Pyridodiazepine derivatives as GABAAγ1 PAM

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 the Invention The present invention relates to an organic compound useful for treatment or prevention in mammals, particularly a novel pyridodiazepine derivative showing activity as a GABAA γ1 receptor positive allosteric modulator (PAM), and thus useful for the treatment or prevention of GABAA γ1 receptor-related diseases or conditions.

Background Art

[0002] Background of the Invention Receptors for the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) are mainly divided into two classes: (1) GABAA receptors, which are members of the ligand-gated ion channel superfamily, and (2) GABAB receptors, which are members of the G-protein-coupled receptor family. The GABAA receptor complex, a membrane-bound heteropentameric protein polymer, is mainly composed of α, β, and γ subunits. The GABAA receptor is a ligand-gated chloride channel and a major mediator of inhibitory neurotransmission in the human brain. A There are 19 genes encoding the subunits of the GABAA receptor. In the most common stoichiometry, two α, two β, and one γ subunits assemble as a pentamer. The combination of GABAA subunits confers functional, circuit, and behavioral specificity. The GABAA receptor containing the γ1 subunit (GABAA γ1) has attracted particular attention due to its abundant expression in the limbic system and its unique physiological and pharmacological properties. The GABAA receptor containing the γ1 subunit is less abundant (GABAA in the brain B receptors, which are members of the G-protein-coupled receptor family. The GABAA receptor complex, a membrane-bound heteropentameric protein polymer, is mainly composed of α, β, and γ subunits. The GABAA receptor is a ligand-gated chloride channel and a major mediator of inhibitory neurotransmission in the human brain. A There are 19 genes encoding the subunits of the GABAA receptor. In the most common stoichiometry, two α, two β, and one γ subunits assemble as a pentamer. The combination of GABAA subunits confers functional, circuit, and behavioral specificity. The GABAA receptor containing the γ1 subunit (GABAA γ1) has attracted particular attention due to its abundant expression in the limbic system and its unique physiological and pharmacological properties. The GABAA receptor containing the γ1 subunit is less abundant (GABAA in the brain A receptors, which are members of the G-protein-coupled receptor family. The GABAA receptor complex, a membrane-bound heteropentameric protein polymer, is mainly composed of α, β, and γ subunits. The GABAA receptor is a ligand-gated chloride channel and a major mediator of inhibitory neurotransmission in the human brain.

[0003] GABAA A There are 19 genes encoding the subunits of the GABAA receptor. In the most common stoichiometry, two α, two β, and one γ subunits assemble as a pentamer. The combination of GABAA subunits confers functional, circuit, and behavioral specificity. The GABAA receptor containing the γ1 subunit (GABAA γ1) has attracted particular attention due to its abundant expression in the limbic system and its unique physiological and pharmacological properties. The GABAA receptor containing the γ1 subunit is less abundant (GABAA in the brain A There are 19 genes encoding the subunits of the GABAA receptor. In the most common stoichiometry, two α, two β, and one γ subunits assemble as a pentamer. The combination of GABAA subunits confers functional, circuit, and behavioral specificity. The GABAA receptor containing the γ1 subunit (GABAA γ1) has attracted particular attention due to its abundant expression in the limbic system and its unique physiological and pharmacological properties. The GABAA receptor containing the γ1 subunit is less abundant (GABAA in the brain A receptors, which are members of the G-protein-coupled receptor family. The GABAA receptor complex, a membrane-bound heteropentameric protein polymer, is mainly composed of α, β, and γ subunits. The GABAA receptor is a ligand-gated chloride channel and a major mediator of inhibitory neurotransmission in the human brain. A γ1) has attracted particular attention due to its abundant expression in the limbic system and its unique physiological and pharmacological properties. The GABAA receptor containing the γ1 subunit is less abundant (GABAA in the brain A The GABAA receptor containing the γ1 subunit is less abundant (GABAA in the brain AReceptors containing the γ2 subunit, representing approximately 5–10% of total receptor expression, exhibit a concentrated brain mRNA and protein distribution in key brain regions such as the amygdala extension (central nucleus, medial nucleus, and bed nucleus of the stria terminalis), lateral septum, hypothalamus, and globus pallidus / substantia nigra. These structures form the interconnected core of the subcortical limbic circuit, which modulates motivated social and emotional behavior. In abnormal or diseased states, over-recruitment of this circuit promotes anxiety, arousal, aggression, fear, and defense, while inhibiting feeding and social interaction.

[0004] Increased activity in the limbic cortex (known to form a functional network in coordination with the amygdala extension / hypothalamic region), a crucial area for processing socially and emotionally relevant stimuli, is a common feature of various psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational, and metabolic disorders. In such disease states, GABA containing the γ1 subunit is present. A Considering the characteristic anatomical distribution of receptors, GABA A γ1-positive allosteric modulators (PAMs) may be effective treatments as symptomatic or disease-modifying agents.

[0005] Multiple pieces of evidence suggest that an imbalance in excitatory / inhibitory (E / I) neurotransmission resulting from dysfunction of the GABAergic signaling pathway, a major inhibitory neurotransmitter in the brain, lies at the core of the pathogenesis of various CNS disorders. A Considering the distribution and function of γ1 subunit-containing receptors, they are highly attractive targets for restoring inhibitory levels in key brain circuits, and consequently, highly attractive targets for restoring the E / I balance under these conditions.

[0006] In the context of this invention, a CNS disorder of particular interest is autism spectrum disorder (ASD), which includes core symptoms and associated comorbidities such as anxiety and irritability, 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 deficits and restricted / repetitive behaviors of ASD, inadequate treatment options are available for most of the emotional and physiological comorbidities of ASD. As a result, this disorder remains an area of ​​high medical need. Currently approved treatments for ASD-related symptoms are limited to antipsychotics (risperidone, aripiprazole) indicated for the treatment of hypersensitivity associated with ASD symptoms. Emerging evidence suggests that the GABAergic system, a major inhibitory neurotransmitter in the brain, plays a crucial 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 genes encoding γ1 and GABRG1 are α2, α4, and β1GABA. AIt is located on chromosome 4 (chromosome 5 in mice) within a cluster of genes encoding the receptor subunit. A rare CNV, including a chromosome 4p12 inversion disrupting GABRG1, has been observed in siblings with autism (Horike et al., 2006), and similarly in GABRG1 loss in one case of ADHD. Mutations in the 4p12 gene cluster are associated with an increased risk of anxiety, substance abuse, and eating disorders, providing a link between GABRG1 / 4p12 and emotional dysfunction. MRS studies have found altered GABA levels in ASD, and recent studies, in particular, have shown decreased GABA and altered somatosensory function in children with ASD. Consistent with these observations, a decrease in the number of inhibitory interneurons has been found in postmortem tissue from ASD and TS patients. Furthermore, reduced GABA synthases, glutamate decarboxylase (GAD) 65 and 67, have been found in the parietal and cerebellar cortices of patients with autism. Strong evidence in humans suggests that GABA A This points to specific dysfunction in limbic cortical regions in ASD, known to form functional networks in coordination with the γ1 subunit-containing amygdala extension / hypothalamic region. These regions—the cortical / lateral amygdala, insula, PFC, and cingulate cortex—are recognized as key to processing socially and emotionally relevant stimuli. Subcortical nuclei that form specific partnerships with these regions modulating behavioral outcomes are often difficult to study due to limitations in spatial resolution, but much evidence points to the over-recruitment of these cortical-subcortical connections in ASD. Furthermore, recent high-resolution studies have revealed a clear link between extended amygdala activity / functional connectivity and emotional states. Targeting such highly specific limbic cortical regions, which exhibit substantial molecular and cellular diversity compared to the neocortex, creates a precise entry point for safe and specific therapeutic modulation of ASD-affected social-emotional circuits while avoiding broader modulation of the overall brain state. GABA with non-selective BZD A While enhancing receptor activity has been shown to improve behavioral disorders in mouse models of ASD, GABA AIt was observed that the limits of therapeutic efficacy were very narrow due to sedation mediated by the α1γ2 subtype. These findings suggest that GABA A This supports the idea that rebalancing GABAergic signaling via γ1 receptors improves ASD symptoms without the side effects of non-selective benzodiazepine drugs. [Overview of the project] [Problems that the invention aims to solve]

[0009] The compound of the present invention, when given a concentration (e.g., EC10), 20 By increasing the GABAergic current (chloride inflow) with gamma-aminobutyric acid (GABA), γ1-containing GABA A Selective GABA that selectively enhances receptor function A The compound of the present invention is a γ1 receptor positive allosteric modulator (PAM). Compared to γ2-containing subtypes (e.g., α1γ2, α2γ2, α3γ2, and α5γ2), the compound of the present invention exhibits high PAM efficacy and binding selectivity for γ1-containing subtypes (α5γ1, α2γ1, α1γ1). Therefore, the compound of the present invention is a γ2-containing GABA A It is selective for certain subtypes and strongly distinguishes it from classic benzodiazepine drugs such as alprazolam, triazolam, estazolam, and midazolam, which have low affinity for γ1-containing subtypes. It is selective GABA adapted to the brain distribution of γ1 subtypes. A γ1PAM is a non-selective GABA A To restore GABAergic signaling in key brain regions (e.g., amygdala extension: central nucleus, medial nucleus and bed nucleus of the stria terminalis, lateral septum, hypothalamus and globus pallidus / substantia nigra) without the side effects of modulators (e.g., benzodiazepines).

