OA19571A

OA19571A - Triazolobenzazepines as vasopressin V1a receptor antagonists.

Info

Publication number: OA19571A
Application number: OA1202000217
Authority: OA
Inventors: Éva Bozó; Ferenc Baska; Imre Bata; KORDÂS Krisztina SZONDINÉ; Krisztina Vukics
Original assignee: Richter Gedeon Nyrt.
Priority date: 2017-12-15
Filing date: 2018-12-14
Publication date: 2020-12-11

Abstract

The present invention relates to 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][l]benzazepine derivatives of general formula (I) and/or salts thereof and/or geometric isomers thereof and/or stereoisomers thereof and/or enantiomers thereof and/or racemates thereof and/or diastereomers thereof and/or biologically active metabolites thereof and/or prodrugs thereof and/or solvates thereof and/or hydrates thereof and/or polymorphs thereof which are centrally and/or peripherally acting Via receptor modulators, particularly V1a receptor antagonists. Additional subject of the present invention is the process for the preparation of the compounds and the intermediates of the preparation process as well. The invention also relates to the pharmaceutical compositions containing the compounds or together with one or more other active substances, as well as to the use in the treatment and/or prophylaxis of a disease or condition associated with V1a receptor function.

Description

TRIAZOLOBENZAZEPÏNES AS VASOPRESSIN V1A RECEPTOR ANTAGONISTS

THE FIELD OF THE INVENTION

The présent invention relates to 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine dérivatives of general formula (I) and/or salts thereof and/or géométrie isomers thereof and/or stereoisomers thereof and/or enantiomers thereof and/or racemates thereof and/or diastereomers thereof and/or biologically active métabolites thereof and/or prodrugs thereof and/or solvatés thereof and/or hydrates thereof and/or polymorphs thereof which are centrally and/or peripherally acting V1a receptor modulators, particularly V1a receptor antagonists. Additional subject of the présent invention is the process for the préparation of the compounds and intermediates of the préparation process as well. The invention also relates to pharmaceutical compositions containing the compounds and to the use thereof in the treatment and/or prophylaxis of a disease or condition associated with V1a receptor function.

THE BACKGROUND OF THE INVENTION

The vasopressin (antidiuretic hormone, ADH, CYIQNCPRG) is a 9-amino acid peptide hormone produced by the magnocellular neurons of the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus and secreted directly into the posterior lobe of the pituitary gland where the hormone is stored until entering into the bloodstream. In the periphery, the major rôle of vasopressin is in the contraction of blood vessels, as well as in glucose metabolism and in the régulation of excrétion.

For this reason, the conditions due to inappropriate sécrétion of vasopressin thus the lack of vasopressin may lead to pathological changes in the body, such as the central form of diabètes insipidus or abnormally low blood pressure (hypotension), while in the case of elevated levels of vasopressin or exogenous administration various forms of strengthening of the aggressive behaviour can be observed (Ferris et al., BMC Neuroscience 2008, 9:111).

Oxytocin (OXT, CYIQNCPLG) is a vasopressin-related peptide hormone, differing from that in one amino acid and its receptor is also related to vasopressin receptors. The effects of compounds on the oxytocin receptor show species-specific différences, but the oxytocin hormone itself is identical in the different mammalian species. Similarly, the vasopressin peptide is the same in ail mammals (except marsupials and pigs) and the effects exerted through its receptors may also show species-specific différences. The anxiolytic effect of oxytocin exerted in the central nervous System is well-known (Neumann ID. J

Neuroendocrinol 2008, 20(6): 858-65), therefore the inhibition of the oxytocin receptor in the centrai nervous system can trigger anxiety as undesirable side effect.

Three vasopressin receptors are distinguished, ail of them are G-protein coupled receptors. The V1a receptor (V1aR) is expressed centrally in the cérébral cortex, hippocampus and pituitary gland, furthermore peripherally in the liver, vascuiar smooth muscle, lung, utérus and testes (Frank et ai., Eur J Pharmacol 2008, 583:226-42). The V1b receptors (V1bR) are also can be found in the cortex, hippocampus and pituitary gland, and in the periphery they play an important rôle in the régulation of the pancréas and the adrenal glands. In contrast to this, the V2 receptor (V2R) is mainly tocalised on the periphery, in the kidneys where it increases water reabsorption, thereby exerting the antidiuretic effect of vasopressin (Robben et al., Am J Physiol Penal Physiol 2007, 292(1): F253-60). Thus, due to changes in the régulation of water balance the effect on the V2 receptor may cause undesirable side effect.

The secondary signalling pathway of V1a and V1b receptors include the change of intracellular Ca²⁺ concentration through phosphatidylinositol, whereas the V2 receptors activate adenylate cyclase enzyme and influence cAMP levels (Gouzenes et al., J Physiol 1999, 517(Pt3):771-9; Tahara et al., Pflugers Arch 1999, 437(2):219-26).

An important rôle is attached to the V1a receptors in the régulation of the circadian rhythm. One-third of the neurons in the suprachiasmatic nucléus (SCN) express vasopressin and the mRNA of V1a receptors exhibit daily fluctuations in this brain région of which the highest values can be observed during night hours (de Vries and Miller, Prog Brain Res 1998, 119:3-20). Vasopressin shows sexual dimorphism in inducing behavioural effects, despite the fact that distribution and amount of the V1aR mRNAs do not differ in men and women (Szot et al., Brain Res Mol Brain Res 1994, 24(1-4):1-10). Experiments in mice hâve shown that the increased water absorption prior to their sleep period was triggered by their internai clock and not their physiologicai necessities (Gizowski et al., Nature 2016, 537(7622):6858). Sleep disorder is a major accompanying symptom of autism (Glickman, Neurosci Biobehav Rev 2010, 34(5):755-68).

Vasopressin acts as a neuromodulator in the brain, its elevated leve! can be detected in the amygdala under stress (Ebner et al., Eur JNeurosci2002, 15(2):384-8). Such stressful life situations are well known to increase the likeîihood of developing dépréssion and anxiety (Kendler et al, Arch Gen Psychiatry 2003, 60(8):789-96; Simon et al., Recent Pat CNS Drug Discov, 2008, 3(2):77-93; Egashira et al., JPharmacol Sci2009, 109(1):44-9; Bielsky et al., Neuropsychopharmacology 2004, 29(3):483-93). The expression of V1aR is high in the brain, especially in certain parts of the limbic system, such as the amygdala, the latéral septum and the hippocampus which play an important rôle in the development of anxiety. Male V1aR gene knocked out mice exhibited reduced anxiety in the elevated plus maze, the open field and the light-dark box tests, but these différences could not be detected in females (Bielsky et al., Behav Brain Res 2005, 164(1):132-6).

The male V1aR knockout mice did not show any phenotypic différence in motor performances. In normal light-dark-cycle experiments, V1aR KO mice showed no différence compared to their wild-type littermates, however, in the experiments carried out in continuous darkness the diurnal rhythm of V1a knockout mice was shifted significantly (Egashira et al., Behav Brain Res 2007, 178(1):123-7).

The V1aR KO mice showed modified activity in the prepulse inhibition test, in the test which is accepted as animal model of sensory motor deficiency observed in most schizophrénie patients. Egashira et al hâve shown decreased function in the social interaction test, which is suitable to measure socio-cognitive behaviour of the V1aR KO mice in both sexes, but it was not observed after the treatment with antagonist (Bleickard et al., Psychopharmacology (Beri), 2009, 202:711-18).

Two microsatellite polymorphisme associated with autism could be determined in the case of variants of the AVPR1A gene encoding the V1a receptor (Kim et al., Mol Psychiatry 2002, 7:503-7; Yirmiya et al., Mol Psychiatry 2006, 11:488-94; Yang et al., Psychiatry Res, 2010, 178(1):199-201; Yang et al., Neurosci Lett 2010, 479(3):197-200). It also refers to a genetic connection that altered activation of amygdala could be detected in patients carrying two risk alleles in the V1aR gene. These modified receptors hâve been shown to be able to alter the activation threshold of amygdala during emotional facial récognition process (MeyerLindenberg étal., Mol Psychiatry 2009, 14:968-75).

Preclinical data also support the efficacy of VI aR antagonists in autism. A wideiy used and accepted animal model of autism is to study the behaviour of rats exposed to valproate (VPA) treatment in utero. The reduced social behaviour of VPA-treated animais could be reversed by the V1aR antagonist compound to the normal level. to a functional magnetic résonance imaging study it was also found that decreased perfusion values were restored by the V1aR antagonist in different brain régions of prenatally VPA-treated animais. The decreased function of the cortex, the inferior colliculus, the hippocampus and the hypothalamus was increased by treatment with the V1aR antagonist, whereas in the ventral tegmentum, the striatum and the colliculus superior, the augmented perfusion was normalised by the V1aR antagonist (Grundschober et al., Poster presented at Annuel Meeting of the American Collège of Neuropsychopharmacology, 2014, Phoenix, USA). For this reason, V1aR antagonist compounds showing favourable blood-brain barrier pénétration are expected to be advantageous.

Influencing V1aR with smal! molecufe antagonists is a promising strategy for the treatmentofvarious pathological conditions ofthefemale sex organs (such as, but not limited to, dysmenorrhea, sexual dysfonction), long-lasting pathological conditions in blood pressure control (such as, but not limited to, hypertension and/or chronic heart failure), conditions resulting from inappropriate sécrétion of vasopressin (such as, but not limited to, diabètes insipidus, rénal failure, nephrotic syndrome and cirrhosis). It can be considered another promising strategy in the treatment of anxiety, dépréssion, aggression, and disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to the latter three diseases or show comorbidity with them. These include, but not limited to, autistic spectrum disorder (well-functioning autism, Asperger's syndrome, Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS), autism spectrum disorder (ASD) and its various syndromic forms: fragile X syndrome, Prader-Wiili syndrome, Rett syndrome, tuberous sclerosis), obsessive compulsive disorder (OCD), various forms of Down syndrome and post-traumatic stress disorder (PTSD). VI aR antagonists are also suitable for the treatment of aggressive behavioural disorders and/or irritability (such as, but not limited to, patients with ASD, or suffering from Huntingtoris disease (HD) or various forms of schizophrénie), behavioural hyperactivity disorders (such as, but not limited to, attention déficit hyperactivity disorder (ADHD)), cognitive disorders (such as, but not limited to, dementia, mild cognitive disorders (MCI), cognitive impairment associated with schizophrénie (CIAS), and Alzheimer’s disease), and other neuropsychiatrie disorders (such as, but not limited to, schizophrenia and associated diseases).

Many patent applications deal with V1a receptor antagonists, for example, Otsuka discloses benzoheterocyclic dérivatives (WO 95/034540 A1, WO 2009/001968 A1, WO 2011/052519 A1), Astellas Pharma (Yamanouchi) discloses condensed benzodiazépine and triazole dérivatives (WO 95/03305 A1, WO 01/87855 A1, WO 02/44179 A1), AbbVie discloses oxindole dérivatives (WO 2006/072458 A2, WO 2006/100082 A2), Bayer Pharma discloses aryl- or heteroaryltriazole dérivatives (WO 2017/191102 A1, WO 2017/191107 A1, WO 2017/191114 A1). Various benzoazulene core containing dérivatives (WO 2005/068466 A1, WO 2006/021213 A2, WO 2006/021882 A1, WO 2011/114109 A1, WO 2011/128265 A1, WO 2011/141396 A1, WO 2014/127350 A1), spiroindolinone and indolylcarbonyl dérivatives (WO 97/15556 A1, WO 2007/009906 A1, WO 2007/014851 A2) are also described as V1a receptor antagonists.

The first clinical developments considérées the V1a receptor as peripheral target, the poor brain pénétration was therefore bénéficiai in the development of compounds. Such was Sanofi’s indoline core compound, relcovaptan (SR-49059, WO 93/03013 A1), which was developed until the Phase 2 clinical trial. Among the indications studied were prématuré birth, pelvic pain observed during the menstruation, dysmenorrhea (Brouard et al., Br J Obstetr Gynaecol 2000, 107:614-9), heart failure, hypertension, and coronary spasm, but itwas also tested as an antineoplastic agent in small-ceil lung carcinoma until the last clinical trial was stopped in 2003 (Serradeil-Le Gai et al., Prog Brain Res 2002, 139:197-210; Adislnsight: Relcovaptan - Latest Information Update: 03 Oct

2006 http://adisinsiqht.sprinaer.com/druqs/800004942). Relcovaptan has been in clinical development since 1993 and it is the most frequently used in vitro tool in the V1aR research (Tahara et al., Br J Pharmacol 2000, 129:131-9).

Pfizer studied its triazole dérivative PF 00738245 (WO 2005/063754 A1) and compound PF-184563 of triazolobenzodiazepine cote (WO 2004/074291 A1) in preclinical development for dysmenorrhea, based on measured data these are efficient V1aR antagonists (Russell et al., Eur. J Pharmacol, 2011, 670(2): 347-355; Johnson et al., Bioorg Med Chem Left 2011, 21:5684-7) buttheir development was terminated.

By the examination of effects exerted on the central nervous system, the treatment of dépréssion and anxiety has also been raised as a novel therapeutic area. Johnson & Johnson’s compound JNJ-17308616 of spirobenzazepine core was one of the first central nervous system acting V1aR antagonist compound (Bleickard et al., Psychopharmacology (Ber!.), 2009, 202:711-18; WO 02/02531 A1) which demonstrated efficacy in a variety of different animal models used for anxiety research: significantly reduced anxiety behaviour in the elevated plus maze test, marble burying test, and in the separation-induced ultrasonic vocalisation of rat pups. Although it proved to be effective in influencing the elevated Olabyrinth and the conditioned lick response, due to its poor metabolic stability measured in rodents, its efficacy was not good and was measurable only at high doses and therefore it was difficult to test.

Azevan’s V1aR antagonist azetidone dérivatives, SRX246 and SRX251 (also known as API246 or API251, WO 03/031407 A2) also reached the clinical trial phase. Clinical trials of SRX246 are also currently ongoing for the treatment of aggression, and intermittent explosive disorder and irritability in Huntington's Disease and post-traumatic stress disorder, as well as in the human behavioural models of anxiety and fear (Adislnsight: SRX 246 Latest information Update: 16 Feb 2017 http://adisinsight.springer.com/druqs/800023656). Clinical triai was conducted with SRX251 to treat dysmenorrhea but both Phase 1 studies were discontinued in 2016 and similarly to SRX246 it was also investigated for aggression in the preclinical development (Adislnsight: SRX 251 - Latest Information Update: 04 Nov 2017 http://adisinsiQht.sprinqer.com/driiQs/800025117). SRX-246 and SRX-251 are active on the human V1a receptor and in rats both compounds were détectable in the brain at approximately 100-fold of the effective concentrations detected in the binding assay (Guillon et al., Bioorg Med Chem 2007, 15:2054-80; Fabio et al., J Pharm Sci2013, 102(6):2033-43).

Vantia’s V1aR antagonist compound, VA 111913 of pyrazolobenzodiazepine core (WO 2010/097576 A1; Adislnsight: VA 111913 - Latest information Update: 25 Aug 2015 http://adisinsiqht.sprinqer.com/druQs/800028777) was tested in Phase 2 clinical trial for the treatment of dysmenorrhea but there is no information about its development since 2015.

Otsuka’s V1aR antagonist, the quinolinone dérivative OPC 21268 (EP0382185A2; Adislnsight: OPC 21268 - Latest Information Update: 06 Oct

2006 http://adisinsiahtsprinQer.com/druqs/800000284) was tested for the indication of gastric mucosal damage indication in the preclinical phase, whereas in Phase 2 clinical trials it was studied for heart failure and hypertension but there is no information on its development since 2015 (Yamamura et al., Science 1991, 252:572; Serradeil-Le Gai et al., J Clin invest 1993, 92(1):224).

When examining the brainstem in post mortem human samples sélective localisation of Via receptors unrelated to oxytocin receptors could be detected in the nucléus prepositus, which plays a rôle in eye gaze stabilisation (Freeman et ai., Soc Neurosci 2017, 12(2): 113123). A fundamental skill required for human social behaviour is the récognition and eyetracking of biologically relevant information (Klin et al., Nature 2009, 459:257-63, Simion et al., PNAS 2008, 105(2):809-13). The most active V1aR researcher Hoffmann-La Roche reached Phase 1 study with their indole dérivative RO5028442 (RG-7713; WO 2007/006688 A1 ), where positive effect on the orientation of eye-gaze pattern could be detected in humans (Umbricht et al., Neuropsychopharmacology 2017, 42 (9):1914-1923; Adislnsight: RG 7713 - Latest Information Update: 05 Nov 2015 http://adisinsight.springer.com/drugs/800043668). Phase 2 clinical trials for the treatment of autism are currently ongoing with balovaptan of the triazolobenzodiazepine core (RG-7314, RO5285119; WO 2010/060836 A1; Adislnsight: RG 7314 - Latest Information Update: 10 Sep

2017 http://adisinsight.springer.com/drugs/800035102).

Despite the numerous V1aR antagonist compounds and clinical studies, unmet medical need still persists to develop a V1aR antagonist that is suitable for the treatment and/or prophylaxis of various pathological conditions of thefemale sexorgans, long-standing conditions in blood pressure control, conditions resulting from inappropriate sécrétion of vasopressin, anxiety, dépréssion, aggression, disorders of the central nervous System where one of the symptoms and/or syndromes of the disease may be related to anxiety, dépréssion, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compuisive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavioural disorders and/or irritabiiity, behavioural hyperactivity disorders, cognitive disorders or other neuropsychiatrie disorders.

SUMMARY OF THE INVENTION

Our aim was to synthetize novel structured V1a receptor antagonists whose physicalchemical (e.g. kinetic or thermodynamic solubility, ionisation, lipophiiicity or permeability) or pharmaceutical properties (e.g. metabolic stability, CYP-450 enzyme inhibition) provide the favourable bioavailability, ADME (absorption, distribution, metabolism, excrétion), membrane pénétration or blood-brain barrier pénétration.

Surprisingly, such novel 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine dérivatives of general formula (i) hâve been prepared which show V1a receptor antagonistic activity profile.

The présent invention relates to compounds of general formula (I)

wherein ring A is a cycloalkyl or heterocyclyl group;

Y is -O-, -C(O)-, -CH2-, -NH-, -Ci-4alkyl-N(R¹⁸)- or bond if ring B is présent; or-N(Ci.4aikyl)₂, C(O)OCi-4alkyl, Ci-4alkyl optionally substituted with halogen, Ci-4alkoxy group or halogen if ring B is not présent;

ring B is an optionally substituted heteroaryi, aryi or heterocyclyl group;

or B-Y-A- jointly represents 3H-spiro[2-benzofuran-1,4’-piperidin-T-yl]; or

R¹ is a hydrogen, halogen, Ci-4alkyl, Ci-4aikoxy, CFs or CN;

R² is a hydrogen or Ci^alkyl group;

R³ is a NR⁴R⁵, OR⁶ group or halogen;

or R² and R³ jointly represent-O-(CH₂)m-O-, oxo or =N-OH group;

R⁴ and R⁵ is independently a hydrogen; Ci.4alkyl optionally substituted with OH, halogen, cycloalkyl, optionally substituted aryl or NR⁸R⁹ group; Cy¹; C(O)R⁷; SfOsJR¹⁰ or C^alkynyl group;

or R⁴ and R^s taken together with the N to which they are attached form a heterocycle;

R⁶ is a hydrogen; Ci.4alkyl optionally substituted with OH, halogen, Cy², Ci^alkoxy, Ci₄aikoxy-S(O)2 or NR¹¹R¹²group; C(O)R¹³; Si(CH3)2-t-butyl or Cz^alkynyl group;

R⁷ is a Ci-4alkyi optionally substituted with OH, CN, halogen, Cy³ or NR¹¹R¹² group; Ci₄alkoxy, C2-4alkenyl, Cy³ or N(Ci-4alkyl)2 group;

R⁸ and R^sis independently a hydrogen, Ci-4alkyl or C(O)OR²¹ group;

R¹⁰ is a Ci-4alkyl, OH or NR¹⁴R¹⁵group;

R¹¹ and R¹² is independently a hydrogen or Ci.4alkyl group;

or R¹¹ and R¹² taken together with the N to which they are attached form an optionally substituted heterocycie;

R¹³ is a Ci-4alkyl optionally substituted with CN or NR¹⁹R²⁰ group; Cy³ or NR¹⁶R¹⁷ group;

R¹⁴ and R¹⁵ is independently a hydrogen or Ci-4alkyl group;

R¹⁶and R¹⁷ is independently a hydrogen, Ci-4alkyi, or optionally substituted aryi group;

or R¹⁶ and R¹⁷ taken together with the N to which they are attached form a heterocycle;

R¹⁸ and R²¹ is a hydrogen or C-Malkyl group;

R¹⁹ and R²⁰is independently a hydrogen or C-Malkyl group;

Cy¹ is an optionally substituted cycloalkyl, heterocyclyl or heteroaryl group;

Cy² is an optionally substituted aryl or cycloalkyl group;

Cy³ is an optionally substituted aryl, cycloalkyl, heterocyclyi or heteroaryl group;

X is a Ci^alkyl, aryl or heteroaryl group;

Z is a Ci-4aikyl group;

m is 2, 3, 4 or 5 and/or salts thereof and/or géométrie isomers thereof and/or stereoisomers thereof and/or enantiomers thereof and/or racemates thereof and/or diastereomers thereof and/or biologically active métabolites thereof and/or prodrugs thereof and/or solvatés thereof and/or hydrates thereof and/or polymorphs thereof.

The présent invention also relates to pharmaceutical compositions containing the compound of general formula (I) and/or sait thereof and/or géométrie isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvaté thereof and/or hydrate thereof and/or polymorph thereof as active substances.

In addition, the présent invention also relates to the préparation of the compound of general formula (I) and/or sait thereof and/or géométrie isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or soivate thereof and/or hydrate thereof and/or polymorph thereof, to the intermediates of the préparation process and to the Chemical and pharmaceutical préparation of pharmaceutical compositions containing the compounds.

The invention also relates to a method for treating a mammai, including humans, suffering from a central and/or peripherai disease, where modulation, preferably antagonism of the V1a receptor may hâve therapeutic benefits wherein the compound of formula (I) and/or sait thereof and/or géométrie isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or soivate thereof and/or hydrate thereof and/or polymorph thereof or a therapeutically effective amount thereof in a composition is administered.

The invention aiso relates to the use of the compound of general formula (i) and/or sait thereof and/or géométrie isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or soivate thereof and/or hydrate thereof and/or polymorph thereof for the manufacture of a médicament for the treatment and/or prophylaxis of a disease or condition associated with V1a receptor function.

DETAILED DESCRIPTION OF THE INVENTION

The présent invention relates to V1a receptor modulators, in particular V1a receptor antagonists. It is a further objective ofthe invention to provide sélective V1a receptor inhibitor compounds since selectivity is iess likely to cause undesirable side effects. Another aspect of the invention is to provide compounds with favourable physicochemical properties as favourable physical-chemical properties are expected to resuit in bénéficiai bioavailability,

ADME (absorption, distribution, metabolism, excrétion), membrane pénétration or bloodbrain barrier pénétration of the compounds.

The compounds of general formula (I) of the présent invention are thus V1a receptor antagonists which are centraliy and/or peripherally acting therapeutic agents in the treatment and/or prophylaxis of various pathological conditions of the female sex organs, long-standing conditions in biood pressure control, conditions resuiting from inappropriate sécrétion of vasopressin, anxiety, dépréssion, aggression, disorders ofthe central nervous System where one ofthe symptoms and/orsyndromes ofthe disease may be reîated toanxiety, dépréssion, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavioura! disorders and/or irritability, behavioural hyperactivity disorders, cognitive disorders or other neuropsychiatrie disorders.

The présent invention relates to compounds of general formula (I)

wherein ring A is a cycloalkyl or heterocyclyl group;

Y is -O-, -C(O)-, -CH2-, -NH-, -Ci-4alkyl-N(R¹⁸)- or bond if ring B is présent; or -N(Ci-4alkyl)2, C(O)OCi-4alkyl, Ci.4alkyl optionally substituted with halogen, Ci.4alkoxy group or haiogen if ring B is not présent;

ring B is an optionally substituted heteroaryl, aryl or heterocyclyl group;

or B-Y-A-jointly represents 3H-spiro[2-benzofuran-1,4^!-pipendin-T-yi]; or

R¹ is a hydrogen, halogen, Ci-4aÎkyî, Ci-4aikoxy, CF3 or CN;

R² is a hydrogen or C^alkyl group;

R³ is a NR⁴R⁵, OR® group or halogen;

or R² and R³ iointly represent -O-(CH₂)_m-O-, oxo or =N-OH group;

R⁴ and R⁵is independently a hydrogen; C<.4alkyl optionally substituted with OH, halogen, cycloalkyl, optionally substituted aryl or NR⁸R⁹ group; Cy¹; C(O)R⁷; S(O2)R¹⁰ or C2-4aîkynyl group;

R⁶ is a hydrogen; Ci.4alkyl optionally substituted with OH, halogen, Cy², Ci.4a!koxy_; Ci. 4aikoxy-S(O)2 or NR¹¹ R¹² group; C(O)R¹³; SKCHsh-Lbutyl or C2-4aikynyl group;

R⁷ is a C^alkyl optionally substituted with OH, CN, halogen, Cy³ or NR^R¹² group; Ci. 4alkoxy, C2-4alkenyl, Cy³ or N(Ci-4alkyl)2 group;

R⁸ and R®is independently a hydrogen, Ci.4alkyl or C(O)OR²¹ group;

R¹⁰ is a Ci-4alkyl, OH or NR¹⁴R¹⁵ group;

R¹¹ and R¹² is independently a hydrogen or Ci.4alkyl group;

or R¹¹ and R¹² taken together with the N to which they are attached form an optionally substituted heterocycle;

R¹³ is a Ci-4alkyl optionally substituted with CN or NR^WR²⁰ group; Cy³ or NR^1SR¹⁷group;

R¹⁴ and R¹⁵ is independently a hydrogen or Ci.4alkyl group;

R¹⁶ and R¹⁷ is independently a hydrogen, Ci.4aikyl, or optionally substituted aryl group;

R¹⁸ and R²¹ is a hydrogen or Ci.4alkyi group;

R¹⁹ and R²⁰is independently a hydrogen or Ci-4alkyl group;

Cy¹ is an optionally substituted cycloalkyl, heterocyclyl or heteroaryl group;

Cy² is an optionally substituted aryl or cycloalkyl group;

Cy³ is an optionally substituted aryl, cycloalkyl, heterocyclyl or heteroaryl group;

X is a Ci.4alkyl, aryl or heteroaryl group;

Z is a Ci-4aikyl group;

Définition of the general terms used herein, whether or not the terms in question are presented individually or in combination with other groups are described below.

The term cycloalkyl group refers alone or in combination with other groups to 3- to

8-membered, preferably 3- to 6-membered, saturated or unsaturated, preferably saturated carbocyclic groups. Examples include cyclopropyl, cyclobutyl, cyclopentyi or cyclohexyl. In ring A, the term cycloalkyl group refers preferably to a 4- to 6-membered, saturated or unsaturated, preferably saturated carbocyclic group. Examples include cyclobutyl, 10 cyclopentyi or cyclohexyl, more preferably cyclobutyl or cyclohexyl. Particularly preferred is the cyclohexyl group. The term substituted cycloalkyl group refers preferably to a cycloalkyl group having geminal halogen substitution.

The term “aryl group” refers alone or in combination with other groups to a 6- to 14membered, preferably 6- to 10-membered aromatic carbocyclic moiety comprising at least 15 one aromatic ring or a condensed ring Systems containing at least one aromatic ring.

Examples include, but are not limited to, phenyl, benzyi, naphthyl, biphenyî, anthryl, azulenyl or indanyl. Particularly preferred is the phenyl group.

The term heterocyclyl group refers alone or in combination with other groups to 3to 8-membered, preferably 4- to 7-membered, saturated or unsaturated, preferably 20 saturated, monocyclic, bicyclic, condensed and/or bridged ring cycle containing 1, 2 or 3 heteroatoms selected from O, S or N. Examples include, but are not limited to, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, piperidine, pyrrolidine, morpholine, piperazine, 1,3-oxazoiidine, 1,3-thiazolidine, thiomorpholine 1,1-dioxide, azepane, 1azabicyclo[2.2.2]octane and the like. Preferably pyrrolidinyl, piperidinyl, piperazinyl or 125 azabicyclo[2.2.2joct-3-yl. More preferably, piperidinyl or piperazinyl

When ring A is heterocyclyl, then heterocyclyl refers preferably to a 4- to 7-membered saturated heterocyclyl group containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to Y or to the triazole ring of the 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine cote. Examples include, but are not limited to, azetidinyl, 1,3-diazetidinyl, pyrrolidinyl, pyrazoîidinyl, 30 imidazolidinyl, piperidinyl, piperazinyl azepanyl, 1,3- or 1,4-diazepanyl. Preferably azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl. Particularly preferred is piperidinyl.

In the case of Cy¹ or Cy³, the heterocycle refers preferably to a 4- to 7-membered saturated heterocyclyl group containing 1 O, more preferably oxetane or tetrahydropyran.

When R⁴ and R⁵ taken together with the N to which they are attached form a heterocycie, the heterocycie refers preferably to a 4- to 7-membered saturated ring containing 1, 2 or 3 heteroatoms selected from O, S or N, more preferably pyrrolidine, 3oxazolidine, 1,3-thiazolidine, piperidine, piperazine, morpholinyl or thiomorpholine-1,1dioxide.

When R¹¹ and R·², or R^1S and R¹⁷ taken together with the N to which they are attached form a heterocycie, the heterocycie is preferably selected from the group comprising morpholin-4-yl, 4-methylpiperazin-1-yi, pyrroiidinyl, piperidinyl, piperazinyl, 1,3oxazolidine, 1,3-thiazoiidine or thiomorpholine-1,1-dioxide.

The term heteroaryl group refers alone or in combination with other groups to a cyclic aromatic group containing a single 5- to 6-membered ring containing 1, 2 or 3 heteroatoms in which group at least one heterocyclic ring is aromatic. The 6-membered mono-heteroaryl refers to a monocyclic aromatic group which is a single 6-membered ring containing 1, 2, or 3 heteroatoms selected from O, S or N. Examples include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl and the like. Preferred single 6-membered mono-heteroaryl groups contain 1 or 2 N. A preferred 6membered ring is pyridinyl, more preferably pyridin-2-yl and pyridin-3-yl. Particularly preferred is pyridin-2-yl. The term 5-membered mono-heteroaryl refers to a monocyclic aromatic group which is a single 5-membered ring containing 1, 2 or 3 heteroatoms selected from O, S or N. Preferred 5-membered mono-heteroaryl groups contain 2 N and 1 O, 2 N and 1 S, 2 N, 1 N or 1 S or 1 N and 1 O. Exemples include, but are not limited to, thiophenyl, furanyl, pyrrolyl, imidazoiyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, 1Hpyrazolyl, triazolyl and the like. A preferred 5-membered ring is isoxazol-3-yl and 1,3,4oxadiazol-5-yl.

In the case of Cy¹, the heteroaryl refers preferably to a 6-membered mono-heteroaryl group containing 1 or 2 N, more preferably pyridine, pyrimidine or pyrazine.

When ring B is an optionally substituted heteroaryl group, the heteroaryl group is preferably 3-chloropyridin-2-yl, 3-methylpyridin-2-yl or 5-methylisoxazol-3-yl.

The term “bond” refers to a single bond, in which one pair of électrons is shared between two atoms.

The term C-Malkyl group refers atone or in combination with other groups to a straight or branched, single or multiple branched, hydrocarbon radical and consists of 1 to 4 carbon atoms. Examples include, but are not limited to, methyl, ethyl, propyl, i-propyl (isopropyl), n-butyi, 2-butyl (sec-butyl) or f-butyl (tert-butyl) group. Preferred alkyl groups are îhose consisting of 1 to 3 carbon atoms. More preferred are methyi, ethyi and isopropyl groups. Particularly preferred is the methyl group.

The term Cz^alkenyl group refers alone or in combination with other groups to a straight or branched, single or multiple branched, hydrocarbon radical having one double bond and consists of 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, propen-1-yi, propen-2-yl, butene-1-yl or butene-3-yl. Preferred alkenyi groups are those consisting of 2 to 3 carbon atoms. Particularly preferred is the vinyl group.

The term C2-4alkynyl group refers alone or in combination with other groups to a hydrocarbon radical having one triple bond and consist of 2 to 4 carbon atoms. Examples include, but are not limited to, ethynyl, propynyi, propargyi, 1-butynyl, 2-butynyl and the like. Preferred aikynyl groups are those consisting of three carbon atoms. More preferred is the propargyi group.

The term Ci-4alkoxy group refers alone or in combination with other groups to -OCi-4alkyl group, wherein the Ci-4alkyl group is as defined above. Examples include, but are not limited ίο, methoxy, ethoxy, propoxy, f-butoxy. Preferred aikoxy groups are meihoxy, propoxy or t-butoxy. Particularly preferred are the methoxy and f-butoxy groups.

The term Boc refers alone or in combination wiih other groups to f-butoxycarbonyl group.

The term halogen” refers alone or in combination with other groups to fluorine, chlorine, bromine or iodine, preferably fluorine, chiorine or bromine, more preferably chlorine or bromine. Particularly preferred is chlorine.

The term optionally substituted on any atom of the relevant group refers to the substitution by one or more Ci^alkyi, Ci-4alkoxy groups, oxo groups or halogens. Here, one or more means from one to the highest possible number of substitution, that is, from repiaoing one hydrogen to replacing ail hydrogens. One, two or three substituants on a given atom are preferred. Even more preferred are one or two, or one substitution. Particularly preferred is one substitution for a substituted aryl or heteroaryi group. The expression Ci₄alkyl optinaily substituted with halogen refers preferably to a Ci-aalkyl group having one, two or three halogen substituents on any atom of the Ci-₄aikyl group, more preferably to a methyl group having three halogen substituents. Particularly preferred is CF3 group.

The term sait refers to pharmaceutically acceptable and/or pharmaceutically nonacceptabie salts. The pharmaceuticaily acceptable sait refers to a conventional acid addition and base addition salts which preserve the biological efficacy and properties of the compounds of general formula (I) and which can be formed with suitable non-ioxic organic or inorganic acids or organic or inorganic bases. Examples of acid addition salts include salts derived from inorganic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, suîfuric acid, sulphamic acid, phosphoric acid, nitric acid and perchloric acid and derived from various organic acids, such as, but not limited to, acetic acid, propionic acid, benzoic acid, glycolic acid, phenylacetic acid, salicylic acid, malonic acid, maleic acid, oleic acid, pamoic acid, palmitic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, oxalic acid, tartaric acid, succinic acid, citric acid, malic acid, lactic acid, glutamic acid, fumaric acid and the like. Examples of base addition salts are salts derived from ammonium-, potassium-, sodium- and quaternary ammonium hydroxides such as tétraméthylammonium hydroxide. These salts often exhibit more favourable solubility properties than the compounds used for their préparation and are therefore more suitabie for use in the préparation for exampie of liquid or émulsion formulations. The pharmaceutically non-acceptable salts may be preferred for the purification and isolation of the compounds of general formula (i) and therefore also fall within the scope of the invention.

The term “prodrug” refers to dérivatives of compounds of general formula (I) according to the invention which themselves hâve no therapeutic effect but containing such groups which, after in vivo Chemical or metabolic dégradation (biotransformation) become “biologically active métabolites” which are responsible for the therapeutic effect. Such decomposing groups associated with the compounds of general formula (I) of the présent invention, in particular those suitabie for prodrugs, are known in the art and may also be applied for the compounds of the présent invention (Rautio et al., Nat RevDrug Discov2008, 7:255-270).

The compounds of general formula (I) may exist in various géométrie isomeric forms. In addition, certain compounds of general formula (I) may contain one or more asymmetric centers, thus exist in the form of stereoisomers and diastereomers. Ail of these compounds, such as c/s isomers, trans isomers, diastereomeric mixtures, racemates, non-racemic mixtures of enantiomers, substantially pure and pure enantiomers also fall within the scope of the invention. The substantially pure enantiomers contain up to 5 wt%, preferably 2 wt%, most preferably 1 wt%, of the corresponding opposite enantiomer.

Optical isomers can be prepared by resoiving the racemic mixtures by known methods, for example, by using an opticaily active acid or base to form diastereoisomeric salts or by forming covalent diastereomers. Suitabie acids include, for exampie, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Diastereoisomeric mixtures can be separated into individual diastereomers based on their physical and/or Chemical différences, by methods known to those skilled in the art, such as chromatography or fractional crystallization. Subsequently, the optically active bases or acids are liberated from the separated diastereoisomeric salts. Varions methods of separating opticai isomers include chiral chromatography (e.g., chiral HPLC columns) optionally used by derivatization with the aim to maximize the séparation of enantiomers. Appropriate chiral HPLC columns are Diacel columns, such as CHIRALPAK or CHIRALCEL columns, which can be routinely chosen as desired. Where applicable, enzymatic séparations carried out by derivatization may also be used. The optically active compounds of general formula (!) can also be prepared using optically active starting materials using chiral synthesis without racemization reaction conditions.

The absolute configuration of the chiral compounds was determined by VCD (vibrational circular dichroism spectroscopy) method described in the literature (Freedman et al., Chirality 2003, 75(9):743-58; Stephens et al., Chirality 2008, 20:643-663) and/or by ¹H NMR spectroscopic assays of the diastereomeric pair of compounds synthesized from chiral compounds (Seco et al., J Org Chem 1999, 64.4669-4675; Seco et al., Tetrahedron Asymmetry 2001, 72:2915-2925; Latypov et al., J.Am.Chem.Soc. 1998, 120, 4741-4751).

The compounds of general formula (I) may exist in various polymorphie forms. As is known in the art, polymorphism is the ability of a compound to crystallize in more than one crystalline form, i.e. in polymorphie form. Polymorphie forms of a particular compound can be defined by identical Chemical formula or composition and differ in their Chemical structure like the crystalline structures of two different Chemical compounds.

The compounds of general formula (I) and salts thereof may also be présent as solvatés or hydrates, which also fall within the scope of the invention. The term solvaté refers to non-covalent combinations of solvent and soluté. The term hydrate refers to noncovalent combinations of water and soluté.

The présent invention further relates to pharmaceutical compositions containing the compound of general formula (I) and/or sait thereof and/or géométrie isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvaté thereof and/or hydrate thereof and/or polymorph thereof.

The présent invention also relates to the Chemical and pharmaceutical préparation of pharmaceutical compositions containing the compound of general formula (!) and/or sait thereof and/or géométrie isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or solvaté thereof and/or hydrate thereof and/or polymorph thereof.

The pharmaceutical compositions of the présent invention may be formulated in various pharmaceutical formulations, such as, but not limited to, solid oral dosage forms such as tablets (e.g. buccal, sublingual, effervescent, chewable, orally dispersible), capsules, pills, pilulas, orally dispersible films, granules, powders; liquid formulations such as solutions, émulsions, suspensions, syrups, élixirs, drops; parenterai dosage forms such as intravenous injections, intramuscular injections, subcutaneous injections; other forms of medicine such as eye drops, semi-solid ophthalmic préparations, semi-solid dermal préparations (such as ointments, creams, pastes), transdermal therapeutic Systems, suppositories, rectal capsules, rectal solutions, émulsions and suspensions, etc.

One embodiment of the invention relates to pharmaceutical compositions for paediatric use, such as, but not limited to, solutions, syrups, élixirs, suspensions, powders for the préparation of suspensions, dispersible or effervescent tablets, chewable tablets, orodispersible tablets, tablets or coated tablets, orally sparkling powders or granules, capsules.

The pharmaceutical compositions of the présent invention may be prepared by methods known perse, such as conventional mixing, dissolution, émulsification, suspending, microencapsulation, lyophilisation, extrusion and spheronisation, lamination, film coating, granulation, encapsulation, drageeing or pressing.

The pharmaceutical compositions of the présent invention may be formulated in the usual way using one or more physiologically acceptable excipients, including binders, which promote the incorporation of the active substance into pharmaceutically acceptable pharmaceutical forms. The proper formulation dépends on the mode of administration chosen. Any of the techniques and excipients well known in the art can be used.

The excipients applicable in the préparation may be selected from the following categories, such as, but not limited to, fillers of tablets and capsules, binders of tablets and capsules, modified drug release agents, disintegrants, glidants, lubricants, sweeteners, taste-masking agents, flavourants, coating materials, surfactants, stabilisers, preservatives or antioxidants, buffering agents, complexing agents, wetting or emulsifying agents, salts for adjusting the osmotic pressure, lyophilisation excipients, microencapsulating agents, ointment materials, pénétration enhancers, solubiiisers, solvents, suppository materials, suspending agents . Suitable pharmaceutical excipients can be for example: starch, microcrystalline cellulose, talc, glucose, lactose, gelatin, silica, talc, magnésium stéarate, sodium stéarate, glycerol monostearate. cellulose dérivatives, sodium chloride, glycerol, propylene glycol, water, éthanol and the like.

Another embodiment of the présent invention relates to the use of spécial binders that can improve the solubiiity, dissolution, pénétration, absorption or bioavailability of the active substance(s), such as, but not limited to, hydrophilic polymers, hot melting extruding excipients, surfactants, buffering agents, complexing agents, emulsifying agents, lyophilization excipients, désintégrants, microencapsulating agents, pénétration promoters, solubilisers, cosolvents, suspending agents.

The excipients described above and the various methods of préparation are only représentative examples. Other materials and process techniques known in the art may also be used.

The terms disease or condition associated with V1a receptor function or disease or condition associated with the central and/or peripheral modulation, preferably antagonisation of the V1a receptor refer to a disease or condition selected from the group consisting of various pathological conditions of the female sex organs, long-standing conditions in blood pressure control, conditions resulting from inappropriate sécrétion of vasopressin, anxiety, dépréssion, aggression, disorders ofthecentral nervous system where one of the symptoms and/or syndromes of the disease may be related to anxiety, dépréssion, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavioural disorders and/or irritebility, behavioural hyperactivity disorders, cognitive disorders or other neuropsychiatrie disorders.

The various pathological conditions of the female sex organs include, but not limited to, dysmenorrhea (primary and/or secondary) or sexual dysfunction.

The long-standing conditions in blood pressure control include, but not limited to, hypertension and/or chronic heart failure.

The conditions resulting from inappropriate sécrétion of vasopressin include, but not limited to, diabètes insipidus, rénal failure, nephrotic syndrome or cirrhosis.

The disorders of the central nervous System where one of the symptoms and/or syndromes of the disease may be related to anxiety, dépréssion, aggression or show comorbidity with them include, but not limited to, autistic spectrum disorder (well-functioning autism, Asperger's syndrome, Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS), autism spectrum disorder (ASD) and its various syndrome forms: fragile X syndrome, Prader-Willi syndrome, Rett syndrome, tuberous sclerosis), obsessive compulsive disorder (OCD), various forms of Down syndrome and post-traumatic stress disorder (PTSD).

The aggressive behavioural disorders and/or irritability include, but not limited to, ASD, Huntingtoris disease or different forms of schizophrenia.

The behavioural hyperactivity disorders include, but not limited to, attention déficit hyperactivity disorder.

The cognitive disorders include, but not limited to, dementia, mild cognitive disorders, cognitive impairment associated with schizophrenia or Alzheimer's disease.

The other neuropsychiatrie disorders include, but not limited to, schizophrenia and associated diseases.

In one embodiment, the disease or condition associated with V1a receptor function w or disease or condition associated with the central and/or peripheral modulation, preferably antagonisation of V1a receptor refers to autistic spectrum disorder.

The présent invention relates to a method for treating and/or preventing a disease or condition associated with V1a receptor function, comprising the administration to a subject in need of treatment and/or prophylaxie, preferably a mammal, more preferably a human 15 being, of a therapeutically effective amount of a compound of general formula (!) and/or sait thereof and/or géométrie isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvaté thereof and/or hydrate thereof and/or polymorph thereof alone or with at least one pharmaceutically acceptable excipient in the form of a pharmaceutical formulation.

The présent invention relates to a method for the treatment of a subject, preferably a mammal, more preferably a human being, suffering from a disease or condition selected from the group consisting of various pathological conditions of the female sex organs, longstanding conditions in blood pressure control, conditions resulting from inappropriate sécrétion of vasopressin, anxiety, dépréssion, aggression, disorders of the central nervous 25 system where one of the symptoms and/or syndromes of the disease may be related to anxiety, dépréssion, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavioural disorders and/or irritability, behavioural hyperactivity disorders, cognitive disorders or other neuropsychiatrie disorders, or combination of the 30 these diseases. This method of treatment comprises the administration to a subject in need of such treatment, preferably a mammal, more preferably a human being, the therapeutically effective amount ofthe compound of general formula (I) and/or saitthereof and/orgéométrie isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvaté thereof and/or hydrate thereof and/or polymorph thereof. The method of treatment may include the administration to a subject in need of such treatment, preferably a mammai, more preferably a human being, of a therapeutically effective amount of a pharmaceutical composition comprising the compound of general formula (I) and/or sait thereof and/or géométrie isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvaté thereof and/or hydrate thereof and/or polymorph thereof.

The présent invention relates to the use ofthe compound of general formula (I) and/or sait thereof and/or géométrie isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvaté thereof and/or hydrate thereof and/or polymorph thereof for the manufacture of a médicament for the treatment and/or prophyiaxis of a disease or condition associated with V1a receptor function.

The term treatment refers to the alleviation of a spécifie pathological condition, the élimination or réduction of one or more of the symptoms of the condition, the slowing or élimination of the progression of the disease State, and the prévention or deiay of récurrence of the pathologicai condition of a patient or subject already suffering from or diagnosed with the disease. Prévention (or prophyiaxis or delay of occurence of the disease) is typically performed by administering the drug in the same or similar way as if it were given to a patient with a disease or condition already developed.

The term therapeutically effective amount refers to the amount of active substance resulting in the treatment, cure, prévention or improvement of the disease or pathological condition or side effect, and reduces the progression of the disease or pathological condition in comparison with the corresponding subject who did not receive such amount. The term also includes effective amounts to enhance normal physiological functioning. For use in therapy the compound of general formula (I) and/or géométrie isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvaté thereof and/or hydrate thereof and/or polymorph thereof as well as any pharmaceutically acceptable sait thereof may be administered in a therapeutically effective amount as a raw Chemical. In addition, the active substance can be made available as a pharmaceutical formulation. The exact therapeutically effective amount ofthe compound ofgeneral formula (I) and/or saitthereof and/orgéométrie isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or soivate thereof and/or hydrate thereof and/or polymorph thereof dépends on a number of factors including, but not limited to, the âge and body weight ofthe subject (patient) treated, the précisé type of disease requiring treatment and its seriousness, the nature of the medicina! product and the route of administration.

The term mammal refers to any member of the Mammalia ciass, including, but not limited to, humans.

The présent invention also relates to pharmaceutical compositions comprising the compound of general formula (I) and/or sait thereof and/or géométrie isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvaté thereof and/or hydrate thereof and/or polymorph thereof suitable for the treatment of a disease or condition associated with the central and/or peripheral modulation, preferably antagonisation of the V1a receptor.

The compound ofthe invention may also be used in combination with one or more of the compounds of the invention or with one or more other active substance (e.g., psycholeptics, psychoanaleptics, antihypertensives, spasmolytics, antiepileptics or other agents) in a mammal, including, but not limited to, humans, suffering from a centrai and/or peripheral disease, where the central and/or peripheral modulation, preferably antagonisation of V1a receptor has therapeutic benefits.

Psycholeptics include, but not limited to, antipsychotics, anxiolytics, and sedatohipnotics or narcotics.

Antipsychotics include, but not limited to, typical and atypicai antipsychotics, such as phenothiazines with ahphatic side chains (chlorpromazine, promazine, ievomepromazine, acepromazine, trifluproazine, ciamemazine, chiorproethazine, protipendyl), piperazinederived phenothiazines (dixyrazine, flufenazine, perazine, perfenazine, prochlorperazine, thiopropazate, trifluoperazine, acetophenazine, thioproperazine, butaperazine, perazine), piperidine-derived phenothiazines (periciazine. thioridazine, mesoridazine, pipothiazine), thioxanthenes (chlorprothixene, clopenthixole, flupentixol, thiothixene, zuclopenthixol), butyrophenone dérivatives (haloperidol, triflupidol, melperone, moperone, pipamperone, bromperidol, benperidol, droperidol, timiperone, fluanisone), diphenylbutylpiperidine dérivatives (fluspirilene, penfluridol, pimozide), diazepine-, oxazepine- or thiazepine dérivatives (clozapine, olanzapine, clotiapine, quetiapine, loxapine, azenapine), indole dérivatives (sertindole, ziprasidone, lurazidone, molindone, oxipertine), benzamide dérivatives (sulpiride, sultropride, tiapride, remoxipride, amisulpride, veralipride, nemonapride, verasulpiride) or other agents (rispéridone, aripiprazole, cariprazine, brexpiprazole, metoclopramide, mosapramine, iloperidone, paliperidone, amoxapine, amperoside, perospirone, carpipramine, clocapramine, tetrabenazine, lithium).

Anxiolytics include, but not limited to, benzodiazépines (diazepam, chlorodiazepoxide, medazepam, oxazepam, potassium chlorazepate, lorazépam, adinazolam, bromazepam, clobazam, ketazolam, prazepam, alprazolam, halazepam, pinazepam, camazepam, nordazepam, fludiazepam, ethyl loflazepate, etizolam, clotiazepam, coxazoiam, tophizopam), diphenyimethane dérivatives (hydroxyzine, captodiame), carbamates (meprobamate, emilcamate, mebutamate), dibenzobicyclooctadiene dérivatives (benzoquinone), azaspirode-diones (buspirone), other agents (mefenoxaîone, gedocarnil, etifoxine, fabomotizole, trimethosine), dérivatives acting by increasing GABA_A-mediated inhibition or compounds acting on a serotonin receptor, and other GABAergic agents (such as GABAa a5 NAMs, e.g. basmisanil, GABAa a5 PAMs, e.g. RG7816).

Sédative hypnotics or narcotics include, but not limited to, barbiturates (pentobarbital, amobarbitai, butobarbital, barbital, aprobarbital, secobarbital, talbutal, vinylbital, vinbarbital, cyclobarbital, heptabarbital, reposai, methohexitol, hexobarbital, thiopental, ethallobarbital, allobarbitol, proxibarbital), aldéhydes (chloral hydrate, chioralodol, acetylglycinamide chloral hydrate, dichloralphenazone, paraldéhyde), benzodiazépines (flurazepam, nitrazepam, flunitrazepam, estazolam, triazolam, lormetazepam, temazepam, midazolam, brotizolam, quazepam, loprazolam, doxefazepam, cinolazepam), piperidindione dérivatives (glutethimide, methypryîon, pyrithyldione), cyclopyrroîone benzodiazépine dérivatives (zopiclone, zolpidem, zaleplon, eszopiclone), meiatonin receptor agonists (melatonin, ramelteon) or other hypnotics and sédatives (methaqualone, clomethiazoie, bromisoval, carbromal, scopolamine, propiomazine, triclofos, ethchlorvynol, Vaierianae Radix, hexapropymate, bromides, apronal, valnoctamide, methylpentynol, niaprazine, dexmedetomidine).

Psychoanaieptics include, but not limited to, psychostimulants or antidepressants.

Psychostimulants include, but not limited to, centrally acting sympathomimetics (amphétamine, dexamphetamine, methamphetamine, methylphenidate, pemoline, fencamfamine, modafinil, phenozolone, atomoxetine, phenetiliine, dexmethylphenidate, lysdexamfetamine), nootropics or other psychostimulants (caffeine, propentofylline, meciofenoxate, pyritinol, piracetam, deanol, fipexide, citocohne, oxiracetam, pirisudanol, linopirdine, nizofenone, aniracetam, acetylcamitine, idebenone, prolintane, pipradroi, pramiracetam, adrafinil, vinpocetine, tacrine, donepezil, rivastigmine, galantamine, ipidachrine, memantine, mebicar, phenibut).

Antidepressants include, but not limited to, non-selective monoamine reuptake inhibitors (desipramine, imipramine, imipramine oxide, clomipramine, opipramol, trimipramine, lofepramine, dibenzepine, amitriptyline, nortriptyline, protriptyline, doxepin, iprindole, melitracene, butriptyline, dosulepin, amoxapine, dimetacrine, amineptin, maprotiline, quinupramine), serotonin modulator and stimulators (vilazodone, vortioxetine), sélective serotonin reuptake inhibitors (zimeldine, fluoxetine, paroxetine, sertraline, aiaproclate, fluvoxamine, etoperidone, citalopram, escitalopram), non-selective hydrazidederived monoamine oxidase inhibitors (isocarboxazide, nialamide, phenelzine, tranylcypromine, iproniazid, iprocloside), non-hydrazide monoamine oxidase inhibitors (moclobemide, toioxatone) or other agents (oxitriptan, tryptophan, mianserin, nomifensin, trazodone, nefazodone, minaprine, bifemeîane, viloxazine, oxafiozane, mirtazapine, medifoxamine, tianeptine, pivagabine, venlafaxine, milnacipran, reboxetine, pyrazidol, duloxetine, agomelatine, desvenlafaxine, bupropion, gepirone, Hyperici herba extractum).

Antihypertensives include, but not limited to, β receptor blockers, thiazide diuretics, angiotensin-converting-enzyme inhibitors, calcium antagonists, angiotensin receptor antagonists (losartan), Rauwoifia alkaloids (rescinnamine, reserpine, deserpidine, methoserpidine, bietaserpine), methyldopa, imidazoline receptor agonists (clonidine, guanfacine, toionidine, moxonidine, rilmenidine), ganglion blocking antiadrenergic agents (sulfonium dérivative trimetaphan, secondary and tertiary amine mecamylamine), peripherally acting antiadrenergic agents, alpha-adrenoreceptor blockers (prazosin, indoramin, trimazosin, doxazosin, urapidil), guanidine dérivatives (betanidine, guanethidine, guanoxane, debrisoquine, guanoclor, guanazodine, guanoxabenz), agents acting on arteriolar smooth muscle, the thiazide dérivative diazoxide, hydrazinophthalazine dérivatives (dihydralazine, hydralazine, endralazine, cadralazine), the pyrimidine dérivative minoxidil, the nitroferricyanide dérivative nitroprusside, the guanidine dérivative pinacidil, the nonRauwolfia alkaloid veratrum, the tyrosine hydroxylase inhibitory metyrosine, the MAO inhibitor pargyline, the serotonin antagonist ketanserin, or other antihypertensives (bosentan, ampbrisentan, sitaxentan, macitentan, riociguat) and a combination of these substances with a diuretic.

Spasmoiytics or antispasmodics include, but not limited to, peripheral muscle relaxants, curare alkaloids, choline dérivatives, other quaternary ammonium muscle relaxants (pancuronium, gallamine, vecuronium, atracurium, hexafluronium, pipecuronium bromide, doxacurium chloride, fazadinium bromide, rocuronium bromide, mivacurium bromide, cisatracurium, botulinum toxin), centra! nervous system muscle relaxants, carbamic acid esters (phenprobamate, carisoprodol, metocarbamol, styramate, febarbamate), oxazole-, thiazine- and triazine dérivatives (chîormezanone, chlorzoxazone), ethers related to antihistamines (orphenadrine, guaifenesin) and other histaminergic agents (such as histamine H₃ receptor antagonists/inverse agonists e.g. ciproxifan, thioperamide, pitolisant, clobenpropit, ABT-239, conessine, A-349,821, betahistine), other centrally acting agents (baciofen, arbaclofen, tizanidine, pridinol, tolperisone, thiocolchicoside, mephenesin, tertazepam. cyclobenzaprine, phenyramidoi), the directly acting muscle relaxant dantrolene and its dérivatives, compounds acting by increasing GABAA-mediated inhibition or decreasing conduction of Na⁺ (phenytoin, carbamazepine, lamotrigine, VPA), gammaaminobutyric acid dérivatives (vigabatrin, gabapentin), other GABAergic agents (such as GABAb PAMs, e.g. ADX71441), esters with a tertiary amino group (oxyphencyclimine, camylofin, mebeverine, trimebutine, rociverine, dicycloverine, dihexyverine, difemerine, piperidoiate), quaternary ammonium compounds (benzilone, glycopyrronium, oxyphenonium, penthienate, propantheline, otilonium bromide, methantheline, tridihexethyl, isopropamide, hexocyclium, poldine, mepenzolate, bevonium, pipenzolate, diphemanil, emetonium iodide, tiemonium iodide, prifinium bromide, timepidium bromide and fenpiverinium), amides with tertiary amines (astra 1397, nicofetamide, tiropramide), papaverine and its dérivatives (drotaverine, moxaverine, etaverine), agents acting on serotonin receptors (alosetron, tegaserod, cilansteron, prucalopride), other agents of functional gastrointestinal disorders (fenpiprane, diisopromine, chiorbenzoxamine, pinaverium, fenoverine, idanpramine, proxazole, alverine, trepibutone, isometheptene, caroverine, phloroglucinol, silicones, trimethyldiphenylpropyîamine), succinimide dehvative (ethosuximide, phensuximide, mesuximide) or Belladonna alkaloids and their dérivatives (atropine, hyoscyamine, butylscopolamine, methylatropine, methylscopolamine, fentonium, cimetropium bromide).

Antiepileptics include, but not limited to, barbiturates and their dérivatives (methylphenobarbital, phénobarbital, primidone, barbexaclone, metharbital), hydantoin dérivatives (ethotion, phenytoin, amino(diphenylhydantoin) valeric acid, mephenytoin, fosphenytoin), oxazolidine dérivatives (paramethadione, trimethadione, ethadion), succinimide dérivatives (ethosuximide, phensuximide, mesuximide), benzodiazépine dérivative clonazepam, carboxamide dérivatives (carbamazepine, oxcarbazepine, rufinamide), fatty acid dérivatives (valproic acid, valpromide, aminobutyric acid, vigabatrin, progabide, tiagabine) and other antiepileptics (suitiame, phenacemide, lamotrigine, felbamate, topiramate, gabapentin, pheneturide, levetiracetam, zonisamide, pregabalin, stiripentol, lacosamide, carisbamate, retigabine, brivaracetam, beclamide).

Other agents include, but not limited to, médicinal products (probiotics, digestive aids/digestives, herbal extracts), vitamins (both water soluble and fat soluble, such as, but not limited to, vitamin A, D3, E, K, B1, B5, B6, B12, C or their dérivatives) and nutritional suppléments (coenzymes e.g. Q10, flavonoids e.g. resveratrol, lecithin, unsaturated fatty acids, including fatty acids ω-3 and ω-6).

The compounds of the invention may aiso be used in combination with phosphodiesterase 5 isoenzyme inhibitors (PDE5), nitric oxide donors, cycîooxygenase inhibitors, other V1a receptor antagonists (such as batovaptan) or L-arginine for the treatment and/or prophylaxis of a disease or condition associated with V1a receptor function.

The combinational composition may comprise the compound of the invention together with another active substance in a single dosage form or separately. The combinational composition may be administered simultaneously, separately or sequentially.

Suitabie dosage forms include oral, rectal, mucous, transdermal or intestinal administration; parenterai administration including intramuscular, subcutaneous, intravenous, intramedullary injections as well as intraarticular, intrathecal, direct intraventricular, intraperitoneal, intranasal or intraocular injections and eye drops.

Aiternatively, the compounds may be administered locally and not systemically, for example by direct injection of the compound to the kidney or the heart, often in a modified release formulation. In addition, the drug may be administered in a targeted carrier system, for example in a tissue-specific antibody encapsulated liposome. The liposomes transfer the active substance selectively to the target organ, which absorbs it.

The pharmaceutical composition may be administered in various ways and in pharmaceutical forms. The compound of the invention may be administered alone or in combination with pharmaceutically acceptable excipients, in single or multiple doses. The dose required to achieve the appropriate therapeutic effect may vary wideîy and must aiways be adapted to individual needs with regard to the stage of disease, the condition and weight of the patient to be treated, and the sensitivity to the active substance, the way of dosage regimen, and the numbers of daily treatments.

For simple administration, it is preferred that the pharmaceutical compositions consist of dosage units that contain the amount of drug to be administered once, or a small number of its multiple, or half, one third, one quarter. Such dosage units are, for example, tablets that can be provided with a half or quarter groove to facilitate halving or quarter-splitting of the tablet in order to measure the required amount of drug.

Pharmaceutical compositions containing the active substance according to the invention generally contain from 0.01 to 500 mg of active substance per dosage unit. It is of course also possible that the amount of active substance in each formulation exceeds the above limit either up or down.

Further preferred groups of compounds of general formula (I) are those wherein each embodiments of ring A, ring B, X, Y, Z, R¹-R²\ Cy¹-Cy³ and m described below are optionally combined. Any combination ofthe preferred, more preferred or most preferred embodiments of ring A, ring B, X, Y, Z, R¹-R²¹, Cy¹-Cy³ or m as defined below are also preferred, more preferred and most preferred groups of compounds of formula (I).

In certain embodiments ofthe invention, ring A in the compounds of general formula (I) is a 4 to 6-membered saturated carbooycle.

In certain preferred embodiments ofthe invention, ring A in the compounds of general formula (I) is cyciobutyl or cyclohexyi.

In certain more preferred embodiments of the invention, ring A in the compounds of general formula (i) is cyclohexyi.

In certain embodiments of the invention, ring A in the compounds of general formula (I) is a 4- to 7-membered saturated heterocyclyl group containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to Y.

in certain embodiments of the invention, ring A in the compounds of general formula (I) is a 4- to 7-membered saturated heterocyclyl group containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to the triazoie ring of the 5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepine core.

In certain embodiments of the invention, ring A in the compounds of general formula (I) is azetidinyi, 1,3-diazetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyi, azepanyl, 1,3- or 1,4-diazepanyl, wherein ring A is attached via a ring nitrogen to Y.

In certain embodiments of the invention, ring A in the compounds of general formula (!) is azetidinyi, 1,3-diazetidinyl, pyrrolidinyl, pyrazoiidinyi, imidazolidinyl, piperidinyl, piperazinyi, azepanyl, 1,3- or 1,4-diazepanyl, wherein ring A is attached via a ring nitrogen to the triazoie ring of the 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine core.

in certain preferred embodiments of the invention, ring A in compounds of générai formuia (I) is azetidin-1,3-diyl, piperidin-1,4-diyi or piperazine-1,4-diyi, wherein ring A is attached via a ring nitrogen to Y or to the triazole ring of the 5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepine core.

In certain embodiments of the invention, ring B in the compounds of general formula (I) is optionally substituted aryl group.

In certain preferred embodiments ofthe invention, ring B in the compounds of general formula (!) is optionally substituted phenyl.

In certain embodiments ofthe invention, ring B in the compounds of general formula (I) is optionally substituted heterocyclyl group.

in certain preferred embodiments ofthe invention, ring B in the compounds of general formula (i) is optionally substituted tetrahydrofurany!, tetrahydropyranyi, pyrrolidinyl, piperidinyl piperazinyl, morpholinyl or azabicyclo[2.2.2]octyl.

In certain more preferred embodiments of the invention, ring B in the compounds of general formula (i) is tetrahydrofuran-3-yl, tetrahydropyran-4-yl, pyrrolidin-1-yl, pyrrolidin-1 yl-2-one, piperidin-1-yl, 4-methyl-piperazin-1-yl, morpholin-4-y! or 1-azabicyclo[2.2.2]oct-3yiIn certain embodiments ofthe invention, ring B in the compounds of general formula (I) is optionally substituted heteroaryl group.

In certain embodiments of the invention, ring B in the compounds of general formula (I) is optionally substituted single 6- or 5-membered mono heteroaryl group.

In certain preferred embodiments ofthe invention, ring B in the compounds of general formula (I) is optionally substituted pyridinyl, pyrimidinyl or isoxazolyl

In certain more preferred embodiments of the invention, ring B in the compounds of general formula (I) is pyridin-2-yl, pyridin-3-yl, 3-chloropyridin-2-yl, 3-methyl-pyridin-2-yl, pyrimidin-2-yl or 5-methyl-isoxazol-3-yl.

In certain most preferred embodiments of the invention, ring B in the compounds of general formula (i) is pyridin-2-yi.

In certain embodiments of the invention, Y in the compounds of general formula (I) is -O-, if ring B is présent.

In certain embodiments of the invention, Y in the compounds of general formula (I) is -C(O)-, if ring B is présent.

In certain embodiments of the invention, Y in the compounds of general formula (I) is -CH2-, if ring B is présent.

In certain embodiments of the invention, Y in the compounds of general formula (I) is -NH-, if ring B is présent.

In certain embodiments of the invention, Y in the compounds of general formula (I) is -Ci-₄alkyi-N(R¹⁸)-, if ring B is présent.

In certain preferred embodiments of the invention, Y in the compounds of general formula (I) is a single bond, if ring B is présent.

in certain embodiments of the invention, Y in the compounds of general formula (I) is -N(C^alkyl)2, C(O)OCi-4alkyl, Ci-₄alkyl optionally substituted with halogen, C1-4alkoxy group or halogen, if ring B is not présent.

In certain embodiments of the invention, Y in the compounds of general formula (I) is

Ci.₄aikyl optionally substituted with haiogen or Ci.₄alkoxy group, if ring B is not présent.

In certain preferred embodiments of the invention, Y in the compounds of general formula (I) is Ci-salkyl group, if ring B is not présent.

In certain more preferred embodiments of the invention, Y in the compounds of 15 general formula (I) is methyl, ethyl, or propyl group, if ring B is not présent.

In certain preferred embodiments of the invention, Y in the compounds of general formula (I) is Ci-salkoxy group, if ring B is not présent.

In certain more preferred embodiments of the invention, Y in the compounds of general formula (i) is methoxy or ethoxy group, if ring B is not présent.

In certain preferred embodiments of the invention, Y in the compounds of general formula (I) is CF₃ group, if ring B is not présent.

In certain embodiments of the invention, Y in the compounds of general formula (I), if ring B is not présent, refers to one group selected from the group consisting of -N(Ci-4alkyl)₂, C(O)OCi.₄alkyl, Ci-₄alkyl optionally substituted with halogen, Ci-₄alkoxy group and halogen.

In certain preferred embodiments of the invention, Y in the compounds of general formula (I), if ring B is not présent, refers to one group selected from the group consisting of dimethyiamine, C(O)OCi-₄alkyl and CF₃ group.

In certain embodiments of the invention, Y in the compounds of general formula (I), if ring B is not présent, refers to two groups selected from the group consisting of Ci.₄alkyl 30 optionally substituted with halogen, Ci.₄alkoxy group and halogen.

In certain preferred embodiments of the invention, Y in the compounds of general formula (I), if ring B is not présent, refers to two groups selected from the group consisting of Cvsaîkyl, Ci-salkoxy, CF₃ group and fluorine.

In certain more preferred embodiments of the invention, Y in the compounds of general formula (I), if ring B is not présent, refers to two groups selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, CF₃ group and fluorine.

In certain even more preferred embodiments of the invention, Y in the compounds of general formula (I), if ring B is not présent, refers to two groups selected from the group consisting of methyl, ethyl, propyl, methoxy and ethoxy group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), ring A is cyclobutyi or cyclohexyl, Y refers to one group selected from the group consisting of -N(Ci-4alkyl)₂, -C(O)OCi-4aiky!, CF₃ and halogen and ring B is not présent.

In certain preferred embodiments of the invention, in the compounds of general formula (I), ring A is cyciobutyl or cyclohexyl, Y refers to two groups selected from the group consisting of Ci.4alkyl optionally substituted with halogen, Ci.4alkoxy group and halogen and ring B is not présent.

In certain preferred embodiments of the invention, in the compounds of general formula (i), ring A is cyciobutyl or cyclohexyl, Y is -O- or bond and ring B is optionally substituted phenyl, piperidin-1-yl, morphoiin-4-yi, 1-azabicyclo[2.2.2]oct-3-yl, pyridin-2-yl, pyridin-3-yl, 3-chloro-pyridin-2-yi, 3-methylpyridin-2-yl, pyrimidin-2-yl or 5-methylisoxazol-3yl.

In certain more preferred embodiments of the invention, in the compounds of general formula (I), ring A is cyclohexyl, Y is -O- and ring B is pyridin-2-yl, pyridin-3-yl, 3-chloropyridin-2-yl, 3-methylpyridin-2-yl, pyrimidin-2-yl or 5-methylisoxazol-3-yl.

In certain most preferred embodiments of the invention, in the compounds of general formula (I), ring A is cyclohexyl, Y is -O- and ring B is pyridin-2-yl.

In certain preferred embodiments of the invention, in the compounds of general formula (I), ring A is azetidin-1,3-diyi, piperidin-1,4-diyl or piperazine-1,4-diyl, wherein ring A is attached via a ring nitrogen to Y or to the triazole ring of the 5,6-dihydro-4H[1,2,4]triazoio[4,3-a][1]benzazepine core, Y is -O- or bond and ring B is optionally substituted phenyl, piperidin-1-yl, morpholin-4-yl, 1-azabicyclo[2.2.2]oct-3-yl, pyridin-2-yl, pyridin-3-yl, 3chloro-pyridin-2-yl, 3-methylpyridin-2-yl, pyrimidin-2-yi or 5-methylisoxazoi-3-yl.

!n certain more preferred embodiments of the invention, in the compounds of general formula (I), ring A is piperidin-1,4-diyl or piperazine-1,4-diyl, wherein ring A is attached via a ring nitrogen to Y or to the triazole ring of the 5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepine core, Y is -O- or bond and ring B is pyridin-2-yl or pyridin-3-yl.

in certain embodiments of the invention, in the compounds of general formula (i), ring A is cyciobutyl, cyclohexyl or pyrrolidinyl, Y is -C(O)- and ring B is pyrrolidin-1 -yl, piperidin-1 yl, morpholin-4-yl, 4-methyl-piperazinyl or pyridine-3-yl.

In certain embodiments of the invention, B-Y-A- in the compounds of general formula (I) jointly represents 3H-spiro[2-benzofuran-1,4'-piperidin-1’-yl], 1-oxa-3-azaspiro[4.5]decan2-on-8-yl substituted at 3-position by Ci-4alkyl or 2-azaspiro[4.5]decan-1-on-8-yl substituted at 2-position by Ci^aîkyl, aryl or heteroaryl.

In certain preferred embodiments of the invention, B-Y-A- in the compounds of general formula (I) jointly represents 3H-spiro[2-benzofuran-1,4'-piperidin-T-yl], (5S,8S)-3methyl-1-oxa-3-azaspiro[4.5]decan-2-on-8-yl, (5R,8R)-3-methyl-1-oxa-3azaspiro[4.5]decan-2-on-8-yl, (5R,8R)-2-(propan-2-yl)-2-azaspiro[4.5jdecan-1-one or (5S,8S)- 2-(propan-2-yl)-2-azaspiro[4.5]decan-1-one.

in certain embodiments of the invention, R¹ in the compounds of general formula (I) is hydrogen.

in certain embodiments of the invention, R¹ in the compounds of general formula (I) is halogen.

In certain preferred embodiments of the invention, R¹ in the compounds of general formula (I) is chlorine, bromine or fluorine.

In certain more preferred embodiments of the invention, R¹ in the compounds of general formula (I) is chlorine.

In certain embodiments of the invention, R¹ in the compounds of formula (I) is Ci₄ alkyl.

In certain preferred embodiments of the invention, R¹ in the compounds of general formula (I) is methyl.

