Novel benzodiazepine derivatives as GABA A gamma 1 PAMs

Abstract

The present invention relates to a compound represented by general formula (I) TIFF2023521572000080.tif49165 (In the formula, R 1 , R 2 , R 3 , R 4 and R 5 The present invention provides novel compounds having the formula (I), compositions comprising the compounds, and methods of using the compounds.

Description

[Technical field]

[0001] The present invention relates to organic compounds, particularly GABA, that are useful for the treatment or prevention of inflammatory bowel disorders in mammals. A γ1 Receptor Related Disorders and GABA A Diseases or conditions that may be treated by modulation of γ1 receptor activity, such as Autism Spectrum Disorder (ASD) targeting core symptoms and associated comorbidities including anxiety and hypersensitivity, Angelman Syndrome, Rett Syndrome, Prader-Willi Syndrome, Fragile X Disorder, schizophrenia including psychosis, cognitive impairment and negative symptoms, tardive dyskinesia, anxiety, separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder (social phobia), panic disorder, agoraphobia, generalized anxiety disorder, substance / drug-induced anxiety disorder, impulse control and behavior disorders, Tourette's Syndrome (TS), Obsessive-Compulsive Disorder (OCD), acute stress disorder, trauma GABA for the treatment or prevention of post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), sleep disorders including narcoleptic attacks, Parkinson's disease (PD), neurodegenerative conditions including Huntington's chorea, Alzheimer's disease (AD), mild cognitive impairment (MCI) dementia, behavioral and psychological symptoms (BPS) in neurodegenerative conditions, multi-infarct dementia, psychotic and aggression disorders, eating disorders including anorexia nervosa, bulimia nervosa, binge eating disorder, depression and related conditions (including treatment-resistant depression (TRD)), chronic apathy, anhedonia, chronic fatigue, seasonal affective disorder, postpartum depression, sexual dysfunction, bipolar disorder, epilepsy and pain. A Concerning γ1 receptor positive allosteric modulators (PAMs). Summary of the Invention

[0002] The present invention relates to a compound represented by formula (I) [ka] (In the formula, R 1 teeth, i) H, ii) C 1-6 -alkyl, iii) C1-6 -alkoxy, iv) C 1-6 -Alkoxy-C 1-6 -alkyl, v) hydroxy, vi) Hydroxy-C 1-6 -alkyl, vii) Optionally, R 7 , R 8 and R 9 C replaced with 3-8 -cycloalkyl, vii) Amino-C 1-6 -alkyl, ix) Optionally, R 7 , R 8 and R 9 Heteroaryl substituted with, x) Optionally, R 7 , R 8 and R 9 Heterocycloalkyl substituted with Selected from; R 2 teeth, I C 1-6 -alkyl, ii) hydroxy, iii) Hydroxy-C 1-6 -alkyl, and iv) C 1-6 -Alkoxy-C 1-6 -Alkyl Selected from; R 3 teeth, i) Cl, and ii) F Selected from; X is i) CR 6 , and ii) N Selected from; R 6 teeth, i) H, ii) Cl, and iii) F Selected from; R 4 teeth, i) Br, and ii) Cl Selected from; R 5 teeth, I C 1-6 -alkyl, I C 1-6 -alkoxy, iii) halogens, iv) Halo-C 1-6 -alkyl, v) cyano, and vi) C 3-8 -Cycloalkyl Selected from; R 7 , R 8 and R 9 teeth, I C 1-6 -alkyl, and ii) C 1-6 -Alkoxy (independently selected from or a pharma- ceutically acceptable salt thereof.

[0003] Receptors for the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) are divided into two main 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 is a membrane-bound heteropentameric protein polymer. A The GABA receptor complex is composed primarily 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] GABA A There are 19 genes encoding the receptor subunits, with the most common stoichiometry being two α, two β, and one γ subunit assembled as a pentamer. ASubunit combinations induce functional, circuit and behavioral specificity (Sieghart, 2006; Vithlani et al., 2011). GABA receptors containing the γ1 subunit A Receptor (GABA A GABA receptor γ1) are of particular interest due to their abundant expression in the limbic system (Seeburg et al., 1990; Pirker et al., 2000; Esmaeili et al., 2008; Durisic et al., 2017; Sequeira et al., 2019) and unique physiological and pharmacological properties (Mohler et al., 1996; Wingrove et al., 1997; Sieghart et al., 2005). A γ1 subunit-containing receptors are less abundant than γ2 subunit-containing receptors (GABA receptors in the brain A The receptors are expressed in the retina (ca. 5–10% of total expression), and show high brain mRNA and protein distribution in key brain regions such as the extended amygdala (central, medial, and bed nuclei of the stria terminalis), lateral septum, hypothalamus, and globus pallidus / substantia nigra. These structures form an interconnected core in the subcortical-limbic circuit that regulates stimulated social and emotional behaviors. In abnormal or diseased conditions, excessive recruitment of this circuit promotes anxiety, sexual arousal, aggression, fear, and defensiveness while inhibiting feeding and social interaction (Goossens et al., 2007; Hofmann et al., 2011; Fox et al., 2012; Martin-Santos et al., 2014; Anderson et al., 2014; Calhoon et al., 2015).

[0005] Hyperactivity in limbic cortical regions, key areas for processing socially and emotionally relevant stimuli (known to form a coordinated functional network with extended amygdala / hypothalamic regions), is a common feature of a variety of psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational and metabolic disorders. In such disease states, γ1-subunit-containing GABAergic receptors are essential for the regulation of stimuli. A Given the distinctive anatomical distribution of the receptor, GABAAγ1 positive allosteric modulators (PAMs) may be an effective treatment as symptomatic or disease-modifying agents.

[0006] Multiple lines of evidence suggest that an imbalance between excitatory / inhibitory (E / I) neurotransmission resulting from dysfunction of the GABAergic signaling system, the main inhibitory neurotransmitter system in the brain, is central to the pathogenesis of various CNS disorders. Given the distribution and function of GABAA γ1 subunit-containing receptors in the CNS, they are highly attractive targets for restoring inhibition levels in key brain circuits and, consequently, for restoring E / I balance in these conditions.

[0007] Thus, the compounds described herein, and their pharma- ceutically acceptable salts, and esters, may be used alone or in combination with other drugs to treat acute neurological disorders, chronic neurological disorders, cognitive disorders, autism spectrum disorders (ASD), Angelman syndrome, Rett syndrome, Prader-Willi syndrome, fragile X disorder, schizophrenia, tardive dyskinesia, anxiety, social anxiety disorder (social phobia), panic disorder, agoraphobia, generalized anxiety disorder, disruptive, impulse control and behavior disorders, Tourette syndrome (TS), obsessive-compulsive disorder (OCD), acute stress disorder, It may be used as a disease modifying or symptomatic agent to treat or prevent post traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), sleep disorders, Parkinson's disease (PD), Huntington's chorea, Alzheimer's disease (AD), mild cognitive impairment (MCI), dementia, behavioral and psychological symptoms in neurodegenerative conditions (BPS), multi-infarct dementia, agitation, psychosis, substance-induced psychotic disorder, aggression, eating disorders, depression, chronic apathy, anhedonia, chronic fatigue, seasonal affective disorder, postpartum depression, sleepiness, sexual dysfunction, bipolar disorder, epilepsy and pain.

[0008] The most preferred indications in accordance with the present invention are anxiety, targeting social anxiety disorder (social phobia) and generalized anxiety disorder, and autism spectrum disorder (ASD), targeting core symptoms and associated comorbidities including anxiety and irritability.

[0009] ASD is a complex and heterogeneous neurodevelopmental disorder characterized by deficits in two core domains: impairments in social interaction and communication, and the presence of repetitive or restricted behaviors, interests, or activities (American Psychiatric Association 2013).

[0010] While there are no approved pharmacological treatments for the core symptoms of social deficits and restricted / repetitive behaviors in ASD, adequate treatment options are not available for the majority of ASD's emotional and physiological comorbidities. As a result, 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) indicated for the treatment of irritability associated with ASD symptoms. Emerging evidence suggests that the GABAergic system, the main inhibitory neurotransmitter system in the brain, plays a key role in the pathophysiology of ASD (Dhossche et al., 2002; Pizzarelli and Cherubini, 2011; Robertson et al., 2016).

[0011] Both genetic and imaging studies using positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) suggest alterations in GABAergic signaling in ASD. The gene encoding GABAAγ1:GABRG1, encodes α2, α4, and β1 GABAergic receptors. AIt is located on chromosome 4 (mouse Chr.5) within a cluster of genes encoding receptor subunits. Rare CNVs involving inversions of chromosome 4p12 disrupting GABRG1 have been found in siblings with autism (Horike et al., 2006), as well as GABRG1 loss in one case of ADHD. Mutations in the 4p12 gene cluster are associated with increased risk of anxiety, substance abuse and eating disorders, leading to an association between GABRG1 / 4p12 and emotional dysfunction. MRS studies have found altered GABA levels in ASD (Gaetz et al., 2014; Rojas et al., 2014), and notably 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, reduced numbers of inhibitory interneurons were found in postmortem tissue from ASD and TS patients (Rapanelli et al., 2017). Furthermore, reduced levels of the GABA-synthesizing enzymes glutamic acid decarboxylase (GAD) 65 and 67 were found in the parietal and cerebellar cortices of autistic patients (Fatemi et al., 2002). Strong evidence in humans points to specific dysfunction in ASD of limbic cortical regions known to form coordinated functional networks with GABAA γ1 subunit-containing extended amygdala / hypothalamic regions. These regions: cortico / lateral amygdala, insula, PFC, and lemniscus, are recognized as key to processing socially and emotionally relevant stimuli. Subcortical nuclei that form specific partnerships with these regions that coordinate behavioral outcomes are often difficult to study due to limitations in spatial resolution, but mounting evidence points to an over-recruitment of these cortical-to-subcortical connections in ASD. Moreover, recent high-resolution studies have provided clear links between extended amygdala activity / functional connectivity and emotional states ( Kleinhans et al., 2009 , 2016 ; Swartz et al., 2013 ; Nordahl et al., 2016 ; Ehrlich et al., 2017 ; Avino et al., 2018 ; Ibrahim et al., 2019 ).Targeting such highly specific limbic subcortical regions, which exhibit substantial molecular and cellular diversity compared to the neocortex, creates a precise entry point for safe and specific therapeutic modulation of social-emotional circuits affected in ASD, while avoiding broad modulation of global brain state GABA with non-selective BZDs. A Enhancement of GABA receptor activity has been shown to improve behavioral deficits in mouse models of ASD. A A very narrow therapeutic margin was observed for sedation mediated by the α1γ2 subtype (Han et al., 2012, 2014; Soto et al., 2013). These findings support the idea that rebalancing GABAergic transmission via GABAAγ1 receptors may improve symptoms of ASD without the side effects of nonselective benzodiazepines.

[0012] The object of the present invention is to provide compounds of formula (I) and their pharma- ceutically acceptable salts and esters, the preparation of said compounds, medicaments containing them and their manufacture, as well as GABA A Diseases associated with γ1 receptor dysfunction and GABA ADiseases or conditions that may be treated by enhancing γ1 receptor activity, such as autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, Prader-Willi syndrome, fragile X disorder, schizophrenia, tardive dyskinesia, anxiety, separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder, panic disorder, agoraphobia, generalized anxiety disorder, substance / drug-induced anxiety disorder, disruptive, impulse control and conduction disorders, Tourette's syndrome (TS), obsessive-compulsive disorder (OCD), acute stress disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), narcolepsy (narcolepsy), and the like. and use of the above compounds in the treatment or prevention of sleep disorders including idiopathic colepsy-cataplexy, neurodegenerative conditions including Parkinson's disease (PD), Huntington's chorea, Alzheimer's disease (AD), mild cognitive impairment (MCI) dementia, behavioral and psychological symptoms (BPS) in neurodegenerative conditions, multi-infarct dementia, psychosis and aggression, eating disorders including anorexia nervosa, bulimia nervosa, binge eating disorder, depression, and related conditions including treatment-resistant depression (TRD), chronic apathy, anorexia, chronic fatigue, seasonal affective disorder, postpartum depression, sleepiness, sexual dysfunction, bipolar disorder, epilepsy and pain.

[0013] The compounds of the present invention are effective at a given concentration (e.g., EC 20 ) by increasing GABAergic currents (chloride influx) with γ1-containing GABA A Selectively enhances the function of GABA receptors A The compound of the present invention is a γ1 receptor positive allosteric modulator (PAM). Compared with γ2-containing subtypes (e.g., α1γ2, α2γ2, α3γ2, and α5γ2), the compound of the present invention has a high PAM effect and high binding selectivity for γ1-containing subtypes (α5γ1, α2γ1, α1γ1). Therefore, the compound of the present invention is a γ2-containing GABA A This is in stark contrast to classical benzodiazepine drugs such as alprazolam, triazolam, estazolam, and midazolam, which have low affinity for the γ1-containing subtypes. Aγ1 PAM is a non-selective GABA A It will restore GABAergic signaling in key brain regions (e.g. extended amygdala: stria terminalis, lateral septum, central, medial and bed nuclei of the hypothalamus and globus pallidus / substantia nigra) without the side effects of modulators (e.g. benzodiazepines).

[0014] The term "amino" refers to the group --NH.

[0015] "Amino-C 1-6 The term "C-alkyl" refers to 1-6 -C where one of the hydrogen atoms of the alkyl group is replaced by an amino group 1-6 -Alkyl group. Amino-C 1-6 Examples of -alkyl include aminomethyl, aminoethyl, aminopropyl, aminomethylpropyl, aminomethylethyl and aminobutyl. A particular example is aminomethyl.

[0016] "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. Particular examples are methoxy and ethoxy. A more particular example is methoxy.

[0017] "C 1-6 -Alkoxy-C 1-6 The term "C-alkyl" refers to 1-6 -At least one hydrogen atom of the alkyl group is C 1-6 -C substituted with an alkoxy group 1-6 -alkyl groups. 1-6 -Alkoxy-C 1-6 -Alkyl groups include methoxymethyl, ethoxymethyl, methoxymethyl, ethoxyethyl, methoxypropyl, ethoxypropyl, etc. A particular example is methoxymethyl.