[0010] Considering the above, the selective GABA described herein Aγ1PAM and their pharmaceutically acceptable salts and esters, alone or in combination with other drugs, are used to treat autism spectrum disorder (ASD), Angelman syndrome, age-related cognitive decline, Rett syndrome, Prader-Willi syndrome, amyotrophic lateral sclerosis (ALS), fragile X disorder, negative and / or cognitive symptoms associated with schizophrenia, tardive dyskinesia, anxiety, social anxiety disorder (sociophobia), panic disorder, agoraphobia, generalized anxiety disorder, and disruptive, impulse-control and conduct disorders. It is useful as a disease modifier or symptomatic agent for the treatment or prevention of acute neurological disorders, chronic neurological disorders and / or cognitive impairments, including bipolar disorder, Tourette syndrome (TS), obsessive-compulsive disorder (OCD), acute stress disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), sleep disorders, Parkinson's disease (PD), Huntington's disease, Alzheimer's disease (AD), mild cognitive impairment (MCI), dementia, behavioral and psychological symptoms in neurodegenerative states (BPS), polyinfarct dementia, agitation, psychosis, substance-induced psychotic disorders, aggression, eating disorders, depression, chronic apathy, anhedonia, chronic fatigue, seasonal affective disorder, postpartum depression, drowsiness, sexual dysfunction, bipolar disorder, epilepsy, and pain. [Means for solving the problem]

[0011] Summary of the Invention In the first aspect, the present invention relates to formula (I) [ka] (In the formula, the variable part is as defined herein.) The present invention provides compounds of or pharmaceutically acceptable salts thereof.

[0012] In one embodiment, the present invention provides a method for producing a compound of formula (I) as described herein, wherein the method is one of any one of schemes 1 to 11 as described herein.

[0013] In a further embodiment, the present invention provides compounds of formula (I) as described herein, when produced according to the method described herein.

[0014] In a further embodiment, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof for use as therapeutic active substances.

[0015] In a further embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, and a therapeutically inactive carrier.

[0016] In a further embodiment, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof for use in methods for treating or preventing acute neurological disorders, chronic neurological disorders and / or cognitive impairments of a subject. [Modes for carrying out the invention]

[0017] Detailed description of the invention definition Features, integers, characteristics, compounds, chemical parts, or groups described in connection with a particular aspect, embodiment, or example of the present invention should be understood to be applicable to any other aspect, embodiment, or example described herein, unless they are incompatible. All features disclosed herein (including any appended claims, abstract, and drawings) and / or all steps of any method or process disclosed herein may be combined in any combination, except for combinations in which at least some of such features and / or steps are mutually exclusive. The present invention is not limited to the details of any of the embodiments described herein. The present invention extends to any novel or novel combination of features disclosed herein (including any appended claims, abstract, and drawings), or any novel or novel combination of any steps of any method or process disclosed herein.

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

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

[0020] The term "halogen" or "halo" refers to fluoro(F), chloro(Cl), bromo(Br), or iodine(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] As used herein, the term "cycloalkyl" refers to a monocyclic or bicyclic hydrocarbon group having 3 to 10 ring carbon atoms, being saturated or partially unsaturated ("C3-C10"). 10"Cycloalkyl"). In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group having 3 to 8 ring carbon atoms. "Bicyclic cycloalkyl" refers to a cycloalkyl moiety consisting of two saturated carbon rings having two common carbon atoms, i.e., the bridging separating the two rings is either a single bond or a chain of one or two ring atoms, and a spirocyclic moiety, i.e., a cycloalkyl moiety in which the two rings are linked via one common ring atom. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group having 3 to 6 ring carbon atoms, e.g., 3, 4, 5, or 6 carbon atoms. Some non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and spiro[2.3]hexane-5-yl. Some preferred but non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, and cyclopentenyl.

[0022] The terms "heterocyclyl" or "heterocycloalkyl" refer to a saturated or partially unsaturated monocyclic or bicyclic ring system, preferably a monocyclic ring system, comprising 3 to 14 ring atoms, preferably 3 to 10 ring atoms, more preferably 3 to 8 ring atoms, wherein one, two, or three of the ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Preferably, one to two of the ring atoms are selected from N and O, and the remaining ring atoms are carbon. A "bicyclic heterocyclyl" refers to a heterocyclic portion consisting of two rings having two common ring atoms, i.e., a spirocyclic portion, i.e., a heterocyclic portion in which the two rings are joined via one common ring atom, where the bridging separating the two rings is either a single bond or a chain of one or two ring atoms. Some non-restrictive examples of heterocyclyl groups include azetidine-3-yl, azetidine-2-yl, oxetan-3-yl, oxetan-2-yl, piperidyl, piperazinyl, pyrrolidinyl, 2-oxopyrrolidine-1-yl, 2-oxopyrrolidine-3-yl, 5-oxopyrrolidine-2-yl, 5-oxopyrrolidine-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 Examples include azetidinyl, 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]hexane-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]pyrrole-5-yl. Some preferred but non-limiting examples of heterocyclyls are azetidinyl, oxetanyl, pyrrolidinyl, and thiomorpholino.

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

[0024] The term "oxo" refers to an oxygen atom bonded to the parent part via 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 a fluoro atom. 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 a fluoro atom. Non-limiting examples of haloalkyls are fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, 2-fluoroethyl, and 2,2-difluoroethyl. A particularly preferred but non-limiting example of a 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 hydroxyl group. Preferably, "hydroxyalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group, most preferably one hydrogen atom, are replaced by a hydroxyl group. Preferred but non-limiting examples of hydroxyalkyls 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 efficacy and properties of a free base or free acid, and is not biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, particularly hydrochloric acid, and with 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, and N-acetylcysteine. Furthermore, these salts can be prepared by adding an inorganic base or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, and magnesium salts. Examples of salts derived from organic bases include, but are not limited to, 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, and polyimine resins. Certain pharmaceutically acceptable salts of the compound of formula (I) are hydrochloride, fumarate, formate, lactate (especially derived from L-(+)-lactic acid), tartrate (especially derived from L-(+)-tartaric acid), and trifluoroacetate.

[0029] The compound of formula (I) may contain several chiral centers and may exist as an optically pure enantiomer, a mixture of enantiomers such as a racemate, an optically pure diastereoisomer, a mixture of diastereoisomers, a diastereoisomer racemate, or a mixture of diastereoisomer racemates.

[0030] According to the Cahn-Ingold-Prelog rule, an asymmetric carbon atom can have either an "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, stopping, reducing, or delaying the onset or recurrence of at least one clinical symptom or asymptomatic disease); and / or (2) alleviating a condition (i.e., causing a regression of at least one of the symptoms, disorder, or condition, or its clinical symptoms or asymptomatics). The benefit to the treated patient is either statistically significant or at least recognizable to the patient or physician. However, it will be understood that when a medicine is administered to a patient to treat a disease, the outcome does not necessarily have to be an effective treatment.

[0032] As used herein, the terms “prophylaxis” or “prevention” include, in particular, preventing or delaying the onset of clinical symptoms of a condition, disorder or condition in a person who is suffering from or susceptible to a condition, disorder or condition but has not yet experienced or shown any clinical symptoms or asymptomatic symptoms of that condition, disorder or condition.

[0033] As used herein, the term “subject” includes both humans and non-humans, and includes, but is not limited to, humans, non-human primates, dogs, cats, mice, cattle, horses, and pigs. In particularly preferred embodiments, the term “mammal” refers to humans.

[0034] The abbreviation uM stands for micromoles and is equivalent to the symbol μM.

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

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

[0037] Compound of the present invention In the first aspect, the present invention relates to formula (I) [ka] (In the formula, [ka] but, [ka] Selected from, R 1 However, hydrogen, C1~C6-alkyl, hydroxy-C1~C6-alkyl-NH-C(O)- and group [ka] Selected from, R 1a Is it hydrogen, or R 1 and R 1a However, together with the carbon atoms to which they are bonded, C3~C 10 -Forms a cycloalkyl group, R 1b However, these are selected from hydrogen, halogen, hydroxyl, oxo, C1-C6-alkyl and C1-C6-alkoxy, R 1c However, selected from hydrogen, hydroxyl, and oxo, R 2 However, it is C1-C6 alkyl, R 3 However, it is chloro or bromo, R 4 However, halogens, C1-C6-alkyls, halo-C1-C6-alkyls, and C3-C 10 - Selected from cycloalkyl, R 5 However, it is a halogen, L is selected from covalent bonds, carbonyl, -C(O)NH-, -NHC(O)-, and -CH2NHC(O)-. A is a 3-14 member heterocycloalkyl and C3-C 10 - Selected from cycloalkyl groups) The present invention provides compounds of or pharmaceutically acceptable salts thereof.

[0038] In a preferred embodiment, the present invention is [ka] but, [ka] The present specification provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, selected from the above.

[0039] In a particularly preferred embodiment, the present invention is [ka] but, [ka] This specification provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0040] In a particularly preferred embodiment, the present invention is [ka] but, [ka] This specification provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0041] In a particularly preferred embodiment, the present invention is [ka] but, [ka] This specification provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

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

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

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

[0045] In a preferred embodiment, the present invention is R 1 However, C1~C6-alkyl, hydroxy-C1~C6-alkyl-NH-C(O)- and group [ka] Selected from, R 1b However, it is C1-C6 alkyl, R 1c However, it is hydroxyl, L is a carbonyl group. The present specification provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is a 3- to 14-membered heterocycle.

[0046] In a particularly preferred embodiment, the present invention is R 1 However, 2-hydroxyethyl-NH-C(O)-, 2-hydroxypropyl-NH-C(O)-, methyl, and group [ka] Selected from, R 1b However, it is methyl, R 1c However, it is hydroxyl, L is a carbonyl group. The following provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is azetidinyl.

[0047] In a preferred embodiment, the present invention is R 1The following provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, wherein is hydroxy-C1-C6-alkyl-NH-C(O)-.

[0048] In a preferred embodiment, the present invention is R 1 The present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein is 2-hydroxy-NH-C(O)-.

[0049] In a preferred embodiment, the present invention is R 2 This specification provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, wherein the compound is methyl.

[0050] In a preferred embodiment, the present invention is R 3 This specification provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, wherein the compound is chloro.

[0051] In a preferred embodiment, the present invention is R 4 This specification provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, wherein is a haloalkyl compound.

[0052] In a particularly preferred embodiment, the present invention is R 4 This specification provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein CF3 is present.

[0053] In one embodiment, the present invention is R 5 This specification provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, wherein is a halogen.

[0054] In one embodiment, the present invention is R 5 This specification provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, wherein is fluoro or chloro.

[0055] In a preferred embodiment, the present invention is R 5This specification provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, wherein the compound is fluoro.

[0056] In a preferred embodiment, the present invention is R 5 This specification provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, wherein the compound is chloro.