In certain embodiments of the invention, R¹ in the compounds of general formula (I) is Ci.4alkoxy.

in certain preferred embodiments of the invention, R¹ in the compounds of general formula (I) is methoxy.

In certain embodiments of the invention, R¹ in the compounds of general formula (I) is CF3.

In certain embodiments of the invention, R¹ in the compounds of general formula (i) is CN.

In certain embodiments of the invention, in the compounds of general formula (I), R² is hydrogen or Ci-4alkyl, R³ is NR⁴R⁵, OR⁶group or halogen.

In certain embodiments of the invention, in the compounds of general formula (I), R²is Ci^alkyl, R³ is NR⁴R⁵, OR® group or halogen.

In certain embodiments of the invention, in the compounds of general formula (I), R²10 is hydrogen, R³ is NR⁴R⁵, OR⁶ group or halogen.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R⁵ or OR⁶ group and the absolute configuration of the carbon at position 5 in the 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine core is (R).

In certain embodiments of the invention, in the compounds of general formula (I), R²15 is hydrogen, R³ is NR⁴R⁵ or OR⁶ group and the absolute configuration of the carbon at position 5 in the 5,6-dihydro-4H-[1,2,4]triazoio[4,3-a][1]benzazepine core is (S).

In certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen, R³ is NR⁴R⁵orOR⁶ group.

In certain embodiments of the invention, in the compounds of general formula (I), R²20 is hydrogen, R³ is NR⁴R⁵group.

In certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen or Ci-4alkyl group, R³ is NR⁴R⁵ group, wherein R⁴ and R⁵ are hydrogen.

In certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen, R³ is NR⁴R⁵group, wherein R⁴ is hydrogen, R⁵is Ci.4aÎkyl group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R⁵group, wherein R⁴ is hydrogen R⁵is isopropyl group.

In certain embodiments of the invention, in the compounds of general formula (i), R²is hydrogen, R³ is NR⁴R⁵ group, wherein R⁴ and R⁵ are Ci-4alkyl groups.

In certain preferred embodiments of the invention, in the compounds of general 30 formula (I), R² is hydrogen, R³ is NR⁴R⁵group, wherein R⁴ and R⁵is independently methyl, ethyl or isopropyl group.

In certain more preferred embodiments ofthe invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R⁵ group, wherein R⁴ and R^sare methyl groups.

In certain embodiments ofthe invention, in the compounds of general formula (I), R²is hydrogen, R³ is NR⁴R⁵group, wherein R⁴ is hydrogen, R⁶ is OH-substituted C Malkyi group.

in certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R⁵group, wherein R⁴ is hydrogen, R^s is hydroxymethyl or hydroxyethyl-group.

in certain embodiments ofthe invention, in the compounds of general formula (I), R²is hydrogen, R³ is NR⁴R⁵ group, wherein R⁴ is hydrogen, R⁵ is halo-substituted Ci.4alkyl 10 group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R⁵ group, wherein R⁴ is hydrogen, R⁵ is trifluorosubstituted Ci-aalkyl group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R^S group, wherein R⁴ is hydrogen, R⁵ is methylcyciopropyl group.

In certain embodiments ofthe invention, in the compounds of general formula (I), R²is hydrogen, R³ is NR⁴R⁵ group, wherein R⁴ is hydrogen, R⁵ is 4-fluorophenyl-substituted methyl or ethyl group.

In certain embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R⁵group, wherein R⁴ is hydrogen, R⁵ is Ci-4alky substituted with NR⁸R⁹group, wherein R⁸ and R⁹ are independently hydrogen, Ci^alkyl group or CiOiOR²' group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R⁵ group, wherein R⁴ is hydrogen, R^s is Ci.4alky 25 substituted with NR⁸R^S group, wherein R^s is hydrogen, R^a is C(O)OR²¹ group.

In certain embodiments ofthe invention, in the compounds of general formula (I), R²is hydrogen, R³ is NR⁴R⁵group, wherein R⁴ is hydrogen, R⁵ is Ci-4alky substituted with NR⁸R⁹group, wherein R^s and R⁹ are independently hydrogen or C-Malkyl group.

In certain preferred embodiments of the invention, in the compounds of general 30 formula (I), R² is hydrogen, R³is NR⁴R^Sgroup, wherein R⁴ is hydrogen, R⁵is aminomethyl or -ethyl group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R⁵group, wherein R⁴ is hydrogen, R^s is dimethylaminomethyl or -ethyl group.

In certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen, R³ is NR⁴R⁵group, wherein R⁴ is hydrogen, R⁵is Cy¹.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R⁵ group, wherein R⁴ is hydrogen, R⁵ is cyclobutyl, cyclopentyl, cyclohexyl, 4,4-difluoro-cyclohexyl, oxetan-2-yl or tetrahydropyranyl.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R^S group, wherein R⁴ is hydrogen, R⁵ is pyridin-2-yl, pyrimidin-2~yl or pyrazin-2-yl.

In certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen, R³ is NR⁴R⁵ group, wherein R⁴ is hydrogen, R⁵is C(O)R⁷ group, wherein R⁷is methyl, ethyl or isopropyl group.

In certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen, R³ is NR⁴R⁵ group, wherein R⁴ is hydrogen, R⁵is C(O)R⁷ group, wherein R⁷is Ci^alkyl substituted with OH, CN, halogen, Cy³ or NR”R¹² group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R^Sgroup, wherein R⁴ is hydrogen, R⁵is C(O)R⁷ group, wherein R⁷ is methyl, ethyl or isopropyl group substituted with OH, CN or trifluoro.

In certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen, R³ is NR⁴R⁵ group, wherein R⁴ is hydrogen, R⁵ is C(O)R⁷ group, wherein R⁷is methyl or ethyl substituted with NR¹¹R¹² group, wherein R¹¹ and R¹² are independently hydrogen or methyl or R¹¹ and R¹² taken together with the N to which they are attached form morpholin-4-yl or 4-methyl-piperazin-1-yl.

in certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R⁵ group, wherein R⁴ is hydrogen, R⁵ is C(O)R⁷group, wherein R⁷ is aminomethyl group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R⁵group, wherein R⁴ is hydrogen, R⁵ is C(O)R⁷group, wherein R⁷ is dimethylaminomethyl group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R^S group, wherein R⁴ is hydrogen, R⁵ is C(O)R⁷ group, wherein R⁷ is phenyl and/or NH₂-substituted methyl.

in certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen, R³ is NR⁴R⁵group, wherein R⁴ is hydrogen, R⁵ is C(O)R⁷ group, wherein R⁷is tbutoxy group.

In certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen, R³ is NR⁴R^S group, wherein R⁴ is hydrogen, R⁵is C(O)R⁷ group, wherein R⁷is vinyl group.

In certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen, R³ is NR⁴R⁵ group, wherein R⁴ is hydrogen, R⁵is C(O)R⁷ group, wherein R⁷ is Gy³ group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R^S group, wherein R⁴ is hydrogen, R⁵is C(O)R⁷ group, wherein R⁷ is 4-fluorophenyl, cyclopropyl, cyclobutyl, dihaîo-cyclobutyl or cyclohexyl, oxetanyl, tetrahydropyran-4yl, 4-methyl-piperidinyL or 5-methyl-1,3,4-oxadiazol-2-yl.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R⁵ group, wherein R⁴ is hydrogen, R⁵is C(O)R⁷group, wherein R⁷ is dimethylamino group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R^S group, wherein R⁴ is hydrogen or methyl, R^s is S(O2)R^w, wherein R^w is methyl, OH, NH2, NH-f-butyî or dimethylamino group.

In certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen, R³ is NR⁴R⁵ group, wherein R⁴ is hydrogen or Ci-^alkyl group, R⁵is C^alkynyl group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R^S group, wherein R⁴ is methyl group, R⁵is propargyl group.

in certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen, R³ is NR⁴R⁵ group, wherein R⁴ and R⁵ taken together with the N to which they are attached form a 4- to 7-membered heterocycie containing optionally one or more heteroatoms selected from O, S or N.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is NR⁴R⁵, wherein R⁴ and R^s taken together with the N to which they are attached form pyrrolidine, piperidine, piperazine, morpholine, 1,3-oxazolidine, 1,3-thiazolidine or thiomorpholine-1,1-oxide.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is OR⁸group, wherein R⁶is hydrogen.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is OR⁸group, wherein R^sis methyl, ethyi or isopropyl group.

in certain more preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is OR⁸ group, wherein R⁸is methyl group.

In certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen, R³ is OR⁶ group, wherein R⁶is OH- or halogen substituted Ci.₄aikyl group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is OR⁶group, wherein R⁶is chioro- orfluoro-substituted methyl or ethyi group.

In certain embodiments of the invention, in the compounds of general formula (i), R²is hydrogen, R³ is OR⁶ group, wherein R⁶is cyclopropyl-methyl group.

in certain embodiments ofthe invention, in the compounds of general formula (I), R²is hydrogen, R³ is OR⁶group, wherein R⁶is Ci.4alkyi substituted with C1.4aik.oxy group.

in certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is OR⁶ group, wherein R⁶is methoxy-ethyi group.

In certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen, R³ is OR⁶ group, wherein R⁶is Ci.4alkyl substituted with Ci-₄aikyl-S(O)2 group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is OR⁶group, wherein R⁶is methylsulfonyl-ethyl group.

In certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen, R³ is OR⁸ group, wherein R^eis methyl or ethyi substituted with NR¹¹R¹² group, wherein R¹¹ and R¹² are independently hydrogen or methyl.

In certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen, R³ is OR⁵group, wherein R⁶is methyl or ethyi substituted with NR^R¹², wherein R¹¹ and R¹² taken together with the N to which they are attached form a morpholin-4-yl.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is OR⁶group, wherein R^sis dimethylamino-ethyl-group.

In certain embodiments of the invention, in the compounds of general formula (i), R²is hydrogen, R³ is OR⁶ group, wherein R^sis C(O)R¹³, wherein R¹³ is Ci.4alkyl group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is OR³ group, wherein R⁶is C(O)R¹³, wherein R¹³ is methyl, ethyl or f-butyl.

In certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen, R³ is OR⁶ group, wherein R⁶ is C(O)R¹³, wherein R¹³ is Ci-4alkyl group 10 substituted with CN.

in certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is OR⁶ group, wherein R⁸ is C(O)R¹³, wherein R¹³ is cyanomethyl group.

In certain embodiments of the invention, in the compounds of general formula (I), R²15 is hydrogen, R³ is OR⁶ group, wherein R⁶ is C(O)R¹³, wherein R¹³ is Ci-4alkyl group substituted with NR^1SR²⁰ group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is OR⁶ group, wherein R⁶ is C(O)R¹³, wherein R¹³ is dimethylamino-methyl group.

In certain embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is OR⁸ group, wherein R⁶is C(O)R'³, wherein R¹³ is Cy³ group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is OR³ group, wherein R⁶is C(O)R¹³, wherein R¹³ is dihalosubstituted cycloalkyl group.

In certain embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is OR⁶group, wherein R⁶is C(O)R¹³, wherein R¹³ is NR¹⁶R¹⁷, wherein R¹⁶and R¹⁷ are independently hydrogen, C^aikyl or optionally substituted aryl.

In certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen, R³ is OR⁸ group, wherein R^s is C(O)R¹³, wherein R¹³ is NR^1SR¹⁷, wherein R¹⁶30 and R¹⁷ taken together with the N to which they are attached form a piperidine or pyrrolidine.

In certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen, R³ is OR⁸ group, wherein R⁶is Si(CH3)₂-f-butyl.

In certain embodiments of the invention, in the compounds of general formula (I), R²is hydrogen, R³ is OR⁶ group, wherein R⁶is C^alkynyl group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² is hydrogen, R³ is OR⁶group, wherein R®is propargyl group.

In certain embodiments of the invention, in the compounds of general formula (I), R² is Ci^alkyl, R³ is NR⁴R⁵or OR⁶group.

In certain embodiments of the invention, in the compounds of general formula (I), R²is C^alkyl, R³ is OR® group.

In certain embodiments of the invention, in the compounds of general formula (I), one 10 of R² and R³ is methyl or isopropyl other is OR⁶, wherein R⁶is hydrogen.

in certain embodiments of the invention, in the compounds of general formula (i), R²is hydrogen and R³ is halogen.

In certain preferred embodiments of the invention, in the compounds of general formula (i), R² is hydrogen and R³ is fluorine.

In certain embodiments of the invention, in the compounds of general formula (I), R² is Ci^alkyl group and R³ is halogen.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² and R³ jointly represent -O-(CH2)m-O- and m = 2, 3 or 4.

In certain more preferred embodiments of the invention, in the compounds of general 20 formula (I), R² and R³ jointly represent -O-(CH₂)_m-O- and m = 2.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R² and R³ jointly represent an oxo-group.

In certain embodiments of the invention, in the compounds of general formula (I), R²and R³ jointly represent a =N-OH group.

'Λ/hile the invention has been described in connection with certain embodiments, certain preferred, more preferred or most preferred embodiments, it is not intended to limit the scope of the invention to the particular form set forth, but on the contrary, it is intended to cover such alternatives, modifications, and équivalents as may be included within the spirit and scope of the invention as defined by the statements of invention. Examples of alternative daims directed to the compounds of the présent invention may include:

(1) The compounds of general formula (i) as described above, or in any other embodiment.

(2) The compound as described in (1), or in any other embodiment wherein R¹ is a hydrogen, fluorine, chlorine, bromine, methyl, methoxy, CFs or CN group.

(3) The compound as described in any of (1) to (2), or in any other embodiment, wherein ring A is a 3- to 6-membered saturated carbocyclic or a 4- to 7-membered saturated heterocycle containing 1 or 2 N;

ring B is an optionally substituted 5- or 6-membered mono-heteroaryl group, 6- to 10membered aromatic carbocycle, or 4- to 7-membered saturated, monocyclic, bicyclic, condensed and/or bridged heterocycle containing 1, 2 or 3 heteroatoms selected from O, S 10 or N;

or B-Y-A- jointly represent a 3H-spiro[2-benzofuran-1,4’-piperidin-T-yl]; or

X is isopropyl group;

Z is methyl group.

(4) The compound as described in any of (1) to (3), or in any other embodiment, wherein ring B is an optionally substituted 6-membered mono-heteroaryl group, phenyl, or 5to 6-membered saturated, monocyclic heterocycle containing 1 or 2 heteroatoms selected from O, S or N.

(5) The compound as described in any of (1) to (4), or in any other embodiment, 20 wherein Y is -O-, -C(O)-, -CH₂-, -NH-, -Ci^alkyl-NiR¹⁸)- or a single bond if ring B is présent and R¹⁸ is a hydrogen or methyl group.

(6) The compound as described in any of (1) to (5), or in any other embodiment, wherein ring A is a 4- to 6-membered saturated carbocyclic group or a 4- to 7-membered saturated heterocycle containing 1 or 2 N attached via a ring nitrogen to Y or to the triazoie ring of the 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine core.

(7) The compound as described in any of (1) to (6), or in any other embodiment, wherein ring A is a cyclohexyl group, Y is -O-, ring B is a pyridin-2-yl and R¹ is chlorine.

(8) The compound as described in any of (1) to (6), or in any other embodiment, wherein ring A is a piperidine, piperazine, or pyrrolidine. Y is -O-, -C(O)-, -CH₂-, or a single bond, ring B is a pyridine, piperidine, tetrahydrofuran, or tetrahydropyran and R¹ is chlorine.

(9) The compound as described in any of (1) to (3), or in any other embodiment, wherein Y is -N(Ci-4alkyl)₂, C(O)OCi-4alkyl, Ci.4alkyl optionally substituted with halogen, Ci4alkoxy group or halogen and ring B is not présent.

(10) The compound as described in (9), or in any other embodiment, wherein ring A is a 4- to 6-membered saturated carbocyclic group.

(11) The compound as described in (10), or in any other embodiment, wherein Y is one group seiected from the group consisting of -N(Ci-*alkyi)2, C(O)OCi-4alkyi, Ci.4alkyl optionally substituted with halogen, Ci.4alkoxy group and halogen.

(12) The compound as described in (10), or in any other embodiment, wherein Y is two groups selected from the group consisting of Ci.4alkyî optionally substituted with halogen, Ci.4alkoxy group and halogen.

(13) The compound as described in any of (1) to (12), or in any other embodiment, wherein R² is a hydrogen or Ci.4alkyl group and R³ is a NR⁴R⁵group.

(14) The compound as described in (13), or in any other embodiment, wherein R² is a hydrogen.

(15) The compound as described in (14), or in any other embodiment, wherein R⁴ and R⁵is independently a hydrogen; C(O)R⁷; Ci.4alkyl optionally substituted with OH, halogen, cycloalkyl, optionally substituted aryl or NR⁸R⁹group.

(16) The compound as described in (15), or in any other embodiment, wherein R⁴ and R⁵ are hydrogens.

(17) The compound as described in (15), or in any other embodiment, wherein R⁴ is a hydrogen, R⁵ is a Ci-4alkyl group.

(18) The compound as described in (15), or in any other embodiment, wherein R⁴ and R⁵ are C-walkyl groups.

(19) The compound as described in (15), or in any other embodiment, wherein R⁴ is a hydrogen, R⁵ is a C(O)R⁷ group.

(20) The compound as described in (14), or in any other embodiment, wherein R⁴ is a hydrogen, R⁵ is Cy¹.

(21) The compound as described in (14), or in any other embodiment, wherein R⁴ is a hydrogen or Ci^alkyl, R⁵ is a S(O2)R¹⁰ group.

(22) The compound as described in (14), or in any other embodiment, wherein R⁴ and R^s taken together with the N to which they are attached form a 4- to 7-membered heterocycle containing optionally 1, 2 or 3 heteroatoms selected from O, S or N.

(23) The compound as described in any of (1) to (12), or in any other embodiment, 5 wherein R² is a hydrogen or C-walkyl group; R³ is an OR⁶ group.

(24) The compound as described in (23), or in any other embodiment, wherein R² is a hydrogen.

(25) The compound as described in (24), or in any other embodiment, wherein R® is a hydrogen.

w (26) The compound as described in (24), or in any other embodiment, wherein R® is a Ci-4alkyl group.

(27) The compound as described in (24), or in any other embodiment, wherein R® is a C(O)R¹³ group.

(28) The compound as described in any of (13) to (27), or in any other embodiment, 15 wherein the absolute configuration of the carbon at position 5 in the 5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepine core is (R).

(29) The compound as described in any of (13) to (27), or in any other embodiment, wherein the absolute configuration of the carbon at position 5 in the 5,6-dihydrc-4H[1,2,4]triazolo[4,3-aH1]benzazepine core is (S).

(30) The compound as described in any of (1) to (12), or in any other embodiment, wherein R² and R³ jointly represent -O-(CH2)_m-O-, oxo or =N-OH group, m is 2, 3, 4 or 5.

(31) The compound as described in (30), or in any other embodiment, wherein R² and R³ jointly represent-O-(CH₂)_m-O- group and m is 2.

A preferred group of compounds of general formula (I) of the présent invention are, 25 for exampie, the following compounds and/or salts and/or solvatés and/or hydrates and/or polymorphs and/or biologically active métabolites and/or prodrugs thereof:

1. fert-butyl [8-chloro-1-[1-(pyridin-2-yl)piperidin-4-yl]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl] carbamate,

2. 8-chloro-1-[1-(pyridin-2-yl)piperidin-4-yl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-

a][1]benzazepine-5-amine,

3. A/-[8-chloro-[1-(pyrid!n-2-yl)piperidin-4-yl]-5,6-d!hydro-4H-[1,2,4]triazolo[4,3-

a][1]benzazepin-5-yl]acetamide,

4. A/-(8-chloro-[1-(pyndin-2-yl)piperidin-4-yl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-

a][1]benzazepin-5-yl)-2-methylpropanamide,

5. tert-butyl {8-chloro-1“[frans-4-(pyridin-2-yioxy)cyclohexyO-5,6“dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepine-5-yl}carbamate,

6. 8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1_!2,4]triazolo[4_>3-

a] [ 1 ] benzazepi ne-5-am ine,

7. (5S)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyciohexyl]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine,

8. (5R)-8-chloro-1-Îfrans-4-(pyridin-2-yloxy)cydohexyÎ]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine_i

9. N-{8-chlorO1-[trans-4-(pyridin-2-yioxy)cydohexyr|-5,6dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}acetamide,

10. /V-{8-chloro-1-[frans-4-(pyrid!n-2-yioxy)cydohexyl]-5,6-dihydro-4H-

[1,2,4]triazo!o[4,3-a][1]benzazepin-5-y!}glydnamide,

11. A/-{(5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cydohexyll-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepin-5-yi}glydnamide_;

12. A/-{(5/?)-8-chioro-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}giycinamide,

13. (2S)-2-amino-A/-{(5R)-8-chioro-1-[toans-4-(pyridin-2-yioxy)cydohexyi]-5,6-dihydro-

4H-[1_!2,4]triazolo[4,3-a][1]benzazepin-5-y!}-2phenylacetamide,

14. (2R)-2-am!no-AA{(5R)-8-dnloro-1-ftrans-4-(pyrid!ri-2-yloxy)cydohexyi]-5,6-dihydro-

4H-[1,2,4]triazolo[4,3-a][1 ]benzazep!n-5-yl}-2-phenylacetamide,

15. A/-{8-chloro-1-[frans-4-(pyridin-2-yloxy)cydohexyi]-5,6-d!hydro-4H[1,2_J4jtriazolo[4,3-a][1]benzazepin-5-yl}-2-hydroxyacetamide,

16. 3-{8-d3loro-1-ftrans-4-(pyridin-2-yloxy)cydohexyH-5,6-dihydro-4/7-[1,2₍4]Îriazolo[4_:3a][ 1 ] benzaze pto-5-yl}-1,1-d i methyl urea,

17. /V-{8-chloro-1-[t/ans-4-(pyridin2-yloxy)cydohexyl]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazep!n-5-yl}-/V²,/V²-dimethylglydnamide_>

18. A/-{8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}methanesulfonamide_i

19. A/-{8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1,2,4]triazoîo[4,3-a][1]benzazepin-5-yl}-/V-methylmethanensulfonamide_:

20. /V-{8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5_l6-dihydro-4/-/-

[1,2,4]tr!azolo[4,3-a][1]benzazepin-5-yl}-A/_lA/-dimethylsulfamide,

21. 8-chloro-A/-methyl-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydrO4H[1_!2,4]triazo!o[4,3-a][1]benzazepine-5-amine,

22. 8-chloro-A/,A/-d!methyl-1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1,2,4]triazo!o[4,3-a][1]benzazep!ne-5-amine,

23. 8-chioro-A/-ethyi-1-[frans-4-(pyridin-2-yloxy)cyclohexyi]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepine-5amine,

24. 8-chloro-A/-(propan-2-yi)-1-[trans-4-(pyridin-2-yioxy)cydohexyl]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine,

25. (5S)-8-chloro-A/-(propan-2-yi)-1-[frans-4-(pyridin-2-y!oxy)cyclohexyl]-5,6-dihydro-4H-

[1,2,43tnazolo[4,3-a][13benzazepine-5-amine,

26. (5R)-8-chloro-/V-(propan-2-yl)-1-[frans-4-(pyridin-2-yloxy)cyclohexy!]-5,6-dihydro4H-[1,2,4]tnazolo[4,3-a][1]benzazepine-5-amine,

27. 8-chloro-A/-cyclobutyi-1-[tfans-4-(pyndin-2-yloxy)cyclohexyl3-5,6-dihydfO-4H-

[1,2,4]triazoio[4,3-a][1]benzazepine-5-amine,

28. 8-chloro-A/-(oxetan-3-yl)-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1,2,4]triazoio[4,3-a][1]benzazepine-5-amine,

29. 8-chloro-1-[frens-4-(pyridin”2-yloxy)cyclohexy!]-A/-(îetrahydro-2H-pyran~4-yl)-5,6dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine,

30. 8-chloro-/V-(4,4-difluorcyclohexyi)-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6- dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine,

31. 8-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,43triazolo[4,3a][1]benzazepine-5-amine hydrochioride,

32. 8-methoxy-/V-(propan-2-yl)-1-[irans-4-(pyridin-2-yloxy)cyciohexyl]-5,6-dihydro-4H-

[1,2,4]tr!azoîo[4,3-a][1]benzazepine-5-amine,

33. fe/ï-butyl {1-[fra/7s-4-(pyndin-2-yioxy)cyclohexylJ-8-(trifiuoromethyl)-5,6~d!hydro-4H[1,2..4]triazolo[4,3-a][1]benzazepin-5-yl}carbamate,

34. 1-[frans-4-(pyridin-2-yloxy)cydohexyl3-8-(tr!iluoromethyl)-5,6-dihyclro-4H-

[1,2,4]triazoÎo[4,3-a][1]benzazepine-5-amine hydrochloride,

35. /\/_l/V-dimethyl-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-8-(trifluoromethyi)-5,6-d!hydro4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine,

36. /V-(propan-2-y0-1-[trans-4-(pyndin-2-y!oxy)cyclohexyl]-8-(trifluoromethyl)-5,6dihydro-4H-[1,2_!4]triazolo[4,3-a][1]benzazepine-5-amine_:

37. 8-methyl·1-[traf}s-4-(ρyπdin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1_i2,4]tπazolo[4,3a][1]benzazepine-5-amine,

38. 8-methyl-/V-(propan-2-yl)-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydiO-4H-

[1,2,4]triazo!o[4,3-a][1]benzazepine-5-amine,

39. 8-bromO1-[frar?s-4-(pyridin-2-yioxy)cyciohexyi]-5,6-dihydro-4H-[1,2,4]triazoio[4,3a][13 benzazepi ne-5-am i ne,

40. 8-bromo-A/-(propan-2-yi)-1~[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H-

[1,2,4]triazo!o[4,3-a][1]benzazepine-5-amine,

41. 8-chloro-1-(3,3difluorocyctobutyl)-/V-(propan-2-yl)-5_l6-dihydro-4H-

[1,2,4]triazoio[4,3-a][1]benzazepine-5-amine,

42. 8-chloro-1-(4,4-difiuorocyclohexyl)-A/-(propan-2-y!)-5,6-dihydro-4H-

[1,2,4]tnazolo[4,3-a][1]benzazepine-5-amine,

43. 8-cNoro-1-[frans-4-(trifiuoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][ 1 ]benzazepine-5-am i ne,

44. 8-chloro-/V-(propan-2-yl)-1-[frans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4/·/-

[1,2,4]triazoio[4,3-a][1]benzazepine-5-amine,

45. 8-bromo-1-[frans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydrc>-4H-[1,2,4]triazolo[4,3a][1]benzazepine-5-amine,

46. 8-bromo-A/-(propan-2-yl)-1-[f/ans-4-(trifuoromethyi)cyclohexyl]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3- a] [ 1 ] benzazepine-5-a mine,

47. 14frans-4-(pyridin2-yloxy)cyclohexyn-8'-(trif!uoromethyl)-4‘H,6'H-spiiO[1,3- dioxolane-2,5'-[1,2,4]triazo!o[4,3-a][1]benzazep!ne],

48. 1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifiuoromethyl)-4/7-[1,2,4]triazoio[4,3a][1]benzazepin-5(6H)-one,

49. 1~[franS4-(pyridin-2-yloxy)cyclohexyi]-8-(Îrifluoromethyl)-5,6-dihydro~4H[1,2,4]triazoio[4,3-a][1]benzazepin-5”O!,

50. 5-methoxy-1-[trans-4-(pyridin-2-yloxy)cyc!ohexyl]-8-(trifluoromethyi)-5,6-dihydro-4H[1,2,4]triazoio[4,3-a][1]benzazepine,

51. 5-(cyciopropy!methoxy)-1-[frans-4-(pyridin-2-yloxy)cyclohexy1]-8“(trifluoromethyl)-

5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine,

52. 5-{[fert-butyl(dimethyl)silyl]oxy}-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyi]-5,6dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine,

53. 8'-chloro-T-[frans-4-(pyridin-2-yloxy)cyclohexyl]-4'H,6'/-/-spiro[1,3-dioxolane-2,5'[1,2,4]triazolo[4,3-a][1îbenzazepine],

54. 8-chloro-1-[frans-4-(pyridin-2-yioxy)cyclohexyl]-4H-[1,2,4]triazolo[4,3a][1jbenzazepin-5(6H)-one,

55. 8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyi]-5,6-dihydro-4H-[1,2,4]triazolo[4_l3a][1]benzazepin-5-ol,

56. (5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyciohexyl]-5,6-dihydro-4H-

[1,2,4]triazo!o[4,3-a][1]benzazepin-5-oi,

57. (5R)-8-chioro-1-[frans-4-(pyridin-2-ytoxy)cyclohexyl]-5,6dihydro-4/7-

[1,2,4]triazoio[4,3-a][1]benzazepin-5-oi,

58. 8-chloro-5-methoxy-1-[trans-4-(pyridfn-2-yloxy)cyciohexyl]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepine,

59. 5-(cyclopropy!methoxy)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyi]-5,6-dihydro4H-[1_:2,4]triazolo[4,3-a][1]benzazepine,

60. 2-({8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexy!]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepin-5-yQoxy)-/V,/V-dimethylethanamine,

61. 8'-chlorO”T-[fra/7S-4-(trifluoromethyi)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane-2,5'-

[1,2.4]triazolo[4,3~a][1]benzazepirie],

62. 8'-bΓomo-T-[frarîs-4-(ρyridin-2-yloxy)cyc!ohexyl]-4Ή,6Ή-sρiro[1,3-dioxolane-2,5^,-

[1,2,4]triazolo[4,3-a][1]benzazepine],

63. T-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4'H,6'H-spiro[1,3dioxolane-2.5^s[I^AjtriazoloH.S-aJfljbenzazepine],

64. 8-bromo-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4/7-[1,2,4]triazolo[4,3a][1]benzazepin-5(6H)-one,

65. 8-bromo-1[frans-4-(pyridin-2-yloxy)cyclohexy!]-5_i6-dihydro-4h-[1,2,4]triazolo[4,3aH1]benzazepin-5-ol,

66. T-[£Ÿans-4-(pyridin-2-yloxy)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane-2,5'[1,2_:4]triazolo[4,3-a][1]benzazep!n]-8'-carbonitrile₍

67. (5S)-8-chloro-Λ/,Λ/-dimethyl·1-[fΓa/7S-4-(ρyrίdiri-2-yloxy)cyciohexyl]5,6-dihydΓO-4H-

[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine,

68. (5S)-A/-{8-chloro-1-|7rans-4-(pyrid!n-2-yloxy)cyciohexyl]-5,6-dihydra-4H[I^AJtriazolo^.S-aKIjbenzazepin-S-yllacetamide,

69. 8'-chloro-T-[frans-4-(pyridin-2-ylmethyl)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane-2,5'[1,2_;4]triazolo[4,3-a][1]benzazepine],

70. [frans-4-(8'-chloro-4'H,6'H-spiro[1 .S-dioxolane-Z.S'-fl ,2,4]triazoioi4,3a][1]benzazepine]-T-yl)cycÎohexyl](pyrrolidin-1-yi)methanone,

71. 8Chloro-1-itrans-4-(trifluoromethyl)cycïohexyl]-4H-[1,2,4]triazolo[4,3-

a][1 ]benzazepin-5(6H)-one,

72. 8-chioro-1-[tra/?s-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepine-5-ol,

73. ('c/s)-8-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3a][1]benzazepin]-T-yl)-3-methyl-1-oxa-3-azaspiro[4.5]decan-2-one,

74. 8-chloro-5-methoxy-1-[frans-4-(trifiuoromethyl)cydohexyn-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepine,

75. (trans)-8-(8‘-chlora-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]tnazoio[4,3a][1]benzazep!n]-T-yl)-3-methyl-1-oxa-3-azaspiro[4.5]decari2-one,

76. A/-{(5S)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}-/V-methylmethanesulfonamide,

77. (5S)-8-chloro-/V-ethyi-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1,2,4]triazoio[4,3-a][1]benzazeplne-5-amine,

78. (5S)-8-chloro-A/-methyi-1-prans-4-(pyridin-2-yloxy)cyclohexyi]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine,

79. 8'-chloro-T-(1-(pyrimidin-2-yl)azetid!n-3-yl]-4Ή,6^,H-spiro[1,3-dioxolane-2,5^,[I^^Jtriazolo^^-aJEljbenzazepine],

80. A/-{(5S)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dïhydro-4H[1,2,4]triazoio(4,3-a][1]benzazepin-5-yl}-4-fluorobenzamide,

81. S'-bromo-T-Etrans^-ftrifiuoromethyijcycîohexylj^'^Ô'H-spiroJI ,3-dioxolane-2,5'~

[1,2,4]triazo!o[4,3-a][1]benzazeplne],

82. 5-(propan-2-ylamino)-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1,2,4]triazoio[4,3-a][1]benzazepin-8-carbonitrile trifluoroacetate,

83. (5S)-8-chloro-/V-(4-fluorabenzyl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyi]-5,6-dihydro-

4H-[1,2,4]triazolo(4,3-a][1]benzazepine-5-amine,

84. 1 Htrans^-CtrifluoromethyQcyclohexyO^’/Le'H-spirofl ,3-dioxolane-2,5’-

[1,2,4]triazolo[4,3-a][1]benzazepine]-8'-carbonitrile,

85. [frans~4-(8'-bromo-4'H,6'H-spiro[1,3-dioxoiane-2,5'-(1,2,4]triazolo[4,3a][1]benzazepin]-T-yl)cydohexyl](piperid!n-1-yl)methanone,

86. methyl f/ans-4-(8-bromo-5-oxo-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1yl)cyclohexanecarboxilaîe,

87. 8-bromo-1-[frans-4-(piperidin-1-ylcarbonyî)cyclohexyl]-4H-[1,2,4jtriazolo[4,3a][1]benzazepin-5(6H)-one,

88. 8'-chloro-T-[frans-4-(trifluoromethyl)cyclohexyl]-4'H,6'H-spiro[1,3-dioxane-2,5'-

[1,2,4]triazolo[4,3-a][1]benzazepine],

89. T-[frans-4-(piperîdin-1-ylcarbonyl)cyclohexyl]-4'H,6'H-sp!ro[1,3~dioxolane-2,5'-

[1,2,4]triazolo[4,3-a][1]benzazepin]-8'-carbonitrile,

90. 8'-chloro-T-[tfans-4-(pyridin-2-yloxy)cyclohexyl]-4'H,6’H-spiro[1_>3-dïoxane-2,5’[l^^triazolo^S-aHljbenzazepine],

91. 8-bromo-1-(frans~4-(trifluoromethyl)cyclohexyl]-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5(6H)-one,

92. [fr3ns-4-(8-bromo-5-hydroxy-5,6-dihydro-4H-[1₁2_l4]triazoio[4,3-a][1]benzazepin-1- yl)cyclohexyi](piperidin-1-yi)methanone,

93. 8-bromo-1“[franS4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-oL

94. 1 '-(1 _;4'-bipiperid!n-1 '-y‘)-8’-chloro-4'H_;6'^ ,3-dioxolane-2,5'-[1,2,4jtriazolo[4,3-

a][1]benzazepine],

95. ten-butyl [1-(1,4'-bipiperidin-T-y!)-8-chloro-5,6dihydro-4H-[1,2,4]triazoioî4,3a][1 ]benzazepin-5-yl]carbamate,

96. 8^l-fluoro-T-[trans-4-(pyridin-2-yioxy)cydohexyn-4'H,6'H-spiro[1,3-dioxolane-2,5'-

[1,2,4]triazolo[4,3-aj[1]benzazepine]_:

97. (5S)-8-diloro*A/-(4-fluorobenzyl)-/V-rnethyl-1-[frans-4-(pyridin-2-yioxy)cydohexyl]-

5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine,

98. /V-{(5S)-8-diÎoro-1-[trans-4-(pyrid!n-2-yloxy)cydohexyÎ]-5,6-dihydro-4H-

[1,2,4]triazo!o[4,3-a][1]benzazepîn-5-yl}prop-2-enamide,

99. (5R)-8-chioro-/V-ethyl·1-[frans-4-(pyrid^n-2-yloxy)cyc!ohexyl]5,6-dihydiΌ-4H-

[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine,

100. (5R)-8-ch!oro-Λ/-methyl·1-[frans-4-(pyridiπ-2-yioxy)cydohexyl]-5,6-dihydΓO-4H-

[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine,

101. (5R)-8-ch!oro-/V,/V-dimethyl-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4/·/-

[1,2,4]triazoio[4,3-a][1jbenzazepin-5-amine,

102. 1-[frans-4-(pyridin-2-yloxy)cydohexyi]-4H-[1.2,4]triazo!o[4,3-a][1]benzazepin-5(6H)one,

103. (5S)-8-chloro-5methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyî]-5,6-dihydro-4H-

[1,2,4]tfiazolo[4,3-a][1]benzazepine,

104. (5R)-8-chloro-5-methoxy-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H-

[1,2_l4]triazoio[4,3-a][1]benzazepine,

105. 8-chlora-5-(propan-2-yloxy)-1-[f/ans-4-(pyridin-2-yloxy)cyclohexyl]-5_i6-dihydro-4H[1,2_l4]triazolo[4,3-a][1]benzazepine_!

106. 8'-chloro-14/rans-4-(pyndin-2-yloxy)cydohexyi]-4'H,6'H-spiro[1,3-dioxepane-2,5'[l^^triazolojA.S-aHljbenzazepinej,

107. 1[rrans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-oL

108. [^ηδ-4-(8'-οήΙθΓθ-4Ή,6Ή-3ρίΓθ[1,3-dioxolane-2₍5'-[1,2,4]triazolo[4,3-

a][1]benzazepin]-T-yl)cyclohexyl](morpholin-4-yl)methanone

109. 5-methoxy-1-[trans-4-(pyndin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4_l3a][1]benzazepine,

110. 8-fluoro-1-[trans-4-(pyridin-2-yioxy)cyclohexy!]-4H-[1,2,4]triazolo[4,3-

a] [ 1 ]benzazepin-5(6H)-one,

111. 8-tiuoro-1-[frans-4-(pyridin-2-y!oxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3aj[1]benzazepin-5-ol·

112. tert-butyl {8-chloro-1-[frans-4-(morpholin-4-yl)cyclohexyl]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1jbenzazepin-5-yl}carbamaÎe,

113. 8-chloro-1-[frans-4-(morphoiin-4-yl)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a] [ 1 ]bgnzazepin-5-amine,

114. 8-chioro-1-[fnans-4-(morpholin-4-yl)cyclohexyl]-/V-(propan-2-yl)-5,6-dihydro-4H-

[1,2,4]triazoio[4,3-a][1]benzazepin-5-amine,

115. (5r,8r)-8-(8'-chioro-4'H,6'H-spiro[1,3-dioxoiane-2,5'-[1,2,4]triazolo[4,3-

a][1]benzazepin]-T-yl)-2-(propan-2-yi)-2-azaspiro[4.5]decan-1-one,

116. (5r,8r)-8-(8-chioro-5-hydroxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1yl)-2-(propan-2-yi)-2-azaspiro[4.5]decan-1-one,

117. (5S)-8-chloro-1-[fra/?s-4-(pyridin-2-yloxy)cyclohexyl]-5-(pyrroiidin-1-yl)-5,6-dihydro-

4H-[1,2,4]triazo!o[4,3-a][1]bgnzazepine,

118. /V-{(5S)-8-ch!oro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H[1,2,4jtriazolo[4,3-a][1ibenzazepin-5-yi}-2,2-dimethyipropanamide_!

119. /V-{(5S)-8-ch!oro-1-[frans-4-(pyridin-2-yloxy)cyciohexyi]-5,6-dihydro-4h'-

[1,2,4]triazoio[4,3~a](1]benzazepin-5-yl}cyciopropanecarboxamide,

120. A/-{(5S)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyÎ]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}-2-methylpropanamide,

121. N-{(5S)-8-chloro-1-(frans-4-(pyridin-2-yloxy)cyciohexyl]-5,6-dihydro-4H-

[1,2,4]triazo!o[4,3-a][1]benzazepin-5-yl}cyclobutanecarboxamide,

122. (5S)-8-chloro-5-(morpholin-4-y!)-1-[ïrans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro4/+(1,2,4]triazoio[4,3-a] [ 1 ] benzazepine,

123. /V“{(5R)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H[1,2_;4]triazolo[4,3-a][1]benzazepin-5-yi}-2,2-dimethylpropanamide,

124. /V-{(5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyn-5,6-dihydro-4H-

[1,2,4]triazo!o[4,3-a][1]benzazepin-5-yl}-2-methylpropanam!de,

125. /V-{(5/?)-8-chloro-1-[ïrans-4-(pyridin-2-yloxy)cyclohexy!]-5,6-dihydro-4H-

[1,2,411032010(4,3-a][1]benzazepin-5-yl}cyclobutanecarboxamide,

126. /V-{(5R)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1,2,4]triazo!o[4,3-al[1]benzazepin-5-yl}cyclopropanecarboxamide,

127. (5S)-8-chloro-5-(piperidin-1-yl)-1-[frans-4-(pyridin-2-yloxy)cyclohexyn“5,6-dihydro4H-[1,2,4]triazoio[4,3-a][1 (benzazepine,

128. (5S)-/V-(butan-2-yÎ)-8-ch!oro-1-[frans-4-(pyridin-2-yioxy)cyclohexyl]-5,6-dihydro-4H-

[1,2,4]triazo!o[4,3-a][1]benzazepin-5-amine,

129. (5s,8s)8“(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-

a][1]benzazepin]-T-yl)-2-(propan-2-yl)-2-azaspiro[4.5]decan-1-one,

130. 8-chloro-5-methoxy-1-[trens-4-(morpho!in-4-y0cyciohexyi]-5,6-dihyclro-4/-/-

[1,2,4]triazolo[4,3-a][1]benzazepine,

131. 8-chloro-5-ethoxy-1-[frans-4-(pyridin-2-yioxy)cydohexyl]-5,6-dihydro-4M-

[1,2,4]triazolo[4,3-a][1]benzazepine,

132. (5R)-8-chloro-5-methoxy-1-[frans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-

[I^AJtriazolo^.S-alfljbenzazepine,

133. (5S)-8-chloro-5-methoxy-1-[frans-4-(trifluoromethyi)cyclohexyl]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepine,

134. 8-fluoro-5-methoxy-1-[frans-4-(pynd!n-2-yloxy)cydohexyl]-5,6-dihydra-4H-

[1,2,4]triazolo[4,3-a][1]benzazepine,

135. 8-chloro-/V-(propan-2-yl)-1-[1-(pyridin-2-yl)pîperid!n-4-yl]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine,

136. 2-({8-chloro-1-[frans-4-(pyrid!n-2-yloxy)cyclohexyl]-5_:6-dihydro-4H[l^^jtriazoloH.S-aljftbenzazepin-S-yQoxyyethanoi,

137. (5S)-8”Chloro-M/V-diethyl-1-[frans-4-(pyridin-2-yloxy)cyc!ohexyl]-5,6-dihydro-4H[I.Z^Jtriazoio^S-aHIJbenzazepin-S-amine,

138. 8-ch!oro-A/-methyl-A/-(propan-2-yî)-1-ifrans-4-(pyridin-2-yioxy)cyclohexyl]-5,6- dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine,

139. teft-butyl {8-chloro-1-[4-(3-chloropyridin-2-yl)piperazin-1-yl]-5,6dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepîn--5-y!}carbarnate,

140. tert-butyl 4-(8-chloro-5-methoxy-5,6-dîhydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin1-yl)piperidine-1-carboxylate,

141. W-{(5/?)-8-ch!oro-1-[tranS4-(pyridin-2-y!oxy)cyclohexyl]-5,6-dihydro-4H-

[1,2,4]triazoio[4,3-a][1]benzazepin-5~yl}-D-vahnamide,

142. ferf-butyl {1-[t/ans-4-(pyridin-2-yloxy)cyclohexyi]-5,6-dihydro-4H-[1_:2,4]triazolo[4,3a][1]benzazepin-5-yl}carbamate,

143. tert-butyl {8-fluora-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6dihydro-4H-

[1,2,4]tnazolo[4,3-a][1]benzazepin-5-yl}carbamate,

144. l-[frans-4-(pyridin-2-yloxy)cyclohexyn-5,6-d!hydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-amine,

145. 8-f!uoro-1-[frans-4-(pyridin-2-yloxy)cyclohexyij-5,6-dihydro-4H-[1,2,4]triazolo[4_i3a][1]benzazepîn-5-amine,

146. 8-fluoro-N-(propan-2-yl)-1-[frans-4-(pyridin-2-yloxy)cydohexyi]-5,6-dihydro-4H[l^^ltriazolofA.S-aHljbenzazepin-S-amine,

147. 8-fluoro-/V,A/-dimethyi-1-[fra/?s-4-(pyridirî-2-yloxy)cyclohexyl]-5,6-dihydro-4H[I.Z^nriazoioH.S-aHljbenzazepin-S-amine,

148. /V,/V-dimeîhyl-1-[frar7S-4-(pyridin-2-yloxy)cycîohexyl]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine,

149. 8'-fluoro-T-[frans-4-(trifluoromethyl)cyclohexyl]-4^!H,6'H-sp!ro[1,3-dioxolane-2,5'-

[ 1,2,4] tri azoi o[4,3-a] [ 1 ] benzazepi ne],

150. A/-(propan-2-yl)-1-|ïrans-4-(pyridin-2-y!oxy)cyclohexyl]-5,6-dihydro-4H[1,2,4jtriazolo[4,3-a][1]benzazepin-5-amine,

151. A/-{(5S)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyi]-5,6-dihydro-4H-

[1,2,4]triazoîo[4,3-a][1]benzazepin-5-y!}tetrahydro-2H-pyran-4-carboxamide,

152. /V-{(5S)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}-2-methylbutanamide,

153. /V-{(5S)-8-chioro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[l^^jtriazoioH.S-aKIjbenzazepin-S-yli-Af^-dimethyl-p-aianinamide,

154. (5S)-8Chloro-A/-cyclopentyi-1-[frans-4-(pyndin-2-yloxy)cyciohexyl]-5,6-dihydro-4H-

[1_s2,4]triazolo[4,3-a][1]benzazepin-5-amine,

155. 8'-chloro-1'-(TH,3H-spiro[2-benzofuran-1,4'-p!peridin]-T-yl)-4'H,6'H-spiro[1,3- dioxo!ane-2,5'-[1,2,4]triazoio[4,3-a][1]benzazepine],

156. 8-chloro-1-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-T-yl)-4H-[1,2,4]triazolo[4,3-

a][1]benzazepin-5(6H)-one,

157. 8'-chloro-T-[4-(pyridin-2-yloxy)piperidin-1-yl]-4'H,6'H-spiro[1,3-dioxolane-2,5'-

[1,2,4]triazolo[4,3-a][1]benzazepine],

158. A/-{(5S)-8-chîoro-1-[frans-4-(pyridin-2-yloxy)cyclohexyi]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}-2,2-dimethylbutanamide,

159. /V-{(5S)-8-chloro-1-[Mans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepin-5yl}-2-hydroxy-2-methylpropanamide,

160. (5S)-8-chloro-/V-ethyi-/V-methyl-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-

4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine,

161. (5S)-8-chloro-AH2-methylpropyl)-1-[frans-4-(pyndin-2-yloxy)cyc!ohexyl]-5,6-dihydro4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine,

162. 8'-chloro-T-[frans-4-(morpholin-4-yi)cyclohexyl]-4'/7,6'H-spiro[1,3-dioxolane-2,5'[1,2,4]tnazoio[4,3-a][1]benzazepine] hydrochloride,

163. 8-chloro-/V,A/-dirnethy!-1-(TH,3H-spiro[2-benzofuran-1,4’-piperidin]-r-yl)-5,6dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine,

164. 8^,“Chloro-T-[4-(3-chloropyridin-2-yl)piperazin-1-yl]-4'H,6'/7-spiro[1,3-dioxolane-2,5'[1,2,4]triazolo[4,3-a][1]benzazepine],

165. (5S)-8-chloro-A/-(2,2-dimethylpropyl)-1-[trans-4-(pyridin-2-yîoxy)cyclohexyl]-5,6- dihydro-4H-[1,2,4]triazolo[4,3~a][1]benzazepin-5-amine,

166. [frans-4-(8-chloro-5-methoxy-5,6-dihydro-4H-[1,2₎4]triazolo[4,3-a][1]benzazepin-1yl)cyclohexyl](4-methylpiperazin-1-yl)methanone_l

167. (5R)-8-chloro-5-(morpholin-4-yl)-1-[frians-4-(pyridin-2-yloxy)cyclohexyl]-5_l6-d!hydro4H-[1,2,4]tnazolo[4,3-a][1]beozazepine,

168. /V-{(5R)v8-chloro-1-[irans-4-(pyridin-2-ytoxy)cydohexyn-5,6-dihydro-4H-

[1,2,4]toazolo[4,3-a][1]beozazepin-5-yl}acetamide,

169. A/-{(5R)-8-chloro~1-[frans-4-(pyridin-2-yloxy)cyclohexyi]-5,6-dihydro-4H-

[1,2,4]triazo!o[4,3-a][1]benzazepin-5-yl}-2-hydroxy-2-methylpropanamide,

170. 8-chloro-5-methoxy-1-[1-(tetrahydro-2H-pyran-4-yi)piperidin-4-yl]-5,6-dihydro-4rL

[1,2,4]triazolo[4,3-a][1]benzazepioe,

171. 8'-chloro-T-[4-(pyridii>2-yi)piperazin-1-yl]-4'H,6'H-spiro[1,3-dioxolane-2,S'- il ,2,4]triazolo[4,3-a][1]benzazepioe],

172. 8-chloro-1-(TH,3H-spiro[2-benzofuran-1,4'-piperidin]-T-yl)-5,6-dihydro-4F/-

[1,2,4]toazolo[4,3-a][1]benzazepin-5-ol,

173. 8-chloro-1-!4-(3-Ghloropyridin-2-yl)piperid!n-1-yl]-5,6-dihydro-4/-f-[1,2,4]toazolo[4,3a][1]beozazepin-5-ol,

174. (5R)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5-(pyrrolidin-1-yl)-5,6-dihydro4H-[1,2,4]triazolo[4,3-a][1]benzazepine,

175. 8-chloro-5-meihoxy-1-{1-[(3S)-tetrahydrofuran-3-yl]pipeodin-4-yl}-5,6-dihydro-4H[1,2,4]triazoio[4,3-a][1]benzazepioe,

176. (5R)-8-fiuoro-5-methoxy-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1,2,4]triazoio[4,3-a][1]beozazepine,

177. (5S)-8-fluoro-5-methoxy-1-[frans-4-(pyridin-2-yioxy)cyc!ohexyl]-5,6-dihydro-4/7-

[1,2,4]toazolo[4,3-a][1]benzazepine,

178. 8-chtoro-5-methoxy-1-{1-[(3R)-tetrahydrofijran-3-y!]pipendin-4-yl}-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepine,

179. /V-{(5R)-8-chloro-1-[fra/7s-4-(pyridin-2-yloxy)cyciohexyl]-5,6-d!hydro-4H-

[1,2,4]triazolo(4,3-a][1]benzazepin-5-

180. /V-{(5R)-8-chloro-1-(frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1,2,4]toazo!o[4,3-a][1]benzazepin-5-yi}tetrahydro-2H-pyran-4-carboxamide,

181. 8-chloro-1-[4-(pyridin-2-yioxy)piperidin-1-yl]-5,6-dihydro-4/7-[1,2,4]toazolo[4,3a][1]benzazepin-5-ol,

182. 8-chÎoro-5-methoxy-1-[frans-4-(4-methylpiperazin-1-yl)cyclohexyl]-5,6-dihydro-4H[1,2,4]triazoio[4,3-a][1]benzazepine,

183. 8-chloro-5-methoxy-1-[c/s-4-(4-methylpiperazin-1-yl)cyclohexyl]-5,6-dihydro-4/7-

[1,2,4]toazoio[4,3-a][1]beozazepine,

184. 8-chloro-5-methoxy-1-[1-(pyridin-3-yimethyl)pyrrohd!n-3-yl]-5,6-d!hydro-4/-/-

[1,2,4]triazo!o[4,3-a][1]benzazepine,

185. 8-chloro-5-methoxy-1-[1-(pyridin-2-ylmethy[)pynOBdin-3-yi]-5,6-dihydro-4H-

[1,2,4]triazo!o[4,3-a][1]benzazepirîe,

186. A/4(5R)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexy!]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}-2-cyanoacetamide,

187. [3-(8-chloro-5-methoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1yl)pyrroÎidin-1-yl](pyridin-3-yl)methanone,

188. 8'-chÎorQ-r4H(3R)-tetrahydrofurarb3-y0pipendirb4-y|}-4‘H,6'H-spiro[1,3-diox.Glane-

2,5'-[1,2,4]triazolo[4,3-a][1jbenzazepine],

189. [3-(8-chtoro-5-rriethGxy-5O-dihydro-4h'-[L2,4]triazolo[4_:3-al[1]benzazepir!-L yl)pyrrolidin-1-yl](pyridin-2-yi)methanone,

190. ίΓ3η5-4-(8'-οήΐθΓθ-4Ή,6Ή-5ρΪΓθ[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3a][1]benzazepin]-T-yr)-/V,A/-dimethylcyclohexanamine,

191. 8-chiora-5-methoxy-1-(1'H,3H-spiro[2-benzofuran“1,4^,-piperid!n]-1'-yl)-5,6-dihydro4H-[1,2,4]triazoio[4_:3-a][1]benzazepine,

192. 8-chloro-1-[4-(3-chlaropyridin-2-yl)piperazin-1-yi]-5-methQxy-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepine,

193. /V-[trans-4-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3a][1]benzazepin]-T”yl)cydohexynpyridin-2-amine

194. /W{(5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexy!]-5_;6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepin-5-yQ-/V_lA/-dimethylethane-1,2-diamine,

195. 8-chloro-1-[trans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-yl acetate,

196. 2-({(5R)-8-chloro-1-[trans-4-(pyridin-2-ytoxy)cyclohexyl]-5,6-dihydro-4H-

[1,2,4]triazoio[4,3-a][1]benzazepin-5-yl}amirio)ethanol·

197. 8-chloro-5-methoxy-1-[4-(pyridin-2-yloxy)piperidin-1-yl]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepine,

198. 8'-chloro-T-(frans-4-methoxy-4-methylcyclohexyi)-4‘H,6^,H-spiro[1,3-dioxolane-2,5’[1,2,4]triazoio[4,3-a][1]benzazepine],

199. (5S)-8-chloro-A/-(cyclopropylmethyl)-1-[trans-4-(pyridin-2-yioxy)cydohexyl]-5,6dihydro-4H-[1,2_!4]triazolo[4,3-a][1]benzazepin-5-amine,

200. /v-{(5S)-8-chÎoro-1-[frans-4-(pyndin-2-yloxy)cyclohexyi]-5_i6-dihydro-4H-

[1,2,4]trÎazoio[4,3-a][1]benzazepin-5-yl}-1-methylpiperidine-4-carboxamide,

201. /V-{(5S)-8-chloro-1-[fra/?s-4-(pyridin“2-yloxy)cyclohexyl]-5,6dihydro-4H[1_!2,4]triazo!o[4,3a][1]benzazepin-5-yl}-2,2,2-'trifluoroacetamide,

202. 8-doloro-5-(2-methoxyethoxy)-1-[frans-4-(pyr!din-2-yloxy)cydohexyi]-5,6-dihydro-

4H-[1,2,4]triazolo[4,3-a][1]benzazepine,

203. 8-diloro-1-(4-methoxy-4-methylcydohexyl)-/V-(propan-2-yi)-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine_!

204. 8'-chloro-T-(frans-4-methoxy-4-methylcyc!ohexyl)-4'H,6'H-spiro[1,3-dioxane-2,5'-

[1,2,4]triazoio[4,3-a][1]benzazepine],

205. 8'-chloro-Γ-(cίs-4-methoxy-4-meΐhylcydohexyl)-4'/7,6Ή-spiro[1,3-dioxane-2,5^,-

[1,2,4]triazolo[4,3-a][1]benzazepine],

206. 8-chloro-5-fluoro-1-[trans-4-(pyridin-2-y!oxy)cydohexyn-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepine,

207. 8-ch!oro-542-(methylsuifoπyl·)eîhoxyΐ-14tians-4-(pyrl·din-2-ytoxy)cyclohexyll·5_l6dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine,

208. 8-chtoro-A/-hydroxy-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5(6H)-imine,

209. (5S)-8-chloΓO-Λ/-methyl·/V-(pΓop-2-yn-1-yl)-1-[f/ans-4-(pyπdin-2-yloxy)cydohexyl]-

5,6-dihydro-4H-[1,2,4]înazolo[4,3-a][1]benzazepin-5-amine,

210. A/-{(5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}-3,3-difluorocydobutanecarboxamide,

211. 8-dfloro-5-(prop-2-yn-1-yloxy)-1-[frans-4-(pyrid!n-2-yloxy)cydohexyi]-5,6-dihydrO4H-[1 ..2,4]triazolo[4,3-a][1 ]benzazepine,

212. 8-chloro-1-[frans-4-(pyndin-2-yloxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-yl 4,4-difluorocydohexanecarboxylate,

213. 8-chloro-1[frans-4-(pyridin-2-yioxy)cydohexyi]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-yl 3,3-difluorocydobutanecarboxylate,

214. A/-{(5S)-8-chloro-1-[trans-4-(pyndin-2-yloxy)cydohexy!]-5,6-dihydro-4H-

[1,2,4]triazoio[4,3-a][1]benzazepin-5-yl}-4,4-difiuorocyclohexaneœrbaxam!de,

215. 8-chloro-1-[Érans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro4/-/-[1,2,4]triazolo[4,3a][1]benzazepin-5-yl cyanoacetate,

216. 8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyi]-5,6-dihydra-4H-[1,2,4]triazo!o[4,3a][1]benzazepin-5-yl /V,/V-dimethylglydnate,

217. A/-{(5R)-8-chloro-1-[frafïs-4-(pyridin-2-yloxy)cyclohexyi]-5,6-dihydro-4H[I.Z/jtriazolofd.S-aJiljbenzazepin-S-ylj-Z^.Z-trifiuoroacetamîde,

218. 1-[c/s-4-(8-ch!oro-5-rrieÎhoxy-5,6-dihydro-4h'-[1_:2,4]triazolo[4_:3-a][1]benzazepÎn-1yl)cyclohexyl]pyrrolidin-2-one,

219. 1-[frans-4-(8-chioro-5-meÎhoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-aj[1]benzazepin-1yOcydohexylJpyrrohdin-Z-one,

220. A/-{(5R)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H[I.SAJtriazoMA.S-aHIJbenzazepin-S-yQ-S^-difluorocycîobutanecarboxamide,

221. /V-{(5R)-8-chloro-1-[trans-4-(pyridin-2-yioxy)cyclohexyl]-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}-4,4-difluorocyclohexanecarboxamide,

222. 8-chloro-5-methoxy-1-[c/s-4-methoxy-4-(trifluoromethyl)cyclohexyî]-5_!6-d!hydro-4H-

[1,2,4]triazoio[4,3-a][1]benzazepine,

223. 8-chloro-5-methoxy-1-[frans-4-methoxy-4-(trifluoromethyi)cyclohexyl]-5,6-dihydro-

4H-[ 1,2,4] tri azoi o[4,3- a] [ 1 ] be nzazep i ne,

224. (5S)-8-chioro-1-[trans-4-(pyridin-2-yloxy)cyclohexy!]-/V-(2_:2,2-trifiuoroethy!)-5,6dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine,

225. /V-{(5S)-8-chioro-1-[frans-4-(pyridin-2-yloxy)cyciohexyl]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}-3-methyloxetane-3-carboxamide,

226. A/-{(5R)-8-chioro-1-[frans-4-(pyridin-2-yloxy)cyclohexy!]-5,6-dihydro-4H[I^AjtriazolopLS-aKfibenzazepin-S-yQ-S-methyioxetane-S-carboxamide,

227. frans-4-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]tnazolo[4,3- aH1]benzazepin]-T-yl)-/V-(4-methoxybenzyl)cyclohexanamine_:

228. tert-butyl [2-({(5R)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H[LZAjtriazolo^.S-aJfllbenzazepin-S-yQaminojethyljcarbamate,

229. 8'-chloro-T-(fram-4-ethoxy-4-ethylcyclohexyO-4'H,6'H-spiro[1,3-dioxolane2,5'[1,2,4]triazolo[4,3-a][1]benzazepine]_:

230. frans-4-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3aH1]benzazepin]-T-yl)-/V-(4-methoxybenzyl)-/V-methylcyciohexanamine,

231. 8'-chloro-T-[1-(pyridin-3-ylmethyi)pyrrolidin-3-yÎ]-4'/7,6ⁱH-spiro[1,3-d!Oxolane-2,5'[1,2,4jtriazolo[4,3-a][1]benzazepine],

232. 8-chloro-5-methoxy-1-[4-(pyridin-2-yl)piperazin-1-yl]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepine,

233. 8-chloro-1-(frans-4-ethyl-4-nΊethoxycydohexyl)/V,/Vdimethyl·5,6-dihydro-4H”

[1,2,4]tnazolo[4,3-a][1]benzazepin-5-amine,

234. 8-chloro-1-(frarJS-4-ethoxy-4-methylcyclohexyl)-Λ/,Λ/-d!methyl·5_>6-dihydro-4H-

[1,2_i4]triazoio[4,3-a][1jbenzazepin-5-amine,

235. 8'-chloro-T-[frans-4-methoxy-4-(trifluoromethyl)cyclohexyl]-4'H_!6'H-spiro[1,3- dioxolane-2,5’-[1,2,4]triazolo[4,3-a][1]benzazepine],

236. 8'-chlorcFl4c/s-4-methoxy-4-(trifluoiOmethyl)cyclohexyl]-4'H,6'H-spiro[1,3- dioxolane-2,5’-[1,2,4]tr!azolo[4_!3-a][1]benzazepine]_:

237. 8'-chloro-T-(trans-4-eihoxy-4-methyicyclohexyl)-4‘H_i6'₎%spiro[1_i3-dioxoiane-2,5'[I^Ajtriazolo^.S-aJillbenzazepine],

238. 8'-chloro-T-(frans-4-ethoxy-4-propylcyciohexyl)-4'H,6’H-spiro[1,3-dioxolane-2,5‘[ 1,2,4]triazo io[4,3- a] [ 1 ] benzazepi n ej,

239. S'-chloro-I^Hpyridin^-yimethyOpyrrolidin-S-yiH'H.e'H-spiroEI.S-diOxoÎane-^ô'-

[1,2,4]triazolo[4,3-a][1]benzazepine],

240. 8‘-chloro-1'-(c/s-4-ethyl·4-methoxycyclohexyl)-4Ή,6'h'-sp!ro[1_l3-dioxolane-2_!5'-

[1,2,4]triazoio[4,3-a][1]benzazepine],

241. 8'-chloro-T-(frans-4-ethyl-4-methoxycyclohexyi)-4'H,6'H-spiro[1,3~d!Oxolane-2.5'-

[1,2,4]triazolo[4,3-a][1]benzazepine],

242. 8'-chIoro-T-(trans-4-methoxy-4-propylcyc!Ohexyl)-4Ή_:6Ή-spiro[1,3-dioxolane-2_l5^,-

[1,2,4]1Π3ζοΙο[4,3-3][1]6θηζ3Ζθρ!ηβ],

243. 8'-chloro-T-(c/s-4-methoxy-4-propylcyclohexy!)-4'H,6'H-spiro[1,3-dioxolane-2,5'-

[1,2,4]triazolo[4,3-a][1]benzazepine]_:

244. 8-chloro-1-(frans-4-ethoxy-4-ethylcyclohexyl)-AHpropan-2-yl)-5,6-dihydro-4H-

[I^AltriazoloK.S-aHljbenzazepin-ô-amine,

245. 8-chloro-1-(trans-4-ethoxy-4-ethytcyclohexyl)-/V,/V-dimeîhy!-5,6-dihydro-4H[I^AjtriazoloH.S-aKIlbenzazepin-S-amine,

246. 8'-chlQro-T-[(3R)-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl]-4’H,6’H-spiro[1,3-dioxolane-

2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine]_!

247. 8-chloro-Smethoxy-1-[(3ft)-1-(pyridin-3-ylmethyi)pyrro!id!n-3-yl]-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepine,

248. 8-chloro-5-methoxy-1-[(3R)-1-(pyridin-2-ylmethyi)pyiToiidin-3-yl]-5,6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepine,

249. S'-chloro-T-^SSj-l-ipyridin-S-ylmethyOpyrroHdin-S-yil-^H^'H-spiroELS-dioxolane-

2,5'-[1,2,4]triazolo[4,3-aH1]benzazepine],

250. 8'-chloro-T-[(3R)-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-4'H,6'H-spiro[1,3-dioxolane-

2,5'-[1,2,4]triazoio[4,3-a][1]benzazepine],

251. 8-chloro-5-methoxy-1-[(3S)-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-5,6-dihydro-4H[l^^tnazoioH.S-aHljbenzazepine,

252. 8’-chloro-14(3S)-1-(pyridîn-2-yimethyl)pyrrol!din-3-yl]-4'H,6'H-spiro[1,3-dioxolane-

2,5'-[1,2./dtriazolo[4,3-a][1]ber!zazepiriel and

253. 8-chloro-5-methoxy-1-[(3S)-1-(pyridin-2-ylmethyl)pyrrolid!n-3-y!]-5_!6-dihydro-4H-

[1,2,4]triazolo[4,3-a][1]benzazepine.

The présent invention also relates to the synthesis of compounds of general formula (I). Accordingly, the compounds of formula (I) of the présent invention can be prepared by one of the following methods:

In so far as, in the compound of formula (I), R² is hydrogen, R³ is -NHBoc or 5 OSi(CH₃)₂-frbutyl group and ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y, the compounds of general formula (I) of the présent invention are prepared by reacting compounds of general formula (II) o - wherein ring B and Y are as defined above for general formula (I) and ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y - and compounds of general formula III (III)

- wherein R¹ is as defined above for general formula (i), R² is hydrogen, R³ is -NHBoc or 15 OSi(CH3)2-Abutyl group - or the compounds of general formula (IV)

- wherein R¹ is as defined above for formula (I), R² is hydrogen, R³ is -NHBoc or-OSi(CH3)2f-butyl group.

The procedure is shown in detail in Scheme 1:

In step a) of Scheme 1 the acid hydrazide of general formula (II) is reacted with the benzazepine-thione of general formula (III) or the methylsulfanyl-benzazepine dérivatives of general formula (IV). The reaction is preferably carried out in a suitable solvent, at the boiling point ofthe solvent, with a reaction time required of 4 to 150 hours. Suitable solvents include xylene, n-butanol, 1,4-dioxane.

Preferred embodiments are, for example, the following:

i) reaction of (II) and (III) in xylene at 140°C for 20 to 150 hours, or

H) reaction of (II) and (III) in π-butanol at 110°C for 20 to 50 hours, or iii) reaction of (II) and (III) in 1,4-dioxane at 110°C for 4 to 20 hours, or iv) reaction of (II) and (IV) in xylene in the presence of catalytic hydrogen chloride at

140°C for 4 to 20 hours, or

v) reaction of (II) and (IV) in 1,4-dioxane in the presence of catalytic hydrogen chloride at 110°C for 4 to 20 hours.

Synthesis of the acid hydrazides of general formula (II) can be carried out in various ways (Scheme 2):

Scheme 2

In step a) of Scheme 2, the carboxylic acid esters of general formula (V) are reacted with hydrazine hydrate in a suitable alcohol at the boiling point of the solvent to obtain the acid hydrazides of general formula (II) or, in step c), the carboxylic acids of general formula (VI) is reacted with ferf-butyl-carbazate and the protecting group of the obtained protected carboxylic acid hydrazide dérivative of general formula (VII) is removed with acid (step d)).

Preferred embodiments are, for example, the following:

step a) methanol or éthanol, hydrazine hydrate, reflux température, 4 to 50 hours;

step b) methanol, thionyl chloride, 0 to 25°C, 4 to 24 hours;

step c) tert-butyl-carbazate, A/,/V-dimethylformamide, Λ/,/V-diisopropylethylamine, Λ/-(3dimethylaminopropyl)-/V-ethylcarbodiimide hydrochloride, 1hydroxybenzotriazole hydrate, room température, 4 to 20 hours;

step d) hydrogen chloride in ethyl acetate, room température, 4 to 20 hours.

The carboxylic acid esters of general formula (V) and the carboxylic acids of general formula (VI) are either commercially available or can be prepared according to the methods described in the Examples.

In so far as, in the compounds of general formula (I), R¹ is as defined above for general formula (I), R² is hydrogen, R³ is -NHBoc, the benzazepine-thione dérivatives of general formula (III) and methylsulfanyl benzazepine dérivatives of general formula (IV) can be prepared according to the following procedures:

The key intermediate benzazepine dérivative of general formula (XIII) can be prepared according to the following Method A (Scheme 3) and Method B (Scheme 4):

Method A:

Scheme 3

In step a) of Scheme 3, amino group of the amino acid dérivative of general formula (VIII), which is commercially available or can be prepared according to the methods described in the Examples, - wherein R¹ is as defined above for general formula (I) - is protected by a tertbutoxycarbonyl protecting group, then with the thus obtained protected amino acid dérivative (IX) - wherein R¹ is as defined above for general formula (I) - the Arndt-Eistert reaction (Arndt, F., Eistert, B. Chem Ber 1935, 68(1):200-208) is carried out in two steps: first, the acid chioride prepared in situ from the compound of general formula (IX) is reacted with diazomethane (steps b) and c)) to give the diazo compound of general formula (X) - wherein R¹ is as defined above for general formula (I) - which in step d) is converted to the amino acid dérivative of general formula (XI) in the presence of a silver sait - wherein R¹ is as defined above for general formula (I). The nitro group of the iatter is reduced (step e)) to obtain the amine of general formula (XII) - wherein R¹ is as defined above for general formula (I) -, which is ring-ctosed by means of a reagent capable of forming an amide bond (step f)) to obtain the benzazepine dérivative of general formula (XIII) - wherein R¹ is as defined above for general formula (I).

Preferred embodiments are, for example, the following:

step a) di-terf-butyl dicarbonate, 1,4-dioxane, aqueous sodium hydroxide solution, room température, 4 to 20 hours;

step b) isobutyl chloroformate, triethylamine, diethyl ether, -30°C, 15 to 45 minutes;

step c) diazomethane solution in ether, -30°C to 0°C, 1 to 3 hours;

step d) silver benzoate, 1,4-dioxane, water, room température, 4 to 20 hours;

step e) i) sodium borohydride, methanoî, nickel chloride, room température, 4 to 20 hours, or ii) hydrogénation in the presence Pt/C cataiyst, toluene, room température, 4 to 20 hours;

step f) /V,A/-dimethylformamide, /VW-diisopropylethylamine, A/-(3-dimethylaminopropyl)Λ/'-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole hydrate, room température, 4 to 20 hours.

