TW201938171A - Tricyclic compounds as vasopressin V1a receptor antagonists - Google Patents

Abstract

The present invention relates to 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1] 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 V1a 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

Tricyclic compounds as vasopressin V1a receptor antagonists

The present invention relates to 5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine derivatives and / or the like of the general formula (I) Salts and / or their geometric isomers and / or their stereoisomers and / or their mirror isomers and / or their racemates and / or their non-mirror isomers Structures and / or their biologically active metabolites and / or their prodrugs and / or their solvates and / or their hydrates and / or their polymorphs, these are central and And / or peripherally acting V1a receptor modulators, particularly V1a receptor antagonists. Another subject of the present invention is a method for preparing the compounds and an intermediate for the process of the preparation. The present invention also relates to a pharmaceutical composition containing the compounds and the use of the pharmaceutical composition for the treatment and / or prevention of diseases or conditions related to the function of the Via receptor.

Angiotensin (antidiuretic hormone; ADH; CYIQNCPRG) is a 9 amino acid peptide hormone, which is produced by giant cell neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus. It is secreted directly into the posterior lobe of the pituitary gland, and vasopressin is stored in the posterior lobe until it enters the blood. In the surrounding tissues, vasopressin's main role is to regulate vasoconstriction, glucose metabolism and excretion.
Accordingly, conditions caused by the lack of vasopressin due to improper secretion of vasopressin can lead to pathological changes in the body, such as central diabetes insipidus or abnormal hypotension. In the case of increased concentrations or exogenous administration, a variety of forms of aggressive behavior can be observed (Ferris et al., BMC Neuroscience 2008, 9: 111).
Oxytocin (OXT; CYIQNCPLG) is a vasopressin-related peptide hormone, which differs from vasopressin by 1 amino acid, and the receptor of oxytocin is also related to the receptor of vasopressin. The compound's effect on the oxytocin receptor shows species-specific differences, but the oxytocin hormone itself is the same in different mammal species. Similarly, the vasopressin peptides are the same in all mammals (except marsupials and pigs) and the effects of the vasopressin peptide through its receptors are species-specific. The anxiolytic effect of oxytocin applied to the central nervous system is known (Neumann ID. J Neuroendocrinol 2008, 20 (6): 858-65), so the inhibitory effect on the oxytocin receptor of the central nervous system can be triggered as Unwanted side effects of anxiety.
Three types of vasopressin receptors can be distinguished, all of which are G protein-coupled receptors. Among them, the V1a receptor (V1aR) is mainly expressed in the cerebral cortex, hippocampus, and pituitary gland and other peripherally in liver, vascular smooth muscle, lung, uterus, and testes (Frank et al., Eur J Pharmacol 2008, 583: 226- 42). V1b receptors (V1bR) can also be found in the cortex, hippocampus, and pituitary gland, and this V1bR plays an important role in regulating the pancreas and adrenals in surrounding tissues. In contrast, V2 receptors (V2R) are mainly confined to surrounding tissues and increase water reabsorption in the kidney, thereby achieving the anti-diuretic effect of vasopressin (Robben et al., Am J Physiol Renal Physiol 2007, 292 (1) : F253-60). Due to changes in water balance regulation, effects on the V2 receptor can cause unwanted side effects.
The secondary signal transduction pathways of the V1a and V1b receptors include changes in intracellular Ca ²⁺ concentration through phosphatidylinositol, and the V2 receptor activates adenylate cyclase and affects cAMP concentration (Gouzenes et al ., J Physiol 1999, 517 (Pt3): 771-9; Tahara et al., Pflugers Arch 1999, 437 (2): 219-26).
An important role linked to this V1a receptor is to regulate circadian rhythm. One third of the neurons in the suprachiasmatic nucleus (SCN) show vasopressin and the mRNA of the V1a receptor in the brain region shows diurnal fluctuations, and the highest value of the mRNA can be observed at night time (de Vries and Miller, Prog Brain Res 1998, 119: 3-20). Although the distribution and amount of this V1aR mRNA is not different in men and women, vasopressin shows a gender difference in behavioral habits (Szot et al., Brain Res Mol Brain Res 1994, 24 (1-4): 1 -10). Experiments in mice have been shown to increase the water absorption by the mouse's internal physiological clock rather than its physiological needs before the mouse sleeps (Gizowski et al., Nature 2016, 537 (7622): 685-8). Sleep disorders are the main concomitant symptoms of autism (Glickman, Neurosci Biobehav Rev 2010, 34 (5): 755-68).
Vasopressin acts as a neuromodulator in the brain, and elevated vasopressin concentrations can be detected in the amygdala under stress (Ebner et al., Eur J Neurosci 2002, 15 (2): 384-8 ). Stress / stressful living conditions are known to increase the likelihood of depression and anxiety (Kendler et al., Arch Gen Psychiatry 2003, 60 (8): 789-96; Simon et al., R ecent Pat CNS Drug Discov , 2008, 3 (2): 77-93; Egashira et al., J Pharmacol Sci 2009, 109 (1): 44-9; Bielsky et al., Neuropsychopharmacology 2004, 29 (3): 483-93). V1aR is highly expressed in the brain, especially in parts of the limbic system, such as the amygdala, lateral septum, and hippocampus, which play an important role in the development of anxiety. Male V1aR knockout mice showed reduced anxiety in the raised plus maze test, the open field test, and the light and dark box test, but these differences were not observed in female mice (Bielsky et al., Behav Brain Res 2005, 164 (1): 132-6).
Male V1aR knockout mice showed no phenotypic differences in athletic performance. In general light-dark cycle experiments, V1aR-excluded mice did not show a difference compared to their wild-type littermates. However, in experiments performed under continuous darkness, the circadian rhythm of the V1a-excluded mice changed significantly (Egashira et al., Behav Brain Res 2007, 178 (1): 123-7).
The V1aR-excluded mice showed improved activity in a prepulse inhibition test, which has been accepted as the animal model of sensorimotor deficits observed in most patients with schizophrenia. Egashira et al. Have shown a decrease in function in a social interaction test suitable for measuring the social cognitive behavior of V1aR knockout mice in both male and female (Bleickard et al. al., Psychopharmacology (Berl) , 2009, 202: 711-18).
In the case of the AVPR1A gene variant encoding the V1a receptor, two minor polymorphisms related to autism can be measured (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). The detectable altered activation of the amygdala in patients with the two dangerous alleles of the V1aR gene also involves genetic linkage. These modified receptors have been shown to alter the activation threshold of the amygdala during the emotional facial recognition process (Meyer-Lindenberg et al., Mol Psychiatry 2009, 14: 968-75).
Preclinical experimental data also support the efficacy of V1aR antagonists in autism. The widely used and accepted animal model of autism is to study the behavior of valproate (VPA) treated rats in the womb. The reduced social behavior of the VPA-treated animal can be restored to normal values by the VIaR antagonist compound. In functional magnetic resonance imaging studies, it was also found that the V1aR antagonist can restore reduced perfusion values in different brain regions of VPA-treated animals before birth. Treatment with this V1aR antagonist can increase the reduced function of the cortex, inferior colliculus, hippocampus, and inferior optic cumulus, but in the ventral striatum, striatum, and superior colliculus, enhanced perfusion is normalized by the V1aR antagonist (Grundschober et al., Poster presented at Annual Meeting of the American College of Neuropsychopharmacology , 2014, Phoenix, USA). For this reason, it is expected that V1aR antagonist compounds that will appear to facilitate blood-brain barrier penetration will be advantageous.
The use of small molecule antagonists to influence V1aR is a variety of pathological symptoms (such as, but not limited to, dysmenorrhea and sexual dysfunction) for the treatment of female sexual organs, persistent pathological symptoms of blood pressure control (such as, but not limited to, hypertension and / or chronic heart failure) ) And promising strategies for symptoms caused by improper secretion of vasopressin, such as, but not limited to, diabetes insipidus, renal failure, kidney syndrome, and cirrhosis. The use of small molecule antagonists to influence V1aR can be considered for the treatment of anxiety, depression, aggressive behavior, and central nervous system diseases (wherein one of the symptoms of the disease and / or multiple symptoms may be related to the aforementioned 3 diseases or related to the aforementioned 3 diseases show comorbidities) is another promising strategy. Such symptoms include, but are not limited to, autism group disorders (good functioning autism, Asperger syndrome, generalized developmental disorder to be classified (PDD-NOS), autism spectrum disorder (ASD), and Many different syndromes: Fragile X chromosome, Prader-Willi syndrome, Rett's disease and tuberous sclerosis), OCD, many different types of Tang (Down) syndrome and post-traumatic stress disorder (PTSD). V1aR antagonists are also suitable for the treatment of aggressive behavior disorders and / or irritability (such as, but not limited to, patients with ASD, Huntington's disease (HD), or many different types of schizophrenia), behavioral hyperactivity Disorders (such as, but not limited to, ADHD), cognitive disorders (such as, but not limited to, dementia, mild cognitive impairment (MCI), schizophrenia-related cognitive impairment (CIAS), and Alzheimer's (Alzheimer's disease) and other neuropsychiatric diseases (such as, but not limited to, schizophrenia and related diseases).
Many patent applications involve V1a receptor antagonists, such as Otsuka's disclosure of benzoheterocyclic derivatives (WO 95/034540 A1; WO 2009/001968 A1; WO 2011/052519 A1), Astellas Pharmaceutical company (Astellas Pharma; Yamanouchi) reveals fused benzodiazepine and triazole derivatives (WO 95/03305 A1; WO 01/87855 A1; WO 02/44179 A1), AbbVie Biopharmaceutical Company (AbbVie) discloses oxindole derivatives (WO 2006/072458 A2; WO 2006/100082 A2), Bayer Pharma discloses aryl or heteroaryltriazole derivatives (WO 2017/191102 A1; WO 2017 / 191107 A1; WO 2017/191114 A1). Many different derivatives containing benzofluorene cores (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), spirolindolinone and indolylcarbonyl derivatives (WO 97/15556 A1; WO 2007/009906 A1; WO 2007/014851 A2) have also been described as V1a receptor antagonists.
For the first clinical development, the V1a receptor was considered as a peripheral target, so poor brain penetration is conducive to compound development. This compound is an indololine nuclear compound "relcovaptan" (SR-49059, WO 93/03013 A1) of Sanofi Pharmaceutical Factory (Sanofi), which has been developed to a Phase 2 clinical trial. The indications studied were premature delivery, pelvic pain observed during menstruation, dysmenorrhea (Brouard et al., Br J Obstetr Gynaecol 2000, 107: 614-9), heart failure, hypertension, and coronary spasm, but also in small cells Lung cancer has been tested as an anti-tumor agent until the last clinical trial was suspended in 2003 (Serradeil-Le Gal et al., Prog Brain Res 2002, 139: 197-210; AdisInsight: Relcovaptan-October 3, 2006 Final Information Update http : //adisinsight.springer.com/drugs/800004942). The clinical development of racuvaptan has been carried out since 1993 and is now the most commonly used in vitro tool in V1aR studies (Tahara et al., Br J Pharmacol 2000, 129: 131-9).
Based on data measured as a potent V1aR antagonist, Pfizer has studied triazole derivatives PF 00738245 (WO 2005/063754 A1) and triazobenzobenzodiazepine core compound PF-184563 ( WO 2004/074291 A1) preclinical development (Russell et al., Eur. J Pharmacol , 2011, 670 (2): 347-355; Johnson et al., Bioorg Med Chem Lett 2011, 21: 5684-7), However, their development has been suspended.
By examining the effects shown on the central nervous system, the treatment of depression and anxiety has also been proposed as a new therapeutic area. Johnson &Johnson's spirobenzoacridine nuclear compound JNJ-17308616 is the first V1aR antagonist compound that acts on the central nervous system (Bleickard et al., Psychopharmacology (Berl.), 2009, 202: 711- 18; WO 02/02531 A1), which has been shown to show efficacy in a variety of different animal models used for anxiety research: raised-arm cross maze test in rat pups, glass bulb burying test, and ultrasonic vocalization caused by separation Significantly reduced anxiety behavior. Although the spirobenzoacridine nuclear compound JNJ-17308616 has been proven to effectively affect the elevated O-maze and conditional licking response, it has poor efficacy due to its poor metabolic stability as measured in rodents. It can only be measured at high doses, making testing difficult.
Tetrahydroacridone derivatives SRX246 and SRX251 (also known as API246 or API251; WO 03/031407 A2), V1aR antagonists of Aivan Pharmaceutical Factory (Azevan), have also reached the clinical trial stage. Clinical trials of SRX246 are also currently underway to treat human behavior patterns of intermittent anger and irritability and anxiety and fear in the treatment of aggressive behavior and Huntington's disease and post-traumatic stress disorder (AdisInsight: SRX 246-February 2017 The last update on the 16th is http://adisinsight.springer.com/drugs/800023656). The clinical trial of SRX251 treats dysmenorrhea, but the first phase of the study was discontinued in 2016, and the efficacy of SRX246 against aggression was similarly developed in the preclinical setting (AdisInsight: SRX 251-November 4, 2017 Last update of data http: // adisinsight.springer.com/drugs/800025117). SRX-246 and SRX-251 are active at human V1a receptors and the concentrations of these two compounds measured in the rat brain are about 100 times their effective concentrations measured by binding analysis (Guillon et al., Bioorg Med Chem 2007 15: 2054-80; Fabio et al., J Pharm Sci 2013, 102 (6): 2033-43).
V1aR antagonist compound of pyrazolobenzodiazepine core of Vantila Pharmaceutical Factory (Vantia) VA 111913 (WO 2010/097576 A1; AdisInsight: VA 111913-August 25, 2015 Last update of the data http: // (adisinsight.springer.com/drugs/800028777) has been tested in a Phase 2 clinical trial to treat dysmenorrhea, but no data on the development of this compound has been available since 2015.
Otsuka Pharmaceutical Co., Ltd.'s V1aR antagonist "quinolinone derivative OPC 21268" (EP 0382185 A2; AdisInsight: OPC 21268-October 6, 2006, last data update http://adisinsight.springer.com/drugs/800000284) The efficacy of gastric mucosal injury indications was tested in the preclinical stage, and the efficacy on heart failure and hypertension was studied in a phase 2 clinical trial, but no data have been developed on the compound since 2015 (Yamamura et al., Science 1991 252: 572; Serradeil-Le Gal et al., J Clin Invest 1993, 92 (1): 224).
When the brain stem is examined in postmortem human samples, selective localization of the V1a receptor that is not related to the oxytocin receptor can be detected in the nucleus prepositus, which plays a role in stability of sight Role (Freeman et al., Soc Neurosci 2017, 12 (2): 113-123). The basic skills required for human social behavior are cognitive and eye tracking of biological-related data (Klin et al., Nature 2009, 459: 257-63; Simion et al., PNAS 2008, 105 (2): 809-13) . The most active V1aR research pharmaceutical company Hoffmann-La Roche's indole derivative RO5028442 has entered the first phase of research (RG-7713; WO 2007/006688 A1), in which positive effects on sight pattern orientation can be detected in the human body (Umbricht et al., Neuropsychopharmacology 2017, 42 (9): 1914-1923; AdisInsight: RG 7713-November 5, 2015, final data update http://adisinsight.springer.com/drugs/800043668). Balovaptan with a triazolobenzodiazepine core is undergoing a Phase 2 clinical trial to treat autism (RG-7314, RO5285119; WO 2010/060836 A1; AdisInsight: RG 7314-2017 (September 10, the latest information update (http://adisinsight.springer.com/drugs/800035102).
Despite many V1aR antagonist compounds and clinical studies, unmet medical needs continue to require the development of V1aR antagonists, which are suitable for the treatment and / or prevention of various pathological symptoms of female sex organs and persistent symptoms of blood pressure control , Symptoms caused by inappropriate secretion of vasopressin, anxiety, depression, aggressive behavior, central nervous system disease (where one of the symptoms of the disease and / or multiple symptoms may be related to anxiety, depression or aggressive behavior or Comorbidities with these three diseases (autism group disorder, obsessive-compulsive disorder, many different types of Down syndrome and post-traumatic stress disorder), aggressive behavior disorder and / or irritability, hyperactivity disorder, Cognitive impairment or other neuropsychiatric disorders.

Brief description of the invention
The objective of the present invention is to synthesize a V1a receptor antagonist with a novel structure, the physicochemical properties (such as kinetic or thermodynamic solubility, ionization, lipophilicity or permeability) or pharmaceutical properties (such as metabolic stability Or CYP-450 enzyme inhibition) can provide favorable bioavailability, ADME (absorption, distribution, metabolism, and excretion), membrane penetration, or blood-brain barrier penetration.
Surprisingly, a novel 5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazepine derivative of the general formula (I) has been prepared , Which shows a profile of V1a receptor antagonistic activity.
The invention relates to compounds of general formula (I):

among them
Ring A is a cycloalkyl or heterocyclic group;
If ring B exists, Y is -O-, -C (O)-, -CH ₂ -, -NH- or bonding; or, if ring B does not exist, Y is -N (C _1-4 alkyl) ₂ , C (O) OC _1-4 Alkyl, optionally halogen-substituted C _1-4 Alkyl, C _1-4 Alkoxy or halogen;
Ring B is optionally substituted heteroaryl, aryl or heterocyclic;
Or BYA-Combined Representative 3 H -Spiro [2-benzofuran-1,4'-piperidine-1'-yl]; or

R ¹ Hydrogen, halogen, C _1-4 Alkyl, C _1-4 Alkoxy, CF ₃ Or CN;
R ² Hydrogen or C _1-4 alkyl;
R ³ Department (CH ₂ ) _n R ⁴ , C (O) R ⁵ Or optionally via R ⁶ Replaced by C _1-4 alkyl;
Or R ² With R ³ Combined Representative-(CH ₂ ) _p -O- (CH ₂ ) _q -Or- (CH ₂ ) _r -;
R ⁴ CN, azide or Cy ¹ ;
R ⁵ Department C _1-4 Alkyl, C _1-4 Alkoxy, OH or NR ⁷ R ⁸ ;
R ⁶ Department of OR ⁹ , NR ¹⁰ R ¹¹ , Pendant oxygen, -O (CH ₂ ) ₂ O- or one or more halogens;
R ⁷ And R ⁸ Independently hydrogen, C _1-4 Alkyl or Cy ² Or R ⁷ And R ⁸ Forms a heterocyclic ring with their attached N;
R ⁹ Hydrogen, optionally via NH ₂ Or optionally substituted C _1-4 Alkyl, Si (CH ₃ ) ₃ Or C (O) R ¹² ;
R ¹⁰ And R ¹¹ Independently hydrogen, optionally via C _1-4 Alkoxy-substituted C _1-4 Alkyl, Cy ³ Or C (O) R ¹³ , Or R ¹⁰ And R ¹¹ Together with the N to which they are attached form an optionally substituted heterocyclic ring;
R ¹² Department C _1-5 Alkyl or NR ¹⁴ R ¹⁵ ;
R ¹³ Department C _1-4 Alkyl, Cy ¹ Or NR ¹⁶ R ¹⁷ ;
R ¹⁴ And R ¹⁵ Independently hydrogen or optionally substituted aryl, or R ¹⁴ And R ¹⁵ Together with the N to which they are attached form an optionally substituted heterocyclic ring;
R ¹⁶ And R ¹⁷ Department C _1-4 Alkyl, or R ¹⁶ And R ¹⁷ Together with the N to which they are attached form an optionally substituted heterocyclic ring;
Cy ¹ Is optionally substituted heteroaryl;
Cy ² Is optionally substituted aryl or heteroaryl;
Cy ³ Is optionally substituted cycloalkyl or heterocyclyl;
X series C _1-4 Alkyl, aryl or heteroaryl;
Z series C _1-4 alkyl;
n is 0 or 1;
p is 1, 2 or 3;
q is 1, 2 or 3;
r is 4, 5 or 6;
And / or their salts and / or their geometric isomers and / or their stereoisomers and / or their mirror isomers and / or their racemates and / or their Non-mirromeric isomers and / or their biologically active metabolites and / or their prodrugs and / or their solvates and / or their hydrates and / or their polymorphs.
The present invention also relates to a pharmaceutical composition containing the compound of general formula (I) and / or their salts and / or their geometric isomers and / or their stereoisomers and / or their Mirror isomers and / or their racemates and / or their non-mirro isomers and / or their prodrugs and / or their solvates and / or their hydrates and / Or their polymorphs as active substances.
In addition, the invention also relates to the compounds of the general formula (I) and / or their salts and / or their geometric isomers and / or their stereoisomers and / or their mirror isomers And / or their racemates and / or their non-mirromeric isomers and / or their prodrugs and / or their solvates and / or their hydrates and / or their Preparation of polymorphs, intermediates in the process of the preparation, and chemical and pharmaceutical preparations of pharmaceutical compositions containing these compounds.
The present invention also relates to a method for treating mammals, including humans, suffering from a central and / or peripheral disease that modulates and preferably antagonizes the V1a receptor, where the compound of formula (I) and / Or their salts and / or their geometric isomers and / or their stereoisomers and / or their mirror isomers and / or their racemates and / or their Non-mirromeric isomers and / or their prodrugs and / or their solvates and / or their hydrates and / or their polymorphs or their therapeutically effective amounts.
The invention also relates to the compounds of general formula (I) and / or their salts and / or their geometric isomers and / or their stereoisomers and / or their mirror isomers and / Or their racemates and / or their non-image isomers and / or their prodrugs and / or their solvates and / or their hydrates and / or their polymorphs For use in the manufacture of a medicament for the treatment and / or prevention of diseases or conditions related to the function of the Via receptor.

