vacuo with azeotropic removal of TFA with heptane. The compound was used in the reductive amination step without further purification. 1 H NMR (400 MHz, DMSO-d6): δ 8.82 (bs, 1H), 8.48 (bs, 1H), 8.08 (d, 1H, J = 4.1 Hz), 7.82 (m, 2H), 7.59 (d, 1H, J = 4.1 Hz), 7.47 (m, 3H), 5.20 (m, 1H), 3.43 (d, 2H, J = 12.1 Hz), 3.16 (q, 2H, J = 11.2 Hz), 2.15-1.99 (m, 4H). 13 C-NMR (101 MHz, DMSO-d6): δ 158.7, 137.9, 137.0, 133.9, 129.3, 128.6, 128.2, 128.0, 51.9, 42.6, 27.0.

[0129] Step 4: 2-(1-benzylpiperidin-4-yl)-4-phenylpyridazin-3(2H)-one (Compound 1). 4-Phenyl-2-(piperidin-4-yl)pyridazin-3(2H)-one trifluoroacetate (94 mg, 0.368 mmol) was dissolved in MeOH (5 mL). Benzaldehyde (58.6 mg, 56 μL, 1.5 equiv.) was added, followed by NaBHCN (46.3 mg, 0.74 mmol, 2 equiv.). The resulting mixture was stirred at 25 °C for 48 h. The volatiles were evaporated, and the crude was dissolved in EtOAc (25 mL). The organic phase was washed with brine, dried, and concentrated in vacuo. The residue was purified by silica gel column chromatography using DCM:MeOH (99:1) as the eluent to afford 2-(1-benzylpiperidin-4-yl)-4-phenylpyridazin-3(2H)-one 1 as a colorless oil (94 mg, 74%). The hydrochloride salt yields a white powder. 1 H NMR (400 MHz, CDCl3): δ 7.85 (d, 1H, J = 4.1 Hz), 7.78-7.75 (m, 2H), 7.45-7.39 (m, 3H), 7.37-7.30 (m, 4H), 7.25 (m, 1H), 7.23 (d, 1H, J = 4.1 Hz), 5.04 (m, 1H), 3.55 (s, 2H), 3.02 (m, 2H), 2.23-2.08 (m, 4H), 1.89-1.86 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ 160.1, 139.3, 138.9, 136.2, 134.5, 129.6, 129.2, 128.9, 128.5, 128.4, 127.2, 127.1, 63.1, 56.1, 53.1, 30.7. LC / MS (M+H) = 346.

[0130] *2-(1-benzylpiperidin-4-yl)-5-phenylpyridazin-3(2H)-one hydrochloride (Compound 2) Using the same procedure as described in Example A.1, 5-phenylpyridazin-3(2H)-one 3Starting from (250 mg, 1.45 mmol, 1 equiv.) and N-Boc-4-(2-((methylsulfonyl)oxy)ethyl)piperidine (279.4 mg, 1.5 equiv.), tert-butyl 4-(6-oxo-4-phenylpyridazin-1(6H)-yl)piperidine-1-carboxylate was obtained in 63% yield after purification on silica gel with EtOAc / Hept 1 / 1. 1 H NMR (200 MHz, CDCl3): δ 8.10 (d, 1H, J= 2.3 Hz), 7.60-7.51 (m, 5H), 7.06 (d, 1H, J= 2.3 Hz), 5.15 (m, 1H), 3.91-3.79 (m, 2H), 3.36-3.23 (m, 2H), 2.17-2.05 (m, 2H), 1.89-1.49 (m, 2H), 1.49 (s, 9H).

[0131] After deprotection of the tert-butoxycarbonyl group with a suitable acid such as trifluoroacetic acid and reductive amination with benzaldehyde, the title compound was obtained as a colorless oil in 88% yield. The hydrochloride salt yields a white powder. 1 H NMR (400 MHz, DMSO-d6): δ 10.60 (bs, 1H), 8.46 (d, 1H, J = 2.4 Hz), 7.85-7.83 (m, 2H), 7.63-7.60 (m, 2H), 7.54-7.51 (m, 3H), 7.49-7.47 (m, 3H), 7.24 (d, 1H, J = 2.4 Hz), 5.07 (m, 1H), 4.31 (d, 2H, J = 5.2 Hz), 3.47-3.44 (m, 2H), 3.25-3.17 (m, 2H), 2.35-2.26 (m, 2H), 2.03-2.00 (m, 2H). 13 C-NMR (101 MHz, DMSO-d6): δ 159.1, 142.2, 135.9, 133.1, 131.4, 130.3, 129.7, 129.5, 129.2, 128.8, 127.2, 123.4, 59.0, 51.4, 50.4, 27.0. LC / MS (M+H) = 346. 3 Tetrahedron, 2004, 60(52), 12177~12189.

[0132] *4-Phenyl-2-[1-(2-phenylethyl)piperidin-4-yl]-2,3-dihydropyridazin-3-one hydrochloride (Compound 3). Using the same procedure as described in Example A.1, starting from 4-phenyl-2-(piperidin-4-yl)pyridazin-3(2H)-one 2,2,2-trifluoroacetate (50 mg, 0.13 mmol, 1 eq.) and phenylacetaldehyde (24.4 mg, 23.7 μl, 0.203 mmol, 1.5 eq.), the title compound was obtained as a white solid (40 mg, 75%). The hydrochloride salt yields a white powder. 1 H NMR (400 MHz, CDCl3): δ 7.80 (d, 1H, J = 4.1 Hz), 7.72-7.70 (m, 2H), 7.39-7.33 (m, 3H), 7.24-7.11 (m, 6H), 4.97 (m, 1H), 3.09 (d, 2H, J= 11.0 Hz), 2.79-2.75 (m, 2H), 2.60-2.56 (m, 2H), 2.22-2.04 (m, 4H), 1.88-1.85 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ 160.2, 140.6, 139.3, 136.2, 134.5, 129.6, 129.0, 128.9, 128.6, 128.5, 127.3, 126.2, 60.6, 56.1, 53.1, 34.1, 30.6. LC / MS (M+H) = 360.

[0133] *2-[1-(cyclopropylmethyl)piperidin-4-yl]-4-phenyl-2,3-dihydropyridazin-3-one hydrochloride (compound 4). Using the same procedure as described in Example A.1, starting from 4-phenyl-2-(piperidin-4-yl)pyridazin-3(2H)-one 2,2,2-trifluoroacetate (50 mg, 0.13 mmol, 1 eq.) and cyclopropylcarboxaldehyde (14.23 mg, 15.17 μl, 0.203 mmol, 1.5 eq.), the title compound was obtained as a colorless oil (30 mg, 64%). The hydrochloride salt yields a white powder. 1 H NMR (400 MHz, CDCl3): δ 7.83 (d, 1H, J = 4.1 Hz), 7.75-7.73 (m, 2H), 7.39-7.35 (m, 3H), 7.21 (d, 1H, J= 4.1 Hz), 4.98 (m, 1H), 3.19 (m, 2H), 2.28 (d, 2H, J= 6.4 Hz), 2.20-2.08 (m, 4H), 1.89-1.87 (m, 2H), 0.87 (septet, 1H, J= 6.4 Hz), 0.52-0.48 (m, 2H), 0.11-0.08 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ 160.1, 139.2, 136.2, 134.4, 129.5, 128.9, 128.5, 127.2, 63.7, 56.0, 30.4, 8.7, 4.1. LC / MS (M+H) = 310.

[0134] *2-[1-(cyclopentylmethyl)piperidin-4-yl]-4-phenyl-2,3-dihydropyridazin-3-one hydrochloride (Compound 5). Using the same procedure as described in Example A.1, starting from 4-phenyl-2-(piperidin-4-yl)pyridazin-3(2H)-one 2,2,2-trifluoroacetate (50 mg, 0.13 mmol, 1 eq.) and cyclopentanecarbaldehyde (20.5 mg, 22.4 μl, 0.203 mmol, 1.5 eq.), the title compound was obtained as a colorless oil (38 mg, 75%). The hydrochloride salt yields a white powder. 1H NMR (400 MHz, CDCl3): δ 7.84 (d,1H, J = 4.1 Hz), 7.75-7.73 (m, 2H), 7.40-7.35 (m, 3H), 7.22 (d, 1H, J= 4.1 Hz), 4.99 (m, 1H), 3.05 (m, 2H), 2.30 (d, 2H, J = 7.2 Hz), 2.17-2.01 (m, 4H), 1.87-1.84 (m, 2H), 1.78-1.74 (m, 2H), 1.62-1.29 (m, 5H), 1.22-1.16 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ 160.1, 139.3, 136.2, 134.4, 129.5, 128.9, 128.5, 127.2, 64.5, 56.1, 53.3, 37.7, 31.7, 30.4, 25.4. LC / MS (M+H) = 338.

[0135] *2-(1-benzylazepan-4-yl)-4-phenyl-2,3-dihydropyridazin-3-one hydrochloride (compound 6), (m'=m=1, n=0). Using the same procedure as described in Example A.1, 4-phenyl-2,3-dihydropyridazin-3-one (45 mg, 0.26 mmol, 1 equiv.) and tert-butyl 4-(methanesulfonyloxy)azepane-1-carboxylate were prepared. 4 Starting from (92.01 mg, 0.31 mmol, 1.2 equiv.), tert-butyl 4-(6-oxo-5-phenyl-1,6-dihydropyridazin-1-yl)azepane-1-carboxylate was obtained in 49% yield. After deprotection of the tert-butoxycarbonyl group using TFA, the resulting trifluoroacetate was subjected to reductive amination using NaBHCN in the presence of benzaldehyde to afford the title compound as a white solid (28.2 mg, 64% yield). 1H NMR (400 MHz, CDCl3): δ 7.70 (d, 1H, J = 4.0 Hz), 7.66-7.59 (m, 2H), 7.32-7.25 (m, 3H), 7.24-7.20 (m, 2H), 7.19-7.14 (m, 2H), 7.11-7.05 (m, 2H), 5.27-5.16 (m, 1H), 3.51 (s, 2H), 2.76-2.64 (m, 1H), 2.59-2.52 (m, 3H), 2.06-1.95 (m, 2H), 1.93-1.85 (m, 2H), 1.80-1.69 (m, 1H), 1.67-1.64 (m, 1H). 13 C NMR (101 MHz, CDCl3): δ ppm 159.5, 139.7, 139.2, 136.0, 134.3, 129.3, 128.8, 128.3, 128.2, 126.9, 126.8, 62.8, 58.2, 55.7, 52.0, 33.7, 32.6, 25.6. LC / MS (M+H) = 360. 4 ACS Medicinal Chemistry Letters, 2016, 7(4), 397~402.

[0136] Example A.2 Preparation of 2-((1-phenethylpiperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride (compound 10) Step 1: Tert-butyl 4-[((methylsulfonyl)oxy)methyl]piperidine-1-carboxylate (Intermediate C, n=1, m=0, m′=1) To an ice-cold solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (5 g, 23.2 mmol, 1 equiv.) and NEt (3.52 g, 4.86 mL, 34.85 mmol, 1.5 equiv.) in DCM (75 mL), mesyl chloride (3.99 g, 2.70 mL, 34.84 mmol, 1.2 equiv.) was added dropwise, and the resulting solution was stirred at room temperature until complete conversion of the starting material. The reaction conversion was monitored by TLC and HPLC and was usually complete within 3 h. The volatiles were evaporated in vacuo, and the crude material was dissolved in EtOAc (100 mL). The organic phase was washed once with 1N KCO (60 mL), water (60 mL), brine (60 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The resulting oil was dissolved in a mixture of ice-cold EtO (15 mL) and pentane (10 mL) and sonicated for 2-3 minutes. The resulting solid was collected by suction filtration on a Buchner funnel, washed with ice-cold pentane (2 × 5 mL), and dried under vacuum to give the title compound as an off-white solid (4.16 g, 61%). The filtrate was evaporated to approximately half its volume to collect additional material (2.0 g, overall yield: 90%). 1 H NMR (400MHZ, CDCl3): δ ppm 4.16-4.12 (m, 2H), 4.06 (d, 2H, J = 6.4 Hz), 3.00 (s, 3H), 2.67 (t, 2H, J = 11.6 Hz), 1.92-1.88 (m, 1H), 1.73 (d, 2H, J = 11.6 Hz), 1.44 (s, 9H), 1.26-1.15 (m, 2H). 13 C NMR (101 MHZ, CDCl3): δ ppm 154.8, 79.7, 73.5, 37.5, 36.1, 28.6, 28.4.

[0137] Step 2: 4-Phenyl-2,3-dihydropyridazin-3-one (Intermediate B) A microwave vial (under oven-dried argon) was charged with phenylboronic acid (2.05 g, 16.85 mmol, 1.1 equiv.), 4-chloro-2,3-dihydropyridazin-3-one (2.0 g, 15.32 mmol, 1.0 equiv.), and sodium carbonate (4.88 g, 45.9 mmol, 3 equiv.). Tetrakis(triphenylphosphine)palladium(0) (885 mg, 5 mol%) was then added, followed by toluene (38 mL), EtOH (8 mL), and HO (8 mL). The vial was properly capped, and the mixing vessel was evacuated and refilled with argon (the process was repeated three times) and heated at 120 °C until complete conversion of the starting material. The reaction conversion was monitored by HPLC and was usually complete within 16 h. After cooling to room temperature, the reaction mixture was evaporated to dryness. The crude material was partitioned between EtOAc (30 mL) and HO (50 mL). The aqueous phase was extracted twice with EtOAc (20 mL). The organic phases were combined, washed with brine, dried over Na2SO4, and evaporated. The crude material was flash chromatographed using a gradient of 50 to 70% EtOAc in heptane to give the title compound as a yellow solid (2.34 g, 13.6 mmol, 89%). Melting point: 217-220 °C. 1 H NMR (400MHz, DMSO-d6): δ ppm 13.20 (bs, 1H), 7.94 (d, 1H, J = 4.0 Hz), 7.86 (m, 2H), 7.58 (d, 1H, J = 4.0 Hz), 7.51-7.42 (m, 3H). 13 C NMR (101 MHz, DMSO-d6): δ ppm 160.9, 138.7, 137.8,134.2, 129.8, 129.2, 128.9, 128.7

[0138] Step 3: tert-butyl 4-((6-oxo-5-phenylpyridazin-1(6H)-yl)methyl)piperidine-1-carboxylate The reaction was carried out under an argon atmosphere under anhydrous conditions. To an ice-cold solution of 4-phenyl-2,3-dihydropyridazin-3-one (450 mg, 2.61 mmol, 1 equiv.) in dry DMF (26.1 mL), sodium hydride (209.1 mg, 5.23 mmol, 2 equiv.) was added in small portions, and the mixture was stirred at 0 °C for 30 min. Then, tert-butyl 4-[(methanesulfonyloxy)methyl]piperidine-1-carboxylate (920.1 mg, 3.14 mmol, 1.2 equiv.) was added in small portions, and the mixture was heated at 110 °C overnight (HPLC monitoring: complete conversion). The mixture was quenched with HO (150 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over NaSO, filtered, and evaporated to dryness. The resulting residue was purified by silica gel flash chromatography using a gradient of 10 to 50% EtOAc in heptane to afford the title compound as a white solid (835.6 mg, 2.26 mmol, 87%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.84-7.78 (m, 3H), 7.45-7.43 (m, 3H), 7.29 (d, 1H, J = 4.0 Hz), 4.15-4.13 (m, 4H), 2.69 (t, 2 H, J = 12.4 Hz), 2.21-2.19 (m, 1H), 1.65 (d, 2H, J = 12.4 Hz), 1.45 (s, 9H), 1.32-1.24 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ ppm 160.3, 154.8, 139.8, 136.1, 133.9, 129.6, 128.7, 128.4, 127.4, 79.3, 60.5, 57.7, 35.4, 29.7, 28.4

[0139] Step 4: 2-((1-phenethylpiperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one (Compound 10) To a solution of tert-butyl-4-[(6-oxo-5-phenyl-1,6-dihydropyridazin-1-yl)methyl]piperidine-1-carboxylate (110 mg, 0.3 mmol, 1 equiv.) in DCM (5 mL) at 0° C., TFA (0.45 mL) was added, and the resulting mixture was stirred at room temperature for 1 h. The crude reaction was concentrated in vacuo with azeotropic removal of TFA with heptane. The residue was triturated with ice-cold ether, the supernatant was removed, and the evaporated crude was directly dissolved in MeOH (5 mL). 4-Phenyl-2-(piperidin-4-ylmethyl)pyridazin-3(2H)-one 2,2,2-trifluoroacetate (150 mg, 0.30 mmol, 1 equiv.) and phenylacetaldehyde (43.5 mg, 42.3 μL, 0.36 mmol, 1.2 equiv.) were added, followed by DIEA (156 mg, 1.20 mmol, 0.20 mL) and NaBHCN (37.9 mg, 0.6 mmol, 2 equiv.). The resulting mixture was stirred at room temperature for 48 hours. The volatiles were evaporated, and the crude material was dissolved in EtOAc (25 mL). The organic phase was washed with brine, dried, and concentrated in vacuo. The residue was purified by silica gel column chromatography using DCM:MeOH (98:2) as the eluent to afford 2-((1-phenethylpiperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one as a colorless viscous gum (79.2 mg, 64%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.84-7.77 (m, 3H), 7.48-7.40 (m, 3H), 7.30-7.26 (m, 3H), 7.21-7.16 (m, 3H), 4.17 (d, 2H, J = 6.8 Hz), 3.01(d, 2H, J = 12.8 Hz), 2.81(m, 2H), 2.59 (m, 2H), 2.07-2.01 (m, 3H), 1.72 (d, 2H, J = 12.8 Hz), 1.49 (q, 2H, J = 12.8 Hz). 13C NMR (101 MHz, CDCl3): δ ppm 160.4, 140.5, 139.9, 136.1, 134.1, 129.7, 128.9, 128.8, 128.5, 127.5, 126.1, 60.9, 58.0, 53.4, 35.3, 33.8, 30.0.

