Novel triazolyl derivatives as GABA ALPHA5 PAMs

Abstract

The present invention relates to a compound represented by general formula (I) or (II): TIFF2023525130000097.tif41170 TIFF2023525130000098.tif37170 [In the formula, R 1 , R 2 , R 3 , X, Y and Z are as described herein, compositions comprising said compounds and methods of using said compounds.

Description

[Technical Field]

[0001] The present invention relates to organic compounds, particularly GABA, useful for the treatment or prevention of inflammatory bowel diseases in mammals. A GABA for the treatment or prevention of α5 receptor-related disorders A α5 receptor positive allosteric modulators (PAMs) and GABA A The present invention relates to diseases or conditions that can be treated by modulating α5 receptor activity, such as Alzheimer's disease, mild cognitive impairment (MCI), age-related cognitive decline, schizophrenia, bipolar disorder, autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), and fragile X disorder.

[0002] The present invention relates to compounds of formula (I) and (II): [ka] [ka] [In the formula, X is i) N, and ii)CR 18 Selected from; Y is i) N, and ii) CH Selected from; Z is i) N, and ii) CH Selected from; R 1 teeth, I C 1-6 -alkyl, ii) H, iii) Halo-C 1-6 -alkyl, iv) C 1-6 -alkoxy, v) Halo-C 1-6 -alkoxy, vi) Hydroxy-C 1-6 - alkyl, vii) C 3-8 -cycloalkyl, and viii) Halogen Selected from; R 2 teeth, i) H, ii) C 1-6 -alkyl, and iii) Halogen Selected from; R 3 teeth, i) optionally R 6 、 R 7 and R 8 C is replaced by 3-8 heteroaryl, ii) R on the nitrogen atom 4 and R 5 an amino substituted with one or two substituents independently selected from iii) optionally R 9 、 R 10 and R 11 C is replaced by 3-8 heterocycloalkyl, iv) R 6 、 R 7 and R 8 C replaced with 3-8 -aryl, v) Halo-C 1-6 -alkoxy, vi) Hydroxy-C 1-6 -alkyl, and vii) Halo-C 1-6 -Alkyl Selected from; R 4 teeth, i) H, and ii) C 1-6 -Alkyl Selected from; R 5 teeth, i) H, and ii) C 1-6 -Alkyl Selected from; R 6 , R 7 and R 8 is, independently, I C 1-6 -alkyl, ii) Hydroxy-C 1-6 -alkyl, iii) C 1-6 -alkoxy, iv) halogens, v) Halo-C 1-6 -alkyl, vi) C 3-8 -cycloalkyl, and vii) Cyano Selected from; R 9 、 R 10 and R 11 is, independently, I C 1-6 -alkyl, ii) C 1-6 -alkoxy, iii) C 1-6 -alkoxycarbonyl, iv) C 3-8 -cycloalkoxy, v) C 3-8 -cycloalkyl, vi) C 3-8 -Cycloalkyl-C 1-6 -alkoxy, vii) Halo-C 1-6 -alkyl, viii) C 1-6 -Alkoxy-C 1-6 -alkyl, ix) C 3-8 -cycloalkylcarbonyl, x) Halo-C 1-6 -alkoxy, xi) cyano, xii) halogens, xiii) optionally R 12 , R 13and R 14 heteroaryl substituted with xiv) optionally R 12 , R 13 and R 14 heteroaryloxy substituted with xv) hydroxy, xvi) Hydroxy-C 1-6 -alkyl, and xvii) oxo Selected from; R 12 , R 13 and R 14 is, independently, i) Halo-C 1-6 - alkyl, ii) C 1-6 - alkyl, iii) C 1-6 -alkoxy, and iv) halogens Selected from; R 18 teeth, i) H, and ii) Halogen Select from or a pharmaceutically acceptable salt thereof. [Background technology]

[0003] Receptors for the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) are divided into two major classes: (1) GABA receptors, which are members of the ligand-binding ion channel superfamily; A receptors, and (2) GABA receptors, which are members of the G protein-coupled receptor family. B Receptor: GABA receptor, a membrane-bound heteropentameric protein polymer A The GABA receptor complex is primarily composed of α, β, and γ subunits. A The receptor is a ligand-bound chloride channel and is the primary mediator of inhibitory neurotransmission in the human brain.

[0004] GABAA There are 19 genes encoding the receptor subunits, with the most common stoichiometry consisting of two α, two β, and one γ subunit assembled as a pentamer. A Subunit combinations give rise to functional, circuit, and behavioral specificity (Sieghart, 2006; Vithlani et al., 2011). The α5 subunit (GABA A GABA containing α5) A GABA receptors are of particular interest due to their restricted expression patterns and unique physiological and pharmacological properties (Sur et al., 1999; Mohler, 2011). A The α5 subunit receptor is preferentially localized in the hippocampus, prefrontal cortex, occipital nuclei, and amygdala, which are important regions thought to be involved in the neuropathology and pathophysiology of various central nervous system disorders.

[0005] GABA A Hippocampal hyperactivity, resulting from reduced α5 expression or GABAergic deficiency, is a common feature of various central nervous system disorders characterized by cognitive decline (memory and executive function). In these disease states, GABAergic pathways, rather than negative allosteric modulators (NAMs), are essential. A The use of α5 positive allosteric modulators (PAMs) may be an effective treatment for the cognitive impairment associated with such diseases.

[0006] Multiple lines of evidence suggest that an imbalance in excitatory / inhibitory neurotransmission resulting from dysfunction of the GABAergic signaling system, the primary inhibitory neurotransmitter in the brain, is central to the pathogenesis of various CNS disorders. AGiven the widespread distribution of α5 receptors, they are highly attractive targets for restoring levels of inhibition within the cortex, thereby restoring (E / I) circuit balance in these conditions. Accordingly, the compounds described herein, and their pharmaceutically acceptable salts and esters, can be used alone or in combination with other agents as disease-modifying or symptomatic agents for the treatment or prevention of: acute neurological disorders, chronic neurological disorders, cognitive impairment, Alzheimer's disease, memory impairment, schizophrenia, positive, negative, and / or cognitive symptoms associated with schizophrenia, bipolar disorder, autism, Angelman syndrome, Prader-Willi syndrome, Rett syndrome, Down syndrome, type I neurofibromatosis, sleep disorders, circadian rhythm disorders, and muscle atrophy. ALS, Fragile X Disorder, AIDS-related dementia, Age-related Memory Impairment, Psychotic Disorder, Substance-Induced Psychotic Disorder, Anxiety Disorder, Generalized Anxiety Disorder, Panic Disorder, Delusional Disorder, Obsessive-Compulsive Disorder, Acute Stress Disorder, Post-Traumatic Stress Disorder (PTSD), Drug Dependence, Movement Disorder, Parkinson's Disease, Restless Legs Syndrome, Mild Cognitive Impairment (MCI), Cognitive Dysfunction Disorder, Age-Related Cognitive Decline, Multicenter Dementia, Mood Disorder, Depression, Neuropsychiatric Disorder, Psychosis, Attention Deficit Hyperactivity Disorder, Neuropathic Pain, Epilepsy, Stroke, and Attention Deficit Disorder.

[0007] The most preferred indication for this invention is autism spectrum disorder (ASD). ASD is a complex and heterogeneous neurodevelopmental disorder characterized by three core symptoms: impairments in social interaction, repetitive behaviors, and cognitive impairment. The estimated prevalence of ASD in the United States is 1 in 68 people (CDC, 2014), and it is estimated that 1% of the world's population has ASD (WHO, 2013).

[0008] There are no approved pharmacological treatments for the social-communication and repetitive deficits that are core to ASD (Autism Spectrum Disorder), and this disorder remains an area of ​​high unmet medical need. Currently approved treatments for ASD-related symptoms are limited to antipsychotic medications (risperidone and aripiprazole), which are indicated for treating irritability associated with ASD symptoms. Emerging evidence suggests that the GABAergic system, the brain's primary inhibitory neurotransmitter system, plays a critical role in the pathophysiology of ASD (Dhossche et al., 2002; Pizzarelli and Cherubini, 2011; Robertson et al., 2016).

[0009] Both genetic and imaging studies using positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) suggest altered GABAergic signaling in ASD. A Receptor binding is 123 It has been reported that PET imaging of [I]-iomazenil dramatically reduces the superior prefrontal cortex and medial frontal cortex in patients with ASD (Mori et al., 2012). 11 C]-RO154513 PET studies have shown reduced binding of this tracer, suggesting GABAergic dysfunction in ASD. A It has been suggested that α5 receptor levels are low (Mendez et al., 2012). MRS studies have found altered GABA levels in ASD (Gaetz et al., 2014; Rojas et al., 2014), and several recent studies have shown decreased GABA and altered somatosensory function in children with ASD (Puts et al., 2016; Robertson et al., 2016). Consistent with these observations, GABA receptors, including GABRB3 (DeLorey, 2005; Abrahams and Geschwind, 2008), have been shown to be involved in the development of GABAergic neurotransmitters. ADecreased postmortem expression of receptor subunits and reduced expression of the GABA-synthesizing enzymes glutamic acid decarboxylase (GAD) 65 and 67 have been observed in the parietal and cerebellar cortices of autistic individuals (Fatemi et al., 2002). Importantly, reduced GABAergic inhibitory activity has been proposed to contribute to the increased excitability observed in ASD, including a high incidence of seizures and auditory-tactile hypersensitivity (Rubenstein and Merzenich, 2003; Frye et al., 2016). Altered GABAergic function may lower the threshold for developing seizures, as indicated by the high comorbidity of epilepsy in ASD, which occurs in up to one-third of affected individuals. Finally, the effects of nonselective BZDs on GABAergic activity have been shown to be related to the increased excitability observed in ASD, including a high incidence of seizures and auditory-tactile hypersensitivity (Rubenstein and Merzenich, 2003; Frye et al., 2016). A Enhancement of GABA receptor activity has been shown to improve behavioral deficits in mouse models of ASD. A It has been observed that α1 subtype-mediated sedation has a very narrow margin of therapeutic efficacy (Han et al., 2012, 2014; Soto et al., 2013). These findings support the idea that GABA A This supports the idea that rebalancing GABAergic transmission via α5 receptors improves ASD symptoms without the side effects of non-selective benzodiazepines. Summary of the Invention

[0010] The object of the present invention is to provide a compound of formula (I) or (II) and its pharmaceutically acceptable salts and esters, the preparation of said compound, a medicament containing the same and the manufacture thereof, and a method for the treatment of GABA A α5 receptor-related disorders and GABA AThe compounds are used in the treatment or prevention of diseases or conditions that can be treated by modulating α5 receptor activity. Examples include Alzheimer's disease, mild cognitive impairment (MCI), age-related cognitive decline, schizophrenia, bipolar disorder, autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), and fragile X disorder. The compounds of the present invention inhibit the activity of gamma-aminobutyric acid (GABA) at a predetermined EC level. 20 α5-containing GABA increases GABAergic current (chloride influx) at high concentrations. A Selective GABA receptor function is enhanced A The compounds of the present invention are α5 receptor positive allosteric modulators (PAMs). The compounds of the present invention have a higher PAM effect than the compounds of the present invention. In a preferred embodiment, the compounds of the present invention are selective for binding to the α5 subunit relative to the α1, α2, and α3 subunits. Selective GABA receptors that are compatible with the brain distribution of the α5 subtype. A α5 PAM is a non-selective GABA receptor A They restore GABAergic signaling in key brain regions (e.g., hippocampus, amygdala, occipital nucleus, prefrontal cortex) without the side effects of modulators (e.g., benzodiazepines). In another preferred embodiment, the compounds of the present invention have increased chemical stability, particularly to low and high pH conditions. DETAILED DESCRIPTION OF THE INVENTION

[0011] "C 1-6 The term "-alkyl" refers to a monovalent straight or branched chain saturated hydrocarbon radical of 1 to 6 carbon atoms. 1-6 Examples of -alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and pentyl. 1-6 Examples of alkyl groups include methyl, ethyl, isopropyl, isobutyl, and tert-butyl. More specific examples are methyl and ethyl.

[0012] "C 1-6 The term "alkoxy" refers to a group of formula -O-R', where R' is C 1-6 - represents an alkyl group. 1-6 Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. Particularly, tert-butoxy, methoxy, ethoxy, isopropoxy, etc. More specific examples include ethoxy, methoxy, and tert-butoxy. Most specific examples are methoxy and ethoxy.

[0013] The terms "halogen" and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo, or iodo. Specific halogens include fluoro, chloro, and the like.

[0014] "Haro-C 1-6 The term "-alkoxy" refers to 1-6 -C in which at least one hydrogen atom of the alkoxy group is replaced by the same or different halogen atom 1-6 -alkoxy group. 1-6 The term "-alkoxy" refers to 1-6 -C in which all hydrogen atoms of the alkoxy group are replaced by the same or different halogen atoms 1-6 -alkoxy group. Halo-C 1-6 Examples of -alkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy, and pentafluoroethoxy. 1-6 Examples of the alkoxy group include trifluoroethoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoromethylethoxy, trifluorodimethylethoxy, etc. More specific examples include trifluoroethoxy, difluoroethoxy, and difluoromethoxy.

[0015] "Haro-C 1-6 The term "-alkyl" refers to 1-6 -C in which at least one hydrogen atom of the alkyl group is replaced by the same or different halogen atom 1-6 -Alkyl group. "Perhalo-C 1-6 -Alkyl-C 1-6 The term "C-alkyl" refers to an alkyl group in which all hydrogen atoms are replaced by the same or different halogen atoms. 1-6 -Alkyl-C 1-6 - represents an alkyl group. 1-6 Examples of halo-C include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl, pentafluoroethyl, etc. 1-6 -alkyl groups include difluoromethyl, trifluoromethyl, fluoromethyl, trifluoroethyl, and difluoroethyl. More specifically halo-C 1-6 The alkyl group includes trifluoromethyl and difluoromethyl.

[0016] The term "hydroxy" refers to the group --OH.

[0017] The term "oxo" refers to the group =O.

[0018] The term "hydroxy-C 1-6 -Alkyl" is C 1-6 -C in which one hydrogen atom of the alkyl group is replaced by a hydroxy group 1-6 - represents an alkyl group. Hydroxy C 1-6 Examples of -alkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylpropyl, hydroxymethylethyl, hydroxybutyl, etc. Specific examples include hydroxymethylpropyl, hydroxymethylethyl, etc.

[0019] The term "amino" refers to the group -NH2.

[0020] "C 1-6-Alkoxy-C 1-6 The term "C-alkyl" refers to 1-6 -At least one of the hydrogen atoms of the alkyl group is C 1-6 -C substituted with an alkoxy group 1-6 -alkyl groups. 1-6 -Alkoxy-C 1-6 Examples of alkyl groups include methoxymethyl, ethoxymethyl, methoxymethyl, ethoxyethyl, methoxypropyl, and ethoxypropyl.

[0021] The term "carbonyl" refers to the group -C(O)-.

[0022] The term “C 1-6 "-alkoxycarbonyl" refers to a group of formula -C(O)-R', where R' is C 1-6 -alkoxy group. 1-6 Examples of -alkoxycarbonyl groups include groups in which R' is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. 1-6 Specific examples of -alkoxycarbonyl groups include when R' is ethoxy or tert-butoxy.

[0023] The term "C" in the formula -C(O)-R' 1-6 -alkylcarbonyl" where R' is C 1-6 -alkyl group. 1-6 Examples of alkylcarbonyl groups include groups of the formula -C(O)-R', where R' is methyl or ethyl. 1-6 Specific examples of alkylcarbonyl groups include groups of the formula -C(O)-R', where R' is methyl.

[0024] The term "cyano" refers to the group --C.ident.N.

[0025] The term “C 3-8"-Cycloalkyl" represents a monovalent saturated monocyclic or bicyclic hydrocarbon group having 3 to 8 ring carbon atoms. Bicyclic means a ring system consisting of two saturated carbocyclic rings having one or two carbon atoms in common. Monocyclic C 3-8 Examples of cycloalkyl include cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl, or cycloheptyl. 3ー8 An example of a -cycloalkyl is spiro[3.3]heptanyl. 3ー8 -cycloalkyl groups are cyclopropyl, cyclobutanyl. More specific monocyclic C 3ー8 Cycloalkyl groups include cyclopropyl.

[0026] The term “C 3-8 The term "cycloalkoxy" refers to a group of formula -O-R', where R' is C 3-8 -cycloalkyl groups. Examples of cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy. A particular example is cyclopropoxy.

[0027] "C 3-8 -Cycloalkyl-C 1-6 The term "C-alkoxy" refers to 1-6 -At least one of the hydrogen atoms of the alkoxy group is C 3-8 -C substituted with cycloalkyl group 1-6 - represents an alkoxy group. 3-8 -Cycloalkyl-C 1-6 Examples of -alkoxy include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cyclopropylethoxy, cyclobutylethoxy, cyclopentylethoxy, cyclohexylethoxy, etc. Particular examples include cyclopropylethoxy.

[0028] The term "aryl" means a monovalent aromatic carbocyclic monocyclic or bicyclic ring system containing 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl. Particular aryl groups include phenyl.