Detailed description of the invention
The present invention relates to V1a receptor modulators, and in particular to V1a receptor antagonists. Another object of the present invention is to provide selective Via receptor inhibitor compounds, because the selectivity is less likely to cause unwanted side effects. Another aspect of the present invention is to provide compounds having advantageous physicochemical properties, such as those that are expected to lead to beneficial bioavailability of the compound, ADME (absorption, distribution, metabolism and excretion), membranes Penetration or blood brain barrier penetration.
Therefore, the compound of general formula (I) of the present invention is a V1a receptor antagonist, which is a central and / or peripherally acting therapeutic agent for the treatment and / or prevention of various pathological symptoms of female sexual organs, persistent symptoms of blood pressure control, causes Symptoms caused by inappropriate secretion of vasopressin, anxiety, depression, aggressive behavior, central nervous system disease (wherein one of the symptoms of the disease and / or multiple symptoms may be related to or related to anxiety, depression or aggressive behavior The aforementioned 3 diseases show comorbidities (autism group disorder, obsessive-compulsive disorder, many different types of Down syndrome and post-traumatic stress disorder), aggressive behavior disorder and / or irritability, hyperactivity disorder, cognitive impairment Or other neuropsychiatric disorders.
The invention relates to compounds of general formula (I):

among them
Ring A is a cycloalkyl or heterocyclic group;
If ring B exists, Y is -O-, -C (O)-, -CH ₂ -, -NH- or bonding; or, if ring B does not exist, Y is -N (C _1-4 alkyl) ₂ , C (O) OC _1-4 Alkyl, optionally halogen-substituted C _1-4 Alkyl, C _1-4 Alkoxy or halogen;
Ring B is optionally substituted heteroaryl, aryl or heterocyclic;
Or BYA-Combined Representative 3 H -Spiro [2-benzofuran-1,4'-piperidine-1'-yl]; or