[0140] Hydrochloride salt formation 60 mg of the above compound was dissolved in a minimum amount of methanol, and the solution was treated with excess 2N HCl in EtO. After stirring for 15 minutes, the resulting mixture was concentrated in vacuo, coevaporated twice with EtO, and then triturated with ice-cold pentane. The supernatant was removed, and the residue was dried in vacuo to afford (79.2 mg of the title compound as a white solid). LC / MS (M+H) = 374.

[0141] *2-((1-benzylpiperidin-4-yl)methyl)-6-methyl-4-phenylpyridazin-3(2H)-one (Compound 7). Using the same procedure as described in Example A.2, 6-methyl-4-phenyl-2,3-dihydropyridazin-3-one 5 Starting from (30 mg, 0.161 mmol, 1 eq.) and tert-butyl 4-[(methylsulfonyl)oxy)methyl]piperidine-1-carboxylate (53.62 mg, 1.2 eq.), after purification on silica gel AcOEt / Hept 1 / 3, tert-butyl 4-[(3-methyl-6-oxo-5-phenyl-1,6-dihydropyridazin-1-yl)methyl]piperidine-1-carboxylate was obtained in 82% yield. 1H NMR (400 MHz, CDCl3): δ 7.77-7.72 (m, 2H), 7.42-7.35 (m, 3H), 7.16 (s, 1H), 4.12-3.99 (m, 4H), 2.82 (t, 2H, J = 11.6 Hz), 2.33 (s, 3H), 2.20-2.08 (m, 1H), 1.61 (d, 2H, J = 12.3 Hz), 1.41 (s, 9H), 1.25 (qd, 2H, J = 12.4 Hz, J = 5.2 Hz). 13 C NMR (101 MHz, CDCl3): δ 159.6, 154.9, 144.3, 139.6, 134.2, 129.7, 129.6, 128.9, 128.5, 79.5, 57.5, 44.0, 43.83, 35.6, 29.9, 28.6, 21.2.

[0142] Deprotection of the tert-butyloxycarbonyl group with TFA, followed by reductive amination using benzaldehyde and NaBH3CN as described for Example A.2, afforded the title compound as a colorless oil (33.4 mg, 62%). The hydrochloride salt yields a white powder. 1 H NMR (400 MHz, MeOD): δ 7.76-7.71 (m, 2H), 7.47-7.39 (m, 4H), 7.48-7.45 (m, 3H), 7.34-7.31 (m, 4H), 7.30-7.20 (m, 1H), 4.08 (d, 2H, J= 7.2 Hz), 3.57 (s, 2H), 3.31 (qt, 1H, J = 1.7 Hz), 2.94 (dt, 2H, J= 11.8, J = 3.4 Hz), 2.36 (s, 3H), 2.09 (td, 2H, J = 11.5 Hz, J = 2.0 Hz), 2.04-1.94 (m, 1H), 1.66 (d, 2H, J= 12.3 Hz), 1.43 (qd, J = 12.6 Hz, J = 4.0 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ 161.0, 1435, 138.7, 135.6, 134.2, 130.4, 129.6, 129.3, 128.3, 127.1, 127.0, 124.8, 63.5, 57.1, 53.4, 35.5, 30.1. LC / MS (M+H) = 374.22 5a Chin. J. Org. Chem., 2014, 34, 722~728; 5b Pest Manag Sci., 2006, 62, 522~530.

[0143] *2-((1-benzylpiperidin-4-yl)methyl)-5-phenylpyridazin-3(2H)-one hydrochloride (Compound 8). Using the same procedure as described in Example A.2, starting from 5-phenylpyridazin-3(2H)-one (25 mg, 0.145 mmol, 1 eq.) and tert-butyl 4-[(methylsulfonyl)oxy)methyl]piperidine-1-carboxylate (51.12 mg, 1.2 eq.), tert-butyl 4-(6-oxo-4-phenylpyridazin-1(6H)-yl)piperidine-1-carboxylate was obtained in 72% yield after purification on silica gel AcOEt / Hept 1 / 3. 1 H NMR (400 MHz, CDCl3): δ 8.01 (d, 1H, J = 2.2 Hz), 7.55-7.53 (m, 2H), 7.46-7.44 (m, 3H), 7.01 (d, 1H, J = 2.2 Hz), 4.06-4.04 (m, 4H), 2.66 (t, 2H, J = 11.7 Hz), 2.13 (m, 1H), 1.62-1.59 (m, 2H), 1.41 (s, 9H), 1.26-1.23 (m, 2H).

[0144] Deprotection of the tert-butyloxycarbonyl group with TFA, followed by reductive amination using benzaldehyde and NaBH3CN as described for Example A.2, afforded the title compound as a colorless oil (16 mg, 39%). The hydrochloride salt yields a white powder. 1 H NMR (400 MHz, CDCl3): δ 7.99 (d, 1H, J= 2.2 Hz), 7.55-7.53 (m, 2H), 7.48-7.45 (m, 3H), 7.31-7.21 (m, 5H), 7.03 (d, 1H, J= 2.2 Hz), 4.09 (d, 2H, J= 7.0 Hz), 3.47 (s, 2H), 2.87 (t, 2H, J= 11.7 Hz), 2.03-1.92 (m, 3H), 1.63 (d, 2H, J= 12.8 Hz), 1.48-1.38 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ 161.0, 1435, 138.7, 135.6, 134.2, 130.4, 129.6, 129.3, 128.3, 127.1, 127.0, 124.8, 63.5, 57.1, 53.4, 35.5, 30.1. LC / MS (M+H) = 360.

[0145] *2-[(1-benzylpiperidin-3-yl)methyl]-4-phenyl-2,3-dihydropyridazin-3-one hydrochloride (Compound 9) Using the same procedure as described in Example A.2, starting from 4-phenyl-2,3-dihydropyridazin-3-one (45 mg, 0.26 mmol, 1 equiv.) and tert-butyl 3-[(methanesulfonyloxy)methyl]piperidine-1-carboxylate (92.01 mg, 0.31 mmol, 1.2 equiv.), tert-butyl 3-[(6-oxo-5-phenyl-1,6-dihydropyridazin-1-yl)methyl]piperidine-1-carboxylate was obtained as a colorless oil (63.3 mg, 66%). 1H NMR (400 MHz, CDCl3): δ ppm 7.70-7.50 (m, 3H), 7.32-7.21 (m, 3H), 7.11 (d, 1H, 4.0Hz), 4.13-3.83 (m, 2H), 3.73 (d, 2H, J = 13.3 Hz), 2.67 (t, 1H, J = 12.7 Hz), 2.67-2.48 (m, 1H), 2.10-1.97 (m, 1H), 1.71-1.47 (m, 2H), 1.35-1.27 (m, 1H), 1.25 (s, 9H), 1.14-1.02 (m, 1H) 13 C NMR (101 MHz, CDCl3): δ ppm 160.2, 154.7, 139.7, 136.1, 133.9, 129.5, 128.7, 128.4, 127.4, 79.3, 55.08, 42.1, 35.5, 28.4, 28.1, 24.4

[0146] TFA-assisted deprotection of the tert-butyloxycarbonyl group, followed by reductive amination using benzaldehyde and NaBH3CN as described for Example A.2, afforded the title compound as a white solid (29.7 mg, 47%). Tr (HPLC) = 7.06 min. 1 H NMR (400 MHz, CDCl3) : δ ppm 7.78-7.70 (m, 3H), 7.45-7.36 (m, 3H), 7.30- 7.15 (m, 6H), 4.19 (dd, 1H, J = 12.9 Hz, 7.2 Hz), 4.07 (dd, 1H, J = 12.9 Hz, J = 7.2 Hz), 3.50 (d, 1H, J = 12.9 Hz), 3.39 (d, 1H, J = 12.9 Hz), 2.66 (d, 1H, J = 10.8 Hz), 2.31 (d, 1H, J = 10.8 Hz), 2.36-2.25 (m, 1H), 2.05-1.92 (m, 2H), 1.67 (d, 2H, J = 10.2 Hz), 1.58-1.45 (m, 1H), 1.18-1.08 (m, 1H). 13C NMR (101 MHz, CDCl3): δ ppm 160.2, 139.6, 138.7 135.9, 134.1, 129.5, 129.0, 128.7, 128.3, 128.1, 127.3, 126.8, 63.5, 57.9, 55.7, 53.9, 35.9, 28.3, 24.6. LC / MS (M+H) = 360.

[0147] 4-Phenyl-2-((1-propylpiperidin-4-yl)methyl)pyridazin-3(2H)-one hydrochloride (Compound 11) Using the same procedure as described in Example A.2, starting from 4-phenyl-2-(piperidin-4-ylmethyl)pyridazin-3(2H)-one 2,2,2-trifluoroacetate (178.6 mg, 0.39 mmol, 1 equiv.) and propanal (27.3 mg, 34.2 μl, 0.46 mmol, 1.2 equiv.), the title compound was obtained as a white solid (115.8 mg, 85%). 1 H NMR (400 MHz, CDCl3) : δ ppm 7.83-7.76 (m, 3H), 7.46-7.39 (m, 3H), 7.27 (d, 1H, J = 4.0 Hz), 4.15 (d, 2H, J = 6.8 Hz), 2.96 (d, 2H, J = 11.6 Hz), 2.31 (t, 2H, J = 8.0 Hz), 2.09-2.01 (m, 1H), 1.96 (t, 2H, J = 11.6Hz), 1.72-1.66 (m, 2H), 1.57-1.42 (m, 4H), 0.88 (t, 3H, J = 7.6Hz). 13 C NMR (101 MHz, CDCl3): δ ppm 160.3, 139.7, 136.0, 134.0, 129.5, 128.7, 128.4, 127.4, 60.8, 57.8, 53.1, 35.1, 29.7, 18.9, 11.7. LC / MS (M+H) = 312.

[0148] *2-((1-(4-chlorobenzyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride (Compound 12) Using the same procedure as described in Example A.2, starting from 4-phenyl-2-(piperidin-4-ylmethyl)pyridazin-3(2H)-one 2,2,2-trifluoroacetate (150 mg, 0.30 mmol, 1 equiv.) and 4-chlorobenzaldehyde (50.9 mg, 0.36 mmol, 1.2 equiv.), the title compound was obtained as a pale yellow solid (36.7 mg, 28%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.82-7.76 (m, 3H), 7.46-7.39 (m, 3H), 7.28-7.21 (m, 5H), 4.15 (d, 2H, J = 6.8 Hz), 3.44 (s, 2H), 2.84 (d, 2H, J = 11.2 Hz), 2.09-2.01 (m, 1H), 1.96 (t, 2H, J = 11.2 Hz), 1.65 (d, 2H J= 12.8 Hz), 1.50-1.37 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ ppm 160.4, 139.8, 137.2, 136.1, 134.1, 132.7, 130.5, 129.7, 128.8, 128.5, 128.4, 127.4, 62.6, 58.0, 53.3, 35.2, 30.0. LC / MS (M+H) = 394.

[0149] *2-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride (Compound 13) Using the same procedure as described in Example A.2, starting from 4-phenyl-2-(piperidin-4-ylmethyl)pyridazin-3(2H)-one 2,2,2-trifluoroacetate (178.6 mg, 0.39 mmol, 1 equiv.) and cyclohexanecarboxaldehyde (52.9 mg, 0.36 mmol, 1.2 equiv.), the title compound was obtained in 60% yield. 1H NMR (400 MHz, CDCl3): δ ppm 7.82-7.76 (m, 3H), 7.46-7.38 (m, 3H), 7.26 (d, 1H, J = 4.0 Hz), 4.13 (d, 2H, J = 6.8 Hz), 2.83 (d, 2H, J = 10.8 Hz), 2.08 (d, 2H, J = 6.8 Hz), 2.03-2.00 (m, 1H), 1.86 (t, 2H, J = 11.6 Hz), 1.78-1.60 (m, 7H), 1.50-1.38 (m, 3H), 1.25-1.11 (m, 3H), 0.91-0.77 (m, 2H). 13 CNMR (101 MHz, CDCl3): δ ppm 160.4, 139.8, 136.0, 134.2, 129.6, 128.8, 126.5, 127.4, 66.1, 58.1, 54.0, 35.4, 32.2, 30.0, 26.9, 26.3. LC / MS (M+H) = 366.

[0150] 4-Phenyl-2-((1-(pyridin-4-ylmethyl)piperidin-4-yl)methyl)pyridazin-3(2H)-one hydrochloride (Compound 14) Using the same procedure as described in Example A.2, starting from 4-phenyl-2-(piperidin-4-ylmethyl)pyridazin-3(2H)-one 2,2,2-trifluoroacetate (150 mg, 0.30 mmol, 1 equiv.) and 4-pyridine-carboxaldehyde (38.8 mg, 34.1 μl, 0.36 mmol, 1.2 equiv.), the title compound was obtained as a beige solid (11.4 mg, 10%). 1H NMR (400 MHz, CDCl3) : δ ppm 8.55-8.49 (m, 2H), 7.83-7.77 (m, 3H), 7.46-7.40 (m, 3H), 7.30-7.23 (m, 3H). 4.16 (d, 2H, J = 6.8 Hz), 3.47 (s, 2H), 2.83 (d, 2H, J = 11.2 Hz). 2.00 (t, 2H, J = 11.6 Hz), 1.91-1.76 (m, 1H), 1.66 (d, 2H, J = 12.0 Hz), 1.51-1.45 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ ppm 154.9, 149.8, 148.2, 139.8, 136.1, 134.1, 129.7, 128.9, 128.5, 127.5, 123.9. 62.1, 57.9, 53.5, 35.1, 30.0. LC / MS (M+H) = 362

[0151] 4-Phenyl-2-((1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)methyl)pyridazin-3(2H)-one dihydrochloride (Compound 15) Using the same procedure as described in Example A.2, starting from 4-phenyl-2-(piperidin-4-ylmethyl)pyridazin-3(2H)-one 2,2,2-trifluoroacetate (178.6 mg, 0.30 mmol, 1 equiv.) and oxane-4-carbaldehyde (53.7 mg, 48.8 μl, 0.47 mmol, 1.2 equiv.), the title compound was obtained in 76% yield (118.7 mg). 1H NMR (400 MHz, DMSO-d6): δ ppm10.1 (s, wide, 1H), 8.00 (d, 1H, J = 4.0 Hz), 7.86-7.80 (m, 2H), 7.60 (d, 1H, J = 4.0 Hz), 7.49-7.42 (m, 3H), 4.06 (d, 2H, J = 6.8 Hz), 3.83 (d, 2H, J = 10.8 Hz), 3.48-3.43 (m, 4H), 3.28 (t, 2H, J = 11.6 Hz), 2.89-2.84 (m, 4H), 2.22-2.11 (m, 1H), 2.09-2.00 (m, 1H), 1.82-1.70 (m, 4H), 1.23-1.19 (m, 2H). 13 C NMR (101 MHz, DMSO-d6): δ ppm 158.8, 137.4, 136.2, 133.3, 128.8, 128.0, 127.7, 127.6, 65.7, 60.9, 55.2, 51.4, 32.2, 30.1, 29.0, 25.7. LC / MS (M+H) = 368.

[0152] *2-{[1-(1H-imidazol-5-ylmethyl)piperidin-4-yl]methyl}-4-phenyl-2,3-dihydropyridazin-3-one dihydrochloride (Compound 16). Using the same procedure as described in Example A.2, starting from 4-phenyl-2-(piperidin-4-ylmethyl)pyridazin-3(2H)-one 2,2,2-trifluoroacetate (250 mg, 0.59 mmol, 1 equiv.) and 4-1H-imidazole-5-carbaldehyde (67.7 mg, 0.70 mmol, 1.2 equiv.), the title compound was obtained as a white solid (20.9 mg, 8%). 1H NMR (400 MHz, CDCl3): δ ppm 7.65 (d, 1H, J = 4.1Hz), 7.63-7.58 (m, 2H), 7.37 (s, 1H), 7.31-7.23 (m, 3H), 7.11 (d, 1H, J = 4.1Hz), 6.71 (s, 1H), 3.98 (d, 2H, J = 6.9 Hz), 3.34 (s, 2H), 2.74 (dt, 2H, J = 11.7 Hz, J = 3.7 Hz), 1.83 (dt, 2H, J = 11.7 Hz, J = 1.7 Hz), 1.57 (d, 2H, J =12.9 Hz), 1.25 (dq, 2H, J = 12.0, J = 3.2Hz), 1.12-1.07 (m, 1H). 13 C NMR (101 MHz, CDCl3): δ ppm 160.3, 139.7, 136.1, 135.1133.9, 129.6, 128.7, 128.4, 127.5, 57.7, 54.1, 53.0, 35.1, 29.8. LC / MS (M+H) = 350.

[0153] *4-Phenyl-2-((1-((tetrahydro-2H-pyran-3-yl)methyl)piperidin-4-yl)methyl)pyridazin-3(2H)-one hydrochloride (Compound 17). Using the same procedure as described in Example A.2, starting from 4-phenyl-2-(piperidin-4-ylmethyl)pyridazin-3(2H)-one 2,2,2-trifluoroacetate (125 mg, 0.32 mmol, 1 equiv.) and oxane-3-carbaldehyde (55.8 mg, 0.49 mmol, 1.2 equiv.), the title compound was obtained in 58% yield (69 mg). 1H NMR (400 MHz, CDCl3): δ ppm 7.81 (d, 1H, J = 4.2 Hz), 7.80-7.77 (m, 2H), 7.46-7.40 (m, 3H), 7.28 (d, 1H, J = 4.2 Hz), 4.13 (d, 2H, J = 7.2 Hz), 3.93 (ddd, 1H, J =10.6 Hz, J = 5.3 Hz, J = 2.6 Hz), 3.85 (dt, 1H, J = 12.5 Hz, J = 4.1 Hz), 3.40-3.33 (m, 1H), 3.08 (dd, 1H, J = 8.4 Hz, J = 12.2 Hz), 2.92-2.85 (m, 1H), 2.82-2.74 (m, 1H), 2.15-1.95 (m, 3H), 1.94-1.77 (m, 4H), 1.671.55 (m, 4H), 1.48-1.34 (m, 2H), 1.20-1.11 (m, 1H). 13 CNMR (101 MHz, CDCl3): δ ppm 160.3, 139.7, 135.9, 134.0, 129.5, 128.7, 128.4, 127.3, 72.5, 68.6, 61.4, 58.0, 54.2, 53.5, 35.2, 33.6, 2930.0, 29.9, 28.6, 25.6. LC / MS (M+H) = 368.

