Benzodiazepine derivatives as positive allosteric modulators of the GABA A γ1 receptor

Abstract

The present invention provides novel heterocyclic compounds having the general formula (I) or (II) and pharma- ceutically acceptable salts thereof, wherein the variables are as described herein. TIFF2024536393000113.tif62161 Further provided are pharmaceutical compositions comprising the compounds, processes for making the compounds and methods of using the compounds as pharmaceuticals, in particular methods of using the compounds for the treatment or prevention of acute neurological disorders, chronic neurological disorders and / or cognitive disorders.

Description

[Technical field]

[0001] The present invention relates to organic compounds useful for therapy or prevention in mammals, in particular novel benzodiazepine derivatives which exhibit activity as GABAAγ1 receptor positive allosteric modulators (PAMs) and are therefore useful for the treatment or prevention of GABAAγ1 receptor-related diseases or conditions. [Background technology]

[0002] Receptors for the major inhibitory neurotransmitter, γ-aminobutyric acid (GABA), are divided into two major classes: (1) GABA receptors, which are members of the ligand-gated ion channel superfamily; A receptors and (2) GABA, a member of the G protein-coupled receptor family B Receptor. GABA is a membrane-bound heteropentameric protein polymer. A The receptor complex is composed primarily of α, β, and γ subunits. A The receptor is a ligand-gated chloride channel and a major mediator of inhibitory neurotransmission in the human brain.

[0003] GABA assembles as a pentamer whose most common stoichiometry is two α, two β, and one γ subunit. A There are 19 genes that code for GABA receptor subunits. A Subunit combinations give rise to functional, circuit and behavioral specificity. GABA containing γ1 subunits A Receptor (GABA A γ1) are of particular interest due to their abundant expression in the limbic system and unique physiological and pharmacological properties. A γ1 subunit-containing receptors are less abundant than γ2 subunit-containing receptors (GABA receptors in the brain AThe receptor shows enriched brain mRNA and protein distribution in key brain regions such as the basal ganglia (approximately 5-10% of total receptor expression), the extended amygdala (central, medial, and bed nuclei of the stria terminalis), the lateral septum, the hypothalamus, and the globus pallidus / substantia nigra. These structures form the interconnected core of the subcortical limbic circuit that regulates motivated social and emotional behaviors. In abnormal or diseased conditions, over-recruitment of this circuit promotes anxiety, arousal, aggression, fear, and defensiveness while inhibiting feeding and social interaction.

[0004] Hyperactivity in limbic cortical regions, key areas for processing socially and emotionally relevant stimuli (known to form a coordinated functional network with the extended amygdala / hypothalamic regions), is a common feature of a variety of psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational and metabolic disorders. In such disease states, γ1-subunit-containing GABAergic receptors are essential for the regulation of stimuli. A Considering the characteristic anatomical distribution of GABA receptors, A γ1 positive allosteric modulators (PAMs) may be an effective treatment as symptom or disease modifying agents.

[0005] Several lines of evidence suggest that an imbalance between excitatory / inhibitory (E / I) neurotransmission resulting from dysfunction of the GABAergic signaling system, the main inhibitory neurotransmitter system in the brain, is central to the pathogenesis of various CNS disorders. A Given the distribution and function of γ1 subunit-containing receptors, they are highly attractive targets for restoring levels of inhibition in key brain circuits and thus restoring E / I balance in these conditions.

[0006] A CNS disorder of particular interest in the context of the present invention is autism spectrum disorder (ASD), including its core symptoms and associated comorbidities such as anxiety and hypersensitivity, social anxiety disorder (social phobia) and generalized anxiety disorder. 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).

[0007] There are no approved pharmacological treatments for the core symptoms of social deficits and restricted / repetitive behaviors of ASD, while only 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 the associated symptoms of ASD are limited to antipsychotics (risperidone and aripiprazole) indicated for the treatment of hypersensitivity associated with ASD symptoms. Emerging evidence suggests that the GABAergic system, the major inhibitory neurotransmitter system in the brain, plays a key role in the pathophysiology of ASD.

[0008] Both genetic and imaging studies using positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) suggest alterations in GABAergic signaling in ASD. A The gene GABRG1, which encodes γ1, encodes α2, α4, and β1 GABA AIt is located on chromosome 4 (mouse Chr. 5) in a cluster with genes encoding receptor subunits. Rare CNVs involving inversions of chromosome 4p12 disrupting GABRG1 have been found in siblings with autism (Horike et al., 2006), as well as GABRG1 loss in one case of ADHD. Mutations in the 4p12 gene cluster have been associated with 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, and in particular several recent studies have shown reduced GABA and altered somatosensory function in children with ASD. Consistent with these observations, reduced numbers of inhibitory interneurons have been found in postmortem tissue from ASD and TS patients. Furthermore, reduced GABA-synthesizing enzymes, glutamic acid decarboxylase (GAD) 65 and 67, have been found in the parietal and cerebellar cortices of autistic patients. Strong evidence in humans suggests that GABA is involved in the regulation of GABA. A Our results point to a specific dysfunction in ASD of limbic cortical regions known to form coordinated functional networks with γ1 subunit-containing extended amygdala / hypothalamic regions. These regions: cortex / lateral amygdala, insular cortex, PFC, and cingulate gyrus are recognized to be key for processing socially and emotionally relevant stimuli. Subcortical nuclei that form specific partnerships with these regions that orchestrate behavioral outcomes are often difficult to study due to spatial resolution limitations, but a growing body of evidence points to an over-recruitment of these cortical to subcortical connections in ASD. Furthermore, recent high-resolution studies provide a clear link between activity / functional connectivity of the extended amygdala and emotional states. Targeting such highly specified limbic subcortical regions that exhibit substantial molecular and cellular diversity compared to the neocortex creates a precise entry point for safe and specific therapeutic modulation of social-emotional circuits affected in ASD, while avoiding widespread modulation of global brain states. GABAergic stimulation with nonselective BZDs A Enhancement of GABA receptor activity has been shown to improve behavioral deficits in mouse models of ASD. AA very narrow therapeutic margin was observed for sedation mediated by the α1γ2 subtype. These findings are consistent with the A This supports the idea that rebalancing GABAergic transmission via γ1 receptors may improve ASD symptoms without the side effects of non-selective benzodiazepines.

[0009] The compounds of the present invention are effective at a given concentration (e.g., EC 20 ) by increasing GABAergic currents (chloride influx) with γ1-containing GABA A Selective GABA that selectively enhances receptor function A The compounds of the present invention are γ1 receptor positive allosteric modulators (PAMs). The compounds of the present invention 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). Thus, the compounds of the present invention are capable of binding to γ2-containing GABA receptors. A It is subtype selective and strongly distinguishes itself from classical benzodiazepine drugs such as alprazolam, triazolam, estazolam and midazolam, which have low affinity for the γ1-containing subtypes. Consistent with the brain distribution of the γ1 subtype, selective GABA A γ1 PAM is a non-selective GABA A It will restore GABAergic signaling in key brain regions (e.g., extended amygdala: central, medial, and bed nuclei of the stria terminalis, lateral septum, hypothalamus, and globus pallidus / substantia nigra) without the side effects of modulators (e.g., benzodiazepines).

[0010] In view of the above, the selective GABA AGamma 1 PAM and its pharma- ceutically acceptable salts and esters, alone or in combination with other drugs, are useful in the treatment of autism spectrum disorders (ASD), Angelman syndrome, age-related cognitive decline, Rett syndrome, Prader-Willi syndrome, amyotrophic lateral sclerosis (ALS), fragile X disorder, negative and / or dementia symptoms associated with schizophrenia, tardive dyskinesia, anxiety, social anxiety disorder (social phobia), panic disorder, agoraphobia, generalized anxiety disorder, disruptive, impulse control and behavior disorders, Tourette syndrome (TS), obsessive-compulsive disorder (OCD), acute stress disorder, post-traumatic stress disorder (PTSD), and other conditions. In some embodiments, the compounds are useful as disease modifying agents or as symptomatic agents for the treatment or prevention of acute neurological disorders, chronic neurological disorders and / or cognitive disorders including ADHD, attention deficit hyperactivity disorder (ADHD), sleep disorders, Parkinson's disease (PD), Huntington's chorea, Alzheimer's disease (AD), mild cognitive impairment (MCI), dementia, behavioral and psychological symptoms in neurodegenerative conditions (BPS), multi-infarct dementia, agitation, psychosis, substance-induced psychotic disorder, aggression, eating disorders, depression, chronic apathy, anhedonia, chronic fatigue, seasonal affective disorder, postpartum depression, sleepiness, sexual dysfunction, bipolar disorder, epilepsy and pain. Summary of the Invention

[0011] In a first aspect, the present invention provides a compound of formula (I) or (II): [ka] where the variables are as defined herein. or a pharma- ceutically acceptable salt thereof.

[0012] In one aspect, the present invention provides a process for the preparation of a compound of formula (I) or (II) as described herein, the process being as depicted in any one of Schemes 1-14 herein.

[0013] In a further aspect, the present invention provides a compound of formula (I) or (II) as described herein when prepared according to the process described herein.

[0014] In a further aspect, the present invention provides a compound of formula (I) or (II) as described herein, or a pharma- ceutically acceptable salt thereof, for use as a therapeutically active substance.

[0015] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or (II) as described herein, or a pharma- ceutically acceptable salt thereof, and a therapeutically inert carrier.

[0016] In a further aspect, the present invention provides a compound of formula (I) or (II) as described herein, or a pharma- ceutically acceptable salt thereof, for use in a method of treating or preventing an acute neurological disorder, a chronic neurological disorder and / or a cognitive disorder in a subject. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] definition It should be understood that any feature, integer, property, compound, chemical moiety or group described in connection with a particular aspect, embodiment or example of the invention is applicable to any other aspect, embodiment or example described herein, except where incompatible. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel one or any novel combination of features disclosed in this specification (including any accompanying claims, abstract and drawings), or any novel one or any novel combination of steps of any method or process so disclosed.

[0018] The term "alkyl" refers to a monovalent or polyvalent, e.g., monovalent or divalent, linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms ("C1-C6-alkyl"), e.g., 1, 2, 3, 4, 5 or 6 carbon atoms. In some embodiments, an alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2 or 3 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl and 2,2-dimethylpropyl. Particularly preferred, but non-limiting examples of alkyl include methyl and ethyl.

[0019] The term "alkoxy" refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. Unless otherwise specified, an alkoxy group contains 1 to 6 carbon atoms ("C1-C6-alkoxy"). In some preferred embodiments, an alkoxy group contains 1 to 4 carbon atoms. In yet other embodiments, an alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred, but non-limiting example of alkoxy is methoxy.

[0020] The term "halogen" or "halo" refers to fluoro (F), chloro (Cl), bromo (Br) or iodo (I). Preferably, the term "halogen" or "halo" refers to fluoro (F), chloro (Cl) or bromo (Br). Particularly preferred, but non-limiting examples of "halogen" or "halo" are fluoro (F) and chloro (Cl).

[0021] The term "cycloalkyl" as used herein refers to a saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms ("C3-C 10"Cycloalkyl"). In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. "Bicyclic cycloalkyl" refers to cycloalkyl moieties consisting of two saturated carbocyclic rings sharing two carbon atoms (i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms) and spirocyclic moieties (i.e., the two rings are connected through one common ring atom). Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., 3, 4, 5, or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and spiro[2.3]hexan-5-yl.

[0022] The term "cycloalkenyl" as used herein refers to a partially unsaturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms ("C3-C 10 In some preferred embodiments, the cycloalkenyl group is a partially unsaturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. "Bicyclic cycloalkenyl" refers to cycloalkenyl moieties (i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms) and spirocyclic moieties (i.e., the two rings are connected through one common ring atom) that consist of two saturated carbocyclic rings sharing two carbon atoms, where at least one of the two carbocyclic rings is partially unsaturated. Preferably, the cycloalkenyl group is a partially unsaturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., 3, 4, 5, or 6 carbon atoms. Some non-limiting examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and spiro[2.3]hex-5-en-5-yl.

[0023] The term "heterocyclyl" or "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic, preferably a monocyclic ring system of 3 to 14 ring atoms, preferably 3 to 10 ring atoms, more preferably 3 to 8, and most preferably 3 to 6 ring atoms, in which 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Preferably, 1 to 2 of the ring atoms are selected from N and O, and the remaining ring atoms are carbon. "Bicyclic heterocyclyl" refers to heterocyclic moieties consisting of two rings that share two ring atoms (i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms) and spirocyclic moieties (i.e., the two rings are connected through one common ring atom).Some non-limiting examples of heterocyclyl groups include azetidin-3-yl; azetidin-2-yl; oxetan-3-yl; oxetan-2-yl; oxazolidinyl; piperidyl; piperazinyl; pyrrolidinyl; 2-oxopyrrolidin-1-yl; 2-oxopyrrolidin-3-yl; 5-oxopyrrolidin-2-yl; 5-oxopyrrolidin-3-yl; 2-oxo-1-piperidinyl. Dyl;2-oxo-3-piperidyl;2-oxo-4-piperidyl;6-oxo-2-piperidyl;6-oxo-3-piperidyl;1-piperidinyl;2-piperidinyl;3-piperidinyl;4-piperidinyl;Morpholino (e.g. morpholin-2-yl or morpholin-3-yl);Thiomorpholino;Pyrrolidinyl (e.g. pyrrolidin-3-yl);1-oxa-6-azaspiro [3.3]heptane;2-oxa-6-azaspiro[3.3]heptane;5-oxa-2-azaspiro[3.4]octane;6-oxa-2-azaspiro[3.4]octane;5-oxa-2-azaspiro[3.5]nonane;6-oxa-2-azaspiro[3.5]nonane;7-oxa-2-azaspiro[3.5]nonane;3-oxa-6-azabicyclo[3.1.1]heptane;3-thi A-6-azabicyclo[3.1.1]heptane; 3-azabicyclo[3.1.0]hexan-6-yl; 2,5-diazabicyclo[2.2.1]heptan-2-yl; 2-azaspiro[3.3]heptan-2-yl; 2,6-diazaspiro[3.3]heptan-2-yl; and 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl. Preferred, but non-limiting examples of heterocyclyl include azetidinyl.

[0024] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a halogen atom, preferably fluoro. Preferably, "haloalkyl" refers to an alkyl group in which one, two or three hydrogen atoms of the alkyl group are replaced by a halogen atom, most preferably fluoro. Non-limiting examples of haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, 2-fluoroethyl and 2,2-difluoroethyl. A particularly preferred but non-limiting example of haloalkyl is trifluoromethyl.

[0025] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, especially hydrochloric acid, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, lactic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, and the like. In addition, these salts can 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, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, etc. Particular pharma- ceutically acceptable salts of the compounds of formula (I) are the hydrochloride, fumarate, formate, lactate (especially derived from L-(+)-lactic acid), tartrate (especially derived from L-(+)-tartaric acid) and trifluoroacetate salts.

[0026] The compounds of formula (I) may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, racemates of diastereoisomers or racemic mixtures of diastereoisomers.

[0027] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0028] The term "treatment" as used herein includes (1) inhibiting a condition, disorder or symptom (e.g., arresting, reducing or delaying the onset of a disease or, in the case of maintenance treatment, the recurrence of the disease, the onset of at least one clinical or subclinical symptom of the disease); and / or (2) alleviating symptoms (i.e., causing the regression of the condition, disorder or symptom, or at least one of its clinical or subclinical symptoms). The benefit to the patient to be treated is either statistically significant or at least discernible to the patient or the physician. However, it will be understood that when a pharmaceutical agent is administered to a patient to treat a disease, the result may not necessarily be an effective treatment.

[0029] The terms "prophylaxis" or "prevention" as used herein include preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition in a subject, particularly a human, who may be susceptible to or predisposed to a condition, disorder or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder or condition.

[0030] As used herein, the term "subject" includes both humans and non-humans, including, but not limited to, humans, non-human primates, canines, felines, murines, bovines, equines, and porcines. In particularly preferred embodiments, the term "subject" refers to a human.

[0031] The abbreviation uM means micromolar and is equivalent to the symbol μM.

[0032] The abbreviation uL means microliter and is equivalent to the symbol μL.

[0033] The abbreviation ug stands for microgram and is equivalent to the symbol μg.

[0034] Compounds of the Invention In a first aspect, the present invention provides a compound of formula (I) or (II): [ka] (In the formula, [ka] is the following: [ka] Selected from; X is CR 6 and nitrogen; W is C or N; R 1 is hydrogen, C1-C6-alkyl, carbamoyl, C1-C6-alkyl-NH-C(O)-, (C1-C6-alkyl)2N-C(O)-, C3-C 10 -cycloalkyl-NH-C(O)-, and 3- to 14-membered heterocycloalkyl-C(O)-; wherein the 3- to 14-membered heterocycloalkyl is optionally substituted with one substituent selected from halogen and C1-C6-alkoxy; R 1a is selected from hydrogen and C1-C6-alkyl; or R 1 and R 1a together with the carbon atoms to which they are attached, C3-C 10 -Forming a cycloalkenyl; R 2 is selected from hydrogen and C1-C6-alkyl; R 3 is selected from chloro and bromo; R 4 is selected from C1-C3-alkyl, halo-C1-C2-alkyl, and halogen; R 5 is selected from hydrogen and halogen; R 6 is selected from hydrogen and halogen. or a pharma- ceutically acceptable salt thereof.

[0035] In one embodiment, the compound according to the invention has formula (I): [ka] where the variables are as described herein. or a pharma- ceutically acceptable salt thereof.

[0036] In one embodiment, the compound according to the invention has formula (II): [ka] where the variables are as described herein. or a pharma- ceutically acceptable salt thereof.

[0037] In a preferred embodiment, the compound according to the invention is [ka] but, [ka] wherein the remaining variables are as described herein, or a pharma- ceutically acceptable salt thereof. In one embodiment, the compound according to the invention is [ka] but, [ka] and the remaining variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0038] In one embodiment, the compound according to the invention is [ka] but, [ka] and the remaining variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0039] In one embodiment, the compound according to the invention is [ka] but, [ka] and the remaining variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0040] In one embodiment, the compound according to the invention is [ka] but, [ka] and the remaining variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0041] In one embodiment, the compound according to the invention is [ka] but, [ka] and the remaining variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0042] In one embodiment, the compound according to the invention is 1 is C1-C6-alkyl, and the remaining variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0043] In one embodiment, the compound according to the invention is 1 is methyl, and the remaining variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0044] In one embodiment, the present invention provides [ka] But the following: [ka] Selected from; R 1 is selected from hydrogen, C1-C6-alkyl, and 3- to 14-membered heterocycloalkyl-C(O)-; said 3- to 14-membered heterocycloalkyl is substituted with one C1-C6-alkoxy substituent; R 1a is C1-C6-alkyl; or a pharma- ceutically acceptable salt thereof.

[0045] In a preferred embodiment, the present invention comprises: [ka] But the following: [ka] Selected from; R 1 is selected from hydrogen, methyl and methoxyazetidine-C(O)-; R 1a is methyl; or a pharma- ceutically acceptable salt thereof.

[0046] In one embodiment, the present invention provides R 1 is selected from hydrogen, C1-C6-alkyl, and 3- to 14-membered heterocycloalkyl-C(O)-; said 3- to 14-membered heterocycloalkyl is substituted with one C1-C6-alkoxy substituent; R 1a is C1-C6-alkyl, or a pharma- ceutically acceptable salt thereof.

[0047] In a preferred embodiment, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: R 1 is selected from hydrogen, methyl and methoxyazetidine-C(O)-; R 1a is methyl; or a pharma- ceutically acceptable salt thereof.

[0048] In a preferred embodiment, the present invention provides a 2 is selected from hydrogen and methyl, or a pharma- ceutically acceptable salt thereof.

[0049] In a preferred embodiment, the present invention provides a 3 is chloro; or a pharma- ceutically acceptable salt thereof.

[0050] In a preferred embodiment, the present invention provides a 4 is selected from methyl, CF3, and chloro, or a pharma- ceutically acceptable salt thereof.

[0051] In a particularly preferred embodiment, the present invention provides 4 is selected from methyl and CF3, or a pharma- ceutically acceptable salt thereof.

[0052] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 4 is methyl; or a pharma- ceutically acceptable salt thereof.

[0053] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 4 is CF3, or a pharma- ceutically acceptable salt thereof.

[0054] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 4 is chloro; or a pharma- ceutically acceptable salt thereof.

[0055] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 5 is halogen; or a pharma- ceutically acceptable salt thereof.

[0056] In a preferred embodiment, the present invention provides a 5 is selected from chloro and fluoro, or a pharma- ceutically acceptable salt thereof.

[0057] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 5 is chloro; or a pharma- ceutically acceptable salt thereof.

[0058] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 5 is fluoro; or a pharma- ceutically acceptable salt thereof.

[0059] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 6 is hydrogen; or a pharma- ceutically acceptable salt thereof.

[0060] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 6 is halogen; or a pharma- ceutically acceptable salt thereof.

[0061] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 6 is fluoro; or a pharma- ceutically acceptable salt thereof.

[0062] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 6 is hydrogen or fluoro; or a pharma- ceutically acceptable salt thereof.

[0063] In one embodiment, the present invention provides [ka] But the following: [ka] Selected from; X is CR 6 and nitrogen; R 1 is hydrogen, C1-C6-alkyl, C1-C6-alkyl-NH-C(O)-, C3-C 10-cycloalkyl-NH-C(O)-, and 3- to 14-membered heterocycloalkyl-C(O)-; wherein the 3- to 14-membered heterocycloalkyl is optionally substituted with one substituent selected from halogen and C1-C6-alkoxy; R 1a is selected from hydrogen and C1-C6-alkyl; or R 1 and R 1a together with the carbon atom to which they are attached, C3-C 10 -Forming a cycloalkenyl; R 2 is selected from hydrogen and C1-C6-alkyl; R 3 is chloro; R 4 is selected from C1-C3-alkyl, halo-C1-C2-alkyl, and halogen; R 5 is a halogen, R 6 is selected from hydrogen and halogen, or a pharma- ceutically acceptable salt thereof.

