Pyridodiazepine Derivatives as GABAAγ1 PAMs

Abstract

The present invention relates to compounds of general formula (I): The present invention provides novel heterocyclic compounds having the formula: and pharma- ceutically acceptable salts thereof. Further provided are pharmaceutical compositions comprising the compounds, methods of making the compounds and methods of using the compounds as pharmaceuticals, in particular methods of using the compounds to treat or prevent acute neurological disorders, chronic neurological disorders and / or cognitive disorders. TIFF2024535343000073.tif70169

Description

[Technical field]

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

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

[0003] GABA A There are 19 genes encoding the receptor subunits, with the most common stoichiometry being two α, two β, and one γ subunit assembled as a pentamer. A Subunit combinations confer functional, circuit, and behavioral specificity. GABA containing the γ1 subunit A Receptor (GABA A GABA gamma 1) has received particular attention due to its abundant expression in the limbic system and its unique physiological and pharmacological properties. A γ1 subunit-containing receptors are less abundant (GABA receptors in the brain AApproximately 5-10% of total receptor expression, γ2 subunit-containing receptors show enriched brain mRNA and protein distribution in key brain regions such as the extended amygdala (central, medial, and bed nuclei of the stria terminalis), lateral septum, hypothalamus, and globus pallidus / substantia nigra. These structures form the interconnected core of a subcortical-limbic circuit that regulates motivated social and emotional behaviors. In abnormal or disease states, over-recruitment of this circuit promotes anxiety, arousal, aggression, fear, and defensiveness while inhibiting feeding and social interaction.

[0004] Hyperactivity in limbic cortical regions, which are 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 various psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational and metabolic disorders. In such disease states, γ1-subunit-containing GABAergic receptors are involved in the regulation of GABAergic receptor signaling. A Given the characteristic anatomical distribution of GABA receptors, A γ1 positive allosteric modulators (PAMs) may be an effective treatment as symptomatic or disease modifying agents.

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

[0006] A CNS disorder of particular interest in the context of the present invention is autism spectrum disorder (ASD), which includes 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] While there are no approved pharmacological treatments for the core symptoms of social deficit and restricted / repetitive behaviors of ASD, inadequate treatment options are available for most of the emotional and physiological comorbidities of ASD. As a result, this disorder remains an area of ​​high unmet medical need. Currently approved treatments for ASD-related symptoms are limited to antipsychotic medications (risperidone, aripiprazole) indicated for treating the irritability associated with ASD symptoms. Emerging evidence suggests that the GABAergic system, the main inhibitory neurotransmitter in the brain, plays an important 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 encoding γ1, GABRG1, is involved in the regulation of α2, α4 and β1GABA AIt is located on chromosome 4 (chromosome 5 in mice) within a cluster of genes encoding receptor subunits. Rare CNVs involving inversions of chromosome 4p12 disrupting GABRG1 have been found in siblings with autism (Horike et al., 2006), as well as GABRG1 loss in one case of ADHD. Mutations in the 4p12 gene cluster 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, with recent studies showing 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. In addition, 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 downregulated in the parietal and cerebellar cortices of autistic patients. A These findings 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, insula, PFC, and cingulate, 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 have provided clear links between extended amygdala activity / functional connectivity and emotional states. Targeting such highly specific 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 ameliorate behavioral deficits in mouse models of ASD. AWe observed that α1γ2 subtype-mediated sedation has a very narrow margin of therapeutic efficacy. These findings support the notion that GABA A This supports the idea that rebalancing GABAergic transmission via γ1 receptors improves ASD symptoms without the side effects of non-selective benzodiazepines. Summary of the Invention [Problem to be solved by the invention]

[0009] The compounds of the present invention may be administered 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 γ1PAM is a non-selective GABA A It restores 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 Aγ1PAM 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 cognitive symptoms associated with schizophrenia, tardive dyskinesia, anxiety, social anxiety disorder (social phobia), panic disorder, agoraphobia, generalized anxiety disorder, disruptive, impulse-control and conduct disorder, and the like. The compounds are useful as disease modifying or symptomatic agents for the treatment or prevention of acute neurological disorders, chronic neurological disorders and / or cognitive disorders including chronic myocardial infarction (CI) syndrome, chronic obstructive pulmonary disease (COPD), chronic myocardial infarction (COPD), chronic pulmonary disease (COPD), chronic pulmonary edema (CPH ... [Means for solving the problem]

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

[0012] In one aspect, the present invention provides a method for preparing a compound of formula (I) as described herein, the method being a method according to any one of Schemes 1-11 as described herein.

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

[0014] In a further aspect, the present invention provides a compound of formula (I) 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) 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) as described herein, or a pharma- ceutically acceptable salt thereof, for use in a method for 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] Detailed Description of the Invention definition It should be understood that features, integers, characteristics, compounds, chemical moieties or groups described in connection with a particular aspect, embodiment or example of the invention are applicable to any other aspect, embodiment or example described herein, except where inconsistent therewith. All of the features disclosed herein (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 or any novel combination of features disclosed herein (including any accompanying claims, abstract, and drawings), or any novel 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 ("C1-C6-alkyl") of 1 to 6 carbon atoms, 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 still 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 an 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 or partially unsaturated, monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms ("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 a cycloalkyl moiety consisting of two saturated carbocyclic rings having two common 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 a spirocyclic moiety, i.e., the two rings are joined 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, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and spiro[2.3]hexan-5-yl. Some preferred, but non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, and cyclopentenyl.

[0022] The term "heterocyclyl" or "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic, preferably monocyclic, ring system of 3 to 14 ring atoms, preferably 3 to 10 ring atoms, more preferably 3 to 8 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 a heterocyclic moiety consisting of two rings having two ring atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and a spirocyclic moiety, i.e., the two rings are joined via one common ring atom. Some non-limiting examples of heterocyclyl groups include azetidin-3-yl, azetidin-2-yl, oxetan-3-yl, oxetan-2-yl, piperidyl, piperazinyl, pyrrolidinyl, 2-oxopyrrolidin-1-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, 5-oxopyrrolidin-3-yl, 2-oxo-1-piperidyl, 2-oxo-3-piperidyl, 2-oxo-4-piperidyl, 6-oxo-2-piperidyl, 6-oxo-3-piperidyl, 1-piperidinyl, 2-piperidinyl, Heterocyclyl includes 3-piperidinyl, 4-piperidinyl, morpholino (e.g., morpholin-2-yl, or morpholin-3-yl), thiomorpholino, pyrrolidinyl (e.g., pyrrolidin-3-yl), 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. Some preferred, but non-limiting examples of heterocyclyl are azetidinyl, oxetanyl, pyrrolidinyl, and thiomorpholino.

[0023] The term "hydroxy" refers to an --OH group.

[0024] The term "oxo" refers to an oxygen atom attached to the parent moiety through a double bond (=O).

[0025] The term "carbonyl" refers to a C=O group.

[0026] 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 haloalkoxy is trifluoromethyl.

[0027] The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a hydroxy group. Preferably, "hydroxyalkyl" refers to an alkyl group in which one, two or three hydrogen atoms, most preferably one hydrogen atom, of the alkyl group is replaced by a hydroxy group. Preferred, but non-limiting examples of hydroxyalkyl are hydroxymethyl, hydroxyethyl (e.g., 2-hydroxyethyl), hydroxypropyl (e.g., 2-hydroxypropyl), and 3-hydroxy-3-methyl-butyl.

[0028] 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, etc. Furthermore, 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 salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, etc. 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.

[0029] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers, e.g. racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0030] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom may be of the "R" or "S" configuration.

[0031] The term "treatment" as used herein includes: (1) suppressing a symptom, disorder or condition (e.g., in the case of maintenance treatment, arresting, reducing or delaying the onset or recurrence of at least one of its clinical symptoms or subclinical disease); and / or (2) alleviating the condition (i.e., causing regression of the symptom, disorder or condition, or at least one of its clinical symptoms or subclinical symptoms). The benefit to the treated patient is either statistically significant or at least perceptible to the patient or the physician. However, it will be understood that when a patient is administered a medicine to treat a disease, the outcome may not necessarily be effective treatment.

[0032] The terms "prophylaxis" or "prevention" as used herein include preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition developing in a subject, particularly in a human suffering from or susceptible to the condition, disorder or condition, but who has not yet experienced or exhibited clinical or asymptomatic symptoms of the condition, disorder or condition.

[0033] The term "subject" as used herein includes both humans and non-humans, including, but not limited to, humans, non-human primates, canines, felines, murines, bovines, equines, and porcines. In a particularly preferred embodiment, the term "mammal" refers to a human.

[0034] The abbreviation uM means micromolar and is equivalent to the symbol μM.

[0035] The abbreviation uL means microliter and is equivalent to the symbol μL.

[0036] The abbreviation ug means microgram and is equivalent to the symbol μg.

[0037] Compounds of the Invention In a first aspect, the present invention provides a compound of formula (I) [ka] (In the formula, [ka] but, [ka] is selected from R 1 is hydrogen, C1-C6-alkyl, hydroxy-C1-C6-alkyl-NH-C(O)- and the group [ka] Selected from R 1a is hydrogen, or R 1 and R 1a However, together with the carbon atoms to which they are attached, C3-C 10 - forming a cycloalkyl R 1b is selected from hydrogen, halogen, hydroxy, oxo, C1-C6-alkyl and C1-C6-alkoxy, R 1c is selected from hydrogen, hydroxy and oxo; R 2 is C1-C6-alkyl; R 3 is chloro or bromo; R 4 is halogen, C1-C6-alkyl, halo-C1-C6-alkyl, and C3-C 10 -cycloalkyl, R 5 is a halogen, L is selected from a covalent bond, carbonyl, -C(O)NH-, -NHC(O)-, -CHNHC(O)-; A is 3-14 membered heterocycloalkyl and C 10 -cycloalkyl) or a pharma- ceutically acceptable salt thereof.

[0038] In a preferred embodiment, the present invention comprises: [ka] but, [ka] The present invention provides a compound of formula (I) as described herein, selected from:

[0039] In a particularly preferred embodiment, the present invention comprises: [ka] but, [ka] or a pharma- ceutically acceptable salt thereof.

[0040] In a particularly preferred embodiment, the present invention comprises: [ka] but, [ka] or a pharma- ceutically acceptable salt thereof.

[0041] In a particularly preferred embodiment, the present invention comprises: [ka] but, [ka] or a pharma- ceutically acceptable salt thereof.

[0042] In one embodiment, the present invention provides R 1 C1-C6-alkyl, hydroxy-C1-C6-alkyl-NH-C(O)- and groups [ka] Selected from R 1a is hydrogen, or R 1 and R 1a However, together with the carbon atoms to which they are attached, C3-C 10 - forming a cycloalkyl R 1b , R 1c The present invention provides compounds of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein A and L are as defined herein.

[0043] In one embodiment, the present invention provides R 1 C1-C6-alkyl, hydroxy-C1-C6-alkyl-NH-C(O)- and groups [ka] Selected from R 1a is hydrogen, R 1b , R 1c The present invention provides a compound of formula (I) as described herein, wherein A and L are as defined in claim 1, or a pharma- ceutically acceptable salt thereof.

[0044] In one embodiment, the present invention provides R 1 and R 1a However, together with the carbon atoms to which they are attached, C3-C10 - forming a cycloalkyl R 1b , R 1c The present invention provides a compound of formula (I) as described herein, wherein A and L are as defined in claim 1, or a pharma- ceutically acceptable salt thereof.

[0045] In a preferred embodiment, the present invention comprises: R 1 C1-C6-alkyl, hydroxy-C1-C6-alkyl-NH-C(O)- and groups [ka] is selected from R 1b is C1-C6-alkyl, R 1c is hydroxy, L is carbonyl; Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt thereof, wherein A is a 3- to 14-membered heterocycle.

[0046] In a particularly preferred embodiment, the present invention comprises: R 1 are 2-hydroxyethyl-NH-C(O)-, 2-hydroxypropyl-NH-C(O)-, methyl, and [ka] is selected from R 1b is methyl, R 1c is hydroxy, L is carbonyl; Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt thereof, wherein A is azetidinyl.

[0047] In a preferred embodiment, the present invention provides 1is hydroxy-C1-C6-alkyl-NH-C(O)-, or a pharma- ceutically acceptable salt thereof.