Method B:

In step a) of Scheme 4, the phenylacetic acid dérivative of general formula (XIV), which is 5 commercially available or can be prepared according to the methods described in the

Examples - wherein R¹ is as defined above for general formula (i) - is reacted with Meldrum’s acid to obtain the compound of general formula (XV) - wherein R¹ is as defined above for general formula (I) -, which is reacted with a suitable alcohol (step b)) to obtain the keto ester dérivative of general formula (XVI) - wherein R¹ is as defined above for general formula (I) 1 o and Alk is Ci^alkyl group -, the latter is converted to the compound of general formula (XVII) by the addition of ammonium acetate (step c)) - wherein R¹ is as defined above for general formula (I) and Alk is C i-4alkyl group -, which is reduced in step d) and the resulting amino compound of general formula (XVIII) is obtained - wherein R¹ is as defined above for general formula (I) and Alk is C-Malkyl group - of which amino group is protected with tert15 butoxycarbonyl group (step e)) to obtain the compound of general formula (XIX) - wherein R¹is as defined above for general formula (I) and Alk is C Malkyl group. The nitro group of the latter is reduced in step f) and the thus obtained compound of general formula (XX) - wherein R¹ is as defined above for general formula (I) and Alk is Cwalkyl group - is ring-closed in the presence of a suitable base (step g)) to obtain the compound of formula (XIII) - wherein R¹20 is as defined above for general formula (I).

The compound of formula (XIII) can also be prepared by hydrolysing the compound of general formula (XIX) - wherein R¹ is as defined above for general formula (I) and Alk is Ci. ₄aikyl group - in the presence of a suitable base (step h)) and the resulting compound of formula (XI) - wherein R¹ is as defined above for general formula (I) - is converted to the compound of general formula (XIII) via the steps shown in Method A (step i) of Method B is identical to step e) of Method A and step j) of Method B is identical to step f) of Method A).

Preferred embodiments are, for example, the following:

step a) Meldrum’s acid, acetonitrile, /V,/V-diisopropylethyiamine, pivaloyl chloride, 4dimethylaminopyridine, 20 to 50°C, 4 to 6 hours;

step b) methanol, toiuene, 110 to 120°C, 1 to 6 hours;

step c) ammonium acetate, methanol, room température, 20 to 75 hours or 60°C for 5 to 20 hours;

step d) sodium triacetoxyborohydride, acetic acid, room température, 2 to 48 hours;

step e) sodium bicarbonate, methanol, di-tert-butyl dicarbonate, 5 to 25°C; 1 to 20 hours; step f) i) hydrogénation in the presence of Pt/C catalyst, toiuene, room température, 4 to 20 hours, or ii) hydrogénation in the presence of Pd/C catalyst, methanol, room température, 4 to 20 hours;

step g) i) methanol, sodium methoxide, room température, 2 to 20 hours, or ii) tetrahydrofuran, potassium tert-butoxide, 0 to 25°C, 2 to 20 hours;

step h) lithium hydroxide, methanol, water, tetrahydrofuran, room température, 4 to 20 hours.

The benzazepine-thione dérivatives of general formula (III) and the methylsulfanylbenzazepine dérivatives of general formula (IV) are prepared {Scheine 5) by reacting a compound of general formula (XIII) obtained by Method A or B

Scheme 5

- wherein R- is as defined above for general formula (I) - with Lawesson reagent (step a)), then the thus obtained benzazepine-thione of general formula (Ni-a) - wherein R¹ is as defined above for general formula (I) - is methylated (step b)) to give the methylsulfanylbenzazepine dérivative of general formula (IV-a) - wherein R¹ is as defined above for general formula (I).

Preferred embodiments are, for example, the following:

step a) i) Lawesson reagent, pyridine, 90 to 120°C, 4 to 20 hours, or ii) Lawesson reagent, tetrahydrofuran, room température, 4 to 20 hours;

step b) iodomethane, potassium carbonate, acetone, room température, 4 to 24 hours.

The compounds of general formula (l-b) are prepared by reacting a compound of general formula (lll-a) or a compound of general formula (IV-a) with a compound of general formula (II) {Scheme 6)

Scheme 6

- wherein ring B, Y, R¹ is as defined above for general formula (I), ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y.

Preferred embodiments of step a) of Scheme 6 are, for example, the following:

i) reaction of (II) and (IH-a) in xylene at 140°C for 20 to 150 hours, or ii) reaction of (II) and (lll-a) in π-butanol at 110°C for 20 to 50 hours, or iii) reaction of (II) and (lll-a) in 1,4-dioxane at 110°C for 4 to 20 hours, or iv) reaction of (II) and (IV-a) in xylene in the presence of cataiytic hydrogen chloride at 140°C for 4 to 20 hours, or

v) reaction of (II) and (IV-a) in 1,4-dioxane in the presence of cataiytic hydrogen chloride at 110°C for 4 to 20 hours.

The thus obtained compounds of general formula (l-b) if desired can also be converted to another compound of the general formula (I) by known methods with the introduction of new substituents and/or with the modification, removal of the existing substituents and/or with salt-formation and/or with releasing the base from salts and/or with the préparation of the enantiomers from the racemic mixtures. This is illustrated in detail in Scheme 7:

Scheme 7

The protecting group of compound of general formula (l-b) can be removed in a suitable acidic medium (step a)), the thus obtained compounds of general formula (l-c) wherein ring B., Y, R¹ are as defined above for general formula (I), ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y - can be sulfonyîated or acylated (step b)) and the compounds of general formula (l-d) - wherein R is C(O)R⁷ or S(O₂)R^W as defined in general formula (I) in the meaning of R⁴ or R⁵ -, may optionally be alkylated (step c)) thus, the compounds of general formula (l-e) are obtained. After the alkylation (step d)) of the compounds of general formula (l-b) followed by deprotection (step g)) gives the mono-alkyl dérivatives of general formula (l-g) which can be converted with further alkylation (step h)) to di-alkyl dérivatives of general formula (l-h). The two alkyl groups can be different and/or identical. The monoalkyl or Cy¹dérivatives of general formula (l-g) can also be prepared by reductive amination (step e)) from the amine dérivative of general formula (l-c). The dialkyl dérivatives of general formula (î-h) can also be prepared from the amine dérivatives of general formula (l-c) by reductive amination (step f)) if the two alkyl groups are identical. The compounds of general formula (l-w) - wherein R⁴ and R⁵ taken together with the N to which they are attached form a heterocycle - can also be obtained from the compounds of general formula (l-c) (step k)) using a suitable dihalogen compound in the presence of a base. Pure enantiomers can be obtained by chiral HPLC or resolution from compounds of general formula (l-c) from which acyl and/or alkyl dérivatives can also be prepared. When the compound of general formula (l-c) is a pure enantiomer, the chiral compound of general formula (l-b) is prepared to produce further chirai monoalkyl dérivatives. In the general formulae (l-e), (l-f), (l-g) and (l-h), the term “alkyl” is optionally substituted C-Malkyl as defined in générai formula (I) in the meaning of R⁴ or R^s and in the générai formula (l-g) Cy¹ is as defined for formula (I).

Preferred embodiments are, for example, the following:

step a) and g) hydrogen chloride in ethyl acetate, room température, 1 to 20 hours step b) i) sulfonyl chloride, pyridine, room température, 4 to 20 hours, or ii) sulfonyl chloride, dichloromethane, triethylamine or N,Ndiisopropylethylamine, room température, 4 to 20 hours, or iii) acyl chloride, pyridine, at room température for 4 to 20 hours, or iv) acyl chloride, dichloromethane, triethylamine or N./V-diisopropylethylamine, room température, 4 to 20 hours, or

v) acid anhydride, pyridine, room température, 4 to 20 hours, or vi) acid, /V,A/_;/V’,/V-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate, /V,/V-dimethylformamide, A/,A/-diisopropylethyîamine or triethylamine, room température, 4 to 20 hours, or vii) acid, N-(3-dimethylaminopropyl)-/V-ethylcarbodiimide hydrochloride, N,Ndiisopropylethyiamine, A/W-dimethylformamide, 1-hydroxybenzotriazole hydrate, room température, 4 to 20 hours;

step c) d) and h) alkyl halide, sodium hydride, tetrahydrofuran or N,Ndimethylformamide, room température, 4 to 20 hours;

stepe) aldéhyde or ketone, 1,2-dichloroethane, acetic acid, sodium triacetoxy borohydride, room température, 4 to 20 hours;

step f) aldéhyde or ketone, methanoi, acetic acid, sodium triacetoxy borohydride, room température, 4 to 20 hours;

step k) dihalogen dérivative, Λ/,/V-dimethylformamide, césium carbonate, 20-60 °C, 10-30 hours.

in so far as, in the compound of general formula (i), R² is hydrogen, R³ is -OSiiCHafr” bbuty! group, the benzazepine-thione dérivatives of general formula (III) can be prepared by the procedure of Schéma 8:

(XXII)

The keto group of the keto ester of general formula (XVI) - wherein R¹ is as defined above for general formula (i) and Aik is Ci^alkyl group - is reduced (step a)) and then the hydroxy group of the compound of general formula (XXI) - wherein R¹ is as defined above for general formula (I) and Alk is Ci-4alkyi group - is protected by a silyl protecting group (step b)) to obtain the compound of general formula (XXII) - wherein R¹ is as defined above for formula (I) and Alk is Ci.4alkyl group. The ester group of the latter is hydroîysed (step c)), then the nitro group of the thus obtained compound of general formula (XXIII) - wherein R¹is as defined above for general formula (I) - is reduced (step d)) to give the amine dérivative of general formula (XXIV) - wherein R¹ is as defined above for general formula (I) - which is ring-closed by means of a reagent capable of forming an amide bond (step e)) to obtain the benzazepine of general formula (XXV) - wherein R¹ is as defined above for general formula (I) - which is reacted with Lawesson reagent (step f)) to give the benzazepine-thione dérivative of general formula (ill-b) - wherein R¹ is as defined above for general formula (I).

Preferred embodiments are, for example, the foilowing:

step a) sodium borohydride, methanol, room température, 4 to 20 hours;

step b) 1H-imidazole, tert-butyl-dimethylchlorosiiane, /V,/V-dimethylformamide, room température, 4 to 20 hours;

step c) lithium hydroxide, methanol, water, tetrahydrofuran, room température, 4 to 20 hours;

step d) hydrogénation in the presence of a Pt/'C catalyst, toluene, room température, 4 to 20 hours;

stepe) A/-(3-dimethylaminopropyl)-/V'-ethylcarbodiimide hydrochloride, N,Ndiisopropylethyîamine, A/,A/-dimethylformamide, 1-hydroxybenzotriazole hydrate, room température, 4 to 20 hours;

step f) Lawesson reagent, pyridine, 120°C, 4 to 20 hours.

The compounds of general formula (l-i) can be prepared by reacting compounds of general formula (Hl-b) and compounds of general formula (II) {Scheme 9):

Scheme 9

- wherein ring B, Y, R¹ are as defined above for general formula (I), ring A is a cycloaikyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y.

A preferred embodiment is, for example, the following: step a) xyîene at 140°C for 20 to 120 hours.

The silyl protecting group of the compounds of general formula (l-i) is removed (Scheme 10) to obtain the hydroxy dérivatives of general formula (l-j),

Scheme 10

A preferred embodiment is, for example, the following:

step a) tetrabutylammonium fluoride, tetrahydrofuran, room température, 3 to 10 hours. hours.

In so far as, in the compound of formula (I), R² and R³ jointly represent -O-(CH2)_m-Ogroup and ring A is a cycloaikyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y, the compounds of general formula (I) of the présent invention are prepared by reacting compounds of formula (II)

(il)

- wherein ring B and Y are as defined above for general formula (I) and ring A is a cycloalkyl 5 or a 4- to 7-membered saturated heterocycie containing 1 N, wherein ring A is attached via the ring nitrogen to Y - with the in situ prepared compound of general formula (XXVI),

- wherein R¹ and m are as defined above for general formula (I).

The procedure is illustrated in detail in Scheme 11:

Schéma 11

A preferred embodiment is, for example, the following: step a) dichloromethane, trifluoroacetic acid, trimethyloxonium tetrafluoroborate, 40°C, 20 to 40 hours.

The methoxybenzazepine dérivative of general formula (XXVI) can be prepared according to the procedure of Scheme 12:

Scheme 12

The keto group of the keto ester of general formula (XVI) is protected by a suitable a.œ-Ci-sdiol (step a)) followed by réduction of the nitro group of the compound of general formula (XXVII) - wherein R¹ and m are as defined above for general formula (I) and Alk is Ci-4alkyl group - to give the compound of general formula (XXVIII) (step b)) - wherein R¹ and m are as defined above for general formula (!) and Alk is Ci.4alkyl group - the latter is ringclosed in the presence of a suitable base (step c)) to obtain the benzazepine of general formula (XXIX) - wherein R¹ and m are as defined above for general formula (I) and Alk is C-^alkyl group - from which the methoxybenzazepine dérivative of general formula (XXVI) wherein R¹ and m are as defined above for general formula (I) and Alk is C Malkyl group - is prepared by méthylation (step d)), and the latter without isolation is reacted with an acid hydrazide of general formula (II) (step e)) - wherein ring B and Y are as defined above for general formula (I), ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y - to obtain the compound of general formula (l-k) - wherein ring B, Y, R¹ and m are as defined above for general formula (I) and ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N. wherein ring A is attached via the ring nitrogen to Y - after removing the ketal protecting group (step f)) to give the oxo compound of general formula (l-l) - wherein ring B, Y, R¹ and m are as defined above for générai formula (I) and ring A is a cycloalkyl or a 4- to 7membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y - then the latter is reduced (step g)) to obtain the hydroxy dérivative of general formula (l-j) - wherein ring B, Y, R¹ and m are as defined above for general formula (I) and ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y.

Preferred embodiments are, for example, the following:

step a) trimethyl orthoformate, methanol, ethylene glycol, p-toluenesulfonic acid, 50°C, 50 to 100 hours;

step b) hydrogénation in the presence of a Pt/C catalyst, toluene, room température, 4 to 20 hours;

step c) tetrahydrofuran, potassium tert-butoxide, room température, 2 to 20 hours;

step d) dichloromethane, trifluoroacetic acid, trimethyloxonium tetrafluoroborate, room température, 20 to 25 hours;

step e) acid hydrazide of formula (II), dichloromethane, 50°C, 6 to 20 hours;

step f) methanol, cc. hydrochloric acid, 70°C, 2 to 6 hours;

step g) methanol, sodium borohydride, 0 to 25°C, 2 to 4 hours.

The compounds of formula (l-k) if desired can also be converted to another compound of the general formula (I) by known methods with the introduction of new substituents and/or with the modification, removal of the existing substituents.

The hydroxy dérivatives of general formula (l-j) prepared from the compound of general formula (l-i) or the compound of general formula (l-î) if desired can also be converted to another compound of general formula (I) by known methods with the introduction of new substituents and/or with the modification, removal of the existing substituents and/or with salt-formation and/or with releasing the base from salts and/or with the préparation of the enantiomers from the racemic mixtures. This is illustrated in detail in Scheme 13.

Preferred embodiments of step a) of Scheme 13 are, for example, the following:

i) alkyl halide, sodium hydride, tetrahydrofuran or Λ/,/V-dimethylformamide, room température, 4 to 20 hours, or ii) acyl chloride, dichloromethane, triethylamine or Λ/,/V-diisopropylethylamine, room température, 4 to 20 hours, or iii) acyl chloride, pyridine, room température, 4 to 20 hours.

Pure enantiomers can be obtained by chiral HPLC from compounds of general formula (l-j) from which acyl and/or alkyl dérivatives can also be prepared.

6S

In so far as, in the compound of general formula (I), R² is hydrogen, R³ is -NHBoc or R² and R³ jointly represent -O-(CH2)_m-O- group and ring A is a 4- to 7-membered saturated heterocycle containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to the triazole ring of the 5_!6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine core, the compounds of general formula (I) of the présent invention are prepared by reacting compounds of general formula (XXX)

Γεη)—Y—^aJnh (XXX)

- wherein ring B and Y are as defined above for general formula (I) and ring A is a 4- to 7membered saturated heterocycle containing 1 or 2 N - and compounds of general formula (XXXI)

- wherein R¹ is as defined above for general formula (I), R² is hydrogen, R³ is -NHBoc or R²and R³ jointly represent -0-(CH2)m-0- group and m is as defined above for general formula (I).

The procedure is illustrated in detail in Scheme 14:

(XXX)

Scheme 14

Preferred embodiment of step a) of Scheme 14 is for example, the following:

i) melt (without solvent) at 120-150°C for 3 to 72 hours.

The amine dérivatives of general formula (XXX) are either commercially available or can be prepared according to the methods described in the Exampies.

In so far as R² is hydrogen, R³ is -NHBoc, the triazolo-benzazepine dérivatives of general formula (XXXI) can be prepared according to the procedure of Scheme 15:

Scheme 15

Th© compounds of general formula (IV-a) are reacted with formylhydrazine (step a)) and the resulting compound of general formula (XXXII) - wherein R¹ is as defined for general formula (i) - is brominated (step b)), thus the bromo dérivative of general formula (XXXI-a) is obtained - wherein R¹ is as defined above for general formula (I).

Preferred embodiments are, for example, the following:

step a) formylhydrazine, 1,4-dioxane, 90°C, 3 to 10 hours;

step b) /V-bromosuccinimide, tetrahydrofuran, 70°C, 10 to 60 minutes.

As shown in Scheme 16, the compounds of general formula (XXXI-a) are reacted with the compound of general formula (XXX) (step a)) - wherein ring B and Y are as defined above for general formula (I) and ring A is a 4- to 7-membered saturated heterocycle containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to the triazole ring of the 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine core - , removing the protecting group from the resulting compound of general formula (l-o) (step b)), then the thus obtained amine dérivatives of general formula (l-p) - wherein ring B, Y and R¹ are as defined above for general formula (I) and ring A is a 4- to 7-membered saturated heterocycle containing 1 or 2 N. wherein ring A is attached via a ring nitrogen to the triazole ring of the 5,6-dihydro-4H[1,2,4]triazolo[4;3-a][1]benzazepine core - can be sulfonylated, acylated or alkylated (step c)) to obtain the compounds of general formula (l-q) - wherein ring B, Y and R¹ are as defined above for general formula (I) and ring A is a 4- to 7-membered saturated heterocycle containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to the triazole ring of the 5,6-dihydro-4H-[1.2,4]triazolo[4,3-a][1]benzazepine core and R’ is optionally substituted Ci4alkyl, C(O)R⁷ or S(O2)R¹⁰ as defined under the meaning of R⁴ or R⁵ in general formula (I).

Scheme 16

Preferred embodiments are, for example, the following:

step a) melt (without solvent), 120-150°C, 3 to 72 hours:

step b) hydrogen chloride in ethyl acetate, room température, 4 to 20 hours;

step c) i) sulfonyl chloride, pyridine, room température, 4 to 20 hours, or ii) sulfonyl chloride, dichloromethane, triethylamine or N,Ndiisopropylethylamine, room température, 4 to 20 hours, or iii) acyl chloride, pyridine, room température, 4 to 20 hours, or iv) acyl chloride, dichloromethane, triethylamine or Λ/,/V-dfisopropyiethylamine, room température, 4 to 20 hours, or

v) acid anhydride, pyridine, room température, 4 to 20 hours, or vi) acid. Ν,Ν,Ν’, /V-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate, Λ/,/V-dimethylformamide, /V,/V-diisopropylethylamine, room température, 4 to 20 hours, or vii) acid, A/-(3-dimethylaminopropyl)-/V-ethylcarbodiimide hydrochloride, N,Ndiisopropylethylamine, A/,A/-dimethylformamide, 1-hydroxybenzotriazole hydrate, room température, 4 to 20 hours, or viii) alkyl halide, sodium hydride, tetrahydrofuran or /VW-dimethylformamide, room température, 4 to 20 hours, or ix) aldéhyde or ketone, 1,2-dichloroethane, acetic acid, sodium triacetoxy borohydride, room température, 4 to 20 hours.

When R² and R³ jointiy represent -O-(CH2)_m-O- group, the triazolo-benzazepine dérivatives of general formula (XXXI) can be prepared according to the procedure of Scheme 17:

(XXIX)

(XXVI)

(XXXIII)

Scheme 17

The methoxybenzazepine dérivative of general formula (XXVI) obtained in situ from compound of general formula (XXIX) is reacted with formylhydrazine (steps a) and b)) and the resulting compounds of general formula (XXXIII) - wherein R¹ and m are as defined above for general formula (I) - are brominated (step c)), thus the bromo compounds of general formula (XXXI-b) are obtained - wherein R¹ and m are as defined above for general formula (!)

Preferred embodiments are, for example, the following:

step a) dichloromethane, trifluoroacetic acid, trimethyloxonium tetrafluoroborate, room température, 20 to 25 hours;

step b) formyl hydrazine, dichloromethane, 40°C, optionally change of solvent to dioxane, 90°C, 15 to 40 hours;

step c) /V-bromosuccinimide, tetrahydrofuran, 70°C, 10 to 60 minutes.

According to Scheme 1S, the compounds of general formula (XXXI-b) are reacted with the compounds of general formula (XXX) (step a)) - wherein ring B and Y are as defined above for general formula (I) and ring A is a 4- to 7-membered saturated heterocycle containing 1 or 2 N -, the protecting group from the resulting compounds of general formula (l-r) is removed (step b)), and the resulting keto dérivatives of general formula (l-s) are reduced (step c)) - wherein ring B, Y, m and R¹ are as defined above for general formula (I) and ring A is a 4- to 7-membered saturated heterocycle containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to the triazole ring of the 5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepine core - to obtain the hydroxy dérivatives of general formula (l-t) which may be acylated or aikylated (step d)), thus the compounds of general formula (l-u) are obtained - wherein ring B, Y, R¹ and R⁵ are as defined above for general formula (I) and ring A is a 4to 7-membered saturated heterocycle containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to the triazole ring of the 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine core.

Schéma 18

Preferred embodiments are, for example, the following:

step a) melt (without solvent), 130 to 140°C, 3 to 72 hours;

step b) methanol, cc. hydrochloric acid, 70°C, 2 to 6 hours;

step c) methanol, sodium borohydride, 0 to 25°C, 2 to 4 hours;

step d) i) acyl chloride, pyridine, room température, 4 to 20 hours, or ii) acyl chloride, dichloromethane, triethylamine or Λ/,/V-diisopropylethylamine, room température, 4 to 20 hours, or iii) alkyl halide, sodium hydride, tetrahydrofuran or /V,/V-dimethyiformamide, room température, 4 to 20 hours.

The hydroxy dérivatives of general formula (l-t) if desired can also be converted to another compound of general formula (I) by known methods with the introduction of new substituents and/or with the modification, removal of the existing substituents and/or with sait-formation and/or with releasing the base from salts and/or with the préparation of the enantiomers from the racemic mixtures.

In so far as, in the compound of general formula (I), R² is hydrogen, R³ is NR⁴R^sand R⁴ and R⁵ taken together with the N to which they are attached form a heterocycle, the compounds of general formula (I) of the présent invention are prepared according to the procedure of Schéma 19 in a way that:

Scheme 19

the compounds of general formulae (l-j) or (l-t) are sulfonylated (step a)) and the resulting compounds of general formula (l-v) are reacted - wherein ring B, Y, ring A and R¹ are as defined above for general formula (I) and R” is methyl, trifluoromethyl or 4-methylphenyl group - with an amine of formula NHR⁴R⁵ (step b)) - wherein R⁴ and R⁵ taken together with the N to which they are attached form a heterocycle - to obtain the compounds of general formula (l-w). Amines of formula NHR⁴R⁵ are commercially available or can be synthesized by known methods.

Preferred embodiments are, for exampie, the following:

step a) i) sulfonyl chloride, pyridine, room température, 4 to 20 hours, or ii) sulfonyl chloride, dichloromethane, triethylamine or N,Ndiisopropylethyîamine, room température, 4 to 20 hours;

step b) NHR⁴R⁵, /V,A/-dimethylformamide, 60 to 120°C, 4 to 24 hours.

In so far as, in the compounds of general formula (I), R² is C i^alkyl, R³ is OR⁶ group, the compounds of general formula (I) of the présent invention are prepared according to Schemes 20 and 21 in a way that:

Scheme 20 the compounds of general formula (XXXIV) is protected (step a)) to obtain the compounds of general formula (XXXIV) - wherein wherein R¹ and m are as defined above for general formula (I) and PG¹ is a protecting group (Peter G. M. Wuts: Greene's Protective Groups in Organic Synthesis: Fifth Edition, Chapter 7. Protection for the Amino Group, pages 8951193), preferably 4-methoxybenzyl protecting group - and then the ketal is removed with a suitable acid (step b)), and the obtained oxo dérivative of general formula (XXXV) which is reacted with a suitable alkyl lithium or Grignard reagent (step c)) to obtain the compound of formula general (XXXVI) - wherein R¹ is as defined above for general formula (i) and PG¹ is a protecting group, preferably 4-methoxybenzyl protecting group and R² is C-i^alkyl group. By protecting the hydroxy group of compounds of general formula (XXXVI) (step d)), protected hydroxy dérivatives of general formula (XXXVII) - wherein wherein R¹ is as defined above for general formula (I), PG¹ is a protecting group, preferably 4-methoxybenzyl protecting group, R² is Ci-4aikyl group and PG² is a protecting group (Peter G. M. Wuts: Greene's Protective Groups in Organic Synthesis: Fifth Edition, Chapter 2 Protection for the Hydroxyl Group, Including 1,2- and 1,3-Diols, pages 17-471), preferably silyl protecting group - are obtained. After deprotection (step e)) of the compounds of general formula (XXXVII), then from the thus obtained compounds of general formula (XXXVIII) the benzazepine-thione dérivatives of general formula (XXXIX) are prepared with Lawesson reagent (step f)), followed by méthylation (step g)) to obtain the compounds of general formula (XL).

Preferred embodiments are, for example, the following:

step a) 4-methoxybenzylchloride, sodium hydride, A/,/V-dimethylformamide, 0 to 25°C, 3 to 6 hours;

step b) acetic acid, reflux, 6 to 20 hours;

step c) i) alkyl lithium, tetrahydrofuran, (-78)°C_: 1 to 4 hours, or ii) R²MgClxLiCL tetrahydrofuran, (-20°C) to (-15°C), 1 to 6 hours, or iii) R²MgCI, tetrahydrofuran, CeCb, (-78) to 0°C, 12 to 70 hours;

step d) 1H-imidazole, silyl chloride, A/,A/-dimethylformamide, room température, 4 to 20 hours;

step e) i) ammonium cérium nitrate, water, acetonitrile, 0 to 25°C, 6 to 18 hours, or ii) trifluoroacetic acid, dichloromethane, room température, 12 to 24 hours, or iii) trifluoromethanesuifonic acid, dichloromethane, room température, 2 to 12 hours;

step f) Lawesson reagent, pyridine, reflux, 4 to 5 hours;

step g) iodomethane, potassium carbonate, acetone, room température, 4 to 24 hours.

The compounds of general formulae (XXXIX) or (XL) are reacted with the compounds of general formula (II) (step a) of Scheme 21), to give the compounds of general formula (i-x) - wherein ring B, Y, ring A and R¹ are as defined above for general formula (I), PG² is a protecting group (Peter G. M. Wuts: Greene's Protective Groups in Organic Synthesis: Fifth

Edition, Chapter2 Protection for the Hydroxy! Group, including 1,2- and 1,3-Diols, pages 17471), preferably silyl protecting group, and R² is Ci^alkyl group. The protecting group is removed (step b)) from the resulting compounds of general formula (l-x) to obtain the compounds of general formula (l-y).

Scheme 21

The hydroxy dérivatives of general formula (i-y) if desired can also be converted to another compound of the general formula (I) by known methods with the introduction of new substituents and/or with the modification, removal of the existing substituents and/or with salt-formation and/or with reîeasing the base from salts and/or with the préparation of the enantiomers from the racemic mixtures, for example using the methods described in step c).

Preferred embodiments are, for example, the following:

step a) i) reaction of (II) and (XXXIX) in xylene at 140°C for 20 to 150 hours, or ii) reaction of (II) and (XXXIX) in n-butanol at 110°C for 20 to 50 hours, or iii) reaction of (II) and (XXXIX) in 1,4-dioxane at 110°C for 4 to 20 hours, or iv) reaction of (II) and (XL) in xylene in the presence of catalytic hydrogen chloride at 140°C for 4 to 20 hours, or

v) reaction of (II) and (XL) in 1,4-dioxane in the presence of catalytic hydrogen chloride at 110°C for 4 to 20 hours;

step b) tetrabutylammonium fluoride, tetrahydrofuran, room température, 3 to 10 hours; step c) i) alkyl halide, sodium hydride, tetrahydrofuran or A/,A/-dimethylformamide, room température, 4 to 20 hours, or ii) acyl chloride, dichloromethane, triethylamine or /V,/V-diisopropylethylamine, room température, 4 to 20 hours, or iii) acyl chloride, pyridine, room température, 4 to 20 hours.

in so far as, in the compound of générai formula (I), R² is hydrogen, R³ is -OCH3 group, the benzazepine-thione dérivatives of general formula (III) can be prepared by the procedure of Scheme 22:

Scheme 22

The hydroxy group of the compound of general formula (XXI) - wherein R¹ is as defined above for general formula (I) and Alk is Ci.4alkyl group - is methylated (step a)) to obtain the compound of general formula (XLI) - wherein R¹ is as defined above for general formula (I) and Alk is C-Malkyi group. The ester group of the latter is hydrolysed (step b)), then the nitro group of the thus obtained compound of general formula (XLII) - wherein R¹ is as defined above for general formula (I) - is reduced (step c)) to give the amine dérivative of générai formula (XLIII) - wherein R¹ is as defined above for general formula (I) - which is ringclosed by means of a reagent capable of forming an amide bond (step d)) to obtain the benzazepine of general formula (XLIV) - wherein R¹ is as defined above for general formula (I) - which is reacted with Lawesson reagent (step e)) to obtain the benzazepine-thione dérivative of general formula (Ill-c) - wherein R¹ is as defined above for general formula (I).

Preferred embodiments are, for example, the following:

step a) dichloromethane, 1,8-bis(dimethylamino)naphthalene, trimethyloxonium tetrafluoroborate, room température, 20 to 25 hours;

step b) sodium hydroxide, methanol, water, room température, 4 to 20 hours;

step c) hydrogénation in the presence of a Pt/C catalyst, toluene, room température, 4 to 20 hours;

step d) /V-(3-dimethylaminopropyl)-A/'-ethylcarbodiimide hydrochloride, N,Ndiisopropylethylamine, Λ/,/V-dimethylformamide, 1-hydroxybenzotriazole hydrate, room température, 4 to 20 hours;

step e) Lawesson reagent, tetrahydrofuran, room température, 2 to 20 hours;

The compounds of general formula (l-aa) can be prepared by reacting compounds of general formula (lll-c) and compounds of general formula (II) (Scheme 23):

Scheme 23

- wherein ring B, Y, R¹ are as defined above for general formula (I), ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycie containing 1 N, wherein ring A is attached via the ring nitrogen to Y.

A preferred embodiment is, for example, the following: step a) butanol at 140^cC for 20 to 120 hours.

The compound of general formula (l-aa) can also be synthesized from compound of general formula (XLIV) according to the method depicted on Scheme 24.

(XL IV)

(XLV)

Scheme 24

The compound of general formula (XLIV) is methylated with trimethyloxonium tetrafluoroborate (step a)) and the so obtained compound of general formula (XLV) is reacted in situ with compound of general formula (II) - wherein ring B, Y, R¹ are as defined above for general formula (I), ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycie containing 1 N, wherein ring A is attached via the ring nitrogen to Y - (step b)) to obtain compounds of general formula (l-aa).

A preferred embodiment is, for example, the following:

step a) dichloromethane, trifluoroacetic acid, trimethyloxonium tetrafluoroborate, room température, 20 to 40 hours;

step b) i) compound of formula (II), dichloromethane, 40°C, 2 to 20 hours ii) compound of formula (II), acetonitrile, reflux température, 1 to 10 hours.

The reagent capable of forming an amide bond used for the préparation of compounds of general formulae (XIII), (XXV) and (XLIV) may be, for example, hydroxybenzotriazole (HOBt) and A/-(3-d!methylaminopropyl)-A/-ethy!carbodiimide hydrochtoride (EDC) or O-(benzotriazol-1-yl)-A/,/V,/V^!,/V'-tetramethyluronium hexafluorophosphate (HBTU). The reaction is preferably carried out in the presence of a base - such as triethylamine or Λ/,/V-diisopropylethylamine (DIPEA) - in a suitable solvent such as Λ/,/V-dimethylformamide, acetonitrile, hydrocarbons or chlorinated hydrocarbons or mixtures thereof - at between room température and 0°C. The reaction is followed by thin layer chromatography. The required reaction time is 4 to 20 hours.

The reagents and detailed process steps required for the above reactions are set forth in the Examples.

An aspect ofthe présent invention is novel intermediates represented by the general formulae (lll-a), (lll-b), (lll-c), (IV-a), (XIII), (XXV), (XXIX) and (XLIV) synthesised in the process for preparing the compound of general formula (I) wherein R¹ is as defined above for general formula (I), especially fert-butyl (7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1benzazepin-4-yl)carbamate (Intermediate 3), tert-butyl (7-chloro-2-thioxo-2,3,4,5-tetrahydro1H-1-benzazepin-4-yi)carbamate (intermediate 4), tert-butyl (7-chîoro-2-(methylsuifanyl)4,5-dihydro-3H-1-benzazepin-4-yl]carbamate (Intermediate 5), tert-butyl-(7-bromo-2-oxo2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate (Intermediate 32), tert-butyl-(7-bromo2-thioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate (Intermediate 33), 7-bromo1_l5-dihydrospiro[1benzazepine-4,2’-[1,3]dioxolane]-2(3H)“One (Intermediate 36), 7-chloro1,5-dihydrospiro[1-benzazepine-4,2’-[1,3]dioxolane]-2(3H)-one (Intermediate 53), 4-{[tertbutyl(dimethyl)silyl]oxy}-7-chloro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Intermediate 62), 4-{[fert-butyl(dimethyl)silyl]oxy}-7-chloro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-thione (Intermediate 63), 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (step d) of Intermediate 103) or 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepine-2-thione (Intermediate 103).

The activity data of each of the compounds of general formula (I) of the présent invention are determined in vitro and in vivo by the methods described below.

Human vasopressîn V1a receptor binding assay

Cells and radioligand

The immortalized 1321N1 cell line (Perkin Elmer, ES-361-M400-UA) constitutively and stably expressing human vasopressîn V1a receptor and vasopressîn (8-L-Arginîne), [Phenylalanyl-3,4,5-³H(N)] labelled compound (Perkin Elmer Life and Analytical Sciences) as radioligand were used to détermine the affinity of the prepared compounds.

Method

Membrane-preparation: Membrane préparation of immortalized 1321N1 cells expressing the propagated human Vasopressîn V1a receptor was made according to Jarvis’s method (Jarvis et al., J Pharmacoi Exp Ther 2004, 310:407-16). Cells were suspended in préparative buffer (50 mM Tris, 1 mM EDTA, 0.1 mM PMSF) and homogenized with glass homogenizing potter. To separate the raw membrane fraction two consecutive centrifugation procedures (40,000 g for 20 minutes at 4°C) were executed, then the membrane was taken into the preparatory buffer during a final washing step, it was dîvîded into aliquots which were stored at -80°C untîl the time of measurement.

The protein content of the prepared membrane was determined according to Lowry’s method using standard dilution line of bovine sérum albumin (BSA) (Lowry et a!., J Biol Chem 1951, 193:265-75).

Receptor binding test: In the receptor binding assay, the substances with unknown affinity were used at a minimum of 8 different concentrations, with 3 parallèle at each concentration. To détermine the final affinity value, the results of at least two indépendant experiments were taken into account. The assay mixture included the incubation buffer (50 mM Tris-HCI, pH 7.4 + 3% BSA), membrane préparation of 1321N1 cells expressing the human Vasopressîn V1a receptor (167 pg/ml) and Vasopressîn (8-L-Arginine), [Phenylalanyl-3,4,5-³H(N)] as radioligand (1 nM).

Non-specific binding values were determined în the presence of unlabelied 1.2x10’⁶M (Arg⁸)-vasopressin. Samples were incubated in a total volume of 0.33 ml for 60 minutes at 27°C. Membrane-bound and free ligands were separated by filtration through a 0.5% poiyethyleneimîne-impregnated UniFilter® GF/B™. After drying the filter plates, 40 pl Microscînt-20 (Packard) scintillation cocktail was added to the samples. Finally, radîoactîvîty was measured using MîcroBeta² Microplate Counter (Perkin Elmer).

The ICso data (i.e. theconcentration ofthe unknown substancewhich displaces 50% of spécifie bound radioligand) is calculated from the concentration-displacement curve using the sigmoid fitting mathematical method y = (A1-A2)/(1+(x/xo)p)+A2 with Origin 7.5. software (OriginLab Corporation, Northampton, USA). During fitting, the asymptotes are not fixed. The Ki values (inhibition constant) are given with Cheng-Prusoff équation Ki = ICso/[1+(L/K_D)] wherein [L] is the radioligand concentration used in the experiment and [Kd] is the affinity of the radioactively labelled ligand for the given receptor. The K_D is determined beforehand using the Scatchard curve.

Functional assay to test compounds on human vasopressin V1a receptor expressing cell line

Cells

The immortalized 1321N1 cell line (Perkin Elmer, ES-361-M400-UA) constitutively and stably expressing human vasopressin V1a receptor were used to measure the prepared compounds. The ordinary secondary messenger pathway of the measured GPCR receptor was used, the endogenous G_q-associated System.

Method

Using 30,000 cells/plate, compounds were measured on 96-well plates. The buffer composition of the measurements was the following (expressed in mM): 140 NaCI, 5 KCI, 2 CaCI₂, 2 MgCh, 10 glucose, 10 HEPES (4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid), 2 probenecid, pH = 7.4. FLIPR Calcium 5 kit (Molecular Devices) was used as fluorescent dye, the medium was not removed prior to filling with the dye and the cells were not washed out either before or after: The incubation was performed at room température, the final concentration of DMSO was 1%. The materials to be measured were administered in 15 to 20 minutes pretreatment, at least two parallels of each compound in each concentration was measured.

Fluorescence signal was used to détermine the intracellular Ca²⁺ level, the reader was FlexStation II96. Cytoplasmic Ca²⁺ concentrations were measured by fluorometry using the FlexStation II96 plate reader (excitation: 485 nm, émission: 525 nm). The fluorescence signal was logged in every 1.4 seconds for 1 minute. The reference compounds used were the following: (Arg⁸)-vasopressin as agonist at concentration of ECeo, determined for each plate, and relcovaptan as antagonist at 1 μΜ. The % of inhibition at each concentration and the IC50 value of the compounds were determined where a concentration line was also measured.

The total AVP concentration-response curve was recorded on each plate. The effect of compounds measured was expressed by percentage of relative inhibition compared to control response. For the graphie représentation of the data, nonlinear four parameter alignments were applied using SoftMaxPro software according to the following formula: y = 5 A-D/(1+(x/C)^AB)+D, wherein: A = 0 and D = 100 - lower / upper fixed asymptotes, y = percentage of inhibition, x = logarithm of concentrations of the tested compound, B = steepness of curve and C - IC50 (the concentration belonging to the 50% inhibition of the control response). The average IC50 values were calculated from at least three independent measurements in ail cases.

Table 1: The effectiveness of the compounds of the présent invention measured in human vasopressin V1a receptor binding assay and functional assay

Example No.	K, (nM) on hV1a cell line	ICso(nM) on hV1a cell line	Example No.	Ki(nM) on hV1a cell line	ICso(nM) on hV1a cell line
1	6	95	21	0.7	4
2	7	170	22	0.5	2.8
3	2.1	16	23	1	6.4
4	70	825	24	1	7
5	3.8	17	25	2.3	23
6	2	9	26	0.7	4.5
7	2.1	20	27	1.1	7
8	1.3	6.8	28	0.7	5.4
9	0.8	3	29	0.6	5.4
10	1.8	12	30	1.4	15
11	32	480	31	17	260
12	0.8	9	32	6	85
13	5	45	33	111	480
14	1.1	10	34	52	700
15	0.4	3.7	35	9.7	160
16	3	10	36	36	610
17	2.1	35	37	7	100
18	0.5	1.6	38	2	30
19	0.4	1.8	39	1.4	8.3
20	0.7	1	40	0.9	8.4

Example No.	Ki (nM) on hV1a cell line	IC_So(nM) on hV1a cell line	Example No.	Ki (nM) on hV1a cell line	ICso(nM) on hV1a cell line
41	600	N.D.	71	14	22
42	42%at1pM	N.D.	72	7.5	21
43	88	210	73	1.6	3.3
44	26	480	74	4	2.6
45	38	870	75	3.7	10.4
46	23	410	76	1.1	2.2
47	0.8	2.3	77	1.9	18
48	18	340	78	1.7	12
49	7.5	140	79	71	1855
50	2.7	20	80	58	520
51	7.6	55	81	0.2	1.4
52	11	60	82	29	445
53	0.3	0.9	83	4.4	44
54	0.6	1.2	84	11.4	72
55	0.3	1.1	85	0.4	1.8
56	0.3	1.2	86	2.2	12
57	0.3	1.8	87	2.5	57
58	0.3	1.4	88	0.3	0.9
59	0.8	2.5	89	0.4	1.9
60	2.0	45	90	10.2	152
61	0.4	2.5	91	9.1	45
62	0.2	1.1	92	1.9	16
63	0.3	1.4	93	3.2	16
64	0.5	1.1	94	2.0	23
65	0.5	1.0	95	547	22% at 1μΜ
66	0.8	2.2	96	0.2	0.8
67	0.6	2.3	97	122	34%at1pM
68	9.4	33	98	2.1	39
69	10	139	99	0.3	2.5
70	0.4	1.2	100	0.2	1.5

Example No.	K_t (nM) on hV1a cell line	ICso(nM) on hV1a cell line	Example No.	Ki (nM) on hV1a cell line	ICso(nM) on hV1 a cell line
101	0.2	1.3	131	0.3	0.7
102	5.9	23	132	0.3	2.5
103	0.2	0.7	133	0.4	6.5
104	0.2	0.6	134	0.2	1.5
105	0.3	1.4	135	2.9	54
106	0.1	1.8	136	0.2	1.6
107	1.0	12	137	0.7	9.2
108	0.2	4.9	138	0.2	5
109	0.4	2.7	139	9.3	130
110	2.1	8.3	140	2.4	57
111	0.3	2.4	141	0.7	8.9
112	45.4	213	142	14.3	225
113	21	305	143	5.0	156
114	26.5	205	144	34	168
115	0.5	0.8	145	12.7	47
116	0.7	2.1	146	3.2	78
117	0.9	4.3	147	1.0	9.4
118	66	251	148	1.2	26
119	27	111	149	0.8	15
120	52	465	150	5.6	94
121	79	442	151	30	209
122	3	14	152	67	737
123	2.1	6.3	153	20.5	307
124	1.7	5.1	154	0.8	21
125	0.8	2.3	155	0.04	0.7
126	0.6	1.8	156	0.5	9.5
127	2.8	17	157	0.1	0.5
128	2	14	158	62	1510
129	0.5	20	159	8	216
130	2.4	6.1	160	0.4	4.9

Example No.	Ki (nM) on hV1a cell line	IC₅o(nM) on hV1a cell line	Example No.	Kj(nM) on hV1a cell line	ICso (nM) on hV1a cell line
161	1.8	34	191	0.3	2.9
162	0.5	2.9	192	0.8	6.3
163	1.0	6.2	193	0.1	0.9
164	0.3	0.9	194	1.1	22
165	1.5	21	195	0.3	1.6
166	6.2	169	196	0.5	2.7
167	0.4	2.6	197	0.3	4.1
168	0.4	0.8	198	0.2	0.9
169	0.9	2.3	199	2.2	23
170	15.3	38	200	114	1187
171	0.6	1.2	201	3.9	19
172	0.7	5.6	202	0.4	1.0
173	1.6	11	203	10.1	210
174	0.7	3	204	0.2	2.7
175	50.5	323	205	0.2	2.7
176	0.4	1.1	206	0.2	0.9
177	0.3	0.9	207	0.3	4.2
178	3.9	19	208	0.1	2.2
179	0.2	1.4	209	0.2	1.6
180	1.1	4.1	210	56	292
181	0.5	1.8	211	0.7	1.3
182	19	416	212	2.8	34
183	102	2120	213	0.6	5.5
184	0.6	25	214	66	672
185	4.1	19	215	0.2	3.7
186	0.4	1.2	216	0.7	1.5
187	86	4750	217	0.3	1.4
188	0.5	5.3	218	97	1253
189	10	229	219	0.2	22
190	5.3	105	220	0.4	2.6

Example No.	Ki (nM) on hV1a cell line	ICso(nM) on hV1a cell line	Exampie No.	Ki(nM) on hV1a cell line	IC₅o(nM) on hV1a cell line
221	0.9	9.8	238	0.7	8.2
222	5.8	40	239	1.2	5.6
223	1.6	8.1	240	0.5	3.1
224	0.7	3.6	241	0.4	2.6
225	48	854	242	0.5	1.8
226	0.5	4.2	243	0.4	2.8
227	1.0	51	244	25	263
228	0.8	6.1	245	7	130
229	0.4	2.1	246	0.5	3.4
230	0.7	12	247	5	30
231	1.1	5.9	248	2.3	22
232	1.3	9.2	249	0.8	7
233	6.9	53	250	2.9	27
234	3.8	57	251	18.5	152
235	0.3	22	252	0.7	8.2
236	0.9	4.2	253	5	66
237	0.2	1.5

Mouse vasopressin V1a receptor binding assay

Cells and radioligand

The immortalized 1321N1 cell line (B9/1321N1 clone) constitutively and stably expressing mouse vasopressin V1a receptor vasopressin (8-L-Arginine), [Phenylalanyl3,4,5-³H(N)] labelled compound (Perkin Elmer Life and Analytical Sciences) as radioligand were used to détermine the affinity of the prepared compounds.

Method

Membrane-preparation: Membrane préparation of immortalized 1321N1 cells expressing the propagated mouse Vasopressin V1a receptor was made according to Jarvis’s method (Jarvis et al., J Pharmacol Exp Ther 2004, 310:407-16). Cells were suspended in préparative buffer (50 mM Tris, 1 mM EDTA, 0.1 mM PMSF) and homogenized with glass homogenizing potter. To separate the raw membrane fraction two consecutive centrifugation procedures (40,000 g for 25 minutes at 4°C) were executed, then the membrane was taken into the preparatory buffer during a final washing step, it was divided into aliquots which were stored at -80°C until the time of measurement

The protein content of the prepared membrane was determined according to Lowry’s method using standard dilution line of bovine sérum albumin (BSA) (Lowry étal., J Biol Chem 1951, 193:265-75).

Receptor binding test: In the receptor binding assay, the substances with unknown affinity were used at a minimum of 8 different concentrations, with 3 parallèle at each concentration. To détermine the final affinity value, the results of at least two independent experiments were taken into account. The assay mixture included the incubation buffer (50 mM Tris-HCI, pH 7.4 + 3% BSA), membrane préparation of 1321N1 cells expressing the mouse vasopressin V1a receptor (152 pg/ml) and vasopressin (8-L-Arginine), [Phenylalanyl3,4,5-³H(N)] as radioligand (~ 35-50% concentration of Kd).

Non-specific binding values were determined in the presence of an unlabelled 1.2x10' ⁶ M (Arg⁸)-vasopressin. Samples were incubated in a total volume of 0.33 ml for 60 minutes at 27°C. Membrane-bound and free ligands were separated by filtration through a 0.5% polyethyleneimine-impregnated UniFilter® GF/B™. After drying the filter plates, 40 pl Microscint-20 (Packard) scintillation cocktail was added to the samples. Finally, radioactivity was measured using MicroBeta² Microplate Counter (Perkin Elmer).

The radioligand clamping ability of a substance is determined in at least two independent experiments. Spécifie radioligand binding can be defined as the différence between total and non-specific binding in the presence of a saturation amount of the unlabelled ligand or different concentrations of the substance to be tested. The results are given as a percentage of inhibition of the spécifie binding achieved in the presence of the substance to be tested.

The IC50 data (i.e. the concentration ofthe unknown substancewhich displaces 50% of spécifie bound radioligand) is calculated from the concentration-displacement curve using the sigmoid fitting mathematical method y = (A1-A2)/(1+(x/xo)p)+A2 with Origin 7.5. software (OriginLab Corporation, Northampton, USA). During fitting, the asymptotes are not fixed. The Ki values (inhibition constant) are given with Cheng-Prusoff équation Ki = ICso/[1+(L/Kd)] wherein [L] is the radioligand concentration used in the experiment and [Kd] is the affinity of the radioactively labelled ligand for the given receptor. The Kd is determined beforehand using the Scatchard curve.

Table 2: The binding affinity of certain compounds of the présent invention measured in mouse vasopressin V1a receptor binding assay

Example No.	Ki (nM) on mV1a cell line
8	161
9	31
24	25
25	353
26	15
53	1.1
54	43
55	21
57	12
62	0.6
63	13

Human vasopressin V2 receptor binding assay

Cells and radioligand

The immortalized 1321N1 cell line (Perkin Elmer, ES-363-M400UA)(LotNo:1765208) stably and constitutively expressing human vasopressin V2 receptor, CHO-K1 cell membrane expressing human Vasopressin V2 receptor (Perkin Elmer, 6110541400UA) and vasopressin (8-L-Arginine), [Phenylalanyl-3,4,5-³H(N)] labelled compound (Perkin Elmer Life 10 and Analytical Sciences) as radioligand were used to détermine the affinity of the prepared compounds.

Method

Receptor binding test: In the receptor binding assay, the substances with unknown affinity were used at a minimum of 8 different concentrations, with 3 parallels at each 15 concentration. To détermine the final affinity value, the results of at least two independent experiments were taken into account. The assay mixture included the incubation buffer (50 mM Tris-HCI, pH 7.4 + 3% BSA), membrane préparation of 1321N1 cells expressing the human vasopressin V2 receptor (1,82 pg/ml) and Vasopressin (8-L-Arginine), [Phenylalanyl3,4,5-³H(N)] as radioligand (-concentration of Kd).

Non-specific binding values were determined in the presence of an unlabelled 1.2x10' ⁸ M (Arg⁸)-vasopressin. Samples were incubated in a total volume of 0.55 ml for 90 minutes at 27°C. Membrane-bound and free ligands were separated by filtration through a 0.5% polyethyleneimine-impregnated UniFilter® GF/B™. After drying the filter plates, 40 μΙ Microscint-20 (Packard) scintillation cocktail was added to the samples. Finally, radioactivity was measured using MicroBeta² Microplate Counter (Perkin Elmer).

The radioligand displacement ability of a substance is determined in at least two independent experiments. Spécifie radioligand binding can be defined as the différence between total and non-specific binding in the presence of a saturation amount of the unlabelled ligand or different concentrations of the substance to be tested. The results are given as a percentage of inhibition of the spécifie binding achieved in the presence of the substance to be tested.

The IC50 data (i.e. the concentration of the unknown substance which displaces 50% of spécifie bound radioligand) is calculated from the concentration-displacement curve using the sigmoid fitting mathematical method y = (A1-A2)/(1+(x/x₀)p)+A2 with Origin 7.5. software (OriginLab Corporation, Northampton, USA). During fitting, the asymptotes are not fixed. The Ki values (inhibition constant) are given with Cheng-Prusoff équation K,= ICso/[1+(L/Kd)] wherein [L] is the radioligand concentration used in the experiment and [Kd] is the affinity of the radioactively labelled ligand for the given receptor. The Kd is determined beforehand using the Scatchard curve.

Table 3: The binding affinity of certain compounds of the présent invention measured in human vasopressîn V2 receptor binding assay on 1321N1 cell line

Example No.	Ki or inhibition % at 1μΜ on hV2 1321N1 cell line
1	4%
6	3%
8	3050 nM
9	1190 nM
18	255 nM
19	610 nM
20	365 nM
21	35%
24	2190 nM

25	6%
26	36%
47	366 nM
53	40 nM
54	662 nM
55	469 nM
57	446 nM
62	53 nM
63	575 nM

Method

Receptor binding assays were performed in at least 8 concentrations, with two or rather three parallel samples in each concentration, in at least two independent experiments using an incubation buffer (50 mM Tris-HCI, 5 mM MgClz, pH 7.4 + 0.1% BSA), membrane préparation of CHO-K1 cells (Perkin Elmer, 6110541400UA) expressing the human vasopressin V2 receptor (7 pg/μΙ) and Vasopressin (8-L-Arginine), [Phenylalanyl3,4,5-³H(N)] as radioligand (-concentration of Kd).

Non-specific binding values can be determined in the presence of an unlabelled 1.2 x 10-⁶ M (Arg⁸)-vasopressin. Samples incubated in a total volume of 0.55 mL for 90 minutes at 27°C. Membrane-bound and free ligands were separated by filtration through a polyethyleneimine-impregnated UniFilter® GF/B™. The f ilterplates were washed three times with 0.5 mL of ice-cold washing buffer (50 mM Tris-HCI, pH 7.4). After drying the filter plates, 40 pl of Microscint20 (Packard) scintillation cocktail was added to each well. Finally, radioactivity was measured using Tri-Carb 2900TR liquid scintillation analyzer (Perkin Elmer).

The IC50 data (i.e. the concentration of the unknown substance which displaces 50% of spécifie bound radioligand) is calculated from the concentration-displacement curve using the sigmoid fitting mathematical method y = (A1-A2)/(1+(x/xo)p)+A2 with Origin 7.5. software (OriginLab Corporation, Northampton, USA). During fitting, the asymptotes are notfixed. The Ki values (inhibition constant) are given with Cheng-Prusoff équation K, = IC5o/[1+(L/Kd)] wherein [L] is the radioligand concentration used in the experiment and [Ko] is the affinity of the radioactively labelled ligand for the given receptor. The Ko is determined beforehand using the Scatchard curve.

Affinity data (K.) measured on the 1321N1 cell line expressing human vasopressin V2 receptor are in very close corrélation with Ki results generated with CHO-K1 cell line expressing human vasopressin V2 receptor.

Functional V1a in vivo test

Animais

Male mice (NMRI, ToxiCoop) weighing 18-40 g were used. Animais were kept at least 5 days after delivery, during housing and measurements they were fed and drink ad libitum. The experiments were permitted by the Local Animal Protection Committee and carried out in accordance with the European Animal Protection Directives (EU Directive 2010/63/EU).

Method

Animal behaviour was measured by an automated behavioral analysis System (LABORAS™). The sensors located below platforms detect the mechanical vibration generated by the movement of animal, and transform into an electrical signal (Quinn et al., J Neurosci Methods 2003, 130:83-92). After analyzing signais, the System analyzes the time spent with the following behavioral parameters: locomotion, immobility, climbing, grooming. The grooming algorithm by définition is able to measure the scratching behavioral response. During the experiment, mice were pretreated with the test substance or vehicle, and after the pretreatment period scratching-inducing compound (s.c. 0.3 mg/kg oxytocin) was administered, and then the animais were individually placed into measuring cages. Their behaviour was observed for 1 hour. To reduce the exploratory activity, the animais were measured after a 1-hour habituation to the cage. The behavioural parameters were compared to the parallel measured parameters of the control animais.

The behavioural inhibitory effect of the substances was calculated with average values of parallel measured vehicle treated groups and presented as the percentage of inhibition: 0% was expressed as average value of scratching behaviour of vehicle pretreated animais (and phys. saline s.c. pretreated with vehicle), while 100% was expressed as average value of scratching of vehicle pretreated animais that received oxytocin subcutaneously. For statistical analysis one-way analysis of variance (ANOVA) with Tukey post hoc test were used.

Surprisingly, it has been found that certain compounds of the présent invention produced significant effect on the mouse V1a receptor in vivo functional test.

Table 4: The efficacy of certain compounds of the présent invention in the mouse in vivo V1 a functional test: the inhibition of oxytocin-induced scratching behaviour response after 10 mg/kg p.o. pretreatment in mice.

Example No.	inhibition (%)	Example No.	inhibition (%)
8	64	63	49
9	106*	66	76
12	34	74	30
23	75	88	79
24	94*	89	50
25	42*	96	49
26	71	99	60
29	89	100	96
53	118	101	105
54	70	103	71
55	91	104	67
56	92	126	43
57	84	157	108
58	96	198	41
60	40	204	65
61	41	205	66
62	99

* after i.p. treatment

The prénatal valproate model of autism spectrum disorder (ASD) in rats

The prénatal valproate model has excellent construct and face validity, thus it is a widely accepted animal model of ASD (Christensen et al, JAMA 2013, 309:1696-1703; Roullet et al, Neurotoxicol Teratol. 2013, 36:45-56). In this model, time-mated female Wistar rats (Harlan, UK) were treated with single-dose of valproic acid (VPA, i.p. 600 mg/kg) on 12.5 days of pregnancy. After birth and séparation, the examined male offsprings were kept under standard laboratory conditions until completion of the studies. Four animais were kept together in standard cages at 22-24°C external température and in 12-12 hour light-dark cycle (07.30 a.m. -07.30 p.m.). Food and water were available ad libitum. After once daily treatment with the test substance for 7 days and pretreatment on the day of measurement, the behaviour of the rats was assessed in the social preference test on the 59^,h or 60^thpostnatal day. The social preference test is a largely accepted test method for determining the autistic behaviour of rodents (Nadler et al, Genes Brain Behav20Q4, 3:303-314; BambiniJunior et al, Brain Res 2011, 1408:8-16). The test consists of two paradigms, the first is the social approach avoidance test. In this paradigm the social behaviour of examined animais can be determined with a spécial three-chamber apparatus. In the apparatus, the contact behaviour of the conspecific and empty separated area surrounded with a perforated wall can be examined and compared. Prenatally valproate-treated rats produce autistic behaviour and spend significantly less time with seeking response toward conspecific than the in utero vehicle-treated control animais. One day later, on the 60^th postnatal day, rats were tested in the social memory and récognition paradigm. In this, the contact behaviour with a new, previously unknown conspecific can be measured compared to a familiar conspecific.

In the social approach avoidance paradigm valproate treated rats (VPA/VEH) showed significant decrease of active time spent with social behaviour compared to the in utero vehicle-treated control animais (VEH/VEH). Certain 5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepine compounds of the présent invention substituted at position 5 were unexpectedly effective in this assay and the treatment statistically significantly reversed the value of VPAA/EH to the value of VEH/VEH treated animais.

Rats treated with SAHA (suberoil anilide or vorinostat) used as positive control also showed statistically significant increase in time spent with social seeking response (Foley et al, Eur J Pharmacol 2014, 727:80-86).

In the social memory récognition paradigm valproate treated rats showed significant decrease of the active time spent with seeking new, non-familiar animal compared to the in utero vehicle-treated control animais. Certain 5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepine compounds of the présent invention substituted at position 5 made the behaviour of animais more socialized and were capable to significantly increase the active time spent with seeking response from the new animais. Unexpectedly, the treatment reversed the value of VPA/VEH to the value of VEH/VEH treated animais. Rats treated with SAHA used as positive control also showed statistically significant increase in the time spent with seeking response.

Certain compounds of the présent invention therefore exhibited signifïcant behavioral benefits in the présent animal model that implies the clinical symptoms of ASD, thus providing a therapeutic opportunity for the treatment of human ASD symptoms.

Table 5: The effects on active contact time in the paradigms of social approach avoidance and social memory récognition of certain compounds of the présent invention

	social approach avoidance	social memory récognition
active contact time [sec]	% effect	active novelty contact time [sec]	% effect
Example 26
VEH/VEH	147.1 ± 13.8		136.6 ±7.6
VPA/VEH	41.1 ±8.2		18.0 ±6.2
VPA/SAHA
5 mg/kg i.p.	156.0 ± 6.7	115	155.5 ±5.8	137
VPA/Example 26
1.5 mg/kg i.p.	71.2 ±15.9	30	83.7 ± 11.8	66
5 mg/kg i.p.	116.4 ±22.5	75	133.5 ±10.0	115
15 mg/kg i.p.	148.7 ± 8.3	107	141.9 ±9.1	124

Data presentedin the table are given as mean ± standarderrorofmean(S.E.M.) androunded up to one décimal form. The percentages were calculated from the raw data and rounded up to integer values (wherein VEH/VEH = 100%, VPA/VEH = 0%).

The présent invention will be further illustrated by the following embodiments without Iimiting the scope of the présent invention to them. From the above description part and from the examples, the person skilled in the art may ascertain the essential features of the invention and without departing from its essence and scope, may make certain changes and modifications in order to adapt the invention to various applications and conditions. As a resuit, the invention is not limited to the following illustrative examples, but rather to the scope determined by the appended claims.

In general, the compounds of general formula (I) can be prepared according to the common general knowledge of the person skilled in the art and/or the methods described for the working examples and/or intermediates. Solvents, températures, pressures and other reaction conditions can be easily selected by the person skilled in the art. Starting materials are commercially available and/or can be easily prepared by the person skilled in the art.

During the préparation of compounds combinatorial techniques can be used, for example, where the présent intermediate groups are suitabie for the use of these methods.

In describing the synthesises, the following terms and abbreviations hâve been used: dry = anhydrous

Boc = fert-butoxycarbonyl

D1PEA = Λ/,/V-diisopropyl-ethylamine

DMAP = 4-dimethylamino-pyridine

DMF = A/,A/-dimethylformamide

EDC = A/-(3-dimethylaminopropyl)-A/'-ethylcarbodiimide hydrochloride

HOBt = 1-hydroxybenzotriazole hydrate

HBTU = /V,/V,A/;/V'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate

K2CO3 = potassium carbonate

Lawesson reagent = 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphethane-2,4-disulfide

Meldrum’s acid = 2,2-dimethyl-1,3-dioxane-4,6-dione

MgSO4 = magnésium sulfate

NaBH4 = sodium borohydride

NaBH(OAc)3 = sodium triacetoxy borohydride

NaHCOs = sodium bicarbonate

NaCl = sodium chloride '

Na₂CO3 = sodium carbonate

NaOH = sodium hydroxide ,

Na₂SO4 = sodium sulfate

Pd/C = palladium on carbon

Phg = phenylglycine

Pt/C = platinum on carbon

THF = tetrahydrofuran

Intermediate 1 3-ntert-butoxvcarbonvl)amino1-4-(5-chloro-2-nitrophenvl)butanoic acid no₂ ^ΟΟΗ

Method A)

a) 2-r(fert-butoxvcarbonvl)aminol-3-(5-chloro-2-nitroDhenvl)propanoic acid no₂

COOH

Cl

To a cooled and stirred mixture of 3.03 g (12.4 mmol) of 2-amino-3-(5-chloro-2nitrophenyl)propanoic acid (N.A. Meanwell et al., J Med Chem 1991, 34:2906-2916), 55 mL of 1,4-dioxane, 12 mL of water and 12.4 mL of 10% NaOH solution, 3.35 g of di-tert-butyl dicarbonate (15.4 mmol) was added and the mixture was stirred at room température ovemight. After completion of the reaction, the pH of the mixture was adjusted to 7 with 10% hydrochloric acid solution, and it was concentrated. Dichloromethane was added to the residue and stirred at room température for 1 hour. The precipitated solid was filtered, washed with dichloromethane, the filtrate was concentrated and the residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus 3.83 g (90%) ofthe title productwas obtained. MS (ESI) m/z 367.1 (M+Na)⁺.

b) tert-butyl /V-f 1 -(5-chloro-2-nitrophenvl)-4-diazo-3-oxobutan-2-vllcarbamate

A mixture of 2.55 g (7.4 mmol) of 2-[(fert-butoxycarbonyl)amino]-3-(5-chloro-2nitrophenyl)propanoic acid, 40 mL of diethyl ether and 1.25 mL (9.0 mmol) of triethylamine was cooled to -30°C and 1.15 mL (8.9 mmol) of isobutyl chloroformate was added dropwise with stirring. The mixture was stirred at -30°C for 15 minutes, then a solution of 0.7 M diazomethane in 50 mL of diethyl ether was added dropwise to keep the température between -25°C and -30°C. The mixture was allowed to warm to 0°C and stirred at this température for 1 hour, then the excess diazomethane was decomposed with acetic acid. The reaction mixture was diluted with ethyl acetate, the pH was adjusted to 7 with saturated NaHCOs solution, the phases were separated and the organic phase was washed with saturated NaCI solution, dried over anhydrous NazSCh, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=95:5 as eluent. Thus, 1.72 g (63%) of the titie product was obtained. MS (ESI) m/z 391.1 (M+Na)*. c) 3-r(tert-butoxycarbonvl)amino1-4-(5-chloro-2-nitrophenvl)butanoic acid

Cl

A mixture of 8.26 g (22.4 mmol) of fert-butyl /V-[1-(5-chloro-2-nitrophenyl)-4-diazo-3oxobutan-2-yl]carbamate, 300 mL of 1,4-dioxane, 60 mL of water and 0.49 g (2.1 mmol) of silver benzoate was stirred at room température for 20 hours, then diluted with 300 mL of ethyl acetate, 300 mL of 5% hydrochloric acid was added and the phases were separated. The organic phase was washed with saturated NaCI, dried over anhydrous NazSOi, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus, 5.28 g (66%) of the titie product was obtained. MS (ESI) m/z 381.1 (M+Na)⁺.

Method B)

a) 5-Γ2-(5-chloro-2-nitrophenvl)-1-hvdroxvethvlidenel·22-dimethvl-1,3-dioxane-4,6-dione

4.925 g (22.84 mmol) of (5-chloro-2-nitrophenyl) acetic acid (Enamine Ltd.) was dissolved in 250 mL of acetonitrile and 8.95 mL (51.4 mmol) of DIPEA, 279 mg (2.3 mmol) of DMAP and 3.72 g (25.1 mmol) of Meldrum’s acid were added while stirring. After cooling, 3.1 mL (25.1 mmol) of pivaloyl chloride was slowly added dropwise to keep the température below 30°C. The reaction mixture was stirred for 4 hours at 45°C, then the solution was cooled to 0°C and 90 mL of 1W hydrochloric acid and 90 mL of water were added. The precipitated material was filtered, washed with water, and dried. Thus, 6.62 g (85%) of the titie product was obtained as white powder which was used without further purification in the next step.

b) methyl 4-(5-chloro-2-nitrophenvl)-3-oxobutanoate

A mixture of 6.62 g (19.4 mmol) of 5-[2-(5-chloro-2-nitrophenyl)-1-hydroxyethylidene]2,2-dimethyl-1,3-dioxane-4,6-dione, 70 mL of methanol and 280 mL of toluene was refluxed for 3 hours. The mixture was cooled to room température, 130 mL of saturated NaCI and 100 mL of ethyl acetate were added, the phases were separated, the organic phase was dried over anhydrous MgSCL, fiitered and concentrated. Thus, 5.21 g (99%) of the title product was obtained as a cream-coloured oil, which was crystallized on standing within a few days. MS (ESI) m/z 272.1 (M+H)⁺.

c) methyl 3-amino-4-(5-chloro-2-nitrophenvl)but-2-enoate no₂

NH_Z

Cl

A mixture of 5.40 g (20 mmol) of methyl 4-(5-chloro-2-nitrophenyl)-3-oxobutanoate, 60 mL of methanol and 7.8 g (101 mmol) of ammonium acetate was heated at reflux for 5 hours then concentrated. Saturated NaHCOs solution was added to the residue and extracted with dichloromethane. The organic phase was dried over anhydrous MgSO4, fiitered and concentrated. Thus, 4.85 g (90%) of the title product was obtained as yellow solid. MS (ESI) m/z 271.7 (M+H)⁺.

d) methyl 3-amino-4-(5-chloro-2-nitrophenyl)butanoate no₂

NH₂

Cl

11.23 g (41.5 mmol) of methyl 3-amino-4-(5-chloro-2-nitrophenyl)but-2-enoate was dissolved in 120 mL of acetic acid and 6.27 g (29.6 mmol) of NaBH(OAc)s was added during cooling and stirring. The mixture was stirred at room température for 2 hours and further 6.27 g (29.6 mmol) of NaBH(OAc)3 was added. The reaction mixture was stirred at room température for 20 hours and poured into ice-cold water. The pH of the mixture was adjusted to 8 with solid K2CO3 and extracted with ethyl acetate, the organic phase was dried over anhydrous MgSO4, fiitered and concentrated. Thus, 11.32 g (100%) ofthe title productwas obtained as yellow oil. MS (ESI) m/z 273.7 (M+H)⁺.

e) methyl 3-F(terLbutoxvcarbonyDaminol-4-(5-chloro-2-nitrophenYDbutanoate

NO₂

JL_x^.NHBoc ^COOMe

Cl

To a mixture of 11.32 g (41.5 mmol) of methyl 3-amino-4-(5-chloro-2nitrophenyl)butanoate, 330 mL of methanol and 6.82 g (82.4 mmol) of NaHCOs 11.32 g (51.9 mmol) of di-tert-butyl dicarbonate was added during cooling and stirring and the mixture was stirred at room température for 20 hours. The reaction mixture was concentrated, 500 mL of water was added to the residue, the precipitated product was filtered, washed with water, and dried. Thus, 13.83 g (89%) of the titie product was obtained as yellow powder. MS (ESI) m/z 395.0 (M+Na)⁺.

f) 3-F(fert-butoxycarbonvl)aminol-4-(5-chloro-2-nitrophenvl)butanoic acid

To a stirred mixture of 13.83 g (37.1 mmol) of methyl 3-[(fert-butoxycarbonyl)amino]4-(5-chloro-2-nitrophenyl)butanoate, 260 mL of THF, 130 mL of methanol and 130 mL of water, 8 g (190 mmol) of lithium hydroxide monohydrate was added while stirred. The reaction mixture was stirred at room température for 20 hours, and then concentrated. 300 mL of water was added to the residue, the pH of the mixture was adjusted to 5 with 10% hydrochloric acid and the mixture was stirred at room température for 1 hour. The precipitated product was filtered, washed with water, and dried. Thus, 13.2 g (99%) of the titie product was obtained. MS (ESI) m/z 381.1 (M+Na)⁺.

Intermediate 2 4-(2-amino-5-chlorophenvl)-3-r(tert-butoxvcarbonvl)amino1butanoic acid nh₂

XOOH Cl

Method A)

To a mixture of 5.28 g (14.7 mmol) of 3-[(tert-butoxycarbonyl)amino]-4-(5-chloro-2nitrophenyl)butanoic acid (Intermediate 1), 140 mL of methanol and 350 mg (1.47 mmol) of nickel chloride hexahydrate, 1.35 g (35.7 mmol) of NaBHi was added under ice-cooling, then the reaction mixture was stirred at room température for 20 hours. The pH of the reaction mixture was adjusted to 6 with 10% hydrochloric acid, the mixture was filtered through Celite, the filtrate was concentrated and the residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus, 2.11 g (44%) of the titie product was obtained. MS (ESI) m/z 351.2 (M+Na)⁺.

Method B)

To a mixture of 3.0 g (8.34 mmol) of 3-[(tert-butoxycarbonyl)amino]-4-(5-chloro-2nitrophenyl)butanoic acid (Intermediate 1) and 400 mLof toluene, 300 mg of 5% Pt/C catalyst was added under argon, then the reaction mixture was stirred at room température in

100 hydrogen atmosphère. After completion of the reaction, the catalyst was filtered through Celite, washed with methanol, and the filtrate was concentrated. Thus, 2.64 g (96%) of the title product was obtained.