[0029] The term "heteroaryl" refers to a monovalent aromatic heterocycle or mono- or bicyclic ring system consisting of 5 to 12 ring atoms, consisting of 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of heteroaryl include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxaaryl. Specific heteroaryl groups include pyridinyl, pyrazolyl, imidazolyl, pyrimidinyl, pyridazinyl, imidazo[1,2-a]pyridinyl, oxadiazolyl. More specific heteroaryl groups include pyrazolyl.

[0030] The term "heteroaryloxy" refers to a group of the formula -O-R', where R' is heteroaryl. Particular examples of R' include pyridinyl.

[0031] The term "heterocycloalkyl" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 11 ring atoms containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, the remaining ring atoms being carbon. Bicyclic means consisting of two rings that have 1 or 2 ring atoms in common. Examples of monocyclic saturated heterocyclyl are 4,5-dihydro-oxazolyl, oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples of bicyclic saturated heterocycloalkyl are oxabicyclo[2.2.1]heptanyl, oxaspiro[3.3]heptanyl, 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocycloalkyl are dihydrofuryl, imidazolinyl, dihydrooxazolyl, tetrahydropyridinyl, or dihydropyranyl.Specific heterocycloalkyls include pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 2-oxa-6-azaspiro[3.3]heptanyl, 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazinyl, 3,5,6,7,8,8a-hexahydro-1H-oxazolo[3,4-a]pyrazinyl, 2-oxa-7-azaspiro[3.5]nonanyl, 1-oxa-7-azaspiro[3.5]nonanyl, 3,3a,4,5,6,6a-hexahydro-1H-furo[3,4-c]pyrrolyl, 2,6-diazaspiro[3.3]heptanyl, 5-oxa-2-azaspiro[3.4]octanyl, 7-oxa-2-azaspiro[3.5]nonanyl, nyl, 3-oxa-9-azaspiro[5.5]undecanyl, 5-oxa-2-azaspiro[3.5]nonanyl, 1-oxa-9-azaspiro[5.5]undecanyl, 5-oxa-2-azaspiro[3.6]decanyl, 2-azaspiro[3.3]heptanyl, 4,7-diazaspiro[2.5]octanyl, 2-azaspiro[3.5]nonanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 1-oxa-8-azaspiro[4.5]decanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, and azetidinyl. More specific examples include morpholinyl, piperazinyl, azetidinyl, 5-oxa-2-azaspiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 5-oxa-2-azaspiro[3.4]acetanyl, and 2-azaspiro[3.3]heptanyl. Even more specific examples include morpholinyl, piperazinyl, azetidinyl, and 5-oxa-2-azaspiro[3.5]nonanyl. Most specific examples include azetidinyl and 5-oxa-2-azaspiro[3.5]nonanyl.

[0032] The term "pharmaceutically acceptable" refers to salts that retain the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, especially hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine. These salts may also be prepared by adding inorganic or organic bases to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, etc. Particular pharmaceutically acceptable salts of compounds of formula (I) are the hydrochloride, methanesulfonate, and citrate salts.

[0033] "Pharmaceutically acceptable ester" means that the compounds of general formula (I) or (II) may be derivatized at functional groups to provide derivatives that can be converted back to the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters, and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of general formula (I) or (II) that are analogous to the metabolically labile esters that the parent compounds of general formula (I) or (II) can produce in vivo are also within the scope of the present invention.

[0034] The term "protecting group" (PG) is used in its conventional sense in synthetic chemistry to mean a group that selectively blocks reactive sites on a polyfunctional compound, allowing chemical reactions to occur selectively at other, unprotected reactive sites. The protecting group can be removed at an appropriate point. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups, or hydroxy-protecting groups. Specific protecting groups are the tert-butoxycarbonyl (Boc) group, the benzyloxycarbonyl (Cbz) group, the fluorenylmethoxycarbonyl (Fmoc) group, and the benzyl (Bn) group. Even more specific protecting groups are the tert-butoxycarbonyl (Boc) group and the fluorenylmethoxycarbonyl (Fmoc) group. An even more specific protecting group is the tert-butoxycarbonyl (Boc) group.

[0035] The abbreviation uM means micromolar and is equivalent to the symbol μM.

[0036] The abbreviation uL stands for microliter and is equivalent to the symbol μL.

[0037] The abbreviation ug stands for microgram and is equivalent to the symbol μg.

[0038] The compounds of formula (I) or (II) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers, e.g. racemates, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0039] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0040] Also an embodiment of the present invention are compounds according to formula (I) or (II) as described herein and pharmaceutically acceptable salts or esters thereof, particularly compounds according to formula (I) or (II) as described herein and pharmaceutically acceptable salts thereof, particularly compounds according to formula (I) or (II) as described herein.

[0041] E1: Certain embodiments of the present invention are X is, i) N, and ii)CR 18 Selected from; Y is, i) N, and ii) CH Selected from; Z, i) N, and ii) CH Selected from; R 1 but, I C 1-6 - alkyl, ii) Halo-C 1-6 -alkyl, and iii) Halogen Selected from; R 2 But C 1-6 is alkyl; R 3 but, i) optionally R 6 and R 7 pyrazolyl substituted with ii) optionally R 6 and R 7 pyridinyl substituted with iii) optionally R 9 and R 10 azetidinyl substituted with iv) optionally R 9 and R 10 isoindolinyl substituted with v) optionally R 9 and R 10 morpholinyl substituted with vi) optionally R 9 and R 10 piperazinyl substituted with vii) optionally R 9 and R 10 piperidinyl substituted with viii) optionally R 9 and R 10 pyrrolidinyl substituted with ix) optionally R 9 and R 10 oxaazaspirooctanyl substituted with x) optionally R 9 and R 10 oxaazaspirononanyl substituted with xi) R on nitrogen atom 4 and R 5 and xii)R 6 and R 7 Phenyl substituted with Selected from; R 4 But C 1-6 is alkyl; R 5 but, i) H, and ii) C 1-6 -Alkyl Selected from; R 6 but, I C 1-6 -alkyl, ii) C 1-6 -alkoxy, iii) halogens, iv) Halo-C 1-6 -alkyl, v) C 3-8 -cycloalkyl, and vi) Cyano Selected from; R 7 but, I C 1-6 -alkyl, and ii) C 1-6 -alkoxy Selected from; R 9 、 R 10 and R 11 But independently, I C 1-6-alkyl, ii) C 1-6 -alkoxy, iii) C 3-8 -cycloalkoxy, iv) C 3-8 -cycloalkyl, v) C 3-8 -Cycloalkyl-C 1-6 -alkoxy, vi) C 1-6 -Alkoxy-C 1-6 -alkyl, vii) C 3-8 -cycloalkylcarbonyl, viii) Halo-C 1-6 -alkoxy, ix) halogens, x) optionally R 12 imidazolyl substituted with xi) optionally R 12 pyridinyl substituted with xii) optionally R 12 pyrazolyl substituted with xiii) optionally R 12 pyridazinyloxy substituted with xiv) optionally R 12 pyridinyloxy substituted with xv) optionally R 12 Pyrimidinyloxy substituted with Selected from; R 12 but, i) Halo-C 1-6 -alkyl, ii) C 1-6 -alkyl, iii) C 1-6 -alkoxy, and iv) halogens Selected from; R 18 but, i) H, and ii) Halogen or a pharmaceutically acceptable salt thereof.

[0042] E2: A particular embodiment of the present invention is R 1 but, I C 1-6 -alkyl, ii) Halo-C 1-6 -alkyl, and iii) Halogen or a pharmaceutically acceptable salt thereof.

[0043] E3: A particular embodiment of the present invention is R 1 but, iv) Halo-C 1-6 -alkyl, and v) halogens or a pharmaceutically acceptable salt thereof.

[0044] E4: A particular embodiment of the present invention is 2 But C 1-6 -alkyl, or a pharmaceutically acceptable salt thereof.

[0045] E5: A particular embodiment of the present invention is R 3 but, i. Optionally, R 6 pyridinyl substituted with ii. Optionally, R 6 Azetidinyl substituted with or a pharmaceutically acceptable salt thereof.

[0046] E6: A particular embodiment of the present invention is 4 But C 1-6 -alkyl, or a pharmaceutically acceptable salt thereof.

[0047] E7: A particular embodiment of the present invention is R 6 but, I C 1-6 -alkyl, ii.C 1-6 -alkoxy, iii. halogens, iv. Halo-C 1-6 -alkyl, vC 3-8 -cycloalkyl, and vi. Cyano or a pharmaceutically acceptable salt thereof.

[0048] E8: A particular embodiment of the present invention is 6 But C 1-6 -alkoxy, or a pharmaceutically acceptable salt thereof.

[0049] E9: A particular embodiment of the present invention is R 7 but, I C 1-6 -alkyl, and ii.C 1-6 -alkoxy or a pharmaceutically acceptable salt thereof.

[0050] E10: A particular embodiment of the present invention is R 9 、 R 10 and R 11 But independently, I C 1-6 -alkyl, ii.C 1-6 -alkoxy, iii.C 3-8 -cycloalkoxy, iv.C 3-8 -cycloalkyl, vC3-8 -Cycloalkyl-C 1-6 -alkoxy, vi.C 1-6 -Alkoxy-C 1-6 - alkyl, vii.C 3-8 -cycloalkylcarbonyl, viii. Halo-C 1-6 -alkoxy, ix. halogens, x.Optionally, R 12 imidazolyl substituted with xi. Optionally, R 12 imidazolyloxy substituted with xii. Optionally, R 12 pyridinyl substituted with xiii. Optionally, R 12 pyridinyloxy substituted with xiv. Optionally, R 12 pyrazolyl substituted with xv. Optionally, R 12 pyrazolyloxy substituted with xvi. Optionally, R 12 pyridazinyl substituted with xvii. Optionally, R 12 pyridazinyloxy substituted with xviii. Optionally, R 12 pyrimidinyl substituted with xix. Optionally, R 12 Pyrimidinyloxy substituted with or a pharmaceutically acceptable salt thereof.

[0051] E11: A particular embodiment of the present invention is R 9 、 R 10 and R 11 But independently I C 1-6 - alkyl, ii.C 1-6-alkoxy, iii.C 3-8 -cycloalkoxy, iv.C 3-8 -cycloalkyl, vC 3-8 -Cycloalkyl-C 1-6 -alkoxy, vi.C 1-6 -Alkoxy-C 1-6 - alkyl, vii.C 3-8 -cycloalkylcarbonyl, viii. Halo-C 1-6 -alkoxy, ix. halogens, x.Optionally, R 12 imidazolyl substituted with xi. Optionally, R 12 pyridinyl substituted with xii. Optionally, R 12 pyrazolyl substituted with xiii. Optionally, R 12 pyridazinyloxy substituted with xiv. Optionally, R 12 Pyrimidinyloxy substituted with or a pharmaceutically acceptable salt thereof.

[0052] E12: A particular embodiment of the present invention is R 9 、 R 10 and R 11 But independently, I C 3-8 -cycloalkoxy, ii.C 3-8 -Cycloalkyl-C 1-6 -alkoxy, iii. Halo-C 1-6 -alkoxy, iv. Optionally, R 12 Pyrimidinyloxy substituted with or a pharmaceutically acceptable salt thereof.

[0053] E13: Certain embodiments of the present invention relate to compounds of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein Z is CH.

[0054] E14: A particular embodiment of the present invention is 12 But, Halo-C 1-6 -alkyl, or a pharmaceutically acceptable salt thereof.

[0055] E15: A particular embodiment of the present invention is 18 is halogen, or a pharmaceutically acceptable salt thereof.

[0056] E16: Certain embodiments of the present invention relate to compounds of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I).

[0057] E17: Certain embodiments of the present invention relate to compounds of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II).

[0058] E18: A particular embodiment of the present invention is 2-[[5-methyl-3-(6-methyl-3-pyridyl)triazol-4-yl]methyl]-5-[rac-(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridazin-3-one; 2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]-5-[rac-(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[rac-(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-morpholino-pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-(dimethylamino)pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[4-(cyclopropanecarbonyl)piperazin-1-yl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[rac-(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridazin-3-one; 2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]-5-pyrrolidin-1-yl-pyridazin-3-one; 2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]-5-morpholino-pyridazin-3-one; 5-(3,3-dimethylpyrrolidin-1-yl)-2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]pyridazin-3-one; 5-(2,2-dimethylmorpholin-4-yl)-2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]pyridazin-3-one; 5-[(2S,6S)-2,6-dimethylmorpholin-4-yl]-2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]pyridazin-3-one; 2-[[3-(4-chlorophenyl)-5-methyl-triazol-4-yl]methyl]-5-(dimethylamino)pyridazin-3-one; 2-[[3-(4-chlorophenyl)-5-methyl-triazol-4-yl]methyl]-5-piperazin-1-yl-pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(dimethylamino)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-morpholino-pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(4-cyclopropylpiperazin-1-yl)pyridazin-3-one; 2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]-5-[(2R)-2-methylpyrrolidin-1-yl]pyridazin-3-one; 5-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]-2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]pyridazin-3-one; 2-[[3-(4-chlorophenyl)-5-methyl-triazol-4-yl]methyl]-5-[rac-(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[4-(cyclopropanecarbonyl)piperazin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(methylamino)pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-(3-ethoxyazetidin-1-yl)pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-isoindolin-2-yl-pyridazin-3-one; 2-[[5-methyl-3-(6-methyl-3-pyridyl)triazol-4-yl]methyl]-5-[(2R)-2-methylpyrrolidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(3-methoxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(3-ethoxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(cyclopropylmethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3-one; 2-[[5-(4-chlorophenyl)-3-methyl-triazol-4-yl]methyl]-5-[rac-(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridazin-3-one; 2-[[5-(4-chlorophenyl)-3-methyl-triazol-4-yl]methyl]-5-(dimethylamino)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[(7S)-7-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[(7R)-7-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[3-(2,2,2-trifluoroethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[(2S)-2-methylmorpholin-4-yl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[(2R)-2-methylmorpholin-4-yl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[(2S,6S)-2,6-dimethylmorpholin-4-yl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[4-(2-methylimidazol-1-yl)-1-piperidyl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[4-(2-methoxy-3-pyridyl)piperazin-1-yl]pyridazin-3-one; 2-[[5-(4-chlorophenyl)-3-methyl-triazol-4-yl]methyl]-5-[(3S)-4-isopropyl-3-methyl-piperazin-1-yl]pyridazin-3-one; 2-[[5-(4-chlorophenyl)-3-methyl-triazol-4-yl]methyl]-5-(3-ethoxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[(3R)-3-isopropoxypyrrolidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(2-pyridyloxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[(3S)-4-isopropyl-3-methyl-piperazin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[(2S)-2-methylmorpholin-4-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[(2R)-2-methylmorpholin-4-yl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[4-(2-ethylimidazol-1-yl)-1-piperidyl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(3-isopropoxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(cyclobutoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(2,2,2-trifluoroethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(3-propoxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-[(6-chloro-3-pyridyl)oxy]azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(difluoromethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(2,2-difluoroethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-[(2-chloro-4-pyridyl)oxy]azetidin-1-yl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-(4-methoxyphenyl)pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[2-(trifluoromethyl)-4-pyridyl]pyridazin-3-one; 2-[[5-(2,4-difluorophenyl)-3-methyl-triazol-4-yl]methyl]-5-[rac-(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridazin-3-one; 2-[[5-(4-chlorophenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(2,2,2-trifluoroethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chlorophenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(2,2-difluoroethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(4-methoxyphenyl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(6-methoxy-3-pyridyl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(2-methoxy-4-pyridyl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(1-methylpyrazol-4-yl)pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-(1-cyclopropylpyrazol-4-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(6-ethoxy-5-methyl-3-pyridyl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(1-cyclopropylpyrazol-4-yl)pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-(5-chloro-6-methoxy-3-pyridyl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(5-chloro-6-methoxy-3-pyridyl)pyridazin-3-one; 2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]-5-(3-isopropoxyazetidin-1-yl)pyridazin-3-one; 5-[3-(difluoromethoxy)azetidin-1-yl]-2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]pyridazin-3-one; 5-(3-ethoxyazetidin-1-yl)-2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(3-pyrazin-2-yloxyazetidin-1-yl)pyridazin-3-one; 2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]-5-[3-(2,2,2-trifluoroethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3-one; 5-[3-(2,2-difluoroethoxy)azetidin-1-yl]-2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]pyridazin-3-one; 5-[3-(cyclobutoxy)azetidin-1-yl]-2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(3-pyrimidin-4-yloxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(3-pyridazin-3-yloxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-[(5-chloro-2-pyridyl)oxy]azetidin-1-yl]pyridazin-3-one; 5-(2-Methoxy-4-pyridyl)-2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]pyridazin-3-one; 5-(5-chloro-6-methoxy-3-pyridyl)-2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]pyridazin-3-one; 2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]-5-(3-pyridazin-3-yloxyazetidin-1-yl)pyridazin-3-one; 2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]-5-[3-(2-pyridyloxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-[3-(cyclobutoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-[3-(2,2-difluoroethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-[3-(2,2,2-trifluoroethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-[3-(difluoromethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]-5-(3-pyrazin-2-yloxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-(3-isopropoxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-(3-ethoxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-[(3S)-4-isopropyl-3-methyl-piperazin-1-yl]pyridazin-3-one; 5-[3-[(6-chloro-3-pyridyl)oxy]azetidin-1-yl]-2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]pyridazin-3-one; 2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]-5-[(3S)-4-isopropyl-3-methyl-piperazin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3-one; 5-(3-tert-butoxyazetidin-1-yl)-2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]pyridazin-3-one; 5-(3-tert-butoxyazetidin-1-yl)-2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-[6-(trifluoromethyl)pyrazin-2-yl]oxyazetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(2-methylpyrimidin-4-yl)oxyazetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-[2-(trifluoromethyl)pyrimidin-4-yl]oxyazetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-[3-[(6-chloro-3-pyridyl)oxy]azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-(3-pyridazin-3-yloxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(6-ethoxy-3-pyridyl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(6-methoxy-5-methyl-3-pyridyl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-(1-cyclopropylpyrazol-4-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[1-(2,2-difluoroethyl)pyrazol-4-yl]pyridazin-3-one; 6-[1-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-6-oxo-pyridazin-4-yl]pyridine-2-carbonitrile; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(6-chloro-5-methoxy-3-pyridyl)pyridazin-3-one; 2-[[5-(6-chloro-3-pyridyl)-3-methyl-triazol-4-yl]methyl]-5-[(2R)-2-methylpyrrolidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-(5-chloro-6-methoxy-3-pyridyl)pyridazin-3-one; 6-[1-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-6-oxo-pyridazin-4-yl]pyridine-2-carbonitrile; 2-[[5-(6-chloro-3-pyridyl)-3-methyl-triazol-4-yl]methyl]-5-[rac-(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(5-methylpyrazol-1-yl)azetidin-1-yl]pyridazin-3-one; 5-(5-chloro-6-methoxy-3-pyridyl)-2-[[3-methyl-5-(6-methylpyridazin-3-yl)triazol-4-yl]methyl]pyridazin-3-one; 5-(3-ethoxyazetidin-1-yl)-2-[[3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazol-4-yl]methyl]pyridazin-3-one; 5-(3-isopropoxyazetidin-1-yl)-2-[[3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazol-4-yl]methyl]pyridazin-3-one; 5-[3-(cyclobutoxy)azetidin-1-yl]-2-[[3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazol-4-yl]methyl]pyridazin-3-one; 5-(5-chloro-6-methoxy-3-pyridyl)-2-[[3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazol-4-yl]methyl]pyridazin-3-one; 5-[3-(2,2-difluoroethoxy)azetidin-1-yl]-2-[[3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazol-4-yl]methyl]pyridazin-3-one; 2-[[3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazol-4-yl]methyl]-5-[3-(2,2,2-trifluoroethoxy)azetidin-1-yl]pyridazin-3-one; 5-[3-(difluoromethoxy)azetidin-1-yl]-2-[[3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazol-4-yl]methyl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-[(7R)-7-methyl-5-oxa-2-azaspiro[3.5]nonan-2-yl]pyridazin-3-one; 5-(5-chloro-6-methoxy-3-pyridyl)-2-[[3-methyl-5-[6-(trifluoromethyl)pyridazin-3-yl]triazol-4-yl]methyl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-[(7S)-7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-[(7R)-7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[(7S)-7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl]pyridazin-3-one or a pharmaceutically acceptable salt thereof.