[0048] In a preferred embodiment, the present invention provides a 1 is 2-hydroxy-NH-C(O)-, or a pharma- ceutically acceptable salt thereof.

[0049] In a preferred embodiment, the present invention provides a 2 is methyl, or a pharma- ceutically acceptable salt thereof.

[0050] In a preferred embodiment, the present invention provides a 3 is chloro; or a pharma- ceutically acceptable salt thereof.

[0051] In a preferred embodiment, the present invention provides a 4 is haloalkyl; or a pharma- ceutically acceptable salt thereof.

[0052] In a particularly preferred embodiment, the present invention provides 4 is CF3, 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: 5 is halogen, 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: 5 is fluoro or chloro, or a pharma- ceutically acceptable salt thereof.

[0055] In a preferred embodiment, the present invention provides a 5is fluoro; or a pharma- ceutically acceptable salt thereof.

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

[0057] In a preferred embodiment, the present invention comprises: R 1 C1-C6-alkyl, hydroxy-C1-C6-alkyl-NH-C(O)- and groups [ka] is selected from R 1b is C1-C6-alkyl, R 1c is hydroxy, R 2 is C1-C6-alkyl, R 3 But it's Chloro. R 4 is halo-C1-C6-alkyl, R 5 is a halogen, L is carbonyl; Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt thereof, wherein A is a 3- to 14-membered heterocycle.

[0058] In a particularly preferred embodiment, the present invention comprises: R 1 are methyl, 2-hydroxyethyl-NH-C(O)-, 2-hydroxypropyl-NH-C(O)-, and the groups [ka] is selected from R 1b is methyl, R 1cis hydroxy, R 2 is methyl, R 3 But it's Chloro. R 4 But CF3, R 5 But it is fluoro. L is carbonyl; Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt thereof, wherein A is azetidinyl.

[0059] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, said compound of formula (I) being (7S)-11,12-dichloro-9-(2,6-difluorophenyl)-3,7-dimethyl-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene, (7S)-11-chloro-12-cyclopropyl-9-(2,6-difluorophenyl)-3,7-dimethyl-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene, (7S)-11-chloro-9-(2,6-difluorophenyl)-3,7,12-trimethyl-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene, (7S)-11-chloro-9-(2,6-difluorophenyl)-3,7-dimethyl-12-(trifluoromethyl)-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene, (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene, Azetidin-1-yl-[(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradec-1(10),3,5,8,11,13-hexaen-4-yl]methanone, [(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradec-1(10),3,5,8,11,13-hexaen-4-yl]-(3-fluoroazetidin-1-yl)methanone, [(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradec-1(10),3,5,8,11,13-hexaen-4-yl]-(3-hydroxyazetidin-1-yl)methanone, [(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradec-1(10),3,5,8,11,13-hexaen-4-yl]-(3-methoxyazetidin-1-yl)methanone, [(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(3-hydroxy-3-methyl-azetidin-1-yl)methanone, [(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(1,1-dioxo-1,4-thiazinane-4-yl)methanone, N-[(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]oxetane-3-carboxamide, 1-[(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]pyrrolidin-2-one, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(2S)-2-hydroxypropyl]-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(2R)-2-hydroxypropyl]-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, (7S)-11-chloro-9-(2-chloro-6-fluoro-phenyl)-3,7-dimethyl-12-(trifluoromethyl)-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene, (7S)-11-chloro-9-(2,6-difluorophenyl)-4,7-dimethyl-12-(trifluoromethyl)-2,5,8,13-tetraazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-7-methyl-12-(trifluoromethyl)-2,5,8,13-tetraazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, (10S)-6-chloro-8-(2,6-difluorophenyl)-10-methyl-5-(trifluoromethyl)-1,4,9,12-tetraazatetracyclo[9.6.0.02,7.013,17]heptadeca-2(7),3,5,8,11,13(17)-hexaene, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-(2-hydroxy-2-methyl-propyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(1-hydroxycyclopropyl)methyl]-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-cis-(3-hydroxycyclobutyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, and (7S)-11-Chloro-9-(2,6-difluorophenyl)-N-trans-(3-hydroxycyclobutyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide is selected from.

[0060] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, said compound of formula (I) being (7S)-11-chloro-9-(2,6-difluorophenyl)-3,7-dimethyl-12-(trifluoromethyl)-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene, [(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(3-hydroxy-3-methyl-azetidin-1-yl)methanone, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(2S)-2-hydroxypropyl]-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(2R)-2-hydroxypropyl]-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, and (7S)-11-Chloro-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-7-methyl-12-(trifluoromethyl)-2,5,8,13-tetraazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide is selected from.

[0061] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is (7S)-11-chloro-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradec-1(10),3,5,8,11,13-hexaene-4-carboxamide.

[0062] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is (7S)-11-chloro-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-7-methyl-12-(trifluoromethyl)-2,5,8,13-tetraazatricyclo[8.4.0.02,6]tetradec-1(10),3,5,8,11,13-hexaene-4-carboxamide.

[0063] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is (7S)-11-chloro-9-(2,6-difluorophenyl)-3,7-dimethyl-12-(trifluoromethyl)-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene.

[0064] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is [(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradec-1(10),3,5,8,11,13-hexaen-4-yl]-(3-hydroxy-3-methyl-azetidin-1-yl)methanone.

[0065] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(2S)-2-hydroxypropyl]-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradec-1(10),3,5,8,11,13-hexaene-4-carboxamide.

[0066] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(2R)-2-hydroxypropyl]-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradec-1(10),3,5,8,11,13-hexaene-4-carboxamide.

[0067] In one embodiment, the present invention provides a pharma- ceutically acceptable salt of a compound of formula (I) as described herein, in particular a pharma- ceutically acceptable salt selected from the hydrochloride, fumarate, lactate (especially derived from L-(+)-lactic acid), tartrate (especially derived from L-(+)-tartaric acid) and trifluoroacetate salts. In an even more specific embodiment, the present invention provides a compound according to formula (I) as described herein (i.e., as the "free base" or "free acid", respectively).

[0068] In some embodiments, the compound of formula (I) is isotopically labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Examples of isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, e.g. 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Certain isotopically labeled compounds of formula (I), for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H and carbon-14, i.e. 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. For example, compounds of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0069] Heavier isotopes, such as deuterium, i.e. 2 Substitutions such as H may confer greater metabolic stability and may confer certain therapeutic advantages, for example through increased in vivo half-life or reduced dosage requirements.

[0070] 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the Examples set forth below, substituting the appropriate isotopically labeled reagent for the non-isotopically labeled reagent previously used.

[0071] Manufacturing method Processes for preparing the compounds of formula (I) described herein are also an object of the present invention.

[0072] The preparation of the A compounds of formula (I) of the present invention may 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 resulting products are known to those skilled in the art. The substituents and indices used in the following method descriptions have the meanings given hereinbefore and in the claims, unless otherwise indicated. More specifically, the compounds of formula (I) 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. 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). The reaction can be easily carried out with or without a solvent. There is no particular restriction regarding the nature of the solvent used, as long as it does not adversely affect the reaction or the reagents involved and is capable of dissolving 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 a temperature range between -78°C and 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, 0.5 hours to several days is usually sufficient to obtain the intermediates and compounds described. The reaction sequence is not limited to that 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.

[0073] The preparation of the A compound of formula (I) of the present invention may be carried out in a sequential or convergent synthetic route. The synthesis of the present invention is shown in the following general scheme. The skills required to carry out the reaction and purification of the obtained product are known to those skilled in the art. The substituents and indices used in the following method description have the meanings previously indicated herein, unless otherwise indicated.

[0074] More specifically, the compounds of formula (I) 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 that shown in Schemes 1-11, 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.

[0075] The compounds of formula (Ia) of the present invention and pharma- ceutically acceptable salts thereof can be prepared by the method described in Scheme 1. [ka] Scheme 1: Synthesis of compound (Ia) described above and claimed.

[0076] According to scheme 1, compounds of formula (Ia) can be prepared in one or two steps starting from lactams of formula (II). After thiolation reaction using Lawesson's reagent or P2S5, lactams (II) are converted to the corresponding thiolactams (III). Their reaction with hydrazides via a Pellizzari-type process gives 1,2,4-triazoles of general formula (I). Alternatively, compounds (Ia) can be obtained directly by reaction of lactams (II) with hydrazides using bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) in the presence of a base (NaH) in tetrahydrofuran. [ka] Scheme 2: R 4 Synthesis of pyrido-diazepines (Ia) where is Me or c-Pr.

[0077] According to Scheme 2, R 4 Pyrido-diazepines (Ia), where I is methyl or cyclopropyl, can be obtained by palladium-catalyzed Suzuki-Miyaura cross-coupling reaction between 2-chloropyridine (IV) and boron reagents such as trimethylboroxine or cyclopropylboronic acid using an inorganic base (e.g., K2CO3 or K3PO4) in 1,4-dioxane or toluene at elevated temperature.

[0078] Triazoles of formula (Ib) can be prepared according to the methods described in Scheme 3. [ka] Scheme 3: As described above and in the claims, 1 Synthesis of pyrido-diazepines of formula (Ib) where is Me.

[0079] According to Scheme 3, starting from thiolactams (III), 1,2,4-triazoles (Ib) can be prepared by treatment with ammonia in methanol to form amidines (V). Following successive reactions with triethyl or trimethyl orthoacetate, treatment with ammonia in methanol, and final ring closure by reaction with sodium hypochlorite in water and methanol, the final derivatives (Ib) were obtained.

[0080] In a further embodiment of the invention, R 1 Compounds of formula (Ib) where is an amide can be prepared according to the method described in Scheme 4. [ka] Scheme 4: As described above and in the claims, R 1 Synthesis of pyrido-diazepines of formula (Ib) where is an amide.

[0081] Electrophilic amination of lactam (II) using O-(diphenylphosphinyl)hydroxylamine gives intermediate of formula (VI). Thermal cyclocondensation reaction with imidate gives 1,2,4-triazole (VII). Final derivative of formula (Ib) can be obtained by saponification of ethyl ester (VII) to carboxylic acid (VIII) under basic conditions (e.g. NaOH or LiBr, Et3N) followed by reaction with amine HNR 5 R 6 (e.g., HATU, DIPEA or PyBOP, DIPEA) or by standard amide coupling of ester (VII) with amine HNR in ethanol. 5 R 6 It can be obtained either by direct reaction with

[0082] R 1 Compounds of formula (Ib) where is a reverse amide can be prepared according to the method described in Scheme 5. [ka] Scheme 5: As described above and in the claims, 1 Synthesis of pyrido-diazepines of formula (Ib) where is the reverse amide.

[0083] According to Scheme 5, N-protected triazoles (IX) can be accessed via a Curtius rearrangement when carboxylic acid (VIII) is heated with diphenylphosphoryl azide in the presence of a base (e.g., Et3N). Removal of the N-Boc protecting group can be achieved with a mineral acid (e.g., HCl) or an organic acid (e.g., trifluoroacetic acid) to give amines of formula (X), which can be reacted with carboxylic acid R 8 Coupling with CO2H (eg, POCl3 in pyridine) can give the final derivative (Ib).

[0084] Additionally, according to Scheme 6, 4-chlorobutanamide (XI) can be cyclized in the presence of a base (eg, Et3N) to form a 5-membered lactam of formula (Ib). [ka] Scheme 6: Synthesis of δ-lactams of formula (Ib).

[0085] In a further embodiment of the invention, the imidazole of formula (Ic) may be prepared according to the method described in Scheme 7. [ka] Scheme 7: Synthesis of pyrido-diazepines of formula (Ic) as described above and claimed.

[0086] According to Scheme 7, thiolactams (III) are reacted with thiolactams of the general formula HOCHCH(NH)R 1 The amino alcohols (XII) can be reacted to form substituted amidines (XII). The final compounds (Ic) can be obtained in a two-step synthesis by Dess-Martin oxidation of the alcohols (XII) to the corresponding aldehydes followed by thermal cyclization. [ka] Scheme 8: Synthesis of pyrido-diazepines of formula (Ic) as described above and claimed.