[0018] "C 1-6 The term "-alkyl" refers to a monovalent linear or branched 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 The alkyl groups are methyl, ethyl and isopropyl. A more specific example is methyl.

[0019] "C 3~8 The term "cycloalkyl" denotes a monovalent saturated monocyclic or bicyclic hydrocarbon radical 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 are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. 3-8 An example of a -cycloalkyl is spiro[3.3]heptanyl. 3-8 -Cycloalkyl groups are cyclopropyl and cyclobutanyl. More specific monocyclic C 3-8 Cycloalkyl groups include cyclopropyl.

[0020] The term "cyano" refers to the group -CN.

[0021] "Haro-C 1-6 The term "C-alkyl" refers to 1-6 - 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 -alkyl group. 1-6Examples of halo-C alkyl include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl. 1-6 -alkyl groups include trifluoromethyl and difluoromethyl. More specific halo-C 1-6 The alkyl group is trifluoromethyl.

[0022] The terms "halogen" and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo or iodo. Particular halogens include fluoro, chloro, and the like.

[0023] The term "heteroaryl" refers to a monovalent aromatic heterocycle or monocyclic or bicyclic ring system 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, benzoisoxazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxaaryl. Particular heteroaryl groups include pyridinyl, pyrazolyl, pyrimidinyl, pyridazinyl and isoxazolyl.More particular heteroaryl groups are pyrazolyl, pyrimidinyl, pyridazinyl and isoxazolyl.

[0024] The term "heterocycloalkyl" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 11 ring atoms containing one, two, or three ring heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. Bicyclic means consisting of two rings that have one or two ring atoms in common. Examples of monocyclic saturated heterocyclyls 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. A particular heterocycloalkyl is tetrahydropyranyl.

[0025] The term "hydroxy" refers to an --OH group.

[0026] "Hydroxy-C 1-6 The term "C-alkyl" refers to 1-6 -C where one of the hydrogen atoms of the alkyl group is replaced by a hydroxy group 1-6 - represents an alkyl group. Hydroxy C 1-6Examples of -alkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylpropyl, hydroxymethylethyl, hydroxybutyl, etc. A particular example is hydroxymethyl.

[0027] The term "pharmaceutically acceptable salt" refers to a salt that retains 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, 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, N-acetylcysteine, etc. These salts may also be prepared by adding an inorganic or organic base 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 pharma- ceutically acceptable salts of the compounds of formula (I) are the hydrochloride, methanesulfonate, and citrate salts.

[0028] By "pharmaceutical acceptable ester" is meant that the compounds of formula (I) can 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 ester, methylthiomethyl ester, and pivaloyloxymethyl ester. In addition, any physiologically acceptable equivalent of the compounds of formula (I) that resembles the metabolically labile esters that the parent compounds of formula (I) can produce in vivo is also within the scope of the present invention.

[0029] The term "protecting group" (PG) is used in its conventional sense in synthetic chemistry to mean a group that selectively blocks reactive sites of a polyfunctional compound, allowing chemical reactions to occur selectively at other unprotected reactive sites. The protecting group may be removed at an appropriate point. Exemplary protecting groups are the amino-, carboxy- or hydroxy-protecting groups. Particular protecting groups are the tert-butoxycarbonyl (Boc) group, the benzyloxycarbonyl (Cbz) group, the fluorenylmethoxycarbonyl (Fmoc) group and the benzyl (Bn) group. More particular protecting groups are the tert-butoxycarbonyl (Boc) group and the fluorenylmethoxycarbonyl (Fmoc) group. An even more particular protecting group is the tert-butoxycarbonyl (Boc) group.

[0030] The abbreviation uM means micromolar and is equivalent to the symbol μM.

[0031] The abbreviation uL means microliter and is equivalent to the symbol μL.

[0032] The abbreviation ug stands for microgram and is equivalent to the symbol μg.

[0033] The compounds of formula (I) may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, e.g. racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0034] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0035] Also an embodiment of the present invention are compounds according to formula (I) as described herein and pharma- ceutically acceptable salts or esters thereof, particularly compounds according to formula (I) as described herein and pharma- ceutically acceptable salts thereof, more particularly compounds according to formula (I) as described herein.

[0036] A specific embodiment of the present invention is a compound according to formula (I) as described herein, R 1 teeth, i) H, ii) C 1-6 -alkyl, iii) C 1-6 -alkoxy, iv) C 1-6 -Alkoxy-C 1-6 -alkyl, v) hydroxy, vi) Hydroxy-C 1-6 -alkyl, vii) Optionally, R 7 , R 8 and R 9 C replaced with 3-8 -cycloalkyl, viii) Amino-C 1-6 -alkyl, ix) Optionally, R 7 , R 8 and R 9 pyrazolyl substituted with x) Optionally, R 7 , R 8 and R 9 pyridinyl substituted with xi) Optionally, R 7 , R 8 and R 9 pyrimidinyl substituted with xii) Optionally, R 7 , R 8 and R 9 pyridazinyl substituted with xiii) Optionally, R 7 , R 8 and R 9 Isoxazolyl substituted with Selected from; R 2 teeth, I C 1-6 -alkyl, ii) hydroxy, iii) Hydroxy-C 1-6 -alkyl, and iv) C 1-6 -Alkoxy-C 1-6 -Alkyl Selected from; R 3 teeth, i) Cl, and ii) F is selected from X is i) CR 6 , and ii) N Selected from; R 6 teeth, i) H, ii) Cl, and iii) F Selected from; R 4 teeth, i) Br, and ii) Cl Selected from; R 5 teeth, I C 1-6 -alkyl, ii) C 1-6 -alkoxy, iii) halogens, iv) Halo-C 1-6 -alkyl, v) C 3-8 -Cycloalkyl Selected from; R 7 , R 8 and R 9 teeth, I C 1-6 -alkyl, and ii) C 1-6 -Alkoxy (selected from or a pharma- ceutically acceptable salt thereof.

[0037] A more particular embodiment of the present invention is a compound of formula (I) according to claim 1, R 1 but, i) H, ii) C 1-6 -alkyl, iii) hydroxy, iv) Hydroxy-C 1-6 -alkyl, v) Optionally, R 7 , R 8 and R 9 C replaced with 3-8 -cycloalkyl, vi) Optionally, R 7 , R 8 and R 9 pyrazolyl substituted with vii) Optionally, R 7 , R 8 and R 9 pyrimidinyl substituted with viii) Optionally, R 7 , R 8 and R 9 pyridazinyl substituted with ix) Optionally, R 7 , R 8 and R 9 Isoxazolyl substituted with Selected from; R 2 but, I C 1-6 -alkyl, ii) hydroxy, iii) Hydroxy-C 1-6 -alkyl, and iv) C 1-6 -Alkoxy-C 1-6 -Alkyl Selected from; R 3 But F, X, i) CR 6 , and ii) N Selected from; R 6 but, i) H, and ii) F Selected from; R 4 but, i) Br, and ii) Cl Selected from; R 5 but, I C 1-6 -alkyl, ii) halogens, and iii) Halo-C 1-6 -Alkyl Selected from; R 7 , R 8 and R 9 But, C 1-6 independently selected from alkyl, The compound or a pharma- ceutically acceptable salt is provided.

[0038] Further specific embodiments of the present invention are compounds according to formula (I) as described herein, R 1 But, C 1-6 is alkyl, R 2 But, C 1-6 is alkyl, R 3 But F, X is CR 6 and R 6 But F, R 4 is Cl, R 5 But, Halo-C 1-6 -alkyl, or a pharma- ceutically acceptable salt thereof.

[0039] Another particular embodiment of the present invention is 1 but, i) H, ii) C 1-6 -alkyl, iii) C 1-6 -alkoxy, iv) C 1-6 -Alkoxy-C 1-6 -alkyl, v) hydroxy, vi) Hydroxy-C 1-6 -alkyl, vii) Optionally R7, R 8 and R 9 C replaced with 3-8 Cycloalkyl, viii) Amino-C 1-6 -alkyl, ix) Optionally, R 7 , R 8 and R 9 pyrazolyl substituted with x) Optionally, R 7 , R 8 and R 9 pyridinyl substituted with xi) Optionally, R 7 , R 8 and R 9 pyrimidinyl substituted with xii) Optionally, R 7 , R 8 and R 9 pyridazinyl substituted with, xiii) Optionally, R 7 , R 8 and R 9 Isoxazolyl substituted with The present invention provides a compound of formula (I) as described herein, selected from:

[0040] Another particular embodiment of the present invention is 1but, i) H, ii) C 1-6 -alkyl, iii) hydroxy, iv) Hydroxy-C 1-6 -alkyl, v) Optionally R7, R 8 and R 9 C replaced with 3-8 -cycloalkyl, vi) Optionally, R 7 , R 8 and R 9 pyrazolyl substituted with vii) Optionally, R 7 , R 8 and R 9 pyrimidinyl substituted with viii) Optionally, R 7 , R 8 and R 9 pyridazinyl substituted with ix) Optionally, R 7 , R 8 and R 9 Isoxazolyl substituted with The present invention provides a compound of formula (I) as described herein, selected from:

[0041] Another particular embodiment of the present invention is 1 C 1-6 -alkyl.

[0042] A particular embodiment of the present invention is 2 C 1-6 Provided herein is a compound of formula (I) wherein:

[0043] Another particular embodiment of the present invention is 3 is F.

[0044] Another particular embodiment of the invention is where X is CR 6

[0023] The present invention provides a compound according to formula (I) as described herein,

[0045] Another particular embodiment of the present invention is 6 is F.

[0046] Another particular embodiment of the present invention is 4 is Cl.

[0047] Another particular embodiment of the present invention is 5 but, I C 1-6 -alkyl, ii) C 1-6 -alkoxy, iii) halogens, iv) Halo-C 1-6 -alkyl, v) C 3-8 -Cycloalkyl The present invention provides a compound of formula (I) as described herein, selected from:

[0048] Another particular embodiment of the present invention is 5 but, I C 1-6 -alkyl, ii) halogens, and iii) Halo-C 1-6 -Alkyl The present invention provides a compound of formula (I) as described herein, selected from:

[0049] Another particular embodiment of the present invention is 5 C 1-6 Provided herein is a compound of formula (I) wherein:

[0050] Another particular embodiment of the present invention is 7 , R 8 and R 9 But, C 1-6 -alkyl.

[0051] Specific examples of compounds of formula (I) described herein include 4S)-8-Bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-Bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-ol; (4S)-8-Bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-Bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-ol; (4S)-8-Bromo-7-chloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-Dichloro-6-(2,6-difluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-Dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-Dichloro-6-(2,6-difluorophenyl)-4-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one; (4S)-7,8-Dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-Dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-Dichloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-Bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-Bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-8-Bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-Bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-Bromo-8-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-Bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(1-methylpyrazol-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-Dichloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-8-Bromo-7-chloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-8-Bromo-7-chloro-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-8-Bromo-7-chloro-6-(3-fluoro-2-pyridyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-Dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyridazin-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 5-[(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]-3-methyl-isoxazole; (4S)-7-Bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyridazin-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-Bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one; (4S)-7-Chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-Chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-Dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyrimidin-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(2-methylpyrimidin-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-1-(2,6-dimethylpyrimidin-4-yl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-Chloro-6-(2,6-difluorophenyl)-1,4,8-trimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-8-Bromo-7-chloro-6-(2,6-difluorophenyl)-4-ethyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-Chloro-8-(difluoromethyl)-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; [(4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]methanol; (4S)-7-chloro-6-(2,6-difluorophenyl)-8-iodo-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; [(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methanol; (4R)-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; [(4R)-7-chloro-6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]methanol; (4S)-7-Chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-chloro-6-(2,6-difluorophenyl)-1-ethyl-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-chloro-6-(2,6-difluorophenyl)-8-ethyl-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; or a pharma- ceutically acceptable salt thereof. is selected from.

[0052] Further specific examples of compounds of formula (I) described herein are selected from (4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine, or a pharma- ceutically acceptable salt thereof.

[0053] In some embodiments, the compound of formula (I) is isotopically labeled by replacing one or more atoms therein with an atom having a different atomic mass or mass number. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Examples of isotopes that can be incorporated into the compound of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, including, but not limited to, 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 Some isotopically labeled compounds of formula (I), 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 straightforward means of detection. For example, compounds of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0054] Heavier isotopes, such as deuterium, i.e. 2 Substitution with H or the like may result in greater metabolic stability and may confer certain therapeutic advantages, for example, by increasing in vivo half-life or requiring a lower dosage.

[0055] 1 1 C. 18 F, 15 O and 13Substitution with positron emitting isotopes such as N can be useful in positron emission tomography (PET) to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I) can be prepared by methods similar to those described in the Examples below, or by conventional techniques known to those skilled in the art, typically using an appropriate isotopically labeled reagent in place of the previously used non-labeled reagent.

[0056] Processes for preparing the compounds of formula (I) described herein are also an object of the present invention.

[0057] The preparation of the compound of formula (I) of the present invention can 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 reaction and purification of the resulting product are known to those skilled in the art.The substituents and indicators used in the following description of the process have the significance previously described herein, unless otherwise stated.

[0058] More specifically, the compounds of formula (I) may be prepared by the methods shown below, the methods shown in the Examples, or similar methods. Suitable reaction conditions for the individual reaction steps are known to those skilled in the art. The reaction sequence is not limited to that shown in Schemes 1-4, but the order of the reaction steps may be freely changed depending on the starting materials and their respective reactivities. The 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.

[0059] The present compounds of formula (I) and their pharma- ceutically acceptable salts may be prepared by the methods described below (Scheme 1). [ka]

[0060] Scheme 1: Synthesis of benzodiazepines (I) where all definitions are as defined above and in the claims. According to scheme 1, compounds of formula (I) can be prepared in two steps starting from lactams of formula (II) (building blocks A, B, G, L, M, O, QU). After a vulcanization reaction using Lawesson's reagent or P2S5, lactams (II) are converted to the corresponding thiolactams (III). Their reaction with hydrazides (IV) via a Pellizzari-type process gives 1,2,4-triazoles of general formula (I). Alternatively, 1,2,4-triazoles (I) can be obtained by reaction of thiolactams (II) with hydrazine to form hydrazones (V), followed by treatment with triethyl orthoacetate or triethyl orthoformate.