Intermediate 3 tert-butvl (7-chloro-2-oxo-2,3.4,5-tetrahydro-1 H-1 -benzazepin-4-vl)carbamate

NHBoc

A mixture of 5.52 g (16.79 mmol) of 4-(2-amino-5-chlorophenyl)-3-[(ferfbutoxycarbonyl)amino]butanoic acid (Intermediate 2), 60 mL of DMF, 3.9 g (20.34 mmol) of EDC, 7 mL (40.2 mmol) of DIPEA and 3.08 g (20.1 mmol) of HOBt was stirred at room température for 20 hours, then the reaction mixture was concentrated. 100 mL of saturated NaHCO₃ solution was added to the residue, and the mixture was stirred at room température for 1 hour. The crystalline product was filtered off, washed with water, and dried. Thus, 4.71 g (90%) of the title product was obtained. MS (ESI) m/z 333.1 (M+Na)⁺.

Intermediate 4 tert-butvl (7-chloro-2-thioxo-2,3,4,5-tetrahvdro-1 H-1 -benzazepin-4-vl)carbamate

H .S

XX ) cr^s<^:i:x^-Ç

NHBoc

A mixture of 2.35 g (7.56 mmol) of ferf-butyl (7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1benzazepin-4-yl)carbamate (Intermediate 3), 65 mL of pyridine and 3.98 g (9.84 mmol) of Lawesson reagent was stirred at 120°C for 4 hours, then the reaction mixture was concentrated. 100 mL of saturated NaHCOs solution was added to the residue and the mixture was stirred at room température for 1 hour. The crystalline product was filtered off, washed with water, and dried. Thus, 2.32 g (94%) of the title product was obtained. MS (ESI) m/z 327.2 (M+H)⁺.

Intermediate 5 fert-butyl R-chloro-2-(methvlsulfanyl)-4,5-dihydro-3H-1-benzazepin-4-vllcarbamate

SMe

NHBoc

A mixture of 2.32 g (7.1 mmol) of fert-butyl (7-chloro-2-thioxo-2,3,4,5-tetrahydro-1H1-benzazepin-4-yl)carbamate (Intermediate 4), 140 mL of acetone, 1.96 g (14.2 mmol) of

101

K2CO3 and 1.33 mL (21.4 mmol) of iodomethane was stirred at room température for 20 hours. The reaction mixture was concentrated, water was added to the residue and extracted with ethyl acetate, the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. Thus, 2.04 g (84%) of the title product was obtained. MS (ESI) m/z 341.2 (M+H)⁺.

Intermediate 6 ethyl (5-methoxy-2-nitrophenyl)acetate

To a mixture of 10.18 g (90.7 mmol) of potassium-tert-butoxide and 90 mL of dry DMF a mixture of 3.86 mL (36.3 mmol) of ethyl chloroacetate, 5.56 g (36.3 mmol) of 4-nitroanisole (Merck) and 40 mL of dry DMF was added dropwise at 0°C under nitrogen. The resulting dark purple reaction mixture was stirred at 0°C for 2.5 hours, then 35 mL of 3N hydrochloric acid was added dropwise and diluted with water. The mixture was extracted twice with ethyl acetate, the combined organic phases were washed with aqueous NaCI, dried over anhydrous Na2SO4, filtered and concentrated. Thus, 7.33 g (84%) of the title product was obtained as brown oil. MS (ESI) m/z 240.2 (M+H)⁺.

Intermediate 7 (5-methoxv-2-nitrophenyl)acetic acid .cooh MeO

A mixture of 7.33 g (30.6 mmol) of ethyl (5-methoxy-2-nitrophenyl)acetate (Intermediate 6), 1.54 g (36,8 mmol) of lithium hydroxide monohydrate, 90 mL of THF and 45 mL of water was stirred at room température for 16 hours. The organic solvent was evaporated and the residue was extracted with ethyl acetate. 40 mL of 1/V hydrochloric acid was added to the aqueous phase, extracted twice with ethyl acetate, the combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. Thus, 2.27 g (35%) ofthe title productwas obtained. MS (ESI) m/z229.1 (Μ+ΝΗ4Γ.

Intermediate 8

5-ri-hvdroxv-2-(5-methoxv-2-nitrophenvl)ethvlidenel-2,2-dimethvl-1,3-dioxane-4.6dione

102

To a mixture of 2.27 g (10.7 mmol) of (5-methoxy-2-nitrophenyl) acetic acid (Intermediate 7), 40 mL of dry acetonitrile, 1.70 g (11.8 mmol) of Meldrum’s acid, 131 mg (1.07 mmol) of DMAP and 4.21 mL (24.2 mmol) of DIPEA, 1.46 mL (11.8 mmol) trimethylacetyl chloride was added dropwise and the reaction mixture was stirred at 40°C for 4 hours. The mixture was cooied to 0°C, 26 mL of 1Λ/ hydrochloric acid was added dropwise and diluted with 60 mL of water. The precipitated product was filtered off, washed with water and dried over phosphorus pentoxide in a vacuum desiccator. Thus, 2.45 g (68%) of the title product was obtained which was used without further purification.

Intermediate 9 methyl 4-(5-methoxv-2-nitrophenvl)-3-oxobutanoate

A mixture of 2.45 g (7.26 mmol) of 5-[1-hydroxy-2-(5-methoxy-2nitrophenyl)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 8), 10 mL of methanol and 30 mL of toluene was stirred at 115°C for 1.5 hours. The mixture was cooied to room température, ethyl acetate and aqueous NaCI were added. The phases were separated, the organic phase was dried over anhydrous Na₂SO4, filtered and concentrated. Cyclohexane was added to the residue, stirred for 1 hour and the product was filtered off. Thus 1.85 g (95%) of the title product was obtained. MS (ESI) m/z 268.2 (M+H)⁺.

Intermediate 10 methyl 3-amino-4-(5-methoxv-2-nitrophenvl)but-2-enoate

A mixture of 1.07 g (4 mmol) of methyl-4-(5-methoxy-2-nitrophenyl)-3-oxobutanoate (Intermediate 9), 20 mL of methanol and 6.17 g (80 mmol) of ammonium acetate was stirred at room température for 16 hours. The mixture was diluted with water, stirred for 1 hour, and the product was filtered off. Thus, 0.92 g (86%) of the title product was obtained which was used without further purification.

Intermediate 11 methyl 3-amino-4-(5-methoxv-2-nitrophenyl)butanoate ’COOMe

To 9 mL of acetic acid, 0.67 g (17.8 mmol) of NaBH4 was added over 45 minutes while keeping the température around 10°C. 0.79 g (3 mmol) of methyl-3-amino-4-(5methoxy-2-nitrophenyl)but-2-enoate (Intermediate 10) was added to the resulting mixture and stirred at room température for 1.5 hours. The mixture was diluted with water during cooling, then basified with solid K2CO3 and extracted twice with ethyl acetate. The combined organic phases were washed with aqueous K2CO3 solution and then with aqueous NaCI solution, dried over anhydrous Na2SO4, filtered and concentrated. Thus, 0.69 g (87%) of the title product was obtained. MS (ESI) m/z 269.2 (M+H)⁺.

Intermediate 12 methyl 3-r(tert-butoxvcarbonvl)aminol-4-(5-methoxv-2-nitrophenyl)butanoate •NHBoc 'COOMe

To a mixture of 0.69 g (2.6 mmol) of methyl 3-amino-4-(5-methoxy-2nitrophenyl)butanoate (Intermediate 11), 20 mL of methanol and 0.7 g (3.22 mmol) di-terfbutyl-dicarbonate, 0.43 g (5.14 mmol) of NaHCO₃ was added at 10°C. The reaction mixture was stirred at room température for 1.5 hours, diluted with water, and the precipitated product was filtered. Thus 0.72 g (76%) of the title product was obtained. MS (ESI) m/z 391.1 (M+Na)⁺.

Intermediate 13 methyl 4-(2-amino-5-methoxyphenvn-3-r(tert-butoxvcarbonvnamino1butanoate .NHBoc 'COOMa

Methyl 0.72 g (2 mmol) of 3-[(terf-butoxycarbonyl)amino]-4-(5-methoxy-2nitrophenyl)butanoate (Intermediate 12) in 50 mL of methanol was hydrogenated in the presence of 80 mg of 10% Pd/C at room température under atmospheric pressure. After

104 filtration of the catalyst, the filtrate was concentrated to yield 0.62 g (94%) of the title product.

MS (ESI) m/z 339.3 (M+H)⁺.

Intermediate 14 fert-butyl (7-methoxv-2-oxo-2,3,4,5-tetrahvdro-1H-1-benzazepin-4-vl)carbamate

NHBoc

0.56 g (1.7 mmol) of methyl 4-(2-amino-5-methoxyphenyl)-3-[(tertbutoxycarbonyl)amino]-butanoate (Intermediate 13) was dissolved in 12 mL of methanol and 0.26 mL of 30% methanolic sodium methoxide solution was added, and the mixture was stirred at room température for 20 hours. 1.7 mL of 1/V hydrochloric acid was added to the mixture during cooling, diluted with water, and the resulting precipitate was filtered, washed with water and dried over phosphorus pentoxide in a vacuum desiccator. Thus, 0.4 g (80%) of the title product was obtained. MS (ESI) m/z 329.2 (M+Na)⁺.

Intermediate 15 tert-butyl (7-methoxv-2-thioxo-2,3,4,5-tetrahvdro-1H-1-benzazepin-4-yl)carbamate

NHBoc

A mixture of 0.44 g (1.4 mmol) of terf-butyl (7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H1-benzazepin-4-yl)carbamate (Intermediate 14), 20 mL of pyridine and 1.34 g (3,3 mmol) of Lawesson reagent was stirred at 120°C for 4.5 hours. The reaction mixture was cooled to room température, diluted with ethyl acetate, and washed twice with 5% NaHCOa solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. Diethyl ether was added to the residue and the precipitated solid was filtered off after 1 hour of stirring. The crude product was recrystallized from 7 mL of éthanol to yield 0.15 g (32%) of the title product. MS (ESI) m/z 345.2 (M+Na)*.

Intermediate 16 5-ri-hvdroxv-2-(5-methyl-2-nitrophenvl)ethvlidene]-2,2-dimethvl-1,3-dioxane-4,6dione

105

The title product was prepared from 2-(5-methyl-2-nitrophenyl) acetic acid (Astatech Inc.) according to the method described for Intermediate 8, and was used without further purification.

Intermediate 17 methyl 4-(5-methvl-2-nitrophenyl)-3-oxobutanoate

NO,

The title product was prepared from 5-[1-hydroxy-2-(5-methyl-2nitrophenyl)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 16) according to the method described for Intermediate 9, and was used without further purification.

Intermediate 18 methyl 3-amino-4-(5-methvl-2-nitrophenyl)but-2-enoate no₂ nh₂

The title product was prepared from methyl-4-(5-methyl-2-nitrophenyl)-3oxobutanoate (Intermediate 17) according to the method described for Intermediate 10, and 15 was used without further purification.

Intermediate 19 methyl 3-amino-4-(5-methvl-2-nitrophenyl)butanoate no₂

LxJ nh₂

The title product was prepared from methyl-3-amino-4-(5-methyl-2-nitrophenyl)but-220 enoate (Intermediate 18) according to the method described for Intermediate 11, and was used without further purification.

Intermediate 20 methyl 3-nte/t-butoxvcarbonvl)aminol-4-(5-methvl-2-nitrophenvnbutanoate no₂

XOOMe

106

The title product was prepared from methyl-3-amino-4-(5-methyl-2nitrophenyl)butanoate (Intermediate 19) according to the method described for Intermediate 12, and was used without further purification.

Intermediate 21 methyl 4-(2-amino-5-methvl-phenvl)-3-r(tert-butoxvcarbonvnaminolbutanoate

The title product was prepared from methyl-3-[(tert-butoxycarbonyl)amino]-4-(5methyl-2-nitrophenyl)butanoate (Intermediate 20) according to the method described for Intermediate 13, and was used without further purification.

Intermediate 22 tërt-butyl (7-methyl-2-oxo-2,3,4,5-tetrahvdro-1 H-1 -benzazepin-4-yl)carbamate

NHBoc

The title product was prepared from methyl 4-(2-amino-5-methyl-phenyl)-3-[(tertbutoxycarbonyl)amino]butanoate (Intermediate 21) according to the method described for Intermediate 14. MS (ESI) m/z 313.1 (M+Na)⁺.

Intermediate 23 tërt-butvl (7-methvl-2-thioxo-2.3.4.5-tetrahvdro-1H-1-benzazepin-4-vncarbamate

NHBoc

A mixture of 0.71 g (2.4 mmol) of fert-butyl (7-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1benzazepin-4-yl)carbamate (Intermediate 22), 25 mL of dry THF and 0.59 g (1.47 mmol) of Lawesson reagent was stirred at room température for 16 hours. The solvent was evaporated and the residue was purified by column chromatography using cyclohexane:ethyl acetate=80:20 as eluent to yield 0.42 g (56%) of the title product. MS (ESI) m/z 307 (M+H)*.

Intermediate 24 ethyl (5-bromo-2-nitrophenyl)acetate

107

The title product was prepared from 4-nitro-bromobenzene (Combi-Blocks Inc.) according to the method described for Intermediate 6. MS (ESI) m/z 305.1 (M+NHa)*.

Intermediate 25 (5-bromo-2-nitrophenyl) acetic acid

The title product was prepared from ethyl-(5-bromo-2-nitrophenyl)acetate (Intermediate 24) according to the method described for Intermediate 7, and was used without further purification.

Intermediate 26

5-ri-hvdroxv-2-(5-bromo-2-nitrophenvl)ethvlidenel-2,2-dimethyl-1,3-dioxane-4,6-

The title product was prepared from (5-bromo-2-nitrophenyl) acetic acid (Intermediate 25) according to the method described for Intermediate 8, and was used without further purification.

Intermediate 27 methyl 4-(5-bromo-2-nitrophenyl)-3-oxobutanoate

The title product was prepared from 5-[1-hydroxy-2-(5-bromo-2nitrophenyl)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 26) according to the method described for Intermediate 9. MS (ESI) m/z 335.0 (Μ+ΝΗ4Γ.

Intermediate 28 methyl 3-amino-4-(5-bromo-2-nitrophenvl)but-2-enoate

108

The title product was prepared from methyl-4-(5-bromo-2-nitrophenyl)-3oxobutanoate (Intermediate 27) according to the method described for Intermediate 10, and was used without further purification.

Intermediate 29 methyl 3-amino-4-(5-bromo-2-nitrophenyl)butanoate no₂ nh₂

The title product was prepared from methyl-3-amino-4-(5-bromo-2-nitrophenyl)but-2enoate (Intermediate 28) according to the method described for Intermediate 11. MS (ESI) m/z 319.0 (M+H)*.

Intermediate 30 methyl 3-r(fert-butoxvcarbonyl)aminol-4-(5-bromo-2-nitrophenvnbutanoate no₂ ^COOMe

The title product was prepared from methyl-3-amino-4-(5-bromo-2nitrophenyl)butanoate (Intermediate 29) according to the method described for Intermediate 12. MS (ESI) m/z 439.1 (M+Na)⁺.

Intermediate 31 methyl 4-(2-amino-5-bromo-phenyl)-3-r(tert-butoxycarbonvl)aminolbutanoate nh₂

ODOMe Br

2.45 g (5.87 mmol) of methyl 3-[(tert-butoxycarbonyl)amino]-4-(5-bromo-2nitrophenyl)butanoate (Intermediate 30) in 200 mL of toluene was hydrogenated at room température under atmospheric pressure in the presence of 0.25 g of 5% Pt/C catalyst. After filtration of the catalyst, the filtrate was concentrated to yield 2.15 g (94%) of the title product. MS (ESI) m/z 409.1 (M+Na)*.

Intermediate 32 tert-butyl (7-bromo-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-4-vl)carbamate

109

NHBoc .

To a mixture of 2.15 g (5.55 mmol) of methyl 4-(2-amino-5-bromo-phenyl)-3-[(tertbutoxycarbonyl)amino]butanoate (Intermediate 31) and 60 mL of dry THF 0.69 g (6.11 mmol) potassium tert-butoxide was added under nitrogen at 0°C over 30 minutes and the reaction mixture was stirred at room température for 3 hours. Dry ice was then added, and then the mixture was diluted with ethyl acetate and water. The phases were separated, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with aqueous NaCI solution, dried over anhydrous Na₂SO4, filtered and concentrated. Diethyl ether was added to the crude product, stirred for 1 hour at room température, filtered and washed with diethyl ether. Thus, 0.83 g (42%) of the titie product was obtained. MS (ESI) m/z 409.1 (M+Na)⁺.

Intermediate 33 fert-butyl (7-bromo-2-thioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-4-vl)carbamate

NHBOC

A mixture of 0.83 g (2.3 mmol) of fert-butyl (7-bromo-2-oxo-2,3,4_l5-tetrahydro-1H-1benzazepin-4-yl)carbamate (Intermediate 32), 28 mL of dry THF and 0.57 g (1.4 mmol) of Lawesson reagent was stirred at room température for 16 hours. The solvent was evaporated, diethyl ether was added to the residue and the precipitated solid was filtered off after 1 hour of stirring. Thus, 0.79 g (91%) of the titie product was obtained. MS (ESI) m/z 371 (M+H)⁺.

Intermediate 34 methyl r2-(5-bromo-2-nitrobenzvn-1,3-dioxolan-2-vHacetate

A mixture of 3.28 g (10.4 mmol) of methyl 4-(5-bromo-2-nitrophenyl)-3-oxobutanoate (Intermediate 27), 1.7 mL of methanol, 118 mg (0.6 mmol) of p-toluene-sulfonic acid monohydrate, 5.68 mL (52 mmol) oftrimethyl orthoformate and 11.6 mL (207 mmol) ethylene glycol was stirred at 50°C for 96 hours. Aqueous K₂CO3 solution was added to the reaction mixture, then extracted twice with ethyl acetate. The organic phases were dried over

110 anhydrous NazSO₄, filtered and concentrated. The residue was purified by column chromatography using cyclohexane:ethyl acetate=80:20 as eluent. Thus, 2.29 g (61%) ofthe title product was obtained. MS (ESI) m/z 379.1 (M+NH₄)*.

Intermediate 35 methyl r2-(2-amino-5-bromobenzyl)-1,3-dioxolan-2-vl1acetate

2.29 g (6.4 mmol) of methyl-[2-(5-bromo-2-nitrobenzyl)-1,3-dioxolan-2-yl]acetate (Intermediate 34) in 200 mL of toluene was hydrogenated at room température under atmospheric pressure in the presence of 0.56 g 5% Pt/C catalyst. After filtration of the catalyst, the filtrate was concentrated to yield 2.1 g (100%) of the title product. MS (ESI) m/z 330.0 (M+H)⁺.

Intermediate 36

7-bromo-1_<5-dihydrospirori-benzazepine-4,2^,-ri.3ldioxolane1-2(3H)-one

The title product was prepared from methyl [2-(2-amino-5-bromobenzyl)-1,3dioxolan-2-yl]acetate (Intermediate 35) according to the method described for Intermediate 32. MS (ESI) m/z 300.0 (M+H)⁺.

Intermediate 37 ethyl r2-nitro-5-(trifluoromethvl)phenyllacetate

7.45 g (66.55 mmol) potassium fert-butoxide was added to 75 mL of DMF under stirring and argon. The mixture was cooled to 0°C and a solution of 5.00 g (26.16 mmol) of 1-nitro-4-(trifluoromethyl)benzene (Apollo Scientific Ltd.) and 2.98 mL (28.00 mmol) of chloroacetic acid ethyl ester in 25 mL of DMF was added dropwise. A dark purple reaction mixture was obtained which was stirred at 0°C for 1.5 hours. Under ice-water cooling, 5% hydrochloric acid was added to the reaction mixture until the pH of the solution was about 3. As a resuit of acidification, the colour of the solution became yellow. The reaction mixture was extracted with 3x50 mL of ethyl acetate and the combined organic phases were washed with saturated NaHCOa solution and saturated NaCI solution. The solution was dried over MgSO4, filtered and concentrated. Thus, 6.86 g (95%) of the title product was obtained as orange oil. MS (ESI) m/z 278.2 (M+H)⁺.

Intermediate 38 r2-nitro-5-(trifluoromethvl)phenvHacetic acid

COOH

6.85 g (24.71 mmol) of ethyl [2-nitro-5-(trifluoromethyI)phenyl]acetate (Intermediate 37) was dissolved in the mixture of 100 mL of THF, 50 mL of methanol and 50 mL of water. 5.18 g (123.45 mmol) of lithium hydroxide monohydrate was added to the orange solution and the reaction mixture was stirred at room température for 12 hours. The reaction mixture was concentrated and after dilution with water the pH was adjusted to about 4-5 with IN hydrochloric acid. Orange precipitate appeared which was filtered off (the starting material of the previous step, 1-nitro-4-(trifluoromethyl)benzene). Further acidification (pH = 2) resulted in further précipitation (expected product), thus the suspension was cooled in an ice-water bath, the yellow crystalline material was filtered off and washed with a little water. The acidic aqueous phase was extracted twice with 30 mL of ethyl acetate, the combined organic phases were washed with saturated NaCI solution, dried over MgSOi, filtered and concentrated. The yellow product was dried in a drying oven. Thus, 4.88 g (79%) of the title product was obtained as yellow powder. MS (ESI) m/z does not ionize.

Intermediate 39

5-f1-hydroxy-2-r2-nitro-5-(trifluoromethvl)phenvnethvlidene}-2,2-dimethvl-1,3dioxane-4,6-dione

OH O

4.79 g (19.23 mmol) of [2-nitro-5-(trifluoromethyl)phenyl]acetic acid (Intermediate 38) was dissolved in 250 mL of acetonitrile. 7.54 mL (43.30 mmol) of DIPEA, 3.05 g (21.20 mmol) of Meldrum's acid and 0.24 g (1.92 mmol) of DMAP was added to the solution. With moderate stirring and measuring the température of the solution, 2.61 mL (21.20 mmol) of trimethylacetyl chloride was added dropwise in a way that the température of the mixture did not exceed 30°C. The reaction mixture was then stirred at 40°C for 4 hours. The solution was cooled in an ice-water bath and the pH was adjusted to acidic by the addition of 90 mL of 1/V

112 hydrochloric acid. After addition of further 90 mL of water, large précipitation occurred which was filtered off, washed with mother liquor and then with water. The product was dried in vacuo using phosphorus pentoxide at room température. Thus, 6.02 g (83%) of the title product was obtained as white powder. MS (ESI) m/z décomposés.

Intermediate 40 methyl 4-r2-nitro-5-(trifluoromethvl)phenvll-3-oxobutanoate

5.11 g (13.60 mmol) of 5-{1-hydroxy-2-[2-nitro-5-(trifluoromethyl)phenyl]ethylidene}2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 39) was dissolved in a mixture of 68 mL of methanol and 264 mL of toluene, and the reaction mixture was stirred at 110°C for 3 hours. After cooling to room température, 130 mL of saturated NaCI solution and 100 mL of ethyl acetate were poured into the solution. The phases were separated and the organic phase was dried over MgSO4, filtered and concentrated. Thus, 4.09 g (98%) of the title product was obtained as yellow, waxy material. MS (ESI) m/z 306.1 (M+H)+; 323.1 (M+NH₄)⁺.

Intermediate 41 methvl{2-r2-nitro-5-(trifluoromethvl)benzvll-1,3-dioxolan-2-yl)acetate

To a mixture of 4.87 g (15.95 mmol) of methyl 4-[2-nitro-5-(trifluoromethyl)phenyl]-3oxobutanoate (Intermediate 40), 2.46 mL (60.80 mmol) of methanol, 15.00 mL (268.00 mmol) of ethylene glycol, and 7.49 mL (68.50 mmol) of trimethyl orthoformate, 0.18 g (0.94 mmol) p-toluenesulfonic acid monohydrate was added. The reaction mixture was stirred at 50°C for 72 hours, then cooled and 70 mL of saturated Na₂CO3 solution and 70 mL of water were added, which resulted in a highly precipitated mixture. The mixture was extracted twice with 100 mL of ethyl acetate and the combined organic phases were washed with saturated NaCI solution. After drying over MgSCU, it was filtered and concentrated. The residue was purified by column chromatography using cyclohexane:ethyl acetate=4:1 as eluent. Thus, 2.75 g (49%) of the title product was obtained as light yellow oil. MS (ESI) m/z 316.1 (M+H)+; 367.1 (M+NH₄)⁺.

113

Intermediate 42 methvl(2-r2-amino-5-(trifluoromethvnbenzyn-1.3-dioxolan-2-vnacetate

COOMe

2.19 g (6.27 mmol) of methyl{2-[2-nitro-5-(trifluoromethyl)benzyl]-1,3-dioxolan-2yl}acetate (Intermediate 41) in 50 mL of toluene was hydrogenated at room température under atmospheric pressure in the presence of 0.219 g 5% Pt/C catalyst. After filtration of the catalyst, the filtrate was concentrated to yield 2.00 g (100%) ofthe titie product as light orange oil. MS (ESI) m/z 320.2 (M+H)⁺.

Intermediate 43

7-(trifluoromethvn-1.5-dihvdrospirori-benzazepine-4,2’-ri.31dioxolane1-2(3H)-one

2.00 g (6.3 mmol) of methyl{2-[2-amino-5-(trifluoromethyl)benzyl]-1,3-dioxolan-2yl}acetate (Intermediate 42) was dissolved in 70 mL of dry THF, then under argon the solution was cooled to 0°C and 0.78 g (6.91 mmol) of potassium fert-butoxide was added. The dark coloured solution was stirred at room température for 4 hours, then dry ice was added to the reaction mixture. The solution was concentrated and the residue was purified by column chromatography using dichloromethane:methanol=95:5 as eluent Thus, 1.05 g (58%) of the titie product was obtained as white powder. MS (ESI) m/z 288.1 (M+H)⁺.

Intermediate 44 methyl 3-amîno-4-r2-nitro-5-(trifluoromethvl)phenyllbutanoate hydrochloride

a) methyl 3-amino-4-F2-nitro-5-(trifluoromethvl)phenvllbut-2-enoate

.00 g (3.3 mmol) of methyl 4-[2-nitro-5-(trifluoromethyl)phenyl]-3-oxobutanoate (Intermediate 40) was dissolved in 30 mL of methanol and 2.78 g (36.0 mmol) of ammonium19571

114 acetate was added. The reaction mixture was stirred at room température for 72 hours. 150 mL of water was added to the light brown solution and extracted twice with 70 mL of ethyl acetate. The combined organic phases were washed with saturated NaCI solution, dried over MgSO4, filtered and concentrated, then dried over phosphorus pentoxide in desiccator. Thus 0.96 g (96%) of the title product was obtained.

b) methyl 3-amino-4-f2-nitro-5-(trifluoromethvDDhenvllbutanoate hvdrochloride

2.00 g (9.4 mmol) of NaBH(OAc)3 was added to 15 mL of glacial acetic acid at 10°C under aqueous cooling. A mixture of 0.96 g (3.2 mmol) of methyl 3-amino-4-[2-nitro-5(trifluoromethyl)phenyl]but-2-enoate in 5 mL of glacial acetic acid was added dropwise to the above obtained solution, and the reaction mixture was stirred at room température for 2 hours. Then, under cooling with ice-water, 50 mL of water and 50 mL of 30% NaOH solution were added to the reaction mixture. The pH was adjusted to approximately 8 with saturated NaHCOs solution and extracted twice with 70 mL of ethyl acetate. The combined organic phases were washed with saturated NaCI solution, dried over MgSO4 and filtered. Calculated amount of 2.5M hydrogen chloride solution in ethyl acetate solution was added to the filtered ethyl acetate solution, and the mixture was concentrated. The residue was crystallized by trituration with diisopropyl ether. Thus, 0.78 g (72%) ofthe title product was obtained as white powder. MS (ESI) m/z 307.1 (M+H)*.

Intermediate 45 methyl 3-r(tert-butoxvcarbonvl)aminol-4-r2-nitro-5-(trifluoromethvl)phenvHbutanoate

0.78 g (2.3 mmol) of methyl 3-amino-4-[2-nitro-5-(trifluoromethyl)phenyl]butanoate hydrochloride (Intermediate 44) was dissolved in 20 mL of methanol. 0.77 g (9.10 mmol) of NaHCOs was added to the so obtained solution and 0.62 g (2.85 mmol) of di-terf-butyl dicarbonate was added to the suspension under ice-cooling and stirring, then the reaction mixture was allowed to warm to room température and stirred for 16 hours. During the workup, 100 mL of water was poured into the mixture, then the precipitated material was filtered, washed with water, and dried. Thus 0.88 g (72%) of the title product was obtained as white powder. MS (ESI) m/z 429.2 (M+Na)⁺.

Intermediate 46 3-F(fert-butoxvcarbonvl)aminol-4-r2-nitro-5-(trifluoromethvnphenyllbutanoic acid

115

F--F

The title product was prepared from methyl 3-[(tert-butoxycarbonyl)amino]-4-[2-nitro5-(trifluoromethyl)phenyl]butanoate (Intermediate 45) according to the method described in step f) of Method B) of Intermediate 1. MS (ESI) m/z 415.1 (M+Na)*.

Intermediate 47 4-r2-amino-5-(trifluoromethvnphenvn-3-r(tert-butoxvcarbonvl)aminolbutanoic acid

The title product was prepared from 3-[(fert-butoxycarbonyl)amino]-4-[2-nitro-5(trifluoromethyl)phenyl]butanoic acid (Intermediate 46) according to the method described for Intermediate 42. MS (ESI) m/z 385.2 (M+Na)⁺.

Intermediate 48 tert-butyl r2-oxo-7-(trifluoromethvl)-2,3,4,5-tetrahydro-1 H-1 -benzazepin-4yllcarbamate

A mixture of 0.60 g (1.7 mmol) of 4-[2-amino-5-(trifluoromethyl)phenyl]-3-[(tertbutoxycarbonyl)amino]butanoic acid (Intermediate 47), 20 mL of DMF, 0.60 mL (3.39 mmol) of DIPEA, 0.30 g (1.99 mmol) of HOBt and 0.38 g (1.99 mmol) of EDC was stirred at room température for 16 hours and then concentrated. 30 mL of saturated NaHCOs solution was poured to the residue and after a short stirring the precipitated material was fiitered, washed with water, and dried. Thus, 0.49 g (87%) ofthe title productwas obtained as brown powder. MS (ESI) m/z 367.1 (M+H)L

Intermediate 49 tert-butyl r2-thioxo-7-(trifluoromethvn-2.3,4,5-tetrahvdro-1H-1-benzazeptn-4yllcarbamate

116

A mixture of 0.46 g (1.3 mmol) of terf-butyl [2-oxo-7-(trifluoromethyl)-2,3,4,5tetrahydro-1 H-1-benzazepin-4-yl]carbamate (Intermediate 48), 10 mL of pyridine and 0.70 g (1.7 mmol) of Lawesson reagent was stirred at 120°C for 3 hours. The reaction mixture was concentrated and stirred at room température for 12 hours after addition of 10 mL of water and 20 mL of saturated NaHCO₃ solution. The precipitated material was filtered, washed with water, and dried. Thus, 0.44 g (92%) of the title product was obtained as brown powder which was used without further purification.

Intermediate 50 terf-butyl r2-(methvlsulfanvl)-7-(trifluoromethvl)-4,5-dihydro-3H-1-benzazepin-4yllcarbamate

SMe

0.44 g (1.2 mmol) of fert-butyl [2-thioxo-7-(trifIuoromethyl)-2,3,4,5-tetrahydro-1H-1benzazepin-4-yl]carbamate (Intermediate 49) was dissolved in 30 mL of acetone, and 0.34 g (2.44 mmol) of K2CO3 was added. 0.23 mL (3.7 mmol) of iodomethane was added dropwise to the reaction mixture and it was stirred at room température for 24 hours. 20 mL of ethyl acetate was poured to the reaction mixture and the organic phase was first washed with water, then with saturated NaCI solution, dried over MgSO₄, filtered and concentrated. Thus, 0.46 g (100%) of the title product was obtained as orange powder. MS (ESI) m/z 375.1 (M+H)⁺.

Intermediate 51 methvl r2-(5-chloro-2-nitrobenzyl)-1.3-dioxolan-2-vllacetate

The title product was prepared from methyl 4-(5-chloro-2-nitrophenyl)-3oxobutanoate (step b) of Method B) of Intermediate 1) according to the method described for Intermediate 41. MS (ESI) m/z 316.1 (M+H)+; 333.1 (M+NH₄)⁺.

Intermediate 52 methvl r2-(2-amino-5-chlorobenzyl)-1.3-dioxolan-2-vnacetate

COOMe

117

The title product was prepared from methyl [2-(5-chloro-2-nitrobenzyl)-1,3-dioxolan2-yl]acetate (Intermediate 51) according to the method described for Intermediate 42. MS (ESI) m/z 286.1 (M+H)*.

Intermediate 53

7-chloro-1.5-dihvdrospiroi1-benzazepine-4,2^,-ri.3ldioxolanel-2(3H)-one

The title product was prepared from methyl [2-(2-amino-5-chlorobenzyl)-1,3-dioxolan2-yl]acetate (Intermediate 52) according to the method described for Intermediate 43. MS (ESI) m/z 254.1 (M+H)⁺.

Intermediate 54 tert-butvl 2-rrfrans-4-(trifluoromethvl)cyclohexvllcarbonvBhvdrazine carboxylate

F /—\ NH—NHBoc ^rKn

2.13 g (10.9 mmol) of frans-4-(trifluoromethyl)cyclohexancarboxylic acid (Manchester Organics Ltd.) was dissolved in 50 mL of DMF. 1.44 g (10.9 mmol) of ferf-butylhydrazine carboxylate, 4.75 mL (27.3 mmol) of DIPEA, 2.00 g (13.10 mmol) of HOBt and 2.51 g (13.1 mmol) of EDC was added to the solution. The reaction mixture was stirred at room température for 36 hours, then concentrated. 40 mL of saturated NaHCOa solution was added to the residue and after a short stirring the precipitate was filtered, washed with water and dried in a vacuum oven over phosphorus pentoxide. Thus, 3.35 g (99%) of the title product was obtained as white powder. GC-MS (El) m/z 310.1.

Intermediate 55 frans-4-(trifluoromethyl)cvclohexanecarboxvlic acid hydrazide

3.35 g (10.8 mmol) of fert-butyl 2-{[trans-4(trifluoromethyl)cyclohexyl]carbonyl}hydrazine carboxylate (Intermediate 54) was dissolved in a mixture of 50 mL of ethyl acetate and 20 mL of éthanol, then 30 mL of 2.5 M hydrogen chloride solution in ethyl acetate was added. The reaction mixture was stirred at room température for 16 hours, then 150 mL of diethyl ether was added and it was cooled in an ice-water bath. The precipitated product was filtered and washed with diethyl ether. The filtered material was stirred with 100 mL of saturated NaHCOs solution (pH ~ 8), filtered,

118 washed with water, and dried in a vacuum oven over phosphorous pentoxide. Thus, 1.77 g (78%) ofthetitie productwas obtained aswhite powder. GC-MS (El) m/z210.1

Intermediate 56 tert-butvl 2-r(3,3-difIuorocvclobutvl)carbonvnhydrazine carboxylate

F

P-jL \—NH // \ O NHBoc

The titie product was prepared from 3,3-difluoro-cyclobutane carboxylic acid (CombiBlocks Inc.) according to the method described for Intermediate 54. GC-MS (El) m/z 250.1.

Intermediate 57

3,3-difluorocvclobutane carboxylic acid hvdrazide

The titie product was prepared from fert-butyl 2-((3,3difluorocyclobutyl)carbonyl]hydrazine carboxylate (Intermediate 56) according to the method described for Intermediate 55. GC-MS (El) m/z 150.1.

Intermediate 58 methyl 4-(5-chloro-2-nitrophenvl)-3-hvdroxvbutanoate

3.13 g (11.5 mmol) of methyl 4-(5-chloro-2-nitrophenyl)-3-oxobutanoate (step b) of Method B) of Intermediate 1) was dissolved in 100 mL of methanol, the solution was cooled to 0°C, and 0.48 g (12.6 mmol) of NaBH4 was added to the reaction mixture. The resulting mixture was stirred at room température for 16 hours. The reaction mixture was concentrated and 100 mL of water was added to the residue, the pH of the solution was adjusted to about 7 with 5% hydrochloric acid. The aqueous phase was extracted with diethyl ether, the organic phase was dried over MgSÛ4, filtered and concentrated. Thus, 2.85 g (90%) of the titie product was obtained which was used without further purification in the next step.

Intermediate 59 methyl 3-(rtert-butyl(dimethvDsilvnoxv}-4-(5-chloro-2-nitrophenvl)butanoate

119

1.36 g (5.0 mmol) of methyl 4-(5-chloro-2-nitrophenyl)-3-hydroxybutanoate (Intermediate 58) was dissolved in 15 mL of DMF, then 0.85 g (12.4 mmol) of 1H-imidazole and 0.90 g (6.0 mmol) of tert-butyl dimethylchlorosilane was added. The solution was stirred at room température for 24 hours. The reaction mixture was poured into water and the product was extracted twice with 50 mL of ethyl acetate. The combined organic phases were washed with saturated NaCI solution, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using n-hexane:ethyl acetate=4:1 as eluent. Fractions containing the expected product were concentrated to yield 1.70 g (88%) of the title product. MS (ESI) m/z 388.2 (M+H)⁺.

Intermediate 60

3-(Γtert-butvl(dimethvl)silvlΊoxvl·-4-(5-chloro-2-nitrophenvl)butanoic acid

The title product was prepared from methyl 3-{[tert-butyl(dimethyl)silyl]oxy}-4-(5chloro-2-nitrophenyl)butanoate (Intermediate 59) according to the method described for Intermediate 38. MS (ESI) m/z 374.2 (M+H)⁺.

Intermediate 61

4-(2-amino-5-chlorophenvl)-3-<Γterf-butvl(dimethvl)silvΠoxvl·butanoic acid

The title product was prepared from 3-{[fert-butyl(dimethyl)silyl]oxy}-4-(5-chloro-2nitrophenyl)butanoic acid (Intermediate 60) according to the method described for Intermediate 42. MS (ESI) m/z 344.2 (M+H)⁺.

Intermediate 62 4-frtert-butvl(dimethvnsilvnoxv1-7-chloro-1.3,4.5-tetrahvdro-2H-1-benzazepine-2-one

120

The title product was prepared from 4-(2-amino-5-chlorophenyl)-3-{[tertbutyl(dimethyl)silyl]oxy}butanoic acid (Intermediate 61) according to the method described for Intermediate 48. MS (ESI) m/z 326.2 (M+H)*.

Intermediate 63

4-flïert-butvl(dimethvl)silvnoxv}-7-chloro-1,3,4,5-tetrahydro-2H-1-benzazepine-2thione

The title product was prepared from 4-{[tert-butyl(dimethyl)silyl]oxy}-7-chloro-1,3,4,5tetrahydro-2H-1-benzazepine-2-one (Intermediate 62) according to the method described for Intermediate 49. MS (ESI) m/z 342.1 (M+H)⁺.

Intermediate 64 methyl trans-4-(piperidin-1-vlmethvl)cvclohexane carboxvlate

0.30 g (1.8 mmol) of methyl frans-4-formylcyclohexane carboxylate (Synthonix) was dissolved in 10 mL of 1,2-dichloroethane, and 0.52 mL (5.3 mmol) piperidine and 0.19 mL (3.4 mmol) acetic acid were added to the solution. The resulting mixture was cooled to 0°C and 1.16 g (5.5 mmol) of NaBH(OAc)3 was added, and the mixture was stirred at room température for 16 hours. Then, 30 mL of water was added to the reaction mixture and the pH of the mixture was adjusted to about 9 with NazCOs solution. The mixture was extracted twice with 20 mL of dichloromethane, the combined organic phases were dried over anhydrous MgSOi, filtered and concentrated. Thus, 0.40 g (95%) of the title product was obtained which was used without further purification.

Intermediate 65 trans-4-(piperidin-1-vlmethvl)cvclohexane carboxylic acid hydrazide

0.40 g (1.7 mmol) of methyl frans-4-(piperidin-1-ylmethyl)cyclohexane carboxylate (Intermediate 64) was dissolved in 5 mL of methanol, and the solution was poured into a pressure-resistant glass reactor. 5 ml (100 mmol) of hydrazine hydrate was added and the reaction mixture was stirred at 75°C for 16 hours. The reaction mixture was concentrated

121 and cyclohexane and anhydrous toluene were evaporated off the residue. Thus, 0.39 g (97%) of the title product was obtained as white powder. GC-MS (El) m/z 239.2.

intermediate 66 terï-butyl 2-r(4,4-difluorocvciohexvhcarbonynhydrazÎne carboxylate

The title product was prepared from 4,4-difluorocyclohexane carboxylic acid (CombiBlocks Inc.) according to the method described for Intermediate 54. MS (ESI) m/z 301.2 (M+Na)⁺.

intermediate 67

4.4-dîfluorocvclohexane carboxylic acid hydrazide

3.39 g (12.2 mmol) of tert-butyl 2-[(4,4-difluorocyclohexyl)carbonyl]hydrazine carboxylate (Intermediate 66) was dissolved in 50 mL of ethyl acetate, then 50 mL of 2.5 M hydrogen chloride solution in ethyl acetate was added to the solution. The reaction mixture was stirred at room température for 16 hours and then concentrated. 15 mL of dichloromethane and 15 mL of distilled water was added to the residue, and the pH of the aqueous phase was basified with saturated NaHCOs solution, then the mixture was concentrated. The obtained residue was suspended in ethyl acetate, the insoluble solid was filtered off, the filtrate was dried over MgSO₄, filtered and concentrated. Thus, 2.08 g (93%) of the title product was obtained as white powder. MS (ESI) m/z 179.2 (Μ+ΗΓ.

Intermediate 68 ethyl f2-(2-nitrobenzvn-1,3-dioxoian-2-vnacetate

2.00 g (8.0 mmol) of ethyl 4-(2-nitrophenyl)-3-oxobutanoate (D. Royer et al., Tetrahedron 2008, 64:9607-9618) was dissolved in 25 mL of toluene, then 4.45 mL (79.6 mmol) of ethylene glycol and 0.23 g (1.19 mmol) p-toluenesulfonic acid monohydrate were added to the resulting solution. Dean-Stark head was applied to the flask and the reaction mixture was boiled for 6 hours and then stirred at 50°C for 48 hours. The resulting mixture was concentrated, the residue was mixed with water and extracted with diethyl ether. The organic phase was dried over MgSO₄, filtered and concentrated. The resulting crude product was purified by column chromatography using cyclohexane.ethyl acetate-4:1 as eluent.

122

Thus, 0.68 g (29%) of the title product was obtained as pale yellow oil. MS (ESI) m/z 296.2 (M+H)⁺.

Intermediate 69 ethyl [2-(2-aminobenzyl)-1,3-dioxolaπ-2-νΠacetate

The title product was prepared from ethyl [2-(2-nitrobenzyl)-1,3-dioxolan-2-yl]acetate (Intermediate 68) according to the method described for Intermediate 42. MS (ESI) m/z 266.2 (M+H)⁺.

Intermediate 70

I.S-dihvdrospiroM-benzazepine-AS’-ri.Sldioxoianel-SOHl-one

The title product was prepared from ethyl [2-(2-aminobenzyl)-1,3-dioxolan-2yljacetate (Intermediate 69) according tothe method described for Intermediate 43. MS (ESI) m/z 220.2 (M+H)⁺.

Intermediate 71 ethyl 3-amino-4-(2-nitrophenyl)but-2-enoate

The title product was prepared from ethyl 4-(2-nitrophenyl)-3-oxobutanoate (D. Royer et al., Tetrahedron 2008, 64:9607-9618) according to the method described in step c) of Method B) of Intermediate 1. MS (ES!) m/z 252,1 (M+H)T

Intermediate 72 ethyl 3-amino-4-(2-nitrophenvnbutanoate

1.29 g (6.1 mmol) of NaBH(OAc)₃ was dissolved in 10 mLof acetic acid and a solution of 0.51 g (2.03 mmol) of ethyl 3-amino-4-(2-nitrophenyl)but-2-enoate (Intermediate 71) in 5 mL of acetic acid was slowly added dropwise to the previous solution. The resulting mixture was stirred at room température for 48 hours. Then, the pH was adjusted to 8 with saturated

123

NaHCOs solution and extracted with dichloromethane, and then the organic phase was dried over anhydrous MgSO4, filtered and concentrated. Thus, 0.19 g (37%) of the title product was obtained as yellow oil. MS (ESI) m/z 253.2 (M+H)⁺.

Intermediate 73 ethyl 3-Rert-butoxycarbonyl)aminol-4-(2-nitrophenyhbutanoate

The title product was prepared from ethyl 3-amino-4-(2-nitrophenyl)butanoate (Intermediate 72) according to the method described in step e) of Method B) of Intermediate 1. MS (ESI) m/z 375.1 (M+Na)⁺.

Intermediate 74 3-Re?t-butoxycarbony0amino]-4-(2-nitrophenyl)butano8C acid

The title product was prepared from ethyl 3-[tert-butoxycarbonyl)amino]-4-(2nitrophenyl)butanoate (Intermediate 73) according to the method described in step f) of Method B) of Intermediate 1. MS (ESI) m/z 347.1 (M-f-Na)*

Intermediate 75 4-(2-aminophenvn-3-r(fe/T-butoxvcarbonvnaminoÎbutanoic acid

The title product was prepared from 3-[tert-butoxycarbonyl)amino]-4-(2nitrophenyl)butanoic acid (Intermediate 74) according to the method described in Method B) of Intermediate 2. MS (ESI) m/z 295.1 (M+H)⁺.

Intermediate 76 fert-butyl (2-oxo-2,3,4,5-tetrahvdro-1 H-1 -benzazepîn-4-vhcarbamate

NHBoc

The title product was prepared from 4-(2-aminophenyl)-3-i(£erfbutoxycarbonyl)amino]butanoic acid (Intermediate 75) according to the method described for Intermediate 3. MS (ESI) m/z 299.0 (M+Na)⁺.

Intermediate 77

124 tert-butyl (2-thioxo-2,3,4,5-tetrahvdro-1H-1-benzazepm-4-yhcarbamate

The titie product was prepared from benzazepin-4-yi)carbamate (Intermediate 76)

NHBoc tert-buty! (2-oxo-2,3,4,5-tetrahydro-1 H-1 according to the method described for intermediate 4, which was used without further purification.

Intermediate 78 frans-4-(pvrroIîdin-1-vlcarbonyncvclohexane carboxylic acid hydrazide

a) methyl frans-4-(pyrrolidin-1-vlcarbonyl)cyclohexane carboxyiate ^^'‘'COOMe

A mixture of 186 mg (1 mmol) of trans-4-(methoxycarbonyl)cyclohexane carboxylic acid (Combi-Blocks Inc.), 83.5 pL (1 mmol) of pyrrolidine, 5 mL of dry DMF, 348 pL (2 mmol) of DIPEA, 230 mg (1.2 mmol) of EDC, and 162 mg (1.2 mmol) of HOBt was stirred at room température for 24 hours. Ethyl acetate and aqueous NaHCOs solution were added to the reaction mixture. The phases were separated and the aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed with 1W hydrochloric acid and water, dried over anhydrous Na₂SO4, filtered and concentrated. Thus, 180 mg (75%) of the title product was obtained. GC-MS (El) m/z 239.

b) fra/7S-4-(pyrrolidin-1-vlcarbonyi)cyclohexane carboxylic acid hydrazide

180 mg (0.75 mmol) of methyl trans-4-(pyrrolidin-1-yicarbonyi)cyciohexane carboxyiate, 1.1 mLof methanol and 1.1 mL of hydrazine-hydrate were stirred in a pressureresistant glass reactor at 75°C for 24 hours. The reaction mixture was concentrated and cyclohexane was added, then evaporated off. Thus, 183 mg (76%) of the titie product was obtained. GC-MS (El) m/z 239.

Intermediate 79 frans-44morpholin-1-vlcarbonyl)cyclohexane carboxylic acid hydrazide

a) methyl trans-4-(morphoiin-4-ylcarbonvi)cyclohexane carboxyiate

125

The titie product was prepared from frans-4-(methoxycarbony!)cyclohexane carboxylic acid (Combi-Blocks Inc.) and morpholine according to the method described in step a) of Intermediate 78. GC-MS (El) m/z 255.

b) frans-4-(Morpholin-1-vlcarbonyl)cyclohexancarboxylic acid hydrazide

The titie product was prepared from methyl frans-4-(morpholin-4ylcarbonyl)cyclohexane carboxylate according to the method described in step b) of Intermediate 78. GC-MS (El) m/z 255.

Intermediate 80 trans-4-(dimethyiamino)cyclohexane carboxylic acid hydrazide \

L nh₂o

The titie product was prepared from methyl f/ans-4-(dimethylamino)cyciohexane carboxylate (EP 1 582 521 A1 (05.10.2005) TANABE SEIYAKU CO.) according to the method described for Intermediate 65. MS (ESI) m/z 186.3 (M+H)⁺.

intermediate 81 ÿrana-4-(morphoiin-4-yi)cyciohexane carboxylic acid hydrazide

The titie product was prepared from methyl frans-4-(morpholin-4-yl)cyciohexane carboxylate (EP 1 582 521 A1 (05.10.2005) TANABE SEIYAKU CO.) according to the method described for intermediate 65. GC-MS (El) m/z 227

Intermediate 82

1-(P¥rimidin-2-vQazetjdine-3-carboxylic acid hydrazide

The titie product was prepared from methyl 1-(pyrimidin-2-yi)azetidine-3-carboxyiate (WO 2006/124748 A2 (23.11.2006) LEXICON GENETICS INCORP.) according to the method described for Intermediate 65. MS (ESI) m/z 194.2 (M+H)·.

126

Intermediate 83 1-(pvrid8n-2-¥l|azetidine-3-carboxvi8C acid hydrazide

The titie product was prepared from methyl 1-(pyridin-2-yl)azetidine-3-carboxylate (WO 2017/007756 A1 (12.01.2017) RODIN THERAPEUTICS INC.) according to the method described for Intermediate 65. GC-MS (E!) m/z 192

Intermediate 84 ethyl (tFans)-3-methyl-2-oxo-1-oxa-3-azasp!ror4.5Îdecane-8-carboxy!ate

and

Intermediate 85 ethyl (cfet-S-methyPS-oxo-l -oxa-3-azaspiro[4.51decane-8-carboxvlate

O

--Q

----N J-''''’''''', ^^^COOEt

1.8 g (45.0 mmol) of 60% sodium hydride dispersion in oil was suspended in 60 mL of dry DMF, cooled to 0-5°C, then 6.00 g (26.4 mmol) of a ~1:1 mixture of ethyl (c/s)-2-oxo1-oxa-3-azaspiro[4.5]decane-8-carboxylate and ethyl (frans)-2-oxo-1-oxa-3azaspiro[4.5]decane-8-carboxyiate (WO 2008/092887 A1, (07.08.2008) GLAXO GROUP LTD.) dissolved in 60 mL of DMF was added dropwise in such a way that the température of the mixture remained between 0 and 5°C. The réaction mixture was stirred for 20 minutes at this température, then 2.46 mL (39.5 mmol) of iodomethane was added dropwise over 20 minutes. The mixture was stirred for a further hour at 0-5°C, then allowed to warm to room température and stirred for 3 hours at this température. Then, 1.8 mL (31 mmol) of acetic acid was added dropwise over 10 minutes, after stirring for 15 minutes, the reaction mixture was concentrated and 90 mL of n-heptane was evaporated off the residue twice. 180 ml of ethyl acetate, 90 mL of saturated NaHCOs solution and 90 mL of water were added to the residue, the phases were separated, the organic phase was washed with 90 mL of NaCI, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography using toluene:isopropanol=93:7 as eluent. The appropriate fractions were concentrated and the residues were crystallized with diisopropyl ether. Thus, 1.38 g (22%)

127 of ethyl (frans)-3-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-carboxylate (Intermediate 84) and 2.45 g (39%) of ethyl (c/s)-3-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-carboxylate (Intermediate 85) were obtained as white powder. GC-MS (El) m/z 241.

Intermediate 86

Urans)-3-methvÎ-2-oxo-1-cxa-3-azaspiror4.S1decane-8-carboxviÎC acid hydrazide

The title product was prepared from ethyl (trans)-3-methyl-2-oxo-1-oxa-3azaspiro[4.5jdecane-8-carboxylate (Intermediate 84) according to the method described for Intermediate 65. GC-MS (El) m/z 227.

Intermediate §7 (c/s)-3-methyl-2-oxo-1-oxa-3-azaspÎror4.5'|decane-8-carboxylic acid hydrazîde

The title product was prepared from ethyl (c/s)-3-methyl-2-oxo-1-oxa-3azaspiro[4.5]decane-8-carboxylate (Intermediate 85) according to the method described for Intermediate 65. GC-MS (El) m/z 227.

Intermediate 88

5-(2-( 5-fluoro-2-nitrophenvlM-hvdroxvethyljdenel-2,2-dimethyl-1,3-dioxane-4,6-dione

The title product was prepared from (5-fluoro-2-nitrophenyl)acetic acid (Combi-Blocks Inc.) according to the method described for Intermediate 39. MS (ESI) m/z 348.0 (M+Na)⁺.

Intermediate 89 methyl 4-(5-fluoro-2-nitroohenyl)-3-oxobutanoate

128

The title product was prepared from 5-[2-(5-fluoro-2-nitrophenyl)-1hydroxyethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (intermediate 88) according to the method described for Intermediate 40. MS (ES!) m/z 273.1 (M+NH₄)⁺.

Intermediate 90 methyl F2-(5-fiuoro-2-nitrobenzvl)-1,3-dioxoian-2-vHacetate

F

The title product was prepared from methyl 4-(5-fiuoro-2-nitrophenyi)-3-oxobutanoate (Intermediate 89) according to the method described for Intermediate 41. MS (ESI) m/z 317.2 (M+NH₄)⁺.

Intermediate 91 methyl F2-(2-amino-5-fluorobenzvÎM,3-dÎOxoian-2-yHacetate

The title product was prepared from methyl [2-(5-fiuoro-2-nitrobenzyl)-1,3-dioxoian~ 2-yl]acetate (Intermediate 90) according to the method described for Intermediate 42. MS (ESI) m/z 270.2 (M+H)T

Intermediate 92

7-fluoro-1,5-dihvdrospiroF1-benzazep!ne-4,2’-n.3ldjoxolanel-2(3H)-one

The title product was prepared from methyl [2-(2-amino-5-fluorobenzyi)-1,3-dioxolan2-yl]acetate (intermediate 91) according to the method described for Intermediate 43. MS (ESi) m/z 238.2 (M+H)T

Intermediate 93 tert-butyl (8-ch!oro-5,6-djhvdro-4H-F1,2,4lÎriazoloF4,3-alF1lbenzazepine-5yOcarbamate

129

164 mg (0.48 mmol) of fert-butil [7-chloro-2-(methylsulfanyl)-4,5-dihydro-3H-1benzazepin-4-yl]carbamate (intermediate 5) was dissolved in 3 mL of 1,4-dioxane and the resuiting solution was heated to 90°C. 145 mg (2.41 mmol) of formyl hydrazide was added over 4 hours under argon. The reaction mixture was then stirred at 90°C for another 8 hours and after cooling to room température, the solvent was evaporated in vacuo. The residue was purified by column chromatography using dichloromethane:methanol=95:5 as eluent. Thus, 145 mg (95%) of the title product was obtained as white solid. MS (ESI) m/z 335.1 (M+Hf.

Intermediate 94 tert-butyl (1-bromo-8-chloro-5,8-dîhydro-4H-n,2,4ltriazoio[4,3-ainibenzazepîn-5vhcarbamate

NH3oc

528 mg (1.58 mmol) of ferf-butyl (8-chloro-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-yl)carbamate (Intermediate 93) was dissolved in 35 mL of THF. 622 mg (3.5 mmol) of /V-bromosuccinimide was added and the resuiting pale yellow solution was stirred at reflux for 60 minutes with illumination by an RH-500 type halogen lamp (Tracon Electric). At this time, the colour of the solution initialiy darkened and then gradually became discoloured. After cooling to room température, the solvent was evaporated in vacuo. The residue was purified by column chromatography using dichloromethane:methanol=97:3 as eluent. Thus, 592 mg (90%) of the title product was obtained as white solid. MS (ESI) m/z 415.1 (M+H)⁺.

Intermediate 9S

8*-chlcro-4'’H,6^,H-spjrori<3-dioxolane-2.5’-n<2,41triazoloF4,3-airilbeinzazepinel

356.5 mg (1.405 mmol) of 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2^![1,3]dioxolane]-2(3H)-one (Intermediate 53) was dissolved in 22 mL of dichloromethane and 11 pL (0.144 mmol) of trifluoroacetic acid was added. Under argon, 249.4 mg (1.686 mmol) of trimethyloxonium tetrafluoroborate was added and the reaction mixture was stirred at room température for 24 hours. At this time, 422.0 mg (7.027 mmol) of formyi hydrazide was added in 5 portions at reflux température over 4 hours, then the reaction mixture was stirred at reflux température for 15 hours. The reaction mixture was concentrated and the residue was dissolved in 22 mL of dioxane and the mixture was stirred at 80°C for 2.5 hours. After cooling to room température, the solvent was evaporated in vacuo. The residue was purified by column chromatography using dichloromethane:methanol=95:5 as eluent. Thus, 248 mg (64%) ofthe title productwas obtained. MS (ESI) m/z 335.1 (M+H)⁺.

Intermediate §6

T-bromo-8'-chloro-4'H,6'H-spiron.3-dîGxolane-2,5^,-M,2,4]trjazolo[4,3aVHbenzazepinel

The title product was prepared from 8'-chloro-4^,H,6'/7-spiro[1,3-dioxolane-2..5’[1,2,4]triazolo[4,3-a][1]benzazepine] (Intermediate 95) according to the method described for Intermediate 94. MS (ESI) m/z 358.0 (M+H)⁺.

Intermediate 97 frans-4-(piperidin-1-vlcarbonvl)cvclohexane carboxylic acid hydrazide

a) methyl trans-4-(piperidin-1-ylcarbony!)cyciohexane carboxylate

The title product was prepared from ira/7s-4-(methoxycarbonyl)cyclohexane carboxylic acid (Combi-Blocks Inc.) and piperidine according to the method described in step a) of Intermediate 78. GC-MS (El) m/z 253.

b) frans-4-(piperidin-1-ylcarbonvl)cvclohexane carboxylic acid hydrazide

The title product was prepared from methyl frans-4-(piperidin-1ylcarbonyl)cyclohexane carboxylate according to the method described in step b) of intermediate 78. GC-MS (El) m/z 253.

131

Intermediate 98

7-chloro-l, 5-dihydrospiroi1-benzazep»ne-4_!2^,41,3ldioxanel-2(3H'j-one

âLffigWiylJ2d^>£tÜ2!^^

The title product was prepared from methyl 4-(5-chloro-2-nitrophenyl)-3oxobutanoate (step b) of Method B) of Intermediate 1) and 1,3-propanediol according to the method described for Intermediate 41. MS (ESI) m/z 330.2 (M+H)T b) methyl i2-(2-amino-5-chlorobenzyl)-1,3-dioxan-2-yllacetate

NHn

The title product was prepared from methyl [2-(5-chloro-2-nitrobenzyl)-1,3-dioxan-2yljacetate (step a) of Intermediate 98) according to the method described for Intermediate 42. MS (ESI) m/z 322.2 (M+Na)⁺.

c) 7-chloro-1.5-dihydrospiro[1-benzazepine-4,2^(1,3]dioxanel-2(3H)-one

The title product was prepared from methyl [2-(2-amino-5-chlorobenzyl)-1,3-dioxan2-yl]acetate (step b) of Intermediate 98) according to the method described for Intermediate 43. MS (ESI) m/z 268.1 (M+H)⁺.

Intermediate 99 methyl (5s,8s)-1-oxo-2-(propan-2-vl)-2-azaspiror4.5ldecane-8-carboxylate

and

Intermediate 100 methyl (5r,8r)-1-oxo-2-(propan-2-yl)-2-azaspiro[4.5ldecane-S-carboxylate

132

A mixture of 0.9 g (4.0 mmol) of dimethyl frans-1-(2-oxoethyi)cyclohexane-1,4dicarboxylate (WO 2011/143150 A1, (05. 10. 2011) SANOFI), 40 mL of 1,2-dichloroethane, 316 pL (3.71 mmol) of isopropyiamine and 637 pL (11.1 mmol) of acetic acid was cooled to 5°C and 2.36 g (11.1 mmol) of sodium triacetoxyborohydride was added to the reaction mixture at such a rate to keep the internai température below 5°C. After completion of the addition the reaction mixture was stirred at room température for 2 h, then diluted with water. The pH of the mixture was adjusted to 8 by addition of 10% K2CO3 solution, the phases were separated and the water phase was extracted with dichloromethane. The combined organic phases were successively washed with 10% K2CO3 solution, water and brine, dried over NazSCU, filtered and concentrated. The residue was dissolved in 40 mL of dry THF and 330 mg (2.94 mmol) of potassium tert-butoxide was added. The reaction mixture was stirred at room température for 3 h, then neutralized by addition of solid CO₂. After addition of water the THF was evaporated and the water phase was extracted with ethyl acetate. The organic phase was dried over Na₂SO4, filtered and concentrated. The residue was purified by flash column chromatography using cyclohexane : ethyl acetate = 45:55 mixture as eluent to yield 56 mg (6%) of methyl (5s,8s)-1-oxo-2-(propan-2-yl)-2-azaspiro[4.5]decane-8-carboxylate (Intermediate 99) as the first fraction and 172 mg (19%) of methyl (5r,8r)-1-oxo-2-(propan-2yl)-2-azaspiro[4.5]decane-8-carboxylate (Intermediate 100) as the second fraction. GC-MS (El) m/z 253.

Intermediate 101 (5s,8s)-1-oxo-2-(propan-2-vl)-2azaspiroi'4.51decane-8-carbohvdrazide

The title compound was prepared methyl (5s,8s)-1-oxo-2-(propan-2-yl)-2azaspiro[4.5]decane-8-carboxylate (Intermediate 99) according to the method described for Intermediate 65. GC-MS (El) m/z 253.

Intermediate 102 (5r,8r)-1-oxo-2-(propan-2-vl)-2-azaspiror4.5ldecane-8-carbohydrazide \ J □0-4 \ / NH—-NH₂

The title compound was prepared from methyl (5r,8r)-1-oxo-2-(propan-2-yl)-2azaspiro[4.5]decane-8-carboxylate (intermediate 100) according to the method described for Intermediate 65. GC-MS (El) m/z 253.

133

Intermediate 103

7-chIero-4-methoxv-'L3.,4,5-tetrahvdro-2H-1l-benzazepine-2-thsone

o-

NO,

Y^^COOMe

Cl

A mixture of 1.37 g (5 mmol) of methyl 4-(5-chloro-2-nitrophenyl)-3-hydroxybutanoate (Intermediate 58), 90 mL of dichloromethane, 1.4 g of 4A molecular sieves, 3.21 g (15 mmol) of 1,8-bis(dimethylamino)naphthaîene and 2.22 g (15 mmol) of trimethyloxonium tetrafluoroborate was stirred at room température for 20 h, then filtered and the solid material was washed with dichloromethane. The fiitrate was washed with 3M HCl solution and water, dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash column chromatography using cyclohexane : ethyl acetate = 65:35 as eluent to yield 1.097g (76%) of the title compound. MS (ESI) m/z 310.1 (M+Na)L b) 4-(5-chlora-2-nitrophenyl)-3-methoxybutanoic acid

A mixture of 0.52 g (1.8 mmol) of methyl 4-(5-chloro-2-nitrophenyl)-3methoxybutanoate (Step a) of Intermediate 103), 5 mL methanol, 0.9 mL of 4M NaOH and 1.6 mL of water was stirred at room température for 20 h, then the reaction mixture was acidified with 1M HCl solution. The precipitated product was filtered off, washed with water and dried to yield 386 mg (78%) of the title compound. MS (ESI) m/z 296.1 (M+Na)⁺. c) 4-(2-amino-5-chlorophenyl)-3-methoxybutanoic acid nh₂

Cl

The title compound was prepared from 4-(5-chloro-2-nitrophenyl)-3-methoxybutanoic acid (Step b) of Intermediate 103) according to the method described in Method B of Intermediate 2. MS (ESI) m/z 244.1 (M+H)⁺

d) 7-chloro-4-methoxv-1.3,4.5-tetrahvdro-2H-1-benzazeDin-2-one

The titie compound was prepared from 4-(2-amino-5-chlorophenyl)-3methoxybutanoic acid (Step c) of Intermediate 103) according to the method described for Intermediate 3. MS (ESi) m/z 226.1 (M+H)⁺.

e) 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepine-2-thione

The titie compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1benzazepin-2-one (Step d) of intermediate 103) according to the method described for intermediate 23. MS (ESi) m/z 242.1 (M+H)*.

Intermediate 104

T-chloro-LS-dihydrospiroFI-benzazepine^^’TLSldioxepanl-zfSHi-one

a) methyl [2-(5-chloro-2-nitrobenzvl)-1,3-dioxepan-2-ynacetate

The title compound was prepared from methyl 4-(5-chioro-2-nitrophenyl)-3oxobutanoate (Step b) of Method B of Intermediate 1) and 1,4-butanediol according to the method described for intermediate 41. MS (ESI) m/z 366.1 (M+Na)⁺.

b) methyl [2-(2-amino-5-chlorobenzyl)-1,3-dioxepan-2-vHacetate

The title compound was prepared from methyl [2-(5-chloro-2-nitrobenzyi)-1,3dioxepan-2-y!]acetate (Step a) of Intermediate 104) according to the method described for Intermediate 42 and it was used without further purification in the next step.

c) 7-chioro-1.5-dihvdrospiro[1benzazepine-4,2'-[1,3ldioxepanl-2(3H)-one

135

The title compound was prepared from methyl [2-(2-amino-5-chlorobenzyi)-1,3dioxepan-2-yl]acetate (Step b) of intermediate 104) according to the method described for Intermediate 43. MS (ESI) m/z 282.1 (M+H)⁺.

Intermediate 105 terï-butyl r2-(methylsulfanyl)-4_;5-dihydro-3H-1-benzazepin-4-vncarbamate s—

NHSoo

The title compound was prepared from ten-butyl (2-thioxo-2,3,4_;5-tetrahydro-1H-1benzazepin-4-yl)carbamate (Intermediate 77) according to the method described for intermediate 5 and it was used without further purification in the next step.

Intermediate 106 tert-butyi r7-fluoro-2-(methvlsulfanvl)-4,5-dihvdro-3H-1-benzazepjn-4-yllcarbamate

F

NH8oc

a) methyl 3-amino-4-(5-fluoro-2-nitrophenyl)but-2-enoate

NO,

COOMe

The title compound was prepared from methyl 4-(5-fluoro-2-nitrophenyi)-3oxobutanoate (Intermediate 89) according to the method described in Step c) of Method B of intermediate 1 and it was used without further purification in the next step.

b) methyl 3-amÎno-4-(5-fluoro-2-nitrophenvDbutanoate

NO,

COOMs

The title compound was prepared from methyl 3-amino-4-(5-fluoro-2-nitrophenyl)but2-enoate (Step a) of Intermediate 106) according to the method described in Step d) of Method B of Intermediate 1 and it was used without further purification in the next step. c) methyl 3-[(tert-butoxycarbonyi)aminol-4-(5-fluoro-2-nitrophenyl)butanoate

NO,

NHBoc

COOMe

136

The title compound was prepared from methyl 3-amino-4-(5-fluoro-2nitrophenyl)butanoate (Step b) of Intermediate 106) according to the method described in Step e) of Method B of Intermediate 1. MS (ESI) m/z 379.1 (M+Na)⁺.

d) methyl 4-(2-amino-5-fluorophenyi)-3-Fitert-butoxycarbonyl)aminolbutanoate

The title compound was prepared from methyl 3-[(tert-butoxycarbonyi)amino]-4-(5fluoro-2-nitrophenyl)butanoate (Step c) of intermediate 106) according to the method described for intermediate 31 and it was used without further purification in the next step. e) tert-butyl (7-fluoro-2-oxo-2.3,4,5-tetrahvdro-1H-1-benzazepin-4-yl)carbamate

NHBoc

The title compound was prepared from methyl 4-(2-amino-5-fluorophenyl)-3-[(tertbutoxycarbonyl)amino]butanoate (Step d) of Intermediate 106) according to the method described for intermediate 32. MS (ESI) m/z 317.1 (M+Na)⁺.

f) tert-butyl (7-fluoro-2-thioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yDcarbamate

The title compound was prepared from tert-butyl (7-fiuoro-2-oxo-2,3,4,5-tetrahydro1H-1-benzazepin-4-yl)carbamate (Step e) of Intermediate 106) according to the method described for Intermediate 33 and it was used without further purification in the next step. q) tert-butvi F7-f!uoro-2-imethvlsulfanyD-4.5-dihydro-3/7-1-benzazepin-4-vllcarbamate

The title compound was prepared from tert-butyl (7-f!uoro-2-thioxo-2,3,4,5tetrahydro-1/7-1-benzazepin-4-yi)carbamate (Step f) of Intermediate 106) according to the method described for Intermediate 5 and it was used without further purification in the next step.

Intermediate 107 trans-4-r(4-methvlpiperazin-1-yl)carbonyncyciohexanecarbohvdrazide

O

a) methyl fra/7s-4-[(4-methylp!perazin-1-yl)carbonyllcvclohexanecarboxvlate

137

The titie compound was prepared from frans-4-(methoxycarbonyl)cyclohexane carboxylic acid and 1-methylpiperazine according to the method described in Step a) of intermediate 78 and it was used without further purification in the next step.

b) frans-44(4-methYlpiperazin-1-yl)carbonyncyciohexanecarbohydrazide

The titie compound was prepared from methyl frans-4-[(4-methylpiperazin-1yi)carbonyl]cyciohexanecarboxyiate (Step a) of intermediate 107) according to the method described in Step b) of Intermediate 78 and it was used without further purification in the next step.

intermediate 108

14tetrahvdro-2H-pyran-4-ynpîpertdine-4-carbohvdrazîde

The titie compound was prepared from ethyi 1-(tetrahydro-2H-pyran-4-yl)piperidine4-carboxylate (WO 2016/138532 Al (01.09.2016) VERSION CORPORATION) according to the method described in Step b) of Intermediate 78 and it was used withoutfurther purification in the next step.

intermediate 109

14(3S)-tetrahydrofuran-3-vilPÎperidine-4-carbohydrazide Ο-<χ·

a) ethyi 1-[(3S)-tetrahydrofuran-3-ynpiperidine-4-carboxylate

A mixture of 1.93 g (7.97 mmol) of (3R)-tetrahydrofuran-3-y! 4methyibenzenesuifonate (WO 2016/91776 A1 (16.06.2016) EVOTEC AG), 2.46 mL (15.9 mmol) of ethyi piperidine-4-carboxylate, 39 mL of acetonitrile and 4.4 g (31.9 mmol) of K₂COj was stirred at 70°C for 24 h, then cooled to room température and diluted with ethyi acetate. The so obtained mixture was washed with water and this water phase was discarded. The organic layer was washed with 1M HCl solution and this acidic water phase was alkalified with 10% K₂COs solution, extracted with ethyi acetate, the combined organic layers were dried over Na₂SO₄, filtered and concentrated. The residue was purified by fiash column chromatography using dichloromethane : methanol = 91:9 as eluent to yield 603 mg (27%) of the titie compound. GC-MS (El) m/z 227.

138

b) 1-((3S)-tetrahydrofuran-3-vnpiperidine-4-carbohydrazide

The titie compound was prepared from ethyl 1-[(3S)-tetrahydrofuran-3-yl]piperidine4-carboxylate (Step a) of Intermediate 109) according to the method described in Step b) of Intermediate 78 and it was used without further purification in the next step.

