Benzodiazepine derivatives as GABA A gamma 1 PAMs

Abstract

The present invention relates to a compound represented by general formula (I) TIFF2023522099000104.tif51161 (In the formula, R 1 , R 3 , R 4 , R 5 and X is as described herein), compositions comprising the compounds, and methods of using the compounds.

Description

[Technical Field]

[0001] The present invention targets core symptoms and associated comorbidities, including anxiety and irritability, in mammals, such as autism spectrum disorder (ASD), 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, disruptive, impulse control, and behavior disorders, Tourette's syndrome (TS), obsessive-compulsive disorder (OCD), acute stress disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), and other conditions. Organic compounds, specifically GABA, useful for the treatment or prevention of ADHD, sleep disorders (including narcolepsy and cataplexy), neurodegenerative conditions (including 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, psychosis and aggression, eating disorders (including anorexia nervosa, bulimia nervosa, and binge eating disorder), depression and related conditions including treatment-resistant depression (TRD), chronic apathy, anhedonia, chronic fatigue, seasonal affective disorder, postpartum depression, sleepiness, sexual dysfunction, bipolar disorder, epilepsy, and pain. A GABA, which can be treated by modulating γ1 receptor activity A GABA for the treatment or prevention of gamma 1 receptor-associated disorders and diseases or conditions A Regarding γ1 receptor positive allosteric modulators (PAMs).

[0002] The present invention relates to a compound of formula (I) [ka] (In the formula, R 1 teeth, i) H, ii) C 1~6 -alkyl, iii) C 1~6 -alkoxy, iv) iC 1~6 -Alkoxy-C 1~6 -alkyl, v) hydroxy, vi) Hydroxy-C 1~6 -alkyl, vii)R 7 , R 8 and R 9 C optionally substituted with 3~8 -cycloalkyl, viii) Amino-C 1~6 -Alkyl ix)R 7 , R 8 and R 9 Heteroaryl optionally substituted with x)R 7 , R 8 and R 9 heterocycloalkyl optionally substituted with; R 3 teeth, i) Cl, and ii) selected from F; X is i)CR 6 , and ii) selected from N; R 6 teeth, i) H, ii) Cl, and iii) selected from F; R 4 teeth, i) Br, and ii) selected from Cl; 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; R 7 , R8 and R 9 is, independently, I C 1~6 -alkyl, and ii) C 1~6 -alkoxy) The present invention provides a novel compound or a pharmaceutically acceptable salt thereof. [Background technology]

[0003] Receptors for gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter, are classified 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 The receptors are divided into membrane-bound heteropentameric protein polymers, called GABA receptors. A The GABA receptor complex is primarily composed of α, β, and γ subunits. A The receptor is a ligand-bound chloride channel and is the primary mediator of inhibitory neurotransmission in the human brain.

[0004] GABA A There are 19 genes encoding the receptor subunits, with the most common stoichiometry consisting of two α, two β, and one γ subunit assembled as a pentamer. A Subunit combinations confer functional, circuit, and behavioral specificity (Sieghart, 2006; Vithlani et al., 2011). GABA receptors containing the γ1 subunit A Receptor (GABA AGABA 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 exhibit enriched mRNA and protein distribution in key brain regions, including the extended amygdala (central, medial, and bed nuclei of the stria terminalis), lateral septum, hypothalamus, and globus pallidus / substantia nigra, accounting for approximately 5-10% of total receptor expression. These structures form the interconnected core of the subcortical-limbic circuit that regulates motivated social and emotional behaviors. In abnormal or disease states, excessive recruitment of this circuit promotes anxiety, 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 the limbic cortex, a key region for processing socially and emotionally relevant stimuli (known to form a coordinated functional network with the extended amygdala / hypothalamic region), is a common feature of various psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational, and metabolic disorders. In such disease states, γ1-subunit-containing GABA receptors are involved. A Given the characteristic anatomical distribution of GABA receptors, A γ1 positive allosteric modulators (PAMs) may be an effective treatment as symptomatic or disease-modifying agents.

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

[0007] Thus, the compounds described herein and their pharmaceutically 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 disorder (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 conduct disorder complex, Tourette syndrome (TS), obsessive-compulsive disorder (OCD), acute stress disorder, traumatic brain injury, and the like. It can 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 diseases (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 disorders, 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 impairments 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 of ASD, inadequate treatment options are available for most of the emotional and physiological comorbidities of ASD. 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, aripiprazole), which are indicated for treating irritability associated with ASD symptoms. Emerging evidence suggests that the GABAergic system, the brain's primary inhibitory neurotransmitter system, plays a critical role in the pathophysiology of ASD (Dhossche et al., 2002; Pizzarelli and Cherubini, 2011; Robertson et al., 2016).

[0011] Both genetic and imaging studies using positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) suggest altered GABAergic signaling in ASD. A The gene encoding γ1:GABRG1 encodes α2, α4, and β1 GABA AIt is located on chromosome 4 (mouse Chr. 5) within a cluster of genes encoding receptor subunits. A rare CNV involving a chromosome 4p12 inversion disrupting GABRG1 has been observed in siblings with autism (Horike et al., 2006), as well as in a case of ADHD with loss of GABRG1. Mutations in the 4p12 gene cluster are associated with an increased risk of anxiety, substance abuse, and eating disorders, providing a link between GABRG1 / 4p12 and emotional dysfunction. MRS studies have found altered GABA levels in ASD (Gaetz et al., 2014; Rojas et al., 2014), and several recent studies have shown decreased GABA and altered somatosensory function in children with ASD (Puts et al., 2016; Robertson et al., 2016). Consistent with these observations, reduced numbers of inhibitory interneurons have been found in postmortem tissue from ASD and TS patients (Rapanelli et al., 2017). Furthermore, reduced GABA-synthesizing enzymes, glutamic acid decarboxylase (GAD) 65 and 67, have been found in the parietal and cerebellar cortices of autistic patients (Fatemi et al., 2002). Strong human evidence supports the role of GABA in the regulation of GABA. AStudies have pointed to specific dysfunction in ASD in limbic cortical regions known to form coordinated functional networks with γ1-subunit-containing extended amygdala / hypothalamic regions. These regions—the cortex / lateral amygdala, insula, PFC, and cingulate cortex—are recognized as key for processing socially and emotionally relevant stimuli. While the subcortical nuclei that form specific partnerships with these regions, which mediate behavioral outcomes, are often difficult to study due to limited spatial resolution, mounting evidence points to an overrecruitment of these cortical-to-subcortical connections in ASD. Furthermore, recent high-resolution studies have provided clear links between the activity / functional connectivity of the extended amygdala 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 the social-emotional circuits affected in ASD, while avoiding broad modulation of global brain state. A Enhancement of GABA receptor activity has been shown to improve behavioral deficits in mouse models of ASD. A It has been observed that α1γ2 subtype-mediated sedation has a very narrow margin of therapeutic efficacy (Han et al., 2012, 2014; Soto et al., 2013). These findings support the notion that GABA A This supports the idea that rebalancing GABAergic transmission via gamma-1 receptors improves ASD symptoms without the side effects of non-selective benzodiazepines.

[0012] The object of the present invention is to provide compounds of formula (I) and their pharmaceutically acceptable salts and esters, the preparation of said compounds, medicaments containing them and their manufacture, as well as the treatment of 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 behavior disorders, Tourette syndrome (TS), obsessive-compulsive disorder (OCD), acute stress disorder, post-traumatic stress disorder. GABA receptor agonists in conditions such as PTSD, attention deficit hyperactivity disorder (ADHD), sleep disorders (including narcolepsy-cataplexy), neurodegenerative conditions (including 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, psychosis and aggression, eating disorders (including anorexia nervosa, bulimia nervosa, and binge eating disorder), depression and related conditions including treatment-resistant depression (TRD), chronic apathy, anhedonia, chronic fatigue, seasonal affective disorder, postpartum depression, sleepiness, sexual dysfunction, bipolar disorder, epilepsy, and pain. A Diseases related to γ1 receptor dysfunction and GABA A The use of the compounds described above in the treatment or prevention of diseases or conditions that can be treated by enhancing γ1 receptor activity.

[0013] The compounds of the present invention may be administered at a given concentration (e.g., EC 20 ) by increasing GABAergic currents (chloride influx) with gamma-aminobutyric acid (GABA) containing γ1 A It selectively enhances the function of GABA receptors, A The compounds of the present invention are γ1 receptor positive allosteric modulators (PAMs). They have high PAM potency and binding selectivity for γ1-containing subtypes (α5γ1, α2γ1, α1γ1) compared to γ2-containing subtypes (e.g., α1γ2, α2γ2, α3γ2, and α5γ2). Therefore, the compounds of the present invention can bind to γ2-containing GABA receptors. AIt is subtype selective, strongly distinguishing it from classical benzodiazepine drugs such as alprazolam, triazolam, estazolam, and midazolam, which have low affinity for γ1-containing subtypes. A γ1 PAM is a non-selective GABA A It will restore GABAergic signaling in key brain regions (e.g., extended amygdala: stria terminalis, lateral septum, hypothalamus, and central, medial, and bed nuclei of the globus pallidus / substantia nigra) without the side effects of modulators (e.g., benzodiazepines).

[0014] The term "amino" refers to the group --NH.sub.2.

[0015] "Amino-C 1~6 The term "-alkyl" refers to 1~6 -C in which one hydrogen atom of the alkyl group is replaced by an amino group 1~6 - represents an alkyl group. Amino-C 1~6 Examples of -alkyl include aminomethyl, amionethyl, aminopropyl, aminomethylpropyl, aminomethylethyl and aminobutyl. A specific 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. Specific examples are methoxy and ethoxy. A more specific example is methoxy.

[0017] "C 1~6 -Alkoxy-C 1~6 The term "-alkyl" refers to 1~6 -At least one of the hydrogen atoms of the alkyl group is C 1~6 -C substituted with an alkoxy group 1~6 -alkyl groups. 1~6 -Alkoxy-C1~6 -Alkyl groups include methoxymethyl, ethoxymethyl, methoxymethyl, ethoxyethyl, methoxypropyl, ethoxypropyl, etc. Specific examples include methoxyethyl.

[0018] "C 1~6 The term "-alkyl" refers to a monovalent straight or branched chain saturated hydrocarbon radical of 1 to 6 carbon atoms. 1~6 Examples of -alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and pentyl. 1~6 The alkyl groups are methyl and ethyl. A more particular example is methyl.

[0019] "C 3~8 The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon group having 3 to 8 ring carbon atoms. Bicyclic refers to 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 "-alkyl" refers to 1~6 -C in which at least one hydrogen atom of the alkyl group is substituted with the same or different halogen atom 1~6 -Alkyl group. "Perhalo-C 1~6 -Alkyl-C 1~6The term "C-alkyl" refers to an alkyl group in which all hydrogen atoms are replaced by the same or different halogen atoms. 1~6 -Alkyl-C 1~6 - represents an alkyl group. 1~6 Examples of halo-C include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl. 1~6 -alkyl groups include trifluoromethyl and difluoroethyl. More specifically, halo- 1~6 The alkyl groups are difluoromethyl and trifluoromethyl.

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

[0023] The term "heteroaryl" refers to a monovalent aromatic heterocycle or mono- 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, benzisoxazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxaaryl. Particular heteroaryl groups include pyridinyl, pyrazolyl, pyrimidinyl, pyridazinyl and isoxazolyl.More particularly, heteroaryl groups are pyrazolyl, pyrimidinyl and pyridazinyl.

[0024] The term "heterocycloalkyl" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 11 ring atoms containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, the remaining ring atoms being carbon. Bicyclic means consisting of two rings that have 1 or 2 ring atoms in common. Examples of monocyclic saturated heterocycloalkyl 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 specific heterocycloalkyl is tetrahydropyranyl.

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

[0026] "Hydroxy-C 1~6 The term "-alkyl" refers to 1~6 -C in which one hydrogen atom of the alkyl group is replaced by a hydroxy group 1~6 - represents an alkyl group. Hydroxy C 1~6Examples of -alkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylpropyl, hydroxymethylethyl, hydroxybutyl, etc. A particular example includes 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, and phosphoric acid, particularly hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine. These salts may also be prepared by adding 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. Specific pharmaceutically acceptable salts of compounds of formula (I) are hydrochloride, methanesulfonate, and citrate salts.

[0028] By "pharmaceutically acceptable ester" is meant that the compounds of general 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 esters, methylthiomethyl esters, and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of compounds of general formula (I) that are analogous to the metabolically labile esters that can be produced in vivo from the parent compounds of general formula (I) are 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 on a polyfunctional compound, allowing chemical reactions to occur selectively at other, unprotected reactive sites. Protecting groups can be removed at an appropriate point. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups, or hydroxy-protecting groups. Specific protecting groups are the tert-butoxycarbonyl (Boc) group, the benzyloxycarbonyl (Cbz) group, the fluorenylmethoxycarbonyl (Fmoc) group, and the benzyl (Bn) group. More specific protecting groups are the tert-butoxycarbonyl (Boc) group and the fluorenylmethoxycarbonyl (Fmoc) group. An even more specific protecting group is the tert-butoxycarbonyl (Boc) group.