R ¹ Hydrogen, halogen, C _1-4 Alkyl, C _1-4 Alkoxy, CF ₃ Or CN;
R ² Hydrogen or C _1-4 alkyl;
R ³ Department (CH ₂ ) _n R ⁴ , C (O) R ⁵ Or optionally via R ⁶ Replaced by C _1-4 alkyl;
Or R ² With R ³ Combined Representative-(CH ₂ ) _p -O- (CH ₂ ) _q -Or- (CH ₂ ) _r -;
R ⁴ CN, azide or Cy ¹ ;
R ⁵ Department C _1-4 Alkyl, C _1-4 Alkoxy, OH or NR ⁷ R ⁸ ;
R ⁶ Department of OR ⁹ , NR ¹⁰ R ¹¹ , Pendant oxygen, -O (CH ₂ ) ₂ O- or one or more halogens;
R ⁷ And R ⁸ Independently hydrogen, C _1-4 Alkyl or Cy ² Or R ⁷ And R ⁸ Forms a heterocyclic ring with their attached N;
R ⁹ Hydrogen, optionally via NH ₂ Or optionally substituted C _1-4 Alkyl, Si (CH ₃ ) ₃ Or C (O) R ¹² ;
R ¹⁰ And R ¹¹ Independently hydrogen, optionally via C _1-4 Alkoxy-substituted C _1-4 Alkyl, Cy ³ Or C (O) R ¹³ , Or R ¹⁰ And R ¹¹ Together with the N to which they are attached form an optionally substituted heterocyclic ring;
R ¹² Department C _1-5 Alkyl or NR ¹⁴ R ¹⁵ ;
R ¹³ Department C _1-4 Alkyl, Cy ¹ Or NR ¹⁶ R ¹⁷ ;
R ¹⁴ And R ¹⁵ Independently hydrogen or optionally substituted aryl, or R ¹⁴ And R ¹⁵ Together with the N to which they are attached form an optionally substituted heterocyclic ring;
R ¹⁶ And R ¹⁷ Department C _1-4 Alkyl, or R ¹⁶ And R ¹⁷ Together with the N to which they are attached form an optionally substituted heterocyclic ring;
Cy ¹ Is optionally substituted heteroaryl;
Cy ² Is optionally substituted aryl or heteroaryl;
Cy ³ Is optionally substituted cycloalkyl or heterocyclyl;
X series C _1-4 Alkyl, aryl or heteroaryl;
Z series C _1-4 alkyl;
n is 0 or 1;
p is 1, 2 or 3;
q is 1, 2 or 3;
r is 4, 5 or 6;
And / or their salts and / or their geometric isomers and / or their stereoisomers and / or their mirror isomers and / or their racemates and / or their Non-mirromeric isomers and / or their biologically active metabolites and / or their prodrugs and / or their solvates and / or their hydrates and / or their polymorphs.
The definitions of the general terms used herein (whether or not the term is discussed) are described below, either independently or in combination with other groups.
"Cycloalkyl" refers to a saturated or unsaturated (preferably saturated) carbocyclic group of 3 to 8 members (preferably 3 to 6 members), alone or in combination with other groups. Examples include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. On rings A and Cy ³ Herein, the "cycloalkyl group" preferably refers to a 4- to 6-membered saturated carbocyclic group. Examples include cyclobutyl, cyclopentyl or cyclohexyl. Preferred is cyclobutyl or cyclohexyl. Particularly preferred is cyclohexyl. "Substituted cycloalkyl" preferably refers to a cycloalkyl having a twin halogen substitution.
"Aryl" alone or in combination with other groups means an aromatic carbocyclic group of 6 to 14 members (preferably 6 to 10 members), which contains at least 1 aromatic ring or contains at least 1 aromatic ring Fused ring system. Examples include, but are not limited to, phenyl, benzyl, naphthyl, biphenyl, anthracenyl, fluorenyl, or dihydroindenyl. Particularly preferred is phenyl.
"Heterocyclyl" alone or in combination with other groups means a saturated or unsaturated (preferably saturated) 3 to 8 member (preferably 4 to 7 member) containing 1, 2, 3 or 4 members selected from A monocyclic, bicyclic, fused and / or bridged ring of a heteroatom of O, S or N. Preferred 4- to 7-membered monocyclic heterocyclic rings contain 1 N, 2 N, 1 O, 1 N and 1 O, or 1 N and 1 S. Examples include, but are not limited to, ethylene oxide, oxetane, tetrahydrofuran, tetrahydropiran, tetrahydroazetidine, pyrrolidine, piperidine, piperazine, morpholine, 1,3-oxazolidine , 1,3-thiazolidine, thiomorpholine-1,1-dioxide and the like. "Substituted heterocyclyl" preferably means C _1-4 Alkyl-substituted heterocyclic ring.
When ring A is a heterocyclic group, the heterocyclic group preferably refers to a saturated heterocyclic group containing 4 to 7 members containing 1 N or 2 N, wherein Ring A is connected to Y via a ring nitrogen atom or the 5 , 6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] triazole ring with a benzazepine core. Examples include, but are not limited to, tetrahydroazepine, 1,3-bis (tetrahydroazepine), pyrrolidinyl, pyrazolyl, imidazolidinyl, piperidinyl, piperazinyl, azacycloheptane Radical, 1,3- or 1,4-diazacycloheptyl. Preferred are tetrahydroacryl, piperidinyl or piperazinyl.
For Cy ³ The heterocyclic ring preferably refers to a saturated heterocyclic group containing 1 to 4 members, and more preferably refers to oxetane or tetrahydropiperan.
When ring B is a heterocyclic group, the heterocyclic group preferably refers to a saturated heterocyclic group of 4 to 7 members containing 1 N or 1 N and 1 O. Examples include, but are not limited to, tetrahydroazino, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.
When R ⁷ And R ⁸ , R ¹⁰ And R ¹¹ , R ¹⁴ And R ¹⁵ Or R ¹⁶ And R ¹⁷ "When forming an optionally substituted heterocyclic ring with the N to which they are attached", the heterocyclic ring preferably means 4 to 7 members containing 1 N, 2 N, 1 N, and 1 O, Or a saturated ring of N and 1 S. Examples include, but are not limited to, morpholine, 4-methyl-piperazinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,3-oxazolidine, 1,3-thiazolidine, or thiomorpholine-1 , 1-dioxide.
"Heteroaryl" alone or in combination with other groups refers to a cyclic aromatic group containing a single 5- to 6-membered ring containing 1, 2, 3 or 4 heteroatoms, at least one Heterocyclic aromatic group. "6-membered monoheteroaryl" 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, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, and the like. Preferred single 6-membered monoheteroaryl groups contain 1 or 2 N. Preferred 6-membered rings are pyridyl, more preferably pyridin-2-yl and pyridin-3-yl. Particularly preferred is pyridin-2-yl. "5-membered monoheteroaryl" means a single 5-membered ring monocyclic aromatic group containing 1, 2, 3, or 4 heteroatoms selected from O, S, or N. Preferred single 5-membered monoheteroaryls contain 2 N and 1 O, 2 N and 1 S, 4 N, 3 N, 2 N, 1 N or 1 S or 1 N and 1 O. Examples include, but are not limited to, thienyl, furyl, pyrrolyl, tetrazolyl, triazolyl, imidazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, 1 H -Pyrazolyl and the like. Preferred are isoxazol-3-yl, tetrazolyl and 1,2,4-oxadiazol-5-yl. "Substituted heteroaryl" preferably means C _1-4 Alkyl or halogen-substituted heteroaryl.
For Cy ¹ , The optionally substituted heteroaryl preferably means C _1-4 Alkyl (preferably methyl) substituted single 5 membered monoheteroaryl containing 2 N and 1 O or 4 N. Preferred is tetrazolyl or 3-methyl-1,2,4-oxadiazol-5-yl.
When ring B is an optionally substituted heteroaryl, the heteroaryl refers to an optionally substituted halogen (preferably chlorine) or C _1-4 Alkyl (preferably methyl) substituted 5 or 6 membered monoheteroaryl groups containing 1 N, 2 N or 1 N and 1 O. Examples include, but are not limited to, pyridin-2-yl, 3-chloro-pyridin-2-yl, 3-methyl-pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, or 5-methyl-iso Oxazol-3-yl.
"Bonding" refers to a single bond in which two atoms share a pair of electrons.
"C _1-4 Alkyl "or" C _1-5 "Alkyl", alone or in combination with other groups, refers to a straight or branched, single or multiple branched hydrocarbon group and is composed of 1 to 4 or 1 to 5 carbon atoms. Examples include, but are not limited to, methyl Methyl, ethyl, propyl, isopropyl, n-butyl, 2-butyl (secondary butyl), tertiary butyl, n-pentyl, tertiary pentyl, neopentyl, isopentyl, 2 -Pentyl (secondary pentyl) or 3-pentyl. Preferred alkyl groups are those having 1 to 3 carbon atoms. Preferred are methyl, ethyl, isopropyl, tertiary butyl and tertiary. Amyl. Particularly preferred is methyl.
"C _1-4 "Alkoxy", alone or in combination with other groups, means -OC _1-4 Alkyl, where the C _1-4 Alkyl is as defined above. Examples include, but are not limited to, methoxy, ethoxy, propoxy, or tertiary butoxy. Preferred alkoxy is methoxy, propoxy or tertiary butoxy. Particularly preferred are methoxy and tertiary butoxy.
"Boc", alone or in combination with other groups, refers to tertiary butoxycarbonyl.
"Halogen", alone or in combination with other groups, means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. For R ¹ And R ⁶ Preferred is fluorine, chlorine or bromine. For R ¹ More preferred is chlorine or bromine, and even more preferred is chlorine. For R ⁶ More preferably, it is fluorine.
"Optionally substituted" for any atom of the relevant group means one or more C _1-4 Alkyl or halogen substituted. Here, "one or more" means 1 to the highest possible number of substitutions, that is, from one hydrogen to all hydrogens. Therefore, 1, 2 or 3 substitutions of a given atom are preferred. Very preferred are 1 or 2 substitutions or 1 substitution. For optionally substituted cycloalkyl, aryl, heterocyclyl or heteroaryl, 1 substitution is particularly preferred.
"C optionally substituted with halogen _1-4 "Alkyl" preferably refers to C _1-4 C with 1, 2 or 3 halogen substitutions on any atom of the alkyl group _1-4 Alkyl refers more preferably to methyl having 3 halogen substitutions. Especially preferred is CF ₃ .
In "Through R ⁶ Replaced by C _1-4 Alkyl ", the C _1-4 Alkyl is as defined above. In "Through R ⁶ Replaced by C _1-4 Alkyl ", the substituted C _1-4 Alkyl is preferably a branched, single or multiple branched hydrocarbon group consisting of 1 to 4 carbon atoms. In "Through R ⁶ Replaced by C _1-4 "Alkyl" means "substituted" means that one or more R ⁶ To replace. The "one or more" means 1 to the highest possible number of substitutions, ie from 1 hydrogen to all hydrogens. When R ⁶ Department of OR ⁹ Or NR ¹⁰ R ¹¹ When "The R ⁶ Replaced by C _1-4 "Alkyl" is, for example, but is not limited to, -CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , Preferably -CH ₂ R ⁶ . When R ⁶ System side oxygen or -O (CH ₂ ) ₂ O-, the " ⁶ Replaced by C _1-4 "Alkyl" is, for example but not limited to, -C (R ⁶ ) CH ₃ . When R ⁶ In the case of one or more halogens, the " ⁶ Replaced by C _1-4 "Alkyl", "one or more", and "halogen" are as defined above. Here, the " ⁶ Replaced by C _1-4 "Alkyl" is, for example, but is not limited to, -CH ₂ Halogen, -CH (halogen) CH ₃ Or -C (halogen) ₂ CH ₃ , Preferably -CH ₂ halogen.
"Salt" means a pharmaceutically acceptable and / or pharmaceutically unacceptable salt. The pharmaceutically acceptable salts refer to the conventional acid addition salts and base addition salts which retain the biological efficacy and properties of the compound of the general formula (I) and can be passed through a suitable non-toxic organic or inorganic acid or organic Or inorganic base formation. Examples of acid addition salts include salts derived from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic 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, binaconic acid, palmitic acid, benzenesulfonic acid, toluenesulfonic acid 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 hydroxide, potassium hydroxide, sodium hydroxide, and quaternary ammonium hydroxide, such as tetramethylammonium hydroxide. These salts generally have more favorable solubility properties than the compounds themselves used to prepare them and are therefore more suitable for use in the preparation of, for example, liquid or emulsion modulators. The pharmaceutically unacceptable salt is preferably used for the purification and isolation of the compound of the general formula (I) and therefore falls within the scope of the present invention.
"Prodrug" means a derivative of the compound of general formula (I) of the present invention, which does not have a therapeutic effect itself, but contains a group that becomes a "bioactive metabolite" after chemical or metabolic degradation (biotransformation) in vivo, The bioactive metabolite assumes the therapeutic effect. The decomposing group (especially suitable for a prodrug) connected to the compound of the general formula (I) of the present invention is well known in this technical field and also applicable to the compound of the present invention (Rautio et al., Nat Rev Drug Discov 2008, 7: 255-270).
The compound of the general formula (I) may exist in various geometrically isomeric forms. In addition, certain compounds of general formula (I) may contain one or more asymmetric centers and may therefore exist as stereoisomers and non-mirror isomers. All such compounds, such as cis isomers, trans isomers, non-mirromeric mixtures, racemates, non-racemic mixtures of mirror isomers, substantially pure and pure mirror isomers Within the scope of the present invention. The substantially pure enantiomer is up to 5% by weight of the corresponding opposite enantiomer, preferably 2% by weight and most preferably 1% by weight.
Optical isomers can be prepared by resolving racemic mixtures by conventional methods, such as by using an optically active acid or base to form a non-mirromeric isomer salt or by forming a covalent non-mirror isomer. Suitable acids include, for example, tartaric acid, diethylfluorenyl tartaric acid, dibenzyl tartaric acid, xylylene tartaric acid, and camphorsulfonic acid. By methods known in this technical field, such as chromatography or fractional crystallization, non-image-isomer mixtures can be separated into individual non-image-isomers based on the physical and / or chemical differences of the individual non-image-isomers. The optically active base or acid is then released from the isolated non-mirromeric isomers. Various methods of separating optical isomers include chiral chromatography (eg, chiral HPLC columns), which are optionally used to derive the goal of optimal separation of mirror isomers. Suitable chiral HPLC columns are Diacel columns, such as CHIRALPAK or CHIRALCEL columns, and they can be routinely selected as desired. Where applicable, catalyzed separation by derivatization can also be used. Optically active compounds of general formula (I) can also be isolated by chiral synthesis without racemic reaction conditions and using optically active starting materials.
With the literature (Freedman et al., Chirality 2003, 15 (9): 743-58; Stephens et al., Chirality 2008, 20 : 643-663) described by the Vibration Circular Dichroism Spectroscopy (VCD) method and / or the ¹ H NMR spectral analysis (Seco et al., J Org Chem 1999, 64: 4669-4675; Seco et al., Tetrahedron Asymmetry 2001, 12: 2915-2925; Latypov et al., J. Am. Chem. Soc . 1998, 120 , 4741-4751), to determine the absolute configuration of the chiral compound.
The compound of the general formula (I) may exist in various polymorphic forms. As is known in the art, the ability of a polymorphic system compound to crystallize into more than one crystalline form (ie, a polymorphic form). Polymorphic forms of specific compounds can be defined by the same chemical formula or composition. The chemical structures of these polymorphic forms are different, as are the crystal structures of two different compounds.
The compounds of the general formula (I) and their salts may also exist in the form of solvates or hydrates, and these solvates and hydrates also fall within the scope of the present invention. The "solvate" refers to a non-covalent combination of a solvent and a solute. The "hydrate" refers to a non-covalent combination of water and solute.
The present invention also relates to a pharmaceutical composition containing the compound of the general formula (I) and / or their salts and / or their geometric isomers and / or their stereoisomers and / or their Mirror isomers and / or their racemates and / or their non-mirro isomers and / or their prodrugs and / or their solvates and / or their hydrates and / Or their polymorphs.
The invention also relates to chemical and pharmaceutical preparations of pharmaceutical compositions containing the compounds of the general formula (I) and / or their salts and / or their geometric isomers and / or their stereoisomers Structures and / or their mirror isomers and / or their racemates and / or their non-mirro isomers and / or their prodrugs and / or their solvates and / Or their hydrates and / or their polymorphs.
The pharmaceutical composition of the present invention can be formulated into a variety of different pharmaceutical formulations, such as, but not limited to, solid oral dosage forms such as tablets (eg, buccal, sublingual, foaming, chewable, and orally dispersible), Capsules, pills, pills, oral dispersible films, granules and powders; liquid preparations such as solutions, emulsions, suspensions, syrups, elixirs and drops; parenteral forms such as intravenous, intramuscular and subcutaneous injections; Other medical types, such as eye drops, semi-solid ophthalmic preparations, semi-solid skin preparations (such as ointments, creams and pastes), transdermal therapeutic systems, suppositories, rectal capsules, rectal solutions, emulsions and suspensions, etc.
One embodiment of the present invention relates to pharmaceutical compositions for pediatrics, such as, but not limited to, solutions, syrups, elixirs, suspensions, powders for preparing suspensions, dispersible or foamable tablets, chewable Tablets, orally dispersible tablets, tablets or coated tablets, orally foaming powders or granules, or capsules.
By methods known per se, such as conventional mixing, dissolving, emulsifying, suspending, microencapsulating, lyophilizing, extrusion and rounding, lamination, film coating, granulation, encapsulation, sugar coating or compression, The pharmaceutical composition of the present invention is prepared.
The pharmaceutical composition of the present invention can be formulated by customary means using one or more physiologically acceptable excipients (including binding agents) which promote the active substance and Into a pharmaceutically acceptable pharmaceutical dosage form. Proper formulation depends on the mode of administration chosen. Any technique and excipient known in the art can be used.
Excipients suitable for preparation can be selected from the following ranges, such as but not limited to fillers for tablets and capsules, binding agents for tablets and capsules, modified drug release agents, disintegrants, glidants, Lubricants, sweeteners, taste-masking agents, flavoring agents, coatings, surfactants, stabilizers, preservatives or antioxidants, buffers, complexing agents, wetting agents or emulsifiers, osmotic salts, lyophilization Excipients, microcapsules, salves, penetration enhancers, solubilizers, solvents, suppositories and suspending agents. Suitable pharmaceutical excipients can be, for example, starch, microcrystalline cellulose, talc, glucose, lactose, gelatin, silica, talc, magnesium stearate, sodium stearate, glyceryl monostearate, cellulose-derived Substances, sodium chloride, glycerol, propylene glycol, water, ethanol, and the like.
Another aspect of the present invention relates to the use of specific binding agents that can improve the solubility, solubility, permeability, absorption, or bioavailability of the active substance, such as but not limited to hydrophilic polymers, hot melt extrusion Forming agents, surfactants, buffering agents, complexing agents, emulsifiers, lyophilized excipients, disintegrating agents, microcapsules, penetration enhancers, solubilizers, co-solvents and suspending agents.
The above-mentioned excipients and various preparation methods are only representative examples. Other materials and process technologies known in the art can also be used.
"Disease or condition related to V1a receptor function" or "Disease or condition related to central and / or peripheral regulation (preferably V1a receptor antagonism)" means a variety of pathological symptoms, blood pressure control selected from the female sex organ Persistent symptoms, symptoms caused by inappropriate secretion of vasopressin, anxiety, depression, aggressive behavior, central nervous system disease (wherein one of the symptoms of the disease and / or multiple symptoms may be related to anxiety, depression or Aggressive behaviors or comorbidities with the aforementioned three diseases (autism group disorder, obsessive-compulsive disorder, many different types of Down syndrome and post-traumatic stress disorder), aggressive behavior disorder and / or irritability, behavior Diseases or disorders of hyperactivity, cognitive impairment, or other neuropsychiatric disorders.
Various pathological symptoms of the female sex organ include, but are not limited to, dysmenorrhea (primitive and / or secondary) or sexual dysfunction.
Persistent symptoms of this blood pressure control include, but are not limited to, hypertension and / or chronic heart failure.
Symptoms caused by the inappropriate secretion of vasopressin include, but are not limited to, diabetes insipidus, renal failure, renal syndrome, or cirrhosis.
The central nervous system diseases (wherein one of the symptoms of the disease and / or multiple symptoms may be related to anxiety, depression or aggressive behavior or show comorbidities with the aforementioned three diseases) include but are not limited to autism group disorders (good Functional Autism, Asperger's Syndrome, PWD-NOS, ASD and ASD and many different syndromes: Fragile X Chromosome, Prideway Syndrome, Leiter's disease and tuberous sclerosis), obsessive-compulsive disorder (OCD), many different types of Down syndrome and post-traumatic stress disorder (PTSD).
This aggressive behavior disorder and / or irritability includes, but is not limited to, ASD, Huntington's disease, or different types of schizophrenia.
The behavioral hyperactivity disorder includes, but is not limited to, attention deficit hyperactivity disorder.
The cognitive impairment includes, but is not limited to, dementia, mild cognitive impairment, cognitive impairment associated with schizophrenia, or Alzheimer's disease.
The other neuropsychiatric diseases include, but are not limited to, schizophrenia and related diseases.
In one embodiment, the disease or condition related to the function of the Via receptor or the disease or condition related to central and / or peripheral regulation (preferably the antagonist of the Via receptor) refers to an autism group disorder.
The present invention relates to a method for treating and / or preventing a disease or condition related to the function of a Via receptor, which comprises administering a treatment effective to an individual (preferably a mammal and more preferably a human) in need of the treatment and / or prevention. Amounts of the compounds of the general formula (I) alone and / or their salts and / or their geometric isomers and / or their stereoisomers and / or their mirror isomers and / or their And other racemates and / or their non-mirromeric isomers and / or their prodrugs and / or their solvates and / or their hydrates and / or their polymorphs or At least one pharmaceutically acceptable excipient is in the form of a pharmaceutical modulator.
The present invention relates to a method for treating an individual (preferably a mammal and more preferably a human) suffering from a disease or condition selected from a variety of pathological symptoms of female sex organs, persistent symptoms of blood pressure control, and vasopressor Symptoms, anxiety, depression, aggressive behavior, central nervous system disease (where one or more of the symptoms of the disease and / or multiple symptoms may be related to anxiety, depression or aggressive behavior or related to the aforementioned three Illnesses showing comorbidities (autism group disorder, obsessive-compulsive disorder, many different types of Down syndrome and post-traumatic stress disorder), aggressive behavior disorder and / or irritability, hyperactivity disorder, cognitive impairment or other nerves Mental illness, or a combination of these disorders. The method of treatment comprises administering a therapeutically effective amount of a compound of general formula (I) and / or their salts and / or their geometric isomerism to an individual (preferably a mammal and more preferably a human) in need of the treatment. And / or their stereoisomers and / or their mirror isomers and / or their racemates and / or their non-image isomers and / or their prodrugs and / Or their solvates and / or their hydrates and / or their polymorphs. The treatment method may include administering a therapeutically effective amount of a pharmaceutical composition to an individual (preferably a mammal and more preferably a human) in need of the treatment, the pharmaceutical composition comprising a compound of general formula (I) and / or Salts and / or their geometric isomers and / or their stereoisomers and / or their mirror isomers and / or their racemates and / or their non-image isomers And / or their prodrugs and / or their solvates and / or their hydrates and / or their polymorphs.
The invention relates to the compounds of the general formula (I) and / or their salts and / or their geometric isomers and / or their stereoisomers and / or their mirror isomers and / or Their racemates and / or their non-image isomers and / or their prodrugs and / or their solvates and / or their hydrates and / or their polymorphs are Use in the manufacture of a medicament for the treatment and / or prevention of a disease or condition related to the function of the Via receptor.
The "treatment" refers to the alleviation of specific pathological symptoms in patients or individuals who have suffered or been diagnosed with the disease, the removal or alleviation of one or more symptoms, the slowing or elimination of the progression of the disease state, and the prevention or recurrence of pathological symptoms or delay. If a drug has been administered to a patient who has developed a disease or disorder, the drug is generally administered by the same or similar method to implement the "prevention" (or prevention or delay in the occurrence of the disease).
A "therapeutically effective amount" refers to the amount of active substance that causes the treatment, cure, prevention, or amelioration of a disease or pathological symptom or side effect, and can reduce the disease or pathological symptom compared to a corresponding individual who has not received the therapeutically effective amount. progress. The therapeutically effective amount also includes an effective amount that enhances normal physiological functions. For the treatment, a therapeutically effective amount of the compound of the general formula (I) and / or their geometric isomers and / or their stereoisomers and / or their mirror isomers and / Or their racemates and / or their non-mirromeric isomers and / or their prodrugs and / or their solvates and / or their hydrates and / or as many of them Forms and any of their pharmaceutically acceptable salts are used as raw chemicals. In addition, the active substance can be provided as a pharmaceutical preparation. The compounds of general formula (I) and / or their salts and / or their geometric isomers and / or their stereoisomers and / or their mirror isomers and / or their Accurate treatment of racemates and / or their non-mirromeric isomers and / or their prodrugs and / or their solvates and / or their hydrates and / or their polymorphs The effective amount depends on many factors, including but not limited to the age and weight of the individual (patient) being treated, the exact type and severity of the disease to be treated, the nature of the drug and the route of administration.
"Mammal" means any member of the "mammalian group", including but not limited to humans.
The present invention also relates to a pharmaceutical composition suitable for treating a disease or condition related to central and / or peripheral regulation (preferably V1a receptor antagonism), which comprises the compound of the general formula (I) and / or their Salts and / or their geometric isomers and / or their stereoisomers and / or their mirror isomers and / or their racemates and / or their non-image isomers And / or their prodrugs and / or their solvates and / or their hydrates and / or their polymorphs.
The compounds of the present invention may also be combined with one or more compounds of the present invention or one or more other active substances (e.g., psycho blockers, psychostimulants, antihypertensives, antispasmodics, antiepileptics or other agents) to For mammals suffering from central and / or peripheral regulation of the V1a receptor and preferably antagonizing central and / or peripheral disease that may have therapeutic benefits, including but not limited to humans.
Psychotic agents include, but are not limited to, antipsychotics, anxiolytics, and sedative hypnotics or anesthetics.
Antipsychotics include, but are not limited to, typical and atypical antipsychotics, such as phenothiazine (chloropromazine, promethazine, methisobutazine, acepromazine, triflurazine, Salmepramine (ciamemazine, chlorpromazine, protipendyl), piperazine-derived phenothiazine (desicillazine, flufenazine, meperpromazine, oxypiperazine, propane) Clopirazine, Thioprazine, Triflurilazine, Epiphenazine, Thipromazine, Butapiperazine, Mepiperazine), Piperidine-derived phenothiazine (piperazine, Methiopiperidine, mesopyrazine, piperazine), thioanthracene (chloroprothione, cloopenthixole, flupentiaxant, meperidine, thioprene, and meclizine) , Butyric acid ketone derivatives (haloperidol, trihaloperidol, mepirone, mopirone, pipipronol, bromperidone, benziprodone, droperidol, and thimeridone , Fluanidone), diphenylbutylpiperidine derivatives (fluspirene, pentafluridol, amimidamine), diazine or oxacridine or thiazine derivatives (clozapine, Austria Azapine, clothiapine, quetiapine, losapine, asena ), Indole derivatives (serindole, ziprasidone, lurasidone, morpholininone, oxipertine), benzamidine derivatives (sulpiride, sutopril, thiopiridine) Rilimb, remabilil, amisulpride, verapride, nemabilil, vilapirab) or other agents (risperidone, aripiprazole, carbazrazine, epiprazole , Metopramine, moxapamine, iperidone, paliperidone, amozapine, ampipirone, piropiron, carbamate, chlorcarbamine, tetrabenazine, lithium).
Anxiolytics include, but are not limited to, benzodiazepine (diazepine, clodazapine, medarazapine, nordazapine, potassium clozapine acid, lenapine, azozolan, bromazepine Ping, Ketazopine, Ketazolol, Ciprodazapine, Alprazota, Trifluzapine, Propynezepine, Carzapine, Prozapine, Fludiazepine, Chlorflurane , Etizolam, clotazapine, oxazolam, tophizopam), diphenylmethane derivatives (hydroxyzine, butylthiodiphenylamine), carbamates (methalamine Esters, emilcamate, mevalyl amine esters), dibenzobicyclooctadiene derivatives (benzoquinones), azaspirodecanediones (buspirone), other agents (mefenam Oxadione, Guidocar, Chlorphenazine, Fabomotizole, Trimethosine), by increasing GABA _A Derivatives or compounds that act on serotonin receptors, and other GABA neurogenic agents (such as GABA _A α5 NAMs (e.g. Parmesani) and GABA _A α5 PAMs (e.g. RG7816)).
Sedative hypnotics or narcotics include, but are not limited to, barbiturates (pentabarbital, isopentabarbital, n-butabarbital, barbiturate, allyl isobarbital, sercobarbital, Tarbbitol, Ethylbital, Pentenylbital, Cycbarbital, Heptobarbital, Westcobarbital, Mesopital, Cyclohexene Barbital, Thiopental Sodium, Ixabi , Alobarbital, proxibarbital), aldehydes (chloral hydrate, chloralhexanol, acetamigamine, chloral hydrate, antichlorin dichloride, Polyacetaldehyde), benzodiazepines (fluzepam, nitrazepam, flunazepam, estazolam, triazolam, clorazepam, temazepam, midazolam, bromozozolam , Quasiazepam, cloproxen, dulozepam, cinozepam), piperidine dione derivatives (acetophenone, mesperidone, diethylpyridine dione), cyclopyrrolidone benzodione Acridine derivatives (zopiclone, zolpidem, zaleplon, eszopiclone), melatonin receptor agonists (melatonin, rismetamine), or other hypnotics and sedatives (a Quinone, clomethiazole, bromisoval , Diethylbromide, sulfonamide, promethazine, trichloroethionic acid, chloropentynol, valerian root, hexyl propyl ester, bromide, propylene isopropyl acetate, pentamidine, methyl Pentynol, nicotinamide piperazine, dexmedetomidine).
Psychostimulants include, but are not limited to, psychostimulants or antidepressants.
Psychological stimulants include, but are not limited to, centrally acting sympathomimetics (amphetamine, dextroamphetamine, methamphetamine, methylphenidate, phenisotoin, fentalamine, modafinil, ethampoxone, alfa Tomoxetine, phenetilline, dextromethylphenidate, amphetamine mesylate), nootropics or other psychostimulants (caffeine, valprofen, meclofenate, pyridoxine Thiols, bisulfentan, dimethylamine ethanol, non-pisetide, citicoline, oxiracetam, pirostano, linopyridine, nizophenone, aniracetam, ethidium carnitine , Idebenone, Propylpyrrolid, Perbenmethanol, Pramiracetam, Averfinib, Vinpocetine, Tacrine, Donepezil, Carbatin, Galantamine, Ipidarin (ipidachrine ), Memantine, mebicar, fenibut).
Antidepressants include, but are not limited to, non-selective monoamine reuptake inhibitors (norpromazine, imipramine, imipramine oxide, clomipramine, opipritol, trimethoprim, rofil Palmin, dibenzepine, amitriptyline, normitamitriptyline, protiline, dushipin, ipindole, melitrazine, dintiline, dutiapine, amozapine, Metformin, aminidine, morphine, quinipramine), serotonin regulators and stimulants (verazolidone, vortioxetine), selective serotonin reuptake inhibitors (Qimimet Dioxetine, fluoxetine, paroxetine, sertraline, alapropionate, fluvoxamine, etoperidone, citalopram, lipunon), non-selective hydrazine-derived monoamine oxidase inhibitors (isoazohydrazine, nepal Yalamine, Phenylhydrazine, Trans-Phenylcypromine, Isonicotine Isoprazine, Isoproline (iprocloside), Non-hydrazine Monoamine Oxidase Inhibitors (Mortochlor, Toloxadone) Or other agents (hydroxytryptamine, tryptophan, mianserin, amine benzisoquine, trazodone, nefazodone, benmorpholine, dibenzilam, clotrimazole, oxafluoxine Mirtazapine, medesamin, tiempritine, pivagabine, venlafaxine, milnacipran, reboxetine, pyrididol, duloxetine, agomelatine , Desvenlafaxine, bupropion, gepirone, grass hypericum extract).
Antihypertensive drugs include, but are not limited to, beta-blockers, thiazide diuretics, angiotensin-converting enzyme inhibitors, calcium antagonists, angiotensin receptor antagonists (losartan), lovum bio Bases (Cinnamide, Reserpine, Norrepinepine, Mesoserpine, Bitaxerpine), Methyldopa, Imidazoline Receptor Agonists (Cronin, Chlophene, Tol Lonidine, Moxonidine, Rimenidine), Ganglion Blocking Anti-Adrenaline Agents (Gadolinium-Derived Mithifene, Secondary and Tertiary Amines Tetramethyl Dicycloheptylamine), Peripheral-acting Anti-Adrenaline Agents, alpha adrenergic receptor blockers (prazosin, indolamin, tramazosin, doxazosin, piperazine), guanidine derivatives (betanidine, guanethidine, guanidine Health, isoquinidine, guanaclofen, guanazodine, guanidinoline), arteriolar smooth muscle agents, thiazine-derived chlorotoxazine, hydrazinophthalazine derivatives (hydrazinophenidazine, hydralazine) (Entrazine, cardazine), pyrimidine-derived minoxidil, nitroferricyanide-derived pentacyannitrosammonium ferric acid, guanidine-derived pinacidil, and philophyllum alkaloids Reed, tyrosine hydroxylase inhibitory methyltyrosine, MAO inhibitor propynemethylbenzylamine, serotonin antagonist ketoserin, or other antihypertensive drugs (bosentan, ambrisentan, sitax Shengtan, Massitidine, Leosizone) and combinations of these agents and diuretics.
Antispasmodics or antispasmodics include, but are not limited to, peripheral muscle relaxants, arrow poison alkaloids, choline derivatives, and other quaternary ammonium muscle relaxants (Pankan Langning, Galatium Ammonium, Vicroine, Atracu Ammonium, hexafluorourea, pipecuronium bromide, doxycycline chloride, fazabromide, rocuronium, micuronium, cis-atracurium, botulinum toxin), central nervous system muscles Relaxants, carbamates (amphetamine, isopropylmethizuron, mesopotamone, methamphetamine, non-pamine esters), oxazole derivatives, thiazine derivatives, and triazine derivatives (Clomezadone, chloroxazolone), ethers related to antihistamines (ofinatlin, guaiacol) and other histaminergic drugs (such as histamine H ₃ Receptor antagonists / inverse agonists, such as saphene, thiomipramine, pethsente, beclomethasone propionate, ABT-239, connexin, A-349,821, betahistine), other central acting agents (Chloroaniline butyric acid, abaclofen, tizanidine, diphenidalyl alcohol, topiradone, thiocolchicoside, cresol glyceryl ether, tetrahydroazepam, amine phenylheptene, benzylamine ), Directly acting muscle relaxant dantrolene and its derivatives, by increasing GABA _A Inhibition of the media or reduction of Na ⁺ Transporting compounds (diphenytoin, carbazapine, lamotrigine, VPA), γ-aminobutyric acid derivatives (aminohexenoic acid, gabapentin), other GABA agents (such as GABA _B PAMs, such as ADX71441), tertiary amine-containing esters (oxybenzamine, camiprofen, mebeverine, trimebutine, rosivirin, dicyclovirin, dihexaverine, diphenvirin Lin, diphenperate), quaternary ammonium compounds (benzyl ammonium, glucopyrrolium, orphenammonium bromide, pentammonium, prilamicillin, oltibromonium, ethamidine, tridemonium, isopropylamine , Hexammonium, poliridine, mepenzolate, benphenate, phenphenate, diphenidate, emetonium iodide, temoperidomide, pirfenammonium bromide, and thipemide Ammonium bromide and tolperiamide), tertiary amines (Astra 1397, nifitazamine, phenamidine ceramide), papaverine, and their derivatives (drotaverine, mosa Verin, ethyl papaverine), serotonin receptor acting agents (alosetron, tegaserod, cilansetron, pukabili), other agents for functional gastrointestinal diseases (diphenylpropidin , Desopramine, chlorpheniramine, pirmonium, fenavirin, edampamin, prozazole, alverin, triethylbutanone, isomethine, carlovirin, resorcinol, Polysiloxane, trimethyldiphenylpropane Amine), succinimine derivatives (ethosuccin, phenylsuccinamide, mesuccinine) or belladonna alkaloids and their derivatives (atropine, celastamine, butyl scopolamine, methyl atropine, methyl atropine, formazan Scopolamine, fentonium, deltamethrin).
Antiepileptic drugs include, but are not limited to, barbiturates and their derivatives (methylphenobarbital, phenobarbital, ethylpyrimidinedione, barbizarone, methapital), hydantoin Derivatives (ethylphenytoin, diphenytoin, amine (diphenytoin) valeric acid, mephenytoin, fosphenytoin), oxazolidine derivatives (methyl ethyl ketone, paradione, trimethylcyclodione, Ethadion), succinimine derivatives (ethosuccin, phenylsuccinidine, mesuccinine), benzodiazepine derivatives clonazepam, carboxamide derivatives (carbazpine , Oxcarbazepine, rufibramide), fatty acid derivatives (valproic acid, valprofen, aminobutyric acid, aminohexic acid, flusalamine, tiagabine) and other antiepileptic drugs (Shu Thiazine, phenethylcarbamuron, lamotrigine, non-amine esters, topiramate, gabapentin, phentermine, levetiracetam, zonisamide, pregabalin, stifol, lakoxamine , Carbamine, retigabine, bovaracetam, chlorpromazine).
Other agents include but are not limited to pharmaceuticals (probiotics, digestive aids / digestants, herbal extracts), vitamins (both water-soluble and fat-soluble, such as, but not limited to, vitamins A, D3, E, K, B1, B5 , B6, B12, C or their derivatives) and nutritional supplements (coenzymes such as Q10; flavones such as resveratrol; lecithin; unsaturated fatty acids including fatty acids omega-3 and omega-6) .
The compounds of the present invention can also be used with phosphodiesterase 5 isoenzyme inhibitors (PDE5), nitric oxide donors, cyclooxygenase inhibitors, other V1a receptor antagonists (such as balofeta) or L- Arginine is used in combination to treat and / or prevent diseases or conditions related to the function of the Via receptor.
The combination composition may contain the compound of the present invention and another active substance in a single dosage form or separately. The combined composition can be administered simultaneously, separately, or sequentially.
Suitable dosage forms include oral, rectal, mucosal, transdermal or enteral administration; parenteral administration includes intramuscular, subcutaneous, intravenous and intramedullary injections as well as intra-articular, intrathecal, direct intraventricular, intraperitoneal, nasal Intra- or intraocular injections and eye drops.
Alternatively, the compound may be administered locally and non-systemically, such as by injecting the compound directly into the kidney or heart by a release modifier that is usually modified. In addition, the drug can be administered via a target carrier system, such as a tissue-specific antibody-encapsulated liposome. The liposome selectively transfers the active substance to a target organ that absorbs the active substance.
The pharmaceutical composition can be administered in a number of different ways and pharmaceutical dosage forms. The compounds of the present invention may be administered in single or multiple doses alone or in combination with pharmaceutically acceptable excipients. The dosage required to achieve proper therapeutic efficacy can vary widely, and considering the stage of the disease, the state and weight of the patient to be treated, the selectivity of the active substance, the dosage formulation form and the number of daily treatments, the dosage must be suitable for the needs of the individual .
For simple administration, it is preferred that the medicinal composition is composed of multiple dosage units containing multiple, 1/2, 1/3 or 1/4 dose. The dosage unit is, for example, a tablet, which may have 1/2 or 1/4 grooves to provide 1/2 or 1/4 divided tablets to determine the required drug dose.
The pharmaceutical composition containing the active substance of the present invention usually contains 0.01 to 500 mg of active substance / dosage unit. Of course, it is also possible that the amount of active substance of each modulator exceeds the above-mentioned upper or lower limit.
A further preferred group of the compound of the general formula (I) is the following ring A, ring B, X, Y, Z, R ¹ -R ¹⁷ , Cy ¹ -Cy ³ , N, p, q, and r. Ring A, Ring B, X, Y, Z, R as defined below ¹ -R ¹⁷ , Cy ¹ -Cy ³ Any combination of the preferred embodiment, the better embodiment, or the best embodiment of, n, p, q, and r is also a preferred, better, or optimal group of a compound of general formula (I).
In certain embodiments of the present invention, the ring A in the compound of the general formula (I) is a 4- to 6-membered saturated carbocyclic ring.
In some preferred embodiments of the present invention, the ring A in the compound of the general formula (I) is cyclobutyl or cyclohexyl.
In some more preferred embodiments of the present invention, the ring A in the compound of the general formula (I) is cyclohexyl.
In certain embodiments of the present invention, in the compound of the general formula (I), ring A is a 4- to 7-membered saturated heterocyclic group containing 1 or 2 N, wherein ring A is connected to Y via a ring nitrogen.
In certain embodiments of the present invention, in the compound of the general formula (I), ring A is a 4 to 7-membered saturated heterocyclic group containing 1 or 2 N, wherein ring A is connected to the 5,6- Dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzotriazine core is attached to the triazole ring.
In certain embodiments of the present invention, the ring A of the compound of the general formula (I) is tetrahydroacryl, 1,3-bis (tetrahydroacryl), pyrrolidinyl, pyrazoridinyl, imidazole Pyridyl, piperidinyl, piperazinyl, azacycloheptyl, 1,3- or 1,4-diazacycloheptyl, wherein ring A is connected to Y via a ring nitrogen.
In certain embodiments of the present invention, the ring A of the compound of the general formula (I) is tetrahydroacryl, 1,3-bis (tetrahydroacryl), pyrrolidinyl, pyrazoridinyl, imidazole Pyridyl, piperidinyl, piperazinyl, azacycloheptyl, 1,3- or 1,4-diazacycloheptyl, wherein ring A is linked to the 5,6-dihydro via a ring nitrogen -4H- [1,2,4] triazolo [4,3-a] [1] benzotriazine nucleus is attached to the triazole ring.
In certain preferred embodiments of the present invention, the ring A of the compound of the general formula (I) is tetrahydroazepine-1,3-diyl, piperidine-1,4-diyl, or piperazine-1, 4-diyl, where ring A is via ring nitrogen with Y or the 5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoacene core The triazole ring is attached.
In certain embodiments of the present invention, the ring B in the compound of the general formula (I) is an optionally substituted heteroaryl group.
In certain preferred embodiments of the present invention, the ring B in the compound of the general formula (I) is optionally substituted and contains 5 or 6 members of 1 N, 2 N or 1 N and 1 O. Single heteroaryl.
In some preferred embodiments of the present invention, the ring B in the compound of the general formula (I) is pyridin-2-yl, 3-chloro-pyridin-2-yl, 3-methyl-pyridin-2-yl, Pyridine-3-yl, pyrimidin-2-yl or 5-methyl-isoxazol-3-yl.
In some preferred embodiments of the present invention, the ring B in the compound of the general formula (I) is pyridin-2-yl.
In certain embodiments of the present invention, the ring B in the compound of the general formula (I) is an optionally substituted aryl group.
In certain preferred embodiments of the present invention, the ring B in the compound of the general formula (I) is an optionally substituted phenyl group.
In certain embodiments of the present invention, the ring B in the compound of the general formula (I) is an optionally substituted heterocyclic group.
In certain preferred embodiments of the present invention, the ring B in the compound of the general formula (I) is optionally substituted and contains a 4- to 7-membered heterocyclic group containing 1 N or 1 N and 1 O.
In certain more preferred embodiments of the present invention, the ring B of the compound of the general formula (I) is tetrahydroazino-1-yl, pyrrolidin-1-yl, piperidinyl, piperazinyl, or morpholine- 4-based.
In certain embodiments of the present invention, if ring B is present, Y is -O- in the compound of the general formula (I).
In certain embodiments of the present invention, if ring B is present, Y in the compound of general formula (I) is -C (O)-.
In certain embodiments of the present invention, if ring B is present, Y is -CH in the compound of formula (I). ₂ -.
In certain embodiments of the present invention, if ring B is present, Y in the compound of general formula (I) is -NH-.
In certain embodiments of the present invention, if ring B is present, Y is a single bond in the compound of general formula (I).
In certain embodiments of the present invention, if ring B does not exist, Y is -N (C _1-4 alkyl) ₂ C, optionally substituted by halogen _1-4 Alkyl, C _1-4 Alkoxy, C (O) OC _1-4 Alkyl or halogen.
In certain embodiments of the present invention, if ring B is absent, Y in the compound of the general formula (I) may be optionally substituted with C. _1-4 Alkyl or C _1-4 Alkoxy.
In certain preferred embodiments of the present invention, if ring B does not exist, Y is C in the compound of formula (I) _1-3 alkyl.
In some preferred embodiments of the present invention, if ring B is absent, Y in the compound of general formula (I) is methyl or ethyl.
In certain preferred embodiments of the present invention, if ring B does not exist, Y is C in the compound of formula (I) _1-3 Alkoxy.
In some preferred embodiments of the present invention, if ring B is absent, Y in the compound of general formula (I) is methoxy or ethoxy.
In certain preferred embodiments of the present invention, if ring B does not exist, Y is CF in the compound of general formula (I) ₃ .
In certain embodiments of the present invention, if ring B does not exist, Y in the compound of general formula (I) means selected from -N (C _1-4 alkyl) ₂ , C (O) OC _1-4 Alkyl, optionally halogen-substituted C _1-4 Alkyl, C _1-4 Either alkoxy or halogen.
In certain preferred embodiments of the present invention, if ring B is absent, Y in the compound of general formula (I) means selected from dimethylamine or CF. ₃ One of them.
In certain embodiments of the present invention, if ring B is absent, Y in the compound of the general formula (I) refers to a group selected from C optionally substituted with halogen. _1-4 Alkyl, C _1-4 Both alkoxy or halogen.
In certain preferred embodiments of the present invention, if ring B does not exist, Y in the compound of the general formula (I) means selected from C _1-3 Alkyl, C _1-3 Both alkoxy or fluorine.
In some preferred embodiments of the present invention, if ring B is absent, Y in the compound of the general formula (I) refers to two selected from methyl, ethyl, methoxy, ethoxy, or fluorine. By.
In some very preferred embodiments of the present invention, if ring B is absent, Y in the compound of general formula (I) refers to both selected from methyl or methoxy.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), ring A is cyclobutyl or cyclohexyl, and Y is selected from -N (C _1-4 alkyl) ₂ CF ₃ Or halogen, and ring B is absent.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), ring A is cyclobutyl or cyclohexyl, and Y is selected from C which is optionally substituted with halogen. _1-4 Alkyl, C _1-4 Either alkoxy or halogen, and ring B is absent.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), ring A is cyclobutyl or cyclohexyl, Y is -O- or a single bond and ring B is phenyl, 2-methyl -Phenyl, tetrahydroacryl-1-yl, pyrrolidin-1-yl, morpholin-4-yl, pyridin-2-yl, 3-chloro-pyridin-2-yl, 3-methyl-pyridine 2-yl, pyridin-3-yl, pyrimidin-2-yl or 5-methyl-isoxazol-3-yl.
In some preferred embodiments of the present invention, in the compound of the general formula (I), ring A is cyclohexyl, Y is -O- and ring B is pyridin-2-yl, pyridin-3-yl, 3 -Chloro-pyridin-2-yl, 3-methyl-pyridin-2-yl, pyrimidin-2-yl, or 5-methyl-isoxazol-3-yl.
In some preferred embodiments of the present invention, in the compound of the general formula (I), ring A is cyclohexyl, Y is -O-, and ring B is pyridin-2-yl.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), ring A is a cyclohexyl group, Y is a single bond, and ring B is a morpholin-4-yl group.
In certain embodiments of the present invention, in the compound of general formula (I), ring A is cyclobutyl or cyclohexyl, Y is -C (O)-, and ring B is tetrahydroacryl-1- Group, pyrrolidin-1-yl or morpholin-4-yl.
In certain embodiments of the present invention, in the compound of the general formula (I), ring A is cyclobutyl or cyclohexyl, and Y is -CH. ₂ -, And Ring B is optionally substituted aryl, heterocyclyl or heteroaryl.
In certain embodiments of the present invention, in the compound of the general formula (I), ring A is cyclobutyl or cyclohexyl, and Y is -CH. ₂ -, And Ring B is optionally substituted 4 to 7 membered heterocyclic group containing 1 N or 1 N and 1 O.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), ring A is tetrahydroazepine-1,3-diyl, piperidine-1,4-diyl, or piperazine- 1,4-diyl, wherein ring A is via ring nitrogen with Y or the 5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine The triazole ring of the fluorene core is connected, Y is -O- or a single bond, and ring B is phenyl, 2-methyl-phenyl, tetrahydroazepine-1-yl, pyrrolidin-1-yl, morpholine 4-yl, pyridin-2-yl, 3-chloro-pyridin-2-yl, 3-methyl-pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, or 5-methyl-iso Oxazol-3-yl.
In some more preferred embodiments of the present invention, in the compound of the general formula (I), ring A is tetrahydroazine-1,3-diyl, wherein ring A is via ring nitrogen and Y or the 5, 6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzotriazine core triazole ring connection, Y is a single bond, and ring B is pyridine-2 -Yl, pyrimidin-2-yl, piperidinyl or optionally substituted phenyl.
In some embodiments of the present invention, the BYA-bond in the compound of the general formula (I) represents 3 H -Spiro [2-benzofuran-1,4'-piperidine-1'-yl], via C at the 3 position _1-4 Alkyl-substituted 1-oxa-3-azaspiro [4.5] dec-2-one-8-yl or via C at the 2 position _1-4 Alkyl, aryl or heteroaryl substituted 2-azaspiro [4.5] dec-1-one-8-yl.
In some embodiments of the present invention, the BYA-bond in the compound of the general formula (I) represents 3 H -Spiro [2-benzofuran-1,4'-piperidine-1'-yl], (5S, 8S) -3-methyl-1-oxa-3-azaspiro [4.5] dec-2 -Keto-8-yl, (5R, 8R) -3-methyl-1-oxa-3-azaspiro [4.5] dec-2-one-8-yl, (5 R ,8 R ) -2- (prop-2-yl) -2-azaspiro [4.5] dec-1-one or (5 S ,8 S ) -2- (prop-2-yl) -2-azaspiro [4.5] dec-1-one.
In certain embodiments of the present invention, R in the compound of general formula (I) ¹ Department of hydrogen.
In certain embodiments of the present invention, R in the compound of general formula (I) ¹ Department of halogen.
In certain preferred embodiments of the present invention, R in the compound of the general formula (I) ¹ Department of chlorine, bromine or fluorine.
In some preferred embodiments of the present invention, R in the compound of the general formula (I) ¹ Department of chlorine.
In certain embodiments of the present invention, R in the compound of general formula (I) ¹ Department C _1-4 alkyl.
In certain preferred embodiments of the present invention, R in the compound of the general formula (I) ¹ Department of methyl.
In certain embodiments of the present invention, R in the compound of general formula (I) ¹ Department C _1-4 Alkoxy.
In certain preferred embodiments of the present invention, R in the compound of the general formula (I) ¹ Department of methoxy.
In certain embodiments of the present invention, R in the compound of general formula (I) ¹ Department of CF ₃ .
In certain embodiments of the present invention, R in the compound of general formula (I) ¹ Department of CN.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² Hydrogen or C _1-4 Alkyl, R ³ Department (CH ₂ ) _n R ⁴ , C (O) R ⁵ Or optionally via R ⁶ Replaced by C _1-4 alkyl.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department (CH ₂ ) _n R ⁴ , C (O) R ⁵ Or optionally via R ⁶ Replaced by C _1-4 alkyl.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department (CH ₂ ) _n R ⁴ Where R ⁴ Is CN, azide, or optionally substituted 5-membered monoheteroaryl containing 2 N and 1 O or 4 N, and n is 0 or 1.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department (CH ₂ ) _n R ⁴ Where R ⁴ Is CN, and n is 0 or 1.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department (CH ₂ ) _n R ⁴ Where R ⁴ Is tetrazolyl or 3-methyl-1,2,4-oxadiazol-5-yl, and n is 0 or 1.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ C (O) R ⁵ Where R ⁵ Department C _1-4 alkyl.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ C (O) R ⁵ Where R ⁵ Methyl, ethyl, isopropyl or tertiary butyl.
In some preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ C (O) R ⁵ Where R ⁵ Department of methyl.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ C (O) R ⁵ Where R ⁵ Department C _1-4 Alkoxy.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ C (O) R ⁵ Where R ⁵ It is methoxy, ethoxy, propoxy or tertiary butoxy.
In some preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ C (O) R ⁵ Where R ⁵ Department of methoxy.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ C (O) R ⁵ Where R ⁵ Department of OH.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ C (O) R ⁵ Where R ⁵ Department of NR ⁷ R ⁸ Where R ⁷ And R ⁸ Independently hydrogen, C _1-4 Alkyl or Cy ² .
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ C (O) R ⁵ Where R ⁵ Department of NR ⁷ R ⁸ Where R ⁷ And R ⁸ For hydrogen.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ C (O) R ⁵ Where R ⁵ Department of NR ⁷ R ⁸ Where R ⁷ Hydrogen and R ⁸ Methyl, ethyl, isopropyl or tertiary butyl.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ C (O) R ⁵ Where R ⁵ Department of NR ⁷ R ⁸ Where R ⁷ And R ⁸ Independently methyl, ethyl, isopropyl or tertiary butyl.
In some preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ C (O) R ⁵ Where R ⁵ Department of NR ⁷ R ⁸ Where R ⁷ And R ⁸ Is methyl.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ C (O) R ⁵ Where R ⁵ Department of NR ⁷ R ⁸ Where R ⁷ Hydrogen and R ⁸ Is optionally substituted aryl or heteroaryl.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ C (O) R ⁵ Where R ⁵ Department of NR ⁷ R ⁸ Where R ⁷ And R ⁸ Together with the N to which they are attached forms an optionally substituted heterocyclic ring.
In some preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ C (O) R ⁵ Where R ⁵ Department of NR ⁷ R ⁸ Where R ⁷ And R ⁸ Together with their linked N, a 4 to 7 membered saturated heterocyclic ring containing 1 N, 2 N, 1 N and 1 O or 1 N and 1 S is optionally substituted.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Optionally via R ⁶ Replaced by C _1-4 Alkyl, where R ⁶ Department of OR ⁹ , NR ¹⁰ R ¹¹ , Pendant oxygen, -O (CH ₂ ) _m O- or one or more halogens.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Methyl, ethyl or isopropyl.
In some preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Is isopropyl.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department of Economics R ⁶ Single or multiple branched C _1-4 Alkyl, where R ⁶ Department of OR ⁹ , NR ¹⁰ R ¹¹ Or one or more halogens.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department of Economics R ⁶ Single or multiple branched C _1-4 Alkyl, where R ⁶ One or more halogens.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ Halogen, -CH (halogen) CH ₃ Or -C (halogen) ₂ CH ₃ .
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ halogen.
In some preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ F.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department of Economics R ⁶ Replaced by C _1-4 Alkyl, where R ⁶ System side oxygen or -O (CH ₂ ) ₂ O-.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department of Economics R ⁶ Single or multiple branched C _1-4 Alkyl, where R ⁶ Department of OR ⁹ Or NR ¹⁰ R ¹¹ .
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ Where R ⁶ Department of OR ⁹ Or NR ¹⁰ R ¹¹ .
In some preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Where R ⁶ Department of OR ⁹ Or NR ¹⁰ R ¹¹ .
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department of Economics R ⁶ Replaced by C _1-4 Alkyl, where R ⁶ Department of OR ⁹ .
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , R ⁶ Department of OR ⁹ Where R ⁹ Department of hydrogen.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , R ⁶ Department of OR ⁹ Where R ⁹ Optionally via NH ₂ Or optionally substituted C _1-4 alkyl.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , R ⁶ Department of OR ⁹ Where R ⁹ Department of NH ₂ Substituted ethyl or isopropyl.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , R ⁶ Department of OR ⁹ Where R ⁹ Is ethyl or isopropyl.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , R ⁶ Department of OR ⁹ Where R ⁹ Department of Si (CH ₃ ) ₃ .
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , R ⁶ Department of OR ⁹ Where R ⁹ C (O) R ¹² , R ¹² Department C _1-5 alkyl.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , R ⁶ Department of OR ⁹ Where R ⁹ C (O) R ¹² , R ¹² Department of methyl.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , R ⁶ Department of OR ⁹ Where R ⁹ C (O) R ¹² , R ¹² Department of NR ¹⁴ R ¹⁵ .
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , R ⁶ Department of OR ⁹ Where R ⁹ C (O) R ¹² , R ¹² Department of NR ¹⁴ R ¹⁵ Where R ¹⁴ And R ¹⁵ Department of hydrogen.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , R ⁶ Department of OR ⁹ Where R ⁹ C (O) R ¹² , R ¹² Department of NR ¹⁴ R ¹⁵ Where R ¹⁴ And R ¹⁵ Independently hydrogen or optionally substituted aryl.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ , R ⁶ Department of OR ⁹ Where R ⁹ C (O) R ¹² , R ¹² Department of NR ¹⁴ R ¹⁵ Where R ¹⁴ System hydrogen, R ¹⁵ Is 4-fluoro-phenyl.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , R ⁶ Department of OR ⁹ Where R ⁹ C (O) R ¹² , R ¹² Department of NR ¹⁴ R ¹⁵ Where R ¹⁴ And R ¹⁵ Together with their linked N, a 4 to 7 membered saturated heterocyclic ring containing 1 N, 2 N, 1 N and 1 O or 1 N and 1 S is optionally substituted.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ , R ⁶ Department of OR ⁹ Where R ⁹ C (O) R ¹² , R ¹² Department of NR ¹⁴ R ¹⁵ Where R ¹⁴ And R ¹⁵ Together with their attached N, they form morpholines.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department of Economics R ⁶ Replaced by C _1-4 Alkyl, where R ⁶ Department of NR ¹⁰ R ¹¹ .
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , R ⁶ Department of NR ¹⁰ R ¹¹ Where R ¹⁰ And R ¹¹ Department of hydrogen.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , R ⁶ Department of NR ¹⁰ R ¹¹ Where R ¹⁰ And R ¹¹ Independently hydrogen or optionally via C _1-4 Alkoxy-substituted C _1-4 alkyl.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , R ⁶ Department of NR ¹⁰ R ¹¹ Where R ¹⁰ And R ¹¹ Independently hydrogen, methyl, ethyl, isopropyl, secondary butyl or tertiary butyl.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , R ⁶ Department of NR ¹⁰ R ¹¹ Where R ¹⁰ And R ¹¹ Independently hydrogen or methyl, ethyl or isopropyl substituted with methoxy or ethoxy.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , R ⁶ Department of NR ¹⁰ R ¹¹ Where R ¹⁰ And R ¹¹ Independently hydrogen or Cy ³ .
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , R ⁶ Department of NR ¹⁰ R ¹¹ Where R ¹⁰ System hydrogen, R ¹¹ 4 to 7-membered saturated heterocyclic group containing 1 O or C substituted with a twin halogen _4-6 Cycloalkyl.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department of Economics R ⁶ Replaced by C _1-4 Alkyl, where R ⁶ Department of NR ¹⁰ R ¹¹ Where R ¹⁰ And R ¹¹ Independently hydrogen or C (O) R ¹³ .
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , R ⁶ Department of NR ¹⁰ R ¹¹ Where R ¹⁰ System hydrogen, R ¹¹ C (O) R ¹³ , R ¹³ Department C _1-4 alkyl.
In some preferred embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department-CH ₂ R ⁶ , R ⁶ Department of NR ¹⁰ R ¹¹ Where R ¹⁰ System hydrogen, R ¹¹ C (O) R ¹³ , R ¹³ Department of methyl.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department of Economics R ⁶ Replaced by C _1-4 Alkyl, where R ⁶ Department of NR ¹⁰ R ¹¹ Where R ¹⁰ And R ¹¹ Independently hydrogen or C (O) R ¹³ Where R ¹³ Department Cy ¹ .
In certain embodiments of the present invention, in the compound of the general formula (I), R ² System hydrogen, R ³ Department of Economics R ⁶ Replaced by C _1-4 Alkyl, where R ⁶ Department of NR ¹⁰ R ¹¹ Where R ¹⁰ And R ¹¹ Independently hydrogen or C (O) R ¹³ Where R ¹³ Department of NR ¹⁶ R ¹⁷ .
In certain embodiments of the present invention, in the compound of the general formula (I), R ² Department C _1-4 Alkyl, R ³ Department (CH ₂ ) _n R ⁴ , C (O) R ⁵ Or optionally via R ⁶ Replaced by C _1-4 alkyl.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² Department C _1-4 Alkyl, R ³ Department (CH ₂ ) _n R ⁴ .
In certain embodiments of the present invention, in the compound of the general formula (I), R ² Department C _1-4 Alkyl, R ³ C (O) R ⁵ .
In certain embodiments of the present invention, in the compound of the general formula (I), R ² And R ³ Department C _1-4 alkyl.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² And R ³ Department C _1-3 alkyl.
In some preferred embodiments of the present invention, in the compound of the general formula (I), R ² And R ³ Independently methyl, ethyl or isopropyl.
In some very preferred embodiments of the present invention, in the compound of formula (I), R ² And R ³ Department of methyl.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² Department C _1-4 Alkyl, R ³ Department of Economics R ⁶ Replaced by C _1-4 Alkyl, where R ⁶ Department of OR ⁹ .
In certain embodiments of the present invention, in the compound of the general formula (I), R ² Department C _1-4 Alkyl, R ³ Department of Economics R ⁶ Replaced by C _1-4 Alkyl, where R ⁶ Department of OR ⁹ Where R ⁹ Department C _1-4 alkyl.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² Methyl or ethyl, R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ , R ⁶ Department of OR ⁹ Where R ⁹ Department of hydrogen.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² Department C _1-4 Alkyl, R ³ Optionally via R ⁶ Replaced by C _1-4 Alkyl, where R ⁶ Department of NR ¹⁰ R ¹¹ , Pendant oxygen, -O (CH ₂ ) _m O- or one or more halogens.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² And R ³ Combined Representative-(CH ₂ ) _p -O- (CH ₂ ) _q -, Where p is 1, 2 or 3 and q is 1, 2 or 3.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² And R ³ Combined Representative-(CH ₂ ) _p -O- (CH ₂ ) _q -, Where the sum of p and q is 3.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² And R ³ Combined Representative-(CH ₂ ) _p -O- (CH ₂ ) _q -, Where the sum of p and q is 4.
In some preferred embodiments of the present invention, in the compound of the general formula (I), R ² And R ³ Combined Representative-(CH ₂ ) _p -O- (CH ₂ ) _q -, Where p is 1 and q is 2.
In some preferred embodiments of the present invention, in the compound of the general formula (I), R ² And R ³ Combined Representative-(CH ₂ ) _p -O- (CH ₂ ) _q -, Where p is 1 and q is 3.
In some preferred embodiments of the present invention, in the compound of the general formula (I), R ² And R ³ Combined Representative-(CH ₂ ) _p -O- (CH ₂ ) _q -, Where p is 2 and q is 2.
In certain embodiments of the present invention, in the compound of the general formula (I), R ² And R ³ Combined Representative-(CH ₂ ) _r -, Where r is 4, 5, or 6.
In certain preferred embodiments of the present invention, in the compound of the general formula (I), R ² And R ³ Combined Representative-(CH ₂ ) _r -, Where r 系 4.
Although the invention has been described in terms of certain embodiments, certain preferred embodiments, certain better embodiments, or certain best practices, it is not intended to limit the scope of the invention to the particular forms disclosed And, on the contrary, the intention is to cover alternatives, modifications, and equivalents as included in the spirit and scope of the invention as defined by the description of the invention. Examples of alternative claimed ranges of compounds of the invention may include:
(1) A compound of general formula (I) as described above or in any other embodiment.
(2) The compound as described in (1) or any other embodiment, wherein R ¹ Based on hydrogen, fluorine, chlorine, bromine, methyl, methoxy, CF ₃ Or CN.
(3) The compound as described in any one of (1) to (2) or any other embodiment, wherein
Ring A is a 3 to 6-membered saturated carbocyclic ring or a 4 to 7-membered saturated heterocyclic ring containing 1 or 2 N;
Ring B is optionally substituted 5 or 6 membered monoheteroaryl, 6 to 10 membered aromatic carbocyclic rings or 4 to 7 members saturated with 1, 2 or 3 heteroatoms selected from O, S or N Monocyclic, bicyclic, fused and / or bridged heterocyclic rings;
Or BYA-Combined Representative 3 H -Spiro [2-benzofuran-1,4'-piperidine-1'-yl]; or

