Sigma-1 receptor ligands and their therapeutic uses

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. TIFF2023507509000021.tif51169

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] [Non-patent literature]

[0010] [Non-Patent Document 1] Matsuno et al., Eur J Pharmacol 312:267~71, 1996 [Non-patent 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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[0011] 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]

[0012] In this respect, the present invention provides a compound having the following formula (I):

[0013] [ka]

[0014] [In the formula, R1 is H, aryl (C1-C6) alkyl groups, aryl(C2-C6)alkenyl groups, aryl groups, heteroaryl groups, heterocycloalkyl groups, a cycloalkyl group, or -QR groups (Q is O or S and R is alkyl, aryl or aralkyl); represents the group is optionally substituted by at least one -OH, halogen, (C1-C6) alkyl optionally substituted by one or more fluorine atoms, or (C1-C6) alkyloxy; Z represents N or CR2; R2 represents H, a (C1-C4) alkyl, or a phenyl group; X and Y are either CR6 and N, or N and CR6, or CR6 and CH, respectively; R6 is H or a (C1-C4) alkyl group; n is 3, 4, 5 or 6; R3 and R4 are independently represent a group selected from a hydrogen atom, (C1-C6) alkyl, (C2-C6) alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aryl(C1-C6) alkyl, the group is optionally substituted with at least one substituent selected from the group consisting of hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; or together with the nitrogen to which they are attached form a nitrogen-based heterocycloalkyl, said nitrogen-based heterocycloalkyl optionally substituted with at least one substituent selected from the group consisting of hydroxy, oxo, (C1-C6)alkyl, (C2-C6)alkenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, aryl(C1-C6)alkyl and hydroxy(C1-C6)alkyl, said nitrogen-based heterocycloalkyl optionally fused to at least one 5- to 14-membered ring selected from aryl and heteroaryl; Each R5 independently represents H, OH, or a (C1-C4) alkyl group. It relates to an isomer, a solvate or any pharmaceutical salt thereof.

[0015] The present invention also relates to a compound as defined above for use as a medicine.

[0016] The present invention further relates to a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable support.

[0017] 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

[0018] 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.

[0019] The term "alkyl" refers to a saturated, straight-chain or branched-chain aliphatic group. Preferably, the alkyl group has 1 to 6 carbon atoms. 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).

[0020] 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 ethenyl.

[0021] 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.

[0022] The term "cycloalkyl" refers to a saturated or unsaturated ("unsaturated" preferably refers to "at least one double carbon-carbon bond") mono-, bi-, or tricyclic alkyl group having between 3 and 20 carbon atoms (C3-C4). 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, cyclohexyl, and cyclohexenyl. The term "cycloalkyl" can also refer to 5- to 10-membered bridged carbocyclyl, such as bicyclo[2,2,1]heptanyl, bicyclo[2,2,2]octanyl, or adamantyl. In preferred embodiments, "cycloalkyl" is cyclohexyl, cyclohexenyl, or adamantanyl.

[0023] 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 morpholinyl, piperidinyl, piperazinyl, oxazepanyl, azepanyl, azocanyl, nortropanyl, decahydroquinolinyl, thiomorpholinyl, or 6-azabicyclo[3.2.1]octanyl.

[0024] 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.

[0025] 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 furanyl, benzofuranyl, pyridyl, pyrrolyl, or thiophenyl.

[0026] The term "nitrogen-based heterocycloalkyl" (also referred to as "nitrogen-containing heterocycloalkyl") refers to a heterocycloalkyl, as defined above, containing at least one nitrogen atom. The nitrogen-based heterocycloalkyl may further contain other heteroatoms such as O or S. Examples of nitrogen-based heterocycloalkyl include, but are not limited to, piperidinyl, pyrrolidinyl, morpholinyl, azepanyl, pyrrolyl, or imidazolyl, preferably piperidinyl.

[0027] The term "nitrogen-based heteroaryl" (also referred to as "nitrogen-containing heteroaryl") refers to a heteroaryl, as defined above, containing at least one nitrogen atom. The nitrogen-based heteroaryl may further contain other heteroatoms such as O or S. Examples of nitrogen-based heteroaryls are imidazolyl, pyrrolyl, and pyrazolyl.

[0028] 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).

[0029] The term "arylalkenyl," as used herein, corresponds to alkenyl, as defined above, substituted by at least one aryl group, as defined above. More specifically, "aryl(C2-C6)alkenyl" refers to (C2-C6)alkenyl, as defined above, substituted by at least one aryl group, as defined above. An example of an aryl(C2-C6)alkenyl is phenylethenyl (also known as "phenethenyl").

[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 (Va) or (Vb):

[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] [In the formula, R1 is H, aryl (C1-C6) alkyl groups, aryl(C2-C6)alkenyl groups, aryl groups, heteroaryl groups, heterocycloalkyl groups, a cycloalkyl group, or -QR group (Q is O or S and R is alkyl, aryl, or aralkyl) represents the group is optionally substituted by at least one -OH, halogen, (C1-C6) alkyl optionally substituted by one or more fluorine atoms, or (C1-C6) alkyloxy; Z represents N or CR2; R2 represents H, a (C1-C4) alkyl, or a phenyl group; X and Y are either CR6 and N, or N and CR6, or CR6 and CH, respectively; R6 is H or a (C1-C4) alkyl group; n is 3, 4, 5 or 6; R3 and R4 are independently represent a group selected from a hydrogen atom, (C1-C6) alkyl, (C2-C6) alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aryl(C1-C6) alkyl, the group is optionally substituted with at least one substituent selected from the group consisting of hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; or together with the nitrogen to which they are attached form a nitrogen-based heterocycloalkyl, said nitrogen-based heterocycloalkyl optionally substituted with at least one substituent selected from the group consisting of hydroxy, oxo, (C1-C6)alkyl, (C2-C6)alkenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, aryl(C1-C6)alkyl and hydroxy(C1-C6)alkyl, said nitrogen-based heterocycloalkyl optionally fused to at least one 5- to 14-membered ring selected from aryl and heteroaryl; Each R5 independently represents H, OH, or a (C1-C4) alkyl group. isomers, solvates or any pharmaceutical salts thereof.

[0050] In certain embodiments, compounds of the present invention are those in which R1 is: an aryl group, such as phenyl, optionally substituted by at least one -OH, halogen, (C1-C6) alkyl optionally substituted by one or more fluorine atoms, or (C1-C6) alkyloxy; heteroaryl, such as thiophenyl, furanyl, benzofuranyl, pyridyl or pyrrolyl; heterocycloalkyl, such as piperidinyl, or A group selected from cyclohexenyl, phenethyl, phenethenyl, -OPh and -SPh Represents, It is of formula (I).

[0051] Preferably, R1 represents phenyl optionally substituted by at least one -OH, halogen (such as fluorine or chlorine), (C1-C6) alkyl (such as -CF3) optionally substituted by one or more fluorine atoms, or (C1-C6) alkyloxy (such as methoxy). According to a particular embodiment, R1 represents phenyl optionally substituted by at least one chlorine.

[0052] In certain embodiments where R1 is heterocycloalkyl, it is preferred that R1 is a nitrogen-based heterocycloalkyl.

[0053] In certain embodiments where R1 is heteroaryl, it is preferred that R1 is a nitrogen-based heteroaryl.

[0054] According to a particular embodiment, when R1 represents a nitrogen-based heterocycloalkyl or heteroaryl group, said group is preferably linked to the rest of the molecule by the nitrogen atom of said nitrogen-based heterocycloalkyl or heteroaryl.

[0055] In certain embodiments, R2 is H or (C1-C4) alkyl. In more particular embodiments, R2 is H, methyl, or a phenyl group. Preferably, R2 is H or methyl, and more preferably, R2 is H.

[0056] In a particular embodiment, the compounds of the invention are of formula (I) wherein Z is CR2. Preferably, Z is CR2 and R2 represents H.

[0057] X and Y in formula (I) may be either CR6 and N, or N and CR6, or CR6 and CH, respectively, where R6 is H or a (C1-C4) alkyl group.

[0058] Preferably, R6 is H or methyl, more preferably R6 is H.

[0059] In certain embodiments, compounds of the invention are of formula (I) where X and Y are N and CR6, respectively (R6 is preferably H or methyl).

[0060] In another particular embodiment, the compounds of the invention are of formula (I) where X and Y are CR6 and CH, respectively (R6 is preferably H).

[0061] In a preferred embodiment, the compounds of the invention are of formula (I) where X and Y are N and CR6, respectively, more preferably N and CH, respectively.

[0062] In a particular embodiment, the compounds of the invention are of formula (I) where n is 4, 5, or 6. In another particular embodiment, n is 3, 4, or 5. Preferably, n is 4.

[0063] In the compounds of formula (I) according to the present invention, each R5 independently represents H, OH or a (C1-C4) alkyl group. Preferably, each R5 independently represents H, OH or methyl, more preferably H or OH, and even more preferably H.

[0064] It is understood that when n is 3, 4, 5, or 6, there are 3, 4, 5, or 6 R5, respectively, and each R5 is as defined above. For example, when n is 4, the compound of formula (I) is represented as follows:

[0065] [ka]

[0066] [wherein X, Y, Z, R1, R3, and R4 are as defined above, and each R5 independently represents H, OH, or a (C1-C4) alkyl group (preferably, H, OH, or methyl, more preferably H or OH, and even more preferably H).

[0067] In certain embodiments, the compounds of the invention are of formula (I) where one of R5 is H, OH, or a (C1-C4) alkyl group (such as methyl) and the other of R5 is H. Preferably, each R5 is H.

[0068] In certain embodiments, compounds of the present invention are those in which R3 and R4 are: Independently, hydrogen atoms, (C1-C6) alkyl, preferably methyl or ethyl, cycloalkyl, preferably cyclohexyl or adamantanyl, and Aryl(C1-C6)alkyl, preferably benzyl represents a group selected from The group is Hydroxy, (C1-C6)alkoxy, preferably methoxy, heterocycloalkyl, preferably tetrahydrofuranyl or tetrahydropyranyl, and Aryl, preferably phenyl or optionally substituted by one or two substituents independently selected from the group consisting of together with the nitrogen to which they are attached form a nitrogen-based heterocycloalkyl, preferably morpholinyl, piperidinyl, piperazinyl, oxazepanyl, azepanyl, azocanyl, nortropanyl, decahydroquinolinyl, thiomorpholinyl or 6-azabicyclo[3.2.1]octanyl, The nitrogen-based heterocycloalkyl is Hydroxy, oxo, (C1-C6) alkyl, preferably methyl, aryl, preferably phenyl, aryl(C1-C6)alkyl, preferably benzyl; hydroxy(C1-C6)alkyl, preferably hydroxymethyl or hydroxyethyl and optionally substituted with up to three substituents independently selected from the group consisting of: The nitrogen-based heterocycloalkyl is optionally fused to one aryl group, preferably phenyl. It is of formula (I).

[0069] In more particular embodiments, R3 and R4 together with the nitrogen to which they are attached form a nitrogen-based heterocycloalkyl, preferably morpholinyl, piperidinyl, piperazinyl, oxazepanyl, azepanyl, azocanyl, nortropanyl, decahydroquinolinyl, thiomorpholinyl, or 6-azabicyclo[3.2.1]octanyl; The nitrogen-based heterocycloalkyl is Hydroxy, oxo, (C1-C6) alkyl, preferably methyl, aryl, preferably phenyl, aryl(C1-C6)alkyl, preferably benzyl; hydroxy(C1-C6)alkyl, preferably hydroxymethyl or hydroxyethyl and optionally substituted with up to three substituents independently selected from the group consisting of: The nitrogen-based heterocycloalkyl is optionally fused to one aryl group, preferably phenyl.

[0070] In particular, R3 and R4, together with the nitrogen to which they are attached, form a nitrogen-based heterocycloalkyl represented by formula (II):

[0071] [ka]

[0072] [In the formula, m is 1 or 2; W represents O, S, NR', (CH2)2 or CHR'; R' represents a hydrogen atom, (C1-C6) alkyl (preferably methyl), aryl (preferably phenyl) or aryl(C1-C6) alkyl (preferably benzyl); each R" independently represents a hydrogen atom, hydroxy, oxo, (C1-C6)alkyl (preferably methyl), aryl (preferably phenyl), aryl(C1-C6)alkyl (preferably benzyl), or hydroxy(C1-C6)alkyl (preferably hydroxymethyl or hydroxyethyl). can be formed.

[0073] In certain embodiments, each R" independently represents a hydrogen atom, a (C1-C6) alkyl (preferably methyl), an aryl (preferably phenyl), or an aryl(C1-C6) alkyl (preferably benzyl).

[0074] In certain embodiments, R3 and R4 together with the nitrogen to which they are attached form a morpholinyl group.

[0075] In certain embodiments, the compounds of the present invention have the following features: ⇒ n is 4 and / or ⇒ X and Y are N and CR6, respectively, where R6 is H or methyl (preferably H), and / or ⇒ R1 represents an aryl group (preferably phenyl) optionally substituted by at least one -OH, halogen (such as fluorine or chlorine), (C1-C6) alkyl (such as -CF3) optionally substituted by one or more fluorine atoms, or (C1-C6) alkyloxy (such as methoxy), and / or ⇒ Z is CR2, where R2 represents H, methyl or phenyl (preferably H), and / or ⇒ R3 and R4 are Independently, hydrogen atoms, (C1-C6) alkyl, preferably methyl or ethyl, cycloalkyl, preferably cyclohexyl or adamantanyl, and Aryl(C1-C6)alkyl, preferably benzyl represents a group selected from The group is Hydroxy, (C1-C6)alkoxy, preferably methoxy, heterocycloalkyl, preferably tetrahydrofuranyl or tetrahydropyranyl, and Aryl, preferably phenyl or optionally substituted by one or two substituents independently selected from the group consisting of together with the nitrogen to which they are attached form a nitrogen-based heterocycloalkyl, preferably morpholinyl, piperidinyl, piperazinyl, oxazepanyl, azepanyl, azocanyl, nortropanyl, decahydroquinolinyl, thiomorpholinyl or 6-azabicyclo[3.2.1]octanyl, The nitrogen-based heterocycloalkyl is Hydroxy, oxo, (C1-C6) alkyl, preferably methyl, aryl, preferably phenyl, aryl(C1-C6)alkyl, preferably benzyl; hydroxy(C1-C6)alkyl, preferably hydroxymethyl or hydroxyethyl and optionally substituted with up to three substituents independently selected from the group consisting of: said nitrogen-based heterocycloalkyl is optionally fused to one aryl group, preferably phenyl; and / or ⇒ Each R5 is H and pharmaceutical salts thereof, wherein at least one, preferably all, of the following conditions are satisfied:

[0076] In certain embodiments, the compounds of the present invention are Z represents CH or N, preferably CH; - X and Y are either N and CR6 or CH and CH (preferably N and CR6), respectively, where R6 is H or (C1-C4) alkyl (e.g. methyl); n is 3 or 4, preferably n is 4, It is of formula (I).

[0077] In certain embodiments, compounds of the present invention are those in which R1 is: aryl groups such as phenyl, heteroaryl groups such as thiophenyl, or Heterocycloalkyl groups such as piperidinyl represents the group is optionally substituted by at least one -OH, halogen, (C1-C6) alkyl optionally substituted by one or more fluorine atoms, or (C1-C6) alkyloxy; It is of formula (I).

[0078] In such embodiments, R1 is preferably an aryl group or a heterocycloalkyl group, more preferably an aryl.

[0079] In certain embodiments, compounds of the invention are of formula (I) wherein R3 and R4 independently represent a group selected from H, (C1-C6) alkyl (e.g., methyl or ethyl), cycloalkyl (e.g., adamantanyl), and aryl(C1-C6) alkyl (e.g., benzyl), which are optionally substituted by at least one substituent selected from the group consisting of (C1-C6) alkoxy, heterocycloalkyl (e.g., tetrahydrofuranyl or tetrahydropyranyl), and aryl (e.g., phenyl).

[0080] In another particular embodiment, the compounds of the present invention are of formula (I) where R3 and R4, together with the nitrogen to which they are attached, form a nitrogen-based heterocycloalkyl, said nitrogen-based heterocycloalkyl optionally substituted with at least one substituent selected from the group consisting of (C1-C6)alkyl, aryl, and aryl(C1-C6)alkyl, and said nitrogen-based heterocycloalkyl optionally fused to at least one 5-14 membered ring selected from aryl (e.g., phenyl).

[0081] Preferred nitrogen-based heterocycloalkyl groups are azepanyl, oxazepanyl, piperidinyl, azocanyl, morpholinyl, thiomorpholinyl, or piperazinyl.

[0082] In certain embodiments, the compounds of the present invention are Z represents CH; - X and Y are either N and CR6, or CH and CH, respectively, where R6 is H or (C1-C4) alkyl (e.g. methyl); n is 3 or 4, preferably n is 4, - R1, aryl groups such as phenyl, heteroaryl groups such as thiophenyl, or Heterocycloalkyl groups such as piperidinyl represents the group is optionally substituted by at least one -OH, halogen, (C1-C6) alkyl optionally substituted by one or more fluorine atoms, or (C1-C6) alkyloxy; R3 and R4 are independently represent a group selected from H, (C1-C6)alkyl (e.g., methyl or ethyl), cycloalkyl (e.g., adamantanyl), and aryl(C1-C6)alkyl (e.g., benzyl); the group is optionally substituted with at least one substituent selected from the group consisting of (C1-C6)alkoxy, heterocycloalkyl (e.g., tetrahydrofuranyl or tetrahydropyranyl), and aryl (e.g., phenyl); or together with the nitrogen to which they are attached to form a nitrogen-based heterocycloalkyl; the nitrogen-based heterocycloalkyl is optionally substituted with at least one substituent selected from the group consisting of (C1-C6) alkyl, aryl, and aryl(C1-C6) alkyl, and the nitrogen-based heterocycloalkyl is optionally fused to at least one 5- to 14-membered ring selected from aryl (e.g., phenyl); each R5 independently represents H; It is of formula (I).

[0083] In certain embodiments, the compounds of the present invention are Z represents CH or N, preferably CH; - X and Y are either N and CR6 or CH and CH (preferably N and CR6), respectively, where R6 is H or (C1-C4) alkyl (e.g. methyl); n is 3 or 4, preferably n is 4, - R1, an aryl group such as phenyl, or Heterocycloalkyl groups such as piperidinyl represents R3 and R4 are independently represent a group selected from H, (C1-C6)alkyl (e.g., methyl or ethyl) and aryl(C1-C6)alkyl (e.g., benzyl), or together with the nitrogen to which they are attached to form a nitrogen-based heterocycloalkyl; the nitrogen-based heterocycloalkyl is optionally substituted with at least one substituent selected from the group consisting of aryl and aryl(C1-C6)alkyl, and the nitrogen-based heterocycloalkyl is optionally fused to at least one 5- to 14-membered ring selected from aryl (e.g., phenyl); each R5 independently represents H; It is of formula (I).

[0084] In certain embodiments, the compounds of the present invention are R1 is selected from H, an aryl(C1-C6)alkyl group, an aryl(C2-C6)alkenyl group, an aryl group, a heteroaryl group or a -QR group, where Q is O or S and R is aryl; the group is optionally substituted by at least one -OH, halogen, (C1-C6) alkyl optionally substituted by one or more fluorine atoms, or (C1-C6) alkyloxy; Z is CR2, where R2 is H or phenyl; - X and Y are N and CR6, respectively; - n is 3, 4, 5 or 6, preferably 4 or 5; R5 is H, provided that one of R1 and R2 is different from a hydrogen atom, and the other of R1 and R2 is a hydrogen atom (preferably, R1 is different from H, and R2 is H); It is of formula (I).

[0085] In such embodiments, R1 is preferably selected from H, an aryl group, and a heteroaryl group.

[0086] Preferably, the compound of the present invention is R1 is H or an aryl group, said aryl group being preferably phenyl, the aryl group is optionally substituted with at least one halogen, preferably chlorine; Z is CR2, where R2 is H or phenyl; - X and Y are N and CR6, respectively; - n is 3, 4, 5 or 6, preferably 4 or 5; R5 is H, provided that one of R1 and R2 is different from a hydrogen atom and the other of R1 and R2 is a hydrogen atom (such as disclosed by the final formula depicted in Scheme 1); It is of formula (I).

[0087] In a more preferred embodiment, the compound of the present invention is R1 is an aryl group, said aryl group being preferably phenyl, optionally substituted by at least one halogen, preferably chlorine, Z is CR2, where R2 is H; - X and Y are N and CR6, respectively; - n is 3, 4, 5 or 6, preferably 4 or 5; R5 is H; It is of formula (I).

[0088] This embodiment can be particularly illustrated by formulas 9-13 depicted in Scheme 1.

[0089] In another more preferred embodiment, the compound of the invention is R1 is H, Z is CR2, where R2 is phenyl; X and Y are N and CR6, respectively (R6 is preferably H or methyl); - n is 4 or 5; R5 is H; It is of formula (I).

[0090] This embodiment can be particularly illustrated by formulas 14-15 depicted in Scheme 1.

[0091] 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.

[0092] 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.

[0093] 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. Therefore, 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. 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 E.L. Eliel (Mcgraw Hill, 1962) and Tables of Resolving Agents, by S.H. Wilen.

[0094] Those skilled in the art of organic chemistry will recognize that many organic compounds can form complexes with the 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) are within the scope of the present invention.

[0095] 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.

[0096] 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.

[0097] For example, preferred salt forms include hydrochloride salts.