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

[0031] The abbreviation uL stands for 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 embodiments of the present invention are compounds according to formula (I) as described herein and pharmaceutically acceptable salts or esters thereof, particularly compounds according to formula (I) as described herein and pharmaceutically 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, iii) H, iv) C 1~6 -alkyl, v) C 1~6 -alkoxy, vi) C 1~6 -Alkoxy-C 1~6 -alkyl, vii) hydroxy, viii) Hydroxy-C 1~6 -alkyl, ix)R 7 , R 8 and R 9 C optionally substituted with 3~8 -cycloalkyl, x) Amino-C 1~6 -Alkyl xi)R 7 , R 8 and R 9 pyrazolyl optionally substituted by xii)R 7 , R 8 and R 9 pyridinyl optionally substituted by xiii)R 7 , R 8 and R 9 pyrimidinyl optionally substituted by xiv)R 7 , R 8 and R 9 pyridazinyl optionally substituted by xv)R 7 , R 8 and R 9 tetrahydropyranyl optionally substituted by; R 3 teeth, i) Cl, and ii) selected from F; X is i)CR 6 , and ii) selected from N; R 6 teeth, i) H, ii) Cl, and iii) selected from F; R 4 teeth, i) Br, and ii) selected from Cl; 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; R 7 , R 8 and R 9 is, independently, I C 1~6 -alkyl, and ii) C 1~6 -alkoxy The compound or a pharmaceutically acceptable salt thereof is provided.

[0037] A more specific embodiment of the present invention is a compound of formula (I) according to claim 1, R 1 teeth, iii) H, iv) C 1~6 -alkyl, v) hydroxy, vi) Hydroxy-C 1~6 -alkyl, vii)R 7 , R 8 and R 9 C optionally substituted with 3~8 -cycloalkyl, viii)R 7 , R 8 and R 9 pyrazolyl optionally substituted by ix)R 7 , R 8 and R 9 pyrimidinyl optionally substituted by x)R 7 , R 8 and R 9 pyridazinyl optionally substituted by xi)R 7 , R 8 and R 9 tetrahydropyranyl optionally substituted by; R 3 is F; X is i)CR 6 , and ii) selected from N; R 6 teeth, i) H, and ii) selected from F; R 4 teeth, i) Br, and ii) selected from Cl; R 5 teeth, I C 1~6 -alkyl, ii) halogens, and iii) Halo-C 1~6 - selected from alkyl; R 7 , R 8 and R 9 independently, C 1~6 - alkyl The compound or a pharmaceutically acceptable salt thereof is provided.

[0038] Further specific embodiments of the present invention are compounds according to formula (I) described herein, R 1 C 1~6 is alkyl; R 3 is F; X is CR 6 and; R 6 is F; R 4 is Cl; R 5 Halo-C 1~6 - alkyl The compound or a pharmaceutically acceptable salt thereof is provided.

[0039] Another embodiment of the present invention is a compound according to formula (I) described herein, R 1 teeth i)R 7 , R 8 and R 9 C optionally substituted with 3~8 -cycloalkyl, ii) Amino-C 1~6 -Alkyl iii)R 7 , R 8 and R 9 pyrazolyl optionally substituted by iv) R 7 , R 8 and R 9 pyridinyl optionally substituted by v)R 7 , R 8 and R 9 pyrimidinyl optionally substituted by vi)R 7 , R 8 and R9 pyridazinyl optionally substituted by vii)R 7 , R 8 and R 9 and optionally substituted tetrahydropyranyl.

[0040] Another embodiment of the present invention is a compound according to formula (I) described herein, R 1 teeth i) H, ii) C 1~6 -alkyl, iii) H, iv) C 1~6 -alkyl, v) hydroxy, vi) Hydroxy-C 1~6 -alkyl, vii)R 7 , R 8 and R 9 C optionally substituted with 3~8 -cycloalkyl, viii)R 7 , R 8 and R 9 pyrazolyl optionally substituted by ix)R 7 , R 8 and R 9 pyrimidinyl optionally substituted by x)R 7 , R 8 and R 9 pyridazinyl optionally substituted by xi)R 7 , R 8 and R 9 and optionally substituted tetrahydropyranyl.

[0041] Another embodiment of the present invention is R 1 C 1~6 Provided are compounds according to formula (I) described herein, wherein:

[0042] Another embodiment of the present invention is R 3 is F.

[0043] Another embodiment of the present invention is a compound in which X is CR 6

[0013] In accordance with the present invention, there is provided a compound according to formula (I) as described herein, wherein:

[0044] Another embodiment of the present invention is R 6 is F.

[0045] Another embodiment of the present invention is R 4 is Cl.

[0046] Another embodiment of the present invention is a compound according to formula (I) described herein, 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.

[0047] Another embodiment of the present invention is a compound according to formula (I) described herein, R 5 teeth I C 1~6 -alkyl, ii) halogens, and iii) Halo-C 1~6 -alkyl.

[0048] Another embodiment of the present invention is R 5 Halo-C 1~6 Provided are compounds according to formula (I) described herein, wherein:

[0049] Another particular embodiment of the present invention is R 7 , R 8 and R 9 independently C 1~6 -alkyl.

[0050] Specific examples of compounds of formula (I) described herein include: 8-Bromo-7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-Bromo-7-chloro-1-cyclopropyl-6-(2-fluorophenyl)-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]benzodiazepine; 7,8-Dichloro-6-(2-fluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-Dichloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-8-cyclopropyl-6-(2,6-difluorophenyl)-1-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]benzodiazepine; 8-Bromo-7-chloro-6-(2-fluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-Dichloro-6-(2,6-difluorophenyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one; 7,8-Dichloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-Dichloro-6-(2,6-difluorophenyl)-1-tetrahydropyran-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-Dichloro-6-(2,6-difluorophenyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-Bromo-7-chloro-6-(2,6-difluorophenyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one; 7,8-Dichloro-6-(2,6-difluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-Dichloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-8-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one; 7-chloro-6-(2,6-difluorophenyl)-8-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-Dichloro-6-(2-fluorophenyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-Dichloro-6-(2,6-difluorophenyl)-1-(2-methoxyethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-1,8-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-8-(difluoromethyl)-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-Bromo-7-chloro-6-(3-fluoro-2-pyridyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-8-(difluoromethyl)-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-Bromo-7-chloro-6-(2-fluorophenyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one; 7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-Dichloro-6-(2,6-difluorophenyl)-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-Bromo-7-chloro-6-(3-fluoro-2-pyridyl)-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-1-yl]methanol; 7-chloro-6-(2,6-difluorophenyl)-8-iodo-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-1-yl]methanamine hydrochloride; 7-chloro-6-(2,6-difluorophenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-1-pyridazin-3-yl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-8-iodo-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-Dibromo-6-(2,6-difluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-Dibromo-6-(2,6-difluorophenyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-Bromo-7-chloro-6-(3-chloro-2-pyridyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-Bromo-7-chloro-6-(3-fluoro-2-pyridyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-Bromo-7-chloro-6-(3-fluoro-2-pyridyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-Bromo-7-chloro-6-(3-chloro-2-pyridyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-8-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-8-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-Bromo-7-chloro-6-(2-chloro-6-fluoro-phenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-Dichloro-6-(3-fluoro-2-pyridyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-Dichloro-6-(3-fluoro-2-pyridyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-8-methoxy-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-Dichloro-6-(3-fluoro-2-pyridyl)-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-Dichloro-6-(3-fluoro-2-pyridyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one; 7,8-Dichloro-6-(3-fluoro-2-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-8-methoxy-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-8-methoxy-1-(3-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-Dichloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(3-fluoro-2-pyridyl)-1-pyrimidin-4-yl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(3-fluoro-2-pyridyl)-1-(1-methylpyrazol-4-yl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-Dichloro-6-(3-fluoro-2-pyridyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(3-fluoro-2-pyridyl)-1-pyridazin-3-yl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-Bromo-7-chloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(3-fluoro-2-pyridyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-1-cyclopropyl-6-(2,6-difluorophenyl)-8-methoxy-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-Dichloro-6-(2,6-difluorophenyl)-1-methoxy-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; trans-7,8-Dichloro-6-(2,6-difluorophenyl)-1-(3-methoxycyclobutyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-Bromo-7-chloro-6-(2,6-difluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; or a pharmaceutically acceptable salt thereof.

[0051] Further specific examples of compounds of formula (I) described herein are: 7-chloro-6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; or a pharmaceutically acceptable salt thereof.

[0052] Even more specific examples of compounds of formula (I) described herein are: 7-chloro-6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, compounds of formula (I) are isotopically labeled by replacing one or more atoms therein with atoms having a different atomic mass or mass number. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Examples of isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, e.g., 2 H, 3 H, 11 C.13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Certain isotopically labeled compounds of formula (I), for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e., 3 H and carbon-14, i.e., 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. For example, compounds of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99% of a given isotope.

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

[0055] Substitution with positron emitting isotopes, such as C, F, O and N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of formula (I) can be prepared by methods analogous to those described in the Examples below, or by conventional techniques known to those skilled in the art, generally using an appropriate isotopically labeled reagent in place of a 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 compounds 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 products 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 specified.

[0058] More specifically, the compound of formula (I) can be prepared by the methods shown below, the methods shown in the Examples, or similar methods. Suitable reaction conditions for each reaction step are known to those skilled in the art. The reaction order is not limited to those shown in Schemes 1 to 3, but the order of reaction steps can be freely changed depending on the starting materials and their respective reactivities. Starting materials are commercially available or can be prepared by methods similar to those shown below, methods described in the references or examples cited herein, or methods known in the art.

[0059] The compounds of formula (I) of the present invention and pharmaceutically acceptable salts thereof can be prepared by the process described below (Scheme 1). [ka]

[0060] Scheme 1: Synthesis of benzodiazepines (I) where all definitions are as defined above and in the claims.

[0061] According to Scheme 1, compounds of formula (I) can be prepared in two steps starting from lactam building blocks of formula (II) (A-F, H-K, N, P). After thionation using Lawesson's reagent or P2S5, lactam (II) is converted to the corresponding thiolactam (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 thiolactam (II) with hydrazine to form hydrazones (V), followed by treatment with triethyl orthoacetate or triethyl orthoformate.

[0062] R 1 In a particular embodiment of the present invention, where V is hydroxyl (OH), the benzodiazepines of formula (I) can be obtained in two steps according to the method 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 represented exclusively in their most stable form (triazolone). To this end, the hydrazones (V) can be reacted with 1,1'-carbonyldiimidazole (CDI) to obtain the triazolones of formula (I) (Scheme 2). [ka]

[0063] Scheme 2: R 1 Synthesis of benzodiazepines (I) wherein is hydroxyl; all other definitions are as defined above and in the claims.

[0064] The synthesis of building blocks of formula (II) (A–F, H–K, N, P) 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 from the corresponding aryl bromide or via kinetic deprotonation) can be reacted with benzoxazin-4-one (electrophile) at controlled temperatures to afford ketones of formula (VII). After N-acetamide hydrolysis under acidic conditions (HCl), compounds of formula (VII) are converted to anilines of formula (VIII). Conveniently, R at this junction can be used. 5 The halogen can be introduced by treatment with N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), or N-iodosuccinimide (NIS) to give intermediates of formula (IX). Final thermal cyclization with ethyl 2-aminoacetate hydrochloride in pyridine gives the desired benzodiazepine (II), presumably via formation of the imine intermediate (X). [ka]

[0065] Scheme 3: R 5 Synthesis of building blocks (A-F, H-K, N, P) where is Cl, Br or I, and all other definitions are as defined above and in the claims.

[0066] Also an embodiment of the present invention is a process for the preparation of a compound of formula (I) as defined above, comprising 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, between room temperature and the reflux of the solvent, particularly at the reflux temperature of the solvent. [ka] (In the formula, R 1 , R3 , R 4 and R 5 is as defined herein).

[0067] Also an object of the present invention are compounds of formula (I), more particularly compounds of formula (I), as described herein for use as therapeutically active substances.

[0068] Likewise, an object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as described herein, more particularly a compound of formula (I), and a therapeutically inert carrier.

[0069] A particular embodiment of the present invention is a compound according to formula (I) as described herein or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of, 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).

[0070] The present invention also relates to the use of a compound according to formula (I) as defined herein or a pharmaceutically acceptable salt thereof, more particularly a compound of formula (I), for the preparation of a medicament for the treatment or prevention, more particularly the treatment of negative and / or cognitive symptoms associated with Alzheimer's disease, mild cognitive impairment (MCI), age-related cognitive decline, 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).

[0071] Also an object of the present invention is a method for the treatment or prevention, more particularly for 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), which method comprises administering an effective amount of a compound according to formula (I), more particularly a compound of formula (I), as described herein.

[0072] Also, one embodiment of the present invention is a compound of formula (I) as described herein, more particularly a compound of formula (I) as described herein when prepared by any of the processes described.