[0064] In a preferred embodiment, the present invention comprises: [ka] But the following: [ka] Selected from; X is CR 6 and nitrogen; R 1 is selected from hydrogen, C1-C6-alkyl, and 3- to 14-membered heterocycloalkyl-C(O)-; said 3- to 14-membered heterocycloalkyl is substituted with one C1-C6-alkoxy substituent; R 1a is C1-C6-alkyl; R 2is selected from hydrogen and C1-C6-alkyl; R 3 is chloro; R 4 is selected from C1-C3-alkyl, halo-C1-C2-alkyl, and halogen; R 5 is a halogen, R 6 is hydrogen, or a pharma- ceutically acceptable salt thereof.

[0065] In a particularly preferred embodiment, the present invention comprises: [ka] But the following: [ka] Selected from; X is CR 6 and nitrogen; R 1 is selected from hydrogen, methyl and methoxyazetidine-C(O)-; R 1a is methyl; R 2 is selected from hydrogen and methyl; R 3 is chloro; R 4 is selected from methyl, CF3, and chloro; R 5 is selected from chloro and fluoro; and R 6 is hydrogen, or a pharma- ceutically acceptable salt thereof.

[0066] In one embodiment, the present invention relates to a compound of formula (I) or (II) comprising: 6,7-Dichloro-5-(2-fluoro-5-hydroxyphenyl)-1-methyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one; 6-Chloro-5-(2-fluoro-5-hydroxyphenyl)-1,7-dimethyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one; 3-(7,8-dichloro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl)-4-fluoro-phenol; 3-[(4S)-7,8-dichloro-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-4-fluorophenol; (5S)-8,9-Dichloro-7-(2-fluoro-5-hydroxyphenyl)-5-methyl-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one; 8,9-Dichloro-7-(2-fluoro-5-hydroxy-phenyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one; [7,8-dichloro-6-(2-fluoro-5-hydroxy-phenyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone; 6-Chloro-5-(2-fluoro-5-hydroxy-phenyl)-1-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one; 3-[7-chloro-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-4-fluoro-phenol; 3-[7-chloro-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-4-fluoro-phenol; 3-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-4-fluoro-phenol; 8-Chloro-7-(2-fluoro-5-hydroxy-phenyl)-9-(trifluoromethyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one; 6,7-Dichloro-5-(2,6-difluoro-3-hydroxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one; 3-(7,8-dichloro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl)-2,4-difluoro-phenol; 8,9-Dichloro-7-(2,6-difluoro-3-hydroxy-phenyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one; 3-[(4S)-7,8-dichloro-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-2,4-difluoro-phenol; [7-chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone; (5S)-8,9-Dichloro-7-(2,6-difluoro-3-hydroxy-phenyl)-5-methyl-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one; [7-chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]-(3-methoxyazetidin-1-yl)methanone; 6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol; [(4S)-7-chloro-6-(3-fluoro-6-hydroxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-fluoroazetidin-1-yl)methanone; 5-Chloro-6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]pyridin-2-ol; 6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol; 6-[(10S)-6-chloro-10-methyl-5-(trifluoromethyl)-1,9,12-triazatetracyclo[9.6.0.02,7.013,17]heptadeca-2,4,6,8,11,13(17)-hexaen-8-yl]-5-fluoro-pyridin-2-ol; 6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-6-yl]-5-fluoropyridin-2-ol; 5-Chloro-6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]pyridin-2-ol; 5-Chloro-6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]pyridin-2-ol; 6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol; 5-Chloro-6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-6-yl]pyridin-2-ol; Azetidin-1-yl-[(4S)-7-chloro-6-(3-fluoro-6-hydroxypyridin-2-yl)-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-2-yl]methanone; (4S)-7-Chloro-N-cyclopropyl-6-(3-fluoro-6-hydroxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxamide; (4S)-7-Chloro-6-(3-fluoro-6-hydroxy-2-pyridyl)-N-isopropyl-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxamide The present invention provides a compound of formula (I) or (II) as described herein, selected from:

[0067] In a preferred embodiment, the present invention relates to a compound of formula (I) or (II) which is 6,7-Dichloro-5-(2-fluoro-5-hydroxyphenyl)-1-methyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one; 6-Chloro-5-(2-fluoro-5-hydroxyphenyl)-1,7-dimethyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one; 6-Chloro-5-(2-fluoro-5-hydroxy-phenyl)-1-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one; [7-chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone; 6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol; 5-Chloro-6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]pyridin-2-ol The present invention provides a compound of formula (I) or (II) as described herein, selected from:

[0068] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharma- ceutically acceptable salt thereof, wherein said compound of formula (I) or (II) is 6,7-dichloro-5-(2-fluoro-5-hydroxyphenyl)-1-methyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one.

[0069] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharma- ceutically acceptable salt thereof, wherein said compound of formula (I) or (II) is 6-chloro-5-(2-fluoro-5-hydroxyphenyl)-1,7-dimethyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one.

[0070] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) or (II) is 6-chloro-5-(2-fluoro-5-hydroxy-phenyl)-1-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one.

[0071] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, wherein the compound of formula (I) or (II) is [7-chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone, or a pharma- ceutically acceptable salt thereof.

[0072] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, wherein the compound of formula (I) or (II) is 6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol, or a pharma- ceutically acceptable salt thereof.

[0073] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, wherein the compound of formula (I) or (II) is 5-chloro-6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]pyridin-2-ol, or a pharma- ceutically acceptable salt thereof.

[0074] In one embodiment, the present invention provides a pharma- ceutically acceptable salt of a compound of formula (I) or (II) as described herein, in particular a pharma- ceutically acceptable salt selected from hydrochloride, fumarate, lactate (especially derived from L-(+)-lactic acid), tartrate (especially derived from L-(+)-tartaric acid) and trifluoroacetate. In yet a further particular embodiment, the present invention provides a compound according to formula (I) or (II) as described herein in their free form (i.e., as the "free base" or "free acid", respectively).

[0075] Manufacturing Process Processes for preparing the compounds of formula (I) and (II) described herein are also an object of the present invention.

[0076] The preparation of the compounds of formula (I) or (II) of the present invention can be carried out in sequential or convergent synthetic routes. The synthesis of the compounds of the present invention is shown in the following scheme. The skills required to carry out the reactions and purification of the products obtained are known to those skilled in the art. The substituents and indices used in the description of the following processes have the meanings indicated hereinbefore and in the claims, unless otherwise indicated. More specifically, the compounds of formula (I) and (II) can be prepared by the methods shown below, the methods shown in the examples, or by analogous methods. Suitable reaction conditions for the individual reaction steps are known to those skilled in the art. Also, for reaction conditions described in the literature that affect the reactions described, see, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 2018). It is convenient to carry out the reaction in the presence or absence of a solvent. There are no particular restrictions regarding the nature of the solvent used, provided that it does not adversely affect the reaction or the reagents involved and that it is able to dissolve the reagents at least to some extent. The reactions described can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. It is convenient to carry out the reactions described at temperatures ranging from -78°C to reflux temperature. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days is usually sufficient to obtain the intermediates and compounds described. The reaction sequence is not limited to the sequence shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities. The starting materials are commercially available or can be prepared by methods similar to those shown below, methods described in the references or examples cited herein, or methods known in the art.

[0077] The preparation of the compounds of formula (I) or (II) of the present invention can be carried out in sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to carry out the reactions and purification of the products obtained are known to those skilled in the art. The substituents and indices used in the description of the following processes have the meanings given hereinbefore, unless otherwise indicated.

[0078] More specifically, the compounds of formula (I) and (II) can be prepared by the methods shown below, the methods shown in the Examples, or similar methods. Suitable reaction conditions for the individual reaction steps are known to those skilled in the art. The reaction sequence is not limited to the sequence shown in Schemes 1-14, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities. The starting materials are commercially available or can be prepared by methods similar to those shown below, methods described in the references or examples cited herein, or methods known in the art.

[0079] The present compounds of formula (I) and (II) and pharma- ceutically acceptable salts thereof can be prepared by the processes described in the following Schemes 1 to 14, without being limited to the routes and conditions specifically exemplified.

[0080] According to Scheme 1, compounds of formula (I) can be obtained in two steps according to the process described in Scheme 1. Lactam (III) can be N-alkylated with an alkyl halide (e.g., iodomethane) in the presence of a base such as potassium carbonate or cesium carbonate to give N-alkyl lactam (IV), which can be deprotected under acidic conditions (e.g., hydrobromic acid, trifluoroacetic acid) or Lewis acidic conditions (e.g., boron tribromide, aluminum trichloride, iodotrimethylsilane) to give compounds of formula (I). [ka]

[0081] Scheme 1: Synthesis of benzodiazepines of formula (I) According to Scheme 2, compounds of formula (IIa) can be prepared from lactams of formula (III). [ka]

[0082] Scheme 2: Synthesis of benzodiazepines of formula (IIa) After thionation reaction using Lawesson's reagent or P2S5, lactams (III) are converted to the corresponding thiolactams (V). Their reaction with hydrazides (VI) via a Pellizzari-type process gives 1,2,4-triazoles of general formula (VII). Alternatively, 1,2,4-triazoles (VII) can be obtained by reaction of thiolactams (V) with hydrazine to form hydrazones (VIII) followed by treatment with the corresponding trialkyl orthoacetates or acid chlorides (IX). Furthermore, lactams (III) can be directly converted to compounds of formula (VII) by treatment with amide coupling reagents such as bis(2-oxo-3-oxazolidinyl)phosphine chloride and hydrazides (VI) in the presence of a strong base such as sodium hydride. The final derivative of formula (IIa) can be obtained by deprotection reaction of compound (VII) under acidic conditions (hydrobromic acid, trifluoroacetic acid, etc.) or Lewis acidic conditions (boron tribromide, aluminum trichloride, iodotrimethylsilane, etc.).

[0083] In a particular embodiment of the present invention, compounds of formula (IIc) can be prepared from lactams (III) according to the process described below (Scheme 3). Electrophilic amination of lactams (III) with a suitable reagent such as O-(diphenylphosphinyl)hydroxylamine gives intermediates of formula (X). Their thermal cyclocondensation reaction with imidates (XI) gives 1,2,4-triazoles of formula (XII), which can be deprotected under acidic conditions (hydrobromic acid, trifluoroacetic acid, etc.) or Lewis acidic conditions (boron tribromide, aluminum trichloride, iodotrimethylsilane, etc.) to give the final derivatives of formula (IIc). [ka]

[0084] Scheme 3: Synthesis of benzodiazepines of formula (IIc) In certain embodiments of the present invention, compounds of formula (IId) can be prepared according to Scheme 4. [ka]

[0085] Scheme 4: Synthesis of benzodiazepines of formula (IId) R 1 Ester (XIII), which is a selection of compound (XII) (described in Scheme 3) defined by =COOAlk, is reacted with amine (XIV) with or without the addition of a suitable catalyst such as isopropylmagnesium chloride to form a compound of formula (XV). Alternatively, ester (XIII) can be saponified to the corresponding acid (XVI) under basic conditions, for example by treatment with an aqueous or alcoholic solution of sodium hydroxide or lithium hydroxide. Derivative (XV) can then be reacted with acid (XVI) and an amine HNR 4 R 5Compound (IId) is obtained by a standard amide coupling reaction between (XIV). Further deprotection of compound (XV) under acidic conditions (hydrobromic acid, trifluoroacetic acid, etc.) or Lewis acidic conditions (boron tribromide, aluminum trichloride, iodotrimethylsilane, etc.) gives compound (IId). Similarly, acid (XVI) can be deprotected as described above to form compound (XVII), which can then be coupled with amine (XIV) in the presence of a coupling reagent to form the final derivative of general formula (IId).

[0086] In a further embodiment of the present invention, the imidazoles of formula (IIe) can be prepared as described below (Scheme 5). [ka]

[0087] Scheme 5: Synthesis of benzodiazepines of formula (IIe) Thiolactam (V) is reacted with ammonia to form amidines of formula (XVIII). After reaction with propargylamine under acid catalysis, amidine (XVIII) can be converted to methylimidazole (XIX), which can then be deprotected under acidic conditions (hydrobromic acid, trifluoroacetic acid, etc.) or Lewis acidic conditions (boron tribromide, aluminum trichloride, iodotrimethylsilane, etc.) to give the final derivatives of formula (IIe).

[0088] In a further embodiment of the present invention, the imidazoles of formula (IIf) can be prepared as described in Scheme 6.

[0089] Lactam (III) reacts with aminoalcohol (XX) upon activation with a suitable coupling reagent such as bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) to form intermediate (XXI), which can be cyclized under oxidative conditions to provide imidazole of formula (XXII). After deprotection reaction under acidic conditions (hydrobromic acid, trifluoroacetic acid, etc.) or Lewis acidic conditions (boron tribromide, aluminum trichloride, iodotrimethylsilane, etc.), the final derivative of formula (IIf) is obtained. [ka]

[0090] Scheme 6: Synthesis of benzodiazepines of formula (IIf) In a further embodiment of the invention, compounds of formula (IIg) may be prepared as shown in Scheme 7. [ka]

[0091] Scheme 7: Synthesis of benzodiazepines of formula (IIg) Amidines of formula (XVIII) can be alkylated with ethyl bromopyruvate to form esters of formula (XXIII), which can be saponified under basic conditions to form acids (XXIV). After amide-forming reaction with amines (XIV) and a suitable coupling reagent, acids (XXIV) can be converted to amides (XXV). Final deprotection reaction of compounds (XXV) under acidic conditions (hydrobromic acid, trifluoroacetic acid, etc.) or Lewis acidic conditions (boron tribromide, aluminum trichloride, iodotrimethylsilane, etc.) gives the final derivatives of general formula (IIg).

[0092] In a further embodiment of the present invention, compounds of formula (IIh) may be prepared as described in Scheme 8. [ka]

[0093] Scheme 8: Synthesis of benzodiazepines of formula (IIh) Amidines of formula (XVIII) are reacted with ethyl propiolate to form pyrimido[1,2-a][1,4]benzodiazepin-3-ones of formula (XXVI), whose final deprotection reaction under acidic conditions (hydrobromic acid, trifluoroacetic acid, etc.) or Lewis acidic conditions (boron tribromide, aluminum trichloride, iodotrimethylsilane, etc.) afford the final derivatives of formula (IIh).

[0094] Furthermore, as detailed in Scheme 9, thiolactams (V) can be reacted with 2-aminocyclopentanol to form alcohols (XXVII), which can be oxidized with Dess-Martin periodinane to give imidazoles (XXVIII). Their final deprotection under acidic conditions (hydrobromic acid, trifluoroacetic acid, etc.) or Lewis acidic conditions (boron tribromide, aluminum trichloride, iodotrimethylsilane, etc.) affords the final derivatives of general formula (IIi). [ka]

[0095] Scheme 9: Synthesis of benzodiazepines of formula (IIi) In a further embodiment of the present invention, compounds of formula (IIj) can be prepared as depicted in Scheme 10. [ka]

[0096] Scheme 10: Synthesis of benzodiazepines of formula (IIj) The lactam (III) is reacted with an alkyl isocyanoacetate (XXIX) to form an imidazole of formula (XXX). Saponification under standard conditions and their final deprotection under acidic conditions (hydrobromic acid, trifluoroacetic acid, etc.) or Lewis acidic conditions (boron tribromide, aluminum trichloride, iodotrimethylsilane, etc.) gives the carboxylic acid (XXXI). Their reaction with an amine (XIV) under standard amide forming conditions gives the final derivative (IIj). Furthermore, the imidazole (XXX) can be reacted with an amine (XIV) with or without the addition of a suitable catalyst such as isopropylmagnesium chloride to form an intermediate of formula (XXXII). After a deprotection reaction under acidic conditions (hydrobromic acid, trifluoroacetic acid, etc.) or Lewis acidic conditions (boron tribromide, aluminum trichloride, iodotrimethylsilane), the final derivative of general formula (IIj) can be obtained.

[0097] The synthesis of lactams (III) and their precursors is highlighted in the scheme below.

[0098] Lactams (III) can be synthesized according to Scheme 11. Commercially available 2-aminobenzoic acids (XXXIII) can be heated in acetic anhydride to form benzoxazin-4-ones (XXXIV). Grignard or organolithium reagents, prepared by metallation from the corresponding aryl compounds (XXXV), can then be reacted with the benzoxazin-4-ones (XXXIV) under controlled temperature to give ketones of formula (XXXVI). After N-acetamide hydrolysis under acidic conditions, the compounds of formula (XXXVI) are converted to aminobenzophenones of formula (XXXVII). Conveniently, at this junction, R 4 The halogen of can be introduced by treatment with N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS) to give intermediates of formula (XXXVIII). A final thermal cyclization reaction with ethyl 2-aminoacetate hydrochloride gives the desired O-protected lactam building blocks of formula (IIIa). Alternatively, amides (XL) can be obtained by coupling with N-Boc protected L-amino acids (XXXIX) upon exposure to phosphoryl chloride (POCl3) in pyridine or reaction with coupling reagents such as HATU, HBTU, etc. Removal of the N-Boc protecting group can be carried out with mineral acids (e.g. HCl) or organic acids (e.g. trifluoroacetic acid) to give amines of formula (XLI). A final intramolecular condensation reaction promoted by acidic medium (e.g. silica in toluene or pivalic acid in ethanol) and heat (80-110 °C) provides the desired lactam building blocks of formula (IIIb). [ka]

[0099] Scheme 11: Synthesis of lactams (IIIa) and (IIIb) Alternatively, according to Scheme 12, anilines (XLII) can be protected with a suitable protecting group such as tert-butyloxycarbonyl by treatment with di-tert-butyl dicarbonate in the presence of a base (e.g. diisopropylethylamine) to give compounds (XLIII). Regioselective metallation of compounds (XLIII) with n-BuLi at low temperature followed by 1,2-addition to aldehydes (XLIV) gives secondary alcohols of formula (XLV). Subsequent oxidation to ketones (XLVI) with manganese dioxide followed by deprotection with an organic acid (e.g. trifluoroacetic acid in dichloromethane) gives aminobenzophenones of formula (XXXVIII). [ka]

[0100] Scheme 12: Alternative synthesis of aminobenzophenones (XXXVIII) Furthermore, according to Scheme 13, regioselective metallation of aryl bromides (XLVII) with n-BuLi at low temperature followed by 1,2-addition to aldehydes (XLIV) affords secondary alcohols of formula (XLVIII). Subsequent oxidation to ketones (XLIX) followed by palladium-catalyzed coupling with carbamates (L) afforded protected aminobenzophenones of formula (XLVI). [ka]

[0101] Scheme 13: Synthesis of aminobenzophenones (XLVI) Additionally, lactams of structure (III) can be synthesized by reacting iodolactam (III) with a trifluoromethylating agent such as methyl 2,2-difluoro-2-(fluorosulfonyl)acetate using copper catalysis (see Scheme 14). [ka]

[0102] Scheme 14: Synthesis of lactam (III) In particular, in the processes described in Schemes 1-14, racemization at the chiral center occurs to various degrees (20-100%) depending on the specific reaction conditions employed. As a result, chiral purification (e.g., by HPLC or SFC) of the final derivatives of formulas (I) and (II) is necessary to obtain single enantiomers (enantiomeric excess (ee) >97%).

[0103] In particular, depending on the particular reaction conditions employed, partial racemization of the chiral center may occur, and as a result, chiral purification (e.g., by HPLC or SFC) of the final derivatives of formulae (I) and (II) is necessary in order to obtain final derivatives with enantiomeric excess (ee) of more than 97%.

[0104] In one aspect, the present invention provides a process for the preparation of compounds of formula (I) and (II) as described herein, the process being as depicted in any one of Schemes 1-14 above.

[0105] In a further aspect, the present invention provides compounds of formula (I) and (II) as described herein, or a pharma- ceutically acceptable salt thereof, when prepared according to the processes disclosed herein.

[0106] Uses of the Compounds of the Invention As explained in the Background section and exemplified in the Experimental section, the compounds of formula (I) or (II), and their pharma- ceutically acceptable salts, possess beneficial pharmacological properties that make them useful for the treatment or prevention of diseases or complications associated with the GABA Aγ1 receptor.

[0107] In one aspect, the present invention provides a compound of formula (I) or (II) as described herein, or a pharma- ceutically acceptable salt thereof, for use as a therapeutically active substance.

[0108] In a further aspect, the present invention provides a method of treating or preventing an acute neurological disorder, a chronic neurological disorder and / or a cognitive disorder in a subject, comprising administering to the subject an effective amount of a compound of formula (I) or (II) as described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0109] In a further aspect, the present invention provides the use of a compound of formula (I) or (II) as described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, in a method for treating or preventing an acute neurological disorder, a chronic neurological disorder and / or a cognitive disorder in a subject.

[0110] In a further aspect, the present invention provides a compound of formula (I) or (II) as described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in a method of treating or preventing an acute neurological disorder, a chronic neurological disorder and / or a cognitive disorder in a subject.

[0111] In a further aspect, the present invention provides the use of a compound of formula (I) or (II) as defined herein, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing an acute neurological disorder, a chronic neurological disorder and / or a cognitive disorder.

[0112] In one embodiment, the acute neurological disorder, chronic neurological disorder and / or cognitive disorder is autism spectrum disorder (ASD), Angelman syndrome, age-related cognitive decline, Rett syndrome, Prader-Willi syndrome, amyotrophic lateral sclerosis (ALS), fragile X disorder, negative and / or dementia symptoms associated with schizophrenia, tardive dyskinesia, anxiety, social anxiety disorder (social phobia), panic disorder, agoraphobia, generalized anxiety disorder, disruptive, impulse control and behavior disorders, Tourette syndrome (TS), obsessive-compulsive disorder (OCD), acute stress disorder, chronic neurological disorder, chronic encephalopathy ... The present invention relates to a method for treating autism, comprising administering to a subject a therapeutically effective amount of medication such as sedatives, antidepressants, anti-inflammatory drugs ...