[0059] E19: A particular embodiment of the present invention is 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(cyclopropylmethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(cyclobutoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(6-methoxy-3-pyridyl)pyridazin-3-one; 5-[3-(2,2-difluoroethoxy)azetidin-1-yl]-2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]pyridazin-3-one; 5-[3-(cyclobutoxy)azetidin-1-yl]-2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-[2-(trifluoromethyl)pyrimidin-4-yl]oxyazetidin-1-yl]pyridazin-3-one; 5-[3-(Difluoromethoxy)azetidin-1-yl]-2-[[3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazol-4-yl]methyl]pyridazin-3-one or a pharmaceutically acceptable salt thereof.

[0060] In certain embodiments, the present invention provides pharmaceutically acceptable salts, particularly hydrochloride salts, of compounds according to Formula (I) or (II) described herein. In more particular embodiments, the present invention provides compounds according to Formula (I) or (II) described herein as the free base.

[0061] In some embodiments, compounds of formula (I) or (II) are isotopically labeled by replacing one or more atoms therein with atoms having a different atomic mass or mass number. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) or (II) are considered within the scope of the present disclosure. Exemplary isotopes that can be incorporated into compounds of formula (I) or (II) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Certain isotopically labeled compounds of formula (I) or (II), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e., 3 H and carbon-14, i.e., 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. For example, compounds of formula (I) or (II) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99% of a given isotope.

[0062] Heavier isotopes, such as deuterium, i.e. 2 Substitutions such as H may result in greater metabolic stability and may confer certain therapeutic advantages, for example, by increasing in vivo half-life or requiring lower dosages.

[0063] 11 C. 18 F, 15 O and 13Substitution with positron emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of formula (I) or (II) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the Examples set forth below, substituting appropriate isotopically labeled reagents for previously employed non-isotopically labeled reagents.

[0064] The present invention also provides processes for preparing compounds of formula (I) or (II) described herein.

[0065] The preparation of the compounds of formula (I) or (II) of the present invention may be carried out by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the description of the following processes have the meanings previously indicated herein, unless otherwise indicated.

[0066] The preparation of compounds of formula Ia or Ib of the present invention can be carried out by sequential or convergent synthetic routes. The synthesis of the compounds of the present invention is shown in the following Schemes 1 to 9 and in the description of Example 126. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following process descriptions have the meanings previously indicated herein, unless otherwise indicated.

[0067] More specifically, compounds of formula (I) or (II) can be prepared by the methods shown below, the methods described in the Examples, or similar methods. Suitable reaction conditions for the individual reaction steps are known to those skilled in the art. The reaction order is not limited to those shown in Schemes 1 to 9, but the order of reaction steps can be freely changed depending on the starting materials and their respective reactivities. Starting materials are commercially available or can be prepared by methods similar to those shown below, methods described in the references or examples cited herein, or methods known in the art.

[0068] The compounds of formula (I) or (II) of the present invention and pharmaceutically acceptable salts thereof can be prepared by the steps described below (Scheme 1). [ka] Scheme 1: Synthesis of pyridazinones (I) and (II); where all definitions are as defined above and in the claims.

[0069] According to Scheme 1, compounds of formula (I) or (II) can be reacted with a base (e.g., K2CO3, Cs2CO3, and KO t The pyridazinones of formula III can be prepared by a simple N-alkylation reaction between alkyl chlorides Ia or IIa and pyridazinones of formula III in the presence of 2-(2-methyl-2-propanol)-2-(4-methyl-2-propanol).

[0070] Alternatively, as shown in Scheme 2, pyridazinones Ia or Ib can be obtained by Mitsunobu reaction between alcohols of formula IVa or IVb and pyridazinones of formula III in the presence of diethyl azodicarboxylate and triphenylphosphine. [ka] Scheme 2: Alternative synthesis of pyridazinones (I) and (II); where all definitions are as defined above and in the claims.

[0071] The synthesis of alkyl chlorides Ia and alcohols IVa is highlighted in Scheme 3. [ka] Scheme 3: Synthesis of alkyl chlorides Ia and alcohols IVa; where all definitions are as defined above and in the claims.

[0072] Commercially available alkynes V undergo Cu(I)-mediated 1,3-dipolar cycloaddition with trimethylsilylmethyl azide in the presence of a base (e.g., DIPEA) to give the corresponding 1,2,3-triazoles VI. Removal of the trimethylsilyl residue is facilitated by treatment with TBAF in tetrahydrofuran. Kinetic deprotonation with a strong base (LiHMDS or LDA) at low temperatures (-78 °C to 0 °C), followed by quenching with ethyl or methyl chloroformate, affords 1,2,3-triazoles of general formula VIII. Their reduction to alcohols IVa can be achieved directly using LiAlH4 or DIBAL-H at controlled temperatures. Final conversion to the desired alkyl chlorides Ia is achieved by exposure to thionyl chloride. [ka] Scheme 4: Synthesis of alkyl chlorides Ia and alcohols IVa; where all definitions are as defined above and in the claims.

[0073] R 2 In certain embodiments of the invention where is ethyl, a slightly modified synthetic route to access alkyl chloride Ia and alcohol IVa is used by replacing trimethylsilylmethyl azide with ethyl azide (see Scheme 4). [ka] Scheme 5: Alternative synthesis of alkyl chloride Ia and alcohol IVa; where all definitions are as defined above and in the claims.

[0074] Alternatively, triazole Ia can be obtained according to the synthetic route described in Scheme 5. Commercially available 4,5-dibromo-1H-1,2,3-triazole is N-alkylated under standard conditions. Regioselective metallation with isopropylmagnesium chloride in tetrahydrofuran followed by quenching with N,N-dimethylformamide affords aldehydes X. Their reduction to alcohols XI under standard conditions (NaBH4, MeOH), followed by protection of the hydroxyl residue with tert-butyldimethylsilyl chloride, affords aryl bromides XII. These can be sp-coated with the in situ formed organozinc intermediate XIII to access triazoles XIV. 2 -sp 2 Their final conversion to the desired alkyl chlorides IIa is achieved in two steps by deprotection with TBAF, followed by exposure to thionyl chloride. [ka] Scheme 6: Synthesis of alkyl chloride IIa and alcohol IVb; where all definitions are as defined above and in the claims.

[0075] The synthesis of regioisomeric triazoles IIa and IVb is shown in Scheme 6. Commercially available aryl azides XV undergo thermal 1,3-dipolar cycloaddition with methyl but-2-ynoate to afford 1,2,3-triazoles XVI. Their reduction to alcohols IVb can be achieved directly using LiAlH or DIBAL-H at controlled temperatures. Final conversion to the desired alkyl chlorides IIa is achieved by exposure to thionyl chloride. [ka] Scheme 7: Synthesis of aryl halides Ic or IIc

[0076] Conveniently, alkyl chloride Ia or IIa can be reacted with commercially available 4-chloro-1H-pyridazin-6-one or 4-iodo-1H-pyridazin-6-one in the presence of base (KCO or CsCO) to give bench-stable 5-chloro- or 5-iodopyridazinones Ic and IIc, as shown in Scheme 7. [ka] Scheme 8: Synthesis of pyridazinones Id or IId from aryl halides Ic or IIc; 3 is amino substituted by one or two substituents at the nitrogen atom, or substituted heterocycloalkyl; all other definitions are as defined above and in the claims.

[0077] R 3 In certain embodiments of the present invention where is nitrogen, the pyridazinones of formula (I) or (II) may be selected from the group consisting of aryl halides Ic or IIc and primary (R 4 =H) or secondary amines HNR 4 R 5 It can be prepared by nucleophilic aromatic substitution reaction between (Scheme 8). [ka] Scheme 9: Synthesis of pyridazinones Ie or IIe from aryl chlorides Ic or IIc; 3 is aryl or heteroaryl; all other definitions are as defined above and in the claims.

[0078] R 3 In further embodiments of the present invention, where Ic is heteroaryl or aryl, pyridazinones of formula (I) or (II) can be obtained by a palladium-mediated Suzuki coupling reaction between aryl chlorides Ic or IIc and commercially available boronic acids or boronates (Scheme 9). Also an embodiment of the present invention is a process for preparing a compound of formula (I) or (II) as defined above, when W is halogen, such as Cl, or when W is hydroxy, which comprises reacting a compound of formula (III) with a compound of formula (Ia1) or (IIa1), respectively, in the presence of a dialkyl azodicarboxylate, such as diethyl azodicarboxylate, and triphenylphosphine, in the presence of a base, in particular KCO, [ka] R 1 , R 2 , R 3 , X, Y and Z are as defined herein, and W is halogen or hydroxy.

[0079] Also an object of the present invention are compounds according to formula (I) or (II) as described herein, more particularly compounds of formula (I), for use as therapeutically active substances.

[0080] Likewise, an object of the present invention is a pharmaceutical composition comprising a compound according to formula (I) or (II) as described herein, more particularly a compound of formula (I), and a therapeutically inert carrier.

[0081] A specific embodiment of the present invention is a compound according to formula (I) or (II) as described herein, more particularly a compound of formula (I), for the treatment or prevention, more particularly the treatment of Alzheimer's disease, mild cognitive impairment (MCI), age-related cognitive decline, negative and / or cognitive symptoms associated with schizophrenia, bipolar disorder, autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), Fragile X disorder, in particular negative and / or cognitive symptoms associated with autism spectrum disorder (ASD), Angelman syndrome, Alzheimer's disease, schizophrenia and post-traumatic stress disorder (PTSD).

[0082] The present invention also relates to the use of a compound according to formula (I) or (II) as defined herein, more particularly a compound of formula (I), for the preparation of a medicament for the treatment or prevention, more particularly the treatment of negative and / or cognitive symptoms associated with Alzheimer's disease, mild cognitive impairment (MCI), age-related cognitive decline, schizophrenia, bipolar disorder, autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), Fragile X disorder, in particular autism spectrum disorder (ASD), Angelman syndrome, Alzheimer's disease, schizophrenia and post-traumatic stress disorder (PTSD).

[0083] A method for the treatment or prevention, more particularly the treatment, of negative and / or cognitive symptoms associated with Alzheimer's disease, mild cognitive impairment (MCI), age-related cognitive decline, schizophrenia, bipolar disorder, autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), Fragile X disorder, in particular autism spectrum disorder (ASD), Angelman syndrome, Alzheimer's disease, schizophrenia and post-traumatic stress disorder (PTSD) is also an object of the present invention, which method comprises administering an effective amount of a compound according to formula (I) or (II) as described herein, more particularly a compound of formula (I).

[0084] Also, one embodiment of the present invention is a compound of formula (I) or (II) as described herein, more particularly a compound of formula (I), when prepared by any of the processes described.

[0085] Assay procedure Membrane preparation and binding assays GABA AThe affinity of compounds at receptor subtypes was measured by competition for binding of [3H]flumazenil (85 Ci / mmol; Roche) to HEK293 cells expressing rat (stably transfected) or human (transiently transfected) receptors of the compositions α1β3γ2, α2β3γ2, α3β3γ2, and α5β3γ2.

[0086] The cell pellet was suspended in Krebs-Tris buffer (4.8 mM KCl, 1.2 mM CaCl, 1.2 mM MgCl, 120 mM NaCl, 15 mM Tris; pH 7.5; binding assay buffer), homogenized with a Polytron for 20 seconds on ice, and centrifuged at 4°C for 60 minutes (50,000 g; Sorvall, rotor: SM24 = 20,000 rpm). The cell pellet was resuspended in Krebs-Tris buffer and homogenized with a Polytron for 15 seconds on ice. Protein was measured (Bradford method, Bio-Rad), and 1 mL aliquots were prepared and stored at -80°C.

[0087] Radioligand binding assays were performed using 100 mL of cell membranes containing 1 nM of [α1, α2, α3 subunits and 0.5 nM of [α5 subunit]]. 3 H]-flumazenil, as well as 10-10 -3 x10 -6 The assay was performed in a volume of 200 mL (96-well plate) containing test compounds ranging in M. Nonspecific binding was determined by 10 -5 The binding was defined as M diazepam and was typically less than 5% of total binding. Assays were incubated at equilibrium for 1 hour at 4°C, filtered using a Packard harvester, and harvested onto GF / C unifilters (Packard) by washing with ice-cold wash buffer (50 mM Tris, pH 7.5). After drying, radioactivity retained on the filters was detected by liquid scintillation counting. i Values ​​were calculated using Excel-Fit (Microsoft) and are the mean of duplicate measurements.

[0088] The compounds of the accompanying examples were tested in the above assay and preferred compounds exhibited a human GABA receptor activity of 100 nM or less. A from the α5 subunit of the receptor 3 H]-Flumazenil substitution for K i Most preferred are K values ​​of less than 35. i (nM) of the compound. In a preferred embodiment, the compounds of the present invention exhibit binding selectivity for the α5 subunit relative to the α1, α2, and α3 subunits. Representative test results obtained by the above assay measuring binding affinity to HEK293 cells expressing the human (h) receptor are shown in the table below.