[0073] Assay procedure γ1-containing GABA A Membrane preparation and binding assays for subtypes GABA AThe affinity of compounds for γ1 subunit-containing receptors was determined by measuring the [ α5β2γ1, α2β2γ1, α1β2γ1 ] binding to membranes from HEK293F cells (ThermoFisher R 79007) expressing human (transiently transfected) receptors of the composition α5β2γ1, α2β2γ1, α1β2γ1. 3 Due to better protein expression of α2 subunit-containing receptors, human GABA receptors were measured by competition for binding with [H]RO7239181 (67.3 Ci / mmol; Roche). A The 28 amino acid long signal peptide (Met1 to Ala28) of the α2 subunit binds to human GABA A The 31 amino acid long signal peptide (Met1 to Ser31) of the α5 subunit was substituted.

[0074] Different GABA APellets collected from HEK293F cells expressing receptor subtypes were resuspended in mannitol buffer pH 7.2–7.4 (0.29 M mannitol, 10 mM triethylamine, 10 mM acetic acid, 1 mM EDTA + protease inhibitors (20 tablets per liter, Roche Diagnostics, catalog number 05 056 489 001)), washed twice, and then resuspended at a 1:10–1:15 dilution in the same buffer. Cell disruption was performed by agitating the suspension at 435 psi for 15 min in a Parr vessel #4637. The suspension was then centrifuged at 1000 × g 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 1500 × g for 10 minutes at 4°C (Beckman Avanti J-HC; rotor JS-4.2). The supernatant (S1) was then transferred to a 2 L Schott flask, and the pellet was discarded. The supernatant (S1) was centrifuged in a 500 ml Beckman polypropylene centrifuge beaker at 15,000 × g for 30 minutes at 4°C (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 in a 100 ml Beckman polypropylene centrifuge tube at 48,000 × g for 50 minutes at 4°C (Beckman Avanti J-20 XP; rotor JA-18). The supernatant (S3) was discarded and the pellet (P3) was resuspended in 1:1 mannitol buffer. P2 and P3 protein concentrations were determined using the BIORAD Standard assay with bovine serum albumin as the standard and measured on a NANO-Drop 1000. The membrane suspension was aliquoted (500 μl / tube) and stored at -80°C until needed.

[0075] Membrane homogenates were resuspended and polytronized (Polytron PT1200E Kinematica AG) in 10 mM potassium phosphate, 100 mM KCl binding buffer, pH 7.4, to the final assay concentration determined in previous experiments.

[0076] Radioligand binding assays were performed using 100 μL of cell membranes containing 1.5 nM (α5β2γ1) or 20–30 nM (α1β2γ1, α2β2γ1) of [ 3 H]RO7239181, and [0.3-10000] x 10 -9 The assay was performed in a volume of 200 μL (96-well plate) containing test compounds ranging in M. Nonspecific binding was 10 × 10 -6 (α5β2γ1) and 30×10 -6 The binding of αββγγ1 was defined by M RO 7235136 and typically represented less than 5% (α5βγγ1) and less than 20% (α1βγγ1, α2βγγ1) of total binding. Assays were incubated at 4°C for 1 hour to equilibrate, and then membranes were filtered onto unifilters (96-well white microplates pre-incubated with GF / C filters in 0.3% polyethyleneimine for 20-50 minutes) 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, filter-retained radioactivity was detected by liquid scintillation counting. i Values ​​were calculated using Excel-Fit (Microsoft) and are the mean of duplicate measurements.

[0077] The compounds of the accompanying examples were tested in the above assay and preferred compounds exhibited a GABA receptor activity of 100 nM or less. A [from γ1 subunit-containing receptors (e.g., α5β2γ1, α2β2γ1, α1β2γ1)] 3 H]RO7239181 substitution iCompounds with a Ki (nM) <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.

[0078] [ 3 H] Preparation of RO7239181, 6-chloro-5-(2,6-difluorophenyl)-7-methyl-1-(tritrithiomethyl)-3H-1,4-benzodiazepin-2-one [ka]

[0079] 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 HO (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 aqueous NaHCO (20 mL), and extracted with EtOAc (2 × 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] + ).

[0080] b) 6-chloro-5-(2,6-difluorophenyl)-7-methyl-1-(tritritiomethyl)-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) in THF (200 μL) 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) 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 the target compound with a radiochemical purity of >99% and 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. 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 for γ2 subunit-containing receptors was determined by transfection of HEK293F cells expressing human (transiently transfected) receptors of the composition α1β3γ2. 3H] flumazenil (81.1 Ci / mmol; Roche) binding was measured by competition.

[0082] Different GABA A Pellets collected from HEK293F cells expressing the γ2 receptor subtype were resuspended in mannitol buffer pH 7.2–7.4 and GABA A Cells expressing γ1 subunit-containing receptors were treated as described 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 ranging in M. Nonspecific binding was determined by 10 -5 The binding of diazepam was defined as M and was typically less than 5% of total binding. Assays were incubated at equilibrium for 1 hour at 4°C, filtered using a Packard harvester, and harvested onto GF / C unifilters (Packard) by washing with ice-cold wash buffer (50 mM Tris, pH 7.5). After drying, radioactivity retained on the filters was detected by liquid scintillation counting. i Values ​​were calculated using Excel-Fit (Microsoft) and are the mean of duplicate measurements.

[0084] The compounds of the accompanying examples were tested in the above assay and preferred compounds exhibited a GABA receptor activity greater than 100 nM. A from the α1β3γ2 subtype of receptor [ 3 H]flumazenil substitution with large K i It was found that the value of K i Most preferred are compounds with α1β3γ2 (nM) > 300. In a preferred embodiment, the compounds of the present invention are γ2 subunit-containing GABA receptors. A γ1 subunit-containing GABA receptors A Specifically, the compounds of the present invention exhibit a greater than 10-fold increase in K iα1β3γ2(nM) / K i The 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 are shown in Table 1 below. [Table 1] JPEG0007754839000008.jpg235161 JPEG0007754839000009.jpg234161 JPEG0007754839000010.jpg190161

[0085] GABA A functional expression of receptors; Preparation of Xenopus oocytes Xenopus laevis oocytes at maturation stages V-VI were treated with GABA A Cloned mRNAs encoding receptor subunits were used for expression. Oocytes prepared for RNA microinjection were purchased from Ecocyte, Kastrup-Rauxel, Germany, and stored 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.

[0086] Xenopus oocyte microinjection Oocytes were plated in 96-well plates for microinjection using the Roboinject automated device (MultiChannelSystems, Reutlingen, Germany). AApproximately 50 nL of aqueous solution containing RNA transcripts of the subunits of the receptor subtype was injected into each oocyte. The RNA concentration ranged between 20 and 200 pg / µL / subunit and was adjusted in pilot experiments to detect GABA receptor subtypes. A GABA responses of appropriate size and maximal effect were obtained with the reference benzodiazepine positive allosteric modulators (PAMs) flunitrazepam, triazolam, and midazolam at the receptor benzodiazepine (BZD) binding site. Oocytes were maintained 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.

[0087] electrophysiology Electrophysiological experiments were performed 3–5 days after mRNA microinjection using a Robocyte instrument (MultiChannelSystems, Reutlingen, Germany). During the experiment, oocytes were constantly 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 1 M KCl + 1.5 M K-acetate 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 with GABA, the maximum current response (EC) was recorded. 20 ) was added for 1.5 min at a concentration that evoked approximately 20% of the K. After another rest interval of 2.5 min, GABA was added again, eliciting responses of similar amplitude and shape. After this second GABA application 0.5 min later, approximately 30-fold higher K i Test compounds were added while GABA was still present, at concentrations corresponding to α2β2γ1. Current traces were recorded at a digitization rate of 10 Hz before, during, and after GABA application.

[0088] 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, stimulated α2β2γ1 GABA receptor-expressing oocytes. A It potentiated GABA-induced currents at the receptor subtype by approximately 60%.

[0089] Data analysis For analysis, the digitized current traces of the first and second GABA responses were overlaid and, if necessary, rescaled to equal maximal amplitude. The ratio between the two responses was calculated point-by-point during the time interval of the test compound experiment. The extreme value of the resulting "ratio trace" was designated the "GABA EC 20 The efficacy of the compound ("fold increase") was taken as "% modulation of the serotonin level" (100*(fold increase-1)).

[0090] The results are shown in Table 2. [Table 2] JPEG0007754839000012.jpg235161 JPEG0007754839000013.jpg233161 JPEG0007754839000014.jpg91161

[0091] reference compound The reference compounds listed below (classical commercial benzodiazepines) and their structural analogs also inhibit GABA A Receptor α1β2γ1 and α2β2γ1 subtypes and GABA A The affinity for the α1β3γ2 receptor subtype was tested, and the results are shown in Table 3. [ka] [Table 3]

[0092] 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, dragees, hard or soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), rectally (e.g., in the form of suppositories), or topically to the eye (e.g., in the form of solutions, ointments, gels or water-soluble polymer inserts). However, administration can also be carried out parenterally, such as intramuscularly, intravenously or intraocularly (e.g., in the form of sterile injection solutions).

[0093] The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the preparation of tablets, coated tablets, dragees, hard gelatin capsules, injections or external preparations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such adjuvants for tablets, dragees and hard gelatin capsules.

[0094] Suitable adjuvants for soft gelatin capsules include, by way of example, vegetable oils, waxes, fats, semisolids, liquid polyols, and the like.

[0095] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.

[0096] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0097] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0098] Suitable adjuvants for topical ophthalmic formulations are, for example, cyclodextrin, mannitol, or many other carriers and additives known in the art.

[0099] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking agents, or antioxidants. The pharmaceutical preparations of the present invention may further contain other therapeutically valuable substances.

[0100] The dosage can vary widely and will, of course, be adapted to the individual requirements of each particular case. Generally, 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 individually in 1 to 3 doses, which, if appropriate, can be composed of equal amounts. For topical administration, the formulation can contain 0.001% to 15% by weight of the drug, and the required amount, which can be between 0.1 and 25 mg, can be administered as a single dose per day, a single dose per week, multiple doses (2 to 4 times per day), or multiple doses per week. However, it is clear that, where indicated, the upper or lower limits set forth herein may be exceeded.

[0101] Preparation of Pharmaceutical Compositions Comprising Compounds of the Invention Tablets of the following composition are prepared in the usual way: [Table 4]

[0102] 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.

[0103] Capsules of the following composition are prepared: [Table 5]

[0104] 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.

[0105] The compound of formula I, lactose, and cornstarch are first mixed in a mixer, then mixed in a grinder. The mixture is returned to the mixer, and talc is added thereto and roughly mixed. The mixture is then filled into a suitable capsule, such as a hard gelatin capsule, by machine.

[0106] An injection solution having the following composition is prepared. [Table 6]

[0107] The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0108] Where preparations are obtained as mixtures of enantiomers, pure enantiomers can be obtained by methods described herein or known to those skilled in the art, such as chiral chromatography or crystallization. [Example]

[0109] Building Block A 7-Bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0110] 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 hours. The reaction mixture was concentrated in vacuo. The crude residue obtained was suspended in ethyl acetate (1000 mL), stirred for 30 minutes, filtered, and dried in vacuo to give the title compound (238 g, 84%) as a gray solid. 1 HnmR(DMSO-d6,400 MHz):δ:7.80(app t,J=8.0Hz,1H),7.62(d,J=8.0Hz,1H),7.49(d,J=7.6Hz,1H),2.36(s,3H).

[0111] 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) under nitrogen at −70 °C, i-PrMgCl·LiCl (1.3 m, 500 mL, 650 mmol) was added dropwise. 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 in vacuo. The residue was suspended in ethyl acetate (150 mL). The resulting suspension was stirred at room temperature for 20 min, filtered, and dried in vacuo to afford the title compound (113 g, 71%) as an off-white solid. 1 HnmR(DMSO-d6,400 MHz):δ:9.85(s,1H),7.65-7.45(m,1H),7.40(t,J=7.2Hz,1H),7.38-7.34(m,2H),7.16(t,J=8.8Hz,2H),1.85(s,3H).

[0112] 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 hour 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 in vacuo. Petroleum ether (120 mL) was added to the crude product, and the suspension was stirred at room temperature for 20 minutes. The solid was filtered and dried to give the title compound (88 g, 90%) as a yellow solid. 1 HnmR(DMSO-d6,400 MHz):δ:7.62-7.56(m,1H),7.21-7.15(m,3H),6.83(d,J=7.6Hz,1H),6.74(s,2H),6.58(d,J=7.6Hz,1H).

[0113] 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 × 500 mL), dried over sodium sulfate, and concentrated in vacuo. 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 in vacuo 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.

[0114] 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 hours. The reaction mixture was concentrated in vacuo to remove pyridine. The residue was diluted with ethyl acetate (2000 mL), washed with aqueous HCl (1.0 m, 3×1500 mL), water (2000 mL), and brine (2×1000 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. 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.