[0113] In one embodiment, the acute neurological disorder, chronic neurological disorder and / or cognitive disorder is selected from Alzheimer's disease, mild cognitive impairment (MCI), age-related cognitive decline, negative and / or dementia 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), and fragile X disorder.

[0114] In a preferred embodiment, the acute neurological disorder, chronic neurological disorder and / or cognitive disorder is selected from autism spectrum disorder (ASD), Angelman syndrome, Alzheimer's disease, negative and / or dementia symptoms associated with schizophrenia and post-traumatic stress disorder (PTSD).

[0115] In a preferred embodiment, the acute neurological disorder, chronic neurological disorder and / or cognitive disorder is selected from autism spectrum disorder (ASD), Rett syndrome, Angelman syndrome, post-traumatic stress disorder and fragile X disorder.

[0116] In a preferred embodiment, the acute neurological disorder, chronic neurological disorder and / or cognitive disorder is selected from autism spectrum disorder (ASD), Rett syndrome, post-traumatic stress disorder and fragile X disorder.

[0117] In a preferred embodiment, the acute neurological disorder, chronic neurological disorder and / or cognitive disorder is selected from Autism Spectrum Disorder (ASD) and Angelman Syndrome.

[0118] In a particularly preferred embodiment, the acute neurological disorder, chronic neurological disorder and / or cognitive disorder is an autism spectrum disorder (ASD).

[0119] In a particularly preferred embodiment, the acute neurological disorder, chronic neurological disorder and / or cognitive disorder is Angelman Syndrome.

[0120] In a further particularly preferred embodiment, the acute neurological disorder, chronic neurological disorder and / or cognitive disorder is Autism Spectrum Disorder (ASD) targeting core symptoms and associated comorbidities such as anxiety and hypersensitivity, social anxiety disorder (social phobia) and generalized anxiety disorder.

[0121] In a further particularly preferred embodiment, the acute neurological disorder, chronic neurological disorder and / or cognitive disorder is selected from social anxiety disorder (social phobia) and generalized anxiety disorder. Pharmaceutical Compositions and Administration

[0122] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or (II) as defined herein, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients. Exemplary pharmaceutical compositions are described in the Examples section below.

[0123] In a further aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or (II) or a pharma- ceutically acceptable salt thereof as defined above, and one or more pharma- ceutically acceptable excipients for the treatment or prevention of acute neurological disorders, chronic neurological disorders and / or cognitive disorders.

[0124] The compounds of formula (I) or (II) and their pharma- ceutically acceptable salts can be used as medicines (e.g., in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered to the body orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g., in the form of nasal drops), or rectally (e.g., in the form of suppositories). However, administration can also be carried out parenterally, such as intramuscularly or intravenously (e.g., in the form of injection or infusion solutions).

[0125] The compounds of formula (I) or (II) and their pharma- ceutically acceptable salts can be processed with pharma- ceutically inert inorganic or organic excipients for the preparation of tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules.Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc., can be used as excipients for tablets, sugar-coated tablets, and hard gelatin capsules, for example. Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc.

[0126] Suitable excipients for the production of solutions and syrups are, by way of example, water, polyols, saccharose, invert sugar, glucose etc.

[0127] Suitable excipients for injection solutions are, by way of example, water, alcohols, polyols, glycerol, vegetable oils etc.

[0128] Suitable excipients for suppositories are, by way of example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0129] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents, or antioxidants. The pharmaceutical preparations of the present invention may further contain other therapeutically valuable substances.

[0130] Dosage can vary widely and will of course be adapted to the individual requirements in each particular case. In general, for oral administration, a daily dosage of about 0.1 mg to 20 mg / kg body weight, preferably about 0.5 mg to 4 mg / kg body weight (e.g., about 300 mg / person) will be appropriate, preferably divided into 1 to 3 individual doses, which may be composed of, for example, the same amount. However, it is clear that the upper limit given in this specification can be exceeded, if indicated. EXAMPLES

[0131] The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the claims to the examples.

[0132] Where the preparations are obtained as mixtures of enantiomers, the pure enantiomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization.

[0133] Unless otherwise noted, all reactions and intermediates were prepared under an argon atmosphere.

[0134] Synthesis of building blocks The building blocks can be prepared according to the following synthetic procedures.

[0135] Component A 6,7-Dichloro-5-(2-fluoro-5-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0136] a) 5-chloro-2-methyl-3,1-benzoxazin-4-one A solution of 2-amino-6-chlorobenzoic acid (15.0 g, 87.4 mmol) in acetic anhydride (200 mL) was stirred at 140° C. for 2 hours. The reaction solution was concentrated in vacuo. The residue was suspended in acetonitrile, the solid was filtered, and the filter cake was dried in vacuo to give the title compound (11.3 g, 66%) as a white solid. 1 H NMR(400MHz,CDCl3)δ ppm 2.47(3H,s)7.47(1H,dd,J=8.1,0.9Hz)7.53(1H,dd,J=7.9,1.0Hz)7.67(1H,dd,J=8.1,8.0Hz).

[0137] b) N-[3-chloro-2-(2-fluoro-5-methoxy-benzoyl)phenyl]acetamide To a solution of 2-bromo-1-fluoro-4-methoxybenzene (5.45 g, 26.6 mmol) in THF (200 mL) was added n-butyllithium (2.5 m in hexane, 12.8 mL, 31.9 mmol) at -78 °C. After stirring for 1 h, 5-chloro-2-methyl-3,1-benzoxazin-4-one (5.20 g, 26.6 mmol) was added to the mixture and stirring was continued for another 1 h at -78 °C. The mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex luna C18, 10 μm, 250 × 50 mm, 0.05% HCl in water / acetonitrile) to give the title compound (3.63 g, 42%) as a pale yellow solid. MS: 322.1 ([{ 35 Cl}M+H] + ),324.1([{ 37 Cl}M+H] + ),ESI pos.

[0138] c) (2-amino-6-chloro-phenyl)-(2-fluoro-5-methoxy-phenyl)methanone To a solution of N-[3-chloro-2-(2-fluoro-5-methoxy-benzoyl)phenyl]acetamide (4.00 g, 12.4 mmol) in ethanol (50 mL) was added aqueous HCl (37%, 53.3 mL, 640 mmol). The mixture was stirred at 100° C. for 2 h and then concentrated in vacuo. The residue was dissolved in DCM and washed successively with saturated aqueous NaHCO3 and water. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (2.87 g, 83%) as an off-white solid. MS: 280.0 ([{ 35 Cl}M+H] + ),282.0([{ 37 Cl}M+H] + ),ESI pos.

[0139] d) (6-amino-2,3-dichloro-phenyl)-(2-fluoro-5-methoxy-phenyl)methanone A solution of (2-amino-6-chloro-phenyl)-(2-fluoro-5-methoxy-phenyl)methanone (1.00 g, 3.58 mmol) and N-chlorosuccinimide (430 mg, 3.22 mmol) in DMF (20 mL) was stirred at 0° C. for 2 h. The mixture was quenched with water and extracted with DCM. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Synergi C18, 10 μm, 150×25 mm, 0.1% trifluoroacetic acid in water / acetonitrile) to give the title compound (367 mg, 33%) as a pale yellow solid. MS: 313.9 ([{ 35 Cl, 35 Cl}M+H] + ),315.9([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0140] e) 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one A solution of glycine ethyl ester hydrochloride (2.89 g, 20.7 mmol) and (6-amino-2,3-dichloro-phenyl)-(2-fluoro-5-methoxy-phenyl)methanone (650 mg, 2.07 mmol) in pyridine (30 mL) was stirred at 100° C. for 16 h. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Synergi C18, 10 μm, 150×25 mm, 0.1% trifluoroacetic acid in water / acetonitrile) to give the title compound (280 mg, 38%) as a yellow solid. MS: 353.0 ([{ 35 Cl, 35 Cl}M+H] + ),355.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0141] Component B 6-Chloro-5-(2-fluoro-5-methoxy-phenyl)-7-methyl-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0142] a) (6-amino-3-bromo-2-chloro-phenyl)-(2-fluoro-5-methoxy-phenyl)methanone Analogously to the experiment for building block Ad, (2-amino-6-chloro-phenyl)-(2-fluoro-5-methoxy-phenyl)methanone (building block Ac) was converted to the title compound (1.63 g, 64%) using N-bromosuccinimide instead of N-chlorosuccinimide, affording a pale yellow solid. MS: 357.9 ([{ 79 Br, 35 Cl}M+H] + ),359.9([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0143] b) 7-Bromo-6-chloro-5-(2-fluoro-5-methoxy-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-fluoro-5-methoxy-phenyl)methanone was converted to the title compound (1.63 g, 64%) as a pale yellow solid (860 mg, 38%). MS: 396.9 ([{ 79 Br, 35 Cl}M+H] + ),398.9([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0144] c) 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-methyl-1,3-dihydro-1,4-benzodiazepin-2-one A solution of 7-bromo-6-chloro-5-(2-fluoro-5-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (600 mg, 1.51 mmol), methylboronic acid (117 mg, 1.96 mmol), potassium phosphate (641 mg, 3.02 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.10 g, 1.51 mmol) in DMF (12 mL) was stirred at 80° C. under nitrogen for 6 h. The reaction was diluted with methanol, filtered through a Celite plug and the filtrate was concentrated in vacuo. The residue was treated with water and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Synergi C18, 10 μm, 150×25 mm, 0.1% trifluoroacetic acid in water / acetonitrile) to give the title compound (230 mg, 45%) as a light brown solid. MS: 333.1 ([{ 79 Br, 35 Cl}M+H] + ),335.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0145] Component C 6,7-Dichloro-5-(2-fluoro-5-methoxy-phenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0146] a) tert-Butyl N-[2-[3,4-dichloro-2-(2-fluoro-5-methoxy-benzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamate To a solution of (6-amino-2,3-dichloro-phenyl)-(2-fluoro-5-methoxy-phenyl)methanone (Building A d, 2.00 g, 6.37 mmol) in pyridine (50 mL) was added Boc-DL-Ala-OH (1.81 g, 9.55 mmol). The reaction mixture was cooled to 0° C., then phosphoryl trichloride (1.56 g, 10.2 mmol) was added, and the mixture was stirred at 0° C. for 1 h. The mixture was quenched by the addition of saturated aqueous NaHCO3 solution and extracted with DCM. The organic layer was washed with brine and concentrated in vacuo. The residue was purified by flash column chromatography (silica, petroleum ether / ethyl acetate 10:1 to 1:1) to give the title compound (2.5 g, 81%) as a yellow oil. MS: 385.1 ([{ 35 Cl, 35 Cl}M+H-Boc] + ),387.1([{ 35 Cl, 37 Cl}M+H-Boc] + ),ESI pos.

[0147] b) 2-amino-N-[3,4-dichloro-2-(2-fluoro-5-methoxy-benzoyl)phenyl]propanamide To a solution of tert-butyl N-[2-[3,4-dichloro-2-(2-fluoro-5-methoxy-benzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamate (2.00 g, 4.12 mmol) in ethyl acetate (10 mL) was added HCl (4 m in ethyl acetate, 10 mL, 40 mmol). The mixture was stirred at 0° C. for 3 h. Water was added, the pH was adjusted to 9 by slow addition of solid NaHCO3, and the product was extracted with ethyl acetate. The organic layer was washed with brine and concentrated in vacuo to give the title compound (1.5 g, 94%) as a yellow oil. MS: 385.1 ([{ 35 Cl, 35 Cl}M+H] + ),387.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0148] c) 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

[0149] To a solution of 2-amino-N-[3,4-dichloro-2-(2-fluoro-5-methoxy-benzoyl)phenyl]propanamide (1.67 g, 4.34 mmol) in toluene (100 mL) was added silica gel (8.00 g, 133 mmol) and the mixture was stirred at 90° C. for 15 h. The mixture was cooled and concentrated in vacuo. The residue was purified by flash column chromatography (silica, petroleum ether / ethyl acetate 10:1 to 0:1) (along with another batch, 0.52 mmol scale) to give the title compound (1.5 g, 84%) as a yellow solid. MS: 367.1 1([{ 35 Cl, 35 Cl}M+H] + ),369.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0150] Component D 6-Chloro-5-(2-fluoro-5-methoxy-phenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0151] a) (6-amino-2-chloro-3-iodo-phenyl)-(2-fluoro-5-methoxy-phenyl)methanone Analogously to the experiment for building block A d, (2-amino-6-chloro-phenyl)-(2-fluoro-5-methoxy-phenyl)methanone (building block A c) was converted to the title compound (1.20 g, 59%) using N-iodosuccinimide instead of N-chlorosuccinimide, affording a yellow solid. MS: 405.9 ([{ 35 Cl}M+H] + ),407.9([{ 37 Cl}M+H] + ),ESI pos.

[0152] b) 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-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-fluoro-5-methoxy-phenyl)methanone was converted to the title compound (2.78 g, 40%) as a yellow solid. MS: 445.1 ([{ 35 Cl}M+H] + ),447.1([{ 37 Cl}M+H] + ),ESI pos. c) 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one

[0153] A mixture of 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one (1.00 g, 1.98 mmol, 88% pure), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.14 g, 5.95 mmol) and copper iodide (756 mg, 3.97 mmol) in DMF (20 mL) containing HMPA (10.0 mL, 1.98 mmol) was stirred at 70° C. for 16 h under nitrogen. The mixture was cooled and poured into water / ethyl acetate 1:1. The suspension was filtered and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-50% ethyl acetate in petroleum ether) to give the title compound (450 mg, 59%) as a brown oil. MS: 387.0 ([{ 35 Cl}M+H] + ),389.0([{ 37 Cl}M+H] + ),ESI pos.

[0154] Component E 6,7-Dichloro-5-(2,6-difluoro-3-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0155] a) tert-Butyl N-[3,4-dichloro-2-[(2,6-difluoro-3-methoxy-phenyl)-hydroxy-methyl]phenyl]carbamate A solution of tert-butyllithium (1m in THF, 18.0 mL, 18 mmol) was added dropwise to a solution of tert-butyl N-(3,4-dichlorophenyl)carbamate (4.00 g, 15.3 mmol) in THF (100 mL) at -78 °C. After stirring for 0.5 h, 2,6-difluoro-3-methoxy-benzaldehyde (3.15 g, 18.3 mmol) was added to the mixture at -78 °C and stirring was continued for another 0.5 h. The mixture was quenched with saturated aqueous NH4Cl, warmed to room temperature and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was suspended in petroleum ether / DCM 50:1 and the solid was filtered and dried in vacuo to give the title compound (2.10 g, 32%) as a white solid. MS: 456.0 ([{ 35 Cl, 35 Cl}M+Na] + ),458.0([{ 35 Cl, 37 Cl}M+Na] + ),ESI pos. b) tert-Butyl N-[3,4-dichloro-2-(2,6-difluoro-3-methoxy-benzoyl)phenyl]carbamate

[0156] To a solution of potassium bromide (80 mg, 0.67 mmol), NaHCO3 (145 mg, 1.73 mmol), TEMPO (73 mg, 0.47 mmol), aqueous sodium hypochlorite (0.4 m, 13 mL, 5.2 mmol) in DCM (130 mL) and water (65 mL) was added tert-butyl N-[3,4-dichloro-2-[(2,6-difluoro-3-methoxy-phenyl)-hydroxy-methyl]phenyl]carbamate (1.80 g, 4.14 mmol) and the reaction mixture was stirred at 25° C. for 16 h. The reaction was diluted with DCM and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (1.50 g, 84%) as a pale yellow oil. MS: 331.9 ([{ 35 Cl, 35 Cl}M+H-Boc] + ),333.9([{ 35 Cl, 37 Cl}M+H-Boc] + ),ESI pos.

[0157] c) (6-amino-2,3-dichloro-phenyl)-(2,6-difluoro-3-methoxy-phenyl)methanone hydrochloride To a solution of tert-butyl N-[3,4-dichloro-2-(2,6-difluoro-3-methoxy-benzoyl)phenyl]carbamate (1.50 g, 3.47 mmol) in ethyl acetate (20 mL) was added HCl (4 m in ethyl acetate, 7.5 mL, 30 mmol). The mixture was stirred at 20° C. for 3 h. The precipitated solid was filtered and dried under high vacuum to give the title compound (1.40 g, quantitative) as a pale yellow oil. MS: 331.9 ([{ 35 Cl, 35 Cl}M+H] + ),333.9([{ 35 Cl, 37 Cl}M+H] + ), ESI pos. This crude material was used directly in the next step without further purification.

[0158] d) 6,7-dichloro-5-(2,6-difluoro-3-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Ae, (6-amino-2,3-dichloro-phenyl)-(2,6-difluoro-3-methoxy-phenyl)methanone hydrochloride was converted to the title compound (500 mg, 37%) as a red solid. MS: 371.0 ([{ 35 Cl, 35 Cl}M+H] + ),373.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0159] Component F 6-Chloro-5-(2-fluoro-5-methoxy-phenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0160] a) tert-Butyl N-[2-[3-chloro-2-(2-fluoro-5-methoxy-benzoyl)-4-iodo-anilino]-1-methyl-2-oxo-ethyl]carbamate Analogously to the experiment for building block Ca, (6-amino-2-chloro-3-iodo-phenyl)-(2-fluoro-5-methoxy-phenyl)methanone (building block Da, 1.00 g, 2.47 mmol) was converted to the title compound (980 mg, 69%) as a pale yellow oil. MS: 599.0 ([{ 35 Cl}M+Na] + ),601.0([{ 37 Cl}M+Na] + ),ESI pos.

[0161] b) 2-Amino-N-[3-chloro-2-(2-fluoro-5-methoxy-benzoyl)-4-iodo-phenyl]propanamide Analogously to the experiment for building block Cb, tert-butyl N-[2-[3-chloro-2-(2-fluoro-5-methoxy-benzoyl)-4-iodo-anilino]-1-methyl-2-oxo-ethyl]carbamate (860 mg, 1.49 mmol) was converted to the title compound (580 mg, 82%) as a pale yellow oil. MS: 476.9 ([{ 35 Cl}M+H] + ),478.9([{ 37 Cl}M+H] + ),ESI pos. c) 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-iodo-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Cc, 2-amino-N-[3-chloro-2-(2-fluoro-5-methoxy-benzoyl)-4-iodo-phenyl]propanamide (650 mg, 1.36 mmol) was converted to the title compound (500 mg, 80%) as a pale yellow oil. MS: 458.9 ([{ 35 Cl}M+H] + ),460.9([{ 37 Cl}M+H] + ),ESI pos.

[0162] d) 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Dc, 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-iodo-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (500 mg, 1.09 mmol) was converted to the title compound (275 mg, 63%), which was obtained as a pale yellow oil. MS: 458.9 ([{ 35 Cl}M+H] + ),460.9([{ 37 Cl}M+H] + ),ESI pos.

[0163] Component G 6,7-Dichloro-5-(2,6-difluoro-3-methoxy-phenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0164] a) tert-Butyl N-[2-[3,4-dichloro-2-(2,6-difluoro-3-methoxy-benzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamate

[0165] Analogously to the experiment for building block Ca, (6-amino-2,3-dichloro-phenyl)-(2,6-difluoro-3-methoxy-phenyl)methanone (building block Ec, 4.1 g, 12 mmol) was converted to the title compound (4.5 g, 72%) as a brown oil. MS: 403.0 ([{ 35 Cl, 35 Cl}M+H-Boc] + ), 405.0([{ 35 Cl, 37 Cl}M+H-Boc] + ), ESI pos. This crude material was used directly in the next step without further purification.

[0166] b) 2-amino-N-[3,4-dichloro-2-(2,6-difluoro-3-methoxy-benzoyl)phenyl]propanamide Analogously to the experiment for building block Cb, tert-butyl N-[2-[3,4-dichloro-2-(2,6-difluoro-3-methoxy-benzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamate was converted to the title compound (3.2 g, 89%) as a brown oil. MS: 403.0 ([{ 35 Cl, 35 Cl}M+H] + ), 405.0([{ 35 Cl, 37 Cl}M+H] + ), ESI pos. This crude material was used directly in the next step without further purification.

[0167] c) 6,7-dichloro-5-(2,6-difluoro-3-methoxy-phenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Cc, 2-amino-N-[3,4-dichloro-2-(2,6-difluoro-3-methoxy-benzoyl)phenyl]propanamide was converted to the title compound (500 mg, 33%) as a pale yellow oil. MS: 385.0 ([{ 35 Cl, 35 Cl}M+H] + ),387.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0168] Component H (3S)-6-Chloro-5-(3-fluoro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0169] a) [6-bromo-2-chloro-3-(trifluoromethyl)phenyl]-(3-fluoro-6-methoxy-2-pyridyl)methanol To a solution of N,N-diisopropylamine (294 mg, 0.414 mL, 2.91 mmol) in anhydrous tetrahydrofuran (8 mL) was added n-BuLi (1.6 m in hexane, 1.68 mL, 2.68 mmol) dropwise at -20°C. After stirring for 15 min at -20°C, the LDA solution was cooled to -60°C. A solution of 4-bromo-2-chloro-1-(trifluoromethyl)benzene (580 mg, 2.24 mmol) in anhydrous tetrahydrofuran (2 mL) was added dropwise. The mixture was stirred at -60°C for 45 min, then 3-fluoro-6-methoxy-pyridine-2-carbaldehyde (486 mg, 3.13 mmol) was added in one portion. The reaction mixture was warmed to 0°C under stirring. The reaction mixture was quenched with aqueous NH4Cl and extracted with ethyl acetate (2 x 60 mL). The organic layer was washed with water (60 mL) and brine (60 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-30% ethyl acetate in heptane) to give the title compound (880 mg, 95%) as a white solid. MS: 414.0 ([{ 79 Br, 35 Cl}M+H] + ), 416.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0170] b) [6-bromo-2-chloro-3-(trifluoromethyl)phenyl]-(3-fluoro-6-methoxy-2-pyridyl)methanone To a solution of [6-bromo-2-chloro-3-(trifluoromethyl)phenyl]-(3-fluoro-6-methoxy-2-pyridyl)methanol (878 mg, 2.12 mmol) in dichloromethane (5 mL) at 23° C. was added manganese dioxide (3.68 g, 42.4 mmol). The reaction mixture was stirred at 23° C. for 60 h. The suspension was filtered off. The filtrate was concentrated in vacuo to give the title compound (855 mg, 97%) as a white solid. MS: 412.0 ([{ 79 Br, 35 Cl}M+H] + ), 414.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0171] c) tert-Butyl N-[3-chloro-2-(3-fluoro-6-methoxy-pyridine-2-carbonyl)-4-(trifluoromethyl)phenyl]carbamate In a sealed tube, [6-bromo-2-chloro-3-(trifluoromethyl)phenyl]-(3-fluoro-6-methoxy-2-pyridyl)methanone (79 mg, 0.191 mmol), tert-butyl carbamate (38.1 mg, 0.326 mmol) and tripotassium phosphate (73 mg, 0.345 mmol) and toluene (2 mL) were added and the suspension was degassed by bubbling argon for 15 min. Then, rac-BINAP-Pd-G4 (57.8 mg, 0.057 mmol) was added and bubbling was continued for 5 min: the tube was sealed and the reaction mixture was stirred at 100° C. for 16 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (2×40 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-30% ethyl acetate in heptane) to give the title compound (49 mg, 57%) as a white foam. MS: 447.1 ([{ 35 Cl}M+H] + ),449.1([{ 37 Cl}M+H] + ),ESI neg.