[0098] In certain embodiments, the compound of formula (I) is 2-(4-morpholinobutyl)-4-phenylpyridazin-3(2H)-one hydrochloride (10b-HCl), 2-(3-(benzyl(methyl)amino)propyl)-4-phenylpyridazin-3(2H)-one (9a); 2-(3-(azepan-1-yl)propyl)-4-phenylpyridazin-3(2H)-one (9b); 2-[3-(morpholin-4-yl)propyl]-4-phenyl-2,3-dihydropyridazin-3-one (9c); 2-(4-morpholinobutyl)-4-phenylpyridazin-3(2H)-one (10b); 2-(4-(benzyl(methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one (10a); 2-(4-(1,4-oxazepan-4-yl)butyl)-4-phenylpyridazin-3(2H)-one (10c); 4-phenyl-2-(4-(piperidin-1-yl)butyl)pyridazin-3(2H)-one (10d); 2-(4-(azepan-1-yl)butyl)-4-phenylpyridazin-3(2H)-one (10e); 2-(4-(azocan-1-yl)butyl)-4-phenylpyridazin-3(2H)-one (10f); 2-(4-(3,4-dihydroisoquinolin-2(1H)-yl)butyl)-4-phenylpyridazin-3(2H)-one (10g); 4-phenyl-2-(4-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)butyl)pyridazin-3(2H)-one (10h); 2-(4-(adamantan-1-ylamino)butyl)-4-phenylpyridazin-3(2H)-one (10i); 2-(4-(adamantan-1-yl(methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one (10j); 4-phenyl-2-(4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)butyl)pyridazin-3(2H)-one (10k); 8-(4-(6-oxo-5-phenylpyridazin-1(6H)-yl)butyl-8-azabicyclo[3.2.1octan-3-one (10l); 2-(4-(benzyl((tetrahydrofuran-2-yl)methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one (10m); 2-(4-((2-methoxy-1-phenylethyl)amino)butyl)-4-phenylpyridazin-3(2H)-one (10n); 2-(4-((2-methoxy-1-phenylethyl)(methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one (10o); 2-(4-((2-hydroxyethyl)(methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one (10p); 2-(4-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one (10q); 4-phenyl-2-(4-(3-phenylpiperidin-1-yl)butyl)pyridazin-3(2H)-one (10r); 4-phenyl-2-(4-(4-phenylpiperidin-1-yl)butyl)pyridazin-3(2H)-one (10s); 2-(4-(3-(hydroxymethyl)piperidin-1-yl)butyl)-4-phenylpyridazin-3(2H)-one (10t); 2-(4-(2-(2-hydroxyethyl)piperidin-1-yl)butyl)-4-phenylpyridazin-3(2H)-one (10u); 4-phenyl-2-(4-(3-phenylmorpholino)butyl)pyridazin-3(2H)-one (10v); 4-phenyl-2-(4-(2-phenylmorpholino)butyl)pyridazin-3(2H)-one (10w); 2-(4-(2,6-dimethylmorpholino)butyl)-4-phenylpyridazin-3(2H)-one (10x); 2-[4-(4-benzylpiperazin-1-yl)butyl]-4-phenyl-2,3-dihydropyridazin-3-one (10z); 2-[4-(4-benzylpiperidin-1-yl)butyl]-4-phenyl-2,3-dihydropyridazin-3-one (11a); 2-{4-[benzyl(ethyl)amino]butyl}-4-phenyl-2,3-dihydropyridazin-3-one (11b); 2-{4-[cyclohexyl(methyl)amino]butyl}-4-phenyl-2,3-dihydropyridazin-3-one (11c); 4-phenyl-2-[4-(4-phenylpiperazin-1-yl)butyl]-2,3-dihydropyridazin-3-one (11d); 2-{4-[(4aR,8aS)-decahydroquinolin-1-yl]butyl}-4-phenyl-2,3-dihydropyridazin-3-one (11e); 2-(4-{2-oxa-6-azaspiro[3.3]heptan-6-yl}butyl)-4-phenyl-2,3-dihydropyridazin-3-one (11t); 4-phenyl-2-[4-(thiomorpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one (11u); 2-{4-[cyclohexyl(ethyl)amino]butyl}-4-phenyl-2,3-dihydropyridazin-3-one (11 g); 4-(4-fluorophenyl)-2-(4-morpholinobutyl)pyridazin-3(2H)-one (11h); 4-(4-hydroxyphenyl)-2-(4-morpholinobutyl)pyridazin-3(2H)-one (11i); 2-(5-morpholinopentyl)-4-phenylpyridazin-3(2H)-one (12); 2-[6-(morpholin-4-yl)hexyl]-4-phenyl-2,3-dihydropyridazin-3-one (13); 2-(4-morpholinobutyl)-5-phenylpyridazin-3(2H)-one (14); 2-(5-morpholinopentyl)-5-phenylpyridazin-3(2H)-one (15); 2-(4-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)butyl)-4-phenylpyridazin-3(2H)-one (16); 4-(4-Methoxyphenyl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one (11j); 4-(4-chlorophenyl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one (11k); 4-(3-chlorophenyl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one (11l); 4-(2-chlorophenyl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one (11m); 2-[4-(morpholin-4-yl)butyl]-4-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazin-3-one (11n); 2-[4-(morpholin-4-yl)butyl]-4-(thiophen-3-yl)-2,3-dihydropyridazin-3-one (11o); 4-(furan-3-yl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one (11p); 4-(3a,7a-dihydro-1-benzofuran-2-yl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one (11q); 2-[4-(morpholin-4-yl)butyl]-4-(pyridin-3-yl)-2,3-dihydropyridazin-3-one (11r); 2-{4-[benzyl(methyl)amino]butyl}-6-methyl-4-phenyl-2,3-dihydropyridazin-3-one (11v); 2-[4-(azepan-1-yl)butyl]-6-methyl-4-phenyl-2,3-dihydropyridazin-3-one (11w); 2-[4-(morpholin-4-yl)butyl]-4-[(E)-2-phenylethenyl]-2,3-dihydropyridazin-3-one (20a); 2-[4-(morpholin-4-yl)butyl]-4-(2-phenylethyl)-2,3-dihydropyridazin-3-one (21a); 4-(cyclohex-1-en-1-yl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one (23a); 2-(4-morpholinobutyl)-4-(piperidin-1-yl)pyridazin-3(2H)-one (25a); 2-[4-(morpholin-4-yl)butyl]-4-(1H-pyrrol-1-yl)-2,3-dihydropyridazin-3-one (27a); 2-[4-(morpholin-4-yl)butyl]-4-(phenylsulfanyl)-2,3-dihydropyridazin-3-one (28a); 2-[4-(morpholin-4-yl)butyl]-4-phenoxy-2,3-dihydropyridazin-3-one (29a); 2-(4-(benzyl(methyl)amino)-3-hydroxybutyl)-4-phenylpyridazin-3(2H)-one (33a); 2-methyl-3-(4-morpholinobutyl)-5-phenylpyrimidin-4(3H)-one (40a); 3-[4-(morpholin-4-yl)butyl]-5-phenyl-3,4-dihydropyrimidin-4-one (40b); 1-[4-(morpholin-4-yl)butyl]-3-phenyl-1,2-dihydropyridin-2-one (41a); 1-[4-(morpholin-4-yl)butyl]-3-phenyl-1,2-dihydropyrazin-2-one (46a); and 1-{4-[benzyl(methyl)amino]butyl}-3-phenyl-1,2-dihydropyrazin-2-one (41b) is selected from the group consisting of:

[0099] Preferably, the compound is 2-(3-(benzyl(methyl)amino)propyl)-4-phenylpyridazin-3(2H)-one (9a); 2-(3-(azepan-1-yl)propyl)-4-phenylpyridazin-3(2H)-one (9b); 2-(4-(benzyl(methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one (10a); 2-(4-(1,4-oxazepan-4-yl)butyl)-4-phenylpyridazin-3(2H)-one (10c); 4-phenyl-2-(4-(piperidin-1-yl)butyl)pyridazin-3(2H)-one (10d); 2-(4-(azepan-1-yl)butyl)-4-phenylpyridazin-3(2H)-one (10e); 2-(4-(azocan-1-yl)butyl)-4-phenylpyridazin-3(2H)-one (10f); 2-(4-(3,4-dihydroisoquinolin-2(1H)-yl)butyl)-4-phenylpyridazin-3(2H)-one (10g); 4-phenyl-2-(4-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)butyl)pyridazin-3(2H)-one (10h); 2-(4-(adamantan-1-ylamino)butyl)-4-phenylpyridazin-3(2H)-one (10i); 2-(4-(benzyl((tetrahydrofuran-2-yl)methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one (10m); 2-(4-((2-methoxy-1-phenylethyl)(methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one (10o); 2-(4-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one (10q); 4-phenyl-2-(4-(3-phenylpiperidin-1-yl)butyl)pyridazin-3(2H)-one (10r); 4-phenyl-2-(4-(4-phenylpiperidin-1-yl)butyl)pyridazin-3(2H)-one (10s); 2-(4-(2,6-dimethylmorpholino)butyl)-4-phenylpyridazin-3(2H)-one (10x); 4-phenyl-2-(4-(2-phenylmorpholino)butyl)pyridazin-3(2H)-one (10w); 2-[4-(4-benzylpiperazin-1-yl)butyl]-4-phenyl-2,3-dihydropyridazin-3-one (10z); 2-[4-(4-benzylpiperidin-1-yl)butyl]-4-phenyl-2,3-dihydropyridazin-3-one (11a); 2-{4-[benzyl(ethyl)amino]butyl}-4-phenyl-2,3-dihydropyridazin-3-one (11b); 2-[4-(morpholin-4-yl)butyl]-4-(thiophen-3-yl)-2,3-dihydropyridazin-3-one (11o); 4-phenyl-2-[4-(thiomorpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one (11u); 2-{4-[benzyl(methyl)amino]butyl}-6-methyl-4-phenyl-2,3-dihydropyridazin-3-one (11v); 2-[4-(azepan-1-yl)butyl]-6-methyl-4-phenyl-2,3-dihydropyridazin-3-one (11w); 2-(4-morpholinobutyl)-4-(piperidin-1-yl)pyridazin-3(2H)-one (25a); and 1-{4-[benzyl(methyl)amino]butyl}-3-phenyl-1,2-dihydropyrazin-2-one (41b) is selected from the group consisting of:

[0100] More preferably, the compound is 2-(3-(benzyl(methyl)amino)propyl)-4-phenylpyridazin-3(2H)-one (9a); 2-(4-(benzyl(methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one (10a); 2-(4-(azocan-1-yl)butyl)-4-phenylpyridazin-3(2H)-one (10f); 2-(4-(3,4-dihydroisoquinolin-2(1H)-yl)butyl)-4-phenylpyridazin-3(2H)-one (10g); 4-phenyl-2-(4-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)butyl)pyridazin-3(2H)-one (10h); 4-phenyl-2-(4-(3-phenylpiperidin-1-yl)butyl)pyridazin-3(2H)-one (10r); 4-phenyl-2-(4-(4-phenylpiperidin-1-yl)butyl)pyridazin-3(2H)-one (10s); 2-[4-(4-benzylpiperazin-1-yl)butyl]-4-phenyl-2,3-dihydropyridazin-3-one (10z); 2-[4-(4-benzylpiperidin-1-yl)butyl]-4-phenyl-2,3-dihydropyridazin-3-one (11a); 2-{4-[benzyl(ethyl)amino]butyl}-4-phenyl-2,3-dihydropyridazin-3-one (11b); 4-phenyl-2-[4-(thiomorpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one (11u); 2-{4-[benzyl(methyl)amino]butyl}-6-methyl-4-phenyl-2,3-dihydropyridazin-3-one (11v); 2-[4-(azepan-1-yl)butyl]-6-methyl-4-phenyl-2,3-dihydropyridazin-3-one (11w); and 2-(4-morpholinobutyl)-4-(piperidin-1-yl)pyridazin-3(2H)-one (25a) is selected from the group consisting of:

[0101] 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.

[0102] 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.

[0103] 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).

[0104] 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).

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] Methods for diagnosing these diseases are well known to those skilled in the art.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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).

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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]

[0129] 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.

[0130] Part A. Preparation of Compounds According to the Invention General Synthetic Methods and Examples Method 1: Preparation of N-substituted 4-Ar(5-Ar)-pyridazin-3(2H)-ones: 9-15 The preparation of compounds of formulas 9–15 can be carried out along various synthetic routes using conventional methods (see Scheme 1). Starting from commercially available or previously described 4- or 5-halogenopyridazinones, Suzuki-Miyaura cross-coupling reactions with arylboronic acids in the presence of tetrakis(triphenylphosphine)palladium afforded the corresponding 4- or 5-arylpyridazinone derivatives 1–2. N-Alkylation of intermediates 1–2 with appropriate alkyl dihalides using NaH in DMF afforded intermediates 3–8. Finally, nucleophilic substitution reactions with appropriate aliphatic amines NHR3R4 afforded compounds of general formulas 9–15.

[0131] [ka]

[0132] Conditions: a) Ar-B(OH)2, Pd(PPh3)4, Na2CO3, toluene, EtOH, H2O, 120 °C, 16 h. b) Br(CH2) n'+3- X, NaH, DMF, 0℃→25℃, 12 hours. c) K2CO3, HNR3R4, MeCN. n'=0, 1, 2 or 3

[0133] 4-Phenylpyridazin-3(2H)-one 1a A microwave vial (under oven-dried argon) was charged with phenylboronic acid (2.06 g, 16.85 mmol, 1.1 equiv.), 4-chloro-2,3-dihydropyridazin-3-one (2.0 g, 15.32 mmol, 1.0 equiv.), sodium carbonate (4.87 g, 45.97 mmol, 3 equiv.), and then tetrakis(triphenylphosphine)palladium(0) (885.3 mg, 5 mol%) was added, followed by toluene (38 mL), HO (8 mL), and EtOH (8 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 typically 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 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 silica gel chromatography (EtOAc / heptane, 1 / 1, 7 / 3 to 1 / 0) to afford a yellow solid (mass = 2.34 g, yield = 89%). 1 H NMR (400 MHz, DMSO-d6) δ 13.20 (bs, 1H), 7.95 (d, J = 3.9 Hz, 1H), 7.89-7.84 (m, 2H), 7.58 (d, J = 3.9 Hz, 1H), 7.49-7.41 (m, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 160.9, 138.7, 137.8, 134.2, 129.8, 129.2, 128.9, 128.7.

[0134] 4-(4-Fluorophenyl)pyridazin-3(2H)-one 1b Using the same procedure as described for the preparation of compound 1a, starting from 4-chloro-2,3-dihydropyridazin-3-one (180.0 mg, 1.37 mmol, 1 equiv.) and 4-fluorobenzeneboronic acid (212.2 mg, 1.51 mmol, 1.1 equiv.), the title compound was obtained as an orange powder (mass=160.1 mg, yield=61%). 1 H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 7.96 -7.90 (m, 2H), 7.89 (d, J = 4.1 Hz, 1H), 7.53 (d, J = 4.1 Hz, 1H), 7.20 (t, J = 8.6 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 163.7, 161.3, 160.3, 137.7, 137.5, 131.2, 131.1, 130.5, 130.4, 129.8, 129.7, 128.1, 114.9, 114.7.

[0135] 4-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)pyridazin-3(2H)-one 1c Using the same procedure as described for the preparation of compound 1a, starting from 4-chloro-2,3-dihydropyridazin-3-one (180.0 mg, 1.37 mmol, 1 equiv.) and 4-(2-tetrahydropyranyloxy)phenylboronic acid (336.8 mg, 1.51 mmol, 1.1 equiv.), the title compound was obtained as a yellow solid (mass=173.1 mg, yield=46%). 1 H NMR (400 MHz, DMSO-d6) δ 13.1 (s, 1H), 7.92 (J = 4.3 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 4.3 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 5.59-5.53 (m, 1H), 3.79-3.71 (m, 1H), 3.61-3.53 (m, 1H), 1.94-1.70 (m, 3H), 168-1.47 (m, 3H).13 C NMR (101 MHz, DMSO-d6) δ 161.1, 157.9, 136.1, 137.8, 130.3, 127.9, 127.2, 116.5, 96.1, 62.0, 30.2, 25.1, 19.0.

[0136] 6-Methyl-4-phenyl-2,3-dihydropyridazin-3-one 1d 1 :For preparation, 1a - Chin. J. Org. Chem., 2014, 34, 722~728; 1b - See Pest Manag Sci., 2006, 62, 522-530.

[0137] 5-Phenylpyridazin-3(2H)-one 2 2 :For preparation, 2 -See Tetrahedron, 2004, 60(52), 12177-12189.

[0138] 2-(3-chloropropyl)-4-phenylpyridazin-3(2H)-one 3a The reaction was carried out under an argon atmosphere under anhydrous conditions. To a solution of 4-phenylpyridazin-3(2H)-one 1 (50 mg, 0.29 mmol, 1 equiv) in dry DMF (1.0 mL) cooled to 0 °C, NaH (1.5 equiv, 10.45 mg, 0.43 mmol) was added in small portions, and the mixture was stirred at 0 °C for 30 min. 1-Bromo-3-chloropropane (137.2 mg, 86 μL, 0.87 mmol, 3.0 equiv) was then added dropwise at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was quenched with HO (5 mL) and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The crude was purified by column chromatography on silica gel (solid loading, eluent: heptane / EtOAc: 3 / 1) to give the title compound as a yellow oil (mass=49 mg, yield=68%). 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 4.2 Hz, 1H), 7.77-7.72 (m, 2H), 7.44-7.37 (m, 3H), 7.26 (d, J = 4.2 Hz, 1H), 4.38 (t, J = 6.8 Hz, 2H), 3.60 (t, J = 6.5 Hz, 2H), 2.31 (quintet, J = 6.8 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.1, 139.8, 136.4, 133.7, 129.6, 128.6, 128.4, 127.6, 50.2, 42.1, 31.2.

[0139] 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a Using the same procedure as described for 3a, starting from 4-phenylpyridazin-3(2H)-one 1 (620 mg, 3.60 mmol, 1 equiv.) and 1-bromo-4-chlorobutane (1.85 g, 1.25 mL, 10.8 mmol, 3 equiv.) and a 60% dispersion of NaH in mineral oil (216 mg, 5.40 mmol, 1.5 equiv.), the title compound was obtained as a yellow gum (mass = 753 mg, yield = 80%). 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 4.1 Hz, 1H), 7.64-7.59 (m, 2H), 7.32-7.22 (m, 3H), 7.12 (d, J = 4.1 Hz, 1 H), 4.12 (t J = 7.1 Hz, 2H), 3.43 (t, J = 6.5 Hz, 2H), 1.87 (quintet, J = 7.1 Hz, 2H), 1.87 (quintet, J = 6.8 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.0, 139.8, 136.3, 133.9, 129.6, 128.7, 128.4, 127.5, 51.6, 44.4, 33.0, 29.6, 25.7.

[0140] 2-(4-chlorobutyl)-4-(4-fluorophenyl)-2,3-dihydropyridazin-3-one 4b Using the same procedure as described for 3a, starting from 4-(4-fluorophenyl)pyridazin-3(2H)-one 1b (150 mg, 0.79 mmol, 1 equiv.) and 1-bromo-4-chlorobutane (405.7 mg, 274 μL, 2.4 mmol, 3 equiv.) and NaH95% (29.9 mg, 1.18 mmol, 1.5 equiv.), the title compound was obtained as a yellow oil (mass=115 mg, yield=52%). HPLC C18: 10%~100% 8 min: 4b (retention time (RT): 3.99 min); diadduct (RT: 4.11 min) 1 H NMR (400 MHz, CDCl3) δ 7.83-7.77 (m, 3H), 7.25 (d, J = 4.2 Hz, 1H), 7.15-7.08 (m, 2H), 4.27 (t, J = 7.2 Hz, 2H), 3.58 (t, J = 6.6 Hz, 2H), 2.06-1.98 (m, 2H), 1.89-1.81 (m, 2H). 1 H NMR diadduct (400 MHz, CDCl3) δ .83-7.77 (m, 3H), 7.25 (d, J = 4.2 Hz, 1H), 7.15-7.08 (m, 2H), 4.27 (t, J = 7.2 Hz, 2H), 3.45 (m, 2H), 2.06-1.90 (m, 2H)

[0141] 2-(4-Chlorobutyl)-4-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)pyridazin-3(2H)-one 4c Using the same procedure as described for 3a, starting from 4-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)pyridazin-3(2H)-one 1c (150 mg, 0.55 mmol, 1 equiv.) and 1-bromo-4-chlorobutane (283.4 mg, 191 μL, 1.65 mmol, 3 equiv.) and NaH95% (20.9 mg, 0.83 mmol, 1.5 equiv.), the title compound was obtained as a yellow oil (mass=80 mg, yield=40%). 1 H NMR (400 MHz, CDCl3) δ 7.79-7.73 (m, 3H), 7.21 (d, J = 4.3 Hz, 1H), 7.10-7.06 (m, 2H), 5.46 (t, J = 3.2 Hz, 1H), 4.25 (t, J = 7.1 Hz, 2 H), 3.85 (ddd, J = 11.4 Hz, J = 9.8 Hz, J = 3.2 Hz, 1H), 3.61-3.54 (m, 1H), 3.56 (t, J = 6.5 Hz, 2H), 2.04-1.95 (m, 3H), 1.87-1.79 (m, 4H), 1.72-1.64 (m, 3H).

[0142] 2-(4-chlorobutyl)-6-methyl-4-phenyl-2,3-dihydropyridazin-3-one 4d Using the same procedure as described for 3a, starting from 6-methyl-4-phenyl-2,3-dihydropyridazin-3-one 1d (75 mg, 0.4 mmol, 1 equiv.) and 1-bromo-4-chlorobutane (207.2 mg, 140 μL, 1.20 mmol, 3 equiv.) and NaH100% (14.5 mg, 0.60 mmol, 1.5 equiv.), the title compound was obtained as a yellow oil (mass=97 mg, yield=87%). 1H NMR (400 MHz, CDCl3) δ 7.77-7.72 (m, 2H), 7.44-7.35 (m, 3H), 7.16 (s, 1H), 4.21 (t, J = 7.222 Hz, 2H), 3.57 (t, J = 6.6 Hz, 2H), 2.35 (s, 3H), 1.99 (quintet, J = 7.2 Hz, 2H), 1.88-1.80 (m, 2H). ). 13 C NMR (101 MHz, CDCl3) δ 159.3, 144.5, 139.4, 134.0, 129.5, 129.4, 128.7, 128.3, 51.3, 44.5, 29.7, 25.8, 21.1.

[0143] 2-(5-Bromopentyl)-4-phenyl-2,3-dihydropyridazin-3-one 5a Using the same procedure as described for 3a, starting from 4-phenylpyridazin-3(2H)-one 1 (120 mg, 0.70 mmol, 1 equiv.), 1,5-dibromopentane (490.8 mg, 0.29 mL, 2.09 mmol, 3 equiv.), and a 60% dispersion of NaH in mineral oil (41.8 mg, 1.04 mmol, 1.5 equiv.), the title compound was obtained as a gum (mass = 110 mg, yield = 49%). The presence of the diadduct 2,2'-(butane-1,4-diyl)bis(4-(4-fluorophenyl)pyridazin-3(2H)-one) was confirmed. 1 Detected by 1 H NMR and HPLC (approximately 20%). The product was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 4.2 Hz, 1H), 7.81-7.77 (m, 2H), 7.48-7.40 (m, 3H), 7.28 (d, J = 4.2 Hz, 1H), 4.26 (t, J = 7.6 Hz, 2H), 3.42 (J = 6.8 Hz, 2H), 1.97-1.90 (m, 4H), 1.58-1.50 (m, 2H).

[0144] 2-(6-chlorohexyl)-4-phenyl-2,3-dihydropyridazin-3-one 6a Using the same procedure as described for 3a, starting from 4-phenylpyridazin-3(2H)-one 1 (50 mg, 0.29 mmol, 1 equiv.) and 1-bromo-6-chlorohexane (173.8 mg, 0.87 mmol, 130 μL, 3 equiv.) and NaH (10.4 mg, 0.43 mmol, 1.5 equiv.), the title compound was obtained as a yellow oil (mass=52.3 mg, yield=62%). 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 4.2 Hz, 1H), 7.64-7.60 (m, 2H), 7.31-7.23 (m, 3H), 7.11(d, J = 4.2 Hz, 1H), 4.08 (t, J = 7.5 Hz, 2H), 3.36 (t, J = 6.7 Hz, 2H), 1.71 (quintet, J = 7.5 Hz, 2H), 1.62 (quintet, J = 6.7 Hz, 2H), 1.39-1.20 (m, 4H). 13 C NMR (101 MHz, CDCl3) δ 160.0, 139.7, 136.2, 134.0, 129.5, 128.7,128.4, 127.4, 52.5, 45.0, 32.4, 28.1, 26.5, 26.0.

[0145] 2-(4-chlorobutyl)-5-phenylpyridazin-3(2H)-one 7a Using the same procedure as described for 3a, starting from 5-phenylpyridazin-3(2H)-one 2 (200 mg, 1.16 mmol, 1 equiv.), 1-bromo-4-chlorobutane (597.5 mg, 0.40 mL, 3.48 mmol, 3 equiv.), and a 60% dispersion of NaH in mineral oil (41.8 mg, 1.04 mmol, 1.5 equiv.), the title compound was obtained as a gum (mass = 209 mg, yield = 68%). The presence of the diadduct (2,2'-(butane-1,4-diyl)bis(5-phenylpyridazin-3(2H)-one) was confirmed. 1Detected by 1 H NMR and HPLC (approximately 20%). The product was used in the next step without further purification. HPLC: C18: 10%~100%, 8 min: 4a (RT: 4.00); diadduct (RT: 4.017) 1 H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 2.3 Hz, 1H), 7.60-7.54(m, 2H), 7.53-7.47 (m, 3H), 7.06 (d, J = 2.3 Hz, 1H), 4.24(t, J = 7.1 Hz, 2H), 3.6 (t, J = 6.5 Hz, 2H), 2.06-1.98 (m, 2H), 1.91-1.83 (m, 2H). 1 HNMR diadduct (400 MHz, CDCl3) δ .06 (d, J = 2.3 Hz, 2H), 7.60-7.54(m, 4H), 7.53-7.47 (m, 6H), 7.06 (d, J = 2.3 Hz, 2H), 4.24(t, J = 7.1 Hz, 2H), 3.6 (t, J = 6.5 Hz, 2H), 2.06-1.98 (m, 2H), 1.98-1.93 (m, 2H).

[0146] 2-(5-chloropentyl)-5-phenylpyridazin-3(2H)-one 8a Using the same procedure as described for 3a, starting from 5-phenylpyridazin-3(2H)-one 2 (200 mg, 1.16 mmol, 1 equiv.), 1,5-dibromopentane (801.3 mg, 0.48 mL, 3.48 mmol, 3 equiv.) and a 60% dispersion of NaH in mineral oil (69.7 mg, 1.74 mmol, 1.5 equiv.), the title compound was obtained (mass = 256 mg, yield = 69%). The presence of the diadduct (2,2'-(pentane-1,5-diyl)bis(5-phenylpyridazin-3(2H)-one) was confirmed. 1 Detected by 1 H NMR and HPLC (approximately 15%). The product was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 2.3 Hz, 1H), 7.61-7.55 (m, 2H), 7.53-7.48 (m, 3H), 7.06 (d, J = 2.3 Hz, 1H), 4.22 (t, J = 7.3 Hz, 2H) , 3.42 (t, J = 6.8 Hz, 2H), 1.98-1.84 (m, 4H), 1.60-1.49 (m, 2H).