[0115] Building Block B 7-Bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0116] 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 (2×250 mL) and ethyl acetate (2×250 mL). The combined organic phases were washed with brine (200 mL), dried over sodium sulfate, and concentrated in vacuo. 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.

[0117] 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%), which was obtained as a yellow solid. MS: 250.1 ([M+H] + ),ESI pos.

[0118] c) (6-amino-3-bromo-2-chloro-phenyl)-(2-fluorophenyl)methanone Similar to the experiment on building block Ad, (2-amino-6-chloro-phenyl)-(2-fluorophenyl)methanone was converted to the title compound (32.4 g, 70%), which was obtained 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.

[0119] 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 hours. The reaction mixture was cooled to room temperature, and most of the pyridine was removed in vacuo. 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 in vacuo. 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 in vacuo 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.

[0120] Building Block C 6,7-Dichloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0121] a) (6-amino-2,3-dichloro-phenyl)-(2-fluorophenyl)methanone As in the experiment for building block A d, (2-amino-6-chloro-phenyl)-(2-fluorophenyl)methanone was converted to the title compound (234 mg, 53%) using 1-chloropyrrolidine-2,5-dione, which was obtained as an orange-yellow solid. MS: 284.0 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0122] b) 6,7-dichloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Bd, (6-amino-2,3-dichloro-phenyl)-(2-fluorophenyl)methanone was converted to the title compound (193 mg, 74%), which was obtained as a grey solid. MS: 323.2 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0123] Building Block D 6,7-Dichloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0124] a) (6-amino-2,3-dichloro-phenyl)-(2,6-difluorophenyl)methanone As in the experiment for building block A d, (2-amino-6-chloro-phenyl)-(2,6-difluorophenyl)methanone was converted to the title compound (3.44 mg, 47%) using 1-chloropyrrolidine-2,5-dione, which was obtained as a yellow solid. MS: 302.0 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0125] b) 6,7-dichloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Ae, (6-amino-2,3-dichloro-phenyl)-(2,6-difluorophenyl)methanone was converted to the title compound (2.6 g, 53%), which was obtained as a yellow solid, MS: 341.0 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0126] Building Block E 7-Bromo-6-chloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0127] a) N-[3-chloro-2-(3-fluoropyridine-2-carbonyl)phenyl]acetamide To a solution of 2-bromo-3-fluoropyridine (18.0 g, 102 mmol) in methyl tert-butyl ether (720 mL) was slowly added n-BuLi (2.5 m in tetrahydrofuran, 36.8 mL, 92.02 mmol) at −60° C. The mixture was stirred for 1 hour, and then a solution of 5-chloro-2-methyl-3,1-benzoxazin-4-one (10.0 g, 51.1 mmol) in tetrahydrofuran (600 mL) was added dropwise. The mixture was stirred at −60° C. for 1 hour and then quenched by the addition of saturated aqueous ammonium chloride solution (50 mL). The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated in vacuo. Purification by flash column chromatography (dichloromethane / methanol 50:1 to 20:1) afforded the title compound (5.20 g, 23.2%) as a pale yellow solid. MS: 293.1 ([M+H] + ),ESI pos.

[0128] b) (2-amino-6-chloro-phenyl)-(3-fluoro-2-pyridyl)methanone A suspension of N-[3-chloro-2-(3-fluoropyridine-2-carbonyl)phenyl]acetamide (4.00 g, 13.7 mmol) in hydrochloric acid (4 m in methanol, 68 mL, 273 mmol) was stirred at 40 °C for 24 h. After cooling to room temperature, a saturated aqueous solution of sodium bicarbonate was added dropwise to pH 8-9. The mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and concentrated in vacuo. Purification by flash column chromatography (petroleum ether / ethyl acetate 3:1 to 20:1) afforded the title compound (3.00 g, 86%) as a yellow solid. MS: 251.1 ([M+H] + ),ESI pos.

[0129] c) (6-amino-3-bromo-2-chloro-phenyl)-(3-fluoro-2-pyridyl)methanone Similar to the experiment on building block Ad, (2-amino-6-chloro-phenyl)-(3-fluoro-2-pyridyl)methanone was converted to the title compound (4.50 g, 74%), which was obtained as a yellow solid, MS: 328.9 ([{ 79 Br, 35 Cl}M+H] + ),ESI pos.

[0130] d) 7-Bromo-6-chloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Bd, (6-amino-3-bromo-2-chloro-phenyl)-(3-fluoro-2-pyridyl)methanone was converted to the title compound (550 mg, 24%), which was obtained as a pale pink solid. MS: 368.0 ([{ 79 Br, 35 Cl}M+H] + ),ESI pos.

[0131] Building Block F 6-chloro-5-(2-fluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0132] a) (6-amino-2-chloro-3-iodo-phenyl)-(2-fluorophenyl)methanone As in the experiment for building block A d, 1-iodopyrrolidine-2,5-dione was used to convert (2-amino-6-chloro-phenyl)-(2-fluorophenyl)methanone to the title compound (3.2 g, 76%) as a brown solid. The crude product was used directly in the next step without further characterization.

[0133] b) 6-chloro-5-(2-fluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Bd, (6-amino-2-chloro-3-iodo-phenyl)-(2-fluorophenyl)methanone was converted to the title compound (1.1 g, 45%), which was obtained as a yellow solid. MS: 415.0 ([M+H] + ),ESI pos.

[0134] Building Block H 6-chloro-5-(2-fluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one [ka] a) (6-amino-2-chloro-3-iodo-phenyl)-(2,6-difluorophenyl)methanone Analogously to the experiment for building block Ad, 1-iodopyrrolidine-2,5-dione was used to convert (2-amino-6-chloro-phenyl)-(2,6-difluorophenyl)methanone to the title compound (7.1 g, 85%), which was obtained as a yellow solid. MS: 393.8 ([M+H] +),ESI pos.

[0135] b) 6-chloro-5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Ae, (6-amino-2-chloro-3-iodo-phenyl)-(2,6-difluorophenyl)methanone was converted to the title compound (2.7 g, 68%), which was obtained as a yellow solid. MS: 432.8 ([M+H] + ),ESI pos.

[0136] Building Block I 6,7-Dibromo-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0137] a) 5-bromo-2-methyl-3,1-benzoxazin-4-one Similar to the experiment for building block Aa, 2-amino-6-bromobenzoic acid was converted to the title compound (15.4 g, 92%), which was obtained as a light brown powder. MS: 240.1 ([{ 79 Br}M+H] + ),ESI pos.

[0138] b) N-[3-bromo-2-(2,6-difluorobenzoyl)phenyl]acetamide Similarly to the experiment for building block Ab, 5-bromo-2-methyl-3,1-benzoxazin-4-one was converted to the title compound (8.3 g, 62%), which was obtained as a brown solid. MS: 354.0 ([{ 79 Br}M+H] + ),ESI pos.

[0139] c) N-[3,4-dibromo-2-(2,6-difluorobenzoyl)phenyl]acetamide To a solution of N-[3-bromo-2-(2,6-difluorobenzoyl)phenyl]acetamide (5.43 g, 15.3 mmol) in N,N-dimethylformamide (100 mL) and acetic acid (44 mL, 767 mmol) was added 1-bromopyrrolidine-2,5-dione (4.09 g, 23 mmol) at 0° C. The reaction mixture was stirred at 60° C. for 22 hours. After adding an additional amount of 1-bromopyrrolidine-2,5-dione (1.36 g, 7.67 mmol), the mixture was stirred at 60° C. for 22 hours. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate (500 mL). The organic phase was washed with water (500 mL) and brine (500 mL). The aqueous layer was back-extracted with ethyl acetate (500 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica, heptane / ethyl acetate, 1:0 to 1:1) to give the title compound (6.18 g, 93%) as a yellow solid. MS: 431.9 ([{ 79 Br, 79 Br}M+H] + ),433.9([{ 79 Br, 81 Br}M+H] + ),ESI pos.

[0140] d) (6-amino-2,3-dibromo-phenyl)-(2,6-difluorophenyl)methanone Similarly to the experiment for building block Ac, N-[3,4-dibromo-2-(2,6-difluorobenzoyl)phenyl]acetamide was converted to the title compound (3.93 g, 70%), which was obtained as a yellow solid. MS: 389.9 ([{ 79 Br, 79 Br}M+H] + ),391.8([{ 79 Br, 81 Br}M+H] + ),ESI pos.

[0141] e) 6,7-dibromo-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Ae, (6-amino-2,3-dibromophenyl)-(2,6-difluorophenyl)methanone was converted to the title compound (270 mg, 37%), which was obtained as a yellow solid. MS: 429.0 ([{ 79 Br, 79 Br}M+H] + ),430.9([{ 79 Br, 81 Br}M+H] + ),ESI pos.

[0142] Building Block J 7-Bromo-6-chloro-5-(3-chloro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0143] a) N-[3-chloro-2-(3-chloropyridine-2-carbonyl)phenyl]acetamide Analogously to the experiment for building block Ea, 5-chloro-2-methyl-3,1-benzoxazin-4-one was converted to the title compound (3.6 g, 40%) using 2-bromo-3-fluoro-pyridine, which was obtained as a pale yellow solid. MS: 309.0 ([M+H] + ),ESI pos.

[0144] b) (2-amino-6-chloro-phenyl)-(3-chloro-2-pyridyl)methanone Similarly to the experiment for building block Ac, N-[3-chloro-2-(3-chloropyridine-2-carbonyl)phenyl]acetamide was converted to the title compound (2.2 g, 71%), which was obtained as a yellow solid. MS: 267.1 ([M+H] + ),ESI pos.

[0145] c) (6-amino-3-bromo-2-chloro-phenyl)-(3-chloro-2-pyridyl)methanone Analogously to the experiment for building block Bc, (2-amino-6-chloro-phenyl)-(3-chloro-2-pyridyl)methanone was converted to the title compound (2.9 g, 66%), which was obtained as a yellow solid. MS: 344.9 ([{ 79 Br, 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0146] d) 7-Bromo-6-chloro-5-(3-chloro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Bd, (6-amino-3-bromo-2-chloro-phenyl)-(3-chloro-2-pyridyl)methanone was converted to the title compound (380 mg, 24%), which was obtained as a white solid. MS: 383.9 ([{ 79 Br, 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0147] Building Block K 7-Bromo-6-chloro-5-(2-chloro-6-fluoro-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0148] a) N-[3-chloro-2-(2-chloro-6-fluoro-benzoyl)phenyl]acetamide To a mixture of 1-chloro-3-fluorobenzene (7.27 g, 55.66 mmol), diisopropylamine (512 mg, 5.06 mmol), and N,N,N',N'-tetramethylethylenediamine (7.06 g, 60.72 mmol) in tetrahydrofuran (100 mL) was added n-BuLi (2.5 m, 24.3 mL, 60.7 mmol) in tetrahydrofuran. The reaction mixture was stirred at -65 °C for 1 hour. A solution of 5-chloro-2-methyl-3,1-benzoxazin-4-one (10.0 g, 50.6 mmol) in tetrahydrofuran (300 mL) was added dropwise, and the reaction mixture was stirred at -65 °C for 0.5 hours before being quenched by the addition of saturated aqueous ammonium chloride (150 mL). The resulting mixture was diluted with ethyl acetate (200 mL). The organic phase was washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (silica, petroleum ether / ethyl acetate 10:1 to 5:1 to 3:1) to give the title compound (2.4 g, 15%) as a pale yellow solid. MS: 325.9 ([M+H] + ),ESI pos.

[0149] b) (2-amino-6-chloro-phenyl)-(2-chloro-6-fluoro-phenyl)methanone Analogously to the experiment for building block Ac, N-[3-chloro-2-(2-chloro-6-fluoro-benzoyl)phenyl]acetamide was converted to the title compound (1.9 g, 91%), which was obtained as a yellow solid. MS: 284.1 ([M+H] + ),ESI pos.

[0150] c) (6-amino-3-bromo-2-chloro-phenyl)-(2-chloro-6-fluoro-phenyl)methanone Similarly to the experiment for building block Ad, (2-amino-6-chloro-phenyl)-(2-chloro-6-fluoro-phenyl)methanone was converted to the title compound (1.74 g, 72%) as a yellow solid. The crude product was used directly in the next step without further characterization.

[0151] d) 7-Bromo-6-chloro-5-(2-chloro-6-fluoro-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Ae, (6-amino-3-bromo-2-chloro-phenyl)-(2-chloro-6-fluoro-phenyl)methanone was converted to the title compound (32.5 mg, 15%), which was obtained as a pale yellow solid. MS: 400.9 ([{ 79 Br, 35 Cl, 35 Cl}M+H] + ),402.8([{ 81 Br, 35 Cl, 35 Cl or 79 Br, 37 Cl, 35 Cl}M+H] + ),ESI pos.