[0172] d) [6-Amino-2-chloro-3-(trifluoromethyl)phenyl]-(3-fluoro-6-methoxy-2-pyridyl)methanone To a solution of tert-butyl N-[3-chloro-2-(3-fluoro-6-methoxy-pyridine-2-carbonyl)-4-(trifluoromethyl)phenyl]carbamate (57 mg, 0.127 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (290 mg, 0.200 mL, 2.54 mmol) at 0° C. The light brown reaction mixture was stirred at 23° C. for 16 h and then concentrated in vacuo. The residue was dissolved in dichloromethane (20 mL) and saturated aqueous NaHCO3 (20 mL) was added. The aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (43 mg, 89%) as a yellow oil. MS: 349.0 ([{ 35 Cl}M+H] + ),351.0([{ 37 Cl}M+H] + ),ESI pos.

[0173] e) tert-Butyl N-[(1S)-2-[3-chloro-2-(3-fluoro-6-methoxy-pyridine-2-carbonyl)-4-(trifluoromethyl)anilino]-1-methyl-2-oxo-ethyl]carbamate Analogously to the experiment for building block C a, [6-amino-2-chloro-3-(trifluoromethyl)phenyl]-(3-fluoro-6-methoxy-2-pyridyl)methanone was converted to the title compound (185 mg, 67%) as a white foam. MS: 518.2 ([{ 35 Cl}M+H] + ),520.2([{ 37 Cl}M+H] + ),ESI neg. f) (2S)-2-amino-N-[3-chloro-2-(3-fluoro-6-methoxy-pyridine-2-carbonyl)-4-(trifluoromethyl)phenyl]propanamide

[0174] Analogously to the experiment for building block Hd, tert-butyl N-[(1S)-2-[3-chloro-2-(3-fluoro-6-methoxy-pyridine-2-carbonyl)-4-(trifluoromethyl)anilino]-1-methyl-2-oxo-ethyl]carbamate was converted to the title compound (153 mg, 100%) as a colorless oil. MS: 420.1 ([{ 35 Cl}M+H] + ),422.1([{ 37 Cl}M+H] + ),ESI pos. g) (3S)-6-chloro-5-(3-fluoro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one

[0175] Analogously to the experiment for building block Cc, (2S)-2-amino-N-[3-chloro-2-(3-fluoro-6-methoxy-pyridine-2-carbonyl)-4-(trifluoromethyl)phenyl]propanamide was converted to the title compound (141 mg, 96%) as a white solid. MS: 402.1 ([{ 35 Cl}M+H] + ), 404.1([{ 37 Cl}M+H] + ),ESI pos.

[0176] Component I (3S)-6-Chloro-5-(3-chloro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0177] a) [6-bromo-2-chloro-3-(trifluoromethyl)phenyl]-(3-chloro-6-methoxy-2-pyridyl)methanol As in the experiment for building block Ha, 4-bromo-2-chloro-1-(trifluoromethyl)benzene was converted to the title compound (13.48 g, 81%) using 3-chloro-6-methoxy-pyridine-2-carbaldehyde instead of 3-fluoro-6-methoxy-pyridine-2-carbaldehyde, afforded as a white solid. MS: 430.0 ([{ 79 Br, 35 Cl}M+H] + ),432.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),434.0([{ 81 Br, 37 Cl}M+H] + ),ESI pos. b) [6-bromo-2-chloro-3-(trifluoromethyl)phenyl]-(3-chloro-6-methoxy-2-pyridyl)methanone

[0178] Analogously to the experiment for component Hb, [6-bromo-2-chloro-3-(trifluoromethyl)phenyl]-(3-chloro-6-methoxy-2-pyridyl)methanol was converted to the title compound (13.54 g, 100%), which was obtained as a colorless oil. MS: 428.0 ([{ 79 Br, 35 Cl}M+H] + ),430.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),432.0([{ 81 Br, 37 Cl}M+H] + ),ESI pos. c) tert-Butyl N-[(1S)-2-[3-chloro-2-(3-chloro-6-methoxy-pyridine-2-carbonyl)-4-(trifluoromethyl)anilino]-1-methyl-2-oxo-ethyl]carbamate

[0179] As in the experiment for building block Hc, [6-bromo-2-chloro-3-(trifluoromethyl)phenyl]-(3-chloro-6-methoxy-2-pyridyl)methanone was converted to the title compound (570 mg, 75%) using tert-butyl N-[(1S)-2-amino-1-methyl-2-oxo-ethyl]carbamate instead of tert-butyl carbamate, afforded as a pale yellow foam. MS: 536.3 ([{ 35 Cl, 35 Cl}M+H] + ),538.2([{ 35 Cl, 37 Cl}M+H] + ),ESI pos. d) (2S)-2-amino-N-[3-chloro-2-(3-chloro-6-methoxy-pyridine-2-carbonyl)-4-(trifluoromethyl)phenyl]propanamide

[0180] Analogously to the experiment for building block Hd, tert-butyl N-[(1S)-2-[3-chloro-2-(3-chloro-6-methoxy-pyridine-2-carbonyl)-4-(trifluoromethyl)anilino]-1-methyl-2-oxo-ethyl]carbamate was converted to the title compound (1.3 g, 99%) as a pale yellow oil. MS: 436.2 ([{ 35 Cl, 35 Cl}M+H] + ),438.2([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0181] e) (3S)-6-chloro-5-(3-chloro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Cc, (2S)-2-amino-N-[3-chloro-2-(3-chloro-6-methoxy-pyridine-2-carbonyl)-4-(trifluoromethyl)phenyl]propanamide was converted to the title compound (1.13 g, 90%) as a pale yellow foam. MS: 418.0 ([{ 35 Cl, 35 Cl}M+H] + ),420.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0182] Component J (3S)-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0183] a) 6-benzyloxy-3-fluoro-pyridine-2-carbaldehyde To a mixture of 2-benzoxy-5-fluoro-pyridine (CAS 1305322-95-5, 2 g, 9.35 mmol) in anhydrous tetrahydrofuran (38 mL) cooled to -25°C to -30°C was added dropwise 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex (1 m in THF / toluene, 11.52 g, 12 mL, 12 mmol). The mixture was stirred at -25°C to -30°C for 0.5 h, then at 0°C for 0.5 h and room temperature for 0.5 h. The reaction mixture was cooled to -25°C to -30°C and N,N-dimethylformamide (2.83 g, 3 mL, 38.74 mmol) was added dropwise. The mixture was stirred at -25°C to 30°C for 45 min and at room temperature for 0.5 h, then warmed in an ice bath and quenched by the addition of water (340 uL, 18.87 mmol) followed by acetic acid (540 uL, 9.43 mmol). The reaction mixture was filtered through a pad of sodium sulfate and rinsed with ethyl acetate. The filtrate was adsorbed onto ISOLUTE HM-N and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-5% ethyl acetate in heptane) to give the title compound (1.21 g, 53%) as a pale yellow solid. MS: 232.1 ([M+H] + ),ESI pos.

[0184] b) (6-benzyloxy-3-fluoro-2-pyridyl)-[6-bromo-2-chloro-3-(trifluoromethyl)phenyl]methanol As in the experiment for building block Ha, 4-bromo-2-chloro-1-(trifluoromethyl)benzene was converted to the title compound (6.8 g, 78%) using 6-benzyloxy-3-fluoro-pyridine-2-carbaldehyde instead of 3-fluoro-6-methoxy-pyridine-2-carbaldehyde to give a pale yellow solid. MS: 490.0 ([{ 79 Br, 35 Cl}M+H] + ),492.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0185] c) (6-benzyloxy-3-fluoro-2-pyridyl)-[6-bromo-2-chloro-3-(trifluoromethyl)phenyl]methanone Analogously to the experiment for component Hb, (6-benzyloxy-3-fluoro-2-pyridyl)-[6-bromo-2-chloro-3-(trifluoromethyl)phenyl]methanol was converted to the title compound (6.44 g, 93%) as a pale yellow solid. MS: 488.0 ([{ 79 Br, 35 Cl}M+H] + ),490.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0186] d) tert-Butyl N-[(1S)-2-[2-(6-benzyloxy-3-fluoro-pyridine-2-carbonyl)-3-chloro-4-(trifluoromethyl)anilino]-1-methyl-2-oxo-ethyl]carbamate As in the experiment for building block Hc, but using tert-butyl N-[(1S)-2-amino-1-methyl-2-oxo-ethyl]carbamate instead of tert-butyl carbamate, (6-benzyloxy-3-fluoro-2-pyridyl)-[6-bromo-2-chloro-3-(trifluoromethyl)phenylmethanone was converted to the title compound (3.09 g, 85%) as a light brown foam. MS: 594.3 ([{ 35 Cl}MH] + ),596.2([{ 37 Cl}MH] + ),ESI neg. e) (3S)-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one

[0187] To a solution of tert-butyl N-[(1S)-2-[2-(6-benzyloxy-3-fluoro-pyridine-2-carbonyl)-3-chloro-4-(trifluoromethyl)anilino]-1-methyl-2-oxo-ethyl]carbamate (4.5 g, 6.8 mmol) in toluene (100 mL) was added room temperature silica gel (40-200 mesh, 26.95 g, 448 mmol), 4A molecular sieves (3 g) and trifluoroacetic acid (1.55 g, 1.05 mL, 13.59 mmol). The mixture was stirred at 110° C. overnight. The reaction mixture was cooled to room temperature, filtered and washed with ethyl acetate and methanol. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-20% ethyl acetate in heptane) to give the title compound (3.3 g, 97%) as a pale yellow solid. MS:478.2([{ 35 Cl}M+H] + ),480.2([{ 37 Cl}M+H] + ),ESI pos.

[0188] 11 C radiolabeled precursor 1 5-[5-[tert-butyl(dimethyl)silyl]oxy-2-fluoro-phenyl]-6,7-dichloro-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0189] a) tert-Butyl N-[3,4-dichloro-2-[(2-fluoro-5-methoxy-phenyl)-hydroxy-methyl]phenyl]carbamate To a solution of tert-butyl N-(3,4-dichlorophenyl)carbamate (5.82 g, 22.2 mmol) in THF (64 mL) at -90°C was added tert-butyllithium, 1.7 m in pentane (28.7 ml, 48.8 mmol) dropwise from a dry ice-cooled dropping funnel, and the resulting mixture was stirred at -85°C for an additional 0.5 h. Then, a solution of 2-fluoro-5-methoxybenzaldehyde (3.76 g, 24.4 mmol) in THF (16 ml) was added dropwise from a dry ice-cooled dropping funnel at -85 to -90°C. After stirring at -90 to -85°C for an additional 0.5 h, the mixture was warmed to -65°C and then quenched by dropwise addition of saturated aqueous NH4Cl. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was suspended in DCM and the solid was filtered and dried under high vacuum to give the title compound (4.29 g, 46%) as a white solid. MS: 414.2 ([{ 35 Cl, 35 Cl}MH] - ),416.2([{ 35 Cl, 37 Cl}MH] - ),ESI neg.

[0190] b) (6-amino-2,3-dichloro-phenyl)-(2-fluoro-5-methoxy-phenyl)methanone To a solution of tert-butyl N-[3,4-dichloro-2-[(2-fluoro-5-methoxy-phenyl)-hydroxymethyl]phenyl]carbamate (8.60 g, 20.8 mmol) in DCM (200 mL) at 22° C. was added trifluoroacetic acid (47.3 g, 415 mmol) and the mixture was stirred at 22° C. for 2 h. The solution was concentrated in vacuo. The residue (combined with another batch-17.9 mmol-scale) was treated with saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (11.0 g, 90%) as a yellow solid. MS: 314.0 ([{ 35 Cl, 35 Cl}M+H] + ),316.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0191] c) 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one A solution of (6-amino-2,3-dichloro-phenyl)-(2-fluoro-5-methoxy-phenyl)methanone (8.35 g, 26.6 mmol) in pyridine (165 mL) was heated to 90° C., then ethyl glycinate hydrochloride (26.0 g, 186 mmol) was added in one portion, and the resulting mixture was stirred at 110° C. for 4 h. The mixture was cooled to 90° C., then more ethyl glycinate hydrochloride (14.8 g, 106 mmol) was added, and stirring at 110° C. was continued for 16 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was treated with saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 10-100% ethyl acetate in heptane) to give the title compound (5.47 g, 58%) as a yellow solid. MS:353.0([{ 35 Cl, 35 Cl}M+H] + ),355.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0192] d) 6,7-dichloro-5-(2-fluoro-5-hydroxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one To a pale yellow solution of 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (500 mg, 1.42 mmol) in DCM (15 mL) was added boron tribromide (1.77 g, 7.08 mmol) dropwise at -65 °C. The mixture was warmed to -20 °C and stirred for 0.5 h. The mixture was quenched with half-saturated NaHCO3 and extracted with DCM. The organic layer was washed with half-saturated aqueous NaHCO3, dried over sodium sulfate, filtered and concentrated in vacuo. The aqueous layer was extracted again with ethyl acetate and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Both residues were combined and purified by flash column chromatography (silica, 10-100% ethyl acetate in heptane) followed by crystallization from MTBE / heptane to give the title compound (220 mg, 46%) as a pale yellow solid. MS:339.0([{ 35 Cl, 35 Cl}M+H] + ),341.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos. e) 5-[5-[tert-butyl(dimethyl)silyl]oxy-2-fluoro-phenyl]-6,7-dichloro-1,3-dihydro-1,4-benzodiazepin-2-one

[0193] To a solution of 6,7-dichloro-5-(2-fluoro-5-hydroxyphenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (175 mg, 0.516 mmol) in DMF (1.75 mL) was added imidazole (77.3 mg, 1.14 mmol) followed by tert-butyldimethylchlorosilane (85.5 mg, 0.568 mmol) at 22° C. and the resulting mixture was stirred at 22° C. for 0.5 h. The mixture was concentrated in vacuo. The residue was treated with aqueous NaOH (0.1 m) and extracted with ethyl acetate. The organic layer was washed successively with aqueous NaOH (0.1 m) and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-30% ethyl acetate in heptane) followed by crystallization from ethyl acetate / heptane to give the title compound (122 mg, 52%) as a white solid. MS:453.2([{ 35 Cl, 35 Cl}M+H] + ),455.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0194] 11 C radiolabeled precursor 2 5-[5-[tert-butyl(dimethyl)silyl]oxy-2-fluoro-phenyl]-6-chloro-7-methyl-1,3-dihydro-1,4-benzodiazepin-2-one [ka]

[0195] a) 5-chloro-2-methyl-3,1-benzoxazin-4-one Analogously to the experiment for building block Aa, 2-amino-6-chloro-benzoic acid was converted to the title compound (23.8 g, 70%) as a brown solid. 1 H NMR(CDCl3,300MHz)δ ppm:2.45(s,3 H),7.45(dd,J=8.06,1.21Hz,1 H),7.51(dd,J=8.06,1.21Hz,1 H),7.65(dd,J=1.00Hz,1 H).

[0196] b) N-[3-chloro-2-(2-fluoro-5-methoxy-benzoyl)phenyl]acetamide Analogously to the experiment for building block Ab, 5-chloro-2-methyl-3,1-benzoxazin-4-one was converted to the title compound (8.84 g, 53%) as a pale yellow solid. MS: 322.1 ([{ 35 Cl}M+H] + ),324.1([{ 37 Cl}M+H] + ),ESI pos.

[0197] c) (2-amino-6-chloro-phenyl)-(2-fluoro-5-methoxy-phenyl)methanone Analogously to the experiment for building block Ac, N-[3-chloro-2-(2-fluoro-5-methoxy-benzoyl)phenyl]acetamide was converted to the title compound (17.96 g, quantitative) as a brown oil. MS: 280.1 ([{ 35 Cl}M+H] + ),282.1([{ 37 Cl}M+H] + ),ESI pos.

[0198] d) (6-amino-3-bromo-2-chloro-phenyl)-(2-fluoro-5-methoxy-phenyl)methanone Analogously to the experiment for building block Bd, (2-amino-6-chloro-phenyl)-(2-fluoro-5-methoxy-phenyl)methanone was converted to the title compound (15.24 g, 66%) as a brown solid. MS: 358.0 ([{ 79 Br, 35 Cl}M+H] + ),360.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0199] e) 7-Bromo-6-chloro-5-(2-fluoro-5-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Be, (6-amino-3-bromo-2-chloro-phenyl)-(2-fluoro-5-methoxy-phenyl)methanone was converted to the title compound (2.47 g, 45%), which was obtained as a green solid. MS: 397.0 ([{ 79 Br, 35 Cl}M+H] + ),399.0([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0200] f) 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-methyl-1,3-dihydro-1,4-benzodiazepin-2-one Analogously to the experiment for building block Bf, 7-bromo-6-chloro-5-(2-fluoro-5-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (3.57 g, 8.98 mmol) was converted to the title compound (2.40 g, 80%) as a pale yellow solid. MS: 333.1 ([{ 79 Br, 35 Cl}M+H] + ),335.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos. g) 6-chloro-5-(2-fluoro-5-hydroxy-phenyl)-7-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

[0201] To a solution of 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (500 mg, 1.50 mmol) in DCM (15 mL) at -65°C was added boron tribromide (1.88 g, 7.51 mmol). The mixture was stirred at -60°C for 0.5 h. The mixture was then warmed to -20°C and stirred for 0.5 h. The mixture was quenched with saturated NaHCO3 and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 10-100% ethyl acetate in petroleum ether) followed by crystallization from ethyl acetate / heptane to give the title compound (177 mg, 37%) as a pale yellow solid. MS: 319.1 ([{ 79 Br, 35 Cl}M+H] + ),321.1([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0202] h) 5-[5-[tert-butyl(dimethyl)silyl]oxy-2-fluoro-phenyl]-6-chloro-7-methyl-1,3-dihydro-1,4-benzodiazepin-2-one To a solution of 6-chloro-5-(2-fluoro-5-hydroxyphenyl)-7-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (184 mg, 0.577 mol) in DMF (1.8 mL) at 22° C. was added imidazole (86.5 mg, 1.27 mmol) followed by tert-butyldimethylchlorosilane (95.7 mg, 0.635 mmol) and the mixture was stirred at 22° C. for 1 h. The mixture was concentrated in vacuo, treated with aqueous NaOH (0.1 m) and extracted with ethyl acetate. The organic layer was washed with aqueous NaOH (0.1 m) and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-45% ethyl acetate in petroleum ether) followed by crystallization from ethyl acetate / heptane to give the title compound (110 mg, 44%) as a white solid. MS: 433.2 ([{ 79 Br, 35 Cl}M+H] + ),435.2([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos. Working Example

[0203] Example 1 6,7-Dichloro-5-(2-fluoro-5-hydroxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one [ka]

[0204] a) 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one A solution of 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (Building A, 120 mg, 0.340 mmol), iodomethane (1.00 g, 7.05 mmol) and potassium carbonate (70 mg, 0.51 mmol) in DMF (3 mL) was stirred at 25° C. for 0.5 h. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Synergi C18, 10 μm, 150×25 mm, 0.1% trifluoroacetic acid in water / acetonitrile) to give the title compound (114 mg, 91%) as a white solid. MS: 367.1 ([{ 35 Cl, 35 Cl}M+H] + ),369.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0205] b) 6,7-dichloro-5-(2-fluoro-5-hydroxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one To a solution of 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one (80 mg, 0.22 mmol) in DCM (9 mL) at 0° C. was added boron tribromide (273 mg, 1.09 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 h, warmed to room temperature and stirred for an additional 5 h. The reaction was quenched with ice water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Synergi C18, 10 μm, 150×25 mm, 0.225% formic acid in water / acetonitrile) to give the title compound (59 mg, 77%) as a white solid. MS: 353.1 ([{ 35 Cl, 35 Cl}M+H] + ),355.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0206] Example 2 6-Chloro-5-(2-fluoro-5-hydroxy-phenyl)-1,7-dimethyl-3H-1,4-benzodiazepin-2-one [ka]

[0207] a) 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-1,7-dimethyl-3H-1,4-benzodiazepin-2-one Analogously to the experiment in Example 1a, 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (Building B) was converted to the title compound (76 mg, 36%) as a yellow solid. MS: 347.1 ([{ 35 Cl}M+H] + ),349.1([{ 37 Cl}M+H] + ),ESI pos.

[0208] b) 6-chloro-5-(2-fluoro-5-hydroxy-phenyl)-1,7-dimethyl-3H-1,4-benzodiazepin-2-one As in the experiment of Example 1b, 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-1,7-dimethyl-3H-1,4-benzodiazepin-2-one was converted to the title compound (72 mg, 83%) as an off-white solid. MS: 333.0 ([{ 35 Cl}M+H] + ),335.0([{ 37 Cl}M+H] + ),ESI pos.