[0147] (Example A-1) 4-Phenyl-2-(4-(piperidin-1-yl)butyl)pyridazin-3(2H)-one 10d To a solution of 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (125 mg, 0.38 mmol, 1 equiv.) in MeCN (1.35 mL) under argon was added piperidine (129.6 mg, 1.52 mmol, 4 equiv.), KCO (105.2 mg, 0.76 mmol, 2 equiv.), and NaI (5.7 mg, 10 mol%), and the reaction mixture was heated at 80° C. under argon overnight. The mixture was then quenched with HO (15 mL) and extracted twice with EtOAc (10 mL). The combined organic layers were dried over NaSO, filtered, and evaporated to dryness. The resulting residue was purified by silica gel flash chromatography using a gradient of 2% to 5% MeOH in EtOAc to give the title compound 10d (mass = 95 mg, yield = 80%). 1 H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 4.2 Hz, 1H), 7.80-7.75 (m, 2H), 7.47-7.38 (m, 3H), 7.27 (d, J = 4.2 Hz, 1H), 4.26 (t, J = 7.4 Hz, 2H), 2.49-2.32 (m, 6H), 1.87 (quintet, J = 7.5 Hz, 2H), 1.66-1.54 (m, 6H), 1.47-1.39 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 160.0, 140.4, 136.1, 134.0, 129.5, 128.7, 128.4, 127.4, 58.9, 54.5, 52.4, 26.5, 25.7, 24.3, 23.9

[0148] 10d 4-phenyl-2-(4-(piperidin-1-yl)butyl)pyridazin-3(2H)-one hydrochloride 95 mg of the above solid was dissolved in a minimum amount of methanol, and the solution was treated with excess 2 N HCl in EtO (180 μL). 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 and then lyophilized to afford the title compound as the hydrochloride salt (mass = 98 mg). LC / MS (M+H) = 312.20

[0149] 2-(4-morpholinobutyl)-4-phenylpyridazin-3(2H)-one, 10b Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (90 mg, 0.325 mmol, 1 equiv.) and morpholine (87.1 mg, 143 μL, 1.62 mmol), NaI (4.9 mg, 10 mol%) and KCO (138.2 mg, 0.65 mmol, 2 equiv.), the title compound was obtained after salification and lyophilization (mass = 58 mg, yield = 94%). 1 H NMR (400MHz, CDCl3): δ ppm 7.81 (d, 1H, J = 4.4 Hz), 7.79-7.76 (m, 2H), 7.46-7.40 (m, 3H) , 7.26 (d, J = 4.4Hz, 1H ), 4.26 (t, J = 7.2 Hz, 2H), 3.71 (t, J = 4.8 Hz, 4H), 2.45-2.37 (m, 6H), 1.90 (quintet, J = 7.5 Hz, 2H), 1.59 (quintet, J = 7.7 Hz, 2H). 13CNMR (100MHz, CDCl3): δ ppm 160.0, 139.7, 136.1, 133.9, 129.5, 128.7, 128.4, 127.4, 66.9, 58.5, 53.7, 52.3, 26.3, 23.6 LC / MS (M+H) = 314.18

[0150] 2-(3-(benzyl(methyl)amino)propyl)-4-phenylpyridazin-3(2H)-one 9a Using the same procedure as described for 10d, starting from 2-(3-chloropropyl)-4-phenylpyridazin-3(2H)-one 3a (96 mg, 0.39 mmol, 1 equiv.) and N-methylbenzylamine (93.5 mg, 0.77 mmol, 2 equiv.), NaI (5.8 mg, 0.039 mmol, 0.1 equiv.), NaCO (61.4 mg, 0.6 mmol, 1.5 equiv.), the title compound was obtained after salification and lyophilization (mass = 62 mg, yield = 43%). 1 H NMR (400 MHz, CDCl3) δ 7.81-7.78 (m, 3H), 7.49-7.40 (m, 3H), 7.33-7.21 (m, 6H), 4.21 (t, J = 7.9 Hz, 2H), 3.51 (s, 2H), 2.51 (t, J = 7.1 Hz, 2H), 2.22 (s, 3H), 2.08 (q, J = 7.1 Hz, 2H) 13 C NMR (101 MHz, CDCl3) δ 160.0, 139.7, 139.2, 136.2, 134.1, 129.5, 129.1, 128.8, 128.4, 128.2, 127.5, 126.9, 62.3, 54.5, 51.2, 42.0, 26.1 LC / MS (M+H) = 334.17

[0151] 2-(3-(azepan-1-yl)propyl)-4-phenylpyridazin-3(2H)-one 9b Using the same procedure as described for 10d, starting from 2-(3-chloropropyl)-4-phenylpyridazin-3(2H)-one 3a (80 mg, 0.32 mmol, 1 equiv.) and azepane (63.8 mg, 72.5 μL, 0.64 mmol, 2 equiv.), NaI (4.8 mg, 0.032 mmol, 0.1 equiv.), NaCO (51.1 mg, 0.48 mmol, 1.5 equiv.), the title compound was obtained after salification and lyophilization (mass = 64 mg, yield = 57%). 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 4.2 Hz, 1H), 7.78-7.74 (m, 2H), 7.44-7.36 (m, 3H), 7.24 (d, J = 4.2 Hz, 1H), 4.26 (t, J = 7.2 Hz, 2H), 2.66-2.56 (m, 6H), 2.02 (quintet, J = 7.2 Hz, 2H), 1.65-1.62 (m, 8H). 13 C NMR (101 MHz, CDCl3) δ 160.1, 139.7, 136.2, 134.2, 129.6, 128.8, 128.5, 127.5, 55.5, 55.4, 51.4, 28.1, 27.1, 26.4. LC / MS (M+H) = 312.18

[0152] 2-[3-(morpholin-4-yl)propyl]-4-phenyl-2,3-dihydropyridazin-3-one 9c Using the same procedure as described for 10d, starting from 2-(3-chloropropyl)-4-phenylpyridazin-3(2H)-one 3a (49 mg, 0.2 mmol, 1 equiv.) and morpholine (85.8 mg, 0.98 mmol, 5 equiv.), NaI (2.9 mg, 0.02 mmol, 0.1 equiv.), NaCO (42 mg, 0.4 mmol, 2 equiv.), the title compound was obtained after salification and lyophilization (mass = 28 mg, yield = 48%). 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 4.2 Hz, 1H), 7.63-7.59 (m, 2H), 7.31-7.23 (m, 3H), 7.11 (d, J = 4.2 Hz, 2H), 4.14 (t, J = 7.1 Hz, 2H), 3.52 (t, J = 4.6 Hz, 4H), 2.33-2.25 (m, 6H), 1.88 (quintet, J = 7.1 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.1, 139.7, 136.1, 134.0, 129.5, 128.7, 128.4, 127.4, 66.9, 56.1, 53.4, 51.2, 25.0. LC / MS (M+H) = 300.16

[0153] 2-(4-(benzyl(methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one 10a Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (37 mg, 0.14 mmol, 1 equiv.) and N-methylbenzylamine (25.6 mg, 27.2 μL, 0.21 mmol, 2 equiv.), NaI (2.1 mg, 0.014 mmol, 0.1 equiv.), NaCO (22.3 mg, 0.21 mmol, 1.5 equiv.), the title compound 10a was obtained after salification and lyophilization (mass = 64 mg, yield = 57%). 1 H NMR (400 MHz, CDCl3) δ 7.65-7.58 (m, 3H), 7.29-7.20 (m, 3H), 7.16-7.03 (m, 6H), 4.08 (t, J = 7.2 Hz, 2H), 3.30 (s, 2H), 2.25 (t, J = 7.2 Hz, 2H), 2.00 (s, 3H), 1.72 (q, J = 7.3 Hz, 2H), 1.43 (q, J = 7.3 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 160.1, 139.8, 139.1, 136.2, 134.2, 129.6, 129.2, 128.9, 128.5, 128.4, 127.5, 127.0, 62.5, 57.1, 52.6, 42.2, 26.4, 24.7 LC / MS (M+H) = 348.2

[0154] 2-(4-(1,4-oxazepan-4-yl)butyl)-4-phenylpyridazin-3(2H)-one 10c Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (90 mg, 0.32 mmol, 1 equiv.) and 1,4-oxazepane (69.3 mg, 0.65 mmol, 2 equiv.), NaI (4.9 mg, 0.032 mmol, 0.1 equiv.), KCO (90.0 mg, 0.65 mmol, 2.0 equiv.), the title compound was obtained after salification and lyophilization (mass = 70 mg, yield = 59%). 1 H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 4.2 Hz, 1H), 7.81-7.75 (m, 2H), 7.48-7.39 (m, 3H), 7.28 (d, J = 4.2 Hz, 1H), 4.27 (t, J = 7.4 Hz, 2H), 3.79 (t, J = 6.1 Hz, 2H), 3.75-3.70 (m, 2H), 2.73-2.67 (m, 4H), 2.59-2.53 (m, 2H), 1.94-1.84 (m, 4H), 1.64-1.52 (m, 2H) 13 C NMR (101 MHz, CDCl3) δ 160.0, 139.7, 136.1, 134.0, 129.5, 128.7, 128.4, 127.4, 69.1, 68.7, 57.8, 57.6, 53.8, 52.4, 29.7, 26.3, 24.7. LC / MS (M+H) = 328.19

[0155] 4-Phenyl-2-(4-(piperidin-1-yl)butyl)pyridazin-3(2H)-one 10d Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (125 mg, 0.38 mmol, 1 equiv.) and piperidine (129.6 mg, 1.52 mmol, 4 equiv.), NaI (5.7 mg, 0.038 mmol, 0.1 equiv.), KCO (105.2 mg, 0.76 mmol, 2.0 equiv.), the title compound was obtained after salification and lyophilization (mass = 95 mg, yield = 80%). 1 H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 4.2 Hz, 1H), 7.80-7.75 (m, 2H), 7.47-7.38 (m, 3H), 7.27 (d, J = 4.2 Hz, 1H), 4.26 (t, J = 7.4 Hz, 2H), 2.49-2.32 (m, 6H), 1.87 (quintet, J = 7.5 Hz, 2H), 1.66-1.54 (m, 6H), 1.47-1.39 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.0, 140.4, 136.1, 134.0, 129.5, 128.7, 128.4, 127.4, 58.9, 54.5, 52.4, 26.5, 25.7, 24.3, 23.9 LC / MS (M+H) = 312.20

[0156] 2-(4-(azepan-1-yl)butyl)-4-phenylpyridazin-3(2H)-one 10e Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (80 mg, 0.30 mmol, 1 equiv.) and azepane (60.4 mg, 0.6 mmol, 2 equiv.), NaI (4.6 mg, 0.030 mmol, 0.1 equiv.), NaCO (48.4 mg, 0.46 mmol, 1.5 equiv.), the title compound was obtained after salification and lyophilization (mass = 96.6 mg, yield = 88%). LC / MS (M+H) = 326.18

[0157] 2-(4-(azocan-1-yl)butyl)-4-phenylpyridazin-3(2H)-one 10f Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (90 mg, 0.32 mmol, 1 equiv.) and azocane (73.7 mg, 0.65 mmol, 2 equiv.), NaI (4.9 mg, 0.03 mmol, 0.1 equiv.), KCO (90.0 mg, 0.65 mmol, 2.0 equiv.), the title compound was obtained after salification and lyophilization (mass = 106.2 mg, yield = 96%). 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 4.2 Hz, 1H), 7.80-7.76 (m, 2H), 7.47-7.38 (m, 3H), 7.27 (d, 1H, J = 4.2 Hz), 4.26 (t, J = 7.4 Hz, 2H), 2.59-2.53 (m, 4H), 2.50 (t, J = 7.1 Hz, 2H), 1.9 (quintet, J = 7.4 Hz, 2H), 1.65-1.48 (m, 12H). 13 C NMR (101 MHz, CDCl3) δ 160.1, 139.7, 136.1, 134.1, 129.5, 128.7, 128.4, 127.4, 58.3, 53.9, 52.5, 27.7, 27.2, 26.3, 26.2, 25.2 LC / MS (M+H) = 320.24

[0158] 2-(4-(3,4-dihydroisoquinolin-2(1H)-yl)butyl)-4-phenylpyridazin-3(2H)-one 10g Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (80 mg, 0.30 mmol, 1 equiv.) and 1,2,3,4-tetrahydroisoquinoline (81.1 mg, 0.61 mmol, 2 equiv.), NaI (4.6 mg, 0.03 mmol, 0.1 equiv.), NaCO (48.4 mg, 0.46 mmol, 1.5 equiv.), the title compound was obtained after salification and lyophilization as a beige solid (mass = 40.0 mg, yield = 33%). 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 4.2 Hz, 1H), 7.81-7.77 (m, 2H), 7.47-7.39 (m, 3H), 7.27 (d, J = 4.2 Hz, 1H), 7.14-7.06 (m, 3H), 7.04-6.98 (m, 1H), 4.3 (t, J = 7.4 Hz, 2H), 3.64 (s, 2H), 2.9 (t, J = 5.8 Hz, 2H), 2.73 (t, J = 5.8 Hz, 2H), 2.58 (t, J = 7.6 Hz, 2H), 1.95 (quintet, J = 7.5 Hz, 2H), 1.70 (m, J = 7.5 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.1, 139.8, 136.2, 134.8, 134.4, 134.1, 129.6, 128.8, 128.7, 128.5, 127.5, 126.7, 126.2, 125.7, 58.0, 56.2, 52.5, 51.0, 29.1, 26.5, 24.4. LC / MS (M+H) = 360.17

[0159] 4-phenyl-2-(4-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)butyl)pyridazin-3(2H)-one 10h Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (80 mg, 0.30 mmol, 1 equiv.) and 1,2,3,4-tetrahydroisoquinoline (89.7 mg, 0.61 mmol, 2 equiv.), NaI (4.6 mg, 0.03 mmol, 0.1 equiv.), NaCO (48.4 mg, 0.46 mmol, 1.5 equiv.), the title compound was obtained as an off-white solid after salification and lyophilization (mass = 85.0 mg, yield = 68%). 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 4.2 Hz, 1H), 7.81-7.76 (m, 2H), 7.48-7.39 (m, 3H), 7.27 (d, J = 4.2 Hz, 1H), 7.13-7.06 (m, 4H), 4.28 (t, J = 7.4 Hz, 2H), 2.91 (dd, J = 6.4 Hz, J = 3.8 Hz, 4H), 2.64 (d, J = 6.4 Hz, 4H), 2.57-2.51 (m, 2H), 1.9 (quintet, J = 7.5 Hz, 2H), 1.67-1.57(m, 2H) 13 C NMR (101 MHz, CDCl3) δ 160.1, 142.3, 139.8, 136.2, 134.1, 129.6, 128.9, 128.8, 128.5, 127.5, 126.3, 58.7, 55.5, 52.6, 36.6, 26.6, 24.2. LC / MS (M+H) = 374.18

[0160] 2-(4-(adamantan-1-ylamino)butyl)-4-phenylpyridazin-3(2H)-one 10i Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (80 mg, 0.30 mmol, 1 equiv.) and 1-adamantylamine (69.1 mg, 0.46 mmol, 1.5 equiv.), NaI (4.6 mg, 0.03 mmol, 0.1 equiv.), NaCO (48.4 mg, 0.46 mmol, 1.5 equiv.), the title compound was obtained after salification and lyophilization as a beige solid (mass = 63.7 mg, yield = 51%). 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 4.2 Hz, 1H), 7.75-7.67 (m, 2H), 7.44-7.37 (m, 3H), 7.26 (d, J = 4.2 Hz, 1H), 4.22 (t, J = 7.3 Hz, 2H), 3.00-2.91 (m, 3H), 2.6 (t, J = 7.6 Hz, 2H), 2.07-1.97 (m, 4H), 1.86 (q, J = 7.6 Hz, 2H), 1.69-1.45 (m, 18H). LC / MS (M+H) = 378.21

[0161] 2-(4-(adamantan-1-yl(methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one 10j Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (80 mg, 0.30 mmol, 1 equiv.) and N-methyladamantyl 1-amine (119.5 mg, 0.72 mmol, 2.5 equiv.), NaI (3.7 mg, 0.03 mmol, 0.1 equiv.), KCO (80.0 mg, 0.58 mmol, 2.0 equiv.), the title compound was obtained as a beige solid after salification and lyophilization (mass = 63.7 mg, yield = 51%). 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 4.2 Hz, 1H), 7.80-7.75 (m, 2H), 7.47-7.37 (m, 3H), 7.27 (d, J = 4.2 Hz, 1H), 4.27 (t, J = 7.4 Hz, 2H), 2.60-2.43 (m, 2H), 2.28 (s, 3H), 2.12-2.05 (m, 3H), 1.88 (quintet, J = 7.4 Hz, 2H),1.80-1.68 (m, 6H), 1.68-1.53 ​​( m, 8H). 13 C NMR (101 MHz, CDCl3) δ 160.0, 139.7, 136.2, 134.0, 129.4, 128.7, 128.3, 127.4, 52.4, 48.9, 38.2, 36.7, 33.5, 29.6, 26.3. LC / MS (M+H) = 392.19

[0162] 4-phenyl-2-(4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)butyl)pyridazin-3(2H)-one, 10kJ Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (80 mg, 0.30 mmol, 1 equiv.) and 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane (88.7 mg, 0.58 mmol, 2.0 equiv.), NaI (4.3 mg, 0.03 mmol, 0.1 equiv.), KCO (80.0 mg, 0.58 mmol, 2.0 equiv.), the title compound was obtained after salification and lyophilization (mass = 71.0 mg, yield = 65%). 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 4.2 Hz, 1H), 7.81-7.77 (m, 2H), 7.47-7.38 (m, 3H), 7.27 (d, J = 4.2 Hz, 1H), 4.25 (t, J = 7.4 Hz, 2H), 3.06-3.00 (m, 1H), 2.89 (d, J = 9.6 Hz, 1H), 2.64 (dt, J = 11.3Hz, J = 7.0 Hz), 2.49 (dt, J = 11.3Hz, J = 7.0 Hz, 1H), 2.07 (d, J = 9.5 Hz, 1H), 1.91 (tt, J = 8.0 Hz, J = 7.0 Hz), 1.60-1.43 (m, 4H), 1.34 (AB, J = 14.0 Hz, 1H), 1.21 (s, 3H), 1.18-1.01 (m, 2H), 0.99 (s, 3H), 0.86 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.0, 139.6, 136.0, 134.1, 129.4, 128.7, 128.3, 127.3, 65.1, 62.4, 57.4, 52.5, 52.1, 45.0, 41.6, 41.2, 36.8, 32.1, 30.1, 26.7, 26.1, 25.9 LC / MS (M+H) = 380.22

[0163] 8-(4-(6-oxo-5-phenylpyridazin-1(6H)-yl)butyl)-8-azabicyclo[3.2.1]octan-3-one 10l Using the same procedure as described for 9b, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (80 mg, 0.30 mmol, 1 equiv.) and 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane hydrochloride (59.1 mg, 0.58 mmol, 2.0 equiv.), NaI (4.6 mg, 0.03 mmol, 0.1 equiv.), NaCO (48.4 mg, 0.46 mmol, 1.5 equiv.), the title compound was obtained as an orange gum (mass = 60.0 mg, yield = 56%). 13 C NMR (101 MHz, CDCl3) δ 7.83 (d, J = 4.2 Hz, 1H), 7.80-7.75 (m, 2H), 7.46-7.38 (m, 3H), 7.28 (d, J = 4.2 Hz, 1H), 4.3 (t, J = 7.3 Hz, 2H), 3.56-3.47 (m, 2H), 2.67-2.57 (m, 4H), 2.17 (d, J = 16.0 Hz, 2H), 2.05-1.901 (m, 4H), 1.64 (quintet, J = 7. 6Hz, 2H), 1.57 (q, 2H, J = 7.4 Hz). 13 C NMR (101 MHz, CDCl3) δ 210.3, 160.2, 139.9, 136.3, 134.1, 129.7, 128.8, 128.5, 127.5, 58.7, 52.4, 49.9, 47.5, 27.9, 26.4, 26.3. LC / MS (M+H) = 352.2

[0164] 2-(4-(benzyl((tetrahydrofuran-2-yl)methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one 10m N-Benzyl-1-(tetrahydrofuran-2-yl)methanamine was prepared from benzaldehyde and tetrahydro-dofurfurylamine according to literature procedures. 3 was prepared by reductive amination according to 3(a) Fujikura, T. Chem. Pharm. Bull. 1996, 44, 1865. 3(b ) Shah, RDJ Org.Chem., 1996, 61, 3849. 3(c) For analytical characteristics, see Kakiuchi, K., J. Org. Chem., 2017, 82, 6748-6763.

[0165] Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (80 mg, 0.30 mmol, 1 equiv.) and N-benzyl-1-(tetrahydrofuran-2-yl)methanamine (116.5 mg, 0.61 mmol, 2.0 equiv.), NaI (4.6 mg, 0.03 mmol, 0.1 equiv.), NaCO (48.4 mg, 0.46 mmol, 1.5 equiv.) in a mixture of MeCN (2.0 mL) and DMF (0.3 mL), the title compound was obtained after salification and lyophilization (mass = 71.0 mg, yield = 51%). 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 4.2 Hz, 1H), 7.79-7.77 (m, 2H), 7.46-7.39 (m, 3H), 7.34-7.27 (m, 4H), 7.26 (d, J = 4.2 Hz, 1H), 7.22-7.18 (m, 1H), 4.22 (t, J = 7.2 Hz, 2H), 3.99 (quintet, J = 6.2 Hz, 1H), 3.79 (dt, J = 8.3 Hz, J = 6.8 Hz, 1H), 3.74-3.66 (m, 2H), 3.55( d, J = 14.2 Hz, 1H), 2.62-2.43 (m, 4H), 1.96-1.76 (m, 5H), 1.56 (quintet, J = 7.7 Hz, 2H), 1.1-1.06 (m, 1H) 13C NMR (101 MHz, CDCl3) δ 160.1, 139.7, 137.9, 136.2, 134.2, 129.6, 129.0, 128.8, 128.5, 128.2, 127.5, 126.9, 77.9, 68.0, 59.4, 58.3, 54.2, 52.6, 30.3, 26.3, 25.5, 24.4 LC / MS (M+H) = 418.21

[0166] 2-(4-((2-methoxy-1-phenylethyl)amino)butyl)-4-phenylpyridazin-3(2H)-one 2-Methoxy-1-phenylethan-1-amine: Commercially available 2-methoxy-1-phenylethan-1-one (200 mg, 1.26 mmol, 1 equiv.) was dissolved in dry EtOH (5 mL). Titanium tetraisopropanolate (741 mg, 0.77 mL, 2.53 mmol, 2 equiv.) was added, followed by 7 M NH (0.90 mL, 6.33 mmol, 5 equiv.), and the resulting mixture was stirred overnight. NaBH (86.2 mg, 2.27 mmol, 1.8 equiv.) was then added in small portions and stirred overnight at room temperature. The reaction progress was monitored by HPLC. The mixture was quenched with aqueous NH (6 mL), resulting in a precipitate. The precipitate was filtered and washed with HO (10 mL) and EtOAc (2 × 20 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (20 mL). The combined organic phases were dried over Na2SO4, filtered and evaporated to yield a yellow gum (mass = 191 mg, purity approx. 70%). The crude material was used without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.39-7.29 (m, 5H), 4.19 (dd, J= 8.7 Hz, J = 4.0 Hz), 3.51(dd, J = 9.2 Hz, J = 3.9 Hz), 3.38 (s, 3H), 3.40-3.35 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 142.5, 128.5, 127.5, 126.9, 78.9, 59.0, 55.5.