[0061] R 1 In a particular embodiment of the invention where is hydroxyl (OH), benzodiazepines of formula (I) can be obtained in two steps according to the process described in Scheme 2. It is widely accepted that 3-hydroxy-1,2,4 triazoles exist in two tautomeric forms, and in the present invention they are exclusively represented in their most stable form (triazolones). To this end, hydrazones (V) can be reacted with 1,1'-carbonyldiimidazole (CDI) to obtain triazolones of formula (I) (Scheme 2). [ka]

[0062] Scheme 2: R 1 Synthesis of benzodiazepines (I) where is hydroxyl; all other definitions are as defined above and in the claims. The synthesis of the building blocks (A, B, G, L, M, O, QU) of formula (II) is highlighted in Scheme 3. Commercially available 2-amino-6-chlorobenzoic acid or 2-amino-6-bromobenzoic acid can be heated in acetic anhydride to form 5-chloro-2-methyl-3,1-benzoxazin-4-one and 5-bromo-2-methyl-3,1-benzoxazin-4-one, respectively. Grignard or organolithium reagents of formula (VI) (prepared by metallation reaction or kinetic deprotonation from the corresponding aryl bromide) can be reacted with benzoxazin-4-one (electrophile) at controlled temperature to give ketones of formula (VII). After N-acetamide hydrolysis under acidic conditions (HCl), compounds of formula (VII) are converted to anilines of formula (VIII). Conveniently, at this junction, R 5 can be introduced by treatment with N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS) to give intermediates of formula (IX). A final thermal cyclization reaction with ethyl 2-aminoacetate hydrochloride in pyridine gives the desired benzodiazepine (II), presumably via the formation of an imine intermediate (X). [ka]

[0063] Scheme 3: R 5 is Cl, Br or I, and R 2 A composition of components (A, B, G, L, M, O, QU) where is H; all other definitions are as defined above and in the claims. R 2 In further embodiments of the invention where is alkyl or substituted alkyl, an alternative process is envisioned and is detailed in Scheme 4. [ka]

[0064] Scheme 4: R 5 is Cl, Br or I, and R 2is alkyl or substituted alkyl; all other definitions are as defined above and in the claims. In such cases, compounds of formula (XI) may be prepared by amide coupling reaction between aniline (IX) and N-Boc protected L-amino acid under exposure to phosphoryl chloride (POCl3) or by other methods known to those skilled in the art. Removal of the N-Boc protecting group can be carried out with mineral acids (e.g. HCl) or organic acids (e.g. trifluoroacetic acid) to give amines of formula (XII). A final intramolecular condensation reaction is promoted by acidic medium (e.g. silica or acetic acid) and heat (80-110 °C) to give the desired benzodiazepine building blocks (A-U) of formula (II). Notably, the processes described in schemes 1 and 4 have different degrees of racemization at the chiral center (20-100%) depending on the specific reaction conditions employed. As a result, chiral purification (e.g. by HPLC or SFC) of the final derivatives of formula (I) is necessary to obtain final derivatives with enantiomeric excess (ee) of more than 97%.

[0065] Also an embodiment of the present invention is a process for preparing a compound of formula (I) as defined above which comprises the reaction of a compound of formula (III) with a compound of formula (IV) in a solvent, particularly an alcohol such as butan-1-ol, at a temperature between room temperature and the reflux of the solvent, particularly the reflux temperature of the solvent. [ka] (In the formula, R 1 , R 2 , R 3 , R 4 and X 5 is as defined herein)

[0066] Also an object of the present invention are the compounds of formula (I), more particularly the compounds of formula (I) as described herein, for use as therapeutically active substances.

[0067] Likewise an object of the present invention is a pharmaceutical composition comprising a compound of formula (I), more particularly a compound of formula (I) as described herein, and a therapeutically inert carrier.

[0068] A particular embodiment of the present invention is a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof for use in the treatment or prophylaxis, more particularly for use in 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, more particularly negative and / or cognitive symptoms associated with Autism Spectrum Disorder (ASD), Angelman syndrome, Alzheimer's disease, schizophrenia and Post-Traumatic Stress Disorder (PTSD).

[0069] The present invention also relates to the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof as described herein, more particularly a compound of formula (I), for the preparation of a medicament for treating or preventing, more particularly for treating, negative and / or cognitive symptoms associated with Alzheimer's disease, mild cognitive impairment (MCI), age-associated cognitive decline, schizophrenia, bipolar disorder, autism spectrum disorder (MCIASD), Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), Fragile X disorder, more particularly autism spectrum disorder (ASD), Angelman syndrome, Alzheimer's disease, schizophrenia and post-traumatic stress disorder (PTSD).

[0070] An object of the present invention is also a method for the treatment or prevention, more particularly the treatment, of Alzheimer's disease, mild cognitive impairment (MCI), age-related cognitive decline, schizophrenia, bipolar disorder, autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, Preder-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), comprising administering an effective amount of a compound of formula (I) as described herein, more particularly a compound of formula (I).

[0071] Also, one embodiment of the present invention is a compound of formula (I), more particularly a compound of formula (I) as described herein, when prepared according to any one of the processes described.

[0072] Assay procedure γ1-containing GABA A Membrane preparation and binding assays for subtypes GABA A The affinity of compounds for γ1 subunit-containing receptors was determined by measuring the [ 3 For better protein expression of α2 subunit-containing receptors, human GABA receptor agonists were used. A The 28 amino acid long signal peptide (Met1~Ala28) of the γ2 subunit is expressed in human GABA A It was replaced with a 31 amino acid long signal peptide (Met1~Ser31) of the α5 subunit.

[0073] Various GABA APellets collected from HEK293F cells expressing receptor subtypes were resuspended in mannitol buffer pH 7.2-7.4 (mannitol 0.29 M, triethylamine 10 mM, acetic acid 10 mM, 1 mM EDTA + protease inhibitors (20 tablets Complete, Roche Diagnostics catalogue. No. 05 056 489 001 per liter)), washed twice and then resuspended at a dilution of 1:10-1:15 in the same buffer. Cell disruption was performed by agitating the suspension for 15 min at 435 psi in a Parr vessel #4637, then the suspension was centrifuged at 1000xg for 15 min at 4 °C (Beckman Avanti J-HC; rotor JS-4.2). The supernatant (S1) was transferred to a 2 l Schott flask and the pellet (P1) was resuspended to 175 ml with mannitol buffer. The resuspended pellet was transferred to a 250 ml Corning centrifuge beaker and centrifuged at 1500xg for 10 min at 4°C (Beckman Avanti J-HC; rotor JS-4.2). The supernatant (S1) was then transferred to a 2 liter Schott flask and the pellet was discarded. The supernatant (S1) was centrifuged at 15,000xg for 30 min at 4°C in a 500 ml Beckman polypropylene centrifuge beaker (Beckman Avanti J-20 XP; rotor JLA-10.500). The pellet (P2) was resuspended 1:1 in mannitol buffer and frozen at -80°C. The supernatant (S2) was centrifuged at 48000xg for 50 min at 4°C in a 100 ml Beckman polypropylene centrifuge tube (Beckman Avanti J-20 XP; rotor JA-18). The supernatant (S3) was discarded and the pellet (P3) was resuspended 1:1 in mannitol buffer. Protein concentrations of P2 and P3 were determined using the BIORAD Standard assay method with bovine serum albumin as standard and measured on a NANO-Drop 1000. Aliquots of the membrane suspension were transferred to tubes (500 μl / tube) and stored at −80° C. until required.

[0074] Membrane homogenates were resuspended and polytronized (Polytron PT1200 E Kinematica AG) in 10 mM potassium phosphate, 100 mM KCl binding buffer, pH 7.4, to final assay concentrations determined in previous experiments.

[0075] Radioligand binding assays were performed using 100 μL of cell membranes and 1.5 nM (α5β2γ1) or 20–30 nM (α1β2γ1, α2β2γ1) concentrations of [ 3 H]RO7239181, and [0.3–10000] × 10 -9 The assay was performed in a volume of 200 μL (96-well plate) containing test compounds in the range of M. Non-specific binding was determined to be 10×10 -6 (α5β2γ1) and 30×10 -6 The binding was defined by MRO7235136 and typically represented less than 5% (α5β2γ1) and 20% (α1β2γ1,α2β2γ1) of the total binding. Assays were incubated at 4°C for 1 h to equilibrium, then membranes were filtered onto 96-well white microplates with GF / C filters preincubated for 20-50 min in Unifil (0.3% polyethyleneimine) using a Filtermate 196 harvester (Packard BioScience) and washed four times with cold potassium phosphate 10 mM pH 7.4, KCl 100 mM binding buffer. After drying, radioactivity retained on the filters was detected by liquid scintillation counting. K i Values ​​were calculated using Excel-Fit (Microsoft) and are the average of duplicate determinations.

[0076] The compounds of the accompanying examples were tested in the above assay and preferred compounds were A [From γ1 subunit-containing receptors (e.g., α5β2γ1, α2β2γ1, α1β2γ1) 3 K of 100 nM or less for displacement of H]RO7239181 iCompounds with a Ki (nM) of <50 are most preferred. Representative test results obtained by the above assay measuring binding affinity to HEK293 cells expressing the human (h) receptor are shown in Table 1.

[0077] [3 H ]RO723918 Preparation of 1,6-chloro-5-(2,6-difluorophenyl)-7-methyl-1-(tritrithiomethyl)-3H-1,4-benzodiazepin-2-one [ka]

[0078] a) 6-chloro-5-(2,6-difluorophenyl)-7-methyl-1,3-dihydro-1,4-benzodiazepin-2-one A microwave tube was charged with 7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (Building Block A (see below), 450 mg, 1.17 mmol), trimethylboroxine (205 mg, 228 μL, 1.63 mmol), potassium carbonate (242 mg, 1.75 mmol) and tetrakis(triphenylphosphine)palladium(0) (67.4 mg, 58.4 μmol). Degassed 1,4-dioxane (8.1 mL) and H2O (2.7 ml) were added and the vial was then capped. The suspension was reacted in a microwave at 130 °C for 30 min to achieve complete conversion. The mixture was evaporated, treated with saturated NaHCO3 solution (20 ml) and extracted with EtOAc (2 x 20 mL). The organic layer was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, 40 g, eluted with CH2Cl2 / EtOAc in heptane 10% to 40% to 70%) to give the title compound (344 mg, 92%) as a pale yellow solid. MS (ESI): 321.1 ([M+H] + ).

[0079] b) 6-chloro-5-(2,6-difluorophenyl)-7-methyl-1-(tritrithiomethyl)-3H-1,4-benzodiazepin-2-one [ in THF (200 μL) 3 To a solution of [H]methyl nosylate (1.85 GBq, 50 mCi, 0.61 μmol) was added the N-desmethyl precursor 6-chloro-5-(2,6-difluorophenyl)-7-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (0.43 mg, 1.34 μmol) dissolved in THF (200 μL) and 10 equivalents of sodium tert-butylate (0.5 m in THF, 13.4 μmol). After stirring at room temperature for 4 h, the reaction mixture was treated with HO, evaporated, and the crude product was purified by HPLC (X-Terra Prep RP-18, 10 × 150 mm, MeCN / HO (containing 5% MeCN) 40:60, 4 ml / min, 230 nm). The pure tritium-labeled compound was isolated by solid-phase extraction (Sep-Pak Plus C18) and eluted from the cartridge as an ethanol solution, yielding 1.6 GBq (43.2 mCi) of target compound in >99% radiochemical purity with a specific activity of 2.49 TBq / mmol (67.3 Ci / mmol) as determined by mass spectrometry (MS). The identity of the labeled compound was confirmed by HPLC (by co-injecting an unlabeled reference standard) and MS.

[0080] MS: m / z=335 [M(H)+H] + (16%), 337 [M( 3 H)+H] + (0%), 339[M( 3 H2)+H] + (16%), 341 [M( 3 H3)+H] + (68%).

[0081] γ2-containing GABA A Membrane preparation and binding assays for subtypes GABA A The affinity of compounds at γ2 subunit-containing receptors was determined by their affinity to HEK293F cells expressing human (transiently transfected) receptors of the composition α1β3γ2.3 H]flumazenil (81.1 Ci / mmol; Roche) binding was measured by competition.

[0082] Various GABA A Pellets collected from HEK293F cells expressing the γ2 receptor subtype were resuspended in mannitol buffer pH 7.2-7.4 and incubated with GABA. A Cells expressing γ1 subunit-containing receptors were treated as above.

[0083] Radioligand binding assays were performed using 100 μL of cell membranes and 1 nM of [ 3 H]flumazenil and 0.1 × 10 -9 ~30×10 -6 The assay was performed in a volume of 200 μL (96-well plate) containing test compounds in the range of M. Non-specific binding was determined by 10 -5 The binding was defined by M diazepam and was usually less than 5% of the total binding. Assays were incubated at equilibrium for 1 h at 4°C and harvested onto GF / C unifilters (Packard) by filtration using a Packard harvester and 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 average of duplicate determinations.

[0084] 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 greater. A [From the α1β3γ2 subtype of receptor 3 H] Flumazenil Substitution i The value was found to be large. i Most preferred are compounds with α1β3γ2 (nM) >300. In a preferred embodiment, the compounds of the present invention are γ2 subunit-containing GABA receptor antagonists. A γ1 subunit-containing GABA receptors A In particular, the compounds of the present invention have a binding selectivity to the receptor that is greater than 10-fold higher than the iα1β3γ2(nM) / K i Selectivity ratio of γ2 / γ1 defined as “α2β2γ1 (nM)” or “Log[K i α1β3γ2(nM) / K i Representative test results obtained by the above assay measuring binding affinity to HEK293 cells expressing the human (h) receptor with LogSel defined as "α2β2γ1 (nM)" are shown in Table 1 below.

[0085] [Table 1] TIFF0007648645000009.tif241165 TIFF0007648645000010.tif87165

[0086] GABA A Receptor Functional Expression: 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, Kastrup-Rauxel, Germany, and kept at 20°C in modified Barth's medium (composition in mM: NaCl 88, KCl 1, NaHCO3 2.4, HEPES 10, MgSO4 0.82, CaNO3 0.33, CaCl2 0.33, pH = 7.5) until the experiment.