[0087] According to Scheme 8, in the case of 2-aminocyclopentanol, the alcohol (XII) can be oxidized with TEMPO and phenyl-λ3-iododiyl diacetate (BAIB) followed by cyclization with POCl3 and pyridine to give the imidazole (Ic).

[0088] Alternatively, imidazoles of general formula (Ic) can be prepared via the ester intermediate (XV) detailed in Scheme 9. [ka] Scheme 9: As described above and in the claims, 1 Synthesis of pyrido-diazepines of formula (Ic) where is an amide.

[0089] According to Scheme 9, lactam (II) can be activated by reaction with [chloro(phenoxy)phosphoryl]oxybenzene in the presence of a base (e.g., NaH) to form a diphenylphosphonate of general formula (XIV), which can be reacted with an amino alcohol HOCHCH(NH)R 1 to form the amidine (XV). Subsequent oxidation with Dess-Martin periodinane followed by thermal cyclization gives the ethyl ester (XVI). Finally, saponification to the carboxylic acid (XVII) can be achieved using saturated aqueous lithium bromide in the presence of a base (e.g., Et3N), followed by amide coupling with HATU, DIPEA to give the desired imidazole of formula (Ic).

[0090] The synthesis of lactam (II) is highlighted in Scheme 10. [ka] Scheme 10: Synthesis of lactam (II).

[0091] Commercially available 5,6-dichloropyridin-3-amine 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) followed by trifluoroacetic acid in dichloromethane to give tert-butyl N-(5,6-dichloro-3-pyridyl)carbamate. Low temperature metallation reaction between n-BuLi and tert-butyl N-(5,6-dichloro-3-pyridyl)carbamate followed by regioselective organolithium formation by 1,2-addition to aldehyde (XVIII) affords secondary alcohols of formula (XIX). Subsequent oxidation to ketones (XX) using manganese dioxide followed by deprotection using an organic acid (e.g., trifluoroacetic acid in dichloromethane) affords aminopyridines of formula (XXI). Amides (XXIII) can be obtained by coupling with N-Boc protected L-amino acids by exposure to phosphoryl chloride (POCl3) in pyridine. 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 (XXIII). A final intramolecular condensation reaction driven by acidic media (e.g. silica in toluene or acetic acid in ethanol) and heat (80-110 °C) gives the desired lactam building blocks of formula (II).

[0092] Alternatively, compounds of formula (XXII) can be prepared according to the method described in Scheme 11. [ka] Scheme 11: R 4 Alternative synthesis of compound (XXII) where is CF3.

[0093] According to Scheme 11, commercially available pyridines (XXIV) can undergo Buchwald-Hartwig amination reactions with primary amides of formula (XXV) using a palladium catalyst (e.g., Pd2(dba)3), a suitable ligand (e.g., xantphos), and a base such as cesium carbonate. Amides (XXVI) can be deprotonated at low temperature (n-BuLi in tetrahydrofuran at -78 °C) and undergo 1,2-carbonyl addition reactions with commercially available aldehydes (XVIII) to give alcohols of formula (XXVII). Final oxidation to the corresponding ketones (XXII) can be achieved using TEMPO and sodium hypochlorite.

[0094] In particular, in the processes described in Schemes 1-11, 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 derivative of formula (I) is necessary to obtain a single enantiomer (enantiomeric excess (ee) >97%).

[0095] In one aspect, the present invention provides a method for preparing a compound of formula (I) described herein, the method being a method according to any one of Schemes 1-11 above.

[0096] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, when prepared according to the processes described herein.

[0097] Uses of the Compounds of the Invention As described in the Background section and exemplified in the Experimental section, the compounds of formula (I) and their pharma- ceutically acceptable salts have valuable pharmacological properties that are useful in the treatment or prevention of diseases or complications associated with the GABAA γ1 receptor.

[0098] In one aspect, the present invention provides a compound of formula (I), as described herein, or a pharma- ceutically acceptable salt thereof, for use as a therapeutically active substance.

[0099] In a further aspect, the present invention provides a method for 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) as described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0100] In a further aspect, the present invention provides the use of a compound of formula (I) 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.

[0101] In a further aspect, the present invention provides a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in a method for treating or preventing an acute neurological disorder, a chronic neurological disorder and / or a cognitive disorder in a subject.

[0102] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis or treatment of an acute neurological disorder, a chronic neurological disorder and / or a cognitive disorder.

[0103] In one embodiment, 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 symptoms 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 conduct disorder, and / or other conditions. disorder), Tourette's syndrome (TS), obsessive-compulsive disorder (OCD), acute stress disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), sleep disorder, 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 disorder, depression, chronic apathy, anhedonia, chronic fatigue, seasonal affective disorder, postpartum depression, sleepiness, sexual dysfunction, bipolar disorder, epilepsy and pain.

[0104] 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 cognitive symptoms associated with schizophrenia, bipolar disorder, autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), and fragile X disorder.

[0105] 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 cognitive symptoms associated with schizophrenia and post-traumatic stress disorder (PTSD).

[0106] 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.

[0107] 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.

[0108] In a particularly preferred embodiment, the acute neurological disorder, chronic neurological disorder and / or cognitive disorder is an autism spectrum disorder (ASD).

[0109] In a further particularly preferred embodiment, said acute neurological disorder, chronic neurological disorder and / or cognitive disorder is Angelman syndrome.

[0110] 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.

[0111] Pharmaceutical Compositions and Administration In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) 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.

[0112] In a further aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients for treating or preventing acute neurological disorders, chronic neurological disorders and / or cognitive disorders.

[0113] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicines (e.g., in the form of pharmaceutical preparations).The pharmaceutical preparations can be administered to the body orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, liquids, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories).However, administration can also be carried out parenterally, for example, intramuscularly or intravenously (e.g., in the form of injections or infusions).

[0114] The compound of formula (I) and its 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.

[0115] Suitable excipients for soft gelatine capsules are, by way of example, vegetable oils, waxes, fats, semisolid and liquid polyols etc.

[0116] Suitable excipients for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose etc.

[0117] Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils etc.

[0118] Suitable excipients for suppositories are, by way of example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0119] In addition, pharmaceutical preparations may contain preservatives, solubilizers, thickening substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents, or antioxidants. They may also contain still other therapeutically valuable substances.

[0120] The dosage can vary in a wide range and can of course be adapted to the individual requirements in each particular case. In general, for oral administration, a 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) per person will be appropriate, preferably divided into 1 to 3 individual dosages, which may be composed, for example, of the same amount. However, it is clear that the upper limit given in this specification can be exceeded in indicated cases. EXAMPLES

[0121] 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.

[0122] 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.

[0123] Unless otherwise stated, all reactions and intermediates were prepared under an argon atmosphere.

[0124] Example 1 (7S)-11,12-Dichloro-9-(2,6-difluorophenyl)-3,7-dimethyl-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene [ka]

[0125] a) tert-Butyl N-tert-butoxycarbonyl-N-(5,6-dichloro-3-pyridyl)carbamate To a mixture of 5,6-dichloropyridin-3-amine (10 g, 61.3 mmol) in tetrahydrofuran (100 mL) under nitrogen atmosphere was added N,N-diisopropylethylamine (3.97 g, 5.36 mL, 30.7 mmol), di-tert-butyl dicarbonate (33.5 g, 35.6 mL, 153 mmol) and 4-dimethylaminopyridine (750 mg, 0.848 ml, 6.13 mmol). The reaction mixture was stirred at room temperature for 18 h. Methyl tert-butyl ether (100 mL) was added and the organic layer was washed with aqueous sodium carbonate (1.0 m, 100 mL), water (150 mL) and brine (50 mL). The aqueous layer was extracted with methyl tert-butyl ether (2 x 50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give the title compound (23.9 g, 99%) as a light brown solid. MS: 363.2 ([{ 35 Cl, 35 Cl}M+H] + ),365.2([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0126] b) tert-Butyl N-(5,6-dichloro-3-pyridyl)carbamate To a pre-cooled solution (0° C.) of tert-butyl N-tert-butoxycarbonyl-N-(5,6-dichloro-3-pyridyl)carbamate (23.93 g, 65.9 mmol) in dichloromethane (226 mL) was slowly added trifluoroacetic acid (12 g, 8.12 ml, 105 mmol). The reaction mixture was stirred under nitrogen at 0° C. for 30 min and allowed to warm to room temperature overnight. The reaction mixture was quenched with sodium bicarbonate (1.0 m, 150 mL) and stirred for 15 min. The organic layer was washed with sodium bicarbonate (1.0 m, 200 mL). The aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (silica, 0-40% ethyl acetate in heptane) to give the title compound (10.5 g, 59%) as a pale yellow solid. MS:207.0([{ 35 Cl,35 Cl}M-C4H8-CO2+H] + ),209.1([{ 35 Cl, 37 Cl}M-C4H8-CO2+H] + ),ESI pos.

[0127] c) tert-Butyl N-[5,6-dichloro-4-[(2,6-difluorophenyl)-hydroxymethyl]-3-pyridyl]carbamate A solution of tert-butyl (5,6-dichloropyridin-3-yl)carbamate (10.47 g, 39.8 mmol) in anhydrous tetrahydrofuran (108 mL) was cooled to -70°C under nitrogen. n-BuLi (2.5 m in hexane, 35 ml, 87.5 mmol) was added dropwise and the mixture was stirred at -70°C for 30 min. 2,6-Difluorobenzaldehyde (6.79 g, 5.15 ml, 47.8 mmol) was added and the mixture was stirred at -70°C for 1 h. The reaction mixture was allowed to warm to -20°C before being quenched by the addition of saturated aqueous ammonium chloride (250 mL). The mixture was stirred at 0°C for 15 min, then more saturated aqueous ammonium chloride (60 mL) was added. The mixture was extracted twice with methyl tert-butyl ether, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 0-40% ethyl acetate in heptane) to give the title compound (9.21 g, 40%) as a yellow solid. MS: 405.2 ([{ 35 Cl, 35 Cl}M+H] + ),407.2([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0128] d) tert-Butyl N-[5,6-dichloro-4-(2,6-difluorobenzoyl)-3-pyridyl]carbamate To a solution of tert-butyl (5,6-dichloro-4-((2,6-difluorophenyl)(hydroxy)methyl)pyridin-3-yl)carbamate (9.21 g, 22.7 mmol) in dichloromethane (500 mL) under nitrogen was added manganese dioxide (22 g, 227 mmol). The reaction mixture was stirred at 50° C. for 3 h, filtered through dicalite, washed with dichloromethane and concentrated in vacuo. The residue was purified by flash chromatography (silica, 0-40% ethyl acetate in heptane) to give the title compound (9.06 g, 65%) as a pale yellow solid. MS: 347.0 ([{ 35 Cl, 35 Cl}M-C4H8-CO2+H] + ),ESI pos.

[0129] e) (5-amino-2,3-dichloro-4-pyridyl)-(2,6-difluorophenyl)methanone To a solution of tert-butyl N-[5,6-dichloro-4-(2,6-difluorobenzoyl)-3-pyridyl]carbamate (9.06 g, 22.5 mmol) in dichloromethane (50 mL) under nitrogen was added trifluoroacetic acid (25.6 g, 17.3 mL, 225 mmol). The reaction mixture was stirred at 25° C. for 3 h, then cooled to 0° C. (ice bath) and slowly quenched by the addition of aqueous sodium carbonate (1.0 m). The organic layer was washed with aqueous sodium carbonate (1.0 m), dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (silica, 0-50% ethyl acetate in heptane) to give the title compound (4.83 g, 55%) as a yellow solid. MS: 303.1 ([{ 35 Cl, 35 Cl}M+H] + ),305.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0130] f) tert-Butyl N-[(1S)-2-[[5,6-dichloro-4-(2,6-difluorobenzoyl)-3-pyridyl]amino]-1-methyl-2-oxoethyl]carbamate A solution of (5-amino-2,3-dichloro-4-pyridyl)-(2,6-difluorophenyl)methanone (49 g, 14.8 mmol) in pyridine (43.9 g, 44.9 ml, 556 mmol) was cooled to 0° C., followed by the addition of Boc-Ala-OH (4.76 g, 25.2 mmol) and phosphorus oxychloride (3.41 g, 2.07 mL, 22.2 mmol). The reaction mixture was stirred at 0° C. for 4 h and then quenched by the addition of aqueous sodium bicarbonate (1.0 m, 100 mL). The resulting mixture was extracted with methyl tert-butyl ether (2×100 mL) and the organic layer was washed with water (100 mL) and brine (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (silica, 0-20% ethyl acetate in heptane) to give the title compound (4.59 g, 55%) as an off-white foam. MS: 472.4 ([{ 35 Cl, 35 Cl}MH] + ),474.4([{ 35 Cl, 37 Cl}MH] + ),ESI neg.