Intermediate 110 lJ(3R)-tetrahvdrofuran-3-vllomerÎdme-4-carbohvdrazjde

a) ethyl 14(3R)-tetrahydrofuran-3-vllpiperidine-4-carboxylate 9^\ / \

I X.uhN \---COOEt

The titie compound was prepared from (3S)-tetrahydrofuran-3-yl 4methylbenzenesulfonate (WO 2016/91776 A1 (16.06.2016) EVOTEC AG) according to the method described in Step a) of Intermediate 109. GC-MS (El) m/z 227.

b) 1-F(3R)-tetrahvdrofuran-3-vllpiperidine-4-carbohydrazide

The titie compound was prepared from ethyl 1-[(3/?)-tetrahydrofuran-3-yl]piperidine4-carboxylate (Step a) of Intermediate 110) according to the method described in Step b) of Intermediate 78 and it was used without further purification in the next step.

intermediate 111 ethyl cfe-4-(4-ffîethvipiperazin-1-yi)cvciohexanecarboxyiate

and

Intermediate 112 ethyl irans-4-(4-methvlpÎperazÎn-1-vhcvclohexanecarboxvlate

A mixture of 1.27 mL (8 mmol) of ethyl 4-oxocyclohexanecarboxylate, 887 pL (8 mmol) of 1-methylpiperazine, 4 mL of methanol and 20 mL of dichloromethane was cooled to 5°C and 3.39 g (16 mmol) of sodium triacetoxyborohydride was added to the reaction mixture at such a rate to keep the internai température below 5°C. After completion of the addition the reaction mixture was stirred at room température for 24 h, then concentrated. The residue was dissolved in 1M HCl solution and extracted with dichloromethane. The acidic water phase was alkalified with 10% K₂CO₃ solution, extracted with ethyl acetate, the combined organic layers were dried over Na₂SO4, filtered and concentrated to yield 640 mg (30%) of the titie compounds as a mixture. GC-MS (El) m/z 254.

139

Intermediate 113 c/s-444-methyipiperazîn-1-vl|cvciohexanecarbohydrazide y K y < NH-NH--NI N·—/ J)—-/ X Z Q and

Intermediate 114 ÿrans-4-{4-meth¥ipiperazin-1-vücvclohexanecarbohvdrazide y ç / y nh-nh₂ __{N N}_/\...... λ f \ f o

The title compounds were prepared from a mixture of ethyl c/s-4-(4-methylpiperazin1-yl)cyclohexanecarboxylate (Intermediate 111) and ethyl trans-4-(4-methylpiperazin-1yl)cyclohexanecarboxylate (Intermediate 112) according to the method described in Step b) of Intermediate 78. GC-MS (El) m/z 240.

Intermediate 115

1-(pyridjn-3-ylrnethyl)pyrroiidine-3-carbohvdrazide ° nh₂

a) methyl 1-(pvridin-3-vlmethyl)pvrrolidine-3-carboxylate cœ boOMe

The title compound was prepared from methyl pyrrolidine-3-carboxylate and pyridine3-carbaldehyde according to the method described for Intermediate 111 and 112 and it was used without further purification in the next step.

b) 1-(pyridin-3-yimethyl)pvrrolidine-3-carbohydrazide

The title compound was prepared from methyl 1-(pyridin-3-ylmethyl)pyrrolidine-3carboxylate (Step a) of Intermediate 115) according to the method described in Step b) of Intermediate 78. GC-MS (El) m/z 220.

Intermediate 116

1-(pyridin-2-vimethyl)pyrrolidine-3-carbohvdrazide

a) methyl 1-Î^,pvridin-2-vlmethyl)pvrrolidÎne-3-carboxylate

140

COOMe

The title compound was prepared from methyl pyrrolidine-3-carboxylate and pyridine2-carbaldehyde according to the method described for Intermediate 111 and 112. MS (ESI) m/z 221.2 (M-i-H)⁺.

b) 1 -(pyridin-2-ylmethyl)pyrrolidine-3-carbohydrazide

The title compound was prepared from methyl 1-(pyridin-2-ylmethyl)pyrrolidine-3carboxylate (Step a) of Intermediate 116) according to the method described in Step b) of Intermediate 78 and it was used without further purification in the next step.

Intermediate 117

1Tpvridi8T-3-vlcarbonvhpvrrolidine-3-caÎ-bohydrazide

a) methyl 1-(pyridin-3-ylcarbonyl)pyrroHdine-3-carboxylate

COOMe

The title compound was prepared from pyridine-3-carboxylic acid and methyl pyrrolidine-3-carboxylate according to the method described in Step a) of Intermediate 78. MS (ESI) m/z 235.1 (M+H)⁺.

b) 1-(pvridin-3-vlcarbonyl)pyrrolidine-3-carbohydrazide

The title compound was prepared from methyl 1-(pyridin-3-ylcarbonyl)pyrrolidine-3carboxylate (Step a) of Intermediate 117) according to the method described in Step b) of Intermediate 78. GC-MS (El) m/z 234.

Intermediate 118

1-(P¥ndm-2-¥lcarbonvnpyrroiÎdÎne-3-carbohvdrazide

a) methyl 1-(pyridin-2-ylcarbonyl)pyrrolidine-3-carboxylate

141

COOMe

The title compound was prepared from pyridine-2-carboxylic acid and methyl pyrrolidine-3-carboxylate according to the method described in Step a) of Intermediate 78. MS (ESI) m/z 235.2 (M+H)⁺.

b) 1-(pyridin-2-ylcarbonyl)pyrrolidine-3-carboxylic acid

The title compound was prepared from methyl 1-(pyridin-2-ylcarbonyl)pyrrolidine-3carboxylate (Step a) of Intermediate 118) according to the method described for Intermediate 7. MS (ESI) m/z 221.1 (M+H)Ÿ c) fert-butyl 2-{[1-(pyridin-2-yicarbonvl)pyrrolidin-3-yl]carbonyl}hydrazinecarboxylate o

The title compound was prepared from 1-(pyridin-2-ylcarbonyl)pyrrolidine-3carboxylic acid (Step b) of Intermediate 118) according to the method described for Intermediate 54. MS (ESI) m/z 335.2 (M+H)⁺.

d) 1-(pvridin-2-vlcarbonvBpyrrolidÎne-3-carbohvdraz!de

The title compound was prepared from fert-butyl 2-{[1-(pyridin-2-ylcarbonyl)pyrrolidin3-yl]carbonyl}hydrazinecarboxy!ate (Step c) of Intermediate 118) according to the method described for Intermediate 55 and it was used without further purification in the next step.

intermediate 119

4-methoxy-4-methvlcvclohexanecarbohydrazide

L J- .NH ^NH2

a) ethyl 4-hydroxy-4-methylcyclohexanecarboxylate

HO ^>^^COOEÎ

Under argon to a stirred solution of 100 mL (220 mmol) of 2M trimethylaluminum in toluene a solution of 8.7 mL (55 mmol) of ethyl 4-oxocyclohexanecarboxylate in 50 mL of

142 toluene was added over 2.5 h at -60°C. After completion of the addition the mixture was stirred at -60°C for 0.5 h, then allowed to warm to -20°C over 2 h. The reaction mixture was transferred over 25-30 min via a cannula to an ice-cold mixture of 180 mL of ethyl acetate, 425 mL of water, 75 mL of concentrated hydrochloric acid and 100 g of crushed ice while keeping the internai température below 10°C. The phases were separated, the organic phase was successively washed with 400 mL of water and 400 mL of brine, dried over Na₂SO₄, filtered and concentrated to yield 5.44 g (53%) of title compound. According to ’HNMR spectroscopy it was a 28:72 mixture of cis- and frans-isomers. This mixture was used in the next step without further purification.

b) ethyl 4-methoxv-4-methvlcvclohexanecarboxylate

Under argon to a stirred mixture of 2.16 g (54 mmol) of 60% sodium hydride in minerai oil, 34 mL of dry THF, 200 mg (0.54 mmol) of tetrabutylammonium iodide, 49 mg (0.72 mmol) of imidazole and 3.36 mL (54 mmoi) of iodomethane a solution of 3.36 g (18 mmol) of ethyl 4-hydroxy-4-methylcyclohexanecarboxylate (Step a) of Intermediate 119) in 21 mL of dry THF was added over 30-40 min at 20-25°C. The reaction mixture was stirred at room température for 3 h, then cooied to 0-5°C and 2.28 mL (40 mmol) of acetic acid was added over 10 min. The mixture was stirred for 15 min, then poured into a mixture of 280 mL of diethyl ether and 120 mL of saturated NaHCOs solution. The phases were separated, the organic phase was washed with brine, dried over Na₂SO4, filtered and concentrated. The residue was purified by column chromatography using n-hexane : ethyl acetate=85:15 as eluent to yield 2.3 g (64%) of the title compound. According to ’HNMR spectroscopy it was a 21:79 mixture of cis- and frans-isomers.

c) 4-methoxv-4-methvlcvciohexanecarbohvdrazide

The title compound was prepared from ethyl 4-methoxy-4methylcyclohexanecarboxylate (Step b) of Intermediate 119) according to the method described for Intermediate 65. According to ’HNMR spectroscopy it was a 21:79 mixture of cis- and frans-isomers.

Intermediate 120

4-(2-oxopyrroljdin-1-yl)cyclohexanecarbohydrazide

143

The title compound was prepared from ethyl 4-(2-oxopyrrolidin-1yl)cyclohexanecarboxyiate (WO2010/108052 A2 (20.03.2009) H. LUNDBECK A/S) according to the method described for Intermediate 65 and it was used without further purification in the next step.

intermediate 121 methyl frans-4-methoxv-44trtfluorometh¥ncyciohexanecarboxylate

.....^cooMe and intermediate 122 methyi c/s-4-methoxv-4-(trifluQromethvücvclohexanecarboxylate F.J __ >”'COOMe

Under argon to a stirred mixture of 573 mg (2.7 mmol) of 4-hydroxy-4(trifluoromethyl)cyciohexanecarboxylic acid, 5 mL of dry DMF and 5 mL of dry THF 324 mg (8.1 mmol) of 60% sodium hydride in minerai oil was added at 0°C. The reaction mixture was stirred at this température for 0.5 h, then 1.18 mL (18.9 mmol) of iodomethane was added and the reaction mixture was allowed to warm to room température. After 3 h stirring at room température 0.59 mL (9.45 mmol) of iodomethane was added and stirring was continued for 5 h. The reaction was quenched by addition of 9 mL of 1M hydrochloric acid solution, then diluted with dichloromethane and the phases were separated. The organic phase was washed with saturated NaHCOs solution, dried over Na₂SO4, filtered and concentrated. The residue was purified by column chromatography using cyclohexane:dichloromethane=1:1 as eluent to yield 242 mg (37%) of methyl frans-4-methoxy-4-(trifluoromethyl)cyclohexanecarboxylate (Intermediate 121) as the first fraction and 277 mg (43%) of methyl c/s-4methoxy-4-(trifluoromethyl)cyctohexanecarboxylate (Intermediate 122) as the second fraction.

Intermediate 123 cfs-4-ffîethoxv-4-(trifluoromethyncvciohexanecarbohydrazide ......( f \ f NH—NH₂

144

The title compound was prepared from methyl c/s-4-methoxy-4(trifluoromethyl)cyclohexanecarboxylate (Intermediate 122) according to the method described for Intermediate 65. GC-MS (El) m/z 240.

Intermediate 124 ÿrans-4-methoxv-4-(trifiuoromethyS)cyclohexanecarbohvdrazide M /—x o xo......< o x f NH—NH2

The title compound was prepared from methyl trans-4-methoxy-4(trifluoromethyl)cyclohexanecarboxylate (Intermediate 121) according to the method described for Intermediate 65. GC-MS (El) m/z 240.

Intermediate 125 trans-4-r(4-methoxvbenzvl)aminolcyclohexanecarbohydrazide

a) methyl trans-4-[(4-methoxybenzyl)aminolcvdohexanecarboxviate

A mixture of 2.0 g (10.3 mmol) of methyl trans-4-aminocyclohexanecarboxylate hydrochloride (Combi-Blocks), 20 mL of 1,2-dichloroethane, 1.38 mL (11.4 mmol) of 4methoxybenzaldehyde and 1.12 mL (19.6 mmol) of acetic acid was cooled to 5°C and 6.78 g (32.0 mmol) of sodium triacetoxyborohydride was added to the reaction mixture at such a rate to keep the internai température below 5°C. After completion of the addition the reaction mixture was stirred at room température for 20 h, then diluted with water. The pH of the mixture was adjusted to 8 by addition of 10% Na₂CO₃ solution, the phases were separated and the water phase was extracted with dichloromethane. The combined organic phases were dried over MgSO<, filtered and concentrated to yield 1.48 g (52%) of the title compound. MS (ESI) m/z 278.2 (M+H)⁺.

b) frar?s-4-|ï4-methoxvbenzyi)amino]cyciohexanecarbohvdrazide

The title compound was prepared from methyl frans-4-[(4methoxybenzyl)amino]cyclohexanecarboxylate (Step a) of Intermediate 125) according to the method described for Intermediate 65 and it was used without further purification in the next step.

145

Intermediate 126 traws-4-ethoxv-4-ethvlcyclohexane-carbohydrazicle

a) ethyl 4-ethvl-4-hydroxycvclohexanecarboxyiate HO

The title compound was prepared from ethyl 4-oxocyclohexanecarboxylate and 25% triethylaluminum solution in toluene according to the method described in Step a) of Intermediate 119. According to ^NMR spectroscopy it was a 27:73 mixture of cis- and transisomers. This mixture was used in the next step without further purification. b) ethyl trans-4-ethoxy-4-ethylcyclohexanecarboxylate \-“«COOEt

Under argon to a stirred mixture of 1.32 g (33 mmol) of 60% sodium hydride in minerai oil, 22 mL of dry toluene, 406 mg (1.1 mmol) of tetrabutyiammonium iodide and 2.85 mL (22 mmol) of ethyl trifluoromethanesulfonate a solution of 2.2 g (11 mmol) of ethyl 4-ethyl-4hydroxycyclohexanecarboxylate (Step a) of Intermediate 126) in 11 mL of dry toluene was added over 30-40 min at 20-25°C. The reaction mixture was stirred at room température for 20 h, then cooied to 0-5°C and it was poured into an ice-coid mixture of 220 mL of ethyi acetate, 110 mL of saturated NaHCOs solution and 30 mL of water. The mixture was stirred at 5°C for 0.5 h, then at room température for 20 h. The phases were separated, the organic phase was washed with brine, dried over Na₂SO4, filtered and concentrated. The residue was purified by column chromatography using n-hexane : ethyl acetate-94:6 as eluent to yield 1.77 g (71%) of the title compound. According to 'HNMR spectroscopy it was a 3:97 mixture of cis- and trans-isomers.

o) frans-4-ethoxv-4-ethyicyclohexane-carbohvdrazide

The titie compound was prepared from ethyl 4-ethoxy-4-ethylcyciohexanecarboxylate (Step b) of Intermediate 126) according to the method described for Intermediate 65. According to ¹HNMR spectroscopy it was a 3:97 mixture of cis- and frans-isomers. This mixture was used in the next step without further purification.

intermediate 127

4-ethvl-4-methoxvcvclohexane-carbohvdrazide

146 y . NH—NH,

Γ ' 'O

a) ethyi 4-methoxy-4-ethvlcydohexanecarboxylate

C. /\ >< )COOEi

The titie compound was prepared from ethyi 4-ethyl-4-hydroxycycîohexanecarboxyiate (Step a) of intermediate 126) and methyl trifluoromethanesuifonate according to the method described in Step b) of Intermediate 126. According to ¹HNMR spectroscopy itwas a 19:81 mixture of c/s- and trans-ïsomers. b) 4-ethvl-4-methoxvcvclohexane-carbohydrazide

The titie compound was prepared from ethyi 4-methoxy-4-ethyicyclohexanecarboxylate (Step a) of Intermediate 127) according to the method described for Intermediate 65. According to ¹HNMR spectroscopy it was a 20:80 mixture of c/s- and transisomers. This mixture was used in the next step without further purification.

Intermediate 128 frans-4-ethoxy-4-methyicyctohexanecarbohydrazîde

a) ethyi frans-4-eÎhoxv-4-methylcyclohexanecarboxylate

The titie compound was prepared from ethyi 4-hydroxy-4methylcyclohexanecarboxyiate (Step a) of Intermediate 119) and ethyi trifluoromethanesuifonate according to the method described in Step b) of Intermediate 126. According to ^!HNMR spectroscopy it was a 4:96 mixture of c/s- and trans-isomers. b) frans-4-ethoxy-4-methyicyciohexanecarbohydrazide

The titie compound was prepared from ethyi 4-methoxy-4-ethylcyclohexanecarboxylate (Step a) of Intermediate 128) according to the method described for Intermediate 65. According to ¹HNMR spectroscopy it was a 7:93 mixture of cis- and transisomers. This mixture was used in the next step without further purification.

Intermediate 129

4-ethoxy-4-propy8cyctohexanecarbohydrazîde

147

a) ethyl 4-h¥draxy-4-(prop-2-en-1-yl)cyclohexanecarboxylate

To a solution of 11.9 mL (12.76 g, 75.0 mmol) of ethyl 4-oxocyclohexanecarboxylate in 225 mL of THF 188 mL of 25% ammonium chloride solution and 9.81 g (150 mmol) of zinc powder were added. The mixture was stirred at room température for 5 min, then 9.7 mL (13.56 g, 112.0 mmol) of allyl bromide was added dropwise over 20 min. At the end of the addition the température of the reaction mixture rose to 42-43°C. The mixture was stirred at ambient température for 4 h, then poured into a mixture of 180 mL of water and 750 mL of ethyl acetate. After addition of 30 mL of 1.0 M hydrochloric acid solution the phases were separated, the organic phase was washed with 2x375 mL of brine, dried over NâaSCU, filtered and concentrated to yield 15.39 g (96%) of the title compound. According to 'HNMR spectroscopy it was a 60:40 mixture of cis- and trans-isomers.

b) ethyi 4-hydroxy-4-propylcyclohexanecarboxyiate

HO / \ )--COOEt ___J

A mixture of 14.86 g (70 mmol) of ethyl 4-hydroxy-4-(prop-2-en-1yQcyclohexanecarboxylate (Step a) of Intermediate 129), 250 mL of THF and 1.49 g 10% Pd on carbon was hydrogenated. After completion of the reaction the mixture was filtered through Ceiite and washed with 3x25 mL of THF. The filtrate was concentrated and 3x100 mL of dichloromethane was evaporated off the residue to yield 14.89 g (99%) of the title compound, which was used without further purification.

c) ethyl 4-ethoxy-4-propylcyclohexanecarboxvlate 'Χ / \

ÎX' )--COOEt

The title compound was prepared from ethyl 4-hydroxy-4propylcyclohexanecarboxylate (Step b) of Intermediate 129) and ethyl trifluoromethanesulfonate according to the method described in Step b) of intermediate 126. According to 'HNMR spectroscopy it was a 16:84 mixture of cis- and trans-isomers. d) 4-ethoxy-4-propylcyclohexanecarbohydrazide

The title compound was prepared from ethyl 4-ethoxy-4propylcyclohexanecarboxylate (Step c) of Intermediate 129) according to the method

148 described for Intermediate 65. According to ¹HNMR spectroscopy it was a 16:84 mixture of as- and frans-isomers. This mixture was used in the next step without further purification.

intermediate 130

4-methoxv-4-propyicvclohexanecarbohvdrazide

a) ethyl 4-methoxy-4-propylcyclohexanecarboxylate

The title compound was prepared from ethyl 4-hydroxy-4propylcyclohexanecarboxylate (Step b) of Intermediate 129) and methyl trifluoromethanesulfonate according to the method described in Step b) of Intermediate 126. According to 'HNMR spectroscopy it was a 57:43 mixture of as- and trans-isomers. b) 4-methoxv-4-propvlcvclohexanecarbohydrazide

The title compound was prepared from ethyl 4-methoxy-4propylcyclohexanecarboxylate (Step a) of Intermediate 130) according to the method described for Intermediate 65. According to ¹HNMR spectroscopy it was a 57:43 mixture of as- and trans-isomers. This mixture was used in the next step without further purification.

Intermediate 131 (3RM-(Pvridin-2-vlmethvhPvrrolidine-3-carbohydrazide

a) methyl (3R)-1-(pvridin-2-vlmethyl)pyrrolidine-3-carboxvlate

COOMe

The title compound was prepared from methyl (3R)-pyrrolidine-3-carboxylate and pyridine-2-carbaldehyde according to the method described for Intermediate 111 and 112. MS (ES!) m/z 221.1 (M+HF.

b) (3R)-1-(pyridin-2Vlmethvi)pyrrolidine-3-carbohvdrazide

The title compound was prepared from methyl (3R)-1-(pyridin-2-ylmethyl)pyrrolidine3-carboxylate (Step a) of Intermediate 131) according to the method described in Step b) of Intermediate 78 and it was used without further purification in the next step.

149

Intermediate 132 (3SM4Pvridm-2-vlmethvBpvrroljdîne-3-carbohydrazide

COQ

ÊO \h₂

a) methyl /SSyi-Îpyridin-Z-vImethyOpyrrolidine-S-carboxylate

QTQ

COOMe

The title compound was prepared from methyl (3S)-pyrrolidine-3-carboxylate and pyridine-2-carbaldehyde according to the method described for Intermediate 111 and 112. MS (ESI) m/z 221.1 (M+H)⁺b) (3S)-1-(pyridin-2-yimethyl)pyrroiidine-3-carbohydrazide

The title compound was prepared from methyl (3S)-1-(pyridin-2-ylmethyl)pyrrolidine3-carboxylate (Step a) of intermediate 132) according to the method described in Step b) of Intermediate 78 and it was used without further purification in the next step.

Intermediate 133 ( 3ffl-1 -(pvridin-3-yl methvüpyrrol idi ne-3-carbohydrazide l >

\—NH ° \ih₂

a) methyl (3/7)-1-(pYridin-2-3ylmethvi)pvrroiidine-3-carboxylate

The title compound was prepared from methyl (3R)-pyrrolidine-3-carboxy!ate and pyridine-3-carbaldehyde according to the method described for Intermediate 111 and 112. MS (ESI) m/z 221.1 (M+H)⁺.

b) (3/7)-1-(pvridin-3-ylmethvi)pyrrolidine-3-carbohydrazide

The title compound was prepared from methyl (3/7)-1-(pyridin-3-ylmethyl)pyrrolidine3-carboxylate (Step a) of Intermediate 133) according to the method described in Step b) of Intermediate 78 and it was used without further purification in the next step.

Intermediate 134 (3SM-(pvridin-3-ylmethvnpyrroHdme-3-carbohvdrazide

QTQ

Λ—NH θ nh₂

150

a) methyl (3S)-1-(pyridin-2-3ylmethvi)pyrrolidine-3-carboxylate cœ

The title compound was prepared from methyl (3S)-pyrrolidine-3-carboxylate and pyridine-3-carbaldehyde according to the method described for Intermediate 111 and 112. MS (ESI) m/z 221.1 (M+H)⁺.

b) (3S)-1-(pyridin-3-ylmethyl)pvrrolidine-3-carbohydrazide

The title compound was prepared from methyl (3S)-1-(pyridin-3-ylmethyl)pyrrolidine3-carboxylate (Step a) of Intermediate 134) according to the method described in Step b) of Intermediate 78 and it was used without further purification in the next step.

Intermediate 135 frans-4-(pvrÎdin-2-ylamino)Gyclohexanecarbohydrazide

a) methyl frans-4-(pyridin-2-vlamino)cvclohexanecarboxvlate >—«COOMe d- °

A mixture of 1.5 g (7.745 mmoi) of methyl transM-aminocyclohexanecarboxylate hydrochloride, 4 mL (46.5 mmol) of 2-fluoropyridine and 1.35 mL (7.75 mmol) of DI PEA was stirred at 125 °C in a pressure-resistant glass reactor for 20 hours, then cooied to room température. The reaction mixture was diluted with 20 mL of ethyl acetate, washed with 2x30 mL of water and saturated NaCI solution, the organic phase was dried over anhydrous Na₂SO4, filtered and concentrated to yield 325 mg (18%) of the title compound. MS (ESI) m/z 235.1 (M+H)⁺.

b) trans-4-(pvridin-2-ylamino)cyclohexanecarbohvdrazide

The title compound was prepared from methyl frans-4-(pyridin-2ylamino)cyclohexanecarboxylate (Step a) of Intermediate 135) according to the method described in Step b) of Intermediate 78 and it was used without further purification in the next step.

Example 1 tert-butyl r8-chloro-1-n-(pyndm-2-yi)piperÎdin-4-yil-5,6-dihydro-4/y-ri_i2,4ltnazolor4_!3aHTlbenzazepm-5-yilcarbamate

151

A mixture of 236 mg (0.72 mmol) of tert-butyl (7-chlorG-2-thioxo-2,3,4,5-tetrahydro1H-1-benzazepin-4-yl)carbamate (Intermediate 4), 15 mL of xylene and 190 mg (0.86 mmol) of 1-(pyridin-2-yl)piperidine-4-carbohydrazide (D. M. Beal et al., Tetrahedron Left 2011, 52:5913-5917) was stirred under argon for 24 hours, then the reaction mixture was concentrated and the residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus, 200 mg (56%) of the title product was obtained. MS (ESI) m/z 495.3 (M+H)⁺.

Example 2

8-chloro-1-n-(pyridin-2-ynp8peridin-4-vn-5,6-dihvdro-4H-[1,2,4]triazoior4,3airnbenzazepine-5-amine

To a solution of 200 mg (0.4 mmol) of tert-butyl [8-chloro-1-[1-(pyridiri-2-yl)piperidin4-yl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl]carbamate (Example 1) in 10 mL of ethyl acetate 5 mL of 2.5M hydrogen chloride solution in ethyl acetate was added and the reaction mixture was stirred at room température for 5 hours. Diethyl ether was added and the mixture was stirred at room température for 30 minutes. The precipitated product was filtered, washed with diethyl ether and dried. The product was dissolved in a mixture of dichloromethane and saturated NaHCOa, after one hour of stirring the phases were separated and the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous NaaSOi, filtered and concentrated. The residue was purified by column chromatography using dichloromethane: methanol=4:1 as eluent. Thus 96 mg (61%) of the title product was obtained. MS (ESI) m/z 395.3 (M*H)⁺.

Exampie 3

A/-r8-chloro-ri-(pvridin-2-vhpiperidÎn-4-vn-5,6-dihvdro-4H-n.2.41triazolo[4,3airUbenzazepin-S-yllacetamide

A mixture of 43 mg (0.1 mmol) of 8-chloro-1-[1-(pyridin-2-yl)piperidin-4-yi]-5,6dihydro-4/-/-[1₁2,4]tr!azolo[4,3-a][1]berizazepine-5-am!ne (Example 2), 1 mL of pyridine and 82 pL (0.9 mmol) of acetic anhydride was stirred at room température for 20 hours, then 5 mL of water was added to the reaction mixture and extracted three times with 20 mL of dichloromethane. The combined organic phases were dried over anhydrous Na₂SO4, filtered and concentrated. Thus, 23 mg (48%) ofthe titie product was obtained. MS (ESI) m/z 437.2 (M+H)⁺.

Example 4 /V-(8-chloro-n-(pyridin-2-vÜpiperidjn-4-vn-5,6-dihvdro-4A/-ri_!2,41triazolo[4,3airHbenzazepin-5-yn-2-methylpropanamide

To a mixture of 62 mg (0.157 mmol) of 8-chloro-1-[1-(pyridin-2-yl)piperidin-4-yl]-5,6dihydro-4,H-[1,2,4]triazoio[4,3-a][1]benzazepine-5-amine (Example 2), 10 mL of dichloromethane and 40 μΙ (0.23 mmol) of DI PEA, 24 μΙ (0.23 mmol) of isobutyryl chloride was added and the reaction mixture was stirred at room température for 20 hours. The reaction mixture was diluted with dichloromethane, washed with water, the organic phase was dried over anhydrous Na₂SO4, filtered and concentrated. The residue was crystallized with hexane to yield 60 mg (82%) ofthe titie product. MS (ESI) m/z 465.2 (M+H)⁺.

Example 5 fert-butyl {8-chloro-1-[ÿrans-4-(pvridin-2-yloxv)cyclohexyn-5,6-dihydro-4Hf1,2.4ltrîazolo[4,3-airi1benzazepine-5-vl|cai±Îamate

153

Method A)

A mixture of 2.26 g (6.9 mmol) of terf-butyl (7-chioro-2-thio.xo-2,3,4,5-tetrahydro-1H1-benzazepin-4-yl)carbamate (Intermediate 4), 140 mL of xylene and 1.96 g (8.33 mmol) of trans-4-(pyridin-2-yloxy)cyclohexane carboxylic acid hydrazide (WO 2010/060836 (03.06.2010) F. HOFFMANN-LA ROCHE AG.) was refluxed for 20 hours under argon, then concentrated and the residue was purified by column chromatography using dichloromethane:methanol^: 1 as eluent. Thus, 2.76 g (78%) of the title product was obtained. MS (ESI) m/z 510.2 (M+H)⁺.

Method B)

To a mixture of 3.75 g (11 mmol) of te/t-butyl [7-chloro-2-(methylsulfanyl)-4,5-dihydro3H-1-benzazepin-4-yl]carbamate (Intermediate 5), 110 mL of xylene and 2.87 g (12.2 mmol) of trans-4-(pyridin-2-yloxy)cyclohexane carboxylic acid hydrazide, 0.1 mL of concentrated hydrochloric acid was added under argon and the reaction mixture was refluxed for 18 hours, then concentrated and the residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent Thus, 3.42 g (61%) of the title product was obtained. MS (ESI) m/z 510.2 (M+H)⁺.

Example 6

To a mixture of 2.76 g (5.41 mmol) of terf-butyl {8-chloro-1-|ïrans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}carbamate (Example 5), 100 mL of ethyl acetate and 100 mL of éthanol, 50 mL of 2.5M hydrogen chloride solution in ethyl acetate was added and the reaction mixture was stirred at room température for 5 hours. Diethyl ether was added and the mixture was stirred ai room température for 30 minutes. The precipitated product was filtered, washed with diethyl ether and dried. The product was dissolved in a mixture of dichloromethane and saturated NaHCOs. After one hour of stirring, the phases were separated and the aqueous phase was

154 extracted with dichloromethane, the combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography using dichloromethane: methanol=9:1 as eluent. Thus, 1.85 g (83%) of the title product was obtained. MS (ESI) m/z 410.2 (M+H)⁺.

Example 7 (5S)-8-chloro-1-rirans-4-(pvridin-2-yjoxv)cvclohexvll-5.6-d!hvdro-4/-L n,2.4ÎtriazoloF4,3-airilbenzazepine-5-amine

and

Exampie 8 (5R)-8-chloro-1-|'irans-4-(pvridin-2-yloxv)cvclohexyll-5,6-dihvdro-4/7n,2,41tnazolor4.3-al[Hbenzazepme-5-amine

The title products were prepared from the racemic 8-chloro-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ^^triazolo^.S-aJflJbenzazepine-S-amine (Example 6) by chiral préparative HPLC (CHIRALPAK IA with préparative 20 pm stationary phase, 2.5x20cm; F=15mL/min, eluent: n-hexane:EtOH=8:2 + 0.3% diethylamine; isocratic, t=25°C) to yield the (5S) enantiomer (T,· 11.7 min; [a]o⁵ = -21.1° (c=0,1; methanol); Example 7) and the (5/?) enantiomer (T_r 14.9 min; [α]π⁵ = *14.5° (c=0.1; methanol); Example 8). The absolute configuration of the compounds was determined by VCD method and by ¹H NMR spectroscopy of the diastereomeric pairs synthesized therefrom.

Example 9 /V-{8-chSoro-1-Rrans-4-(pyridin-2-vloxv)cvclohexyll-5,e-dihvclro-4H-n,2,4ltriazolor4,3airilbenzazepm-5-yl}acetamide

155

A mixture of 82 mg (0.2 mmol) of 8-chloro-1-[trans-4-(pyridin-2-yioxy)cyclohexyl]-5,6dihydro-4H-i1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 6), 2 mL of pyridine and 190 pL (2.0 mmoi) of acetic anhydride was stirred at room température for 20 hours, then 5 mL of water was added to the reaction mixture and extracted three times with 20 mL of dichloromethane. The combined organic phases were dried over anhydrous Na₂SO4, filtered and concentrated. Thus, 67 mg (74%) of the title product was obtained. MS (ESI) m/z 452.2 (M+H)⁺.

Example 10

A48-chjoro-14trans-44bvridin-2~vloxv}cyclohexvll-5,6-dihydro-4H-ri,2,4ltriazolo[4,3-

a)ferf-butyl[2-({8--chloro~1-!^,fra/7s-4-(P¥ridin-2-yloxy)cyclohexyn-5,6-dihydro-4H;1,2,4]triazo;o[4.3-aH1lbe.nzazepirr5-vl)amino')-2-oxoethyl]carbarnate

A mixture of 87 mg (0.21 mmol) of 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amir:e (Example 6), 3 mL of DMF, 40 mg (0.23 mmol) of Boc-glycine, 95 mg (0.25 mmol) of HBTU and 44 pL (0.32 mmol) of TEA was stirred at room température for 20 hours, then the reaction mixture was concentrated and saturated NaHCOs solution was added to the residue. The precipitated product was filtered, washed with water, and dried. Thus, 91 mg (76%) of the title product was obtained. MS (ESI) m/z 567.3 (M+H)⁺.

b) /V-{8-chloro-1-[trans-4-(pvridin-2-yioxv)cyclohexvn-5.6-dihvdro-4H-[1.2,4ltriazoio [4.3-a][11benzazepiri-5-vl}glycinamide

To a mixture of 90 mg (0.16 mmol) of tert-butyi [2-({8-chloro-1-[trans-4-(pyridin-2yloxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}amino)-2oxoethyl]carbamate (step a) of Example 10), 5 mL of ethyl acetate and 5 mL of éthanol, 2 mL of 2.5M hydrogen chloride soiution in ethyl acetate was added and the reaction mixture was stirred at room température for 5 hours, then concentrated. The residue was dissolved in a mixture of dichloromethane and saturated NaHCOs, after one hour of stirring, the phases were separated, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous Na₂SO4, filtered and concentrated. Thus, 49 mg (66%) ofthe title productwas obtained. MS (ESI) m/z467.2 (M+H)⁺.

156

Example 11 /V-{(5S)8--chioro-1-Firans-4-(pyridin-2-yloxv)cvclohexyn-5_ie-dihydro-4Wri_;2,4]triazolof4,3-ainibenzazepin-5-yi}giycinamjde

a) te/f-butyl F2-({(5S)-8-chtoro-1-ftrans-4-(pvridin-2-vloxv)c¥ctohexyll~5,6-dihydro-4HF1.2,4ltriazolo[4,3-a1[1]benzazepin-5-yl}amino)-2-oxoethvllcarbamate

The title product was prepared from (5S)-8-chloro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 7) according to the method described in step a) of Example 10. MS (ESI) m/z 567.2 (M+H)⁺. b) A/-f(5S)-8-chioro-1-ffrans-4-(p¥ridin-2-yloxv)cvclohexvll-5,6-dÎhydro-4H-[1,2,41triazolo [4,3-al[1lbenzazepin-5-yi}glycinamide

The title product was prepared from fert-butyl [2-({(5S)-8-chloro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazoloF4,3-a][1]benzazepin-5-yl}amino)-2oxoethyl]carbamate (step a) of Example 11) according to the method described in step b) of Example 10. [«Jd⁵ = -33.2° (c=0.1; methanol); MS (ESi) m/z 467.2 (M+H)⁺.

Example 12

ALf(5R)-8-chloro-1-Rrans-4-(pyridm--2-vloxv)C¥Clohexvfl-5.6-dihvdro-4Hri,2,41triazoloF4,3-ainibenzazepin-5-vnqlycjnamjde

a) tert-butyl F2-6F(5R)-8-chloro-1-[frans-4-(pyridÎn-2~vloxy)cvclohexyn-5.6-dihydro-4H[1,2,4ltriazolo[4,3-aH1lbenzazepin-5-yl}amino)-2-oxoethyilcarbamate

The title product was prepared from (5R)-8rohloro-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 8) according to the method described in step a) of Example 10. MS (ESI) m/z 567.2 (M+H)⁺. b) /V-i(5R)-8-chloro-1-[trans-4-(pvrid!n-2-vloxv)cyclohexyl]-5_l6-dihvdro-4(-/[1,2,4ltriazolor4,3-aU1lbenzazepin-5-vl}qlvcinamide

The title product was prepared from tert-butyl [2-({(5R)-8-chloro-1[frans-4-(pyridin”2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}amino)-219571

157 oxoethyljcarbamate (step a) of Example12) according to the method described in step b) of Exemple 10. [a]²/ - +18.4° (c=0.1; methanol); MS (ESI) m/z 467.2 (M+H)⁺.

Example 13 (2S)-2-amino-/V-|(5/?)-8-chloro-1-[ÿrans-4-(pyridjri-2-yiox¥)cvcSohexvn-5,6-dîhvdro-4Hri,2,41triazoÎoi4,3-ainibenzazepîn-5-vn-2-phenyiacetamide

a) tert-butyi [(1S)-2-ffî5R)-8-ch!oro-1~ffrans-4-(pyridin-2~¥loxy)cydohexyll-5,6-clihydro-4H[1,2,4]triazolo(4,3-a1[1]benzazepin-5-yl}amino)-2-oxo-1-phenvlethyllcarbamaÎe

The title product was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-210 yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazoio[4,3-a][1]benzazepine-5-amine (Example 8) and Boc-Phg-OH according to the method described in step a) of Example 10. MS (ESI) m/z 643.2 (M+H)\ b) (2S)-2-amino-/V-{(5R)-8-chloro-1-jïrans-4-(pyridin-2-yloxy)cvclohexyll-5_;6-dihydro-4/-/[1,2,4ltriazolo[4.3-al[1lbenzazepin-5-yl)-2-phenylacetamide

The title product was prepared from tert-butyl [(1S)-2-({(5R)-8-chloro-1-[frans-4(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yi}amino)2-oxo-1-phenylethyl]carbamate (step a) of Example 13) according to the method described in step b) of Example 10. MS (ESI) m/z 543.2 (M+H)⁺.

Example 14 ²⁰ (2R)-2-amlno-/V-{(5R)-8-chloro-1-rfrans-4-(pvridin-2-yloxy)cyclohexyll-5,6-dihydro-4H[1,2,4]triazolo[4,3-ain]benzazepin-5-yl}-2-phenylaceiamide »RMfenn>wvMMM>vw<eHMVVMW<MMWMW>A>WMeM»MMiaN«WM>vwvl>imn>winnnnn>vi>vinnnnww0«v<Mww

a) tert-butyl (i1R)-2-ffî5/^:?)-8-chloro-1-[franS4--(pvridÎn-2-yloxy)cyclohexvn-5,6-dihydro-4Hf1,2.4ltriazolo(4,3-al[1lbenzazepin-5-vr}amino)-2-oxo-1-phenyiethvncarbamate

The title product was prepared from (5R)-8-chloro-1-[tra/7s-4-(pyridin-2yloxy)cyclohexyi]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 8)

158 and Boc-D-Phg-OH according to the method described in step a) of Exampie 10. MS (ESI) m/z 643.2 (M+H)*.

b) (2/?)-2-amino-AHÏ5R)-8-chioro-1-[frans-4-ÎPvridin-2-vloxv)cyclohexvll-5,6-dihvdro-4Hi1,2,41triazolor4,3-a][1lbenzazepin-5-vl)-2-phenylacetamide

The titie product was prepared from te/t-butyl [(1R)-2-({(5R)-8-chloro-1-[frans-4(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}amino)2-oxo-1-phenylethyl]carbamate (step a) of Example 14) according to the method described in step b) of Example 10. MS (ESI) m/z 543.2 (M+H)T

Exampie 15 /V-(8-chloro-14trans-4-(pvridjn-2-vÎoxv)cvGlohexvll-5.6-dihvdro-4W-[1,2,4ltriazolor4.,3aïï1lbenzazepin-5-vn-2-hvdroxyacetamide

0.10 g (0.24 mmol) of 8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexylj-5,6-dihydro4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 6) was dissolved in 5 mL of DMF, then 0.10 g (0.27 mmol) of HBTU, 0.17 mL (1.22 mmoi) of triethylamine and 0.02 g (0.27 mmol) of hydroxyacetic acid were added. The reaction mixture was stirred for 16 hours at room température. The solution was concentrated, 20 mL of saturated NaHCOs solution was added to the residue, extracted twice with 20 mL of dichioromethane, the combined organic phases were dried over MgSOa, filtered and concentrated. The residue was purified by column chromatography using dichioromethane:methanol=9:1 as eluent. The expected product was crystallized by trituration with diethyl ether to yield 0.07 g (62%) of the titie product. LC-MS (ESI) m/z 468.2 (M+H)⁺.

Example 16

348-chloro-14frans-4-(pYridm-2-vioxy)cvclohexvn-5,6-dihvdro-4H-H,2.4ltriazolor4,3aH1]benzazepin-5-vlV1.1-dimethylijrea

To a stirred solution of 37 mg (0.23 mmol) of 1,1-carbonyldiimidazole and 3 mL of dichioromethane a solution of 94 mg (0.23 mmol) of 8-chloro-1-[frans-4-(pyridin-2

159 y!oxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazoîo[4,3-a][1]benzazepine-5-amine (Example 6) in 3 mL of DMF and 80 pL of DIPEA was added dropwise and the reaction mixture was stirred at room température for 1 hour. Then 1 mL of a 2M solution of dimethylamine in THF was added dropwise to the mixture and the mixture was stirred for further 2 hours at room température, then concentrated. The residue was dissolved in 20 mL of ethyl acetate and washed with saturated NaCI solution. The organic phase was dried over anhydrous NazSO4, filtered and concentrated. The residue was purified by column chromatography using ammonium hydroxide:1,4-dioxane:ethanol=1:40:1 as eluent. Thus, 22 mg (20%) of the title product was obtained. MS (ESI) m/z 481.2 (M+H)⁺.

Example 17

AH8-chloro-1-Rrans-4-(pvridin-2-vloxv)cyclohexvll-5,6-dihvdro-4#-n,2,4ltnazolof4.3ainibenzazepin-S-vil-^A^-dimethyigivcinamÎde oxv .XX / ,° NH-X ! X--N

The title product was prepared from 8-chloro-1-[frans-4-(pyridin-2~yloxy)cyclohexy!]5,6-dihydro-4/7-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 6) according to the method described in Example 16. LC-MS (ESI) m/z 495.2 (M+H)⁺.

Exampie 18 /V-{8-chioro-1-Rrans-4-(pvridin-2-vioxv)cyciohexvil-5.6-dihvdro-4H-f1,2.4ltriazolor4,3airilbenzazepin-5-vi}methanesuifonamide

To a solution of 200 mg (0.49 mmol) of 8-ch!oro-1-[.Tans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 6), 10 mL of dichloromethane and 84 pL (0.6 mmol) of triethylamine, 46 pL (0.6 mmol) of methanesulfonylchloride was added and the reaction mixture was stirred at room température overnight. Then, additional 84 pL (0.6 mmol) of triethylamine and 46 pL (0.6 mmol) of methanesuîfonylchloride were added to the reaction mixture and stirred at room température overnight. The reaction mixture was then diluted with dichloromethane, washed with saturated NaHCOs solution and saturated NaCI solution, the organic phase was dried

160 over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography using dichloromethane: methanol=9:1 as eluent. Thus 93 mg (39%) of the title product was obtained. MS (ESI) m/z 488.2 (M+H)⁺.

Example 19 /y-f8-chloro-1-Rrans-4-(pvricljn-2-yloxy)cvclohexyn-5,6-djhydro-4H-n,2,4ltriazoloÎ'4,3alMlbenzazepm-5-vlWV-methylmethanesulfonamide

To a solution of 50 mg (0.1 mmol) of A/-{8-chloro-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5yljmethanesulfonamide (Example 18) in 10 mL of DMF 10 mg (0.25 mmol) of sodium hydride (60% dispersion in oil) was added and the reaction mixture was stirred at room température for 15 minutes. 15 pL (0.24 mmol) of iodomethane was then added and the reaction mixture was stirred at room température overnight. Then, additional 10 mg of sodium hydride (60% dispersion in oil) and 15 pL of iodomethane were added to the reaction mixture and stirred at room température overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=95:5 as eluent. Thus, 33 mg (65%) of the title product was obtained. MS (ESI) m/z 502.2 (M+H)⁺.

Example 20

M-i8-chiorQ-1-Rrans-4-(pvridin-2-vlQxv)cvcÎohexyll-5.6-dihvdro-4£/41,2,4]f:riazolor4.3alHlbenzazepin-S-vll-MÀFdjmethvIsulfamide

To a solution of 82 mg (0.2 mmol) of 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 6), 5 mL of dichloromethane and 35 pL (0.25 mmol) of triethylamine, 25 pL (0.23 mmol) of N,Ndimethylsulfamoyl chloride was added and the reaction mixture was stirred at room température for 20 hours. Then, additional 35 pL of triethylamine and 25 pL of N,N

161 dimethylsulfamoyl chloride were added, and the mixture was stirred at 40°C for 48 hours. The reaction mixture was diiuted with dichloromethane, washed with saturated NaHCCL and saturated NaCI solution, the organic phase was dried over anhydrous NazSCU, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus 38 mg (37%) of the title product was obtained. MS (ESI) m/z 517.2 (M+H)⁺.

Exampie 21

8-chloro-M-methy1-1-rirans-4-(pvr8din-2-vioxy)cvclohexyn-5,6-djhydro-4HF1,2.4ltriazoiof4.3-airilbenzazepine-5-amine

a) tert-butvl{8-chlora-1-[tfans-4-(pvridin-2-vloxv)cvclohexvll-5.6-dihydro-4HM,2,4ltriazola[4,3-al[1lbenzazepin-5-vrknethvlcarbamate

BOC

To a solution of 98 mg (0.19 mmol) of ferAbutyl {8-chloro-1-[trans-4-(pyridin-2yloxy)cyclohexyi]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}carbamate (Example 5) in 10 mL of DMF 20 mg (0.5 mmol) of sodium hydride (60% dispersion in oil) was added and the reaction mixture was stirred at room température for 15 minutes. Then, 30 pL (0.48 mmol) of iodomethane was added and the mixture was stirred at room température overnight. Then, additional 20 mg of sodium hydride (60% dispersion in oil) and 30 pL of iodomethane were added to the réaction mixture and stirred at room température overnight. The reaction mixture was then diiuted with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous NaaSCU, filtered and concentrated. The residue was purified by column chromatography using dichloromethane: methanol=9:1 as eluent. Thus 58 mg (58%) of the title product was obtained. MS (ESI) m/z 524.3 (M+H)⁺.

b)8Chloro-A/-methvl-1-jfrans-4-(pvridin-2-vloxv)cvclohexvil-5,6-dihvdro-4/-/n,2,4ltriazoio[4,3-al[1lberizazepine-5-amine

The title product was prepared from fert-butyl {8-chloro-1-[trans-4-(pyridin-2yloxy)cyc!ohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}methy!carbamate

162 (step a) of Example 21) according to the method described in Example 6. MS (ESI) m/z 424.1 (M+HF.

Example 22

S-chioro-^N-dimethyl-l-frrans-^fpyridin-S-vloxvlcvclohexvn-S.S-dihydro-^HF1.2,4ltriazolo[4,3-ain]benzazep!ne-5-amine

To a solution of 100 mg (0.24 mmol) of 8-chloro-1-[frens-4-(pyridin-2y!oxy)cyc!ohexyl]-5,6-dihydro-4/7-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 6), 15 mL of methanol, 182 pL (2.44 mmol) of 37% formaidehide and 28 pL (0.488 mmol) acetic acid, 168 mg (0.79 mmol) of NaBH(OAc)3 was added under ice-cooiing, and the reaction mixture was stirred at room température for 20 hours. Then 10 mL of saturated NaHCOs solution was added to the réaction mixture and concentrated. 30 mL of water was added to the residue and extracted with dichloromethane. The combined organic phases were dried over Na₂SO₄, fiitered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus, 68 mg (64%) of the title product was obtained. MS (ESI) m/z 438.2 (M+H)⁺-

Example 23

8-Ghloro-/V-ethvi-1-Rrans-4-(pvridin-2-vtoxy)cyctohexyn-5,6-dihydro-4H[1,2,4]triazolo[4,3-airi]benzazepine-5-amine

a)tert-butyl(8-chloro-1-(frar?s-4-(pvridin-2-vloxy)cyclohexyll-5,6-dihvdro-4/7[1,2,4ltriazo!oi4,3-alF1lbenzazepin-5-yl}ethylcarbamate

163

The title product was prepared from terf-butyl {8-chloro-1-[trans-4-(pyridin-2yloxy)cyc!ohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}carbamate (Example 5) and ethyl iodide according to the method described in step a) of Example 21. b) 8-chloro-A/-ethyl-1-[trans-4-(pvridin-2-vloxy)cyciohexyll-5,6-dihvdro-4H-(1,2,41triazoio[4,3alHlbenzazepine-5-amine

The title product was prepared from ferf-butyl {8-chîoro-1-[tra/?s-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}ethylcarbamate (step a) of Example 23) according to the method described in Example 6. MS (ESI) m/z 438.2 (M+H)⁺.

Example 24

8-chtoro-AMpropan-2-yÎM-rfrans-4-(pvridin-2-vloxy)cvcSohexvn-5,6-dîhydro-4HΓ1,2,41triazoloF4,3-alF 1 lbenzazepine-5-ami ne

To a mixture of 0.5 g (1.22 mmol) of 8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 6), 50 mL of 1,2dichloroethane, 0.45 mL (6.13 mmol) of acetone and 134 pL (2.34 mmol) of acetic acid, 0.8 g (3.77 mmol) of NaBH(OAc)j was added in small portions under ice-water cooling, and the reaction mixture was stirred at room température for 20 hours. Then, 50 mL of water was added to the reaction mixture, the pH was adjusted to 12 with 5% NaOH solution and extracted with dichloromethane. The combined organic phases were dried over Na₂SÛ4, filtered and concentrated. The residue was purified by column chromatography using dichloromethane: methanol=95:5 as eluent. Thus, 0.434 g (79%) of the title product was obtained. MS (ESI) m/z 452.2 (M+H)⁺.

Exampie 25 (5S)-8-chl0ro-/V-(propan-2-vlM-krans-4-(pvridjn-2-ytoxv)cyclohexvn-5,6-dihydro-4Hri^^ltriazoloPLS-airilbenzazepme-S-amine

The title product was prepared from (5S)-8-chloro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ^Ajtriazolo^.S-aKIJbenzazepine-S-amine (Example 7)

164 according to the method described in Example 24. [αβ⁵ = -29.3° (c=0.1 ; methanol); MS (ESI) m/z 452.3 (M+H)L

Example 26 (5/?)-8-chloro-AHpropan-2-v!)-14frans-4-(pvridîn-2-¥ioxv)cvcSohexyn-5,6-d8hydro-4/YM,2,4ltrjazoio[4,3-ali1lbenzazemiTe-5-amme

The titie product was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2yloxy)cyclohexy!]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 8) according to the method described in Example 24. [αβ⁵ - +30.7° (c=0.1; methanol); MS 10 (ESI) m/z 452.3 (M+H)⁺.

Example 27

8-chloro-/V-cycÎobutyl-1-[frans-4-(pyrÎdin-2-yloxy)cycjohexyn-5_;6-dihydro-4Hn^^ltriazoloPM-airilbenzazepine-S-amme

The titie product was prepared from 8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 6) and cyclobutanol according to the method described in Example 24. MS (ESI) m/z 464.2 (M+H)⁺.

Example 28

8“Chioro-ftF-(oxetan-3-vh-1-[trans-4-(pvridin-2-vioxv)GycSohexvn“5,6-dihydro-4H20 [1_;2_;4]triazolo[4,3-airi]benzazepine-5-amine

The titie product was prepared from 8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 6) and oxetane-3one according to the method described in Example 24. LC-MS (ESI) m/z 466.2 (M+H)⁺.

Example 29

165

8-chloro-1-|ïrans-4-(pyridin-2-yloxy)cyclohexyl]-/V~(tetrahydro-2A/-pyran-4-yl)-5_Î6dihvdro-4H-[1,2,4ltrîazolof4,3-ali1lbenzazepîne-5-amine

The title product was prepared from 8-chloro-1-[trens-4-(pyridin-2-yloxy)cydohexyl]5,6-d!hydro-4.h'-[1,2,4]tnazolo[4,3-a][1]benzazepine-5-arr!ine (Example 6) and tetrahydro4H-pyran-4-one according to the method described in Example 24. MS (ESI) m/z 494.2 (M+H)⁺.

Example 30

8-chloro-AM4^-d8fluorc¥CÎohexvh-1-Rrans-44pyridlin-2-vloxv)cvclohexvjl-5.6-dih¥dro4H-H,2,4ltnazoior4,3-al[1lbenzazepine-5-ai7iine

The title product was prepared from 8-chloro-1-[frans-4-(pyridin-2-yloxy)cydohexyl]5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 6) and 4,4difluorocyclohexanone according to the method described in Example 24. MS (ESI) m/z 528.2 (M+H/.

Example 31 8-methox¥-1-Rrar?s-4-(pvridïn-2-¥loxy)c¥dQhexvn-5,6-dihvdro-4H-ri,2,4ltr8azoloF4,3aïï1lbenzazepine-5-amme hydrochloride

a) tert-butyl f8-methoxy-1-[tra/?s-4-(pyridin-2-yioxy)cyclohexvll-5,6-dihydro-4/-/F1,2,4lÎriazoio[4,3-al[1lbenzazepin-5-yl}carbamate

166

A mixture of 113 mg (0.35 mmol) of fert-butyl (7-methoxy-2-thioxo-2,3,4,5-tetrahydro1H-1-benzazepin-4-yl)carbamate (Intermediate 15), 91 mg (0.39 mmol) of frans-4-(pyridin2-yloxy)cyclohexane carboxylic acid hydrazide and 2 mL of 1,4-dioxane was stirred at 120°C for 2 hours under microwave irradiation (200W), then 80 mg (0.35 mmol) of silver benzoate was added and the reaction mixture was stirred under the same conditions for 2 more hours. The reaction mixture was fiitered through Celite, washed with dichloromethane and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=96:4 as eiuent. Thus, 103 mg (58%) of the title product was obtained. MS (ESI) m/z 506.3 (M+H)⁺.

b) 8-methoxv-1-ftrans-4-(pvridin-2-vloxv')cvciohexvn-5.6-dihvdro-4H-n,2.4ltrÎazolo[4.3al[1lbenzazepine-5-amine hydrochloride

A mixture of 103 mg (0.2 mmol) of tert-butyl {8-methoxy-1-[Tans-4-(pyridin-2yloxy)cyclohexy!]-5,6-dihydro-4/7-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}carbamate (step a) of Exampie 31) and 3 mL of 2.5M hydrogen chloride solution in ethyl acetate was stirred at room température for 2 hours. The precipitated crystals were filtered and washed with ethyl acetate. Thus, 65.4 mg (79%) ofthe title product was obtained. MS (ESI) m/z 406.2 (M+H)’.

Exampie 32

8-methoxy-AHpropan-2-vn-1-nrans-4-(pvrid!n-2-yloxv)cvclohex¥l]-5,6-dihydro-4Hri.2,41triazoto[4,3-airilbenzazepine-5-amine

ch₃

The title product was prepared from 8-methoxy-1-[trans-4-(pyridin-2yloxy)cyciohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine hydrochloride (Example 31) according to the method described in Example 24. MS (ESI) m/z 448.3 (M+H)⁺.

Example 33 ferLbutyi f14trans-4-4pyridm-2-vlox¥)cvctohexvil-8-(trifluoromethvl)-5,6-dihydro-4#n,2,41triazoloF4_;3-ainibenzazepm-5-yl}carbamate

167

0.46 g (1.22 mmol) ferf-butyl[2-(methylsulfanyl)-7-(trifluoromethy!)-4,5-dihydro-3H-1benzazepin-4-yl]carbamate (Intermediate 50) was dissolved in 30 mL of xylene and 0.45 g (1.83 mmol) of frans-4(pyridin-2-yloxy)cyclohexane carboxylic acid hydrazide was added to the solution. A drop of concentrated hydrochioric acid was added to the reaction mixlure and the mixture was refluxed for 2 hours. After cooling to room température, the solution was concentrated. The residue was purified by flash chromatography using dichloromethane:methanol=95:5 as eluent. Fractions containing the expected product were concentrated and the product crystallized by trituration with ether. Thus, 0.52 g (78%) of the title product was obtained. MS (ESI) m/z 544.2 (M+H)⁺

Exampie 34

1-rfrans-4-(pvridin-2-vÎoxv)cvclohexvn-8-(trifluoromethvh-5,ë-dîhvdro-4Hn,2,41triazotor4,3-aimbenzazepine-5-amine hydrochioride

0.52 g (0.95 mmol) of ferf-butyl{1-[frans-4-(pyridin-2-yloxy)cyclohexylj-8(trifluoromethyl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3-aH1]benzazepin-5-yl}carbamate (Example 33) was dissolved in 30 mL of ethyl acetate, and then 10 mL of 2.5M hydrogen chloride solution in ethyl acetate was added with ice-water cooling. The reaction mixture was stirred at room température for 4 hours, then 30 mL of diethyl ether was added and the mixture was cooled again in an ice-water bath. The precipitated product was filtered, washed with diethyl ether and dried. Thus, 0.39 g (86%) of the title product was obtained. MS (ESI) m/z 444.2 (M+H)⁺ The product was used in the further reactions as a free base.

Example 35

MAFdimethvl-1-rfrans-4-(pvridÎn-2-vloxy)cvclohexyn-8-n:rifiuoromethvl)-5,6-dihvdro4/-/-Π ,2,41triazolo[4,3-alHlbenzazepine-5-amine

The title product was prepared from 1-[frans-4-(pyridin-2-y!oxy)cyclohexyl]-8(trifluoromethyl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 34) according to the method described in Example 22. MS (ESI) m/z 472.2 (M+H)⁺.

168

Example 36 /V-(propan-2-yi)-1-Ffrans-4-(pvridin-2-yloxy)cyclohexyn-8-(trifluoromethyl)-5_!§dihydro-4H-n,2,41triazolo[4,3-e]ri]benzazepme-6-amme

The title product was prepared from 1-[frans-4-(pyridin-2-yloxy)cyctohexyl]-8(trifluoromethyl)-5,6-dihydro-4H-[1 ^^Itriazolo^S-aKIjbenzazepine-S-amine (Example 34) according to the method described in Example 24. MS (ESI) m/z 486.2 (M+H)⁺.

Example 37

8-methyl·1-F¢raπs-4-ίpvridin-2-¥loxv)cvclohe¾vll-5,6djhydro-4H-F1,2,4ltΓiazotoΓ4_i3 alHlbenzazepine-S-amme

nh₂

a)________tert-butyl________{8-methyl-1-ftrans-4-(pyridin-2-vloxy)cyclohexyll-5,6-dihydro-4H(1,2,4ltriazolo[4,3-al[1lbenzazepin-5-yl}carbamate

A mixture of 30.6 mg (0.1 mmoi) of tert-butyl (7-methyî-2-thioxo-2,3,4,5-tetrahydro1/7-1-benzazepin-4-yl)carbamate (Intermediate 23), 35.3 mg (0.15 mmol) of toans-4-(pyndin2-yloxy)cyclohexane carboxylic acid hydrazide and 1 mL of n-butanol was refluxed for 48 hours, then concentrated. The residue was used without further purification. MS (ESI) m/z 490.3 (M+H)T b)________8-methyl-1-ftrans-4-(pyridin-2-yiQxy)cvclohexvll-5,6-dihydro-4H-[1,2,4lÎriazolo[4,3al[1lbenzazepine-5-amine

A mixture of 91 mg (0.19 mmol) of tert-butyl {8-methyl-1-[frans-4-(pyridin-2yloxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}carbamate (step a) of Example 37) and 4.8 mL of 2.5M hydrogen chloride solution in ethyl acetate was stirred at room température for 2.5 hours. The precipitated crystais were fiitered and washed with ethyl

169 acetate. Ethyi acetate and aqueous K2CO3 solution were added to the filtered hydrochloride sait and stirred for 10 minutes at room température. The phases were separated, the organic phase was dried over anhydrous NazSCh, filtered and concentrated. The residue was purified by gradient chromatography using dichioromethane: methanol=93:7—>90:10 as eluent. Thus, 35 mg (49%) ofthe titie product was obtained. MS (ESI) m/z 390.2 (M+H)⁺.

Example 38

8-methvl-AMpropan-2-vlM-rfrans-4-(pvridin-2-vioxv)cyclohexyll-5,6-dihvclro-4/l·

M ,2,41triazolor4,3-ainilbenzazepÊne-5-amme

The titie product was prepared from 8-methyl-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 37) according to the method described in Example 24. MS (ESI) m/z 432.3 (M+H)⁺.

Example 39

8-bromo-1-Ffrans-4-(pvndin-2-vloxv)cvclohexvll-5_<6-dihvdro-4^-rL2,4ltriazoloi4,3-

A mixture of 0.68 g (1.8 mmol) of fert-butyl{1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-8(trifluoromethyl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3-aH1]benzazepin-5-yl}carbamate (Example 33), 0.65 g (2.75 mmol) frans-4-(pyridin-2~yloxy)cyclohexane carboxylic acid hydrazide and 18 mL of n-butanol was refiuxed for 29 hours, then concentrated. 25 mL of 2.5M hydrogen chloride solution in ethyi acetate was added to the residue and stirred at room température for 1.5 hours. The precipitated crystals were filtered and washed with ethyi acetate. Ethyi acetate and aqueous K2CO3 solution were added to the filtered hydrochloride sait and stirred for 10 minutes at room température. The phases were separated, the organic phase was dried over anhydrous Na₂SO4, filtered and concentrated. The residue was purified by gradient chromatography using dichloromethane:methanol 95:5—>85:15 as eluent. Thus, 0.64 g (78%) of the titie product was obtained. MS (ESI) m/z 454.1 (M+H)⁺.

Example 40

170

8-bromo-/V-(propan-2-yj)-1-Rrans-4-(pyrjdin-2-vloxy)cycÎohexyn-5,6-dihydro-4H n,2,4ftriazoic>r4,3-ainibenzazepîne-5-amme

The title product was prepared from 8-bromo-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]5,6-όίί^Γθ-4/7-[1,2,4]1π3ζοΙο[4,3-8][1φβηζ3ζβρίηθ-5-3Γπίηβ (Example 39) according to the method described in Example 24. MS (ESI) m/z 498.1 (M+H)⁺.

Exemple 41

8-chloro-1-(3,3-difluarocyclobutyl)-AMpr^,opan-2-yl)-5.6-dihydro-4H-n,2,4lÎfiazolOs4.,3alHlbenzazepme-5-amine

a)tert-butyl f8-chioro-1-(3,3-difluorocyclobutyl)-5.6-dihydro-4H-[1,2,4ltriazolo[4,3-

0.19 g (0.59 mmol) of fert-butyl (7-chloro-2-thioxo-2,3,4,5-tetrahydro-1H-1benzazepin-4-yl)carbamate (Intermediate 4) was dissolved in 10 mL of xylene and 0.14 g (0.90 mmol) of 3,3-difiuorocyclobutane carboxylic acid hydrazide (intermediate 57) was added to the solution. The reaction mixture was refluxed under argon for 6 days and then concentrated. The product was purified by column chromatography using dichloromethane:methanol:25% ammonia solution=18:1:0.1 as eluent. The appropriate fractions were concentrated and the residue was crystallized by trituration with ether. Thus, 0.11 g (42%) of the title product was obtained. MS (ESI) m/z 425.2 (M+H)⁺.

b) 8-chloro-1-(3.3-difluorocvclobutvl)-5.6-dihydro-4H-[1,2,41triazolo[4,3-a][1lbenzazepine-5amine

171 k— ci^x ---Z nh₂

0.10 g (0.25 mmol) of tert-butyl [8-chloro-1-(3,3-difluorocyclobutyl)-5,6-dihydro-4/7[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl]carbamate (step a) of Example 41) was dissolved in 10 mL of ethyl acetate, then 2 mL of 2.5M hydrogen chloride solution in ethyl acetate was added to the solution. The reaction mixture was stirred at room température for 5 hours, then diethyl ether was added and the product was extracted twice with 20 mL of water. The pH of the combined aqueous phases was basified with saturated Na₂CO3 solution and the highly precipitated mixture was extracted twice with 20 mL of dichloromethane. The combined organic phases were dried over MgSOi, filtered and concentrated. Thus, 0.05 g (66%) of the title product was obtained. MS (ESI) m/z 325.2 (Μ+Η)⁺.

c) 8-chioro-1-(3,3-difluorocvciobutyi)-/V-(propan-2-vi)-5.6-dihydro-4H-n,2,4ltriazolo[4,3a][11benzazepine-5-amine

The title product was prepared from 8-chloro-1-(3,3-difluorocyclobuty])-5,6-dihydro4/7-(1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (step b) of Example 41) according to the method described in Example 24. MS (ESI) m/z 367.2 (M+H)⁺.

Example 42

8-chloro-1-(4,4-difIuorocvdohexvB-AMprooan-2~vn-5.6-dihvdro-4H-ri,2,4ltriazoloi4,3ainibenzazepine-5-amine

a)tert-butyl r8-chloro-1-(4,4-difluorocyclohexyl)-5,6-dihydro-4/7-(1,2,41triazoio[4,3ali1]benzazepin-5-vl]carbamate F y cr —Ç

NHBoc

The title product was prepared from tert-butyl (7-chloro-2-thioxo-2,3,4,5-tetrahydro1/7-1-benzazepin-4-yl)carbamate (Intermediate 4) and 4,4-difluorocyclohexane carboxylic acid hydrazide (Intermediate 67) according to the method described in step a) of Example

41. MS (ESI) m/z 453.2 (M+H)⁺.

172

b) 8-chloro-1-(4.4-difluorocyclohexyl)-5.6-dihvdro-4/7-[1.2₁4ltriazolo(4_l3-a'i[1lbenzazepine-5amine ¹

NH_Z

The title product was prepared from teri-butyl [8-chloro-1-(4,4-difluorocycÎohexyl)-5,6dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl]carbamate (step a) of Exampie 42) according to the method described in step b) of Example 41. MS (ESI) m/z 353.1 (M+H)⁺.

c) 8-chloro-1-(4,4-difluorocvclohexyl)-/V-(propan-2-vi)-5,6-dihydro--4/7-(1,2,4ltriazolo[4,3al(1]benzazepine-5-amine

The title product was prepared from 8-chloro-1-(4,4-difluorocyclohexyl)-5,6-dihydro4/7-(1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (step b) of Example 42) according to the method described in Example 24. MS (ESI) m/z 395.1 (M+H)⁺.

Example 43

8-chioro-1-Rrans-4-(trifiuoromelhvl)cyclohexyl]-5_; 6-dihydro-4#-[1,2,41^32010(4,3alFHbenzazepine-5-amine

a)ferf-butyl {8-chloro-1-(trans-4-(trifluoromethy0cyclohexvll-5,6-dihydiO-4H[1.2.4ltriazolo[4,3-a][1lbenzazepin-5-yl}carbamate

The title product was prepared from terf-butyl [7-chloro-2-(methy!sulfanyl)-4,5dihydro-3/7-1-benzazepin-4-yl]carbamate (Intermediate 5) and trans-4(trifluoromethyl)cyclohexane carboxylic acid hydrazide (Intermediate 55) according to the method described in Method B) of Example 5. MS (ESI) m/z 485.2 (M+H)⁺.

b) 8-chioro-1-[f/ans-4-(trifiuoromethvi)cvciohexvll-5.6-dihydro-4/7-(1.2.4ltriazolo[4.3aKHbenzazepine-5-amine

173

The titie product was prepared from fert-butyl {8-chloro-1-[frans-4(trifÎuoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5yljcarbamate (step a) of Exemple 43) according to the method described in Example 6. MS (ESI) m/z 385,2 (M+H) \

Example 44

8-chloro-AMpropan-2-vn-1-rfrans-4-(tnflu0romethvhcvclohexvÎl-5<6-dihvdro-4£A Π ,2,41ίπ3ζοΙο(4, 3-al(1lbenzazepine-5-amine

The titie product was prepared from 8-chloro-1-[frans-4-(trifluoromethyl)cyclohexyl]5_!6“dihydro-4fT41,2,4]triazolo[4,3-a]['1]benzazepine-5-amine (Example 43) according to the method described in Example 24. MS (ESI) m/z 427.2 (M+H)⁺.

Example 45

8-bromo-1-Rrans-4-(trifiuoromethyl)cyclohexyll-5,6-dîhydro-4H-[1,2,4ltriazolo(4,3-

The titie product was prepared from tert-butyl (7-bromo-2-thioxo-2,3,4,5-tetrahydro1H-1-benzazepin-4-yl)carbamate (Intermediate 33) and frans-4-(trifluoromethyl)cyclohexane carboxylic acid hydrazide (Intermediate 55) according to the method described in Example 39. MS (ESI) m/z 431.1 (M+Hf-

Example 46 g-bromo-AMpropan-2-vn-1-r&'ans-4-(tnfuoromethvncyclohexyll-5,6-dihydro-4H· H,2,41triazoio[4,3-al(11benzazepine-5-amine

174

The title product was prepared from 8-bromo-1-[rra/7s-4-(trifluoromethyl)cyclohexyl]5,6-dihydro-4/T'-[1,2,4]triazQlo[4,3-a][1]benzazepine-5-amine (Example 45) according to the method described in Exampîe 24. MS (ESI) m/z 471.1 (M+H)⁺.

Example 47 r-Rrans-4-(PVridin~2-vloxv)cvclohexvn-8Mtrifiuoromethvn-4^;H,6^sH-sp!ron,3djOxoiane-ZS’-ri^AltriazoloiO-alFIlbenzazepinel

0.80 g (2.79 mmol) of 7-(trifluoromethyl)-1,5-dihydrospiro[1-benzazepine-4,2’[1,3]dioxolane]-2(3/^)-one (Intermediate 43) was dissolved in 60 mL of dichloromethane, then 0.02 mL (0.28 mmol) of trifluoroacetic acid and 0.50 g (3.34 mmol) of trimethyloxonium tetrafluoroborate were added to the solution under argon. The reaction mixture was stirred at room température for 24 hours and then 0.80 g (3.34 mmol) of trans-4-(pyridin-2yloxy)cyclohexane carboxylic acid hydrazide was added to the solution. The reaction mixture was refluxed for 6 hours, then the solution was concentrated. The residue was purified by column chromatography using dichloromethane:methanol=95:5 as eluent. The fractions containing the product were concentrated to yield 0.53 g (39%) of the title product. MS (ESI) m/z 487.2 (M+H)⁺.