[0209] Example 3 3-(7,8-dichloro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl)-4-fluoro-phenol [ka]

[0210] a) 6,7-dichloro-5-(2-fluoro-5-hydroxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one To a solution of 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (Building A, 500 mg, 1.42 mmol) in DCM (15 mL) was added boron tribromide (1.77 g, 7.08 mmol) dropwise at -65 °C and the mixture was stirred at -20 °C for 0.5 h. The mixture was quenched with half-saturated NaHCO3 and extracted with ethyl acetate. The organic layer was washed with half-saturated aqueous NaHCO3, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 10-100% ethyl acetate in petroleum ether) followed by crystallization from MTBE / petroleum ether to give the title compound (220 mg, 46%) as a pale yellow solid. MS: 339.0 ([{ 35 Cl, 35 Cl}M+H] + ),341.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0211] b) 5-[5-[tert-butyl(dimethyl)silyl]oxy-2-fluoro-phenyl]-6,7-dichloro-1,3-dihydro-1,4-benzodiazepin-2-one To a solution of 6,7-dichloro-5-(2-fluoro-5-hydroxyphenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (300 mg, 0.885 mmol) in DMF (12 mL) was added tert-butyldimethylchlorosilane (162 mg, 1.07 mmol) and imidazole (90 mg, 1.3 mmol). The mixture was stirred at 25° C. for 16 h, quenched with water and extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 10-50% ethyl acetate in petroleum ether) to give the title compound (380 mg, 95%) as a pale yellow solid. MS: 453.2 ([{ 35 Cl, 35 Cl}M+H] + ),455.2([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0212] c) 5-[5-[tert-butyl(dimethyl)silyl]oxy-2-fluoro-phenyl]-6,7-dichloro-1,3-dihydro-1,4-benzodiazepine-2-thione A mixture of 5-[5-[tert-butyl(dimethyl)silyl]oxy-2-fluoro-phenyl]-6,7-dichloro-1,3-dihydro-1,4-benzodiazepin-2-one (380 mg, 0.838 mmol) and Lawesson's reagent (407 mg, 1.01 mmol) in toluene (20 mL) was stirred at 100° C. for 5 h. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-33% ethyl acetate in petroleum ether) to give the title compound (110 mg, 28%) as a white solid. MS: 469.2 ([{ 35 Cl, 35 Cl}M+H] + ),471.2([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0213] d) tert-Butyl-[3-(7,8-dichloro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl)-4-fluoro-phenoxy]-dimethyl-silane A solution of 5-[5-[tert-butyl(dimethyl)silyl]oxy-2-fluoro-phenyl]-6,7-dichloro-1,3-dihydro-1,4-benzodiazepine-2-thione (100 mg, 0.213 mmol) and acetyl hydrazide (63 mg, 0.85 mmol) in 1-butanol (10 mL) was stirred at 115° C. for 16 h. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography (silica, 0-25% methanol in DCM) to give the title compound (95 mg, 91%) as a pale yellow oil. MS: 491.2 ([{ 35 Cl, 35 Cl}M+H] + ),493.2([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0214] e) 3-(7,8-dichloro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl)-4-fluoro-phenol To a solution of tert-butyl-[3-(7,8-dichloro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl)-4-fluoro-phenoxy]-dimethyl-silane (95 mg, 0.19 mmol) in DCM (1 mL) was added trifluoroacetic acid (2.0 mL, 25.96 mmol) and the mixture was stirred at 50° C. for 5 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (Phenomenex Luna C18, 15 μm, 150×40 mm, 0.1% trifluoroacetic acid in water / acetonitrile) and further by preparative TLC (silica, DCM / methanol 10:1) to give the title compound (35 mg, 48%) as a white solid. MS: 377.1 ([{ 35 Cl, 35 Cl}M+H] + ),379.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0215] Example 4 4-Fluoro-3-[(4S)-7,8-dichloro-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]phenol [ka]

[0216] a) 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione In a similar manner to the experiment in Example 3c, 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (building block C) was converted to the title compound (530 mg, 85%) as a yellow solid. MS: 383.0 ([{ 35 Cl, 35 Cl}M+H] + ),385.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0217] b) 7,8-dichloro-6-(2-fluoro-5-methoxy-phenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a manner similar to that of the experiment in Example 3d, 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (200 mg, 95%) as a yellow solid. MS: 405.1 ([{ 35 Cl, 35 Cl}M+H] + ),407.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos. c) 4-Fluoro-3-[(4S)-7,8-dichloro-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]phenol

[0218] To a mixture of 7,8-dichloro-6-(2-fluoro-5-methoxy-phenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (190 mg, 0.470 mmol) in DCM (10 mL) was added boron tribromide (143 mg, 0.570 mmol) and the mixture was stirred at 0° C. for 3 h. The reaction mixture was quenched with methanol, then water was added and the product was extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Gemini-NX C18, 3 μm, 75×30 mm, 0.1% trifluoroacetic acid in water / acetonitrile) followed by chiral SFC (Daicel Chiralpak AD, 10 μm, 250×30 mm, 0.1% NH4OH in ethanol; 40%) (combined with another batch, 0.02 mmol scale) to give the title compound (39 mg, 20%) as a white solid. MS: 391.0 ([{ 35 Cl, 35 Cl}M+H] + ),393.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0219] Example 5 (5S)-8,9-Dichloro-7-(2-fluoro-5-hydroxy-phenyl)-5-methyl-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one [ka]

[0220] a) 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-3-methyl-3H-1,4-benzodiazepin-2-amine A mixture of 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione (300 mg, 0.783 mmol) and aqueous ammonium hydroxide (33%, 0.20 mL, 0.78 mmol) in THF / methanol 5:1 (7.2 mL) was stirred at 50° C. for 16 h. The reaction mixture was cooled and concentrated in vacuo to give the title compound (280 mg, 98%) as a yellow oil. The crude material was used directly in the next step without further characterization.

[0221] b) 8,9-dichloro-7-(2-fluoro-5-methoxy-phenyl)-5-methyl-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one A mixture of 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-3-methyl-3H-1,4-benzodiazepin-2-amine (280 mg, 0.765 mmol) and ethyl propiolate (375 mg, 3.82 mmol) in ethanol (6 mL) was stirred at 50° C. for 16 h. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by flash column chromatography (silica, DCM / methanol 1:0 to 10:1) (combined with another batch, 0.115 mmol scale) to give the title compound (310 mg, 97%) as a pale yellow solid. MS: 418.1 ([{ 35 Cl, 35 Cl}M+H] + ),420.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0222] c) (5S)-8,9-dichloro-7-(2-fluoro-5-hydroxy-phenyl)-5-methyl-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one In a similar manner to the experiment in Example 4c, 8,9-dichloro-7-(2-fluoro-5-methoxy-phenyl)-5-methyl-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one was converted to the title compound (50 mg, 17%) as a white solid. MS: 404.1 ([{ 35 Cl, 35 Cl}M+H] + ),406.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0223] Example 6 8,9-Dichloro-7-(2-fluoro-5-hydroxy-phenyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one [ka]

[0224] a) 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione In a manner similar to that of Example 3c, 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (Building A) was converted to the title compound (230 mg, quantitative) as a yellow solid. MS: 369.1 ([{ 35 Cl, 35 Cl}M+H] + ),371.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0225] b) 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-3H-1,4-benzodiazepin-2-amine As in the experiment of Example 5a, 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (260 mg, quantitative) as a yellow oil. The crude product was used directly in the next step without further characterization.

[0226] c) 8,9-dichloro-7-(2-fluoro-5-methoxy-phenyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one In a similar manner to the experiment in Example 5b, 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-3H-1,4-benzodiazepin-2-amine was converted to the title compound (180 mg, 89%) as a brown oil. MS: 404.0 ([{ 35 Cl, 35 Cl}M+H] + ), 406.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0227] d) 8,9-dichloro-7-(2-fluoro-5-hydroxy-phenyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one In a manner similar to that of the experiment in Example 1b, 8,9-dichloro-7-(2-fluoro-5-methoxy-phenyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one was converted to the title compound (44 mg, 25%) as a yellow solid. MS: 390.1 ([{ 35 Cl, 35 Cl}M+H] + ),392.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0228] Example 7 [7,8-Dichloro-6-(2-fluoro-5-hydroxy-phenyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone [ka]

[0229] a) 1-amino-6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-3H-1,4-benzodiazepin-2-one To a mixture of 6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (Building A, 350 mg, 0.991 mmol) in DMF (10 mL) was added cesium carbonate (327 mg, 1.00 mmol). The mixture was stirred at 25° C. for 0.5 h, then O-diphenylphosphinylhydroxylamine (255 mg, 1.09 mmol) was added. The mixture was stirred at 25° C. for an additional 4 h, then diluted with water, extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica, petroleum ether / ethyl acetate 5:1 to 0:1) to give the title compound (290 mg, 79%) as a yellow oil. MS: 368.1 ([{ 35 Cl, 35 Cl}M+H] + ),370.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0230] b) Ethyl 7,8-dichloro-6-(2-fluoro-5-methoxy-phenyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine-2-carboxylate A mixture of 1-amino-6,7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-3H-1,4-benzodiazepin-2-one (280 mg, 0.760 mmol) and ethyl 2-ethoxy-2-imino-acetate (105 mg, 0.720 mmol) in ethanol (10 mL) was stirred at reflux for 4 h, then warmed to 100° C. and stirred for an additional 4 h. The mixture was cooled and then more ethyl 2-ethoxy-2-imino-acetate (105 mg, 0.720 mmol) was added and heating at reflux was continued for 16 h. This procedure was repeated three times to give half conversion as monitored by LCMS. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by flash column chromatography (silica, petroleum ether / ethyl acetate 5:1 to 1:1) to give the title compound (160 mg, 65%) as a yellow oil. MS:449.0([{ 35 Cl, 35 Cl}M+H] + ),451.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0231] c) 7,8-dichloro-6-(2-fluoro-5-methoxy-phenyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic acid To a mixture of ethyl 7,8-dichloro-6-(2-fluoro-5-methoxy-phenyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine-2-carboxylate (160 mg, 0.494 mmol) in ethanol (5 mL) was added aqueous NaOH (1 m, 1.0 mL, 1.0 mmol) dropwise. The reaction mixture was stirred at 25 °C for 1 h. Aqueous HCl (1 m) was added slowly until pH 4-5. The formed suspension was filtered. The collected solid was washed with water and dried under high vacuum to give the title compound (90 mg, 43%) as a white solid. MS: 421.0 ([{ 35 Cl, 35 Cl}M+H] + ),423.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0232] d) [7,8-Dichloro-6-(2-fluoro-5-methoxy-phenyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone To a solution of 3-methoxyazetidine hydrochloride (38 mg, 0.31 mmol) in DMF (5 mL) was added 7,8-dichloro-6-(2-fluoro-5-methoxy-phenyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic acid (88 mg, 0.21 mmol), N,N-diisopropylethylamine (0.10 mL, 0.57 mmol) and T3P (50% in ethyl acetate, 1.0 mL, 1.7 mmol). The mixture was stirred at 25° C. for 2 hours, then dissolved in water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue (combined with another batch, 5 μmol scale) was purified by preparative HPLC (Phenomenex Gemini-NX C18, 3 μm, 75×30 mm, 0.1% trifluoroacetic acid in water / acetonitrile) to give the title compound (35 mg, 33%) as a pale yellow solid. MS: 490.1 ([{ 35 Cl, 35 Cl}M+H] + ),492.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0233] e) [7,8-dichloro-6-(2-fluoro-5-hydroxy-phenyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone Analogously to the experiment in Example 1b, [7,8-dichloro-6-(2-fluoro-5-methoxy-phenyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone was converted to the title compound (3.4 mg, 13%) as a white solid. MS: 476.1 ([{ 35 Cl, 35 Cl}M+H] + ),478.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0234] Example 8 6-Chloro-5-(2-fluoro-5-hydroxy-phenyl)-1-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one [ka]

[0235] a) 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-1-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one Analogously to the experiment in Example 1a, 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block D) was converted to the title compound (142 mg, 86%) as a yellow solid. MS: 401.2 ([{ 35 Cl}M+H] + ), 403.2([{ 37 Cl}M+H] + ),ESI pos.

[0236] b) 6-chloro-5-(2-fluoro-5-hydroxy-phenyl)-1-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one In a manner similar to that of the experiment in Example 1b, 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-1-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one was converted to the title compound (68 mg, 50%) as a yellow solid. MS: 387.0 ([{ 35 Cl}M+H] + ),389.0([{ 37 Cl}M+H] + ),ESI pos.

[0237] Example 9 3-[7-chloro-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-4-fluoro-phenol [ka]

[0238] a) 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione In a similar manner to the experiment in Example 3c, 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block D) was converted to the title compound (290 mg, 62%) as a yellow solid. MS: 403.0 ([{ 35 Cl}M+H] + ), 405.0([{ 37 Cl}M+H] + ),ESI pos.

[0239] b) 7-chloro-6-(2-fluoro-5-methoxy-phenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a manner similar to that of the experiment in Example 3d, 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (85 mg, 90%) as a yellow oil. MS: 425.1 ([{ 35 Cl}M+H] + ),427.1([{ 37 Cl}M+H] + ),ESI pos.

[0240] c) 3-[7-chloro-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-4-fluoro-phenol In a manner similar to that of Example 1b, 7-chloro-6-(2-fluoro-5-methoxy-phenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted to the title compound (10 mg, 12%) as a yellow solid. MS: 411.1 ([{ 35 Cl}M+H] + ),413.1([{ 37 Cl}M+H] + ),ESI pos.

[0241] Example 10 3-[7-chloro-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-4-fluoro-phenol [ka]

[0242] a) 7-chloro-6-(2-fluoro-5-methoxy-phenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine Using formic acid hydrazide instead of acetyl hydrazide, 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione (Example 9a) was converted to the title compound (74 mg, 81%) as a yellow oil in analogy with the experiment in Example 3d. MS: 411.0 ([{ 35 Cl}M+H] + ), 413.0([{ 37 Cl}M+H] + ),ESI pos. b) 3-[7-chloro-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-4-fluoro-phenol In a manner similar to that of the experiment in Example 1b, 7-chloro-6-(2-fluoro-5-methoxy-phenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted to the title compound (22 mg, 31%) as a white solid. MS: 397.0 ([{ 35 Cl}M+H] + ),399.0([{ 37 Cl}M+H] + ),ESI pos.

[0243] Example 11 8-Chloro-7-(2-fluoro-5-hydroxy-phenyl)-9-(trifluoromethyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one [ka]

[0244] a) 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-amine As in the experiment of Example 5a, 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (106 mg, quantitative) as a yellow oil. The crude product was used directly in the next step without further characterization.

[0245] b) 8-chloro-7-(2-fluoro-5-methoxy-phenyl)-9-(trifluoromethyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one In a similar manner to the experiment in Example 5b, 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-amine was converted to the title compound (93 mg, 86%) as a brown oil. MS: 438.1 ([{ 35 Cl}M+H] + ),440.1([{ 37 Cl}M+H] + ),ESI pos.

[0246] c) 8-chloro-7-(2-fluoro-5-hydroxy-phenyl)-9-(trifluoromethyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one In a similar manner to the experiment in Example 1b, 8-chloro-7-(2-fluoro-5-methoxy-phenyl)-9-(trifluoromethyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one was converted to the title compound (23 mg, 26%) as a white solid. MS: 424.0 ([{ 35 Cl}M+H] + ),426.0([{ 37 Cl}M+H] + ),ESI pos.

[0247] Example 12 6,7-Dichloro-5-(2,6-difluoro-3-hydroxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one [ka]

[0248] a) 6,7-dichloro-5-(2,6-difluoro-3-methoxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one Analogously to the experiment in Example 1a, 6,7-dichloro-5-(2,6-difluoro-3-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block E) was converted to the title compound (50 mg, 48%) as a pale yellow oil. MS: 384.9 ([{ 35 Cl, 35 Cl}M+H] + ),386.9([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0249] b) 6,7-dichloro-5-(2,6-difluoro-3-hydroxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one In a manner similar to that of the experiment in Example 1b, 6,7-dichloro-5-(2,6-difluoro-3-methoxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one was converted to the title compound (26 mg, 54%) as a yellow solid. MS: 370.9 ([{ 35 Cl, 35 Cl}M+H] + ),372.9([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0250] Example 13 3-(7,8-dichloro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl)-2,4-difluoro-phenol [ka]

[0251] a) 6,7-dichloro-5-(2,6-difluoro-3-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione In a similar manner to the experiment in Example 3c, 6,7-dichloro-5-(2,6-difluoro-3-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block E) was converted to the title compound (300 mg, 72%) as a yellow solid. MS: 387.0 ([{ 35 Cl, 35 Cl}M+H] + ),389.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0252] b) 7,8-dichloro-6-(2,6-difluoro-3-methoxy-phenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a manner similar to that of the experiment in Example 3d, 6,7-dichloro-5-(2,6-difluoro-3-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (77 mg, 73%) as a pale yellow solid. MS: 409.0 ([{ 35 Cl, 35 Cl}M+H] + ), 411.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0253] c) 3-(7,8-dichloro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl)-2,4-difluoro-phenol In a similar manner to the experiment in Example 1b, 7,8-dichloro-6-(2,6-difluoro-3-methoxy-phenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted to the title compound (28 mg, 40%) as a white solid. MS: 394.9 ([{ 35 Cl, 35 Cl}M+H] + ),396.9([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0254] Example 14 8,9-Dichloro-7-(2,6-difluoro-3-hydroxy-phenyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one [ka]

[0255] a) 6,7-dichloro-5-(2,6-difluoro-3-methoxy-phenyl)-3H-1,4-benzodiazepin-2-amine As in the experiment of Example 5a, 6,7-dichloro-5-(2,6-difluoro-3-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (210 mg, quantitative) as a yellow solid. This crude material was used directly in the next step without further characterization.

[0256] c) 8,9-dichloro-7-(2,6-difluoro-3-methoxy-phenyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one In a similar manner to the experiment in Example 5b, 6,7-dichloro-5-(2,6-difluoro-3-methoxy-phenyl)-3H-1,4-benzodiazepin-2-amine was converted to the title compound (105 mg, 48%) as a pale yellow oil. MS: 422.0 ([{ 35 Cl, 35 Cl}M+H] + ),424.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0257] d) 8,9-dichloro-7-(2,6-difluoro-3-hydroxy-phenyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one In a similar manner to the experiment in Example 1b, 8,9-dichloro-7-(2,6-difluoro-3-methoxy-phenyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one was converted to the title compound (13 mg, 13%) as a white solid. MS: 408.0 ([{ 35 Cl, 35 Cl}M+H] + ), 410.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0258] Example 15 [7-Chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]-(3-methoxyazetidin-1-yl)methanone [ka]

[0259] a) Methyl 7-chloro-6-(2-fluoro-5-methoxy-phenyl)-8-(trifluoromethyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate A solution of 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one (Building D, 100 mg, 0.259 mmol), dimethyl-p-toluidine (280 mg, 2.07 mmol) and phosphorus oxychloride (0.04 mL, 0.4 mmol) in DCE (5 mL) was stirred at 85° C. for 3 h. The reaction solution was cooled to room temperature, quenched with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. Meanwhile, methyl isocyanoacetate (27 mg, 0.27 mmol) was added to a mixture of potassium tert-butoxide (29 mg, 0.26 mmol) in DMF (3 mL) at −30° C. and stirred for 5 min. The crude imidoyl chloride-intermediate from above was then added to the reaction solution at -30°C and stirred for an additional 30 min. The reaction mixture was warmed to room temperature and quenched with acetic acid. After stirring for 5 min, the mixture was poured into ice water, saturated with solid NaHCO3, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica, DCM / methanol 1:0 to 5:1) followed by preparative HPLC (Phenomenex Synergi C18, 10 μm, 150 x 25 mm, 0.1% trifluoroacetic acid / acetonitrile in water) to give the title compound (23 mg, 19%) as a pale yellow solid. MS: 468.1 ([{ 35 Cl}M+H] + ),470.1([{ 37 Cl}M+H] + ),ESI pos.

[0260] b) 7-chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid To a solution of methyl 7-chloro-6-(2-fluoro-5-methoxy-phenyl)-8-(trifluoromethyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (23 mg, 0.050 mmol) in DCM (1 mL) was added boron tribromide (15 mg, 0.060 mmol). The mixture was stirred at 20° C. for 40 h. Additional boron tribromide (15 mg, 0.060 mmol) was added and stirring at 20° C. was continued for 16 h to complete the conversion. The reaction mixture was quenched with ice water and concentrated in vacuo to give the title compound (17 mg, 79%) as a yellow solid. The crude material was used directly in the next step without further characterization.

[0261] c) [7-chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]-(3-methoxyazetidin-1-yl)methanone To a solution of 3-methoxyazetidine hydrochloride (8.5 mg, 0.070 mmol) in DMF (2 mL) was added 7-chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid (15 mg, 0.034 mmol), N,N-diisopropylethylamine (0.02 mL, 0.1 mmol) and T3P (50% in ethyl acetate, 0.5 mL, 0.8 mmol). The mixture was stirred at 25° C. for 2 h. Additional 3-methoxyazetidine hydrochloride (8.5 mg, 0.070 mmol), N,N-diisopropylethylamine (0.02 mL, 0.1 mmol) and T3P (50% in ethyl acetate, 0.5 mL, 0.8 mmol) were added. The reaction mixture was stirred at 25° C. for a further 40 h, then (with another batch, 5 μmol scale) was dissolved in water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Synergi C18, 10 μm, 150×25 mm, 0.1% trifluoroacetic acid in water / acetonitrile) followed by SFC (Daicel Chiralpak IC, 10 μm, 250×30 mm, 0.1% NH4OH in methanol, 40%) to give the title compound (3.1 mg, 16%) as a pale yellow solid. MS: 509.1 ([{ 35 Cl}M+H] + ),511.1([{ 37 Cl}M+H] + ),ESI pos.