[0057] In a preferred embodiment, the present invention is R 1 However, C1~C6-alkyl, hydroxy-C1~C6-alkyl-NH-C(O)- and group [ka] Selected from, R 1b However, it is C1-C6 alkyl, R 1c However, it is hydroxyl, R 2 However, it is C1-C6 alkyl, R 3 However, it is Chlor, R 4 However, it is a halo-C1~C6-alkyl, R 5 However, it is a halogen, L is a carbonyl group. The present specification provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is a 3- to 14-membered heterocycle.

[0058] In a particularly preferred embodiment, the present invention is R 1 However, methyl, 2-hydroxyethyl-NH-C(O)-, 2-hydroxypropyl-NH-C(O)-, and group [ka] Selected from, R 1b However, it is methyl, R 1cHowever, it is hydroxyl, R 2 However, it is methyl, R 3 However, it is Chlor, R 4 However, it is CF3, R 5 However, it is fluoro, L is a carbonyl group. The following provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is azetidinyl.

[0059] In one embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (7S)-11,12-dichloro-9-(2,6-difluorophenyl)-3,7-dimethyl-2,4,5,8,13-pentazatricyclo[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-pentazatricyclo[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-pentazatricyclo[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-pentazatricyclo[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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene, Azethidine-1-yl-[(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-hexaen-4-yl]methanone, [(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-hexaen-4-yl]-(3-fluoroazetidine-1-yl)methanone, [(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-hexaen-4-yl]-(3-hydroxyazetidine-1-yl)methanone, [(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-hexaen-4-yl]-(3-methoxyazetidine-1-yl)methanone, [(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-hexaen-4-yl]-(3-hydroxy-3-methylazetidine-1-yl)methanone, [(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-hexaen-4-yl]-(1,1-dioxo-1,4-thiadinan-4-yl)methanone, N-[(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-hexaen-4-yl]oxetane-3-carboxamide, 1-[(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-hexaen-4-yl]pyrrolidine-2-one, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(2S)-2-hydroxypropyl]-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-carboxamide, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-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-carboxamide, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(2R)-2-hydroxypropyl]-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-carboxamide, (7S)-11-chloro-9-(2-chloro-6-fluorophenyl)-3,7-dimethyl-12-(trifluoromethyl)-2,4,5,8,13-pentazatricyclo[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-pentazatricyclo[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-pentazatricyclo[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-pentazatricyclo[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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide Selected from.

[0060] In preferred embodiments, the present invention provides a compound of formula (I) described herein, or a pharmaceutically 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-pentazatricyclo[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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(3-hydroxy-3-methylazetidine-1-yl)methanone, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(2S)-2-hydroxypropyl]-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-carboxamide, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-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-carboxamide, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(2R)-2-hydroxypropyl]-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-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 Selected from.

[0061] In particularly preferred embodiments, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, the compound of formula (I) being (7S)-11-chloro-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-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-carboxamide.

[0062] In particularly preferred embodiments, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, the compound of formula (I) being (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.

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

[0064] In particularly preferred embodiments, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, the compound of formula (I) being [(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-hexaen-4-yl]-(3-hydroxy-3-methylazetidine-1-yl)methanone.

[0065] In particularly preferred embodiments, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, the compound of formula (I) being (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(2S)-2-hydroxypropyl]-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-carboxamide.

[0066] In particularly preferred embodiments, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, the compound of formula (I) being (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(2R)-2-hydroxypropyl]-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-carboxamide.

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

[0068] In some embodiments, the compound of formula (I) is isotopically labeled by having incorporated therein one or more atoms replaced by atoms having different atomic masses or mass numbers. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Examples of isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as, for example 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 I, but are not limited thereto. Certain isotopically labeled compounds of formula (I), for example, those incorporating a radioisotope, are useful in the study of the tissue distribution of drugs and / or substrates. The radioisotopes tritium, i.e., 3 H and carbon-14, i.e., 14 C are particularly useful for this purpose in view of their ease of incorporation and means of immediate detection. For example, the compounds of formula (I) can be enriched to 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0069] Heavier isotopes, such as deuterium, 2 Substitution with H, for example, can increase metabolic stability, potentially leading to specific therapeutic benefits such as a longer in vivo half-life or a lower required dosage.

[0070] 11 C, 18 F, 15 O and 13 Substitution with positron-emitting isotopes such as 1N may be useful in positron emission tomography (PET) studies to examine the receptor occupancy of a substrate. Compounds of formula (I) labeled with isotope can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the examples below, using a suitable isotope-labeled reagent instead of the previously used unlabeled reagent.

[0071] Manufacturing method Methods for producing the compound of formula (I) described herein are also an object of the present invention.

[0072] The preparation of compound A of formula (I) of the present invention may be carried out by 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 reaction and purification of the obtained products are known to those skilled in the art. The substituents and indices used in the following description of the method have the meaning shown previously herein and in the claims, unless otherwise indicated. More specifically, the compounds of formula (I) can be prepared by the method shown below, the method shown in the examples, or similar methods. Appropriate reaction conditions for each reaction step are known to those skilled in the art. For reaction conditions described in the literature that may affect the reactions described, see, for example, the following: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd edition, Richard C. Larock, John Wiley & Sons, New York, NY. 2018). The reactions can be carried out readily with or without a solvent. The properties of the solvent used are not particularly limited, as long as it does not adversely affect the reagents reacting or involved and can dissolve the reagents at least to some extent. The described reactions can occur over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. It is preferable to carry out the described reactions in a temperature range between -78°C and reflux temperature. The time required for the reaction can also vary considerably depending on many factors, particularly the reaction temperature and the properties of the reagents. However, it is usually sufficient to obtain the described intermediates and compounds within 0.5 hours to several days. 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 reactivity. Starting materials can be commercially available or prepared by methods similar to those shown below, by methods described in the references or examples cited herein, or by methods known in the art.

[0073] The preparation of compound A of formula (I) of the present invention may be carried out by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to react and purify the obtained products are known to those skilled in the art. The substituents and indices used in the following description of the method have the meanings set forth herein unless otherwise indicated.

[0074] More specifically, 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 each reaction step are known to those skilled in the art. The reaction sequence is not limited to those shown in schemes 1 to 11, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivity. 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 compound of formula (Ia) of the present invention and its pharmaceutically acceptable salts can be prepared by the method described in Scheme 1. [ka] Scheme 1: Synthesis of compound (Ia) as described above and in the claims.

[0076] According to Scheme 1, the compound of formula (Ia) can be prepared in one or two steps starting from the lactam of formula (II). After a thiolation reaction using Lawesson's reagent or P2S5, lactam(II) is converted to the corresponding thiolactam(III). Reaction of these with a hydrazide via a Pellizzari-type process yields 1,2,4-triazole of general formula (I). Alternatively, compound (Ia) can be obtained directly by the reaction of lactam(II) with hydrazide using bis(2-oxo-3-oxazolidinyl)phosphinate chloride (BOP-Cl) in the presence of a base (NaH) in tetrahydrofuran. [Chemical] Scheme 2: R 4 Synthesis of pyrido-diazepine (Ia) where R is Me or c-Pr.

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

[0078] The triazole of formula (Ib) can be prepared according to the method described in Scheme 3. [Chemical] Scheme 3: Synthesis of pyrido-diazepine of formula (Ib) where R 1 is Me as described above and in the claims.

[0079] According to Scheme 3, starting from thiolactam (III), 1,2,4-triazole (Ib) can be prepared by treating with ammonia in methanol to form amidine (V). The final derivative (Ib) was obtained following a sequential reaction with triethyl or trimethyl orthoacetate, treatment with ammonia in methanol, and a final ring closure reaction with sodium hypochlorite in water and methanol.

[0080] In a further embodiment of the present invention, the compound of formula (Ib) where R 1 is an amide can be prepared according to the method described in Scheme 4. [Chemical] Scheme 4: R as described above and in the claims. 1 Synthesis of pyridodiazepine of formula (Ib) where is an amide.

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

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

[0083] According to Scheme 5, heating carboxylic acid (VIII) with diphenyl phosphoryl azide in the presence of a base (e.g., Et3N) allows access to the N-protected triazole (IX) via Curtius rearrangement. Removal of the N-Boc protecting group can be achieved using a mineral acid (e.g., HCl) or an organic acid (e.g., trifluoroacetic acid) to obtain the amine of formula (X), which can then be converted to carboxylic acid R 8 The final derivative (Ib) can be obtained by coupling it with CO2H (for example, POCl3 in pyridine).

[0084] Furthermore, according to Scheme 6, 4-chlorobutanamide (XI) can be cyclized in the presence of a base (e.g., Et3N) to form the 5-membered lactam of formula (Ib).

Chemical formula

[0085] In a further embodiment of the present invention, the imidazole of formula (Ic) can be prepared according to the method described in Scheme 7. <--Deleted content:

Chemical formula

[0086] According to Scheme 7, the thiolactam (III) can be reacted with an amino alcohol of the general formula HOCH2CH(NH2)R 1 to form a substituted amidine (XII). The final compound (Ic) is obtained by a two-step synthesis involving Dess-Martin oxidation of the alcohol (XII) to the corresponding aldehyde followed by thermal cyclization.

Chemical formula

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

[0088] Alternatively, the imidazole of general formula (Ic) can be prepared via the ester intermediate (XV) detailed in Scheme 9. [ka] Scheme 9: R as described above and in the claims. 1 Synthesis of pyridodiazepine 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 then be converted into the amino alcohol HOCH2CH(NH2)R 1 By reacting with [another compound], amidine (XV) can be formed. Subsequent oxidation with Dess-Martin periodinane and subsequent thermocyclization yield ethyl ester (XVI). Finally, saponification to carboxylic acid (XVII) can be carried out using a saturated aqueous lithium bromide solution in the presence of a base (e.g., Et3N), and amide coupling with HATU and DIPEA yields 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-dichloropyridine-3-amine can be protected with a suitable protecting group such as tert-butyloxycarbonyl by treating it with di-tert-butyl dicarbonate in the presence of a base (e.g., diisopropylethylamine), followed by treatment with trifluoroacetic acid in dichloromethane to obtain tert-butyl N-(5,6-dichloro-3-pyridyl)carbamate. A low-temperature metallation reaction between n-BuLi and tert-butyl N-(5,6-dichloro-3-pyridyl)carbamate, followed by regioselective organolithium formation via 1,2-addition to aldehyde (XVIII), yields the secondary alcohol of formula (XIX). Subsequent oxidation to ketone (XX) using manganese dioxide, followed by deprotection using an organic acid (e.g., trifluoroacetic acid in dichloromethane), yields the aminopyridine of formula (XXI). The amide (XXIII) can be obtained by exposing it to phosphoryl chloride (POCl3) in pyridine and coupling it with an N-Boc protected L-amino acid. Removal of the N-Boc protecting group can be carried out using a mineral acid (e.g., HCl) or an organic acid (e.g., trifluoroacetic acid) to obtain the amine of formula (XXIII). The final intramolecular condensation reaction can be accelerated by an acidic medium (e.g., silica in toluene or acetic acid in ethanol) and heat (80-110°C) to obtain the desired lactam component of formula (II).