[0154] *2-((1-(4-hydroxybenzyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride (compound 18). Using the same procedure as described in Example A.2, starting from 4-phenyl-2-(piperidin-4-ylmethyl)pyridazin-3(2H)-one 2,2,2-trifluoroacetate (131 mg, 0.34 mmol, 1 equiv.) and para-hydroxy-benzaldehyde (62.6 mg, 0.51 mmol, 1.5 equiv.), the title compound was obtained in 51% yield (66 mg). 11H NMR (400 MHz, CDCl3): δ ppm 7.80 (d, 1H, J = 4.2 Hz), 7.79 - 7.75 (m, 2H), 7.46 - 7.38 (m, 3H), 7.27 (d, 1H, J = 4.2 Hz), 7.08 (d, 2H, J = 8.6 Hz), 6.64 (d, 1H, J = 8.6 Hz), 4.14 (d, 2H, J = 7.2 Hz), 3.46 (s, 2H), 2.97 (dt, 2H, J = 11.5 Hz, J = 5.1 Hz), 2.12 - 1.97 (m, 3H), 1.72 - 1.63 (m, 2H), 1.5 (qd, 2H, J = 11.5 Hz, J = 5.1 Hz). 13 13C NMR (101 MHz, CDCl3): δ ppm 160.3, 155.8, 155.7, 139.7, 136.0, 133.9, 130.9, 129.6, 128.7, 128.4, 127.5, 115.4, 62.4, 57.8, 52.7, 34.8, 29.2. LC / MS (M + H) = 376.

[0155] (Example A.3) 2 - ((1 - (2 - methoxyethyl)piperidin - 4 - yl)methyl)-4 - phenylpyridazin - 3(2H)-one hydrochloride (Compound 19). To a solution of tert-butyl-4-[(6-oxo-5-phenyl-1,6-dihydropyridazin-1-yl)methyl]piperidine-1-carboxylate (100 mg, 0.27 mmol, 1 equiv.) in DCM (1.5 mL) at 0 °C, TFA (0.41 mL) was added, and the resulting mixture was stirred at room temperature for 1 h. The crude reaction was concentrated in vacuo with azeotropic removal of TFA with heptane. The residue was triturated with ice-cold ether, the supernatant was removed, and the evaporated crude was directly dissolved in DMF (1.0 mL). 1-Bromo-2-methoxyethane (44.8 mg, 30.7 μL, 1.2 equiv.) was added, followed by KCO (148.5 mg, 1.07 mmol, 4 equiv.). The resulting mixture was refluxed for 18 h. The volatiles were evaporated, and the crude was dissolved in EtOAc (25 mL). The organic phase was washed with brine, dried and concentrated in vacuo, and the residue was purified by silica gel column chromatography using EtOAc / MeOH / NH4OH 95 / 5 / 0.5 as the eluent to afford, after salification with 2M HCl in Et2O, the title compound as an off-white solid (67%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.80 (d, 1H, J = 4.0 Hz), 7.79- 775 (m, 2H), 7.45-7.39 (m, 3H), 7.26 (d, 1H, J= 4.0 Hz), 4.13 (d, 2H, J= 6.8 Hz), 3.47 (t, 2H, J = 5.6 Hz), 3.33 (s, 3H), 2.97-2.91 (m, 2H), 2.54 (t, 2H, J = 5.6 Hz), 2.07-1.95 (m, 3H), 1.68-1.65 (m, 2H), 1.53-1.43 (m, 2H). LC / MS (M+H) = 328.

[0156] *2-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride (Compound 20). Using the same procedure as described in Example A.3, starting from 4-phenyl-2-(piperidin-4-ylmethyl)pyridazin-3(2H)-one 2,2,2-trifluoroacetate (178.6 mg, 0.39 mmol, 1 equiv.) and 2-chloroethanol (37.8 mg, 31.5 μl, 0.47 mmol, 1.2 equiv.), the title compound was obtained in 79% yield. 1 H NMR (400 MHz, DMSO-d6): δ 10.30 (bs, 1H), 8.01 (d, 1H, J= 4.3 Hz), 7.84-7.82 (m, 2H), 7.60 (d, 1H, J= 4.3 Hz), 7.47-7.44 (m, 3H), 5.33 (t, 1H, J= 5.0 Hz), 4.05 (d, 2H, J= 6.9 Hz), 3.76 (q, 2H, J= 5.0 Hz), 3.29-3.23 (m, 2H), 3.07 (q, 2H, J= 5.0 Hz), 2.97-2.88 (m, 2H), 2.19-2.12 (m, 1H), 1.76-1.65 (m, 4H). 13 LC / MS (M+H) = 314.

[0157] *2-((1-(2-Methoxy-1-phenylethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride (Compound 21) Using the same procedure as described in Example A.3, 4-phenyl-2-(piperidin-4-ylmethyl)pyridazin-3(2H)-one 2,2,2-trifluoroacetate (160 mg, 0.42 mmol, 1 equiv.) and 1-bromo-2-methoxyethyl)benzene 5 Starting from (107.7 mg, 0.50 mmol, 1.2 eq), the title compound was obtained in 28% yield. 1H NMR (400 MHz, CDCl3) : δ ppm 7.81-7.74 (m, 3H), 7.47-7.37 (m, 3H), 7.33-7.21 (m, 6H), 3.813.71 (m, 1H), 3.67-3.62 (m, 1H), 3.59-3.52 (m, 1H), 3.30 (s, 3H), 3.09-2.99 (m, 1H), 2.85-2.74 (m, 1H), 2.12-2.05 (m, 1H)1.98-1.87 (m, 2H), 1.72-1.33 (m, 4H). 13 C NMR (101 MHz, CDCl3): δ ppm 160.2, 139.7, 135.9, 134.0, 129.5, 128.7, 128.4, 128.3, 128.0, 127.3, 74.1, 69.2, 58.7, 57.9, 51.1, 50.3, 35.7, 30.0. LC / MS (M+H) = 314. 5 Neuss JC, Orchard MG; Scopes, DIC, WO2003070239

[0158] *N-(2-{4-[(6-oxo-5-phenyl-1,6-dihydropyridazin-1-yl)methyl]piperidin-1-yl}ethyl)acetamide hydrochloride (compound 22). Using the same procedure as described in Example A.3, starting from 4-phenyl-2-(piperidin-4-ylmethyl)pyridazin-3(2H)-one 2,2,2-trifluoroacetate (60 mg, 0.16 mmol, 1 equiv.) and N-(2-chloroethyl)acetamide (19 mg, 0.16 mmol, 1.0 equiv.), the title compound was obtained in 34% yield (19 mg). 1H NMR (400 MHz, CDCl3): δ ppm 7.79 (d, 1H, J = 4.0 Hz), 7.77-7.74 (m, 2H), 7.42-7.39 (m, 3H), 7.26 (d, 1H, J = 4.0 Hz), 6.44 (bs, 1H), 4.13 (d, 2H, J = 7.2 Hz), 3.34 (dd, 2H, J = 10.6 Hz, J = 5.9 Hz), 2.95 (d, 2H, J = 11.4 Hz), 2.53 (t, 2H, J = 5.8 Hz), 2.09 (m, 3H), 1.95 (s, 3H), 1.7 (d, 2H, J = 11.8 Hz), 1.52-1.44 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ ppm 170.4, 160.3, 139.7, 136.2, 133.8, 129.6, 128.7, 128.4, 127.5, 57.4, 56.7, 53.0, 35.8, 34.7, 29.9, 23.2. LC / MS (M+H) = 355.

[0159] Example A.4 2-((1-(2-(4-Fluorophenyl)-2-hydroxyethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride (compound 23). Step 1: 2-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride (compound 24). To a solution of 4-phenyl-2-(piperidin-4-ylmethyl)pyridazin-3(2H)-one 2,2,2-trifluoroacetate (350 mg, 0.82 mmol, 1 equiv.) in MeCN (6.3 mL) was added 2-chloro-4'-fluoroacetophenone (170 mg, 0.99 mmol, 1.2 equiv.) followed by K2CO3 (454.2 mg, 3.29 mmol, 4 equiv.). The resulting mixture was refluxed for 17 h. The volatiles were evaporated and the crude product was dissolved in EtOAc (25 mL). The organic phase was washed with brine, dried, and concentrated in vacuo. The residue was purified by reverse-phase chromatography using MeOH / HO+0.05% TFA. The resulting product was dissolved in EtOAc and washed with a saturated solution of NaHCO3. After evaporation, the resulting oil (170 mg) was dissolved in a minimum amount of methanol, and the solution was treated with excess 2N HCl in EtO. After stirring for 15 minutes, the resulting mixture was concentrated in vacuo, coevaporated twice with EtO, and then triturated with ice-cold pentane. The supernatant was removed, and the residue was dried in vacuo to afford the title compound in 53% yield. 1 H NMR (400 MHz, CDCl3): δ ppm 7.89 (dd, 2H, J = 8.9 Hz, J = 5.3 Hz), 7.84 (d, 1H, J = 4.2 Hz), 7.75-7.69 (m, 2H), 7.46-7.36 (m, 3H), 7.30 (d, 1H, J = 4.2 Hz), 7.13 (t, 2H, J = 8.5 Hz), 4.62 (s, 2H), 4.32-4.15 (m, 2H), 3.79-3.65 (m, 2H), 3.23-3.06 (m, 2H), 2.45-2.30 (m, 1H), 2.01-1.87 (m, 4H). 13 C NMR (101 MHz, CDCl3): δ ppm 195.4, 167.0, 164.5, 160.3, 139.7, 136.0, 133.9, 132.5, 131.1, 130.9, 129.5, 128.7, 128.4, 127.4, 115.6, 115.4, 65.1, 57.8, 53.6, 34.7, 29.7. 19F NMR (376 MHz, CDCl3): δ ppm -104.9. LC / MS (M+H) = 406.

[0160] Step 2: 2-((1-(2-(4-fluorophenyl)-2-hydroxyethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride (compound 23). To a solution of 2-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one (112 mg, 0.28 mmol, 1 equiv.) in MeOH (3 mL) was added NaBH (21.1 mg, 0.55 mmol, 2 equiv.), and the resulting mixture was stirred for 6.5 h. Then, HO (0.8 mL) was added, and the volatiles were evaporated. The crude was purified by reverse-phase chromatography using MeOH / HO+0.05% TFA. The resulting product was dissolved in EtOAc and washed with a saturated solution of NaHCO. After evaporation, the resulting oil was dissolved in a minimum of methanol, and the solution was treated with excess 2 N HCl in EtO. After stirring for 15 min, the resulting mixture was concentrated in vacuo, coevaporated twice with EtO, and then triturated with ice-cold pentane. The supernatant was removed and the residue was dried under vacuum to afford the title compound as a white solid (36 mg, 32%). 1H NMR (400 MHz, CDCl3): δ ppm 7.66 (d, 1H, J = 4.0 Hz), 7.63 (dd, J = 7.2 Hz, J = 2.3 Hz), 4.51 (dd, 1H, J = 10.8 Hz, J = 3.2 Hz), 4.0 (d, 2H, J = 7.1 Hz), 2.97 (d, 1H, J = 12.0 Hz), 2.64 (d, 1H , J = 11.6 Hz), 2.30 (dd, 1H, J = 12.3 Hz, J = 3.6 Hz), 2.23 (d, 1H, J = 10.6 Hz), 2.14 (dt 1H, J = 11.3 Hz, J = 2.8 Hz), 1.99-1.81(m, 2H), 1.61-1.48 (m, 2H), 1.39-1.23 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ ppm 163.4, 160.9, 160.3, 139.7, 138.0, 137.9, 136.0, 133.9, 129.6, 128.7, 128.4, 128.3, 127.5, 127.4, 127.3, 115.2, 115.0, 67.9, 66.3, 57.8, 54.8, 51.6, 34.9, 30.1, 29.8 . 19 F NMR (376 MHz, CDCl3): δ ppm -115.5. LC / MS (M+H) = 408

[0161] *2-((1-(2-hydroxy-2-phenylethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride (Compound 25). Using the same procedure as described in Example A.4, starting from 4-phenyl-2-(piperidin-4-ylmethyl)pyridazin-3(2H)-one 2,2,2-trifluoroacetate and 2-chloro-1-phenylethan-1-one, the title compound was isolated in 35% yield after a carbonyl group reduction step with NaBH4. 1H NMR (400 MHz, CDCl3): δ ppm 7.73 (d, 1H, J = 4.0 Hz), 7.72-7.68 (m, 2H), 7.39-7.31 (m, 3H), 7.29-7.12 (m, 6H), 4.69 (dd, 1H, J = 10.9 Hz, J = 3.5 Hz), 4.08 (d, 2H, J = 8.2 Hz), 3.02 (d, 1H, J = 11.7 Hz), 2.72 (d, 1H, J = 11.3 Hz), 2.41 (dd, 1H, J = 12.4 Hz, J = 4.5 Hz), 2.35 (q, 1H, J = 11.9 Hz), 2.21 (dt, 1H, J = 11.7 Hz, J = 2.8 Hz), 2.06-1.89 (m, 2H), 1.68-1.57 (m, 2H), 1.47-1.30 (m, 2H). 13 CNMR (101 MHz, CDCl3): δ ppm 160.3, 142.3, 139.7, 136.0, 133.9, 129.6, 128.7, 128.4, 128.3, 127.4, 127.3, 125.8, 68.8, 66.4, 57.8, 54.8, 51.6, 35.0, 30.2, 29.9. LC / MS (M+H) = 390.

[0162] Example A.5 2-(2-(1-benzylpiperidin-4-yl)ethyl)-4-phenylpyridazin-3(2H)-one hydrochloride (compound 26). Step 1: tert-butyl 4-(2-((chlorosulfonyl)oxy)ethyl)piperidine-1-carboxylate Under nitrogen at room temperature, mesyl chloride (0.52 mL, 2 equiv.) was added dropwise to a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (840 mg, 3.7 mmol, 1.0 equiv.) and triethylamine (1.0 mL, 2 equiv.) in anhydrous DCM (20 mL). The solution was stirred for 4 hours and quenched with 20 mL of 1 M HCl. The aqueous phase was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with brine (20 mL), dried over Na SO , filtered, and then concentrated in vacuo. The residual oil was crystallized from heptane (40 mL) to give the title compound (1.05 g, 93%). 1 H NMR (400 MHz, CDCl3): δ ppm 4.30 (t, 2H, J =6.4 Hz), 3.04 (s, 3H), 2.71 (t, 2H, J = 12.5 Hz), 1.75-1.60 (m, 7H), 1.47 (s, 9H), 1.21-1.15 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ ppm 154.8, 79.4, 77.4, 67.4, 37.5, 35.6, 32.4, 31.7, 28.5.

[0163] Step 2: tert-butyl 4-(2-(6-oxo-4-phenylpyridazin-1(6H)-yl)ethyl)piperidine-1-carboxylate A 50 mL flask (under oven-dried argon) was charged with 4-phenyl-2,3-dihydropyridazin-3-one (200 mg, 1.16 mmol, 1.0 equiv.), tert-butyl 4-(2-((chlorosulfonyl)oxy)ethyl)piperidine-1-carboxylate (357.2 mg, 1.16 mmol, 1.0 equiv.), and K2CO3 (160.6 mg, 1.16 mmol, 1.0 equiv.). 2-Butanone (10 mL) was added, and the mixture was heated at 85 °C for 16 h (HPLC monitoring: complete conversion). The mixture was quenched with HO (150 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, filtered, and evaporated to dryness. The resulting residue was purified by silica gel flash chromatography using EtOAc / heptane:1:2 as eluent to afford the title compound as a white solid (357 mg, 80%). 1 H NMR (200 MHz, CDCl3): δ ppm 7.87 (d, 1H, J = 4.1 Hz), 7.83-7.80 (m, 2H), 7.49-7.46 (m, 3H), 7.32 (d, 1H, J = 4.1 Hz), 4.32 (t, 2H, J = 7.4 Hz), 4.15-4.08 (m, 2H), 2.73 (td, 2H, J =13.0 Hz, 2.4 Hz), 1.88-1.75 (m, 4H), 1.52-1.49 (m, 1H), 1.49 (s, 9H), 1.32-1.17 (m, 2H).

[0164] Step 3: 2-(2-(1-benzylpiperidin-4-yl)ethyl)-4-phenylpyridazin-3(2H)-one (compound 26). To a solution of tert-butyl 4-(2-(6-oxo-5-phenylpyridazin-1(6H)-yl)ethyl)piperidine-1-carboxylate (357 mg, 0.93 mmol, 1 equiv.) in DCM (5 mL) at 0° C. was added TFA (2 mL), and the resulting mixture was stirred at room temperature for 1 h. The crude reaction was concentrated in vacuo with azeotropic removal of TFA with heptane. The crude was quenched with saturated aqueous NaHCO (10 mL) and extracted twice with EtOAc (2×8 mL). The combined organic layers were washed with brine (2×50 mL), dried over NaSO, filtered, and evaporated to dryness to give 4-phenyl-2-(2-(piperidin-4-yl)ethyl)pyridazin-3(2H)-one as a viscous oil (252 mg, 96%). The compound was used in the reductive amination step without further purification. 1 H NMR (200 MHz, CDCl3): δ ppm 7.86 (d, 1H, J = 4.1 Hz), 7.84-7.80 (m, 2H), 7.50-7.43 (m, 3H), 7.32 (d, 1H, J = 4.1 Hz), 4.32 (t, 2H, J = 7.4 Hz), 3.53 (s, 1H), 3.22-3.14 (m, 2H), 2.67 (td, 2H, J =13.0 Hz, 2.4 Hz), 1.99-1.79 (m, 4H), 1.52-1.49 (m, 1H), 1.41-1.26 (m, 2H).