[0152] Building Block N 6,7-Dichloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0153] a) N-[3,4-dichloro-2-(3-fluoropyridine-2-carbonyl)phenyl]acetamide As in the experiment for building block A d, 1-chloropyrrolidine-2,5-dione was used to convert N-[3-chloro-2-(3-fluoropyridine-2-carbonyl)phenyl]acetamide to the title compound (36 g, 84%), which was obtained as a white solid. MS: 327.0 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0154] b) (6-amino-2,3-dichloro-phenyl)-(3-fluoro-2-pyridyl)methanone Similar to the experiment for building block Eb, N-[3,4-dichloro-2-(3-fluoropyridine-2-carbonyl)phenyl]acetamide was converted to the title compound (11.0 g, 85%), which was obtained as an orange solid. MS: 285.0 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0155] c) 6,7-dichloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepin-2-one Similar to the experiment for building block Bd, N-[3,4-dichloro-2-(3-fluoropyridine-2-carbonyl)phenyl]acetamide was converted to the title compound (3.76 g, 28%), which was obtained as a white solid. MS: 323.7 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0156] Building Block P 6-chloro-5-(3-fluoro-2-pyridyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0157] a) (6-amino-2-chloro-3-iodo-phenyl)-(3-fluoro-2-pyridyl)methanone Analogously to the experiment for building block Ad, (2-amino-6-chloro-phenyl)-(3-fluoro-2-pyridyl)methanone was converted to the title compound (28 g, 93%) using 1-iodopyrrolidine-2,5-dione, which was obtained as a yellow solid. MS: 376.9 ([M+H] + ),ESI pos.

[0158] b) 6-chloro-5-(3-fluoro-2-pyridyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Bd, (6-amino-2-chloro-3-iodo-phenyl)-(3-fluoro-2-pyridyl)methanone was converted to the title compound (9.0 g, 58%), which was obtained as a pale pink solid. MS: 416.0 ([M+H] + ),ESI pos.

[0159] Example 1 8-Bromo-7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0160] 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 block A, 6.7 g, 17.4 mmol) in toluene (167 mL) at room temperature was added Lawesson's reagent (8.43 g, 20.9 mmol). 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 in vacuo. The crude material was purified by flash column chromatography (silica, 15-30% ethyl acetate in heptane) to afford 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.

[0161] b) 8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine A microwave vial was charged with 7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione (4.53 g, 11.3 mmol), acetohydrazide (1.67 g, 22.6 mmol), and butan-1-ol (45 mL). The vial was capped and heated to 150 °C in a microwave oven for 1 h. The reaction mixture was purified directly by flash column chromatography (silica, 0-5% methanol in dichloromethane) to afford the title compound (3.01 g, 63%) as a yellow foam. MS: 423.1 ([{ 79 Br, 35 Cl}M+H] + ),425.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0162] Example 2 8-Bromo-7-chloro-1-cyclopropyl-6-(2-fluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0163] a) 7-bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione In a similar manner to the experiment in Example 1a, 7-bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block B) 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.

[0164] b) 8-bromo-7-chloro-1-cyclopropyl-6-(2-fluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine To a solution of 7-bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione (80 mg, 0.210 mmol) in butan-1-ol (1.5 mL) was added cyclopropanecarbohydrazide (41 mg, 0.420 mmol). The reaction mixture was stirred at 130° C. for 12 hours. The mixture was diluted with ethyl acetate (100 mL), washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Gemini, 0.05% ammonia hydroxide in water / acetonitrile) and lyophilized to give the title compound (5.5 mg, 6%) as a white solid. MS: 431.1 ([{ 79 Br, 35 Cl}M+H] + ),433.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0165] Example 3 8-Bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0166] In a manner similar to that described in Example 1b, 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, which was obtained 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.

[0167] Example 4 7,8-Dichloro-6-(2-fluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0168] To a suspension of 6,7-dichloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block C, 70 mg, 0.217 mmol) in 1,4-dioxane (1 mL) was added Lawesson's reagent (114 mg, 0.282 mmol). The reaction mixture was heated to 80° C. for 4 h and then cooled to room temperature. A solution of acetohydrazide (32.1 mg, 0.433 mmol) in 1,4-dioxane (0.5 mL) was added, and the mixture was heated to 140° C. in a microwave oven for 1 h. An additional amount of acetohydrazide (64.2 mg, 0.866 mmol) was added, and the mixture was heated to 140° C. in a microwave oven for 1 h. The reaction mixture was diluted with ethyl acetate (10 mL), and the organic phase was washed with water (10 mL) and brine (10 mL). The aqueous layer was back-extracted with ethyl acetate (10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-20% methanol in ethyl acetate) to afford the title compound (17.2 mg, 22%) as an off-white solid. MS: 361.2 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0169] Example 5 7,8-Dichloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0170] In a manner similar to that described in Example 4, 6,7-dichloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block D) was converted to the title compound (21 mg, 32%), which was obtained as an off-white solid. MS: 379.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0171] Example 6 7-chloro-8-cyclopropyl-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0172] To a solution of 8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (5.29 g, 12.5 mmol) in degassed toluene (70 mL) and water (14 mL) was added cyclopropylboronic acid (1.29 g, 15 mmol), palladium(II) acetate (280 mg, 1.25 mmol), tricyclohexylphosphine (350 mg, 1.25 mmol), and potassium phosphate tribasic (7.95 g, 37.5 mmol). The mixture was heated to 100 °C for 16 h and then diluted with ethyl acetate and water. The phases were separated, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (silica, 0–10% methanol in dichloromethane). The solid was recrystallized in ethyl acetate to give the title compound (1.78 g, 35%) as a white solid. MS: 385.2 ([M+H] + ),ESI pos.

[0173] Example 7 8-Bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0174] As in the experiment in Example 2b, 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, which was obtained 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.

[0175] Example 8 8-Bromo-7-chloro-6-(2-fluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0176] As in the experiment in Example 2b, 7-bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (35.9 mg, 20%) using formohydrazide, which was obtained as a white solid. MS: 391.0 ([{ 79 Br, 35 Cl}M+H] + ),393.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0177] Example 9 7,8-Dichloro-6-(2,6-difluorophenyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one [ka]

[0178] a) 6,7-dichloro-5-(2,6-difluorophenyl)-1,3-dihydro-2H-benzo[e][1,4]diazepine-2-thione To a solution of 6,7-dichloro-5-(2,6-difluorophenyl)-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (building block D, 409 mg, 1.2 mmol) in diglyme (3.7 mL) was added phosphorus pentasulfide (300 mg, 1.35 mmol) followed by sodium bicarbonate (300 mg, 3.58 mmol) at room temperature. The reaction mixture was heated to 80 °C for 17 h and then cooled to room temperature. The mixture was poured onto ice (20 mL) and stirred for an additional 1 h before being extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (1 × 20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting dark red diglyme solution was purified by flash column chromatography (silica, 0–40% ethyl acetate in heptane). The final product was dried under high vacuum at 70°C for 1 hour to give the title compound (334 mg, 78%) as a pale red solid. MS: 357.0 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0179] b) 6,7-dichloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone To a solution of 6,7-dichloro-5-(2,6-difluorophenyl)-1,3-dihydro-2H-benzo[e][1,4]diazepine-2-thione (200 mg, 0.560 mmol) in propan-2-ol (0.88 mL) and tetrahydrofuran (4.4 mL) was added hydrazine monohydrate (54.3 μL, 1.12 mmol) at room temperature, and the mixture was stirred at room temperature under argon for 3 hours. The suspension was concentrated in vacuo to give a pale yellow solid. The residue was combined with methyl tert-butyl ether (1 mL) and pentane (2 mL) to give a suspension that was stirred for 10 minutes. The solid was collected by filtration, washed with pentane (2 × 3 mL), and dried under high vacuum to give the title compound (199 mg, 100%) as an orange solid. MS: 355.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0180] c) 7,8-dichloro-6-(2,6-difluorophenyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one To a solution of 6,7-dichloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone (64.5 mg, 0.182 mmol) in tetrahydrofuran (1.25 mL) was added 1,1'-carbonyldiimidazole (35.3 mg, 0.218 mmol) at room temperature. The reaction mixture was heated to 70 °C for 2.5 hours, then cooled to room temperature and left overnight. Saturated aqueous sodium bicarbonate (10 mL) was added, and the mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 20-100% ethyl acetate in heptane) to afford the title compound (33 mg, 48%) as an off-white solid. MS: 381.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0181] Example 10 7,8-Dichloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0182] a) 6,7-dichloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione In a manner similar to that of Example 9a, 6,7-dichloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block C) was converted to the title compound (2.62 g, 78%), which was obtained as an orange solid. MS: 339.0 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0183] b) 7,8-dichloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine As in the experiment in Example 1b, 6,7-dichloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (312 mg, 70%) using pyridazine-3-carbohydrazide as an off-white solid. MS: 425.2 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0184] Example 11 7,8-Dichloro-6-(2,6-difluorophenyl)-1-tetrahydropyran-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0185] As in the experiment in Example 1b, 6,7-dichloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (29 mg, 46%) using tetrahydropyran-4-carbohydrazide, which was obtained as a white solid. MS: 449.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0186] Example 12 7,8-Dichloro-6-(2,6-difluorophenyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0187] As in the experiment in Example 1b, pyrimidine-4-carbohydrazide was used to convert 6,7-dichloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione to the title compound (21 mg, 34%), which was obtained as an off-white solid. MS: 443.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0188] Example 13 8-Bromo-7-chloro-6-(2,6-difluorophenyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one [ka]

[0189] a) 7-Bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone In a manner similar to that of Example 9b, 7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (127 mg, 80%), which was obtained as a light brown solid. MS: 399.0 ([{ 79 Br, 35 Cl}M+H] + ),401.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0190] b) 8-bromo-7-chloro-6-(2,6-difluorophenyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one In a manner similar to that described in Example 9c, 7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone was converted to the title compound (51 mg, 38%), which was obtained as a pale yellow solid. MS: 425.0 ([{ 79 Br, 35 Cl}M+H] + ),427.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0191] Example 14 7,8-Dichloro-6-(2,6-difluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0192] As in the experiment in Example 1b, 6,7-dichloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (33 mg, 53%) as an off-white solid using pyridazine-3-carbohydrazide. MS: 443.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0193] Example 15 7,8-Dichloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0194] As in the experiment in Example 1b, 6,7-dichloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (512 mg, 67%) using formohydrazide, which was obtained as a pale yellow solid. MS: 365.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0195] Example 16 7-chloro-6-(2,6-difluorophenyl)-8-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one [ka]

[0196] a) 6-chloro-5-(2,6-difluorophenyl)-7-methyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one A microwave vial was charged with 7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block A, 50 mg, 0.130 mmol), trimethylboroxine (19.5 mg, 21.8 μL, 0.156 mmol), potassium carbonate (26.9 mg, 0.195 mmol), and tetrakis(triphenylphosphine)palladium(0) (7.49 mg, 6.48 μmol). Degassed 1,4-dioxane (0.9 mL) and water (0.3 mL) were added. The vial was capped and heated to 130 °C in a microwave oven for 30 min. The mixture was directly purified by flash column chromatography (silica, 10–70% ethyl acetate in heptane) to afford the title compound (24 mg, 58%) as an off-white solid. MS: 321.1 ([M+H] + ),ESI pos.

[0197] b) 6-chloro-5-(2,6-difluorophenyl)-7-methyl-1,3-dihydro-2H-benzo[e][1,4]diazepine-2-thione To a solution of 6-chloro-5-(2,6-difluorophenyl)-7-methyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (96.2 mg, 0.3 mmol) in diglyme (0.9 mL) was added phosphorus pentasulfide (75 mg, 0.337 mmol) followed by sodium bicarbonate (75.1 mg, 0.894 mmol) at room temperature. The reaction mixture was heated to 80° C. for 16 hours and then cooled to room temperature. The mixture was poured onto ice (10 mL) and stirred for an additional hour. The resulting precipitate was filtered through a sintered funnel. The collected residue was washed with water (4×3 mL) and dried under high vacuum to give the title compound (94 mg, 93%) as a light brown solid. MS: 337.1 ([M+H] + ),ESI pos.

[0198] c) 6-chloro-5-(2,6-difluorophenyl)-7-methyl-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone In a manner similar to that described in Example 9b, 6-chloro-5-(2,6-difluorophenyl)-7-methyl-1,3-dihydro-2H-benzo[e][1,4]diazepine-2-thione was converted to the title compound (25 mg, 63%), which was obtained as a pale yellow solid. MS: 335.1 ([M+H] + ),ESI pos.

[0199] d) 7-chloro-6-(2,6-difluorophenyl)-8-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one In a manner similar to that described in Example 9c, 6-chloro-5-(2,6-difluorophenyl)-7-methyl-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone was converted to the title compound (17 mg, 63%), which was obtained as a white solid. MS: 361.1 ([M+H] + ),ESI pos.