Example 48

1-rtran5-4-fpvridjn-2-vlox¥)cvclohexvn-B-(trifSuoromethyi)-4H-f1.2.4ltnazoloF4,3aH1]lbenzazepin-5(6H)-one Ι,.Ί,ί^ί···^-/.1,1,.1,1, m, Hll.ll ·|*··*·|*·*|, ,,* Ifl? ί*|ί··^Ι·Ί| .,.1..,,

0.54 g (1.11 mmol) of T-[trans-4-(pyrid!n-2-yloxy)cyclohexyl]-8’-(trifluoromethyi)4Ή,6Ή-8ρίτο[1,3-dioxolane-2,5’-[1,2,4]triazolo[4,3-a][1]benzazepine] (Example 47) was dissolved in 20 mL of methanol and 25 mL of concentrated hydrochloric acid was added to the solution. The reaction mixture was refluxed for 2 hours and then, after cooling to room température, 50 mL of water was added and the pH was adjusted to 7-8 with 30% NaOH solution. The solution was extracted three times with 30 mL of ethyl acetate, and the combined organic phases were washed with water, then with saturated NaCI solution, dried

175 over MgSO₄, filtered and concentrated. The residue was purified by column chromatography using ethyl acetate:ethanol=3:1 as eluent. The appropriate fractions were concentrated and the residue was crystallized by trituration with ether. Thus, 0.30 g (61%) of the title product was obtained. MS (ESI) m/z 443.2 (M+H)⁺.

Example 49

1-rÿrans-44Pvridin-2-vloxv)cvclohexvil-8-(trifluorornethvl)-5.6-dihvdro-4HF1,2,4ltriazolor4,3-ainibenzazepjn-5-oi

0.32 g (0.72 mmol) of 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-4H[1,2,4]triazolo[4,3-a][1]benzazepine-5(6H)-one (Example 48) was dissolved in 20 mL of methanol and the solution was cooled to 0°C. Under stirring and cooling with ice-water, 0.03 g (0.87 mmol) of NaBH₄ was added to the reaction mixture. The solution was stirred at 0 °C for 10 min and then at room température for further 2 hours. The reaction mixture was concentrated, 10 mL of water was added to the residue and the pH of the solution was adjusted to about 7 with 5% hydrochloric acid solution. The aqueous phase was extracted twice with 20 mL of dichloromethane, the combined organic phases were dried over MgSO₄₁filtered and concentrated. The residue was crystallized by trituration with ether. Thus, 0.32 g (99%) of the title product was obtained. MS (ESI) m/z 445.2 (M+H)⁺.

Example 50

5-methoxy-1-Rrans-4-(pyrjdin-2-yloxy)cÿclohexyl]-8-(trifluorometh¥0-5,6-dih¥dro-4/ïF1,2,4]triazoloF4,3-alFnbenzazepme

0.10 g (0.23 mmol) of 1-[t/anS4-(pyridin-2-yloxy)cyclohexyl]-8-(trifîuoromethyl)-5,6dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-ol (Exemple 49) was dissolved in 10 mL of DMF and the solution was cooled to 0°C. 8.1 mg (0.34 mmol) of sodium hydride (60% dispersion in oil) was added to the solution and the mixture was stirred at 0°C for 1 hour. 28.0 pL (0.45 mmol) of iodomethane was added to the reaction mixture and it was allowed to warm to room température and stirred for 16 hours. The reaction mixture was poured into water and extracted twice with 20 mL of ethyi acetate. The combined organic phases were washed with water and saturated NaC! solution, dried over anhydrous MgSCL, filtered and concentrated. The residue was purified by column chromatography using dichloromethane: methanol=95:5 as eluent. The expected product was crystallized by triturationwith n-hexane to yield 0.05 g (47%) ofthetitle product. MS (ESI) m/z459.2 (M+H)⁺

Example 51

5-(cycÎopropvlmethoxv)-14trans-4-(pvrjdm-2-vloxv)cyclohexvl1-8-(trifÎuoromethyn5,6-dihvdrG-4H41_!2,4]triazoÎo[4,3°aïï11benzazepine

0.10 g (0.23 mmol) of 1-[frai?s-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifiuoromethyl)-5,6dihydro-4H-[1,2,4]triazoio[4,3-a][1]benzazepin-5-ol (Example 49) was dissolved in 10 mL of DMF and the solution was cooled to 0°C. 8.1 mg (0.34 mmol) of sodium hydride (60% dispersion in oil) was added to the solution and the mixture was stirred at 0°C for 1 hour. 87.3 pL (0.90 mmol) of (bromomethyl)cyclopropane was added to the reaction mixture, and then it was ailowed to warm to room température and stirred for 16 hours. Then the solution was cooled again and further 4.0 mg (0.17 mmol) of sodium hydride (60% dispersion in oil) and 43.7 pL (0.45 mmol) of (bromomethyl)cyclopropane were added to the reaction mixture. After stirring at room température for 6 hours, the reaction mixture was poured into water and extracted twice with 20 mL of dichloromethane. The combined organic phases were washed with water, dried over anhydrous MgSCU, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=95:5 as eluent. The appropriate fractions were concentrated and the residue was crystallized by trituration with n-hexane to yield 0.07 g (65%) ofthe title product. MS (ESI) m/z 499.3 (M+H)*.

Example 52

54Re^butvl(dimethyI)sHvlloxvl-§-ch!oro-1-rfrans-4-(PVridin-2-vtoxv)cvclohexyll-5,6 dïh¥dro-4H-[1,2,4tt:riazoloF4,3-aïï1lbenzazepme

177

0.36 g (1.06 mmol) of 4-{[tert-butyl(dimethyl)silyl]oxy}-7-chloro-1,3,4,5-tetrahydro-2^/1-benzazepine-2-thione (Intermediate 63) was dissolved in 20 mL of xylene and 0.42 g (1.80 mmol) of frans-4-(pyridin-2-yloxy)cydohexane carboxylic acid hydrazide was added to the solution. The reaction mixture was refluxed for 96 hours, cooled to room température and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=95:5 as eluent The appropriate fractions were concentrated and the residue was crystallized by trituration with ether. Thus, 0.21 g (37%) of the titie product was obtained. MS (ESI) m/z 525.2 (M+H)⁺,

Example 53 g’-chloro-T-Rrans-é-fpyridin-g-vloxylcyclohexvIM’H.SW-spirori.S-dioxolane-Z.S⁵n,2,4)triazolof4,3-aK1lbenzazepinel

The titie product was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2^![1,3]dioxolane]-2(3H)-one (Intermediate 53) according tothe method described in Exemple 47. MS (ESI) m/z 453.2 (M+H)⁺.

Example 54 §-chioro-1-ftrans-4-(pvndin-2-yloxv)cyclohexyll-4H-M,2,4]|tiriazoio[4,3-

The titie product was prepared from 8^,-chloro-T-[frans-4-(pyridin-2-yloxy)cyclohexyl]4’H,6’H-spiro[1,3-dioxolane-2_>5’-[1,2,4]triazolo[4,3-a][1]benzazepine] (Example 53) according to the method described in Example 48. MS (ESI) m/z 409.2 (M+H)⁺.

Example 55 8-chloro-1-ftraπs-4-(p¥rίdiΩ-2-yloxy)cyclQhexyll·5,6-dih¥dro-4A/-[1_;2,4]triazolo[4,3-

a]j1 jbenzazepm-5-ol

178

Method A)

0.28 g (0.53 mmol) of 5-{[t®rt-butyl(dimethyl)siiyl]oxy}-8-chloro-1-[tranS4-(pyridin-2y!oxy)cyciohexyl]-5,6-dihydro-4H-[1,2,4]Îriazolo[4,3-a][1]benzazepine (Example 52) was dissolved in 20 mL of THF. 1.07 mL (1.07 mmol) of 1M tetrabutylammonium fluoride (TBAF) solution in THF was added dropwise to the above solution and the reaction mixture was stirred at room température for 5 hours. 50 mL of water was added to the reaction mixture and extracted twice with 50 mL of ethyl acetate. The combined organic phases were washed with saturated NaCI solution, dried over Na₂SO4, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=90:10 as eluent. The appropriate fractions were concentrated and the residue was crystallized by trituration with ether. Thus, 0,19 g (86%) of the title product was obtained. MS (ESI) m/z 411.1 (M+H)⁺.

Method B)

The title product was prepared from 8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5(6H)-one (Example 54) according to the method described in Exampie 49. MS (ESI) m/z 411.2 (M+H)⁺.

Example 56 (5S)-§-chloro-1-jÎrans-4-(pvridin-2-yloxv)cvclohexyn-5,6-dihydro-4Hri,2,41triazolor4,3-ainibenzazepin-5-oi

and Example 57 (5R)-8-chloro-1-Ffrans-4-(pvrid8n-2-vloxv)cyclohexvn-5_i6-dîhydro-4Hn^^ltriazoloF^S-ainibenzazepin-S-ol

179

The title products were prepared from the racem 8-chloro-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-oi (Example 55) by chiral préparative HPLC (CHIRALPAK IA with préparative 20 pm stationary phase, 2.5x20cm; F=15ml_/min, eluent: tert-butyl methyl ethendichloromethane:ethanol=85:10:5; isocratic, t=25°C) to yield the (5S) enantiomer (T_r 16.2 min; [α]ο^Ξ = -15.6° (c=0,1; chloroform); Example 56) and the (5R) enantiomer (T_r 19.8 min; [a]Q = +11.6° (c=0.1; chloroform); Example 57). The absolute configuration of the compounds was determined by VCD method and by ¹H NMR spectroscopy of the diastereomeric pairs synthesized therefrom.

Example 58

8-chloro-5-methQxy-1-rtrans-4-{pvndjn-2-vtoxv)cyclohexyn-5,6-dihydro-4Hri,2,41triazoioR,3-al[1lbenzazepine

The title product was prepared from 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]5_!6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-ol (Example 55) according to the method described in Exampîe 50. MS (ESI) m/z 425.2 (M+H)⁺.

Exempte 59

5-(Cvclopropvimethoxv)-8-chloro-1-Rrans-4-(pvridin-2-vioxv)cvctohexylÎ-5,6-dîhvdro

4Η-Π,2,4Ηπ3ΖθΙοΓ4,3-31Π166ΠΖ5Ζ6ρΐη6

The title product was prepared from 8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]5_l6-dihydro-4H-[1_!2,4]triazolo[4,3-a][1]benzazepin-5-ol (Example 55) according to the method described in Example 51. MS (ESI) m/z 465.2 (M+H)T

Example 60

2-(i§-chioro-1-frrans-4-(pvrid!n-2-¥toxv)cvclohexvll-5.6-dihvdro-4H-[1.2,4ltnazotof4,3a] Μ1 benzazepi n-5-yi}oxy )-M N-di meth yiethanam i ne

0.08 g (0.19 mmol) of 8-chloro-1-[frans-4-(pyridin-2-yloxy)cyciohexyl]-5,6-dihydro4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-ol (Example 55) was dissolved in 8 mL of DMF, the solution was cooied to 0°C and 0.05 g (1.32 mmol) of sodium hydride (60% dispersion in oil) was added and the resulting mixture was stirred at 0°C for half an hour. Then, 0.08 g (0.56 mmol) of 2-chloro-/V,/V-dimethylethanamine hydrochloride was added to the reaction mixture and it was stirred at room température for 16 hours. The reaction mixture was poured on ice and extracted twice with 20 mL of ethyl acetate. The combined organic phases were washed with water and saturated NaCI solution, dried over anhydrous MgSCu, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol:25% ammonia solution=18:1:0.1 as eluent. The appropriate fractions were concentrated and the residue was crystallized by trituration with diethyi ether to yield 0.04 g (47%) of the title product. MS (ESI) m/z 482.2 (M+H)⁺.

Exemple 61

8^;<;hloro-Γ-[fΓaπs-44trjfluoromethvl)cvclohexyΠ-4^ίH,6^,^/-spiroΓ1,3-djOxoίane-25^,F1,2,4ltriazolof4,3-ainibenzazeoinel

The title product was prepared from 7-chloro-1,5-dihydrospiro(1-benzazepine-4,2’[1,3]dioxolane]-2(3H)-one (Intermediate 53) and frans-4-(trifluoromethyl)cyclohexane carboxylic acid hydrazide (Intermediate 55) according to the method described in Example 47. MS (ESI) m/z 428.1 (M+H)⁺.

Example 62

8’-bromo-r-rfrans-4-(pvridin-2-vioxv)cvclohexvn-4’H.6^,H-spiroF1,3-dioxolane-2.5^!’ri,2,4ltriazolof4,3-alF11lbenzazepinel

181

To a solution of 121 mg (0.41 mmol) of 7-bromo-1,5-dihydrospîro[1-benzazepine-4,2’[1,3]dioxolane]-2(3H)-one (Intermediate 36) and 8 mL of dry dichloromethane, 3.11 pL (0.04 mmol) of trifluoroacetic acid and 72 mg (0.49 mmol) of trimethyloxonium tetrafluoroborate were added under nitrogen atmosphère at room température. The reaction mixture was stirred at room température for 17 hours, then 107 mg (0.45 mmol) of frans-4-(pyridin-2yloxy)cyclohexane carboxylic acid hydrazide was added and refluxed for 6.5 hours. The reaction mixture was concentrated, 10 mL of toluene and 1 drop of acetic acid was added to the residue and refluxed for 3 hours, then the reaction mixture was concentrated. The residue was purified by gradient chromatography using dichloromethane:methanol=^:97:3—^90:10 as eluent. Thus, 121 mg (60%) ofthe titie product was obtained. MS (ESI) m/z 499.1 (M+H)⁺.

Example 63

T-[irans-4-(pvndjn-2-vloxv)cyclohexvn-4’H,GW-spironj-dioxolane-g,S’il,2,4ltriazoloi4,3-aK11benzazepine1

The titie product was prepared from 1,5-dihydrospiro[1-benzazepine-4,2’[1,3]dioxolane]-2(3H)-one (Intermediate 70) according to the method described in Example 47. MS (ESI) m/z 419.2 (M+H)⁺.

Example 64

8-bromc>-1-[trans-4-(P¥ridin-2-yloxy)cvcjohex¥n~4H-[1,2,4ltriazolor4,3airilbenzazepin-5(6#)-one

The titie product was prepared from 8’-bromo-T-[trans-4-(pyridin-2-yloxy)cyclohexyl]4’H,6’H-spiro[1,3-dioxoiane-2,5’-[1,2,4]triazolo[4,3-a][1]benzazepine] (Example 62) according to the method described in Example 48. MS (ESI) m/z 453.0 (M+H)⁺

182

Example 65

8-bromo-1-rtrans-4-fPYridin-2-yloxy)cvclohexyi1-5,6-dihydro-4//41,2,4ltriazotor4,3alFHbenzazepin-5-ol

The title product was prepared from 8-bromo-1-[f/ans~4-(pyridin-2”yloxy)cyclohexyl]4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5(6H)-one (Example 64) according to the method described in Example 49. MS (ESI) m/z 457.1 (M+H)*

Exempte 66

Γ-RΓaπs-4-(pvridjn-2-yloxv)cyclohexvil-4Ή6^,H-spiro[1,3-dioxojane-2_l5^,rUAltriazoloFAS-ainibenzazepinel-S’-carbonitrite

A mixture of 49.7 mg (0.1 mmol) of8’-bromo-T-[tra/7s-4-(pyridin-2-yloxy)cyclohexyl]4’H,6’H-spiro[1,3-dioxolane-2,5’-[1,2,4]triazolo[4,3-a][1]benzazepine] (Exampie 62), 13.4 mg (0.15 mmol) of copper(l) cyanide and 0.6 mL of dry DMF under microwave irradiation conditions in a CEM Explorer microwave reactor was stirred at 220°C for 30 minutes. The reaction mixture was diiuted with dichloromethane, filtered through Celite, washed with dichloromethane. The filtrate was concentrated and ethyl acetate and aqueous ammonia solution were added to the residue. The phases were separated, the organic phase was washed once with aqueous ammonia, dried over anhydrous NazSCL, filtered and concentrated. The residue was purified by reversed-phase chromatography using acetonitrile:water containing 1% trifluoroacetic acid=1:1 as eluent. Thus, 17.8 mg (40%) of the title product was obtained. MS (ESI) m/z 444.2 (M+H)⁺.

Exampte 67 (5S)-8-chSoro-JV,M-dimethvl-1-rtrans-4-(pyridjn-2-vloxvtevclohexvn-5,6-dihydro-4Hri,2,41triazolor4.3-airilbenzazepme-5-amme

The title product was prepared from (5S)-8-chloro-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Exampie 7) according to the method described in Example 22. [αβ⁵= -36.8° (c=0.1; methanol); MS (ESI) m/z 438.2 (M+H)⁺

Example 68 (5S4-A/48rohioroU4frans-4-(pyridm--2-vloxy)cyciohexvn-5.6djhvdro-4/T· Γ1,2,41^1 azololAS-alHIbenzazepin-S-yllacetamide

The title product was prepared from (5S)-8-chloro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Exampie 7) according to the method described in Example 9. [a]o⁵= -24.3° (c=0.1; methanol); MS (ESI) m/z 452.2 (M+H)⁺.

Example 69

8^!-chiGro-T4irar?s-4-(pjperid8n-1-vlmethyl)cyc!ohexy!l-4^Î,H,67-/-spjron,3-dioxo!ane

2,5^;-n,2,41triazolo[4,3-airilbenzazepme]

The title product was prepared from 7-chloro-1_:5-dihydrospiro[1-benzazepine-4,2’[1,3]dioxolane]-2(3H)-one (Intermediate 53) and trans-4-(piperidin-1-ylmethyl)cyclohexane carboxylic acid hydrazide (Intermediate 65) according to the method described in Example 47. MS (ESI) m/z 457.2 (M+H)⁺.

Example 70

[trans-448^!-chloro-4^,H,e^;H-spiron.3--dîoxoiane-2,5^!-n,2,41triazola[4,3·· airilbenzazepinel-l’-vncvdohexvllipvrroiidin-l-vhmethanone

184

The title product was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2’[1,3]dioxolane]-2(3/-/)-one (Intermediate 53) and trans-4-(pyrrolidin-1ylcarbonyl)cyclohexane carboxylic acid hydrazide (Intermediate 78) according to the method 5 described in Exampie 47. MS (ESI) m/z 457.2 (M+H)⁺

Example 71

8-chloro-1-rfrans-4-(trifluoromethyncyclohexyl]-4H-ri_;2,4]triazolor4.3-

o The title product was prepared from 8'-chloro-T-[frans-4-(trifluoromethyl)cyclohexyll477,6^JH-spiro[1,3-dioxolane-2,5’-[1,2,4]triazolo[4,3-a][1]benzazepine] (Example 61) according to the method described in Example 48. MS (ESI) m/z 384.1 (M+H)⁺.

Example 72

8-chloro-1-Rrans-4-(tnfiuorometh¥0c¥clohexyn-5_Î6-djhydro-4H-H_;2,4ltriazolor4,3-

The title product was prepared from 8-chloro-1-[frans-4-(trifluoromethyl)cyclohexyl]4/-/-(1,2,4]triazolo[4,3-a][1]benzazepine-5(6/T)-one (Example 71) according to the method described in Example 49. MS (ESI) m/z 386.1 (M+H)⁺.

Example 73 (c/sl-B-fe’-chloro^’H.eTI-spiron^-dioxolane-S^’-ri^^ltriazogoK.gal[1lbenzazep8nel-r-i0-3-methvl-1-oxa-3-azaspiroF4.5ldecan-2-one

185

The title product was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2’[1,3]dioxolane]-2(3H)-one (Intermediate 53) and (c/s)-3-methyl-2-oxo-1-oxa-3azaspiro[4.5]decane-8-carboxylic acid hydrazide (Intermediate 87) according to the method described in Example 47. MS (ESI) m/z 445.2 (M+HF.

Exampie 74

8-chloro-5-methoxv-1-krans-4-(trifluoromethvl)cvclohexvn-5,6-dihydro-4Hn,2,41triazolor4.3-all'Hbenzazepine

F

O Me

The title product was prepared from 8-chloro-1-[frans-4-(trifluoromethyl)cyclohexyi]5,6-dihydrQ-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-ol (Intermediate 72) according to the method described in Example 50. MS (ESI) m/z 400.1 (M+H)⁺.

Example 75 (frans)-8-(8’-chloro-4ⁱH6⁾H-spiro[^,1,3-dioxoiane-2,5^Î41_i2,4ltriazoÎor4_Î3aïï1lbenzazepin]-r-yl)-3-methyl-1-oxa-3-azaspjror4.5]decan-2-one

The title product was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2’[1,3]dioxolane]-2(3H)-one (Intermediate 53) and (frans)-3-methyl-2-oxo-1-oxa-3azaspiro[4.5]decane-8-carboxylic acid hydrazide (Intermediate 86) according to the method described in Exampie 47. MS (ESI) m/z 445.1 (M+H)⁺.

Example 76

186

N-{(5S)-8-cNoro-1-rfrans‘-44pyridm-2-yioxyjcydohex¥n-5,6-dihvdr0-4Hn,2,4Kriazo!or4,3-alMlbenzazepin-5-yi}-N-methvimethanesLüfonamîde

a) /V-{(5S)-8-chloro-1-ifrans-4-(pyridin-2-yloxy)cvclohexyll-5,6-dihydro-4Hi1,2,4ltriazolo[4,3-al[1]benzazepin-5-yl}methanesulfonamide

To a solution of 204 mg (0.5 mmol) of (5S)-8-chloro-1-ïtrans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 7) and 5 mL of pyridine, 46 pL (70.6 mmol) of methanesulfonyl chloride was added and the réaction mixture was stirred at room température overnight. The reaction mixture was then diluted with dichloromethane, washed with saturated NaHCO₃ solution and saturated NaCI solution, the organic phase was dried over anhydrous Na₂SO4, filtered and concentrated. The residue was purified by column chromatography using dich!oromethane:methanol-9:1 as eluent. Thus, 90 mg (37%) of the title product was obtained. MS (ESI) m/z 488.3 (M+H)⁺. b) A/-{(5S)-8-chloro-1-ffrar?s-4-(pyridin-2-yloxv)cvciohexyll-5,6-dihydro~4H[1,2,4]triazolo[4,3-ainibenzazepin-5-vl}-A/-methyimethanesulfonamide

The title product was prepared from /V-{(5S)-8-chloro-1-[frans-4-(pyridin-2yloxy)cyclohexyi]-5,6-dihydro-4H-[1,2,4]triazoio[4,3-a][1]benzazepin-5yl}methanesulfonamide (step a) of Example 76) according to the method described in Example 19. MS (ESi) m/z 502.2 (M+H)⁺.

Example 77 (5S)-8rohloro-ALethvl-1-rfrans-4-(pvridin-2-viaxv)c¥clohexvIl-5,6-dihydro-4HF1,2,41triazolor4.3-ain 1benzazepine-5-amî ne

187

a), ferLbutyi______f(5S)-8-chloro-1-[tfans-4-(pyridin-2-yloxy)cyclohexyn-5,6-dihydro-4/-/[1,2,4ltriazolor4,3-al[1lbenzazepin-5-v!|œrbam

To a solution of 204 mg (0.5 mmol) of (5S)-8-chloro-1-[trans-4-(pyridin-2yioxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 7) and 10 mLof dichloromethane 275 pl_ (1.5 mmol) DIPEA and 130 mg (0.6 mmol) di-tert-butyl dicarbonate were added and the reaction mixture was stirred at room température overnight. The reaction mixture was diluted with dichloromethane, washed with saturated NaHCO₃solution and with water, the organic phase was dried over anhydrous Na₂SO4, filtered and concentrated. Thus, 246 mg (97%) of the title product was obtained. MS (ESI) m/z 510.2 (M+H)⁺.

b)_................terf-butyl {(5S)-8-chloro-1-|ï/ians-4-ÎDvridin-2-yloxv)cyclohexvll-5,6-dihvdro-4HH,2.4ltriazoio[4,3-al[1lbenzazepin-5-vl}ethylcarbamate

/

The title product was prepared from terf-butyl {(5S)-8-chloro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}carbamate (step a) of Example 77) according to the method described in step a) of Example 23. MS (ESI) m/z 538.2 (M+H)⁺.

c)______________(5S)-8-chloro-A/-ethyl-1-[fra/7s-4-(pvridin-2-yloxv)cvciohexyll-5,6-dihydro-4H[1,2.4]triazolo[4.3-al[1lbenzazepine-5-amine

The title product was prepared from terf-butyl {(5S)-8-chloro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}ethylcarbamate (step b) of Example 77) according to the method described in Example 6. MS (ESI) m/z 438.3 (M+H)⁺.

Example 78 (5S)-8-chloro-N-methyl-1-Ftrans-4-(pyridm-2-ySoxy)cyclohexyn-5,e-dih¥dro--4Hn,2,41triazolor4,3-ainibenzazepme-5-amme

a) tert-butyl {(5S)-8-chloro-1-ftrar?s-4-ipvridin-2-vloxy)cyclohexvll-5.6-dihvdro-4H[1,2,4]triazolor4,3-al[1]benzazepin-5-yi}methylcarbamate

The title product was prepared from fert-butyi {(5S)-8-chloro-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}carbamate (step a) of Example 77) according to the method described in step a) of Example 21. MS (ESI) m/z 524.3 (Μ+Η)Λ

b)____________(5S)-8-chloro-A/-methyl-1-[frans-4-(pvridin-2-vloxy)cyclohexvll-5,6-dihydro-4Hi 1,2,4]triazolo[4,3-a][ 1 ]benzazepine-5-amine

The title product was prepared from tert-butyl {(5S)-8-chloro-1-[trans-4-(pyridin-2yloxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}methyîcarbamate (step a) of Example 78) according to the method described in Example 6. MS (ES!) m/z 424.2 (M+H)⁺.

Example 79 ri,2,41triazojor4,3-airilbenzazepioel

The title product was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2’[1,3]dioxoiane]-2(3H)-one (Intermediate 53) and 1-(pyrimidin-2-yl)azetidin-3-carboxylic acid hydrazide (Intermediate 82) according to the method described in Example 47. MS (ESI) m/z 411.1 (M+Hf.

Example 80

189

Af-{(5S)-8-chloro-1-rtrans-4-(pyridin-2-vloxy)cvclohexvn-5_i6-dihydro-4Hri,2,41Îrîazolor4,3-airilbenzazepin-5-yn-4-fluorobenzamÎde

To a solution of 204 mg (0.5 mmol) of (5S)-8-chloro-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 7) and 3 mL of pyridlne, 90 pL (0.76 mmol) 4-fluorobenzoyl-chloride was added and the reaction mixture was stirred at room température ovemight. The reaction mixture was then diluted with ethyl acetate, washed with water, the organic phase was dried over anhydrous Na₂SCu, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus, 155 mg (58.5%) ofthe title product was obtained. [αβ⁵= -69.8° (c=0.1; methanol); MS (ES!) m/z 532.2 (M+H)T

Example 81

8^!-bromo-T-Rrans-4-(trifluorometh¥l)cvclohexvll-4^,H,6^!H-snjron,3-dioxolane-2,5^?M,2,41triazolor4,3-airiÎbenzazepine]

The title product was prepared from 7-bromo-1,5-dihydrospiro[1-benzazepine-4,2’[1,3]dioxolane]-2(3H)-one (Intermediate 36) and trans-4-(trifluoromethyl)cyclohexane carboxylic acid hydrazide (Intermediate 55) according to the method described in Example 47. MS (ESI) m/z 472.1 (M+H)⁺.

Example 82

5-(propan-2-vlamino)-1-rtrans-4-(pvrïdïn-2-¥loxv)cvclohexvn-5,6-dihydro-4Hn^^ltriazoloKS-airUbenzazepin-S-carbonitrile trifluoroacetate

190

The titie product was prepared from 8-bromo-A/-(propan-2-yl)-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 40) according to the method described in Example 66. MS (ESI) m/z 443.3 (Μ+ΗΓ.

Exampîe 83 (5S)-8Chloro-/V-(4-fluorobenzyn-1-[frans-4-(pyndm-2-vloxy)cyclohexyn-5_ÎS-dihydro

4H-rL2.41trjazolof4,3-3inibenzazepine-5-amine

To a solution of 204 mg (0.5 mmol) of (5S)-8-chloro-1-iïra/7s-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazoio[4,3-a][1]benzazepine-5-amine (Example 7) and 5 mL of DMF, 30 mg (0.75 mmol) sodium-hydride (60% dispersion in oil) was added and the reaction mixture was stirred at room température for 15 minutes. Then 90 pL (0.75 mmol) of 4-fîuorobenzyl chloride was added and it was stirred at room température overnight. At this time, the reaction mixture was diluted with ethyi acetate, washed with water, the organic phase was dried over anhydrous NaaSCh, filtered and concentrated. The residue was purified by column chromatography using dichioromethane: methanol=9:1 as eluent. Thus, 55 mg (21%) ofthe titie product was obtained. [a]p⁵= -22.1° (c=0.1; methanol); MS (ESI) m/z 518.3 (M+H)⁺.

Example 84 r-Rrans-4-(irifluoromethyncyctohexyn-4^;H.6’H-spiro[1,3-dioxolane-2_Î5^?F1,2,4]triazolor4,3-ainibenzazepine]-8’-carbonitrite

The titie product was prepared from 8’-bromo-T-[frans-4-(trifluoromethyl)cyclohexyl]4’H,6^!H-spiro[1,3-dioxolane-2,5’-[1,2,4]triazolo[4,3-a][1]benzazepine] (Example 81) according to the method described in Example 66. MS (ESI) m/z 419.2 (M+H)⁺.

Example 85

[trar?s-4-(8'-bromo-4^,H,6^!H-spjro|'113-dÎoxolane-2;5^,-[1,2Î4ltriazolof4_;3ainibenzazepinÎ-l’-vücvciohexyntPîperidin-l-vDmethanone

The titie product was prepared from 7-bromo-1,5-dihydrospiro(1-benzazepine-4,2’[1,3]dioxolane]-2(3H)-one (Intermediate 36) and frans-4-(piperidin-1-ylcarbonyl)cyclohexane carboxylic acid hydrazide (Intermediate 97) according to the method described in Example 62. MS (ESI) m/z 517.2 (M+H)\

Example 86 methyl frans-448-bromo-5-oxo-5,6-dihydro-4H-n.2,4ltriazolor4,3-ainibenzazepin-1vhcyclohexane carboxylate

and Example 87

8-bromo-14tran.s-4-(pÎperidin-1-vlcarbonvncvclohexvn-4#-F'L2,4ltriazoM4,3alj~1lbenzazepm-5(6>/)-one

192

A mixture of 118 mg (0.23 mmol) of [frans-4-(8’-bromo-4’H,6’H-spiro[1,3-dioxolane2_;5’-[1,2,4]triazolo[4,3-a][1]benzazepin]-T-yl)cyclohexyl](piperidin-1-yi)methanone (Example 85), 3.1 mL of methanol and 4.7 mL concentrated hydrochloric acid was refluxed for 2,5 hours, then cooled to room température. The pH of the reaction mixture was adjusted to basicwith 10% K2CO3 solution and extracted with dichloromethane, the combined organic phases were dried over anhydrous NazSCN, fiitered and concentrated. The residue was purified by coiumn chromatography using ethyl acetate:methanol=4:1 as eluent. Concentration of the first fraction yielded 17 mg (18%) of methyl frans-4-(8-bromo-5-oxo-5,6- dihydro-4H-[1_>2,4]triazo!o[4,3-a][1]benzazepin-1-yl)cyclohexane carboxylate (Example 86).

MS (ES!) m/z 420.1 (M+H)⁺. Concentration ofthe second fraction yielded 35 mg (32%) of 8bromo-1-[frans-4-(piperidin-1-ylcarbonyl)cyclohexyl]-4H-[1,2,4]triazolo[4,3-a][1]benzazepin5(6H)-one (Example 87). MS (ESI) m/z 471.1 (M+H)⁺.

Example 88 ¹⁵ 8’-chioro-r-[trans-4-(trifluorOmethyi)cyclohexvn-4^,H,6^,H-spirori,3-dioxane-2,5^>[1,2,4]triazolo[4,3-aK1lbenzazepinel

The title product was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2’-

[1,3]di oxane]-2(3H)-one (Intermediate 98) according to the method described in Example 47.

MS (ES!) m/z 467.2 (M+H)⁺.

Example 89 l’-frrans^-ipiperidm-l-vIcarbonvDcvclohexyn-^H.S’H-spiroFU-dioxolane-Î.S’n^ÆtriazololAS-airTlbenzazepml-g’-carbonjtrile

193

The title product was prepared from 7-chioro-1,5-dihydrospirc-[1-benzazepine-4_:2'[1,3]dioxane]-2(3/7)-one (Intermediate 98) and frans-4-(trifluoromethyl)cyclohexane carboxyîic acid hydrazide (Intermediate 55) according to the method described in Example 47. MS (ESI) m/z 442.1 (M+H)⁺.

Example 90

8¹-chtoro-T-[frans-44pyndin-2-yIoxyicvclohexyl]-4^!H,6^,H--spiroM_Î3-dioxane-2,5^![l^^ltriazoioKg-ainibenzazepinel

The title product was prepared from [tians-4-(8’-bromo-4’H_;6’H-spiro[1,3-d!Oxoiarie2,5’-[1_J2_!4]triazolo[4_l3-a][1]benzazepin]-T-yl)cyclohexyl](piperidin-1-yl)methanone (Example 85) according to the method described in Example 66. MS (ESI) m/z 462.2 (M+H)⁺.

Example 91

8-bromo-1-ffrans-4-(trifiuoromethvhcvclohexyn-4H-[1,2.4Îtriazolor4,3-

The title product was prepared from 8’-bromo-r-[frans-4-(trifluoromethyl)cyclohexyl]4Ή,6^!Η-ερίΐΌ[1,3-dioxolane-2,5’-[1,2,4]triazolo[4,3-a][1]benzazepine] (Example 81) according to the method described in Exampie 48. MS (ESI) m/z 429.2 (M+H)⁺.

Example 92

Rrans-4-(§-bromo-5-hydroxy-5_;6-dihydro-4H-[1_i2,4ltriazoloi'4,3-al[1lbenzazepin--1vncvclohexyn(PÎPeridin-1-vnmethanone

194

The title product was prepared from 8-bromo-1-frrans-4-(piperidin-1yicarbonyl)cyciohexyl]-4H-[1,2,4]tnazolo[4,3-a][1]benzazepine-5(6H)-one (Exampie 87) according to the method described in Example 49. MS (ESI) m/z 473.1 (M+H)⁺.

Example 93

8-bromo-1-[irans-4-(trifluoromethvrtcvclohexvn-5_i6-dihydro-4H-n,2,4ltriazo!oF4,3-

The title product was prepared from 8-bromo-1-[fra/7s-4-(trifiuoromethyl)cyclohexyi]4H-[1_!2,4]triazolo[4,3-a][1]benzazepine-5(6H)-one (Exampie 91) according to the method described in Exampie 49. MS (ESi) m/z 432.0 (M-HH)⁺.

Example 94

IMM’-bipiperidin-r-vIbB’-chioro-^Me’f+spÎroFI.S-dioxoiane^S’-ri^ltriazoloKSaHIlbenzazepine

A mixture of 60 mg (0.168 mmol) of 1’-bromo-8’-chioro-4^!H,6’H-spiro[1,3-dioxoiane2,5’-[1,2,4]triazolo[4,3-a][1]benzazepine] (Intermediate 96) and 255 mg (1.514 mmol) of 4piperidinopiperidine was stirred at 130-140°C for 3-4 hours under argon. After cooling to room température it was purified by column chromatography using dichloromethane:methanol:ammonium hydroxide=18:1:0.1 as eluent. The resulting crude product was further purified on a préparative TLC plate using dichloromethane:methanoi:ammonium hydroxide= 18:1:0.1 as eluent. Thus, 20.5 mg (27%) of the title product was obtained. MS (ESI) m/z 444.2 (M+H)⁺.

195

Exemple 95 fert-butyl fl-n^-bipjperidin-r-ylTS-chioro-S.S-dihvdro-AH-rLS^ltriazoloR.Sa] Π1 benzazepi n-5-yl] carbam aie

NH-Bcc

The title product was prepared from terf-butyl (1-bromo-8-chloro-5,6-dihydro-4H[1,2,4]ίΓί3ζοΙο[4,3-a][1]benzazepin-5-yî)carbamate (Intermediate 94) according to the method described in Example 94, MS (ESI) m/z 501.3 (M+H)⁺.

Exampte 96

8^;-fluoro-T-[tra»s-4-(pvridin-2-vloxv)cvcïohexyn-4^,H,6^,H-spirorL3-dioxoiarie--2_i5^![LZ^ltriazoior^S-airUbenzazepineÏ

The title product was prepared from 7-fiuoro-1,5-dihydrospiro[1-benzazepine-4,2’[1,3]dioxolane]-2(3H)-one (Intermediate 92) according to the method described in Example 47. MS (ESI) m/z 437.3 (M+H)⁺.

Exemple 97 (5S)-8-chloro-/V-(4-fluorobenzvn-ÂFffîeÎhvi-1-|ïrans-4-(Dvridin-2-yloxv)c¥clahexvllë.S-dîhydroAH-ri^^ltriazoloKS-airilbenzazepin-S-amîne

The title compound was prepared from (5S)-8-chloro-/V-(4-fluorobenzyl)-1-[trans-4(pyridin-2-yîoxy)cyclohexyl]-5,6-dihydro-4H-[1_!2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 83) and iodomethane according to the method described in Step a) of Example 21. [αβ°= -68.7° (c=0.1; methanol); MS (ESI) m/z 532.3 (M+H)⁺.

Example 96

196

A/-n5S)-8-chiorori4frans-4TPVridm-2-yloxy)cydohexvn-5,6-dihydro-4H n,2.41triazojor4_t3-ainibenzazepin-5-yS}prop-2-enarmde

The titie compound was prepared from (5S)-8-chioro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Exampie 7) and acrylic add according to the method described in Step a) of Example 10. [αβ°= -24° (c=0.1; methanol); MS (ESI) m/z 464.2 (M+H)L

Example 99 (5^)-8-chloro-/V-eth¥l-1-rgrans-4-(pyridm-2-yloxv)cyciohexvn-5_l6-djhydro-4H n,2,4ÎtnazQior4.3-airHbenzazepin-5-amîne

a) fert-butyl______f(5ffl-8-chloro-1-ifrans-4-(pvridin-2-vloxv)c¥clohexvll-5.6-dihvdro-4H

[1,2,4ltriazolo[4.3-ani)benzazepin-5-yl}carbamate

A mixture of 400 mg (0.976 mmol) of (5R)-8-chloro-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 8), 20 mL of dichloromethane, 260 mg (1.19 mmol) of di-tert-butyl-dicarbonate and 0.55 mL (3.16 mmol) of N.N-diisopropylethylamine was stirred at room température for 18 h, then diiuted with dichioromethane and water, the organic layer was separated and the water phase was extracted with dichloromethane. The combined organic phases were dried over Na₂SO4, filtered and concentrated to yield 500 mg (100%) ofthe titie compound, which was used in the next step without further purification.

b) tert-butyl{(5R)-8-chloro-1-frrans-4-(pyridin-2-vloxy)cyciohexyll-5,6-dihvdro-4H[1,2.4]triazo lo[4,3-a] [1 Ibenzazepi n-5-y l}ethy Icarbamate

197

The titie compound was prepared from fert-butyl {(5R)-8-chloro-1-[fra/?s-4-(pyridin-2yioxy)cyclohexyl]-5,6-dihydro-4/7-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}carbamate (Step a) of Example 99) and ethyi iodide according to the method described in Step a) of Example 21. MS (ESI) m/z 538.3 (M+H)⁺.

c)(5R)-8-chloro-/V-ethyl-1-[frans-4-(pyndin-2-yloxy)cyciohexyl]-5,6-dihydro-4H[1,2.4ltriazoio[4.3-a][1lbenzazepin-5-amine

The titie compound was prepared from ferf-butyl {(5R)-8-chloro-1-[fra/?s-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2_;4]triazolo[4,3-a][1]benzazepin-5-yl}ethylcarbamate (Step b) of Example 99) according to the method described in Example 6. [αβ°= +23.1° (c=0.1; methanol); MS (ESI) m/z 438.1 (M+H)⁺.

Exampie 100 (5R)-8-chtoro-/V-methvl·1-Rrar?s-4-(pvrid8π-2-yloxv)cyctohexyΠ-5,S-d!hydro-4HfL2,41Înazolor4,3-al[Hbenzazej3jn-5-amme

a) tert-butyl f(5R)-8-chloro-14trans-4-fDvridin-2-¥ioxv)cvc'ohexvn-5,6-dihvdrc-4/7ri,2,41triazoloF4,3-ainibenzazepin-5-vl}methvlcarbamate

The titie compound was prepared from tert-butyl {(5R)-8-chloro-1-[fra/?s-4-(pyhdin-2yloxy)cyclohexyl]-5,6-dihydra-4H-[1,2_;4]triazolo[4,3-a][1]benzazepin-5-yi}carbamate (Step a) of Example 99) and iodomethane according to the method described in Step a) of Exampie 21. MS (ESI) m/z 524.3 (M+H)⁺.

b)(5R)-8-chloro-A/-methyl-1-[frar?s-4-(pvridin-2-vloxy)cyciohexyl]-5.6-dihydro-4/7[1,2,4]triazolo[4,3-al[1lbenzazepin-5-amine

198

The title compound was prepared from tert-butyl {(5R)-8-chioro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}methylcarbamate (Step a) of Exampîe 100) according to the method described in Example 6. [a]^°= +21.4° (c=0.1; methanol); MS (ESI) m/z 424.1 (M+H)⁺

Example 101 (5ffi)-8-chlQro-M&-djmethyl-1-[irans-4-(pyridin-2-¥loxv)cvclchexvn-5,6-dihydro-4Hri,2,4Îtriazolor4,3-alMlbenzazepin-5-amine

A mixture of 5.93 g (14.5 mmol) of (5R)-8-chloro-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4/7-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Exampie 8), 11 mL of 37% formaldéhyde solution in water, 100 mL of methanol and 65 mL of dichloromethane was cooled to 5°C and 15.3 g (75 mmol) of sodium triacetoxyborohydride was added to the reaction mixture at such a rate to keep the internai température below 5°C. After completion of the addition the reaction mixture was stirred at room température for 5 h, then concentrated. The residue was dissolved in water and the pH was adjusted to 8 by addition of 10% NaOH solution. The precipitated product was filtered off, washed with water and dried to yield 5.75 g (91%) of the title compound. [αβ°= +25.6° (c=0.1; methanol); MS (ESI) m/z 438.2 (M+H)⁺.

Example 102 14trans-4-(pvridÎn-2-viox¥)c¥clohexyll-4H-M,2.4ltriazoior4,3-alF1lbenzazepin-5(6iAone

The title compound was prepared from T-[frans-4-(pyridin-2-yloxy)cyclohexyl]4’H,6'H-spiro[1₎3-dioxoiane-2,5'-[1,2,4]triazolo[4_>3-a][1]benzazepine] (Example 63) according to the method described in Example 48. MS (ESI) m/z 375.1 (M+H)⁺

Example 103

199 (5S)-8-chloro-5-methoxv-1-Ftrans-4-(pyridin-2-yloxy)cvciohex¥n-5_!6-djhydro-4HFl^^ltriazoSoF^S-alFUbenzazepine

and

Example 104 i5R|-8-chloro-5-methoxv-1-Ffrans-4-ÎPvridjn-2-Yloxv)cyclohexyH-5,6-djhydro4H- rL2,41triazoloF4.3-a1Mlbenzazepine

The title compounds were obtained from the racemic 8-chloro-5-methoxy-1-[frans-4(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine (Example 58) by chiral préparative HPLC (CHIRALPAK IA préparative 20 pm stationary phase; 2.5x20cm; F=18mL/min; eluent: terf-butyl methyl ether : dichloromethane : éthanol = 85:10:5; isocratic; t=25°C). The first eluting compound was the (5S) enantiomer (T_r 15.4 min; [αβ° = +11.8° (c=0.1; chloroform); Example 103) and the second eluting compound was the (5R) enantiomer (T_r 21.5 min; [αβ° = -12.0° (c=0.1; chloroform); Example 104). The absolute configuration of the compounds was determined by VCD spectroscopy.

Example 105 8-chloro-5-(propan-2-vloxv)-1-rtrans-4-(pynd!n-2-vloxv)cyclohexvll-5,6-dÎhvdro-4H[1_;2,4ltriazoloF4,3-airilbenzazepine

A mixture of 100 mg (0.243 mmol) of8-chloro-1-[frar7s-4-(pyridin-2-yloxy)cyclohexyl]5_:6-dihydro-4H-[i_i2,4]triazoio[4,3-a][1]benzazepin-5-ol (Example 55), 5 mLof DMF and 12.7 mg (0.316 mmol) of 60% sodium hydride in minerai oil was stirred at 0°C for 30 min, then 52.4 pL (0.316 mmol) of diisopropyl sulfate was added and the reaction mixture was stirred at room température for 18 h. The mixture was diluted with water, extracted with ethyl

200 acetate, the combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane : methanol = 95:5 as eluent to yield 32 mg (29%) of the title compound. MS (ESI) m/z 453.2 (M+H) \

Example WG

8^ί-chloro-Γ-Krans-4-(Pvridin-2-yioxv)cyclohexyΠ-4^,H.8W-spiroΓ1,3-dίoxepane-2.5^,Γ1,2,4]tri azoi o [4,3-a] Γ11 benzazepine]

o \__>

The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'1 o [1,3]dioxepan]-2(3H)-one (Step c) of Intermediate 104) according to the method described in Example 47. MS (ESI) m/z 481.2 (M+H)'¹.

Example 107

14ίΓ3η£-44ρνπάΐη-2-νΙοχν)ενΕΐοΚ6χνΠ-5,6-άΐΚνάΓθ-4Η-·||Ί,2,41ί8·Ϊ3ζοίο[4,3airilbenzazepm-5-ol

The title compound was prepared from 1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-4H[1,2_l4]triazolo[4_!3-a][1]benzazepin-5(6H)-one (Example 102) according to the method described in Example 49. MS (ESI) m/z 377.2 (M+H)⁺.

Exemple 108 ²⁰ rfrans^-fS'-chloro^'H.e'W-spiron.S-dioxolane^.S'-n^^ltriazoior^Saïï1lbenzazepjnl-T-vnevciohexvn(morpholin-4-vl)methanone

Under argon to a mixture of 100 mg (0.39 mmol) of 7-chloro-1,5-dihydrospiro[1benzazepine-4,2'-[1,3]dioxolan]-2(3H)-one (intermediate 53) and 10 mL of dichloromethane

201 pL (0.04 mmol) of trifluoroacetic acid and 70 mg (0.47 mmol) of trimethyloxonium tetrafluoroborate were added. The reaction mixture was stirred at room température for 6 h, then 151 mg (0.59 mmol) of frans-4-(morpholin-4-ylcarbonyl)cyclohexane carbohydrazide (Intermediate 79) and 10 mL of acetonitrile were added and the mixture was refluxed for 8 h. After concentration the residue was purified by flash column chromatography using dichloromethane:methanol:ammonium hydroxide solution = 180:10:1 as eluent to yield 72 mg (39%) of the title compound. MS (ESI) m/z 473.2 (M+H)⁺.

Example 109

5-methoxv-1-n:rans-4-(pyridin-2-yloxy)cvciohexyl]-5,6-djhydro-4/7-n_i2,4ltrïazoto[4_s3alfUbenzazepine

OThe title compound was prepared from 1-[trans-4-(pyridin-2-yloxy)cyciohexyl]-5,6dihydro-4H-[l,2,4]triazolo[4,3-a][1]benzazepin-5-ol (Example 107) according to the method described in Example 50. MS (ESI) m/z 391.2 (M+H)⁺

Example 110 8-fluoro-1-Rrans-4-(pvridin-2-vloxy)cyclohexyn-4/7-ri,2,4ltriazolo(4,3--aU1lbenzazepin-

The title compound was prepared from 8'-fluoro-T-[frans-4-(pyridin-2yloxy)cyclohexyl]-4ⁱH_!6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine] (Example 96) according to the method described in Example 48. MS (ESI) m/z 393.3 (M+H)⁺

Example 111 8-fluoro--1-ftrans-4-(pvrjdm-2-vtoxvlc¥clohexYll-5,6-dihydro-4H-[1,2_<4ltnazolo[4,3a][1lbenzazepm-5-ol

OH

202

The title compound was prepared from 8-fluoro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-4H-[1,2_!4]triazolo[4,3-a][1]benzazepin-5(6H)-one (Example 110) according to the method described in Example 49. MS (ESI) m/z 395.2 (M+H)⁺.

Example 112 tert-butyl Î8-chtoro-1-rtrans-4-(morpholin-4-vhcyctohexyn-5,6-dihvdro-4Hri,2,4]triazotor4,3-ainibenzazepÎn-5-vl>carbamate

MHBoc

The title compound was prepared from tert-butyl (7-chloro-2-oxo-2,3,4,5-tetrahydro1H-1-benzazepin-4-yl)carbamate (Intermediate 5) and frans-4-(morpholin-4-yl)cyclohexane carbohydrazide (Intermediate 81) according to the method described in Method B of Example 5. MS (ESI) m/z 502.2 (M+H)⁺.

Example 113 8-chtoro-1-rfrans-4-(morphoHm4-vhcvclohexvn-5._Îe-dih¥dro-4/7-i1_!2,4ltnazo!or4,3alMlbenzazepin-S-amîne

The title compound was prepared from tert-butyl {8-chloro-1-[tra/?s-4-(morpholin-4yl)cyclohexyl]-5,6-dihydrO4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}carbamate (Example 112) according to the method described in Example 6. MS (ESI) m/z 402.1 (M+H)\

Example 114 8-chtor^,o-1-Rrans-4-(morpholin-4-yl)cyclohexyn-/V-(propan-2-v0-5_;6-dihydro-4H· n^41triazoto[4₁3-a]Hlbenzazepin-5-amme

203

The titie compound was prepared from tert-butyl 8-chloro-1-[trans~4-(morpholin-4yl)cyclohexyl]-5,6-dihydro-4^-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 113) according to the method described in Example 24. MS (ESI) m/z 444.2 (M+H)⁺.

Example 115 (S^grj-B-fa'-chJpro-^W'H-spirorLS-dro^^ alfllbenzazepinl^

The titie compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2’[1,3]dioxolan]-2(3H)-one (Intermediate 53) and (5η 8/)-1 -oxo-2-(propan-2-yl)-210 azaspiro[4.5]decane-8-carbohydrazide (Intermediate 102) according to the method described in Example 62. MS (ESI) m/z 471.2 (M+H)⁺.

Example 116 Lg.ù8jjr§-ig-chloro-5-hvdrox¥-5,6-djhvdro-4H-ri.2,4ltriazoloF4_Î3-airilbenzazepin-1-¥i)2-(propan-2-vn-2-azaspiro[4.5ldecan-1-one λ--N O

C!^ 15 oh

a) 8-chloro-1 -F(5r, 8r)-1 -oxo-2-(propan-2-yl)-2-azaspiroF4.5]dec-8-yll-4H-f 1,2.41triazoÎoF4,3alFUbenzazepin-S/ef-Q-one

The titie compound was prepared from (5η8/)-8-(8^!-οήΙθΓο-4Ή,6Ή-3ρίΓθ[1,320 dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepin]-T-yl)-2-(propan-2-yl)-2azaspiro[4.5]decan-1-one (Example 115) according to the method described in Example 48. MS (ESI) m/z 427.3 (M+H)⁺.

b) (5r,8r)-8-(8-chloro-5-hydroxy-5,6-dihydro-4H-F1,2.4]triazoloF4,3-a]F1lbenzazepin-1-yl)-2(propan-2-¥l)-2-azaspiroF4.5ldecan-1-one

204

The title compound was prepared from 8-chloro-1-[(5r_:8r)-1-oxo-2-(propan-2-yl)-2azaspiro[4.5]dec-8-yl]-4H-[1,2,4]triazolo[4,3-a](1]benzazepin-5(6H)-one (Step a) of Example 116) according to the method described in Example 49. MS (ESI) m/z 429.1 (M+H)⁺.

Example 117 (5Sl-8-chl0ro-1-Rrazîs-4-(pyndm-2-ylQxv)cyciohexyn-5-(py^ 4H-H,2,41triazolor4.3-alMlbenzazepine

A mixture of 400 mg (0.976 mmol) of (5S)-8-chloro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 7), 20 mL of DMF, 117 pL (0.98 mmol) of 1,4-dibromobutane and 954 mg (2.93 mmol) of CS2CO3 was stirred at 40°C for 24 h, then concentrated. The residue was dissolved in water and extracted with ethyl acetate. The combined organic phases were dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane:methanol = 95:5 as eluent to yield 35 mg (8%) of the title compound. MS (ESI) m/z 464.3 (M+H)⁺.

Example 118 ^-ii5S)-8-chloro-1-Rrans-4-fpvridin-2-vSoxv)cvclohexvn-5_i6-dihvdro-4F/ri,2.41triazo!or4,3-airilbenzazepÎn-5-vl)-2,2-dimethvlpropanamide

A mixture of 82 mg (0.2 mmol) of (5S)-8-chîoro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 7), 5 mL of dichloromethane, 35 pL (0.25 mmol) of triethylamine and 30 pL (0.24 mmol) of trimethylacetyl chloride was stirred at room température for 3 h, then diluted with dichloromethane and successively washed with saturated NaHCOs solution and brine. The organic phase was dried over Na₂SO₄, filtered and concentrated to yield 93 mg (94%) of the title compound. [αβ⁵= -32.1° (c=0.1 ; methanol); MS (ESI) m/z 494.3 (M+H)⁺.

Example 119

205

Z£Î(5S)-8-chioro~1-[frang-4-(pyridin-2-vloxy'jcyciohexyn-5,6-dihydro-4H[1,2_;4ltriazolof4,3-airnbenzazepin-5-vi}cvclopropanecarboxamÎde

The title compound was prepared from (5S)-8-chloro-1-[frans-4-(pyridin-2yioxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and cyciopropanecarboxylic acid according to the method described in Step a) of Exampie 10. [αβ⁵= -45.3° (c=0.1; methanol); MS (ES!) m/z 478.3 (M+H)⁺.

Example 120

M-{(5S)-8-chloro-1-rtrans-4-(pyridin-2-yioxy)cvcjohexvll-5.6-d»hvdro-4Hri,2,41triazoioF4,3-airilbenzazepin-5-vlT-2-methvlpropanamjde

O

The title compound was prepared from (5S)-8-chloro-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Exampie 7) and isobutyric acid according to the method described in Step a) of Exampie 10. [αβ⁵= 30.6° (c=0.1; methanol); MS (ESI) m/z 480.3 (M+H)⁺.

Example 121 /V4(5Sb8-chloro-1-rtran,s-4-(pvridm-2-vloxy)cyciohexvn-5,6-dihydro-4/+ [1,2,4Itriazolof4,3-airilbenzazepm-5-vik:vclobutanecarboxamide

The title compound was prepared from (5S)-8-chloro-1-[frans-4-(pyridin-2yloxy)cyciohexyl]-5,6-dihydro-4H-[1,2,4]triazoio[4,3-a][1 jbenzazepin-5-amine (Exampie 7) and cyciobutanecarboxylic acid according to the method described in Step a) of Exampie 10. [αβ⁵= -39.3° (c=0.1; methanol); MS (ESI) m/z 492.3 (M+H)⁺.

206

Example 122 (5S)-8-chSoro-5-(morphonn-4-vlM-Rrans-4-(pyndjn-2-vSoxy)cyclohexvn-5,6-djh¥dro4H41,2,4lfnazoic[4,3--al[1lbenzazepme

The title compound was prepared from (5S)-8-chiaro-1-irrans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and bis(2-iodoethyl)ether according to the method described in Example 117. MS (ESI) m/z 480.2 (M+H)⁺.

Example 123 &-{(5/?)-8-chtoro-1-[ïrans-44pvridin-2-ytoxy)cvctohex¥n-5,6-dshvdro-4#Ll.tgÆtriazolpI^^

The title compound was prepared from (5R)-8-chloro-1-[frans-4-(pyridin-2yloxy)cyciohexyl]-5,6-dihydro-4H-[1,2,4]triazo!o[4,3-a][1]benzazepin-5-amine (Example 8) according to the method described in Example 118. [a]^°= +21.6° (c=0.1; methanol); MS (ESI) m/z 494.2 (M+H)⁺.

Exampîe 124 /V-{(5R)-8-chtoro~1-rirans-4-(pvridin-2Vloxy)cvcÎohexyll-5,6-dihvdro-4H[1,2,4ltriazoto[4,3-airi]benzazepin-5-yl}-2-methylpropanamide

The title compound was prepared from (5R)-8-chloro-1-[frans-4-(pyridin-2yloxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 8)

207 and isobutyric acid according to the method described in Step a) of Exampie 10. [αβ°= +29.4° (c=0.1; methanol); MS (ESI) m/z 480.2 (M+H)⁺.

Example 125

A/-{(5R)-8-chloro-1-Rrans-4-(PVridm-2-vloxv)cvclohexvn-5,6-djhvdro-4Hn,2,4]triazotor4,3-aKT|benzazepin-5-vl}cvclobutanecarboxamide

The title compound was prepared from (5R)-8-chioro-1-[frar?s-4-(pyridin-2yioxy)cyclohexyl]-5_i6-dihydro-4H-[1 ^^Jtriazolo^S-aHIlbenzazepin-S-amine (Exampie 8) and cyclobutanecarboxylic acid according to the method described in Step a) of Example 10. [«]d°= +29.8° (c=0.1; methanol); MS (ESI) m/z 492.2 (M+H)⁺.

Example 126 /V4(5R)-8-chSoro-1-rÿrans-4-(pyridin-2-vloxy)cycÎohexvn-5,6dihydro~4Hn.2,41triazoloF4.3-ainibenzazepin-5-vl}cyclopropanecarboxamide

The title compound was prepared from (5f?)-8-chioro-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4jtriazolo[4,3-a][1 jbenzazepin-5-amine (Example 8) and cyclopropanecarboxylic acid according to the method described in Step a) of Exampie 10. [αβ°= +30.5° (c=0.1; methanol); MS (ESi) m/z 478.2 (M+H)⁺.

Example 127 (5S)-8tohtoro-5-(piperidin-1-ylM-[frans-44Pvridm-2-vloxy)cyclohexvn-5,6-dihydro-4Hri^^ltriazotor^S-ainibenzazepine

208

The title compound was prepared from (5S)-8-chloro-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4W-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and 1,5-dibromopentane according to the method described in Example 117. MS (ESI) m/z 478.4 (M+H)⁺.

Example 128

Γ1, Z^ltriazol o[4,3-a) Γ11benzazepi π-5-ami ne

The title compound was prepared from (5S)-8-chloro-1-[frans-4-(pyridin-2yloxy)cyciohexyl]-5,6-dihydro-4H-[1,2_I4]triazoio[4_I3-a][1]benzazepin-5-amine (Example 7) and 2-butanone according to the method described in Example 24. MS (ESI) m/z 466.4 (M+H)⁺.

Example 129 (55,85)-8-^^^0-471,6^^18-0(1.3-0^01306-2,5^1,2,41^132010(4,3al(1lbenzazepinl-r-vn-2-(propan-2-vl)-2-azaspiro(4.5ldecan-1-one

The title compound was prepared from 7-chloro-l5-dihydrospiro[1-benzazepine-4,2'[1,3]dioxolan]-2(3H)-one (Intermediate 53) and (5$,85)-1-οχο-2-(ρΓορ3η-2-γΙ)-2azaspiro[4.5]decane-8-carbohydrazide (Intermediate 101) according to the method described in Example 62. MS (ESI) m/z 471.2 (M+H)⁺.

Example 130 §-chloro-5-methoxv-1-RraH5-4-(morpholin-4-vncvcjohexvn-5,6-dÎhvdro-4HÎ1.2,4ltriazolo(4,3-ainibenzazepine

209

The title compound was prepared from 7rohloro-4-methoxy-1,3_>4,5-tetrahydro-2H-1benzazepine-2-thione (Step e) of intermediate 103) and frans-4-(morpho!in-4-yl)cyclohexane carbohydrazide (intermediate 81) according to the method described in Step a) of Exampie 5 37. MS (ESI) m/z 417.3 (M+H)⁺.

Example 131

8-çhjoro-5-ethoxy-1-Rra/îs-4-(pyridin-2-ylox¥)cycIohexvH~5,e-dihvdro-4H-

The title compound was prepared from 8-chloro-1-[frans-4-(pyridin-2yioxy)cyclohexyl]-5,6-dihydro-4W-[1,2_î4]triazolo[4,3-a][1]benzazepin-5-ol (Exampie 55) and ethyl iodide according to the method described in Example 50. MS (ES!) m/z 439.3 (M+H)⁺.

Example 132 (5f?)-8-ch!oro-5-methoxv-1-[fraffs-4-(trifluQromethvl}cvc!ohexvn-5.6-d8hvdro-4H¹⁵ n,2,41triazolor4,3-a]rilbenzazepine

and

Exampie 133 (5Sb8-chloro-5-methoxv-14irans-4-(trifluoromeÎhvl)cyclohexvn-5,6-clihvdro-4H[1_;2,4ltriazoloF4,3-a]M1benzazeplne

The titie compounds were obtained from the racemic 8-chloro-5-methoxy-1-[frans-4(trifluoromethyl)cyciohexyl]-5,6-dihydro-4H-[1,2,4]tr!azolo[4,3-a][1]benzazepfne (Example /4) by chiral préparative HPLC (CHIRALPAK IG préparative 20 pm stationary phase; 1.6x25cm; F=12mL/min; eluent: tert-butyl methyl ether : dichioromethane : éthanol = 90:8:2; isocratic; t=25°C). The opticai rotation ofthe first eluting compound (T,· 18.0 min) was [αβ⁰= +15.6° (c=0.1; chioroform); and thaï of the second eluting compound (T, 23.3 min) was Ε^α]ο° ~ -13.5“ (c=0.1; chioroform). The absolute configuration of the compounds was not determined.

Example 134 ^uoro-5-methoxy-1-rfrans-4-(pyridin-2-vioxy)cvclohexvH-5,6-d^

The titie compound was prepared from 8-fluoro-1-[frans-4-(pyridin-2y!oxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-ol (Example 111) according to the method described in Example 50. MS (ESI) m/z 409.3 (M+H)⁺.

Example 135

8-cNoro-AMpropan-2-yl)-1-T1 -(pvridin-2-vl)piperidm-4-vll-5_;6-dlhydro-4Ffi1,2,4ltrjazolor4,3-aïï1lb6nzazej3jn-5-amme

The titie compound was prepared from 8-chloro-1-[1-(pyridin-2-yi)pîperidin-4-yl]-5,6dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 2) according to the method described in Example 24. MS (ESI) m/z 437.4 (M+H)⁺.

211

Exampîe 136

2-({8-chloro-Wans-44pvridjn-2-vloxy)cyclohexvil-5,6-dihvdro-4W-ri.2,4W ainibenzazepin-5-yl}oxy)et:hanoi

^W \__OH

S)______________8-chloro-1-ffrans-4-(pyridin-2-vloxy)cvclohexyll-5-[2-(tetrahydro-2H-pyran-2yioxy)ethoxyl-5,6-dihydro-4H-i1,2,4]triazolo[4,3-a][1lbenzazepine

The title compound was prepared from 8-ch!oro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2_>4]triazolo[4,3-a][1]benzazepin-5-ol (Example 55) and 2-(2-bromoethoxy)tetrahydro-2H-pyran according to the method described in Example 50. MS (ESI) m/z 539.1 (M+H)⁺.

b) 2-({8-chloro-1-ffrans-4-(pyridin-2-vloxy)cvclohexvH-5,6-dihydro-4H-F1,2,4ltriazoio[4,3alMlbenzazepin-S-vlloxylethanol

A mixture of 146 mg (0.27 mmol) of 8-chioro-1-[frans-4-(pyridin-2-yioxy)cyclohexyl]5-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]-5,6-dihydro-4H-[1,2,4]triazo!o[4,3a][1]benzazepine (Step a) of Example 136), 4 mL of acetic acid, 2 mL of THF and 1 mL of water was stirred at 45°C for 20 h, then diluted with water. The so obtained mixture was alkalified with saturated NaHCOs solution, extracted with ethyl acetate, the combined organic layers were dried over MgSO₄, filtered and concentrated to yield 118 mg (96%) of the title compound. MS (ESI) m/z 455.4 (M+H)T

Exampto 137 (5S)-8-chloro-/y,/V-dieth¥i-1-[trans-4-(pyridm-2-yloxy)cyciohexyn-5_i6-dihydro-4Hri,2,41tnazoior4,3-a]nibenzazepin-5-amine

212

The title compound was prepared from (5S)-8-chloro-1-(frans-4-(pyridin-2yloxy)cyciohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a](1]benzazepin-5-amine (Example 7) and acetaidehyde according to the method described in Example 24. MS (ESI) m/z 466.4 5 (M+H)⁺.

Exampie 138 8-chIoΓo-/V-me¾hyl·M(propan-2-vΠ-1-[traπs-4-(p¥ridiπ-2-yloxy)cycIohexyΠ-5,6dihvdro-4H-[1,2,4ltriazalo(4,3-ajrilbenzazepÎn-5-amme

A mixture of 110 mg (0.24 mmol) of 8-chioro-/V-(propan-2-yl)-1-(trans-4-(pyridin-2yIoxy)cyclohexyl]-5,6-dihydro-4H-[1,2,411032010(4,3-a][1]benzazepin-5-amine (Exampie 24), 15 mL of methanol, 182 pL of 37% formaldéhyde solution in water and 28 pL of acetic acid was cooled to 5°C and 169 mg (0.8 mmol) of sodium triacetoxyborohydride was added to the reaction mixture at such a rate to keep the internai température below 5°C. After completion 15 of the addition the reaction mixture was stirred at room température for 24 h, then concentrated. The residue was dissolved in water and the pH was adjusted to 8 by addition of saturated NaHCOs solution, then the mixture was extracted with ethyl acetate, the combined organic layers were dried over Na₂SO4, filtered and concentrated to yield 107 g (94%) of the title compound. MS (ESI) m/z 466.2 (M+H)⁺.

Example 139 torLbutyl Î8-chloroA4443-chloroovr8din42-vnpiperazm-1-vn-5,6-dihvdro-4HM,2,4ltriazolor4,3-alf1lbenzazepm-5-yi)carbamate

CN [t

CI

NH8oc

213

The title compound was prepared from te/ï-butyl (1-bromo-8-chloro-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl)carbamate (Intermediate 94) and 1-(3-chloropyridin2-yl)piperazine according to the method described in Example 94. MS (ESI) m/z 530.4 (M+H)⁺.

Exemple 140 vl)piperidine-1-carboxylate

The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-110 benzazepin-2-one (Step d) of Intermediate 103) and fert-butyl 4(hydrazinylcarbonyl)piperidine-l-carboxylate according to the method described in Example 47. MS (ESI) m/z 433.2 (Μ+ΗΓ.

Example 141

AM(5ffl-8-chloro-1-rfrans-4-(pvridin-2-vloxv)cvclohexvn-5,6-dihydro-4H-

a) fert-butyl [(2/R)-1-({(5R)-8-chloro-1-ffrans-4-(pyridin-2-Yloxy)cvclohexyll-5,6-dihydro-4Hri,2,4ltrjazolo[4,3~anilbenzazepin-5-vl}amino)-3-methyl-1-oxobutan-2-yllcarbamate

The title compound was prepared from (5f?)-8-chloro-1-[trans-4-(pyridin-2yloxy)cycîohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Exemple 8) and cyclobutanecarboxylic acid according to the method described in Step a) of Example 10 and it was used without further purification in the next step.

214 bl__________________ JH(5g)-8-chloro-1-rfrans-4-(pv ri,2,4ltriazoloF4,3-aK1'lbenzazepin-5-yl}-D-valinamide

Th© title compound was prepared from terf-butyl [(2R)-1-({(5R)-8-chloro-1-[frans-4(pyridin-2-yloxy)cycîohexyi]-5,6-dihydro-4H-[1,2,4]triazoîo[4_!3-a][1]benzazepin-5-yl}amino)3-methyl-1-oxobutan-2-yl]carbamate (Step a) of Example 141) according to the method described in Example 6. [a]£°= +7° (c=0.1 ; methanol); MS (ESI) m/z 509.2 (M+H)⁺.

Example 142 terf-butyl {1-Fÿrans-4-(pvridjn-2-vlox¥)cvctohexvll-5₁6-dihvdro-4/7-n,2.4ltriazoioF4..3alMlbenzazepin-5-vl)carbamate

A mixture of 552 mg (1.8 mmol) of fert-butyl [2-(methylsulfanyl)-4,5-dihydro-3H-1benzazepin-4-yl]carbamate (Intermediate 105), 27 mL of 1,4-dioxane, 464 mg (1.97 mmol) of trans-4-(pyridin-2-yloxy)cyclohexanecarbohydrazide (WO 2010/060836 (03.06.2010) F. HOFFMANN-LA ROCHE AG.) and 10 pL of concentrated hydrochloric acid was refluxed under argon for 6.5 h, then concentrated. The residue was purified by column chromatography using dichloromethane : methanol = 95:5 as eluent to yield 567 mg (66%) of the title compound. MS (ESI) m/z 476.2 (M+H)⁺.

Example 143 fert-butyl (8-fguoro-1-Fÿ/'ana-4-(pyridin-2-ytox¥)cvclohexyn-5,6-dÎhydro-4/7n.^ltriazololAS-alFIlbenzazepin-S-yllcarbamate

The title compound was prepared from feft-butyl [7-fluoro-2-(methylsulfanyl)-4,5dihydro-3H-1-benzazepin-4-yl]carbamate (Step g) of Intermediate 106) according to the method described in Example 142. MS (ESI) m/z 494.2 (M+H)⁺.

Example 144

1-krans-4-ÎpyridÎn-2-vloxv)cvciohexvn-5,6-dihydro-4H41,2₁41triazolor4,3a]F1lbenzazepin-5-amine

The title compound was prepared from tert-butyl {1-[frans-4-(pyridin-2yloxy)cyciohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}carbamate (Example 142) according to the method described in Example 6. MS (ESI) m/z 376.2 (M+H)⁺.

Example 145 8-fluoro-1-Rrans-4-(pvndm-2-vioxv)cvclohexvn-5.6-dihvdro-4H-n,2,4ltriazolor4,3ainibenzazepin-5-amine

The title compound was prepared from tert-butyl {8-f!uoro-1-[frans-4-(pyridin-2yloxy)cycîohexyl]-5,6-dihydro-4H-[1,2_l4]triazolo[4,3-a][1]benzazepin-5-yl}carbamate (Example 143) according to the method described in Example 6. MS (ESI) m/z 394.2 (M+H)⁺.

Example 146 8-fiuoro-/V-(propan-2-vü-1-rtrans-4-(pvridm-2-vloxv)cvclohexvll-5,6-dihydro-4Hn,2,4]|triazoior4,3-airilbenzazepin-5-amine

The title compound was prepared from 8-fluoro-1-[fra/?s-4-(pyridin-2yloxy)cyclohexyl]-5_:6-dihydro-4/7-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 145) according to the method described in Example 24. MS (ESI) m/z 436.2 (M+H)*.

Example 147 8-fiuoro-M/V-dîmethvl-1-[trans-4-(pyridin-2-vloxv)c¥Gtohexyn-5,6-dihvdro-4Hn.2,41triazolo[4.3-a]rUbenzazepin-5-amine

216

The title compound was prepared from 8-fluoro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 145) according to the method described in Example 101. MS (ESI) m/z 436.2 (M+H)⁺.