[0167] Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (80 mg, 0.30 mmol, 1 equiv.) and 2-methoxy-1-phenylethan-1-amine (146.2 mg, 0.61 mmol, 2.0 equiv.), NaI (4.6 mg, 0.03 mmol, 0.1 equiv.), NaCO (48.6 mg, 0.46 mmol, 1.5 equiv.), the title compound was obtained as a beige solid after salification and lyophilization (mass = 45.0 mg, yield = 36%). 1 H NMR (400 MHz, CDCl3) 7.79 (d, J = 4.2 Hz, 1H),7.80-7.76 (m, 2H), 7.47-7.40 (m, 3H), 7.37-7.29 (m, 4H), 7.27-7.23 (m, 2H), 4.22 (t, J = 7.3 Hz, 1H), 3.46-3.36 (m, 2H), 3.35 (s, 3H), 2.50 (qt, J = 12.2 Hz, J = 7.1 Hz, 2H), 1.96-1.80 (m, 3H), 1.56 (quintet, J = 7.5 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.1, 140.9, 139.8, 136.2, 134.2, 129.6, 128.9, 128.5, 128.4, 127.7, 127.5, 127.4, 77.9, 63.1, 59.0, 52.7, 47.4, 27.6, 26.3. LC / MS (M+H) = 378.17

[0168] 2-(4-((2-methoxy-1-phenylethyl)(methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one 2-Methoxy-N-methyl-1-phenylethan-1-amine: Using the same procedure as described for the preparation of 2-methoxy-1-phenylethan-1-amine, starting from 2-methoxy-1-phenylethan-1-one (500 mg, 0.46 mL, 3.33 mmol) and NHMe (5 equiv.), the title compound was obtained as a yellow oil (m = 90 mg, 16%). 1 H NMR (400 MHz, CDCl3) δ 7.39-7.29 (m, 5H), 3.67 (dd, J= 9.1 Hz, J = 3.9 Hz), 3.37(dd, J = 9.2 Hz, J = 3.9 Hz, 1H). 1H)

[0169] Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (65 mg, 0.23 mmol, 1 equiv.) and 2-methoxy-N-methyl-1-phenylethan-1-amine (73.8 mg, 0.45 mmol, 1.9 equiv.), NaI (3.5 mg, 0.02 mmol, 0.1 equiv.), KCO (64.9 mg, 0.47 mmol, 2.0 equiv.), the title compound was obtained after salification and lyophilization (mass = 31.0 mg, yield = 34%). 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 4.2 Hz, 1H), 7.80-7.76 (m, 2H), 7.47-7.39 (m, 3H), 7.34-7.22 (m, 6H), 4.23 (t, J = 7.3 Hz, 2H), 3.81-3.75 (m, 1H), 3.72-3.67 (m, 1H), 3.59-3.57 (m, 1H), 3.32 (s, 3H), 2.55-2.30 (m, 2H), 2.22 (s, 3H), 1.84-1.82 (m, 2H), 1.56 (quintet, J = 7.9 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 160.0, 139.6, 136.0, 134.0, 129.5, 128.7, 128.5, 128.4, 128.1, 127.4, 127.2, 74.2, 67.6, 58.9, 54.2, 52.5, 38.8, 26.1; 24.4. LC / MS (M+H) = 392.23

[0170] 2-(4-((2-hydroxyethyl)(methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one 10p Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (80 mg, 0.30 mmol, 1 equiv.) and 2-methylaminoethanol (45.7 mg, 0.61 mmol, 2.0 equiv.), NaI (4.6 mg, 0.03 mmol, 0.1 equiv.), NaCO (48.5 mg, 0.46 mmol, 1.5 equiv.), the title compound was obtained as a beige solid after salification and lyophilization (mass = 76.0 mg, yield = 74%). 1 H NMR (400 MHz, CDCl3) δ 7.83(d, J = 4.2 Hz, 1H), 7.81-7.76 (m, 2H), 7.46-7.38 (m, 3H), 7.26(d, J = 4.2 Hz, 1H), 4.27 (t, J = 7.5 Hz, 2H), 3.59 (t, J = 5.3 Hz, 2H), 3.12-3.03 (bs, 1H), 2.53 (t, J = 5.4 Hz, 2H), 2.48 (t, J = 7.3 Hz, 2H), 2.25 (s, 3H), 1.89 (quintet; J = 7.6 Hz, 2H), 1.58 (quintet, J = 7.4 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.1, 139.8, 136.3, 134.0, 129.6, 128.8, 128.5, 127.6, 59.1, 58.5, 57.1, 52.4, 41.6, 26.1, 24.3. LC / MS (M+H) = 302.18

[0171] 2-(4-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one 10q Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (80 mg, 0.30 mmol, 1 equiv.) and N-methyl-1-(tetrahydro-2H-pyran-4-yl)methanamine (74.8 mg, 0.58 mmol, 1.9 equiv.), NaI (4.3 mg, 0.03 mmol, 0.1 equiv.), KCO (79.6 mg, 0.47 mmol, 2.0 equiv.), the title compound was obtained after salification and lyophilization (mass = 36.0 mg, yield = 35%). 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 4.2 Hz, 1H), 7.80-7.75 (m, 2H), 7.48-7.37 (m, 3H), 7.27 (d, J = 4.2 Hz, 1H), 4.25 (t, J = 7.3 Hz, 2H), 3.95 (ddd, J = 11.8 Hz, J = 10.9 Hz, J = 4.4 Hz, 2H), 3.41-3.32 (m, 2H), 2.48 (d, J = 6.8 Hz, 1H), 2.35 (t, J = 7.4 Hz, 2H), 2.17 (s, 3H), 2.16-2.13 (m, 2H), 1.91-1.82 (m, 2H), 1.77-1.62 (m, 2H), 1.53 (quintet, J = 7.4 Hz, 2H), 1.35-1.15 (m, 2H). LC / MS (M+H) = 356.21

[0172] 4-phenyl-2-(4-(3-phenylpiperidin-1-yl)butyl)pyridazin-3(2H)-one 10r Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (80 mg, 0.30 mmol, 1 equiv.) and 3-phenylpiperidine (98.2 mg, 0.60 mmol, 2.0 equiv.), NaI (4.6 mg, 0.30 mmol, 0.1 equiv.), KCO (84.2 mg, 0.60 mmol, 2.0 equiv.), the title compound was obtained after salification and lyophilization (mass = 81.0 mg, yield = 69%). 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 4.2 Hz, 1H), 7.79-7.75 (m, 2H), 7.46-7.39 (m, 3H), 7.32-7.17 (m, 6H), 4.26 (t, J = 7.2 Hz, 2H), 3.00 (t, J = 12.9 Hz, 2H), 2.87-2.76 (m, 1H), 2.42 (ddd, J = 9.2 Hz, J = 6.2 Hz, J = 1.8 Hz, 2H), 2.01-1.83 (m, 5H), 1.81-1.67 (m, 2H), 1.66-1.57 (m, 2H), 1.45 (qd, J = 12.4 Hz, J = 4.6 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 160.0, 144.7, 139.6, 134.0, 129.5, 128.7, 128.4, 127.4, 127.2, 126.3, 61.3, 58.7, 53.9, 52.5, 42.9, 31.6, 26.5, 25.8, 24.1. LC / MS (M+H) = 388.22

[0173] 4-Phenyl-2-(4-(4-phenylpiperidin-1-yl)butyl)pyridazin-3(2H)-one 10s Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (80 mg, 0.30 mmol, 1 equiv.) and 4-phenylpiperidine (39.28 mg, 0.30 mmol, 1.0 equiv.), NaI (3.6 mg, 0.03 mmol, 0.1 equiv.), KCO (84.2 mg, 0.60 mmol, 2.0 equiv.), the title compound was obtained after salification and lyophilization (mass = 81.0 mg, yield = 69%). 1 H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 4.2 Hz, 1H), 7.81-7.76 (m, 2H), 7.49-7.39 (m, 3H), 7.32-7.16 (m, 6H), 4.29 (t, J = 7.2 Hz, 2H), 3.1 (dq, J = 11.2 Hz, J = 2.8 Hz, 2H), 2.56-2.45 (m, 3H), 2.15-2.05 (m, 2H),1.96- 1.81 (m, 6H), 1.72-1.61 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ160.0, 146.1, 139.7, 136.2, 134.0, 129.5, 128.7, 128.4, 128.3, 127.4, 126.9, 126.2, 58.5, 54.3, 52.3, 42.6, 33.2, 26.4, 24.0. LC / MS (M+H) = 388.23

[0174] 2-(4-(3-(hydroxymethyl)piperidin-1-yl)butyl)-4-phenylpyridazin-3(2H)-one 10t Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (80 mg, 0.30 mmol, 1 equiv.) and piperidin-3-ylmethanol (70.1 mg, 0.61 mmol, 1.0 equiv.), NaI (3.6 mg, 0.03 mmol, 0.1 equiv.), KCO (84.2 mg, 0.60 mmol, 2.0 equiv.), the title compound was obtained after salification and lyophilization (mass = 94.0 mg, yield = 83%). 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 4.2 Hz, 1H), 7.80-7.76 (m, 2H), 7.47-7.38 (m, 3H), 7.27 (d, J = 4.2 Hz, 1H), 4.26 (t, J = 7.3 Hz, 2H), 3.62 (dd, J = 10.5 Hz, J = 5.3 Hz, 1H), 3.53 (dd, J = 10.5 Hz, J = 6.0 Hz, 1H), 2.82-2.76 (m, 1H), 2.68-2.55 (m, 2H), 2.38 (dd, J = 8.8 Hz, J = 6.9 Hz, 2H), 2.20-2.00 (m, 2H), 1.87 (quintet, J = 7.2 Hz, 2H), 1.83-1.73 (m, 2H), 1.72-1.52 (m, 4H), 1.20-1.08 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 160.0, 139.7, 136.2, 134.0, 129.5, 128.7, 128.4, 127.4, 67.1, 58.6, 57.4, 54.3, 52.4, 37.8, 27.6, 26.4, 24.5, 23.9. LC / MS (M+H) = 342.20

[0175] 2-(4-(2-(2-hydroxyethyl)piperidin-1-yl)butyl)-4-phenylpyridazin-3(2H)-one 10u Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (80 mg, 0.30 mmol, 1 equiv.) and 2-piperidineethanol (75.3 mg, 0.6 mmol, 2.0 equiv.), NaI (4.3 mg, 0.03 mmol, 0.1 equiv.), KCO (80.0 mg, 0.57 mmol, 2.0 equiv.), the title compound was obtained after salification and lyophilization (mass = 44.0 mg, yield = 45%). 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 4.2 Hz, 1H), 7.80-7.75 (m, 2H), 7.46-7.38 (m, 3H), 7.27 (d, J = 4.2 Hz, 1H), 4.26 (t, J = 7.3 Hz, 2H), 3.87 (ddd, J = 10.8 Hz, J = 6.6 Hz, J = 4.4 Hz, 1H), 3.72 (ddd, J = 10.8 Hz, J = 7.4 Hz, J = 4.2 Hz, 1H), 3.05 (ddd, J = 12.7 Hz, J = 7.1 Hz, J = 2.9 Hz, 1H), 2.88 (ddd, J = 12.8 Hz, J = 9.0 Hz, J = 6.7 Hz, 1H), 2.73-2.66 (m, 1H), 2.55 (ddd, J = 12.8 Hz, J = 9.1 Hz, J = 5.8 Hz, 1H), 2.35-2.27 (m, 1H), 1.93-1.78 (m, 3H), 1.72-1.63 (m, 3H), 1.62-1.51 (m, 3H),1.48-1.35 (m, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.0, 139.6, 136.2, 134.0, 129.5, 128.7, 128.4, 127.5, 61.9, 52.6, 52.2, 49.5, 31.6, 27.3, 26.2, 24.1, 22.6, 22.5. LC / MS (M+H) = 356.22

[0176] 4-Phenyl-2-(4-(3-phenylmorpholino)butyl)pyridazin-3(2H)-one 10v Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (80 mg, 0.30 mmol, 1 equiv.) and 3-phenylmorpholine (85.0 mg, 0.52 mmol, 1.8 equiv.), NaI (4.3 mg, 0.03 mmol, 0.1 equiv.), KCO (80.0 mg, 0.57 mmol, 2.0 equiv.), the title compound was obtained after salification and lyophilization (mass = 50.0 mg, yield = 39%). 1 H NMR (400 MHz, CDCl3) δ 7.82-7.72 (m, 3H), 7.46-7.38 (m, 3H), 7.37-7.21 (m, 5H), 7.25 (d, J = 4.2 Hz, 1H), 4.16 (t, J = 7.4 Hz, 2H), 3.95-3.88 (m, 1H), 3.78-3.65 (m, 2H), 3.37 (t, J = 11.3 Hz, 1H), 3.26 (dd, J = 9.9 Hz, J = 3.2 Hz, 1H), 2.97 (dt, J = 11.6 Hz, J = 2.0 Hz, 1H), 2.57-2.46 (m, 1H), 2.3 (td, J = 11.8 Hz, J = 3.1 Hz, 1H), 2.02-1.95 (m, 1H), 1.90-1.77 (m, 1H), 1.73-1.61 (m, 1H), 1.57-1.42 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 159.9, 139.6, 136.0, 134.0, 129.5, 128.7, 128.5, 128.4, 128.2, 127.6, 127.3, 73.5, 67.7, 67.5, 54.3, 52.5, 51.7, 26.0, 23.4 LC / MS (M+H) = 390.21

[0177] 4-phenyl-2-(4-(2-phenylmorpholino)butyl)pyridazin-3(2H)-one 10w Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (80 mg, 0.30 mmol, 1 equiv.) and 3-phenylmorpholine (85.0 mg, 0.52 mmol, 1.8 equiv.), NaI (4.3 mg, 0.03 mmol, 0.1 equiv.), KCO (80.0 mg, 0.57 mmol, 2.0 equiv.), the title compound was obtained after salification and lyophilization (mass = 71.0 mg, yield = 63%). 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 4.2 Hz, 1H), 7.81-7.75 (m, 2H), 7.48-7.41 (m, 3H), 7.39-7.31 (m, 4H), 7.30-7.25 (m, 1H), 7.28 (d, J = 4.2 Hz, 1H), 4.56 (dd, J = 10.0 Hz, J = 2.4Hz, 1H), 4.26 (t, J = 7.2 Hz, 2H), 4.03 (ddd, J = 11.4 Hz, J = 3.5 Hz, J = 1.8 Hz, 1H), 3.84 (td, J = 11.7 Hz, J = 2.7 Hz, 1H), 2.94 dt, J = 11.5 Hz, J = 2.1 Hz, 1H), 2.81 (dt, J = 11.4 Hz, J = 1.9 Hz, 1H), 2.44 (dd, J = 8.5 Hz, J = 6.6 Hz, 2H), 2.24 (td, J = 11.2 Hz, J = 3.2 Hz, 1H), 2.06 (t, J = 10.9 Hz, 1H), 1.92 (quintet, J = 7.4 Hz, 2H), 1.82 (quintet, J = 7.6 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 160.0, 140.4, 139.7, 136.1, 134.0, 129.5, 128.7, 128.4, 128.3, 127.7, 127.4, 126.2, 78.2, 67.1, 60.6, 52.9, 52.4, 26.3, 23.7. LC / MS (M+H) = 390.21

[0178] 2-(4-(2,6-dimethylmorpholino)butyl)-4-phenylpyridazin-3(2H)-one 10x Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (80 mg, 0.30 mmol, 1 equiv.) and 2,6-dimethylmorpholine (58.3 mg, 0.50 mmol, 2.0 equiv.), NaI (3.8 mg, 0.03 mmol, 0.1 equiv.), KCO (70.0 mg, 0.50 mmol, 2.0 equiv.), the title compound was obtained after salification and lyophilization (mass = 61.0 mg, yield = 71%). 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 4.2 Hz, 1H), 7.78-7.73 (m, 2H), 7.45-7.36 (m, 3H), 7.25 (d, J = 4.2 Hz, 1H), 4.25 (t, J = 7.2 Hz), 3.70-3.60 (m, 2H), 2.72 (dd, J = 11.1 Hz, J = 1.8 Hz), 2.34 (dd, J = 8.5 Hz, J = 6.6 Hz), 1.87 (tt, J = 8. 1Hz, J = 6.8 Hz), 1.67 (t, J = 10.7 Hz, 2H), 1.61-1.52 (m, 2H), 1.12 (d, J = 6.1 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 160.0, 139.7, 136.1, 134.0, 129.5, 128.7, 128.4, 127.4, 71.6, 59.5, 58.2, 52.3, 26.3, 23.7, 19.2.

[0179] 2-[4-(4-benzylpiperazin-1-yl)butyl]-4-phenyl-2,3-dihydropyridazin-3-one 10z Using the same procedure as described for 10d, starting with 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (50 mg, 0.19 mmol, 1 equiv.) and 1-benzylpiperazine (67.1 mg, 0.38 mmol, 2.0 equiv.), NaI (2.9 mg, 0.019 mmol, 0.1 equiv.), NaCO (40.5 mg, 0.38 mmol, 2.0 equiv.), the title compound was obtained after purification by silica gel flash chromatography using a gradient of 0% to 10% MeOH in EtOAc (mass = 71.8 mg, yield = 94%). Saltification and lyophilization afforded the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 4.2 Hz, 1H), 7.74-7.70 (m, 2H), 7.41-7.33 (m, 3H), 7.28-7.23 (m, 4H),7.23 -7.15 (m, 1H), 7.20 (d, J = 4.2 Hz, 1H), 4.21 (t, J = 7.4 Hz, 2H), 3.45 (s, 2H), 2.57-2.30 (m, 8H), 2.34 (t, J = 7.7 Hz, 2H), 1.83 (quintet, J = 7.5 Hz, 2H), 1.53 (quintet, J = 7.6 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.0, 139.6, 138.1, 136.1, 134.0, 129.5, 129.2, 128.7, 128.4, 128.2, 127.4, 127.0, 63.0, 58.2, 53.2, 53.0, 52.5, 26.4, 24.1. LC / MS (M+H) = 403.25

[0180] 2-[4-(4-benzylpiperidin-1-yl)butyl]-4-phenyl-2,3-dihydropyridazin-3-one 11a Using the same procedure as described for 10d, starting with 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (50 mg, 0.19 mmol, 1 equiv.) and 4-benzylpiperazine (66.7 mg, 0.38 mmol, 2.0 equiv.), NaI (2.9 mg, 0.019 mmol, 0.1 equiv.), NaCO (40.5 mg, 0.38 mmol, 2.0 equiv.), the title compound was obtained after purification by silica gel flash chromatography using a gradient of 0% to 10% MeOH in EtOAc (mass = 59 mg, yield = 77%). Saltification and lyophilization afforded the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 4.2 Hz, 1H), 7.83-7.77 (m, 2H), 7.48-7.40 (m, 3H), 7.32-7.24 (m, 3H), 7.22-7.12 (m, 3H), 4.27 (t, J = 7.3 Hz, 2H), 2.31 (dt, J = 11.0 Hz, J = 3.2 Hz, 2H), 2.53 (d, J = 7.1 Hz, 2H), 2.37 (t, J = 7.6 Hz, 2H), 1.93-1.80 (m, 4H), 1.71-1.47 (m, 5H), 1.32 (qd, J = 12.0 Hz, J = 3.2Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.0, 140.7, 139.6, 136.1, 134.0, 129.5, 129.1, 128.7, 128.4, 128.1, 127.4, 125.7, 58.6, 54.0, 52.5, 43.2, 37.9, 32.1, 26.5, 24.2. LC / MS (M+H) = 402.25

[0181] 2-{4-[benzyl(ethyl)amino]butyl}-4-phenyl-2,3-dihydropyridazin-3-one 11b Using the same procedure as described for 10d, starting with 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (50 mg, 0.19 mmol, 1 equiv.) and N-ethylbenzylamine (77.2 mg, 0.57 mmol, 3.0 equiv.), NaI (2.9 mg, 0.019 mmol, 0.1 equiv.), NaCO (40.5 mg, 0.38 mmol, 2.0 equiv.), the title compound was obtained after purification by silica gel flash chromatography using a gradient of 0% to 10% MeOH in EtOAc (mass = 15 mg, yield = 22%). Saltification and lyophilization afforded the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 4.2 Hz, 1H), 7.80-7.76 (m, 2H), 7.47-7.38 (m, 3H), 7.33-7.24 (m, 4H), 7.25 (d, J = 4.2 Hz, 1H), 7.23-7.18 (m, 1H), 4.23 (t, J = 7.3 Hz, 2H), 3.54 (s, 2H), 2.53-2.44 (m, 4H), 1.86 (quintet, J = 7.7 Hz, 2H), 1.55 (quintet, J = 7.4 Hz, 2H), 1.01 (t, J =7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.1, 140.0, 139.6, 136.1, 134.2, 129.5, 128.8, 128.7, 128.4, 128.1, 127.4, 126.7, 58.1, 52.8, 52.6, 47.2, 26.3, 24.3, 14.2. LC / MS (M+H) = 362.21

[0182] 2-{4-[cyclohexyl(methyl)amino]butyl}-4-phenyl-2,3-dihydropyridazin-3-one 11c Using the same procedure as described for 10d, starting with 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (50 mg, 0.19 mmol, 1 equiv.) and N-methylcyclohexylamine (64.6 mg, 0.57 mmol, 3 equiv.), NaI (2.9 mg, 0.019 mmol, 0.1 equiv.), NaCO (40.5 mg, 0.38 mmol, 2 equiv.), the title compound was obtained after purification by silica gel flash chromatography using a gradient of 0% to 10% MeOH in EtOAc (mass = 43.7 mg, yield = 68%). Saltification and lyophilization afforded the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J =4.2 Hz, 1H), 7.79-7.74 (m, 2H), 7.45-7.36 (m, 3H), 7.25 (d, J =4.2 Hz, 1H), 4.25 (t, J = 7.5 Hz, 2H), 2.46 (t, J = 7.6 Hz, 2H), 2.41-2.29 (m, 2H), 2.22 (s, 3H), 1.85 (quintet, J = 7.5 Hz, 2H), 1.79-1.68 (m, 4H), 1.64-1.46 (m, 3H), 1.20-1.12 (m, 3H), 1.11-0.99 (m, 1H). ). 13 C NMR (101 MHz, CDCl3) δ 160.0, 139.6, 136.1, 134.0, 129.4, 128.7, 128.3, 127.4, 62.4, 53.12, 52.5, 37.6, 28.5, 26.4, 26.3, 26.0, 25.1. LC / MS (M+H) = 340.23

[0183] 4-Phenyl-2-[4-(4-phenylpiperazin-1-yl)butyl]-2,3-dihydropyridazin-3-one 11d Using the same procedure as described for 10d, starting with 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (50 mg, 0.19 mmol, 1 equiv.) and 1-phenylpiperazine (61.7 mg, 0.38 mmol, 2.0 equiv.), NaI (2.9 mg, 0.019 mmol, 0.1 equiv.), NaCO (40.5 mg, 0.38 mmol, 2.0 equiv.), the title compound was obtained after purification by silica gel flash chromatography using a gradient of 0% to 10% MeOH in EtOAc (mass = 57.3 mg, yield = 78%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 4.2 Hz, 1H), 7.81-7.76 (m, 2H), 7.48-7.39 (m, 3H), 7.30-7.22 (m, 3H), 6.96-6.89 (m, 2H), 6.85 (t, J = 7.3 Hz, 1H), 4.29 (t, J = 7.2 Hz, 2H), 3.22-3.17 (m, 4H), 2.66-2.55 (m, 4H), 2.45 (t, J = 7.7 Hz, 2H), 1.92 (quintet, J = 7.6 Hz, 2 H), 1.63 (quintet, J = 7.6 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.3, 151.3, 139.7, 136.2, 134.0, 129.5, 129.1, 128.7, 128.4, 127.4, 119.6, 116.0, 58.2, 53.3, 52.4, 49.2, 26.4, 24.1. LC / MS (M+H) = 389.23

[0184] 2-{4-[(4aR,8aS)-decahydroquinolin-1-yl]butyl}-4-phenyl-2,3-dihydropyridazin-3-one 11e Using the same procedure as described for 10d, starting with 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (50 mg, 0.19 mmol, 1 equiv.) and (4aR,8aS)-decahydroquinoline (47.7 mg, 0.34 mmol, 1.8 equiv.), NaI (2.9 mg, 0.019 mmol, 0.1 equiv.), NaCO (40.5 mg, 0.38 mmol, 2.0 equiv.), the title compound was obtained after purification by silica gel flash chromatography using a gradient of 0% to 10% MeOH in EtOAc (mass = 27.6 mg, yield = 40%). Saltification and lyophilization afforded the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 4.2 Hz, 1H), 7.77-7.72 (m, 2H), 7.44-7.35 (m, 3H), 7.24 (d, J = 4.2 Hz, 1H), 4.23 (t, J = 7.3 Hz, 1H), 3.02 (d, J = 11.4 Hz, 1H), 2.86-2.77 (m, 1H), 2.69-2.58 (m, 1H), 2.31 (t, J = 11.4 Hz, 1H), 2.07-1.99 (m, 1H), 1.94-1.69 (m, 6H), 1.65-1.51 (m, 6H), 1.44-1.31 (m, 1H), 1.28-0.89 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ 160.1, 139.7, 136.3, 134.0, 129.5, 128.7, 128.4, 127.5, 66.1, 53.2, 52.1, 51.9, 41.0, 33.1, 32.0, 29.3, 26.4, 25.7, 25.5, 24.7, 21.1. LC / MS (M+H) = 366.25

[0185] 4-phenyl-2-[4-(thiomorpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one 11u Using the same procedure as described for 10d, starting with 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (50 mg, 0.19 mmol, 1 equiv.) and tetrahydro-2H-1,4-thiazine (98.2 mg, 0.95 mmol, 5 equiv.), NaI (2.9 mg, 0.019 mmol, 0.1 equiv.), NaCO (40.5 mg, 0.38 mmol, 2 equiv.), the title compound was obtained after purification by silica gel flash chromatography using a gradient of 0% to 10% MeOH in EtOAc (mass = 55.4 mg, yield = 88%). Saltification and lyophilization afforded the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 4.2 Hz, 1H), 7.76-7.71 (m, 2H), 7.23 (d, J =4.1 Hz, 1H), 4.21 (t, J = 7.3 Hz, 2H), 2.67-2.59 (m, 10H), 2.36 (t, J = 7.4 Hz, 2H), 1.82 (quintet, J = 7.8 Hz, 2H), 1.25 (quintet, J = 7.3 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.1, 139.8, 136.2, 134.0, 129.5, 128.7, 128.4, 127.4, 58.8, 55.0, 52.4, 27.9, 26.3, 23.6. LC / MS (M+H) = 330.16