X is isopropyl;
Z is methyl.
(4) The compound as described in any one of (1) to (3) or any other embodiment, wherein ring B is optionally substituted 6-membered monoheteroaryl, phenyl, or contains 1 or 2 4- to 6-membered saturated monocyclic heterocycles of heteroatoms selected from O, S or N.
(5) The compound as described in any one of (1) to (4) or any other embodiment, wherein if ring B exists, Y is -O-, -C (O)-, -CH ₂ -, -NH- or single bond.
(6) The compound as described in any one of (1) to (5) or any other embodiment, wherein ring A is a 4- to 6-membered saturated carbocyclic group or via ring nitrogen with Y or the 5,6- Dihydro-4 H -[1,2,4] triazolo [4,3-a] [1] benzotriazine core with a triazole ring containing 1 to 2 4 to 7 membered saturated heterocyclic rings.
(7) The compound as described in any one of (1) to (6) or any other embodiment, wherein ring A is cyclohexyl, Y is -O-, ring B is pyridin-2-yl, and R ¹ Department of chlorine.
(8) The compound as described in any one of (1) to (6) or any other embodiment, wherein ring A is tetrahydroacridine, piperidine or piperazine, Y is -O- or a single bond, Ring B is pyridine, pyrimidine or piperidine, and R ¹ Department of chlorine.
(9) The compound as described in any one of (1) to (3) or any other embodiment, wherein Y is -N (C _1-4 alkyl) ₂ , C (O) OC _1-4 Alkyl, optionally halogen-substituted C _1-4 Alkyl, C _1-4 Alkoxy or halogen, and ring B is absent.
(10) The compound as described in (9) or any other embodiment, wherein ring A is a 4- to 6-membered saturated carbocyclic group.
(11) The compound as described in (10) or any other embodiment, wherein Y is selected from -N (C _1-4 alkyl) ₂ , C (O) OC _1-4 Alkyl, optionally halogen-substituted C _1-4 Alkyl, C _1-4 One of alkoxy and halogen.
(12) A compound as described in (10) or any other embodiment, wherein Y is selected from C optionally substituted with halogen _1-4 Alkyl, C _1-4 Both alkoxy and halogen.
(13) The compound as described in any one of (1) to (12) or any other embodiment, wherein R ² Hydrogen or C _1-4 Alkyl and R ³ Department (CH ₂ ) _n R ⁴ .
(14) The compound as described in (13) or any other embodiment, wherein R ² System hydrogen, R ³ Department (CH ₂ ) _n R ⁴ , R ⁴ Is CN, azide, or optionally C _1-4 Alkyl substituted 5-membered monoheteroaryl containing 2 N and 1 O or 4 N.
(15) The compound as described in any one of (1) to (12) or any other embodiment, wherein R ² Hydrogen or C _1-4 Alkyl, and R ³ C (O) R ⁵ .
(16) The compound as described in (15) or any other embodiment, wherein R ² Department of hydrogen.
(17) The compound as described in (16) or any other embodiment, wherein R ⁵ Methyl, methoxy, OH or NR ⁷ R ⁸ Where R ⁷ And R ⁸ Independently hydrogen, methyl, ethyl or isopropyl.
(18) The compound as described in any one of (1) to (12) or any other embodiment, wherein R ² Hydrogen or C _1-4 Alkyl and R ³ Optionally via R ⁶ Replaced by C _1-4 alkyl.
(19) The compound as described in (18) or any other embodiment, wherein R ² Hydrogen or C _1-4 Alkyl, and R ³ Department C _1-4 alkyl.
(20) The compound as described in (19) or any other embodiment, wherein R ² Hydrogen or C _1-3 Alkyl, and R ³ Department C _1-3 alkyl.
(21) The compound as described in (18) or any other embodiment, wherein R ² Hydrogen or C _1-4 Alkyl, and R ³ Department of Economics R ⁶ Single or multiple branched C _1-4 alkyl.
(22) A compound as described in (21) or any other embodiment, wherein R ³ Department-CH ₂ R ⁶ Or -CH (R ⁶ ) CH ₃ .
(23) The compound as described in any one of (21) to (22) or any other embodiment, wherein R ² Is hydrogen, and R ⁶ Department of OR ⁹ .
(24) A compound as described in (23) or any other embodiment, wherein R ⁹ Hydrogen, optionally C substituted with phenyl _1-4 Alkyl or C (O) R ¹² Where R ¹² Department of methyl.
(25) The compound as described in any one of (21) to (22) or any other embodiment, wherein R ² Department C _1-4 Alkyl, and R ⁶ Department of OR ⁹ .
(26) The compound as described in (25) or any other embodiment, wherein R ² Methyl or ethyl, and R ⁹ Department of hydrogen.
(27) The compound as described in any one of (21) to (22) or any other embodiment, wherein R ² Is hydrogen, and R ⁶ Department of NR ¹⁰ R ¹¹ .
(28) The compound as described in (27) or any other embodiment, wherein R ¹⁰ And R ¹¹ Independently hydrogen, optionally via C _1-4 Alkoxy-substituted C _1-4 Alkyl, Cy ³ Or C (O) R ¹³ , Or R ¹⁶ And R ¹⁷ Together with the N to which they are attached forms an optionally substituted heterocyclic ring.
(29) The compound as described in any one of (21) to (22) or any other embodiment, wherein R ² Department C _1-4 Alkyl, and R ⁶ Department of NR ¹⁰ R ¹¹ .
(30) The compound as described in any one of (21) to (22) or any other embodiment, wherein R ² Is hydrogen, and R ⁶ One or more halogens.
(31) The compound as described in (30) or any other embodiment, wherein the halogen is fluorine.
(32) The compound as described in any one of (21) to (22) or any other embodiment, wherein R ² Department C _1-4 Alkyl, and R ⁶ One or more halogens.
(33) A compound as described in (21) or any other embodiment, wherein R ⁶ System side oxygen or -O (CH ₂ ) ₂ O-.
(34) The compound as described in any one of (13) to (33) or any other embodiment, wherein the 5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] Absolute configuration of the carbon at position 5 of the benzoacridine core (R).
(35) The compound as described in any one of (13) to (33) or any other embodiment, wherein the 5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] Absolute configuration of the carbon at position 5 of the benzoacridine core (S).
(36) The compound as described in any one of (1) to (12) or any other embodiment, wherein R ² And R ³ Combined Representative-(CH ₂ ) _p -O- (CH ₂ ) _q -, Where p is 1, 2 or 3 and q is 1, 2 or 3.
(37) A compound as described in (36) or any other embodiment, wherein the sum of p and q is 3 or 4.
(38) A compound as described in any one of (1) to (12) or any other embodiment, wherein R ² And R ³ Combined Representative-(CH ₂ ) _r -, Where r is 4, 5, or 6.
Preferred compounds of the general formula (I) according to the invention are, for example, the following compounds and / or their salts and / or solvates and / or hydrates and / or polymorphs and / or bioactive metabolites and / or medicine:
1. 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] methyl benzoazine-5-carboxylic acid;
2. 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] benzoazine-5-carboxylic acid;
3. 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] benzoazine-5-carboxamide;
4. 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] benzoazine-5-carbonitrile;
5. 8-chloro-N, N-dimethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazepine-5-carboxamide;
6. (5S) -8-chloro-N, N-dimethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1 , 2,4] triazolo [4,3-a] [1] benzoazine-5-carboxamidine;
7. (5R) -8-chloro-N, N-dimethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1 , 2,4] triazolo [4,3-a] [1] benzoazine-5-carboxamidine;
8. 8-chloro-N- (prop-2-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazepine-5-carboxamide;
9. {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazepine-5-yl} (pyrrolidin-1-yl) methanone;
10. {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazin-5-yl} (morpholin-4-yl) methanone;
11. {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazin-5-yl} (1,1-dioxythiomorpholin-4-yl) methanone;
12. {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazepine-5-yl} methanol;
13. {(5S) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazole Ac [4,3-a] [1] benzoazepine-5-yl} methanol;
14. {(5R) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazole Ac [4,3-a] [1] benzoazepine-5-yl} methanol;
15. 8-chloro-5- (methoxymethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazine;
16. Morpholine-4-formate {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2, 4] triazolo [4,3-a] [1] benzoazin-5-yl} methyl;
17. (4-fluorophenyl) carbamic acid {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazin-5-yl} methyl ester;
18. 5- (azidomethyl) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazine;
19. 1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazin-5-yl} methylamine;
20. 8-chloro-5- (morpholin-4-ylmethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [ 1,2,4] triazolo [4,3-a] [1] benzoazine;
21. 1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazin-5-yl} -N, N-dimethylmethylamine;
22. N-({8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazepine-5-yl} methyl) propan-2-amine;
23. 8-chloro-1- [1- (pyrimidin-2-yl) tetrahydroazepine-3-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] Methylbenzoazine-5-carboxylic acid;
24. 8-Chloro-1- [trans-4- (dimethylamino) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Methyl benzoazine-5-carboxylic acid;
25. 8-chloro-1- [trans-4- (trifluoromethyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] methyl benzoazine-5-carboxylic acid;
26. 8-chloro-1- [trans-4- (morpholin-4-yl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Methylbenzoazine-5-carboxylic acid;
27. {1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazepine-5-yl} methanol;
28. 8-chloro-1- [trans-4- (pyrrolidin-1-ylcarbonyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] methyl benzoazine-5-carboxylic acid;
29. {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazin-5-yl} acetonitrile;
30. 8-chloro-5-[(4-methylpiperazin-1-yl) methyl] -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6- Dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine;
31. 8-chloro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazine;
32. 8-chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl]- 5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine;
33. 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5- (2H-tetrazol-5-yl) -5,6-dihydro-4H- [ 1,2,4] triazolo [4,3-a] [1] benzoazine;
34. N-({8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazepine-5-yl} methyl) tetrahydro-2H-piperan-4-amine;
35. N, N-dimethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -8- (trifluoromethyl) -5,6-dihydro-4H- [ 1,2,4] triazolo [4,3-a] [1] benzoazine-5-amine;
36. 8-Chloro-1- [trans-3-methyl-2-oxo-1-oxa-3-azaspiro [4.5] dec-8-yl] -5,6-dihydro- 4H- [1,2,4] triazolo [4,3-a] [1] benzoazine-5-carboxylic acid methyl ester;
37. N-({8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazepine-5-yl} methyl) acetamide;
38. N-({8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazepine-5-yl} methyl) oxetan-3-amine;
39. 8-chloro-1- [trans-4- (morpholin-4-ylcarbonyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] methyl benzoazine-5-carboxylic acid;
40. 8-Chloro-1- [cis-3-methyl-2-oxo-1-oxa-3-azaspiro [4.5] dec-8-yl] -5,6-dihydro- 4H- [1,2,4] triazolo [4,3-a] [1] benzoazine-5-carboxylic acid methyl ester;
41. 8-chloro-1- [1- (pyridin-2-yl) tetrahydroazepine-3-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] Methylbenzoazine-5-carboxylic acid;
42. 1- [trans-4- (tetrahydroazepine-1-ylcarbonyl) cyclohexyl] -8-chloro-5,6-dihydro-4H- [1,2,4] triazolo [4 , 3-a] [1] Methylbenzoazine-5-carboxylic acid;
43. 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5- (pyrrolidin-1-ylmethyl) -5,6-dihydro-4H- [ 1,2,4] triazolo [4,3-a] [1] benzoazine;
44. N-({8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazepine-5-yl} methyl) -2-methyl-N- (2-methylpropyl) propan-1-amine;
45. 8-chloro-1- [trans-4- (piperidin-1-ylcarbonyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] methyl benzoazine-5-carboxylic acid;
46. 1- (trans-4-{[4- (tertiary butoxycarbonyl) piperazin-1-yl] carbonyl} cyclohexyl) -8-chloro-5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazine-5-carboxylic acid methyl ester;
47. 8-Chloro-1- [trans-4- (piperazin-1-ylcarbonyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] Methylbenzoazine-5-carboxylic acid hydrochloride;
48. 8-methoxy-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4 , 3-a] [1] Methylbenzoazine-5-carboxylic acid;
49. 8-methyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] Methylbenzoazine-5-carboxylic acid;
50. 8-Chloro-N- (4-fluorophenyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazepine-5-carboxamide;
51. 8-bromo-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] methyl benzoazine-5-carboxylic acid;
52. 1- (1,4'-bipiperidin-1'-yl) -8-chloro-5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] Benzacene-5-carboxamide;
53. 8-chloro-1-[(5r, 8r) -1-oxo-2- (prop-2-yl) -2-azaspiro [4.5] dec-8-yl] -5,6- Dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine-5-carboxylic acid methyl ester;
54. 1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazepine-5-yl} ethanol;
55. 1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazin-5-yl} ethanone;
56. 8-chloro-5- (fluoromethyl) -1- (trans-4-methoxy-4-methylcyclohexyl) -5,6-dihydro-4H- [1,2,4] Triazolo [4,3-a] [1] benzoazine;
57. 1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazin-5-yl} -N- (2-methoxyethyl) ethylamine;
58. 8-fluoro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] methyl benzoazine-5-carboxylic acid;
59. 8-chloro-5- (fluoromethyl) -1- [trans-4- (trifluoromethyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazole Ac [4,3-a] [1] benzoazine;
60. 5- (fluoromethyl) -1- (trans-4-methoxy-4-methylcyclohexyl) -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazine;
61. {8-fluoro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazepine-5-yl} methanol;
62. 8-fluoro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazine;
63. cis- (racemic) -1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol;
64. trans- (racemic) -1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol;
65. (1R) -1-{(5R) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol;
66. (1S) -1-{(5S) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol;
67. (1S) -1-{(5R) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol;
68. (1R) -1-{(5S) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol;
69. 5- (fluoromethyl) -8-methyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2, 4] triazolo [4,3-a] [1] benzoazine;
70. (5S) -8-chloro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1 , 2,4] triazolo [4,3-a] [1] benzoazine;
71. (5R) -8-chloro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1 , 2,4] triazolo [4,3-a] [1] benzoazine;
72. 8-fluoro-1- [trans-4- (trifluoromethyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] methyl benzoazine-5-carboxylic acid;
73. 8-chloro-1- [4- (2,3-dimethylphenyl) piperazin-1-yl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazepine-5-carboxamide;
74. {8-fluoro-1- [trans-4- (trifluoromethyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Benzacridin-5-yl} methanol;
75. {8-chloro-5-methyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] tri Zolo [4,3-a] [1] benzoazepine-5-yl} methanol;
76. {8-chloro-5-ethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] tri Zolo [4,3-a] [1] benzoazepine-5-yl} methanol;
77. (5S) -8-fluoro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1 , 2,4] triazolo [4,3-a] [1] benzoazine;
78. (5R) -8-fluoro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1 , 2,4] triazolo [4,3-a] [1] benzoazine;
79. 8-chloro-1- [4- (3-chlorophenyl) piperazin-1-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzacridin-5-carboxamide;
80. 8-chloro-1- [4- (pyridin-2-yl) piperazin-1-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzacridin-5-carboxamide;
81. 8-chloro-1- [4- (pyridin-2-yloxy) piperidin-1-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazine-5-carboxamide;
82. 5-[(Benzyloxy) methyl] -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1 , 2,4] triazolo [4,3-a] [1] benzoazine;
83. 8-chloro-1- (3,3-difluorocyclobutyl) -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzene And methyl acridine-5-carboxylate;
84. 8-chloro-1- [trans-4- (piperidin-1-ylmethyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] Methylbenzoazine-5-carboxylic acid;
85. Acetic acid {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4 , 3-a] [1] benzoazine-5-yl} methyl ester;
86. 8-chloro-1- (1'H, 3H-spiro [2-benzofuran-1,4'-piperidine] -1'-yl) -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazine-5-carboxamide;
87. 8-Chloro-N- (pyridin-2-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazepine-5-carboxamide;
88. 8-Chloro-1- (1'H, 3H-spiro [2-benzofuran-1,4'-piperidine] -1'-yl) -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazine-5-carbonitrile;
89. 8-chloro-1- [4- (2,3-dimethylphenyl) piperazin-1-yl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazine-5-carbonitrile;
90. 8-chloro-1- [4- (pyridin-2-yl) piperazin-1-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzacene-5-carbonitrile;
91. 8-fluoro-5,5-dimethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazine;
92. 8-fluoro-5- (prop-2-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazine;
93.8'-Bromo-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -4'H, 6'H-spiro [cyclopentane-1,5'-[1 , 2,4] triazolo [4,3-a] [1] benzoazine];
94. 8-bromo-5- (prop-2-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazine;
95.8'-bromo-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -2,3,5,6-tetrahydro-4'H, 6'H-spiro [ Piperan-4,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine];
96. 8-fluoro-5,5-dimethyl-1- [trans-4- (trifluoromethyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazole Ac [4,3-a] [1] benzoazine;
97. (5R) -8-bromo-5- (prop-2-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine;
98. (5S) -8-bromo-5- (prop-2-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine;
99. 8'-Bromo-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -4,5-dihydro-4'H, 6'H-spiro [furan-3, 5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine];
100. 8'-Chloro-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -2,3,5,6-tetrahydro-4'H, 6'H-spiro [ Piperan-4,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine];
101. 8'-Chloro-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H, 4'H, 6'H-spiro [piperan -3,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine];
102. 8'-Chloro-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -4,5-dihydro-4'H, 6'H-spiro [furan-3, 5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine];
103. 8'-Chloro-1 '-[trans-4- (trifluoromethyl) cyclohexyl] -2,3,5,6-tetrahydro-4'H, 6'H-spiro [piperan- 4,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine];
104. (3R) -8'-bromo-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -4,5-dihydro-4'H, 6'H-spiro [ Furan-3,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine];
105. (3S) -8'-bromo-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -4,5-dihydro-4'H, 6'H-spiro [ Furan-3,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine];
106. (3S) -8'-chloro-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H, 4'H, 6'H- Spiro [piperan-3,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazepine];
107. (3R) -8'-chloro-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H, 4'H, 6'H- Spiro [piperan-3,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazepine];
108. 8-fluoro-1- (trans-4-methoxy-4-methylcyclohexyl) -5,5-dimethyl-5,6-dihydro-4H- [1,2,4] Triazolo [4,3-a] [1] benzoazine;
109. 8-fluoro-1- (cis-4-methoxy-4-methylcyclohexyl) -5,5-dimethyl-5,6-dihydro-4H- [1,2,4] Triazolo [4,3-a] [1] benzoazine;
110. 8'-Chloro-1 '-(trans-4-methoxy-4-methylcyclohexyl) -2,3,5,6-tetrahydro-4'H, 6'H-spiro [pipe Ran-4,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine];
111. 8'-Chloro-1 '-(cis-4-methoxy-4-methylcyclohexyl) -2,3,5,6-tetrahydro-4'H, 6'H-spiro [pipe Ran-4,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine]; or
112. 8-chloro-1- [trans-4- (pyridin-2-ylamino) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] Benzoazine-5-carboxylic acid methyl ester.