[0089] GABA A functional expression of receptors; Preparation of Xenopus oocytes Xenopus laevis oocytes at maturation stages V-VI were treated with GABA A Oocytes prepared for RNA microinjection were purchased from Ecocyte, Castrop-Rauxel, Germany, and stored at 20°C in modified Barth's medium (composition in mM: NaCl 88, KCl 1, NaHCO 3 2.4, HEPES 10, MgSO 4 0.82, CaNO 3 0.33, CaCl 2 0.33, pH = 7.5) until the experiment. Xenopus oocyte microinjection

[0090] Oocytes were plated in 96-well plates and used in an automated device (Robo-ocyte, MultiChannelSystems, Reutlingen, Germany) for microinjection and electrophysiological recording. AApproximately 50 nL of an aqueous solution containing RNA transcripts of the receptor subunits was injected into each egg. The RNA concentration ranged between 0.3 and 16 ng / µL / subunit, and was adjusted in pilot experiments to obtain an appropriate magnitude of GABA response. The maximal effect was achieved using one of the following: reference modulator, β-CCM (β-CCM), or GABA. A Betacarboline negative allosteric modulators (NAMs) of the receptor benzodiazepine (BZD) binding site, or midazolam, GABA A The benzodiazepine-positive allosteric modulator (PAM) of the receptor benzodiazepine (BZD) binding site was expressed in the γ2 subunit. The concentration of the RNA encoding the γ2 subunit was typically 5-10 times higher than that of the RNA encoding the other subunits. Oocytes were maintained in modified Barth's medium (composition in mM: NaCl 88, KCl 1, NaHCO 34, HEPES 10, MgSO 4 0.82, CaNO 3 0.33, CaCl 2 0.33, pH = 7.5) at 20°C until the experiment. electrophysiology

[0091] Electrophysiological experiments were performed on days 3 to 5 after mRNA microinjection. During the experiments, oocytes were constantly superfused in a solution containing (in mM): NaCl 90, KCl 1, HEPES 5, MgCl 2 1, and CaCl 2 1 (pH 7.4). Oocytes were filled with a solution containing 1 M KCl and 1.5 M K-acetate and impinged with two glass microelectrodes (resistance: 0.4 MΩ) voltage-clamped at -80 mV. Recordings were performed at room temperature using a Robocyte two-electrode voltage-clamp system (Multichannel system). After an initial equilibration period of 1.5 min with GABA, the maximum current response (EC 20 ) was added for 1.5 min at a concentration eliciting approximately 20% of the K. After another 2.5 min rest interval, GABA was added again, eliciting responses of similar amplitude and shape. 0.5 min after this second GABA application, test compounds were added while GABA was still present, at a concentration corresponding to approximately 30-fold the K. Current traces were recorded at a 10 Hz digitizing rate before, during, and after GABA application.

[0092] Each compound and concentration was tested on at least three oocytes. Different compound concentrations were used. The negative allosteric modulator β-CCM or the positive allosteric modulator midazolam was tested as a positive control at maximum effect on several oocytes (3–6) in each 96-well plate. β-CCM inhibited GABA-evoked currents by approximately 50% (fold increase of ~0.5), whereas midazolam enhanced GABA-evoked currents by approximately 150% (fold increase of ~2.5).

[0093] Data analysis For analysis, the digitized current traces of the first and second GABA responses were superimposed and, if necessary, rescaled to equal maximal amplitude. The ratio between the two responses was calculated point-by-point during the time interval of the test compound experiment. The extremes of the resulting "ratio traces" were designated as "GABA ECs." 20 The efficacy of the compound ("fold increase") was taken as "% modulation of the agonist activity" (100 * (fold increase - 1)). The results are shown in Table 1. [Table 1] TIFF0007739336000014.tif250165 TIFF0007739336000015.tif250170 TIFF0007739336000016.tif142170

[0094] WO 2014 / 001280 discloses as Example 1 the reference compound RO-07.

[0095] WO 2012 / 062687 discloses reference compounds RO-052 as Example 52 and RO-045 as Example 45.

[0096] The reference compound was also GABA A Affinity for receptor α5β3γ2 subtypes, and GABA ATheir efficacy in α5β3γ2-overexpressing oocytes was also tested. The results are shown in Table 2. [Table 2] [ka]

[0097] The compounds of formula (I) or (II) and their pharmaceutically acceptable salts can be used as pharmaceuticals (e.g., in the form of pharmaceutical preparations). The pharmaceutical preparations of the present invention can be administered orally (e.g., in the form of tablets, coated tablets, dragees, hard / soft gelatin capsules, solutions, emulsions, or suspensions), nasally (e.g., in the form of nasal drops), rectally (e.g., in the form of suppositories), or topically to the eye (e.g., in the form of solutions, ointments, gels, or water-soluble polymer inserts). However, administration can also be carried out parenterally (e.g., in the form of sterile injectable solutions), such as intramuscularly, intravenously, or intraocularly.

[0098] The compounds of formula (I) or (II) and their pharmaceutically acceptable salts can be treated with pharmaceutically inert, inorganic or organic adjuvants for the preparation of tablets, coated tablets, dragees, hard gelatin capsules, injections or external preparations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such adjuvants for tablets, dragees and hard gelatin capsules.

[0099] Suitable adjuvants for soft gelatin capsules include, by way of example, vegetable oils, waxes, fats, semisolids, liquid polyols, etc.

[0100] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.

[0101] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0102] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0103] Suitable adjuvants for topical ophthalmic formulations are, for example, cyclodextrin, mannitol, or many other carriers and additives known in the art.

[0104] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking agents, or antioxidants, and may also contain other therapeutically valuable substances.

[0105] Dosages can vary widely and will, of course, be tailored to the individual requirements of each particular case. Generally, for oral administration, the daily dose is about 0.1 mg to about 20 mg per kg of body weight, preferably about 0.5 mg to about 4 mg per kg of body weight (e.g., about 300 mg per person), preferably administered in 1 to 3 separate doses, which, if appropriate, can be composed of equal amounts. For topical administration, the formulation can contain 0.001% to 15% by weight of the drug, and the required amount, which can be between 0.1 and 25 mg, can be administered as a single dose per day, a single dose per week, multiple doses (2 to 4 times per day), or multiple doses per week. However, it is clear that, where indicated, the upper or lower limits set forth herein may be exceeded.

[0106] Preparation of Pharmaceutical Compositions Comprising Compounds of the Invention Tablets of the following composition are prepared in the usual way: [Table 3]

[0107] Manufacturing Procedure 1. Mix ingredients 1, 2, 3, and 4 and granulate with purified water. 2. Dry the granules at 50°C. 3. Pass the granules through a suitable grinding device. 4. Add ingredient 5, mix for 3 minutes and compress in a suitable press.

[0108] Capsules of the following composition are prepared: [Table 4]

[0109] Manufacturing Procedure 1. Mix ingredients 1, 2, and 3 in a suitable mixer for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes. 3. Fill into suitable capsules.

[0110] The compound of formula I, lactose and cornstarch are first mixed in a mixer, then mixed in a grinder.The mixture is returned to the mixer, and talc is added thereto and roughly mixed.The mixture is filled into a suitable capsule, such as a hard gelatin capsule, by machine.

[0111] An injection solution of the following composition is prepared: [Table 5]

[0112] The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0113] Where preparative examples are obtained as mixtures of enantiomers, pure enantiomers can be obtained by methods described herein or known to those skilled in the art, such as chiral chromatography or crystallization. [Example]

[0114] Component A [5-(4-fluorophenyl)-3-methyl-triazol-4-yl]methanol [ka]

[0115] Described in U.S. Patent Application Publication No. 20120115844 and U.S. Patent Application Publication No. 20120115868

[0116] Component B [3-(4-fluorophenyl)-5-methyl-triazol-4-yl]methanol [ka]

[0117] Described in U.S. Patent Application Publication No. 20120115868 and U.S. Patent Application Publication No. 20120115844

[0118] Component C [5-methyl-3-(6-methyl-3-pyridyl)triazol-4-yl]methanol [ka]

[0119] a) Ethyl 5-methyl-3-(6-methyl-3-pyridyl)triazole-4-carboxylate

[0120] To a solution of 5-azido-2-methyl-pyridine (25.0 g, 186 mmol) in toluene (100 mL) in a sealed tube was added ethyl but-2-ynoate (23 mL, 205 mmol) and the reaction mixture was heated to 150° C. for 16 h. The solvent was removed by rotary evaporation and the residue was purified by flash chromatography (silica, 100% ethyl acetate) to give the title compound (10 g, 60%) as a yellow solid. MS (ESI): 246.8 ([M+H] + ).

[0121] b) [5-methyl-3-(6-methyl-3-pyridyl)triazol-4-yl]methanol

[0122] To a solution of ethyl 5-methyl-3-(6-methyl-3-pyridyl)triazole-4-carboxylate (3.00 g, 12.2 mmol) in tetrahydrofuran (13 mL) was added dropwise a solution of LiAlH in tetrahydrofuran (1.0 m, 13 mL, 13 mmol) at 10° C., and the reaction mixture was stirred at 10° C. for 15 minutes. The reaction mixture was then cooled to 0° C. before being quenched by the addition of sodium sulfate decahydrate. The resulting suspension was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. Purification by flash chromatography (silica, 100% ethyl acetate) afforded the title compound (1.5 g, 60%) as a white solid. MS (ESI): 205.2 ([M+H] + ).

[0123] Component D [5-methyl-3-(6-methyl-3-pyridyl)triazol-4-yl]methanol [ka]

[0124] a) Trimethyl-[[4-(6-methyl-3-pyridyl)triazol-1-yl]methyl]silane

[0125] To a solution of 5-ethynyl-2-methyl-pyridine (10.0 g, 85.5 mmol) in DMF (100 mL) was added DIPEA (15.2 mL, 85.5 mmol) and CuI (11 g, 85.5 mmol) at room temperature. After 5 minutes, trimethylsilylmethyl azide (55.5 g, 427 mmol) was added and the reaction mixture was stirred for 16 hours. The reaction mixture was poured into water and the aqueous layer was extracted with ethyl acetate (3 x 200 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by flash chromatography (silica, 60% ethyl acetate in hexanes) afforded the title compound (15 g, 73%) as a white solid. MS (ESI): 246.0 ([M+H] + ).

[0126] b) 2-methyl-5-(1-methyltriazol-4-yl)pyridine

[0127] To a solution of trimethyl-[[4-(6-methyl-3-pyridyl)triazol-1-yl]methyl]silane (10.0 g, 40.6 mmol) in tetrahydrofuran (50 mL) was added a solution of TBAF in tetrahydrofuran (1.0 m, 61 mL, 61 mmol). The reaction mixture was stirred at room temperature for 1 hour. Purification by flash chromatography (silica, 100% ethyl acetate) afforded the title compound (6.0 g, 87%) as an off-white solid. MS (ESI): 175.3 ([M+H] + ).

[0128] c) Methyl 3-methyl-5-(6-methyl-3-pyridyl)triazole-4-carboxylate

[0129] To a stirred solution of 2-methyl-5-(1-methyltriazol-4-yl)pyridine (6.0 g, 34 mmol) in anhydrous tetrahydrofuran (100 mL) at −78° C. under an argon atmosphere, a solution of LDA in tetrahydrofuran (2.0 m, 35 mL, 70 mmol) was added dropwise. After 30 min, methyl chloroformate (8.60 mL, 103 mmol) was added, and the reaction mixture was stirred at −78° C. After 1.5 h, the reaction mixture was quenched by the addition of ice-cold saturated aqueous NH4Cl solution. The resulting mixture was extracted with ethyl acetate (2×250 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by flash chromatography (silica, 65% ethyl acetate in hexanes) afforded the title compound (4 g, 50%) as a yellow solid. MS (ESI): 232.7 ([M+H] + ).

[0130] d) [3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methanol

[0131] As in the experiment in Example Cb, methyl 3-methyl-5-(6-methyl-3-pyridyl)triazole-4-carboxylate was used instead of ethyl 5-methyl-3-(6-methyl-3-pyridyl)triazole-4-carboxylate to convert to the title compound (2.4 g, 67%), which was obtained as an off-white solid. MS (ESI): 205.3 ([M+H] + ).

[0132] Component E [5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methanol [ka]

[0133] a) [4-(4-chloro-2-fluoro-phenyl)triazol-1-yl]methyl-trimethyl-silane

[0134] Similar to the experiment in Example Da, 4-chloro-1-ethynyl-2-fluoro-benzene was converted to the title compound (7.85 g, 85%) in place of 5-ethynyl-2-methyl-pyridine, which was obtained as an off-white solid. MS (ESI): 283.7 ([M+H] + ).

[0135] b) 4-(4-chloro-2-fluoro-phenyl)-1-methyl-triazole

[0136] As in the experiment of Example Db, [4-(4-chloro-2-fluoro-phenyl)triazol-1-yl]methyl-trimethyl-silane was used instead of trimethyl-[[4-(6-methyl-3-pyridyl)triazol-1-yl]methyl]silane to convert to the title compound (4.7 g, 80%), which was obtained as a white solid. MS (ESI): 211.9 ([M+H] + ).

[0137] c) methyl 5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazole-4-carboxylate

[0138] As in the experiment in Example Dc, 4-(4-chloro-2-fluoro-phenyl)-1-methyl-triazole was used instead of 2-methyl-5-(1-methyltriazol-4-yl)pyridine to obtain the title compound (4.75 g, 71%) as a colorless sticky solid. MS (ESI): 283.9 ([M+H] + ).

[0139] d) [5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methanol

[0140] As in the experiment of Example Cb, methyl 5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazole-4-carboxylate was used instead of ethyl 5-methyl-3-(6-methyl-3-pyridyl)triazole-4-carboxylate to convert to the title compound (2.4 g, 67%), which was obtained as an off-white solid. MS (ESI): 205.3 ([M+H] + ).

[0141] Component F [3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methanol [ka]

[0142] a) Methyl 3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazole-4-carboxylate

[0143] To a solution of 1-azido-4-chloro-2-fluoro-benzene (20.0 g, 117 mmol) in toluene (15 mL) was added methyl but-2-ynoate (14.0 mL, 117 mmol). The reaction mixture was heated to 120° C. in a sealed tube. After 15 h, the mixture was cooled to room temperature, and then all volatiles were evaporated under reduced pressure to give a crude residue. Purification by flash chromatography (silica, 30% ethyl acetate in hexanes) gave the title compound (7.6 g, 26%) as a brown liquid. MS (ESI): 283.8 ([M+H] + ).

[0144] b) [3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methanol

[0145] To a solution of methyl 3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazole-4-carboxylate (5.70 g, 20.1 mmol) in tetrahydrofuran (300 mL) at 0° C. was added a solution of DIBAL-H in toluene (1.8 m, 28 mL, 50.4 mmol). After 1 h, the reaction mixture was carefully quenched at 0° C. by the addition of aqueous potassium sodium tartrate tetrahydrate (10 wt %, 100 mL). The mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography (silica, 60% ethyl acetate in hexane) afforded the title compound (4.4 g, 90%) as an off-white solid. MS (ESI): 242.1 ([M+H]+ ).

[0146] Component G [3-(4-chlorophenyl)-5-methyl-triazol-4-yl]methanol [ka]

[0147] a) Methyl 3-(4-chlorophenyl)-5-methyl-triazole-4-carboxylate

[0148] As in the experiment in Example Fa, 1-azido-4-chloro-benzene was used instead of 1-azido-4-chloro-2-fluoro-benzene to convert to the title compound (5.0 g, 25%), which was obtained as a light brown solid. MS (ESI): 266.2 ([M+H] + ).

[0149] b) [3-(4-chlorophenyl)-5-methyl-triazol-4-yl]methanol

[0150] To a solution of methyl 3-(4-chlorophenyl)-5-methyl-triazole-4-carboxylate (2.00 g, 8.20 mmol) in tetrahydrofuran (20 mL) was added dropwise a solution of LiAlH4 in tetrahydrofuran (1.0 m, 9.1 mL, 9.1 mmol) at 0 °C. After 30 min, the reaction mixture was quenched by careful addition of sodium sulfate decahydrate. The mixture was diluted with ethyl acetate (250 mL) and then directly filtered through a sintered funnel. The inorganic salts were rinsed with ethyl acetate and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (silica, 60% ethyl acetate in hexane) afforded the title compound (800 mg, 44%) as a brown solid. MS (ESI): 224 ([M+H] + ).

[0151] Component H [5-(4-chlorophenyl)-3-methyl-triazol-4-yl]methanol [ka]

[0152] a) [4-(4-chlorophenyl)triazol-1-yl]methyl-trimethyl-silane

[0153] As in the experiment in Example Da, 1-chloro-4-ethynyl-benzene instead of 5-ethynyl-2-methyl-pyridine was converted to the title compound (14 g, 90%), which was obtained as an off-white solid. MS (ESI): 265.8 ([M+H] + ).

[0154] b) 4-(4-chlorophenyl)-1-methyl-triazole

[0155] As in the experiment of Example Db, [4-(4-chlorophenyl)triazol-1-yl]methyl-trimethyl-silane was used instead of trimethyl-[[4-(6-methyl-3-pyridyl)triazol-1-yl]methyl]silane to convert to the title compound (4.2 g, 82%), which was obtained as a white solid. MS (ESI): 194.1 ([M+H] + ).

[0156] c) Ethyl 5-(4-chlorophenyl)-3-methyl-triazole-4-carboxylate

[0157] The title compound (4.1 g, 86%) was obtained as a colorless sticky solid in the same manner as in Example Dc, except that 4-(4-chlorophenyl)-1-methyl-triazole was used instead of 2-methyl-5-(1-methyltriazol-4-yl)pyridine and ethyl chloroformate were used instead of methyl chloroformate. MS (ESI): 252 ([M+H] + ).

[0158] d) [5-(4-chlorophenyl)-3-methyl-triazol-4-yl]methanol

[0159] As in the experiment in Example Cb, ethyl 5-(4-chlorophenyl)-3-methyl-triazole-4-carboxylate was used instead of ethyl 5-methyl-3-(6-methyl-3-pyridyl)triazole-4-carboxylate to convert to the title compound (3.0 g, 84%), which was obtained as a white solid. MS (ESI): 224 ([M+H] + ).