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

[0093] According to Scheme 11, commercially available pyridine (XXIV) can undergo a Buchwald-Hartwig amination reaction with the primary amide of formula (XXV) using a palladium catalyst (e.g., Pd2(dba)3), a suitable ligand (e.g., xanthophos), and a base such as cesium carbonate. The amide (XXVI) can be deprotonated at low temperature (n-BuLi in tetrahydrofuran at -78°C) and subjected to a 1,2-carbonyl addition reaction with commercially available aldehyde (XVIII) to obtain the alcohol of formula (XXVII). The final oxidation to the corresponding ketone (XXII) can be achieved using TEMPO and sodium hypochlorite.

[0094] In particular, in the processes described in schemes 1 to 11, racemization at the chiral center occurs to varying degrees (20-100%) depending on the specific reaction conditions adopted. As a result, chiral purification of the final derivative of formula (I) (e.g., by HPLC or SFC) is required to obtain a single enantiomer (with an enantiomer excess (ee) exceeding 97%).

[0095] In one embodiment, the present invention provides a method for producing a compound of formula (I) described herein, wherein the method is one of any one of schemes 1 to 11 described above.

[0096] In further embodiments, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, as prepared according to the methods described herein.

[0097] Use of the compound of the present invention As described in the background section and illustrated in the experimental section, the compounds of formula (I) and their pharmaceutically acceptable salts possess valuable pharmacological properties useful for the treatment or prevention of diseases or complications associated with the GABAA γ1 receptor.

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

[0099] In a further embodiment, the present invention provides a method for treating or preventing acute neurological disorders, chronic neurological disorders and / or cognitive impairments in a subject, comprising administering an effective amount of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, to the subject.

[0100] In a further embodiment, the present invention provides the use of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in a method for treating or preventing a target acute neurological disorder, chronic neurological disorder, and / or cognitive impairment.

[0101] In a further embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in methods for treating or preventing acute neurological disorders, chronic neurological disorders and / or cognitive impairments of a subject.

[0102] In a further embodiment, the present invention provides the use of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of acute neurological disorders, chronic neurological disorders and / or cognitive impairments.

[0103] In one embodiment, the acute neurological disorder, chronic neurological disorder, and / or cognitive disorder may be 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 (sociophobia), panic disorder, agoraphobia, generalized anxiety disorder, or disruptive, impulse-control and conduct disorder. The following conditions are selected: disorder, Tourette syndrome (TS), obsessive-compulsive disorder (OCD), acute stress disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), sleep disorders, Parkinson's disease (PD), Huntington's disease, Alzheimer's disease (AD), mild cognitive impairment (MCI), dementia, behavioral and psychological symptoms in neurodegenerative states (BPS), multiple infarct dementia, agitation, psychosis, substance-induced psychotic disorder, aggression, eating disorders, depression, chronic apathy, anhedonia, chronic fatigue, seasonal affective disorder, postpartum depression, drowsiness, sexual dysfunction, bipolar disorder, epilepsy, and pain.

[0104] In one embodiment, the acute neurological disorder, chronic neurological disorder, and / or cognitive disorder are 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 preferred embodiments, the acute neurological disorder, chronic neurological disorder, and / or cognitive disorder are selected from autism spectrum disorder (ASD), Angelman syndrome, Alzheimer's disease, negative symptoms and / or cognitive symptoms associated with schizophrenia, and post-traumatic stress disorder (PTSD).

[0106] In preferred embodiments, the acute neurological disorder, chronic neurological disorder, and / or cognitive disorder are selected from autism spectrum disorder (ASD), Rett syndrome, Angelman syndrome, post-traumatic stress disorder, and fragile X disorder.

[0107] In preferred embodiments, the acute neurological disorder, chronic neurological disorder, and / or cognitive impairment are 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 autism spectrum disorder (ASD).

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

[0110] In a 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 irritability, social anxiety disorder (social phobia), and generalized anxiety disorder.

[0111] Pharmaceutical composition and administration In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Exemplary pharmaceutical compositions are described in the following Examples section.

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

[0113] Compounds of formula (I) and their pharmaceutically acceptable salts may be used as pharmaceuticals (e.g., in the form of pharmaceutical formulations). Pharmaceutical formulations may be administered into the body orally (e.g., in the form of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, administration may also be carried out parenterally, for example, intramuscularly or intravenously (e.g., in the form of injections or infusions).

[0114] Compounds of formula (I) and their pharmaceutically acceptable salts can be treated with pharmaceutically inert inorganic or organic excipients for the manufacture 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 gelatin capsules include, for example, vegetable oils, waxes, fats and oils, semi-solids, and liquid polyols.

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

[0117] Suitable excipients for injection solutions include, for example, water, alcohol, polyol, glycerol, and vegetable oil.

[0118] Suitable excipients for suppositories include, for example, natural or hydrogenated oils, waxes, fats, and semi-solid or liquid polyols.

[0119] Furthermore, pharmaceutical formulations may contain preservatives, solubilizers, thickeners, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts to alter osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other substances of therapeutic value.

[0120] Dosages can vary over a wide range and, of course, can be adapted to the individual requirements of each specific case. Generally, for oral administration, a per capita dose 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), may be appropriately divided into 1 to 3 individual doses, each consisting of, for example, the same amount. However, it is clear that the upper limits given herein can be exceeded where indicated. [Examples]

[0121] The present invention will be better understood by referring to the following embodiments. However, the claims should not be construed as being limited to the scope of these embodiments.

[0122] If the preparation is obtained as a mixture 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 specified, all reaction examples 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-pentazatricyclo[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 Under a nitrogen atmosphere, a mixture of 5,6-dichloropyridine-3-amine (10 g, 61.3 mmol) in tetrahydrofuran (100 mL) was mixed with 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 hours. Methyl tert-butyl ether (100 mL) was added, and the organic layer was washed with aqueous sodium carbonate solution (1.0 m, 100 mL), water (150 mL), and brine (50 mL). The aqueous layer was extracted with methyl tert-butyl ether (2 × 50 mL). The combined organic layers were dried (MgSO4) and concentrated in a vacuum, yielding 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 Trifluoroacetic acid (12 g, 8.12 ml, 105 mmol) was slowly added 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). The reaction mixture was stirred under nitrogen at 0°C for 30 minutes and then warmed overnight to room temperature. The reaction mixture was quenched with sodium bicarbonate (1.0 m, 150 mL) and stirred for 15 minutes. 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 under vacuum. The residue was purified by flash chromatography (silica, heptane with 0-40% ethyl acetate) to obtain 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-dichloropyridine-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 mL, 35 mL, 87.5 mmol) in hexane was added dropwise, and the mixture was stirred at -70°C for 30 minutes. 2,6-difluorobenzaldehyde (6.79 g, 5.15 mL, 47.8 mmol) was added, and the mixture was stirred at -70°C for 1 hour. The reaction mixture was heated to -20°C and then quenched by adding saturated ammonium chloride aqueous solution (250 mL). The mixture was stirred at 0°C for 15 minutes, and then a further saturated ammonium chloride aqueous solution (60 mL) was added. The mixture was extracted twice with methyl tert-butyl ether, dried to (MgSO4), and concentrated under vacuum. When the crude product was purified by flash column chromatography (silica, heptane, 0-40% ethyl acetate), the title compound (9.21 g, 40%) was obtained 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 Under nitrogen, manganese dioxide (22 g, 227 mmol) was added to a solution of tert-butyl(5,6-dichloro-4-((2,6-difluorophenyl)(hydroxy)methyl)pyridine-3-yl)carbamate (9.21 g, 22.7 mmol) in dichloromethane (500 mL). The reaction mixture was stirred at 50 °C for 3 hours, filtered through dikalyte, washed with dichloromethane, and concentrated under vacuum. The residue was purified by flash chromatography (silica, heptane, 0-40% ethyl acetate) to obtain 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 Under nitrogen, trifluoroacetic acid (25.6 g, 17.3 mL, 225 mmol) was added 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). The reaction mixture was stirred at 25°C for 3 hours, then cooled to 0°C (ice bath) and slowly quenched by adding aqueous sodium carbonate (1.0 m). The organic layer was washed with aqueous sodium carbonate (1.0 m), dried (MgSO4), and concentrated under vacuum. The residue was purified by flash chromatography (silica, heptane, 0-50% ethyl acetate) to obtain 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 hours, 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), the organic layer was washed with water (100 mL) and brine (100 mL), dried, and concentrated under vacuum in (MgSO4). The residue was purified by flash chromatography (silica, heptane with 0-20% ethyl acetate) to obtain the title compound (4.59 g, 55%) as a grayish-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 hours. After cooling to 0°C, methyl tert-butyl ether (50 mL) was added, and the mixture was basicized by the addition of aqueous sodium bicarbonate solution (1.0 m, 250 mL). The aqueous layer was extracted with methyl tert-butyl ether (2 × 50 mL), dried to (MgSO4), and concentrated under vacuum to obtain 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]diazepine-2-one 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 mixed with silica gel (40-63 μm, 15 g, 8.85 mmol). The reaction mixture was stirred at 100 °C for 6 hours, 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 under vacuum, and the residue was purified by flash chromatography (silica, heptane, 0-50% ethyl acetate) to obtain 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-pentazatricyclo[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]diazepine-2-one (1.91 g, 5.36 mmol) in tetrahydrofuran (764 mL), acetylhydrazide (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) were added 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 solution (5% by weight, 15 mL). After 15 minutes, the mixture was basicized by adding an aqueous sodium bicarbonate solution (1.0 m, 50 mL). The aqueous layer was extracted with methyl tert-butyl ether (2 × 50 mL). The combined organic layers were dried (MgSO4) and concentrated under vacuum. The residue was purified by flash chromatography (silica, heptane, 50-100% ethyl acetate) to obtain a 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 solution / ethanol containing heptane) to obtain an enantiopurine (-)-title compound (78 mg, 60%) as a grayish-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-pentazatricyclo[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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene (93.8 mg, 0.238 mmol), cyclopropylboronic acid (22.5 mg, 0.262 mmol) and potassium phosphate (202 mg, 79 μL, 0.952 mmol) were added. The vial was evacuated and filled with argon three times. Tricyclohexylphosphine (6.67 mg, 24 μmol) and palladium(II) acetate (2.67 mg, 12 μmol) were added, the vial was capped, and filled with argon. The reaction mixture was stirred at 80°C for 18 hours. After cooling the reaction mixture to room temperature, it was filtered through a Celite pad. The filter cake was rinsed with ethyl acetate, and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography (silica, heptane, 0-100% ethyl acetate), followed by preparative HPLC (Reprosil Chiral NR, 0.1% aqueous ammonium acetate solution / ethanol containing heptane) to obtain an enantiopurine (-)-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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene [ka]