[0165] 4-Phenyl-2-(2-(piperidin-4-yl)ethyl)pyridazin-3(2H)-one (118 mg, 0.41 mmol) was dissolved in MeOH (5 mL). Benzaldehyde (66.2 mg, 63.2 μL, 1.5 equiv.) was added, followed by NaBHCN (52.3 mg, 0.83 mmol, 2 equiv.) and AcOH. The resulting mixture was stirred at room temperature for 48 h. The volatiles were evaporated, and the crude was dissolved in EtOAc (25 mL). The organic phase was washed with brine, dried, and concentrated in vacuo. The residue was purified by silica gel column chromatography using DCM:MeOH (95:5) as the eluent to afford 2-(2-(1-benzylpiperidin-4-yl)ethyl)-4-phenylpyridazin-3(2H)-one as a colorless oil (112 mg, 72%). The hydrochloride salt yields a white powder. 1 H NMR (400 MHz, DMSO-d6): δ ppm 10.06 (bs, 1H), 8.00 (d, 1H, J = 4.2 Hz), 7.84-7.81 (m, 2H), 7.59 (d, 1H, J = 4.2 Hz), 7.57-7.54 (m, 2H), 7.47-7.37 (m, 6H), 4.24 (d, 2H, J = 5.2 Hz), 4.18 (t, 2H, J = 7.1 Hz), 3.32-3.30 (m, 2H), 2.87 (q, 2H, J = 10.6 Hz), 1.94-1.86 (m, 3H), 1.69 (q, 2H, J = 6.6 Hz), 1.53-1.43 (m, 2H). 13 C NMR (101 MHz, DMSO-d6): δ ppm 159.1, 137.9, 136.9, 133.9, 131.4, 129.7, 129.5, 129.3, 128.7, 128.6, 128.3, 128.2, 59.1, 51.4, 48.8, 33.9, 30.6, 28.5. LC / MS (M+H) = 374.

[0166] *2-(2-(1-benzylpiperidin-4-yl)ethyl)-5-phenylpyridazin-3(2H)-one hydrochloride (Compound 27). Using the same procedure as described in Example A.3, starting from 5-phenylpyridazin-3(2H)-one (100 mg, 0.58 mmol) and N-Boc-4-(2-((methylsulfonyl)oxy)ethyl)piperidine (178.5 mg, 0.58 mmol, 1 equiv.), after purification on silica gel using EtOAc / heptane 1 / 2 as the eluent, tert-butyl 4-(2-(6-oxo-5-phenylpyridazin-1(6H)-yl)ethyl)piperidine-1-carboxylate was obtained (206 mg, 93%). 1 H NMR (400 MHz, CDCl3): δ ppm 8.01 (d, 1H, J = 2.0 Hz), 7.54-7.52 (m, 2H), 7.46-7.45 (m, 3H), 7.00 (d, 1H, J = 2.0 Hz), 4.20 (t, 2H, J = 7.3 Hz), 4.04 (bs, 2H), 2.64 (t, 2H, J =13.0 Hz), 1.78-1.70 (m, 4H), 1.47-1.41 (m, 1H), 1.41 (s, 9H), 1.18-1.11 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ ppm 160.6, 155.0, 143.6, 135.8, 134.1, 130.4, 129.5, 127.0, 124.7, 79.4, 49.3, 35.1, 33.7, 32.1, 28.7, 28.6.

[0167] Deprotection of the tert-butoxycarbonyl group with TFA, followed by reductive amination using benzaldehyde and NaBH3CN, afforded the title compound in 75% yield. The hydrochloride salt yields a white powder. 1H NMR (400 MHz, CDCl3): δ ppm 8.00 (d, 1H, J = 2.1 Hz), 7.54-7.52 (m, 2H), 7.46-7.45 (m, 3H), 7.27-7.26 (m, 4H), 7.22-7.19 (m, 1H), 7.00 (d, 1H, J = 2.1 Hz), 4.19 (t, 2H, J = 7.5 Hz), 3.45 (s, 2H), 2.84 (d, 2H, J =10.8 Hz), 1.91 (t, 2H, J =10.8 Hz), 1.77-1.70 (m, 4H), 1.34-1.28 (m, 3H). 13 C NMR (101 MHz, CDCl3): δ ppm 160.7, 143.5, 138.7, 135.8, 134.2, 130.4, 129.6, 129.4, 128.3, 127.1, 127.0, 124.8, 63.7, 53.9, 49.6, 35.2, 33.6, 32.4. LC / MS (M+H) = 374.

[0168] Piperidine substitution The present invention also provides a process for the preparation of compounds of general formula (I) bearing small substituents R' (fluoro, methyl or hydroxyl) or R'' (C1-C5-alkyl, C3-C7 cycloalkyl) on the C-4 carbon of the piperidine. An illustrative general synthetic method is set out below by describing an exemplary synthesis of a specific compound of the invention, as illustrated in Scheme 2.

[0169] [ka]

[0170] Conditions: a) n=0, K2CO3, 2-butanone, 85°C, 24 hours; b) n=1, NaH, DMF, 110°C, 18 hours; c) TFA, DCM, 25°C, 45 minutes; d) R3CHO, NaBH3CN; DIEA, MeOH, 25°C, 18 hours or R3-CH2Br, K2CO3, DMF or MeCN, 80°C, 18 hours.

[0171] Example A.6 2-(1-(1-benzylpiperidin-4-yl)ethyl)-4-phenylpyridazin-3(2H)-one hydrochloride (compound 28). Using the same procedure as described in Example A.2, 4-phenyl-2,3-dihydropyridazin-3-one (200 mg, 1.16 mmol, 1.0 equiv.) and tert-butyl 4-(1-((methylsulfonyl)oxy)ethyl)piperidine-1-carboxylate were prepared. 6 Starting from (357.1 mg, 1.16 mmol, 1.0 equiv), tert-butyl 4-(1-(6-oxo-5-phenylpyridazin-1(6H)-yl)ethyl)piperidine-1-carboxylate was obtained as an off-white solid (145 mg, 33%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.87 (d, 1H, J = 4.0Hz), 7.79-7.75 (m, 2H), 7.49-7.38 (m, 3H), 7.24(d 1H, J= 4.0 Hz), 5.15-5.06 (m, 1H), 4.23-3.91 (m, 2H), 2.80-2.53 (m, 2H), 2.04-1.92 (m, 1H), 1.85-1.61(m, 2H), 1.42 (s, 9H), 1.39 (d, 3H, J = 6.6 Hz), 1.36-1.16 (m, 2H).

[0172] After TFA-assisted BOC deprotection, the resulting trifluoroacetate salt was subjected to reductive amination with benzaldehyde using NaBH3CN to afford the title compound (44 mg, 35%). 1H NMR (400 MHz, CDCl3): δ ppm 7.86 (d, 1H, J = 4.0 Hz), 7.80-7.75 (m, 2H), 7.47-7.39 (m, 3H), 7.32-7.20 (m, 6H), 5.17-5.08 (m, 1H), 3.74 (t, 2H, J = 6.1 Hz), 3.46 (s, 2H), 2.93 (d, 1H, J = 11.2 Hz), 2.82 (d, 1H, J = 11.2 Hz), 1.99 (t, 1H, J = 11.3 Hz), 1.91-1.75 (m, 2H), 1.52-1.31 (m, 2H), 1.38 (d, 3H, J = 6.8 Hz). 13 C NMR (101 MHz, CDCl3): δ ppm 160.4, 139.4, 138.5, 136.1, 134.4, 129.5, 129.2, 128.8, 128.4, 128.2, 127.0, 126.9, 68.1, 63.2, 57.8, 53.5, 40.5, 28.04, 25.7, 17.1. LC / MS (M+H) = 374. 6 ACS Medicinal Chemistry letters, 4 (11), 1064~1068, 2013.

[0173] *2-((1-benzyl-4-hydroxypiperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride (compound 29). Using the same procedure as described in Example A.6, 4-phenyl-2,3-dihydropyridazin-3-one (200 mg, 1.16 mmol, 1.0 equiv.) and freshly prepared tert-butyl 4-hydroxy-4-((tosyloxy)methyl)piperidine-1-carboxylate (1.0 equiv. from tert-butyl 4-hydroxy-4-(hydroxymethyl)piperidine-1-carboxylate) were added. 7Starting from tert-butyl 4-hydroxy-4-((6-oxo-5-phenylpyridazin-1(6H)-yl)methyl)piperidine-1-carboxylate was obtained in 75% yield. 1 H NMR (400 MHz, CDCl3): δ ppm 7.87 (d, 1H, J = 4.0 Hz), 7.77-7.73 (m, 2H), 7.46-7.42 (m, 3H), 7.33-7.29 (m, 5H), 4.37 (s, 2H), 3.75-3.72 (m, 3H), 3.63-3.58 (m, 2H), 2.72-2.69 (m, 2H), 2.55 (t, 2H, J = 11.0 Hz), 1.81-1.77 (m, 2H), 13 C NMR (101 MHz, CDCl3) : δ ppm 162.2, 140.4, 136.9, 133.5, 129.8, 129.4, 128.7, 128.5, 128.4, 128.1, 127.4 , 70.4, 67.7, 62.7, 48.9, 35.4. LC / MS (M+H) = 376 7 Hartman GD, Flores, OA, WO2013096744

[0174] Alternatively, a Suzuki-Miyaura cross-coupling reaction can be carried out later in the sequence, allowing for a more convergent approach for i) the introduction of various aryls at the 4- or 5-position of the pyridazinone ring (Method a) or ii) the functionalization of the piperidine moiety (Method b). Using the same conditions described above, N-alkylation of chloropyridazinone derivative A with the appropriate tert-butyl 4-methylsulfonyloxy-piperidine-1-carboxylate derivative of general formula C gave intermediate E. A derivatization step of E with a suitable reagent, performed by methods well known in the art, led to intermediate F, which was finally involved in a Suzuki-Miyaura reaction to give an example of the present invention (Example A.9). A Suzuki-Miyaura reaction can also be carried out to give the previously described intermediate D from intermediate E, as illustrated in Scheme 3 (Examples A.7-8).

[0175] [ka]

[0176] Conditions: a) K2CO3, 2-butanone, 85 °C, 24 h; b) NaH, DMF, 110 °C, 18 h; c) TFA, DCM, 25 °C, 45 min; d) R3CHO, NaBH3CN; DIEA, MeOH, 25 °C, 18 h, or R3-CH2Br, K2CO3, DMF or MeCN, 80 °C, 18 h. e) K2CO3, Pd(PPh3)4, PhB(OH)2, toluene, EtOH, HO, 120 °C, 16 h.

[0177] Example A.7 2-(1-benzylpiperidin-4-yl)-4-(4-methoxyphenyl)pyridazin-3(2H)-one hydrochloride (compound 30). Step 1: tert-butyl 4-((5-chloro-6-oxopyridazin-1(6H)-yl))piperidine-1-carboxylate The reaction was carried out under an argon atmosphere. To a solution of 4-chloro-2,3-dihydropyridazin-3-one (100 mg, 0.77 mmol, 1.0 equiv.) in butanone (7.0 mL) was added tert-butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (321.0 mg, 1.15 mmol, 1.5 equiv.) and K2CO3. The resulting mixture was heated at 85 °C overnight (HPLC monitoring: complete conversion). The mixture was quenched with H2O (150 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, filtered, and evaporated to dryness. The resulting residue was purified by silica gel flash chromatography using a gradient of 0% to 50% EtOAc in heptane to give the title compound (180 mg, 0.57 mmol, 75%). 1H NMR (400 MHz, CDCl3): δ ppm 7.71 (d, 1H, J = 4.4 Hz), 7.33 (d, 1H, J = 4.4 Hz), 5.21-5.00 (m, 1H), 4.40-4.20 (m, 2H,), 1.90-1.80 (m, 4H), 1.47 (s, 9H).

[0178] Step 2: tert-butyl 4-(5-(4-methoxyphenyl)-6-oxopyridazin-1(6H)-yl)piperidine-1-carboxylate A microwave vial (under oven-dried argon) was charged with 4-methoxyphenylboronic acid (125.9 mg, 0.83 mmol, 1.3 equiv.), tert-butyl 4-(5-chloro-6-oxopyridazin-1(6H)-yl)piperidine-1-carboxylate (200 mg, 0.64 mmol, 1.0 equiv.), and sodium carbonate (135.1 mg, 1.27 mmol, 2 equiv.). Tetrakis(triphenylphosphine)palladium(0) (74.4 mg, 10 mol%) was then added, followed by DME (3.34 mL) and HO (1.1 mL). The vial was properly capped, and the mixing vessel was evacuated and backfilled with argon (the process was repeated three times) and heated at 100 °C until complete conversion of the starting material. The reaction conversion was monitored by HPLC and was usually complete within 16 h. After cooling to room temperature, the reaction mixture was evaporated to dryness. The crude material was partitioned between EtOAc (30 mL) and H2O (50 mL). The aqueous phase was extracted twice with EtOAc (20 mL). The organic phases were combined, washed with brine, dried (Na2SO4), and evaporated. The crude material was flash chromatographed using a gradient of 0 to 40% EtOAc in heptane to give the title compound as a white solid (193 mg, 0.5 mmol, 79%). 1H NMR (400MHz, CDCl3): δ ppm 7.84 (d, 1H, J = 4.0 Hz), 7.81 (d, 2H, J = 8.4 Hz), 7.21 (d, 1H, J = 4.4 Hz), 6.96 (d, 2H, J = 8.4 Hz), 5.18 (m, 1H), 4.28-4.21 (m, 2H), 2.95-2.90 (m, 2H), 2.05-1.90 (m, 4H), 1.44 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ ppm 160.9, 160.1, 154.8, 138.8, 136.4, 130.3, 126,6, 125.9, 113.979.6, 56.5, 43.3, 30.4, 28.6.

[0179] Step 3: 2-(1-benzylpiperidin-4-yl)-4-(4-methoxyphenyl)-2,3-dihydropyridazin-3-one hydrochloride (compound 30). To a solution of tert-butyl 4-(5-(4-methoxyphenyl)-6-oxopyridazin-1(6H)-yl)piperidine-1-carboxylate (180 mg, 0.467 mmol, 1 equiv.) in DCM (2 mL) at 0° C., TFA (2.0 mL) was added, and the resulting mixture was stirred at room temperature for 1 h. The crude reaction was concentrated in vacuo with azeotropic removal of TFA with heptane. The residue was triturated with ice-cold ether, the supernatant was removed, and the evaporated crude was directly dissolved in MeOH (4 mL). Benzaldehyde (74.3 mg, 70.8 μL, 1.5 equiv.) was added, followed by NaBHCN (61.8 mg, 0.9 mmol, 2 equiv.) and AcOH (2.7 μL). The resulting mixture was stirred at room temperature for 16 h. The volatiles were evaporated, and the crude was dissolved in EtOAc (25 mL). The organic phase was washed with brine, dried, and concentrated in vacuo. The residue was purified by silica gel column chromatography using DCM:MeOH (98:2) as the eluent to afford, after salification with 2N HCl in EtO, 2-(1-benzylpiperidin-4-yl)-4-(4-methoxyphenyl)-2,3-dihydropyridazin-3-one hydrochloride as a white solid (78 mg, 41%). Tr (HPLC) = 7.35 min. 1 H NMR (400 MHz, CDCl3): δ ppm 7.76 (d, 1H, J = 4.2 Hz), 7.73(d, 2H, J = 9.0 Hz), 7.36 (d, 2H, J = 6.4 Hz), 7.34(m, 2H), 7.14 (d, 1H, J= 4.2 Hz), 7.24 (t, 2H, J = 7.9 Hz), 7.19-7.15 (m, 1H), 6.88 (d, 2H, J = 9.2 Hz), 5.02-4.93 (m, 1H), 3.83 (s, 3H), 3.54 (s, 2H), 3.04-3.02 (m, 2H), 2.18 (qd, J = 11.5 Hz, J = 1.5 Hz), 2.12 (qd, J = 11.9 Hz, J= 3.6 Hz), 1.89-1.86 (m, 2H). 13 C NMR (101 MHz, CDCl 3,DEPT 135) : δ ppm 136.1, 130.2, 129.1, 128.2, 127.0, 125.8, 113.8, 62.8, 55.7, 55.4, 52.8, 30.4. LC / MS (M+H) = 376.

[0180] *2-(1-benzylpiperidin-4-yl)-4-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazin-3-one hydrochloride (Compound 31). Using the same procedure as described in Example A.7, starting from tert-butyl 4-((5-chloro-6-oxopyridazin-1(6H)-yl))piperidine-1-carboxylate (100 mg, 0.32 mmol, 1 equiv.) and 4-trifluoromethylphenylboronic acid (78.7 mg, 0.41 mmol, 1.3 equiv.), tert-butyl 4-{6-oxo-5-[4-(trifluoromethyl)phenyl]-1,6-dihydropyridazin-1-yl}piperidine-1-carboxylate was obtained as a white solid (65 mg, 48%). 1 H NMR (400 MHz, CDCl3): δ ppm 8.05-7.98 (m, 3H), 7.71 (d, 2H, J = 8.0 Hz), 7.31 (d, 1H, J = 4.0 Hz), 5.22-5.13 (m, 1H), 4.30-4.26 (m, 2H), 2.96-2.88 (m, 2H), 2.02-1.90 (m, 4H), 1.49 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ ppm 159.6, 154.8, 138.1, 137.7,136.2, 129.2, 127.9, 125.5, 125.4, 79.9, 55.9, 43.1, 30.5, 28.6. 19 F NMR (376 MHz, CDCl3): δ ppm - 62.84.