[0160] Component I [5-(2,4-difluorophenyl)-3-methyl-triazol-4-yl]methanol [ka]

[0161] a) [4-(2,4-difluorophenyl)triazol-1-yl]methyl-trimethyl-silane

[0162] Similar to the experiment in Example Da, 1-ethynyl-2,4-difluoro-benzene instead of 5-ethynyl-2-methyl-pyridine was converted to the title compound (520 mg, 54%), which was obtained as an off-white solid. MS (ESI): 267.6 ([M+H] + ).

[0163] b) 4-(2,4-difluorophenyl)-1-methyl-triazole

[0164] As in the experiment of Example Db, [4-(2,4-difluorophenyl)triazol-1-yl]methyl-trimethyl-silane (3.2 g, 94%) was used instead of trimethyl-[[4-(6-methyl-3-pyridyl)triazol-1-yl]methyl]silane to convert to the title compound, which was obtained as a white solid. MS (ESI): 196.0 ([M+H] + ).

[0165] c) methyl 5-(2,4-difluorophenyl)-3-methyl-triazole-4-carboxylate

[0166] To a solution of 4-(2,4-difluorophenyl)-1-methyl-triazole (2.25 g, 11.5 mmol) in tetrahydrofuran (70 mL) was added dropwise a solution of LiHMDS in tetrahydrofuran (1.0 m, 17.3 mL, 17.3 mmol) at 0 °C. After 30 min, methyl chloroformate (1.92 mL, 23 mmol) was added and the reaction mixture was stirred at 0 °C. The reaction mixture was allowed to warm to room temperature for 1.5 h before being quenched by the addition of ice-cold saturated aqueous NH4Cl. The mixture was extracted with ethyl acetate (2 x 250 mL), and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography (silica, 60% ethyl acetate in hexanes) afforded the title compound (2.4 g, 82%) as a white solid. MS (ESI): 254 ([M+H] + ).

[0167] d) [5-(2,4-difluorophenyl)-3-methyl-triazol-4-yl]methanol

[0168] As in the experiment of Example Gb, methyl 5-(2,4-difluorophenyl)-3-methyl-triazole-4-carboxylate was used instead of methyl 3-(4-chlorophenyl)-5-methyl-triazole-4-carboxylate to convert to the title compound (3.0 g, 96%), which was obtained as a white solid. MS (ESI): 225.9 ([M+H] + ).

[0169] Component J [5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methanol [ka]

[0170] a) [4-[2-fluoro-4-(trifluoromethyl)phenyl]triazol-1-yl]methyl-trimethyl-silane

[0171] As in the experiment in Example D, 1-ethynyl-2-fluoro-4-(trifluoromethyl)benzene was converted to the title compound (12 g, 60%) instead of 5-ethynyl-2-methyl-pyridine, which was obtained as an off-white solid. MS (ESI): 317.6 ([M+H] + ).

[0172] b) 4-[2-fluoro-4-(trifluoromethyl)phenyl]-1-methyl-triazole

[0173] As in the experiment of Example Db, [4-[2-fluoro-4-(trifluoromethyl)phenyl]triazol-1-yl]methyl-trimethyl-silane was used instead of trimethyl-[[4-(6-methyl-3-pyridyl)triazol-1-yl]methyl]silane to convert to the title compound (6.9 g, 94%), which was obtained as a white solid. MS (ESI): 246 ([M+H] + ).

[0174] c) methyl 5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazole-4-carboxylate

[0175] As in the experiment in Example Ic, 4-[2-fluoro-4-(trifluoromethyl)phenyl]-1-methyl-triazole was used instead of 4-(2,4-difluorophenyl)-1-methyl-triazole to convert to the title compound (7.5 g, 87%), which was obtained as a white solid. MS (ESI): 303.8 ([M+H] + ).

[0176] d) [5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methanol

[0177] As in the experiment of Example Gb, methyl 5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazole-4-carboxylate was used instead of methyl 3-(4-chlorophenyl)-5-methyl-triazole-4-carboxylate to convert to the title compound (5.6 g, 82%), which was obtained as a white solid. MS (ESI): 275.8 ([M+H] + ).

[0178] Component K [5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methanol [ka]

[0179] a) 4-(4-chloro-2-fluoro-phenyl)-1-ethyl-triazole

[0180] To a solution of 4-chloro-1-ethynyl-2-fluoro-benzene (4.50 g, 29.1 mmol) in DMF (50 mL) at room temperature was added DIPEA (5.2 mL, 29 mmol), CuI (5.5 g, 29 mmol), and ethyl azide (11 g, 146 mmol). The reaction mixture was stirred for 16 hours and then quenched by the addition of water. The aqueous layer was extracted with ethyl acetate (3×200 mL). The organic layer was washed with brine, dried (NaSO), filtered, and concentrated in vacuo. Purification by flash chromatography (silica, 15% ethyl acetate in hexanes) afforded the title compound (5.0 g, 80%) as a white solid. MS (ESI): 226 ([M+H] + ).

[0181] b) Methyl 5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazole-4-carboxylate

[0182] As in the experiment in Example Ic, 4-(4-chloro-2-fluoro-phenyl)-1-ethyl-triazole was used instead of 4-(2,4-difluorophenyl)-1-methyl-triazole to obtain the title compound (4.1 g, 81%) as a colorless sticky solid. MS (ESI): 284.3 ([M+H] + ).

[0183] c) [5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methanol

[0184] As in the experiment of Example Gb, methyl 5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazole-4-carboxylate was used instead of methyl 3-(4-chlorophenyl)-5-methyl-triazole-4-carboxylate to convert to the title compound (3.0 g, 83%), which was obtained as a white solid. MS (ESI): 256.1 ([M+H] + ).

[0185] Component L [5-(6-chloro-3-pyridyl)-3-methyl-triazol-4-yl]methanol [ka]

[0186] a) [4-(6-chloro-3-pyridyl)triazol-1-yl]methyl-trimethyl-silane

[0187] Analogously to experiment a in Example D, 2-chloro-5-ethynyl-pyridine instead of 5-ethynyl-2-methyl-pyridine was converted to the title compound (8.5 g, 63%), which was obtained as a white solid. MS (ESI): 266.9 ([M+H] + ).

[0188] b) 2-chloro-5-(1-methyltriazol-4-yl)pyridine

[0189] As in the experiment of Example Db, [4-(6-chloro-3-pyridyl)triazol-1-yl]methyl-trimethyl-silane was used instead of trimethyl-[[4-(6-methyl-3-pyridyl)triazol-1-yl]methyl]silane to convert to the title compound (4.5 g, 77%), which was obtained as a white solid. MS (ESI): 195 ([M+H] + ).

[0190] c) Methyl 5-(6-chloro-3-pyridyl)-3-methyl-triazole-4-carboxylate

[0191] As in the experiment in Example Ic, 2-chloro-5-(1-methyltriazol-4-yl)pyridine was used instead of 4-(2,4-difluorophenyl)-1-methyl-triazole to convert to the title compound (4.7 g, 95%), which was obtained as an off-white solid. MS (ESI): 252.6 ([M+H] + ).

[0192] d) [5-(6-chloro-3-pyridyl)-3-methyl-triazol-4-yl]methanol

[0193] As in the experiment of Example Gb, methyl 5-(6-chloro-3-pyridyl)-3-methyl-triazole-4-carboxylate was used instead of methyl 3-(4-chlorophenyl)-5-methyl-triazole-4-carboxylate to convert to the title compound (3.0 g, 67%), which was obtained as a yellow solid. MS (ESI): 224.9 ([M+H] + ).

[0194] Component M [3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazol-4-yl]methanol [ka]

[0195] a) Methyl 5-tributylstannyl-3-(trimethylsilylmethyl)triazole-4-carboxylate

[0196] To a solution of methyl-3-tributylstannylprop-2-ynoate (13.0 g, 34.8 mmol) in toluene (50 mL) was added trimethylsilylmethyl azide (6.50 g, 50.3 mmol). The reaction mixture was heated to 120 °C and stirred in a sealed tube. After 16 h, the reaction mixture was allowed to cool to room temperature and all volatiles were evaporated under reduced pressure to give a crude residue. Purification by flash chromatography (silica, 10% ethyl acetate in hexanes) afforded the title compound (5.8 g, 30%) as a colorless liquid.

[0197] b) methyl 5-[5-(trifluoromethyl)pyrimidin-2-yl]-3-(trimethylsilylmethyl)triazole-4-carboxylate

[0198] To a degassed solution of 2-chloro-5-(trifluoromethyl)pyrimidine (2.0 g, 11 mmol) in 1,4-dioxane (50 mL) was added methyl 5-tributylstannyl-3-(trimethylsilylmethyl)triazole-4-carboxylate (6.0 g, 12 mmol), lithium chloride (1.40 g, 32.9 mmol), copper iodide (42 mg, 0.22 mmol), and tetrakis(triphenylphosphine)palladium(0) (253 mg, 0.220 mmol). The reaction mixture was heated to 100 °C and stirred for 3 h. After cooling to room temperature, the mixture was filtered directly through a Celite pad, and the filter cake was rinsed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo and purified by flash chromatography (silica, 65% ethyl acetate in hexanes) to give the title compound (2.0 g, 50%) as a yellow solid. MS(ESI): 359.8 ([M+H] + ).

[0199] c) methyl 3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazole-4-carboxylate

[0200] To a solution of methyl 5-[5-(trifluoromethyl)pyrimidin-2-yl]-3-(trimethylsilylmethyl)triazole-4-carboxylate (1.50 g, 4.17 mmol) in a mixture of dichloromethane (12 mL) and methanol (6 mL) was added K2CO3 (1.70 g, 12.5 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (50 mL) and water. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (750 mg, 62%) as a white solid. MS (ESI): 287.9 ​​([M+H] + ).

[0201] d) 3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazole-4-carboxylic acid

[0202] To an ice-cold solution of methyl 3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazole-4-carboxylate (2.7 g, 9.4 mmol) in a mixture of tetrahydrofuran (20 mL) and water (20 mL) was added lithium hydroxide monohydrate (788 mg, 18.8 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was diluted with water (5 mL). The aqueous layer was acidified to pH 1 by the addition of aqueous HCl (1.0 m) and then extracted with 10% MeOH in CHCl (3×20 mL). The organic layer was washed with brine, dried (NaSO), filtered, and concentrated in vacuo. The residue was collected, washed with n-pentane, and dried under vacuum to give the title compound (2.4 g, 88%) as an off-white solid. MS (ESI): 273.8 ([M+H] + ).

[0203] e) [3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazol-4-yl]methanol

[0204] To a solution of 3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazole-4-carboxylic acid (2.60 g, 9.52 mmol) in tetrahydrofuran (70 mL) was added triethylamine (8.5 mL, 46.4 mmol) followed by isobutyl chloroformate (4.70 mL, 35.9 mmol) at −15° C. The reaction mixture was stirred at −15° C. for 1.5 hours and then directly filtered through a sintered funnel. The collected solid was rinsed with a minimum amount of THF (1 mL). The filtrate was allowed to reach −15° C., and then sodium borohydride (874 mg, 23.1 mmol) was added and the mixture was stirred for 3 minutes. The reaction mixture was quenched with water (10 mL), and the resulting mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (1.7 g, 60%) as an off-white solid. MS (ESI): 259.8 ([M+H] + ).

[0205] Component N [3-methyl-5-[6-(trifluoromethyl)pyridazin-3-yl]triazol-4-yl]methanol [ka]

[0206] a) 4,5-dibromo-1-methyl-1H-1,2,3-triazole

[0207] To a solution of di-4,5-dibromo-1H-1,2,3-triazole (2 g, 8.38 mmol) in dichloromethane (40 mL) at room temperature under nitrogen, triethylamine (932 mg, 1.28 mL, 9.21 mmol) was added, followed by iodomethane (1.31 g, 0.574 mL, 9.21 mmol). The reaction mixture was stirred at room temperature for 48 hours, then diluted with water and extracted three times with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude orange oil was purified by flash chromatography (silica, 0% to 10% ethyl acetate in heptane) to afford the title compound (489 mg, 24% yield) as a white solid. MS (ESI): 241.9 ([M+H] + ).

[0208] b) 4-Bromo-1-methyl-1H-1,2,3-triazole-5-carbaldehyde

[0209] To a solution of 4,5-dibromo-1-methyl-1H-1,2,3-triazole (487 mg, 2.02 mmol) in dry tetrahydrofuran (8 mL) was added dropwise a solution of isopropylmagnesium chloride in tetrahydrofuran (2.0 m, 1.82 mL, 3.64 mmol) under argon at 0 °C. After stirring at 0 °C for 1 h, N,N-dimethylformamide (443 mg, 0.470 mL, 6.07 mmol) was added dropwise. The mixture was allowed to warm to room temperature over 1.5 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl and extracted three times with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude yellow oil was purified by flash column chromatography (silica, 0% to 50% ethyl acetate in heptane) to afford the title compound (271 mg, 71% yield) as a pale yellow solid. MS(ESI): 189.9 ([M+H] + ).

[0210] c) (4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)methanol

[0211] To a stirred solution of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carbaldehyde (252 mg, 1.33 mmol) in MeOH (4 mL) was added sodium borohydride (60.8 mg, 1.59 mmol). The reaction mixture was stirred at room temperature for 1 hour, then poured into water and extracted twice with dichloromethane. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (185 mg, 73% yield) as a pale yellow solid. MS (ESI): 191.8 ([M+H] + ).

[0212] d) 4-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-1,2,3-triazole

[0213] To a stirred solution of (4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)methanol (500 mg, 2.47 mmol) in dichloromethane (10 mL) was added imidazole (255 mg, 3.71 mmol), followed by tert-butylchlorodimethylsilane (423 mg, 2.72 mmol). The reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was poured into water and extracted twice with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica, 0% to 50% ethyl acetate in heptane) to afford the title compound (654 mg, 86% yield) as a white solid. MS (ESI): 307.8 ([M+H] + ).

[0214] e) 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-6-(trifluoromethyl)pyridazine

[0215] To a stirred solution of 4-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-1,2,3-triazole (200 mg, 0.653 mmol) in tetrahydrofuran (4 mL) under argon was added dropwise a solution of n-butyllithium in hexanes (1.6 m, 0.449 mL, 0.718 mmol) at −68 °C. The reaction mixture was stirred at −68 °C for 30 minutes, after which a solution of ZnCl in 2-methyl-tetrahydrofuran (2.0 m, 0.392 mL, 0.784 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for an additional 1 hour. 3-Bromo-6-(trifluoromethyl)pyridazine (148 mg, 0.653 mmol) was added, followed by X-Phos Pd G3 (56.4 mg, 0.0653 mmol) and 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (31.8 mg, 0.0653 mmol). The reaction mixture was heated to 70 °C and stirred for 15 h before being concentrated in vacuo. The crude material was purified by flash chromatography (silica, 0% to 100% ethyl acetate in heptane) to afford the title compound (122 mg, 35% yield) as a pale yellow solid. MS (ESI): 374.1 ([M+H] + ).

[0216] f) (1-methyl-4-(6-(trifluoromethyl)pyridazin-3-yl)-1H-1,2,3-triazol-5-yl)methanol

[0217] A stirred solution of 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-6-(trifluoromethyl)pyridazine (118 mg, 0.316 mmol) in tetrahydrofuran (3 mL) was cooled to 0 °C and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 m, 0.348 mL, 0.348 mmol) was added dropwise. After stirring at 0 °C for 30 minutes, the reaction mixture was diluted with ethyl acetate and washed twice with saturated aqueous NaHCO3. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica, 0% to 100% ethyl acetate in heptane) to afford the title compound (23 mg, 28% yield) as a white solid. MS (ESI): 259.9 ([M+H] + ).

[0218] Component O [3-methyl-5-(6-methylpyridazin-3-yl)triazol-4-yl]methanol [ka]

[0219] a) 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-6-methylpyridazine

[0220] A three-necked round-bottom flask was evacuated and backfilled with argon three times, then 4-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-1,2,3-triazole ((Component N, step d), 179 mg, 0.583 mmol) and tetrahydrofuran (1.5 mL) were added. The resulting solution was cooled to 0 °C, and then a solution of isopropylmagnesium chloride in tetrahydrofuran (2.0 m, 0.370 mL, 0.740 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. A solution of ZnCl in 2-methyl-tetrahydrofuran (2.0 m, 0.404 mL, 0.807 mmol) was added dropwise, and stirring was continued for an additional 1 h. 3-Bromo-6-methylpyridazine (80 mg, 0.449 mmol) was added quickly, followed by X-Phos Pd G3 (38.7 mg, 0.0449 mmol) and 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (21.8 mg, 0.0449 mmol). The reaction mixture was heated to 70 °C and stirred for 2 h before being concentrated in vacuo. The crude material was purified by flash chromatography (silica, 0% to 100% ethyl acetate in heptane) to afford the title compound (159 mg, 89% yield) as a pale yellow solid. MS (ESI) m / z: 320.1 ([M+H] + ).

[0221] b) (1-methyl-4-(6-methylpyridazin-3-yl)-1H-1,2,3-triazol-5-yl)methanol

[0222] Similar to the experiment for building block Nf, 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-6-methylpyridazine was converted to the title compound (53 mg, 66%) as a white solid, using 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-6-methylpyridazine instead of 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-6-(trifluoromethyl)pyridazine. MS(ESI): 205.9 ([M+H] + ).