[0200] Example 17 7-chloro-6-(2,6-difluorophenyl)-8-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0201] A mixture of 8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (110 mg, 0.270 mmol), tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.030 mmol), and trimethylaluminum (2.0 m in toluene, 0.2 mL, 0.410 mmol) in N,N-dimethylformamide (1.5 mL) was heated to 70 °C for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (30 mL), brine (2 × 30 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC (Boston Prime C18, 0.1% trifluoroacetic acid / acetonitrile in water) and lyophilized to give the title compound (51.6 mg, 56%) as a white solid. MS: 345.2 ([M+H] + ),ESI pos.

[0202] Example 18 7,8-Dichloro-6-(2-fluorophenyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0203] As in the experiment in Example 1b, pyrimidine-4-carbohydrazide was used to convert 6,7-dichloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione to the title compound (42 mg, 67%), which was obtained as a pale yellow solid. MS: 425.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0204] Example 19 7,8-Dichloro-6-(2,6-difluorophenyl)-1-(2-methoxyethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0205] As in the experiment in Example 1b, 6,7-dichloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (20 mg, 38%) using 3-methoxypropanehydrazide, which was obtained as a white solid. MS: 423.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0206] Example 20 7-chloro-6-(2,6-difluorophenyl)-1,8-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0207] In a manner similar to that described in Example 17, 8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted to the title compound (25 mg, 29%), which was obtained as a white solid. MS: 359.1 ([M+H] + ),ESI pos.

[0208] Example 21 7-chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0209] a) 7-chloro-6-(2,6-difluorophenyl)-8-(1-ethoxyvinyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine To a suspension of 8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (200 mg, 0.490 mmol) and tributyl(1-ethoxyvinyl)tin (352 mg, 0.980 mmol) in N,N-dimethylformamide (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (56.42 mg, 0.050 mmol). The reaction mixture was heated to 100 °C for 16 h. The mixture was diluted with ethyl acetate (100 mL), washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (silica, petroleum ether / ethyl acetate 10:1, dichloromethane / methanol 80:1) to afford the title compound (160 mg, 82%) as a yellow gum. The crude product was used directly in the next step without further characterization.

[0210] b) 1-[7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl]ethanone To a solution of 7-chloro-6-(2,6-difluorophenyl)-8-(1-ethoxyvinyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (160 mg, 0.400 mmol) in 1,4-dioxane (10 mL) was added aqueous hydrochloric acid (2.0 m, 0.99 mL, 1.98 mmol). The mixture was stirred at room temperature for 0.5 h. The mixture was diluted with ethyl acetate (100 mL), washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC (Boston Prime C18, 0.1% trifluoroacetic acid / acetonitrile in water) and lyophilized to give the title compound (70 mg, 47%) as a white solid. MS: 372.9 ([M+H] + ),ESI pos.

[0211] c) 7-chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine To a solution of 1-[7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl]ethanone (60 mg, 0.160 mmol) in dichloromethane (0.2 mL) was added diethylaminosulfur trifluoride (0.8 mL). The mixture was stirred at room temperature for 120 hours, then poured into saturated aqueous sodium bicarbonate (20 mL) and extracted with dichloromethane (2 x 50 mL). The organic layer was separated, washed with brine (30 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Synergi C18, 0.1% trifluoroacetic acid / acetonitrile in water) and lyophilized to give the title compound (10.5 mg, 16%) as a white solid. MS: 395.1 ([M+H] + ),ESI pos.

[0212] Example 22 7-chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0213] a) 7-chloro-6-(2,6-difluorophenyl)-8-(1-ethoxyvinyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a manner similar to that described in Example 21a, 8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted to the title compound (250 mg, 85%), which was obtained as a gray solid. MS: 414.9 ([M+H] + ),ESI pos.

[0214] b) 1-[7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl]ethanone In a manner similar to that described in Example 21b, 7-chloro-6-(2,6-difluorophenyl)-8-(1-ethoxyvinyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted to the title compound (110 mg, 47%), which was obtained as a white solid. MS: 386.9 ([M+H] + ),ESI pos.

[0215] c) 7-chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a manner similar to that described in Example 21c, 1-[7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl]ethanone was converted to the title compound (33.6 mg, 31%), which was obtained as a white solid. MS: 409.1 ([M+H] + ),ESI pos.

[0216] Example 23 7-chloro-8-(difluoromethyl)-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka] a) 7-chloro-6-(2,6-difluorophenyl)-8-vinyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

[0217] To a solution of 8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (300.0 mg, 0.730 mmol) in ethanol (6 mL) was added potassium vinyltrifluoroborate (196 mg, 0.15 mmol), triethylamine (222 mg, 2.2 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (54 mg, 0.07 mmol). The reaction mixture was stirred at 8 °C for 12 hours, and then water (60 mL) was added. The reaction mixture was extracted with ethyl acetate (100 mL). The organic layer was separated, washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. 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 (180 mg, 69%) as a pale yellow solid. MS: 357.1 ([M+H] + ),ESI pos.

[0218] b) 7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-8-carbaldehyde To a solution of 7-chloro-6-(2,6-difluorophenyl)-8-vinyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (170 mg, 0.48 mmol) in acetone (6 mL) and water (1 mL) was added osmium tetroxide (12 mg, 0.05 mmol). After stirring at room temperature for 10 minutes, sodium periodate (203 mg, 0.95 mmol) was added and the mixture was stirred for an additional 2 hours. The reaction mixture was diluted with water (10 mL) and ethyl acetate (30 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica, dichloromethane / methanol 200:1 to 60:1) to give the title compound (120 mg, 70%) as a black solid. MS: 359.0 ([M+H] + ),ESI pos.

[0219] c) 7-chloro-8-(difluoromethyl)-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine To a solution of 7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-8-carbaldehyde (160 mg, 0.45 mmol) in dichloromethane (3 mL) was added diethylaminosulfur trifluoride (359 mg, 2.23 mmol) at −78° C. Upon addition, the reaction mixture was allowed to warm to room temperature and stirred for an additional 12 hours. The reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate (10 mL) and then extracted with dichloromethane (30 mL). The organic layer was washed with brine (10 mL), filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Boston Prime C18, 0.1% trifluoroacetic acid / acetonitrile in water) and lyophilized to give the title compound (8.8 mg, 5%) as a white solid. MS: 381.0 ([M+H] + ),ESI pos.

[0220] Example 24 8-Bromo-7-chloro-6-(3-fluoro-2-pyridyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0221] a) 7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepine-2-thione In a manner similar to that described in Example 1a, 7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block E) was converted to the title compound (110 mg, 53%), which was obtained as a brown solid. MS: 384.0 ([{ 79 Br, 35 Cl}M+H] +),386.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0222] b) 8-bromo-7-chloro-6-(3-fluoro-2-pyridyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a manner similar to that described in Example 1b, 7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (9.5 mg, 8.5%), which was obtained as a white solid. MS: 406.0 ([{ 79 Br, 35 Cl}M+H] + ),408.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0223] Example 25 7-chloro-8-(difluoromethyl)-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0224] a) 7-chloro-6-(2,6-difluorophenyl)-1-methyl-8-vinyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a manner similar to that described in Example 23a, 8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted to the title compound (120 mg, 69%), which was obtained as a pale yellow solid. MS: 371.0 ([M+H] + ),ESI pos.

[0225] b) 1-[7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl]ethanone In a manner similar to that described in Example 23b, 7-chloro-6-(2,6-difluorophenyl)-1-methyl-8-vinyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted to the title compound (100 mg, 83%), which was obtained as an off-white solid. MS: 387.0 ([M+H] + ),ESI pos.

[0226] c) 7-chloro-8-(difluoromethyl)-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a manner similar to that described in Example 23c, 1-[7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl]ethanone was converted to the title compound (10.1 mg, 19%), which was obtained as a white solid. MS: 395.1 ([M+H] + ),ESI pos.

[0227] Example 26 8-Bromo-7-chloro-6-(2-fluorophenyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one [ka]

[0228] a) 7-Bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone In a manner similar to that of Example 9b, 7-bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (798 mg, 91%), which was obtained as a pale yellow solid. MS: 381.0 ([{79 Br, 35 Cl}M+H] + ),383.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0229] b) 8-bromo-7-chloro-6-(2-fluorophenyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one In a manner similar to that described in Example 9c, 7-bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone was converted to the title compound (38 mg, 31%), which was obtained as a pale yellow solid. MS: 407.0 ([{ 79 Br, 35 Cl}M+H] + ),409.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0230] Example 27 7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0231] a) 6-chloro-5-(2-fluorophenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one A solution of 6-chloro-5-(2-fluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one (building block F, 250 mg, 0.600 mmol), copper iodide (229 mg, 1.21 mmol), and methyl 2,2-difluoro-2-fluorosulfonyl acetate (289 mg, 1.51 mmol) in N,N-dimethylformamide (7.5 mL) was heated to 70 °C for 16 h. The mixture was diluted with ethyl acetate (50 mL). The organic layer was filtered, washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by preparative HPLC (Phenomenex Synergi C18, 0.1% trifluoroacetic acid / acetonitrile in water) and lyophilized to give the title compound (150 mg, 70%) as a white solid. MS: 356.8 ([M+H] + ),ESI pos.

[0232] b) 6-chloro-5-(2-fluorophenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione In a manner similar to that described in Example 1a, 6-chloro-5-(2-fluorophenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one was converted to the title compound (246 mg, 89%), which was obtained as a yellow solid. MS: 372.9 ([M+H] + ),ESI pos.

[0233] c) 7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine As in the experiment in Example 2b, 6-chloro-5-(2-fluorophenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (6.9 mg, 4%) using pyridazine-3-carbohydrazide, which was obtained as a white solid. MS: 458.8 ([M+H] + ),ESI pos.

[0234] Example 28 7,8-Dichloro-6-(2,6-difluorophenyl)-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0235] As in the experiment in Example 1b, 6,7-dichloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (31 mg, 46%) using 1-methylpyrazole-4-carbohydrazide, which was obtained as an off-white solid. MS: 445.2 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0236] Example 29 8-Bromo-7-chloro-6-(3-fluoro-2-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0237] As in the experiment in Example 1b, 7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (8.0 mg, 7.0%) using formohydrazide, which was obtained as a pale yellow solid. MS: 392.0 ([{ 79 Br, 35 Cl}M+H] + ),394.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0238] Example 33 [8-Bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methanol [ka]

[0239] Similar to the experiment in Example 1b, 7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (348 mg, 77%) as a white powder using 2-hydroxyacetohydrazide. MS: 439.1 ([{ 79 Br, 35 Cl}M+H] + ),441.2([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0240] Example 34 7-chloro-6-(2,6-difluorophenyl)-8-iodo-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0241] a) 6-chloro-5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepine-2-thione In analogy to the experiment in Example 1a, 6-chloro-5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one (building block H) was converted to the title compound (460 mg) as a dark green solid. The crude product was used directly in the next step without further characterization.

[0242] b) 7-chloro-6-(2,6-difluorophenyl)-8-iodo-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine As in the experiment in Example 2b, 6-chloro-5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (134 mg, 28%) using formohydrazide, which was obtained as a white solid. MS: 456.8 ([M+H] + ),ESI pos.

[0243] Example 36 [8-Bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methanamine hydrochloride [ka]

[0244] a) tert-Butyl N-[[8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methyl]carbamate In a manner similar to that described in Example 1b, 7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (126 mg, 63%) as a white powder using tert-butyl N-(2-hydrazino-2-oxo-ethyl)carbamate. MS: 538.0 ([{ 79 Br, 35 Cl}M+H] + ),540.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0245] b) [8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methanamine hydrochloride To a suspension of tert-butyl N-[[8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methyl]carbamate (126 mg, 0.234 mmol) in 1,4-dioxane (2 mL) was added hydrochloric acid (4.0 m in 1,4-dioxane, 585 μL, 2.34 mmol) dropwise. The reaction mixture was stirred at room temperature for 4 hours. The solid was filtered and dried in vacuo to give the title compound (100 mg, 90%) as a pale orange solid. MS: 438.1 ([{ 79 Br, 35 Cl}M+H] + ),440.2([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0246] Example 37 7-chloro-6-(2,6-difluorophenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0247] a) 6-chloro-5-(2,6-difluorophenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one In a manner similar to that of Example 27a, 6-chloro-5-(2-fluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one (building block H) was converted to the title compound (120 mg, 69%), which was obtained as a dark red oil. MS: 375.0 ([M+H] + ),ESI pos.

[0248] b) 6-chloro-5-(2,6-difluorophenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione In a similar manner to the experiment in Example 1a, 6-chloro-5-(2,6-difluorophenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one was converted to the title compound (72 mg, 57%) as a yellow solid. The crude product was used directly in the next step without further characterization.

[0249] c) 7-chloro-6-(2,6-difluorophenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine As in the experiment in Example 2b, 6-chloro-5-(2,6-difluorophenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (8.0 mg, 10%) using formohydrazide, which was obtained as a white solid. MS: 399.0 ([M+H] + ),ESI pos.

[0250] Example 38 7-chloro-6-(2,6-difluorophenyl)-1-pyridazin-3-yl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0251] In a manner similar to that described in Example 2b, 6-chloro-5-(2,6-difluorophenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (31 mg, 24%) using pyridazine-3-carbohydrazide, which was obtained as a pale pink solid. MS: 477.1 ([M+H] + ),ESI pos.