[0137] Potassium carbonate (56.4 mg, 0.408 mmol) was added to a solution of (7S)-11,12-dichloro-9-(2,6-difluorophenyl)-3,7-dimethyl-2,4,5,8,13-pentazatricyclo[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). The vial was evacuated and refilled with argon three times. After adding 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 refilled with argon. The reaction mixture was stirred at 80°C for 18 hours. After cooling the reaction mixture to room temperature, it was filtered through a Celite pad. The filter cake was rinsed with ethyl acetate, and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography (50-100% ethyl acetate in silica and heptane, followed by 0-10% methanol in ethyl acetate) and then by preparative HPLC (Reprosil Chiral NR, 0.1% aqueous ammonium acetate solution / ethanol containing heptane) to obtain an enantiopurine (-)-title compound (54.6 mg, 67%) as a grayish-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-pentazatricyclo[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), 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) were added. Argon was vigorously blown into the mixture. Xanthophos (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 hours. The reaction mixture was diluted with dichloromethane and water. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried and concentrated under vacuum in (Na2SO4). When the residue was purified by flash chromatography (silica, heptane, 0-55% ethyl acetate), the title compound (6.34 g, 73%) was obtained 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 Similar to the experiment in Example 1c, when 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%), it was obtained 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), potassium bromide (2.73 g, 22.9 mmol), sodium bicarbonate (514 mg, 6.12 mmol), and TEMPO (239 mg, 1.53 mmol) were added at 0°C. Finally, an aqueous sodium hypochlorite solution (10-15% by weight, 16 ml, 26 mmol) was added dropwise, and the reaction mixture was stirred at 0°C for 2 hours. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium carbonate and brine, dried to (Na2SO4), and concentrated under vacuum. The residue was purified by flash chromatography (silica, heptane with 0-30% ethyl acetate) to obtain 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 Similar 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 (3.36g, 100%), yielding 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]diazepine-2-one Similar 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%), which was obtained 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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene Similar to the experiment in Example 1h, (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepine-2-one was converted to the enantiopure (-)-title compound (118 mg, 49%), which was obtained 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-pentazatricyclo[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 Lawesson's reagent (372 mg, 0.920 mmol) was added to a mixture of (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepine-2-one (598 mg, 1.53 mmol) in toluene (10 mL) and 1,4-dioxane (10 mL). The yellow suspension was stirred at 90°C for 29 hours. After adding an additional amount of Lawesson's reagent (372 mg, 0.920 mmol), the mixture was stirred for 68 hours. After the reaction mixture cooled to room temperature, it was 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 under vacuum. When the residue was purified by flash chromatography (silica, heptane, 0-25% ethyl acetate), the title compound (416 mg, 65%) was obtained 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]diazepine-2-amine 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 mixed with ammonia in methanol (7.0 mL, 3.27 mL, 22.9 mmol). The reaction mixture was stirred at 50°C for 15 hours. The reaction mixture was concentrated under vacuum 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-pentazatricyclo[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]diazepine-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 obtain a brown oil. The residue was dissolved in methanol (1 mL), and then ammonia in methanol (7.0 mL, 57 μL, 0.396 mmol) was added, and the reaction mixture was stirred for 25 minutes. The reaction mixture was concentrated under vacuum, 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 under vacuum. The residue was purified by flash chromatography (silica, heptane, 0-30% ethyl acetate), followed by SFC (Chiralcel OD-H, 5% isopropanol) to obtain an enantiopurine (-)-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 Azethidine-1-yl-[(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-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]diazepine-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]diazepine-2-one (800 mg, 2.05 mmol) in N,N-dimethylformamide (20.5 ml), (aminooxy)diphenylphosphine oxide (586 mg, 2.46 mmol) and cesium carbonate (1.0 g, 3.08 mmol) were added. The suspension was stirred at 0°C for 2 hours and then concentrated under vacuum. 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, and concentrated under vacuum with (Na₂SO₄). When the residue was purified by flash chromatography (silica, heptane, 0-35% ethyl acetate), the title compound (445 mg, 54%) was obtained 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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylate A solution of (3S)-1-amino-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-3H-pyrido[3,4-e][1,4]diazepine-2-one (386 mg, 0.954 mmol) in toluene (2 mL) was mixed with a solution of 2-ethoxy-2-iminoethyl acetate (415 mg, 2.86 mmol) in toluene (3.2 mL). The reaction mixture was stirred at 80°C for 2 hours, 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. After adding a further amount of 2-ethoxy-2-iminoethyl acetate (138 mg, 0.954 mmol) in toluene (0.8 mL), the reaction mixture was stirred for 4 hours. Finally, additional amounts of p-TsOH monohydrate (181 mg, 0.954 mmol) and 2-ethoxy-2-iminoethyl acetate (138.44 mg, 0.954 mmol) in toluene (0.5 mL) were added, and the reaction mixture was stirred overnight at 120 °C. Ethyl acetate (20 mL) and saturated aqueous NaHCO3 (20 mL, 1:1 dilution 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 to (Na2SO4), and concentrated under vacuum. The residue (706 mg, brown oil) was purified by preparative HPLC (Gemini NX, 0.1% formic acid-containing water / acetonitrile) to obtain 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-pentazatricyclo[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-pentazatricyclo[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), sodium hydroxide (11.5 mg, 0.288 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours, 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 under vacuum to obtain 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) Azethidine-1-yl-[(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-hexaen-4-yl]methanone To a solution of (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 (28 mg, 0.061 mmol), azetidine hydrochloride (17.17 mg, 0.184 mmol), HATU (27.91 mg, 0.073 mmol), and DIPEA (39.53 mg, 53.27 μL, 0.306 mmol) were added. The reaction mixture was stirred at 40°C for 16 hours, then at 70°C for 4 hours. The reaction mixture was concentrated under vacuum. 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 × 10 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated under vacuum. The residue was purified by flash chromatography (silica, heptane, 40-100% ethyl acetate), followed by SFC (Chiralcel OD-H, 20% methanol) to obtain an enantiopurine (-)-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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(3-fluoroazetidine-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 minutes. Then, ethyl(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-carboxylate (200 mg, 0.41 mmol) was added. The reaction mixture was stirred at 50°C for 12 hours 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, and concentrated under vacuum using (Na2SO4). The residue was purified by preparative HPLC (Waters Xbridge, 0.05% ammonia-containing water / acetonitrile), followed by SFC (Daicel Chiralpak AS, methanol containing 0.1% ammonia-containing water), yielding an enantiopurine (-)-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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(3-hydroxyazetidine-1-yl)methanone [ka]

[0157] Similar to the experiment in Example 7, ethyl(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-carboxylate was converted to an enantiopurine (-)-titled 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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(3-methoxyazetidine-1-yl)methanone [ka]

[0159] Similar to the experiment in Example 7, ethyl(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-carboxylate was converted to an enantiopurine (-)-titled compound (25 mg, 6%) as a white solid by 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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(3-hydroxy-3-methylazetidine-1-yl)methanone [ka]

[0161] Similar to the experiment in Example 7, ethyl(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-carboxylate was converted to an enantiopurine (-)-titled compound (54 mg, 16%) as a white solid by using 3-methylazetidine-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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]-(1,1-dioxo-1,4-thiadinan-4-yl)methanone [ka]

[0163] (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 (110 mg, 0.290 mmol) was added to a mixture of (7S)-11-chloro-9-(2,6-difluorophenyl)-7-methyl-12-(trifluoromethyl)-2,3,5,8,11,13-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxylic acid (110 mg, 0.290 mmol), benzotriazole-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 hours, and then purified by preparative HPLC (Waters Xbridge, 10 mM ammonium bicarbonate-containing water / acetonitrile), followed by SFC (Daicel Chiralpak AS, methanol containing 0.1% aqueous ammonia), yielding an enantiopurine (-)-title compound (19.0 mg, 13%) as a grayish-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-pentazatricyclo[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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]carbamate Diphenyl phosphoryl azide (1.14 g, 4.15 mmol) was slowly added to a mixture of (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 (950 mg, 2.08 mmol) and triethylamine (630 mg, 6.23 mmol) in 1,4-dioxane (10 mL). The mixture was stirred at room temperature for 1 hour, then stirred at 50°C for a further 2 hours. After the mixture cooled to room temperature, tert-butanol (10 mL) was added. The reaction mixture was stirred at 100°C for 16 hours, then poured into water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), and concentrated under vacuum. The residue was suspended in ethyl acetate, and the precipitate was filtered. The filtrate was purified by flash chromatography (silica, petroleum ether with 20-60% ethyl acetate) to obtain 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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-amine Trifluoroacetic acid (2 mL) was slowly added to a mixture of tert-butyl N-[(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-hexaen-4-yl]carbamate (370 mg, 0.70 mmol) in dichloromethane (5 mL). The mixture was stirred at room temperature for 1 hour, after which saturated sodium bicarbonate aqueous solution (until the pH exceeded 8) was added. The mixture was extracted with dichloromethane (3 × 10 mL). The combined organic layer was washed with brine (10 mL), dried, and concentrated under vacuum to obtain 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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]oxetane-3-carboxamide A mixture of (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-amine (150.0 mg, 0.350 mmol) and oxetane-3-carboxylic acid (53.6 mg, 0.520 mmol) in pyridine (2 mL) was to be mixed with phosphoryl chloride (0.05 mL, 0.520 mmol) at 0°C. The mixture was stirred at 0°C for 1 hour, then poured into ice water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with water (3 × 10 mL) and brine (10 mL), dried, and concentrated under vacuum in (Na2SO4). The residue was purified by preparative HPLC (Waters Xbridge, 10 mM ammonium bicarbonate water / acetonitrile), followed by preparative HPLC (Phenomenex Gemini-NX C18, 0.05% ammonia water / acetonitrile), and finally by SFC (Daicel Chiralcel OJ-H, 25% isopropanol) to obtain an enantiopurine (-)-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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]pyrrolidine-2-one [ka]