[0131] g) (2S)-2-Amino-N-[5,6-dichloro-4-(2,6-difluorobenzoyl)-3-pyridyl]propanamide A mixture of tert-butyl N-[(1S)-2-[[5,6-dichloro-4-(2,6-difluorobenzoyl)-3-pyridyl]amino]-1-methyl-2-oxoethyl]carbamate (4.51 g, 9.51 mmol) and hydrochloric acid (4.0 m in 1,4-dioxane, 45 mL, 180 mmol) was stirred at room temperature for 2 h. After cooling to 0° C., methyl tert-butyl ether (50 mL) was added and the mixture was basified by addition of aqueous sodium bicarbonate (1.0 m, 250 mL). The aqueous layer was extracted with methyl tert-butyl ether (2×50 mL), dried (MgSO4), and concentrated in vacuo to give the title compound (3.15 g, 73%) as a light brown oil. MS: 374.1 ([{ 35 Cl, 35 Cl}M+H] + ),376.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0132] h) (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydropyrido[3,4-e][1,4]diazepin-2-one To a mixture of (2S)-2-amino-N-[5,6-dichloro-4-(2,6-difluorobenzoyl)-3-pyridyl]propanamide (3.31 g, 8.85 mmol) in toluene (100 mL) was added silica gel (40-63 μm, 15 g, 8.85 mmol). The reaction mixture was stirred at 100 °C for 6 h, then cooled to room temperature and diluted with ethyl acetate. The mixture was filtered and the silica gel was washed with ethyl acetate (300 mL). The solution was concentrated in vacuo and the residue was purified by flash chromatography (silica, 0-50% ethyl acetate in heptane) to give the title compound (2.36 g, 75%) as a yellow solid. MS: 356.1 ([{ 35 Cl, 35 Cl}M+H] + ),358.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0133] i) (7S)-11,12-dichloro-9-(2,6-difluorophenyl)-3,7-dimethyl-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene To a solution of (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydropyrido[3,4-e][1,4]diazepin-2-one (1.91 g, 5.36 mmol) in tetrahydrofuran (764 mL) was added acetyl hydrazide (795 mg, 10.7 mmol), bis(2-oxo-3-oxazolidinyl)phosphine chloride (2.73 g, 10.7 mmol) and sodium hydride (60%, 429 mg, 10.7 mmol) at 0° C. After stirring in a melting ice bath for 18 hours, the mixture was stirred at 60° C. for 3 hours. After cooling to room temperature, the reaction mixture was diluted with methyl tert-butyl ether (50 mL) and then treated with aqueous citric acid (5 wt %, 15 mL). After 15 min, the mixture was basified by the addition of aqueous sodium bicarbonate (1.0 m, 50 mL). The aqueous layer was extracted with methyl tert-butyl ether (2 x 50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (silica, 50-100% ethyl acetate in heptane) to give the racemic mixture (1.49 g, 70%). Approximately 130 mg of this mixture was purified by preparative HPLC (Reprosil Chiral NR, 0.1% aqueous ammonium acetate / heptane in ethanol) to give the enantiopure (-)-title compound (78 mg, 60%) as an off-white foam. MS: 394.2 ([{ 35 Cl, 35 Cl}M+H] + ),396.2([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0134] Example 2 (7S)-11-Chloro-12-cyclopropyl-9-(2,6-difluorophenyl)-3,7-dimethyl-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene [ka]

[0135] To a solution of (7S)-11,12-dichloro-9-(2,6-difluorophenyl)-3,7-dimethyl-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene (93.8 mg, 0.238 mmol) in toluene (1 mL) was added cyclopropylboronic acid (22.5 mg, 0.262 mmol) and potassium phosphate (202 mg, 79 μL, 0.952 mmol). The vial was evacuated and backfilled with argon three times. Tricyclohexylphosphine (6.67 mg, 24 μmol) and palladium(II) acetate (2.67 mg, 12 μmol) were added, after which the vial was capped and backfilled with argon. The reaction mixture was stirred at 80 °C for 18 h. The reaction was cooled to room temperature and then filtered through a pad of Celite. The filter cake was rinsed with ethyl acetate and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica, 0-100% ethyl acetate in heptane) followed by preparative HPLC (Reprosil Chiral NR, 0.1% aqueous ammonium acetate / heptane in ethanol) to give the enantiopure (-)-title compound (17.5 mg, 18%) as a colorless oil. MS: 400.1 ([{ 35 Cl}M+H] + ),402.1([{ 37 Cl}M+H] + ),ESI pos.

[0136] Example 3 (7S)-11-Chloro-9-(2,6-difluorophenyl)-3,7,12-trimethyl-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene [ka]

[0137] To a solution of (7S)-11,12-dichloro-9-(2,6-difluorophenyl)-3,7-dimethyl-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene (107 mg, 0.272 mmol) in 1,4-dioxane (1 mL) was added potassium carbonate (56.4 mg, 0.408 mmol). The vial was evacuated and backfilled with argon three times. After addition of tetrakis(triphenylphosphine)palladium(0) (15.7 mg, 13.6 μmol) and trimethylboroxine (37.6 mg, 41.9 μL, 0.299 mmol), the vial was evacuated and backfilled with argon. The reaction mixture was stirred at 80 °C for 18 h. The reaction was cooled to room temperature and then filtered through a pad of Celite. The filter cake was rinsed with ethyl acetate and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica, 50-100% ethyl acetate in heptane, then 0-10% methanol in ethyl acetate) followed by preparative HPLC (Reprosil Chiral NR, 0.1% aqueous ammonium acetate / heptane in ethanol) to give the enantiopure (-)-title compound (54.6 mg, 67%) as an off-white foam. MS: 374.2 ([{ 35 Cl}M+H] + ),376.2([{ 37 Cl}M+H] + ),ESI pos.

[0138] Example 4 (7S)-11-Chloro-9-(2,6-difluorophenyl)-3,7-dimethyl-12-(trifluoromethyl)-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene [ka]

[0139] a) tert-Butyl N-[(1S)-2-[[5-chloro-6-(trifluoromethyl)-3-pyridyl]amino]-1-methyl-2-oxo-ethyl]carbamate To a solution of 3,5-dichloro-2-(trifluoromethyl)pyridine (5 g, 23.1 mmol) in 1,4-dioxane (74.9 mL) was added cesium carbonate (9.05 g, 27.8 mmol) and tert-butyl N-[(2S)-1-amino-1-oxopropan-2-yl]carbamate (5.23 g, 27.8 mmol). Argon was vigorously bubbled through the mixture. Xantphos (1.34 g, 2.31 mmol) and tris(dibenzylideneacetone)dipalladium (1.06 g, 1.16 mmol) were added and the reaction mixture was stirred at 100° C. for 17 h. The reaction mixture was diluted with dichloromethane and water. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (silica, 0-55% ethyl acetate in heptane) to give the title compound (6.34 g, 73%) as a white solid. MS: 368.0 ([{ 35 Cl}M+H] + ),370.0([{ 37 Cl}M+H] + ),ESI pos.

[0140] b) tert-Butyl N-[(1S)-2-[[5-chloro-4-[(2,6-difluorophenyl)-hydroxy-methyl]-6-(trifluoromethyl)-3-pyridyl]amino]-1-methyl-2-oxoethyl]carbamate In a similar manner to the experiment in Example 1c, tert-butyl N-[(1S)-2-[[5-chloro-6-(trifluoromethyl)-3-pyridyl]amino]-1-methyl-2-oxo-ethyl]carbamate was converted to the title compound (8.78 g, 100%) as an orange solid. MS: 510.2 ([{ 35 Cl}M+H] + ),512.2([{ 37 Cl}M+H] + ),ESI pos.

[0141] c) tert-Butyl N-[(1S)-2-[[5-chloro-4-(2,6-difluorobenzoyl)-6-(trifluoromethyl)-3-pyridyl]amino]-1-methyl-2-oxoethyl]carbamate To a solution of tert-butyl N-[(1S)-2-[[5-chloro-4-[(2,6-difluorophenyl)-hydroxy-methyl]-6-(trifluoromethyl)-3-pyridyl]amino]-1-methyl-2-oxoethyl]carbamate (8.76 g, 15.3 mmol) in dichloromethane (102 mL) and water (102 mL) was added potassium bromide (2.73 g, 22.9 mmol), sodium bicarbonate (514 mg, 6.12 mmol) and TEMPO (239 mg, 1.53 mmol) at 0 °C. Finally, aqueous sodium hypochlorite (10-15 wt%, 16 ml, 26 mmol) was added dropwise and the reaction mixture was stirred at 0 °C for 2 h. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium carbonate and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (silica, 0-30% ethyl acetate in heptane) to give the title compound (4.99 g, 63%) as a white solid. MS m / e: 508.1 ([{ 35 Cl}M+H] + ),510.1([{ 37 Cl}M+H] + ),ESI pos.

[0142] d) (2S)-2-Amino-N-[5-chloro-4-(2,6-difluorobenzoyl)-6-(trifluoromethyl)-3-pyridyl]propanamide In a similar manner to the experiment in Example 1g, tert-butyl N-[(1S)-2-[[5-chloro-4-(2,6-difluorobenzoyl)-6-(trifluoromethyl)-3-pyridyl]amino]-1-methyl-2-oxoethyl]carbamate was converted to the title compound (3.36 g, 100%) as a brown oil. MS: 406.0 ([{ 35 Cl}MH] + ),408.1([{ 37 Cl}MH] + ),ESI neg.

[0143] e) (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepin-2-one In a similar manner to the experiment in Example 1h, (2S)-2-amino-N-[5-chloro-4-(2,6-difluorobenzoyl)-6-(trifluoromethyl)-3-pyridyl]propanamide was converted to the title compound (2.84 g, 87%) as a yellow solid. MS: 390.0 ([{ 35 Cl}M+H] + ),392.0([{ 37 Cl}M+H] + ),ESI pos.

[0144] f) (7S)-11-chloro-9-(2,6-difluorophenyl)-3,7-dimethyl-12-(trifluoromethyl)-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene As in the experiment of Example 1h, (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepin-2-one was converted to the enantiopure (-)-title compound (118 mg, 49%) as a pale yellow solid. MS: 428.2 ([{35 Cl}M+H] + ),430.1([{ 37 Cl}M+H] + ),ESI pos.

[0145] Example 5 (7S)-11-Chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene [ka]

[0146] a) (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepine-2-thione To a mixture of (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepin-2-one (598 mg, 1.53 mmol) in toluene (10 mL) and 1,4-dioxane (10 mL) was added Lawesson's reagent (372 mg, 0.920 mmol). The yellow suspension was stirred at 90° C. for 29 h. After an additional amount of Lawesson's reagent (372 mg, 0.920 mmol) was added, the mixture was stirred for 68 h. The reaction mixture was cooled to room temperature and then filtered through 20 g of silica gel. The filter cake was rinsed with toluene (2×20 mL) and ethyl acetate (3×20 mL). The filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica, 0-25% ethyl acetate in heptane) to give the title compound (416 mg, 65%) as a yellow solid. MS: 404.2 ([{ 35 Cl}MH] + ),406.1([{ 37 Cl}MH] + ),ESI neg.

[0147] b) (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-3H-pyrido[3,4-e][1,4]diazepin-2-amine To a solution of (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepine-2-thione (124 mg, 0.306 mmol) in tetrahydrofuran (1.84 mL) and methanol (0.707 mL) was added ammonia in methanol (7.0 m, 3.27 ml, 22.9 mmol). The reaction mixture was stirred at 50° C. for 15 hours. The reaction mixture was concentrated in vacuo and used directly in the next step without further purification. MS: 387.1 ([{ 35 Cl}MH] + ),389.0([{ 37 Cl}MH] + ),ESI neg.