[0186] 2-{4-[cyclohexyl(ethyl)amino]butyl}-4-phenyl-2,3-dihydropyridazin-3-one 11g Using the same procedure as described for 10d, starting with 2-(4-chlorobutyl)-4-phenylpyridazin-3(2H)-one 4a (50 mg, 0.19 mmol, 1 equiv.) and N-ethylcyclohexanamine (43.6 mg, 0.34 mmol, 1.8 equiv.), NaI (2.9 mg, 0.019 mmol, 0.1 equiv.), NaCO (40.5 mg, 0.38 mmol, 2.0 equiv.), the title compound was obtained after purification by silica gel flash chromatography using a gradient of 0% to 10% MeOH in EtOAc (mass = 19.6 mg, yield = 29%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 4.2 Hz, 1H), 7.78-7.72 (m, 2H), 7.44-7.35 (m, 3H), 7.25 (d, J = 4.2 Hz, 1H), 4.24 (t, J = 7.2 Hz, 2H), 2.85-2.49 (m, 5H), 1.95-1.82 (m, 4H), 1.80-1.73 (m, 2H), 1.68-1.56 (m, 3H), 1.31-1.02 (m, 8H). 13 C NMR (101 MHz, CDCl3) δ 139.7, 136.3, 134.0, 129.5, 128.7, 128.4, 127.5, 60.4, 52.0, 49.4, 44.5, 28.5, 26.2, 26.1, 26.0, 25.9, 16.0 LC / MS (M+H) = 354.25

[0187] 4-(4-fluorophenyl)-2-(4-morpholinobutyl)pyridazin-3(2H)-one Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-4-(4-fluorophenyl)-2,3-dihydropyridazin-3-one 4b (28 mg, 0.1 mmol, 1 eq.) and 2,6-dimethylmorpholine (16.8 mg, 0.20 mmol, 2.0 eq.), NaI (1.5 mg, 0.01 mmol, 0.1 eq.), KCO (26.6 mg, 0.19 mmol, 2.0 eq.), the title compound 11h was obtained (mass = 23.0 mg, yield = 72%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.85-7.75 (m, 3H), 7.25 (d, J = 4.2 Hz, 1H), 7.16-7.08 (m, 2H), 4.26 (t, J = 7.2 Hz, 2 H), 3.70 (dd, J = 5.4 Hz, J= 4.1 Hz, 4H), 2.47-2.33 (m, 6H), 1.89 (quintet., J = 7.6 Hz, 2H), 1.58 (m, J = 7.7 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 164.7, 162.3, 159.9, 103.6, 136.1, 130.7, 130.6, 127.1, 115.5, 115.3, 66.9, 58.6, 53.7, 52.4, 26.3, 23.7, LC / MS (M+H) = 332.15

[0188] 4-(4-hydroxyphenyl)-2-(4-morpholinobutyl)pyridazin-3(2H)-one 11i Step 1: 2-(4-morpholinobutyl)-4-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)pyridazin-3(2H)-one Using the same procedure as described for 10d, starting with 2-(4-chlorobutyl)-4-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)pyridazin-3(2H)-one 4c (80 mg, 0.22 mmol, 1 equiv.) and morpholine (38.4 mg, 0.44 mmol, 2.0 equiv.), NaI (3.3 mg, 0.02 mmol, 0.1 equiv.), KCO (61.0 mg, 0.44 mmol, 2.0 equiv.), the title compound 11i was obtained after purification by chromatography on silica gel using AcOEt / MeOH 95 / 5 as the eluent (mass = 47.0 mg, yield = 50%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 4.3 Hz, 1H), 7.78-7.73 (m, 2H), 7.21 (d, J = 4.3 Hz, 1H), 7.10-7.06 (d, 2H), 5.47 (t, J = 3.2 Hz, 1H), 4.23 (t, J = 7.5 Hz, 2H), 3.86 (ddd, J = 11.4 Hz, J = 9.8 Hz, J = 3.2 Hz, 1 H), 3.68 (dd, J = 4.8 Hz, J = 4.4 Hz, 4H), 3.69 (dt, J = 11.5 Hz, J = 4.1 Hz, 1H), 2.43-2.33 (m, 6H), 2.07-1.94 (m, 1H), 1.91-1.81 (m, 4H), 1.73-1.61 (m, 2H), 1.62-1.50 (m, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.4, 158.4, 139.4, 136.4, 130.3, 127.3, 126.4, 116.4, 96.3, 67.2, 62.2, 58.8, 53.9, 52.6, 30.5, 26.5, 25.4, 23.9, 18.8.

[0189] Step 2: 4-(4-hydroxyphenyl)-2-(4-morpholinobutyl)pyridazin-3(2H)-one hydrochloride 11i The above product (47 mg, 0.11 mmol, 1 equiv.) was dissolved in THF (0.45 mL) and 1 N HCl (0.22 mL, 2 equiv.) was added. The resulting mixture was then stirred at room temperature for 1 h. The volatiles were evaporated in vacuo and the crude material was triturated with dry EtO. The precipitate was filtered to afford the title product as a hydrochloride salt (mass = 25 mg, yield = 60%). LC / MS (M+H) = 330.13.

[0190] 2-(4-{2-oxa-6-azaspiro[3.3]heptan-6-yl}butyl)-4-phenyl-2,3-dihydropyridazin-3-one, 11t Using the same procedure as described for 10d, starting with 2-(4-chlorobutyl)-4-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)pyridazin-3(2H)-one 4c (60 mg, 0.23 mmol, 1 equiv.) and 2-oxa-6-azaspiro[3.3]heptane hemioxalate (90.5 mg, 0.91 mmol, 4.0 equiv.), NaI (3.4 mg, 0.02 mmol, 0.1 equiv.), NaCO (48.6 mg, 0.46 mmol, 2.0 equiv.), the title compound 11t was obtained after purification by chromatography on silica gel using AcOEt / MeOH 95 / 5 as the eluent (mass = 43.1 mg, yield = 58%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 4.2 Hz, 1H), 7.63-7.58 (m, 2H), 7.31-7.22 (m, 3H), 7.11 (d, J = 4.2 Hz, 1H), 4.56 (s, 4H), 4.07 (t, ), 3.18 (s, 4H), 2.26 (t, J = 7.3 Hz, 2H), 1.69 (quintet, J = 7.5 Hz, 2H), 1.24 (quintet, J = 7.6 Hz, 2H). ). 13C NMR (101 MHz, CDCl3) δ 160.2, 139.8, 136.3, 134.1, 129.6, 128.8, 128.5, 127.6, 81.2, 63.8, 59.1, 52.3, 50.8, 26.2, 24.7 LC / MS (M+H) = 330.16

[0191] 2-{4-[benzyl(methyl)amino]butyl}-6-methyl-4-phenyl-2,3-dihydropyridazin-3-one 11v Using the same procedure as described for 10d, starting with 2-(4-chlorobutyl)-6-methyl-4-phenyl-2,3-dihydropyridazin-3-one 4d (60 mg, 0.22 mmol, 1 eq.) and N-methylbenzylamine (39.4 mg, 42 μL, 0.32 mmol, 1.5 eq.), NaI (3.2 mg, 0.02 mmol, 0.1 eq.), NaCO (34.5 mg, 0.32 mmol, 1.5 eq.), the title compound was obtained after purification by silica gel flash chromatography using a gradient of 0% to 10% MeOH in EtOAc (mass = 38.3 mg, yield = 49%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.77-7.72 (m, 2H), 7.42-7.38 (m, 3H), 7.33-7.27 (m, 4H), 7.25-7.21 (m, 1H), 7.15 (s, 1H), 4.18 (t, J = 7.4 13C NMR (101 MHz, CDCl3) δ 159.3, 144.4, 139.6, 134.3, 129.7, 129.5, 129.4, 128.9, 128.6, 128.5, 127.5, 62.1, 56.9, 52.2, 41.9, 26.4, 24.2, 21.1. LC / MS (M+H) = 362.16

[0192] 2-[4-(azepan-1-yl)butyl]-6-methyl-4-phenyl-2,3-dihydropyridazin-3-one 11w Using the same procedure as described for 10d, starting with 2-(4-chlorobutyl)-6-methyl-4-phenyl-2,3-dihydropyridazin-3-one 4d (50 mg, 0.18 mmol, 1 eq.) and hexamethyleneimine (26.9 mg, 30.5 μL, 0.27 mmol, 1.5 eq.), NaI (2.7 mg, 0.018 mmol, 0.1 eq.), NaCO (28.7 mg, 0.27 mmol, 1.5 eq.), the title compound was obtained after purification by silica gel flash chromatography using a gradient of 0% to 10% MeOH in EtOAc (mass = 37.3 mg, yield = 61%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.74-7.71 (m, 2H), 7.40-7.35 (m, 3H), 7.13 (s, 1H), 4.16 (t, J = 7.4 Hz, 2H), 2.60 (t, J = 5.4 Hz, 4H), 2.50 (t, 13C NMR (101 MHz, CDCl3) δ 159.3, 144.3, 139.5, 134.3, 129.6, 129.5, 128.9, 128.4, 57.9, 55.6, 52.3, 27.8, 27.1, 26.6, 24.7, 21.1. LC / MS (M+H) = 340.18

[0193] 2-(5-morpholinopentyl)-4-phenylpyridazin-3(2H)-one 12 Using the same procedure as described for 10d, starting from 2-(5-bromopentyl)-4-phenyl-2,3-dihydropyridazin-3-one 5a (110 mg, 0.34 mmol, 1 equiv.) and morpholine (149.2 mg, 151 μL, 1.7 mmol, 5.0 equiv.), NaI (4.3 mg, 0.03 mmol, 0.1 equiv.), KCO (80.0 mg, 0.57 mmol, 2.0 equiv.), the title compound was obtained after salification and lyophilization (mass = 92.0 mg, yield = 82%). 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 4.2 Hz, 1H), 7.80-7.76 (m, 2H), 7.48-7.39 (m, 3H), 7.28 (d, J = 4.2 Hz, 1H), 4.24 (t, J = 7.4 Hz, 2H), 3.70 (t, J =4.7 Hz, 4H), 2.46-2.39 (m, 4H), 2.27-2.29 (m, 2H), 1.88 (quintet, J = 7.6 Hz, 2H), 1.60-1.52 (m, 2H), 1.47-1.37 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.2, 139.7, 136.5, 133.9, 129.6, 128.7, 128.4, 127.7, 63.6, 57.7, 51.8, 51.7, 27.6, 23.8, 22.7. LC / MS (M+H) = 328.20

[0194] 2-[6-(morpholin-4-yl)hexyl]-4-phenyl-2,3-dihydropyridazin-3-one 13 Using the same procedure as described for 10d, starting with 2-(6-chlorohexyl)-4-phenyl-2,3-dihydropyridazin-3-one 6a (50 mg, 0.17 mmol, 1 eq.) and morpholine (74.9 mg, 76 μL, 0.86 mmol, 5 eq.), NaI (2.6 mg, 0.017 mmol, 0.1 eq.), NaCO (36.6 mg, 0.34 mmol, 2 eq.), the title compound was obtained after purification by silica gel flash chromatography using a gradient of 0% to 10% MeOH in EtOAc (mass = 43 mg, yield = 73%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 4.2 Hz, 1H), 7.65-7.60 (m, 2H), 7.30-7.23 (m, 3H), 7.11 (d, J = 4.2 Hz, 1H), 4.08 (t, J = 7.4 Hz, 2H), 3.54 (t, J = 4.8 Hz, 4H), 2.31-2.21 (m, 4H), 2.16 (t, J = 7.4 Hz, 2H), 1.7 (quintet J = 7.3 Hz, 2H), 1.34 (quintet, J = 7.0 Hz, 2H), 1.28-1.16 (m, 4H). 13 C NMR (101 MHz, CDCl3) δ 160.0, 139.6, 136.1, 134.0, 129.5, 128.7, 128.3, 127.4, 67.0, 59.0, 53.7, 52.6, 28.2, 27.1, 26.6, 26.3. LC / MS (M+H) = 342.22

[0195] 2-(4-morpholinobutyl)-5-phenylpyridazin-3(2H)-one 14 Using the same procedure as described for 10d, starting from 2-(4-chlorobutyl)-5-phenylpyridazin-3(2H)-one 6a (120 mg (approximately 80% pure), 0.45 mmol, 1.0 equiv.) and morpholine (199 mg, 200 μL, 2.28 mmol, 5.0 equiv.), NaI (6.3 mg, 0.045 mmol, 0.1 equiv.), KCO (126.2 mg, 0.91 mmol, 2.0 equiv.), the title compound was obtained (mass = 94.0 mg, yield = 66%). Saltification and lyophilization afforded the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 2.3 Hz, 1H), 7.59-7.54 (m, 2H), 7.53-7.47 (m, 3H), 7.04 (d, J = 2.3 Hz, 1H), 4.22 (t, J = 7.3 Hz, 2H), 3.71 (t, J = 4.8 Hz, 4H), 2.45-2.38 (m, 6H), 1.88 (quintet, J = 7.4 Hz, 2H), 1.63-1.54 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.6, 143.5, 135.7, 133.9, 130.2, 129.4, 126.8, 124.6, 66.9, 58.5, 53.7, 51.3, 26.4, 23.6 LC / MS (M+H) = 314.18

[0196] 2-(5-morpholinopentyl)-5-phenylpyridazin-3(2H)-one 15 Using the same procedure as described for 9b, starting from 2-(4-chlorobutyl)-5-phenylpyridazin-3(2H)-one 6a (120 mg (approximately 85% pure), 0.37 mmol, 1 equiv.) and morpholine (162.7 mg, 164 μL, 1.87 mmol, 5.0 equiv.), NaI (5.6 mg, 0.04 mmol, 0.1 equiv.), KCO (103.3 mg, 0.74 mmol, 2.0 equiv.), the title compound was obtained (mass = 104.0 mg, yield = 85%). Saltification and lyophilization afforded the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 2.3 Hz, 1H), 7.60-7.55 (m, 2H), 7.53-7.47 (m, 3H), 7.05 (d, J = 2.3 Hz, 1H), 4.2 (t, J = 7.6 Hz, 2H), 3.71 (t, J = 4.9 Hz, 4H), 2.45-2.41 (m, 4H), 2.37-2.31 (m, 2H), 1.87 (quintet, J = 7.3 Hz, 2H), 1.59-1.52 (m, 2H), 1.46-1.37 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.5, 143.4, 135.6, 134.0, 130.2, 129.4, 126.8, 124.6, 67.0, 58.9, 53.8, 51.5, 28.3, 26.2, 24.6. LC / MS (M+H) = 328.20

[0197] Method 2: When the nitrogen heterocycloalkyl group of general formulas 9-15 presents a ketone in its structure, in this particular case, the oxo functionality can be easily reduced to an alcohol using a borohydride reagent (e.g., sodium borohydride) to afford the product of general formula 16.

[0198] [ka]

[0199] (Example A-2) Preparation of 2-(4-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)butyl)-4-phenylpyridazin-3(2H)-one 16 To a solution of 8-(4-(6-oxo-5-phenylpyridazin-1(6H)-yl)butyl)-8-azabicyclo[3.2.1]octan-3-one 101 (50 mg, 0.14 mmol, 1 equiv.) in MeOH (1 mL), NaBH (10.9 mg, 0.28 mmol, 2 equiv.) was added portionwise, and the resulting mixture was stirred at 25 °C for 1 h. The reaction progress was monitored by TLC (EtOAc / MeOH / 33% NH OH 85 / 15 / 1). The resulting mixture was quenched with saturated NH Cl solution (3 mL), diluted with HO (2 mL), and extracted twice with EtOAc (8 mL). The combined organic layers were dried over Na SO , filtered, and evaporated in vacuo. The crude material was purified by flash chromatography on silica gel using EtOAc / MeOH / 33% NHOH 85 / 15 / 1 as the eluent to afford the title compound (mass = 43.0 mg, yield = 78%). Saltification and lyophilization gave the corresponding hydrochloride salt. LC / MS (M+H) = 354.19

[0200] Method 3: Alternatively, a Suzuki-Miyaura cross-coupling reaction can be carried out later in the sequence, allowing for a more convergent approach for the introduction of various aryl or aralkyl substituents at the 4-position. Using the same conditions described above, N-alkylation of a chloropyridazinone derivative with an appropriate alkyl dihalide gave intermediate 17. Derivatization of 17 with a suitable boronic acid reagent under Suzuki-Miyaura conditions afforded intermediates 18, 19, and 22, which ultimately participated in a nucleophilic substitution reaction to give examples of the present invention (compounds 11 and 20). Catalytic hydrogenation of 20 using Pd / C (10%) at atmospheric pressure afforded compounds of general formula 21 as depicted in Scheme 3.

[0201] [ka]

[0202] Condition:a)Br(CH2) n'+3-Cl, NaH, DMF, 0°C → 25°C, 12 hours; b) Ar-B(OH)2 or Ar(CH2=CH2)-B(OH)2, Na2CO3, Pd(PPh3)4, DME-H2O, 100°C, 30 minutes, microwave irradiation; c) NHR3R4, NaI, Na2CO3, MeCN, 80°C, overnight.

[0203] 4-Chloro-2-(4-chlorobutyl)-2,3-dihydropyridazin-3-one 17 The reaction was carried out under an argon atmosphere under anhydrous conditions. To a solution of 4-chloropyridazin-3(2H)-one 1 (1.0 g, 7.67 mmol, 1 equiv) in dry DMF (26.5 mL) cooled to 0 °C, NaH (1.5 equiv, 276 mg, 11.5 mmol) was added in small portions, and the mixture was stirred at 0 °C for 30 min. 1-Bromo-4-chlorobutane (3.95 g, 2.66 mL, 22.9 mmol, 3.0 equiv) was then added at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was quenched with HO (5 mL) and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The crude was purified by column chromatography on silica gel (solid loading, eluent: heptane / EtOAc:1 / 2) to give the title compound as a yellow oil (mass=1.48 g, yield=88%). 1 H NMR (400 MHz, CDCl3) δ 7.85 - 7.77 (m, 3H), 7.25 (d, J = 4.3 Hz, 1H), 7.00 - 6.94 (m, 2H), 4.28 (t, J = 7.1 Hz, 2H), 3.85 (s, 3H), 3.59 (t, J = 6.5 Hz, 2H), 2.10 - 1.97 (m, 2H), 1.91 - 1.81 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.9, 160.4, 139.3, 136.5, 130.3, 126.3, 114.0, 55.5, 51.7, 44.6, 29.8, 25.9.

[0204] 2-(4-chlorobutyl)-4-(4-methoxyphenyl)-2,3-dihydropyridazin-3-one 18a A microwave vial (under oven-dried argon) was charged with 4-methoxyphenylboronic acid (68.7 mg, 0.45 mmol, 2.0 equiv.), 4-chloro-2-(4-chlorobutyl)-2,3-dihydropyridazin-3-one 17 (50 mg, 0.23 mmol, 1.0 equiv.), and sodium carbonate (72.3 mg, 0.68 mmol, 3 equiv.). Tetrakis(triphenylphosphine)palladium(0) (13.2 mg, 5 mol%) was then added, followed by DME (1.2 mL) and HO (0.36 mL). The vial was properly capped, and the mixing vessel was evacuated and refilled with argon (the process was repeated three times) and heated under microwave irradiation at 100 °C until complete conversion of the starting material. The reaction conversion was monitored by HPLC and was usually complete within 30 min. After cooling to room temperature, the reaction mixture was evaporated to dryness. The crude product 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 silica gel chromatography (EtOAc / heptane, 1 / 4) to afford the title compound (mass = 60 mg, yield = 91%). 1 H NMR (400 MHz, CDCl3) δ 7.85 - 7.77 (m, 3H), 7.25 (d, J = 4.3 Hz, 1H), 7.00 - 6.94 (m, 2H), 4.28 (t, J = 7.1 Hz, 2H), 3.85 (s, 3H), 3.59 (t, J = 6.5 Hz, 2H), 2.10 - 1.97 (m, 2H), 1.91 - 1.81 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.9, 160.4, 139.3, 136.5, 130.3, 126.3, 114.0, 55.5, 51.7, 44.6, 29.8, 25.9.

[0205] 2-(4-chlorobutyl)-4-(4-chlorophenyl)-2,3-dihydropyridazin-3-one 18b Using the same procedure as described for the preparation of compound 18a, starting from 4-chloro-2-(4-chlorobutyl)-2,3-dihydropyridazin-3-one 17 (50 mg, 0.23 mmol, 1.0 equiv.) and 4-chlorobenzeneboronic acid (70.7 mg, 0.45 mmol, 2 equiv.), the title compound was obtained (mass = 45.2 mg, yield = 67%). 1 H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 4.2 Hz, 1H), 7.78 - 7.73 (m, 2H), 7.45 - 7.39 (m, 2H), 7.28 (d, J = 4.2 Hz, 1H), 4.28 (t, J = 7.1 Hz, 2H), 3.59 (t, J = 6.5 Hz, 2H), 2.09 - 1.97 (m, 2H), 1.92 - 1.82 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.0, 138.6, 136.3, 135.9, 132.4, 130.2, 128.8, 127.5, 51.8, 44.5, 29.8, 25.9.

[0206] 2-(4-chlorobutyl)-4-(3-chlorophenyl)-2,3-dihydropyridazin-3-one 18c Using the same procedure as described for the preparation of compound 18a, starting from 4-chloro-2-(4-chlorobutyl)-2,3-dihydropyridazin-3-one 17 (50 mg, 0.23 mmol, 1.0 equiv.) and 3-chlorophenylboronic acid (70.7 mg, 0.45 mmol, 2 equiv.), the title compound was obtained (mass = 61 mg, yield = 90%). 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J =4.2 Hz, 1H), 7.81 t, J = 1.9 Hz, 1H), 7.68 (dt, J = 6.9 Hz, J = 1.9 Hz), 7.40-7.32 (m, 2H), 7.27 (d, J = 4.2 Hz, 1H), 4.27 (t, J = 7.1 Hz, 2H), 3.58 (t, J = 6.6 Hz, 2H), 2.01 (quintet, J = 7.1 Hz, 2H), 1.88-1.80 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 159.8, 138.3, 136.3, 135.7, 134.5, 129.8, 129.7, 128.9, 127.9, 126.9, 51.6, 44.5, 29.8, 25.8.

[0207] 2-(4-chlorobutyl)-4-(2-chlorophenyl)-2,3-dihydropyridazin-3-one 18d Using the same procedure as described for the preparation of compound 18a, starting from 4-chloro-2-(4-chlorobutyl)-2,3-dihydropyridazin-3-one 17 (50 mg, 0.23 mmol, 1.0 equiv.) and 2-chlorophenylboronic acid (70.7 mg, 0.45 mmol, 2 equiv.), the title compound was obtained (mass = 66 mg, yield = 98%). 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 4.2 Hz, 1H), 7.45-7.42 (m, 1H), 7.36-7.28 (m, 3H), 7.19 (d, J = 4.2 Hz, 1H), 4.25 (t, J = 7.1 Hz, 2H), 3.56 (t, J = 6.5 Hz, 2H), 2.0 (quintet, J = 7.3 Hz, 2H), 1.82 (quintet, J = 7.0 Hz, 2H). ). 13C NMR (101 MHz, CDCl3) δ 159.5, 139.3, 135.7, 133.1, 133.0, 131.0, 130.5, 130.2, 130.0, 126.7, 51.4, 44.3, 29.5, 25.8

[0208] 2-(4-chlorobutyl)-4-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazin-3-one 18e Using the same procedure as described for the preparation of compound 18a, starting from 4-chloro-2-(4-chlorobutyl)-2,3-dihydropyridazin-3-one 17 (50 mg, 0.23 mmol, 1.0 equiv.) and 4-trifluoromethylphenylboronic acid (85.9 mg, 0.45 mmol, 2 equiv.), the title compound was obtained (mass = 72.5 mg, yield = 97%). 1 H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.2 Hz, 2H, 7.81 (d, J = 4.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 4.2 Hz, 1H), 4.23(t, J = 7.1 Hz, 2H), 3.53 (t, J = 6.6 Hz, 2H), 1.97 (quintet, J = 7.4 Hz, 2H), 1.8 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 130.0, 138.3, 137,4, 136.1, 131.3 (q, J = 32.4 Hz), 129.1, 128.2, 125.3 (q, J 3.7 Hz), 125.2 (q, J = 265.6 Hz), 51.6, 44.3, 29.5, 25.5. 19 F (376 MHz, CDCl3) - 62.70

[0209] 2-(4-chlorobutyl)-4-(thiophen-3-yl)-2,3-dihydropyridazin-3-one 18f Using the same procedure as described for the preparation of compound 18a, starting from 4-chloro-2-(4-chlorobutyl)-2,3-dihydropyridazin-3-one 17 (50 mg, 0.23 mmol, 1.0 equiv.) and 3-thiopheneboronic acid (57.9 mg, 0.45 mmol, 2 equiv.), the title compound was obtained (mass = 53.7 mg, yield = 88%). 1 H NMR (400 MHz, CDCl3) δ 8.61 (dd, J = 3.0, 1.3 Hz, 1H), 7.82 (d, J = 4.3 Hz, 1H), 7.53 (dd, J = 5.1, 1.3 Hz, 1H), 7.42 (d, J = 4.3 Hz, 1H), 7.38 (dd, J = 5.2, 3.1 Hz, 1H), 4.30 (t, J = 7.1 Hz, 2H), 3.59 (t, J = 6.6 Hz, 2H), 2.10 - 1.97 (m, 2H), 1.93 - 1.80 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 159.8, 136.4, 134.0, 133.7, 129.3, 126.2, 125.8, 124.9, 51.8, 44.6, 29.8, 25.9.