[0262] Example 16 [7-Chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone [ka]

[0263] a) 1-amino-6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one Analogously to the experiment in Example 7a, 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block D) was converted to the title compound (264 mg, 74%) as a yellow oil. MS: 402.2 ([{ 35 Cl}M+H] + ), 404.2([{ 37 Cl}M+H] + ),ESI pos.

[0264] b) Ethyl 7-chloro-6-(2-fluoro-5-methoxy-phenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine-2-carboxylate In a similar manner to the experiment in Example 7b, 1-amino-6-chloro-5-(2-fluoro-5-methoxy-phenyl)-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one was converted to the title compound (151 mg, 48%) as a yellow oil. MS: 483.1 ([{ 35 Cl}M+H] + ),485.1([{ 37 Cl}M+H] + ),ESI pos.

[0265] c) 7-chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic acid In a similar manner to the experiment in Example 15b, ethyl 7-chloro-6-(2-fluoro-5-methoxy-phenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine-2-carboxylate (149 mg, 0.309 mmol) was converted to the title compound (98 mg, 72%) as a yellow solid. MS: 441.0 ([{ 35 Cl}M+H] + ),443.0([{ 37 Cl}M+H] + ), ESI pos. This crude material was used directly in the next step without purification.

[0266] b) [7-chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone As in the experiment of Example 7d, 7-chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic acid (98 mg, 0.22 mmol) was converted to the title compound (17.4 mg, 15%) using 3-methoxyazetidine hydrochloride as a pale yellow solid. MS: 510.1 ([{ 35 Cl}M+H] + ),512.1([{ 37 Cl}M+H] + ),ESI pos.

[0267] Example 17 4-Fluoro-3-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]phenol [ka]

[0268] a) 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione In a similar manner to the experiment in Example 3c, 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block F) was converted to the title compound (170 mg, 59%) as a yellow solid. MS: 417.0 ([{ 35 Cl}M+H] + ),419.0([{ 37 Cl}M+H] + ),ESI pos.

[0269] b) 7-chloro-6-(2-fluoro-5-methoxy-phenyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine Analogously to the experiment in Example 3d, 6-chloro-5-(2-fluoro-5-methoxy-phenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione (160 mg, 0.384 mmol) was converted to the title compound (125 mg, 74%) as a pale yellow solid. MS: 439.0 ([{ 35 Cl}M+H] + ),441.0([{ 37 Cl}M+H] + ),ESI pos.

[0270] c) 4-Fluoro-3-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]phenol In a similar manner to the experiment in Example 4c, 7-chloro-6-(2-fluoro-5-methoxy-phenyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted to the title compound (23 mg, 24%) as a white solid. MS: 425.1 ([{ 35 Cl}M+H] + ),427.1([{ 37 Cl}M+H] + ),ESI pos.

[0271] Example 18 (5S)-8,9-Dichloro-7-(2,6-difluoro-3-hydroxy-phenyl)-5-methyl-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one [ka]

[0272] a) 6,7-dichloro-5-(2,6-difluoro-3-methoxy-phenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione In a similar manner to the experiment in Example 3c, 6,7-dichloro-5-(2,6-difluoro-3-methoxy-phenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (building block G) was converted to the title compound (680 mg, quantitative) as a yellow solid. MS: 400.9 ([{ 35 Cl, 35 Cl}M+H] + ), 402.9([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0273] b) 6,7-dichloro-5-(2,6-difluoro-3-methoxy-phenyl)-3-methyl-3H-1,4-benzodiazepin-2-amine As in the experiment of Example 5a, 6,7-dichloro-5-(2,6-difluoro-3-methoxy-phenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (800 mg, quantitative) as a yellow oil. This crude material was used directly in the next step without further characterization.

[0274] c) 8,9-dichloro-7-(2,6-difluoro-3-methoxy-phenyl)-5-methyl-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one In a similar manner to the experiment in Example 5b, 6,7-dichloro-5-(2,6-difluoro-3-methoxy-phenyl)-3-methyl-3H-1,4-benzodiazepin-2-amine was converted to the title compound (540 mg, 83%) as a brown oil. MS: 435.9 ([{ 35 Cl, 35 Cl}M+H] + ),437.9([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0275] d) (5S)-8,9-dichloro-7-(2,6-difluoro-3-hydroxy-phenyl)-5-methyl-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one In a similar manner to the experiment in Example 4c, 8,9-dichloro-7-(2,6-difluoro-3-methoxy-phenyl)-5-methyl-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one was converted to the title compound (64 mg, 12%) as a pale yellow solid. MS: 422.0 ([{ 35 Cl, 35 Cl}M+H] + ),424.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0276] Example 19 2,4-Difluoro-3-[(4S)-7,8-dichloro-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]phenol [ka]

[0277] a) 7,8-dichloro-6-(2,6-difluoro-3-methoxy-phenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a similar manner to the experiment in Example 3d, 6,7-dichloro-5-(2,6-difluoro-3-methoxy-phenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (220 mg, 67%) as a pale yellow solid. MS: 423.0 ([{ 35 Cl, 35 Cl}M+H] + ),425.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0278] b) 2,4-Difluoro-3-[(4S)-7,8-dichloro-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]phenol In a similar manner to the experiment in Example 4c, 7,8-dichloro-6-(2,6-difluoro-3-methoxy-phenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted to the title compound (39 mg, 19%) as a white solid. MS: 408.9 ([{ 35 Cl, 35 Cl}M+H] + ), 410.9([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0279] Example 20 6-[(4S)-7-Chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol [ka]

[0280] a) (4S)-7-chloro-6-(3-fluoro-6-methoxy-2-pyridyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine To a solution of (3S)-6-chloro-5-(3-fluoro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one (Component H, 200 mg, 0.498 mmol) in tetrahydrofuran (10 mL) was added NaH (60% dispersion in mineral oil, 39.8 mg, 0.996 mmol) at 0° C. to give a pale yellow suspension. After stirring at 0° C. for 10 min, bis(2-oxo-3-oxazolidinyl)phosphinic chloride (253.5 mg, 0.996 mmol) was added and the reaction mixture was stirred at 0° C. for 2 h. Acetyl hydrazide (92.2 mg, 1.24 mmol) was then added and the reaction mixture was stirred at room temperature for 60 min. Further acetyl hydrazide (92.2 mg, 1.24 mmol) was added and stirring was continued at 50° C. for a further 2 h to give a dark orange suspension. The reaction mixture was then diluted with 1,4-dioxane (10 mL) and stirred at 80° C. for 16 h, then quenched with water (10 mL) and extracted with ethyl acetate (2×30 mL). The organic layer was washed with water (30 mL) and brine (30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-50% ethyl acetate in heptane, then 10% methanol in ethyl acetate) to give the title compound (80 mg, 36%) as a colourless oil. MS: 440.1 ([{ 35 Cl}M+H] + ),442.1([{ 37 Cl}M+H] + ),ESI pos.

[0281] b) 5-fluoro-6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]pyridin-2-ol In a similar manner to the experiment in Example 4c, (4S)-7-chloro-6-(3-fluoro-6-methoxy-2-pyridyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted to the enantiopure (+)-title compound (25 mg, 59%) as an off-white solid. MS: 426.2 ([{ 35 Cl}M+H] + ),428.2([{ 37 Cl}M+H] + ),ESI pos.

[0282] Example 21 [(4S)-7-Chloro-6-(3-fluoro-6-hydroxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-fluoroazetidin-1-yl)methanone [ka]

[0283] a) (3S)-1-amino-6-chloro-5-(3-fluoro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one In a similar manner to the experiment in Example 7a, (3S)-6-chloro-5-(3-fluoro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block H) was converted to the title compound (289 mg, 94%) as a pale yellow foam. MS: 417.2 ([{ 35 Cl}M+H] + ),419.2([{ 37 Cl}M+H] + ),ESI pos.

[0284] b) Ethyl (4S)-7-chloro-6-(3-fluoro-6-methoxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine-2-carboxylate In a similar manner to the experiment in Example 7b, (3S)-1-amino-6-chloro-5-(3-fluoro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one was converted to the title compound (254 mg, 74%) as a pale yellow foam. MS: 498.3 ([{ 35 Cl}M+H] + ),500.3([{ 37 Cl}M+H] + ),ESI pos.

[0285] c) (4S)-7-chloro-6-(3-fluoro-6-methoxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic acid In a similar manner to the experiment in Example 7c, ethyl (4S)-7-chloro-6-(3-fluoro-6-methoxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine-2-carboxylate was converted to the title compound (242 mg, 95%) as a white solid, which was used directly in the next step without further purification. MS: 470.1 ([{ 35 Cl}M+H] + ),472.1([{ 37 Cl}M+H] + ),ESI pos.

[0286] d) [(4S)-7-Chloro-6-(3-fluoro-6-methoxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-fluoroazetidin-1-yl)methanone Using 3-fluoroazetidine hydrochloride instead of T3P and 1-propanephosphonic anhydride (50% in ethyl acetate) in analogy to the experiment in Example 7d, (4S)-7-chloro-6-(3-fluoro-6-methoxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic acid was converted to the title compound (193 mg, 79%) as a white foam. MS: 527.1 ([{ 35 Cl}M+H] + ),529.1([{ 37 Cl}M+H] + ),ESI pos.

[0287] e) [(4S)-7-chloro-6-(3-fluoro-6-hydroxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-fluoroazetidin-1-yl)methanone Analogously to the experiment in Example 4c, [(4S)-7-chloro-6-(3-fluoro-6-methoxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-fluoroazetidin-1-yl)methanone was converted to the enantiopure title compound (3 mg, 38%) as a colorless oil. MS: 513.3 ([{ 35 Cl}M+H] + ),515.3([{ 37 Cl}M+H] + ),ESI pos.

[0288] Example 22 5-Chloro-6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]pyridin-2-ol [ka]

[0289] a) (4S)-7-chloro-6-(3-chloro-6-methoxy-2-pyridyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine In a similar manner to the experiment in Example 20a, (3S)-6-chloro-5-(3-chloro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one (Building I) was converted to the title compound (61 mg, 36%) as a pale yellow foam. MS: 456.1 ([{ 35 Cl, 35 Cl}M+H] + ),458.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0290] b) 5-chloro-6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]pyridin-2-ol In a similar manner to the experiment in Example 4c, (4S)-7-chloro-6-(3-chloro-6-methoxy-2-pyridyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted to the enantiopure (+)-title compound (18 mg, 56%) as a pale yellow foam. MS: 442.2 ([{ 35 Cl}M+H] + ),444.2([{ 37 Cl}M+H] + ),ESI pos.

[0291] Example 23 6-[(4S)-7-Chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol [ka]

[0292] a) (3S)-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione In a similar manner to the experiment in Example 3c, (3S)-5-(6-benzoxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block J) was converted to the title compound (478 mg, 81%) as a yellow solid. MS: 494.2 ([{ 35 Cl}M+H] + ),496.2([{ 37 Cl}M+H] + ),ESI pos.

[0293] b) (3S)-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-imine In a similar manner to the experiment in Example 5a, (3S)-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (165 mg, 84%) as a brown oil. MS: 477.3 ([{ 35 Cl}M+H] + ),479.2([{ 37 Cl}M+H] + ),ESI pos.

[0294] c) (4S)-6-(6-benzyloxy-3-fluoro-2-pyridyl)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine To a solution of (3S)-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-imine (103 mg, 0.247 mmol) in 1-butanol (3 mL) was added propargylamine (108.8 mg, 0.126 mL, 1.98 mmol) and p-toluenesulfonic acid monohydrate (9.4 mg, 0.049 mmol) at room temperature. The reaction mixture was stirred at 120° C. in a sealed tube for 4 h and then concentrated in vacuo. The residue was diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 1% methanol in DCM) to give the title compound (137 mg, 73%) as an orange oil. MS: 515.3 ([{ 35 Cl}M+H] + ),517.3([{ 37 Cl}M+H] + ),ESI pos.

[0295] d) 6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol To a solution of (4S)-6-(6-benzyloxy-3-fluoro-2-pyridyl)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine (137 mg, 0.253 mmol) in dichloromethane (7 ml) at 25° C., N,N-dimethylaniline (612.6 mg, 0.64 mL, 5.06 mmol) and aluminum chloride (505.6 mg, 3.79 mmol) were added dropwise in one portion. The reaction mixture was stirred at room temperature for 1 h, then filtered through a pad of Celite and washed with MeOH / DCM 1:1. The filtrate was concentrated in vacuo. The residue was partitioned between Dublecco's phosphate buffer and DCM. The aqueous phase was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-100% ethyl acetate in heptane, then 0-5% methanol in ethyl acetate) followed by chiral SFC (Daicel Chiralcel OJ-H, 15% methanol) to give the enantiopure (+)-title compound (17 mg, 33%) as a pale yellow solid. MS: 425.2 ([{ 35 Cl}M+H] + ),427.2([{ 37 Cl}M+H] + ),ESI pos.

[0296] Example 24 6-[(10S)-6-chloro-10-methyl-5-(trifluoromethyl)-1,9,12-triazatetracyclo[9.6.0.02,7.013,17]heptadeca-2(7),3,5,8,11,13(17)-hexaen-8-yl]-5-fluoro-pyridin-2-ol [ka]

[0297] a) (1S)-2-[(E / Z)-[(3S)-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-ylidene]amino]cyclopentanol To a mixture of (3S)-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione (Example 23a, 455 mg, 0.737 mmol) in ethanol (5.4 mL) and water (2.7 mL) was added sodium carbonate (242 mg, 2.28 mmol) followed by trans-2-aminocyclopentanol hydrochloride (305 mg, 2.22 mmol). The reaction mixture was stirred at 80° C. overnight, cooled to room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate (60 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (60 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-50% ethyl acetate in heptane) to give the title compound (300 mg, 69%) as an off-white foam. MS: 561.3 ([{ 35 Cl}M+H] + ),563.2([{ 37 Cl}M+H] + ),ESI pos.

[0298] b) (10S)-8-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-10-methyl-5-(trifluoromethyl)-1,9,12-triazatetracyclo[9.6.0.02,7.013,17]heptadeca-2(7),3,5,8,11,13(17)-hexaene To a solution of (1S)-2-[(E / Z)-[(3S)-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-ylidene]amino]cyclopentanol (296 mg, 0.501 mmol) in dichloromethane (3.6 mL) was added Dess-Martin periodinane (256 mg, 0.604 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1.5 h. Another Dess-Martin periodinane (255 mg, 0.602 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 2.5 h, then quenched with saturated aqueous NaHCO3 (5 mL) and aqueous Na2S2O3 (5 mL) and stirred vigorously at room temperature for 15 min. The biphasic mixture was then extracted with dichloromethane (2 x 60 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was adsorbed onto ISOLUTE HM-N and purified by flash column chromatography (silica, 0-5% methanol in dichloromethane) to afford the title compound (134 mg, 49%) as a pale yellow oil. MS: 541.2 ([{ 35 Cl}M+H] + ),543.2([{ 37 Cl}M+H] + ),ESI pos.

[0299] c) 6-[(10S)-6-chloro-10-methyl-5-(trifluoromethyl)-1,9,12-triazatetracyclo[9.6.0.02,7.013,17]heptadeca-2(7),3,5,8,11,13(17)-hexaen-8-yl]-5-fluoro-pyridin-2-ol In a similar manner to the experiment in Example 23d, (10S)-8-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-10-methyl-5-(trifluoromethyl)-1,9,12-triazatetracyclo[9.6.0.02,7.013,17]heptadeca-2(7),3,5,8,11,13(17)-hexaene was converted to the enantiopure (+)-title compound (19 mg, 46%) as a brown foam. MS: 451.2 ([{ 35 Cl}M+H] + ),453.2([{ 37 Cl}M+H] + ),ESI pos.

[0300] Example 25 6-[(4S)-7-Chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol [ka]

[0301] a) (3S)-1-amino-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one In a similar manner to the experiment in Example 7a, (3S)-5-(6-benzoxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block J) was converted to the title compound (817 mg, 85%) as a yellow foam. MS: 493.3 ([{ 35 Cl}M+H] + ),495.2([{ 37 Cl}M+H] + ),ESI pos.

[0302] b) (4S)-6-(6-benzyloxy-3-fluoro-2-pyridyl)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine Using ethyl acetimidate hydrochloride instead of ethyl 2-ethoxy-2-imino-acetate in a similar manner to experiment 7b, (3S)-1-amino-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one was converted to the title compound (617 mg, 58%) as a pale yellow waxy solid. MS: 516.3 ([{ 35 Cl}M+H] + ),518.3([{ 37 Cl}M+H] + ),ESI pos.

[0303] c) 6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol In a similar manner to the experiment in Example 23d, (4S)-6-(6-benzyloxy-3-fluoro-2-pyridyl)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine was converted to the enantiopure (+)-title compound (83 mg, 42%) as a pale yellow solid. MS: 426.2 ([{ 35 Cl}M+H] + ),428.2([{ 37 Cl}M+H] + ),ESI pos.

[0304] Example 26 5-Chloro-6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]pyridin-2-ol [ka]

[0305] a) (3S)-6-chloro-5-(3-chloro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione In a similar manner to the experiment in Example 3c, (3S)-6-chloro-5-(3-chloro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one (Building I) was converted to the title compound (531 mg, 74%) as a yellow solid. MS: 434.2 ([{ 35 Cl, 35 Cl}M+H] + ),436.2([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0306] b) (3S)-6-chloro-5-(3-chloro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-imine In a similar manner to the experiment in Example 5a, (3S)-6-chloro-5-(3-chloro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted to the title compound (541 mg, 94%) as a yellow foam. MS: 417.2 ([{ 35 Cl, 35 Cl}M+H] + ),419.2([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0307] c) (4S)-7-chloro-6-(3-chloro-6-methoxy-2-pyridyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine In a similar manner to the experiment in Example 23c, (3S)-6-chloro-5-(3-chloro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-imine was converted to the title compound (389 mg, 70%) as a pale yellow foam. MS: 455.2 ([{ 35 Cl, 35 Cl}M+H] + ),457.2([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0308] d) 5-chloro-6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]pyridin-2-ol In a similar manner to the experiment in Example 23d, (4S)-7-chloro-6-(3-chloro-6-methoxy-2-pyridyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine was converted to the enantiopure (+)-title compound (132 mg, 44%) as a light brown foam. MS: 441.2 ([{ 35 Cl}M+H] + ),443.2([{ 37 Cl}M+H] + ),ESI pos.

[0309] Example 27 5-Chloro-6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]pyridin-2-ol [ka]

[0310] a) 2-[(E / Z)-[(3S)-6-chloro-5-(3-chloro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-ylidene]amino]propan-1-ol To a solution of (3S)-6-chloro-5-(3-chloro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one (Building I, 203 mg, 0.485 mmol) in tetrahydrofuran (9.7 mL) was added sodium hydride (60% dispersion in mineral oil, 58.3 mg, 1.46 mmol) at 0° C. After stirring for 10 minutes at 10° C., bis(2-oxo-3-oxazolidinyl)phosphinic chloride (247.1 mg, 0.97 mmol) was added and the reaction mixture was stirred at 0° C. for 2 hours. dl-Alaninol (182 mg, 0.19 mL, 2.43 mmol) was then added and the reaction mixture was stirred at 23° C. for 1 h, then quenched with water and aqueous NH4Cl (20 mL) and extracted with ethyl acetate (2×60 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-50% ethyl acetate in heptane, then 0-10% methanol in ethyl acetate) to give the title compound (91 mg, 38%) as a pale yellow oil. MS: 475.1 ([{ 35 Cl, 35 Cl}M+H] + ),477.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0311] b) (4S)-7-chloro-6-(3-chloro-6-methoxy-2-pyridyl)-2,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine In a similar manner to the experiment in Example 24b, 2-[(E / Z)-[(3S)-6-chloro-5-(3-chloro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-ylidene]amino]propan-1-ol was converted to the title compound (77 mg, 86%) as a pale yellow oil. MS: 455.1 ([{ 35 Cl, 35 Cl}M+H] + ),457.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0312] c) 5-chloro-6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]pyridin-2-ol In a similar manner to the experiment in Example 4c, (4S)-7-chloro-6-(3-chloro-6-methoxy-2-pyridyl)-2,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine was converted to the enantiopure (-)-title compound (13 mg, 44%) as a white solid. MS: 441.2 ([{ 35 Cl}M+H] + ),443.1([{ 37 Cl}M+H] + ),ESI pos.

[0313] Example 28 6-[(4S)-7-Chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol [ka]

[0314] a) 2-[(E / Z)-[(3S)-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-ylidene]amino]propan-1-ol In a similar manner to the experiment in Example 27a, (3S)-5-(6-benzoxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block J) was converted to the title compound (269 mg, 40%) as an orange foam. MS: 535.3 ([{ 35 Cl}M+H] + ),537.3([{ 37 Cl}M+H] + ),ESI pos.

[0315] b) (4S)-6-(6-benzyloxy-3-fluoro-2-pyridyl)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine In a similar manner to the experiment in Example 24b, 2-[(E / Z)-[(3S)-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-ylidene]amino]propan-1-ol was converted to the title compound (154 mg, 59%) as a pale yellow foam. MS: 515.4 ([{ 35 Cl}M+H] + ),517.3([{ 37 Cl}M+H] + ),ESI pos.

[0316] c) 6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol In a similar manner to the experiment in Example 4c, (4S)-6-(6-benzyloxy-3-fluoro-2-pyridyl)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine was converted to the enantiopure (+)-title compound (75 mg, 47%) as a light brown solid. MS: 425.3 ([{ 35 Cl}M+H] + ),427.2([{ 37 Cl}M+H] + ),ESI pos.