[0148] c) (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene A mixture of (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-3H-pyrido[3,4-e][1,4]diazepin-2-amine (154 mg, 0.396 mmol) and triethyl orthoacetate (352 mg, 0.398 mL, 2.06 mmol) was stirred at 150° C. for 10 minutes. The reaction mixture was concentrated under high vacuum to give a brown oil. The residue was dissolved in methanol (1 mL) and then ammonia in methanol (7.0 m, 57 μL, 0.396 mmol) was added and the reaction was stirred for 25 minutes. The reaction mixture was concentrated in vacuo and the residue was dissolved in methanol (1 mL). Sodium hypochlorite solution (448 mg, 0.372 mL, 0.904 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 30 minutes, then diluted with water and extracted with dichloromethane. The organic layers were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (silica, 0-30% ethyl acetate in heptane) followed by SFC (Chiralcel OD-H, 5% isopropanol) to give the enantiopure (-)-title compound (8 mg, 6%) as a pale yellow solid. MS m / e: 426.1 ([{ 35 Cl}M+H] + ),428.1([{ 37 Cl}M+H] + ),ESI pos.

[0149] Example 6 Azetidin-1-yl-[(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]methanone [ka]

[0150] a) (3S)-1-amino-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-3H-pyrido[3,4-e][1,4]diazepin-2-one To a solution of (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepin-2-one (800 mg, 2.05 mmol) in N,N-dimethylformamide (20.5 ml) was added (aminooxy)diphenylphosphine oxide (586 mg, 2.46 mmol) and cesium carbonate (1.0 g, 3.08 mmol). The suspension was stirred at 0° C. for 2 h and then concentrated in vacuo. The residue was diluted with ethyl acetate (25 mL) and water (25 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (silica, 0-35% ethyl acetate in heptane) to give the title compound (445 mg, 54%) as a yellow solid. MS: 405.0 ([{ 35 Cl}M+H] + ), 407.0([{ 37 Cl}M+H] + ),ESI pos.

[0151] b) Ethyl (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylate To a solution of (3S)-1-amino-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-3H-pyrido[3,4-e][1,4]diazepin-2-one (386 mg, 0.954 mmol) in toluene (2 mL) was added a solution of ethyl 2-ethoxy-2-iminoacetate (415 mg, 2.86 mmol) in toluene (3.2 mL). The reaction mixture was stirred at 80° C. for 2 hours and then at 120° C. for 2 hours. At this point, p-TsOH monohydrate (181 mg, 0.954 mmol) was added and the reaction mixture was stirred at 120° C. for 23 hours. An additional amount of ethyl 2-ethoxy-2-iminoacetate (138 mg, 0.954 mmol) in toluene (0.8 mL) was added and the reaction was stirred for 4 hours. Finally, further amounts of p-TsOH monohydrate (181 mg, 0.954 mmol) and ethyl 2-ethoxy-2-iminoacetate (138.44 mg, 0.954 mmol) in toluene (0.5 mL) were added and the reaction was stirred at 120° C. overnight. Ethyl acetate (20 mL) and saturated aqueous NaHCO3 (20 mL, diluted 1:1 with water) were added. The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with brine (3×40 mL), dried (Na2SO4) and concentrated in vacuo. The residue (706 mg, brown oil) was purified by preparative HPLC (Gemini NX, 0.1% formic acid in water / acetonitrile) to give the title compound (149 mg, 32%) as a light brown foam. MS: 486.2 ([{ 35 Cl}M+H] + ),488.2([{ 37 Cl}M+H] + ),ESI pos.

[0152] c) (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylic acid To a solution of ethyl (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylate (35 mg, 0.072 mmol) in methanol (0.5 mL) was added sodium hydroxide (11.5 mg, 0.288 mmol). The reaction mixture was stirred at room temperature for 1.5 h and then acidified with aqueous hydrochloric acid (1.0 m, 2 mL). The aqueous layer was extracted with dichloromethane (3×5 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the title compound (28 mg, 83%) as a yellow solid. The compound was used directly in the next step without further purification. MS: 458.1 ([{ 35 Cl}M+H] + ),460.0([{ 37 Cl}M+H] + ),ESI pos.

[0153] d) Azetidin-1-yl-[(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]methanone To a solution of (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylic acid (28 mg, 0.061 mmol) in N,N-dimethylformamide (0.5 mL) was added azetidine hydrochloride (17.17 mg, 0.184 mmol), HATU (27.91 mg, 0.073 mmol) and DIPEA (39.53 mg, 53.27 uL, 0.306 mmol). The reaction mixture was stirred at 40° C. for 16 hours and then at 70° C. for 4 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (5 mL) and washed with water (2×5 mL). The aqueous phase was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (silica, 40-100% ethyl acetate in heptane) followed by SFC (Chiralcel OD-H, 20% methanol) to give the enantiopure (-)-title compound (3 mg, 3%) as a white solid. MS: 497.2 ([{ 35 Cl}M+H] + ),499.2([{ 37 Cl}M+H] + ),ESI pos.

[0154] Example 7 [(7S)-11-Chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(3-fluoroazetidin-1-yl)methanone [ka]

[0155] A mixture of 3-fluoroazetidine hydrochloride (230 mg, 2.06 mmol) and sodium carbonate (218 mg, 2.06 mmol) in ethanol (5 mL) was stirred at 15° C. for 10 min. Then, ethyl (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylate (200 mg, 0.41 mmol) was added. The reaction mixture was stirred at 50° C. for 12 h and then cooled to room temperature. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative HPLC (Waters Xbridge, 0.05% aqueous ammonia / acetonitrile) followed by SFC (Daicel Chiralpak AS, methanol containing 0.1% aqueous ammonia) to give the enantiopure (-)-title compound (55 mg, 17%) as a white solid. MS: 515.1 ([{ 35 Cl}M+H] + ),517.1([{ 37 Cl}M+H] + ),ESI pos.

[0156] Example 8 [(7S)-11-Chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(3-hydroxyazetidin-1-yl)methanone [ka]

[0157] Analogously to the experiment in Example 7, ethyl (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylate was converted to the enantiopure (-)-title compound (24 mg, 2%) as a white solid using 3-hydroxyazetidine hydrochloride instead of 3-fluoroazetidine hydrochloride. MS: 513.0 ([{ 35 Cl}M+H] + ),515.0([{ 37 Cl}M+H] + ),ESI pos.

[0158] Example 9 [(7S)-11-Chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(3-methoxyazetidin-1-yl)methanone [ka]

[0159] As in the experiment of Example 7, ethyl (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylate was converted to the enantiopure (-)-title compound (25 mg, 6%) as a white solid using 3-methoxyazetidine hydrochloride instead of 3-fluoroazetidine hydrochloride and trimethylamine instead of sodium carbonate. MS: 527.0 ([{ 35 Cl}M+H] + ),529.0([{ 37 Cl}M+H] + ),ESI pos.

[0160] Example 10 [(7S)-11-Chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(3-hydroxy-3-methyl-azetidin-1-yl)methanone [ka]

[0161] As in the experiment of Example 7, ethyl (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylate was converted to the enantiopure (-)-title compound (54 mg, 16%) as a white solid using 3-methylazetidin-3-ol hydrochloride instead of 3-fluoroazetidine hydrochloride and trimethylamine instead of sodium carbonate. MS: 527.2 ([{ 35 Cl}M+H] + ),529.2([{ 37 Cl}M+H] + ),ESI pos.

[0162] Example 11 [(7S)-11-Chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(1,1-dioxo-1,4-thiazinane-4-yl)methanone [ka]

[0163] To a mixture of (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylic acid (110 mg, 0.290 mmol) in N,N-dimethylformamide (2.0 mL) was added benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 150 mg, 0.290 mmol), thiomorpholine 1,1-dioxide hydrochloride (124 mg, 0.720 mmol) and DIPEA (0.25 mL, 1.44 mmol). The reaction mixture was stirred at room temperature for 16 h and then purified by preparative HPLC (Waters Xbridge, 10 mM ammonium bicarbonate in water / acetonitrile) followed by SFC (Daicel Chiralpak AS, 0.1% aqueous ammonia in methanol) to give the enantiopure (-)-title compound (19.0 mg, 13%) as an off-white solid. MS: 575.1 ([{ 35 Cl}M+H] + ),577.1([{ 37 Cl}M+H] + ),ESI pos.

[0164] Example 12 N-[(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]oxetane-3-carboxamide [ka]

[0165] a) tert-Butyl N-[(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]carbamate To a mixture of (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylic acid (950 mg, 2.08 mmol) and triethylamine (630 mg, 6.23 mmol) in 1,4-dioxane (10 mL) was slowly added diphenylphosphoryl azide (1.14 g, 4.15 mmol). The mixture was stirred at room temperature for 1 h and then at 50 °C for an additional 2 h. After the mixture was cooled to room temperature, tert-butanol (10 mL) was added. The reaction mixture was stirred at 100 °C for 16 h and then poured into water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4) and concentrated in vacuo. The residue was suspended in ethyl acetate and the precipitate was filtered. The filtrate was purified by flash chromatography (silica, 20-60% ethyl acetate in petroleum ether) to give the title compound (370 mg, 34%) as a light brown solid. MS: 473.1 ([{ 35 Cl}M-C4H8+H] + ),ESI pos.

[0166] b) (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-amine To a mixture of tert-butyl N-[(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]carbamate (370 mg, 0.70 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL) slowly. The mixture was stirred at room temperature for 1 h, and then saturated aqueous sodium bicarbonate (until pH was greater than 8) was added. The mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), and concentrated in vacuo to afford the title compound (298 mg, 99%) as a light brown solid, which was used directly in the next step without further purification. MS:429.0([{ 35 Cl}M+H] + ),ESI pos.

[0167] c) N-[(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]oxetane-3-carboxamide To a mixture of (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-amine (150.0 mg, 0.350 mmol) and oxetane-3-carboxylic acid (53.6 mg, 0.520 mmol) in pyridine (2 mL) was added phosphoryl chloride (0.05 mL, 0.520 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h, then poured into ice water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (3×10 mL) and brine (10 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by preparative HPLC (Waters Xbridge, 10 mM ammonium bicarbonate in water / acetonitrile), followed by preparative HPLC (Phenomenex Gemini-NX C18, 0.05% ammonia in water / acetonitrile) and finally SFC (Daicel Chiralcel OJ-H, 25% isopropanol) to give the enantiopure (-)-title compound (2.0 mg, 1%) as a white solid. MS: 513.1 ([{ 35 Cl}M+H] + ),515.1([{ 37 Cl}M+H] + ),ESI pos.

[0168] Example 13 1-[(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]pyrrolidin-2-one [ka]

[0169] a) 4-chloro-N-[(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]butanamide To a solution of (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-amine (130 mg, 0.30 mmol) and pyridine (757 mg, 5.36 mmol) in acetonitrile (10 mL) was added 4-chlorobutyryl chloride (812 mg, 10.2 mmol) slowly at −20° C. The mixture was stirred at −20° C. for 18 h and then concentrated in vacuo. The residue was diluted with ethyl acetate (10 mL), washed with water (3×5 mL), brine (5 mL), dried (Na2SO4) and concentrated in vacuo to give the title compound (200 mg, crude) as a brown oil, which was used directly in the next step without further purification. MS: 533.3 ([{ 35 Cl, 35 Cl}M+H] + ),ESI pos.

[0170] b) 1-[(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]pyrrolidin-2-one To a solution of 4-chloro-N-[(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]butanamide (200 mg, 0.38 mmol) in N,N-dimethylformamide (3 mL) was added triethylamine (0.26 mL, 1.88 mmol). The reaction mixture was stirred at 100° C. for 3 h, then poured into water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (3×10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate 0:1), followed by preparative HPLC (Waters Xbridge, 10 mM ammonium bicarbonate in water / acetonitrile) and then SFC (REGIS(s,s)WHELK-O1, 40% isopropanol) to give the enantiopure (-)-title compound (8.0 mg, 4%) as a white solid. MS: 497.1 ([{ 35 Cl}M+H] + ),499.1([{ 37 Cl}M+H] + ),ESI pos.