The invention also relates to the synthesis of compounds of general formula (I). Thus, the compound of the general formula (I) of the present invention can be prepared by one of the following methods.
So far, in the compound of general formula (I), R ² System hydrogen, R ³ C (O) R ⁵ , R ⁵ Department C _1-4 Alkoxy and ring A is a cycloalkyl or a 4- to 7-membered saturated heterocyclic ring containing 1 N, in which ring A is connected to Y via a ring nitrogen, by combining a compound of general formula (II) with general formula (III) Compounds are reacted to prepare compounds of general formula (I) of the present invention, wherein the compounds of general formula (II) are

Wherein ring B and Y are as defined in the general formula (I) above and ring A is a cycloalkyl group or a 4- to 7-membered saturated heterocyclic ring containing one N, wherein ring A is connected to Y via a ring nitrogen, and the general Compound of formula (III)

Where R ¹ Is defined by the general formula (I) above, R ³ C (O) R ⁵ And R ⁵ Department C _1-4 Alkoxy.
The reaction is shown in detail in Figure 1:

In step a) of FIG. 1, the hydrazine of the general formula (II) is reacted with a benzoazepine-thione of the general formula (III). The reaction is preferably carried out in a suitable solvent and at the boiling point of the solvent with a required reaction time of 4 to 120 hours. Suitable solvents include, for example, xylene, n-butanol and 1,4-dioxane.
Preferred implementations are, for example, the following:
i) the reaction of formula (II) and formula (III) in xylene at 140 ° C for 20 to 120 hours; or
ii) The reaction of formula (II) and formula (III) is carried out in n-butanol at 110 ° C for 20 to 50 hours.
The hydrazine of general formula (II) can be synthesized by a number of different methods (Figure 2):

In step a) of FIG. 2, the formate of the general formula (IV) is in a suitable alcohol and reacted with the hydrazine hydrate at the boiling point of the solvent to obtain the hydrazine of the general formula (II), or in step c ), The formic acid of the general formula (V) is reacted with tert-butyl hydrazinoformate and the protecting group of the protected formamidine hydrazine derivative of the general formula (VI) is removed using an appropriate acid (step d)).
Preferred implementations are, for example, the following:
Step a) methanol or ethanol; hydrazine hydrate; reflux temperature; 4 to 50 hours;
Step b) methanol; thionyl chloride; 0 to 25 ° C; 4 to 24 hours;
Step c) tert-butyl hydrazinecarboxylic acid; N, N-dimethylformamide; N, N-diisopropylethylamine; N- (3-dimethylaminopropyl) -N'- Ethylcarbodiimide hydrochloride; 1-hydroxybenzotriazole hydrate; room temperature; 4 to 20 hours;
Step d) Hydrochloric acid in ethyl acetate; room temperature; 4 to 20 hours.
The formate of the general formula (IV) and the formic acid of the general formula (V) are commercially available or can be prepared according to the method described in the examples.
According to the method shown in FIG. 3, the main intermediate benzoazepine-thione derivative (wherein R is ¹ (As defined by the general formula (I) above):

Acid derivatives of general formula (VII) (where R ¹ (As defined by the general formula (I) above) is esterified (step a)) to form an ester derivative of the general formula (VIII), and the general formula (IX) is prepared from the ester derivative of the general formula (VIII) Oxime derivative (step b)). By Beckmann rearrangement, the oxime derivative of the general formula (IX) is converted into a benzoacridine compound of the general formula (X) (step c)), and from the benzene of the general formula (X) The acridine compound is used to prepare a benzoacridine-thione derivative of the general formula (III-a) (step d)).
Preferred implementations are, for example, the following:
Step a) methanol; concentrated sulfuric acid; reflux temperature; 4 to 20 hours;
Step b) methanol; sodium acetate; hydroxylamine hydrochloride; reflux temperature; 2 to 6 hours;
Step c) polyphosphoric acid; 100 to 120 ° C; 15 to 60 minutes;
Step d) i) Lawesson's reagent; pyridine; reflux temperature; 2 to 10 hours; or
ii) Lawson's reagent; tetrahydrofuran; room temperature; 6 to 20 hours.
Benzacridine derivatives of general formula (X) ¹ (As defined by the general formula (I) above) to prepare other intermediates shown in FIG. 4 to FIG. 6.

In step a) of FIG. 4, an ethylamidine derivative of the general formula (XI) can be prepared by one step or three consecutive steps. The compound of the general formula (XI) is a main intermediate, and from the compound of the general formula (XI), a dioxane compound of the general formula (XII) (step b)) and a difluoro derivative of the general formula (XIII) can be prepared. (Step c)), protected compounds of the general formula (XIV) (step d)) (where PG ¹ Is a protective group (Peter GM Wuts: Greene's Protective Groups in Organic Synthesis: Fifth Edition, Chapter 7. Protection for the Amino Group, pages 895-1193), preferably 4-methoxybenzyl-) and the general formula (XV -a) a hydroxy compound (step e-1)). A hydroxy derivative of the general formula (XV) is prepared by reducing the compound of the general formula (XIV) (step e-2)), and a unit of the general formula (XVI) can be prepared from the hydroxy derivative of the general formula (XV) Fluorine compound (step f)). A compound of the general formula (XVII) can be obtained by removing the protecting group of the monofluoro compound of the general formula (XVI) (step g)). By protecting the free hydroxyl group, this unprotected hydroxyl derivative of formula (XV-a) can be converted into a compound of formula (XIX) (step h)), where PG ² Department and PG ¹ Different protective groups (Peter GM 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 silicon Radical protection radical.
Preferred implementations are, for example, the following:
Step a) methyl lithium solution; tetrahydrofuran; diethyl ether; (-10 ° C) to 5 ° C; 2 to 3 hours; or
Step i) aqueous sodium hydroxide solution; methanol; room temperature; 0.5 to 3 hours;
Step ii) N-methoxymethylamine hydrochloride; N -(3-dimethylaminopropyl)- N ' -Ethylcarbodiimide hydrochloride; N, N-dimethylformamide; N, N-diisopropylethylamine or triethylamine; 1-hydroxybenzotriazole hydrate; room temperature; 2 to 20 hours; then
Step iii) Diethyl ether solution of methyl magnesium bromide; tetrahydrofuran; (-10 ° C) to 0 ° C; 2 to 12 hours;
Step b) ethylene glycol; p-toluenesulfonic acid; toluene; reflux temperature; 6 to 12 hours;
Steps c) and f) diethylaminosulfur trifluoride; dichloromethane; (-78) to 10 ° C; 4 to 12 hours;
Step d) 4-methoxybenzyl chloride; sodium hydride; N, N-dimethylformamide; 0 to 25 ° C; 3 to 6 hours;
Steps e-1) and e-2) sodium borohydride; ethanol or methanol; room temperature; 0.5 to 2 hours;
Step g) i) ammonium cerium nitrate; water; acetonitrile; 0 to 25 ° C; 6 to 18 hours; or
ii) trifluoroacetic acid; dichloromethane; room temperature; 12 to 24 hours; or
iii) trifluoromethanesulfonic acid; dichloromethane; room temperature; 2 to 12 hours;
Step h) tert-butyldimethylsilyl trifluoromethanesulfonate; 2,6-dimethylpyridine; dichloromethane; N, N- Dimethylformamide; 0 to 25 ° C; 6 to 18 hours.
In FIG. 5, a protective group is provided for the alcohol derivative of the general formula (XV) (step a)), where PG ¹ Is a protecting group, preferably 4-methoxybenzyl, and PG ² Department and PG ¹ Different protection groups, preferably silicon protection groups (Peter GM 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) to obtain a compound of formula (XVIII). Removal of the protecting group PG from the compound of formula (XVIII) ¹ (Step b)) to obtain a compound of general formula (XIX). By alkylating the hydroxy compound of the general formula (XV), a compound of the general formula (XX) (wherein the alkyl group represents C _1-4 Alkyl) (step c)), and then by removing the PG of the compound of formula (XX) ¹ A protecting group can prepare a compound of the general formula (XXI).

Preferred implementations are, for example, the following:
Step a) trimethylchlorosilane; imidazole; N, N-dimethylformamide; room temperature; 4 to 12 hours;
Steps b) and d) i) cerium ammonium nitrate; water; acetonitrile; 0 to 25 ° C; 6 to 18 hours; or
ii) trifluoroacetic acid; dichloromethane; room temperature; 12 to 24 hours; or
iii) trifluoromethanesulfonic acid; dichloromethane; room temperature; 2 to 12 hours;
Step c) i) sodium hydride; haloalkane; N, N-dimethylformamide; 0 to 100 ° C; 12 to 48 hours; or
ii) sodium hydride; dialkyl sulfonate; N, N-dimethylformamide; 0 to 100 ° C; 12 to 48 hours; or
iii) silver oxide; halothane; N, N-dimethylformamide; room temperature; 48 to 120 hours.
As shown in FIG. 6, the nitrogen atom of the benzoazine derivative of the general formula (X) is protected by a protecting group (step a)) to obtain the protected benzoazine derivative of the general formula (XXII) (wherein PG ¹ Is a protective group (Peter GM Wuts: Greene's Protective Groups in Organic Synthesis: Fifth Edition, Chapter 7. Protection for the Amino Group, pages 895-1193), preferably 4-methoxybenzyl), and then the ester group Reduction (step b)) to obtain a hydroxy compound of the general formula (XXIII). A compound of the general formula (XXV) is prepared by alkylating the hydroxy compound of the general formula (XXIII) (wherein the alkyl group represents C _1-4 Alkyl) (step c)), and then by removing the protecting group PG ¹ (Step d)) to obtain a compound of the general formula (XXIV). In step e), a benzoazine-thione derivative of the general formula (III-b) is prepared.

Preferred implementations are, for example, the following:
Step a) 4-methoxybenzyl chloride; sodium hydride; N, N-dimethylformamide; 0 to 25 ° C; 3 to 6 hours;
Step b) lithium aluminum hydride; tetrahydrofuran; (-20) to 0 ° C; 0.1 to 1 hour;
Step c) i) sodium hydride; haloalkane; N, N-dimethylformamide; 0 to 100 ° C; 12 to 48 hours; or
ii) sodium hydride; dialkyl sulfonate; N, N-dimethylformamide; 0 to 100 ° C; 12 to 48 hours; or
iii) silver oxide; halothane; N, N-dimethylformamide; room temperature; 48 to 120 hours;
Step d) i) ammonium cerium nitrate; water; acetonitrile; 0 to 25 ° C; 6 to 18 hours; or
ii) trifluoroacetic acid; dichloromethane; room temperature; 12 to 24 hours; or
iii) trifluoromethanesulfonic acid; dichloromethane; room temperature; 2 to 12 hours;
Step e) i) Lawson's reagent; pyridine; reflux temperature; 2 to 10 hours; or
ii) Lawson's reagent; tetrahydrofuran; room temperature; 6 to 20 hours.
By reacting a compound of the general formula (II) with a compound of the general formula (III-a), a compound of the general formula (Ib) can be prepared (FIG. 7).

Where rings B, Y, and R ¹ As defined in the above general formula (I), ring A is a cycloalkyl group or a 4- to 7-membered saturated heterocyclic ring containing 1 N, wherein ring A is connected to Y via a ring nitrogen.
Preferred implementations are, for example, the following:
i) the reaction of formula (II) and formula (III-a): xylene; 140 ° C; 20 to 120 hours; or
ii) the reaction of formula (II) and formula (III-a): n-butanol; 110 ° C; 20 to 50 hours; or
iii) Reaction of formula (II) with formula (III-a): 1,4-dioxane; 110 ° C; 20 to 50 hours.
As desired, mirror image isomers are prepared by conventional methods by introducing new substituents and / or modifying or removing existing substituents and / or forming a salt and / or liberating a base from a salt and / or a racemic mixture. The compound of the general formula (Ib) thus obtained can also be converted into another compound of the general formula (I). This reaction scheme is described in detail in FIGS. 8 and 9.