[0087] Xenopus oocyte microinjection Oocytes were plated in 96-well plates for microinjection using the Roboinject automated device (MultiChannelSystems, Reutlingen, Germany). AApproximately 50 nL of an aqueous solution containing RNA transcripts of the subunits of the receptor subtypes was injected into each oocyte. RNA concentrations ranged between 20 pg / μL / subunit and 200 pg / μL / subunit and were adjusted in pilot experiments to obtain the GABA A GABA responses of appropriate size and maximal effect were obtained for the reference benzodiazepine positive allosteric modulators (PAMs) flunitrazepam, triazolam and midazolam at the receptor benzodiazepine (BZD) binding site. Oocytes were kept at 20°C in modified Barth's medium (composition in mM: NaCl 88, KCl 1, NaHCO3 4, HEPES 10, MgSO4 0.82, CaNO3 0.33, CaCl2 0.33, pH = 7.5) until the experiment.

[0088] Electrophysiology Electrophysiological experiments were performed 3–5 days after microinjection of mRNA using a Robocyte apparatus (MultiChannelSystems, Reutlingen, Germany). During the experiments, oocytes were always superfused in a solution containing (in mM): NaCl 90, KCl 1, HEPES 5, MgCl2 1, CaCl2 1 (pH 7.4). Oocytes were filled with a solution containing KCl 1 M + K-acetate 1.5 M and impinged with two glass microelectrodes (resistance: 0.5–0.8 MΩ) voltage-clamped at -80 mV. Recordings were performed at room temperature using a Robocyte two-electrode voltage-clamp system (Multichannelsystem). After an initial equilibration period of 1.5 min GABA, the maximum current response (EC 20 ) was added for 1.5 min at a concentration evocative of approximately 20% of the K. After another rest interval of 2.5 min, GABA was added again, eliciting responses of similar amplitude and shape. 0.5 min after the start of this second GABA application, while GABA was still present, the K i Test compounds were added at a concentration approximately 30-fold greater than that of α2β2γ1. Current traces were recorded at a digitization rate of 10 Hz before, during and after GABA application.

[0089] Each compound and concentration was tested in at least three oocytes. Different oocytes were used for different compound concentrations. The reference PAMs, flunitrazepam, triazolam and midazolam, inhibited α2β2γ1 GABA receptor-expressing oocytes. A It enhanced GABA-induced currents at the receptor subtype by approximately 60%.

[0090] 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 during the time interval of the test compound experiment was calculated point-by-point. The extremes of the resulting "ratio traces" were designated as "GABA EC 20 The efficacy of the compound was taken as "fold increase" expressed as "% modulation of the agonist activity" (100*(fold increase-1)).

[0091] The results are shown in Table 2. [Table 2] TIFF0007648645000012.tif216165

[0092] (Reference compound) The reference compounds listed below (classical commercial benzodiazepines) and their structural analogs also A Receptor α1β2γ1 and α2β2γ1 subtypes and GABA A The affinity to the α1β3γ2 receptor subtype was tested, and the results are shown in Table 3. [ka]

[0093] [Table 3]

[0094] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicines (e.g., in the form of pharmaceutical preparations). The pharmaceutical preparations of the present invention can be administered internally, such as orally (e.g., in the form of tablets, coated tablets, sugar-coated tablets, hard and 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 polymeric inserts). However, administration can also be carried out parenterally, such as intramuscularly, intravenously, or intraocularly (e.g., in the form of sterile injectable solutions).

[0095] The compound of formula (I) and its pharma- ceutically acceptable salts can be processed with pharma- ceutically inert, inorganic or organic adjuvants for the preparation of tablets, coated tablets, doraz, 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, doraz and hard gelatin capsules.

[0096] Suitable adjuvants for soft gelatine capsules include, by way of example, vegetable oils, waxes, fats, semisolids, liquid polyols, etc.

[0097] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.

[0098] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like.

[0099] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols etc.

[0100] Suitable adjuvants for topical ophthalmic formulations are, by way of example, cyclodextrin, mannitol, or many other carriers and excipients known in the art.

[0101] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying osmotic pressure, buffers, masking agents, or antioxidants, and may also contain other therapeutically valuable substances.

[0102] The dosage can vary widely and will of course be adapted to the individual requirements in each particular case. In general, for oral administration, the daily dose is about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (e.g. about 300 mg per person), preferably administered separately in 1 to 3 doses, which may, if appropriate, be composed of the same amount, for example. For topical administration, the preparation may contain 0.001% to 15% by weight of the medicament, and the required amount, which may be between 0.1 and 25 mg, may be a single dose per day, a single dose per week, multiple doses per day (2 to 4 times), or multiple doses per week. However, it is clear that, where this is indicated, the upper or lower limits described herein may be exceeded.

[0103] Preparation of pharmaceutical compositions comprising the compounds of the present invention Tablets of the following composition are prepared in the usual manner: [Table 4]

[0104] 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 and mix for 3 minutes, then compress using a suitable press.

[0105] A capsule formulation is prepared having the following composition: [Table 5]

[0106] 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.

[0107] The compound of formula I, lactose and cornstarch are mixed in a mixer, then in a grinder. The mixture is returned to the mixer, talc is added thereto and mixed thoroughly. The mixture is filled into a suitable capsule, such as a hard gelatin capsule, by machine.

[0108] An injection solution having the following composition is prepared. [Table 6]

[0109] The present invention will be described below with reference to examples, but the present invention is not limited to these.

[0110] Where preparative examples are obtained as mixtures of enantiomers, the pure enantiomers can be obtained by methods described herein or known to those skilled in the art, such as chiral chromatography or crystallization.

[0111] Working Example Component A 7-Bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0112] a) 5-chloro-2-methyl-3,1-benzoxazin-4-one A solution of 2-amino-6-chlorobenzoic acid (250 g, 1.46 mol) in acetic anhydride (1250 mL) was stirred at 140° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The crude residue obtained was suspended in ethyl acetate (1000 mL), stirred for 30 min, filtered, and dried under reduced pressure to give the title compound (238 g, 84%) as a grey solid. 1 H NMR (DMSO-d6,400 MHz): δ:7.80(app t,J=8.0 Hz,1H),7.62(d,J=8.0 Hz,1H),7.49(d,J=7.6 Hz,1H),2.36(s,3H).

[0113] b) N-[3-chloro-2-(2,6-difluorobenzoyl)phenyl]acetamide To a solution of 5-chloro-2-methyl-3,1-benzoxazin-4-one (100 g, 511.2 mmol) and 2-bromo-1,3-difluorobenzene (118.4 g, 613.5 mmol) in tetrahydrofuran (1000 mL) was added i-PrMgCl·LiCl (1.3 m, 500 mL, 650 mmol) dropwise at −70 °C under nitrogen. The mixture was allowed to warm to room temperature within 1 h, quenched with saturated aqueous ammonium chloride (1500 mL) and extracted with ethyl acetate (2×1500 mL). The organic phase was washed with brine (2000 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was suspended in ethyl acetate (150 mL). The resulting suspension was stirred at room temperature for 20 min, filtered and dried under reduced pressure to give the title compound (113 g, 71%) as an off-white solid. 1 H NMR (DMSO-d6,400 MHz): δ:9.85(s,1H),7.65-7.45(m,1H),7.40(t,J=7.2 Hz,1H),7.38-7.34(m,2H),7.16(t,J=8.8 Hz,2H),1.85(s,3H).

[0114] c) (2-amino-6-chloro-phenyl)-(2,6-difluorophenyl)methanone To a solution of N-[3-chloro-2-(2,6-difluorobenzoyl)phenyl]acetamide (113 g, 364.9 mmol) in ethanol (250 mL) was added aqueous hydrochloric acid (12 m, 200 mL). The reaction mixture was stirred at 100° C. for 1 h and then diluted with ethyl acetate (1100 mL). The organic phase was washed with water (1100 mL), saturated aqueous sodium bicarbonate (1100 mL) and brine (1100 mL), dried over sodium sulfate and concentrated under reduced pressure. Petroleum ether (120 mL) was added to the crude product and the suspension was stirred at room temperature for 20 min. The solid was filtered and dried to give the title compound (88 g, 90%) as a yellow solid. 1 H NMR (DMSO-d6,400 MHz): δ:7.62-7.56(m,1H),7.21-7.15(m,3H),6.83(d,J=7.6 Hz,1H),6.74(s,2H),6.58(d,J=7.6 Hz,1H).

[0115] d) (6-amino-3-bromo-2-chloro-phenyl)-(2,6-difluorophenyl)methanone To a solution of (2-amino-6-chloro-phenyl)-(2,6-difluorophenyl)methanone (88.0 g, 328.8 mmol) in dichloromethane (225 mL) and N,N-dimethylformamide (225 mL) was added 1-bromopyrrolidine-2,5-dione (64.4 g, 362 mmol) at 0 °C. The reaction mixture was stirred at 30 °C for 1 h. The mixture was diluted with dichloromethane (600 mL), washed with water (500 mL) and brine (4 x 500 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate, 1:0 to 2:1). The solid was suspended in petroleum ether (200 mL) and stirred at room temperature for 20 min. The suspension was filtered and the solid was dried under reduced pressure to give the title compound (96.0 g, 84%) as a yellow solid. MS: 345.9 ([{ 79 Br, 35 Cl}M+H] + ),347.8([{ 81 Br, 35 Cl or 79 Br,37 Cl}M+H] + ),ESI pos.

[0116] e) 7-Bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one To a solution of (6-amino-3-bromo-2-chloro-phenyl)-(2,6-difluorophenyl)methanone (25.0 g, 72.1 mmol) in pyridine (625 mL) was added ethyl 2-aminoacetate hydrochloride (70.5 g, 505 mmol). The reaction mixture was stirred at 135° C. for 36 h. The reaction mixture was concentrated under reduced pressure to remove pyridine. The residue was diluted with ethyl acetate (2000 mL), washed with HCl (1.0 m, 3×1500 mL), water (2000 mL) and brine (2×1000 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica, petroleum ether / ethyl acetate 10:1 to 2:1) to give the title compound (10.1 g, 12%) as an off-white solid. MS: 385.0 ([{ 79 Br, 35 Cl}M+H] + ),ESI pos.

[0117] Component B 7-Bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0118] a) N-[3-chloro-2-(2-fluorobenzoyl)phenyl]acetamide To a solution of 5-chloro-2-methyl-3,1-benzoxazin-4-one (20.0 g, 102.3 mmol) and 1-bromo-2-fluorobenzene (17.9 g, 102.3 mmol) in tetrahydrofuran (600 mL) was added n-BuLi in tetrahydrofuran (2.5 m, 49 mL, 123 mmol) dropwise at -70 °C. The reaction mixture was stirred at -60 °C for 1 h and then quenched with aqueous ammonium chloride (200 mL). The aqueous layer was extracted with tetrahydrofuran (2 x 250 mL) and ethyl acetate (2 x 250 mL). The combined organic phases were washed with brine (200 mL), dried over sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (silica, petroleum ether / ethyl acetate 20:1 to 3:1) afforded the title compound (21 g, 70%) as a white solid. MS: 292.3 ([M+H] + ),ESI pos.

[0119] b) (2-amino-6-chloro-phenyl)-(2-fluorophenyl)methanone Similarly to the experiment for building block Ac, N-[3-chloro-2-(2-fluorobenzoyl)phenyl]acetamide was converted to the title compound (10 g, 58%) as a yellow solid. MS: 250.1 ([M+H] + ),ESI pos.

[0120] c) (6-amino-3-bromo-2-chloro-phenyl)-(2-fluorophenyl)methanone Analogously to the experiment for building block Ad, (2-amino-6-chloro-phenyl)-(2-fluorophenyl)methanone was converted to the title compound (32.4 g, 70%) as a yellow solid. MS: 327.9 ([{ 79 Br, 35 Cl}M+H] + ),330.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0121] d) 7-Bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one To a solution of (6-amino-3-bromo-2-chloro-phenyl)-(2-fluorophenyl)methanone (35.0 g, 98.3 mmol) in pyridine (210 mL) was added ethyl 2-aminoacetate hydrochloride (96.0 g, 688 mmol) at 90° C. The reaction mixture was stirred at 110° C. for 16 h. The reaction mixture was cooled to room temperature and most of the pyridine was removed under reduced pressure. The residue was diluted with ethyl acetate (1250 mL). The organic phase was washed with aqueous HCl (1.0 m, 1250 mL), water (500 mL) and brine (1000 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica, petroleum ether / ethyl acetate, 1:0, 25:1, 1:1). The product was dissolved in ethyl acetate (15 mL). Petroleum ether (45 mL) was added dropwise to give a white slurry. The solid was collected by filtration and dried under reduced pressure to give the title compound (30.4 g, 39%) as an off-white solid. MS: 367.0 ([{ 79 Br, 35 Cl}M+H] + ),368.9([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0122] Component G (rac)-7-Bromo-6-chloro-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0123] a) (rac)-tert-Butyl N-[2-[4-bromo-3-chloro-2-(2-fluorobenzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamate To a solution of (6-amino-3-bromo-2-chloro-phenyl)-(2-fluorophenyl)methanone (2.0 g, 6.09 mmol) and 2-(tert-butoxycarbonylamino)propanoic acid (1.73 g, 9.13 mmol) in pyridine (20 mL) was added phosphoryl chloride (1.22 g, 7.98 mmol) slowly at -5°C. The reaction mixture was stirred at -5°C for 1 h, then slowly poured into water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic phase was washed with brine (2 x 50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate 5:1) to give the title compound (2.95 g, 97%) as a yellow solid. MS: 399.1 ([{ 79 Br, 35 Cl}M-C4H8-CO2+H] + ), 401.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M-C4H8-CO2+H] + ),ESI pos.