[0169] a) 4-Chloro-N-[(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-hexaen-4-yl]butanamide To a solution of (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-amine (130 mg, 0.30 mmol) and pyridine (757 mg, 5.36 mmol), 4-chlorobutyryl chloride (812 mg, 10.2 mmol) was slowly added at -20°C. The mixture was stirred at -20°C for 18 hours and then concentrated under vacuum. The residue was diluted with ethyl acetate (10 mL), washed with water (3 × 5 mL) and brine (5 mL), dried, and concentrated under vacuum to obtain the title compound (200 mg, crude product) 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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaen-4-yl]pyrrolidine-2-one Triethylamine (0.26 mL, 1.88 mmol) was added to a solution of 4-chloro-N-[(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-hexaen-4-yl]butanamide (200 mg, 0.38 mmol) in N,N-dimethylformamide (3 mL). The reaction mixture was stirred at 100°C for 3 hours, 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, and concentrated under vacuum in (Na₂SO₄). The residue was purified by preparative TLC (petroleum ether / ethyl acetate 0:1), followed by preparative HPLC (Waters Xbridge, 10 mM ammonium bicarbonate-containing water / acetonitrile), and then by SFC (REGIS(s,s)WHELK-O1, 40% isopropanol) to obtain an enantiopurine (-)-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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide [ka]

[0172] Similar to the experiment in Example 7, ethyl(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-carboxylate was converted to an enantiopurine (-)-titled 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-pentazatricyclo[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-pentazatricyclo[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-pentazatricyclo[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), triethylamine (2.5 mL, 17.9 mmol) and saturated lithium bromide aqueous solution (2.5 mL) were slowly added. The reaction mixture was stirred at 15°C for 2 hours and then acidified with hydrochloric acid aqueous solution (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, and concentrated under vacuum to obtain 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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide Similar to the experiment in 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 an enantiopurine (-)-titled compound (111 mg, 23%) as a grayish-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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide [ka]

[0177] Similar to the experiment in Example 7, ethyl(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-carboxylate was converted to an enantiopurine (-)-titled compound (16 mg, 15%) as a grayish-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-fluorophenyl)-3,7-dimethyl-12-(trifluoromethyl)-2,4,5,8,13-pentazatricyclo[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-fluorophenyl)-hydroxymethyl]-6-(trifluoromethyl)-3-pyridyl]amino]-1-methyl-2-oxoethyl]carbamate Similar to the experiment in Example 1c, when 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%), it was obtained 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-fluorobenzoyl)-6-(trifluoromethyl)-3-pyridyl]amino]-1-methyl-2-oxo-ethyl]carbamate Similar to the experiment in Example 1d, when tert-butyl N-[(1S)-2-[[5-chloro-4-[(2-chloro-6-fluorophenyl)-hydroxymethyl]-6-(trifluoromethyl)-3-pyridyl]amino]-1-methyl-2-oxo-ethyl]carbamate was converted to the title compound (1.7g, 85%), it was obtained 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-fluorobenzoyl)-6-(trifluoromethyl)-3-pyridyl]propanamide Similar 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 (1.3g, 95%), yielding 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-fluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepine-2-one Similar 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%), yielding 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-fluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepine-2-thione Similar to the experiment in Example 5a, when (3S)-6-chloro-5-(2-chloro-6-fluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepine-2-one was converted to the title compound (110 mg, 56%), it was obtained 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-fluorophenyl)-3,7-dimethyl-12-(trifluoromethyl)-2,4,5,8,13-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene A acethydrazide (35.1 mg, 0.47 mmol) was added to a mixture of (3S)-6-chloro-5-(2-chloro-6-fluorophenyl)-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). The reaction mixture was stirred at 120 °C for 16 hours, then cooled to room temperature and concentrated under vacuum. The residue was purified by preparative HPLC (Waters Xbridge, 0.05% ammonia-containing water / acetonitrile), followed by SFC (Daicel Chiralcel OD, methanol containing 0.1% ammonia-containing water) to obtain an enantiopurine (-)-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]diazepine-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), (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) were added. The reaction mixture was stirred at 80°C for 12 hours and then concentrated under vacuum. The residue was purified by flash chromatography (C18, 0.1% formic acid-containing water / acetonitrile) to obtain 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 Dess Martin periodinane (157 mg, 0.370 mmol) was added 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]diazepine-2-ylidene]amino]propan-1-ol (110 mg, 0.250 mmol) and sodium bicarbonate (83 mg, 0.98 mmol) in dichloromethane (6 mL). The reaction mixture was stirred at room temperature for 1 hour, then poured into water (10 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic layer was washed with brine (10 mL), dried, and concentrated under vacuum in (Na₂SO₄). The residue was purified by preparative HPLC (Waters Xbridge, 10 mM ammonium bicarbonate-containing water / acetonitrile), followed by SFC (Phenomenex-Cellulose-2, isopropanol), yielding an enantiopurine (-)-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]diazepine-2-yl]diphenylphosphate To a mixture of (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepine-2-one (500 mg, 1.3 mmol) in tetrahydrofuran (5 mL), sodium hydride (103 mg, 2.6 mmol) was gradually added at 0°C. The mixture was stirred for 15 minutes, and then [chloro(phenoxy)phosphoryl]oxybenzene (517 mg, 2 mmol) was slowly added at 0°C. The reaction mixture was stirred further at 0°C for 1 hour, diluted with water (50 mL), and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with brine (2 × 30 mL), dried, and concentrated under vacuum using (Na₂SO₄). The residue was purified by flash column chromatography (petroleum ether / ethyl acetate 3:1) to obtain 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]diazepine-2-yl]amino]-3-hydroxypropanoate Triethylamine (0.34 mL, 2.4 mmol) was added to a solution of ethyl 2-amino-3-hydroxy-propanoate hydrochloride (409 mg, 2.4 mmol) in tetrahydrofuran (5 mL). The mixture was stirred at 15°C for 20 minutes, and then [(3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-3H-pyrido[3,4-e][1,4]diazepine-2-yl]diphenyl phosphate (500 mg, 0.8 mmol) was added at -20°C. The reaction mixture was heated to 15°C and stirred for 16 hours. The mixture was slowly poured into saturated ammonium chloride aqueous 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, and concentrated under vacuum in (Na₂SO₄). Purification of the residue by preparative TLC (silica, dichloromethane / methanol 20:1) yielded 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 Similar to the experiment in Example 18b, ethyl 2-[[(3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-3H-pyrido[3,4-e][1,4]diazepine-2-yl]amino]-3-hydroxypropanoate was converted to the title compound (100 mg, 33%), yielding a yellow solid. 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 Similar to the experiment in Example 15a, 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%), yielding a yellow solid. 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 Similar 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 an enantiopurine (-)-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]diazepine-2-ylidene]amino]cyclopentanol To a mixture of sodium carbonate (240.3 mg, 2.27 mmol) in tert-butanol (5 mL), (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 hours, 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, and concentrated under vacuum. The residue was purified by flash chromatography (silica, petroleum ether with 40-60% ethyl acetate) to obtain 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]diazepine-2-ylidene]amino]cyclopentanone A mixture of 2-[(E / Z)-[6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydropyrido[3,4-e][1,4]diazepine-2-ylidene]amino]cyclopentanol (300.0 mg, 0.630 mmol) in dichloromethane (6 mL) was mixed with phenyl-λ3-iododiyl diacetate (BAIB, 817 mg, 2.54 mmol) and (2,2,6,6-tetramethylpiperidine-1-yl)oxidanil (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 under vacuum, and the residue was purified by flash chromatography (C18, formic acid-containing water / acetonitrile) to obtain the title compound (140 mg, 0.30 mmol, 47%) as yellow rubber. 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 POCl3 (228 mg, 1.49 mmol) was added 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]diazepine-2-ylidene]amino]cyclopentanone (140 mg, 0.30 mmol) in pyridine (2 mL). The reaction mixture was stirred at 25 °C for 1 hour, then poured into ice water (10 mL) and extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated under vacuum. The residue was purified by preparative HPLC (Waters Xbridge, ammonia-containing water / acetonitrile), followed by SFC (REGIS(S,S)WHELK-O1, methanol) to obtain an enantiopurine (-)-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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide [ka]

[0199] Similar to the experiment in Example 7, ethyl(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-carboxylate was converted to an enantiopurine (-)-titled compound (118 mg, 36%) as a white solid using 1-amino-2-methyl-propane-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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide [ka]

[0201] Similar to the experiment in Example 7, ethyl(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-carboxylate was converted to an enantiopurine (-)-titled 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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide [ka]

[0203] Similar to the experiment in 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 an enantiopurine (-)-title compound (7.1 mg, 6%) using cis-3-aminocyclobutanol hydrochloride instead of azetidine hydrochloride, resulting in a yellow solid. 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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide [ka]

[0205] Similar to the experiment in 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 an enantiopurine (-)-title compound (27 mg, 11%) using trans-3-aminocyclobutanol hydrochloride instead of azetidine hydrochloride, yielding a grayish-white solid. 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 a compound in γ1 subunit-containing receptors was determined from HEK293F cells (ThermoFisher R79007) expressing human (transient transfect) receptors of composition α5β2γ1, α2β2γ1, and α1β2γ1 to the membrane. 3 Measured by competition for binding of [H]RO7239181 (67.3 Ci / mmol; Roche). For better protein expression of α2 subunit-containing receptors, human GABA A The 28-amino acid signal peptides (Met1~Ala28) of the α2 subunit are used in human GABA A The α5 subunit was substituted with a 31-amino acid signal peptide (Met1~Ser31).