By hydrolyzing the compound of the general formula (Ib) (step a)), the compound of the general formula (Ic) (wherein rings B, Y and R ¹ Is as defined in the above general formula (I), ring A is a cycloalkyl group or a 4- to 7-membered saturated heterocyclic ring containing 1 N, wherein ring A is connected to Y via a ring nitrogen), and then from this general formula ( Ic) Compounds can be prepared from amidines of the general formula (Id) (step b)) or amidines of the general formula (Ig) (step e)) (wherein rings B, Y and R ¹ As defined by the general formula (I) above, ring A is a cycloalkyl group or a 4- to 7-membered saturated heterocyclic ring containing one N, wherein ring A is connected to Y via a ring nitrogen, R 'represents hydrogen, and R "represents C _1-4 Alkyl or Cy ² , Or R 'and R "together with the N to which they are attached form a heterocycle). Nitriles of the general formula (Id) can be prepared from nitriles of the general formula (Ie) (step c)), and from the general formula ( Tetrazoles of general formula (If) can be prepared from nitriles of Ie) (step d)). Oxadiazole derivatives of general formula (Ih) can also be prepared from steps (f) of acids of the general formula (Ic).
Preferred implementations are, for example, the following:
Step a) methanol; sodium hydroxide; room temperature; 1 to 20 hours;
Step b) ammonium chloride; N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride; N, N-dimethylformamide; N, N-di Isopropylethylamine or triethylamine; 1-hydroxybenzotriazole hydrate; room temperature; 4 to 20 hours;
Step c) pyridine; phosphorous chloride; room temperature; 2 to 20 hours;
Step d) sodium azide; ammonium chloride; N, N-dimethylformamide; 100 to 130 ° C; 2 to 8 hours;
Step e) i) Appropriate amine derivative; N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride; N, N-dimethylformamide; N , N-diisopropylethylamine or triethylamine; 1-hydroxybenzotriazole hydrate; room temperature; 4 to 20 hours; or
ii) chloramphenicol; dichloromethane; room temperature; 0.5 to 2 hours; subsequent pyridine and appropriate amine derivatives; room temperature; 1 to 5 hours;
Step f) N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride; N, N-dimethylformamide; 1-hydroxybenzotriazole hydrate N-hydroxyacetamidamine; 80 to 120 ° C; 4 to 20 hours.
In addition, by reducing the compound of the general formula (Ib), a hydroxymethyl derivative of the general formula (Ii) can be prepared (FIG. 9; step a)).

Where rings B, Y, and R ¹ As defined in the above general formula (I), ring A is a cycloalkyl group or a 4- to 7-membered saturated heterocyclic ring containing 1 N, wherein ring A is connected to Y via a ring nitrogen.
As desired, mirror image isomers are prepared by conventional methods by introducing new substituents and / or modifying or removing existing substituents and / or forming a salt and / or liberating a base from a salt and / or a racemic mixture. Structure, the compound of general formula (Ii) can also be converted into another compound of general formula (I). For example, compounds can be prepared by catalytic hydrogenation reactions where R ¹ A hydrogen atom (not shown). By alkylation or halogenation reaction, other derivatives can be prepared to obtain compounds of general formula (Ij) (step b)), in which ring B, Y and R ¹ As defined in the above general formula (I), ring A is a cycloalkyl group or a 4- to 7-membered saturated heterocyclic ring containing 1 N, wherein ring A is connected to Y via a ring nitrogen, and R is an alkyl group or a fluorenyl group. .
From the compound of the general formula (Ik) obtained by the methane sulfonation of the compound of the general formula (Ii) (step c)), a nitrile derivative of the general formula (Il) (step d)), A fluorine compound of formula (Im) (step e)) and an amine derivative of formula (In) (step f)), wherein rings B, Y and R ¹ As defined in the above general formula (I), ring A is a cycloalkyl group or a 4- to 7-membered saturated heterocyclic ring containing 1 N, wherein ring A is connected to Y via a ring nitrogen, and R ¹⁰ And R ¹¹ Is optionally substituted C as defined by the general formula (I) above _1-4 Alkyl, or R ¹⁰ And R ¹¹ Together with the N to which they are attached forms an optionally substituted heterocyclic ring. In the general formula (Ij), when OR represents a carbamate, a compound can be prepared from the compound of the general formula (Ik) according to step g).
Preferred implementations are, for example, the following:
Step a) methylene chloride; diethyl ether; lithium aluminum hydride; (-30) to (-10) ° C; 15 to 60 minutes;
Step b) i) sodium hydride; haloalkane; N, N-dimethylformamide or tetrahydrofuran; (-5) to 40 ° C; 2 to 10 hours; or
ii) sodium hydride; acetonitrile; isocyanate derivatives; room temperature; 4 to 20 hours; or
iii) fluorenyl chloride; pyridine; room temperature; 4 to 20 hours; or
iv) fluorenyl chloride; methylene chloride; triethylamine or N, N-diisopropylethylamine; room temperature; 4 to 20 hours; or
v) anhydride; pyridine; room temperature; 4 to 20 hours; or
vi) acid; hexafluorophosphate N, N, N ', N'-tetramethyl-O- (1H-benzotriazol-1-yl) urenium; N, N-dimethylformamide; N , N-diisopropylethylamine; room temperature; 4 to 20 hours; or
vii) acid; N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride; N, N-diisopropylethylamine; N, N-dimethylformamide Amidine; 1-hydroxybenzotriazole hydrate; room temperature; 4 to 20 hours;
Step c) methanesulfonyl chloride; dichloromethane; triethylamine; 4-dimethylaminopyridine; room temperature; 2 to 20 hours;
Step d) sodium cyanide; N, N-dimethylformamide; 70 to 100 ° C; 3 to 20 hours;
Step e) tetrabutylammonium fluoride; tetrahydrofuran; 50 to 70 ° C; 4 to 20 hours;
Step f) amine; N, N-dimethylformamide; N, N-diisopropylethylamine; 80 to 120 ° C; 3 to 20 hours;
Step g) secondary amine; N, N-dimethylformamide; triethylamine; cesium carbonate; 100 ° C; 12 to 48 hours.
From this compound of general formula (Ik), other derivatives shown in FIG. 10 can be prepared.

Step a) generates an azide compound of general formula (Io), wherein rings B, Y and R ¹ As defined in the above general formula (I), ring A is a cycloalkyl group or a 4- to 7-membered saturated heterocyclic ring containing 1 N, wherein ring A is connected to Y via a ring nitrogen, and from this general formula (Io) The azide compound can be reduced to prepare an amine derivative of the general formula (Ip) (step b)). The amine derivative of the general formula (Ip) is a starting material of an alkyl compound of the general formula (Iq) (step c)) and a fluorenyl compound of the general formula (Ir) (step d)), in which ring B, Y And R ¹ As defined in the general formula (I) above, ring A is a cycloalkyl group or a 4- to 7-membered saturated heterocyclic ring containing 1 N, wherein ring A is connected to Y via a ring nitrogen, and R "'stands for optionally via Replaced by C _1-4 Alkyl or R as in the general formula (I) above ¹⁰ And R ¹¹ Defined Cy ³ And the fluorene group is as R in the general formula (I) ¹⁰ And R ¹¹ C (O) R as defined ¹³ . According to step e), the compound of general formula (In) can also be prepared from the compound of general formula (Ip), where R ¹⁰ And R ¹¹ Is optionally substituted C _1-4 alkyl.
Preferred implementations are, for example, the following:
Step a) sodium azide; N, N-dimethylformamide; 60 to 100 ° C; 2 to 8 hours;
Step b) triphenylphosphine; tetrahydrofuran; water; room temperature; 4 to 20 hours;
Step c) i) sodium hydride; haloalkane; N, N-dimethylformamide or tetrahydrofuran; (-5) to 40 ° C; 2 to 10 hours; or
ii) ketones; 1,2-dichloroethane; acetic acid; sodium triethoxylate borohydride; room temperature; 4 to 20 hours;
Step d) i) fluorenyl chloride; pyridine; room temperature; 4 to 20 hours; or
ii) fluorenyl chloride; dichloromethane; triethylamine or N, N-diisopropylethylamine; room temperature; 4 to 20 hours; or
iii) acid anhydride; pyridine; room temperature; 4 to 20 hours; or
iv) acid; hexafluorophosphate N, N, N ', N'-tetramethyl-O- (1H-benzotriazol-1-yl) urenium; N, N-dimethylformamide; N , N-diisopropylethylamine; room temperature; 4 to 20 hours; or
v) acid; N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride; N, N-diisopropylethylamine; N, N-dimethylformamide Amidine; 1-hydroxybenzotriazole hydrate; room temperature; 4 to 20 hours;
Step e) Aldehyde; 1,2-dichloroethane; acetic acid; sodium triethoxyalkoxyborohydride; room temperature; 4 to 20 hours.
According to FIG. 11, a methoxybenzoazine derivative of the general formula (XXVI) is prepared from methylation of a compound of the general formula (XII) (step a)), where R ¹ Is as defined in the above general formula (I), and the methoxybenzoacridine derivative of the general formula (XXVI) is further reacted with the hydrazine of the general formula (II) without isolation (step b)) to Generates compounds of general formula (Is), in which rings B, Y, and R ¹ As defined in the above general formula (I), ring A is a cycloalkyl group or a 4- to 7-membered saturated heterocyclic ring containing 1 N, wherein ring A is connected to Y via a ring nitrogen. After removing the ketal protecting group (step c)), a pendant oxygen compound of the general formula (It) is obtained, in which the rings B, Y and R ¹ As defined in the above general formula (I), ring A is a cycloalkyl group or a 4- to 7-membered saturated heterocyclic ring containing 1 N, wherein ring A is connected to Y via a ring nitrogen. Reduction of the compound of general formula (It) produces a hydroxy compound of general formula (Iu) (step d)). The compound of the general formula (Iu) can be oxidized (step e)) using an appropriate oxidant to form the compound of the general formula (It), and the compound of the general formula (It) can be further reacted to obtain the general formula (I) -aa), wherein R represents C optionally substituted with alkoxy _1-4 alkyl.

Preferred implementations are, for example, the following:
Step a) methylene chloride; trifluoroacetic acid or potassium carbonate; trimethyloxonium tetrafluoroborate; room temperature; 20 to 25 hours;
Step b) hydrazine of general formula (II); dichloromethane or acetonitrile; 50 ° C; 6 to 20 hours;
Step c) methanol; concentrated hydrochloric acid; 70 ° C; 2 to 6 hours;
Step d) sodium borohydride; ethanol or methanol; room temperature; 1 to 2 hours;
Step e) Dess-Martin periodinane; methylene chloride; 0 ° C to room temperature; 1 to 5 hours;
Step f) Appropriate amine; 1,2-dichloroethane; sodium triethoxyhoxyborohydride; acetic acid; room temperature;
A compound of the general formula (Ij) can be prepared by reacting a compound of the general formula (II) with a compound of the general formula (III-b), wherein the alkyl group represents C _1-4 Alkyl and rings B, Y, and R ¹ As defined in the above general formula (I), ring A is a cycloalkyl group or a 4- to 7-membered saturated heterocyclic ring containing 1 N, wherein ring A is connected to Y via a ring nitrogen (FIG. 12).

Preferred implementations are, for example, the following:
i) the reaction of formula (II) and formula (III-b): xylene; 140 ° C; 20 to 120 hours; or
ii) the reaction of formula (II) and formula (III-b): n-butanol; 110 ° C; 20 to 50 hours; or
iii) Reaction of formula (II) with formula (III-b): 1,4-dioxane; 110 ° C; 20 to 50 hours.
A benzoazine-thione derivative of the general formula (III-c) is prepared from the difluoro derivative of the general formula (XIII) (Figure 13; step a)), where R ¹ Is as defined in the above general formula (I), and the benzoazepine-thione derivative of the general formula (III-c) is reacted with hydrazine of the general formula (II) (step b)) to obtain the general formula (Iv) a compound in which Rings B, Y and R ¹ As defined in the above general formula (I), ring A is a cycloalkyl group or a 4- to 7-membered saturated heterocyclic ring containing 1 N, wherein ring A is connected to Y via a ring nitrogen.

Preferred implementations are, for example, the following:
Step a) i) Lawesson reagent; pyridine; reflux temperature; 2 to 10 hours; or
ii) Lawson's reagent; tetrahydrofuran; room temperature; 6 to 20 hours;
Step b) i) the reaction of formula (II) and formula (III-c): xylene; 140 ° C; 20 to 120 hours; or
ii) the reaction of formula (II) and formula (III-c): n-butanol; 110 ° C; 20 to 50 hours; or
iii) Reaction of formula (II) with formula (III-c): 1,4-dioxane; 110 ° C; 20 to 50 hours.
A benzoazine-thione derivative of the general formula (III-d) is prepared from a monofluoro derivative of the general formula (XVII), where R ¹ Is as defined in the above general formula (I) (FIG. 14; step a)) and the benzoazepine-thione derivative of the general formula (III-d) is reacted with the hydrazine of the general formula (II) ( Step b)) to obtain a compound of general formula (Iw), wherein rings B, Y and R ¹ As defined in the above general formula (I), ring A is a cycloalkyl group or a 4- to 7-membered saturated heterocyclic ring containing 1 N, wherein ring A is connected to Y via a ring nitrogen.

Preferred implementations are, for example, the following:
Step a) i) Lawson's reagent; pyridine; reflux temperature; 2 to 10 hours; or
ii) Lawson's reagent; tetrahydrofuran; room temperature; 6 to 20 hours;
Step b) i) the reaction of formula (II) and formula (III-d): xylene; 140 ° C; 20 to 120 hours; or
ii) the reaction of formula (II) and formula (III-d): n-butanol; 110 ° C; 20 to 50 hours; or
iii) Reaction of formula (II) with formula (III-d): 1,4-dioxane; 110 ° C; 20 to 50 hours.
A benzoazine-thione derivative of general formula (III-e) is prepared from a protected hydroxy compound of general formula (XIX) (Figure 15; step a)), where R ¹ As defined by the general formula (I) above, PG ¹ Department of protection (Peter GM 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 silicon-based A protecting group, and reacting the benzoazine-thione derivative of the general formula (III-e) with the hydrazine of the general formula (II) (step b)) to obtain a compound of the general formula (Ix), wherein the ring B , Y and R ¹ As defined in the above general formula (I), ring A is a cycloalkyl group or a 4- to 7-membered saturated heterocyclic ring containing 1 N, wherein ring A is connected to Y via a ring nitrogen.

Through this synthetic route, a hydroxyl derivative of the general formula (Iu) can also be prepared by removing the protective group of the compound of the general formula (Ix).
Preferred implementations are, for example, the following:
Step a) i) Lawson's reagent; pyridine; reflux temperature; 2 to 10 hours; or
ii) Lawson's reagent; tetrahydrofuran; room temperature; 6 to 20 hours;
Step b) i) the reaction of formula (II) and formula (III-e): xylene; 140 ° C; 20 to 120 hours; or
ii) the reaction of formula (II) and formula (III-e): n-butanol; 110 ° C; 20 to 50 hours; or
iii) reaction of formula (II) and formula (III-e): 1,4-dioxane; 110 ° C; 20 to 50 hours;
Step c) tetrabutylammonium fluoride; tetrahydrofuran; room temperature; 3 to 10 hours.
A benzoazepine-thione derivative of general formula (III-f) is prepared from an alkyl derivative of general formula (XXI), where R ¹ Is as defined in the general formula (I) above and alkyl represents C _1-4 Alkyl group (Figure 16; step a)), and the benzoazepine-thione derivative of the general formula (III-f) is reacted with the hydrazine of the general formula (II) (step b)) to obtain the general formula (Iy) a compound in which Rings B, Y, and R ¹ As defined in the above general formula (I), ring A is a cycloalkyl group or a 4- to 7-membered saturated heterocyclic ring containing 1 N, wherein ring A is connected to Y via a ring nitrogen.

Preferred implementations are, for example, the following:
Step a) i) Lawson's reagent; pyridine; reflux temperature; 2 to 10 hours; or
ii) Lawson's reagent; tetrahydrofuran; room temperature; 6 to 20 hours;
Step b) i) the reaction of formula (II) and formula (III-f): xylene; 140 ° C; 20 to 120 hours; or
ii) the reaction of formula (II) and formula (III-f): n-butanol; 110 ° C; 20 to 50 hours; or
iii) Reaction of formula (II) with formula (III-f): 1,4-dioxane; 110 ° C; 20 to 50 hours.
As long as in the compound of general formula (I), R ² Department C _1-4 Alkyl, R ³ C (O) R ⁵ , R ⁵ Department C _1-4 Alkoxy and ring A is a cycloalkyl or a 4- to 7-membered saturated heterocyclic ring containing 1 N, in which ring A is connected to Y via a ring nitrogen, by combining a compound of general formula (II) with general formula (XXVII) Compounds are reacted to prepare compounds of general formula (I) of the present invention, wherein the compounds of general formula (II) are
,
Wherein ring B and Y are as defined in the general formula (I) above, ring A is a cycloalkyl group or a 4- to 7-membered saturated heterocyclic ring containing 1 N, wherein ring A is connected to Y via a ring nitrogen, and the general Compound of formula (XXVII)
,
Where R ¹ Is defined by the general formula (I) above, R ² Department C _1-4 Alkyl, R ³ C (O) R ⁵ And R ⁵ Department C _1-4 Alkoxy.
The reaction is shown in detail in Figure 17:

A preferred embodiment of step a) in FIG. 17 is, for example, the following:
i) xylene; 140 ° C; 20 to 120 hours; or
ii) n-butanol; 110 ° C; 20 to 50 hours; or
iii) 1,4 dioxane; 110 ° C; 20 to 50 hours.
The main intermediates for the synthesis of benzoazine-thione derivatives of general formula (XXVII) can be prepared by one of the following synthesis:

Method A (Figure 18):
Protecting the keto group of the compound of general formula (VIII) by a dioxane ring (step a)) and alkylating the resulting compound of general formula (XXVIII) (step b)) to obtain a compound of general formula (XXIX), Where R ¹ Is as defined by the general formula (I) above and R ² Department C _1-4 alkyl. The compound of the general formula (XXIX) is deprotected (step c)) and an oxime compound of the general formula (XXXI) is prepared from the resulting derivative of the general formula (XXX) (step d)). This oxime of the general formula (XXXI) is converted to a benzoazepine compound of the general formula (XXXII) by a Beckman rearrangement (step e)).

Preferred implementations are, for example, the following:
Step a) ethylene glycol; toluene; p-toluenesulfonic acid; reflux temperature; 2 to 12 hours;
Step b) lithium diisopropylamide; alkyl iodide; tetrahydrofuran; (-78) ° C; 0.5 to 2 hours;
Step c) i) methanol; concentrated hydrochloric acid; 70 ° C; 2 to 6 hours; or
ii) aqueous acetic acid; 110 ° C; 5 to 20 hours;
Step d) methanol; sodium acetate; hydroxylamine hydrochloride; reflux temperature; 3 to 6 hours;
Step e) Polyphosphoric acid; 100 to 120 ° C; 15 to 60 minutes.

Method B (Figure 19):
The protected benzoazine derivative (XXII) is alkylated (step a)), where R ¹ Is as defined in the general formula (I) above and PG ¹ Is a protective group (Peter GM Wuts: Greene's Protective Groups in Organic Synthesis: Fifth Edition, Chapter 7. Protection for the Amino Group, pages 895-1193), preferably 4-methoxybenzyl, and then the general formula ( The compound of XXXIII) is deprotected (step b)) to obtain a compound of general formula (XXXII).

Preferred implementations are, for example, the following:
Step a) i) sodium hydride; N, N-dimethylformamide; alkyl iodide; 0 to 100 ° C; 1 to 12 hours; or
ii) lithium diisopropylamide; alkyl iodide; tetrahydrofuran; (-78) ° C; 0.5 to 2 hours;
Step b) i) cerium ammonium nitrate; water; acetonitrile; 0 to 25 ° C; 6 to 18 hours; or
ii) trifluoroacetic acid; dichloromethane; room temperature; 12 to 24 hours; or
iii) trifluoromethanesulfonic acid; dichloromethane; room temperature; 2 to 12 hours.

Method C (Figure 20):
A compound of formula (XXXV) is prepared from a compound of formula (XXXIV) (step a)), where R ¹ Is as defined by the general formula (I) above and R ² Department C _1-4 An alkyl group, and subjecting the resulting compound of general formula (XXXV) to hydrolysis (step b)) to obtain a compound of general formula (XXXVI). The compound of the general formula (XXXVI) is ring-closed (step c)) and the compound of the general formula (XXXVII) is esterified (step d)). The generated compound of the general formula (XXX) is converted into a compound of the general formula (XXXII) by the steps of FIG. 18.

Preferred implementations are, for example, the following:
Step a) lithium diisopropylamide; tetrahydrofuran; tert-butyl bromoacetate; 0 to 20 ° C; 3 to 6 hours;
Step b) methanol; sodium hydroxide; room temperature; 3 to 6 hours;
Step c) sulfuric acid; room temperature; 0.5 to 1.5 hours;
Step d) sulfenyl chloride; methanol; 60 ° C; 6 to 8 hours.
Amine derivatives of general formula (XXXIV) are commercially available or can be prepared according to the methods described in the examples.
A benzoazine-thione derivative of the general formula (XXVII-a) is prepared from a main intermediate of the general formula (XXXII) (FIG. 21; step a)) and the benzoazine of the general formula (XXVII-a) is made The hydrazone-thione derivative is reacted with hydrazine of the general formula (II) to obtain a compound of the general formula (Iz) (step b)), wherein the rings B, Y and R ¹ As defined in the above general formula (I), ring A is a cycloalkyl group or a 4- to 7-membered saturated heterocyclic ring containing 1 N, wherein ring A is connected to Y via a ring nitrogen and R ² Department C _1-4 alkyl. The compound of general formula (Iz) can also be synthesized from the compound of general formula (XL-a) (step d)), and the general formula (XL-a) can be obtained from the compound of general formula (XXVII-a) by a methylation reaction. Compound (step c)).

Preferred implementations are, for example, the following:
Step a) i) Lawson's reagent; pyridine; reflux temperature; 2 to 10 hours; or
ii) Lawson's reagent; tetrahydrofuran; room temperature; 6 to 20 hours;
Step b) i) the reaction of formula (II) and formula (XXVII-a): xylene; 140 ° C; 20 to 120 hours; or
ii) the reaction of formula (II) and formula (XXVII-a): n-butanol; 110 ° C; 20 to 50 hours; or
iii) reaction of formula (II) with formula (XXVII-a): 1,4-dioxane; 110 ° C; 20 to 50 hours;
Step c) methyl iodide; potassium carbonate; acetone; room temperature; 4 to 24 hours;
Step d) i) the reaction of formula (II) and formula (XXVII-a): xylene; in the presence of catalytic hydrochloric acid; 140 ° C; 4 to 20 hours; or
ii) Reaction of formula (II) with formula (XXVII-a): 1,4-dioxane; in the presence of catalytic hydrochloric acid; 110 ° C; 4 to 20 hours.
Similar to compounds of general formula (Ib) or (Ii), as desired, by the introduction of new substituents and / or modification or removal of existing substituents and / or formation of salts and / or self-salts by conventional methods The base and / or the racemic mixture is released to prepare a mirror image isomer. For example, any method shown in FIG. 8 to FIG. 10 can also convert a compound of the general formula (Iz) into another compound of the general formula (I).