[0124] b) (rac)-2-amino-N-[4-bromo-3-chloro-2-(2-fluorobenzoyl)phenyl]propanamide To a solution of (rac)-tert-butyl N-[2-[4-bromo-3-chloro-2-(2-fluorobenzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamate (2.9 g, 5.8 mmol) in dichloromethane (14.5 mL) was slowly added hydrochloric acid (4.0 m in dioxane, 14.5 mL, 58.0 mmol). The reaction mixture was stirred at 25 °C for 2 h. Saturated aqueous sodium bicarbonate was slowly added until pH > 8, and then the mixture was extracted with dichloromethane (3 x 100 mL). The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (2.2 g, 92%) as a yellow oil. MS: 399.0 ([{ 79 Br, 35 Cl}M+H] + ), 401.0([{ 81Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0125] c) (rac)-7-Bromo-6-chloro-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one To a solution of (rac)-2-amino-N-[4-bromo-3-chloro-2-(2-fluorobenzoyl)phenyl]propanamide (2.2 g, 5.5 mmol) in ethanol (20 mL) was added acetic acid (4 mL). The reaction mixture was stirred at 80 °C for 16 h and then concentrated under reduced pressure. The formed crystals were filtered and purified by trituration with ethyl acetate (15 mL), then collected by filtration and dried under reduced pressure to give the title compound (1.6 g, 76%) as a yellow solid. MS: 381.0 ([{ 79 Br, 35 Cl}M+H] + ),383.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0126] Component L (3S)-7-Bromo-6-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0127] a) tert-Butyl N-[(1S)-2-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)anilino]-1-methyl-2-oxoethyl]carbamate As in the experiment for building block Ga, (6-amino-3-bromo-2-chloro-phenyl)-(2,6-difluorophenyl)methanone was converted to the title compound (1.50 g, 98%) using (2S)-2-(tert-butoxycarbonylamino)propanoic acid, which was obtained as a yellow solid. MS: 418.7 ([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M-C4H8-CO2+H] + ),540.7([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+Na] + ),ESI pos.

[0128] b) (2S)-2-amino-N-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]propanamide Analogously to the experiment for building block Gb, tert-butyl N-[(1S)-2-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)anilino]-1-methyl-2-oxoethyl]carbamate was converted to the title compound (1.1 g, 94%) as a yellow oil which was used directly in the next step without further characterization.

[0129] c) (3S)-7-Bromo-6-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one To a solution of (2S)-2-amino-N-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]propanamide (960 mg, 2.30 mmol) in toluene (9.19 mL) was added silica (138 mg, 2.30 mmol). The reaction mixture was stirred at 90° C. for 15 h and then concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate 3:1) to give the title compound (920 mg, 95%) as a yellow solid. MS: 399.1 ([{ 79 Br, 35 Cl}M+H] +), 401.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0130] Component M (3S)-6,7-Dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0131] a) tert-Butyl N-[(1S)-2-[3,4-dichloro-2-(2,6-difluorobenzoyl)anilino]-1-methyl-2-oxoethyl]carbamate As in the experiment for building block Ga, (2S)-2-(tert-butoxycarbonylamino)propanoic acid was used to convert (6-amino-2,3-dichloro-phenyl)-(2,6-difluorophenyl)methanone to the title compound (5.0 g, 64%) as a yellow foam. The crude product was used directly in the next step without further characterization.

[0132] b) (2S)-2-amino-N-[3,4-dichloro-2-(2,6-difluorobenzoyl)phenyl]propanamide Analogously to the experiment for building block Gb, tert-butyl N-[(1S)-2-[3,4-dichloro-2-(2,6-difluorobenzoyl)anilino]-1-methyl-2-oxoethyl]carbamate was converted to the title compound (3.6 g, 91%) as a yellow oil. MS: 373.0 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0133] c) (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Lc, (2S)-2-amino-N-[3,4-dichloro-2-(2,6-difluorobenzoyl)phenyl]propanamide was converted to the title compound (3.20 g, 93%), which was obtained as a yellow foam. MS: 355.0 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0134] Component O (3S)-6,7-Dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0135] a) tert-Butyl N-[(1S)-2-[3,4-dichloro-2-(3-fluoropyridine-2-carbonyl)anilino]-1-methyl-2-oxoethyl]carbamate As in the experiment for building block Ga, (2S)-2-(tert-butoxycarbonylamino)propanoic acid was used to convert N-[3,4-dichloro-2-(3-fluoropyridine-2-carbonyl)phenyl]acetamide to the title compound (8.6 g, 67%) as a white solid. MS: 456.0 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0136] b) (2S)-2-amino-N-[3,4-dichloro-2-(3-fluoropyridine-2-carbonyl)phenyl]propanamide Analogously to the experiment for building block Gb, tert-butyl N-[(1S)-2-[3,4-dichloro-2-(3-fluoropyridine-2-carbonyl)anilino]-1-methyl-2-oxoethyl]carbamate was converted to the title compound (6.6 g, 100%) as a yellow solid. MS: 356.0 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0137] c) (3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Lc, (2S)-2-amino-N-[3,4-dichloro-2-(3-fluoropyridine-2-carbonyl)phenyl]propanamide was converted to the title compound (5.5 g, 88%) as a yellow solid. MS: 338.0 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0138] Component Q (3S)-6-Bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0139] a) N-[3-bromo-4-chloro-2-(2,6-difluorobenzoyl)phenyl]acetamide As in the experiment for component Ad, 1-chloropyrrolidine-2,5-dione was used, and N-(3-bromo-2-(2,6-difluorobenzoyl)phenyl)acetamide was used. The title compound (10.1 g, 70%) was obtained as a pale yellow solid. MS: 388.0 ([{ 79 Br, 35 Cl}M+H] + ),390.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0140] b) (6-amino-2-bromo-3-chloro-phenyl)-(2,6-difluorophenyl)methanone As in the experiment for building block Ac, N-[3-bromo-4-chloro-2-(2,6-difluorobenzoyl)phenyl]acetamide was converted to the title compound (8.2 g, 92%) as a yellow solid. MS: 346.0 ([{ 79 Br, 35 Cl}M+H] + ),348.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0141] c) tert-Butyl N-[(1S)-2-[3-bromo-4-chloro-2-(2,6-difluorobenzoyl)anilino]-1-methyl-2-oxoethyl]carbamate As in the experiment for building block Ga, (6-amino-2-bromo-3-chloro-phenyl)-(2,6-difluorophenyl)methanone was converted to the title compound (8.64 g, 69%) using (2S)-2-(tert-butoxycarbonylamino)propanoic acid as a yellow solid. MS: 515.2 ([{ 79 Br, 35 Cl}MH] - ),517.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}MH] - ),ESI neg.

[0142] d) (2S)-2-amino-N-[3-bromo-4-chloro-2-(2,6-difluorobenzoyl)phenyl]propanamide Analogously to the experiment for building block Gb, tert-butyl N-[(1S)-2-[3-bromo-4-chloro-2-(2,6-difluorobenzoyl)anilino]-1-methyl-2-oxoethyl]carbamate was converted to the title compound (6.27 g, 90%) as a light brown oil. MS: 417.1 ([{ 79 Br, 35 Cl}M+H] + ),419.0([{ 81 Br,35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0143] e) (3S)-6-Bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Lc, (2S)-2-amino-N-[3-bromo-4-chloro-2-(2,6-difluorobenzoyl)phenyl]propanamide was converted to the title compound (3.98 g, 68%) as a yellow solid. MS: 399.1 ([{ 79 Br, 35 Cl}M+H] + ), 401.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0144] Component R (3S)-7-Bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0145] a) tert-Butyl N-[(1S)-2-[4-bromo-3-chloro-2-(3-fluoropyridine-2-carbonyl)anilino]-1-methyl-2-oxo-ethyl]carbamate As in the experiment for building block Ga, (2S)-2-(tert-butoxycarbonylamino)propanoic acid was used to convert (6-amino-3-bromo-2-chloro-phenyl)-(3-fluoro-2-pyridyl)methanone to the title compound (1.4 g, 97%) as a yellow foam. The crude product was used directly in the next step without further characterization.

[0146] b) (2S)-2-amino-N-[4-bromo-3-chloro-2-(3-fluoropyridine-2-carbonyl)phenyl]propanamide As in the experiment for building block Gb, tert-butyl N-[(1S)-2-[4-bromo-3-chloro-2-(3-fluoropyridine-2-carbonyl)anilino]-1-methyl-2-oxo-ethyl]carbamate was converted to the title compound (1.1 g, 98%) as a yellow oil. The crude product was used directly in the next step without further characterization.

[0147] c) (3S)-7-Bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Lc, (2S)-2-amino-N-[4-bromo-3-chloro-2-(3-fluoropyridine-2-carbonyl)phenyl]propanamide was converted to the title compound (430 mg, 40%) as a yellow solid. MS: 381.9 ([{ 79 Br, 35 Cl}M+H] + ),383.9([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0148] Component S (3S)-6-Chloro-5-(2,6-difluorophenyl)-7-iodo-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0149] a) tert-Butyl N-[(1S)-2-[3-chloro-2-(2,6-difluorobenzoyl)-4-iodo-anilino]-1-methyl-2-oxoethyl]carbamate As in the experiment for building block Ga, (6-amino-2-chloro-3-iodo-phenyl)-(2,6-difluorophenyl)methanone was converted to the title compound (5.8 g, 81%) using (2S)-2-(tert-butoxycarbonylamino)propanoic acid as a yellow solid. MS: 465.0 ([M-C4H8-CO2+H] + ),509.0([M-C4H8+H] + ),ESI pos.

[0150] b) (2S)-2-amino-N-[3-chloro-2-(2,6-difluorobenzoyl)-4-iodo-phenyl]propanamide As in the experiment for building block Gb, tert-butyl N-[(1S)-2-[3-chloro-2-(2,6-difluorobenzoyl)-4-iodo-anilino]-1-methyl-2-oxoethyl]carbamate was converted to the title compound (4.7 g, 99%) as a yellow solid. The crude product was used directly in the next step without further characterization.

[0151] c) (3S)-6-chloro-5-(2,6-difluorophenyl)-7-iodo-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Lc, (2S)-2-amino-N-[3-chloro-2-(2,6-difluorobenzoyl)-4-iodo-phenyl]propanamide was converted to the title compound (3.8 g, 94%) as a yellow solid. MS: 446.8 ([M+H] + ),ESI pos.

[0152] Component T (3S)-7-Bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0153] a) tert-Butyl N-[(1S)-1-[[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]carbamoyl]propyl]carbamate

[0154] As in the experiment for building block Ga, (6-amino-3-bromo-2-chloro-phenyl)-(2,6-difluorophenyl)methanone was converted to the title compound (1.08 g, 68%) using (2S)-2-(tert-butoxycarbonylamino)butanoic acid as a yellow solid. MS: 433.1 ([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M-C4H8-CO2+H] + ),477.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M-C4H8+H] + ),ESI pos.

[0155] b) (2S)-2-amino-N-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]butanamide As in the experiment for building block Gb, tert-butyl N-[(1S)-1-[[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]carbamoyl]propyl]carbamate was converted to the title compound (730 mg, 90%) as a yellow oil. MS: 433.0 ([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0156] c) (3S)-7-Bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Lc, (2S)-2-amino-N-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]butanamide was converted to the title compound (650 mg, 97%) as a light brown foam. MS: 414.9 ([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0157] component U (3S)-7-Bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl)-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0158] a) tert-Butyl N-[(1S)-2-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)anilino]-1-(methoxymethyl)-2-oxoethyl]carbamate As in the experiment for building block Ga, (2S)-2-(tert-butoxycarbonylamino)-3-methoxy-propanoic acid was used to convert (6-amino-3-bromo-2-chloro-phenyl)-(2,6-difluorophenyl)methanone to the title compound (4.3 g, 85%) as a yellow solid. The crude product was used directly in the next step without further characterization.

[0159] b) (2S)-2-amino-N-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]-3-methoxy-propanamide As in the experiment for building block Gb, tert-butyl N-[(1S)-2-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)anilino]-1-(methoxymethyl)-2-oxoethyl]carbamate was converted to the title compound (3.0 g, 96%) as a yellow oil. MS: 447.0 ([{ 79 Br, 35Cl}M+H] + ),449.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0160] c) (3S)-7-Bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl)-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Lc, (2S)-2-amino-N-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]-3-methoxy-propanamide was converted to the title compound (1.9 g, 78%) as a white solid. The crude product was used directly in the next step without further characterization. MS: 429.1 ([{ 79 Br, 35 Cl}M+H] + ),431.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0161] Example 30 (4S)-8-Bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0162] a) (rac)-7-bromo-6-chloro-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione To a suspension of (rac)-7-bromo-6-chloro-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (Building G, 500 mg, 1.31 mmol) in toluene (8.33 mL) was added Lawesson's reagent (635 mg, 1.57 mmol) at room temperature. The reaction mixture was stirred at 110 °C for 1 h and then concentrated under reduced pressure. The crude material was purified by flash column chromatography (silica, 15-25% ethyl acetate in heptane) to give the title compound (820 mg, 91%) as a yellow solid. The crude product was used directly in the next step without further characterization.