Exampie 148 /VÆdïmethyi-l-Ftrans^-ipyridin-Z-yioxvtëvciohexvn-S.G-dihvdro^ ri,2Ætriaz0loF4.3-alF1lbenzazepjn-5-amine

The title compound was prepared from 1-[frans-4-(pyridin-2-yioxy)cyclohexyl]-5,6dihydnMH-fl^^Jtriazoio^S-aJiljbenzazepjn-S-arnine (Exampie 144) according to the method described in Example 101. MS (ESI) m/z 404.2 (M+H)⁺.

Exampie 149 8^,-f|uoro-1’-F¢rans-4-Ftrifiuoromethvncvclohexyίl4^lR6Ή-spiroF1,3-dioxolaπe-25^,ri,2,4ltriazoio[4,3-alF1lbenzazepinel

The title compound was prepared from 7-fiuoro-1 _!5-dihydrospiro[1-benzazepine-4,2'[1,3]dioxoian]-2(3H)-one (Intermediate 92) and frans-4-(trifïuoromethyi)cyclohexane carbohydrazide (Intermediate 55) according to the method described in Exampie 47. MS (ESI) m/z 404.2 (M+H)⁺.

Exampie 150

M-(propan~2-yi)-1-Ffrar?s-4-(pvridin-2-vlox¥)cvciohexvn-5.,6-dihvdro-4HF1,2,4ltrÎaz0lof4,3-alF1lbenzazepin-5-amîne

217

The titie compound was prepared from 1-[trans-4-(pyridin-2-yloxy)cyclohexyn-5,6dihydro-4H-[1,2,4]triazolo[4,3-a][1 ]benzazepin-5-amine (Example 144) according to the method described in Example 24. MS (ESI) m/z 418.2 (M+H)T

Example 151 /V-{(5S)--8-chloro-1-rrrans-4-fpvr!din-2-vloxv)c¥clohexvn-5.6-d!hvdro-4/-/Il.J.ÆQag.QjoI.4Jrg]L11be^^^

The titie compound was prepared from (5S)-8-chloro-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6dihydro-4H”[1,2,4]Îriazolo[4,3-a][1]benzazepin-5-amine (Example 7) and tetrahydro-2H-pyran-4-carboxylic acid according to the method described in Step a) of Example 10. [αβ°= -41° (c=0.1; methanol); MS (ESI) m/z 522.2 (M+H)L

Example 152

A/-{(5S)-8-chloro-1-rtrans-4-(pyridin-2-yioxv)cycSohexyn-5,6-dihydrQ-4Hri,2.4ltriazoio[4,3-aK1lbenzazepin-5-yl}-2-methylbirtanamide

The titie compound was prepared from (5S)-8-chloro-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5_i6-dihydro-4H-[1,2,4]triazolo[4,3-aj[1]benzazepin-5-amine (Example 7) and 2-methylbutyric acid according to the method described in Step a) of Example 10. MS (ESI) m/z 494.2 (M+H)⁺.

Example 153

AL{(5S)-8-chloro-1-rtrans-4~(Dvridin-2-yloxv)cvclohexvn-5.6-dihydro-4HΓ1,2,41triazoioR,3-airilbenzazepin-5-yi|-A& ΛΑ-dimethyl-B-alaninamide iftnnani ———————JL—οι—,——————————

The title compound was prepared from (5S)-8-chloro-1-[trans-4-(pyridin-2yioxy)cyclohexyl]-5,6-dihydro-4/-f-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and 3-(dimethylamino)propanoic acid according to the method described in Step a) of Example 10. [αβ°= -15° (c=0.1; methanol); MS (ESI) m/z 509.2 (M+H)T

Exampie 154 (5S)-8-chloro-ALcyclopent¥l-1-Rrans-4-(pyridin-2-¥ioxy)cvclohexvn-5,6-dihydro-4HFl^^ltriazoloFAS-alFIlbenzazepin-S-amme

The title compound was prepared from (5S)-8-chloro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and cyclopentanone according to the method described in Exampie 24. -19° (c=0.1;

methanol); MS (ESI) m/z 478.2 (M+H)⁺.

Example 155 g'-chloro-l M 1 ^,HÎ3H-spiroF2-benzofuran-1 ^'-piperidinl-l '-vIM'H.e'H-spîron ,3dioxolane-2Î5^Î-F1,2]4]triazoioF4,3-ainibenzazepjne'Î

The title compound was prepared from T-bromo-8'-chloro-4’H,6'H-spiro[1,3dioxolane-2,5'-[1,2,4]triazo!o[4_;3-a][1]benzazepine] (Intermediate 96) and 3H-spiro[2benzofuran-1,4'-piperidine] (Combi-Blocks) according to the method described in Example 94. MS (ESI) m/z 465.2 (M+H)⁺.

Exampie 156

219

8-chlGro-14rK3H-spiro[2-benzofuran-1,4^!-pipendin]-T-vn-4H-[^^ alHlbenzazepin-Sie/^-one

The titie compound was prepared from 8'-chloro-1'-(TH,3H-spiro[2-benzofuran-1,4'piperidin]-T-y!)-4'H,6‘H-spiro[1,3-dioxoiane-2_:5'-[1,2_l4]triazolo[4,3-a][1]ber'îzazepine] (Example 155) according to the method described in Example 48. MS (ESI) m/z 421.2 (M+H)⁺.

Exampie 157

S'-chloro-l '-MTPVridin^-vioxylpiperidm-l -yiM'H.e'H-spiroH J-dioxoSane-^.S’ n,2,41triazolo[4,3-airilbenzazepinel

Cl

The title compound was prepared from T-bromo-8'rohloro-4W,6'H-spiro[1,3dioxo!ane-2_;5'-[L2,4]triazolo[4,3~a][1]benzazepine] (Intermediate 96) and 2-(piperidin-4yloxy)pyridine according to the method described in Example 94. MS (ESI) m/z 454.1 (M+H)⁺.

Exampie 158

M4(5S)-8-chioro-1-ltrans-4-(pvridin-2-yiox¥)cyciohexyn~5.6-dihvdro-4Hn,2.41triazoioF4,3-airilbenzazep»n-5~vil-2.2-dimethvlbutanamide

The titie compound was prepared from (5S)-8-chloro-1-[fra/7s-4-(pyridin~2yloxy)cyc!ohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and 2,2-dimethylbutyric acid according to the method described in Step a) of Example 10. [à$>= -16° (c=0.1; methanol); MS (ESi) m/z 508.2 (M+Hy.

Exampie 159

220 /V-{(5S)-8-chjoro-1-Rrans-4~(pyridin-2-vlcxy)cyclohexvn-5,6-d^ F1,2₁4ltriazotoi4,3-a]nibenzazepin-5-vl}-2-hvdroxy-2-methvlprapanamide

The title compound was prepared from (5S)-8-chloro-1-[fra/?s-4-(pyridin-25 yloxy)cyclohexyl]-5.6-dihydro-4H-[1,2.4]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and 2-hydroxy-2-methylpropanoic acid according to the method described in Step a) of Example 10. [αβ°= -30° (c=0.1; methanol); MS (ESI) m/z 496.2 (M+H)⁺.

Exampîe 160 (5S)-8-chloro-Λ/-ethvl·/ⁱ/-methyl·1-Γÿraπs-4-(pyr^din-2-vloxy¾cyclohex¥Π-5_i6-djhydro¹⁰ 4Η-Π, 2,41triazolor4,3-ainibenzazepm-5-amine il Y [ ]

The title compound was prepared from (5S)-8-chloro-/V-methyM-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 78) and acetaldehyde according to the method described in Example 24. [α]π°= -37° (c=0.1; 15 methanol); MS (ESI) m/z 452.2 (M+H)⁺.

Example 161 (5Sb8-chloro-AM2-methvlpropyjM-rfrans-4-(pyridÎn-2-¥toxy)cycSohexvn-5.6-dihvdro-

The title compound was prepared from (5S)-8-chloro-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2_:4]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and isobutyraldéhyde according to the method described in Example 24. [îx]o°= -22° (c=0.1;

methanol); MS (ESI) m/z 466.2 (M+H)⁺.

Example 162

8^,-chloro-Γ-Rraπs-4-(morphol8Ω-4-vl)cyclohexvΠ-4Ή.6W-spίroΓ1,3-dioxolane-2,5^,F1.2,4ltriazoioF4,3-aU1lbenzazepïne] hydrochloride

The titie compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2^![1,3]dioxolan]-2(3H)-one (Intermediate 53) and frans-4-(morpholin-4-yi)cyclohexane carbohydrazide (Intermediate 81) according to the method described in Example 47. MS (ESI) m/z 445.2 (M+H)T

Example 163

8-chlaro-WA/-djmethvM-(rH.3H-spiroi2-benzQfuran-1,4^l-pjperidinl-T-yl)-5,6-dihvdro

4/-H1,2,4ltriazoloF4,3-airilbenzazepin-5-amine

a) ferf-butyl [8-chloro-1-(TH,3/7-spiro[2-benzofuran-1,4'-piperidjnl-T-yl)-5,6-dihydro-4H[1,2,4ltriazoloF4.3-al[T|benzazepin-5-yHcarbamate

NHBoc

The titie compound was prepared from tert-butyl (1-bromo-8-chloro-5,6-dihydro-4H[I^^Jtriazolo^S-aHljbenzazepin-S-yOcarbamate (Intermediate 94) and 3H-spiro[2benzofuran-1,4'-piperidine] (Combi-Blocks) according to the method described in Example 94. MS (ESI) m/z 522.4 (M+H)⁺.

8-chloro-1-(TH.3H~spiroF2-benzofuran-1,4'-piperidinl-T-vl)-5,6-dihydro-4HF1,2,4ltriazoloF4,3-al[1lbenzazepin-5-amine

222

The title compound was prepared from fert-butyl [8-chloro-1-(TH,3H-spiro[2benzofuran-1₎4'’PÎperidin]-T-yl)-5,6-dihydro-4H-[1,2₎4]triazolo[4,3-a][1]benzazepin-5yljcarbamate (Step a) of Example 163) according to the method described Example 6 and it was used without further purification in the next step.

c) 8-chloro-A/,A/-dimethyl-1-(TH,3H-spiroi2-benzofuran-1,4^l-piperidinl-T-yl)-5,6-dihydro-4Hf1,2.4ltriazolo[4.3-al[1lbenzazepin-5-amine

The title compound was prepared from 8-chloro-1-(TH,3H-spiro[2-benzofuran-1,4'piperidinl-T-ylj-S.e-dihydro-^H-tl^^jtriazolo^S-aHljbenzazepin-S-amine (Step b) of Example 163) according to the method described in Example 101. MS (ESI) m/z 450.1 (M+Hf.

Exampie 164 8'rohioro-T-r443-^hIoropyrÎdin-2-vl)pjperazm-1 ^0-4^6^^^0(1,3-^^01306-2.,5^

The title compound was prepared from T-bromo-8^,-chloro-4’H,6'H-sp!ro[1,3dioxolane-2_:5'-[1,2,4]triazo'o[4_?3-a][1]benz.azepine] (Intermediate 96) and 1-(3-chloropyridin2-yl)piperazine according to the method described in Example 94. MS (ESI) m/z 473.1 (M+H)⁺.

Exampie 165 (SSj-B-chioro-M-fê^-dimethyiprOpyiM-Fÿrans^-ipvridin-g-yloxylcyciohexyil-S.Gdihydro-4H-(1,2,4ltriazolo(4,3-al(1lbenzazepÎn-5-amine

223

The title compound was prepared from (5S)-8-chloro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and trimethylacetaldehyde according to the method described in Example 24. [a]p°= -19° (c=0.1; methanol); MS (ESI) m/z 522.2 (M+H)⁺.

Example 166

Ffrans-4-(8-chloro-5-methoxy-5,6-dihydro-4F/-[1 _t2,4]trïazolor4,3-ainibenzazepjn-1yl)cyclohexyll(4-methylpiperazin-1-vl)methanone

The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1benzazepin-2-one (Step d) of Intermediate 103) and t/ans-4-[(4-methylpiperazin-1yl)carbonyl]cyclohexanecarbohydrazide (Step b) of Intermediate 107) according to the method described in Example 108. MS (ESI) m/z 458.3 (M+H)⁺.

Example 167 (5R)-8-chloro-5-(morpholin-4-yl)-1-Rrans-4-(pvrid!n-2-vloxv)cyclohexyn-5,6-dihvdro4H-n,2,41triazolor4,3-ainibenzazepine

The title compound was prepared from (5/R)-8-chloro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) and bis(2-iodoethyl)ether according to the method described in Example 117. MS (ESI) m/z 480.2 (M+H)⁺.

Example 168 /V-i(5R)-8-chloro-1-[ÿrans-4-(pvridm-2-v!oxv)cvc!ohexvH-5.6-dihvdro~4Hn_;2,4TtriazoloF4,3-airilbenzazepin-5-vl}acetam8de

224

The title compound was prepared from (5/?)-8-chioro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) according to the method described in Example 9. [a]^°= +29° (c=0.1; methanol); MS (ESI) m/z 452.2 (M+H)⁺

Example 169

A/-{(5R)-8°chioro-1-RF'ans-4-(pvridjn-2-vjox¥)cvclohexvll-5,6-dîhvdro-4HH,2,41triazolo[4,3-ainibenzazepm-5-yn-2-hydrGxy-2-methy!propanamide

The title compound was prepared from (5Æ)-8-chloro-1-[fra/?s-4-(pyridin-2yloxy)cyclohexyl]-5_!6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) and 2-hydroxy-2-methylpropanoic acid according to the method described in Step a) of Example 10. [αβ°= +32° (c=0.1; methanol); MS (ESI) m/z 496.2 (M+H)⁺.

Example 170 8-chloro-5-methoxv-1-[1-(tetrahydro-2H-pvran-4-ÿüpjperidin-4-yn-5,6-dîhvdro-4H[1,2,4ltriazolor4,3-aK11benzazepine

The title compound was prepared from 7-chloro-4-methoxy-1,3_!4,5-tetrahydro-2H-1benzazepin-2-one (Step d) of Intermediate 103) and 1-(tetrahydro-2H-pyran-4-yl)piperidine4-carbohydrazide (Intermediate 108) according tothe method described in Example 108. MS (ESI) m/z 417.2 (M+H)⁺.

Example 171

8^î-chloro-Γ-Γ4-{pvridin-2-v0p8perazir^1-vΠ-4^ίH6Ή^spiro|Ί,3-dioxolane-2,5^,n,2,41triazoior4,3-airilbenzazepinel

225

The title compound was prepared from T-bromo-8'-chloro-4’H,6’H-spiro[1,3dioxolane-2,5'-[1,2,4]triazolo[4_:3-a][1]benzazepine] (intermediate 96) and 1-(pyridin-2yl)piperazine according to the method described in Exampie 94. MS (ESI) m/z 439.2 (M+H)⁺

Example 172 g-chioro-l-iTHiSH-snirofS-benzofuran-l^’-pipendinl-T-vn-S'ë-dihvdro-Wn,2,4]triazolo[4,3-aH1lbenzazepm-5-ol

The title compound was prepared from 8-chloro-1-(1'H,3H-spiro[2-benzofuran-1,4'10 piperidin]-T-yl)-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5(6H)-one (Example 156) according to the method described in Example 49. MS (ESI) m/z 423.2 (M+H)⁺.

Example 173

8-chloro-1-f4-(3-chioropvridin-2-yl)pjperidin-1-vl]-5,6-dihvdro-4H-M,2,4ltnazc>ior4,315

a) 8-chloro-1-[4-(3-chloropyridin-2-¥l)piperidin-1-yl]-4/7-i'1,2,4ltriazolo[4,3-anilbenzazepin5(6H)-one

226

The title compound was prepared from 8'-chloro-T-[4-(3-chloropyridin-2-yl)piperazin1-yl]-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine] (Example 164) according to the method described in Example 48. MS (ESI) m/z 429.0 (M+H)⁺.

b) 8-chioro-1-[4-(3-chioropyridin-2-yDpiperidin-1-vn-5,6-dihydro-4H-[1,2,4ltriazoiof4,3al[1lbenzazepin-5-oi

The title compound was prepared from 8-chioro-1-[4-(3-chloropyridin-2-yl)piperidin1-yl]-4H-[1,2_l4]triazolo[4,3-a][1]benzazepin-5(6H)-one (Step a) of Example 173) according to the method described in Example 49. MS (ESI) m/z 431.1 (M+H)⁺.

Example 174 (5R)-8-chloro-1-[trarts-4-(pyridm-2-¥toxy)c¥clohexyn-5-(0vrrolidin-1-vü-5,6-dihydro

4//-(1.2,4ltriazolo[4_>3-al(1lbenzazepi ne

The title compound was prepared from (5/7)-8-chloro-1-ftrans-4-(pyridfn-2yloxy)cyc!ohexyl]-5,6-dihydro-4H-[1 ^Ajtriazolo^S-aKIjbenzazepin-S-amine (Example 8) and 1,4-dibromobutane according to the method described in Example 117. MS (ESI) m/z 464.2 (M+H)T

Example 175

8-chioro-5-methoxv-1-f1-F(3S)-tetrahydrofuran-3-ynpiperidÎn-4-yl]-5,6-dihvdro-4H[1,2,4ltriazolo[4,3-al(11benzazepine

The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1benzazepin-2-one (Step d) of Intermediate 103) and 1-[(3S)-tetrahydrofuran-3-yl]piperidine4-carbohydrazide (Step b) of Intermediate 109) according to the method described in Example 108. MS (ESI) m/z 403.2 (M+H)⁺.

Example 176 (5/7)-8-fltioro-5-methox¥~1°Firans-4-(pyrïdîn-2-vioxy)cydohexvn-5,6-dihy d ro -4H[1,2,4ltriazolo[4,S-aKUbenzazepine

Exampie 177 (5S^8-fiuoro-5-methoxy-1-Rrans-44PVridjn-2-vloxv)cvciohexvll-5_ί6-dihvdr0-4W(1,2,4ltriazolor4,3-airi1benzazepine

The title compounds were obtained from the racemic 8-fliioro-5-methoxy-1-[frans-4(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1_!2,4]triazolo[4,3-a][1]benzazepine (Example 134) by chiral préparative HPLC (CHIRALPAK IG préparative 20 pm stationary phase;

5x30cm; F=50mL/min; eluent tert-butyl methyl ether : dichloromethane : éthanol = 92:3:5;

isocratic: t=25°C). The optical rotation of the first eluting compound (T_r 17.3 min) was [a]o°= -7° (c=0.1 ; methanol); and that of the second eluting compound (T_r 21.7 min) was [a]|° = +12° (c=0.1 ; methanol). The absolute configuration of the compounds was not determined.

Example 178

8-chl0ro-5-methoxy-1-Î1-[(3R)-tetrahydrofuran-3-ynpiperid»n-4-yi|-5,6-dihydro-4HH^^ltnazQloFO-aKTIbenzazepme

The title compound was prepared from 7-chloro-4-methoxy-1,3_i4,5-tetrahydro-2H-1benzazepin-2-one (Step d) of Intermediate 103) and 1-[(3R)-tetrahydrofuran-3-yl]piperidine20 4-carbohydrazide (Step b) of Intermediate 110) according to the method described in Example 108. MS (ESI) m/z 403.2 (M+H)⁺.

Example 179

Af-{(5R)-8-chioro-1-rfrans-4-(pvridin-2-vioxy)cyciohexyi]-5_i6-djhydro-4Hri,2,41triazoiof4,3-ainibenzazepin-5-vn-f^.A/+dimethyl-B--alan!namide

The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-5_l6-dihydro-4H-[1,2,4]ίη3ζοΙο[4,3-a][1]benzazepin-5-amine (Example 8) and 3-(dimethylamino)propanoic acid according to the method described in Step a) of 5 Example 10. [αβ°= +20° (c=0.1; methanol); MS (ESI) m/z 509.2 (M+H)⁺.

Exampie 180 /V-{(5f?)-8-chloro-1-r^rans-4-(pvrid8n-2-vloxv)cvclohexyi]-5,6-dihydro-4Hn,2,41triazoM4,3-al[Hbenzazepin-5-yntetrahydro-2H-pyran-4-carboxamide

w The title compound was prepared from (5R)-8-chloro-1-[rrans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4/-/-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) and tetrahydro-2H-pyran-4-carboxylic acid according to the method described in Step a) of Example 10. [α]ο°= +29° (c=0.1; methanol); MS (ES!) m/z 522.2 (M+H)⁺.

Example 181 ¹⁵ 8-chlorp-1-r4-(pvridin-2-vloxv)piperidin-1-vll-5,6-dihvdro-4H-ri,2,4ltriazolor4.3 al[11benzazepin-5-ol

a) 8-chloro-1-r4-(pvridin-2-yloxv)piperidin-1-vl]-4H-ri.2,4lthazolo[4,3-aK1lbenzazepin5(6/7)-one

229

The titie compound was prepared from 8'-chloro-T-[4-(pyridin-2-yloxy)piperidin-1-yi]4'/7,6'H-spiro[1_;3-dioxo!ane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine] (Example 157) according to the method described in Example 48 and it was used without further purification in the next step.

b) 8-chloro-1-i4-(3-chloropvridin-2-¥i)piperidin-1-yil-5,6-dihydro-4/7-(1,2,4ltriazolo(4.3a] [ 1 lbenzazepin-5-ol

The titie compound was prepared from 8-chloro-1-[4-(3-chloropyridin-2-y!)piperidin1-yi]-4/7-(1., 2,4]triazolo[4_:3-a](1]benzazepin-5(6H)-one (Step a) of Example 181) according to the method described in Exampie 49. MS (ESI) m/z 412.2 (M+H)⁺.

Exampte 182

8-chl0ro-5-methoxy-1-Rrans-4-(4-methvipjperazin-1-vl)cyclohexvn-5,6-dihvdro-4Mri_!2,41triazolor4_Î3-aÎnibenzazep!ne

and

Example 183

8-chloro-5-methoxy-1l-j'cis-4-(4-meth¥lpiperazin-1-vl)cyclohexvn-5,6-dilwdro-4H[1 J,41triazoior4J-alH1benzazepme

O·

The titie compounds were prepared from 7-ch!oro-4-methoxy-1,3,4,5-tetrahydro-2H1-benzazepin-2-one (Step d) of Intermediate 103) and a mixture of c/s-4-(4-methyipiperazin1-yl)cyciohexanecarbohydrazide (intermediate 113) and frans-4-(4-methyipiperazin-1yl)cyclohexanecarbohydrazide (intermediate 114) according to the method described in Example 108. The c/s- and trans isomers were separated by préparative HPLC (Lux

230

Amylose with 1.5pm stationary phase; 150x21.2 mm; F = 22mL/min; eluent: A: water+0.1% TFA, B: acetonitrile+0.1% TFA, gradient: B% 10 —> 90; t-40°C) According to 'HNMR spectroscopy the first fraction (rétention time: 6.6 min) was 8-chloro-5-methoxy-1-[frans-4(4-methylpiperazin-1-yl)cyclohexyl]-5,6-dihydro-4H-[1_i2,4]triazolo[4,3-a][1]benzazepine (Example 182), while the second fraction (rétention time: 8.6 min) was 8-chioro-5-methoxy1-[c/s-4-(4-methylpiperazin-1-yi)cyclohexyl]-5,6-dihydro-4/7-[1,2,4]triazolo[4,3a][1]benzazepine (Example 183). MS (ESI) m/z 430.2 (M-f-H)⁺.

Example 184 B-chloro-S-methoxy-l-M-ÎPYridin-S-ylmethynpyiTOlidin-S-ynAe-dihydro^H[1_;2,4ltriazoio[4,3-ali1lbenzazepÎne

oThe title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1benzazepin-2-one (Step d) of Intermediate 103) and 1-(pyridin-3-ylmethyl)pyrrolidine-3carbohydrazide (Step b) of Intermediate 115) according to the method described in Example 108. MS (ESI) m/z 410.2 (M+H)⁺.

Example 185 8-chloro-5-methoxy-1-n -(pyr!din-2-vimeth¥np¥rrolidin-3-yll-5,6-dihydro-4H[1,2,4ltriazolor4,3-aïï1lbenzazepine

The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1benzazepin-2-one (Step d) of Intermediate 103) and 1-(pyridin-2-ylmethyl)pyrrolidine-3carbohydrazide (Step b) of Intermediate 116) according to the method described in Example 108. MS (ESI) m/z 410.2 (M+H)⁺·

Example 186 /V-{(5/?)-8-chloro-1-rirans-4-(pyridin-2-vioxy)cvclohexvll-5,6-dihydro-4Hn.2,4ltriazoior4,3-aU1lbenzazepin-5-¥ft-2-cvanoacetamide

The title compound was prepared from (5R)-8-chloro-1-[tra/7s-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) and cyanoacetic acid according to the method described in Step a) of Example 10. [a]o°= +32° (c=0.1; methanol); MS (ESI) m/z 477.3 (M+H)⁺.

Example 187 (3-(8-chloro-5-methoxV“5.e-dihvdro-4H-ri,2,4ltriazoÎoF4.3-ainibenzazepin-1vi)Pvrrolid8n-1-vn(pyridin-3-vnmethanone

The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1benzazepin-2-one (Step d) of Intermediate 103) and 1-(pyridin-3-ylcarbonyl)pyrrolidine-3carbohydrazide (Step b) of Intermediate 117) according to the method described in Exampie 108. MS (ESI) m/z 424.2 (M+H)⁺.

Example 188 B'-chloro-T-fl-nS/^MetrahvdrofuramS-ynpiperidin-A-ylM'/ie'H-spiroH.S-dioxolane· 2_t5M1_;2.4ltr1azolor4.3-a1irilbenzazepme

The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'[1,3]dioxolan]-2(3H)-one (Intermediate 53) and 1-[(3R)-tetrahydrofuran-3-yl]piperidine-4carbohydrazide (Step b) of Intermediate 110) according to the method described in Example 108. MS (ESI) m/z 431.2 (M*H)⁺.

Example 189

232 r3~(8-chlor^,a-5-meÎh0xv-5_;G-djhydr0-4/7-n_Î2,41triazGSo[4,3-ainibenzazepsn-1vl)pyrroSidïn-1-vll(pyridin-2-vnmethanone

The titie compound was prepared from 7-chioro-4-methoxy-1,3,4,5-tetrahydro-2H-1benzazepin-2-one (Step d) of Intermediate 103) and 1-(pyridin-2-ylcarbonyl)pyrrolidine-3carbohydrazide (Step d) of Intermediate 118) according to the method described in Example 108. MS (ESI) m/z 424.2 (M+H)⁺.

Exampte 190 irans~4-(8¹-chioro-4¹H.6^,/7-spirori,3-dioxolane-2.5^!-ri,2.41tnazoIoF4,3-airilbenzazepinl10

T-vITM/V-dimethylcyclohexanamme

Under argon to a mixture of 100 mg (0.69 mmol) of 7-chloro-1,5-dihydrospiro[1benzazepine-4,2'-[1,3]dioxolan]-2(3H)-one (Intermediate 53), 10 mL of dichloromethane and 218 mg (1.58 mmol) of K2CO3 117 mg (0.788 mmol) of trimethyloxonium tetrafluoroborate 15 was added. The reaction mixture was stirred at room température for 20 h, then filtered. The filtrate was concentrated and the residue was dissolved in 20 mL of acetonitrile. 39 pL (0.51 mmol) of trifîuoroaœîic acid and 87.6 mg (0.47 mmol) of trans-4(dimethylamino)cyclohexanecarbohydrazide (Intermediate 80) were added and the reaction mixture was stirred at 70°C for 3 h. After concentration the residue was dissolved in 20 dichloromethane and washed with 5% HCl solution. The organic phase was discarded. The pH of the acidic water phase was adjusted to 8 by addition of saturated Na₂CO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO₄, filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane^ethanohammonium hydroxide solution = 180:10:1 as eluent to yield 56 25 mg (35%) of the titie compound. MS (ESI) m/z 403.2 (M+H)⁺.

Example 191 §-chioro-5-methoxv-1-(ΓH,3/7-spiroΓ2-beπzofuΓ¾n-1_ί4''-pjperidml-Γ-vΠ-5,6-dih¥dro-477^,[1,2,41triazoior4,3-aïï1lbenzazepine

233

The titie compound was prepared from 8-chloro-1-(1'H,3/-/-spiro[2-benzofuran-1,4'piperidinj-T-yij-S.e-dihydro-AH-tl^AJtriazolo^^-alEljbenzazepin-S-ol (Exampie 172) according to the method described in Exampie 50. MS (ESi) m/z 437.2 (M+H)T

Exampie 192

8-chtoro-1-F4-(3-chlor0Pvridin-2-vnpiperazin-1-vll-5-methoxy-5,6-dihvdro-4Hn,2,4ltriazoio(4,3-aïï1lbenzazep!ne

The title compound was prepared from 8~chloro-1-[4-(3-chloropyridin-2-yl)pipericlin1-y;]-5,6-dihydra-4H-[1,2_i4]triazoioi4.3-a][1]benzazepin-5--oi (Exampie 173) according to the method described in Example 50. MS (ESI) m/z 445.2 (M+H)⁺.

Example 193 /V-[irans-4-(8'-chioro-4*H,6'H-spirori_Î3-dioxolane-2,5^,-n,2,41tnazotor4,3ainibenzazepjnl-T-vl)cyc8ohexyilpvndin-2-amjne

The titie compound was prepared from 7-chioro-1,5-dihydrospiro[1-benzazepine-4,2'~ [1,3]dioxolan]-2(3/7)-one (Intermediate 53) and frans-4-(pyridin-2-ylamino)cyciohexanecarbohydrazide (Step b) of intermediate 135) according to the method described in Exampie 190. MS (ESI) m/z 452.2 (M+H)⁺.

Example 194

Af4(5R)-8-chtoro-1-Rrana-4-(Pvndin-2-¥ioxv)cyclohexyil-5,6-dÎhydro-4H[1,2,4ltriazoior4,3-aïï1lbenzazepin-5-yi}-M/V-d8methylethane-1,2-diamine

A mixture of 100 mg (0.24 mmol) of (5R)-8-chiorO1[tra/7s-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Exampie 8), 15 mL of ethanoi, 14 pL (0.24 mmol) of acetic acid, 30 mg (0.24 mmol) of 2(dimethylamino)acetaldehyde hydrochloride and 46 mg (0.73 mmol) of sodium cyanoborohydride was stirred at room température for 20 h, then concentrated. The residue was dissolved in saturated NaHCCh solution and extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The residue was purified by fiash column chromatography using dichloromethane:methanoi:ammonium hydroxide solution = 95:5:0.1 as eluent to yield 39 mg (33%) of the titie compound. MS (ESI) m/z 481.3 (M+H)⁺.

Example 195 8-chlDro-1-ftrans-4-fovridin-2-vioxv)cvclahexvll-5,6-djhydro-4H41,2,4ltriazolo[4_;3-

Α mixture of 100 mg (0.24 mmol) of 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]5,6-dihydro-4H-[1,2,4]triazoio[4,3-a][1]benzazepin-5-ol (Example 55), 10 mL of dichloromethane, 23 pL (0.24 mmol) of acetic anhydride and 34 pL (0.24 mmol) of ΤΕΑ was stirred at room température for 24 h, then 23 pL (0.24 mmol) of acetic anhydride and 34 pL (0.24 mmoi) of ΤΕΑ were added and stirring was continued at room température for further 24 h. Then 23 pL (0.24 mmol) of acetic anhydride and 34 pL (0.24 mmol) of ΤΕΑ were added and stirring was continued at room température for further 24 h. The mixture was concentrated and purified by fiash column chromatography using dichloromethane:methanol:ammonium hydroxide solution - 9:1:0.1 as eluent to yield 47 mg (43%) of the title compound. MS (ESI) m/z 453.2 (M+H)⁺.

Exampie 196

2-({(5R)-8-chtoro-1-Ffoans-4-(pyridin-2-vloxy)cvctohexvn-5,6-djhvdro-4Hri,2,41triazoioF4,3-aimbenzazepin-5-vl}amino)ethanol

235

a) (5/?)-/V-[2-(benzyloxy)ethyl]-8-chloro-1-rfrans-4-(pyridin-2-yloxy)cyclohexyll-5,6-dihydro4H-M ,2,41103201014,3-a][1lbenzazepin-5-amine

The title compound was prepared from (5/?)-8-chloro-1-(trans-4-(pyridin-2yioxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) and benzyloxyacetaldehyde according to the method described in Example 194. MS (ESI) m/z 544.3 (M+H)⁺.

b)__________________2-({(5/?)-8-chioro-1-[trans-4-(pvridin-2-yloxv)cyclohexyll-5,6-dihydro-4H[1,2.4ltriazoÎo[4,3-al[1lbenzazepin-5-vl}amino)ethanoi

A mixture of 144 mg (0.26 mmol) of (5R)-/V-(2-(benzy!oxy)ethyl]-8-chloro-1-(frans-4(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1_!2,4]triazolo[4,3-a][1]benzazepin-5-amine (Step a) of Exampie 196) and 30 mL of 6N HCl solution was refiuxed for 1 h, then cooled to room température and the pH of the mixture was adjusted to 7 by addition of saturated Na₂COs solution. The so obtained mixture was extracted with ethyl acetate, the combined organic layers were dried over Na₂SO4, filtered and concentrated. The residue was crystallized with chioroform to yield 53 mg (44%) of the title compound. The mother liquor was purified by flash column chromatography using dichioromethane:methanol - 95:5 as eluent to yield 59 mg (49%) ofthe title compound. MS (ESI) m/z 454.2 (M+H)⁺.

Example 197

8-chloro-5-methoxy-1 -R-lpyridin-S-yloxylpiperidin-l-yn-S.S-dihydro^H[1_i2,4]triazolor4_Î3-a][1]benzazepjne

236

The title compound was prepared from 8-chloro-1-[4-(3-chloropyridin-2-yl)piperidin1-yl]-5,6-dihydro-4H-[1,2,4]triazo!o[4,3-a][1]benzazepin-5-ol (Example 181) according to the method described in Exemple 50. MS (ESI) m/z 426.2 (M+H)⁺.

Example 198 g'-chloro-T-Firans-A-methoxy-A-methvIcvciohexvIM'blS’/l-spiroM.S-dioxolane-S.S'ri,2,41triazolo[4,3-ainibenzazepinel

Under argon to a mixture of 100 mg (0.39 mmol) of 7-chloro-1,5-dihydrospiro[1benzazepine-4,2'-[1.3]dioxolan]-2(3H)-one (Intermediate 53) and 10 mL of dichloromethane 3 pL (0.04 mmol) of trifluoroacetic acid and 70 mg (0.47 mmol) of trimethyloxonium tetrafiuoroborate were added. The reaction mixture was stirred at room température for 20 h, then 147 mg (0.79 mmol) of a 21:79 mixture of c/s-4-methoxy-4methylcyclohexanecarbohydrazide and frans-4-methoxy-4methylcyclohexanecarbohydrazide (Intermediate 119) was added and the reaction mixture was refluxed for 8 h. After concentration the residue was dissolved in 20 mL of 1,4-dioxane and the mixture was refluxed for 6 h, then concentrated. The residue was purified by flash column chromatography using dichloromethane:methanol:ammonium hydroxide solution = 180:10:1 as eluent to yield 82 mg (52%) of the title compound. MS (ESI) m/z 404.1 (M+H)⁺.

Example 199 (gS)-8-chloro-AHcvcloprop¥lmethyn-1-rirans-44pvridin-2-vloxv)cvclohex¥n-5,6dihvdro-4H-F1,2,4ltriazoloF4.3-alF1lbenzazepin-5-amîne

The title compound was prepared from (5S)-8-chloro-1-[tra/7s-4-(pyridin-2yîoxy)cyclohexyl]-5,6-dihydro-4H-[1 ^AltriazolopLS-aHIJbenzazepin-S-amine (Example 7) and cyclopropanecarboxaldehyde according to the method described in Example 24. [αβ°= -28° (c=0.1; methanol); MS (ESI) m/z 464.2 (M+H)⁺.

237

Exampie 200

Λ^{(5Sl·8-chioro-1-Γfr^ans-4-(pyridîπ-2-vioxv)cvclohexvΠ-5_t6-d^hvdro-4H ri.2,4ltriazoloH,3-aïï1lbenzazepin-5-vn-1-methvipiperidine-4-carboxamicie

The title compound was prepared from (5S)-8-chloro-1-[trans-4-(pyridin--2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1 jbenzazepin-5-amine (Example 7) and 1-methylpiperidine 4-carboxylic acid according to the method described in Step a) of Example 10. [αβ°= -31° (c=0.1; methanol); MS (ESI) m/z 535.5 (M+HF.

Exampie 201 /V-((5S)-8-chloro-1-rÿrans-4-(pvridîn-2-vioxv)cYclohexv!l-5_t6-dihydro-4Hf1,2,4ltnazolo[4,3ainibenzazepin-5-v!}-2,2,2-trifluoroacetamide

A mixture of 82 mg (0.2 mmol) of (5S)-8-chloro-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 7), 5 mL of dichloromethane, 73 pL (0.4 mmol) of DIPEA and 55 pL (0.4 mmol) of trifluoroacetic anhydride was stirred at room température for 20 h, then 73 pL (0.4 mmol) of DIPEA and 55 pL (0.4 mmol) of trifluoroacetic anhydride were added and stirring was continued for 3 h. The mixture was diluted with dichloromethane, washed with saturated NaHCOs solution, dried over Na₂SO4, filtered and concentrated to yield 100 mg (99%) of the title compound. [αβ°= -13° (c=0.1; methanol); MS (ESI) m/z 506.2 (M+H)⁺.

Example 202

8-chloro-5-(2-meÎhoxyethoxvM-Rrans~4-(pyridm-2-yl0xy)C¥ciohexvil-5_;8-dihvdro-4Hri,2,41triazoior4,3-ainibenzazepine

238

The titie compound was prepared from 8-chioro-1-[frar?s-4-(pyridin-2yioxy)cyclohexyl]-5,6-dihydro-4/7-[1,2,4]triazoio[4,3-a][1]benzazepin-5-ol (Example 55) and 2-bromoethyl methyl ether according to the method described in Example 50. MS (ESI) m/z 469.4 (M+H)⁺.

Example 203

8-chioro-1-(4-methoxy-4-methyicyclohexvi)-/V-(propan-2-vn-5,6-dihvdro-4H[1,2_;4]triazoio[4,3-airilbenzazepin-5-amirie

a) fert-butyl F8-chioro-1-(4-rnethoxy-4-methvlcvclohexvi)-5,6-dihydro-4H-f1,2,41triazolo[4,3a] i 11benzazepi n-5-yilcarbamate

O

Nî-Soc

The titie compound was prepared from fert-butyi (7-ch!oro-2-thioxo-2,3,4,5tetrahydro-1H-1-benzazepin-4-yl)carbamate (Intermediate 4) and a 21:79 mixture of c/s-4methoxy-4-methyicyclohexanecarbohydrazide and frans-4-methoxy-4methylcyclohexanecarbohydrazide (Intermediate 119) according to the method described in Exampie 1. MS (ESI) m/z 461.4 (M+H)⁺.

b) 8-chloro-1-(4-methoxv-4-methylcyclohexvl)-5,6-dihydro-4H-i1.2,4]triazolo[4.3ali1lbenzazepin-5-amine

239

The title compound was prepared from fert-buty! [8-chloro-1-(4-methoxy-4methylcyclohexyl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl]carbamate (Step a) of Example 203) according to the method described in Example 2 and it was used without further purification in the next step.

ç) 8-chloro-1-(4-methoxv-4-methylcyciohexvl)-/V-Î'propan-2-vl)-5.6-dihydro-4H[1,2.4ltriazolo[4,3-a]nibenzazepin-5-amine

The title compound was prepared from 8-chloro-1-(4-methoxy-4-methylcyclohexyl)5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Step b) of Example 203) according to the method described in Example 24, it was a 8:92 mixture of cis- and transisomers. MS (ESI) m/z 403.2 (M+H)⁺.

Example 204 8’-chioro-T4irans-4-methoxv-4-methvlC¥Ctohexvl)-4'H,6'H-spiron,3-dicxane-2.5'n.2.41iriazolo[4.3-aÎnibenzazepinel

and

Exemple 205

8^,-chloro--T-(c/s-4-methQxv-4-methvic¥ciohexyrj-4¹H,6^ÎH-spirori,3-dioxarie-2.5^!F1,2,4ltriazoior4<3-ainibenzazepÎnel

The title compounds were prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine4,2‘-[1,3]dioxan]-2(3H)-one (Intermediate 98) and a 21:79 mixture of c/s-4-methoxy-4methyicyclohexanecarbohydrazide and frans-4-methoxy-4methylcyclohexanecarbohydrazide (Intermediate 119) according to the method described in Example 198. The cis- and trans- isomers were separated by flash column chromatography using dichloromethane:methanol:ammonium hydroxide solution = 180:10:1 as eluent. According to ’HNMR spectroscopy the first fraction was 8'-chloro-T-(frans-4-methoxy-4methyicyclohexyl)-4'/-<6'/7-spiro[1.3-dioxane-2,5'-[1>2,4]triazolo[4,3-a][1]benzazepine] (Example 204), while the second fraction was 8'-chloro-T-(c/s-4-methoxy-419571

240 methylcyclohexyl)-4'H,6^,H-spiro[1,3-dioxane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine] (Example 205). MS (ESI) m/z 418.2 (M+H)⁺.

Exampie 206

8-chlaro-5-fiu0ro-1-Firans-4-(pvndin-2-vloxv)cvclohexyn-5,6-dihvdro-4H( 1 _!2,41triazoloF4_Î3-air 1Ibenzazepi ne

Under argon a stirred solution of 170 mg (0.41 mmol) of 8-chloro-1-[trans-4-(pyridin2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-ol (Example 55) in 10 mL of dichloromethane was cooied to -78°C and a solution of 147 mg (0.91 mmol) of (diethylamino)sulfur trifluoride in 5 mL of dichloromethane was added. The reaction mixture was allowed to warm to room température over 5 h, then diluted with saturated NaHCOs solution, the phases were separated and water phase was extracted with dichloromethane. The combined organic phases were dried over MgSO₄, filtered and concentrated. The residue was purified by reversed phase flash column chromatography using acetonitriie and 0.1% TFA containing water = 35:65 as eluent to yield 15 mg (9%) of the title compound. MS (ESI) m/z 413.1 (M+H)⁺.

Example 207 §-Ghloro-5-r2-(methvSsulfonvl)ethoxv]-1-rfrans-4-(PYridin-2-vlox¥)cyclohexvn-5,6dihvdro-4H-[1.2.4ltriazoloF4,3--aK1lbenzazepme

The title compound was prepared from 8-chloro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-ol (Example 55) and 1-bromo-2-(methylsulfonyl)ethane according to the method described in Example 50. MS (ESI) m/z 517.1 (M+H)T

Example 208

8-chloro-/V-hvdroxv-1-r&^,ans-4-(P¥ridin-2-vloxv)cvclohexvll-4H-M,2,4ltriazoloF4,3a1F1lbenzazepm-5(6H)-imine

241

A mixture of 100 mg (0.245 mmol) of 8-chloro-1-(frans-4-(pyridin-2-yloxy)cyclohexyl]4/7-(1,2,4]triazolo[4,3-a][1]benzazepin-5(6/7)-one (Example 54), 5 mL of pyridine, 5 mL of methanol and 17 mg (0.245 mmol) of hydroxylamine hydrochloride was refluxed for 3 h, then concentrated. The residue was dissolved in dichloromethane, washed with 5% citric acid solution and water, the organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane:methanol:ammonium hydroxide solution = 180:10:1 as eluent to yield 34 mg (33%) of the title compound. MS (ESI) m/z 424.1 (M+H)⁺.

Exampie 209 (5S)-§-chioro-/V-methvi-Af-Îprop-2-vn-1-viM-r7rans-4-(pvridin-2-vioxv)cvcSohexyil-5,6dÎhvdro-4/7-n.2,41triazoio[4.3-airilbenzazepin-5-amine

A mixture of 43 mg (0.1 mmol) of (5S)-8-chloro-/V-methyl-1-(trans-4-(pyridin-2yloxy)cyciohexyl]-5,6-dihydro-4/7-(1,2,4]triazolo(4,3-a][1]benzazepin-5-amine (Example 78), 5 mL of acetone, 20 pL (0.13 mmol) of 80% propargyl bromide solution in toluene and 42 mg (0.13 mmol) of césium carbonate was stirred at room température for 20 h, then 20 pL (0.13 mmol) of 80% propargyl bromide solution in toluene and 42 mg (0.13 mmol) of césium carbonate were added and stirring was continued for 20 h. The reaction mixture was filtered, the filtrate was concentrated and the residue was purified by column chromatography using dichloromethane:methanol = 9:1 as eluent to yield 30 mg (64%) of the title compound. [αβ°= -22° (c=0.1; methanol); MS (ESI) m/z 462.1 (M+H)⁺.

Example 210 /7-((5S)-8-chloro-1-Rrans-4-(pvridin-2-vioxv)cvciohexvn-5,6-dihydro-4/7i1,2,4ltriazoior4,3-.all'1lbenzazepin-5-vi}-3,3-difjuorocyciobutanecarboxamÎde

The title compound was prepared from (5S)-8-chîoro-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Exampie 7) and 3,3-difluorocyclobutanecarboxyîic acid according to the method described in Step a) of 5 Example 10. [α]|,^ο= -37° (c=0.1; methanol); MS (ESI) m/z 528.2 (M+Hf.

Example 211 8-chlorQ-5--(orop-2-vn-1-vloxv)-1-[frans-4-(pvridin-2-vlGxyicvciohexvn-5,6-dihvdro-4Hf 1,2.41tr8azoloF4,3-ain Ibenzazepi ne

The title compound was prepared from 8-chloro-1-[frans-4-(pyridin-2yloxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-oi (Example 55) and 80% propargyl bromide solution in toluene according to the method described in Example 50. MS (ESI) m/z 449.2 (M+H)⁺.

Example 212 ¹⁵ 8-chloro-1-Firans-4-(pvridin-2-vloxy)cvclohexvn-5,6-dihvciro-4H-F1.,2,4ltriazolor4,3~ alf1lbenzazepin-5-vl 4,4-dîfluorocyclohexanecarboxvlate

Under argon a mixture of 80 mg (0.19 mmol) of 8-chloro-1-[trans-4-(pyridin-2yloxy)cyclohexyi]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-oi (Example 55), 15 mL of dichloromethane, 35 mg (0.21 mmol) of 4.4-difluorocyclohexanecarboxylic acid, 44 mg (0.21 mmol) of A/^’-dicyclohexyîcarbodiimide and 2.4 mg (0.02 mmol) of 4(dimethylamino)pyridine was stirred at room température for 20 h. After compietion of the reaction the mixture was diluted with water, 10% NaHCOs solution and dichloromethane.

243

The phases were separated, the organic phase was dried over MgSCU, filtered and concentrated. The residue was purified by fiash column chromatography using dichloromethane;methanol= 95:5 as eluent to yield 66 mg (61%) of the title compound. MS (ESI) m/z 557.2 (M+H)T

Example 213

8-chlQro-1-Rrans-44Pvridin-2-vloxv)GvclohexvH-5.6-dihvdrO-4H-ri.,2,4lfTiazolor4.3 alFUbenzazepin-5-yl 3,3-difluorocyclobutanecarboxyiate

The title compound was prepared from 8-chloro-1-[frans-4-(pyridin-2yloxyjcyclohexyll-S.e-dihydro^H-n^^triazolopLS-aHIJbenzazepin-S-ol (Example 55) and 3,3-difluorocyclobutane carboxylic acid according to the method described in Example 212. MS (ESI) m/z 529.2 (M+H)⁺.

Example 214 ^-{(5S)-8-chloro-1-Rrans-4-(pyr!din-2-v!oxy)cvciohexvl]-5,6-dih¥dro-4Hri,2,4ltriazoloF4,3-aïï1lbenzazepin-5-vll-4,4-djfluorocvclohexanecarboxamide

The title compound was prepared from (5S)-8-chloro-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and 4,4-difluorocyclohexanecarboxylic acid according to the method described in Step a) of Exampie 10. [αβ°= -34° (c=0.1; methanol); MS (ESI) m/z 556.2 (M+H)T

Exampie 215 8-chloro-1-Rrans-4-(pvridin-2-yloxy)cvclohexvll-15,6-dihvdro-4W-F1,2,4]triazolof4.3ainibenzazepin-5-yl cyanoacetate

The title compound was prepared from 8-chloro-1-[frans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-ol (Example 55) and cyanoacetic acid according to the method described in Example 212. MS (ESI) m/z 478.1 (M+H)⁺.

Exampie 216

8-chloro-14trans-44pyridin-2-vioxy)G¥clohexvn-5.6-dshvdro-4H“F1,2,4'|tnazoloÎ4_l3aïïnbenzazepin-5-yl MAZ-dimethylglycinate

The titie compound was prepared from 8-chloro-1-[trans-4-(pyhdin-2yioxy)cyciohexyl]-5,6-dihydro-4H-[1,2,4]triazoio[4,3-a][1]benzazepin-5-oi (Exampie 55) and /V,/V-dimethylglycine according to the method described in Exampie 212. MS (ESI) m/z 496.2 (M+H)⁺.

Example 217 jV-i(5R)8-chloro-1-rtrans-4-(pyridin-2-¥ioxy)cvclohexvn-5,6-dihydro-4H n,2,41triazolor4_Î3-a]rilbenzazepîn-5-yl}-2,2,2-trifiiioroacetamide

The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2yloxy)cyclohexyi]“5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) according to the method described in Exampie 201. [a]p°= +21°(c=0.1; methanol); MS (ESI) m/z 506.1 (M+H)⁺.

Example 218 1-Fc/s-4-(8-chloro-5-methoxv-5,6-djh¥dro-4H-[L2,4ltriazolo(4,3-aK1lbenzazepjn-1 yncvc8ohexyllpyrrohdin-2-one

245

and

Example 219

1-rtrans-4-(8-chloro-5-methox¥-5.6-dihvdro-4H-ri.2,4ltriazolor4,3-a][1lbenzazepm-1vncycÎohexvnpvrrolidîn-2-one

The title compounds were prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H1-benzazepin-2-one (Step d) of intermediate 103) and 4-(2-oxopyrrolidin-1yl)cyclohexanecarbohydrazide (Intermediate 120) according to the method described in Example 108. The cis- and trans isomers were separated by préparative HPLC (Kinetex EVO C18 with 5pm stationary phase; 150x21.2 mm; F = 20mL/min; eluent: A: water+0.1% TFA, B: acetonitrile+0.1% TFA, gradient: B% 0.6 -> 35; t=40°C) According to ¹HNMR spectroscopy the first fraction (rétention time: 18.5 min) was 1-[c/s-4-(8-chioro-5-methoxy5₎6-d!hydro-4/7-[1,2,4]triazolo[4,3-a][1]benzazepin-1-y!)cyclohexyl]pyrro!idin-2-one (Example 218), while the second fraction (rétention time: 19.2 min) was 1-[frans-4-(8-chioro5-methoxy-5,6-dihydro-4H-[1_i2,4]triazolo[4,3a][1]benzazepin-1-yl)cyclohexyl]pyrrolidin-2one (Example 219). MS (ESI) m/z 415.2 (M+H)⁺.

Exemple 220 /V-{(5R)-8-chloro-1-frrans-4-(pyridm-2-vloxy)c¥clohexvn-5,6-dÎhvdro-4HΠ,2,4l¾riazoloΓ4,3-alr1lbenzazepin-5-¥ll·3,3-difluorocvclobutanecarboxamide

F

The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2ytoxy)cyclohexyi]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 8)

246 and 3,3-difluorocyciobutanecarboxylic acid according to the method described in Step a) of Example 10. [α]θ°= +48° (c=0.1; methanol); MS (ESI) m/z 528.2 (M+H)⁺.

Example 221

Mn5R)-8-chloro-1-Rrans-4-(pvridïn-2-vloxv)cvclohexyn-5.6-djhvdro-4HF1,2,4ltriazoiQF4.3“aïï1lbenzazep8n-5-vlM.4-djfluorocvclohexanecarboxamîde

The titie compound was prepared from (5R)-8-chloro-1-[frans-4-(pyridin-2yioxy)cyciohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) and 4,4-difiuorocyclohexanecarboxylic acid according to the method described in Step a) of Exampie 10. [αβ°= +38° (c=0.1; methanol); MS (ESI) m/z 556.2 (M+H)⁺.

Example 222

8-chloro-5-methoxy-1-[c/s-4-rriethox¥-4-(trifiuorOmeth¥ncyclohex¥n-5,6-dih¥dro-4Hn,2_;4ltrÎazoior4,3-al[1lbenzazepine

The titie compound was prepared from 7-chloro-4-methoxy-1,3_i4_l5-tetrahydro-2H-1benzazepin-2-one (Step d) of intermediate 103) and C7S-4-methoxy-4(trifiuoromethyi)cyciohexanecarbohydrazide (Intermediate 123) according to the method described in Example 108. MS (ESI) m/z 430.2 (M+H)⁺.

Example 223 8-chloro-5-methoxy-1-[trans-4-methoxv-44trifluoromeÎhyl)C¥Clohexyil-5,6-dîhydro-

The titie compound was prepared from 7rohloro-4-methoxy-1,3₅4,5-tetrahydro-2/7-1benzazepin-2-one (Step d) of intermediate 103) and trans-4-methoxy-419571

247 (trifluoromethyl)cyclohexanecarbohydrazide (Intermediate 124) according to the method described in Example 108. MS (ESI) m/z 430.2 (M+H)⁺.

Example 224 (5S)-8-chloro-1-Firans-4-(pvridin-2-vloxv)cvclohexvil-/V-(2,2.2-trîfluoroethvi)-5,6dihydro-4H-F1,2,4ltriazoSor4.3-ainibenzazepin-5-amme αχ., T /N xc ’nh—\.F F ^F

A mixture of 82 mg (0.2 mmol) of (5S)-8-chioro-1-[frans-4-(pyndin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 7), 10 mL of dichloromethane, 190 pL (1.32 mmol) of 2,2,2-trifluoroethyl trifluoromethanesulfonate and 230 pL (1.32 mmol) of DI PEA was stirred at room température for 20 h, then 190 pL (1.32 mmol) of 2,2,2-trifluoroethyl trifluoromethanesulfonate and 230 pL (1.32 mmol) of DIPEA were added and stirring was continued at 40°C for 90 h. The reaction mixture was concentrated and water was added to the residue. The precipitated solid material was filtered off, washed with water and purified by column chromatography using dichloromethane:methanol = 9:1 as eluent to yield 8 mg (8%) of the title compound. MS (ESI) m/z 492.2 (M+H)⁺.

Example 225 fi/-n5S)-8-chloro-1-Rrans-4-(pvridin-2-yloxv)cvcSohexvn-5.6-dihydro-4H[I.SAltriazoloFO-alFIlbenzazepin-S-vfi-S-methvloxeiane-S-carboxamide

The title compound was prepared from (5S)-8-chloro-1-[trans-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and 3-methyioxetane-3-carboxylic acid according to the method described in Step a) of Example 10. [α]θ°= -28° (c=0.1; methanol); MS (ESI) m/z 508.3 (M+H)T

Example 226

AHÎ5ffi-8-Ghloro-1-Firans-4-(pvridïn-2-vloxv)cyciohexvn-5,6-cÎihvciro-4HM,2,41triazoÎoF4,3-airilbenzazepin-5-vn-3-methyloxetane-3-carboxamjde

248

The title compound was prepared from (5R)-8-chloro-1-[fra/?s-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) and 3-methyloxetane-3-carboxylic acid according to the method described in Step a) of Example 10. [αβ^ο= +26° (c=0.1; methanol): MS (ESI) m/z 508.2 (M+H)⁺.

Exampie 227 trans-4-(8'-chtoro-4^,H,6^,H-spîroi1,3-dioxoiane-2.5'-n,2,4ltriazolo[4.3-al[1lbenzazepinlT-yl)JV-(4- methoxybenzyncyclohexanamine

The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'[1,3]dioxolan]-2(3/7)-one (Intermediate 53) and frans-4-[(4-methoxybenzyl)amino]cydohexanecarbohydrazide (Intermediate 125) according to the method described in Example 108. MS (ESI) m/z 495.2 (M+H)⁺·

Example 228 tert-butyl [2-(((5ffl-8-chloro-1-Rrans-4-Îpyridin-2-vloxv)cyclohexvll-5,6-dîhydro-4H[I.SAltriazoiolAS-ainibenzazepin-S-yllaminolethyncarbamate

The title compound was prepared from (5R)-8-chloro-1-[fra/7S-4-(pyridin-2yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2.4]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) and tert-butyl (2-oxoethyl)carbamate according tothe method described in Exampie 190. MS (ESI) m/z 432.2 (M+Hy·

Example 229

249

8^!-chloro-1^,-(trar?s-4-ethoxv-4-e¾hylcvclohexyi)-4Ή,67+sρiro[13-dîoxolane-2_ί5^,F1,2,4ltriazolof4,3-alF1lbenzazepine]

The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'[1,3]dioxolan]-2(3H)-one (Intermediate 53) and fra/?s-4-ethoxy-4-ethylcyclohexanecarbohydrazide (Step c) of Intermediate 126) according to the method described in Example 190. MS (ESI) m/z 432.2 (M+H)⁺·

Exampie 230 ?rans-4-(8^,-chioro-4^,^,6^,^-spiron.3-dîoxoiane-2,5‘-ri,2,4]triazo!o|'4,3-aK1lbenzazepinlT-vl)-/V-(4-methoxvbenzvi)-/V-methyicvclohexanamine

The title compound was prepared from fra/7s-4-(8'-chloro-4'H,6'H-spiro[1_:3-dioxolane2.5'-[1,2,4]triazolo[4_i3-a][1]benzazepin]-T-yl)-A/-(4-methoxybenzyl)-cyclohexanamine (Example 227) according to the method described in Example 101. MS (ESI) m/z 509.2 (M+H)⁺.

Exampie 231 8^,-chloro-T-M-(Pvridin~3-vimethvnpvrroHdjn-3-vil-4^,H6^,H-spiroM,3-dioxoiane-2,5^<ri,2,41triazoio[4,3-.ainibenzazepmel

The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'[1,3]dioxolan]-2(3H)-one (Intermediate 53) and 1-(pyridin-3-ylmethyl)pyrrolidine-3carbohydrazide (Step b) of Intermediate 115) according to the method described in Example 108. MS (ESI) m/z 438.2 (M+HF.

Example 232

250

8-chloro-5-methoxy-1-r4-(pvridin-2-vj)piperazjn-1-yn-5,6-dihydro-4HM^^ltriazolorO-alMlbenzazepine

a) 8-chloro-1-f4-ipyridin-2-vDpiperazin-1-vn-4H-(1,2,4ltriazolo[4,3-aK1]benzazepin-5(6H)one

The titie compound was prepared from 8-chloro-T-[4-(pyridin-2-yl)piperazin-1-yl]4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4_i3-a][1]benzazepinej (Example 171) according to the method described in Example 48. MS (ESI) m/z 395.1 (M+H)⁺.

b)8-chioro-1 -[4-(pyridi n-2-yi)piperazin-1 -yl]-5,6-dihydro-4H-[1,2,4]triazoio[4,3a1F1lbenzazepin-5-ol

The titie compound was prepared from 8-chloro-1-[4-(pyridin-2-yl)piperazin-1-yl]-4H[1,2,4]triazolo[4,3-a][1]benzazepin-5(6H)-one (Step a) of Example 232) according to the method described in Example 49. MS (ESI) m/z 397.2 (M*H)⁺.

c) 8-chioro-5-methoxv-1-[4-(pvrid!n-2-yl)piperazin-1-yll-5,6-dihydro-4H-[1,2,4ltriazolo[4,3a][1lbenzazepine

The titie compound was prepared from 8-chloro-1-[4-(pyridin-2-yl)piperazin-1-yl]-5,6dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-oi (Step b) of Example 232) according to the method described in Example 50. MS (ESI) m/z 411.3 (M+H)⁺.

Example 233

8-chloro-1-(¢ra/îs-4-ethyl·4-me¾hox¥cyclohexyh-Λ/,/V-dîmethv^5,6-dihydro-4Hi~1,2,4ltriazolor4,3-alMlbenzazepin-5-amîne

a)terf-butyl r8-chloro-1-(frans-4-ethyl-4-methoxycycÎohexyl)-5,6-dihydro-4H[1,2,4Hriazolo(4,3-al(1]benzazepin-5-vl]carbamate

The title compound was prepared from fert-butyl (7-chioro-2-oxo-2,3,4,5-tetrahydro1H-1-benzazepin-4-yl)carbamate (Intermediate 5) and 4-ethyl-4-methoxycyclohexanecarbohydrazide (Step b) of Intermediate 127) according to the method described in Method B of Example 5. MS (ESI) m/z 475.3 (M+H)⁺.

b) 8-ch!oro-1-(frans-4-ethyl-4-rnethoxvcvclohexyl)-5,6-dihvdro-4/7-[1,2,4ltriazolo[4,3al(1lbenzazepin-5-amine

The title compound was prepared from ferf-butyl [8-chloro-1-(trans-4-ethyl-4methoxycyc!ohexyl)-5,6-dihydro-4/7-[1,2,41triazolo(4,3-a][1]benzazepin-5-yllcarbamate (Step a) of Example 233) according to the method described in Example 2. MS (ESI) m/z 375.1 (M+H)L

c) 8-chloro-1-(trans-4-ethyl-4-methoxvc¥ciohexvl)-/V,/V-dimethyl-5,6-dihydro-4/7[1,2_;4ltriazolo[4,3-al[1lbenzazepin-5-amine

The title compound was prepared from 8-chioro-1-(irans-4-ethyl-4methoxycyclohexyl)-5,6-dihydro-4/-f-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Step b) of Example 233) according to the method described in Example 101. MS (ESI) m/z 403.3 (M+H)⁺.

Example 234 8-chioΓo-1-{ίraπs-4-e¾hoxv-4-methvlcvciohex¥Π-fy./V-dimethvl·5,6-dihvdro-4Hn,2,4]triazolo(4,3-aimbenzazepin-5-amîne

252

a)tert-butyl[8-c.hloro-1-(Yan.s-4-ethoxv-4-methyicyciohexvi)-5,6-dihydro-4Hf1,2_;4ltriazolo[4,3-aH11benzazepin-5-yl]carbamate

The title compound was prepared from tert-butyl (7-chloro-2-oxo-2,3,4,5-tetrahydro1H-1-benzazepin-4-yl)carbamate (Intermediate 5) and trans-4-ethoxy-4-methylcyclohexanecarbohydrazide (Step b) of Intermediate 128) according to the method described in Method B of Example 5. MS (ESI) m/z 475.3 (M+H)⁺.

b)8-chioro-1-(trans-4-ethoxv-4-methylcyclQhexy!)-5,6-dihydro-4H-i1,2,4lÎriazolo[4,310 alF1lbenzazepin-5-amine

The title compound was prepared from tert-butyl [8-chloro-1-(trans-4-ethoxy-4methylcyclohexyl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl]carbamate (Step a) of Example 234) according to the method described in Example 2. MS (ESI) m/z 375.2 15 (M+H)⁺.

c)8-chloro-1-(trans-4-ethoxy-4-rnethvlcvclohexyl)-A/,A/-dimethyl-5,6-dihydro-4H[1,2,4ltriazolo[4,3-a][1lbenzazepin-5-amine

The title compound was prepared from 8-chloro-1-(frans~4-ethoxy-4methyicyclohexyl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Step b) of 20 Example 234) according to the method described in Exampie 101. MS (ESI) m/z 403.3 (M+H)⁺.

Example 235

8'-chioro-r-[frans-4-methox¥-4-{trÎfiuoromethvi)cvciohexyll-4^,fi6'H-snirof1,3dioxolane^S'-ri^^ltriazoÎor^S-ainibenzazepinel

253

The titie compound was prepared from 7-chioro-1,5-dihydrospiro[1-benzazepine-4,2'[1,3]dioxolan]-2(3H)-one (Intermediate 53) and trans-4-methoxy-4(trifluoromethyl)cyclohexanecarbohydrazide (Intermediate 124) according to the method described in Example 108. MS (ESI) m/z 458.2 (M+H)⁺.

Exampie 236 e’-chioro-T-rc/s-^methoxv^-ttnfÎuoromethvOcvclohexyll-^Ke'H-spirori.Sdsoxoiane-2,5^Î-n_!2,41triazoioF4,3-al[Ubenzazepjnel ^F?^:O..... j ^v—— n—

0Lo -AJ Cl

The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'[1,3]dioxolan]-2(3H)-one (Intermediate 53) and c/s-4-methoxy-4(trifluoromethyl)cyclohexanecarbohydrazide (intermediate 123) according to the method described in Example 108. MS (ESI) m/z 458.2 (M+H)⁺.

Exampie 237

8^ί-chl0ro-Γ-(traΛS-4-ethoxy-4-methvlcvcSohexvΠ-4Ή6^,H-spiroΓ1.3-djoxolane-2.5^,-

The titie compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'[1,3]dioxolan]-2(3H)-one (Intermediate 53) and frans-4-ethoxy-4-methylcyclohexanecarbohydrazide (Step b) of intermediate 128) according to the method described in Exampie 190. MS (ESI) m/z 418.2 (M+H)⁺.

Exampie 238 8^Î-chioro-r-(trans-4-ethoxv-4-propylcvcIohexyll)-4^,H6^,H-spiroF1,3-dÎOxolane-2,5^Îfl^^ltriazoloH.S-airilbenzazepinel

254

/ Cl

The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'[1,3]dioxolan]-2(3H)-one (Intermediate 53) and 4-ethoxy-4-propylcyclohexanecarbohydrazide (Step d) of Intermediate 129) according to the method described in Example 190. MS (ESI) m/z 446.3 (M-f-H)⁺.

Example 239

8^0^0^-1^1-(07^0-2-7^6^71^7^018^-3-711-4^,6^-^^0(1,3-0^0^6-2,5^ ri,2,4ltriazoior4,3-aïï1lbenzazepjne]

The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'[1,3]dioxolan]-2(3H)-one (Intermediate 53) and 1-(pyridin-2-ylmethyl)pyrrolidine-3carbohydrazide (Step b) of Intermediate 116) according to the method described in Example 190. MS (ESI) m/z 438.3 i>H)⁺.

Example 240 8^ί-chloro-T-(cfs-4-ethvl·4-methoxvc7clohexyl)-4^ίH6Ή-spïroΠ,3-dioxolane-2.5'n^^ltriazoloKS-ainibenzazepinel

Cl and

Example 241 §^,-chloro-T-(¢ra/îs-4-ethvl-4-meίhoxvcvc!ohexvΠ-4Ή6W-spiro[1,3-dioxolane-2,5^,ri,2,41triazolor4,3-airT|benzazepmel

255

The title compounds were prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine4,2-(1,3]dioxolan]-2(3H)-one (Intermediate 53) and 4-ethyl-4-methoxycyclohexanecarbohydrazide (Step b) of Intermediate 127) according to the method described in Example 190. The cis and trans isomers were separated by flash column chromatography using dichioromethane:methanol = 9:1 as eluent. MS (ESI) m/z 418.2 (M+H)⁺.

Example 242 β^,-Ghloro-Γ4riaσs-4-metho¾y-4-propylcyclohexyΠ-4^,H,6^,H^^spjrΌΠ,3^djoxolane-2,5^,-

and

Example 243

8^,-chioro-r-(cré-4-methoxv-4-propylcvclohexvi1-4¹/ï,6^,H-spiroi'l,3-dîoxt3iane-2.5¹F1,2,4ltriazolo[4,3-airHbenzazepinel

Cl

The title compounds were prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine4,2'-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and 4-methoxy-4-propylcyciohexanecarbohydrazide (Step b) of intermediate 130) according to the method described in Example 190. The cis and trans isomers were separated by fiash column chromatography using dichloromethane:methanol = 95:5 as eluent. MS (ESI) m/z 432.2 (M+H)⁺.

Example 244

8-chloro-1-(ÿrans-4-ethoxv-4-ethvIcvclohexyi)-AA(propan-2-vl)-5,6-dih¥dro-4H[1,2,4]triazolo[4,3-airi]benzazepÎn-5-amme

n,2,4ltriazolo[4,3-al[11benzazepin-5-yncarbamate

The title compound was prepared from fert-butyl (7-chloro-2-oxo-2,3,4,5-Îetrahydro1H-1-benzazepin-4-yl)carbamate (Intermediate 5) and trans-4-ethoxy-4-ethylcyclohexanecarbohydrazide (Step c) of Intermediate 126) according to the method described in Method B of Example 5. MS (ESI) m/z 489.3 (M+H)⁺.

b)8-chloro-1-(trans-4-ethoxy-4-ethylcyciQhexyl)-5,6-dihYdro-4H-i1.2,4]triazolof4,3alillbenzazepin-5-amine

The title compound was prepared from tert-butyl [8-chloro-1-(trans-4-ethoxy-4ethylcyciohexyl)-5,6-dihydro-4H-[1,2,4]ίπ8ζοΙο[4,3-θ][1 jbenzazepin-5-yl]carbamate (Step a) of Example 244) according to the method described in Example 2. MS (ESI) m/z 389.3 (M+H)⁺.

c)8-chloro-1-(trans-4-ethoxy-4-ethylcyclohexyi)-/V-(propan-2-yl)-5,6-dihydro-4H[1,2.4ltriazoio[4,3-a][11benzazepin-5-amine

The title compound was prepared from 8-chloro-1-(frarîs-4-ethoxy-4-ethylcyclohexyl)S^-dihydro^H-fl^AJtriazoloH.S-aJdbenzazepin-S-amine (Step b) of Example 244) according to the method described in Example 24. MS (ESI) m/z 431.3 (M+H)⁺

Example 245

8-chloro-1-(ÿrans-4-ethox¥-4-ethvlC¥Clohexv0-MAAd8methyl-5,§-djhydro-4HF1,2,4ltn'azolor4,3-airilbenzazep8n-5amîne

The titie compound was prepared from 8-chloro-1-(frans-4-ethoxy-4-ethylcyclohexyi)5,6-dihydro-4H-[1_;2,4]triazoio[4,3-a][1]benzazepin-5-amine (Step b) of Example 244) according to the method described in Example 101. MS (ESI) m/z 417.3 (M+H)⁺.

Example 246 8^Î-chlorod^,-R3R)-14PVi’'idin-2-vimethyl)P¥rrolicilm-3¥Îl-4^,H6W-spirori,3-djoxolarie2,5^,-F1.2,4ltrÎazotor4,3-ainiberizazepinel

The titie compound was prepared from 7-chioro-1,5-dihydrospiro[1-benzazepine-4,2'[1,3]dioxolan]-2(3H)-one (Intermediate 53) and (3R)U-(pyridin4Lylmethyl)pyrroiidine-3carbohydrazide (Step b) of Intermediate 131) according to the method described in Example 190. MS (ESI) m/z 438.1 (M+H)⁺.

Exampîe 247 8rohloro-5-methoxy-1-FF3ffi)-1-(Pvridin-3-ylmethvnp¥rrolidin-3-yll-5_;6-dihydro-4HF1.2.4ltriazoloF4.3-aïï1lbenzazepÎne

The titie compound was prepared from 7-chloro-4-rnethoxy-1,3_>4,5-tetrahydrc-2H-1benzazepin-2-one (Step d) of Intermediate 103) and (3R)-1-(pyridin-3-ylmethyl)pyrrolidine3-carbohydrazide (Step b) of intermediate 133) according to the method described in Example 108. MS (ESI) m/z 410.1 (M+H)⁺.