[0181] After deprotection of the tert-butyloxycarbonyl group with TFA, the crude material (74 mg, 0.229 mmol, 1 equiv.) was subjected to reductive amination assisted by benzaldehyde (36.45 mg, 34.7 μL, 0.34 mmol, 1.5 equiv.), NaBHCN (30.3 mg, 0.46 mmol, 2 equiv.) and DIEA (4 equiv.) to afford, after salification, the title compound as a white solid (30 mg, 29%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.95 7.85 (m, 3H), 7.69 (d, 2H, J = 8.0 Hz), 7.40 -7.26 (m, 6H), 5.08-5.00 (m, 1H), 3.57 (s, 2H), 3.10-3.02 (m, 2H), 2.28-3.02 (m, 4H), 1.92-1.87 (m, 2H). 13 C NMR-DEPT-135 (101 MHz, CDCl3): δ ppm 135.9, 129.2, 128.4, 127.8, 127.2, 125.4, 125.4, 62.9, 56.2, 52.9, 30.5. 19 F NMR (376MHz, CDCl3); δ ppm - 62.86. LC / MS (M+H) = 414.

[0182] *2-(1-benzylpiperidin-4-yl)-4-[4-(chlorophenyl]-2,3-dihydropyridazin-3-one hydrochloride (compound 32). Using the same procedure as described in Example A.6, starting from tert-butyl 4-((5-chloro-6-oxopyridazin-1(6H)-yl))piperidine-1-carboxylate (200 mg, 0.64 mmol, 1 equiv.) and 4-chlorophenylboronic acid (99.7 mg, 0.63 mmol, 1.0 equiv.), tert-butyl 4-{6-oxo-5-[4-chlorophenyl]-1,6-dihydropyridazin-1-yl}piperidine-1-carboxylate was obtained as a yellow solid (195 mg, 78%). 1H NMR (400 MHz, CDCl3): δ ppm 7.87 (d, 1H, J = 4.0 Hz) 7.76 (d, 2H, J = 8.0 Hz), 7.42 (d, 2H, J = 8.0 Hz), 7.26 (d, 1H, J = 4.0 Hz), 5.22-5.13 (m, 1H), 4.40-4.20 (m, 2H), 2.98-2.91 (m, 2H), 2.02-1.90 (m, 4H), 1.49 (s, 9H).

[0183] After deprotection of the tert-butyloxycarbonyl group with TFA, the crude material (150 mg, 0.229 mmol, 1 equiv.) was subjected to reductive amination assisted by benzaldehyde (79.6 mg, 75.8 μL, 0.75 mmol, 1.5 equiv.) and NaBHCN (66.1 mg, 1 mmol, 2 equiv.) to afford, after salification with 2 N HCl, the title compound as a white solid (32 mg, 15%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.87 (d, 1H, J = 4.0 Hz), 7.75 (d, 2H, J = 8.0 Hz), 7.40 (d, 2H, J = 8.0 Hz), 7.37-7.23 (m, 6H), 5.05-4.99 (m, 1H), 3.57 (s, 2H), 3.05-3.00 (m, 2H), 2.28-2.10 (m, 4H), 1.90-1.88 (m, 2H). 13 C NMR-DEPT-135 (101 MHz, CDCl3): δ ppm 159.8, 138.7, 137.9, 136.0, 135.6, 132.7, 130.2, 129.2, 128.7, 128.3, 127.1, 127.0, 62.9, 56.1, 52.9, 30.5. LC / MS (M+H) = 380.

[0184] Example A.8 2-[(1-benzylpiperidin-4-yl)methyl]-4-(2-chlorophenyl)-2,3-dihydropyridazin-3-one hydrochloride (compound 33). Step 1: tert-butyl 4-((5-chloro-6-oxopyridazin-1(6H)-yl)methyl)piperidine-1-carboxylate The reaction was carried out under an argon atmosphere under anhydrous conditions. To an ice-cold solution of 4-chloro-2,3-dihydropyridazin-3-one (110 mg, 0.84 mmol, 1 equiv.) in dry DMF (8.42 mL), sodium hydride (67.41 mg, 1.68 mmol, 2 equiv.) was added in small portions, and the mixture was stirred at 0° C. for 30 minutes. Then, tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (296.7 mg, 1.01 mmol, 1.2 equiv.) was added in small portions, and the mixture was heated at 110° C. overnight (HPLC monitoring: complete conversion). The mixture was quenched with HO (150 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (2×50 mL), dried over NaSO, filtered, and evaporated to dryness. The resulting residue was purified by silica gel flash chromatography using a gradient of 10 to 50% EtOAc in heptane to afford the title compound 3 as a white solid (164 mg, 0.50 mmol, 60%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.66 (d, 1H, J = 4.4 Hz), 7.35 (d, 1H, J = 4.4 Hz), 4.11-4.08 (m, 4H), 2.66 (t, 2H, J = 12.4 Hz), 2.16-2.11 (m, 1H), 1.59 (d, 1H, J = 12.4 Hz), 1.44 (s, 9H), 1.29-1.19 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ ppm 157.9, 154.7, 137.2, 134.8, 129.0, 79.4, 58.1, 43.4, 35.3, 29.6, 28.4. Purity (100%), t R (HPLC): 3.71 minutes.

[0185] Step 2: tert-butyl 4-{[5-(2-chlorophenyl)-6-oxo-1,6-dihydropyridazin-1-yl]methyl}piperidine-1-carboxylate A microwave vial (under oven-dried argon) was charged with 2-chlorophenylboronic acid (78.7 mg, 0.50 mmol, 1.1 equiv.), tert-butyl 4-[(5-chloro-6-oxo-1,6-dihydropyridazin-1-yl)methyl]piperidine-1-carboxylate (150 mg, 0.46 mmol, 1.0 equiv.), and sodium carbonate (145.5 mg, 1.37 mmol, 3 equiv.). Tetrakis(triphenylphosphine)palladium(0) (26.4 mg, 5 mol%) was then added, followed by toluene (1.74 mL), HO (0.35 mL), and EtOH (0.35 mL). The vial was properly capped, and the mixing vessel was evacuated and backfilled with argon (a process repeated three times), and heated at 120 °C until complete conversion of the starting material. The reaction conversion was monitored by HPLC and was usually complete within 17 h. After cooling to room temperature, the reaction mixture was evaporated to dryness. The crude material was partitioned between EtOAc (30 mL) and H2O (50 mL). The aqueous phase was extracted twice with EtOAc (20 mL). The organic phases were combined, washed with brine, dried (Na2SO4), and evaporated. The crude material was flash chromatographed using a gradient of 0 to 40% EtOAc in heptane to give the title compound as a yellow oil (138 mg, 0.34 mmol, 75%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.83(d, 1H, J= 4.0 Hz), 7.48 (d, 1H, J = 7.6 Hz), 7.99-7.26 (m, 3H), 7.23 (d, 1H, J = 4.0 Hz), 4.20-4.00 (m, 4H), 2.69 (m, 2H), 2.20-2.16 (m, 1H), 1.66-1.60 (m, 2H), 1.45 (s, 9H), 1.32-1.20 (m, 2H). 13C NMR (101 MHz, CDCl3): δ ppm 160.1, 154.8, 139.3, 135.5, 133.1, 133.0, 130.9, 130.2, 129.9, 126.7, 79.37, 60.4, 57.6, 35.5, 29.7, 28.4.

[0186] Step 3: 2-[(1-benzylpiperidin-4-yl)methyl]-4-(2-chlorophenyl)-2,3-dihydropyridazin-3-one hydrochloride (compound 33). To a solution of tert-butyl 4-{[5-(2-chlorophenyl)-6-oxo-1,6-dihydropyridazin-1-yl]methyl}piperidine-1-carboxylate (123 mg, 0.30 mmol, 1 equiv.) in DCM (0.8 mL) at 0 °C, TFA (0.8 mL) was added, and the resulting mixture was stirred at room temperature for 1 h. The crude reaction was dissolved in water, and ammonium hydroxide was added until pH = 10. The residue was extracted with EtOAc (twice) and dried over Na2SO4. After evaporation, the crude was directly dissolved in MeOH (4 mL). Benzaldehyde (36.5 mg, 34.7 μL, 1.2 equiv.) was added, followed by NaBH3CN (35.9 mg, 0.57 mmol, 2 equiv.). The resulting mixture was stirred at room temperature for 19 h. The volatiles were evaporated, and the crude was dissolved in EtOAc (25 mL). The organic phase was washed with brine, dried, and concentrated in vacuo. The residue was purified by silica gel column chromatography using DCM:MeOH (98:2) as the eluent to afford, after salification with 2N HCl in EtO, 22-[(1-benzylpiperidin-4-yl)methyl]-4-(2-chlorophenyl)-2,3-dihydropyridazin-3-one hydrochloride as a white solid (62.1 mg, 50%). Tr (HPLC) = 7.30 min. 1H NMR (400 MHz, CDCl3): δ ppm 7.79 (d, 1H, J = 4.0 Hz), 7.50-7.17 (m, 10H), 4.10 (d, 2H, J = 7.2 Hz), 3.46 (s, 2H), 2.84 (t, 2H, J = 11.8 Hz), 2.05-1.90 (m, 3H), 1.65-1.60 (m, 2H), 1.47-1.35 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ ppm 159.6, 139.2, 138.4, 135.3, 133.2, 133.0, 131.0, 130.3, 130.1 129.9, 129.1, 128.1, 126.9, 126.7, 63.3, 57.8, 53.2, 35.3, 29.8. LC / MS (M+H) = 394.

[0187] *2-[(1-benzylpiperidin-4-yl)methyl]-4-(4-hydroxyphenyl)-2,3-dihydropyridazin-3-one hydrochloride (Compound 34) Using the same procedure as described in Example A.8, starting from tert-butyl 4-[(5-chloro-6-oxo-1,6-dihydropyridazin-1-yl)methyl]piperidine-1-carboxylate (150 mg, 0.46 mmol, 1 equiv.) and 4-hydroxyphenylboronic acid (88.36 mg, 1.4 equiv.), tert-butyl 4-{[5-(4-hydroxyphenyl)-6-oxo-1,6-dihydropyridazin-1-yl]methyl}piperidine-1-carboxylate was obtained in 77% yield (135 mg). 1H NMR (400 MHz, CDCl3): δ ppm 7.81 (d, 1H, J = 4.0 Hz), 7.67 (d, 2H, J = 8.8 Hz), 7.45-7.30 (bs, 1H), 7.25 (d, 1H, J = 4.0 Hz), 6.86 (d, 2H, J = 1.46 (s, 9H), 1.37-1.23 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ ppm 160.7, 157.9, 154.9, 139.7, 136.6, 130.3, 126.3, 125.4, 115.7, 79.7, 57.7, 43.6, 35.4, 29.7, 28.5.

[0188] After deprotection of the tert-butyloxycarbonyl group with TFA, the crude trifluoroacetate salt (140 mg, 0.35 mmol, 1 equiv.) was subjected to reductive amination assisted by benzaldehyde (55.8 mg, 53.1 μL, 0.52 mmol, 1.5 equiv.), NaBHCN (44.1 mg, 0.7 mmol, 2 equiv.), and DIEA (181.2 mg, 1.40 mmol, 4 equiv.) to afford the title compound in 54% yield (71 mg) after salification with 2 N HCl. 1H NMR (400 MHz, CDCl3): δ ppm 7.74 (d, 1H, J= 4.0 Hz), 7.60 (d, 2H, J = 8.8 Hz), 7.28-7.22 (m, 5H), 7.16 (d, 1H, J = 4.0 Hz), 6.74 (d, 2H, J = 8.8 Hz), 4.11 (d, 2H, J = 6.8 Hz), 3.51 (s, 2H), 2.90 (dt, J = 12.0 Hz, J = 5.2 Hz), 2.01 (td, 3H, J = 11.6 Hz, J = 2.0 Hz), 1.68-1.59 (m, 2H), 1.50 (qd, 2H, J = 12.0 Hz, J = 4.0 Hz). 13 C NMR (101 MHz, CDCl3): δ ppm 160.7, 157.9, 139.5, 137.2, 136.4, 130.3, 129.5, 128.2, 127.3, 126.2, 125.4, 115.7, 16.1, 57.7, 53.1, 35.1, 29.4. LC / MS (M+H) = 376.

[0189] Example A.9 2-((1-benzylpiperidin-4-yl)methyl)-4-(4-fluorophenyl)pyridazin-3(2H)-one hydrochloride (compound 35). Step 1: tert-butyl 4-((5-chloro-6-oxopyridazin-1(6H)-yl)methyl)piperidine-1-carboxylate The reaction was carried out under an argon atmosphere under anhydrous conditions. To an ice-cold solution of 4-chloro-2,3-dihydropyridazin-3-one (110 mg, 0.84 mmol, 1.0 equiv.) in dry DMF (8.42 mL), sodium hydride (67.41 mg, 1.68 mmol, 2.0 equiv.) was added in small portions, and the mixture was stirred at 0° C. for 30 minutes. Then, tert-butyl 4-[(methylsulfonyl)oxy)methyl]piperidine-1-carboxylate (296.7 mg, 1.01 mmol, 1.2 equiv.) was added in small portions, and the mixture was heated at 110° C. overnight (HPLC monitoring: complete conversion). The mixture was quenched with HO (150 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (2×50 mL), dried over NaSO, filtered, and evaporated to dryness. The resulting residue was purified by silica gel flash chromatography using a gradient of 10% to 50% EtOAc in heptane to afford the title compound as a white solid (164 mg, 0.50 mmol, 60%). 1 H NMR (400 MHZ, CDCl3): δ ppm 7.66 (d, 1H, J = 4.4 Hz), 7.35 (d, 1H, J = 4.4 Hz), 4.11-4.08 (m, 4H), 2.66 (t, 2H, J = 12.4 Hz), 2.16-2.11 (m, 1H), 1.59 (d, 1H J = 12.4Hz), 1.44 (s, 9H), 1.29-1.19 (m, 2H); 13 C NMR (101 MHz, CDCl3): δ ppm 157.9, 154.7, 137.2, 134.8, 129.0, 79.4, 58.1, 43.4, 35.3, 29.6, 28.4.Purity (100%), tr (HPLC): 3.71 min.

[0190] Step 2: 2-((1-benzylpiperidin-4-yl)methyl)-4-chloropyridazin-3(2H)-one To a solution of tert-butyl 4-((5-chloro-6-oxopyridazin-1(6H)-yl)methyl)piperidine-1-carboxylate (1 g, 3.05 mmol, 1 equiv.) in DCM (15 mL) at 0° C. was added TFA (4.7 mL), and the resulting mixture was stirred at room temperature for 1 h 30 min. The crude reaction was concentrated in vacuo with azeotropic removal of TFA with heptane. The residue was triturated with ice-cold ether, the supernatant was removed, and the evaporated crude was directly dissolved in MeOH (4 mL). Benzaldehyde (388 mg, 370 μL, 1.2 equiv.) was added, followed by NaBHCN (61.8 mg, 0.9 mmol, 2 equiv.) and DIEA (2.0 mL, 4 equiv.). The resulting mixture was stirred at room temperature for 16 h. The volatiles were evaporated, and the crude was dissolved in EtOAc (25 mL). The organic phase was washed with brine, dried, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 5% to 7% MeOH in EtOAc (98:2) to afford 2-((1-benzylpiperidin-4-yl)methyl)-4-chloropyridazin-3(2H)-one as a yellow viscous gum (516 mg, 53%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.64 (d, 1H, J = 4.4 Hz), 7.33 (d, 1H, J = 4.4 Hz), 7.30-7.22 (m, 5H), 4.10 (d, 2H), 3.5 (s, 2H), 2.90-2.87 (m, 2H), 2.00-1.95 (m, 3H), 1.64-1.56 (m, 2H), 1.49-1.37 (m, 2H). 13 C NMR (101 MHZ, CDCl3): δ ppm 157.9, 138.0, 137,1, 134.7, 129.2, 129.0, 128.2, 127.1, 63.2, 60.4, 58.3, 53.1, 35.0, 29.6.

[0191] Step 3: 2-((1-benzylpiperidin-4-yl)methyl)-4-(4-fluorophenyl)pyridazin-3(2H)-one hydrochloride (compound 35). A microwave vial (under oven-dried argon) was charged with 4-fluorophenylboronic acid (48.4 mg, 0.32 mmol, 1.1 equiv.), 2-((1-benzylpiperidin-4-yl)methyl)-4-chloropyridazin-3(2H)-one (100 mg, 0.31 mmol, 1.0 equiv.), and sodium carbonate (100 mg, 0.94 mmol, 3 equiv.). Tetrakis(triphenylphosphine)palladium(0) (18.2 mg, 5 mol%) was then added, followed by toluene (1.0 mL), EtOH (0.2 mL), and HO (0.2 mL). The vial was properly capped, and the mixing vessel was evacuated and backfilled with argon (the process was repeated three times) and heated at 120 °C until complete conversion of the starting material. The reaction conversion was monitored by HPLC and was usually complete within 16 h. After cooling to room temperature, the reaction mixture was evaporated to dryness. The crude material was partitioned between EtOAc (30 mL) and H2O (50 mL). The aqueous phase was extracted twice with EtOAc (20 mL). The organic phases were combined, washed with brine, dried (Na2SO4), and evaporated. The crude material was purified by flash chromatography using DCM:MeOH (98:2) as the eluent to give, after salification with 2N HCl in Et2O, the title compound as an orange viscous gum (23.9 mg, 18%). 1 H NMR (400 MHz, CDCl3) 1 H NMR (400 MHz, CDCl3): δ ppm 7.80-7.73 (m, 2H), 7.30-7.25 (m, 4 H), 7.23-7.17 (m, 3H), 7.09 (t, 2H, J = 8.6 Hz), 4.11 (d, 2H, J = 7.2 Hz), 3.48 (s, 2H), 2.85 (d, 2H, J = 11.5 Hz), 1.97-1.89 (m, 2H), 1.61 (d, 2H, J= 12.7 Hz), 1.42 (dq, 2H, J = 11.8 Hz, J = 5.5 Hz). 13C NMR (101 MHz, CDCl3): δ ppm 164.8, 160.3, 138.7, 136.6, 136.0, 130.9, 130.8, 129.3, 128.3, 127.2, 127.0, 115.7, 115.4, 63.4, 58.5, 53.3, 35.3, 30.0. LC / MS (M+H) = 378

[0192] Alternatively, starting from the title intermediate of general structure E, a Sonogashira cross-coupling reaction can be carried out (see Scheme 4). The resulting alkyne derivative of general structure F (where R7 is an aryl group, such as phenyl) was hydrogenated using Pd / C as a catalyst. Deprotection of the tert-butyloxycarbonyl group, followed by alkylation or reductive amination of the resulting piperidine derivative, afforded examples of the present invention. The Suzuki-Miyaura cross-coupling reaction assisted by alkylboronic acids can be an alternative approach for introducing alkyl or aralkyl groups at the 4- or 5-position of the pyridazinone moiety. The general conditions used are depicted in Scheme 4.