[0163] b) (rac)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine To a solution of (rac)-7-bromo-6-chloro-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione (240 mg, 0.600 mmol) in butan-1-ol (3.2 mL) was added formohydrazide (108 mg, 1.81 mmol). The reaction mixture was stirred at 120° C. for 16 h. The mixture was diluted with dichloromethane (20 mL), washed with water (20 mL), brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA) to give the title compound (250 mg, 100%) as a white solid. MS: 404.8 ([{ 79 Br, 35 Cl}M+H] + ), 406.7([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0164] c) (4S)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (rac)-8-Bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (254 mg, 0.630 mmol) was purified by SFC (Chiralcel OJ-3, 0.05% diethylamine in methanol, 5-40%) The enantiopure (-)-(S)-title compound (88.1 mg) was obtained as a white solid. MS: 404.8 ([{ 79 Br, 35 Cl}M+H] + ),406.8([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos. The enantiopure (+)-(R)-title compound (80.4 mg) was obtained as a white solid. MS: 404.9 ([{ 79 Br, 35 Cl}M+H] + ),406.8([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0165] Example 31 8-Bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-ol [ka]

[0166] a) 7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione To a suspension of 7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (Building A, 6.7 g, 17.4 mmol) in toluene (167 mL) was added Lawesson's reagent (8.43 g, 20.9 mmol) at room temperature. The reaction mixture was stirred at 120 °C for 1.5 h and then diluted with ethyl acetate (400 mL). The organic layer was washed with water (300 mL) and brine (300 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (silica, 15-30% ethyl acetate in heptane) to give the title compound (6.98 g, 100%) as a yellow solid. MS: 400.8 ([{ 79 Br, 35 Cl}M+H] + ), 402.9([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0167] b) 8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine As in the experiment in Example 30b, 7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (2.4 g, 32%) using formohydrazide as a white solid. MS: 409.1 ([{ 79 Br, 35 Cl}M+H] + ),411.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0168] c) 8-Bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-ol

[0169] To a solution of sodium bis(trimethylsilyl)amide (1.0 m in tetrahydrofuran, 0.37 mL, 0.370 mmol) in tetrahydrofuran (5 mL) was added 8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (100.0 mg, 0.240 mmol) at −65° C. The mixture was stirred at −65° C. for 30 min, then 2-(benzenesulfonyl)-3-phenyl-oxaziridine (97 mg, 0.370 mmol) was added. The reaction mixture was stirred at −65° C. for 2 h before being quenched by the addition of saturated aqueous ammonium chloride. The aqueous phase was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (2×30 mL), filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (BostonPrime C 18, 0.1% trifluoroacetic acid in water / acetonitrile) followed by chiral HPLC (Daicel Chiralcel OJ-H, methanol) to give the title compound (30 mg, 29%) as a white solid. MS: 424.9 ([{ 79 Br, 35 Cl}M+H] + ),426.8([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0170] Example 32 (4S)-8-Bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0171] a) (rac)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine Using pyridazine-3-carbohydrazide in a similar manner to the experiment in Example 30b, (rac)-7-bromo-6-chloro-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (220 mg, 75%) as a white solid. MS: 482.9 ([{ 79 Br, 35 Cl}M+H] + ),484.8([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0172] b) (4S)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (rac)-8-Bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (220 mg, 0.450 mmol) was purified by SFC (Chiralcel OJ-3, 0.05% diethylamine in methanol, 5-40%) followed by lyophilization to give: The enantiopure (-)-(S)-title compound (64.3 mg) was obtained as a white solid. MS: 483.1 ([{ 79 Br, 35 Cl}M+H] + ),485.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos. The enantiopure (+)-(R)-title compound (61.4 mg) was obtained as a white solid. MS: 483.1 ([{79 Br, 35 Cl}M+H] + ),485.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0173] Example 35 8-Bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-ol [ka]

[0174] a) 7-bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione

[0175] In a similar manner to the experiment in Example 30a, 7-bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one was converted to the title compound (390 mg, 54%) as a yellow solid. The crude product was used directly in the next step without further characterization.

[0176] b) 8-bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine As in the experiment of Example 30b, 7-bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (294 mg, 73%) using pyridazine-3-carbohydrazide as a white solid. MS: 469.1 ([{ 79 Br, 35 Cl}M+H] + ),471.1([{ 81 Br, 35 Cl or 79 Br,37 Cl}M+H] + ),ESI pos.

[0177] c) [8-bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetate

[0178] To a solution of 8-bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (100 mg, 0.21 mmol) in acetic acid (2 mL) was added iodine (27 mg, 0.11 mmol), potassium acetate (42 mg, 0.43 mmol) and potassium persulfate (58 mg, 0.21 mmol). The reaction mixture was heated at 90° C. for 12 h and then quenched by the addition of saturated aqueous Na2SO3 (10 mL). The mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with water (10 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, dichloromethane / methanol 100:1 to 80:1) to give the title compound (55 mg, 49%) as a white solid. MS:526.9([{ 79 Br, 35 Cl}M+H] + ),528.9([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0179] d) 8-Bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-ol

[0180] To a solution of [8-bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetate (55 mg, 0.10 mmol) in ethanol (2.75 mL) was added sodium carbonate (22 mg, 0.21 mmol). The reaction mixture was stirred at room temperature for 4 h, then filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane / methanol) and then preparative HPLC (Shim-pack C18, 0.225% trifluoroacetic acid in water / acetonitrile) and lyophilized to give the title compound (13.1 mg, 26%) as a white solid. MS: 485.0 ([{ 79 Br, 35 Cl}M+H] + ),487.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0181] Example 51 (4S)-8-Bromo-7-chloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0182] a) (3S)-7-Bromo-6-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione In a similar manner to the experiment in Example 30a, (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (Building L) was converted to the title compound (410 mg, 96%) as a yellow solid. MS: 415.1 ([{ 79 Br, 35 Cl}M+H] + ),417.0([{ 81 Br,35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0183] b) (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

[0184] As in the experiment of Example 30b, (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted using formohydrazide to the (-)-enantiopure (S)-title compound (66 mg, 43%) after chiral purification, which was obtained as a white solid. MS: 423.0 ([{ 79 Br, 35 Cl}M+H] + ),425.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0185] Example 52 (4S)-7,8-Dichloro-6-(2,6-difluorophenyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0186] a) (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione

[0187] In a similar manner to experiment example 30a, (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (building block M) was converted to the title compound (4.2 g, 90%) as a yellow solid. The crude product was used directly in the next step without further characterization.

[0188] b) (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine As in the experiment of Example 30b, pyrimidine-4-carbohydrazide was used to convert (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione to the (-)-enantiopure (S)-title compound (71.6 mg, 31%) after chiral purification, which was obtained as a white solid. MS: 456.9 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0189] Example 53 (4S)-7,8-Dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0190] As in the experiment of Example 30b, 1-methylpyrazole-4-carbohydrazide was used to convert (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione to the (-)-enantiopure (S)-title compound (60.8 mg, 29%) after chiral purification, which was obtained as a white solid. MS: 459.1 ([{ 35 Cl, 35 Cl}M+H] +),ESI pos.

[0191] Example 56 (4S)-7,8-Dichloro-6-(2,6-difluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0192] As in the experiment of Example 30b, pyridazine-3-carbohydrazide was used to convert (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione to the (-)-enantiopure (S)-title compound (80.0 mg, 21%) after chiral purification, which was obtained as a white solid. MS: 457.0 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0193] Example 63 (4S)-7,8-Dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0194] a) (3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione In a manner similar to that of Example 30a, (3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (Building O) was converted to the title compound (2.56 g, 67%) as a pale yellow solid. MS: 354.0 ([{ 35 Cl, 35 Cl}M+H] +),ESI pos.

[0195] b) (4S)-7,8-dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine As in the experiment of Example 30b, (3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the (+)-enantiopure (S)-title compound (8.8 mg, 2%) after chiral purification, obtained as a white solid. MS: 440.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0196] Example 64 (4S)-7,8-Dichloro-6-(2,6-difluorophenyl)-4-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one [ka]

[0197] a) (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone

[0198] To a solution of (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione (400 mg, 1.08 mmol) in tetrahydrofuran (8.7 mL) at room temperature was added hydrazine monohydrate (109 mg, 104 μl, 2.15 mmol). The mixture was stirred at room temperature under argon for 2 hours. The suspension was concentrated under reduced pressure to give a pale yellow solid which was treated with methyl tert-butyl ether (2 mL) and diluted with pentane (4 mL). The mixture was scraped off to give a suspension which was stirred for 10 minutes. The solid was filtered, washed with pentane (2×3 mL) and dried under high vacuum to give the title compound (300 mg, 75%) which was obtained as a yellow solid. MS: 369.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0199] b) (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one

[0200] To a solution of (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone (250 mg, 0.68 mmol) in tetrahydrofuran (6 mL) was added 1,1'-carbonyldiimidazole (132 mg, 0.81 mmol) at room temperature. The reaction mixture was stirred at 70°C for 5 h and then concentrated under reduced pressure. The residue was purified by SFC (Chiralcel OJ-3, 0.05% diethylamine in methanol, 5-40%) to give the (-)-enantiopure (S)-title compound (141.2 mg, 53%), which was obtained as a white solid. MS: 395.1 ({ 35 Cl, 35 Cl}[M+H] + ),ESI pos.

[0201] Example 66 (4S)-7,8-Dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0202] As in the experiment of Example 30b, pyrimidine-4-carbohydrazide was used to convert (3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione to the (+)-enantiopure (S)-title compound (17 mg, 3%) after chiral purification, which was obtained as a white solid. MS: 440.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0203] Example 67 (4S)-7,8-Dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0204] As in the experiment of Example 30b, 1-methylpyrazole-4-carbohydrazide was used to convert (3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione to the (+)-enantiopure (S)-title compound (86 mg, 46%) after chiral purification, which was obtained as a white solid. MS: 442.2 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0205] Example 68 (4S)-7,8-Dichloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0206] As in the experiment of Example 30b, (3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the (+)-enantiopure (S)-title compound (123 mg, 21%) after chiral purification using cyclopropanecarbohydrazide, which was obtained as a white solid. MS: 402.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0207] Example 73 (4S)-7-Bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(pyridazin-3-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine [ka]

[0208] a) (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione In a similar manner to the experiment in Example 30a, (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (building block Q) was converted to the title compound (2.72 g, 77%) as a yellow powder. MS: 415.1 ([{ 79 Br, 35 Cl}M+H] + ),417.0([{ 81 Br, 35 Cl or79 Br, 37 Cl}M+H] + ),ESI pos. b) (4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

[0209] As in the experiment of Example 30b, pyridazine-3-carbohydrazide was used to convert (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione to the (-)-enantiopure (S)-title compound (24 mg, 20%) after chiral purification, which was obtained as a white solid. MS: 501.0 ([{ 79 Br, 35 Cl}M+H] + ),503.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0210] Example 74 (4S)-7-Bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0211] As in the experiment of Example 30b, pyrimidine-4-carbohydrazide was used to convert (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione to the (-)-enantiopure (S)-title compound (13 mg, 11%) after chiral purification, which was obtained as a white solid. MS: 501.1 ([{ 79 Br, 35 Cl}M+H] +),503.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0212] Example 75 (4S)-8-Bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0213] As in the experiment of Example 30b, (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the (-)-enantiopure (S)-title compound (36 mg, 23%) after chiral purification using acetohydrazide, which was obtained as a white solid. MS: 437.0 ([{ 79 Br, 35 Cl}M+H] + ),439.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0214] Example 76 (4S)-7-Bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0215] As in the experiment of Example 30b, 1-methylpyrazole-4-carbohydrazide was used to convert (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione to the (-)-enantiopure (S)-title compound (13 mg, 11%) after chiral purification to give a white solid. MS: 503.1 ([{ 79 Br, 35 Cl}M+H] + ),505.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0216] Example 80 (4S)-7-Bromo-8-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0217] Using acetohydrazide, (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the (-)-enantiopure (S)-title compound (13 mg, 11%) after chiral purification as a white solid, similar to the experiment in Example 30b. MS: 436.9 ([{ 79 Br, 35 Cl}M+H] + ),438.9([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0218] Example 81 (4S)-7-Bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(1-methylpyrazol-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0219] As in the experiment of Example 30b, using 1-methylpyrazole-3-carbohydrazide, (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the (-)-enantiopure (S)-title compound (38 mg, 26%) after chiral purification as a white solid. MS: 503.0 ([{ 79 Br, 35 Cl}M+H] + ),505.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0220] Example 82 (4S)-7,8-Dichloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0221] Using acetohydrazide, (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the (-)-enantiopure (S)-title compound (62.3 mg, 19%) after chiral purification as a white solid, similar to the experiment in Example 30b. MS: 393.0 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0222] Example 83 (4S)-8-Bromo-7-chloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0223] a) (3S)-7-Bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione In a similar manner to the experiment in Example 30a, (3S)-7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (building block R) was converted to the title compound (720 mg, 46%) as a yellow solid. MS: 398.0 ([{ 79 Br, 35 Cl}M+H] + ), 400.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0224] b) (4S)-8-bromo-7-chloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

[0225] As in the experiment of Example 30b, (3S)-7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the (+)-enantiopure (S)-title compound (38 mg, 11%) after chiral purification using cyclopropanecarbohydrazide, which was obtained as a pale yellow solid. MS: 446.1 ([{ 79 Br, 35 Cl}M+H] +),448.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0226] Example 84 (4S)-8-Bromo-7-chloro-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0227] As in the experiment of Example 30b, (3S)-7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the (+)-enantiopure (S)-title compound (38 mg, 12%) after chiral purification using formohydrazide, which was obtained as a pale yellow solid. MS: 406.0 ([{ 79 Br, 35 Cl}M+H] + ),408.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0228] Example 85 (4S)-8-Bromo-7-chloro-6-(3-fluoro-2-pyridyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0229] As in the experiment of Example 30b, (3S)-7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the (+)-enantiopure (S)-title compound (31 mg, 8%) after chiral purification using acetohydrazide, which was obtained as a white solid. MS: 420.0 ([{ 79 Br, 35 Cl}M+H] + ),422.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0230] Example 86 (4S)-7,8-Dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyridazin-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0231] a) 6-Methylpyridazine-3-carbohydrazide

[0232] A solution of ethyl 6-methylpyridazine-3-carboxylate (3.71 g, 22.3 mmol) in methanol (40 mL) was heated to 60° C. After 10 min, hydrazine monohydrate (1.62 mL, 33.5 mmol) was carefully added and the reaction mixture was cooled to room temperature. Diethyl ether (60 mL) was added and the reaction mixture was cooled to 0° C. After 2 h, the resulting suspension was filtered through a sintered funnel. The collected solid was washed with diethyl ether and dried under high vacuum to give the title compound (1.4 g, 41%) as an off-white powder. MS: 153.1 ([M+H] + ),ESI pos.

[0233] b) (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyridazin-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

[0234] As in the experiment of Example 30b, using 6-methylpyridazine-3-carbohydrazide, (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the (-)-enantiopure (S)-title compound (52.6 mg, 44%) after chiral purification as a white solid. MS: 471.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0235] Example 87 5-[(4S)-7,8-Dichloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]-3-methyl-isoxazole [ka]

[0236] a) 3-Methyl-1,2-didehydroisoxazole-5-carbohydrazide Methyl 3-methyl-1,2-didehydroisoxazole-5-carboxylate was converted to the title compound (800 mg, 74%) as a white solid in a similar manner to the experiment in Example 86a. MS: 142.1 ([M+H] + ),ESI pos.