Example 248 8-chloro-5-methoxv-1-r(3ffl-1-(Pvridin-2-ylmethvnp¥rrolidin-3-vll-5,6-dihydro-4Hn,2,4ltriazoio[4,3-alF1lbenzazepine

The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1benzazepin-2-one (Step d) of Intermediate 103) and (3R)-1-(pyridin-2-ylmethyl)pyrrolidine3-carbohydrazide (Step b) of Intermediate 131) according to the method described in Example 108. MS (ESI) m/z 410.2 (M+H)⁺.

Example 249

S'-chSoro-T-rHSM-fpyridin-S-vSmethvÜpvrrojidiri-S-vi'M'H.S'fcf-spirol'I.S-dioxolaneZ.S’-FLZ^ltriazoioFAS-alfllbenzazepinel

The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'~ [1,3jdioxolan]2(3H)-one (Intermediate 53) and (3S)-1-(pyridin-3-ylmethyl)pyrrolidine-3carbohydrazide (Step b) of Intermediate 134) according to the method described in Example 190. MS (ESI) m/z 438.1 (M+H)⁺.

Exampie 250

8'-chioro-r-F(3R)-1-(pyridin-3-vlmethyl)pyrroiidin-3-yl]-4’/7,6’H-spirori,3-dioxolaneÎ.S’-FU^ltriazoioFAS-airilbenzazepmel

The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'[1,3]dioxo!an]-2(3H)-one (intermediate 53) and (3R)-1-(pyridin-3-ylmethyl)pyrrolidine-3carbohydrazide (Step b) of Intermediate 133) according to the method described in Example 190. MS (ESI) m/z 438.1 (M+H)A

Exampie 251 8-chioro-5-methoxy-1-r(3S)-1-ÎPvridin-3-vlmethyiFpvrrolidin-3-yil-5,6-dîhydro-4/Tf ri,2.41Îriazo8or4,3-alnl»enzazepjne

259

The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1benzazepin-2-one (Step d) of Intermediate 103) and (3S)-1-(pyridin-3-yimethyl)pyrroiidine-3carbohydrazide (Step b) of Intermediate 134) according to the method described in Example 108. MS (ESI) m/z 410.1 (M+H)⁺.

Example 252 8^Î-chioro-r-r(3S)-1(Pvridin-2-vlmethvnpvrrolidÎn-3“Vll-4'H6^,H-spiron.3dioxolane2i5^,-n,2,4]triazoior4!3-alMlbenzazepinel

The title compound was prepared from 7-chioro-1,5-dihydrospiro[1-benzazepine-4,2'[1,3]dioxoian]-2(3H)-one (Intermediate 53) and (3S)-1-(pyridin-2-ylmethyi)pyrrolidine-3carbohydrazide (Step b) of Intermediate 132) according to the method described in Example 190. MS (ESI) m/z 438.1 (M+H)⁺.

Example 253 8-chioro-5-methoxv-1-r(3SM4pvridin-2-vlffîethvhpvrrolidin-3-vll-5,6-dihvdro-4HrLZ^ltriazoloR.B-aïïIlbenzazepine

The title compound was prepared from 7-chloro-4-methoxy-1,3_!4,5-tetrahydro-2H-1benzazepin-2-one (Step d) of intermediate 103) and (3S)-1-(pyridin-2-ylmethyl)pyrrolidine-3carbohydrazide (Step b) of Intermediate 132) according to the method described in Example 108. MS (ESI) m/z 410.1 (M+H)⁺.

260

The following formulation exemples iliustrate représentative pharmaceutical compositions of this invention. The présent invention however is not limited to the following

pharmaceutical compositions.
A) Solid oral dosage forms
I. Tablets
Active substance(s)	0.01 - 90%
Pilier	1 - 99.9%
Binder	0 - 20%
Disintegrant	0 - 20%
Lubricant	0-10%
Other spécifie excipient(s)	0 - 50%
ii. Orodispersible fiims
Active substance(s)	0.01 -90%
Film forming agent	1 - 99.9%
Plasticiser	0 - 40%
Other spécifie excipient(s)	0 - 50%
B) Liquid oral dosage forms
Iii. Orai suspensions
Active substances(s)	0.01 -50%
Liquid vehicle	10 — 99.9%
Wetting agent	0 - 50%
Thickener	0 - 50%
Buffering agent	q.s.
Osmotic agent	0 - 50%
Preservatives	q.s.
IV. Syrups
Active substance(s)	0.01 - 50%
Solvent	10-99.9%
Sugar component	1 - 20%
Fiavouring agents	0-10%

	261
C) Parentéral dosage forms
V. Intravenous injections
Active substance(s)	0.01 - 50%
Solvent	10-99.9%
Co-solvent	0 - 99.9%
Osmotic agent	0 - 50%
Buffering agent	q.s.
D) Other dosage forms
VI. Suppositories
Active substance(s)	0.01 - 50%
Suppository base	1 - 99.9%
Surface-active agents	0 - 20%
Lubricant	0 - 20%
Preservatives	q.s.
VII. Eye drops
Active substance(s)	0.01 - 50%
Water	0 - 99.9%
Solvent	0 - 99.9%
Osmotic agent	0 - 20%
Viscosity enhancer	0 - 20%
Bufferin agent	q.s.
Preservatives	q.s.

Claims

Claims

1. The compound of general formula (I)

wherein ring A is a cycloalkyl or heterocyclyl group;

Y is -O-, -C(O)-, -CH₂-, -NH-, -Ci-₄alkyl-N(R¹⁸)- or bond if ring B is présent; or -N(Ci-₄alkyl)2, C(O)OCi-₄alkyl, Ci.4alkyl optionally substituted with halogen, Ci^alkoxy group or halogen if ring B is not présent;

ring B is an optionally substituted heteroaryl, aryl or heterocyclyl group;

or B-Y-A- jointly represents a 3H-spiro[2-benzofuran-1,4’-piperidin-T-yl]; or

R¹ is a hydrogen, haiogen, Ci.₄alkyl, Ci-₄alkoxy, CF₃ or CN;

R² is a hydrogen or Ci-₄alkyl group;

R³ is a NR⁴R⁵, OR⁶group or halogen;

or R² and R³ jointly represent -O-(CH2)_m-O-, oxo or =N-OH group;

R⁴ and R⁵ is independently a hydrogen; Cq^alkyl optionally substituted with OH, halogen, cycloalkyl, optionally substituted aryl or NR⁸R^S group; Cy·; C(O)R⁷; -S(O2)R¹⁰ or C2-₄alkynyl group;

or R⁴ and R⁵ taken together with the N to which they are attached form a heterocycle;

R⁶ is a hydrogen; Ci-4alkyl optionaliy substituted with OH, halogen, Cy², Ci-4alkoxy, -S(O)₂Ci.₄alkyl or NR¹¹ R¹² group; C(O)R¹³; Si(CH₃)₂-Lbutyl or C₂.₄alkynyl group;

R⁷ is a Ci.4alkyl optionally substituted with OH, CN, halogen, Cy³ or NR¹¹R¹² group; Ci. 4alkoxy, C₂-4alkenyl, Cy³ or N(Ci-₄aikyl)₂ group;

R⁸ and R⁹is independently a hydrogen, Ci.₄alkyl or C(O)OR²¹ group;

R¹⁰ is a Ci.₄alkyl, OH or NR¹⁴R¹⁵ group;

263

R¹¹ and R¹² is independently a hydrogen or Ci.₄alkyl group;

or R¹ ' and R¹² taken together with the N to which they are attached form an optionally substituted heterocycle;

R¹³ is a Ci.₄alkyl optionally substituted with CN or NR^1SR²⁰ group; Cy³ or NR^1SR·⁷ group;

R¹⁴and R·⁵ is independently a hydrogen or Ci-₄alkyl group;

R¹⁶ and R¹⁷ is independently a hydrogen, Ci.₄alkyl, or optionally substituted aryl group;

or R¹⁶ and R¹⁷ taken together with the N to which they are attached form a heterocycle;

R¹⁸ and R²¹ is a hydrogen or Ci.₄alkyl group;

R^1S and R²⁰ is independently a hydrogen or Ci.₄aikyl group;

Cy¹ is an optionally substituted cycloaikyl, heterocyclyl or heteroaryl group;

Cy² is an optionally substituted aryl or cycloaikyl group;

Cy³ is an optinally substituted aryl, cycloaikyl, heterocyclyl or heteroaryl group;

X is a Ci.₄alkyl, aryl or heteroaryl group;

Z is a C-Malkyl group;

m is 2, 3, 4 or 5 and/or salts thereof and/or géométrie isomers thereof and/or stereoisomers thereof and/or enantiomers thereof and/or racemates thereof and/or diastereomers thereof and/or biologically active métabolites thereof and/or prodrugs thereof and/or solvatés thereof and/or hydrates thereof and/or polymorphe thereof.
2. The compound according to claim 1, wherein R¹ is a hydrogen, fluorine, chiorine, bromine, methyl, methoxy, CF3 or CN.
3. The compound according to any of ciaims 1 to 2, wherein ring A is a 3- to 6-membered saturated carbocyclic group or a 4- to 7-membered saturated heterocycle containing 1 or 2 N;

ring B is an optionally substituted 6- or 5-membered mono-heteroaryl group, 6- to 10membered aromatic carbocycle, or 4- to 7-membered saturated, monocyclic, bicyclic, fused and/or bridged heterocycle containing 1, 2 or 3 heteroatoms selected from O, S or N;

or B-Y-A- jointly represents a 3H-spiro[2-benzofuran-1,4’-piperidin-T-yl]; or

OO

V VxP /—⁰/~9

11 ilII group; or group; or group; X is isopropyl group;

Z is methyl group.

264
4. The compound according to any of daims 1 to 3, wherein ring B is an optionally substituted 6-membered mono-heteroaryl group, or 5- to 6-membered saturated, monocyclic heterocycle containing 1 or 2 heteroatoms selected from O, S or N.
5. The compound according to any of daims 1 to 4, wherein Y is -O-, -C(O)-, -CH₂-, -NH-, -Ci.4alkyl-N(R¹⁸)- or a single bond if ring B is présent and R¹⁸ is hydrogen or methyl group.
6. The compound according to any of daims 1 to 5, wherein ring A is a 4- to 6-membered saturated carbocyclic group or a 4- to 7-membered saturated heterocyde containing 1 or 2 N attachée! via a ring nitrogen to Y or to the triazole ring of the 5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepine core.
7. The compound according to any of daims 1 to 6, wherein ring A is cyclohexyl, Y is O-, ring B is pyridin-2-yl and R¹ is chlorine.
8. The compound according to any of daims 1 to 6, wherein ring A is piperidine, piperazine, or pyrrolidine, Y is -O-, -C(O)-, -CH2-, or a single bond, ring B is pyridine, piperidine, tetrahydrofuran, or tetrahydropyran, and R¹ is chlorine.
9. The compound according to any of daims 1 to 3, wherein Y is -N(Ci^.alkyl)₂, C(O)OCwalkyl, Ci.4alkyl optionally substituted with halogen, Ci.4aikoxy group or halogen and ring B is not présent.
10. The compound according to daim 9, wherein ring A is a 4- to 6-membered saturated carbocyclic group.
11. The compound according to claim 10, wherein Y is one group selected from the group consisting of -N(Ci-4alkyl)₂, C(O)OCi.₄alkyl, Ci^alkyl optionally substituted with halogen, CMalkoxy group and halogen.
12. The compound according to daim 10, wherein Y is two groups selected from the group consisting of Ci^alkyl optionally substituted with halogen, Cwalkoxy group and halogen.
13. The compound according to any of daims 1 to 12, wherein

R² is a hydrogen or Ci.₄alkyl group;

R³ is a NR⁴R^S group;

265

R⁴ and R⁵ is independently a hydrogen; Ci-4aîkyl optionally substituted with OH, halogen, cycloalkyl, optionally substituted aryl or NR⁸R^S group; Cy¹; C(O)R⁷; -S(O2)R’° or C2-₄alkynyl group;

or R⁴ and R⁵ taken together with the N to which they are attached form a heterocycie;

R⁷ is a Ci.4alkyl optionally substituted with OH, CN, halogen, Cy³ or NR”R¹² group; Ci. 4alkoxy, C2-₄alkenyl, Cy³ or N(Ci-₄alkyl)₂ group;

R⁸and R^sis independently hydrogen, Ci-₄alkyl orC(O)OR²’ group;

R¹⁰ is a Ci.₄alkyl, OH or NR¹⁴R¹⁵ group;

R¹¹ and R¹² is independently a hydrogen or Ci.₄alkyl group;

or R¹¹ and R¹² taken together with the N to which they are attached form an optionally substituted heterocycie;

R¹⁴and R¹⁸ is independently a hydrogen or Ci.₄alkyl group;

R²¹ is a hydrogen or C^alkyl group;

Cy’ is an optionally substituted cycloalkyl, heterocyclyl or heteroaryl group;

Cy³ is an optionally substituted aryl, cycloalkyl, heterocyclyl or heteroaryl group.
14. The compound according to claim 13, wherein R² is a hydrogen.
15. The compound according to claim 14, wherein

R⁴ and R⁵is independently a hydrogen; C(O)R⁷; Ci.4alkyl optionally substituted with OH, halogen, cycloalkyl, optionally substituted aryl or NR^SR⁹ group; R⁸ and R^eis independently hydrogen or Ci-4alkyl group.
16. The compound according to daim 15, wherein R⁴ and R⁵ are hydrogens.
17. The compound according to claim 15, wherein R⁴ is a hydrogen, R^s is a Ci.₄alkyl group.
18. The compound according to daim 15, wherein R⁴ and R⁵ are Ci.₄alkyl groups.
19. The compound according to claim 15, wherein

R⁴ is a hydrogen;

R⁵ is a C(O)R⁷ group;

R⁷ is a Ci.4alkyl optionally substituted with OH, CN, halogen, Cy³ or NR”R¹² group; Ci. 4alkoxy, C₂.₄alkenyl, Cy³ or N(Ci-₄alky!)₂ group;

R” and R¹² is independently a hydrogen or Ci.₄alkyl group;

or R” and R’² taken together with the N to which they are attached form an optionally substituted heterocycie;

266

Cy³ is an optionally substituted aryl, cycloalkyl, heterocyclyl or heteroaryl group.
20. The compound according to claim 14, wherein R⁴ is a hydrogen, R⁵ is a Cy¹ and Cy¹is an optionally substituted cycloalkyl, heterocyclyl or heteroaryl group.
21. The compound according to claim 14, wherein

5 R⁴ is a hydrogen or CiMalkyl group;

R⁵ is a S(O2)R¹⁰group;

R¹⁰ is a CiMalkyl, OH or NR¹⁴R¹⁵ group;

R¹⁴ and R¹⁵ is independently a hydrogen or Ci-4alkyl group.
22. The compound according to claim 14, wherein R⁴ and R⁵ taken together with the N to 10 which they are attached form a 4- to 7-membered heterocycle containing optionally 1, 2 or 3 heteroatoms selected from O, S or N.
23. The compound according to any of claims 1 to 12, wherein

R² is a hydrogen or Cmalkyl group;

R³ is an OR⁶ group;

15 R⁶ is a hydrogen; CiMalkyl group optionally substituted with OH, halogen, Cy², Ci-4aikoxy, S(O)2-Ci-4alkyl or NR¹¹R¹²group; C(O)R¹³, Si(CH3)2-f-butyl or C^alkynyl group;

R¹¹ and R¹² is independently a hydrogen or CiMalkyl group;

or R¹¹ and R¹² taken together with the N to which they are attached form an optionally substituted heterocycle;

20 R¹³ is a Ci.₄alkyl group optionally substituted with CN or NR¹⁹R²⁰ group; Cy³ or

NR¹⁶R¹⁷ group;

R¹⁶and R¹⁷ is independently a hydrogen, CiMalkyl or optionally substituted aryl group;

or R^1S and R¹⁷ taken together with the N to which they are attached form a heterocycle;

R¹⁹ and R²⁰is independently a hydrogen or CiMalkyl group;

25 Cy² is an optionally substituted aryl or cycloalkyl group.
24. The compound according to claim 23, wherein R² is a hydrogen.
25. The compound according to claim 24, wherein R^s is a hydrogen.
26. The compound according to daim 24, wherein R⁶ is a CiMalkyl group.
27. The compound according to daim 24, wherein

30 R⁶ is a C(O)R¹³ group;

267

R¹³ is a Ci^aikyl group optionally substituted with CN or NR¹⁹R²⁰ group; Cy³ or NR¹⁶R¹⁷ group;

R¹⁶ and R¹⁷ is independently a hydrogen, Ci.4aîkyl or optionaliy substituted aryl group;

or R¹⁶ and R¹⁷ taken together with the N to which they are attached form a heterocycle;

5 R¹⁹ and R²⁰is independently a hydrogen or Ci-4alkyl group.
28. The compound according to any of claims 13 to 27, wherein the absolute configuration of the carbon at position 5 in the 5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepine core is (R).
29. The compound according to any of claims 13 to 27, wherein the absolute 10 configuration of the carbon at position 5 in the 5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepine core is (S).
30. The compound according to any of daims 1 to 12, wherein R² and R³ jointly represent -O-(CH₂)_m-O-, oxo or =N-OH group, m is 2, 3, 4 or 5.
31. The compound according to claim 30, wherein R² and R³ jointly represent -0-(CH₂)m15 O- and m is 2.
32. The compound according to any of daims 1 to 31, wherein the compound is selected from the group consisting of:

fert-butyl [8-chtoro-1-[1-(pyridin-2-yl)piperidin-4-yl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-yl] carbamate,

20 8-chloro-1-[1-(pyridin-2-yl)piperidin-4-yl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepine-5-amine, /V-[8-chloro-[1-(pyridin-2-y!)piperidin-4-yl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1jbenzazepin-5-yi]acetamide, /V-(8-chloro-[1-(pyridin-2-yl)piperidin-4-yl]-5,6-dihydro~4H-[1,2,4]triazolo[4,325 a][1]benzazepin-5-yl)-2-methyîpropanamide, terf-butyl {8-chloro-1-[frai7s-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a]benzazepine-5-yl]carbamate,

8-chloro-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydfO-4H-[1,2,4]triazolo[4,3a][1]benzazepine-5-amine,

268 (5S)-8-chloro-1-[frar;s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1jbenzazepine-5-amine, (5/7)-8-ch!oro-1-[frans-4-(pyridin-2-yloxy)cyc!ohexyl]-5,6-dihydro-4H-[1_!2,4]triazoio[4,3a][1]benzazepine-5-amine,

5 /V-{8Chloro-1-[frans-4-(pyridin-2-y!oxy)cyclohexyl]-5_i6-d!hydro-4H-[1,2,4]triazolo[4,3a] [ 1 ] benzazepi n- 5-y l}acetam ide, /V-{8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3al[1]benzazepin-5-yl}glycinamide, /V-{(5S)-8-chloro-1-[ffaf7s-4-(pyridin-2-yloxy)cyclohexyi]-5,6-dihydro-4H-[1,2_:4]triazolo[4_!3w a][1]benzazepin-5-yl}glycinamide, /V-{(5R)-8-ch!oro-1-[frans-4-(pyrîdin-2-y!oxy)cyc!ohexyl]-5_>6-dihydro-4/7-[1_i2,4]triazolo[4,3a][1]benzazepin-5-yl}glycinamide, (2S)-2-amino-A/-{(5R)-8-chloro-1-[trans-4-(pyridin-2-yioxy)cyciohexyl]-5,6-dihydro-4/7“ [1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}-2-phenyiacetamide,

15 (2R)-2-amino-A/-{(5R)-8-chloro-1-[frans-4-(pyridin-2-yioxy)cyc!ohexyi]-5,6-d!hydro-4H[1,2_!4]triazolo[4,3-al[1]benzazepin-5-yl}-2-phenylacetamide, /V-{8-chloro-1-[/ra/7s-4-(pyridin-2-yloxy)cyclohexyi]-5,6-dihydro-4H-[1_:2,4]iriazolo[4,3a][1]benzazepin-5-yl}-2-hydroxyaœtamide,

3-{8-chloro-1-[frans-4-(pyridin-2-yioxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,320 a][1]benzazepÎn-5-yl}1J-dimethylurea, /V{8-chioro-1-[frans-4-(pyridin-2-ytoxy)cyclohexyl]-5_>6-dihydro-4H-[1_!2,4]triazoio[4,3 aKIJbenzazepin-S-yQ-^.AF-dimethyiglycinamide, /V-{8Ch!oro-1-[frans-4-(pyridin-2-yloxy)cyc!ohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3al[1]benzazepin-5-y!}methanesulfonamide_:

25 /V-{8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyi]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1jbenzazepin-5-yi}-/V-methylmethanensulfonamîde,

A/'-{8-ch!oro-1-[frans-4-(pyridin-2-yloxy)cyctohexyl]-5,6-dihydro-4/T^f-[1,2,4]triazolo[4_!3a][1]benzazepin-5-y!}-/V,/V-dÎmethylsu!famîde,

8-ch!oro-A/-methyl-1-[lrans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4//-[1,2,4]triazolo[4,330 a][1]benzazepine-5-amine,

263

8-chioro-A/,/V-dimethyl-1-(tra/7s-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H[1,2,4]triazolo[4,3-aH1]benzazepfne-5-amine,

8-chloro-Λ/-ethyl·1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazep!ne-5*amine,

8-chîoro-/V-(propan-2-yi)-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H[1,2,4]triazoio[4,3-a][1]benzazepine-5-amine, (5S)-8rehloroW-(propan-2-yl)-T(frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine, (5R)-8-chloroW-(propan-2-yl)-1-[frans-4-(pyridin-2-yloxy)cyciohexyr|-5,6-dihydro-4H(1,2,4]triazolo[4,3-a][1]benzazepine-5-amine,

8rohloro-A/-cydobutyl-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5_>6-dihydro-4H(1,2,4]triazolo[4,3-a][1]benzazepine-5-amine,

8rohloroW-(oxetan-3-yi)-1-[frans-4-(pyridin-2-yioxy)cyciohexyl]-5,6-dihydro-4H[1,2,4]triazoio[4,3-a][1]benzazepine5-amine,

8-chloro-1-[frans-4-(pyridîn-2-yîoxy)cydohexyi]-/V-(tetrahydro-2H-pyrar!-4-yi)-5,6“dihydro4/7-[1,2,4]triazoîo(4,3-a][1]benzazepine-5-amine,

8-chioro-/V-(4_>4-difluorcydohexyl)-1-[trans-4-(pyridin-2-y!oxy)cydohexyi]-5,6-dihydro-4H[l^^triazoloH.S-aHljbenzazepine-ô-amîne,

8-rnethoxy-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a] [ 1 ]benzazepi ne-5-am ine hydrochl ori de,

8-methoxyW-(propan-2-yi)-14frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4/7[1,2,4]triazolo[4,3-a](1]benzazepine-5-amine, fert-butyl {1-[frans-4-(pyridin-2-yloxy)cydohexyn8-(trifluoromethy!)-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl}carbamate,

1-[tra/?s-4-(pyndïn-2-yloxy)cyclohexyi]-8-(trifluoromethyl)-5,6-dihydro-4/7-[1,2,4]triazolo[4,3a][1]benzazepine-5-amine hydrochloride, /V,/V-dimethyl-1-(frans-4-(pyridin-2-yloxy)cydohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H[1,2,4]Îriazoio(4,3-a][1]benzazepine-5-amine,

A/-(propan-2-yl)-1-[frans-4-(pyridin-2-yloxy)cydohexyl]--8-(trifluoromethyl)-5,6-dihydro-4H[1,2,4]Îriazolo[4,3-a][1]benzazepine-5-am!ne,

270

8-methyM-[frans-4-(pyridin-2-yioxy)cyc!ohexyi]-5,6-dihydro-4H-[1,2,4]triazo!o[4,3a][1]benzazepine-5-amine,

8-methyl-/V-(propan-2-yl)-1-[frans-4-(pyridin~2-y!oxy)cyctohexyn-5,6-dihydrci-4H[1,2,4]triazoto[4,3-a][1]benzazepine-5-amine,

5 8-bromo-1-[frans-4-(pyrid!n-2-yloxy)cyclohexyn-5,6-dihydro-4/-/-[1,2,4]triazolo[4,3a][1]benzazepine-5-amine,

8-bromo-A/-(propan-2-yl)-1-[tfans-4-(pyridin-2-yloxy)cyclGhexyl]-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine,

8-chloro-1-(3_:3-difluorocyclobutyl)-/V-(propan-2-yl)-5_l6-dihydro-4/-/-[1,2,4]triazolo[4,310 a][1]benzazepine-5-amine,

8-chloro-1-(4,4-difluorocyclohexy!)-A/-(propan-2-y!)-5,6-dihydro-4H-[1,2,4]triazolo[4_!3aJjllbenzazepine-S-amine,

8-0ή!0Γ01-[ίΓ3η5-4-(ίΓϊίΙυ0Γ0ΠΊθ1ή¥Ϊ)0¥0ΐ0ή©χγΙ]-5,6-άίήγάΓ0-4Η-[1_:2,4]ΐΓί3Ζ0ΐ0[4,3a][1]benzazepine-5-amine,

15 8-chioro-A/-(propan-2-yl)-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H[1,2,4]tr!azolo[4_:3-a][1]berizazepine--5-arri!ne.

8-bromo-1-[trans-4-(trifiuoromethyi)cyclohexyl]-5,6-dihydro-4H-[1_l2,4]triazolo[4_:3a][1]benzazepine-5-amine,

8-bromo-/V-(propan-2-yO-1-[frans-4-(trifuoîOmethyl)cyclohexyî]-5,6-dihydro-4H20 [1,2,4]triazdo[4,3-a][1]benzazepine-5-amine,

T-[frans-4-(pyridin-2-yloxy)cyclohexyl]-8'-(trifluoromethyO-4'H,6'H-spiro[1,3-dioxolane-2,5'[1,2,4]triazolo[4,3-a][1]benzazepine],

1-[frarts-4~(pyndin-2-yloxy)cyclohexy!]-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5(6H)-one,

25 1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[1,2,4]triazolo[4_:3a][1]benzazepin-5-ol,

5-methoxy-1-[trar?s-4-(pyridin-2-yloxy)cyc!ohexyl]-8-(trifluoromethy0-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepine,

5-(cyclopropylmethoxy)-1-[trans-4-(pyndin-2-yioxy)cyciohexyÎ]-8-(trifluoromethyi)-5,630 dihydro-4H-[1,2,4]triazolo[4_:3-a][1]benzazepine,

271

5-{[feiT-buty!(dimethyl)siiyl]oxy}-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro4H-[1,2,4]triazolo[4,3-a][1]benzazepine,

8'-chtoro-T-[frans-4-(pyridin-2-yloxy)cyclohexyl]-4'H,6'/7-spiro[1,3-dioxolane-2,5‘[1,2,4]triazolo[4,3-a][1]benzazepine],

5 8-chioro-1-[frans-4-(pyridin-2-yloxy)cyc!ohexyi]-4H-[1,2,4]triazoio[4,3-a][1]benzazepin5(6H)-one,

8-ch!oro-1-[frans-4-(pyridin-2-yloxy)cyclohexyi]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a] [1 jbenzazepi n-5-ol, (5S)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyc!ohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,310 a][1]benzazepin-5-oi, (5R)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-ol,

8-chloro-5methoxy-1-[frans-4-(pyridin-2-yloxy)cydohexyi]-5,6-dihydr(>-4H[I^AJtriazolo^.S-alilJbenzazepine,

15 5-(cyclopropyimethoxy)-8-chloro-1-[frans-4-(pyndin-2-yioxy)cyclohexyl]-5,6-dihydro-4/7[1,2,4]triazolo[4,3-a][1]benzazepine,

2-({8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5₎6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-y!}oxy)-A/,/V-dimethylethanamine,

8'-chloro-T-[frans-4-(trifluoromethyl)cydohexyn-4'H_!6'H-spiro[1,3-dioxolane-2,5‘20 [1 ^Ajtriazolo^.S-aHljbenzazepine],

8'-bromo-T-[frans-4-(pyridin-2-yloxy)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane-2,5'[1,2_:4]triazolo[4,3-a][1]benzazepine],

1'-[trans-4-(pyridin-2-yloxy)cyc!ohexyn-4^,H_i6'r/-spiroi1,3-dioxoÎarie-2,5'41,2,4jiriezolo[4,3a][1]benzazepine],

25 8-bromo-1-[fraas-4-(pyridin-2-yloxy)cydohexyl]-4H-[1,2,4]tnazolo[4,3-a][1]benzazepin5(6H)-one,

8-bromo-1-[frans-4-(pyridin-2-yloxy)cyclohexyi]-5,6-dihydro-4H-[1,2,4]triazoto[4,3a] [ 1 ] benzaze pi n-5-o I,

T-[frans-4-(pyr!din-2-yioxy)cyciohexyi]-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2_:4]triazolo[4,330 aKIJbenzazepinJ-S'-carbonitrile,

272 (5S)-8-chtoro-/V,A/-dimethyl-1-[frans-4-(pyridin-2-yloxy)cyciohexyi]-5,6-d!hydro-4/7[1,2,4]triazolo[4,3-a][1]benzazepine-5-amîne, (5S)-A/-{8-chloro-1-[frans-4-(pyridin-2-yioxy)cyclohexyl]-5,6-dihydro-4/7-[1,2_!4]tr!azolo[4,3a][1]benzazepin-5-yl}acetamide,

5 8'-chloro-14frans-4-(pyridin-2-ylmethyi)cyc!ohexyl]-4'/7,6’/7-spiro[1,3-dioxolane-2_i5‘[1,2,4]triazo!o[4,3-a][1]benzazepine], [frans-4-(8'-chioro-4^,H,6'H-spÈfo[1,3-dioxoiane-2_!5'-[1.2,4]triazolo[4_:3-a][1]benzazepine]-1’yl)cyclohexyl](pyrrolidin-1-yl)methanone,

8-ch!oro-1-[frans-4-(trifluoromethyl)cyclohexyl]-4H-[1,2,4]triazoto[4,3-a][1]benzazepinw 5(6H)-one,

8-chloro-1-[frans-4-(trifluoromethyi)cyctohexyi]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a] [ 1 ]benzazepin-5~oi, (c/s)-8-(8'-chioro-4W6'H-spiro[1,3-dioxolane-2,5^;41,2,4]triazoio[4,3-a][1]benzazepin]-1'-yi)·3-methyl-1-oxa-3-azaspiro[4.5]decan-2-one_:

15 8-chloro-5-methoxy-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4/7[1,2_l4]triazolo[4,3-aj|[1]benzazepine_l (frar/5j-8-(8-chlûro-4'H,67“/-spiro[1_l3-d!Oxoiane-2,5'-[1,2_!4]tnazolo[4,3-a][1]benz8zepin]-Tyl)-3-methyl-1-oxa-3-azaspiro[4.5]decan-2-one,

A/-{(5S)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2_!4]tr!azolo[4,320 a][1]benzazepin-5-yl}-/V-methylmethanesuifonamide, (5S)-8-chloro-/V-ethyl-1-ifrans-4-(pyridin-2-yloxy)cyclohexyl]-5_i6-dihydrO4/7 [1,2,4]ίΠ3ζοΙο[4,3-3][1]όθηζ3ζθρίηθ·-5-3Γηίηθ, (5S)-8-chloro-/V-methyi-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H[l^^ltriazolo^.S-aKIJbenzazepine-S-amine,

25 8'-chloro-1'-[1-(pyrimidin-2-y!)azetidin-3-yl]-4'H,6'/7-spiro[1,3-dioxolarie-2_!5'[I^^Jtriazolo^S-aHIlbenzazepine], /V-{(5S)-8-chloro-1-[frans-4-(pyridin-2-yioxy)cydohexyi]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-yl}-4-fluorobenzamide,

8'-bromo-T-[irans-4-(trifiLioromethyl)cyclohexyl]-4'H,6’H-spiro[1,3-dioxolane-2,5^!30 [1,2,4]triazolo[4,3-aH1]benzazepine],

273

5-(propan-2-ylamino)-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H[1,2,4]triazolo[4,3-a](1]benzazepin-8-carbonitrile trifluoroacetate, (5S)-8-chloro-A/-(4-fluorobenzyl)-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H(1,2,4]triazolo[4,3-a][1]benzazepine-5-amine,

5 1 ’-[fra/?s-4-(trifluoromethyl)cyclohexyl]-4’H,6’HSpiro[1,3-dioxolane-2,5’-(1,2,4]triazolo(4,3a][1]benzazepine]-8^:-carbonitrîle, ifrar?s-4-(8^!-bromo-4'H,6'H-spiro[1,3-dioxoiarie-2,5'-(1,2,4lt.riazoloi4,3-a][1]benz8zepin]-1'yl)cyclohexyl](piperidin-1-yl)methanone, methyl f/ans-4-(8-bromo-5-oxo-5,6-dihydro-4H-[1,2,4]triazolo[4_:3-a][1]benzazepin-110 yi)cyclohexane carboxilate,

8-bromo-1-[traas-4-(piperidfn-1-ylcarbony!)cyclohexyl]-4H-(1,2,4]triazolo[4,3a][1]benzazepin-5(6H)-one,

8'-chloro-T-[frans-4-(trifluoromethyl)cyclohexyl]-4'H,6'H-spiro[1,3-dîoxane-2,5'[1,2,4]ίΓΪ3ζοΐο[4,3-3][1]όΘηζ3ΖΘρίηβ],

15 1'-[frans-4-(piperidin-1-ylcarbonyi)cyclohexyl]-4'H,6'/7-spiro[1,3-dioxolane-2,5'[1,2,4]triazolo[4,3-a](1]benzazepin]-8'-carbonîtnle,

8’-chloro-1'-[frans-4-(pyridÎn-2-yloxy)cyclohexyl]-4^!H,6’H-spiro[1,3-dioxane-2_;5'[ 1,2,4]triazo I o[4,3-a][ 1 ] benzazepi n e],

8-bromo-1-[frans-4-(trifiuoromethyl)cyclohexyl]-4H-[1,2,4]triazolo[4,3-a][1]benzazepin20 5(6H)-one, [frans-4-(8-bromo-5~hydroxy-5_i6-d!hydro-4/-f-[1,2,4]triazolo[4,3a][1]benzazepin-1yl)cyclohexyl](piperidin-1-yl)methanone,

8-bromo-1-[frans-4-(trifiuoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,4^132010(4,3a][1]benzazepin-5-ol,

25 1'-(1,4'-bfpiperidin-T-yl)-8'-chloro-4'H,6‘H-spiro[1,3-dÎOxolane-2,5'-[1,2,4]tnazolo[4,3a](1]benzazepine], te/t-butyl (1-(1_;4^,-bip:peridiri-1^,-yÎ)-8--chlorc>-5_l6-dihydro-4h'-[1_?2,4jtriazoio[4,3

a][1]benzazepin-5-yl]carbamate,

8'-fluoro-T-[frans-4-(pyridÎn-2-yloxy)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane~2,5'30 (1,2,4]triazolo(4,3-a][1]benzazepine],

274 (5S)-8-ch!oro-/V-(4-fluorobenzyl)-A/-methy!-1-[frans-4-(pyridin-2-yioxy)cydohexyi]-5,6dihydro-4/7-[1_i2,4]triazo!o[4,3-a][1]benzazepin-5-amine, /V-{(5S)-8-chioro-1-[fra/?s-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4f7-[1,2,4]Îriazolo[4,3a][1]benzazepin-5-yl}prop-2-enamide, (5R)-8-chloro-/V-ethyl-1-[t/ans-4-(pyridin-2-yloxy)cydohexyi]-5,6-dihydro-4/-/[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine, (5/?)-8-chloro-/V-methyi-1-[trans-4-(pyridin-2-yloxy)cydohexyi]-5,6-dihydro-4/7[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine, (5R)-8-chloro-A/,A/-dimethyl-1-[trans-4-(pyridin-2-yioxy)cydohexyl]-5,6-dihydra-4H[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine,

1-[frans-4-(pyridin-2-yloxy)cydohexyl]-4H-[1,2,4]triazo!o[4,3-a][1]benzazepin-5(6H)-one, (5S)-8-ddoro-5-methoxy-1-[frans-4-(pyridin-2-y!oxy)cydohexyi]-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepine, (5R)-8-ddoro-5-rnethoxy-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro--4/-/[1,2,4]tn azd o [4,3-aJ [ 1 ] benzaze pi n e,

8-chloro-5-(propan-2-yloxy)-1-[trans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepine,

8'-chloro-1'-[frans-4-(pyridin-2-yloxy)cydohexy!]-4'H,6^,H-spiro[1,3-dioxepane-2,5^>[ 1,2,4]tri azoi o [4,3-a] [ 1 ] benzazepi n e],

1-[frans-4-(pyridin-2-yioxy)cydohexyi]-5_:6-dihydro-4W-[1,2,4]triazoio[4,3-a][1]benzazepin-5ol, [ffans-4-(8‘-chloro-4’H,6'H-spiro[1,3-dioxo!ane-2,5’-[1,2,4]triazolo[4,3-a][1]benzazepin]-ryl)cyciohexyl](morphoHn-4y!)methanone

5-methoxy-1-[t/ians-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepine,

S-fhjoro-1-ÎtYar/s-4-(pyridri-2-yÎoxy)cydohexyl]-4H-[1,2,4jtriazoto[4,3-a][1]benz.azepin5(6H)-one,

8-fiuora-1-[irans-4-(pyridin-2-yiOxy)cydohexy!]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-oi, tert-butyi {8-chioro-1~[trans-4-(morphoiin-4-yi)cydohexyl]-5,6-dihydro-4/-f-[1,2,4]triazolo[4,3a] [ 1 ] benzazepi n- 5-y !}carbama te,

275

8-chioro-1-[irans-4-(morphoHrx4-yl)cydohexyl]-5_:6-dihydro-4/7-[1,2,4]triazolo^ a][1]benzazepin-5-amine,

8-chloro-1-[frans-4-(morphoiin-4-yi)cyclohexyl]-/V-(propan-2-yl)-5,6-dihydro-4H[1,2,4]triazoio[4,3-aï[1]benzazepin-5-arnine,

5 (Sr.SrLS-CS'-chloro-THO'H-spiraFI.S-dioxoiane-^.S'-fl^Ajtnazolo^^-ajjllbenzazepinl-l’yl)-2-(propan-2-yl)-2-azaspiro[4.5]decan-1-one_! (5r,8r)-8-(8-chloro-5-hydroxy-5,6-dihydro-4H41,2,4]Îriazolo[4,3-a][1]berizazepin-1-yl)-2(propan-2-yi)-2-azaspiro[4.5]decan-1-one, (5S)-8-chloro-1-[frans-4-(pyridin-2-yioxy)cydohexyl]-5-(pyrrolid!n-1-yl)-5_:6-dihydro-4H10 [1,2,4]triazolo[4,3-a][1]benzazepine, /V-{(5S)-8-chloro-1-[trans-4-(pyridin-2-ytoxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazo!o[4,3a][1]benzazepin-5-yl}-2,2-dimethylpropanamide, /V-{(5S)-8-chloro-1-[frans-4-(pyridin-2-yioxy)cyciohexyi]-5,6-dihydro-4H-[1,2,4]triazolo[4_i3aj[1]benzazepin-5-yl}cydopropanecarboxamide,

15 A/-{(5S)-8-chtoro-1-[tra/7s-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H-[1,2,4jtriazolo[4_!3a][1]benzazepin-5-yl}-2-methylpropanamide,

A/-{(5Sy8-chloro-1-[frans-4-(pyridin-2-yloxy)cydohexy!]-5,6-dihydro-4H-[1,2_!4]triazoio[4,3a][1]benzazepin-5-yl}cydobutanecarboxamide, (5S)-8-cNoro-5-(morpholin-4-yl)-1-[trans-4-(pyridin-2-y!oxy)cyciohexy!]-5,6-dihydro-4/720 [1,2,4]triazolo[4,3-a][1]benzazepine, /V-{(5/?)-8-chloro-1-[irans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepiri-5-yl}-2,2-dimethylprOpanamide,

A/{(5R)-8-chloro~1-[franS”4-(pyridin-2-yloxy)cydohexyi]-5,6-dihydro-4/7-[1,2,4]triazolo[4_!3a][1]benzazepin-5-yÎ}-2-methylpropanamide,

25 A/-{(5R)-8-ch!oro-1-[trans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4_!3a][1]benzazepin-5-yl}cydobutanecarboxamide,

A/-{(5R)-8-chloro-1-[irans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H-[1_i2,4]triazoÎo[4_:3a][1jbenzazepin-5-y!}cydopropanecarboxamide, (5S)-8-chtoro-5-(piperidin-1-yl)-1-[frans-4-(pyridin-2-yioxy)cydohexyi]-5,6-dihydro-4/-A30 [1,2,4]ίΓί3ΖθΙθ[4,3-3][1]0ΘΠΖ3ΖΘρίηθ,

276 (5S)-/V-(butan-2-yl)-8-chloro-1-[(rans-4-(pyridin-2-yloxy)cyc!ohexyl]-5,6-dihydro-4H[1,2,4]triazoio[4,3-al[1]benzazep!n-5-amine, (5s_;8sj-8-(8^,-ch!oro-4^,.H,ô'h'-spiro[1_I3-d!Oxoiane-2,5'-[1,2,4jtriazolo[4_l3-a][1jbenz.az.ep!ri]-Tyl)-2-(propan-2-yi)-2-azaspiro[4.5]decan-1-one,

5 8-chloro-5-methoxy-1-[1rans-4-(morphoiin-4-yi)cyclohexy!]-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepine,

8-chloro-5-ethoxy-1-[frens-4-(pyridin-2-yioxy)cyciohexy!]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepine, (5F?)-8-chloro-5-methoxy-1-[frens-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H10 [1,2,4]triazol o [4,3-a] [ 1 ] benzaze pi n e, (5S)-8-ch!oro-5-methoxy-1-[f/ans-4-(trifluoromethyi)cyclohexyi]-5,6-dihydro-4H[1,2,4]Îriazolo[4,3-a][1[benzazepine,

8-fluoro-5-methoxy-1-[fra/?s-4-(pyridin-2-yloxy)cyclohexyl[-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepine,

15 8-chioro-/V-(propan-2-yl)-1-[1-(pyridiri-2-yi)piperidin-4-yl]-5,6-dihydro-4H-[1,2,4]triazoio[4,3a][1]benzazepin-5-amine,

2-({8-chioro-1-[frans-4-(pyridin-2-yioxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-yi}oxy)ethanol, (5S)-8-ch!oro-A/,A/-diethyl-1-[frans-4-(pyridin-2-yloxy)cyclohexy!]-5,6-dihydro-4A/20 [1,2,4]triazolo[4,3-a][1]benzazepin-5-amine,

8-chioro-/V-methyl-A/-(propan-2-yl)-1-[franS'-4-(pyrid!n-2-yloxy)cyciohexyl]-5,6-dihydro-4/-i^f[1,2,4]triazoîo[4,3-aj[1]benzazepin-5-amine, tert-butyl {8-chioro-1-[4-(3-ch!oropyridin-2-yl)piperazin-1-yi]-5,6-dihydro-4/7[1,2,4]triazoio[4,3-a][1]benzazepin-5-yl}carbamate,

25 tefr-butyl 4-(8-ch!oro-5-methoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1yl)piperidine-1-ca rboxy ΐ a te,

A/-{(5R)-8-chloro-1-[fzans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazo!o[4,3a][1]benzazepin-5-yl}-D-valinamide, fert-butyi {1^rens-4-(pyridin-2-yioxy)cyciohexyn“5,6-dihydro-4H-[1,2_!4]triazoio[4,330 a][1]benzazepin-5-y!}carbamate,

277 teri-butyl {8-fluoro-1-[frans-4-(pyridin-2-yioxy)cydohexyl]-5,6-dihydro-4H-[1_i2,4]triazoio[4,3a][1]benzazepin-5-yl}carbamate,

1-[fre/7s-4-(pyridin-2-yioxy)cyclohexyi]-5_!6-dihydro-4H-[1,2,4]triazoio[4,3-a][1]benzazepin-5amine,

5 84luoroU-!frans-4-(pyr!din-2-yioxy)cydohexyn-5,6to!hydro-4/-L[1,2,4jtriszolo[4,3a][1]benzazepin-5-amine,

8-f!uoro-/V-(propan-2-yi)-1-[trans-4-(pyridin-2-yloxy)cydohexyl]-5_!6-dihydro-4H[1,2_:4]triazo!o[4,3-a][1]benzazepin-5-amine,

8-fluoro-/V,A/-dimethyl-1-[frans-4-(pyridin-2-yloxy)cyc!ohexyl]-5_!6-dihydro-4W10 [l^^triazolo^S-ajlIjbenzazepin-S-amine, /V,A/-dimethyl-1-[frans-4-(pyridin-2-yioxy)cydohexyl]-5,6-dfhydro-4H-[1,2,4]tnazo!o[4,3a][1]benzazepin-5-amine,

8'-fluoro-1’-[frans-4-(trifluoromethyi)cydohexyl]-4'H,6'H-spiro[1,3-dioxolane-2,5'[1,2,4]triazoio[4,3-a][1]benzazepine],

15 A/-(propan-2-yl)-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6~dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-amine,

A/-{(5S)-8-chloroU-[frans-4-(pyridin-2-yioxy)cydohexyi]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-y!}tetrahydro-2H-pyran-4-carboxamide,

A/-{(5S)-8-chioro-1-[trans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,320 a][1]benzazepin-5-yl}-2-methyibutanamide, /V-{(5S)-8-chioro-1-[trans-4-(pyridin-2-yloxy)cydohexyi]-5,6-dihydro~4H-[1,2_i4]triazolo[4,3~ ajlIlbenzazepin-S-yll-^./^-dimethyl-p-aianinamide, (5S)-8-chloro-/V-cyciopentyl-1-[fra/-}s-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4/-iⁱ[1,2,4]triazoio[4,3-a][1]benzazepin-5-amine,

25 8'-chioro-T-(TH,3H-spira[2-benzofuran-1,4'-piperidin]-T-yl)-4’H,6’H-spiro[1,3-dioxoiane2,5'-[ 1,2,4]triazolo[4,3-a][1 Jbenzazepi ne],

8-chiQro-1-(TH,3H-spiro[2-benzofuran-1,4'-piperidin]-T-yÎ)-4H-[1,2,4]tnazolo[4_;3a][1]benzazepin-5(6H)-one,

8'-chioro-T-[4-(pyridin-2-y!oxy)piperidin-1-yi]-4'H,6'H-spiro[1,3-dioxolane-2,5'30 [1,2,4]triazolo[4,3-a][1]benzazepine],

278 /V-{(5S)-8-chioro-1-[frans-4-(pyridin-2-y!oxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazoio[4,3a][1]benzazepin-5-yl}-2,2-d!methylbutanamide, /V-{(5S)-8~chloro-1-[frans-4-(pyridin-2-y!oxy)cydohexyn-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-y!}-2-hydroxy-2-methylpropanamide,

5 (5S)-8-chioro-/V-ethy!-/V-methyl-1-[trans-4-(pyridin-2-y!oxy)cydohexyl]-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepin-5-amfne, (5S)-8-chloro-/V-(2-methy!propyi)-1-[frans-4-(pyridin-2-y!oxy)cyclohexyl]-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine,

8'-chioro-T-[f/ans-4-(ΠΊOΓphoiin-4-yl)cydohexyl]-4Ή,6Ή-spίΓo[1,3-dioxolane-2,5^,10 [1,2,4]triazolo[4,3-a][1]benzazepine] hydrochloride,

8-Ghloro-/V,/V-dimethyl-1-(rH,3H-spiro[2-benzofuran-1,4'-piperidin]-1‘-yl)-5,6-dihydro-4H[1,2,4]triazoio[4,3-a][1]benzazepin-5-amine,

8'-ch!oro-T-[4-(3-chloropyridin-2-yl)piperazin-1-yi]-4'H,6'H-spiro[1,3-dioxoiane-2,5'[1,2,4]triazoi o[4,3-a] [ 1 ] benzaze pi n e],

15 (5S)-8-chloro-/V-(2,2-dimethylpropyi)-1-[irans-4-(pyridin-2-yioxy)cyclohexyi]-5,6-dihydro-4H[1,2,4]triazoio[4,3-a][1]benzazepin-5-amine, [frans-4-(8-chloro-5-methoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1y!)cyclohexyi](4-methylpiperazin-1-yl)methanone, (5R)-8-chloro-5-(morpholin-4-yl)-1-[irans-4-(pyridin-2-yloxy)cydohexyi]-5,6-dihydro-4H20 [1,2,4]triazolo[4,3-a][1]benzazepine, /V-{(5f?)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cydohexyi]-5,6-dihydro-4H-[1,2_l4]triazolo[4,3a][1]benzazepin-5~yl}acetamide,

A/-{(5R)-8-chÎoro-1-[frans-4-(pyridin-2-yioxy)cydohexyÎ]-5,6-dihydro-4/7-[1_>2,4]tr!azolo[4,3a][1]benzazepin-5-yi}-2-hydroxy-2-methylpropanamide,

25 8-chloro-5-methoxy-1-[1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl]-5,6-dihydro-4HÎI.S^triazolQ^S-aKIlbenzazepina

8'-chloro-T-[4-(pyridin-2-yl)piperazin-1-yl]-4'/-/,6'H-spiro[1,3-dioxolane-2,5‘[ 1,2,4]triazol o[4,3-a][ 1 ] benzaze pi n e],

S-chloro-l-CTH^H-spirop-benzofuran-I.A'-piperidinET-yrFS.e-dihydro-AH30 [1,2,4]triazoio[4,3-a][1]benzazepin-5-ol,

279

8-chloro-1-[4-(3-chloropyridin-2-yi)piperidin-1-yn-5,6-dihydro-4H-[1,2,4]triazolo[4_;3a][1]benzazepin-5-ol, (5R)-8-chioro-1-[irans-4-(pyridin-2-yloxy)cyclohexyi]-5-(pyrro!idin-1-yl)-5,6-dihydro-4H[1,2,4]ίΠ3ζοΙο[4,3-a](1]benzazepine,

8-chloro-5-methoxy-1-{1-((3S)-telrahydrofuran-3-yi]piperidin-4-yl}-5,6-dihydro-4H[1,2,4]triazoio[4,3-a](1]benzazepine, (5R)-8-fluoro-5-methoxy-1-[f/ans-4-(pyridin-2-yloxy)cyclohexyl]-5₎6-dihydro-4.H[1,2,4]tnazolo[4,3-a](1]benzazepine, (5S)-8-fluoro-5-methoxy-1-[frans-4-(pyridin-2-yioxy)cydohexylj-5,6-dihydfO-4H[1,2,4111^010(4,3-3)(1 ]benzazepine,

8-chloro-5-methoxy-1-{1-[(3R)-tetrahydrofuran-3-yl)piperidin-4-yl}-5_l6-dihydro-4H[1,2,4]triazolo[4,3-a](1]benzazepine, /V-{(5R)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyn-5,6-dihydro-4H-[1,2,4]triazoio(4,3aKljbenzazepin-S-yll-AP^-dimethyl-p-alaninamide,

A/-{(5R)-8-chioro-1-(irans-4-(pyridin-2-yloxy)cyclohexy!]-5,6-dihydro-4H-(1,2,4]triazolo(4,3a][1]benzazepin-5-yl}tetrahydro-2H-pyran-4-carboxamide,

8-chloro-1-[4-(pyridin-2-yloxy)piperidfn-1-yl]-5,6-d!hydro-4H-[1,2_;4]triazolo[4,3a][1]benzazepin-5-ol,

8-chioro-5-methoxy-1-[frai7s-4-(4-melhylpiperazin-1-yl)cydohexyl]-5,6-dihydro-4H[1,2,4]1Π3ΖθΙθ[4,3-3][1]0ΘΠΖ3Ζθρ!ΠΘ,

8-chloro-5-methoxy-1-[C7S-4-(4-methylpiperazin-1-yl)cyclohexyl]-5,6-dihydro-4H[1,2,4]triazolo(4,3-a](1]benzazepine,

8-chloro-5-methoxy-1-[1-(pyridin-3-ylmethyl)pyrroiidin-3-yi]-5,6-dihydro-4H[1,2,4]triazolo(4,3-a](1]benzazepine,

8-chloro-5-melhoxy-1-[1-(pyrid!n-2-ylmethy0pyrroiidin-3-yi]-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepine, /V-{(5R)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyi]-5,6-dihydro-4H-[1,2,4]tnazolo[4,3a][1]benzazepin-5-yi}-2-cyanoacetamide_! [3-(8-chloro-5-methoxy-5,6-dihydro-4H-(1,2_l4]triazolo[4,3-a][1]benzazepin-1-yl)pyrrolidin-1yl](pyridin-3-yi)methanone,

280

8’-ch!oro-T-{1-[(3/x)-tetrahydrofuran-3-yl]piperidin-4-yl}-4'H,6'H-spiro[1,3-dioxolane-2,5'[1,2,4]triazolo[4,3-a][1jbenzazepine], [3-(8-chloro-5-methoxy-5,6-dihydro-4H-[1,2_l4]triazolo[4,3-a][1]benzazepin-1-yi)pyrrolidin-1yl](pyridin-2-yl)methanone,

5 trans-4-(8'-chtoro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepin]-T-yl)Λ/,/V-dimethylcyclohexanamine,

8-chloro-5-methoxy-1-(TH,3H-spiro[2-benzofuran-1,4'-piperidin]-T-yl)-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepine,

8-chloro-1-[4-(3-chloropyridin-2-yl)piperazin-1-yi]-5-methoxy-5,6-dihydro-4H1 o [1,2,4]triazolo[4,3-a][1]benzazepine,

A/-[tra/?s-4-(8'-ch!oro-4'H_l6'H-spiro[1,3-dioxolane-2,5'-[1,2_l4]triazolo[4,3-a][1]benzazepin]-Ty!)cyclohexyl]pyridin-2-amine, /V’-{(5R)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyciohexyl]-5,6-dihydro-4H-[1_!2,4]triazoio[4,3 a][1]benzazepin-5-yl}-/V,A/-dimethylethane-1,2-diamine,

15 8-chioro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-yl acetate,

2-({(5R)-8-chloro-1-[frans-4-(pyrid!n-2-y!oxy)cyclohexyl]-5,6-dfhydro-4H-[1,2,4]triazoio[4,3a][1]benzazepin-5-yl}amino)ethanoL

8-chloro-5-methoxy-1-[4-(pyridin-2-yloxy)piperidin-1-yl]-5,6-dihydro-4H-[1,2,4]tnazo!o[4,320 a][1]benzazepine,

8'-chloro-T~(trans-4-methoxy-4-methylcyclohexyi)-4'H_î6'/-/-spiro[1,3-dioxolane-2,5'[1,2,4]triazolo[4,3-aH1]benzazepine], (5S)-8-chloro-/V-(cyclopropyimethyl)-1-[f.rans-4-(pyridin-2-yioxy)cyclohexyl]-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine,

25 A/-{(5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-yl}-1-methylpipendine-4-carboxamide, /V-{(5S)-8-chiaro-1-[rrans-4-(pyridin-2-ytoxy)cyclohexy!]-5,6-dihydro-4H-[1,2,4]triazolo[4,3s][1]benzazepin-5-yi}-2,2,2-trifîuoroacetamide,

8-chloro-5-(2-methoxyethoxy)-1-[trans-4-(pyrid!n-2-yioxy)cyclohexyl]'-5_!6-dihydΓO-4h^,30 [1,2,4]triazolo[4,3-a][1]benzazepine,

281

8-chloro-1-(4-methoxy-4-methylcydohexyl)-/V-(propan-2-yl)-5,6-dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine,

8'-chloro-T-(frans-4-methoxy-4-methyicydohexyl)-4'/7,6‘H-sp!ro[1,3-dioxane-2,5'[l^^jtriazolo^.S-aHfibenzazepine],

5 8'-chioro-T-(c/s-4-methoxy-4-methylcydohexy!)-4'H,6'H-sp!ro[1,3-dioxane-2,5'[1,2,4]triazo lo[4,3-a] [ 1 ] benzazepi n e],

8-ch!oro-5-fluoro-1-[frans~4-(pyrid!n-2-yloxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepine,

8-chloro-5-[2-(methy!su!fony!)eîhoxy]-1-[frans-4-(pyridin-2-y!oxy)cydohexyl]-5,6-dihydro-4H10 [1,2,4]triazdo[4,3-a][1]benzazapine,

8-chloro-/V-hydroxy-1-[frans-4-(pyridin-2-yloxy)cydohexy!]-4H-[1,2,4^037010(4,3aKIlbenzazepin-SCSHI-imine, (5S)-8-chloro-/V-methyl-/V-(prop-2-yn-1-yl)-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6dihydro-4/7-[1,2,4]triazolo[4_;3-a][1 ]benzazepin-5-amine,

15 /V-{(5S)-8-chioro-1-[fraz?s-4-(pyridin-2-yloxy)cydohexy!]-5,6-d!hydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-yl}-3,3-difluorocydobutanecarboxamide,

8-chloro-5~(prop-2-yn-1-yloxy)-1-[fra/?s-4-(pyridin-2-yloxy)cydohexyl]-5,6-d!hydro-4/7[1,2,4]tr!azolo[4,3-aH1]benzazepine,

8-do!oro-1-[trans-4-(pyrid!n-2-yloxy)cydohexyi]-5,6-dihydro-4H-[1,2,4]triazolo[4,320 a][1]benzazepin-5-yi 4,4-difluorocyclohexanecarboxylate,

8-chloro-1-[frans-4-(pyodin-2-yloxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazoio[4,3a][1]benzazepin-5-yl 3,3-difluorocydobufanecarboxylate,

A/-{(5S)-8-ch!oro-1-[f/ans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazoio[4,3a][1]benzazepin-5-yl}-4,4-difiuorocydohexanecarboxamide,

25 8-chloro-1-[irans-4-(pyridin-2-y!oxy)cydohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-yl cyanoaœtate,

8-chioro-1-[irans-4-(pyridin-2-yloxy)cydohexy!]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-yi A/,/V-dimethyig!ydnate, /V-{(5R)-8-chioro-1-[fra/7s-4-(pyridin-2-yloxy)cydohexyn-5,6-dihydro-4H-[1,2,4]toazolo[4,330 aHIlbenzazepin-S-yll^^^-trifluoroacetamide,

282

1-[c/s-4-(8-chloro-5-methoxy-5,6-dihydro-4H-(1,2,4]triazolo[4,3-al(1lbenzazepin-1yl)cyc!ohexyl]pyrrolidin-2-one,

1-[frans-4-(8-ch!oro-5-methoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1lbenzazepin-1yl)cyclohexyl]pyrroiidin-2-one,

5 /V“{(5R)-8-ch!oro-1[trans-4-(pyndin-2-yloxy)cyclohexyi]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-yl}-3,3“difiuorocyclobutanecarboxamide, /V-{(5R)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyciohexyÎ]-5,6-dihydro-4H-[1,2,4]triazolo[4,3a][1]benzazepin-5-y!}-4_!4-difluorocyciohexanecarboxamide_;

8-chloro-5-methoxy-1-[c/s-4-methoxy-4-(trifluoromethy!)cyciohexyl]-5,6-dihydro-4H1 o [1 ^Xltriazolo^.S-aHIJbenzazepine,

8-chloro-5-methoxy-1-[ffans-4-methoxy-4-(trifluoromethyi)cyclohexyl]-5,6-dihydro-4/7[1,2,4]triazolo(4,3-a][1]benzazepine, (5S)-8-chtoro-1-[frans-4-(pyridin-2-yloxy)cydohexyi]-A/-(2,2,2-trifiuoroeihyl)-5,6-dihydro-4H[1,2,4]triazolo(4,3-a][1]benzazepfn-5-amine,

15 /V-{(5S)-8-chioro-1-[frans-4-(pyridin-2-yioxy)cyclohexyl]-5,6-d!hydro-4H-(1,2,4ltriazolo[4,3al[1]benzazepin-5-y!}-3-methyloxetane-3-carboxamide,

A/-{(5R)-8-chloro-1-(irans-4-(pyndin-2-yloxy)cycÎohexyll-5,6-dihydro-4H-[1,2,4}tnazolo[4,3al(1lbenzazepin-5-yl}-3-methyloxetane-3-carboxamide, frans-4-(8'-chloro-4^l/7,6'/7-spiro(1,3-dioxolane-2,5'-(1_!2,4]triazolo[4,3-a][1]benzazep!n]-T-yl)20 A/(4-methoxybenzyl)cyclohexanamine, tert-butyl [2-({(5R)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyll-5,6-dihydro-4H[1,2,4]triazoio[4,3-a][1lbenzazepin-5-yl}amino)ethyi]carbamaÎe,

8'-chloro-T-(frans-4-ethoxy-4-ethyicyclohexyl)-4'H,6'/7Spiro(1,3-dioxoiane-2,5'[1,2,4]triazoto[4,3-al(1]benzazepine],

25 trans-4-(8'-chloro-4'A7,6'/7-spiro[1,3-dioxolane-2,5'-[1_:2,4]triazolo(4,3-al[1lbenzazepinl-T-yl)A/-(4-methoxybenzy!)-A/-methyicyclohexanamine,

8'-chioro-T-[1-(pyrid!n-3-yÎrnethy!)pyrrolid!n-3-yii-4'H,677-spiro[1,3-dioxolane-2,5'[1,2,4]Îriazoio[4,3-a][1]benzazepine],

8-chloro- 5- rnethoxy-1-[4-(pyridin-2-yl)piperazin-1-y!]-5,6-dihydro-4H-(1,2,4]triazolo[4,330 al(1lbenzazepine,

283

8-chloro-1-(trans-4-ethyi-4-methoxycyclohexyi)-/V,A/-dimethy!-5,6-dihydro-4H[1,2.4]triazo!o[4_:3-aH1 ]benzazepin-5-amine,

8-diioro-1-(f/ans-4-ethoxy-4-methylcydohexyl)-/V,/V-dimethyi-5,6-dihydro-4H[1,2,4]triazolo[4_!3-a][1]benzazepin-5amine,

5 8'-chiora-T-[trans-4-methoxy-4-(Îrifluoromethyl)cydohexyl]-4'/7,6'H-spiro[1,3-dsoxolane”2,5’ [1,2,4]triazolo[4,3-a][1]benzazepine],

8'-chloro-T-[c/s-4-methoxy-4-(trifiuoromethyl)cydohexyl]-4'H,6'H-spiro[1,3-dioxolane-2,5'[1,2,4]triazolo[4,3-a][1]benzazepine],

8'-ch!oro-T-(frans-4-ethoxy-4-methyicydohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'1 o [1 ^AJtriazolo^S-aHIJbenzazepine],

8'-chloro-r-(tra/7S-4-ethoxy-4-propyicydohexyl)-4'/7,6'H-spiro[1,3-dioxolane-2,5'[ 1,2,4]triazo lo[4,3- a] [ 1 ] benzazepi ne],

8'-ch!oro-14Hpyrîdin~2-yîmethyi)pyrrolidin3-yî]-4'H,6'H-spiro[1,3-dioxolane-2,5'[1,2,4]triazolo[4,3-a][1]benzazepine],

15 8'-chloro-T-(c/s-4-ethy!-4-methoxycydohexyl)-4'H_!6'H-spiro[1,3-dioxolane-2,5'[1,2,4]triazolo[4_:3-a][1]benzazepine],

8'-chloro-T-(trans-4-ethyl-4-methoxycyciohexyl)-4^,H,6'H-spiro[1,3-dioxolane-2,5’[1,2,4]triazolo[4,3-a][1]benzazepine],

8'-chioro-T-(frans-4-methoxy-4-propylcydohexyl)-4'H,6'H-spiro[1,3-dioxoiane-2,5'20 [1,2,4]triazdo[4,3-a][1]benzazepine],

8'-chloro-T-(c/s-4-methoxy-4-propylcydohexyi)-4'/7_i6'H-spiro[1,3-dioxoiane-2,5'[1,2,4]tnazolo[4,3-aH1]benzazepine],

8-chioro-1-(frans-4-ethoxy-4-ethylcydohexyl)-A/-(propan-2-y!)-5,6-dihydro-4/7[I^^Jtriazoîo^S-aJfljbenzazepin-S-amine,

25 8-chloro-1-(irans-4-ethoxy-4-ethylcydohexyl)-/V,A/-dimethyl-5_!6-dihydro-4/7[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine,

8'-chloro-T-[(3i^c?)-1-(pyridin-2-ylmethyl)pyrroÎidin-3-yn-4^!r<6'H-spiro[1,3-dioxO!ane-2,5’[1,2,4]tri azo lo[4,3- a] [ 1 ] benzazepi n e],

8-chloro-5-meÎhoxy-1-[(3R)-1-(pyrid!n-3-ylmethyl)pyrrolidin-3-yl]-5,6-dihydro-4H30 [1 ^^Jtriazolo^S-aHftbenzazepine,

284

8-chioro-5-methoxy-1-[(3R)-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl]-5,6-dihydro-4H[1,2,4]triazolo[4,3-a](1]benzazepine,

8'-chloro-T-[(3S)-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-4'H,6'H-spiro[1,3-dioxolane-2,5'[1,2,4]triazoio[4,3-al[1]benzazepine],

5 8'-chioro-T-[(3R)-1-(pyridin-3-ylmethyi)pyrroiidin-3-yI]-4'H,6'H-spiro(1,3-dioxolane-2,5'[1,2,4]triazoio[4,3-a](1]benzazepine],

8-chloro-5-methoxy-1-[(3S)-1-(pyridin-3-ylmethyl)pyrroiidin-3-yl]-5,6~dihydro-4H[1,2,4]triazolo[4,3-a][1]benzazepine,

8^l-chÎoro-T-[(3S)-1-(pyridin-2-yimethyl)pyr'roHdin-3-yn-4‘/-/_>6‘/7-spiro[1,3-dioxolane-2_r510 (1,2,4]triazolo(4,3-a][1]benzazepine] and

8-ch!oro-5-methoxy-1-[(3S)-1-(pyridin-2-yimethyl)pyrrolidin-3-yl]-5,6-dihydro-4H(1,2,4]triazolo(4,3-a][1]benzazepine.
33. A pharmaceuticai composition comprising therapeutically effective amount of a compound of general formula (I) and/or sait thereof and/or géométrie isomer thereof and/or 15 stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or biologically active métabolite thereof and/or prodrug thereof and/or soivate thereof and/or hydrate thereof and/or polymorph thereof according to any of daims 1 to 32 as active substance and a pharmaceuticaily acceptable excipient.
34. A combinational composition comprising therapeutically effective amount of a 20 compound of general formula (i) and/or sait thereof and/or géométrie isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or biologicaily active métabolite thereof and/or prodrug thereof and/or soivate thereof and/or hydrate thereof and/or poiymorph thereof according to any of daims 1 to 32 and one or more other active substances.

25
35. The combinationai composition according to claim 34, wherein the one or more other active substances are selected from the group consisting of psycholeptics, psychoanaleptics, antihypertensives, spasmolytics, antiepiieptics or other agents.
36. The composition of any of daims 33 to 35 for use in the treatment and/or prophylaxie of a disease or condition associated with the centrai and/or peripheral antagonisation of V1a 30 receptor.

285
37. A process for the préparation of a pharmaceutical composition having V1a receptor antagonist activity comprising a therapeutically effective amount of a compound of general formula (I) and/or sait thereof and/or géométrie isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or biologically active métabolite thereof and/or prodrug thereof and/or solvaté thereof and/or hydrate thereof and/or polymorph thereof according to any of daims 1 to 32 as active substance with pharmaceutically acceptable excipients.
38. The compound of general formula (I) and/or sait thereof and/or géométrie isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or biologically active metabdite thereof and/or prodrug thereof and/or solvaté thereof and/or hydrate thereof and/or polymorph thereof according to any of daims 1 to 32 for use in the treatment and/or prophyiaxis of a disease or condition associated with the central and/or peripheral antagonisation of V1a receptor.
39. The compound for use according to daim 38, wherein the disease or condition associated with the central and/or peripheral antagonisation of V1a receptor is selected from the group consisting of various pathological conditions of the female sex organs, longstanding conditions in blood pressure control, conditions resulting from inappropriate sécrétion of vasopressin, anxiety, dépréssion, aggression, disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to anxiety, dépréssion, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavioural disorders and/or irritability, behavioural hyperactivity disorders, cognitive disorders or other neuropsychiatrie disorders.
40. Use of a compound of general formula (I) and/or sait thereof and/or géométrie isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or biologically active métabolite thereof and/or prodrug thereof and/or solvaté thereof and/or hydrate thereof and/or polymorph thereof according to any of daims 1 to 32 for the treatment and/or prophyiaxis of a disease or condition associated with the central and/or peripheral antagonisation of V1a receptor.
41. The use according to claim 40, wherein the disease or condition associated with the central and/or peripheral antagonisation of V1 a receptor is selected from the group consisting of various pathological conditions ofthe female sexorgans, long-standing conditions in blood pressure control, conditions resulting from inappropriate sécrétion of vasopressin, anxiety,

286 dépression, aggression, disorders of the centra! nervous system where one of the symptoms and/or syndromes of the disease may be reiated to anxiety, dépréssion, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavioural disorders and/or irritability, behavioural hyperactivity disorders, cognitive disorders or other neuropsychiatrie disorders.
42. Method for treating and/or preventing a disease or condition associated with V1a receptor function comprising administering, to the mammal to be treated, of a therapeutically effective amount of a compound of general formula (I) and/or sait thereof and/or géométrie isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or biologically active métabolite thereof and/or prodrug thereof and/or solvaté thereof and/or hydrate thereof and/or polymorph thereof according to any of claims 1 to 32 alone or with pharmaceutically acceptable excipients.
43. The method according to claim 42, wherein the disease or condition associated with the central and/or peripherai antagonisation of V1a receptor is selected from the group consisting of various pathological conditions of the female sex organs, long-standing conditions in blood pressure control, conditions resulting from inappropriate sécrétion of vasopressin, anxiety, dépréssion, aggression, disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be reiated to anxiety, dépression, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavioural disorders and/or irritability, behavioural hyperactivity disorders, cognitive disorders or other neuropsychiatrie disorders.
44. The compound of general formula (I) and/or sait thereof and/or géométrie isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or biologically active métabolite thereof and/or prodrug thereof and/or solvaté thereof and/or hydrate thereof and/or polymorph thereof according to any of claims 1 to 32 and one or more other active substances for use in the treatment and/or prophylaxis of a disease or condition associated with the central and/or peripherai antagonisation of V1a receptor.
45. The combination for use according to claim 44, wherein the one or more other active substances are selected from the group consisting of psycholeptics, psychoanaleptics, antihypertensives, spasmolytics, antiepileptics or other agents.

237
46. The compound of formula (XIII) wherein R¹ is chlorine or bromine

NHBoc.
47. The compound of formula (III) wherein R¹ is chlorine or bromine

NHBoc.

5
48. The compound of formula (IV-a), the tert-butyl-(7-chloro-2-(methylsulfanyl)-4,5dihydro-3H-1-benzazepin-4-yl)carbamate

SMe

NHBoc.
49. The compound of formula (XXIX) wherein R¹ is chlorine or bromine

10
50. The compound of formula (XXV), the 4-{[fert'-butyl(dimethyi)silyl]oxy}-7-chloro1,3,4,5-tetrahydro-2H-1 -benzazepin-2-one
51. The compound of formula dll-b), the 4-{[tert-butyi(dimethyl)silyl]oxy}-7-chloro-1,3,4,5tetrahydro-2H-1-benzazepin-2-thione
52. The compound of formula (XLIV), the 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1benzazepi n-2-one

288
53. The compound of formula (lll-c), the 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1benzazepine-2-thione