[0210] 2-(4-chlorobutyl)-4-(furan-3-yl)-2,3-dihydropyridazin-3-one 18g Using the same procedure as described for the preparation of compound 18a, starting from 4-chloro-2-(4-chlorobutyl)-2,3-dihydropyridazin-3-one 17 (50 mg, 0.23 mmol, 1.0 equiv.) and 3-furanboronic acid (50.6 mg, 0.45 mmol, 2 equiv.), the title compound was obtained (mass = 43.8 mg, yield = 77%). 1H NMR (400 MHz, CDCl3) δ 8.66 (t, J = 1.2 Hz, 1H), 7.80 (d, J = 4.3 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.29 (d, J = 4.3 Hz, 1H), 6.73 (dd, J = 2.0, 0.8 Hz, 1H), 4.29 (t, J = 7.1 Hz, 2H), 3.58 (t, J = 6.5 Hz, 2H), 2.08 - 1.96 (m, 2H), 1.90 - 1.78 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 159.2, 146.2, 143.4, 136.2, 132.5, 123.8, 119.0, 107.5, 51.6, 44.5, 29.8, 25.9.

[0211] 4-(1-benzofuran-2-yl)-2-(4-chlorobutyl)-2,3-dihydropyridazin-3-one 18h Using the same procedure as described for the preparation of compound 18a, starting from 4-chloro-2-(4-chlorobutyl)-2,3-dihydropyridazin-3-one 17 (50 mg, 0.23 mmol, 1.0 equiv.) and benzofuran-2-boronic acid (73.2 mg, 0.45 mmol, 2 equiv.), the title compound was obtained (mass = 43.4 mg, yield = 63%). 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 1.0 Hz, 1H), 7.90 (d, J = 4.3 Hz, 1H), 7.79 (d, J = 4.3 Hz, 1H), 7.67 (ddd, J = 7.7, 1.3, 0.7 Hz, 1H), 7.50 (dq, J = 8.3, 0.9 Hz, 1H), 7.37 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.30 - 7.22 (m, 1H), 4.33 (t, J = 7.1 Hz, 2H), 3.61 (t, J = 6.5 Hz, 2H), 2.06 (tt, J = 8.7, 6.8 Hz, 2H), 1.93 - 1.83 (m, 2H).13 C NMR (101 MHz, CDCl3) δ 157.8, 155.0, 148.9, 136.3, 129.1, 126.5, 123.5, 122.6, 112.9, 111.2, 51.6, 44.5, 29.8, 25.9.

[0212] 2-(4-chlorobutyl)-4-(pyridin-3-yl)-2,3-dihydropyridazin-3-one 18i Using the same procedure as described for the preparation of compound 18a, starting from 4-chloro-2-(4-chlorobutyl)-2,3-dihydropyridazin-3-one 17 (50 mg, 0.23 mmol, 1.0 equiv.) and 3-pyridylboronic acid (55.6 mg, 0.45 mmol, 2 equiv.), the title compound was obtained (mass = 53.1 mg, yield = 89%). 1 H NMR (400 MHz, CDCl3) δ 8.86 (dd, J = 2.3 Hz, J = 0.9 Hz, 1H), 8.60 (dd, J = 4.9 Hz, J = 1.6 Hz, 1H), 8.21 (dt, J = 8.0 Hz, J = 2.4 Hz, 1H), 7.83 (d, J = 4.2 Hz, 1H), 7.34 (ddd, J = 8.0 Hz, J = 4.9Hz, J = 0.9 Hz, 1H), 7.31 (d, J = 4.2 Hz, 1H), 4.25 (t, J = 7.0 Hz, 2H), 3.55 (t, J = 6.7 Hz, 2H), 1.99 (quintet, J = 7.3 Hz, 2H), 1.82 (quintet, J = 6.9 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 159.7, 150.4, 149.0, 136.6, 136.4, 136.2, 129.9, 127.7, 123.0, 51.4, 44.2, 29.5, 25.7.

[0213] 2-(4-chlorobutyl)-4-(3,5-dichlorophenyl)-2,3-dihydropyridazin-3-one 18j Using the same procedure as described for the preparation of compound 18a, starting from 4-chloro-2-(4-chlorobutyl)-2,3-dihydropyridazin-3-one 17 (50 mg, 0.23 mmol, 1.0 equiv.) and 3,5-dichlorophenylboronic acid (43.1 mg, 0.23 mmol, 1 equiv.) at 85°C under classical heating (3 h), the title compound was obtained as a brown oil (mass = 52.6 mg, yield = 70%). 1 H NMR (400 MHz, CDCl3) δ 7.84 (d, J =4.2 Hz, 1H), 7.69 (d, J = 1.9 Hz, 2H), 7.39 (t, J = 1.9 Hz, 1H), 7.27 (d, J = 4.2 Hz, 1H), 4.26 (t, J = 7.1 Hz, 2H), 3.57 (t, J = 6.5 Hz, 2H), 2.05-1.96 (m, 2H), 1.88-1.79 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 159.4, 136.9, 136.6, 136.0, 135.1, 129.5, 128.1, 127.1, 51.8, 44.4, 29.6, 25.7.

[0214] 2-(4-chlorobutyl)-4-[(E)-2-phenylethenyl]-2,3-dihydropyridazin-3-one 19a Using the same procedure as described for the preparation of compound 18a, starting from 4-chloro-2-(4-chlorobutyl)-2,3-dihydropyridazin-3-one 17 (50 mg, 0.23 mmol, 1.0 equiv.) and (£)-styrylboronic acid (66.9 mg, 0.45 mmol, 2 equiv.), the title compound was obtained (mass = 52.9 mg, yield = 81%). 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 16.3 Hz, 1H), 7.76 (d, J = 4.3 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.40 - 7.34 (m, 2H), 7.34 - 7.28 (m, 1H), 7.24 - 7.20 (m, 2H), 7.17 (d, J = 0.7 Hz, 0H), 4.26 (t, J = 7.1 Hz, 2H), 3.59 (t, J = 6.6 Hz, 2H), 2.02 (ddt, J = 8.5, 7.2, 6.1 Hz, 2H), 1.91 - 1.81 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.1, 137.0, 136.6, 136.4, 136.4, 129.1, 128.9, 127.5, 124.8, 121.6, 51.4, 44.5, 29.7, 25.9.

[0215] 2-(4-chlorobutyl)-4-(cyclohex-1-en-1-yl)-2,3-dihydropyridazin-3-one 22a Using the same procedure as described for the preparation of compound 18a, starting from 4-chloro-2-(4-chlorobutyl)-2,3-dihydropyridazin-3-one 17 (50 mg, 0.23 mmol, 1.0 equiv.) and (cyclohex-1-en-1-yl)boronic acid (57.0 mg, 0.45 mmol, 2 equiv.), the title compound was obtained as a yellow oil (mass = 29.6.9 mg, yield = 49%). 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 4.4 Hz, 1H), 7.04 (tt, J = 4.1 Hz, J = 1.5 Hz, 1H), 6.96 (d, J = 4.3 Hz, 1H), 4.19 (t, J = 7.1 Hz, 2H), 3.54 (t, J = 6.6 Hz, 2H), 2.33-2.27 (m, 2H), 2.27-2.20 (m, 2H), 2.00-1.90 (m, 2H), 1.84-1.77 (m, 2H), 1.75-1.69 (m, 2H), 1.66-1.58 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.2, 140.6, 136.3, 134.6, 131.6, 124.3, 51.2, 44.2, 29.4, 26.7, 25.7, 22.6, 21.7.

[0216] (Example A-3) Preparation of 4-(4-methoxyphenyl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one, 11j To a solution of 2-(4-chlorobutyl)-4-(4-methoxyphenyl)-2,3-dihydropyridazin-3-one 18a (55.3 mg, 0.19 mmol) in MeCN (1.05 mL) under argon was added morpholine (82.3 mg, 83.1 μL, 0.94 mmol), NaCO (40.2 mg, 0.38 mmol, 2 equiv.), and NaI (3.7 mg, 10 mol%), and the reaction mixture was heated at 80° C. under argon overnight. The mixture was then quenched with HO (15 mL) and extracted twice with EtOAc (10 mL). The combined organic layers were dried over NaSO, filtered, and evaporated to dryness. The resulting residue was purified by silica gel flash chromatography using a gradient of 0% to 10% MeOH in EtOAc to give the title compound (mass = 43.3 mg, yield = 67%). Salification and lyophilization gave the corresponding hydrochloride salt. 1H NMR (400 MHz, CDCl3) δ 7.84 - 7.77 (m, 3H), 7.24 (d, J = 4.2 Hz, 1H), 6.98 - 6.93 (m, 2H), 4.26 (t, J = 7.3 Hz, 2H), 3.85 (s, 3H), 3.70 (t, J = 4.7 Hz, 4H), 2.43 (t, J = 4.6 Hz, 4H), 2.42 -2.34 (m, 2H), 1.89 (p, J = 7.5 Hz, 2H), 1.63-1.52 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.9, 160.3, 139.2, 136.4, 130.3, 126.5, 126.2, 114.0, 67.1, 58.7, 55.5, 53.9, 52.5, 26.4, 23.9. LC / MS (M+H) = 344.19

[0217] 4-(4-chlorophenyl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one 11k Using the same procedure as described for the preparation of compound 11j, starting from 2-(4-chlorobutyl)-4-(4-chlorophenyl)-2,3-dihydropyridazin-3-one 18b (45 mg, 0.15 mmol, 1.0 equivalent) and morpholine (65.9 mg, 66.6 μL 0.75 mmol, 5 equivalents), the title compound was obtained (mass=18.1 mg, yield=34%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 4.2 Hz, 1H), 7.78 - 7.71 (m, 2H), 7.44 - 7.38 (m, 2H), 7.27 (d, J = 4.2 Hz, 1H), 4.26 (t, J = 7.3 Hz, 2H), 3.71 (t, J = 4.7 Hz, 4H), 2.49 - 2.42 (m, 4H), 2.42 - 2.35 (m, 2H), 1.89 (quintet, J = 7.5 Hz, 2H), 1.58 (tdd, J = 9.4, 6.7, 5.5 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 159.9, 138.5, 136.2, 135.8, 132.5, 130.1, 128.8, 127.4, 67.0, 58.6, 53.8, 52.6, 26.4, 23.8. LC / MS (M+H) = 348.15

[0218] 4-(3-chlorophenyl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one Using the same procedure as described for the preparation of compound 11j, starting from 2-(4-chlorobutyl)-4-(3-chlorophenyl)-2,3-dihydropyridazin-3-one 18c (72 mg, 0.24 mmol, 1.0 equivalent) and morpholine (105.5 mg, 106.6 μL 1.21 mmol, 5 equivalents), the title compound was obtained (mass=62.0 mg, yield=74%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 4.2 Hz, 1H), 7.75-7.72 (m, 1H), 7.60 (dt, J = 6.8 Hz, J = 1.9 Hz, 1H), 7.34-7.26 (m, 2H), 7.20 (d, J = 4.2 Hz, 1H), 4.14 (t, J = 7.3 Hz, 2H), 3.63 (t, J = 4.6 Hz, 4H), 2.40-2.29 (m, 6H), 1.77 (quintet, J = 7.6 Hz, 2H), 1.48 (m,2H). 13 C NMR (101 MHz, CDCl3) δ 159.6, 138.1, 135.6, 134.3, 129.6, 129.5, 128.7, 127.7, 126.8, 67.0, 58.5, 53.7, 52.4, 26.3, 23.7. LC / MS (M+H) = 348.14

[0219] 4-(2-chlorophenyl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one 11m Using the same procedure as described for the preparation of compound 11j, starting from 2-(4-chlorobutyl)-4-(2-chlorophenyl)-2,3-dihydropyridazin-3-one 18d (65 mg, 0.22 mmol, 1.0 equivalent) and morpholine (95.3 mg, 96.2 μL 1.10 mmol, 5 equivalents), the title compound was obtained (mass=56.0 mg, yield=74%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 4.2 Hz, 1H), 7.45-7.40 (m, 1H), 7.36-7.32 (m, 1H), 7.31-7.26 (m, 2H), 7.18 (d, J = 4.2 Hz, 1H), 4.22 (t, J = 7.3 Hz, 2H), 3.66 (t, J = 4.7 Hz, 4H), 2.43-2.31 (m, 6H), 1.85 (quintet, J = 7.5 Hz, 2H), 1.54 (quintet J = 7.4 Hz, 2H). 1 H NMR (400 MHz, CDCl3) δ 159.3, 139.2, 135.6, 133.2, 132.9, 131.0, 130.4, 130.1, 129.9, 126.6, 66.9, 58.5, 53.7, 52.0, 26.3, 23.6. LC / MS (M+H) = 348.14

[0220] 2-[4-(morpholin-4-yl)butyl]-4-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazin-3-one 11n Using the same procedure as described for the preparation of compound 11j, starting from 2-(4-chlorobutyl)-4-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazin-3-one 18e (72 mg, 0.22 mmol, 1.0 equivalent) and morpholine (94.8 mg, 95.8 μL 1.10 mmol, 5 equivalents), the title compound was obtained (mass=53.8 mg, yield=65%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 4.1 Hz, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 4.1 Hz, 1H), 4.24 (t, J = 7.4 Hz, 2H), 3.66 (t, J = 4.8 Hz, 4H), 2.44-2.30 (m, 6H), 1.86 (quintet, J = 7.7 Hz, 2H), 1.54 (quintet, J = 7.6 Hz, 2H). 1 H NMR (400 MHz, CDCl3) δ 159.6, 138.2, 137.5, 136.0, 131.2 (q, J = 32.9 Hz), 129.0, 128.1, 122.6, 66.9, 58.5, 53.7, 52.5, 26.2, 23.6. LC / MS (M+H) = 382.17

[0221] 2-[4-(morpholin-4-yl)butyl]-4-(thiophen-3-yl)-2,3-dihydropyridazin-3-one Using the same procedure as described for the preparation of compound 11j, starting from 2-(4-chlorobutyl)-4-(thiophen-3-yl)-2,3-dihydropyridazin-3-one 18f (53 mg, 0.19 mmol, 1.0 equivalent) and morpholine (85.9 mg, 86.7 μL 0.98 mmol, 5 equivalents), the title compound was obtained (mass=50.9 mg, yield=81%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1H NMR (400 MHz, CDCl3) δ 8.60 (dd, J = 3.0, 1.3 Hz, 1H), 7.80 (d, J = 4.3 Hz, 1H), 7.52 (dd, J = 5.2, 1.3 Hz, 1H), 7.40 (d, J = 4.4 Hz, 1H), 7.37 (dd, J = 5.1, 3.0 Hz, 1H), 4.32 - 4.23 (m, 2H), 3.74 - 3.68 (m, 4H), 2.44 (t, J = 4.6 Hz, 4H), 2.42 - 2.35 (m, 2H), 1.95 - 1.83 (m, 2H), 1.58 (tdd, J = 9.4, 6.7, 5.5 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 159.7, 136.2, 134.1, 133.6, 129.2, 126.2, 125.8, 124.8, 67.0, 58.7, 53.8, 52.5, 26.4, 23.7. LC / MS (M+H) = 320.14

[0222] 4-(furan-3-yl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one 11p Using the same procedure as described for the preparation of compound 11j, starting from 2-(4-chlorobutyl)-4-(furan-3-yl)-2,3-dihydropyridazin-3-one 18g (43 mg, 0.17 mmol, 1.0 equivalent) and morpholine (74.1 mg, 74.9 μL 0.85 mmol, 5 equivalents), the title compound was obtained (mass=34.3 mg, yield=66%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1H NMR (400 MHz, CDCl3) δ 8.68 - 8.62 (m, 1H), 7.78 (d, J = 4.2 Hz, 1H), 7.48 (t, J = 1.8 Hz, 1H), 7.28 (d, J = 4.3 Hz, 1H), 6.72 (dd, J = 2.0, 0.8 Hz, 1H), 4.26 (t, J = 7.3 Hz, 2H), 3.72 - 3.66 (m, 4H), 2.45 - 2.40 (m, 4H), 2.39 - 2.33 (m, 2H), 1.87 (p, J = 7.6 Hz, 2H), 1.62 - 1.51 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 159.1, 146.2, 143.4, 136.1, 132.5, 123.7, 119.1, 107.5, 67.1, 58.7, 53.8, 52.4, 26.4, 23.8. LC / MS (M+H) = 304.16

[0223] 4-(3a,7a-dihydro-1-benzofuran-2-yl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one 11q Using the same procedure as described for the preparation of compound 11j, starting from 2-(4-(1-benzofuran-2-yl)-2-(4-chlorobutyl)-2,3-dihydropyridazin-3-one 18h (43.4 mg, 0.14 mmol, 1.0 equiv.) and morpholine (62.4 mg, 63.1 μL 0.72 mmol, 5 equiv.), the title compound was obtained (mass = 36.9 mg, yield = 72%). Saltification and lyophilization afforded the corresponding hydrochloride salt. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 1.0 Hz, 1H), 7.78 (d, J = 4.4 Hz, 1H), 7.66 (d, J = 4.4 Hz, 1H), 7.56 (dt, J = 7.7, 1.1 Hz, 1H), 7.39 (dq, J = 8.2, 0.9 Hz, 1H), 7.26 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.20 - 7.11 (m, 1H), 4.21 (dd, J = 7.9, 6.8 Hz, 2H), 3.65 - 3.55 (m, 4H), 2.37 - 2.32 (m, 4H), 2.31 - 2.26 (m, 2H), 1.81 (p, J = 7.7 Hz, 2H), 1.49 (tdd, J = 9.4, 6.7, 5.5 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 157.7, 154.9, 148.9, 136.0, 129.1, 128.6, 126.4, 123.4, 122.5, 112.7, 111.2, 67.0, 58.6, 53.8, 52.4, 26.4, 23.8. LC / MS (M+H) = 354.18

[0224] 2-[4-(morpholin-4-yl)butyl]-4-(pyridin-3-yl)-2,3-dihydropyridazin-3-one 11r Using the same procedure as described for the preparation of compound 11j, starting from 2-(4-chlorobutyl)-4-(pyridin-3-yl)-2,3-dihydropyridazin-3-one 18i (53.1 mg, 0.20 mmol, 1.0 equivalent) and morpholine (87.7 mg, 88.6 μL 1.00 mmol, 5 equivalents), the title compound was obtained (mass=20.1 mg, yield=32%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1H NMR (400 MHz, CDCl3) δ 8.78 (dd, J = 2.3, 0.9 Hz, 1H), 8.53 (dd, J = 4.8, 1.7 Hz, 1H), 8.14 (dt, J = 8.0, 2.0 Hz, 1H), 7.75 (d, J = 4.2 Hz, 1H), 7.26 (ddd, J = 8.0, 4.9, 0.9 Hz, 1H), 7.22 (d, J = 4.2 Hz, 1H), 4.22 - 4.11 (m, 2H), 3.65 - 3.53 (m, 4H), 2.37 - 2.30 (m, 4H), 2.30 - 2.22 (m, 2H), 1.78 (p, J = 7.5 Hz, 2H), 1.47 (tdd, J = 10.3, 6.7, 5.5 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 159.8, 150.5, 149.1, 136.7, 136.5, 136.1, 130.1, 127.7, 123.1, 67.1, 58.6, 53.8, 52.6, 26.4, 23.8. LC / MS (M+H) = 315.18

[0225] 2-[4-(morpholin-4-yl)butyl]-4-[(E)-2-phenylethenyl]-2,3-dihydropyridazin-3-one 20a Using the same procedure as described for the preparation of compound 11j, starting from 2-(4-chlorobutyl)-4-[(E)-2-phenylethenyl]-2,3-dihydropyridazin-3-one 19a (52.9 mg, 0.18 mmol, 1.0 equivalent) and morpholine (79.8 mg, 80.6 μL 1.00 mmol, 5 equivalents), the title compound was obtained (mass=40.5 mg, yield=73%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 16.4 Hz, 1H), 7.76 (d, J = 4.3 Hz, 1H), 7.60 - 7.53 (m, 2H), 7.37 (ddt, J = 8.1, 5.7, 1.9 Hz, 2H), 7.34 - 7.28 (m, 1H), 7.23 (d, J = 4.3 Hz, 1H), 7.20 (d, J = 16.4 Hz, 1H), 4.25 (dd, J = 7.7, 6.9 Hz, 2H), 3.74 - 3.68 (m, 4H), 2.43 (t, J = 4.8 Hz, 4H), 2.41 - 2.34 (m, 2H), 1.94 - 1.82 (m, 2H), 1.63 - 1.53 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.1, 137.0, 136.7, 136.5, 136.3, 129.1, 128.9, 127.5, 124.8, 121.7, 67.1, 58.7, 53.9, 52.3, 26.5, 23.8. LC / MS (M+H) = 340.20

[0226] 2-[4-(morpholin-4-yl)butyl]-4-(2-phenylethyl)-2,3-dihydropyridazin-3-one 21a Pd / C 10% (3.6 mg) and MeOH (10 mL) were placed in a reactor (20 mL capacity) equipped with a magnetic stirrer. 2-[4-(morpholin-4-yl)butyl]-4-[(E)-2-phenylethenyl]-2,3-dihydropyridazin-3-one 20a (36.7 mg, 0.11 mmol) 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 (36.8 mg, 99%). Saltification and lyophilization afforded the corresponding hydrochloride salt. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 4.0 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.30 - 7.22 (m, 3H), 6.93 (dd, J = 4.0, 1.0 Hz, 1H), 4.27 (t, J = 7.2 Hz, 2H), 3.77 (t, J = 4.8 Hz, 4H), 3.04 - 2.92 (m, 4H), 2.54 - 2.47 (m, 4H), 2.47 - 2.41 (m, 2H), 1.92 (quintet, J = 7.8 Hz, 2H), 1.66-1.58 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 161.2, 143.0, 140.9, 135.9, 128.5, 128.5, 127.8, 126.3, 67.1, 58.6, 53.8, 51.8, 33.4, 32.2, 26.4, 23.7. LC / MS (M+H) = 342.22

[0227] Method 4: Introduction of a secondary aliphatic amine at the 4-position Alternatively, the 4-aryl group of the pyridazine moiety can be replaced by a secondary aliphatic amine NR7R8, as illustrated in Scheme 4. First N-alkylation of the 4-halogenopyridazinone with an appropriate alkyl-dihalide using NaH in DMF gave intermediate 17, as illustrated in Scheme 3. Then, a nucleophilic substitution reaction with an appropriate aliphatic amine NHR3R4 was carried out to give 24. Finally, the S-aryl group can be obtained by utilizing HNR7R8. N Ar reaction provided compounds of general formula 25.

[0228] [ka]

[0229] Condition:a)Br(CH2) n'+3-X, NaH, DMF, 0°C → 25°C, 12 hours. b) HNR3R4, NaI, K2CO3, MeCN, 80°C, overnight c) HNR7R8, K2CO3, MeCN, 80°C, 18 hours.

[0230] wherein -NR7R8 can form a nitrogen-containing heterocycloalkyl as defined above.

[0231] 4-Chloro-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one 24a Using the same procedure as described for 10d, starting with 4-chloro-2-(4-chlorobutyl)-2,3-dihydropyridazin-3-one 17 (100 mg, 0.45 mmol, 1 equiv.) and morpholine (78.8 mg, 0.90 mmol, 2 equiv.), NaI (6.8 mg, 0.04 mmol, 0.1 equiv.), KCO (125.0 mg, 0.90 mmol, 2.0 equiv.), the title compound was obtained after purification by silica gel chromatography using EtOAc / MeOH / NHOH 85 / 13 / 2 as the eluent (mass = 63 mg, yield = 51%). 1 H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 4.2 Hz, 1H), 7.31 (d, J = 4.3 Hz, 1H), 4.18 (t, J = 7.3 Hz, 2H), 3.67-3.61 (m, 4H), 2.40-2.29 (m, 6H), 1.85-1.76 (m, 2H), 1.54-1.44 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 157.6, 137.1, 134.8, 128.9, 66.9, 58.4, 53.7, 52.8, 26.1, 23.5.