[0171] Example 14 (7S)-11-Chloro-9-(2,6-difluorophenyl)-N-[(2S)-2-hydroxypropyl]-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide [ka]

[0172] Analogously to the experiment in Example 7, ethyl (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylate was converted to the enantiopure (-)-title compound (13.0 mg, 8%) as a white solid using (2S)-1-aminopropan-2-ol instead of 3-fluoroazetidine hydrochloride. MS: 515.1 ([{ 35 Cl}M+H] + ),517.1([{ 37 Cl}M+H] + ),ESI pos.

[0173] Example 15 (7S)-11-Chloro-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide [ka]

[0174] a) (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylic acid To a solution of ethyl (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylate (450 mg, 0.93 mmol) in tetrahydrofuran (2.5 mL) was added triethylamine (2.5 mL, 17.9 mmol) and slowly saturated aqueous lithium bromide solution (2.5 mL). The reaction mixture was stirred at 15° C. for 2 h and then acidified with aqueous hydrochloric acid (1.0 m, 10 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), and concentrated in vacuo to give the title compound (400 mg, 94%) as a yellow solid. The compound was used directly in the next step without further purification. MS: 458.0 ([{ 35 Cl}M+H] + ),460.0([{ 37 Cl}M+H] + ),ESI pos.

[0175] b) (7S)-11-chloro-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide In a similar manner to the experiment in Example 6d, (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylic acid was converted to the enantiopure (-)-title compound (111 mg, 23%) as an off-white solid using 2-aminoethanol instead of azetidine hydrochloride. MS: 501.1 ([{ 35 Cl}M+H] + ),503.1([{ 37 Cl}M+H] + ),ESI pos.

[0176] Example 16 (7S)-11-Chloro-9-(2,6-difluorophenyl)-N-[(2R)-2-hydroxypropyl]-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide [ka]

[0177] Analogously to the experiment in Example 7, ethyl (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylate was converted to the enantiopure (-)-title compound (16 mg, 15%) as an off-white solid using (2R)-1-aminopropan-2-ol instead of 3-fluoroazetidine hydrochloride. MS: 515.4 ([{ 35 Cl}M+H] + ),517.4([{ 37 Cl}M+H] + ),ESI pos.

[0178] Example 17 (7S)-11-Chloro-9-(2-chloro-6-fluoro-phenyl)-3,7-dimethyl-12-(trifluoromethyl)-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene [ka]

[0179] a) tert-Butyl N-[(1S)-2-[[5-chloro-4-[(2-chloro-6-fluoro-phenyl)-hydroxy-methyl]-6-(trifluoromethyl)-3-pyridyl]amino]-1-methyl-2-oxo-ethyl]carbamate In a similar manner to the experiment in Example 1c, tert-butyl N-[(1S)-2-[[5-chloro-6-(trifluoromethyl)-3-pyridyl]amino]-1-methyl-2-oxo-ethyl]carbamate was converted to the title compound (2.2 g, 38%) as a yellow solid. MS: 510.2 ([{ 35 Cl, 35 Cl}M+H] + ),512.2([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0180] b) tert-Butyl N-[(1S)-2-[[5-chloro-4-(2-chloro-6-fluoro-benzoyl)-6-(trifluoromethyl)-3-pyridyl]amino]-1-methyl-2-oxo-ethyl]carbamate In a similar manner to the experiment in Example 1d, tert-butyl N-[(1S)-2-[[5-chloro-4-[(2-chloro-6-fluoro-phenyl)-hydroxymethyl]-6-(trifluoromethyl)-3-pyridyl]amino]-1-methyl-2-oxo-ethyl]carbamate was converted to the title compound (1.7 g, 85%) as a yellow solid. MS: 524.0 ([{ 35 Cl, 35 Cl}M+H] + ),526.0([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0181] c) (2S)-2-amino-N-[5-chloro-4-(2-chloro-6-fluoro-benzoyl)-6-(trifluoromethyl)-3-pyridyl]propanamide In a similar manner to the experiment in Example 1g, tert-butyl N-[(1S)-2-[[5-chloro-4-(2-chloro-6-fluorobenzoyl)-6-(trifluoromethyl)-3-pyridyl]amino]-1-methyl-2-oxoethyl]carbamate was converted to the title compound (1.3 g, 95%) as a yellow oil. MS: 423.9 ([{ 35 Cl, 35 Cl}M+H] + ),425.9([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0182] d) (3S)-6-chloro-5-(2-chloro-6-fluoro-phenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepin-2-one In a similar manner to the experiment in Example 1h, (2S)-2-amino-N-[5-chloro-4-(2-chloro-6-fluorobenzoyl)-6-(trifluoromethyl)-3-pyridyl]propanamide was converted to the title compound (420 mg, 34%) as a yellow oil. MS: 405.9 ([{ 35 Cl, 35 Cl}M+H] + ),407.9([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0183] e) (3S)-6-chloro-5-(2-chloro-6-fluoro-phenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepine-2-thione As in the experiment of Example 5a, (3S)-6-chloro-5-(2-chloro-6-fluoro-phenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepin-2-one was converted to the title compound (110 mg, 56%) as a yellow foam. MS: 421.9 ([{ 35 Cl, 35 Cl}M+H] +),423.9([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0184] f) (7S)-11-chloro-9-(2-chloro-6-fluoro-phenyl)-3,7-dimethyl-12-(trifluoromethyl)-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene To a mixture of (3S)-6-chloro-5-(2-chloro-6-fluoro-phenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepine-2-thione (100 mg, 0.24 mmol) in 1-butanol (0.5 mL) was added acetohydrazide (35.1 mg, 0.47 mmol). The reaction mixture was stirred at 120° C. for 16 h, then cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC (Waters Xbridge, 0.05% ammonia in water / acetonitrile) followed by SFC (Daicel Chiralcel OD, 0.1% ammonia in methanol) to give the enantiopure (-)-title compound (9.0 mg, 9%) as a pale yellow solid. MS: 444.1 ([{ 35 Cl, 35 Cl}M+H] + ),446.1([{ 35 Cl, 37 Cl}M+H] + ),ESI pos.

[0185] Example 18 (7S)-11-Chloro-9-(2,6-difluorophenyl)-4,7-dimethyl-12-(trifluoromethyl)-2,5,8,13-tetraazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene [ka]

[0186] a) 2-[(E / Z)-[6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepin-2-ylidene]amino]propan-1-ol To a mixture of sodium carbonate (180 mg, 1.7 mmol) in ethanol (7.2 mL) and water (3.6 mL) was added (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepine-2-thione (300 mg, 0.740 mmol) and 2-aminopropan-1-ol (111 mg, 1.48 mmol). The reaction mixture was stirred at 80° C. for 12 h and then concentrated in vacuo. The residue was purified by flash chromatography (C18, 0.1% formic acid in water / acetonitrile) to give the title compound (130 mg, 39%) as a yellow solid. MS: 447.0 ([{ 35 Cl}M+H] + ),449.0([{ 37 Cl}M+H] + ),ESI pos.

[0187] b) (7S)-11-chloro-9-(2,6-difluorophenyl)-4,7-dimethyl-12-(trifluoromethyl)-2,5,8,13-tetraazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene To a mixture of 2-[(E / Z)-[6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepin-2-ylidene]amino]propan-1-ol (110 mg, 0.250 mmol) and sodium bicarbonate (83 mg, 0.98 mmol) in dichloromethane (6 mL) was added Dess-Martin periodinane (157 mg, 0.370 mmol). The reaction mixture was stirred at room temperature for 1 h, then poured into water (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative HPLC (Waters Xbridge, 10 mM ammonium bicarbonate in water / acetonitrile) followed by SFC (Phenomenex-Cellulose-2, isopropanol) to give the enantiopure (-)-title compound (1.1 mg, 1%) as a white solid. MS: 427.1 ([{ 35 Cl}M+H] + ),429.1([{ 37 Cl}M+H] + ),ESI pos.

[0188] Example 19 (7S)-11-Chloro-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-7-methyl-12-(trifluoromethyl)-2,5,8,13-tetraazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide [ka]

[0189] a) [(3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-3H-pyrido[3,4-e][1,4]diazepin-2-yl]diphenyl phosphate To a mixture of (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepin-2-one (500 mg, 1.3 mmol) in tetrahydrofuran (5 mL) was added sodium hydride (103 mg, 2.6 mmol) portionwise at 0° C. The mixture was stirred for 15 min and then [chloro(phenoxy)phosphoryl]oxybenzene (517 mg, 2 mmol) was added slowly at 0° C. The reaction mixture was stirred for an additional 1 h at 0° C., diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (2×30 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate 3:1) to give the title compound (300 mg, 22%) as a yellow solid. MS:621.9([{ 35 Cl}M+H] + ),623.9([{ 37 Cl}M+H] + ),ESI pos.

[0190] b) ethyl 2-[[(3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-3H-pyrido[3,4-e][1,4]diazepin-2-yl]amino]-3-hydroxypropanoate To a solution of ethyl 2-amino-3-hydroxy-propanoate hydrochloride (409 mg, 2.4 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.34 mL, 2.4 mmol). The mixture was stirred at 15° C. for 20 min, then [(3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-3H-pyrido[3,4-e][1,4]diazepin-2-yl]diphenylphosphate (500 mg, 0.8 mmol) was added at −20° C. The reaction mixture was warmed to 15° C. and stirred for 16 h. The mixture was poured slowly into saturated aqueous ammonium chloride solution (50 mL) and diluted with water (50 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative TLC (silica, dichloromethane / methanol 20:1) to give the title compound (300 mg, 65%) as a yellow solid. MS: 505.0 ([{ 35 Cl}M+H] + ),507.0([{ 37 Cl}M+H] + ),ESI pos.

[0191] c) Ethyl (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,5,8,13-tetrazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylate Ethyl 2-[[(3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-3H-pyrido[3,4-e][1,4]diazepin-2-yl]amino]-3-hydroxypropanoate was converted to the title compound (100 mg, 33%) as a yellow solid in a similar manner to the experiment in Example 18b. MS: 485.0 ([{ 35 Cl}M+H] + ),487.0([{ 37 Cl}M+H] + ),ESI pos.

[0192] d) (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,5,8,13-tetrazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylic acid Ethyl (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,5,8,13-tetrazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylate was converted to the title compound (70 mg, 68%) as a yellow solid in a similar manner to the experiment in Example 15a. MS: 457.0 ([{ 35 Cl}M+H] + ),459.0([{ 37 Cl}M+H] + ),ESI pos.

[0193] e) (7S)-11-chloro-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-7-methyl-12-(trifluoromethyl)-2,5,8,13-tetraazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide In a similar manner to the experiment in Example 6d, (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,5,8,13-tetraazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylic acid was converted to the enantiopure (-)-title compound (1.0 mg, 2%) as a white solid using 2-aminoethanol instead of azetidine hydrochloride. MS: 500.1 ([{ 35 Cl}M+H] + ),502.1([{ 37 Cl}M+H] + ),ESI pos.

[0194] Example 20 (10S)-6-Chloro-8-(2,6-difluorophenyl)-10-methyl-5-(trifluoromethyl)-1,4,9,12-tetraazatetracyclo[9.6.0.02,7.013,17]heptadeca-2(7),3,5,8,11,13(17)-hexaene [ka]

[0195] a) 2-[(E / Z)-[6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepin-2-ylidene]amino]cyclopentanol To a mixture of sodium carbonate (240.3 mg, 2.27 mmol) in tert-butanol (5 mL) was added (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepine-2-thione (400 mg, 0.990 mmol), followed by 2-aminocyclopentanol (199 mg, 1.97 mmol). The reaction mixture was stirred at 100 °C for 12 h, then poured into water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (silica, 40-60% ethyl acetate in petroleum ether) to give the title compound (450 mg, 97%) as a yellow foam. MS: 473.1 ([{ 35 Cl}M+H] + ),475.1([{ 37 Cl}M+H] + ),ESI pos.