[0193] [ka]

[0194] Conditions: a) Pd(PPh3)2Cl2, CuI, Et3N, MeCN, 80°C, 24 hours; b) H2, Pd / C, MeOH, 18 hours; c) TFA, DCM, 45 minutes; 25°C; d) R3CHO, DIEA, NaBH3CN, MeOH, 25°C, 18 hours; e) R3-CH2Br, K2CO3, DMF or MeCN, 80°C, 18 hours. f) R7-(CH2)2B(OH)2 (1.5 eq.), K2CO3 (3 eq.), Pd(PPh3)4 (5 mol%), 1,4-dioxane, 100°C, 16 hours.

[0195] Example A.10 2-((1-benzylpiperidin-4-yl)methyl)-4-phenethylpyridazin-3(2H)-one (compound 36). Step 1: tert-butyl 4-((6-oxo-5-(phenylethynyl)pyridazin-1(6H)-yl)methyl)piperidine-1-carboxylate A microwave vial (under oven-dried argon) was charged with ethynylbenzene (40.5 mg, 43 μL, 0.40 mmol, 1.3 equiv.), tert-butyl 4-((5-chloro-6-oxopyridazin-1(6H)-yl)methyl)piperidine-1-carboxylate (100 mg, 0.30 mmol, 1.0 equiv.), and EtN (277.8 mg, 2.75 mmol, 9 equiv.). Bis(triphenylphosphine)palladium(II) chloride (6.42 mg, 3 mol%) and CuI (2.9 mg, 5 mol%) were then added, followed by MeCN (1.5 mL). The vial was properly capped, and the mixing vessel was evacuated and backfilled with argon (a process repeated three times) and heated at 80 °C until complete conversion of the starting material. Reaction conversion was monitored by HPLC and was typically complete within 24 h. After cooling to room temperature, the reaction mixture was evaporated to dryness. The crude material was partitioned between EtOAc (30 mL) and H2O (50 mL). The aqueous phase was extracted twice with EtOAc (20 mL). The organic phases were combined, washed with brine, dried (Na2SO4), and evaporated. The crude material was purified by flash chromatography using a gradient of 20 to 50% EtOAc in heptane to give the title compound as a light brown viscous gum (85 mg, 71%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.73 (d, 1H, J = 4.0 Hz), 7.60-7.56 (m, 2H), 7.40-7.32 (m, 4H), 4.17-3.92 (m, 4H), 2.75-2.60 (m, 2H), 2.19-2.14 (m, 1H), 1.66-1.54 (m,2H), 1.30-1.19 (m, 2H). 13C NMR (101 MHz, CDCl3): δ ppm 159.7, 154.9, 135.6, 132.3,132.0, 129.7, 128.5, 125.7, 125.6, 122.0, 100.8, 83.3, 79.5, 58.1, 57.940.3, 35.4, 29.7, 28.6

[0196] Step 2: tert-butyl 4-((6-oxo-5-phenethylpyridazin-1(6H)-yl)methyl)piperidine-1-carboxylate Pd / C 10% (4.75 mg, 0.05 equiv.) and MeOH (1.5 mL) were placed in a reactor (2 mL capacity) equipped with a magnetic stirrer. tert-Butyl 4-((6-oxo-5-(phenylethynyl)pyridazin-1(6H)-yl)methyl)piperidine-1-carboxylate (85 mg, 0.22 mmol, 1 equiv.) was added, and the microreactor was purged by flushing first with argon and then with hydrogen four times at atmospheric pressure. The resulting mixture was magnetically stirred overnight at room temperature. The catalyst particles were removed from the solution by filtration through Celite, and the volatiles were evaporated to give the title compound as a pale yellow viscous gum (83 mg, 97%). The crude product was used directly without further purification. 1 H NMR (400 MHz, CDCl3): δ ppm 7.60 (d, 1H, 4 Hz), 7.31-7.22 (m, 2H), 7.21-7.16 (m, 3H), 6.86 (d, 1H, 4Hz), 4.19-4.00 (m, 4H), 2.95-2.90 (m, 4H), 2.76-2.62 (m, 1H), 1.65-1.57 (m, 2H), 1.34-1.24 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ ppm 161.5, 154.9, 143.1, 140.8, 135.6, 128.6, 128.5, 127.8, 126.3, 79.5, 57.2, 35.5, 33.5, 32.2, 29.8, 28.6.

[0197] Step 3: 2-((1-benzylpiperidin-4-yl)methyl)-4-phenethylpyridazin-3(2H)-one hydrochloride (compound 36). To a solution of tert-butyl 4-((6-oxo-5-phenethylpyridazin-1(6H)-yl)methyl)piperidine-1-carboxylate (83 mg, 0.21 mmol, 1 equiv.) in DCM (1 mL) at 0° C. was added TFA (0.32 mL), and the resulting mixture was stirred at room temperature for 1 h. The crude reaction was concentrated in vacuo with azeotropic removal of TFA with heptane. The residue was triturated with ice-cold ether, the supernatant was removed, and the evaporated crude was directly dissolved in MeOH (1 mL). Benzaldehyde (26.6 mg, 25 μL, 1.2 equiv.) was added, followed by NaBHCN (26.2 mg, 0.42 mmol, 2 equiv.) and DIEA (145 μL, 4 equiv.). The resulting mixture was stirred at room temperature for 16 h. The volatiles were evaporated, and the crude was dissolved in EtOAc (25 mL). The organic phase was washed with brine, dried, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0% to 2% MeOH in EtOAc to afford, after salification, 2-((1-benzylpiperidin-4-yl)methyl)-4-phenethylpyridazin-3(2H)-one as a colorless foam (36.5 mg, 41%). Tr (HPLC) = 8.11 min; 1 H NMR (400 MHz, CDCl3): δ ppm 7.59 (d, 1H, J= 4.0 Hz), 7.32-7.21 (m, 7H), 7.20-7.14 (m, 3H), 6.85(d, 1H, J= 4.0 Hz), 4.08 (d, 2H, J = 7.2 ). 13 C NMR (101 M H Z, CDCl3): δ ppm 161.5, 143.0, 140.9, 138.3, 135.7, 129.3, 128.6, 128.5, 128.3, 127.8, 127.1, 126.3, 63.4, 57.4, 53.3, 35.3, 33.5, 32.3, 29.9. LC / MS (M+H) = 388.

[0198] Example A.11 2-(1-Benzylpiperidin-4-yl)-4-(2-phenylethyl)-2,3-dihydropyridazin-3-one hydrochloride (compound 37). Step 1: tert-butyl 4-[6-oxo-5-(2-phenylethyl)-1,6-dihydropyridazin-1-yl]piperidine-1-carboxylate A microwave vial (under oven-dried argon) was charged with tert-butyl 4-(5-chloro-6-oxo-1,6-dihydropyridazin-1-yl)piperidine-1-carboxylate (200 mg, 0.64 mmol, 1.0 equiv.), (2-phenylethyl)boronic acid (143.4 mg, 0.96 mmol, 1.5 equiv.), and K2CO3 (264.3 mg, 1.91 mmol, 3 equiv.). Tetrakis(triphenylphosphine)palladium (37.2 mg, 5 mol%) was added, followed by dioxane (2.2 mL). The vial was properly capped, and the mixing vessel was evacuated and refilled with argon (the process was repeated three times) and heated at 100 °C until complete conversion of the starting material. The reaction conversion was monitored by HPLC and was typically complete within 16 h. After cooling to room temperature, the reaction mixture was evaporated to dryness. The crude material was partitioned between EtOAc (30 mL) and H2O (50 mL). The aqueous phase was extracted twice with EtOAc (20 mL). The organic phases were combined, washed with brine, dried (Na2SO4), and evaporated. The crude material was flash chromatographed using a gradient of 0% to 100% EtOAc in heptane to give the title compound as a colorless oil (66 mg, 27%). 1H NMR (400 MHz, CDCl3): δ ppm 7.67 (d, 1H, J = 4.0 Hz), 7.32-7.25 (m, 2H), 7.22-7.17 (m, 3H), 6.88 (d, 1H, J = 4.0 Hz), 5.16-5.05 (m, 1H), 4.38-4.15 (m, 2H), 2.97- 2.88 (m, 6H), 1.96-1.84 (m, 4H), 1.82 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ ppm 161.0, 154.8, 142.6, 141.0, 136.0, 128.6, 127.4, 126.3, 79.8, 55.1, 33.5, 32.4, 30.4, 28.6.

[0199] Step 2: 2-(1-benzylpiperidin-4-yl)-4-(2-phenylethyl)-2,3-dihydropyridazin-3-one hydrochloride (compound 37). To a solution of tert-butyl 4-[6-oxo-5-(2-phenylethyl)-1,6-dihydropyridazin-1-yl]piperidine-1-carboxylate (88 mg, 0.23 mmol, 1 equiv.) in DCM (1 mL) at 0 °C, TFA (0.32 mL) was added, and the resulting mixture was stirred at room temperature for 1 h. The crude reaction was concentrated in vacuo with azeotropic removal of TFA with heptane. The residue was triturated with ice-cold ether, the supernatant was removed, and the evaporated crude was directly dissolved in MeOH (1 mL). Benzaldehyde (36.6 mg, 35 μL, 1.5 equiv.) was added, followed by NaBHCN (30.4 mg, 0.46 mmol, 2 equiv.) and AcOH (1-2 drops). The resulting mixture was stirred at room temperature for 16 h. The volatiles were evaporated, and the crude was dissolved in EtOAc (25 mL). The organic phase was washed with brine, dried, and concentrated in vacuo. The residue was purified by flash chromatography using a gradient of 0% to 5% iPrOH in DCM to afford, after salification with HCl 2N in MeOH, the title compound as a white solid (52 mg, 55%). Tr (HPLC) = 8.03 min. 1H NMR (free base, 400 MHz, CDCl3): δ ppm 7.67(d, 1H, J = 4.0 Hz), 7.36-7.19 (m, 10H), 6.86 (d, 1H, J = 4.0 Hz), 5.02-4.95 (m, 1H), 3.55 (s, 2H), 3.03-3.00 (d, 2H, J = 12.0 Hz), 2.96-2.86 (m, 4H), 2.18-2.10 (m, 4H), 2.05-1.83 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ ppm 161.1, 142.4, 141.1, 138.8, 135.8, 129.1, 128.6, 128.3, 127.3, 127.1, 126.3, 63.0, 55.5, 53.0, 33.5, 32.4, 30.6. LC / MS (M+H) = 388

[0200] Alternatively, a Pd(dba) and RuPhos-assisted Buchwald-Hartwig cross-coupling reaction can be carried out starting from the previously described intermediates E or F. Either route provided examples of the present invention, as outlined in Scheme 5.

[0201] [ka]

[0202] wherein -NR8R9 forms a nitrogen-containing heterocycle as defined above.

[0203] Conditions: a) tris((1E,4E)-1,5-diphenylpenta-1,4-dien-3-one)dipalladium (5 mol%), RuPhos (20 mol%), Cs2CO3, dioxane, 100-120 °C, 16 h; b) TFA, DCM, 45 min, 25 °C; c) R3CHO, DIEA, NaBH3CN, MeOH, 25 °C, 18 h.

[0204] Example A.12 2-(1-Benzylpiperidin-4-yl)-4-(piperidin-1-yl)-2,3-dihydropyridazin-3-one hydrochloride (compound 38). A microwave vial (under oven-dried argon) was charged with 2-(1-benzylpiperidin-4-yl)-4-chloro-2,3-dihydropyridazin-3-one (50 mg, 0.16 mmol, 1.0 equiv.), piperidine (28.0 mg, 0.33 mmol, 2.0 equiv.), and CsCO (135.4 mg, 0.41 mmol, 2.5 equiv.). Tris((1E,4E)-1,5-diphenylpenta-1,4-dien-3-one)dipalladium (7.7 mg, 5 mol%) and RuPhos (15.3 mg, 20 mol%) were then added, followed by dioxane (1.5 mL). The vial was properly capped, and the mixing vessel was evacuated and backfilled with argon (a process repeated three times), and heated at 100 °C until complete conversion of the starting material. The reaction conversion was monitored by HPLC and was usually complete within 16 h. After cooling to room temperature, the reaction mixture was evaporated to dryness. The crude material was partitioned between EtOAc (30 mL) and H2O (50 mL). The aqueous phase was extracted twice with EtOAc (20 mL). The organic phases were combined, washed with brine, dried (Na2SO4), and evaporated. The crude material was purified by flash chromatography using a gradient of 1% to 5% MeOH in EtOAc to give, after salification with 2 M HCl in Et2O, the title compound as a pale yellow solid (44 mg, 69%). Tr (HPLC) = 7.38 min. 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.69 (d, 1H, J = 4.8 Hz), 7.32-7.24 (m, 5H), 6.41 (d, 1H, J = 4.8 Hz). 4.80-4.7 (m, 1H), 3.49 (s, 2H), 3.37-3.28 (m, 4H), 2.95-2.88 (m, 2H), 2.15-1.99 (m, 2H), 1.90-1.88 (m, 2H), 1.69-1.62 (m, 2H), 1.58-1.49 (m, 6H). 13C NMR (101 MHz, DMSO-d6): δ ppm 158.0, 148.2, 139.0, 137.1, 129.1, 128.3, 127.0, 107.8, 63.0, 60.5, 55.5, 53.1, 49.2, 30.4, 25.6, 24.6, 21.2. LC / MS (M+H) = 353.

[0205] *2-[(1-benzylpiperidin-4-yl)methyl]-4-(piperidin-1-yl)-2,3-dihydropyridazin-3-one hydrochloride (compound 39). Using the same procedure as described in Example A.12, starting with 2-((1-benzylpiperidin-4-yl)methyl)-4-chloropyridazin-3(2H)-one (60 mg, 0.16 mmol, 1 eq.) and piperidine (27.2 mg, 0.32 mmol, 2 eq.), the title compound was obtained after purification and salification by flash chromatography using a gradient of 1% to 5% MeOH in EtOAc as a white solid (38%). Tr (HPLC) = 7.41 min. 1 H NMR (400 MHz, CDCl3): δ ppm 7.50 (d, 1H, J= 4.4 Hz), 7.25-7.15 (m, 5H), 6.18 (d, 1H, J = 4.4 Hz), 3.98(d, 1H, J = 7.2 Hz), 3.43 (s, 2H), 3.35-3.32 (m, 4H), 2.81 (d, 2H, J = 12.0 Hz), 2.02- 1. 2.03-1.85 (m, 4H), 1.70-1.52 (m, 4H), 1.45-1.38 (m, 4H), 1.38-1.34 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ ppm 158.1, 148.5, 138.6, 136.8, 129.1, 128.1, 126.8, 107.7, 63.3, 57.6, 53.3, 49.1, 35.1, 30.0, 25.5, 24.4. LC / MS (M+H) = 367.

[0206] Example A.13 2-((1-benzylpiperidin-4-yl)methyl)-4-morpholinopyridazin-3(2H)-one hydrochloride (compound 40). Step 1: tert-butyl 4-((5-morpholino-6-oxopyridazin-1(6H)-yl)methyl)piperidine-1-carboxylate A microwave vial (under oven-dried argon) was charged with tert-butyl 4-((5-chloro-6-oxopyridazin-1(6H)-yl)methyl)piperidine-1-carboxylate (100 mg, 0.30 mmol, 1.0 equiv.), morpholine (53.1 mg, 0.61 mmol, 53 μL, 2.0 equiv.), and CsCO (298.2 mg, 0.91 mmol, 3.0 equiv.). Tris((1E,4E)-1,5-diphenylpenta-1,4-dien-3-one)dipalladium (14.0 mg, 5 mol%) and RuPhos (28.5 mg, 20 mol%) were then added, followed by dioxane (1.5 mL). The vial was properly capped, and the mixing vessel was evacuated and backfilled with argon (the process was repeated three times) and heated at 120 °C until complete conversion of the starting material. The reaction conversion was monitored by HPLC and was usually complete within 16 h. After cooling to room temperature, the reaction mixture was evaporated to dryness. The crude material was partitioned between EtOAc (30 mL) and H2O (50 mL). The aqueous phase was extracted twice with EtOAc (20 mL). The organic phases were combined, washed with brine, dried (Na2SO4), and evaporated. The crude material was purified by flash chromatography using DCM / MeOH 98 / 2 as the eluent to give the title compound as a yellow viscous gum (86.9 mg, 75%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.59 (d, 1H, J = 4.8 Hz), 6.24 (d, 1H, J = 4.8 Hz), 4.14-3.96 (m, 4H), 3.87-3.82 (m, 4H), 3.44-3.37 (m, 4H), 2.73-2.59 (m, 2H), 2.19-2.07 (m, 1H), 1.60-1.54 (m, 2H), 1.44 (s, 9H), 1.31-1.18 (m, 2H).13 C NMR (101 MHz, DMSO-d6): δ ppm 158.0, 154.9, 147.9, 136.9, 108.2, 79.4, 66.5, 57.3, 53.6, 48.2, 35.5, 29.8, 28.6.