[0232] (Example A-4) Preparation of 2-(4-morpholinobutyl)-4-(piperidin-1-yl)pyridazin-3(2H)-one 25a To a solution of 4-chloro-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one 24a (63 mg, 0.23 mmol) in MeCN (1.0 mL) under argon was added piperidine (38.9 mg, 45.1 μL, 0.45 mmol), KCO (63.07 mg, 0.46 mmol), and NaI (3.7 mg, 10 mol%), and the reaction mixture was heated at 80° C. under argon for 16 h. The mixture was then quenched with HO (8 mL) and extracted twice with EtOAc (10 mL). The combined organic layers were dried over NaSO, filtered, and evaporated to dryness. The resulting residue was purified by silica gel flash chromatography using EtOAc / MeOH / NH4OH:85 / 15 / 0.1 as the eluent to give, after salification and lyophilization, the title compound 25a (mass=52 mg, yield=71%). 1 H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 5.0 Hz, 1H), 6.22 (d, J = 5.0 Hz, 1H), 4.14 (t, J = 7.3 Hz, 2H), 3.74 (dd, J = 5.3 Hz, J = 4.1 Hz, 4H), 3.37 (dd, J = 6.3 Hz, J = 4.2 Hz, 4 H), 2.53-2.41 (m, 6H), 2.1 (quintet, J = 7.3 Hz, 2H), 1.73-1.68 (m, 4H), 1.66-1.54 (m, 4H). 13 C NMR (101 MHz, CDCl3) δ 158.2, 148.7, 137.5, 108.1, 68.9, 58.8, 53.8, 52.1, 49.4, 26.4, 25.8, 24.7, 23.6 LC / MS (M+H) = 312.23

[0233] Method 5: Introduction of heterocyclic aromatic amines at the 4-position Alternatively, the 4-aryl group of the pyridazine moiety can be replaced by heterocyclic aromatic amines (pyrrole, pyrazole, and imidazole). A Buchwald-Hartwig cross-coupling reaction utilizing Pd(dba) and RuPhos can be carried out starting from the previously described intermediate 17. A nucleophilic substitution reaction with an appropriate aliphatic amine NHR3R4 then led to compounds of general formula 27. The use of pyrrole provided an example of the present invention.

[0234] [ka]

[0235] Conditions: a) Pd2(dba)3, (5 mol%), RuPhos (20 mol%), Cs2CO3 (2.5 equiv), dioxane, 100 °C, 18 h; b) NHR3R4, NaI, Na2CO3, MeCN, 80 °C, overnight.

[0236] 2-(4-chlorobutyl)-4-(1H-pyrrol-1-yl)-2,3-dihydropyridazin-3-one 26a A microwave vial (under oven-dried argon) was charged with 4-chloro-2-(4-chlorobutyl)-2,3-dihydropyridazin-3-one 17 (60 mg, 0.27 mmol, 1.0 equiv.), pyrrole (36.4 mg, 0.54 mmol, 2.0 equiv.), and CsCO (223.3 mg, 0.68 mmol, 2.5 equiv.). Tris((1E,4E)-1,5-diphenylpenta-1,4-dien-3-one)dipalladium (12.8 mg, 5 mol%) and RuPhos (25.3 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 18 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 Hept / EtOAc:5 / 1 as the eluent to give the title compound 26a as an orange oil (mass = 40.8 mg, yield = 60%). 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 4.6 Hz, 1H), 7.49 (t, J = 2.3 Hz, 2H), 7.03 (d, J = 4.6 Hz, 1H), 6.33 (t, J =2.3 Hz, 2H), 4.27 (t, J = 7.1 Hz, 2H), 3.57 (t, J = 6.5 Hz, 2H), 2.01 (quintet, J = 7.1 Hz, 2H), 1.87-1.76 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 156.6, 137.1, 137.0, 120.9, 115.6, 111.8, 51.7, 44.2, 29.5, 25.7.

[0237] (Example A-5) Preparation of 2-[4-(morpholin-4-yl)butyl]-4-(1H-pyrrol-1-yl)-2,3-dihydropyridazin-3-one 27a Using the same procedure as described for 10d, starting with 2-(4-chlorobutyl)-4-(1H-pyrrol-1-yl)-2,3-dihydropyridazin-3-one 26a (40.8 mg, 0.16 mmol, 1 eq.) and morpholine (70.6 mg, 71.3 μL, 0.81 mmol, 5 eq.), NaI (2.4 mg, 0.016 mmol, 0.1 eq.), NaCO (34.5 mg, 0.32 mmol, 2 eq.), the title compound was obtained after purification by silica gel flash chromatography using a gradient of 0% to 15% MeOH in EtOAc (mass = 40 mg, yield = 80%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 4.7 Hz, 1H), 7.47 (t, J = 2.3 Hz, 2H), 7.01 (d, J = 4.7 Hz, 1H), 6.31 (t, J = 2.3 Hz, 2H), 4.23 (t, J = 7.3 Hz, 2H), 3.66 (t, J = 4.8 Hz, 4H), 2.42-2.31(m, 6H), 1.84(m, J = 7.7 Hz), 1.53 (m, J = 6.9 Hz, 2H). LC / MS (M+H) = 303.18

[0238] Method 6: Alternatively, the 4-aryl group of the pyridazine moiety can be replaced by an aryl sulfide or aryl alkoxide, as illustrated in Scheme 5. Starting from the above-mentioned 4-chloropyridazinone 24, reaction with sodium arylthiolate or sodium aryloxide under nucleophilic aromatic substitution conditions afforded compounds of general formulae 28 and 29, respectively. The use of thiophenols and phenols provided examples of the present invention.

[0239] [ka]

[0240] Conditions: NaH, DMF, 45°C, 0°C, 30 min, then addition of 25, 45°C, 3 hr

[0241] (Example A-6) 2-[4-(morpholin-4-yl)butyl]-4-(phenylsulfanyl)-2,3-dihydropyridazin-3-one 28a The reaction was carried out under an argon atmosphere under anhydrous conditions. To a solution of 4-chloro-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one 24a (62.9 mg, 0.23 mmol, 1 equiv.) in dry DMF (1.0 mL) cooled to 0 °C, NaH (5.8 mg, 0.24 mmol, 1.05 equiv.) was added in small portions, and the mixture was stirred at 0 °C for 30 min. Thiophenol (28.0 mg, 0.25 mmol, 1.1 equiv.) was then added dropwise at 0 °C, and the mixture was heated at 45 °C for 3 h. The mixture was quenched with HO (15 mL) and extracted twice with EtOAc (2 × 15 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. After evaporation to dryness, the residue was purified by silica gel flash chromatography using a gradient of 0% to 10% MeOH in EtOAc (mass = 31.5 mg, yield = 39%). Saltification and lyophilization afforded the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.54-7.50 (m, 2H), 7.48-7.44 (m, 3H), 7.43 (d, J = 4.5 Hz, 1H), 6.25 (d, J = 4.5 Hz, 1H), 4.18 (t, J = 7.3Hz, 2H), 3.67 (t, J = 4.8 Hz, 4H), 2.44-2.30 (m, 6H), 1.83 (quintet, J = 7.5 Hz, 2H), 1.55-1.45 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 158.0, 147.0, 135.7, 135.5, 130.2, 128.5, 121.4, 67.0, 58.4, 53.6, 51.6, 26.2, 23.5. LC / MS (M+H) = 346.16

[0242] 2-[4-(morpholin-4-yl)butyl]-4-phenoxy-2,3-dihydropyridazin-3-one, 29a Using the same procedure as described for 28a, starting with 4-chloro-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one 24a (45.0 mg, 0.16 mmol, 1 equiv.) and phenol (18.7 mg, 17.5 μL, 0.20 mmol, 1.2 equiv.), the title compound was obtained after purification by silica gel flash chromatography using a gradient of 0% to 10% MeOH in EtOAc (mass = 39.1 mg, yield = 71.7%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 4.8 Hz, 1H), 7.44-7.38 (m, 2H), 7.28-7.22 (m, 1H), 7.12-7.07 (m, 2H), 6.20 (d, J = 4.8 Hz, 1H), 4.23 (t, J = 7.1 Hz, 2H), 3.69 (t, J = 4.8 Hz, 1H), 2.48-2.33 (m, 6H), 1.86 (quintet, J = 4.7 Hz, 2H), 1.60-1.49 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 156.9, 155.6, 153.3, 136.3, 130.3, 126.3, 120.9, 108.1, 66.8, 58.3, 53.6, 51.6, 26.2, 23.7. LC / MS (M+H) = 330.18

[0243] Method 7: N-Alkylation of 1 with the 1,3-dioxolane-methylsulfate derivative 30 using NaH in DMF gave, after deprotection of the dioxolane moiety in acidic medium, diol 31. Chemoselective tosylation of the primary alcohol 31 with TsCl in the presence of dibutyltin oxide and EtN afforded compound 32. Finally, nucleophilic substitution reaction with an appropriate aliphatic amine NHR3R4 was carried out to afford compounds of general formula 33.

[0244] [ka]

[0245] Conditions: a) NaH, DMF, 0°C, 30 min, then 18, 0°C → 25°C, overnight; b) 1N HCl, 25°C, 2 h; c) Bu2SnO (4 mol%), TSCl, Et3N, DCM, 25°C, 16 h; d) NHR3R4, K2CO3, KI, MeCN, 80°C, 16 h.

[0246] 2-(3,4-Dihydroxybutyl)-4-phenylpyridazin-3(2H)-one 31a The reaction was carried out under anhydrous conditions under an argon atmosphere. To a solution of 4-phenylpyridazin-3(2H)-one 1 (172.2 mg, 0.93 mmol, 1 equiv.) in dry DMF (3.6 mL) cooled to 0 °C, NaH (44.6 mg, 1.86 mmol, 2.0 equiv.) was added in small portions, and the mixture was stirred at 0 °C for 30 min. Then, 2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl methanesulfonate 30 was added. ref(250 mg, 1.11 mmol, 1.2 equiv) was added dropwise at 0° C., and the mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with HO (15 mL) and extracted twice with EtOAc (2×15 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The crude was then dissolved in THF, 1N HCl (5.2 ml, 10 equiv) was added, and the resulting mixture was stirred at 25° C. for 2 hours. After evaporation to dryness, the residue was purified by silica gel flash chromatography using heptane / EtOAc (6 / 4) as the eluent. The title compound was obtained (mass=130 mg, yield=57%). 1 H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 4.2 Hz, 1H), 7.80-7.71 (m, 2H), 7.50-7.41 (m, 3H), 7.33, (d, J = 4.2 Hz, 1H), 4.72 (ddd, J = 13.0 Hz, J = 10.1 Hz, J = 4.8 Hz, 1H), 4.18 (ddd, J = 13.2 Hz, J = 5.1 Hz, J = 4.1 Hz, 1H), 3.67-3.57 (m, 2H), 3.56-3.48 (m, 1H), 3.21 (bs, OH), 2.03-1.94 (m, 1H), 1.91-1.81 (m, 1H). Ref Eur. J. Org. Chem., 2015(27), 6075~6083; 2015

[0247] 2-Hydroxy-4-(6-oxo-5-phenylpyridazin-1(6H)-yl)butyl 4-methylbenzenesulfonate 32a To a solution of 2-(3,4-dihydroxybutyl)-4-phenylpyridazin-3(2H)-one 31a (148 mg, 0.57 mmol, 1 equiv.) in DCM (5.2 mL) was added BuSnO (5.7 mg, 0.02 mmol, 0.04 equiv.), p-TsCl (195.1 mg, 1.02 mmol, 1.8 equiv.), and EtN (103.6 mg, 142 μL, 1.02 mmol, 1.8 equiv.). The reaction mixture was stirred until TLC showed complete consumption of the starting material (approximately 16 h). The mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel pretreated with EtO / EtN:95 / 5. Using EtOAc / heptane:4 / 1, the title compound was obtained (mass = 138 mg, 59%). 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 4.2 Hz, 1H), 7.77-7.71 (m, 4H), 7.45-7.38 (m, 3H), 7.33-7.27 (m, 3H), 4.63 (ddd, J = 13.3 Hz, J = 10.4 Hz, J = 4.5 Hz, 1H), 4.13 (ddd, J = 13.5 Hz, J = 5.3 Hz, J = 4.4 Hz, 1H), 3.97 (d, J = 5.3 Hz, 2H, 1H), 3.78-3.70 (m, 1H), 2.40 (s, 3H), 2.10-2.00 (m, 1H), 1.79 (ddt, J = 14.2 Hz, J = 10.6 Hz, J = 4.4 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 161.0, 144.9, 139.9, 137.3, 133.5, 132.7, 129.9, 129.8, 128.7, 128.5, 128.0, 127.9, 73.1, 65.9, 48.7, 32.5, 21.7.

[0248] (Example A-7) 2-(4-(benzyl(methyl)amino)-3-hydroxybutyl)-4-phenylpyridazin-3(2H)-one, 33a Using the same procedure as described for 10d, starting from 2-hydroxy-4-(6-oxo-5-phenylpyridazin-1(6H)-yl)butyl 4-methylbenzenesulfonate 32a (30 mg, 0.072 mmol, 1 equiv.) and N-methylbenzylamine (17.54 mg, 18.7 μL, 0.14 mmol, 2.0 equiv.), NaI (1.0 mg, 0.1 equiv.), KCO (24.0 mg, 0.17 mmol, 2.4 equiv.), the title compound was obtained after salification and lyophilization (mass = 8.0 mg, yield = 30%). 1 H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 4.2 Hz, 1H), 7.82-7.76 (m, 2H), 7.47-7.40 (m, 3H), 7.34-7.21 (m, 6H), 4.48 (dt, J = 12.9 Hz, J = 7.5 Hz, 1H), 4.37 (ddd, J = 12.9 Hz, J = 7.8 Hz, J = 5.4 Hz), 3.82-3.75 (m, 1H), 3.65(d, J = 13.0 Hz, 1H), 3.49 (d, J = 13.1 Hz, 1H), 2.49 (dd, J = 12.1 Hz, J = 9.6 Hz, 1H), 2.4 (dd, J = 12.3 Hz, J = 3.7 Hz, 1H), 2.24 (S , 3H), 2.07-1.99 (m, 1H), 1.90-1.81 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 160.3, 139.7, 136.4, 134.0, 129.5, 129.0, 128.7, 128.4, 128.3, 127.5, 127.2, 64.9, 63.0, 62.5, 49.8, 42.2, 33.7. LC / MS (M+H) = 364.12

[0249] General methods and examples derived from pyridones and pyrimidones. Alternatively, the pyridazinone ring can be replaced by a pyridone or pyrimidone ring of general formulas 40 and 41 following Route 1 or 2 in a four-step sequence similar to that depicted in Scheme 7.

[0250] [ka]

[0251] Conditions: a) Na2CO3, Pd(PPh3)4, DME, H2O, μwave, 100℃, 30 minutes. b)Br-(CH2) n'+3 -Cl, K2CO3, MeCN, 25°C, overnight. C) HNR3R4, K2CO3, NaI, MeCN, 80°C, 16 hours.

[0252] 2-Methyl-5-phenylpyrimidin-4-ol 36a A microwave vial (under oven-dried argon) was charged with phenylboronic acid (257.4 mg, 2.12 mmol, 2.0 equiv.), 2-methyl-5-bromopyrimidin-4-ol 34a (200 mg, 1.06 mmol, 1.0 equiv.), and sodium carbonate (148 mg, 1.40 mmol, 1.3 equiv.). Tetrakis(triphenylphosphine)palladium(0) (61.3 mg, 5 mol%) was then added, followed by DME (4.2 mL) and HO (1.4 mL). The vial was properly capped, and the mixing vessel was evacuated and refilled with argon (the process was repeated three times) and heated under microwave irradiation at 100 °C until complete conversion of the starting material. The reaction conversion was monitored by HPLC and was usually complete within 30 min. After cooling to room temperature, the reaction mixture was evaporated to dryness. The crude was partitioned between DCM (20 mL) and HO (15 mL). The aqueous phase was extracted twice with DCM (10 mL). The organic phases were combined, washed with brine, dried (NaSO), and evaporated. The crude material was purified by silica gel chromatography using DCM / MeOH 95:5 as the eluent to afford the title compound (mass = 120 mg, yield = 61%). 1H NMR (400 MHz, CDCl3) δ 13.27 (bs, 1H), 7.96 (s, 1H), 7.53-7.49 (m, 2H), 7.29-7.16 (m, 3H), 2.33 (s, 3H).

[0253] 5-Bromo-3-(4-chlorobutyl)-3,4-dihydropyrimidin-4-one 36b The reaction was carried out under anhydrous conditions under an argon atmosphere. To a solution of 5-bromopyrimidin-4-ol (100 mg, 0.57 mmol, 1.0 equiv.) in dry MeCN (3.1 mL), 1-bromo-4-chlorobutane (196 mg, 1.14 mmol, 2 equiv.) and K2CO3 (158 mg, 1.14 mmol, 2 equiv.) were added, and the mixture was stirred at 80 °C overnight. The mixture was quenched with HO (5 mL) and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by column chromatography on silica gel (solid loading, eluent: heptane / EtOAc: 3 / 1 to 1 / 1) to give the title compound (mass = 47 mg, yield = 31%). 1 H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 8.04(s, 1H), 3.98 (t, J = 7.3 Hz, 2H), 3.55 (t, J = 6.3 Hz, 2H), 1.97-1.88 (m, 2H), 1.85-1.76 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ 157.8, 153.9, 150.0, 114.4, 47.6, 44.0, 29.3, 26.5.

[0254] 3-Phenylpyridin-2-ol 37 Using the same procedure as described for 36a, starting with 3-bromopyridin-2-ol 35 (400 mg, 2.23 mmol, 1.0 equiv), phenylboronic acid (336.4 mg, 2.76 mmol, 1.2 equiv), and potassium carbonate (490.0 mg, 4.60 mmol, 2 equiv), the title compound was obtained after purification by silica gel chromatography using a gradient of 50 to 80% EtOAc in heptane to give the title compound as a white solid (mass = 183 mg, yield = 46%). 1 H NMR (400 MHz, CDCl3) δ 12.93 (br s, 1H), 7.69 (d, J = 7.3 Hz, 2H), 7.57 (dd, J = 6.9, 2.0 Hz, 1H), 7.41 (t, J = 7.5 Hz, 2H), 7.38-7.30 (m, 2H), 6.34 (t, J = 6.7 Hz, 1H). 13 C NMR (101 MHz, CDCl3): δ 164.2, 139.9, 136.8, 134.0, 131.9, 128.8, 128.5, 128.0, 107.3.

[0255] 3-(4-Chlorobutyl)-2-methyl-5-phenyl-3,4-dihydropyrimidin-4-one 38a To a solution of 2-methyl-5-phenylpyrimidin-4-ol 36a (110 mg, 0.59 mmol, 1 equiv.) in MeCN (4.4 mL) was added KCO (245 mg, 1.77 mmol, 3 equiv.) and 1-bromo-4-chlorobutane (304 mg, 1.77 mmol, 3 equiv.), and the resulting mixture was stirred overnight at room temperature under argon. The reaction mixture was then evaporated to dryness. The crude product was partitioned between EtOAc (20 mL) and HO (15 mL). The aqueous phase was extracted twice with EtOAc (10 mL). The organic phases were combined, washed with brine, dried (NaSO), and evaporated. The crude material was purified by silica gel chromatography using DCM as the eluent (mass = 55 mg, yield = 34%). 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.63-7.60 (m, 2H), 7.41-7.30 (m, 3H), 4.12(t, J = 6.1 Hz, 2H), 3.61 (t, J = 6.1 Hz, 2H), 2.63 (s, 3H), 1.94-1.91 (m, 4H). ). 13 C NMR (101 MHz, CDCl3) δ 166.8, 165.8, 156.4, 133.5, 129.0, 128.6, 128.1, 119.1, 85.7, 44.7, 29.4, 26.3, 25.9.

[0256] 3-(4-Chlorobutyl)-5-phenyl-3,4-dihydropyrimidin-4-one 38b Using the same procedure as described for the preparation of compound 18a, starting from 5-bromo-3-(4-chlorobutyl)-3,4-dihydropyrimidin-4-one 36b (47 mg, 0.18 mmol, 1.0 equiv.) and phenylboronic acid (43.2 mg, 0.35 mmol, 2 equiv.), the title compound was obtained (mass = 44.6 mg, yield = 96%). 1 H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 8.03 (s, 1H), 7.66-7.61 (m, 2H), 7.41-7.33 (m, 3H), 3.99 (t, J = 7.3 Hz, 2H), 3.55 (t, J = 6.3 Hz, 2H), 2.00-1.90 (m, 2H), 1.87-1.78 (m, 2H).

[0257] 1-(4-chlorobutyl)-3-phenyl-1,2-dihydropyridin-2-one 39 Using the same procedure as described for 38a, starting from 3-phenylpyridin-2-ol (100 mg, 0.58 mmol, 1 equiv.) and 1-bromo-4-chlorobutane (300.5 mg, 1.75 mmol, 3 equiv.), the title compound was obtained as an opaque oil (mass = 84.3 mg, yield = 55%). 1H NMR (400 MHz, CDCl3) δ 7.68-7.63 (m, 2H), 7.46 (dd, J = 6.9 Hz, J = 2.2 Hs), 1H), 7.40-7.35 (m, 2H), 7.32-7.29 (m, 1H), 7.26 (dd, J = 6.7 Hz, J = 2.1 Hz, 1H), 4.02 (t, J = 7.1 Hz, 2H), 3.56 (t, J = 6.4 Hz, 2H), 1.99-1.90 (m, 2H), 1.89-1.80 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 161.5, 137.5, 136.8, 136.5, 132.0, 128.7, 128.1, 127.7, 49.3, 44.5, 29.5, 26.5.

[0258] (Example A-8) 2-Methyl-3-(4-morpholinobutyl)-5-phenylpyrimidin-4(3H)-one, 40a Using the same procedure as described for 9b, starting from 3-(4-chlorobutyl)-2-methyl-5-phenyl-3,4-dihydropyrimidin-4-one 39 (63 mg, 0.23 mmol, 1 eq.) and morpholine (49.6 mg, 50.1 μL, 0.57 mmol, 2.5 eq.), NaI (0.9 mg, 0.023 mmol, 0.1 eq.), KCO (62.9 mg, 0.45 mmol, 2.0 eq.), the title compound was obtained (mass = 44 mg, yield = 59%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.64-7.58 (m, 2H), 7.41-7.29 (m, 3H), 4.10-4.05 (m, 2H), 3.70 (dd, J = 5.3 Hz, J = 4.3 Hz, 4H), 2.50-2.37 (m, 6H), 1.76 (quintet, J = 8.0 Hz, 2H), 1.62 (quintet, J = 7.4 Hz, 2H) 13C NMR (101 MHz, CDCl3) δ 161.3, 158.3, 149.9, 133.7, 128.6, 128.5, 128.3, 124.9, 66.9, 58.2, 53.8, 45.1, 26.2, 23.8, 23.2. LC / MS (M+H) = 328.20

[0259] 3-[4-(morpholin-4-yl)butyl]-5-phenyl-3,4-dihydropyrimidin-4-one 40b Using the same procedure as described for 9b, starting from 3-(4-chlorobutyl)-5-phenyl-3,4-dihydropyrimidin-4-one 38b (44 mg, 0.16 mmol, 1 eq.) and morpholine (72.9 mg, 73.7 μL, 0.83 mmol, 5.0 eq.), NaI (2.5 mg, 0.016 mmol, 0.1 eq.), NaCO (35.7 mg, 0.34 mmol, 2.0 eq.), the title compound was obtained (mass = 34 mg, yield = 65%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.98 (s, 1H), 7.61-7.57 (m, 2H), 7.38-7.33 (m, 2H), 7.32-7.28 (m, 1H), 3.95 (t, J = 7.3 Hz, 2H), 3.64 (t, J = 4.6 Hz, 4H), 2.39-2.29 (m, 6H), 1.82-165 (m, 2H), 1.55-1.47 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.3, 150.7, 149.9, 133.0, 128.5, 128.4, 128.3, 127.7, 66.7, 58.2, 53.6, 47.6, 27.0, 23.2. LC / MS (M+H) = 314.19

[0260] 1-[4-(morpholin-4-yl)butyl]-3-phenyl-1,2-dihydropyridin-2-one, 41a Using the same procedure as described for 9b, starting from 1-(4-chlorobutyl)-3-phenyl-1,2-dihydropyridin-2-one 36b (84 mg, 0.32 mmol, 1 eq.) and morpholine (139.8 mg, 141 μL, 1.60 mmol, 5 eq.), NaI (4.8 mg, 0.032 mmol, 0.1 eq.), NaCO (68.0 mg, 0.64 mmol, 2.0 eq.), the title compound was obtained (mass = 84.3 mg, yield = 84%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.67-7.63 (m, 2H), 7.45 (dd, J = 6.9 Hz, J = 2.1 Hz, 1H), 7.40-7.34 (m, 2H), 7.32-7.27 (m, 1H), 7.25 (dd, JJ = 6.9 Hz, J = 2.1 Hz, 1H), 4.0 (t, J = 7.6 Hz), 3.68 (J = 4.8 Hz), 2.45-2.32 (m, 6H), 1.81 (quintet, J = 7.5 Hz, 2H), 1.55 (quintet, J = 7.7 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 161.3, 106.0, 137.4, 136.9, 136.6, 131.9, 128.6, 128.1, 127.6, 67.0, 58.1, 53.6, 50.2, 27.0, 23.7. LC / MS (M+H) = 313.19

[0261] 1-{4-[benzyl(methyl)amino]butyl}-3-phenyl-1,2-dihydropyrazin-2-one 41b Using the same procedure as described for 9b, starting from 1-(4-chlorobutyl)-3-phenyl-1,2-dihydropyridin-2-one 36b (38 mg, 0.14 mmol, 1 eq.) and N-methylbenzylamine (26.4 mg, 28 μL, 0.22 mmol, 1.5 eq.), NaI (2.2 mg, 0.014 mmol, 0.1 eq.), NaCO (23.1 mg, 0.22 mmol, 1.5 eq.), the title compound was obtained (mass = 32.7 mg, yield = 65%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 7.58-7.56 (m, 2H), 7.38 (dd, J = 6.8, 1.9 Hz, 1H), 7.32-7.18 (m, 9H), 6.18 (t, J = 6.9 Hz, 1H), 3.91 (t, J = 7.1 13C NMR (101 MHz, CDCl3) δ 161.6, 137.8, 137.0, 136.9, 135.0, 131.9, 130.1, 128.9, 128.8, 128.4, 128.2, 127.8, 103.3, 61.6, 56.1, 50.1, 41.2, 26.9, 23.4, LC / MS (M+H) = 347.15

[0262] General methods and examples derived from pyrazinones Alternatively, the pyridazinone ring can be replaced by a pyrazinone ring, as depicted in Scheme 8. Starting from 2,3-Cl-pyrazine, a Pd(PPh)-assisted Suzuki-Miyaura reaction followed by treatment with HCl afforded the key intermediate 3-phenylpyrazin-2-ol 44. Alkylation of 44 with 1-bromo-4-chlorobutane in the presence of NaH in DMF afforded intermediate 45. Finally, nucleophilic substitution with an appropriate aliphatic amine NHR3R4 afforded compounds of general formula 46.