Figure 10
As long as the compound of the general formula (I), R ² System hydrogen, R ³ C (O) NH ₂ And ring A contains 1 or 2 4 to 7 membered saturated heterocyclic rings of N, wherein ring A is connected to the 5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] The benzoazine nucleus is connected with a triazole ring, and a compound of the general formula (I) is prepared by reacting a compound of the general formula (XXXVIII) with a compound of the general formula (XXXIX), wherein the general Compound of formula (XXXVIII)
,
Wherein ring B and Y are as defined in the above general formula (I), ring A contains 1 to 2 4 to 7 membered saturated heterocyclic rings of N, and ring A is connected to the 5,6-dihydro through the ring nitrogen- 4H- [1,2,4] triazolo [4,3-a] [1] benzotriazine core triazole ring is connected, and the compound of general formula (XXXIX) is
,
Where R ¹ Is defined by the general formula (I) above, R ² Hydrogen and R ³ C (O) NH ₂ .
The reaction is shown in detail in Figure 22:

A preferred embodiment of step a) in FIG. 22 is, for example, the following:
i) melt (solvent-free); 120 to 150 ° C; 3 to 72 hours; or
ii) Cyclopyridine; 140 to 180 ° C; 3 to 72 hours.
Amine derivatives of general formula (XXXVIII) are commercially available or can be prepared according to the methods described in the examples.
By the method of FIG. 23, a triazolo-benzoazine derivative of the general formula (XXXIX) can be prepared, in which R ¹ It is as defined in the above general formula (I).

Methylating the compound of the general formula (III-a) (step a)) and reacting the resulting compound of the general formula (XL-b) with formamidine (step b)) to obtain a compound of the general formula (XLI), Where R ¹ It is as defined in the above general formula (I). The compound of general formula (XLI) is brominated (step c)) to obtain a bromine derivative of general formula (XLII), where R ¹ It is as defined in the above general formula (I). A compound of the general formula (XLIII) is prepared by hydrolysis of the bromine derivative of the general formula (XLII) produced (step d)) and then amidamine of the general formula (XXXIX) is formed in step e). A nitrile derivative of the general formula (LII) can also be synthesized from the amidine of the general formula (XXXIX) (step f)) and the nitrile derivative of the general formula (LII) can be reacted with a compound of the following general formula (XXXVIII) to Formation of compounds of general formula (I-ac):
,
Wherein ring B and Y are as defined in the above general formula (I), ring A contains 1 to 2 4 to 7 membered saturated heterocyclic rings of N, and ring A is connected to the 5,6-dihydro through the ring nitrogen- The 4H- [1,2,4] triazolo [4,3-a] [1] benzoazine nucleus is attached to the triazole ring.
Preferred implementations are, for example, the following:
Step a) methyl iodide; potassium carbonate; acetone; room temperature; 4 to 24 hours;
Step b) Formamylhydrazine; 1,4-dioxane; 90 ° C; 3 to 10 hours;
Step c) N-bromosuccinimide; tetrahydrofuran; 70 ° C; 10 to 60 minutes;
Step d) methanol; sodium hydroxide; room temperature; 1 to 20 hours;
Step e) Ammonium chloride; N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride; N, N-dimethylformamide; N, N-di Isopropylethylamine or triethylamine; 1-hydroxybenzotriazole hydrate; room temperature; 4 to 20 hours;
Step f) trifluoroacetic anhydride; dichloromethane; triethylamine; 0 ° C to room temperature; 1 to 5 hours;
Step g) i) melt (solvent-free); 120 to 150 ° C; 3 to 72 hours; or
ii) Cyclopyridine; 140 to 180 ° C; 3 to 72 hours.
As desired, mirror image isomers are prepared by conventional methods by introducing new substituents and / or modifying or removing existing substituents and / or forming a salt and / or liberating a base from a salt and / or a racemic mixture. For example, using steps c) and d) shown in FIG. 8, the compound of general formula (I-aa) prepared according to FIG. 22 can also be converted into another compound of general formula (I).
By the method described in detail in FIG. 24, the compound of the general formula (I) can be prepared, in which R ¹ Is defined by the general formula (I) above, R ² Hydrogen or C _1-4 Alkyl, R ³ Department C _1-4 Alkyl, or R ² And R ³ Combined Representative-(CH ₂ ) _p -O- (CH ₂ ) _q -Or- (CH ₂ ) _r -, Where p is 1, 2, or 3; q is 1, 2, or 3; and r is 4, 5, or 6.

By a Grignard reaction (step a)), a diethyl malonate derivative of the general formula (XLIV) (where R ² Hydrogen or C _1-4 Alkyl, R ³ Department C _1-4 Alkyl, or R ² And R ³ Combined Representative-(CH ₂ ) _p -O- (CH ₂ ) _q -Or- (CH ₂ ) _r -, Wherein p is 1, 2, or 3; q is 1, 2, or 3; r is 4, 5, or 6) is converted to a benzyl derivative of the general formula (XLV), where R ¹ Represents hydrogen or fluorine. Under basic conditions, a free acid of the general formula (XLVI) is prepared by hydrolyzing a compound of the general formula (XLV) (step b)). Decarboxylation of the compound of the general formula (XLVI) (step c)) generates a compound of the general formula (XLVII), and the compound of the general formula (XLVII) is treated with concentrated sulfuric acid to prepare a compound of the general formula (XLVIII) (step d)). An oxime derivative of the general formula (XLIX) is then prepared from the compound of the general formula (XLVIII) (step e)), and the oxime derivative of the general formula (XLIX) is converted to Benzacridine compounds of general formula (L). If R ³ Based on hydrogen, the compound of general formula (L) is chlorinated or brominated (step g)) to obtain the compound of general formula (LI). Convert a compound of general formula (LI) or (L) into a compound of general formula (I-ad) (step h)), where R ¹ Is defined by the general formula (I) above, R ² Hydrogen or C _1-4 Alkyl, R ³ Department C _1-4 Alkyl, or R ² And R ³ Combined Representative-(CH ₂ ) _p -O- (CH ₂ ) _q -Or- (CH ₂ ) _r -, Wherein p is 1, 2, or 3; q is 1, 2, or 3; r is 4, 5, or 6, ring B and Y are as defined in the above general formula (I) and ring A is cycloalkyl or contains A 4- to 7-membered saturated heterocyclic ring of N, wherein ring A is connected to Y via a ring nitrogen.
A preferred embodiment of the synthesis of FIG. 24 is, for example, the following:
Step a) benzyl magnesium chloride or 3-fluorobenzyl magnesium chloride; diethyl ether; room temperature; 2 to 12 hours;
Step b) 2M aqueous sodium hydroxide solution; ethanol; reflux temperature; 2 hours;
Step c) heating at 180 to 200 ° C for 3 to 5 minutes;
Step d) sulfuric acid; 35 to 40 ° C; 60 minutes;
Step e) methanol; sodium acetate; hydroxylamine hydrochloride; reflux temperature; 2 to 6 hours;
Step f) polyphosphoric acid; 100 to 120 ° C; 15 to 60 minutes;
Step g) bromine; acetic acid / water; room temperature; 30 to 90 minutes; or, N-chlorosuccinimide; DMF; room temperature; 30 to 90 minutes;
Step h) i) Lawson's reagent; pyridine; reflux temperature; 2 to 10 hours;
ii) methyl iodide; potassium carbonate; acetone; 40 ° C; 1 to 3 hours;
iii) hydrazine of general formula (II); concentrated hydrochloric acid (a few drops); 1,4-dioxane; reflux; 1 to 8 hours;
or
i) trimethyloxonium tetrafluoroborate; trifluoroacetic acid or potassium carbonate; dichloromethane; room temperature; 2 to 4 hours;
ii) hydrazine of general formula (II); trifluoroacetic acid (several drops); 1,4-dioxane or acetonitrile; reflux; 1 to 8 hours.
By different methods described in FIG. 2, hydrazine of general formula (II) can be synthesized, in which ring B and Y are as defined in general formula (I) above and ring A is cycloalkyl or 4 to 4 containing 1 N. A 7-membered saturated heterocyclic ring in which ring A is connected to Y via a ring nitrogen.
According to the method shown in FIG. 25, a compound of the general formula (Im) can also be synthesized.

Let the compound of formula (X) (where R ¹ (As defined in the above general formula (I)) is reduced (step a)) and the obtained hydroxy compound of general formula (LIII) is converted into a fluorine derivative of general formula (LIV) (step b)). Directly from a benzoazepine-thione of the general formula (LV) (which is derived from a compound of the general formula (LIV) from step c)) (step e)) or a methylthio derivative from the general formula (LVII) (Step h)), a compound of the general formula (Im) can be synthesized. The methylthio derivative of the general formula (LVII) can be prepared from the benzoazepine-thione of the general formula (LV) by methylation (step f)). An alternative synthetic route is to methylate the compound of general formula (LIV) (step d)) and in situ obtain the methoxy derivative of general formula (LVI) and general formula (II) The compound is reacted (step g)) to produce the compound of the general formula (Im).
A preferred embodiment of the synthesis of FIG. 25 is, for example, the following:
Step a) lithium aluminum hydride; diethyl ether; tetrahydrofuran; (-40) to 0 ° C; 0.1 to 2 hours;
Step b) diethylaminosulfur trifluoride; dichloromethane; (-78) to 10 ° C; 4 to 12 hours;
Step c) i) Lawson's reagent; pyridine; reflux temperature; 2 to 10 hours; or
ii) Lawson's reagent; tetrahydrofuran; room temperature; 6 to 20 hours;
Step d) trimethyloxonium tetrafluoroborate; trifluoroacetic acid or potassium carbonate; dichloromethane; room temperature; 2 to 4 hours;
Step e) i) reacting hydrazine of general formula (II) with general formula (LV); xylene; 140 ° C; 20 to 120 hours; or
ii) reaction of hydrazine of general formula (II) with general formula (LV); n-butanol; 110 ° C; 20 to 50 hours; or
iii) reaction of hydrazine of general formula (II) with general formula (LV); 1,4-dioxane; 110 ° C; 20 to 50 hours;
Step f) methyl iodide; potassium carbonate; acetone; room temperature; 4 to 24 hours;
Step g) hydrazine of general formula (II); dichloromethane or acetonitrile; 50 ° C; 6 to 20 hours;
Step h) The hydrazine of the general formula (II) is reacted with the general formula (LVII); 1,4-dioxane; 110 ° C; 2 to 20 hours.
According to the method shown in FIG. 26, the compound of the general formula (I-ad) of the present invention can be prepared, in which R ¹ Is defined by the general formula (I) above, R ² Hydrogen or C _1-4 Alkyl, R ³ Department C _1-4 Alkyl, or R ² And R ³ Combined Representative-(CH ₂ ) _p -O- (CH ₂ ) _q -Or- (CH ₂ ) _r -, Wherein p is 1, 2, or 3; q is 1, 2, or 3; r is 4, 5, or 6, and ring A contains 1 or 2 4 to 7-membered saturated heterocyclic rings of N, wherein ring A is The triazole ring of the 5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine core is connected via a ring nitrogen.

Let the compound of general formula (LI) (R ¹ Is defined by the general formula (I) above, R ² Hydrogen or C _1-4 Alkyl, R ³ Department C _1-4 Alkyl, or R ² And R ³ Combined Representative-(CH ₂ ) _p -O- (CH ₂ ) _q -Or- (CH ₂ ) _r -, Wherein p is 1, 2, or 3; q is 1, 2, or 3; r is 4, 5, or 6) and a Lawson reactant (step a)) to form a benzoacene of the general formula (LVIII) -A thioketone derivative, and the benzoazine-thione derivative of the general formula (LVIII) is methylated (step b)) and the obtained compound of the general formula (LIX) is reacted with formamidine hydrazine (step c)) to form a compound of general formula (LX). The compound of general formula (LX) is brominated (step d)) to obtain a bromine derivative of general formula (LXI), and the bromine derivative of general formula (LXI) is reacted with a compound of general formula (XXXVIII) e)) to form compounds of general formula (I-ae):
,
Wherein ring B and Y are as defined in the above general formula (I), ring A contains 1 to 2 4 to 7 membered saturated heterocyclic rings of N, and ring A is connected to the 5,6-dihydro through the ring nitrogen- The 4H- [1,2,4] triazolo [4,3-a] [1] benzoazine nucleus is attached to the triazole ring.
A preferred embodiment of the synthesis of FIG. 26 is, for example, the following:
Step a) i) Lawson's reagent; pyridine; reflux temperature; 2 to 10 hours; or
ii) Lawson's reagent; tetrahydrofuran; room temperature; 6 to 20 hours;
Step b) methyl iodide; potassium carbonate; acetone; room temperature; 4 to 24 hours;
Step c) Formamylhydrazine; 1,4-dioxane; 90 ° C; 3 to 10 hours;
Step d) N-bromosuccinimide; tetrahydrofuran; 70 ° C; 10 to 60 minutes;
Step e) i) melt (solvent-free); 120 to 150 ° C; 3 to 72 hours; or
ii) Cyclopyridine; 140 to 180 ° C; 3 to 72 hours.
The reagents and detailed process steps required for the above reactions are described in the examples.
One aspect of the present invention is a novel intermediate represented by the general formula (III-a), (X), (XLII), (LI), and (LIV) synthesized by a process for preparing a compound of general formula (I), wherein R ¹ As defined by the general formula (I) above, especially 7-chloro-2- pendantoxy-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid (intermediate 3), 7-chloro-2- pendant thio-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid (intermediate 4), 1-bromo-8-chloro-5,6-dihydro-4 H -[1,2,4] triazolo [4,3- a ] [1] Methylbenzoazine-5-carboxylic acid (intermediate 24), 7-chloro-4- (fluoromethyl) -1,3,4,5-tetrahydro-2 H -1-benzoazin-2-one (Intermediate 36), or R ² And R ³ Combined Representative-(CH ₂ ) _p -O- (CH ₂ ) _q -Or- (CH ₂ ) _r -, Where p is 1, 2, or 3; q is 1, 2, or 3; and r is 4, 5, or 6.
The activity data of each compound of the general formula (I) of the present invention was measured in vitro or in vivo by the following method.

Human Vasopressin V1a Receptor Binding Analysis
Cells and radioligands
Immortalized 1321N1 cell line (Perkin Elmer, ES-361-M400-UA) that structurally and stably expresses human vasopressin V1a receptor and vasopressin (8-L-arginine) as a radioligand ) Via [phenylpropylaminomethyl-3,4,5- ³ H (N)]-labeled compounds (Perkin Elmer Life and Analytical Sciences) to determine the affinity of the compounds prepared.

method
Cell membrane preparation: Cell membrane preparation of immortalized 1321N1 cells expressing proliferated human vasopressin V1a receptors according to the Jarvis method (Jarvis et al., J Pharmacol Exp Ther 2004, 310: 407-16). The cells were suspended in a preparative buffer (50 mM Tris, 1 mM EDTA, 0.1 mM PMSF) and homogenized by a glass homogenizer. In order to separate the crude cell membrane fraction, two continuous centrifugation operations (40,000 g, 20 minutes, 4 ° C.) were performed, and then the cell membrane was placed in the preparative buffer in the final washing step. The resulting cell membrane preparation was divided into several portions and stored in Use at -80 ° C until measurement.
According to the Lowry's method, a standard dilution series of bovine serum albumin (BSA) was used to measure the protein content of the prepared cell membrane (Lowry et al., J Biol Chem 1951, 193: 265-75).
Receptor binding assay: In receptor binding analysis, at least 8 different concentrations of each substance with 3 parallel unknown affinities are used. To determine the final affinity value, the results of at least two independent experiments were taken into account. The analysis mixture included incubation buffer (50 mM Tris-HCl, pH 7.4 + 3% BSA), a cell membrane preparation of 1321N1 cells expressing human vasopressin V1a receptor (167 µg / ml), and vascular as a radioligand. (8-L-arginine) [phenylalaninino-3,4,5- ³ H (N)] (1 nM).
At 1.2x10 ^-6 M unlabeled (Arg ⁸ )-Non-specific binding values are measured in the presence of vasopressin. A sample with a total volume of 0.33 ml was incubated at 27 ° C for 60 minutes. By passing UniFilter® GF / B impregnated with 0.5% polyethyleneimine ^TM Filtration to separate cell-bound and free ligands. After drying the filter pan, 40 μl of Microscint-20 (Packard) scintillation liquid was added to the sample. Finally, use MicroBeta ² Microdisk counter (Perkin Elmer) measures radioactivity.
Use S-shape fitting mathematical method y = (A1-A2) / (1+ (x / x ₀ ) p) + A2 and Origin 7.5. Software (OriginLab Corporation, Northampton, USA) concentration shift curve calculation IC ₅₀ Value (ie, the concentration of the unknown substance that replaces 50% of the specifically bound radioligand). When fitting, the asymptotes are not fixed. Use Cheng-Prusoff equation K _{i =} IC ₅₀ / [1+ (L / K _D )] Calculate the inhibition constant (K _i ) Value, where [L] is the concentration of radioligand used in the experiment and [K _D ] Is the affinity of the radiolabeled ligand to the recipient. Pre-determining K using a Scatchard curve _D .

Functional analysis of test compounds on cell lines expressing human vasopressin V1a receptor
cell
The immortalized 1321N1 cell line (Perkin Elmer, ES-361-M400-UA) that structurally and stably expresses human vasopressin V1a receptor was used to measure the compounds prepared. General secondary messenger pathway using the GPCR receptor to be tested, endogenous G _q Related systems.

method
Compounds were measured using a 96-well trough plate (30,000 cells / plate). The composition of the buffer used for this measurement (expressed in mM) is as follows: 140 NaCl, 5 KCl, 2 CaCl ₂ , 2 MgCl ₂ , 10 glucose, 10 HEPES (4- (2-hydroxyethyl) -1-piperazine-ethanesulfonic acid), 2 probenecid, pH 7.4. The FLIPR Calcium 5 kit (Molecular Devices) was used as the fluorescent dye, and the matrix was not removed before the dye was filled and the cells were not washed before and after. Incubate at room temperature and the final DMSO concentration is 1%. The substances to be tested are pretreated for 15 to 20 minutes and at least 2 parallel measurements are performed for each concentration of each compound.
Use of fluorescent signals to determine intracellular Ca ²⁺ Concentration and reading meter is FlexStation II96. Cytoplasmic Ca was measured by fluorometry and using a FlexStation II 96 disk reader (excitation: 485 nm; emission: 525 nm) ²⁺ concentration. Records fluorescent signal for 1 minute every 1.4 seconds. The reference compounds used are as follows: ₈₀ (Arg ⁸ )-Vasopressin as an agonist, and rivasuvaptan measured at 1 μM as an antagonist. Determination of% inhibition and IC for each concentration of compound ₅₀ Value, where the concentration line is also determined.
The total AVP concentration-response curve was recorded for each plate. The measured efficacy of a compound is expressed as a relative inhibition% response relative to a control group. For the graph of the data, use SoftMaxPro software and according to the following formula: y = AD / (1+ (x / C) ^ B) + D, where A = 0 and D = 100-fixed asymptote below / above, y =% Inhibition, x = logarithmic concentration of test compound, B = steepness of curve and C = IC ₅₀ (Concentration of 50% inhibition of the response of the control group), a non-linear 4 parameter juxtaposition was performed. For all compounds, calculate the average IC from at least 3 independent measurements ₅₀ value.





Mouse Vasopressin V1a Receptor Binding Analysis
Cells and radioligands
Using the immortalized 1321N1 cell line (B9 / 1321N1 selective strain) which structurally and stably expresses the vasopressin V1a receptor in mice and the vasopressin (8-L-arginine) as a radioligand [Phenylaminopropyl-3,4,5- ³ H (N)]-labeled compounds (Perkin Elmer Life and Analytical Sciences) to determine the affinity of the compounds prepared.

method
Cell membrane preparation: Cell membrane preparation of immortalized 1321N1 cells expressing proliferating mouse vasopressin V1a receptors according to the Jarvis method (Jarvis et al., J Pharmacol Exp Ther 2004, 310: 407-16). The cells were suspended in a preparative buffer (50 mM Tris, 1 mM EDTA, 0.1 mM PMSF) and homogenized by a glass homogenizer. In order to separate the crude cell membrane fraction, two continuous centrifugation operations (40,000 g, 20 minutes, 4 ° C.) were performed, and then the cell membrane was placed in the preparative buffer in the final washing step. The resulting cell membrane preparation was divided into several portions and stored in Use at -80 ° C until measurement.
According to the Lowry's method, a standard dilution series of bovine serum albumin (BSA) was used to measure the protein content of the prepared cell membrane (Lowry et al., J Biol Chem 1951, 193: 265-75).
Receptor binding assay: In receptor binding analysis, at least 8 different concentrations of each substance with 3 parallel unknown affinities are used. To determine the final affinity value, the results of at least two independent experiments were taken into account. The analysis mixture included an incubation buffer (50 mM Tris-HCl, pH 7.4 + 3% BSA), a cell membrane preparation (152 µg / ml) of 1321N1 cells expressing mouse vasopressin V1a receptor, and blood vessels as radioligands Vasopressin (8-L-arginine) [phenylalaninino-3,4,5- ³ H (N)) (about K _D (35 to 50% concentration).
At 1.2x10 ^-6 M unlabeled (Arg ⁸ )-Non-specific binding values are measured in the presence of vasopressin. A sample with a total volume of 0.33 ml was incubated at 27 ° C for 60 minutes. By passing UniFilter® GF / B impregnated with 0.5% polyethyleneimine ^TM Filtration to separate cell-bound and free ligands. After drying the filter pan, 40 μl of Microscint-20 (Packard) scintillation liquid was added to the sample. Finally, use MicroBeta ² Microdisk counter (Perkin Elmer) measures radioactivity.
The radioligand clamping ability of the substance was measured by at least 2 independent experiments. Specific radioligand binding can be defined as the difference between total binding and non-specific binding in the presence of saturated amounts of unlabeled ligand or different concentrations of the test substance. Results are expressed as% inhibition of specific binding achieved in the presence of the analyte.
Use S-shape fitting mathematical method y = (A1-A2) / (1+ (x / x ₀ ) p) + A2 and Origin 7.5. Software (OriginLab Corporation, Northampton, USA) Concentration shift curve calculation IC ₅₀ Value (ie, the concentration of the unknown substance that replaces 50% of the specifically bound radioligand). When fitting, the asymptotes are not fixed. Use Cheng-Prusoff equation K _{i =} IC ₅₀ / [1+ (L / K _D )] Calculate the inhibition constant (K _i ) Value, where [L] is the concentration of radioligand used in the experiment and [K _D ] Is the affinity of the radiolabeled ligand to the recipient. Pre-determining K using a Scatchard curve _D .