[0317] Example 29 5-Chloro-6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-6-yl]pyridin-2-ol [ka]

[0318] a) (3S)-1-amino-6-chloro-5-(3-chloro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one Analogously to the experiment in Example 7a, (3S)-6-chloro-5-(3-chloro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block I) was converted to the title compound (267 mg, 91%) as a white foam. MS: 433.2 ([{ 35 Cl, 35 Cl}M+H] + ),435.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos. b) (4S)-7-chloro-6-(3-chloro-6-methoxy-2-pyridyl)-2,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine

[0319] In a similar manner to the experiment in Example 7b, (3S)-1-amino-6-chloro-5-(3-chloro-6-methoxy-2-pyridyl)-3-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one was converted to the title compound (193 mg, 67%) as a white foam. MS: 456.1 ([{ 35 Cl, 35 Cl}M+H] + ),458.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0320] c) 5-chloro-6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-6-yl]pyridin-2-ol In a similar manner to the experiment in Example 23d, (4S)-7-chloro-6-(3-chloro-6-methoxy-2-pyridyl)-2,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine was converted to the enantiopure (+)-title compound (32 mg, 44%) as a light brown foam. MS: 442.1 ([{ 35 Cl}M+H] + ),444.1([{ 37 Cl}M+H] + ),ESI pos.

[0321] Example 30 Azetidin-1-yl-[(4S)-7-chloro-6-(3-fluoro-6-hydroxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-2-yl]methanone [ka]

[0322] a) 3-[(3S)-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-2-imino-3-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-1-yl]-2-oxopropanoic acid A mixture of (3S)-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-imine (473 mg, 0.893 mmol), K2CO3 (370.2 mg, 2.68 mmol) and ethyl bromopyruvate (580.3 mg, 0.374 mL, 2.68 mmol) was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo to give the product. The residue was heated in ethanol (1 mL) at 90° C. for 4 h and then concentrated in vacuo to give the title compound (0.8 g, 78%) as a dark brown viscous oil. MS561.2 ([{ 35 Cl}MH] + ),563.1([{ 37 Cl}MH] + ),ESI neg.

[0323] b) Azetidin-1-yl-[(4S)-6-(6-benzyloxy-3-fluoro-2-pyridyl)-7-chloro-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-2-yl]methanone A mixture of 3-[(3S)-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-2-imino-3-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-1-yl]-2-oxopropanoic acid (319 mg, 0.340 mmol), HATU (193.9 mg, 0.510 mmol), azetidine (58.2 mg, 1.02 mmol) and N,N-diisopropylethylamine (219.7 mg, 0.29 mL, 1.7 mmol) in N,N-dimethylformamide (3.2 mL) was stirred at 25° C. for 90 min. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-70% ethyl acetate in heptane) to give the title compound (41 mg, 21%) as a pale yellow powder. MS: 584.3 ([{ 35 Cl}M+H] + ),586.2([{ 37 Cl}M+H] + ),ESI pos.

[0324] c) Azetidin-1-yl-[(4S)-7-chloro-6-(3-fluoro-6-hydroxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-2-yl]methanone To a mixture of azetidin-1-yl-[(4S)-6-(6-benzyloxy-3-fluoro-2-pyridyl)-7-chloro-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-2-yl]methanone (41 mg, 0.070 mmol) in acetonitrile (1.1 mL) was added trimethyliodosilane (43.5 mg, 30 uL, 0.211 mmol) at room temperature. The mixture was stirred at 80° C. for 3 h and then concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-10% MeOH in DCM) followed by chiral SFC (Daicel Chiralcel IH, 15-30% methanol containing 0.2% DEA) to give the enantiopure (+)-title compound (2 mg, 12%) as a white viscous oil. MS:494.3([{ 35 Cl}M+H] + ),496.2([{ 37 Cl}M+H] + ),ESI pos.

[0325] Example 31 (4S)-7-Chloro-N-cyclopropyl-6-(3-fluoro-6-hydroxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxamide [ka]

[0326] a) tert-Butyl N-[(1S)-2-(cyclopropylamino)-1-(hydroxymethyl)-2-oxo-ethyl]carbamate To a solution of (2R)-2-(tert-butoxycarbonylamino)-3-hydroxy-propanoic acid (1.5 g, 7.31 mmol) in anhydrous tetrahydrofuran (37 ml) was added cyclopropylamine (1.28 g, 1.58 mL, 21.93 mmol), N,N-diisopropylethylamine (2.83 g, 3.74 mL, 21.93 mmol) and T3P (11.63 g, 10.77 mL, 18.27 mmol). The reaction mixture was stirred at room temperature for 2 h. Saturated aqueous sodium bicarbonate solution (10 mL) was added and the mixture was stirred for 5 min. The aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-2% MeOH in DCM) to afford the title compound (618 mg, 31%) as a white powder, which was used directly in the next step without further characterization.

[0327] b) (2S)-2-Amino-N-cyclopropyl-3-hydroxy-propanamide hydrochloride To a solution of tert-butyl N-[(1S)-2-(cyclopropylamino)-1-(hydroxymethyl)-2-oxo-ethyl]carbamate (618 mg, 2.28 mmol) in ethyl acetate (15 mL) was added dropwise HCl (4 m in dioxane, 5.7 mL, 22.77 mmol) at 0° C. and the mixture was stirred at 0° C. to room temperature overnight. The reaction mixture was filtered and the solid was dried in vacuo to give the title compound (380 mg, 92%) as a white powder, which was used directly in the next step without further purification. 1 H NMR(D2O,300MHz)δ ppm:0.40-0.56(m,2 H),0.61-0.81(m,2 H),2.51-2.64(m,1 H),3.77-4.00(m,3 H).

[0328] c) 2-[(E / Z)-[(3S)-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-ylidene]amino]-N-cyclopropyl-3-hydroxypropanamide To a solution of (3S)-5-(6-benzoxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block J, 120 mg, 0.251 mmol) in anhydrous tetrahydrofuran (4 mL) was added NaH (60% dispersion in mineral oil, 30.1 mg, 0.753 mmol) at 0° C. After stirring for 10 min at 10° C., bis(2-oxo-3-oxazolidinyl)phosphinic chloride (127.9 mg, 0.502 mmol) was added and the reaction mixture was stirred at 0° C. for 1 h. Finally, (2S)-2-amino-N-cyclopropyl-3-hydroxy-propanamide hydrochloride (164.2 mg, 0.753 mmol) and DIPEA (129.8 mg, 0.172 mL, 1 mmol) were added and the reaction mixture was stirred at room temperature for 60 min. The reaction mixture was quenched with water and saturated aqueous NH4Cl (10 ml) and extracted with ethyl acetate (2 x 10 ml). The combined organic layers were washed with water (10 ml) and brine (10 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-80% ethyl acetate in heptane) to give the title compound (48 mg, 32%) as a pale yellow powder. MS: 604.5 ([{ 35 Cl}M+H] + ),606.4([{ 37 Cl}M+H] + ),ESI pos.

[0329] d) (4S)-6-(6-benzyloxy-3-fluoro-2-pyridyl)-7-chloro-N-cyclopropyl-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxamide In analogy to the experiment in Example 24b, 2-[(E / Z)-[(3S)-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-ylidene]amino]-N-cyclopropyl-3-hydroxy-propanamide was converted to the title compound (26 mg, 45%) as a pale yellow powder. MS: 584.4 ([{ 35 Cl}M+H] + ),586.3([{ 37 Cl}M+H] + ),ESI pos.

[0330] e) (4S)-7-chloro-N-cyclopropyl-6-(3-fluoro-6-hydroxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxamide In a manner similar to that of Example 23d, (4S)-6-(6-benzyloxy-3-fluoro-2-pyridyl)-7-chloro-N-cyclopropyl-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxamide was converted to the enantiopure (+)-title compound (5 mg, 39%) as a light grey powder. MS: 494.3 ([{ 35 Cl}M+H] + ),496.2([{ 37 Cl}M+H] + ),ESI pos.

[0331] Example 32 (4S)-7-Chloro-6-(3-fluoro-6-hydroxy-2-pyridyl)-N-isopropyl-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxamide [ka]

[0332] a) tert-Butyl N-[(1S)-1-(hydroxymethyl)-2-(isopropylamino)-2-oxo-ethyl]carbamate Using isopropylamine instead of cyclopropylamine in a similar manner to experiment example 31a, (2R)-2-(tert-butoxycarbonylamino)-3-hydroxy-propanoic acid was converted to the title compound (139 mg, 12%) as an off-white viscous oil, which was used directly in the next step without further characterization.

[0333] b) (2S)-2-Amino-3-hydroxy-N-isopropyl-propanamide hydrochloride In a similar manner to the experiment in Example 31b, tert-butyl N-[(1S)-1-(hydroxymethyl)-2-(isopropylamino)-2-oxo-ethyl]carbamate was converted to the title compound (144 mg, 95%) as a white powder, which was used directly in the next step without further purification. 1 H NMR(DMSO-d6,300MHz)δ ppm:1.04-1.14(m,6 H),3.23-3.56(m,2 H),3.64-3.77(m,2 H),3.86(dd,J=13.90,6.65Hz,1 H),5.30-5.70(m,1 H),8.17(br s,2 H),8.37(br d,J=7.05Hz,1 H).

[0334] c) 2-[(E / Z)-[(3S)-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-ylidene]amino]-3-hydroxy-N-isopropyl-propanamide In a similar manner to experiment 31c, using (2S)-2-amino-3-hydroxy-N-isopropyl-propanamide hydrochloride instead of (2S)-2-amino-N-cyclopropyl-3-hydroxy-propanamide hydrochloride, (3S)-5-(6-benzoxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block J) was converted to the title compound (88 mg, 42%) as an orange viscous oil. MS: 606.4 ([{ 35 Cl}M+H] + ),608.4([{ 37 Cl}M+H] + ),ESI pos.

[0335] d) (4S)-6-(6-benzyloxy-3-fluoro-2-pyridyl)-7-chloro-N-isopropyl-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxamide In a similar manner to the experiment in Example 24b, 2-[(E / Z)-[(3S)-5-(6-benzyloxy-3-fluoro-2-pyridyl)-6-chloro-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-ylidene]amino]-3-hydroxy-N-isopropyl-propanamide was converted to the title compound (42 mg, 55%) as a pale yellow powder. MS: 586.4 ([{ 35 Cl}M+H] + ),588.3([{ 37 Cl}M+H] + ),ESI pos.

[0336] e) (4S)-7-Chloro-6-(3-fluoro-6-hydroxy-2-pyridyl)-N-isopropyl-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxamide In a manner similar to that of Example 23d, (4S)-6-(6-benzyloxy-3-fluoro-2-pyridyl)-7-chloro-N-isopropyl-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxamide was converted to the enantiopure (+)-title compound (9 mg, 36%) as a light pink powder. MS: 496.3 ([{ 35 Cl}M+H] + ),498.3([{ 37 Cl}M+H] + ),ESI pos.

[0337] Reference compound RE-A 7-Chloro-5-(2-chloro-5-hydroxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one [ka]

[0338] a) 6-chloro-1-[(4-methoxyphenyl)methyl]-3,1-benzoxazine-2,4-dione To a mixture of 6-chloro-1H-3,1-benzoxazine-2,4-dione (1.00 g, 5.06 mmol) in tetrahydrofuran (15 mL) was added 1-(chloromethyl)-4-methoxy-benzene (832 mg, 0.746 mL, 5.31 mmol) and tetra-n-butylammonium iodide (935 mg, 2.53 mmol). The mixture was stirred at room temperature for 5 minutes before sodium hydride (60% dispersion in mineral oil, 223 mg, 5.57 mmol) was added. The reaction mixture was stirred for 19 hours and then quenched by the dropwise addition of acetic acid (1.05 g, 1 mL, 17.5 mmol). The reaction mixture was stirred for 30 minutes and then quenched by the dropwise addition of Dicalite. (登録商標) The extract was filtered through ethyl acetate, washed with tetrahydrofuran, and the filtrate was concentrated in vacuo The residue was purified by flash column chromatography (silica, 0-40% ethyl acetate in heptane) to afford the title compound (1.28 g, 80%) as a pale yellow solid. 1 H NMR(CDCl3,300MHz)δ ppm:3.79(3H,s,OCH3),5.23(2H,s,ArCH2N),6.86-6.91(2H,m,ArH),7.11(1H,d,J=8.87Hz,A rH),7.20-7.25(2H,m,ArH),7.57(1H,dd,J=8.87,2.62Hz,ArH),8.11(1H,d,J=2.62Hz,ArH).

[0339] b) 7-chloro-1-[(4-methoxyphenyl)methyl]-3,4-dihydro-1,4-benzodiazepine-2,5-dione To a mixture of 6-chloro-1-[(4-methoxyphenyl)methyl]-3,1-benzoxazine-2,4-dione (4.80 g, 15.1 mmol) and glycine (1.36 g, 18.1 mmol) was added acetic acid (50 mL). The reaction mixture was stirred at 130 °C for 43 h, allowed to cool and concentrated in vacuo. The residue was partitioned between dichloromethane (50 mL) and water (40 mL). The aqueous layer was buffered to approximately pH 8 with saturated aqueous sodium bicarbonate. The phases were separated and the aqueous layer was extracted with dichloromethane (2 x 75 mL) and ethyl acetate (2 x 50 mL). The organic layers were washed separately with brine (2 x 100 mL), dried (Na2SO4), filtered, combined and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-70% ethyl acetate in heptane) to give the title compound (3.59 g, 72%) as a white solid. MS:331.1[{ 35 Cl}M+H] + ,333.1[{ 37 Cl}M+H] + ,ESI pos.

[0340] c) 5,7-dichloro-1-[(4-methoxyphenyl)methyl]-3H-1,4-benzodiazepin-2-one To a solution of 7-chloro-1-[(4-methoxyphenyl)methyl]-3,4-dihydro-1,4-benzodiazepine-2,5-dione (211 mg, 0.638 mmol) in toluene (3 mL) was added N,N-dimethylaniline (155 mg, 0.162 mL, 1.28 mmol) and phosphoryl trichloride (127 mg, 0.077 mL, 0.829 mmol). The reaction mixture was stirred at 80° C. for 18 hours, allowed to cool, and then quenched with ice-cold water (5 mL). The mixture was stirred for 15 minutes and then partitioned between ice-cold water (5 mL) and ethyl acetate (10 mL). The phases were separated and the organic layer was quickly washed with ice-cold water (2×10 mL) and ice-cold brine (2×10 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (193 mg, 90% purity, 78%) as a brown waxy solid. The residue was used directly in the next step without further purification. MS: 349.1[{ 35 Cl}M+H] + ,351.1[{ 37 Cl}M+H] + ,ESI pos.

[0341] d) 7-chloro-5-(2-chloro-5-methoxy-phenyl)-1-[(4-methoxyphenyl)methyl]-3H-1,4-benzodiazepin-2-one To a mixture of 5,7-dichloro-1-[(4-methoxyphenyl)methyl]-3H-1,4-benzodiazepin-2-one (40.0 mg, 0.115 mmol) in 1,2-dimethoxyethane (0.400 mL) was added (2-chloro-5-methoxyphenyl)boronic acid (21.4 mg, 0.115 mmol), tetrakis(triphenylphosphane)palladium(0) (2.65 mg, 2.29 μmol) and aqueous sodium carbonate (2 m, 0.172 mL, 0.344 mmol). The reaction mixture was stirred at 80° C. for 3 h, cooled and then partitioned between ethyl acetate (10 mL) and water (10 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (2×20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-50% ethyl acetate in heptane) to give the title compound (46.0 mg, 88%) as a white solid. MS: 455.1[{ 35 Cl, 35 Cl}M+H] + ,457.1[{ 35 Cl, 37 Cl}M+H] + ,459.1[{ 37 Cl, 37 Cl}M+H] + ,ESI pos.

[0342] e) 7-chloro-5-(2-chloro-5-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one To a mixture of 7-chloro-5-(2-chloro-5-methoxy-phenyl)-1-[(4-methoxyphenyl)methyl]-3H-1,4-benzodiazepin-2-one (320 mg, 0.703 mmol) in acetonitrile (20.1 mL) and water (3.35 mL) was added diammonium cerium(IV) nitrate (1.35 g, 2.46 mmol) in portions. The reaction mixture was stirred at room temperature for 6.5 h and then partitioned between water (50 mL) and ethyl acetate (50 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (2×100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-50% ethyl acetate in heptane) to give the title compound (187 mg, 79%) as an off-white solid. MS: 335.1[{ 35 Cl, 35 Cl}M+H] + ,337.1[{ 35 Cl, 37 Cl}M+H] + ,339.1[{ 37 Cl, 37 Cl}M+H] + ,ESI pos.

[0343] f) 7-Dichloro-5-(2-chloro-5-methoxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one To a mixture of 7-chloro-5-(2-chloro-5-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (30.0 mg, 89.5 μmol) in N,N-dimethylformamide (0.500 mL) was added methyl iodide (22.9 mg, 10.1 μL, 0.161 mmol) and sodium hydride (60% dispersion in mineral oil, 4.3 mg, 0.107 mmol). The mixture was stirred at room temperature for 5 h and then partitioned between water (20 mL) and ethyl acetate (20 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-5% ethyl acetate in heptane) to give the title compound (17.0 mg, 54%) as a light brown waxy solid. MS: 349.1[{ 35 Cl, 35 Cl}M+H] + ,351.1[{ 35 Cl, 37 Cl}M+H] + ,353.1[{ 37 Cl, 37 Cl}M+H] + ,ESI pos.

[0344] g) 7-chloro-5-(2-chloro-5-hydroxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one To a mixture of 7-chloro-5-(2-chloro-5-methoxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one (10.0 mg, 0.0286 mmol) in dichloromethane (0.130 mL) was added boron tribromide (1 m in dichloromethane, 0.100 mL, 0.100 mmol) at -20°C. The mixture was allowed to warm to room temperature and stirred for 1 h, then quenched by careful addition of methanol (0.100 mL) and aqueous sodium hydroxide (2 m, 0.100 mL) and stirred for 30 min. The mixture was then partitioned between water (10 mL) and dichloromethane (10 mL). The phases were separated and the aqueous layer was extracted with dichloromethane (2 x 10 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (6.60 mg, 69%) as an off-white solid. MS: 335.1[{ 35 Cl, 35 Cl}M+H] + ,337.1[{ 35 Cl, 37 Cl}M+H] + ,339.1[{ 37 Cl, 37 Cl}M+H] + ,ESI pos. 1 H NMR(CDCl3,300MHz)δ ppm:3.44(3H,s,NCH3),3.83(1H,br d,J=10.7Hz,COCH2N),4.85(1H,br d,J=10.7Hz,COCH2N),6.80(1H,dd,J=8.7,3.0Hz,ArH),7.03(1H,d,J=3.0Hz,ArH),7.09(1H,d,J=2.4Hz, ArH),7.12(1H,d,J=8.7Hz,ArH),7.29(1H,d,J=8.9Hz,ArH),7.50(1H,dd,J=8.9,2.4Hz,ArH),7.72(1H,br s,ArOH).

[0345] Reference compound RE-B 7-Chloro-5-(2-fluoro-5-hydroxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one [ka]

[0346] a) 2-amino-5-chloro-N-methoxy-N-methyl-benzamide To a mixture of 2-amino-5-chloro-benzoic acid (4.0 g, 23.3 mmol) in tetrahydrofuran (50 mL) was added N,N'-carbonyldiimidazole (4.16 g, 25.6 mmol) followed by triethylamine (4.42 mL, 35.0 mmol). The mixture was stirred at room temperature for 2 h and then O,N-dimethylhydroxylamine hydrochloride (2.5 g, 25.6 mmol) was added. The reaction mixture was stirred at room temperature for 16 h and then diluted with ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium carbonate (100 mL) and brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 30% ethyl acetate in heptane) to give the title compound (3.4 g, 54%) as a white solid. MS: 215.1[{ 35 Cl}M+H] + ,ESI pos.

[0347] b) (2-amino-5-chloro-phenyl)-(2-fluoro-5-methoxy-phenyl)methanone To a mixture of 2-amino-5-chloro-N-methoxy-N-methyl-benzamide (1.57 g, 7.32 mmol) and 2-bromo-1-fluoro-4-methoxy-benzene (1.5 g, 7.32 mmol) in anhydrous tetrahydrofuran (40 mL) was added n-butyllithium (1.6 m in hexanes, 9.15 mL, 14.63 mmol) at −78° C. under nitrogen. The resulting solution was stirred for 30 minutes, then quenched with dilute aqueous hydrochloric acid (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 60% ethyl acetate in heptane) to give the title compound (800 mg, 30%) as a yellow oil. MS: 279.8[{ 35 Cl}M+H] + ,281.8([{ 37 Cl}M+H] + ),ESI pos.

[0348] c) 7-chloro-5-(2-fluoro-5-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one To a mixture of (2-amino-5-chloro-phenyl)-(2-fluoro-5-methoxy-phenyl)methanone (250 mg, 0.89 mmol) in pyridine (15 mL) was added glycine methyl ester hydrochloride (997 mg, 8.94 mmol). The reaction mixture was stirred at 110° C. for 16 h and then concentrated in vacuo. The residue was purified by flash column chromatography (silica, 50% ethyl acetate in heptane) to give the title compound (30 mg, 11%) as a pale yellow solid. MS: 318.9[{ 35 Cl}M+H] + ,320.8([{ 37 Cl}M+H] + ),ESI pos.

[0349] d) 7-Dichloro-5-(2-fluoro-5-methoxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one To a mixture of 7-chloro-5-(2-fluoro-5-methoxy-phenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (300 mg, 0.94 mmol) in N,N-dimethylformamide (10 mL) was added iodomethane (2672 mg, 18.82 mmol) and potassium carbonate (195 mg, 1.41 mmol). The reaction mixture was stirred at 25° C. for 1 h, then quenched with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 50% ethyl acetate in heptane) to give the title compound (160 mg, 44%) as a pale yellow solid. MS: 332.9[{ 35 Cl}M+H] + ,334.8([{ 37 Cl}M+H] + ),ESI pos.