[0223] General Method 1 [ka] [ka]

[0224] a) To a solution of the alcohol (Ia or IIa) (0.965 mmol, 1 equiv.) in dichloromethane (2 mL) was added thionyl chloride (1.93 mmol, 2 equiv.) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and then basified by dropwise addition of a 1.0 m aqueous solution of NaHCO3. The mixture was extracted with ethyl acetate, and the organic phase was then washed with water and brine. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo.

[0225] b) To a mixture of alkyl chloride (IIa or IIIa) (0.31 mmol, 1 equiv.), 1H-pyridazin-6-one (0.37 mmol, 1.2 equiv.), and potassium carbonate (0.62 mmol, 2 equiv.) was added acetonitrile (2 mL). The reaction mixture was stirred at 40 °C for 70 h and then cooled to room temperature. The mixture was concentrated under reduced pressure by rotary evaporation, and the resulting residue was directly purified by flash chromatography to give the desired pyridazinone (Ia or Ib).

[0226] General Method 2 [ka] [ka]

[0227] A solution of 1H-pyridazin-6-one (1.47 mmol, 1.2 equiv.) in DMF (5 mL) was treated with KO under an argon atmosphere. tBu (3.1 mmol, 2.5 equiv.) was added. After 5 min, the alcohol (Ia or IIa) (1.23 mmol, 1 equiv.) was added and the reaction mixture was heated to 150 °C for 6 h. The reaction mixture was quenched by the addition of ice-cold water, and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by preparative HPLC afforded the desired pyridazinone (Ia or Ib).

[0228] Common Method 3 [ka]

[0229] To a solution of alcohol (Ia) (4.13 mmol, 1 equiv.) and 1H-pyridazin-6-one (4.96 mmol, 1.2 equiv.) in anhydrous tetrahydrofuran (70 mL) was added triphenylphosphine (4.96 mmol, 1.2 equiv.) at room temperature. The mixture was cooled to 0° C., and then a solution of DEAD (4.9 mmol, 1.2 equiv.) in anhydrous tetrahydrofuran (10 mL) was slowly added. The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure by rotary evaporation, and the resulting residue was directly purified by flash chromatography to give the desired pyridazinone (Ia).

[0230] Common Method 4 [ka] [ka]

[0231] To a mixture of 5-iodo-pyridazin-3-one (IVa or IVb) (0.224 mmol, 1 equiv.) and amine (0.26 mmol, 1.2 equiv.) in DMSO (5 mL) was added potassium carbonate (1.12 mmol, 5 equiv.) at room temperature. The reaction mixture was heated to 90° C. and stirred for 16 h, then cooled to room temperature. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (NaSO), and concentrated in vacuo. Purification by preparative HPLC afforded the desired pyridazinone (Ia or Ib).

[0232] Common Method 5 [ka]

[0233] a) To a cold (0 °C) solution of alcohol (IIa) (15.4 mmol, 1 equiv.) in dichloromethane (20 mL) was added methanesulfonyl chloride (46 mmol, 3 equiv.) and triethylamine (46 mmol, 3 equiv.). After 10 min, the reaction mixture was warmed to room temperature and stirred for 2 h. The mixture was diluted with cold water and extracted with dichloromethane. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography afforded alkyl chloride (IIIa).

[0234] b)KO t To a suspension of Bu (0.97 mmol, 1.25 equiv.) in tetrahydrofuran (10 mL) at room temperature was added pyridazinone (V) (0.927 mmol, 1.2 equiv.). After 10 min, alkyl chloride (IIIa) (0.770 mmol, 1 equiv.) was added, and the reaction mixture was heated to reflux for 16 h. The mixture was allowed to warm to room temperature and then directly filtered through a pad of Celite, and the filtrate was concentrated in vacuo. Purification by preparative HPLC afforded the desired pyridazinone (Ib).

[0235] Common Method 6 [ka]

[0236] a) To a mixture of alkyl chloride (IIa) (8.53 mmol, 1 equiv.), 5-iodo-2,3-dihydropyridazin-3-one (9.38 mmol, 1.1 equiv.), and potassium carbonate (12.8 mmol, 1.5 equiv.), acetone (100 mL) was added, and the reaction mixture was stirred at 50° C. under an argon atmosphere for 16 hours. The resulting suspension was filtered, and the filtrate was concentrated in vacuo. Purification by flash chromatography afforded aryl iodide (IVa).

[0237] b) Under an argon atmosphere, aryl iodide (IVa) (0.250 mmol, 1 equiv.), amine (0.30 mmol, 1.2 equiv.), and cesium carbonate (0.610 mmol, 2.4 equiv.) were dissolved in 1,4-dioxane (5 mL). The reaction mixture was purged with a stream of argon for 10 minutes, after which tris(dibenzylideneacetone)dipalladium(0) (0.012 mmol, 0.05 equiv.) and X-phos (0.024 mmol, 0.1 equiv.) were added. The mixture was flushed with a stream of argon for 5 minutes, then heated to 110°C and stirred for 16 hours. After cooling to room temperature, the mixture was diluted with 10% methanol in dichloromethane (20 mL). The suspension was filtered off, and the filtrate was concentrated in vacuo. Purification by flash chromatography afforded the desired pyridazinone (Ia).

[0238] Common Method 7 [ka] [ka]

[0239] a) To a solution of alkyl chloride (IIa, IIIa) (2.13 mmol, 1 equiv.) in acetone (6 mL) was added a mixture of 5-chloropyridazin-3(2H)-one or 5-iodo-2,3-dihydropyridazin-3-one (2.77 mmol, 1.3 equiv.) and potassium carbonate (5.32 mmol, 2.5 equiv.). After 30 min, the resulting thick suspension was diluted with acetone (6 mL). The reaction mixture was stirred at room temperature for 20 h. The suspension was then filtered, and the filter cake was thoroughly rinsed with acetone. The filtrate was concentrated in vacuo and purified by flash chromatography to give aryl iodide (IVa) or aryl chloride (Vb).

[0240] b) To a solution of aryl iodide or chloride (IVa, Vb) (0.282 mmol, 1 equiv.) in acetonitrile (1 mL), the amine (0.339 mmol, 1.2 equiv.) as the hydrochloride salt or free base and potassium carbonate (1.41 mmol, 5.0 equiv.) were added. The vial was capped and heated to 50 °C for 18-48 h. After cooling to room temperature, the reaction mixture was filtered, and the filter cake was rinsed thoroughly with acetonitrile. The filtrate was concentrated in vacuo and purified by flash chromatography to afford the desired pyridazinones (Ia, Ib).

[0241] General method 8 [ka]

[0242] a) To a suspension of alkyl chloride (IIa) (3.00 g, 1 equiv.) in acetonitrile (50 mL) was added cesium carbonate (10 g, 2.5 equiv.) and 5-chloro-2H-pyridazin-3-one (1.7 g, 1.1 equiv.). The reaction mixture was heated to 90° C. and stirred for 1 h, then cooled to room temperature. The mixture was diluted with cold water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography afforded aryl chloride (Va).

[0243] b) Analogously to the experiment in General Method 4, the aryl chloride (Va) was converted to the desired pyridazinones (Ia).

[0244] General method 9 [ka]

[0245] To a solution of alcohol (VIa) (0.256 mmol, 1 equiv.) in anhydrous 1,4-dioxane (7 mL) was added sodium hydride (60% dispersion in mineral oil) (0.384 mmol, 1.5 equiv.) at 0 °C. After 15 min, a solution of heteroaryl chloride (0.384 mmol, 1.5 equiv.) in 1,4-dioxane (2 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 16 h before being quenched by the addition of saturated aqueous NH4Cl. The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by HPLC afforded the desired pyridazinone (VIa).

[0246] General method 10 [ka] [ka]

[0247] To a solution of aryl chlorides (Va, Vb) (0.19 mmol, 1 equiv.) in 1,4-dioxane (4 mL) at room temperature, water (0.5 mL) and sodium carbonate (0.59 mmol, 3.1 equiv.) were added. The mixture was purged with argon for 10 minutes, and then heteroarylboronic acid or heteroarylboronic acid pinacol ester (0.49 mmol, 2.6 equiv.) and tetrakis(triphenylphosphine)palladium(0) (0.006 mmol, 0.03 equiv.) were added. The mixture was again purged with argon for 5 minutes. The vial was capped, heated to 100 °C, and stirred for 16 hours. After cooling to room temperature, the reaction mixture was filtered through a Celite pad, and the filter cake was rinsed with ethyl acetate (10 mL). The filtrate was concentrated in vacuo and purified by preparative HPLC or flash chromatography to give the desired pyridazinones (Ia, Ib).

[0248] Preparation of amines and heterocyclic compounds (S)-5-Oxa-2-azaspiro[3.4]octan-7-ol 2,2,2-trifluoroacetic acid [ka]

[0249] a) tert-butyl-7-benzoyloxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[0250] To a solution of tert-butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (0.200 g, 0.872 mmol) in dichloromethane (3.4 mL) at 0 °C, pyridine (0.22 mL, 2.72 mmol) was added, followed by the dropwise addition of benzoyl chloride (0.20 mL, 1.72 mmol). After 15 min, the ice bath was removed, and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of aqueous HCl (1.0 m, 5 mL), and the mixture was extracted with dichloromethane (20 mL). The aqueous layer was back-extracted with dichloromethane (20 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography (silica, 0–30% ethyl acetate in heptane) afforded the title compound (257 mg, 89%) as a white solid. MS(ESI): 278.2 ([M-C4H8+H] + ).

[0251] b) tert-butyl (7S)-7-benzoyloxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate and tert-butyl (7R)-7-benzoyloxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[0252] tert-Butyl 7-(benzoyloxy)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (1.160 g, 3.48 mmol) was separated by chiral preparative HPLC (Reprosil Chiral NR, 15% isopropanol in heethane, 220 nm) to give the following: (-) Enantiopure (S)-title compound (470 mg, 41%) as a colorless oil. MS (ESI): Indeterminate. (+) Enantiopure (R)-title compound (549 mg, 47%) as a colorless oil. MS (ESI): Indeterminate.

[0253] c) (S)-tert-butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[0254] In a sealed flask, (S)-tert-butyl 7-(benzoyloxy)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (465 mg, 1.39 mmol) was dissolved in a solution of ammonia in methanol (7.0 mL, 8.0 mL, 56 mmol). The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was directly purified by flash chromatography (silica, 0-70% ethyl acetate in heptane) to afford the (+)-title compound (317 mg, 99%) as a colorless oil. MS (ESI): Indeterminate. 1 H NMR (300 MHz; CDCl3): δ(ppm)4.53(1H,m),4.08(1H,d,J=9.5 Hz),4.03(2H,s),3.96(1H,dd,J=9.9,4.2 Hz),3.92(1H,d,J=8.9 Hz),3.84(1H,app dt,2.14,J=9.9,1.2 Hz),2.26(1H,dq,J=13.7,2.0,1.0 Hz),2.18(1H,dd,J=13.7,5.1 Hz),1.61(1H,d,J=3.8 Hz),1.44(9H,s).

[0255] d) (7S)-5-oxa-2-azaspiro[3.4]octan-7-ol; 2,2,2-trifluoroacetic acid

[0256] (S)-tert-Butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (0.210 g, 0.916 mmol) was dissolved in dichloromethane (2.4 mL), and the colorless solution was cooled to 0° C. before adding trifluoroacetic acid (0.38 mL, 4.93 mmol) dropwise. After 15 min, the ice bath was removed, and the reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo to give the title compound (342 mg, 92%) as a colorless oil. MS (ESI): 130.1 ([M+H] + ).

[0257] (7R)-5-Oxa-2-azaspiro[3.4]octan-7-ol 2,2,2-trifluoroacetic acid [ka]

[0258] a) (R)-tert-butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[0259] Similar to the experiment with (S)-tert-butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate, (R)-tert-butyl 7-(benzoyloxy)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate was used instead of (S)-tert-butyl 7-(benzoyloxy)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate to obtain the (-)-title compound (326 mg, 87%) as a colorless oil. MS (ESI): Indeterminate. 1 H NMR (300 MHz; CDCl3): δ(ppm)4.53(1H,m),4.08(1H,d,J=9.5 Hz),4.03(2H,s),3.96(1H,dd,J=9.9,4.2 Hz),3.92(1H,d,J=8.9 Hz),3.84(1H,app dt,2.14,J=9.9,1.2 Hz),2.26(1H,dq,J=13.7,2.0,1.0 Hz),2.18(1H,dd,J=13.7,5.1 Hz),1.61(1H,d,J=3.8 Hz),1.44(9H,s).

[0260] b) (7R)-5-oxa-2-azaspiro[3.4]octan-7-ol; 2,2,2-trifluoroacetic acid

[0261] (7S)-5-Oxa-2-azaspiro[3.4]octan-7-ol; Analogously to the experiment with 2,2,2-trifluoroacetic acid, (R)-tert-butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate instead of (S)-tert-butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate was converted to the title compound (367 mg, 94%), which was obtained as a colorless oil. MS(ESI): 130.1 ([M+H] + ).

[0262] (7R)-7-Methoxy-5-oxa-2-azaspiro[3.4]octane hydrochloride [ka]

[0263] a) tert-butyl (7R)-7-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[0264] To a solution of (R)-tert-butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (200 mg, 0.741 mmol) in a mixture of DMF (2 mL) and tetrahydrofuran (2 mL) was added NaH (60% dispersion in mineral oil, 47.4 mg, 1.19 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, and then iodomethane (0.93 mL, 1.48 mmol) was added. After 16 hours, the reaction mixture was quenched by the addition of water (10 mL). The resulting mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed twice with water (10 mL) and brine (10 mL), dried (NaSO), filtered, and concentrated in vacuo. Purification by flash chromatography (silica, 0-5% methanol in dichloromethane) gave the title compound (124 mg, 65%) as a colorless oil. 1H NMR (300 MHz; CDCl3): δ(ppm)3.89-4.08(7H,m),3.30(3H,s),2.34(1H,dd,J=13.6,1.7 Hz),2.05(1H,dd,J=13.7,5.4 Hz),1.43(9H,s).

[0265] b) (R)-7-Methoxy-5-oxa-2-azaspiro[3.4]octane hydrochloride

[0266] To a stirred solution of (R)-tert-butyl 7-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (124 mg, 0.484 mmol) in 1,4-dioxane (2 mL) was added a solution of HCl in 1,4-dioxane (4.0 m, 1.82 mL, 7.26 mmol). The reaction mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration through a sintered funnel, washed with more 1,4-dioxane, and then dried under high vacuum to give the title compound (95.8 mg, 99%) as a white solid. MS (ESI): 144.0 ([M+H] + ).

[0267] (7S)-7-Methoxy-5-oxa-2-azaspiro[3.4]octane hydrochloride [ka]

[0268] a) tert-butyl (7S)-7-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[0269] To a solution of (S)-tert-butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (202 mg, 0.881 mmol) in a mixture of DMF (2 mL) and tetrahydrofuran (2 mL) was added NaH (60% dispersion in mineral oil, 56.4 mg, 1.41 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, and then iodomethane (0.110 mL, 1.76 mmol) was added. After 16 hours, the reaction mixture was quenched by the addition of water (10 mL). The resulting mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed twice with water (10 mL) and brine (10 mL), dried (NaSO), filtered, and concentrated in vacuo. Purification by flash chromatography (silica, 0% to 60% ethyl acetate in heptane) afforded the title compound (176 mg, 82%) as a colorless oil. 1 H NMR (300 MHz; CDCl3): δ(ppm)3.89-4.08(7H,m),3.30(3H,s),2.34(1H,dd,J=13.6,1.7 Hz),2.05(1H,dd,J=13.7,5.4 Hz),1.43(9H,s).

[0270] b) (S)-7-Methoxy-5-oxa-2-azaspiro[3.4]octane hydrochloride

[0271] Similar to the experiment with (R)-7-methoxy-5-oxa-2-azaspiro[3.4]octane hydrochloride, tert-butyl (7S)-7-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate was used instead of (R)-tert-butyl 7-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate to convert the title compound (132 mg, 71%) as a white solid. MS(ESI): 144.1 ([M+H] + ).

[0272] 3-(2,2,2-trifluoroethoxy)azetidine 2,2,2-trifluoroacetic acid [ka]

[0273] a) tert-butyl 3-(2,2,2-trifluoroethoxy)azetidine-1-carboxylate

[0274] To a solution of tert-butyl-3-hydroxyazetidine-1-carboxylate (500 mg, 2.89 mmol) in DMF (8.0 mL) was added NaH (60% dispersion in mineral oil, 173 mg, 4.33 mmol) at room temperature. After 30 minutes, the reaction mixture was cooled to 0°C, and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.67 mL, 4.65 mmol) was added dropwise. After 15 minutes, the ice bath was removed, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with water and then extracted with TBME (90 mL) and water (15 mL). The aqueous layer was back-extracted with TBME (90 mL). The combined organic layers were washed with water (3 x 15 mL) and brine (15 mL), dried (Na2SO4), filtered, and evaporated under reduced pressure. Purification by flash chromatography (silica, 0% to 30% ethyl acetate in heptane) afforded the title compound (428 mg, 58%) as a pale yellow oil. MS (ESI): 256.3 ([M+H] + ). 1 H NMR (300 MHz; CDCl3): δ(ppm)4.36(1H,tt,J=6.3,4.5 Hz),4.07-4.15(2H,m),3.86-3.94(2H,m),3.80-3.85(1H,m),3.74-3.80(1H,m),1.44(9H,s).