[0252] Example 39 7-chloro-6-(2,6-difluorophenyl)-8-iodo-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0253] In a manner analogous to the experiment in Example 2b, pyridazine-3-carbohydrazide was used to convert 6-chloro-5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepine-2-thione (Example 34a) to the title compound (19.4 mg, 13%), which was obtained as a pale pink solid. MS: 535.1 ([M+H] + ),ESI pos.

[0254] Example 40 7-chloro-6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0255] As in the experiment in Example 2b, 6-chloro-5-(2,6-difluorophenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (39.6 mg, 31%) using acetohydrazide, which was obtained as a white solid. MS: 413.1 ([M+H] + ),ESI pos.

[0256] Example 41 7-chloro-6-(2,6-difluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0257] As in the experiment in Example 2b, 6-chloro-5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (18.0 mg, 12%) using acetohydrazide, which was obtained as a white solid. MS: 471.0 ([M+H] + ),ESI pos.

[0258] Example 42 7,8-Dibromo-6-(2,6-difluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0259] a) 6,7-dibromo-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione In a manner similar to that described in Example 1a, 6,7-dibromo-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block I) was converted to the title compound (170 mg, 49%), which was obtained as an off-white solid. MS: 444.9 ([{ 79 Br, 79 Brl}M+H] + ),446.8([{ 81 Br, 79 Br}M+H] + ),448.9([{ 81 Br, 81 Br}M+H] + ),ESI pos.

[0260] b) 7,8-dibromo-6-(2,6-difluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine As in the experiment in Example 1b, pyridazine-3-carbohydrazide was used to convert 6,7-dibromo-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione to the title compound (57 mg, 56%), which was obtained as an off-white solid. MS: 531.1 ([{ 79 Br, 79 Brl}M+H] + ),533.0([{ 81 Br, 79 Br}M+H] + ),535.1([{ 81 Br, 81 Br}M+H] + ),ESI pos.

[0261] Example 43 7,8-Dibromo-6-(2,6-difluorophenyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0262] As in the experiment in Example 1b, pyrimidine-4-carbohydrazide was used to convert 6,7-dibromo-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione to the title compound (51 mg, 50%), which was obtained as an off-white solid. MS: 531.1 ([{ 79 Br, 79 Brl}M+H] + ),533.1([{ 81 Br, 79 Br}M+H] + ),535.1([{ 81 Br, 81 Br}M+H] + ),ESI pos.

[0263] Example 44 8-Bromo-7-chloro-6-(3-chloro-2-pyridyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0264] a) 7-bromo-6-chloro-5-(3-chloro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepine-2-thione In a manner similar to that described in Example 1a, 7-bromo-6-chloro-5-(3-chloro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block J) was converted to the title compound (490 mg, 97%), which was obtained as a brown solid. MS: 399.9 ([{ 79 Br, 35 Cl, 35 Cl}M+H] + ),401.9([{ 81 Br, 35 Cl, 35 Cl or 79 Br, 37 Cl, 35 Cl}M+H] + ),ESI pos.

[0265] b) 8-bromo-7-chloro-6-(3-chloro-2-pyridyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a manner similar to that described in Example 1b, 7-bromo-6-chloro-5-(3-chloro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (6.6 mg, 5.3%) using pyrimidine-4-carbohydrazide, which was obtained as a white solid. MS: 486.0 ([{ 79 Br, 35 Cl, 35 Cl}M+H] + ),488.0([{ 81 Br, 35 Cl, 35 Cl or 79 Br, 37 Cl, 35 Cl}M+H] + ),ESI pos.

[0266] Example 45 8-Bromo-7-chloro-6-(3-fluoro-2-pyridyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0267] In a manner similar to that described in Example 1b, 7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (8.6 mg, 7%) using pyridazine-3-carbohydrazide, which was obtained as a pale yellow solid. MS: 470.0 ([{ 79 Br, 35 Cl}M+H] + ),472.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0268] Example 46 8-Bromo-7-chloro-6-(3-fluoro-2-pyridyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0269] In a manner similar to that described in Example 1b, 7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (6.7 mg, 5.4%) using pyrimidine-4-carbohydrazide, which was obtained as a white solid. MS: 470.0 ([{ 79 Br, 35 Cl}M+H] + ),472.1([{ 81 Br, 35 Cl or 79 Br, 37Cl}M+H] + ),ESI pos.

[0270] Example 47 8-Bromo-7-chloro-6-(3-chloro-2-pyridyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0271] In a manner similar to that described in Example 1b, 7-bromo-6-chloro-5-(3-chloro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (18 mg, 25%) using pyridazine-3-carbohydrazide, which was obtained as a white solid. MS: 485.8 ([{ 79 Br, 35 Cl, 35 Cl}M+H] + ),487.9([{ 81 Br, 35 Cl, 35 Cl or 79 Br, 37 Cl, 35 Cl}M+H] + ),ESI pos.

[0272] Example 48 7-chloro-6-(2,6-difluorophenyl)-8-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0273] In a manner similar to that described in Example 1b, 6-chloro-5-(2,6-difluorophenyl)-7-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (15.5 mg, 12%) using pyridazine-3-carbohydrazide, which was obtained as a pale pink solid. MS: 423.1 ([M+H] +),ESI pos.

[0274] Example 49 7-chloro-6-(2,6-difluorophenyl)-8-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0275] In a manner analogous to the experiment in Example 1b, 6-chloro-5-(2,6-difluorophenyl)-7-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (6.3 mg, 5%) using pyrimidine-4-carbohydrazide, which was obtained as a pale yellow solid. MS: 423.1 ([M+H] + ),ESI pos.

[0276] Example 50 8-Bromo-7-chloro-6-(2-chloro-6-fluoro-phenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0277] a) 7-bromo-6-chloro-5-(2-chloro-6-fluoro-phenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione In a similar manner to the experiment in Example 1a, 7-bromo-6-chloro-5-(2-chloro-6-fluoro-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block K) was converted to the title compound (88 mg, 95%) as a yellow solid. The crude product was used directly in the next step without further characterization.

[0278] b) 8-bromo-7-chloro-6-(2-chloro-6-fluoro-phenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a manner similar to that described in Example 1b, 7-bromo-6-chloro-5-(2-chloro-6-fluoro-phenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (22.5 mg, 24%), which was obtained as a yellow solid. MS: 439.0 ([{ 79 Br, 35 Cl, 35 Cl}M+H] + ),441.0([{ 81 Br, 35 Cl, 35 Cl or 79 Br, 37 Cl, 35 Cl}M+H] + ),ESI pos.

[0279] Example 54 7,8-Dichloro-6-(3-fluoro-2-pyridyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0280] a) 6,7-dichloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepine-2-thione In a manner similar to that described in Example 1a, 6,7-dichloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block N) was converted to the title compound (2.56 g, 67%), which was obtained as a pale yellow solid. MS: 340.0 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0281] b) 7,8-dichloro-6-(3-fluoro-2-pyridyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine As in the experiment in Example 1b, 6,7-dichloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (111 mg, 44%) using pyridazine-3-carbohydrazide, which was obtained as an off-white solid. MS: 426.0 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0282] Example 55 7,8-Dichloro-6-(3-fluoro-2-pyridyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0283] Using pyrimidine-4-carbohydrazide, 6,7-dichloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepine-2-thione (Example 54a) was converted to the title compound (111 mg, 44%) as an off-white solid, similar to the experiment in Example 1b. MS: 426.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0284] Example 57 7-chloro-6-(2,6-difluorophenyl)-8-methoxy-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0285] A solution of 8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (110 mg, 0.230 mmol), [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (40 mg, 0.050 mmol) and triethylamine (0.16 mL, 1.13 mmol) in methanol (15 mL) was heated to 80°C for 16 hours. The reaction mixture was filtered through a plug of celite, concentrated in vacuo, and purified directly by preparative HPLC (Phenomenex Luna C18, 0.075% trifluoroacetic acid / acetonitrile in water) to give the title compound (47 mg, 46%) as a pale pink solid. MS: 439.0 ([M+H] + ),ESI pos.

[0286] Example 58 7,8-Dichloro-6-(3-fluoro-2-pyridyl)-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0287] As in the experiment in Example 1b, 6,7-dichloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (74 mg, 29%) using 1-methylpyrazole-4-carbohydrazide, which was obtained as a white solid. MS: 428.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0288] Example 59 7,8-Dichloro-6-(3-fluoro-2-pyridyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one [ka]

[0289] a) 6,7-dichloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone In a manner similar to that of Example 9b, 6,7-dichloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (400 mg, 80%), which was obtained as a yellow solid. MS: 338.0 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0290] b) 7,8-dichloro-6-(3-fluoro-2-pyridyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one In a similar manner to the experiment in Example 9c, 6,7-dichloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone was converted to the title compound (98 mg, 60%), which was obtained as a yellow solid. MS: 364.0 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0291] Example 60 7,8-Dichloro-6-(3-fluoro-2-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0292] As in the experiment in Example 1b, 6,7-dichloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (54 mg, 35%) using formohydrazide, which was obtained as a pale yellow solid. MS: 348.0 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0293] Example 61 7-chloro-6-(2,6-difluorophenyl)-8-methoxy-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0294] a) 8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a manner similar to that described in Example 2b, 7-bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (133 mg, 33%) using pyrimidine-4-carbohydrazide, which was obtained as a pale yellow solid. MS: 486.9 ([{ 79 Br, 35 Cl}M+H] + ),488.9([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0295] b) 7-chloro-6-(2,6-difluorophenyl)-8-methoxy-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a manner similar to that described in Example 57, 8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted to the title compound (24 mg, 20%), which was obtained as an off-white solid. MS: 439.0 ([M+H] + ),ESI pos.

[0296] Example 62 7-chloro-6-(2,6-difluorophenyl)-8-methoxy-1-(3-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0297] a) 8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-(3-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine As in the experiment in Example 2b, nicotinic acid hydrazide was used to convert 7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione to the title compound (188 mg, 31%), which was obtained as a brown solid. MS: 485.9 ([{ 79 Br, 35 Cl}M+H] + ),487.9([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0298] b) 7-chloro-6-(2,6-difluorophenyl)-8-methoxy-1-(3-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a manner similar to that described in Example 57, 8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-(3-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted to the title compound (29 mg, 17%), which was obtained as a white solid. MS: 438.1 ([M+H] + ),ESI pos.

[0299] Example 65 7,8-Dichloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0300] As in the experiment in Example 1b, 6,7-dichloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (77 mg, 44%) as a white solid using cyclopropanecarbohydrazide. MS: 387.9 ([{ 35 Cl, 35 Cl}M+H] + ),389.8([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0301] Example 69 7-chloro-6-(3-fluoro-2-pyridyl)-1-pyrimidin-4-yl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0302] a) 6-chloro-5-(3-fluoro-2-pyridyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one In a manner similar to that of Example 27a, 6-chloro-5-(3-fluoro-2-pyridyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one (building block P) was converted to the title compound (1.0 g, 26%), which was obtained as a brown solid. MS: 358.0 ([M+H] + ),ESI pos.

[0303] b) 6-chloro-5-(3-fluoro-2-pyridyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione In a manner similar to that described in Example 1a, 6-chloro-5-(3-fluoro-2-pyridyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one was converted to the title compound (430 mg, 91%), which was obtained as a brown solid. MS: 373.8 ([M+H] + ),ESI pos.

[0304] c) 7-chloro-6-(3-fluoro-2-pyridyl)-1-pyrimidin-4-yl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a manner similar to that described in Example 1b, pyrimidine-4-carbohydrazide was used to convert 6-chloro-5-(3-fluoro-2-pyridyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione to the title compound (20 mg, 27%), which was obtained as a white solid. MS: 460.1 ([M+H] + ),ESI pos.

[0305] Example 70 7-chloro-6-(3-fluoro-2-pyridyl)-1-(1-methylpyrazol-4-yl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0306] As in the experiment in Example 1b, 6-chloro-5-(3-fluoro-2-pyridyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (14 mg, 18%) using 1-methylpyrazole-4-carbohydrazide, which was obtained as a white solid. MS: 462.2 ([M+H] + ),ESI pos.

[0307] Example 71 7,8-Dichloro-6-(3-fluoro-2-pyridyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0308] As in the experiment in Example 1b, 6,7-dichloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (60 mg, 47%) using acetohydrazide, which was obtained as a white solid. MS: 362.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0309] Example 72 7-chloro-6-(3-fluoro-2-pyridyl)-1-pyridazin-3-yl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0310] In a manner analogous to the experiment in Example 1b, pyridazine-3-carbohydrazide was used to convert 6-chloro-5-(3-fluoro-2-pyridyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione to the title compound (15 mg, 32%), which was obtained as a white solid. MS: 460.2 ([M+H]+ ),ESI pos.