[0207] Different GABA APellet cells harvested from HEK293F cells expressing the receptor subtype were resuspended in mannitol buffer pH 7.2–7.4 (0.29 M mannitol, 10 mM triethylamine, 10 mM acetate, 1 mM EDTA + protease inhibitor (20 tablets Complete, Roche Diagnostics, catalog no. 05056489001, per liter)), washed twice, and then resuspended in the same buffer at a dilution of 1:10–1:15. Cell lysis was performed by stirring the suspension at 435 psi for 15 minutes in a Parr container #4637, and then the suspension was centrifuged at 1000 × g for 15 minutes at 4°C (Beckman Avanti J-HC; Rota JS-4.2). The supernatant (S1) was transferred to a 2 L Schott flask, and the pellet (P1) was resuspended in mannitol buffer up to 175 mL. The resuspended pellet was transferred to a 250 mL Corning centrifuge beaker and centrifuged at 1500 × g for 10 minutes at 4°C (Beckman Avanti J-HC; Rotor JS-4.2). The supernatant (S1) was then transferred to a 2 L Schott flask and the pellet was discarded. The supernatant (S1) was centrifuged in a 500 mL Beckman polypropylene centrifuge beaker at 15,000 × g for 30 minutes at 4°C (Beckman Avanti J-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 48,000 × g for 50 minutes 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 with bovine serum albumin as a standard, and measured with NANO-Drop1000. The membrane suspension was aliquoted (500 μL / tube) and stored at -80°C until needed.

[0208] The membrane homogenate was resuspended and polytronized in 10 mM potassium phosphate and 100 mM KCl-bound buffer at pH 7.4 (Polytron PT1200E Kinematica AG) to the final assay concentration determined in previous experiments.

[0209] The radioligand binding assay was performed on 100 μL of cell membrane with concentrations of 1.5 nM (α5β2γ1) or 20-30 nM (α1β2γ1, α2β2γ1) [ 3 H]RO7239181, and [0.3~10000]×10 -9 The test was performed using a 200 μL volume (96-well plate) containing test compounds in the M range. Nonspecific binding was observed at 10 × 10⁻⁶. -6 (α5β2γ1) and 30×10 -6 M RO7239181 was defined as representing less than 5% (α5β2γ1) and less than 20% (α1β2γ1, α2β2γ1) of fully bound radioactive material. The assay was incubated to equilibrium at 4°C for 1 hour, and the membrane was then filtered on a unifilter (a 96-well white microplate bound with a GF / C filter pre-incubated in 0.3% polyethyleneimine for 20–50 minutes) using a Filtermate 196 harvester (Packard BioScience), and washed four times with 10 mM cold potassium phosphate pH 7.4 and 100 mM KCl-bound buffer. After dehydration, the radioactivity retained on the filter was detected by liquid scintillation counting. i The values ​​were calculated using Excel-Fit (Microsoft) and are the average of two measurements.

[0210] The compounds in the attached examples were tested using the above assay, and the preferred compound was GABA with a concentration of 100 nM or less. A From γ1 subunit-containing receptors (e.g., α5β2γ1, α2β2γ1, α1β2γ1) [ 3 K for substitution of H]RO7239181 iIt was found that the compound had a value of less than 50 Ki(nM). Representative test results obtained by the above assay to measure binding affinity to HEK293 cells expressing the human (h) receptor are shown in Table 1.

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

[0212] a) 5-Chloro-2-methyl-3,1-benzoxazine-4-one A solution of 2-amino-6-chlorobenzoic acid (250 g, 1.46 mol) in acetic anhydride (1250 mL) was stirred at 140 °C for 2 hours. The reaction mixture was concentrated under vacuum. The resulting crude residue was suspended in ethyl acetate (1000 mL), stirred for 30 minutes, filtered, and dried under vacuum to obtain the title compound (238 g, 84%) as a gray 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-difluorobenzole)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), i-PrMgCl·LiCl (1.3 m, 500 mL, 650 mmol) was added dropwise under nitrogen at -70°C. The mixture was warmed to room temperature within 1 hour, quenched with saturated ammonium chloride aqueous solution (1500 mL), and extracted with ethyl acetate (2 × 1500 mL). The organic phase was washed with brine (2000 mL), dried, and concentrated under vacuum. The residue was suspended in ethyl acetate (150 mL). The resulting suspension was stirred at room temperature for 20 minutes, filtered, and dried under vacuum to obtain the title compound (113 g, 71%) as a grayish-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), aqueous hydrochloric acid (12 m, 200 mL) was added. The reaction mixture was stirred at 100 °C for 1 hour and then diluted with ethyl acetate (1100 mL). The organic phase was washed with water (1100 mL), saturated sodium bicarbonate aqueous solution (1100 mL), and brine (1100 mL), dried over sodium sulfate, and concentrated under vacuum. Petroleum ether (120 mL) was added to the crude product, and the suspension was stirred at room temperature for 20 minutes. The solid was filtered and dried to obtain 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), 1-bromopyrrolidine-2,5-dione (64.4 g, 362 mmol) was added at 0°C. The reaction mixture was stirred at 30°C for 1 hour. The mixture was diluted with dichloromethane (600 mL), washed with water (500 mL) and brine (4 × 500 mL), dried, and concentrated under vacuum in (Na₂SO₄). The residue was purified by chromatography (silica, petroleum ether / ethyl acetate, 1:0-2:1). The solid was suspended in petroleum ether (200 mL) and stirred at room temperature for 20 minutes. The suspension was filtered, and the solid was dried under vacuum to obtain 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-benzodiazepine-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), 2-aminoethyl hydrochloride (70.5 g, 505 mmol) was added. The reaction mixture was stirred at 135 °C for 36 hours. The reaction mixture was concentrated under vacuum to remove the 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, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (silica, petroleum ether / ethyl acetate 10:1 to 2:1) to obtain the title compound (10.1 g, 12%) as a grayish-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-benzodiazepine-2-one 7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-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) were charged into a microwave tube. 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 minutes to achieve complete conversion. The mixture was evaporated, treated with saturated NaHCO3 (20 mL), and extracted with SiO2 (2 × 20 mL). The organic layer was dried with (Na2SO4), filtered, and the solvent was evaporated. The residue was purified by flash column chromatography (CH2Cl2 / siRNA in 40g silica and 10%-40%-70% heptane) to obtain the title compound (344mg, 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-benzodiazepine-2-one [ in THF (200 μL)] 3 To a solution of [H]methylnosilate (1.85 GBq, 50 mCi, 0.61 μmol), 0.43 mg (1.34 μmol) of the N-desmethyl precursor 6-chloro-5-(2,6-difluorophenyl)-7-methyl-1,3-dihydro-1,4-benzodiazepine-2-one dissolved in THF (200 μL) and 10 equivalents of sodium tert butyrate (0.5 m in THF, 13.4 μmol) were added. After stirring at room temperature for 4 hours, the reaction mixture was treated with H2O and evaporated, and the crude product was purified by HPLC (X-Terra Prep RP-18, 10 × 150 mm, MeCN / H2O (containing 5% MeCN) 40:60, 4 mL / min, 230 nm). Pure tritium-labeled compounds were isolated by solid-phase extraction (Sep-Pak Plus C18), eluted from the cartridge as an ethanol solution, and determined by mass spectrometry (MS) to obtain 1.6 GBq (43.2 mCi) of the target compound with a radiochemical purity of over 99% and a specific activity of 2.49 TBq / mmol (67.3 Ci / mmol). The identity of the labeled compound was confirmed by HPLC (by co-injection of 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 a compound in a γ2 subunit-containing receptor is used to improve the affinity of a compound to HEK293F cells expressing a human (transient transfect) receptor with the composition α1β3γ2. 3 The measurement was performed by competition for the [H]flumazenyl (81.1 Ci / mmol; Roche) bond.

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

[0221] The radioactive ligand binding assay was performed on 100 μL of cell membrane with a concentration of 1 nM [ 3 [H] flumazenil and [0.1·10 -3 -10] × 10 -6 The test was performed using a 200 μL volume (96-well plate) containing test compounds in the M range. Nonspecific binding was observed in 10 -5 The assay was defined by M diazepam and was typically less than 5% of fully bound. The assay was incubated to equilibrium at 4°C for 1 hour, filtered using a Packard harvester, and recovered onto a GF / C unifilter (Packard) by washing with ice-cold wash buffer (50 mM Tris, pH 7.5). After dehydration, the radioactivity retained on the filter was detected by liquid scintillation counting. i The values ​​were calculated using Excel-Fit (Microsoft) and are the average of two measurements.