[0275] b) 3-(2,2,2-trifluoroethoxy)azetidine 2,2,2-trifluoroacetic acid

[0276] To a solution of tert-butyl 3-(2,2,2-trifluoroethoxy)azetidine-1-carboxylate (340 mg, 1.33 mmol) in dichloromethane (3.5 mL) under nitrogen at 0° C. was added trifluoroacetic acid (616 μl, 7.99 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to give the title compound (463 mg, 91%) as a colorless oil. MS (ESI): 156.1 ([M+H] + ).

[0277] 3-(2,2,2-trifluoro-1,1-dimethylethoxy)azetidine hydrochloride [ka]

[0278] a) (1-benzhydrylzetidin-3-yl)methanesulfonate

[0279] To a solution of 1-(diphenylmethyl)-3-hydroxyazetidine (1.087 g, 4.54 mmol) in dichloromethane (6.0 mL) was added triethylamine (1.27 mL, 9.08 mmol). After the mixture was cooled to 0° C., methanesulfonyl chloride (0.425 mL, 5.45 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 minutes, then warmed to room temperature and stirred for an additional hour. The reaction mixture was poured into water (5 mL) and extracted with dichloromethane (2×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (1.563 g, 100%) as an off-white solid. MS (ESI): 318.2 ([M+H] + ).

[0280] b) 1-benzhydryl-3-(2,2,2-trifluoro-1,1-dimethylethoxy)azetidine

[0281] To a solution of 1,1,1-trifluoro-2-methylpropan-2-ol (144 mg, 0.123 mL, 1.12 mmol) in DMF (1 mL) was added NaH (60% dispersion in mineral oil, 44.9 mg, 1.12 mmol). After stirring at room temperature for 30 minutes, 1-benzhydrylazetidin-3-yl methanesulfonate (178 mg, 0.561 mmol) was added in one portion. The suspension was heated to 70°C for 18 hours, then to 110°C for 2 hours, and finally to 130°C for 4 hours before being cooled to room temperature. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mL). The aqueous layer was back-extracted with ethyl acetate (20 mL). The combined organic extracts were washed with brine (20 mL), dried (NaSO), filtered, and concentrated in vacuo. Purification by flash chromatography (silica, 0-40% ethyl acetate in heptane) afforded the title compound (71 mg, 36%) as a brown oil. MS (ESI): 350.2 ([M+H] + ).

[0282] c) 3-(2,2,2-trifluoro-1,1-dimethylethoxy)azetidine hydrochloride

[0283] To a solution of 1-benzhydryl-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)azetidine (71 mg, 0.203 mmol) in methanol (4 mL) under nitrogen chloride was added 1,4-dioxane (4.0 m, 0.152 mL, 0.610 mmol), followed by Pd / C (10 wt%, 35 mg, 32.9 μmol). The resulting suspension was purged by evacuation and then backfilled with a stream of hydrogen (balloon) three times. The reaction mixture was heated to 50° C. under a hydrogen atmosphere for 8 hours and then directly filtered through a pad of Hyflo®. The filter cake was rinsed with methanol (10 mL), and the filtrate was concentrated in vacuo to give the title compound (77.3 mg, 100%) as an off-white solid. MS (ESI): 184.1 ([M+H] + ).

[0284] (S)-7-Fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride [ka]

[0285] a) 2-fluoro-2-en-1-ol

[0286] To a mixture of LiAlH4 (131.2 g, 3.46 mol) in diethyl ether (3 L) was carefully added AlCl3 (63.0 mL, 1.15 mol) at -5 °C. The mixture was stirred at -5 °C for 30 minutes, and then methyl 2-fluoroprop-2-enoate (240 g, 2.31 mol) was added dropwise at -5 °C. The mixture was stirred at -5 °C for an additional 3.5 hours. Wet sodium sulfate was added at 0 °C, and the mixture was filtered. The filtrate was distilled at 50 °C under atmospheric pressure to give the title compound (163.0 g, 46%) as a colorless liquid in ether. 1 H NMR(400 MHz,CDCl3):4.63(1H,dd,J=17.2,2.8 Hz),4.53(1H,dd,J=51.6,2.8 Hz),4.08(1H,dd,J=10.8,3.2 Hz),3.30(1H,m).

[0287] b) 2-Fluoro-2-enyl methanesulfonate

[0288] To a mixture of 2-fluoroprop-2-en-1-ol (160.0 g, 1.05 mol) and triethylamine (219 mL, 1.58 mol) in dichloromethane (400 mL) was added MsCl (97.6 mL, 1.26 mol) at −30° C. The mixture was stirred at −30° C. for 1 hour. The mixture was diluted with dichloromethane (500 mL) and washed with water (3×700 mL). The organic phase was dried (NaSO), filtered, and concentrated in vacuo to give the title compound (119.3 g, crude) as a yellow oil. 1 H NMR(400 MHz, CDCl3):4.95(1H,dd,J=15.2,3.6 Hz),4.86-4.70(3H,m),3.08(3H,s).

[0289] c) tert-butyl-3-allyl-3-hydroxyazetidine-1-carboxylate

[0290] To a mixture of tert-butyl 3-oxoazetidine-1-carboxylate (150.0 g, 876 mmol) in tetrahydrofuran (1 L) was added allylmagnesium bromide (1.0 m, 876 mL) at −78° C. The mixture was stirred at −78° C. for 1.5 h, then quenched with saturated aqueous NH4Cl (10 L) and extracted with ethyl acetate (3×2 L). The combined organic phases were dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (192.5 g, crude) as an orange oil. MS (ESI): 158.1 ([M-C4H8+H] + ).

[0291] d) tert-Butyl-3-allyl-3-(((2-fluoroallyl)oxy)azetidine-1-carboxylate

[0292] To a mixture of tert-butyl 3-allyl-3-hydroxyazetidine-1-carboxylate (150.0 g, 703 mmol) in DMF (750 mL) was added sodium hydride (60% dispersion in mineral oil, 42.2 g, 1.05 mol) at 0 °C and stirred for 1 h. 2-Fluoroprop-2-enyl methanesulfonate (119.2 g, 773 mmol) was added to the mixture at 0 °C and stirred for 1 h. The mixture was quenched with saturated aqueous NH4Cl (1.5 L) and extracted with MTBE (3 × 800 mL). The combined organic phases were washed with water (3 × 500 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Purification by chromatography (silica, petroleum ether / ethyl acetate) afforded the title compound (80.0 g, crude) as an orange oil. Used directly in the next step. 1 H NMR(400 MHz,CDCl3):5.86-5.76(1H,m),5.25-5.20(2H,m),4.77(1H,d,J=16.4 Hz),4.62(1H,d,J=48.4 Hz),3.99-3.92(4H,m),3.80-3.73(2H,m),2.58-2.54(2H,m),1.47(9H,s).

[0293] e) tert-butyl 7-fluoro-5-oxa-2-azaspiro[3.5]non-7-ene-2-carboxylate

[0294] To a solution of tert-butyl-3-allyl-3-((2-fluoroallyl)oxy)azetidine-1-carboxylate (1.51 g, 5.57 mmol) in dry, degassed toluene (928 mL) at room temperature under argon was added (1,3-dimesityimidazolidin-2-ylidene)(2-isopropoxybenzyllidene)ruthenium(VI) chloride (349 mg, 557 μmol) and the mixture was allowed to warm to room temperature. The mixture was stirred at 100° C. for 1.5 hours and then filtered over dicalite. The filtrate was concentrated in vacuo. Purification by flash chromatography (silica, ethyl acetate / heptane) afforded the title compound (1.28 g, 95%) as a green oil. MS(ESI): 188.1 ([M-CH+H] + ).

[0295] f) tert-butyl 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate

[0296] To a solution of tert-butyl 7-fluoro-5-oxa-2-azaspiro[3.5]non-7-ene-2-carboxylate (1.26 g, 5.18 mmol) in methanol (51.8 mL) at room temperature was added Pd / C (10 wt%, 276 mg, 0.259 mmol). The mixture was stirred under a hydrogen atmosphere at room temperature for 18 hours. The reaction mixture was filtered through a pad of dicalite and washed with methanol. The filtrate was concentrated in vacuo to give the title compound (1.18 g, 93%) as a green solid. MS (ESI): 190.1 ([M-C4H8+H] + ).

[0297] g) 7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride

[0298] To a solution of tert-butyl 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate (1.18 g, 4.81 mmol) in dichloromethane (14.5 mL) at room temperature was added hydrochloric acid in 1,4-dioxane (4.0 m, 6.01 mL, 24.1 mmol). The mixture was stirred at room temperature for 24 hours, concentrated in vacuo, and dried to give the title compound (845 mg, 97%) as an off-white solid. MS (ESI): 146.1 ([M+H] + ).

[0299] h) (S)-benzyl 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate and (R)-benzyl 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate

[0300] To a suspension of 7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride (4.43 g, 23.9 mmol) in dichloromethane (44.4 mL) at 0-5°C, triethylamine (10.4 mL, 74.6 mmol) and benzyl chloroformate (7.13 mL, 49.9 mmol) were added. The mixture was stirred at room temperature. After 2 hours, triethylamine (2.5 mL, 17.9 mmol) and benzyl chloroformate (1.71 mL, 12.0 mmol) were added. After stirring at room temperature for 3 hours, the reaction mixture was diluted with 1.0 m HCl. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried (NaSO), filtered, and concentrated in vacuo. The mixture was separated by chiral preparative HPLC (Chiralpak AD, 60:40 heptane / ethanol, 203 nm) to give the following: (+) Enantiopure (R)-title compound (2.06 g, 31%) as an orange oil, MS(ESI): 280.2 ([M+H] + ). (-) Enantiopure (S)-title compound (2.07 g, 31%) as an orange oil, MS(ESI): 280.2 ([M+H] + ).

[0301] i) (S)-7-Fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride or enantiomer

[0302] To a solution of (S)-benzyl 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate (2 g, 7.16 mmol) in methanol (71.6 mL) at room temperature was added Pd / C (10 wt%, 762 mg, 0.716 mmol) and aqueous hydrochloric acid (4.0 m, 2.15 mL, 8.59 mmol). The mixture was stirred under a hydrogen atmosphere at room temperature for 18 hours. The reaction mixture was filtered through a pad of dicalite and washed with methanol. The filtrate was concentrated in vacuo to give the title compound (1.27 g, 97%) as an off-white solid. MS (ESI): 146.2 ([M+H] + ), specific rotation: -41.5° (methanol, 0.667g / 100mL).

[0303] (R)-7-Fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride or enantiomer [ka]

[0304] To a solution of (R)-benzyl 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate or enantiomer (2 g, 7.16 mmol) in methanol (71.6 mL) at room temperature was added Pd / C (10 wt%, 762 mg, 0.716 mmol) and aqueous hydrochloric acid (4.0 m, 2.15 mL, 8.59 mmol). The mixture was stirred under a hydrogen atmosphere at room temperature for 19 hours. The reaction mixture was filtered through a pad of dicalite and washed with methanol. The filtrate was concentrated in vacuo to give the title compound (1.10 g, 85%) as an off-white solid. MS (ESI): 146.2 ([M+H] + ), specific rotation: +38.6° (methanol, 0.667g / 100mL).

[0305] (R)-7-Methyl-5-oxa-2-azaspiro[3.5]nonane hydrochloride or enantiomer [ka]

[0306] a) tert-butyl 3-allyl-3-((2-methylallyl)oxy)azetidine-1-carboxylate

[0307] Following the same experimental procedure as for tert-butyl 3-allyl-3-((2-fluoroallyl)oxy)azetidine-1-carboxylate, 3-bromo-2-methylprop-1-ene was used instead of 2-fluoroprop-2-enyl methanesulfonate to convert to the title compound (1.05 g, 84%), which was obtained as a pale yellow liquid. MS (ESI): 265.5 ([M+H] + ).

[0308] b) tert-butyl 7-methyl-5-oxa-2-azaspiro[3.5]non-7-ene-2-carboxylate

[0309] To a solution of tert-butyl 3-allyl-3-((2-methylallyl)oxy)azetidine-1-carboxylate (1.02 g, 3.82 mmol) in anhydrous, degassed dichloromethane (636 mL) at room temperature under argon was added Grubbs II (324 mg, 0.382 mmol). The mixture was stirred at 40° C. for 19 hours. The reaction mixture was concentrated in vacuo. Purification by flash chromatography (silica, ethyl acetate / heptane) afforded the title compound (859 mg, 94%) as a brown oil. MS (ESI): 184.4 ([M-C4H8+H] + ).

[0310] c) tert-butyl 7-methyl-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate

[0311] Following the same experimental procedure as for tert-butyl 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate, tert-butyl 7-methyl-5-oxa-2-azaspiro[3.5]non-7-ene-2-carboxylate was used instead of tert-butyl 7-fluoro-5-oxa-2-azaspiro[3.5]non-7-ene-2-carboxylate to convert the title compound (807 mg, 100%), which was obtained as a colorless oil. MS(ESI): 186.5 ([M-CH+H] + ).

[0312] d) 7-methyl-5-oxa-2-azaspiro[3.5]nonane hydrochloride

[0313] Following the same experimental procedure as for 7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride, tert-butyl 7-methyl-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate was used instead of tert-butyl 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate to convert the title compound (592 mg, 100%) into a pale gray solid. MS (ESI): 142.3 ([M+H] + ).

[0314] e) (S)-benzyl 7-methyl-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate and (R)-benzyl 7-methyl-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate

[0315] Similar to the experimental procedure for (S)-benzyl 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate, 7-methyl-5-oxa-2-azaspiro[3.5]nonane hydrochloride was used to convert benzyl 7-methyl-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate instead of 7-fluoro-5-oxa-2-azaspiro[3.5]nonane hydrochloride. The mixture was separated by chiral SFC (AD-H, 10% ethanol) to give the following: (+) Enantiopure (S)-title compound or enantiomer (8.60 g, 42%) as a yellow oil, MS(ESI): 276.0 ([M+H] + ), specific rotation: +31.6° (methanol, 0.1g / L). (-) Enantiopure (R)-title compound or enantiomer (9.01 g, 44%) as a yellow oil, MS(ESI): 276.1 ([M+H] + ), specific rotation: -36.0° (methanol, 0.1g / l).

[0316] f) (R)-7-methyl-5-oxa-2-azaspiro[3.5]nonane hydrochloride or enantiomer

[0317] Analogously to the procedure for (S)-benzyl 7-fluoro-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate, (R)-benzyl 7-methyl-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate or enantiomer was converted to the title compound (5.82 g, 100%) as a white solid. MS(ESI): 142.3 ([M+H] + ).

[0318] 2-(Azetidin-3-yloxy)-6-(trifluoromethyl)pyrazine hydrochloride [ka]

[0319] a) tert-butyl 3-[6-(trifluoromethyl)pyrazin-2-yl]oxyazetidine-1-carboxylate

[0320] To a solution of 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (500 mg, 2.89 mmol) in 1,4-dioxane (25 mL) was added sodium hydride (60% dispersion in mineral oil, 174 mg, 4.33 mmol) at 0 °C. After stirring for 15 min, a solution of 2-chloro-6-trifluoromethyl-pyrazine (527 mg, 2.89 mmol) in 1,4-dioxane (5 mL) was added, and the reaction mixture was stirred at 50 °C for 45 min. After cooling to room temperature, the reaction mixture was quenched by the addition of saturated aqueous NH Cl and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried (Na SO ), filtered, and concentrated in vacuo. Purification by flash chromatography (silica, 40% ethyl acetate in hexanes) afforded the title compound (660 mg, 71%) as a colorless liquid.