[0263] [ka]

[0264] Conditions: a) ArB(OH)2, Na2CO3, Pd(PPh3)4, DME / H2O, 85°C, 16 hours; b) HCl 15%, 85°C, 5 hours. c) NaH, Br(CH2)4Cl, room temperature, 3 hours; d) HNR3R4, Na2CO3, NaI catalyst, MeCN, 80°C, 16 hours.

[0265] 2-Chloro-3-phenylpyrazine 43: A microwave vial (under oven-dried argon) was charged with 4,2,3-dichloropyrazine 42 (116 mg, 0.78 mmol, 1.0 equiv.), phenylboronic acid (94.9 mg, 0.78 mmol, 1.0 equiv.), and Na2CO3 (82.9 mg, 0.78 mmol, 1.0 equiv.). Tetrakis(triphenylphosphine)palladium (45.4 mg, 5 mol%) was then added, followed by DME (2.7 mL) and water (1.16 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 85 °C for 16 h. The crude product 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 Hept / EtOAc:6 / 1 as the eluent to give the title compound 43 (mass=84.0 mg, yield=57%). 1 H NMR (400 MHz, CDCl3) δ 8.61(d, J = 2.4Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 7.81-7.79(m, 2H), 7.50-7.44 (m, 3H).

[0266] 3-Phenylpyrazin-2-ol 44 2-Chloro-3-phenylpyrazine (57 mg, 0.3 mmol) was suspended in HCl 15% (6 mL), and the resulting mixture was heated under reflux for 5 h. After cooling, the solution was treated with NaOH 2N until the pH reached approximately 5-6. The aqueous layer was then extracted with DCM (3x). The organic phase was collected, dried over NaSO, filtered, and the solvent removed in vacuo to afford a white solid (m = 46 mg, yield = 89%). The solid was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 13.24 (broad s, 1H) 8.12-8.06 (m, 2H), 7.43 (d, J = 4.0 Hz, 1H), 7.30-7.22 (m, 3H), 7.02 (d, J = 4.0 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 157.7, 153.8, 135.7, 130.1, 128.8, 128.2, 125.1, 124.8.

[0267] 1-(4-chlorobutyl)-3-phenyl-1,2-dihydropyrazin-2-one 45 The reaction was carried out under anhydrous conditions under an argon atmosphere. To a solution of 3-phenylpyrazin-2-ol 44 (45 mg, 0.26 mmol, 1 equiv) in dry DMF (0.9 mL) cooled to 0 °C, NaH (1.5 equiv, 9.4 mg, 0.39 mmol, 1.5 equiv) was added in small portions, and the mixture was stirred at 0 °C for 30 min. 1-Bromo-4-chlorobutane (134.4 mg, 91 μL, 0.78 mmol, 3.0 equiv) was then added at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was quenched with HO (5 mL) and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The crude was purified by column chromatography on silica gel (solid loading, eluent: heptane / EtOAc:1 / 2) to give the title compound (mass=25.6 mg, yield=37%). 1 H NMR (400 MHz, CDCl3) δ 8.15-8.07 (m, 2H), 7.30-7.23 (m, 1H), 6.94 (d, J = 4.2 Hz, 1H), 3.84 (t, J = 7.3 Hz, 2H), 3.42(t, J = 6.3 Hz, 2H), 1.86-1.77 (m, 2H), 1.73-1.65 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 155.5, 153.7, 135.9, 129.9, 129.0, 128.0, 127.7, 123.4, 49.2, 44.2, 29.4, 26.1.

[0268] (Example A-9) 1-[4-(morpholin-4-yl)butyl]-3-phenyl-1,2-dihydropyrazin-2-one 46a Using the same procedure as described for 9b, starting from 1-(4-chlorobutyl)-3-phenyl-1,2-dihydropyrazin-2-one 45 (25.6 mg, 0.97 mmol, 1 equiv.) and morpholine (42.4 mg, 42.9 μL, 0.48 mmol, 2.5 equiv.), NaI (1.5 mg, 0.001 mmol, 0.1 equiv.), NaCO (20.8 mg, 0.19 mmol, 2.0 equiv.), the title compound was obtained (mass = 22.9 mg, yield = 75%). Saltification and lyophilization gave the corresponding hydrochloride salt. 1 H NMR (400 MHz, CDCl3) δ 8.31-8.20(m, 2H), 7.45-7.34 (m, 4H), 7.08 (d, J = 4.2Hz), 3.96 (t, J = 7.3 Hz, 2H), 3.67 (t, J = 4.9 Hz), 2.43-2.30 (m, 6H), 1.82 (quintet, J = 7.5 Hz, 2H), 1.54 (m, J = 7.4 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 155.5, 153.2, 136.1, 129.8, 128.9, 128.0, 127.8, 123.3, 66.9, 58.0, 53.0, 49.9, 26.5, 23.5. LC / MS (M+H) = 314.18

[0269] Part B. In vitro pharmacology: binding assays σ1 receptor binding assay The σ1 binding assay was performed according to Ganapathy et al. (Ganapathy, ME et al. (1999), J. Pharmacol. Exp. Ther., 28:251-260). The σ1 binding assay was performed by incubating Jurkat cell membranes (10-20 mg of protein per tube) in a [ 3 The assay was performed by incubating [3H](+)-pentazocine, a selective S1R ligand (15 nM), and a range of concentrations of test compound in 5 mM Tris / HCl buffer (pH = 7.4) for 2 hours at 37°C. Inhibition assays of [3H]-(+)-pentazocine binding are primarily used to determine the inhibition constant (Ki) of potential S1R ligands. These assays were performed using a single concentration of [ 3 H]-(+)-pentazocine at its K D Tests are performed at concentrations near and increasing concentrations of non-radioactive ligand.

[0270] [Table 1]

[0271] [Table 2A]

[0272] [Table 2B]

Claims

1. A compound having the following formula (I): 【Chemical 1】 [In the formula, R 1 teeth, ・ Aryl (C 1 ~C 6 ) alkyl groups, ・ Aryl (C 2 ~C 6 ) an alkenyl group, an aryl group, heteroaryl groups, heterocycloalkyl groups, a cycloalkyl group, or -QR groups (Q is O or S and R is alkyl, aryl or aralkyl); represents The group is optionally substituted with at least one —OH, halogen, one or more fluorine atoms (C 1 ~C 6 ) alkyl, or (C 1 ~C 6 ) optionally substituted by alkyloxy; Z is CR 2 represents R 2 is H, (C 1 ~C 4 ) represents an alkyl or phenyl group, X and Y are N and CR, respectively. 6 and R 6 is H or (C 1 ~C 4 ) alkyl group, n is 3, 4, 5 or 6; R 3 and R 4 teeth, independently a hydrogen atom, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aryl (C 1 ~C 6 ) alkyl, The groups include hydroxy, (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) optionally substituted with at least one substituent selected from the group consisting of alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; together with the nitrogen to which they are attached form a nitrogen-based heterocycloalkyl; The nitrogen-based heterocycloalkyl may be hydroxy, oxo, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, aryl (C 1 ~C 6 ) alkyl, hydroxy (C 1 ~C 6 ) alkyl, wherein the nitrogen-based heterocycloalkyl is optionally fused to at least one 5- to 14-membered ring selected from aryl and heteroaryl; R 5 each independently represents H, OH, or (C 1 ~C 4 ) represents an alkyl group] A stereoisomer, diastereoisomer, enantiomer, solvate or any pharmaceutical salt thereof.

2. R 1 but, an aryl group, heteroaryl, heterocycloalkyl, or a group selected from cyclohexenyl, phenethyl, phenethenyl, -OPh and -SPh Represents, 2. The compound of claim 1.

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

4. 4. The compound of claim 1, wherein Y is CH.

5. 5. The compound of claim 1, wherein n is 4.

6. R 3 and R 4 but, ・Become independent hydrogen atoms, ・ (C 1 ~C 6 ) alkyl, cycloalkyl, and ・ Aryl (C 1 ~C 6 ) alkyl represents a group selected from The group is Hydroxy, ・ (C 1 ~C 6 ) alkoxy, heterocycloalkyl, and ・Aryl or optionally substituted by one or two substituents independently selected from the group consisting of together with the nitrogen to which they are attached form a nitrogen-based heterocycloalkyl; The nitrogen-based heterocycloalkyl is ・Hydroxy, oxo, ・ (C 1 ~C 6 ) alkyl, aryl, ・ Aryl (C 1 ~C 6 ) alkyl, Hydroxy (C 1 ~C 6 ) alkyl and optionally substituted with up to three substituents independently selected from the group consisting of: said nitrogen-based heterocycloalkyl optionally fused to an aryl group; 6. A compound according to any one of claims 1 to 5.

7. R 3 and R 4 together with the nitrogen to which they are attached to form a nitrogen-based heterocycloalkyl, said nitrogen-based heterocycloalkyl having the following formula (II): 【Chemistry 2】 [In the formula, m is 1 or 2; W is O, S, NR', (CH 2 ) 2 or CHR', R' is a hydrogen atom, (C 1 ~C 6 ) alkyl, aryl or aryl(C 1 ~C 6 ) alkyl, Each R" is independently a hydrogen atom, hydroxy, oxo, (C 1 ~C 6 ) Alkyl, aryl, aryl (C 1 ~C 6 ) alkyl or hydroxy (C 1 ~C 6 ) represents alkyl] 7. The compound of any one of claims 1 to 6, represented by:

8. -R 1 is an aryl group, the aryl group is optionally substituted with at least one halogen; -R 2 is H, -R 5 But H, 8. A compound according to any one of claims 1 to 7.

9. Features include: ⇒ n is 4 and / or ⇒ R 6 is H or methyl, and / or ⇒ R 1 is optionally substituted with at least one —OH, halogen, one or more fluorine atoms (C 1 ~C 6 ) alkyl, or (C 1 ~C 6 ) represents an aryl group optionally substituted by alkyloxy, and / or ⇒ R 2 represents H, methyl or phenyl, and / or ⇒ R 3 and R 4 but, ・Become independent hydrogen atoms, ・ (C 1 ~C 6 ) alkyl, cycloalkyl, and ・ Aryl (C 1 ~C 6 ) alkyl represents a group selected from The group is Hydroxy, ・ (C 1 ~C 6 ) alkoxy, heterocycloalkyl, and ・Aryl or optionally substituted by one or two substituents independently selected from the group consisting of together with the nitrogen to which they are attached form a nitrogen-based heterocycloalkyl; The nitrogen-based heterocycloalkyl is ・Hydroxy, oxo, ・ (C 1 ~C 6 ) alkyl, aryl, ・ Aryl (C 1 ~C 6 ) alkyl, Hydroxy(C 1 ~C 6 ) alkyl and optionally substituted with up to three substituents independently selected from the group consisting of: said nitrogen-based heterocycloalkyl is optionally fused to an aryl group; and / or ⇒ Each R 5 But it is H The compound according to any one of claims 1 to 8, and pharmaceutical salts thereof, wherein at least one of the following is satisfied.

10. 2-(4-morpholinobutyl)-4-phenylpyridazin-3(2H)-one hydrochloride, 2-(3-(benzyl(methyl)amino)propyl)-4-phenylpyridazin-3(2H)-one; 2-(3-(azepan-1-yl)propyl)-4-phenylpyridazin-3(2H)-one; 2-[3-(morpholin-4-yl)propyl]-4-phenyl-2,3-dihydropyridazin-3-one; 2-(4-morpholinobutyl)-4-phenylpyridazin-3(2H)-one; 2-(4-(benzyl(methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one; 2-(4-(1,4-oxazepan-4-yl)butyl)-4-phenylpyridazin-3(2H)-one; 4-phenyl-2-(4-(piperidin-1-yl)butyl)pyridazin-3(2H)-one; 2-(4-(azepan-1-yl)butyl)-4-phenylpyridazin-3(2H)-one; 2-(4-(azocan-1-yl)butyl)-4-phenylpyridazin-3(2H)-one; 2-(4-(3,4-dihydroisoquinolin-2(1H)-yl)butyl)-4-phenylpyridazin-3(2H)-one; 4-phenyl-2-(4-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)butyl)pyridazin-3(2H)-one; 2-(4-(adamantan-1-ylamino)butyl)-4-phenylpyridazin-3(2H)-one; 2-(4-(adamantan-1-yl(methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one; 4-phenyl-2-(4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)butyl)pyridazin-3(2H)-one; 8-(4-(6-oxo-5-phenylpyridazin-1(6H)-yl)butyl)-8-azabicyclo[3.2.1]octan-3-one; 2-(4-(benzyl((tetrahydrofuran-2-yl)methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one; 2-(4-((2-methoxy-1-phenylethyl)amino)butyl)-4-phenylpyridazin-3(2H)-one; 2-(4-((2-methoxy-1-phenylethyl)(methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one; 2-(4-((2-hydroxyethyl)(methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one; 2-(4-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one; 4-phenyl-2-(4-(3-phenylpiperidin-1-yl)butyl)pyridazin-3(2H)-one; 4-phenyl-2-(4-(4-phenylpiperidin-1-yl)butyl)pyridazin-3(2H)-one; 2-(4-(3-(hydroxymethyl)piperidin-1-yl)butyl)-4-phenylpyridazin-3(2H)-one; 2-(4-(2-(2-hydroxyethyl)piperidin-1-yl)butyl)-4-phenylpyridazin-3(2H)-one; 4-phenyl-2-(4-(3-phenylmorpholino)butyl)pyridazin-3(2H)-one; 4-phenyl-2-(4-(2-phenylmorpholino)butyl)pyridazin-3(2H)-one; 2-(4-(2,6-dimethylmorpholino)butyl)-4-phenylpyridazin-3(2H)-one; 2-[4-(4-benzylpiperazin-1-yl)butyl]-4-phenyl-2,3-dihydropyridazin-3-one; 2-[4-(4-benzylpiperidin-1-yl)butyl]-4-phenyl-2,3-dihydropyridazin-3-one; 2-{4-[benzyl(ethyl)amino]butyl}-4-phenyl-2,3-dihydropyridazin-3-one; 2-{4-[cyclohexyl(methyl)amino]butyl}-4-phenyl-2,3-dihydropyridazin-3-one; 4-phenyl-2-[4-(4-phenylpiperazin-1-yl)butyl]-2,3-dihydropyridazin-3-one; 2-{4-[(4aR,8aS)-decahydroquinolin-1-yl]butyl}-4-phenyl-2,3-dihydropyridazin-3-one; 2-(4-{2-oxa-6-azaspiro[3.3]heptan-6-yl}butyl)-4-phenyl-2,3-dihydropyridazin-3-one; 4-phenyl-2-[4-(thiomorpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one; 2-{4-[cyclohexyl(ethyl)amino]butyl}-4-phenyl-2,3-dihydropyridazin-3-one; 4-(4-fluorophenyl)-2-(4-morpholinobutyl)pyridazin-3(2H)-one; 4-(4-hydroxyphenyl)-2-(4-morpholinobutyl)pyridazin-3(2H)-one; 2-(5-morpholinopentyl)-4-phenylpyridazin-3(2H)-one; 2-[6-(morpholin-4-yl)hexyl]-4-phenyl-2,3-dihydropyridazin-3-one; 2-(4-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)butyl)-4-phenylpyridazin-3(2H)-one; 4-(4-methoxyphenyl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one; 4-(4-chlorophenyl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one; 4-(3-chlorophenyl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one; 4-(2-chlorophenyl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one; 2-[4-(morpholin-4-yl)butyl]-4-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazin-3-one; 2-[4-(morpholin-4-yl)butyl]-4-(thiophen-3-yl)-2,3-dihydropyridazin-3-one; 4-(furan-3-yl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one; 4-(3a,7a-dihydro-1-benzofuran-2-yl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one; 2-[4-(morpholin-4-yl)butyl]-4-(pyridin-3-yl)-2,3-dihydropyridazin-3-one; 2-{4-[benzyl(methyl)amino]butyl}-6-methyl-4-phenyl-2,3-dihydropyridazin-3-one; 2-[4-(azepan-1-yl)butyl]-6-methyl-4-phenyl-2,3-dihydropyridazin-3-one; 2-[4-(morpholin-4-yl)butyl]-4-[(E)-2-phenylethenyl]-2,3-dihydropyridazin-3-one; 2-[4-(morpholin-4-yl)butyl]-4-(2-phenylethyl)-2,3-dihydropyridazin-3-one; 4-(cyclohex-1-en-1-yl)-2-[4-(morpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one; 2-(4-morpholinobutyl)-4-(piperidin-1-yl)pyridazin-3(2H)-one; 2-[4-(morpholin-4-yl)butyl]-4-(1H-pyrrol-1-yl)-2,3-dihydropyridazin-3-one; 2-[4-(morpholin-4-yl)butyl]-4-(phenylsulfanyl)-2,3-dihydropyridazin-3-one; 2-[4-(morpholin-4-yl)butyl]-4-phenoxy-2,3-dihydropyridazin-3-one; and 2-(4-(benzyl(methyl)amino)-3-hydroxybutyl)-4-phenylpyridazin-3(2H)-one 10. The compound according to any one of claims 1 to 9, selected from the group consisting of:

11. 2-(3-(benzyl(methyl)amino)propyl)-4-phenylpyridazin-3(2H)-one; 2-(3-(azepan-1-yl)propyl)-4-phenylpyridazin-3(2H)-one; 2-(4-(benzyl(methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one; 2-(4-(1,4-oxazepan-4-yl)butyl)-4-phenylpyridazin-3(2H)-one; 4-phenyl-2-(4-(piperidin-1-yl)butyl)pyridazin-3(2H)-one; 2-(4-(azepan-1-yl)butyl)-4-phenylpyridazin-3(2H)-one; 2-(4-(azocan-1-yl)butyl)-4-phenylpyridazin-3(2H)-one; 2-(4-(3,4-dihydroisoquinolin-2(1H)-yl)butyl)-4-phenylpyridazin-3(2H)-one; 4-phenyl-2-(4-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)butyl)pyridazin-3(2H)-one; 2-(4-(adamantan-1-ylamino)butyl)-4-phenylpyridazin-3(2H)-one; 2-(4-(benzyl((tetrahydrofuran-2-yl)methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one; 2-(4-((2-methoxy-1-phenylethyl)(methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one; 2-(4-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one; 4-phenyl-2-(4-(3-phenylpiperidin-1-yl)butyl)pyridazin-3(2H)-one; 4-phenyl-2-(4-(4-phenylpiperidin-1-yl)butyl)pyridazin-3(2H)-one; 2-(4-(2,6-dimethylmorpholino)butyl)-4-phenylpyridazin-3(2H)-one; 4-phenyl-2-(4-(2-phenylmorpholino)butyl)pyridazin-3(2H)-one; 2-[4-(4-benzylpiperazin-1-yl)butyl]-4-phenyl-2,3-dihydropyridazin-3-one; 2-[4-(4-benzylpiperidin-1-yl)butyl]-4-phenyl-2,3-dihydropyridazin-3-one; 2-{4-[benzyl(ethyl)amino]butyl}-4-phenyl-2,3-dihydropyridazin-3-one; 2-[4-(morpholin-4-yl)butyl]-4-(thiophen-3-yl)-2,3-dihydropyridazin-3-one; 4-phenyl-2-[4-(thiomorpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one; 2-{4-[benzyl(methyl)amino]butyl}-6-methyl-4-phenyl-2,3-dihydropyridazin-3-one; 2-[4-(azepan-1-yl)butyl]-6-methyl-4-phenyl-2,3-dihydropyridazin-3-one; and 2-(4-morpholinobutyl)-4-(piperidin-1-yl)pyridazin-3(2H)-one (25a) 11. The compound according to any one of claims 1 to 10, selected from the group consisting of:

12. 2-(3-(benzyl(methyl)amino)propyl)-4-phenylpyridazin-3(2H)-one; 2-(4-(benzyl(methyl)amino)butyl)-4-phenylpyridazin-3(2H)-one; 2-(4-(azocan-1-yl)butyl)-4-phenylpyridazin-3(2H)-one; 2-(4-(3,4-dihydroisoquinolin-2(1H)-yl)butyl)-4-phenylpyridazin-3(2H)-one; 4-phenyl-2-(4-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)butyl)pyridazin-3(2H)-one; 4-phenyl-2-(4-(3-phenylpiperidin-1-yl)butyl)pyridazin-3(2H)-one; 4-phenyl-2-(4-(4-phenylpiperidin-1-yl)butyl)pyridazin-3(2H)-one; 2-[4-(4-benzylpiperazin-1-yl)butyl]-4-phenyl-2,3-dihydropyridazin-3-one; 2-[4-(4-benzylpiperidin-1-yl)butyl]-4-phenyl-2,3-dihydropyridazin-3-one; 2-{4-[benzyl(ethyl)amino]butyl}-4-phenyl-2,3-dihydropyridazin-3-one; 4-phenyl-2-[4-(thiomorpholin-4-yl)butyl]-2,3-dihydropyridazin-3-one; 2-{4-[benzyl(methyl)amino]butyl}-6-methyl-4-phenyl-2,3-dihydropyridazin-3-one; 2-[4-(azepan-1-yl)butyl]-6-methyl-4-phenyl-2,3-dihydropyridazin-3-one; and 2-(4-morpholinobutyl)-4-(piperidin-1-yl)pyridazin-3(2H)-one 12. The compound according to any one of claims 1 to 11, selected from the group consisting of:

13. A medicament comprising a compound according to any one of claims 1 to 12.

14. 13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and a pharmaceutically acceptable adjuvant.

15. 15. The pharmaceutical composition of claim 14 for use in the treatment of disorders modulated by the sigma-1 receptor.

16. 16. The pharmaceutical composition for use according to claim 15, wherein the disorder is selected from the group consisting of: (1) neurodegenerative diseases; (2) cognitive and memory alterations; (3) developmental cognitive disorders; and (4) genetic diseases associated with MAM dysfunction.

17. 17. The pharmaceutical composition for use according to claim 16, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, or multiple sclerosis.

18. 17. The pharmaceutical composition for use according to claim 16, wherein the cognitive and memory alteration is pathological aging, ischemic amnesia, schizophrenia-related cognitive deficits, or depression.

19. 17. The pharmaceutical composition for use according to claim 16, wherein the developmental cognitive disorder is an autism-related disorder or a mental retardation-related disorder.

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