[0237] b) 5-[(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]-3-methyl-isoxazole

[0238] As in the experiment of Example 30b, 3-methyl-1,2-didehydroisoxazole-5-carbohydrazide was used to convert (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione to the (-)-enantiopure (S)-title compound (54.1 mg, 31%) after chiral purification, which was obtained as a white solid. MS: 460.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0239] Example 88 (4S)-7-Bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyridazin-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0240] As in the experiment of Example 30b, 6-methylpyridazine-3-carbohydrazide was used to convert (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione to the (-)-enantiopure (S)-title compound (30 mg, 24%) after chiral purification as a white solid, MS: 515.0 ([{ 79 Br, 35 Cl}M+H] + ),517.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0241] Example 89 (4S)-7-Bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one [ka]

[0242] a) (3S)-6-Bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone In a manner similar to that of Example 64a, (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (40 mg, 20%) as a powder. MS: 413.0 ([{ 79 Br, 35 Cl}M+H] + ), 415.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0243] b) (4S)-7-Bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one

[0244] As in the experiment of Example 64b, (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone was converted to the (-)-enantiopure (S)-title compound (12 mg, 28%) after chiral purification, obtained as a white solid. MS: 439.0 ([{ 79 Br, 35 Cl}M+H] + ),441.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0245] Example 92 (4S)-7-Chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0246] a) (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one

[0247] A solution of (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one (building block S, 500 mg, 1.12 mmol), copper iodide (426 mg, 2.24 mmol), hexamethylphosphoramide (2.5 mL, 1.12 mmol) and methyl 2,2-difluoro-2-fluorosulfonyl-acetate (645 mg, 3.36 mmol) in N,N-dimethylformamide (5 mL) was stirred for 16 hours at 70° C. Methyl 2,2-difluoro-2-fluorosulfonyl-acetate (430 mg, 2.24 mmol) and copper iodide (213 mg, 1.12 mmol) were added and the reaction mixture was stirred at 70° C. for an additional 4 hours. The mixture was diluted with ethyl acetate (150 mL), washed with saturated aqueous ammonium chloride solution (80 mL) and the organic layer was filtered through a sintered funnel. The filtrate was washed with water (50 mL) and brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica, petroleum ether / ethyl acetate, 20:1 to 1:1) to give the title compound (550 mg, 127%), which was obtained as a dark red oil. MS: 389.0 ([M+H] + ),ESI pos.

[0248] b) (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione In a similar manner to the experiment in Example 30a, (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one was converted to the title compound (400 mg, 77%) as a yellow solid. MS: 405.0 ([M+H] + ),ESI pos.

[0249] c) (4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine As in the experiment of Example 30b, (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the (-)-enantiopure (S)-title compound (63.5 mg, 32%) after chiral purification using acetohydrazide, obtained as a white solid. MS: 427.1 ([M+H] + ),ESI pos.

[0250] Example 93 (4S)-7-Chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0251] a) (4S)-7-chloro-6-(2,6-difluorophenyl)-8-(1-ethoxyvinyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

[0252] To a suspension of (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (Example 75, 210.0 mg, 0.480 mmol) and tributyl(1-ethoxyvinyl)tin (346.57 mg, 0.960 mmol) in N,N-dimethylformamide (2.1 mL) was added tetrakis(triphenylphosphine)palladium(0) (56.42 mg, 0.050 mmol). The reaction mixture was stirred at 80 °C for 1 h. The mixture was diluted with dichloromethane (2 x 20 mL), washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, petroleum ether / ethyl acetate 10:1, dichloromethane / methanol 80:1) to give the title compound (300 mg, 98%) as a colorless oil. MS: 429.1 ([M+H] + ),ESI pos.

[0253] b) 1-[(4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl]ethanone

[0254] To a solution of (4S)-7-chloro-6-(2,6-difluorophenyl)-8-(1-ethoxyvinyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (280 mg, 0.650 mmol) in 1,4-dioxane (7 mL) was added aqueous hydrochloric acid (2.0 m, 1.62 mL, 3.23 mmol). The mixture was stirred at room temperature for 0.5 h and then diluted with dichloromethane (100 mL). The organic layer was washed with water (3×10 mL), aqueous sodium bicarbonate (3×50 mL) and brine (50 mL), then dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (BostonPrime C 18, 0.1% trifluoroacetic acid / acetonitrile in water) and lyophilized to give the title compound (220 mg, 84%), which was obtained as a pale yellow solid. MS: 401.1 ([M+H]+ ),ESI pos.

[0255] c) (4S)-7-chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

[0256] To a solution of 1-[(4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl]ethanone (100 mg, 0.250 mmol) in dichloroethane (2 mL) was added diethylaminosulfur trifluoride (120.6 mg, 0.750 mmol) at 0° C. The mixture was stirred at room temperature for 24 h and then poured into saturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with dichloromethane (2×50 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Synergi C18, 0.1% trifluoroacetic acid in water / acetonitrile) to give the (-)-enantiopure (S)-title compound (20.1 mg, 18%), which was obtained as a white solid. MS: 423.0 ([M+H] + ),ESI pos.

[0257] Example 94 (4S)-7,8-Dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyrimidin-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0258] As in the experiment of Example 30b, using 6-methylpyrimidine-4-carbohydrazide, (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the (-)-enantiopure (S)-title compound (70.0 mg, 35%) after chiral purification as a white solid. MS: 471.2 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0259] Example 95 (4S)-7,8-Dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(2-methylpyrimidin-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0260] As in the experiment of Example 30b, using 2-methylpyrimidine-4-carbohydrazide, (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the (-)-enantiopure (S)-title compound (12.0 mg, 20%) after chiral purification as a white solid. MS: 471.2 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0261] Example 96 (4S)-7,8-Dichloro-6-(2,6-difluorophenyl)-1-(2,6-dimethylpyrimidin-4-yl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0262] As in the experiment of Example 30b, using 2,6-dimethylpyrimidine-4-carbohydrazide, (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the (-)-enantiopure (S)-title compound (66.8 mg, 44%) after chiral purification as a white solid. MS: 485.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0263] Example 97 (4S)-7-Chloro-6-(2,6-difluorophenyl)-1,4,8-trimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0264] A mixture of (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (300 mg, 0.690 mmol), tetrakis(triphenylphosphine)palladium(0) (79.2 mg, 0.070 mmol), trimethylaluminum (2.0 m in toluene, 0.51 mL, 1.03 mmol) in N,N-dimethylformamide (6 mL) was heated to 70° C. After 16 h, the mixture was diluted with dichloromethane (30 mL). The organic layer was washed with water (20 mL), brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (BostonPrime, 0.1% trifluoroacetic acid in water / acetonitrile) and lyophilized to give the (-)-enantiopure (S)-title compound (27.3 mg, 58%), which was obtained as a white solid. MS: 373.2 ([M+H] + ),ESI pos.

[0265] Example 98 (4S)-8-Bromo-7-chloro-6-(2,6-difluorophenyl)-4-ethyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0266] a) (3S)-7-Bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepine-2-thione In a similar manner to the experiment in Example 30a, (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepin-2-one (Building T) was converted to the title compound (600 mg, 92%) as a yellow solid. MS: 429.0 ([{ 79 Br, 35 Cl}M+H] + ),431.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0267] b) (3S)-7-Bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone

[0268] A solution of (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepine-2-thione (500 mg, 1.16 mmol) and hydrazine hydrate (117 mg, 2.33 mmol) in tetrahydrofuran (5 mL) was cooled to 15° C. and stirred for 1 h. The mixture was concentrated under reduced pressure to give the title compound (450 mg, 90%) as a pale green foam. MS: 427.2 ([{ 79 Br, 35 Cl}M+H] + ),429.3([{ 81 Br, 35 Cl or79 Br, 37 Cl}M+H] + ),ESI pos.

[0269] c) (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-ethyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

[0270] A solution of (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone (450 mg, 1.05 mmol) and triethyl orthoacetate (854 mg, 5.26 mmol) in toluene (5 mL) was heated to 120° C. After 1 h, the reaction mixture was concentrated under reduced pressure. The residue was directly purified by flash column chromatography (dichloromethane / methanol 20:1) followed by chiral purification to give the (-)-enantiopure (S)-title compound (400 mg, 82%) as a pale yellow foam. MS: 451.0 ([{ 79 Br, 35 Cl}M+H] + ),453.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0271] Example 99 (4S)-7-Chloro-8-(difluoromethyl)-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0272] a) (4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-8-vinyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

[0273] To a solution of (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (3.0 g, 6.85 mmol) in ethanol (70 mL) was added potassium vinyltrifluoroborate (1.85 g, 1.37 mmol), triethylamine (2.08 g, 20.56 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.5 g, 0.690 mmol). The reaction mixture was heated to 80 °C. After 16 h, water (100 mL) was added and the reaction mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate / ethanol 20:3:1 to 8:3:1) to give the title compound (2.8 g, 88%), which was obtained as a brown solid. MS: 385.1 ([M+H] + ),ESI pos.

[0274] b) (4S)-7-Chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-8-carbaldehyde

[0275] To a solution of (4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-8-vinyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (2.8 g, 7.28 mmol) in acetone (56 mL) and water (14 mL) was added osmium tetroxide (184.99 mg, 0.730 mmol). After stirring at room temperature for 10 min, sodium periodate (3.1 g, 14.5 mmol) was added and the mixture was stirred at room temperature for an additional 1 h. The reaction mixture was diluted with water (10 mL) and ethyl acetate (100 mL). The organic layer was washed with brine (2×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, dichloromethane / methanol 200:1 to 60:1) to give the title compound (1.8 g, 47%), which was obtained as a yellow solid. MS:387.1([M+H] + ),ESI pos.

[0276] c) (4S)-7-chloro-8-(difluoromethyl)-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

[0277] To a solution of (4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-8-carbaldehyde (1.8 g, 4.65 mmol) in dichloroethane (37.0 mL) was added diethylaminosulfur trifluoride (2.25 g, 14.0 mmol) at 0° C. Upon addition, the reaction mixture was allowed to warm to room temperature and stirred for an additional 2 h. The reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate (10 mL) and then extracted with dichloromethane (2×30 mL). The combined organic extracts were washed with brine (2×50 mL), filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Boston Prime C18, 0.1% trifluoroacetic acid in water / acetonitrile) and lyophilized to give the (-)-enantiopure (S)-title compound (359 mg, 50%), which was obtained as a white solid. MS: 409.1 ([M+H] + ),ESI pos.

[0278] Example 100 (4R)-8-Bromo-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0279] a) (3S)-7-Bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione

[0280] In a similar manner to the experiment in Example 30a, (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl)-1,3-dihydro-1,4-benzodiazepin-2-one (Building U) was converted to the title compound (1.2 g, 76%) as a yellow solid. MS: 445.0 ([{ 79 Br, 35 Cl}M+H] +),447.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0281] b) (3R)-7-Bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl)-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone In a similar manner to the experiment in Example 98b, (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (1.1 g, 96%) as a yellow solid. MS: 443.1 ([{ 79 Br, 35 Cl}M+H] + ),445.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0282] c) (4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

[0283] As in the experiment of Example 98c, (3R)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl)-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone was converted to the (-)-enantiopure (R)-title compound (68 mg, 6%) after chiral purification, obtained as a white solid. MS: 467.2 ([{ 79 Br, 35 Cl}M+H] + ),469.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0284] Example 101 [(4R)-8-Bromo-7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]methanol [ka]

[0285] To a stirred suspension of (4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (230.0 mg, 0.490 mmol) and sodium iodide (147.43 mg, 0.980 mmol) in dichloromethane (3 mL) was added a solution of boron tribromide (308.0 mg, 1.23 mmol) in dichloromethane (0.5 mL) at −30° C. The reaction mixture was allowed to warm to room temperature and stirred for an additional 1 h before being concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenexluna, 0.1% trifluoroacetic acid in water / acetonitrile) followed by SFC (Daicel Chiralpak AD-H, 0.1% ammonia in methanol) to give the (-)-enantiopure (R)-title compound (71 mg, 47%) as a white solid. MS: 453.2 ([{ 79 Br, 35 Cl}M+H] + ),455.2([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0286] Example 102 (4S)-7-Chloro-6-(2,6-difluorophenyl)-8-iodo-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0287] To a mixture of (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (100 mg, 0.228 mmol), rac-trans-N1,N2-dimethylcyclohexane-1,2-diamine (35.3 μL, 0.228 mmol), sodium iodide (342 mg, 2.28 mmol) and copper(I) iodide (21.8 mg, 114 μmol) was added 1,4-dioxane (10 mL) under argon. The resulting suspension was heated at 115° C. for 6 days. An additional amount of sodium iodide (685 mg, 4.57 mmol) and copper(I) iodide (218 mg, 1.14 mmol) was added and the reaction mixture was stirred for an additional 2 days. The mixture was diluted with ethyl acetate and the organic layer was washed twice with aqueous ammonia, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash column chromatography (silica, 0-15% methanol in dichloromethane) followed by chiral HPLC (Chiracel OD; eluent: 20% (0.1 mol ammonium acetate in ethanol) in heptane) to give the (-)-enantiopure (S)-title compound (41.2 mg, 37%) as a white solid. MS: 485.0 ([M+H] + ),ESI pos.

[0288] Example 103 [(4S)-7-Chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methanol [ka]

[0289] a) [(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methoxytriisopropylsilane As in the experiment of Example 30b, (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (300 mg, 33%) using 2-triisopropylsilyloxyacetohydrazide as a pale yellow oil. MS: 599.2 ([M+H] + ),ESI pos.

[0290] b) [(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methanol

[0291] To a solution of [(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methoxy-triisopropylsilane (200.0 mg, 0.270 mmol) in tetrahydrofuran (4 mL) was added TBAF (1.0 m in tetrahydrofuran, 0.81 mL, 0.810 mmol) slowly. The mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane / methanol 50:1 to 20:1), followed by preparative HPLC (UniSil3-100C18Uitra, 0.225% trifluoroacetic acid / acetonitrile in water) and SFC separation (DaicelChiralcelOJ, 0.1% ammonia in ethanol) to give the (-)-enantiopure (S)-title compound (13.6 mg, 10%) as a white solid. MS: 443.0 ([M+H] + ),ESI pos.