[0196] b) 2-[(E / Z)-[6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepin-2-ylidene]amino]cyclopentanone To a mixture of 2-[(E / Z)-[6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepin-2-ylidene]amino]cyclopentanol (300.0 mg, 0.630 mmol) in dichloromethane (6 mL) was added phenyl-lambda3-iododiyl diacetate (BAIB, 817 mg, 2.54 mmol) and (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO, 198 mg, 1.27 mmol). The reaction mixture was stirred at 30° C. for 4 hours, then poured into water and extracted with dichloromethane. The organic layer was concentrated in vacuo and the residue was purified by flash chromatography (C18, formic acid in water / acetonitrile) to give the title compound (140 mg, 0.30 mmol, 47%) as a yellow gum. MS: 471.1 ([{ 35 Cl}M+H] + ),473.1([{ 37 Cl}M+H] + ),ESI pos.

[0197] c) (10S)-6-chloro-8-(2,6-difluorophenyl)-10-methyl-5-(trifluoromethyl)-1,4,9,12-tetraazatetracyclo[9.6.0.02,7.013,17]heptadeca-2(7),3,5,8,11,13(17)-hexaene To a mixture of 2-[(E / Z)-[6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepin-2-ylidene]amino]cyclopentanone (140 mg, 0.30 mmol) in pyridine (2 mL) was added POCl3 (228 mg, 1.49 mmol). The reaction mixture was stirred at 25° C. for 1 h, then poured into ice water (10 mL) and extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative HPLC (Waters Xbridge, ammonia-containing water / acetonitrile) followed by SFC (REGIS(S,S)WHELK-O1, methanol) to give the enantiopure (-)-title compound (16 mg, 9%) as a white solid. MS: 453.1 ([{ 35 Cl}M+H] + ),455.1([{ 37 Cl}M+H] + ),ESI pos.

[0198] Example 21 (7S)-11-Chloro-9-(2,6-difluorophenyl)-N-(2-hydroxy-2-methyl-propyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide [ka]

[0199] Analogously to the experiment in Example 7, ethyl (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylate was converted to the enantiopure (-)-title compound (118 mg, 36%) as a white solid using 1-amino-2-methyl-propan-2-ol instead of 3-fluoroazetidine hydrochloride. MS: 529.2 ([{ 35 Cl}M+H] + ),531.2([{ 37 Cl}M+H] + ),ESI pos.

[0200] Example 22 (7S)-11-Chloro-9-(2,6-difluorophenyl)-N-[(1-hydroxycyclopropyl)methyl]-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide [ka]

[0201] Analogously to the experiment in Example 7, ethyl (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylate was converted to the enantiopure (-)-title compound (86 mg, 27%) as a yellow solid using 1-(aminomethyl)cyclopropanol instead of 3-fluoroazetidine hydrochloride. MS: 527.1 ([{ 35 Cl}M+H] + ),529.1([{ 37 Cl}M+H] + ),ESI pos.

[0202] Example 23 (7S)-11-Chloro-9-(2,6-difluorophenyl)-N-cis-(3-hydroxycyclobutyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide [ka]

[0203] As in the experiment of Example 6d, (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylic acid was converted to the enantiopure (-)-title compound (7.1 mg, 6%) as a yellow solid using cis-3-aminocyclobutanol hydrochloride instead of azetidine hydrochloride. MS: 527.1 ([{ 35 Cl}M+H] + ),529.1([{ 37 Cl}M+H] + ),ESI pos.

[0204] Example 24 (7S)-11-Chloro-9-(2,6-difluorophenyl)-N-trans-(3-hydroxycyclobutyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide [ka]

[0205] As in the experiment of Example 6d, (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylic acid was converted to the enantiopure (-)-title compound (27 mg, 11%) as an off-white solid using trans-3-aminocyclobutanol hydrochloride instead of azetidine hydrochloride. MS: 527.1 ([{ 35 Cl}M+H] + ),529.1([{ 37 Cl}M+H] + ),ESI pos.

[0206] 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.

[0207] Different GABA APellets harvested from HEK293F cells expressing receptor subtypes were resuspended in mannitol buffer pH 7.2-7.4 (0.29 M mannitol, 10 mM triethylamine, 10 mM acetic acid, 1 mM EDTA + protease inhibitors (20 tablets Complete, Roche Diagnostics, Cat. No. 05056489001, 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, and then the suspension was centrifuged at 1000 x g for 15 min at 4 °C (Beckman Avanti J-HC; rotor JS-4.2). The supernatant (S1) was transferred to a 2 L Schott flask and the pellet (P1) was resuspended to 175 mL with mannitol buffer. The resuspended pellet was transferred to a 250 mL Corning centrifuge beaker and centrifuged at 1500×g for 10 min at 4° C. (Beckman Avanti J-HC; rotor JS-4.2). The supernatant (S1) was then transferred to a 2 L Schott flask and the pellet was discarded. The supernatant (S1) was centrifuged in a 500 mL Beckman polypropylene centrifuge beaker at 15,000×g for 30 min at 4° C. (Beckman Avanti J-20XP; rotor JLA-10.500). The pellet (P2) was resuspended in mannitol buffer 1:1 and frozen at −80° C. The supernatant (S2) was centrifuged in a 100 mL Beckman polypropylene centrifuge tube at 48000×g for 50 min at 4° C. (Beckman Avanti J-20XP; rotor JA-18). The supernatant (S3) was discarded and the pellet (P3) was resuspended in 1:1 mannitol buffer. P2 and P3 protein concentrations were determined using the BIORAD Standard assay method with bovine serum albumin as standard and measured on a NANO-Drop1000. The membrane suspension was aliquoted (500 μL / tube) and stored at -80°C until required.

[0208] 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.

[0209] Radioligand binding assays were performed using 100 μL of cell membranes, 1.5 nM (α5β2γ1) or 20–30 nM (α1β2γ1, α2β2γ1) of [ 3 H]RO7239181, and [0.3–10000] × 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 the total binding. The assay was incubated at 4°C for 1 h to equilibrium, then the 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 10 mM potassium phosphate pH 7.4, 100 mM KCl binding buffer. After dehydration, radioactivity retained on the filters was detected by liquid scintillation counting. K i Values ​​were calculated using Excel-Fit (Microsoft) and are the average of duplicate determinations.

[0210] 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 iValues ​​were found to be 0.01 to 0.01. Compounds with a Ki (nM) of less than 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.

[0211] [ 3 H] Preparation of RO7239181, 6-chloro-5-(2,6-difluorophenyl)-7-methyl-1-(tritrithiomethyl)-3H-1,4-benzodiazepin-2-one [ka]

[0212] a) 5-chloro-2-methyl-3,1-benzoxazin-4-one A solution of 2-amino-6-chlorobenzoic acid (250 g, 1.46 mol) in acetic anhydride (1250 mL) was stirred at 140° C. for 2 h. The reaction mixture was concentrated in vacuo. The crude residue obtained was suspended in ethyl acetate (1000 mL), stirred for 30 min, filtered, and dried in vacuo to give the title compound (238 g, 84%) as a grey solid. 1 H NMR (DMSO-d6,400MHz): δ:7.80(app t,J=8.0Hz,1H),7.62(d,J=8.0Hz,1H),7.49(d,J=7.6Hz,1H),2.36(s,3H).

[0213] b) N-[3-chloro-2-(2,6-difluorobenzoyl)phenyl]acetamide To a solution of 5-chloro-2-methyl-3,1-benzoxazin-4-one (100 g, 511.2 mmol) and 2-bromo-1,3-difluorobenzene (118.4 g, 613.5 mmol) in tetrahydrofuran (1000 mL) was added i-PrMgCl·LiCl (1.3 m, 500 mL, 650 mmol) dropwise at −70 °C under nitrogen. The mixture was allowed to warm to room temperature within 1 h, quenched with saturated aqueous ammonium chloride (1500 mL) and extracted with ethyl acetate (2×1500 mL). The organic phase was washed with brine (2000 mL), dried (Na2SO4) and concentrated in vacuo. The residue was suspended in ethyl acetate (150 mL). The resulting suspension was stirred at room temperature for 20 min, filtered and dried in vacuo to give the title compound (113 g, 71%) as an off-white solid. 1 H NMR (DMSO-d6,400MHz): δ:9.85(s,1H),7.65-7.45(m,1H),7.40(t,J=7.2Hz,1H),7.38-7.34(m,2H),7.16(t,J=8.8Hz,2H),1.85(s,3H).

[0214] c) (2-amino-6-chlorophenyl)-(2,6-difluorophenyl)methanone To a solution of N-[3-chloro-2-(2,6-difluorobenzoyl)phenyl]acetamide (113 g, 364.9 mmol) in ethanol (250 mL) was added aqueous hydrochloric acid (12 m, 200 mL). The reaction mixture was stirred at 100° C. for 1 h and then diluted with ethyl acetate (1100 mL). The organic phase was washed with water (1100 mL), saturated aqueous sodium bicarbonate (1100 mL) and brine (1100 mL), dried over sodium sulfate and concentrated in vacuo. Petroleum ether (120 mL) was added to the crude product and the suspension was stirred at room temperature for 20 min. The solid was filtered and dried to give the title compound (88 g, 90%) as a yellow solid. 1 H NMR (DMSO-d6,400MHz): δ:7.62-7.56(m,1H),7.21-7.15(m,3H),6.83(d,J=7.6Hz,1H),6.74(s,2H),6.58(d,J=7.6Hz,1H).

[0215] d) (6-amino-3-bromo-2-chlorophenyl)-(2,6-difluorophenyl)methanone To a solution of (2-amino-6-chlorophenyl)-(2,6-difluorophenyl)methanone (88.0 g, 328.8 mmol) in dichloromethane (225 mL) and N,N-dimethylformamide (225 mL) was added 1-bromopyrrolidine-2,5-dione (64.4 g, 362 mmol) at 0° C. The reaction mixture was stirred at 30° C. for 1 h. The mixture was diluted with dichloromethane (600 mL), washed with water (500 mL) and brine (4×500 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate, 1:0 to 2:1). The solid was suspended in petroleum ether (200 mL) and stirred at room temperature for 20 min. The suspension was filtered and the solid was dried in vacuo to give the title compound (96.0 g, 84%) as a yellow solid. MS:345.9([{ 79 Br, 35 Cl}M+H] + ),347.8([{ 81 Br, 35 Cl or 79 Br, 37 Cl}M+H] + ),ESI pos.

[0216] e) 7-Bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one To a solution of (6-amino-3-bromo-2-chlorophenyl)-(2,6-difluorophenyl)methanone (25.0 g, 72.1 mmol) in pyridine (625 mL) was added ethyl 2-aminoacetate hydrochloride (70.5 g, 505 mmol). The reaction mixture was stirred at 135° C. for 36 h. The reaction mixture was concentrated in vacuo to remove pyridine. The residue was diluted with ethyl acetate (2000 mL), washed with aqueous HCl (1.0 m, 3×1500 mL), water (2000 mL) and brine (2×1000 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, petroleum ether / ethyl acetate 10:1 to 2:1) to give the title compound (10.1 g, 12%) as an off-white solid. MS: 385.0 ([{ 79 Br, 35 Cl}M+H] + ),ESI pos.

[0217] f) 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 (450 mg, 1.17 mmol), trimethylboroxine (205 mg, 228 μL, 1.63 mmol), potassium carbonate (242 mg, 1.75 mmol) and tetrakis(triphenylphosphine)palladium(0) (67.4 mg, 58.4 μmol). Degassed 1,4-dioxane (8.1 mL) and H2O (2.7 mL) were added and the vial was then capped. The suspension was reacted in a microwave at 130 °C for 30 min to achieve complete conversion. The mixture was evaporated, treated with saturated NaHCO3 (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%-40%-70%) to give the title compound (344 mg, 92%) as a pale yellow solid. MS(ESI): 321.1 ([M+H]+ ).