[0350] e) 7-chloro-5-(2-fluoro-5-hydroxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one To a mixture of 7-dichloro-5-(2-fluoro-5-methoxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one (160 mg, 0.48 mmol) in dichloromethane (10 mL) was added BBr3 (1 m in dichloromethane, 2.4 mL, 2.4 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 h, warmed to room temperature and stirred for an additional 5 h. The reaction was quenched with ice water (10 mL) and extracted with dichloromethane (2×20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (X-Select CSH C18, water / acetonitrile containing 0.1% formic acid) to give the title compound (40 mg, 25%) as a white solid. MS: 319.3[{ 35 Cl}M+H] + ,ESI pos. 1 H NMR(DMSO-d6,400MHz)δ ppm:3.31(3H,s,NCH3),3.84(1H,br d,J=9.6Hz,COCH2N),4.65(1H,br d,J=10.5Hz,COCH2N),6.93-6.97(1H,m),7.00(1H,br s),7.07(1H,br d,J=8.3Hz),7.64(1H,br s),9.68(1H,br s).

[0351] Assay procedure γ1-containing GABA A Membrane preparation and binding assays for subtypes GABA A The affinity of compounds at γ1 subunit-containing receptors was determined by measuring the [ 3 For better protein expression of α2 subunit-containing receptors, human GABA receptor agonists were used. A The 28 amino acid long signal peptide (Met1~Ala28) of the α2 subunit is expressed in human GABA A It was replaced with a 31 amino acid long signal peptide (Met1~Ser31) of the α5 subunit.

[0352] Different GABA A Pellets collected from HEK293F cells expressing receptor subtypes were resuspended in mannitol buffer pH 7.2-7.4 (mannitol 0.29 M, triethylamine 10 mM, acetic acid 10 mM, EDTA 1 mM + protease inhibitors (20 tablets Complete, Roche Diagnostics Catalogue No. 05 056 489 001 per liter)), washed twice and then resuspended at a dilution of 1:10-1:15 in the same buffer. Cell disruption was performed by agitating the suspension for 15 min at 435 psi in a Parr vessel #4637, then the suspension was centrifuged at 1000xg for 15 min at 4 °C (Beckman Avanti J-HC; rotor JS-4.2). The supernatant (S1) was transferred to a 2 l Schott flask and the pellet (P1) was resuspended to 175 ml with mannitol buffer. The resuspended pellet was transferred to a 250 ml Corning centrifuge beaker and centrifuged at 1500xg for 10 min at 4°C (Beckman Avanti J-HC; rotor JS-4.2). The supernatant (S1) was then transferred to a 2 liter Schott flask and the pellet was discarded. The supernatant (S1) was centrifuged at 15'000xg for 30 min at 4°C in a 500 ml Beckman polypropylene centrifuge beaker (Beckman Avanti J-20 XP; rotor JLA-10.500). The pellet (P2) was resuspended in mannitol buffer 1:1 and frozen at -80°C. The supernatant (S2) was centrifuged at 48000xg for 50 min at 4°C in a 100 ml Beckman polypropylene centrifuge tube (Beckman Avanti J-20 XP; rotor JA-18). The supernatant (S3) was discarded and the pellet (P3) was resuspended in 1:1 mannitol buffer. P2 and P3 protein concentrations were determined by BIORAD Standard assay using bovine serum albumin as standard and measured on a NANO-Drop 1000. The membrane suspension was aliquoted (500 μl / tube) and stored at -80°C until required.

[0353] Membrane homogenates were resuspended and polytronized (Polytron PT1200E Kinematica AG) in 10 mM potassium phosphate, 100 mM KCl binding buffer (pH 7.4) to final assay concentrations determined in previous experiments.

[0354] Radioligand binding assays were performed using 100 μL of cell membranes and 1.5 nM (α5β2γ1) or 20–30 nM (α1β2γ1, α2β2γ1) of [ 3 H]RO7239181, and [0.3-10000] x 10 -9 The experiments were carried out in a volume of 200 μL (96-well plate) containing test compounds in the range of M. Non-specific binding was determined to be 10×10 -6 (α5β2γ1) and 30×10 -6 M was defined by RO7239181 and typically represented less than 5% (α5β2γ1) and less than 20% (α1β2γ1, α2β2γ1) of total binding. Assays were incubated to equilibrium for 1 h at 4°C, then membranes were filtered onto unifilters (96-well white microplates with bound GF / C filters preincubated for 20-50 min in 0.3% polyethyleneimine) using a Filtermate 196 harvester (Packard BioScience) and washed four times with cold potassium phosphate 10 mM pH 7.4, KCl 100 mM binding buffer. After dehydration, filter-retained radioactivity was detected by liquid scintillation counting. K i Values ​​were calculated using Excel-Fit (Microsoft) and are the means of two determinations.

[0355] The compounds of the accompanying examples were tested in the above assay, and preferred compounds had a GABA receptor activity of 100 nM or less. A [from γ1 subunit-containing receptors (e.g., α5β2γ1, α2β2γ1, α1β2γ1) 3 H]K for displacement of RO7239181 i Values ​​were found to be 0.01 to 0.01. Compounds with 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.

[0356] [ 3 H] Preparation of RO723918 1,6-chloro-5-(2,6-difluorophenyl)-7-methyl-1-(tritrithiomethyl)-3H-1,4-benzodiazepin-2-one [ka]

[0357] 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 A (see below), 450 mg, 1.17 mmol), trimethylboroxine (205 mg, 228 μL, 1.63 mmol), potassium carbonate (242 mg, 1.75 mmol) and tetrakis(triphenylphosphine)palladium(0) (67.4 mg, 58.4 μmol). Degassed 1,4-dioxane (8.1 mL) and H2O (2.7 ml) were added and the vial was then capped. The suspension was reacted in a microwave at 130 °C for 30 min to achieve complete conversion. The mixture was evaporated, treated with saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (2 x 20 mL). The organic layer was dried (Na2SO4), filtered and the solvent was evaporated. The residue was purified by flash column chromatography (silica, 40 g, 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] + ).

[0358] b), 6-chloro-5-(2,6-difluorophenyl)-7-methyl-1-(tritrithiomethyl)-3H-1,4-benzodiazepin-2-one [3 H To a solution of methyl nosylate (1.85 GBq, 50 mCi, 0.61 μmol) was added the N-desmethyl precursor 6-chloro-5-(2,6-difluorophenyl)-7-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (0.43 mg, 1.34 μmol) dissolved in THF (200 μL) and 10 equivalents of sodium tert-butylate (0.5 m in THF, 13.4 μmol). After stirring at room temperature for 4 h, the reaction mixture was treated with HO, evaporated, and the crude product was purified by HPLC (X-Terra Prep RP-18, 10×150 mm, MeCN / HO (containing 5% MeCN) 40:60, 4 ml / min, 230 nm). The pure tritium-labeled compound was isolated by solid-phase extraction (Sep-Pak Plus C18) and eluted from the cartridge as an ethanol solution to give 1.6 GBq (43.2 mCi) of target compound in >99% radiochemical purity with a specific activity of 2.49 TBq / mmol (67.3 Ci / mmol) as determined by mass spectrometry (MS). The identity of the labeled compound was confirmed by HPLC (by co-injecting an unlabeled reference standard) and MS. 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%).

[0359] γ2-containing GABA A Membrane preparation and binding assays for subtypes GABA A The affinity of compounds at γ2 subunit-containing receptors was determined by their affinity to HEK293F cells expressing human (transiently transfected) receptors of the composition α1β3γ2. 3 H]flumazenil (81.1 Ci / mmol; Roche) binding.

[0360] Different GABA A Pellets collected from HEK293F cells expressing the γ2 receptor subtype were resuspended in mannitol buffer pH 7.2–7.4 and incubated with GABA A Cells expressing γ1 subunit-containing receptors were treated as above.

[0361] Radioligand binding assays were performed using 100 μL of cell membranes and 1 nM of [ 3 H]flumazenil and [0.1·10 -3 -10]×10 -6 The assay was performed in a volume of 200 μL (96-well plate) containing test compounds in the range of M. Non-specific binding was determined by 10 -5 M diazepam was defined as binding and was typically less than 5% of total binding. Assays were incubated to equilibrium for 1 h at 4°C and harvested onto GF / C unifilters (Packard) by filtration using a Packard harvester and washing with ice-cold wash buffer (50 mM Tris; pH 7.5). After dehydration, filter-retained radioactivity was detected by liquid scintillation counting. i Values ​​were calculated using Excel-Fit (Microsoft) and are the means of two determinations.

[0362] The compounds of the accompanying examples were tested in the above assay, and preferred compounds exhibited a human GABA receptor activity of 100 nM or greater. A [From the α1β3γ2 subtype of receptor 3 Large K for the substitution of [H]flumazenil i It was found that the value of K i Most preferred are compounds having α1β3γ2 (nM)>300. In a preferred embodiment, the compounds of the present invention are γ2 subunit-containing GABA receptor antagonists. A Compared with γ1 subunit-containing GABA receptors, A In particular, the compounds of the present invention selectively bind to the receptor with a 10-fold or greater "K i α1β3γ2(nM) / K i γ2 / γ1 selectivity ratio, 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] TIFF2024536393000092.tif40165

[0363] GABA A Functional expression of the receptor: Preparation of Xenopus oocytes Xenopus laevis oocytes at maturation stages V–VI were treated with GABA A They were used for the expression of cloned mRNAs encoding receptor subunits. Oocytes ready for RNA microinjection were purchased from Castrop-Rauxel, Ecocyte, Germany, and kept at 20°C in modified Barth's medium (composition in mM: NaCl 88, KCl 1, NaHCO3 2.4, HEPES 10, MgSO4 0.82, CaNO3 0.33, CaCl2 0.33, pH = 7.5) until the experiment.

[0364] Microinjection of Xenopus oocytes Oocytes were plated in 96-well plates for microinjection using the Roboinject automated device (MultiChannelSystems, Reutlingen, Germany). A Approximately 50 nL of an aqueous solution containing RNA transcripts of the subunits of the receptor subtype was injected into each oocyte. RNA concentrations ranged between 20 and 200 pg / μL / subunit and were adjusted in pilot experiments to determine the RNA concentration of GABA receptor subtypes. A GABA responses of appropriate size and maximal effect were obtained for the reference benzodiazepine positive allosteric modulators (PAMs) flunitrazepam, triazolam and midazolam at the receptor benzodiazepine (BZD) binding site. Oocytes were kept 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) at 20 °C until the experiment.

[0365] Electrophysiology Electrophysiological experiments were performed 3–5 days after microinjection of mRNA using a Robocyte instrument (MultiChannelSystems, Reutlingen, Germany). During the experiments, oocytes were constantly heated by a solution (pH 7.4) containing (in mM): NaCl 90, KCl 1, HEPES 5, MgCl2 1, CaCl2 1. Oocytes were filled with a solution containing KCl 1 M + K-acetate 1.5 M and impaled by two glass microelectrodes (resistance: 0.5–0.8 MΩ) voltage-clamped at -80 mV. Recordings were performed at room temperature using a Robocyte two-electrode voltage-clamp system (Multichannelsystem). After an initial equilibration period of 1.5 min, GABA was administered at maximal current response (EC 20 ) for 1.5 min. After another resting interval of 2.5 min, GABA was added again, eliciting responses of similar amplitude and shape. 0.5 min after the start of this second GABA application, while GABA was still present, its K i Test compounds were added at a concentration approximately 30-fold greater than α2β2γ1.Current traces were recorded at a digitization rate of 10 Hz during, immediately prior to, and after GABA application.

[0366] Each compound and concentration was tested in at least three oocytes. Different oocytes were used for different compound concentrations. The reference PAMs, flunitrazepam, triazolam and midazolam, inhibited the α2β2γ1 GABA receptor. A It enhanced GABA-induced currents in oocytes expressing the receptor subtype by approximately 60%.

[0367] Data analysis For analysis, the digitized current traces of the first and second GABA responses were superimposed and, if necessary, rescaled to equal maximal amplitude. The ratio between the two responses during the time interval of test compound application was calculated point-by-point. The extreme value of the resulting "ratio trace" was designated the "GABA EC 20 Compound efficacy ("fold increase") was expressed as "% modulation of IL-1 expression" (100*(fold increase-1)).

[0368] The results are shown in Table 2. [Table 2] TIFF2024536393000094.tif40161

[0369] reference compound Benzodiazepine reference compounds (classical commercially available benzodiazepines) and their structural analogues listed below were compared with GABA A Receptor α1β2γ1 and α2β2γ1 subtypes and GABA A Their affinity for the receptor α1β3γ2 subtype was tested and the results are shown in Table 3. Reference Examples RE-A and RE-B were prepared as described herein. [ka]

[0370] [Table 3]

[0371] Preparation of pharmaceutical compositions containing compounds of the invention

[0372] A tablet containing a compound of formula (I) is prepared as follows. [Table 4]

[0373] 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 suitable grinding equipment. 4. Add ingredient 5 and mix for 3 minutes; compress in a suitable press.

[0374] Capsules containing a compound of formula (I) are prepared as follows. [Table 5]

[0375] 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.

[0376] The compound of formula I, lactose and cornstarch are mixed first in a mixer, then in a grinder. The mixture is returned to the mixer; talc is added and mixed thoapproximatively. The mixture is filled into a suitable capsule, for example a hard gelatin capsule, by machine.

[0377] Injection solutions containing a compound of formula (I) are prepared as follows. [Table 6]

Claims

1. Formula (I) or (II): 【Chemical 1】 (In the formula, 【Chemistry 2】 Below: 【Chemistry 3】 Selected from: X is C-R ６ and nitrogen; W is C or N; R １ is hydrogen, C １ -C ６ -Alkyl, carbamoyl, C １ -C ６ -alkyl-NH-C(O)-, (C １ -C ６ -alkyl) ２ N—C(O)—, C ３ -C １０ -cycloalkyl-NH-C(O)-, and 3- to 14-membered heterocycloalkyl-C(O)-; said 3- to 14-membered heterocycloalkyl is selected from halogen and C １ -C ６ - optionally substituted with one substituent selected from alkoxy; R １ａ is hydrogen and C １ -C ６ - alkyl; or R １ and R １ａ together with the carbon atoms to which they are attached, form C ３ -C １０ -forming a cycloalkenyl; R ２ is hydrogen and C １ -C ６ - selected from alkyl; R ３ is selected from chloro and bromo; R ４ is C １ -C ３ -Alkyl, halo-C １ -C ２ - selected from alkyl and halogen; R ５ is selected from hydrogen and halogen; R ６ is selected from hydrogen and halogen or a pharmaceutically acceptable salt thereof. 【Request 2】 【Chemical 4】 but the following: 【Chemistry 5】 Selected from: R １ But hydrogen, C １ -C ６ -alkyl, and 3- to 14-membered heterocycloalkyl-C(O)—; said 3- to 14-membered heterocycloalkyl is selected from one C １ -C ６ - substituted with alkoxy substituents; R １ａ But C １ -C ６ -alkyl, or a pharmaceutically acceptable salt thereof. 【Request 3】 【Chemical 6】 but the following: 【Chemistry 7】 Selected from: R １ is selected from hydrogen, methyl and methoxyazetidine-C(O)-; R １ａ 3. The compound of formula (I) or (II) according to claim 2, or a pharmaceutically acceptable salt thereof, wherein is methyl.

4. R ２ 2. A compound of formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen and methyl.

5. R ３ 2. The compound of formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is chloro.

6. R ４ is methyl, CF ３ 2. The compound of formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is selected from chloro and chloro.

7. R ５ 2. The compound of formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is halogen.

8. R ５ 8. A compound of formula (I) or (II) according to claim 7, or a pharmaceutically acceptable salt thereof, wherein is selected from chloro and fluoro.

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

10. 【Chemical 8】 but the following: 【Chemistry 9】 Selected from: X is C-R ６ and nitrogen; R １ But hydrogen, C １ -C ６ -Alkyl, C １ -C ６ -alkyl-NH-C(O)-, C ３ -C １０ -cycloalkyl-NH-C(O)-, and 3- to 14-membered heterocycloalkyl-C(O)-; wherein said 3- to 14-membered heterocycloalkyl is selected from halogen and C １ -C ６ - optionally substituted with one substituent selected from alkoxy; R １ａ is hydrogen and C １ -C ６ - alkyl; or R １ and R １ａ together with the carbon atoms to which they are attached, C ３ -C １０ -forming a cycloalkenyl; R ２ is hydrogen and C １ -C ６ - selected from alkyl; R ３ is chloro; R ４ But C １ -C ３ -Alkyl, halo-C １ -C ２ - selected from alkyl and halogen; R ５ is a halogen; R ６ 2. The compound of formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen and halogen.

11. [Catalog 10] but the following: 【Chemistry 11】 Selected from: X is C-R ６ and nitrogen; R １ But hydrogen, C １ -C ６ -alkyl, and 3- to 14-membered heterocycloalkyl-C(O)—; said 3- to 14-membered heterocycloalkyl is selected from one C １ -C ６ - substituted with alkoxy substituents; R １ａ But C １ -C ６ - alkyl; R ２ is hydrogen and C １ -C ６ - selected from alkyl; R ３ is chloro; R ４ But C １ -C ３ -Alkyl, halo-C １ -C ２ - selected from alkyl and halogen; R ５ is a halogen; R ６ 11. The compound of formula (I) or (II) according to claim 10, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

12.

12. but the following: 【Chemistry 13】 Selected from: X is C-R ６ and nitrogen; R １ is selected from hydrogen, methyl and methoxyazetidine-C(O)-; R １ａ is methyl; R ２ is selected from hydrogen and methyl; R ３ is chloro; R ４ But methyl, CF ３ and chloro; R ５ is selected from chloro and fluoro; and R ６ 12. The compound of formula (I) or (II) according to claim 11, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

13. The compound of formula (I) or (II) is 6,7-dichloro-5-(2-fluoro-5-hydroxyphenyl)-1-methyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one; 6-chloro-5-(2-fluoro-5-hydroxyphenyl)-1,7-dimethyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one; 3-(7,8-dichloro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl)-4-fluoro-phenol; 3-[(4S)-7,8-dichloro-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-4-fluorophenol; (5S)-8,9-dichloro-7-(2-fluoro-5-hydroxyphenyl)-5-methyl-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one; 8,9-dichloro-7-(2-fluoro-5-hydroxy-phenyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one; [7,8-dichloro-6-(2-fluoro-5-hydroxy-phenyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone; 6-chloro-5-(2-fluoro-5-hydroxy-phenyl)-1-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one; 3-[7-chloro-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-4-fluoro-phenol; 3-[7-chloro-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-4-fluoro-phenol; 3-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-4-fluoro-phenol; 8-chloro-7-(2-fluoro-5-hydroxy-phenyl)-9-(trifluoromethyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one; 6,7-dichloro-5-(2,6-difluoro-3-hydroxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one; 3-(7,8-dichloro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl)-2,4-difluoro-phenol; 8,9-dichloro-7-(2,6-difluoro-3-hydroxy-phenyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one; 3-[(4S)-7,8-dichloro-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-2,4-difluoro-phenol; [7-chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone; (5S)-8,9-dichloro-7-(2,6-difluoro-3-hydroxy-phenyl)-5-methyl-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one; [7-chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]-(3-methoxyazetidin-1-yl)methanone; 6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol; [(4S)-7-chloro-6-(3-fluoro-6-hydroxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-fluoroazetidin-1-yl)methanone; 5-chloro-6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]pyridin-2-ol; 6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol; 6-[(10S)-6-chloro-10-methyl-5-(trifluoromethyl)-1,9,12-triazatetracyclo[9.6.0.02,7.013,17]heptadeca-2,4,6,8,11,13(17)-hexaen-8-yl]-5-fluoro-pyridin-2-ol; 6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-6-yl]-5-fluoropyridin-2-ol; 5-chloro-6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]pyridin-2-ol; 5-chloro-6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]pyridin-2-ol; 6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol; 5-chloro-6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-6-yl]pyridin-2-ol; Azetidin-1-yl-[(4S)-7-chloro-6-(3-fluoro-6-hydroxypyridin-2-yl)-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-2-yl]methanone; (4S)-7-chloro-N-cyclopropyl-6-(3-fluoro-6-hydroxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxamide; (4S)-7-chloro-6-(3-fluoro-6-hydroxy-2-pyridyl)-N-isopropyl-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxamide 2. The compound of formula (I) or (II) according to claim 1, selected from: or a pharmaceutically acceptable salt thereof.

14. The compound of formula (I) or (II) is 6,7-dichloro-5-(2-fluoro-5-hydroxyphenyl)-1-methyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one; 6-chloro-5-(2-fluoro-5-hydroxyphenyl)-1,7-dimethyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one; 6-chloro-5-(2-fluoro-5-hydroxy-phenyl)-1-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one; [7-chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone; 6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol; 5-chloro-6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]pyridin-2-ol 14. A compound of formula (I) or (II) according to claim 13, selected from: or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound of formula (I) or (II) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

16. 16. The pharmaceutical composition according to claim 15 for treating or preventing acute neurological disorders, chronic neurological disorders and / or cognitive disorders.

17. The acute neurological disorder, chronic neurological disorder and / or cognitive disorder is selected from the group consisting of autism spectrum disorder (ASD), Angelman syndrome, age-related cognitive decline, Rett syndrome, Prader-Willi syndrome, amyotrophic lateral sclerosis (ALS), fragile X disorder, negative and / or cognitive symptoms associated with schizophrenia, tardive dyskinesia, anxiety, social anxiety disorder (social phobia), panic disorder, agoraphobia, generalized anxiety disorder, disruptive, impulse control and behavior disorders, Tourette syndrome (TS), obsessive-compulsive disorder (OCD), acute stress disorder, post-traumatic stress disorder, and the like.

17. The pharmaceutical composition of claim 16, wherein the therapeutic effect is selected from posttraumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), sleep disorders, Parkinson's disease (PD), Huntington's chorea, Alzheimer's disease (AD), mild cognitive impairment (MCI), dementia, behavioral and psychological symptoms in neurodegenerative conditions (BPS), multi-infarct dementia, agitation, psychosis, substance-induced psychotic disorder, aggression, eating disorders, depression, chronic apathy, anhedonia, chronic fatigue, seasonal affective disorder, postpartum depression, sleepiness, sexual dysfunction, bipolar disorder, epilepsy, and pain.

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