[0222] The compounds in the attached examples were tested using the above assay, and the preferred compound was human GABA with a concentration of 100 nM or higher. A From the α1β3γ2 subtype of the receptor [ 3 H] Regarding the substitution of flumazenyl, large K i It was found that it has a value greater than 300. i Compounds having α1β3γ2(nM) are most preferred. In preferred embodiments, the compound of the present invention is a γ2 subunit-containing GABA. ACompared to the receptor, GABA containing the γ1 subunit A It selectively binds to the receptor. In particular, the compounds of the present invention have a K2 ratio of more than 10. i α1β3γ2(nM) / K i The γ2 / γ1 selectivity ratio defined as "α2β2γ1(nM)", or "Log[K]" which is greater than 1. i α1β3γ2(nM) / K i It possesses a LogSel defined as "α2β2γ1(nM)". Representative test results obtained by the above assay, which measures binding affinity to HEK293 cells expressing the human (h) receptor, are shown in Table 1 below. [Table 1]

[0223] GABA A Functional expression of receptors: Preparation of Xenopus oocytes African clawed frog oocytes in maturation stages V-VI, GABA A Cloned mRNA encoding receptor subunits was used for expression. Oocytes ready for RNA microinjection were purchased from Ecocyte, Castrol Lauxcell, Germany, and stored at 20°C in modified Baas medium (mM composition: 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 a Roboinject automated system (MultiChannelSystems, Reutlingen, Germany). A Approximately 50 nL of aqueous solution containing the RNA transcript of the receptor subtype subunit was injected into each oocyte. RNA concentrations ranged from 20 to 200 pg / μL / subunit and were adjusted in pilot experiments to GABA. AAppropriate size and maximum effect GABA responses were obtained for flunitrazepam, triazolam, and midazolam, which are reference benzodiazepine-positive allosteric modulators (PAMs) at the receptor benzodiazepine (BZD) binding site. Oocytes were kept at 20°C until the experiment in modified Barth medium (composition in mM: NaCl 88, KCl 1, NaHCO34, HEPES 10, MgSO4 0.82, CaNO3 0.33, CaCl2 0.33, pH=7.5).

[0225] Electrophysiology Electrophysiological experiments were performed 3–5 days after mRNA microinjection using Roboocyte instruments (MultiChannelSystems, Reutlingen, Germany). Throughout the experiment, oocytes were continuously perfused with a solution containing NaCl 90, KCl 1, HEPES 5, MgCl21, and CaCl21 (pH 7.4) (in mM). Oocytes were filled with a solution containing KCl 1M + potassium acetate 1.5M and punctured with two glass microelectrodes (resistance: 0.5–0.8 MΩ) with a voltage fixed at -80 mV. Recording was performed at room temperature using a Roboocyte two-electrode voltage clamp system (Multichannelsystem). After the initial GABA equilibration period of 1.5 minutes, the maximum current response (EC) was recorded. 20 Approximately 20% of the K was added for 1.5 minutes. After another rest interval of 2.5 minutes, GABA was added again to induce a similar amplitude and shape response. 0.5 minutes after the start of this second GABA application, while the GABA was still present, its K i A test compound was added at a concentration approximately 30 times that of α2β2γ1. Current traces were recorded at a digitalization speed of 10 Hz during GABA application, immediately before and after it.

[0226] Each compound and concentration was tested in at least three oocytes. Different oocytes were used for different compound concentrations. Reference PAM, flunitrazepam, triazolam, and midazolam were α2β2γ1GABA A This enhanced GABA-induced current in receptor subtype-expressing oocytes by approximately 60%.

[0227] Data Analysis For analysis, the digitized current traces of the first and second GABA responses were superimposed and, where necessary, rescaled to equal maximum amplitude. The ratio between the two responses during the time interval of test compound application was calculated point by point. The extreme values ​​of the obtained “ratio traces” were defined as “GABA EC 20 The compound's effectiveness ("increase factor") was adopted as "adjustment %" (100 * (increase factor - 1)).

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

[0229] reference compound The following benzodiazepine reference compounds (representative commercially available benzodiazepines) and reference thienodiazepines are used in GABA A Receptors α1β2γ1 and α2β2γ1 subtypes and GABA A We tested their affinity for the α1β3γ2 receptor subtype. 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-diazepine-2-one).

[0231] Preparation of pharmaceutical compositions containing the compound of the present invention Tablets containing the compound of formula (I) are manufactured 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°C. 3. Pass the granules through an appropriate grinding device. 4. Add ingredient 5, mix for 3 minutes, and compress using a suitable press.

[0233] Capsules containing the compound of formula (I) are manufactured as follows: [Table 5]

[0234] Manufacturing procedure 1. Mix ingredients 1, 2, and 3 in a suitable blender for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes. 3. Fill into appropriate capsules.

[0235] The compound of formula I, lactose, and corn starch are first mixed in a mixer, and then mixed in a pulverizer. The mixture is returned to the mixer, and talc is added and roughly mixed. The mixture is then filled into appropriate capsules, such as hard gelatin capsules, by machine.

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

Claims

1. Equation (I) 【Chemistry 1】 (In the formula, 【Chemistry 2】 but, 【Transformation 3】 Selected from, R １ However, hydrogen, C １ ~C ６ -Alkyl, hydroxy-C １ ~C ６ -Alkyl-NH-C(O)- and groups 【Chemistry 4】 Selected from, R １ａ Is it hydrogen, or R １ and R １ａ together with the carbon atoms to which they are attached form C ３ -C １０ -cycloalkyl, R １ｂ However, hydrogen, halogen, hydroxyl, oxo, C １ ~C ６ - Alkyl and C １ ~C ６ - Selected from alkoxy, R １ｃ However, selected from hydrogen, hydroxyl, and oxo, R ２ However, C １ ~C ６ -It is alkyl, R ３ However, it is chloro or bromo, R ４ However, halogen, C １ ~C ６ -Alkyl, Halo-C １ ~C ６ - Alkyl, and C ３ ~C １０ - Selected from cycloalkyl groups, R ５ However, it is a halogen, L is a covalent bond, carbonyl, -C(O)NH-, -NHC(O)-, and -CH ２ Selected from NHC(O)- A is a 3- to 14-membered heterocycloalkyl and C ３ ~C １０ (Selected from cycloalkyl) Compounds thereof, or pharmaceutically acceptable salts thereof.

2. R １ However, C １ ~C ６ -Alkyl, hydroxy-C １ ~C ６ -Alkyl-NH-C(O)- and groups 【Transformation 5】 Selected from, R １ａ Is it hydrogen, or R １ and R １ａ However, together with the carbon atoms to which they are bonded, C ３ ~C １０ - Forms a cycloalkyl group, R １ｂ , R １ｃ A and L are as defined in claim 1. A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

3. R １ However, C １ ~C ６ -Alkyl, hydroxy-C １ ~C ６ -Alkyl-NH-C(O)- and groups 【Transformation 6】 Selected from, R １ｂ However, C １ ~C ６ -It is alkyl, R １ｃ However, it is hydroxyl, L is a carbonyl group, A is a 3- to 14-membered complex ring. A compound of formula (I) as described in claim 2, or a pharmaceutically acceptable salt thereof.

4. R １ However, 2-hydroxyethyl-NH-C(O)-, 2-hydroxypropyl-NH-C(O)-, methyl, and group 【Transformation 7】 Selected from, R １ｂ However, it is methyl, R １ｃ However, it is hydroxyl, L is a carbonyl group, A is azetidinyl. A compound of formula (I) as described in claim 3, or a pharmaceutically acceptable salt thereof.

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

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

7. R ４ A compound of formula (I) according to claim 4, or a pharmaceutically acceptable salt thereof, wherein is a halo-C1 to C6 alkyl group.

8. R ４ ga CF ３ The compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof.

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

10. R １ However, C １ ~C ６ -Alkyl, hydroxy-C １ ~C ６ -Alkyl-NH-C(O)- and groups 【Transformation 8】 Selected from, R １ｂ However, C １ ~C ６ -It is alkyl, R １ｃ However, it is hydroxyl, R ２ However, C １ ~C ６ -It is alkyl, R ３ However, it is Chlor, R ４ However, Hello C １ ~C ６ -It is alkyl, R ５ However, it is a halogen, L is a carbonyl group, A is a 3- to 14-membered complex ring. A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

11. R １ However, methyl, 2-hydroxyethyl-NH-C(O)-, 2-hydroxypropyl-NH-C(O)-, and group 【Chemistry 9】 Selected from, R １ｂ However, it is methyl, R １ｃ However, it is hydroxyl, R ２ However, it is methyl, R ３ However, it is Chlor, R ４ However, CF ３ And, R ５ However, it is fluoro, L is a carbonyl group, A is azetidinyl. A compound of formula (I) according to claim 10, or a pharmaceutically acceptable salt thereof.

12. The compound of formula (I) above, (7S)-11,12-dichloro-9-(2,6-difluorophenyl)-3,7-dimethyl-2,4,5,8,13-pentazatricyclo[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-pentazatricyclo[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-pentazatricyclo[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-pentazatricyclo[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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene, Azethidine-1-yl-[(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-hexaen-4-yl]methanone, [(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-hexaen-4-yl]-(3-fluoroazetidine-1-yl)methanone, [(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-hexaen-4-yl]-(3-hydroxyazetidine-1-yl)methanone, [(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-hexaen-4-yl]-(3-methoxyazetidine-1-yl)methanone, [(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-hexaen-4-yl]-(3-hydroxy-3-methylazetidine-1-yl)methanone, [(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-hexaen-4-yl]-(1,1-dioxo-1,4-thiadinan-4-yl)methanone, N-[(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-hexaen-4-yl]oxetane-3-carboxamide, 1-[(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-hexaen-4-yl]pyrrolidine-2-one, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(2S)-2-hydroxypropyl]-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-carboxamide, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-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-carboxamide, (7S)-11-chloro-9-(2,6-difluorophenyl)-N-[(2R)-2-hydroxypropyl]-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-carboxamide, (7S)-11-chloro-9-(2-chloro-6-fluorophenyl)-3,7-dimethyl-12-(trifluoromethyl)-2,4,5,8,13-pentazatricyclo[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-pentazatricyclo[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-pentazatricyclo[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-pentazatricyclo[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-pentazatricyclo[8.4.0.02,6]tetradeca-1(10),3,5,8,11,13-hexaene-4-carboxamide A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

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

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 inactive carrier.

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

16. The aforementioned acute neurological disorders, chronic neurological disorders, and / or cognitive impairments include 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, and disruptive, impulse-control and conduct disorders. The pharmaceutical composition according to claim 15, selected from: disorder), Tourette syndrome (TS), obsessive-compulsive disorder (OCD), acute stress disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), sleep disorders, Parkinson's disease (PD), Huntington's disease, Alzheimer's disease (AD), mild cognitive impairment (MCI), dementia, behavioral and psychological symptoms in neurodegenerative states (BPS), multiple infarct dementia, agitation, psychosis, substance-induced psychotic disorder, aggression, eating disorders, depression, chronic apathy, anhedonia, chronic fatigue, seasonal affective disorder, postpartum depression, drowsiness, sexual dysfunction, bipolar disorder, epilepsy, and pain.

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