[0218] g) 6-chloro-5-(2,6-difluorophenyl)-7-methyl-1-(tritrithiomethyl)-3H-1,4-benzodiazepin-2-one [ in THF (200 μL) 3 To a solution of [H]methyl nosylate (1.85 GBq, 50 mCi, 0.61 μmol) was added the N-desmethyl precursor 6-chloro-5-(2,6-difluorophenyl)-7-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (0.43 mg, 1.34 μmol) dissolved in THF (200 μL) and 10 equivalents of sodium tert-butylate (0.5 m in THF, 13.4 μmol). After stirring at room temperature for 4 h, the reaction mixture was treated with HO, evaporated, and the crude product was purified by HPLC (X-Terra Prep RP-18, 10 × 150 mm, MeCN / HO (containing 5% MeCN) 40:60, 4 mL / min, 230 nm). The pure tritium-labeled compound was isolated by solid-phase extraction (Sep-Pak Plus C18) and eluted from the cartridge as an ethanol solution, yielding 1.6 GBq (43.2 mCi) of target compound with a radiochemical purity of >99% and a specific activity of 2.49 TBq / mmol (67.3 Ci / mmol) as determined by mass spectrometry (MS). The identity of the labeled compound was confirmed by HPLC (by co-injecting an unlabeled reference standard) and MS. MS: m / z=335 [M(H)+H] + (16%), 337 [M( 3 H)+H] + (0%), 339[M( 3 H2)+H] + (16%), 341 [M( 3 H3)+H] + (68%).

[0219] γ2-containing GABA A Membrane preparation and binding assays for subtypes GABA AThe affinity of compounds at γ2 subunit-containing receptors was determined by their affinity to HEK293F cells expressing human (transiently transfected) receptors of the composition α1β3γ2. 3 H]flumazenil (81.1 Ci / mmol; Roche) binding was measured by competition.

[0220] Different GABA A Pellets collected from HEK293F cells expressing the γ2 receptor subtype were resuspended in mannitol buffer, pH 7.2–7.4, and GABA A Cells expressing γ1 subunit-containing receptors were treated as above.

[0221] 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, typically less than 5% of total binding. Assays were incubated to equilibrium at 4°C for 1 h, filtered using a Packard harvester, and harvested onto GF / C unifilters (Packard) by washing with ice-cold wash buffer (50 mM Tris, pH 7.5). After dehydration, radioactivity retained on the filters was detected by liquid scintillation counting. i Values ​​were calculated using Excel-Fit (Microsoft) and are the average of duplicate determinations.

[0222] 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 to have a K value of more than 300. i Compounds having α1β3γ2 (nM) are most preferred. In a preferred embodiment, the compounds of the present invention are γ2 subunit-containing GABA receptor antagonists. ACompared 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 A 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]

[0223] GABA A Functional expression of the receptor: Preparation of Xenopus oocytes Xenopus laevis oocytes at maturation stages V–VI were treated with GABA A Oocytes prepared for RNA microinjection were purchased from Ecocyte, Kastrup-Rauxel, Germany, and stored at 20°C in modified Barth's medium (composition in mM: NaCl 88, KCl 1, NaHCO3 2.4, HEPES 10, MgSO4 0.82, CaNO3 0.33, CaCl2 0.33, pH = 7.5) until the experiment.

[0224] Microinjection of Xenopus oocytes Oocytes were seeded into 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. AGABA responses of appropriate size and maximal effect were obtained for the reference benzodiazepine positive allosteric modulators (PAMs) flunitrazepam, triazolam and midazolam at the receptor benzodiazepine (BZD) binding site. Oocytes were kept at 20°C in modified Barth's medium (composition in mM: NaCl 88, KCl 1, NaHCO3 4, HEPES 10, MgSO4 0.82, CaNO3 0.33, CaCl2 0.33, pH = 7.5) until the experiment.

[0225] 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 perfused with a solution containing (in mM) NaCl 90, KCl 1, HEPES 5, MgCl2 1, CaCl2 1 (pH 7.4). Oocytes were filled with a solution containing KCl 1 M + potassium 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, the maximum current response (EC 20 ) for 1.5 min. After another resting interval of 2.5 min, GABA was added again to elicit 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.

[0226] Each compound and concentration was tested in at least three oocytes. Different oocytes were used for different compound concentrations. The reference PAMs, flunitrazepam, triazolam and midazolam, inhibited α2β2γ1 GABA A It enhanced GABA-induced currents in oocytes expressing the receptor subtype by approximately 60%.

[0227] 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 extremes of the resulting "ratio traces" were designated as "GABA EC 20 The efficacy of the compound was taken as "fold increase" expressed as "% modulation of the agonist activity" (100*(fold increase-1)).

[0228] The results are shown in Table 2. [Table 2]

[0229] reference compound The benzodiazepine reference compounds (representative commercially available benzodiazepines) and reference thienodiazepines listed below were compared with GABA A Receptor α1β2γ1 and α2β2γ1 subtypes and GABA A Their affinity for the receptor subtype α1β3γ2 was tested, and the results are shown in Table 3. [ka] [Table 3]

[0230] RE-A is disclosed in Drug Design and Discovery (1993), 10(1), 45-55 (Synthesis and anticonvulsant activity of 1,3-dihydro-5-phenyl-2H-pyrido[3,4-e]-1,4-diazepin-2-ones).

[0231] Preparation of pharmaceutical compositions containing compounds of the invention A tablet containing a compound of formula (I) is prepared as follows. [Table 4]

[0232] Manufacturing procedure 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at 50℃. 3. Pass the granules through a suitable grinding device. 4. Add ingredient 5, mix for 3 minutes and compress in a suitable press.

[0233] Capsules containing a compound of formula (I) are prepared as follows. [Table 5]

[0234] 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.

[0235] The compound of formula I, lactose and cornstarch are mixed in a mixer first, then in a grinder.The mixture is returned to the mixer, talc is added therein and roughly mixed.The mixture is filled into a suitable capsule, for example a hard gelatin capsule, by machine.

[0236] An injectable solution containing a compound of formula (I) is prepared as follows. [Table 6]

Claims

1. Formula (I) 【Chemical 1】 (In the formula, 【Chemistry 2】 but, 【Chemistry 3】 is selected from R １ But hydrogen, C １ ~C ６ -Alkyl, hydroxy-C １ ~C ６ -alkyl-NH-C(O)- and groups 【Chemistry 4】 and R １ａ is hydrogen, or R １ and R １ａ together with the carbon atoms to which they are attached, ３ ~C １０ - forms a cycloalkyl, R １ｂ is hydrogen, halogen, hydroxy, oxo, C １ ~C ６ -Alkyl and C １ ~C ６ -alkoxy, R １ｃ is selected from hydrogen, hydroxy and oxo; R ２ But C １ ~C ６ - alkyl, R ３ is chloro or bromo, R ４ But halogen, C １ ~C ６ -Alkyl, halo-C １ ~C ６ -alkyl, and C ３ ~C １０ -cycloalkyl, R ５ is a halogen, L is a covalent bond, a carbonyl, —C(O)NH—, —NHC(O)—, and —CH ２ NHC(O)—; A is 3- to 14-membered heterocycloalkyl and C ３ ~C １０ -cycloalkyl) or a pharmaceutically acceptable salt thereof.

2. R １ But C １ ~C ６ -Alkyl, hydroxy-C １ ~C ６ -alkyl-NH-C(O)- and groups 【Chemistry 5】 and R １ａ is hydrogen, or R １ and R １ａ together with the carbon atoms to which they are attached, ３ ~C １０ - forms a cycloalkyl, R １ｂ , R １ｃ , A and L are as defined in claim 1; 2. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

3. R １ But C １ ~C ６ -Alkyl, hydroxy-C １ ~C ６ -alkyl-NH-C(O)- and groups 【Chemistry 6】 is selected from R １ｂ But C １ ~C ６ - alkyl, R １ｃ is hydroxy, L is carbonyl; A is a 3- to 14-membered heterocycle; 3. A compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof.

4. R １ 2-hydroxyethyl-NH—C(O)—, 2-hydroxypropyl-NH—C(O)—, methyl, and groups 【Chemistry 7】 is selected from R １ｂ is methyl, R １ｃ is hydroxy, L is carbonyl; A is azetidinyl; 4. A compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt thereof.

5. R ２ 5. The compound of formula (I) according to claim 4, or a pharmaceutically acceptable salt thereof, wherein is methyl.

6. R ３ 6. The compound of formula (I) according to claim 5, or a pharmaceutically acceptable salt thereof, wherein is chloro.

7. R ４ The compound of formula (I) according to claim 4, or a pharmaceutically acceptable salt thereof, wherein is halo-C 1 -C 6 alkyl.

8. R ４ is CF ３ 8. The compound of formula (I) according to claim 7, wherein:

9. R ５ 5. The compound of formula (I) according to claim 4, or a pharmaceutically acceptable salt thereof, wherein is fluoro.

10. R １ But C １ ~C ６ -Alkyl, hydroxy-C １ ~C ６ -alkyl-NH-C(O)- and groups 【Chemistry 8】 is selected from R １ｂ But C １ ~C ６ - alkyl, R １ｃ is hydroxy, R ２ But C １ ~C ６ - alkyl, R ３ But it's Chloro. R ４ But, Halo-C １ ~C ６ - alkyl, R ５ is a halogen, L is carbonyl; A is a 3- to 14-membered heterocycle; 2. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

11. R １ is methyl, 2-hydroxyethyl-NH—C(O)—, 2-hydroxypropyl-NH—C(O)—, and the group 【Chemistry 9】 is selected from R １ｂ is methyl, R １ｃ is hydroxy, R ２ is methyl, R ３ But it's Chloro. R ４ But CF ３ and R ５ But it is fluoro, L is carbonyl; A is azetidinyl; 11. A compound of formula (I) according to claim 10, or a pharmaceutically acceptable salt thereof.

12. The compound of formula (I) (7S)-11,12-dichloro-9-(2,6-difluorophenyl)-3,7-dimethyl-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene, (7S)-11-chloro-12-cyclopropyl-9-(2,6-difluorophenyl)-3,7-dimethyl-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene, (7S)-11-chloro-9-(2,6-difluorophenyl)-3,7,12-trimethyl-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene, (7S)-11-chloro-9-(2,6-difluorophenyl)-3,7-dimethyl-12-(trifluoromethyl)-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene, (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene, Azetidin-1-yl-[(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]methanone, [(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(3-fluoroazetidin-1-yl)methanone, [(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(3-hydroxyazetidin-1-yl)methanone, [(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(3-methoxyazetidin-1-yl)methanone, [(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(3-hydroxy-3-methyl-azetidin-1-yl)methanone, [(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone, N-[(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]oxetane-3-carboxamide, 1-[(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]pyrrolidin-2-one, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(2S)-2-hydroxypropyl]-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(2R)-2-hydroxypropyl]-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, (7S)-11-chloro-9-(2-chloro-6-fluoro-phenyl)-3,7-dimethyl-12-(trifluoromethyl)-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene, (7S)-11-chloro-9-(2,6-difluorophenyl)-4,7-dimethyl-12-(trifluoromethyl)-2,5,8,13-tetraazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-7-methyl-12-(trifluoromethyl)-2,5,8,13-tetraazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, (10S)-6-chloro-8-(2,6-difluorophenyl)-10-methyl-5-(trifluoromethyl)-1,4,9,12-tetraazatetracyclo[9.6.0.02,7.013,17]heptadeca-2(7),3,5,8,11,13(17)-hexaene, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-(2-hydroxy-2-methyl-propyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(1-hydroxycyclopropyl)methyl]-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-cis-(3-hydroxycyclobutyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, and (7S)-11-chloro-9-(2,6-difluorophenyl)-N-trans-(3-hydroxycyclobutyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide 2. The compound of formula (I) according to claim 1, selected from: or a pharmaceutically acceptable salt thereof.

13. The compound of formula (I) (7S)-11-chloro-9-(2,6-difluorophenyl)-3,7-dimethyl-12-(trifluoromethyl)-2,4,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene, [(7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(3-hydroxy-3-methyl-azetidin-1-yl)methanone, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(2S)-2-hydroxypropyl]-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(2R)-2-hydroxypropyl]-7-methyl-12-(trifluoromethyl)-2,3,5,8,13-pentaazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide, and (7S)-11-chloro-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-7-methyl-12-(trifluoromethyl)-2,5,8,13-tetraazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide 13. The compound of formula (I) according to claim 12, selected from: or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

15. The pharmaceutical composition of claim 14 for treating or preventing acute neurological disorders, chronic neurological disorders and / or cognitive disorders.

16. 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 symptoms 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 conduct disorder, and the like.

16. The pharmaceutical composition of claim 15, wherein the therapeutic effect is selected from: chronic apathy, anhedonia, chronic fatigue, seasonal affective disorder, postpartum depression, sleepiness, sexual dysfunction, bipolar disorder, epilepsy, and pain.

Images