[0292] Example 105 (4R)-7-Chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0293] To an oven-dried vial equipped with a magnetic stir bar and a Teflon septum was added (4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (10 mg, 21.4 μmol), sodium carbonate (9.06 mg, 85.5 μmol), CuBr2·2LiBr (4.28 μmol), Mes-Umemoto's reagent (22 mg, 42.8 mol), Ir[dFMeppy]2-(4,4'-dCF3bpy)PF6 (56 μg, 0.0535 μmol) and (Me3Si)3SiOH (8.5 mg, 32.1 μmol). The vial was then evacuated and backfilled with nitrogen, degassed, and degassed acetone (0.2 mL) was added via syringe. The reaction mixture was stirred at room temperature for 16 h under illumination with a blue LED (Kessil lamp 40 W, 420 nm). The vial was opened and the reaction mixture was directly filtered through a Celite plug. The filter cake was rinsed with ethyl acetate (2.0 mL) and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), washed with water and brine (3×15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by preparative HPLC (GeminiNX5Y, 0.1% formic acid in water / acetonitrile) to give the (-)-enantiopure (R)-title compound (3 mg, 30%) as a white solid. MS: 457.2 ([M+H] + ),ESI pos.

[0294] Example 106 [(4R)-7-Chloro-6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]methanol [ka]

[0295] Analogously to the experiment in Example 105, [(4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]methanol was converted to the (-)-enantiopure (R)-title compound (9 mg, 31%), which was obtained as a white lyophilized powder. MS: 443.1 ([M+H] + ),ESI pos.

[0296] Example 107 (4S)-7-Chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0297] In a similar manner to the experiment in Example 105, (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted to the (-)-enantiopure (S)-title compound (1 mg, 10%) as a white solid. MS: 413.2 ([M+H] + ),ESI pos.

[0298] Example 108 (4S)-7-Chloro-6-(2,6-difluorophenyl)-1-ethyl-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0299] As in the experiment of Example 30b, (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the (-)-enantiopure (S)-title compound (16.4 mg, 13%) after chiral purification using propanehydrazide, obtained as a white solid. MS: 444.1 ([M+H] + ),ESI pos.

[0300] Example 109 (4S)-7-Chloro-6-(2,6-difluorophenyl)-8-ethyl-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0301] To a solution of (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (120 mg, 0.274 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·CHCl (4.5 mg, 5.5 μmol) in anhydrous tetrahydrofuran (1.2 mL) was added diethylzinc (1.0 m in heptane, 0.823 mL, 0.823 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and then heated at 55 °C for 15 h. The reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (Gemini NX, 0.1% triethylamine / methanol in water) followed by chiral HPLC (Reprosil Chiral NR, 0.01M ammonium acetate in ethanol, 30%) to give the (-)-enantiopure (S)-title compound (31.7 mg, 30%) as a white powder. MS: 387.3 ([M+H] + ),ESI pos.

[0302] (Reference compound) RE-A 8-Bromo-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0303] a) N-[2-(2,6-difluorobenzoyl)phenyl]acetamide Analogously to the experiment for component Ab, 2-methyl-3,1-benzoxazin-4-one (CAS no. 525-76-8) was converted to the title compound (40 g, 80%) as a pale yellow solid. MS: 276.2 ([M+H] + ),ESI pos.

[0304] b) (2-aminophenyl)-(2,6-difluorophenyl)methanone Similarly to the experiment for building block Ac, N-[2-(2,6-difluorobenzoyl)phenyl]acetamide was converted to the title compound (19.5 g, 75%) as a yellow solid. MS: 234.1 ([M+H] + ),ESI pos.

[0305] c) (2-amino-5-bromo-phenyl)-(2,6-difluorophenyl)methanone

[0306] To a solution of (2-aminophenyl)-(2,6-difluorophenyl)methanone (5.00 g, 21.4 mmol) in dichloromethane (50 mL) was added N-bromosuccinimide (4.02 g, 22.51 mmol) portionwise at -15 °C. The reaction mixture was stirred at -15 °C for 1 h until the starting material was completely consumed (as judged by LCMS analysis). The mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Shim-pack C18, 0.225% trifluoroacetic acid in water / acetonitrile). The combined fractions were diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3 x 200 mL). The organic phase was washed with brine (2 x 100 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound (4.44 g, 66%) as a yellow solid. MS: 311.9 ([{ 79 Br}M+H] + ),314.0([{ 81 Br}M+H] + ),ESI pos.

[0307] d) 7-Bromo-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Ae, (2-amino-5-bromo-phenyl)-(2,6-difluorophenyl)methanone was converted to the title compound (300 mg, 13%) as a yellow solid. MS: 351.0 ([{ 79 Br}M+H] + ),353.0([{ 81 Br}M+H] + ),ESI pos.

[0308] e) 7-bromo-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione

[0309] In a similar manner to experiment example 30a, 7-bromo-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one was converted to the title compound (310 mg, 92%) as a yellow solid. The crude product was used directly in the next step without further characterization.

[0310] f) 8-bromo-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine As in the experiment in Example 30b, 7-bromo-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (5.1 mg, 4%) using acetohydrazide as a white solid. MS: 389.0 ([{ 79 Br}M+H] + ),391.0([{ 81 Br}M+H] + ),ESI pos.

[0311] RE-B 6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0312] a) (2-amino-5-iodo-phenyl)-(2,6-difluorophenyl)methanone

[0313] To a solution of (2-aminophenyl)-(2,6-difluorophenyl)methanone (1.6 g, 6.86 mmol) in DMF (15 mL) was added N-iodosuccinimide (1.62 g, 7.2 mmol) in portions. The reaction mixture was stirred at 20° C. for 16 h and then diluted with water (20 mL). The mixture was extracted with ethyl acetate (3×20 mL), and the combined organic extracts were then washed with brine (2×10 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate, 10:1 to 5:1) to give the title compound (2.0 g, 81%) as a yellow solid. MS: 360.0 ([M+H] + ),ESI pos.

[0314] b) 5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Ae, (2-amino-5-iodo-phenyl)-(2,6-difluorophenyl)methanone was converted to the title compound (650 mg, 12%) as a yellow solid. MS: 399.0 ([M+H] + ),ESI pos.

[0315] c) 5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepine-2-thione In a similar manner to the experiment in Example 30a, 5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one was converted to the title compound (200 mg, 82%) as a yellow solid. MS: 414.9 ([M+H] + ),ESI pos.

[0316] d) 5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone In a similar manner to the experiment in Example 64a, 5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (220 mg, 98%) as a yellow solid. MS: 413.0 ([M+H] + ),ESI pos.

[0317] e) 6-(2,6-difluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a similar manner to the experiment in Example 98c, 5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone was converted to the title compound (150 mg, 64%) as a yellow solid. MS: 437.0 ([M+H] + ),ESI pos.

[0318] f) 6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a similar manner to the experiment in Example 92a, 6-(2,6-difluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted to the title compound (5 mg, 6%) as a white solid. MS: 379.0 ([M+H] + ),ESI pos.

[0319] RE-C 6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0320] To a stirred solution of 8-bromo-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (30 mg, 0.08 mmol) in methanol (0.5 mL) was added 10 wt% Pd / C (2.5 mg, 2.4 μmol) and the resulting black suspension was purged by evacuation and then filled with a stream of hydrogen (balloon) three times. The mixture was stirred under a hydrogen atmosphere at room temperature for 16 h and then filtered through a pad of dicalite. The filter cake was rinsed with methanol and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Gemini-NX C18, 0.1% trifluoroacetic acid / acetonitrile in water) followed by preparative TLC (silica, dichloromethane / methanol, 20:1) to give the title compound (5 mg, 20%) as a white solid. MS:276.2([M+H] + ),ESI pos.

[0321] RE-D (4S)-7-Chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0322] Similar to the experiment for the reference compound RE-C, (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted to the title compound (2 mg, 15%) as a white solid. MS: 359.1 ([M+H] + ),ESI pos.

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, R １ teeth, i) H; ii) C １－６ -alkyl, iii) C １－６ -alkoxy, iv) C １－６ -Alkoxy-C １－６ -alkyl, v) hydroxy, vi) Hydroxy-C １－６ -alkyl, vii) optionally R ７ , R ８ and R ９ C substituted with ３－８ -cycloalkyl, viii) Amino-C １－６ -alkyl, ix) optionally R ７ , R ８ and R ９ Heteroaryl substituted with, x) optionally R ７ , R ８ and R ９ Heterocycloalkyl substituted with Selected from: R ２ teeth, i) C １－６ -alkyl, ii) hydroxy, iii) Hydroxy-C １－６ -alkyl, and iv) C １－６ -Alkoxy-C １－６ -Alkyl Selected from: R ３ teeth, i) Cl, and ii) F Selected from: X is i) CR ６ , and ii) N Selected from: R ６ teeth, i) H; ii) Cl, and iii) F Selected from: R ４ teeth, i) Br, and ii) Cl Selected from: R ５ teeth, i) C １－６ -alkyl, ii) C １－６ -alkoxy, iii) halogens, iv) halo-C １－６ -alkyl, v) cyano, and vi) C ３－８ -Cycloalkyl Selected from: R ７ , R ８ and R ９ teeth, i) C １－６ -alkyl, and ii) C １－６ -Alkoxy (independently selected from or a pharma- ceutically acceptable salt thereof.

2. R １ but, i) H; ii) C １－６ -alkyl, iii) C １－６ -alkoxy, iv) C １－６ -Alkoxy-C １－６ -alkyl, v) hydroxy, vi) Hydroxy-C １－６ -alkyl, vii) optionally R ７ , R ８ and R ９ C substituted with ３－８ -cycloalkyl, viii) Amino-C １－６ -alkyl, ix) optionally R ７ , R ８ and R ９ pyrazolyl substituted with x) optionally R ７ , R ８ and R ９ pyridinyl substituted with xi) optionally R ７ , R ８ and R ９ pyrimidinyl substituted with xii) optionally R ７ , R ８ and R ９ pyridazinyl substituted with xiii) optionally R ７ , R ８ and R ９ Isoxazolyl substituted with Selected from: R ２ but, i) C １－６ -alkyl, ii) hydroxy, iii) Hydroxy-C １－６ -alkyl, and iv) C １－６ -Alkoxy-C １－６ -Alkyl Selected from: R ３ but, i) Cl, and ii) F Selected from: X, i) CR ６ , and ii) N Selected from: R ６ but, i) H; ii) Cl, and iii) F Selected from: R ４ but, i) Br, and ii) Cl Selected from: R ５ but, i) C １－６ -alkyl, ii) C １－６ -alkoxy, iii) halogens, iv) halo-C １－６ -alkyl, v) C ３－８ -Cycloalkyl Selected from: R ７ , R ８ and R ９ but, i) C １－６ -alkyl, and ii) C １－６ -Alkoxy are independently selected from 2. A compound of formula (I) according to claim 1, or a pharma- ceutically acceptable salt thereof.

3. R １ but, i) H; ii) C １－６ -alkyl, iii) hydroxy, iv) Hydroxy-C １－６ -alkyl, v) optionally R ７ , R ８ and R ９ C substituted with ３－８ -cycloalkyl, vi) optionally R ７ , R ８ and R ９ pyrazolyl substituted with vii) optionally R ７ , R ８ and R ９ pyrimidinyl substituted with viii) optionally R ７ , R ８ and R ９ pyridazinyl substituted with, ix) optionally R ７ , R ８ and R ９ Isoxazolyl substituted with Selected from: R ２ but, i) C １－６ -alkyl, ii) hydroxy, iii) Hydroxy-C １－６ -alkyl, and iv) C １－６ -Alkoxy-C １－６ -Alkyl Selected from: R ３ is F, X, i) CR ６ , and ii) N Selected from: R ６ but, i) H, and ii) F Selected from: R ４ but, i) Br, and ii) Cl Selected from: R ５ but, i) C １－６ -alkyl, ii) a halogen, and iii) Halo-C １－６ -Alkyl Selected from: R ７ , R ８ and R ９ But, C １－６ independently selected from alkyl, 3. A compound of formula (I) according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof.

4. R １ But, C １－６ is alkyl, R ２ But, C １－６ is alkyl, R ３ is F, X is CR ６ and R ６ is F, R ４ is Cl, R ５ But, Hello-C １－６ - alkyl, 4. The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

5. (4S)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-ol; (4S)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-ol; (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one; (4S)-7,8-dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-dichloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(1-methylpyrazol-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-8-bromo-7-chloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-8-bromo-7-chloro-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-8-bromo-7-chloro-6-(3-fluoro-2-pyridyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyridazin-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 5-[(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]-3-methyl-isoxazole; (4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyridazin-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-Bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one; (4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyrimidin-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(2-methylpyrimidin-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-1-(2,6-dimethylpyrimidin-4-yl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-chloro-6-(2,6-difluorophenyl)-1,4,8-trimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-ethyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-chloro-8-(difluoromethyl)-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; [(4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]methanol; (4S)-7-chloro-6-(2,6-difluorophenyl)-8-iodo-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; [(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methanol; (4R)-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; [(4R)-7-chloro-6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]methanol; (4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-chloro-6-(2,6-difluorophenyl)-1-ethyl-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; (4S)-7-chloro-6-(2,6-difluorophenyl)-8-ethyl-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 5. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, selected from:

6. The compound is (4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine, or a pharma- ceutically acceptable salt thereof.

7. A compound of formula (III) and a compound of formula (IV) １ , R ２ , R ３ , R ４ and R ５ is as defined in any one of claims 1 to 4) with a compound of formula (I) as defined in any one of claims 1 to 4. 【Chemistry 2】

8. A compound according to any one of claims 1 to 6 for use as a therapeutically active substance.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 and a therapeutically inert carrier.

10. A compound according to any one of claims 1 to 6 for use in the treatment or prevention of autism spectrum disorders, Rett syndrome, post-traumatic stress disorder and fragile X disorder.

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