[0311] Example 77 8-Bromo-7-chloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0312] As in the experiment in Example 1b, 7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (283 mg, 31%) using cyclopropanecarbohydrazide, which was obtained as a white solid. MS: 432.0 ([{ 79 Br, 35 Cl}M+H] + ),434.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0313] Example 78 7-chloro-6-(3-fluoro-2-pyridyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0314] As in the experiment in Example 1b, 6-chloro-5-(3-fluoro-2-pyridyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (38 mg, 52%) using acetohydrazide, which was obtained as a white solid. MS: 396.1 ([M+H] + ),ESI pos.

[0315] Example 79 7-chloro-1-cyclopropyl-6-(2,6-difluorophenyl)-8-methoxy-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0316] a) 8-bromo-7-chloro-1-cyclopropyl-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine As in the experiment in Example 2b, 7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (180 mg, 54%) using cyclopropanecarbohydrazide, which was obtained as a brown solid. MS: 448.9 ([{ 79 Br, 35 Cl}M+H] + ),450.9([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0317] b) 7-chloro-1-cyclopropyl-6-(2,6-difluorophenyl)-8-methoxy-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a manner similar to that described in Example 57, 8-bromo-7-chloro-1-cyclopropyl-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted to the title compound (6 mg, 5%), which was obtained as a white solid. MS: 401.1 ([M+H] + ),ESI pos.

[0318] Example 90 7,8-Dichloro-6-(2,6-difluorophenyl)-1-methoxy-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0319] a) 1-bromo-7,8-dichloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine To a mixture of 7,8-dichloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (400 mg, 1.1 mmol) in toluene (25 mL) was added 1-bromopyrrolidine-2,5-dione (214 mg, 1.2 mmol) at room temperature. The reaction mixture was stirred for 2.5 hours and then heated to 60° C. for 2 hours. An additional amount of 1-bromopyrrolidine-2,5-dione (214 mg, 1.2 mmol) was added, and the reaction mixture was maintained at 60° C. for an additional 30 minutes. The reaction mixture was poured into saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica, ethyl acetate / ethanol 3:1 in heptane 0-60%) to give the title compound (496 mg, 86%) as an off-white solid. MS: 443.0 ([{ 79 Br, 35 Cl, 35 Cl}M+H] + ),445.1([{ 81 Br, 35 Cl, 35 Cl or 79 Br, 37 Cl, 35 Cl}M+H] + ),ESI pos.

[0320] b) 7,8-dichloro-6-(2,6-difluorophenyl)-1-methoxy-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine A Schlenk tube was charged with 1-bromo-7,8-dichloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (30 mg, 0.068 mmol), rac-BINAP (8.4 mg, 13.5 μmol), cesium carbonate (66 mg, 203 μmol), and toluene (0.9 mL). The tube was degassed by bubbling argon through the reaction mixture for 5 minutes. Palladium(II) acetate (3.03 mg, 0.0135 mmol) was added, then the tube was sealed and the reaction mixture was heated to 80 °C for 30 minutes. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (1 × 5 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica, ethyl acetate / ethanol (3:1) in 0-100% heptane) followed by preparative HPLC (YMC-Triart C18, 0.1% HCOOH / acetonitrile in water) to give the title compound (6.4 mg, 24%) as an off-white solid. MS: 395.1 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0321] Example 91 trans-7,8-Dichloro-6-(2,6-difluorophenyl)-1-(3-methoxycyclobutyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0322] In a manner similar to that described in Example 2b, 6,7-dichloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione (Example 9a) was converted to the title compound (69 mg, 60%) as a white solid using 3-methoxycyclobutanecarbohydrazide. MS: 449.3 ([{ 35 Cl,35 Cl}M+H] + ),ESI pos.

[0323] Example 104 8-Bromo-7-chloro-6-(2,6-difluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0324] In a manner similar to that described in Example 1b, 7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (20.7 mg, 17%) using pyridazine-3-carbohydrazide, which was obtained as a white solid. MS: 487.0 ([{ 79 Br, 35 Cl}M+H] + ),489.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0325] reference compound RE-A 8-Bromo-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0326] a) N-[2-(2,6-difluorobenzoyl)phenyl]acetamide Similarly to the experiment for building block Ab, 2-methyl-3,1-benzoxazin-4-one (CAS no. 525-76-8) was converted to the title compound (40 g, 80%), which was obtained as a pale yellow solid. MS: 276.2 ([M+H] + ),ESI pos.

[0327] 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%), which was obtained as a yellow solid. MS: 234.1 ([M+H] + ),ESI pos.

[0328] c) (2-amino-5-bromo-phenyl)-(2,6-difluorophenyl)methanone 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 (3×200 mL). The organic phase was washed with brine (2×100 mL), dried (NaSO), and concentrated in vacuo 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.

[0329] 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%), which was obtained as a yellow solid, MS: 351.0 ([{ 79 Br}M+H] + ),353.0([{81 Br}M+H] + ),ESI pos.

[0330] e) 7-bromo-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione In a similar manner to the experiment in 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.

[0331] 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, which was obtained as a white solid. MS: 389.0 ([{ 79 Br}M+H] + ),391.0([{ 81 Br}M+H] + ),ESI pos.

[0332] RE-B 6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0333] a) (2-amino-5-iodo-phenyl)-(2,6-difluorophenyl)methanone 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 (Na SO ), and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate, 10:1 to 5:1) to afford the title compound (2.0 g, 81%) as a yellow solid. MS: 360.0 ([M+H] + ),ESI pos.

[0334] 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%), which was obtained as a yellow solid. MS: 399.0 ([M+H] + ),ESI pos.

[0335] 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%), which was obtained as a yellow solid. MS: 414.9 ([M+H] + ),ESI pos.

[0336] 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%), which was obtained as a yellow solid. MS: 413.0 ([M+H] + ),ESI pos.

[0337] 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%), which was obtained as a yellow solid. MS: 437.0 ([M+H] + ),ESI pos.

[0338] f) 6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a manner similar to that described 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%), which was obtained as a white solid. MS: 379.0 ([M+H] + ),ESI pos.

[0339] RE-C 6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0340] 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 backfilled with a stream of hydrogen (balloon) three times. The mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours and then filtered through a pad of dicalite. The filter cake was rinsed with methanol, and the filtrate was concentrated in vacuo. 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.

[0341] RE-G 7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine [ka]

[0342] a) 6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one Similar to the experiment for building block Ae, (2-amino-6-chloro-phenyl)-(2,6-difluorophenyl)methanone was converted to the title compound (3.0 g, 44%), which was obtained as a yellow solid, MS: 307.0 ([M+H] + ),ESI pos.

[0343] b) 6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione In a manner similar to that described in Example 1a, 6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one was converted to the title compound (2.8 g, 89%) as a yellow solid. MS: 323.0 ([M+H] + ),ESI pos.

[0344] c) 6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone Similar to the experiment in Example 9b, 6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (220 mg, 98%), which was used directly without further purification. MS: 321.1 ([M+H] + ),ESI pos.

[0345] d) 7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine A solution of 6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone (220 mg, 0.690 mmol) and triethyl orthoacetate (556 mg, 3.43 mmol) in toluene (3 mL) was heated to 120 °C. After 1 h, the solvent was removed under reduced pressure and the resulting residue was partitioned between ethyl acetate (100 mL) and water (2 × 20 mL). The combined organic extracts were dried (NaSO), filtered, and concentrated in vacuo. The residue was directly purified by preparative HPLC (Boston Prime C18, 0.1% trifluoroacetic acid / acetonitrile in water) and lyophilized to give the title compound (73 mg, 31%) as a white solid. MS: 344.9 ([M+H] + ),ESI pos.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof. 【Chemical 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) R ７ , R ８ and R ９ C optionally substituted with ３～８ -cycloalkyl, viii) Amino-C １～６ -Alkyl ix) R ７ , R ８ and R ９ Heteroaryl optionally substituted with x) R ７ , R ８ and R ９ heterocycloalkyl optionally substituted with R ３ teeth, i) Cl, and ii) F is selected from: X is i) CR ６ , and ii) selected from N; R ６ teeth, i) H, ii) Cl, and iii) selected from F; R ４ teeth, i) Br, and ii) selected from Cl; R ５ teeth, i) C １～６ - alkyl, ii) C １～６ -alkoxy, iii) halogens, iv) Halo-C １～６ -alkyl, and v) C ３～８ -cycloalkyl; R ７ , R ８ and R ９ is, independently, i) C １～６ -alkyl, and ii) C １－６ -alkoxy)

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) R ７ , R ８ and R ９ C optionally substituted with ３～８ -cycloalkyl, viii) Amino-C １～６ -Alkyl ix) R ７ , R ８ and R ９ pyrazolyl optionally substituted by x) R ７ , R ８ and R ９ pyridinyl optionally substituted by xi) R ７ , R ８ and R ９ pyrimidinyl optionally substituted by xii) R ７ , R ８ and R ９ pyridazinyl optionally substituted by xiii) R ７ , R ８ and R ９ tetrahydropyranyl optionally substituted by R ３ but, i) Cl, and ii) selected from F; X is, i) CR ６ , and ii) selected from N; R ６ but, i) H, ii) Cl, and iii) selected from F; R ４ but, i) Br, and ii) selected from Cl; 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; R ７ , R ８ and R ９ But independently, i) C １～６ -alkyl, and ii) C １～６ - selected from alkoxy, 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

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

4. R １ is C １～６ is alkyl, R ３ is F, X is CR ６ and R ６ is F, R ４ is Cl, R ５ Halo-C １～６ - is alkyl, 4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3.

5. 8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-bromo-7-chloro-1-cyclopropyl-6-(2-fluorophenyl)-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]benzodiazepine; 7,8-dichloro-6-(2-fluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-dichloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-8-cyclopropyl-6-(2,6-difluorophenyl)-1-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]benzodiazepine; 8-bromo-7-chloro-6-(2-fluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-dichloro-6-(2,6-difluorophenyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one; 7,8-dichloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-dichloro-6-(2,6-difluorophenyl)-1-tetrahydropyran-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-dichloro-6-(2,6-difluorophenyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-bromo-7-chloro-6-(2,6-difluorophenyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one; 7,8-dichloro-6-(2,6-difluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-dichloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-8-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one; 7-chloro-6-(2,6-difluorophenyl)-8-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-dichloro-6-(2-fluorophenyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-dichloro-6-(2,6-difluorophenyl)-1-(2-methoxyethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-1,8-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-8-(difluoromethyl)-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-bromo-7-chloro-6-(3-fluoro-2-pyridyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-8-(difluoromethyl)-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-bromo-7-chloro-6-(2-fluorophenyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one; 7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-dichloro-6-(2,6-difluorophenyl)-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-bromo-7-chloro-6-(3-fluoro-2-pyridyl)-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-1-yl]methanol; 7-chloro-6-(2,6-difluorophenyl)-8-iodo-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-1-yl]methanamine hydrochloride; 7-chloro-6-(2,6-difluorophenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-1-pyridazin-3-yl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-8-iodo-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-dibromo-6-(2,6-difluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-dibromo-6-(2,6-difluorophenyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-bromo-7-chloro-6-(3-chloro-2-pyridyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-bromo-7-chloro-6-(3-fluoro-2-pyridyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-bromo-7-chloro-6-(3-fluoro-2-pyridyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-bromo-7-chloro-6-(3-chloro-2-pyridyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-8-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-8-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-bromo-7-chloro-6-(2-chloro-6-fluoro-phenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-dichloro-6-(3-fluoro-2-pyridyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-dichloro-6-(3-fluoro-2-pyridyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-8-methoxy-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-dichloro-6-(3-fluoro-2-pyridyl)-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-dichloro-6-(3-fluoro-2-pyridyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one; 7,8-dichloro-6-(3-fluoro-2-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-8-methoxy-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(2,6-difluorophenyl)-8-methoxy-1-(3-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-dichloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(3-fluoro-2-pyridyl)-1-pyrimidin-4-yl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(3-fluoro-2-pyridyl)-1-(1-methylpyrazol-4-yl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-dichloro-6-(3-fluoro-2-pyridyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(3-fluoro-2-pyridyl)-1-pyridazin-3-yl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-bromo-7-chloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-6-(3-fluoro-2-pyridyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-1-cyclopropyl-6-(2,6-difluorophenyl)-8-methoxy-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7,8-dichloro-6-(2,6-difluorophenyl)-1-methoxy-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; trans-7,8-dichloro-6-(2,6-difluorophenyl)-1-(3-methoxycyclobutyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, selected from:

6. The compound is 7-chloro-6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine 6. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 5, selected from:

7. The compound is 7-chloro-6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein:

8. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 7, comprising reacting a compound of formula (III) with a compound of formula (IV). 【Chemistry 2】 (In the formula, R １ , R ３ , R ４ and R ５ is as defined in any one of claims 1 to 4)

9. A compound according to any one of claims 1 to 7 for use as a therapeutically active substance.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 and a therapeutically inert carrier.

11. A compound according to any one of claims 1 to 7 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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