[0207] Step 2: 2-((1-benzylpiperidin-4-yl)methyl)-4-morpholinopyridazin-3(2H)-one hydrochloride (compound 40). To a solution of tert-butyl 4-((5-morpholino-6-oxopyridazin-1(6H)-yl)methyl)piperidine-1-carboxylate (86 mg, 0.21 mmol, 1 equiv.) in DCM (1.5 mL) at 0° C. was added TFA (0.35 mL), and the resulting mixture was stirred at room temperature for 1 h. The crude reaction was concentrated in vacuo with azeotropic removal of TFA with heptane. The residue was triturated with ice-cold ether, the supernatant was removed, and the evaporated crude was directly dissolved in MeOH (4 mL). Benzaldehyde (36.3 mg, 34.5 μL, 1.5 equiv.) was added, followed by NaBHCN (28.6 mg, 0.46 mmol, 2 equiv.) and DIEA (117.8 mg, 158 μL, 4 equiv.). The resulting mixture was stirred at room temperature for 48 h. The volatiles were evaporated, and the crude was dissolved in EtOAc (25 mL). The organic phase was washed with brine, dried, and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / MeOH (97:3) as the eluent to afford, after salification with 2N HCl in EtO, 2-((1-benzylpiperidin-4-yl)methyl)-4-morpholinopyridazin-3(2H)-one hydrochloride as a pale yellow solid (63.8 mg, 63%). Tr (HPLC, short column) = 2.42 min. 1H NMR (400MHz, CDCl3): δ ppm 7.58 (d, 1H, J = 5.2 Hz), 7.33-7.21 (m, 5H), 6.23 (d, 1H, J= 2.0 Hz), 4.03 (d, 2H, J = 7.2 Hz), 3.89-3.81 (m, 4H), 3.52 (s, 2H), 3.44-3.37 (m, 4H), 2.93-2.85 (m, 2H), 2.05-1.95 (m, 3H), 1.67-1.57 (m, 2H), 1.52-1.38 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ ppm 157.9, 147.8, 137.8, 136.8, 129.4, 128.3, 127,3 108.2, 66.5, 63.2, 57.5, 53.2, 48.2, 35.1, 29.8; LC / MS (M+H) = 369.

[0208] *2-((1-benzylpiperidin-4-yl)methyl)-4-(4-phenylpiperazin-1-yl)pyridazin-3(2H)-one hydrochloride (Compound 41) Step 1: tert-butyl 4-((6-oxo-5-(4-phenylpiperazin-1-yl)pyridazin-1(6H)-yl)methyl)piperidine-1-carboxylate Using the same procedure as described in Example A.13, starting from tert-butyl 4-((5-chloro-6-oxopyridazin-1(6H)-yl)methyl)piperidine-1-carboxylate (100 mg, 0.30 mmol, 1 equiv.) and 1-phenylpiperazine (99.0 mg, 93 μl, 0.6 mmol, 1.5 equiv.), the title compound was obtained as a yellow viscous gum (78.6 mg, 57%). 1H NMR (400 MHz, CDCl3): δ ppm 7.61 (d, 1H, J = 4.0 Hz), 7.29 (t, J = 2H, J = 6.4 Hz), 6.96 (d, 1H, J = 6.4 Hz), 6.90 (t, 1H, J = 6.0 Hz), 6.31 (d, 1H, J = 4.0 Hz), 4.10-4.04 (m, 2H), 3.62-3.58 (m, 4H), 3.56-3.32 (m, 4H), 2.72-2-61 (m, 2H), 2.19-2.13 (m, 1H), 1.62-1.58 (m, 2H), 1.44 (s, 9H), 1.32-1.21 (m, 3H). 13 C NMR (101 MHz, CDCl3): δ ppm 158.0, 154.9, 151.1, 147.9, 137.0, 129.3, 120.5, 116.6, 108.5, 79.4, 57.4, 53.6, 49.1, 47.8, 35.5, 29.8, 28.6

[0209] Step 2: 2-(1-benzylpiperidin-4-yl)-4-(4-phenylpiperazin-1-yl)pyridazin-3(2H)-one hydrochloride (compound 41). Starting from tert-butyl 4-((6-oxo-5-(4-phenylpiperazin-1-yl)pyridazin-1(6H)-yl)methyl)piperidine-1-carboxylate (87 mg, 0.17 mmol, 1 equiv.), sequential Boc deprotection followed by reductive amination using benzaldehyde (27.48 mg, 26.2 μl, 0.25 mmol, 1.5 equiv.) as described in Example A.13, after salification with HCl 2N, afforded the title product as a white solid (68 mg, 71%). 1H NMR (400 MHz, CDCl3) : δ ppm 7.0 (d, 1H, J = 4.8 Hz), 7.32-7.24 (m, 7H), 6.96 (d, 2H, J = 8.0 Hz). 6.90 (t, 1H, J = 8.0 Hz), 6.30 (d, 1H, J = 4.8 Hz), 4.06 (d, 2H, J = 7.2 Hz), 3.61-3.58 (m, 4H), 3.53 (s, 2H), 3.35-3.57 (m, 4H), 2.93-2.88 (m, 2H), 2.04-1.97 (m, 3H), 1.66-1.63 (m, 2H), 1.51-1.40 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ ppm 158.0, 151.2, 147.8, 137.8, 136.8, 129.4, 129.3, 128.3, 127.3, 120.4, 116.5, 108.5, 63.2, 57.6, 53.2, 49.1, 47.8, 35.1, 29.8. LC / MS (M+H) = 444.

[0210] *2-((1-benzylpiperidin-4-yl)methyl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)pyridazin-3(2H)-one hydrochloride (compound 42). Step 1: tert-butyl 4-((5-(3,4-dihydroisoquinolin-2(1H)-yl)-6-oxopyridazin-1(6H)-yl)methyl)-piperidine-1-carboxylate Using the same procedure as described in Example A.13, starting from tert-butyl 4-((5-chloro-6-oxopyridazin-1(6H)-yl)methyl)piperidine-1-carboxylate (100 mg, 0.30 mmol, 1 equiv.) and 1,2,3,4-tetrahydroisoquinoline (81.2 mg, 76.6 μl, 0.6 mmol, 1.5 equiv.), the title compound was obtained as a yellow viscous gum (97 mg, 75%). 1H NMR (500 MHz, CDCl3): δ ppm 7. 57(d, 1H, J = 5.0 Hz), 7.20-7.11(m, 4H), 6.27 (d, 1H, J = 5.0 Hz), 4.59 (s, 2H), 4.10-4.03 ((m, 4H), 3.90 (t, 2H, J = 6.0 Hz), 3.01 (t, 2H, J = 6.0 Hz), 2.71-2.61 (m, 2H), 2.18-2.13 (m, 1H), 1.65-1.57 (m, 2H), 1.43 (s, 9H), 1.40-1.21 (m, 2H). 13 C NMR (125 MHz, CDCl3): δ ppm 158.0, 154.9, 146.9, 137.3, 134.7, 133.3, 128.9, 126.8, 126.5, 126.3, 106.5, 79.4, 57.4, 50.4, 45.7, 35.5, 29.8, 29.7, 28.8.

[0211] Step 2 2-(1-Benzylpiperidin-4-yl)-4-(4-phenylpiperazin-1-yl)pyridazin-3(2H)-one hydrochloride (compound 42). Starting from tert-butyl 4-((5-(3,4-dihydroisoquinolin-2(1H)-yl)-6-oxopyridazin-1(6H)-yl)methyl)piperidine-1-carboxylate (97 mg, 0.23 mmol, 1 equiv.), sequential Boc deprotection followed by reductive amination using benzaldehyde (34.0 mg, 32.4 μl, 0.32 mmol, 1.5 equiv.) as described in Example A.13, after salification with HCl 2N, afforded the title product as a yellow solid (69 mg, 66%). 1H NMR (400 MHz, CDCl3): δ ppm 7.56 (d, 1H, J = 5.2 Hz), 7.32-7.10 (m, 9H), 6.25 (d, 1H, J = 5.2 Hz), 4.58 (s, 2H), 4.05 (d, 2H, J = 6.8 Hz), 3.90(t, 2H, J = 6.0 Hz), 3.52 (s, 2H), 3.00 (t, 2H, J = 6.0 Hz), 2.92-2.86 (m, 2H), 2.89 (dt, 2H, J = 8.0 Hz, J =3.2 Hz), 2.04-1.96 (m, 2H), 1.68-1.60 (m, 2H), 1.45 (dq, 2H, J = 12.0 Hz, J = 4.0 Hz). 13 C NMR (125 MHz, CDCl3): δ ppm 158.0, 147.0, 137.1, 134.7, 133.4, 129.3, 128.9, 128.3, 127.2, 126.8, 126.5, 126.3, 106.6, 63.3, 57.6, 53.3, 50.4, 45.7, 35.1, 29.9, 28.9. LC / MS (M+H) = 415.

[0212] General methods and examples derived from pyridones and pyrimidones. Alternatively, the pyridazinone ring can be replaced by a pyridone or pyrimidone ring of general structure H in a four-step sequence similar to that depicted in Scheme 6 below.

[0213] [ka]

[0214] Conditions: a) n = 0, K2CO3, 2-butanone, 85 °C, 24 h; b) NaH, DMF, 110 °C, 18 h; c) K2CO3, Pd(PPh3)4, Ar-PhB(OH)2, toluene, EtOH, HO, 120 °C, 16 h; d) TFA, DCM, 25 °C, 45 min; e) NaBH3CN; DIEA, MeOH, 25 °C, 18 h or R3-CH2Br, K2CO3, DMF or MeCN, 80 °C, 18 h.

[0215] (Example A.14) 3-(1-Benzylpiperidin-4-yl)-5-phenylpyrimidin-4(3H)-one hydrochloride (compound 43). Step 1: tert-butyl 4-(6-oxo-5-phenylpyrimidin-1(6H)-yl)piperidine-1-carboxylate A microwave vial (under oven-dried argon) was charged with 5-bromopyrimidin-4-ol hydrobromide (345 mg, 1.35 mmol, 1.0 equiv.), tert-butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (564.9 mg, 2.02 mmol, 1.5 equiv.), and K2CO3 (462.5 mg, 3.36 mmol, 2.5 equiv.). 2-Butanone (12.3 mL) was added, and the mixture was heated at 110 °C for 24 h (HPLC monitoring: complete conversion). The mixture was quenched with HO (150 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, filtered, and evaporated to dryness. The resulting residue was purified by silica gel flash chromatography using a gradient of 0% to 50% EtOAc in heptane to give tert-butyl 4-(6-oxo-5-phenyl-1,6-dihydropyrimidin-1-yl)piperidine-1-carboxylate as a yellow oil (191 mg, approximately 70% pure). The compound was used without further purification.

[0216] A microwave vial (under oven-dried argon) was charged with tert-butyl 4-(6-oxo-5-phenyl-1,6-dihydropyrimidin-1-yl)piperidine-1-carboxylate (191 mg, 0.53 mmol, 1.0 equiv.), phenylboronic acid (102.6 mg, 0.80 mmol, 1.5 equiv.), and Na2CO3 (113 mg, 1.06 mmol, 2.0 equiv.). Tetrakis(triphenylphosphine)palladium (62.3 mg, 5 mol%, 0.1 equiv.) was then added, followed by DME (2.8 mL) and water (0.85 mL). The vial was properly capped, and the mixing vessel was evacuated and refilled with argon (the process was repeated three times) and heated at 100 °C until complete conversion of the starting material. The reaction conversion was monitored by HPLC and was usually complete within 16 h. After cooling to room temperature, the reaction mixture was evaporated to dryness. The crude product was partitioned between EtOAc (30 mL) and HO (50 mL). The aqueous phase was extracted twice with EtOAc (20 mL). The organic phases were combined, washed with brine, dried (NaSO), and evaporated. The crude material was purified by flash chromatography using a gradient of 0% to 40% EtOAc in heptane to give tert-butyl 4-(6-oxo-5-phenylpyrimidin-1(6H)-yl)piperidine-1-carboxylate (108 mg, 86% purity). 1 H NMR (400 MHz, CDCl3): δ ppm 8.72 (s, 1H), 8.51 (s, 1H), 7.60-7.50 (m, 2H), 7.46-7.42 (m, 3H), 5.49-5.44 (m, 1H), 3.60-3.52 (m, 2H), 3.44-3.39 (m, 2H), 2.00-1.95 (m, 2H), 1.86-1.82 (m, 2H), 1.46 (s, 9H).

[0217] Step 2: 3-(1-benzylpiperidin-4-yl)-5-phenylpyrimidin-4(3H)-one hydrochloride (Compound 43) To a solution of tert-butyl 4-(6-oxo-5-phenylpyrimidin-1(6H)-yl)piperidine-1-carboxylate (108 mg, 0.30 mmol, 1 equiv.) in DCM (1.3 mL) at 0° C., TFA (1.3 mL) was added, and the resulting mixture was stirred at room temperature for 1 h. The crude reaction was concentrated in vacuo with azeotropic removal of TFA with heptane. The residue was triturated with ice-cold ether, the supernatant was removed, and the evaporated crude was directly dissolved in MeOH (2.6 mL). Benzaldehyde (48.4 mg, 46.1 μL, 1.5 equiv.) was added, followed by NaBHCN (40.22 mg, 0.6 mmol, 2 equiv.) and AcOH (1.7 μL). The resulting mixture was stirred at room temperature for 16 h. The volatiles were evaporated, and the crude was dissolved in EtOAc (25 mL). The organic phase was washed with brine, dried, and concentrated in vacuo. The residue was purified by silica gel column chromatography using DCM / iPrOH (92 / 8) as the eluent to afford, after salification with 2N HCl in EtO, 3-(1-benzylpiperidin-4-yl)-5-phenylpyrimidin-4(3H)-one hydrochloride as a white solid (41 mg, 35%). mp 144 °C, Tr (HPLC) = 7.14 min. 1 H NMR (400 MHz, CDCl 3, Free base): δ ppm 8.72 (s, 1H), 8.50 (s, 1H), 7.60-7.55 (m, 2H), 7.48-7.40 (m, 3H), 7.35-7.26 (m, 5H), 5.36-5.32 (m, 1H), 3.54 (s, 2H), 2.75-2.60 (m, 2H), 2.45-2.30 (m, 2H), 2.10- 2.04 (m, 2H), 1.95-1.85 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ ppm 165.3, 157, 0, 156.3, 138.3, 133.2, 129.2, 129.1, 128.5, 128.3, 127.2, 122.5, 72.1, 63.1, 50.5, 30.7. LC / MS (M+H) = 346.

[0218] *1-(1-benzylpiperidin-4-yl)-3-phenyl-1,2-dihydropyridin-2-one hydrochloride (Compound 44) Using the same procedure as described in Example A.14, starting from 3-bromopyridin-2-ol (300 mg, 1.27 mmol, 1 equiv.), the title compound was obtained after salification with 2N HCl as a white solid (45 mg, 11% overall yield). Melting point = 152 °C, Tr (HPLC) = 7.21 min. 1 H NMR (400 MHz, CDCl 3, free base): δ ppm 7.67 (d, 2H, J = 7.6 Hz), 7.46-7.26 (m, 10H), 6.31 (t, 1H, J = 6.8 Hz), 5.07-5.01 (m, 1H), 3.57 (s, 2H), 3.06 (d, 2H, J = 11.6 Hz), 2.24(t, 2H, J = 11.6 Hz), 1.97-1.85 (m, 4H). 13 C NMR (101 MHz, CDCl3): δ ppm 161.3, 138.2, 137.3, 137.0, 132.5, 131.6, 129.3, 128.8, 128.4, 128.1, 127.7, 127.3, 62.9, 53.1, 52.9, 31.7. LC / MS (M+H) = 345.

[0219] *3-((1-benzylpiperidin-4-yl)methyl)-5-phenylpyrimidin-4(3H)-one (compound 45). Using the same procedure as described in Example A.14, starting from 5-bromopyrimidin-4-ol hydrobromide (200 mg, 0.78 mmol, 1 equiv.) and tert-butyl 4-[(methanesulfonyloxy)methyl]piperidine-1-carboxylate (298.1 mg, 1.01 mmol, 1.3 equiv.), tert-butyl 4-[(5-bromo-6-oxo-1,6-dihydropyrimidin-1-yl)methyl]piperidine-1-carboxylate was obtained as a yellow oil (51.7 mg, 18%) after flash chromatography on silica gel (Hept / EtOAc). 1 H NMR (400 MHz, CDCl3) : δ ppm 8.63 (s, 1H), 8.57 (s, 1H), 4.29 (d, 2H, J = 6.8 Hz), 4.21-4.04 (m, 2H), 2.78-2.71 (m, 2H), 2.04-2.00 (m, 1H), 1.80 (d, 2H, J = 12.8 Hz), 1.40 (s, 9H), 1.31-1.25 (m, 2H).

[0220] Starting from tert-butyl 4-[(5-bromo-6-oxo-1,6-dihydropyrimidin-1-yl)methyl]piperidine-1-carboxylate (73 mg, 0.19 mmol, 1 equiv.), Suzuki-Miyaura cross-coupling reaction assisted by phenylboronic acid (26.3 mg, 0.21 mmol, 1.1 equiv.) afforded tert-butyl 4-[(6-oxo-5-phenyl-1,6-dihydropyrimidin-1-yl)methyl]piperidine-1-carboxylate as a yellow oil (32.7 mg, 45%) after flash chromatography on silica gel (Hept / EtOAc). 1H NMR (400 MHz, CDCl3): δ ppm 8.72 (s, 1H), 8.49 (s, 1H), 7.54-7.47 (m, 2H), 7.45-7.39 (m, 3H), 4.29 (d, 2H, J = 6.4 Hz), 4.13-4.07 (m, 2H), 2.73-2.69 (m, 2H), 1.99-1.96 (m, 1H), 1.75-1.71 (m, 2H), 1.46 (s, 9H), 1.26-1.23 (m, 2H). 13 C NMR (101 MHZ, CDCl3): δ ppm 157.0, 156.2, 154.8, 128.9, 128.5, 128.3, 79.4, 70.9, 35.6, 28.8, 28.5, 28.4.