[0321] b) 2-(azetidin-3-yloxy)-6-(trifluoromethyl)pyrazine hydrochloride

[0322] A solution of tert-butyl 3-[6-(trifluoromethyl)pyrazin-2-yl]oxyazetidine-1-carboxylate (650 mg, 2.036 mmol) in hydrochloric acid (4.0 m, 5 mL) in 1,4-dioxane was stirred at room temperature for 5 hours. The reaction mixture was concentrated in vacuo to give the title compound as a light brown solid (380 mg, 73%). MS (ESI): 220.1 ([M+H] + ). [Table 6] TIFF0007739336000063.tif250170 TIFF0007739336000064.tif245170 TIFF0007739336000065.tif205170 TIFF0007739336000066.tif218170 TIFF0007739336000067.tif217170 <h2 style=";text-align:left;direction:ltr">TIFF0007739336000068.tif221170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000069.tif250170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000070.tif233170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000071.tif222170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000072.tif230170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000073.tif233170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000074.tif230170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000075.tif222170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000076.tif216170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000077.tif218170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000078.tif230170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000079.tif238170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000080.tif245170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000081.tif218170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000082.tif238170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000083.tif233170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000084.tif241170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000085.tif236170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000086.tif241170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000087.tif250170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000088.tif225170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000089.tif230170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000090.tif238170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">TIFF0007739336000091.tif190170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000092.tif216170<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007739336000093.tif89170

Claims

1. Formula (I) or (II): 【Chemical 1】 【Chemistry 2】 [In the formula, X is i) N, and ii)CR １８ Selected from: Y is, i) N, and ii) From CH Selected; Z is i) N, and ii) CH Selected from: R １ teeth, i) C １－６ - alkyl, ii) halo-C 1-6 -alkyl, and iii) halogen Selected from: R ２ is C 1-6 -alkyl; R ３ teeth, i) optionally R ６ 、 R ７ and R ８ heteroaryl substituted with ii) R on the nitrogen atom ４ and R ５ Amino substituted with 1 or 2 substituents independently selected from iii) optionally R ９ 、 R １０ and R １１ heterocycloalkyl substituted with iv) R ６ 、 R ７ and R ８ aryl substituted with Selected from: R ４ teeth, i) H, and ii) C １－６ -Alkyl Selected from: R ５ teeth, i) H, and ii) C １－６ -Alkyl Selected from: R ６ , R ７ and R ８ is, independently, i) C １－６ - alkyl, ii) Hydroxy-C １－６ - alkyl, iii) C １－６ -alkoxy, iv) halogens, v) Halo-C １－６ - alkyl, vi) C ３－８ -cycloalkyl, and vii) cyano Selected from: R ９ 、 R １０ and R １１ is, independently, i) C １－６ - alkyl, ii) C １－６ -alkoxy, iii) C １－６ -alkoxycarbonyl, iv) C ３－８ -cycloalkoxy, v) C ３－８ -cycloalkyl, vi) C ３－８ -cycloalkyl-C １－６ -alkoxy, vii) Halo-C １－６ - alkyl, viii) C １－６ -alkoxy-C １－６ - alkyl, ix) C ３－８ -cycloalkylcarbonyl, x) Halo-C １－６ -alkoxy, xi) cyano, xii) halogens, xiii) optionally R １２ , R １３ and R １４ heteroaryl substituted with xiv) optionally R １２ , R １３ and R １４ heteroaryloxy substituted with xv) hydroxy, xvi) hydroxy-C １－６ -alkyl, and xvii) oxo Selected from: R １２ , R １３ and R １４ is, independently, i) Halo-C １－６ - alkyl, ii) C １－６ - alkyl, iii) C １－６ -alkoxy, and iv) halogen Selected from: R １８ teeth, i) H, and ii) halogen Selected from or a pharmaceutically acceptable salt thereof.

2. X is, i) N, and ii)CR １８ Selected from: Y is, i) N, and ii) CH Selected from: Z is, i) N, and ii) CH Selected from: R １ but, i) C １－６ - alkyl, ii) Halo-C １－６ - alkyl, and iii) halogen Selected from: R ２ But C １－６ is alkyl; R ３ but, i) optionally R ６ and R ７ pyrazolyl substituted with ii) optionally R ６ and R ７ pyridinyl substituted with iii) optionally R ９ and R １０ azetidinyl substituted with iv) optionally R ９ and R １０ isoindolinyl substituted with v) optionally R ９ and R １０ morpholinyl substituted with vi) optionally R ９ and R １０ piperazinyl substituted with vii) optionally R ９ and R １０ piperidinyl substituted with viii) optionally R ９ and R １０ pyrrolidinyl substituted with ix) optionally R ９ and R １０ oxaazaspirooctanyl substituted with x) optionally R ９ and R １０ oxaazaspirononanyl substituted with xi) R on the nitrogen atom ４ and R ５ and xii) R ６ and R ７ Phenyl substituted with Selected from: R ４ But C １－６ is alkyl; R ５ but, i) H, and ii) C １－６ -Alkyl Selected from: R ６ but, i) C １－６ - alkyl, ii) C １－６ -alkoxy, iii) halogens, iv) Halo-C １－６ - alkyl, v) C ３－８ -cycloalkyl, and vi) cyano Selected from: R ７ but, i) C １－６ -alkyl, and ii) C １－６ -alkoxy Selected from: R ９ 、 R １０ and R １１ But independently, i) C １－６ - alkyl, ii) C １－６ -alkoxy, iii) C ３－８ -cycloalkoxy, iv) C ３－８ -cycloalkyl, v) C ３－８ -cycloalkyl-C １－６ -alkoxy, vi) C １－６ -alkoxy-C １－６ - alkyl, vii) C ３－８ -cycloalkylcarbonyl, viii) Halo-C １－６ -alkoxy, ix) halogens, x) optionally R １２ imidazolyl substituted with xi) optionally R １２ pyridinyl substituted with xii) optionally R １２ pyrazolyl substituted with xiii) optionally R １２ pyridazinyloxy substituted with xiv) optionally R １２ pyridinyloxy substituted with xv) optionally R １２ Pyrimidinyloxy substituted with is selected from R １２ but, i) Halo-C １－６ - alkyl, ii) C １－６ - alkyl, iii) C １－６ -alkoxy, and iv) halogen Selected from: R １８ but, i) H, and ii) halogen 2. A compound of formula (I) or (II) according to claim 1, selected from:

3. R ４ But C １－６ 2. The compound of formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: - is alkyl.

4. R ６ but, i) C １－６ - alkyl, ii) C １－６ -alkoxy, iii) halogens, iv) Halo-C １－６ - alkyl, v) C ３－８ -cycloalkyl, and vi) cyano 2. A compound of formula (I) or (II) according to claim 1, selected from:

5. R ９ 、 R １０ and R １１ But independently, i) C １－６ - alkyl, ii) C １－６ -alkoxy, iii) C ３－８ -cycloalkoxy, iv) C ３－８ -cycloalkyl, v) C ３－８ -cycloalkyl-C １－６ -alkoxy, vi) C １－６ -alkoxy-C １－６ - alkyl, vii) C ３－８ -cycloalkylcarbonyl, viii) Halo-C １－６ -alkoxy, ix) halogens, x) optionally R １２ imidazolyl substituted with xi) optionally R １２ imidazolyloxy substituted with xii) optionally R １２ pyridinyl substituted with xiii) optionally R １２ pyridinyloxy substituted with xiv) optionally R １２ pyrazolyl substituted with xv) optionally R １２ pyrazolyloxy substituted with xvi) optionally R １２ pyridazinyl substituted with xvii) optionally R １２ pyridazinyloxy substituted with xviii) optionally R １２ pyrimidinyl substituted with xix) optionally R １２ Pyrimidinyloxy substituted with 2. A compound of formula (I) or (II) according to claim 1, selected from:

6. R １８ 2. The compound of formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is halogen.

7. 2. The compound of formula (I) or (II) according to claim 1, which is a compound of formula (I), or a pharmaceutically acceptable salt thereof.

8. 2. The compound of formula (I) or (II) according to claim 1, which is a compound of formula (II), or a pharmaceutically acceptable salt thereof.

9. 2-[[5-methyl-3-(6-methyl-3-pyridyl)triazol-4-yl]methyl]-5-[rac-(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridazin-3-one; 2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]-5-[rac-(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[rac-(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-morpholino-pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-(dimethylamino)pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[4-(cyclopropanecarbonyl)piperazin-1-yl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[rac-(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridazin-3-one; 2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]-5-pyrrolidin-1-yl-pyridazin-3-one; 2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]-5-morpholino-pyridazin-3-one; 5-(3,3-dimethylpyrrolidin-1-yl)-2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]pyridazin-3-one; 5-(2,2-dimethylmorpholin-4-yl)-2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]pyridazin-3-one; 5-[(2S,6S)-2,6-dimethylmorpholin-4-yl]-2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]pyridazin-3-one; 2-[[3-(4-chlorophenyl)-5-methyl-triazol-4-yl]methyl]-5-(dimethylamino)pyridazin-3-one; 2-[[3-(4-chlorophenyl)-5-methyl-triazol-4-yl]methyl]-5-piperazin-1-yl-pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(dimethylamino)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-morpholino-pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(4-cyclopropylpiperazin-1-yl)pyridazin-3-one; 2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]-5-[(2R)-2-methylpyrrolidin-1-yl]pyridazin-3-one; 5-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]-2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]pyridazin-3-one; 2-[[3-(4-chlorophenyl)-5-methyl-triazol-4-yl]methyl]-5-[rac-(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[4-(cyclopropanecarbonyl)piperazin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(methylamino)pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-(3-ethoxyazetidin-1-yl)pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-isoindolin-2-yl-pyridazin-3-one; 2-[[5-methyl-3-(6-methyl-3-pyridyl)triazol-4-yl]methyl]-5-[(2R)-2-methylpyrrolidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(3-methoxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(3-ethoxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(cyclopropylmethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3-one; 2-[[5-(4-chlorophenyl)-3-methyl-triazol-4-yl]methyl]-5-[rac-(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridazin-3-one; 2-[[5-(4-chlorophenyl)-3-methyl-triazol-4-yl]methyl]-5-(dimethylamino)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[(7S)-7-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[(7R)-7-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[3-(2,2,2-trifluoroethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[(2S)-2-methylmorpholin-4-yl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[(2R)-2-methylmorpholin-4-yl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[(2S,6S)-2,6-dimethylmorpholin-4-yl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[4-(2-methylimidazol-1-yl)-1-piperidyl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[4-(2-methoxy-3-pyridyl)piperazin-1-yl]pyridazin-3-one; 2-[[5-(4-chlorophenyl)-3-methyl-triazol-4-yl]methyl]-5-[(3S)-4-isopropyl-3-methyl-piperazin-1-yl]pyridazin-3-one; 2-[[5-(4-chlorophenyl)-3-methyl-triazol-4-yl]methyl]-5-(3-ethoxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[(3R)-3-isopropoxypyrrolidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(2-pyridyloxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[(3S)-4-isopropyl-3-methyl-piperazin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[(2S)-2-methylmorpholin-4-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[(2R)-2-methylmorpholin-4-yl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[4-(2-ethylimidazol-1-yl)-1-piperidyl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(3-isopropoxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(cyclobutoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(2,2,2-trifluoroethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(3-propoxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-[(6-chloro-3-pyridyl)oxy]azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(difluoromethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(2,2-difluoroethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-[(2-chloro-4-pyridyl)oxy]azetidin-1-yl]pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-(4-methoxyphenyl)pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-[2-(trifluoromethyl)-4-pyridyl]pyridazin-3-one; 2-[[5-(2,4-difluorophenyl)-3-methyl-triazol-4-yl]methyl]-5-[rac-(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridazin-3-one; 2-[[5-(4-chlorophenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(2,2,2-trifluoroethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chlorophenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(2,2-difluoroethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(4-methoxyphenyl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(6-methoxy-3-pyridyl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(2-methoxy-4-pyridyl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(1-methylpyrazol-4-yl)pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-(1-cyclopropylpyrazol-4-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(6-ethoxy-5-methyl-3-pyridyl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(1-cyclopropylpyrazol-4-yl)pyridazin-3-one; 2-[[3-(4-chloro-2-fluoro-phenyl)-5-methyl-triazol-4-yl]methyl]-5-(5-chloro-6-methoxy-3-pyridyl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(5-chloro-6-methoxy-3-pyridyl)pyridazin-3-one; 2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]-5-(3-isopropoxyazetidin-1-yl)pyridazin-3-one; 5-[3-(difluoromethoxy)azetidin-1-yl]-2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]pyridazin-3-one; 5-(3-ethoxyazetidin-1-yl)-2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(3-pyrazin-2-yloxyazetidin-1-yl)pyridazin-3-one; 2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]-5-[3-(2,2,2-trifluoroethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]-5-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridazin-3-one; 5-[3-(2,2-difluoroethoxy)azetidin-1-yl]-2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]pyridazin-3-one; 5-[3-(cyclobutoxy)azetidin-1-yl]-2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(3-pyrimidin-4-yloxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(3-pyridazin-3-yloxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-[(5-chloro-2-pyridyl)oxy]azetidin-1-yl]pyridazin-3-one; 5-(2-methoxy-4-pyridyl)-2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]pyridazin-3-one; 5-(5-chloro-6-methoxy-3-pyridyl)-2-[[3-methyl-5-(6-methyl-3-pyridyl)triazol-4-yl]methyl]pyridazin-3-one; 2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]-5-(3-pyridazin-3-yloxyazetidin-1-yl)pyridazin-3-one; 2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]-5-[3-(2-pyridyloxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-[3-(cyclobutoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-[3-(2,2-difluoroethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-[3-(2,2,2-trifluoroethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-[3-(difluoromethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]-5-(3-pyrazin-2-yloxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-(3-isopropoxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-(3-ethoxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-[(3S)-4-isopropyl-3-methyl-piperazin-1-yl]pyridazin-3-one; 5-[3-[(6-chloro-3-pyridyl)oxy]azetidin-1-yl]-2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]pyridazin-3-one; 2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]-5-[(3S)-4-isopropyl-3-methyl-piperazin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(5-oxa-2-azaspiro[3.5]nonan-2-yl)pyridazin-3-one; 5-(3-tert-butoxyazetidin-1-yl)-2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]pyridazin-3-one; 5-(3-tert-butoxyazetidin-1-yl)-2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-[6-(trifluoromethyl)pyrazin-2-yl]oxyazetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(2-methylpyrimidin-4-yl)oxyazetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-[2-(trifluoromethyl)pyrimidin-4-yl]oxyazetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-[3-[(6-chloro-3-pyridyl)oxy]azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-(3-pyridazin-3-yloxyazetidin-1-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(6-ethoxy-3-pyridyl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(6-methoxy-5-methyl-3-pyridyl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-(1-cyclopropylpyrazol-4-yl)pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[1-(2,2-difluoroethyl)pyrazol-4-yl]pyridazin-3-one; 6-[1-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-6-oxo-pyridazin-4-yl]pyridine-2-carbonitrile; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(6-chloro-5-methoxy-3-pyridyl)pyridazin-3-one; 2-[[5-(6-chloro-3-pyridyl)-3-methyl-triazol-4-yl]methyl]-5-[(2R)-2-methylpyrrolidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-(5-chloro-6-methoxy-3-pyridyl)pyridazin-3-one; 6-[1-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-6-oxo-pyridazin-4-yl]pyridine-2-carbonitrile; 2-[[5-(6-chloro-3-pyridyl)-3-methyl-triazol-4-yl]methyl]-5-[rac-(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(5-methylpyrazol-1-yl)azetidin-1-yl]pyridazin-3-one; 5-(5-chloro-6-methoxy-3-pyridyl)-2-[[3-methyl-5-(6-methylpyridazin-3-yl)triazol-4-yl]methyl]pyridazin-3-one; 5-(3-ethoxyazetidin-1-yl)-2-[[3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazol-4-yl]methyl]pyridazin-3-one; 5-(3-isopropoxyazetidin-1-yl)-2-[[3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazol-4-yl]methyl]pyridazin-3-one; 5-[3-(cyclobutoxy)azetidin-1-yl]-2-[[3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazol-4-yl]methyl]pyridazin-3-one; 5-(5-chloro-6-methoxy-3-pyridyl)-2-[[3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazol-4-yl]methyl]pyridazin-3-one; 5-[3-(2,2-difluoroethoxy)azetidin-1-yl]-2-[[3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazol-4-yl]methyl]pyridazin-3-one; 2-[[3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazol-4-yl]methyl]-5-[3-(2,2,2-trifluoroethoxy)azetidin-1-yl]pyridazin-3-one; 5-[3-(difluoromethoxy)azetidin-1-yl]-2-[[3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazol-4-yl]methyl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-[(7R)-7-methyl-5-oxa-2-azaspiro[3.5]nonan-2-yl]pyridazin-3-one; 5-(5-chloro-6-methoxy-3-pyridyl)-2-[[3-methyl-5-[6-(trifluoromethyl)pyridazin-3-yl]triazol-4-yl]methyl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-[(7S)-7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-ethyl-triazol-4-yl]methyl]-5-[(7R)-7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[(7S)-7-fluoro-5-oxa-2-azaspiro[3.5]nonan-2-yl]pyridazin-3-one 9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, selected from:

10. 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(cyclopropylmethoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-(cyclobutoxy)azetidin-1-yl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-(6-methoxy-3-pyridyl)pyridazin-3-one; 5-[3-(2,2-difluoroethoxy)azetidin-1-yl]-2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]pyridazin-3-one; 5-[3-(cyclobutoxy)azetidin-1-yl]-2-[[5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-triazol-4-yl]methyl]pyridazin-3-one; 2-[[5-(4-chloro-2-fluoro-phenyl)-3-methyl-triazol-4-yl]methyl]-5-[3-[2-(trifluoromethyl)pyrimidin-4-yl]oxyazetidin-1-yl]pyridazin-3-one; 5-[3-(difluoromethoxy)azetidin-1-yl]-2-[[3-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]triazol-4-yl]methyl]pyridazin-3-one 10. The compound according to any one of claims 1 to 9, wherein:

11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

13. 11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of Alzheimer's disease, mild cognitive impairment, age-related cognitive decline, negative and / or cognitive symptoms associated with schizophrenia, bipolar disorder, autism spectrum disorder, Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder, amyotrophic lateral sclerosis, fragile X disorder.

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