[0221] After TFA-assisted deprotection of the BOC group, the crude was subjected to benzaldehyde-assisted reductive amination reaction to afford the title compound after salification with 2N HCl (light yellow solid, 18.6 mg, 54%). 1 H NMR (400 MHz, CDCl3) : δ ppm 8.65 (s, 1H), 8.42 (s, 1H), 7.47-7.45 (m, 2H), 7.40-7.30 (m, 3H), 7.28-.7.21 (m, 5H), 4.23 (d, 1H, J = 6.7 Hz), 3.56 (s, 2H), 2.95 (d, 2H, J = 11.3 Hz), 2.12-2.00 (m, 2H), 1.86-1.78 (m, 1H), 1.72 (d, 2H, J = 13.5Hz), 1.42 (q, 2H, J = 12.5 Hz). 13 C NMR (101 MHz, CDCl3): δ ppm 165.5, 156.9, 156.1, 133.0, 129.6, 128.9, 128.5, 128.4, 128.3, 127.6, 122.3, 70.9, 62.8, 52.8, 34.9, 28.3. LC / MS (M+H) = 360.

[0222] *1-[(1-benzylpiperidin-4-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one hydrochloride (compound 46). Using the same procedure as described in Example A.14, starting from 3-bromopyridin-2-ol (180 mg, 1.035 mmol, 1 equiv.) and tert-butyl 4-[(methanesulfonyloxy)methyl]piperidine-1-carboxylate (364.2 mg, 1.24 mmol, 1.2 equiv.), tert-butyl 4-[(3-bromo-2-oxo-1,2-dihydropyridin-1-yl)methyl]piperidine-1-carboxylate was obtained as a white solid (133.5 mg, 35%) after flash chromatography on silica gel (Hept / EtOAc). 1 H NMR (400 MHz, CDCl3): δ ppm 8.07 (d, 1H, J = 4.3 Hz), 7.8 (d, 1H, J = 7.5 Hz), 6.76 (t, 1H, J = 6.2 Hz), 4.21 (d, 2H J = 6.8 Hz), 4.19-4.09 (m, 2H), 2.75 (t, 2H, J = 12.7 Hz), 2.09-1.95 (m, 1H), 1.83 (d, 2H, J = 13.3 Hz) 1.47 (s, 9H), 1.3 (dq, 2H, J = 12.7 Hz, J = 3.8 Hz). 13 C NMR (101 MHz, CDCl3): δ ppm 159.8, 154.9, 154.4, 141.6, 117.8, 107.3, 79.3, 71.0, 35.8, 28.8, 28.5.

[0223] Starting from tert-butyl 4-[(3-bromo-2-oxo-1,2-dihydropyridin-1-yl)methyl]piperidine-1-carboxylate (123 mg, 0.33 mmol, 1 equiv.), Suzuki-Miyaura cross-coupling reaction assisted by phenylboronic acid (44.4 mg, 0.36 mmol, 1.1 equiv.) afforded tert-butyl 4-[(2-oxo-3-phenyl-1,2-dihydropyridin-1-yl)methyl]piperidine-1-carboxylate as a yellow oil (100 mg, 82%) after flash chromatography on silica gel (Hept / EtOAc). 1 H NMR (40 0MHz, CDCl3): δ ppm 7.97 (dd, 1H, J = 4.1 Hz, J = 1.3 Hz), 7.46 (dd, J = 7.6 Hz, J = 1.3 Hz), 7.42-7.35 (m, 2H), 7.30-7.23 (m, 2H), 7.22-7.16 (m, 1H), 6.81(dt, 1H, J = 6.3 Hz, J = 1.3 Hz), 4.05 (d, 2H, J = 6.2 Hz), 4.02-3.88 (m, 2H), 2.55 (t, 2H, J = 12.7 Hz), 1.85-1.64 (m, 1H), 1.58 (d, 2H, J = 13.2 Hz), 1.31 (s, 9H), 1.15-1.00 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ ppm 160.6, 154.8, 145.7, 138.7, 136.8, 129.1, 128.1, 127.4, 124.7, 117.1, 79.3, 70.3, 35.9, 29.0, 28.5.

[0224] After TFA-assisted deprotection of the BOC group, the crude was subjected to benzaldehyde-assisted reductive amination reaction to afford, after salification with 2N HCl, the title compound 46 (light yellow solid, 44.4 mg, 55%). 1H NMR (400 MHz, CDCl3): δ ppm 8.08 (dd, 1H, J = 4.4 Hz, J = 1.3 Hz), 7.57 (dd, 1H, J = 7.2 Hz, J = 1.3 Hz), 7.53-7.47 (m, 2H), 7.40-7.33 (m, 2H), 7.32-7.25 (m, 5H), 7.22-7.15 (m, 1H), 6.91 (dt, 1H, J = 6.9 Hz, J = 1.3 Hz), 4.15 (d, 2H, J = 6.7 Hz), 3.45( s, 2H), 2.85 (d, 2H, J = 11.5 Hz), 1.92 (t, 2H, J = 12.1 Hz), 1.80-1.62 (m, 3H), 1.34 (q, 2H, J = 12.4 Hz). 13 C NMR (101 MHz, CDCl3): δ ppm 160.7, 145.7, 138.6, 136.8, 129.2, 128.1, 127.4, 126.9, 124.6, 116.9, 70.7, 63.4, 53.4, 35.6, 29.2. LC / MS (M+H) = 359.

[0225] B. In Vitro Pharmacology: Sigma-1 Receptor Binding Assay The sigma-1 receptor binding assay was performed according to Ganapathy et al. (J Pharmacol Exp Ther 28:251-60, 1999). The sigma-1 receptor binding assay was performed by incubating Jurkat cell membranes (10-20 mg of protein per tube) with [ 3 The assay was performed by incubation with [H](+)-pentazocine, a selective sigma-1 radiotracer (15 nM), and a range of concentrations of test compound in 5 mM Tris / HCl buffer (pH=7.4) at 37°C for 2 hours. 3 Inhibition assays for [H](+)-pentazocine binding are primarily used to determine the inhibition constants (Ki) of potential sigma-1 receptor ligands. These assays utilize a single concentration of [ 3 H](+)-pentazocine at its K DAssays are performed at concentrations near and increasing concentrations of non-radioactive ligand.

[0226] [Table 1]

[0227] The results of the sigma-1 receptor binding assay are shown in Table 2.

[0228] [Table 2A]

[0229] [Table 2B]

Claims

1. A compound having the following formula (I): 【Chemical 1】 [In the formula, R 1 is, independently, ・ H、 ・ Aryl (C 1 ~C 6 ) alkyl groups, an aryl group, cycloalkyl groups, a heterocyclic group, or ・SR p (R p is alkyl, aryl or aralkyl) represents R 2 is, independently, ・ H、 ・ Aryl (C 1 ~C 6 ) alkyl groups, an aryl group, a cycloalkyl group, or ・SR p (R p is alkyl, aryl or aralkyl) represents where R 1 and R 2 One of them is H and the other is R 1 and R 2 The other side is different from H, X and Y are, respectively, CH and N, or ・N and CR 4 , or CH and CR 4 Either where R 4 is H or (C 1 ~C 4 ) alkyl, n is 0, 1 or 2, m is 0 or 1, and m' is 0 or 1; R 3 teeth, ・ (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (C 1 ~C 6 ) alkoxy and aryl (C 1 ~C 6 ) alkyl, The group is (C 1 ~C 6 ) alkyl, OH, halogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (C 1 ~C 6 )alkoxy, -C(O)R, -CHOHR, C(O) 2 R, C(O)NRR', -CONHOR, -CONHSO 2 R, -NRR', -N(R)C(O)R', -N(R)NR'R'', -N(R)C(O) 2 R', -N(R)C(O)NR'R'', -N(R)S(O) 2 R', -SR, -S(O)R, -S(O) 2 R, -S(O)NR R', and -S(O) 2 NRR' (R, R' and R'' are independently H, (C 1 ~C 6 ) alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, (C 1 ~C 6 ) alkylcycloalkyl, (C 1 ~C 6 ) alkylaryl, (C 1 ~C 6 ) alkylheterocycloalkyl or (C 1 ~C 6 ) alkyl; ・OH, -C(O)R, -CHOHR, C(O) 2 R, C(O)NRR', -CONHOR, -CONHSO 2 R, -NRR', -N(R)C(O)R', -N(R)NR'R'', -N(R)C(O) 2 R', -N(R)C(O)NR'R'', -N(R)S(O) 2 R', -SR, -S(O)R, -S(O) 2 R, -S(O)NR R' and -S(O) 2 NRR' (R, R' and R'' are independently H, (C 1 ~C 6 ) alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, (C 1 ~C 6 ) alkylcycloalkyl, (C 1 ~C 6 ) alkylaryl, (C 1 ~C 6 ) alkylheterocycloalkyl or (C 1 ~C 6 ) alkylheteroaryl) represents R 5 represents H or OH, R 6 Each of 1 ~C 6 ) represents an alkyl group] A stereoisomer, diastereoisomer, enantiomer, solvate or any pharmaceutical salt thereof.

2. R 1 but, ・ Aryl (C 1 ~C 6 ) alkyl groups, an aryl group, cycloalkyl groups, a heterocyclic group, or ・SR p (R p is alkyl, aryl or aralkyl) represents R 2 But H, 2. The compound of claim 1.

3. R 1 but, ・ Aryl (C 1 ~C 6 ) alkyl groups, an aryl group, or Heterocyclic groups represents R 2 represents H, 3. The compound of claim 1 or 2.

4. X and Y are N and CR, respectively. 4 where R 4 But H or (C 1 ~C 4 4. The compound of claim 1, wherein R is 1 or 2. 5.) alkyl.

5. R 5 and each R 6 5. The compound of claim 1, wherein

6. Features include: n is 1, and / or m is 0, and / or m' is 1, and / or R 1 represents an aryl group, and / or R 2 is H, and / or R 3 but, Aryl, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, cycloalkyl, heterocycloalkyl, heteroaryl, (C 1 ~C 6 ) alkoxy, aryl (C 1 ~C 6 ) alkyl, The group may be one or two (C 1 ~C 6 ) alkyl, OH, halogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (C 1 ~C 6 ) alkoxy, -C(O) 2 R, -N(R)C(O)R' (R and R' are independently H, (C 1 ~C 6 ) alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, (C 1 ~C 6 ) alkylcycloalkyl, (C 1 ~C 6 ) alkylaryl, (C 1 ~C 6 ) alkylheterocycloalkyl or (C 1 ~C 6 ) alkylheteroaryl) or -CHOHR, -C(O)R, -C(O) 2 R(R is H, (C 1 ~C 6 ) alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, (C 1 ~C 6 ) alkylcycloalkyl, (C 1 ~C 6 ) alkylaryl, (C 1 ~C 6 ) alkylheterocycloalkyl or (C 1 ~C 6 ) alkylheteroaryl) represents and / or R 5 is H, and / or Each R 6 But it is H The compound according to any one of claims 1 to 5, wherein at least one of the following is satisfied:

7. When R 1 represents an aryl group, said aryl group is a phenyl group optionally substituted by at least one substituent, said at least one substituent being - halogens, alkyl optionally substituted with at least one halogen; -OH, and -OR (R is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) 7. The compound according to any one of claims 1 to 6, selected from:

8. 2-(1-benzylpiperidin-4-yl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-(1-benzylpiperidin-4-yl)-5-phenylpyridazin-3(2H)-one hydrochloride; 4-phenyl-2-[1-(2-phenylethyl)piperidin-4-yl]-2,3-dihydropyridazin-3-one hydrochloride; 2-[1-(cyclopropylmethyl)piperidin-4-yl]-4-phenyl-2,3-dihydropyridazin-3-one hydrochloride; 2-[1-(cyclopentylmethyl)piperidin-4-yl]-4-phenyl-2,3-dihydropyridazin-3-one hydrochloride; 2-(1-benzylazepan-4-yl)-4-phenyl-2,3-dihydropyridazin-3-one hydrochloride; 2-((1-benzylpiperidin-4-yl)methyl)-6-methyl-4-phenylpyridazin-3(2H)-one; 2-((1-benzylpiperidin-4-yl)methyl)-5-phenylpyridazin-3(2H)-one hydrochloride; 2-[(1-benzylpiperidin-3-yl)methyl]-4-phenyl-2,3-dihydropyridazin-3-one hydrochloride; 2-((1-phenethylpiperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 4-phenyl-2-((1-propylpiperidin-4-yl)methyl)pyridazin-3(2H)-one hydrochloride; 2-((1-(4-chlorobenzyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 4-phenyl-2-((1-(pyridin-4-ylmethyl)piperidin-4-yl)methyl)pyridazin-3(2H)-one hydrochloride; 4-phenyl-2-((1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)methyl)pyridazin-3(2H)-one hydrochloride; 2-{[1-(1H-imidazol-5-ylmethyl)piperidin-4-yl]methyl}-4-phenyl-2,3-dihydropyridazin-3-one hydrochloride; 4-phenyl-2-((1-((tetrahydro-2H-pyran-3-yl)methyl)piperidin-4-yl)methyl)pyridazin-3(2H)-one hydrochloride; 2-((1-(4-hydroxybenzyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-((1-(2-methoxyethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; N-(2-{4-[(6-oxo-5-phenyl-1,6-dihydropyridazin-1-yl)methyl]piperidin-1-yl}ethyl)acetamide hydrochloride; 2-((1-(2-(4-fluorophenyl)-2-hydroxyethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-((1-(2-hydroxy-2-phenylethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-(2-(1-benzylpiperidin-4-yl)ethyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-(2-(1-benzylpiperidin-4-yl)ethyl)-5-phenylpyridazin-3(2H)-one hydrochloride; 2-(1-(1-benzylpiperidin-4-yl)ethyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-((1-benzyl-4-hydroxypiperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 2-(1-benzylpiperidin-4-yl)-4-(4-methoxyphenyl)pyridazin-3(2H)-one hydrochloride; 2-(1-benzylpiperidin-4-yl)-4-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazin-3-one hydrochloride; 2-(1-benzylpiperidin-4-yl)-4-[4-chlorophenyl]-2,3-dihydropyridazin-3-one hydrochloride; 2-[(1-benzylpiperidin-4-yl)methyl]-4-(2-chlorophenyl)-2,3-dihydropyridazin-3-one hydrochloride; 2-[(1-benzylpiperidin-4-yl)methyl]-4-(4-hydroxyphenyl)-2,3-dihydropyridazin-3-one hydrochloride; 2-((1-benzylpiperidin-4-yl)methyl)-4-(4-fluorophenyl)pyridazin-3(2H)-one hydrochloride; 2-((1-benzylpiperidin-4-yl)methyl)-4-phenethylpyridazin-3(2H)-one, 2-(1-benzylpiperidin-4-yl)-4-(2-phenylethyl)-2,3-dihydropyridazin-3-one hydrochloride; 2-(1-benzylpiperidin-4-yl)-4-(piperidin-1-yl)-2,3-dihydropyridazin-3-one hydrochloride; 2-[(1-benzylpiperidin-4-yl)methyl]-4-(piperidin-1-yl)-2,3-dihydropyridazin-3-one hydrochloride; 2-((1-benzylpiperidin-4-yl)methyl)-4-morpholinopyridazin-3(2H)-one hydrochloride; 2-((1-benzylpiperidin-4-yl)methyl)-4-(4-phenylpiperazin-1-yl)pyridazin-3(2H)-one hydrochloride; 2-((1-benzylpiperidin-4-yl)methyl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)pyridazin-3(2H)-one hydrochloride; 3-(1-benzylpiperidin-4-yl)-5-phenylpyrimidin-4(3H)-one hydrochloride; 1-(1-benzylpiperidin-4-yl)-3-phenyl-1,2-dihydropyridin-2-one hydrochloride; 3-((1-benzylpiperidin-4-yl)methyl)-5-phenylpyrimidin-4(3H)-one; and 1-[(1-benzylpiperidin-4-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one hydrochloride 8. The compound according to any one of claims 1 to 7, selected from the group consisting of:

9. 2-(1-benzylpiperidin-4-yl)-4-phenylpyridazin-3(2H)-one hydrochloride; 3-(1-benzylpiperidin-4-yl)-5-phenylpyrimidin-4(3H)-one hydrochloride; 2-((1-benzylpiperidin-4-yl)methyl)-4-phenethylpyridazin-3(2H)-one; 2-[(1-benzylpiperidin-4-yl)methyl]-4-(piperidin-1-yl)-2,3-dihydropyridazin-3-one hydrochloride; 2-((1-benzyl-4-hydroxypiperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride; 4-phenyl-2-((1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)methyl)pyridazin-3(2H)-one hydrochloride; 2-(1-(1-benzylpiperidin-4-yl)ethyl)-4-phenylpyridazin-3(2H)-one hydrochloride; and 2-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-4-phenylpyridazin-3(2H)-one hydrochloride 9. The compound according to any one of claims 1 to 8, selected from the group consisting of:

10. A medicament comprising a compound according to any one of claims 1 to 9.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable adjuvant.

12. 12. The pharmaceutical composition of claim 11 for use in the treatment of disorders modulated by the sigma-1 receptor.

13. 13. The pharmaceutical composition of claim 12, wherein the disorder is selected from the group consisting of neurodegenerative diseases; cognitive and memory alterations; developmental cognitive disorders; and genetic diseases associated with MAM dysfunction.

14. 14. The pharmaceutical composition of claim 13, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, or multiple sclerosis.

15. 14. The pharmaceutical composition of claim 13, wherein the cognitive and memory alteration is pathological aging, ischemic amnesia, schizophrenia-related cognitive deficits or depression.

16. 14. The pharmaceutical composition according to claim 13, wherein the developmental cognitive disorder is an autism-related disorder or a mental retardation-related disorder.

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