Human Vasopressin V2 Receptor Binding Analysis
Cells and radioligands
Immortalized 1321N1 cell line (Perkin Elmer, ES-363-M400-UA) (lot 1765208), which expresses human vasopressin V2 receptor, and CHO-K1, which express human vasopressin V2 receptor, were used Cell membrane (Perkin Elmer, 6110541400UA) and vasopressin (8-L-arginine) as a radioligand via [phenylalanine-3,4,5- ³ H (N)]-labeled compounds (Perkin Elmer Life and Analytical Sciences) to determine the affinity of the compounds prepared.

method
Receptor binding assay: In receptor binding analysis, at least 8 different concentrations of each substance with 3 parallel unknown affinities are used. To determine the final affinity value, the results of at least two independent experiments were taken into account. The analysis mixture included an incubation buffer (50 mM Tris-HCl, pH 7.4 + 3% BSA), a cell membrane preparation (1.82 µg / ml) of 1321N1 cells expressing human vasopressin V2 receptor, and a vasoliter as radioligand (8-L-arginine) [phenylalaninino-3,4,5- ³ H (N)) (about K _D Concentration).
At 1.2x10 ^-6 M unlabeled (Arg ⁸ )-Non-specific binding values are measured in the presence of vasopressin. A sample with a total volume of 0.55 ml was incubated at 27 ° C for 90 minutes. By passing UniFilter® GF / B impregnated with 0.5% polyethyleneimine ^TM Filtration to separate cell-bound and free ligands. After drying the filter pan, 40 μl of Microscint-20 (Packard) scintillation liquid was added to the sample. Finally, use MicroBeta ² Microdisk counter (Perkin Elmer) measures radioactivity.
The radioligand substitution capacity of a substance is measured by at least 2 independent experiments. Specific radioligand binding can be defined as the difference between total binding and non-specific binding in the presence of saturated amounts of unlabeled ligand or different concentrations of the test substance. Results are expressed as% inhibition of specific binding achieved in the presence of the analyte.
Use S-shape fitting mathematical method y = (A1-A2) / (1+ (x / x ₀ ) p) + A2 and Origin 7.5. Software (OriginLab Corporation, Northampton, USA) calculates IC from concentration shift curve ₅₀ Value (ie, the concentration of the unknown substance that replaces 50% of the specifically bound radioligand). When fitting, the asymptotes are not fixed. Use Cheng-Prusoff equation K _{i =} IC ₅₀ / [1+ (L / K _D )] Calculate the inhibition constant (K _i ) Value, where [L] is the concentration of radioligand used in the experiment and [K _D ] Is the affinity of the radiolabeled ligand to the recipient. Pre-determining K using a Scatchard curve _D .

method
Use at least 2 incubation buffers (50 mM Tris-HCl, 5 mM MgCl ₂ , PH 7.4 + 0.1% BSA), CHO-K1 cell membrane preparation (7 µg / µl) (Perkin Elmer, 6110541400UA) showing human vasopressin V2 receptor and vasopressin (8-L) as a radioligand -Arginine) (phenylalaninino-3,4,5- ³ H (N)) (about K _D Concentration)), independent receptor experiments were performed using at least 8 concentrations and 2 or 3 parallel samples each.
At 1.2x10 ^-6 M unlabeled (Arg ⁸ )-Non-specific binding values can be measured in the presence of vasopressin. A sample with a total volume of 0.55 ml was incubated at 27 ° C for 90 minutes. By passing through UniFilter® GF / B impregnated with polyethyleneimine ^TM Filtration to separate cell-bound and free ligands. Rinse the filter plate 3 times with 0.5 ml ice-cold wash buffer (50 mM Tris-HCl, pH 7.4). After drying the filter disc, 40 μl of Microscint-20 (Packard) scintillation liquid was added to each well. Finally, the radioactivity was measured using a Tri-Carb 2900TR liquid scintillation analyzer (Perkin Elmer).
The radioligand substitution capacity of a substance is measured by at least 2 independent experiments. Specific radioligand binding can be defined as the difference between total binding and non-specific binding in the presence of saturated amounts of unlabeled ligand or different concentrations of the test substance. Results are expressed as% inhibition of specific binding achieved in the presence of the analyte.
Use S-shape fitting mathematical method y = (A1-A2) / (1+ (x / x ₀ ) p) + A2 and Origin 7.5. Software (OriginLab Corporation, Northampton, USA) calculates IC from concentration shift curve ₅₀ Value (ie, the concentration of the unknown substance that replaces 50% of the specifically bound radioligand). When fitting, the asymptotes are not fixed. Use Cheng-Prusoff equation K _{i =} IC ₅₀ / [1+ (L / K _D )] Calculate the inhibition constant (K _i ) Value, where [L] is the concentration of radioligand used in the experiment and [K _D ] Is the affinity of the radiolabeled ligand to the recipient. Pre-determining K using a Scatchard curve _D .
Affinity data measured in this 1321N1 cell line expressing human vasopressin V2 receptor _i K) and K obtained from CHO-K1 cell line expressing human vasopressin V2 receptor _i The results are extremely closely related.

Functional V1a in vivo test
animal
Male mice weighing 18 to 40 g (NMRI, ToxiCoop) were used. Animals have been kept for at least 5 days since delivery, and animals are allowed to eat and drink freely during captivity and measurement. The experiments were approved by the Regional Animal Protection Committee and in accordance with European Animal Protection Guidelines ( EU Directive 2010/63 / EU ) Implementation.

method
With automated behavior analysis system (LABORAS ^TM ) Measure animal behavior. Sensors located under the plate detect mechanical vibrations generated by animal movements and convert them into electronic signals (Quinn et al., J Neurosci Methods 2003, 130: 83-92). After analyzing the signal, the system analyzes the time spent on the following behavioral parameters: movement, standing still, climbing and grooming. The defined grooming algorithm measures the response to scratching behavior. During the experimental period, the mice were pretreated with the test substance or carrier, and after this pretreatment period, the compounds causing the scratching (0.3 mg / kg oxytocin subcutaneously) were administered, and then the animals were individually placed in the measurement cage. The behavior of these mice was observed for 1 hour. To reduce exploration activities, the animals were measured after 1 hour in the cage. These behavioral parameters were compared to those measured in parallel in control animals.
The behavior inhibitory effect of the test substance was calculated from the mean value of the carrier treatment group measured in parallel and expressed as% inhibition, where 0% represents the scratching behavior of the carrier-pretreated animals (and the carrier-pretreated subcutaneous saline). The average value, and 100% represents the average scratching value of the vehicle pretreated with subcutaneously received oxytocin. For statistical analysis, a single factor analysis of variance (ANOVA) using Tukey's post hoc comparison test was used.
Surprisingly, in vivo functional tests of certain compounds of the present invention have been found to produce significant effects on mouse Vla receptors.

The present invention will be further explained by the following embodiments, but the scope of the present invention is not limited to these embodiments. With the above description and the following examples, those skilled in the art can determine the essential features of the invention, and without departing from the spirit and scope of the invention, certain changes and modifications can be made to make the invention suitable for many different Applications and conditions. Therefore, the present invention is not limited to the following illustrative embodiments, but is limited to the scope determined by the scope of the attached patent application.
In general, the compound of general formula (I) can be prepared according to the general knowledge of those skilled in the art and / or methods of preparing the compounds of the examples and / or intermediates. Those skilled in the art can easily select solvents, temperatures, pressures, and other reaction conditions. The starting materials are commercially available and / or can be easily prepared by those skilled in the art. In preparing the compounds, for example, combinatorial techniques can be used, and the intermediate groups present therein are suitable for use in these methods.
In the synthesis, the following terms and abbreviations are used:
dry = No water
Boc = tertiary butoxycarbonyl
Dess-Martin periodinane = 1,1,1-tris (ethoxyl) -1,1-dihydro-1,2-benzoiodoxazole-3- (1H) -ketone
DIPEA = N, N-diisopropyl-ethylamine
DMAP = 4-dimethylamino-pyridine
DMF = N, N-dimethylformamide
EDC = N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride
HOBt = 1-hydroxybenzotriazole hydrate
HBTU = N, N, N ', N'-tetramethyl-O- (1H-benzotriazol-1-yl) urenium hexafluorophosphate
K ₂ CO ₃ = Potassium carbonate
Lawesson reagent = 2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphacyclobutane-2,4-disulfide
Meldrum's acid = 2,2-dimethyl-1,3-dioxane-4,6-dione
MgSO ₄ = Magnesium sulfate
NaBH ₄ = Sodium borohydride
NaBH (OAc) ₃ = Sodium triethylsulfoxyborohydride
NaCl = Sodium chloride
Na ₂ CO ₃ = Sodium carbonate
NaHCO ₃ = Sodium bicarbonate
NaOAc = Sodium acetate
NaOH = Sodium hydroxide
Na ₂ SO ₄ = Sodium sulfate
Pd / C = palladium on carbon
Pt / C = platinum on carbon
THF = tetrahydrofuran

Intermediate 1
7-Chloro-4-lanthoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid methyl ester

Let 7-chloro-4- pendantoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (6.0 g, 26.7 mmol) (RD Haworth et al., J Chem Soc 1943, 10) was dissolved in methanol (100 ml) and concentrated sulfuric acid (0.5 ml) was added and the mixture was stirred overnight at reflux temperature and concentrated. The residue was dissolved in a mixture of diethyl ether and ethyl acetate (1: 1) and subjected to 10% Na ₂ CO ₃ Rinse with solution and water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated. Thus, the target product (6.27 g, 98.4%) was obtained as beige crystals. MS (ESI) m / z 239.1 (M + H) ⁺ .

Intermediate 2
7-chloro-4- (hydroxyimino) -1,2,3,4-tetrahydronaphthalene-2-carboxylic acid methyl ester

Dissolve methyl 7-chloro-4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (Intermediate 1) (6.27 g, 26.3 mmol) in methanol (220 ml), And then anhydrous NaOAc (6.57 g, 80 mmol) and hydroxylamine hydrochloride (5.55 g, 80 mmol) were added. The mixture was refluxed for 3 hours and then stirred overnight at room temperature. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, and filtered and concentrated. Thus, the target product was obtained as slightly yellow crystals (6.63 g, 99.4%). MS (ESI) m / z 254.1 (M + H) ⁺ .

Intermediate 3
7-chloro-2- pendantoxy-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid

Add 7-chloro-4- (hydroxyimino) -1,2,3,4-tetrahydronaphthalene-2-carboxylic acid methyl ester (Intermediate 2) (6.57 g, 25.9 mmol) to the polyphosphoric acid (60.0 g) and stirred at 110 ° C for 20 minutes. Ice was added to the reaction mixture and stirred for 10 minutes. It was then extracted with ethyl acetate, and the combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, and filtered and concentrated. The residue was purified by column chromatography (using cyclohexane: ethyl acetate = 2: 1 as eluent). Thus, the target product (3.03 g, 46.2%) was obtained as white crystals. MS (ESI) m / z 254.1 (M + H) ⁺ .

Intermediate 4
7-chloro-2- pendant thio-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid

Let 7-chloro-2- pendantoxy-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid (Intermediate 3) (1.50 g, 5.9 mmol) was dissolved in pyridine (80 ml), Lawson's reagent (3.11 g, 7.7 mmol) was added and The reaction mixture was allowed to stir at reflux temperature for 2 hours and then concentrated. Water (15 ml) and saturated NaHCO ₃ The solution (60 ml) was added to the residue and the highly precipitated suspension was stirred for 30 minutes. The precipitated yellow product was filtered off and dried under vacuum at 50 ° C over phosphorus pentoxide. Thus, the target product (1.58 g, 99.9%) was obtained as yellow crystals. MS (ESI) m / z 270.1 (M + H) ⁺ .

Intermediate 5
2-{[trans-4- (trifluoromethyl) cyclohexyl] carbonyl} tert-butyl hydrazine formate

Trans-4- (trifluoromethyl) cyclohexanecarboxylic acid (Manchester Organics Ltd) (2.13 g, 10.9 mmol) was dissolved in DMF (50 ml). To this solution was added tert-butyl hydrazineformate (1.44 g, 10.9 mmol), DIPEA (4.75 ml, 27.3 mmol), HOBt (2.00 g, 13.10 mmol), and EDC (2.51 g, 13.1 mmol) ear). The reaction mixture was allowed to stir at room temperature for 36 hours and then concentrated. Saturated NaHCO ₃ The solution (40 ml) was added to the residue and the precipitate was filtered after brief stirring, rinsed with water and dried on phosphorus pentoxide in a vacuum oven. Thus, the target product was obtained as a white powder (3.35 g, 99%). GC-MS (EI) m / z 310.1.

Intermediate 6
Trans-4- (trifluoromethyl) cyclohexanemethanehydrazine

Soluble tert-butyl 2-{[trans-4- (trifluoromethyl) cyclohexyl] carbonyl} hydrazine formate (Intermediate 5) (3.35 g, 10.79 mmol) in ethyl acetate (50 ml) And ethanol (20 ml) and then 2.5 M hydrochloric acid in ethyl acetate (30 ml) was added to the solution. The reaction mixture was allowed to stir at room temperature for 16 hours, then diethyl ether (150 ml) was added and cooled in an ice-water bath. The precipitated product was filtered and washed with diethyl ether. Pass the filter through saturated NaHCO ₃ The solution (pH about 8) (100 ml) was stirred, filtered, washed with water and dried in a vacuum oven over phosphorus pentoxide. Thus, the target product (1.77 g, 78%) was obtained as a white powder. GC-MS (EI) m / z 210.1.

Intermediate 7
Methyl trans-4- (piperidin-1-ylmethyl) cyclohexanecarboxylate

Dissolve methyl trans-4-formylcyclohexanecarboxylate (Synthonix) (0.30 g, 1.8 mmol) in 1,2-dichloroethane (10 ml) and add piperidine (0.52) to the solution. ml, 5.3 mmoles) and acetic acid (0.19 ml, 3.4 mmoles). The resulting mixture was cooled to 0 ° C and NaBH (OAc) was added. ₃ (1.16 g, 5.5 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then added with water (30 ml) and Na ₂ CO ₃ The solution adjusted the pH of the mixture to about 9. The mixture was extracted twice with dichloromethane (20 ml), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. Thus, the target product (0.40 g, 95%) was obtained, which was used without further purification.

Intermediate 8
Trans-4- (piperidin-1-ylmethyl) cyclohexanemethanehydrazine

Dissolve methyl trans-4- (piperidin-1-ylmethyl) cyclohexanecarboxylate (Intermediate 7) (0.40 g, 1.68 mmol) in methanol (5 ml) and pour the solution under pressure Glass reactor. Hydrazine hydrate (5 ml, 100 mmol) was added and the reaction mixture was stirred at 75 ° C for 16 hours. The reaction mixture was concentrated and cyclohexane and anhydrous toluene were evaporated to give a residue. Thus, the target product (0.39 g, 97%) was obtained as a white powder. GC-MS (EI) m / z 239.2.

Intermediate 9
Trans-4- (pyrrolidin-1-ylcarbonyl) cyclohexanemethanehydrazine

a) Methyl trans-4- (pyrrolidin-1-ylcarbonyl) cyclohexanecarboxylate

Let trans-4- (methoxycarbonyl) cyclohexanecarboxylic acid (Combi-Blocks Inc.) (186 mg, 1 mmol), pyrrolidine (83.5 µl, 1 mmol), anhydrous DMF (5 ml ), A mixture of DIPEA (348 µl, 2 mmol), EDC (230 mg, 1.2 mmol) and HOBt (162 mg, 1.2 mmol) at room temperature with stirring for 24 hours. Add ethyl acetate and NaHCO to the reaction mixture ₃ The aqueous layer was separated and the layers were separated and the aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed with 1N hydrochloric acid and water, dried over anhydrous sodium sulfate, filtered and concentrated. Thus, the target product was obtained (180 mg, 75%). GC-MS (EI) m / z 239.

b) trans-4- (pyrrolidin-1-ylcarbonyl) cyclohexanemethanehydrazine
Put trans-4- (pyrrolidin-1-ylcarbonyl) cyclohexanecarboxylic acid methyl ester (180 mg, 0.75 mmol), methanol (1.1 ml) and hydrazine hydrate (1.1 ml) in a pressure-resistant glass reactor The mixture was stirred at 75 ° C for 24 hours. The reaction mixture was concentrated and cyclohexane was added and then evaporated. Thus, the target product was obtained (183 mg, 76%). GC-MS (EI) m / z 239.

Intermediate 10
Trans-4- (morpholin-1-ylcarbonyl) cyclohexanemethanehydrazine

a) Methyl trans-4- (morpholin-4-ylcarbonyl) cyclohexanecarboxylate

The target product was prepared from trans-4- (methoxycarbonyl) cyclohexanecarboxylic acid (Combi-Blocks Inc.) and morpholine according to the method described in step a) of Intermediate 9. GC-MS (EI) m / z 255.

b) trans-4- (morpholin-1-ylcarbonyl) cyclohexanemethanehydrazine
The target product was prepared from trans-4- (morpholin-4-ylcarbonyl) cyclohexanecarboxylic acid methyl ester according to the method described in step 9) of intermediate 9. GC-MS (EI) m / z 255.

Intermediate 11
Trans-4- (dimethylamino) cyclohexanemethylhydrazine

The target product was prepared from trans-4- (dimethylamino) cyclohexanecarboxylic acid methyl ester (EP 1 582 521 A1 (05.10.2005), TANABE SEIYAKU CO.) According to the method described in Intermediate 8. MS (ESI) m / z 186.3 (M + H) ⁺ .

Intermediate 12
Trans-4- (morpholin-4-yl) cyclohexanemethanehydrazine

The target product was prepared according to the method described in Intermediate 8 from methyl trans-4- (morpholin-4-yl) cyclohexanecarboxylate (EP 1 582 521 A1 (05.10.2005) TANABE SEIYAKU CO.). GC-MS (EI) m / z 227.

Intermediate 13
1- (pyrimidin-2-yl) tetrahydroazepine-3-formamidine

The target product was prepared according to the method described in Intermediate 8 from methyl 1- (pyrimidin-2-yl) tetrahydroazepine-3-carboxylic acid (WO 2006/124748 A2 (23.11.2006) LEXICON GENETICS INCORP.). MS (ESI) m / z 194.2 (M + H) ⁺ .

Intermediate 14
1- (pyridin-2-yl) tetrahydroazepine-3-formamidine

The target product was prepared according to the method described in Intermediate 8 from methyl 1- (pyridin-2-yl) tetrahydroazepine-3-carboxylic acid (WO 2017/007756 A1 (12.01.2017) RODIN THERAPEUTICS INC.). GC-MS (EI) m / z 192.

Intermediate 15
(Trans) -3-methyl-2-oxo-1-oxo-3-azaspiro [4.5] decane-8-carboxylic acid ethyl ester

with
Intermediate 16
(Cis) -3-methyl-2-oxo-1-oxo-3-azaspiro [4.5] decane-8-carboxylic acid ethyl ester

A 60% sodium hydride oil dispersion (1.8 g, 45.0 mmol) was suspended in anhydrous DMF (60 ml), cooled to 0 to 5 ° C, and then dissolved in DMF (60 ml) (cis. (Formula) -2-Phenoxy-1-oxa-3-azaspiro [4.5] decane-8-carboxylic acid ethyl ester and (trans) -2-Phenoxy-1-oxa-3-nitro Approximately 1: 1 mixture of heterospiro [4.5] decane-8-carboxylic acid ethyl ester (WO 2008/092887 A1 (07.08.2008) GLAXO GROUP LTD.) (6.00 g, 26.4 mmol) so that the temperature of the mixture Maintain between 0 and 5 ° C. The reaction mixture was allowed to stir at this temperature for 20 minutes, and then methyl iodide (2.46 ml, 39.5 mmol) was added dropwise over 20 minutes. The mixture was allowed to stir for an additional hour at 0 to 5 ° C, returned to room temperature and stirred for 3 hours at this temperature. Acetic acid (1.8 ml, 31 mmol) was then added dropwise over 10 minutes, and after stirring for 15 minutes, the reaction mixture was concentrated and n-heptane (90 ml) was evaporated twice to obtain a residue. To the residue was added ethyl acetate (180 ml), saturated NaHCO ₃ The solution (90 ml) and water (90 ml) were separated into layers, and the organic phase was washed with NaCl (90 ml), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography using toluene: isopropanol = 93: 7 as the eluent. The appropriate fractions were concentrated and the residue was crystallized from diisopropyl ether. Thus, (trans) -3-methyl-2-oxo-1-oxo-3-azaspiro [4.5] decane-8-carboxylic acid ethyl ester (Intermediate 15) was obtained as a white powder (Intermediate 15) ( 1.38 g, 22%) and (cis) -3-methyl-2-oxo-1-oxa-3-azaspiro [4.5] decane-8-carboxylic acid ethyl ester (Intermediate 16) ( 2.45 g, 39%). GC-MS (EI) m / z 241.

Intermediate 17
(Trans) -3-methyl-2-oxo-1-oxa-3-azaspiro [4.5] decane-8-formamidine

According to the method described for intermediate 8, ) Preparation of the target product. GC-MS (EI) m / z 227.

Intermediate 18
(Cis) -3-methyl-2-oxo-1-oxa-3-azaspiro [4.5] decane-8-formamidine

According to the method described in Intermediate 8, from (cis) -3-methyl-2-oxo-1-oxa-3-azaspiro [4.5] decane-8-carboxylic acid ethyl ester (Intermediate 16 ) Preparation of the target product. GC-MS (EI) m / z 227.

Intermediate 19
Trans-4- (tetrahydroazepine-1-ylcarbonyl) cyclohexanemethylhydrazine


a) Methyl trans-4- (tetrahydroazepine-1-ylcarbonyl) cyclohexanecarboxylate

The target product was prepared from trans-4- (methoxycarbonyl) cyclohexanecarboxylic acid (Combi-Blocks Inc.) and tetrahydroacridine according to the method described in step a) of Intermediate 9. GC-MS (EI) m / z 225.

b) trans-4- (tetrahydroacryl-1-ylcarbonyl) cyclohexanemethylhydrazine
The title product was prepared from methyl trans-4- (tetrahydroacryl-1-ylcarbonyl) cyclohexanecarboxylate according to the method described in Step 9) of Intermediate 9. GC-MS (EI) m / z 225.

Intermediate 20
Trans-4- (piperidin-1-ylcarbonyl) cyclohexanemethanehydrazine

a) Methyl trans-4- (piperidin-1-ylcarbonyl) cyclohexanecarboxylate

The target product was prepared from trans-4- (methoxycarbonyl) cyclohexanecarboxylic acid (Combi-Blocks Inc.) and piperidine according to the method described in step a) of Intermediate 9. GC-MS (EI) m / z 253.

b) trans-4- (piperidin-1-ylcarbonyl) cyclohexanemethylhydrazine
The target product was prepared from trans-4- (piperidin-1-ylcarbonyl) cyclohexanecarboxylic acid methyl ester according to the method described in Intermediate 9 step b). GC-MS (EI) m / z 253.

Intermediate 21
4-{[trans-4- (hydrazinocarbonyl) cyclohexyl] carbonyl} piperazine-1-carboxylic acid tert-butyl ester

a) 4-{[trans-4- (methoxycarbonyl) cyclohexyl] carbonyl} piperazine-1-carboxylic acid tert-butyl ester

Prepare the target product from trans-4- (methoxycarbonyl) cyclohexanecarboxylic acid (Combi-Blocks Inc.) and piperazine-1-carboxylic acid tert-butyl ester according to the method described in step a) of Intermediate 9, It was used without further purification.

b) trans-4- (morpholin-1-ylcarbonyl) cyclohexanemethanehydrazine
The target product was prepared from 4-{[trans-4- (methoxycarbonyl) -cyclohexyl] carbonyl} piperazine-1-carboxylic acid tert-butyl ester according to the method described in step 9) of Intermediate 9. Used with further purification.

Intermediate 22
7-chloro-2- (methylthio) -4,5-dihydro-3H-1-benzoazine-4-carboxylic acid methyl ester

Let 7-chloro-2- pendant thio-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid (Intermediate 4) (250 mg, 0.93 mmol), acetone (18.5 ml), K ₂ CO ₃ (259 mg, 1.87 mmol) and iodomethane (0.18 ml, 2.89 mmol) were stirred at room temperature for 20 hours. The reaction mixture was concentrated, water was added to the residue and extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and filtered and concentrated. Thus, the target product was obtained (261 mg, 99%). MS (ESI) m / z 284.1 (M + H) ⁺ .

Intermediate 23
8-chloro-5,6-dihydro-4 H -[1,2,4] triazolo [4,3- a ] [1] Methylbenzoazine-5-carboxylic acid

7-Chloro-2- (methylthio) -4,5-dihydro-3H-1-benzoazine-4-carboxylic acid methyl ester (Intermediate 22) (261 mg, 0.92 mmol) was dissolved in 1,4-dioxane (6 ml) and warm the solution to 90 ° C. Methylhydrazine (277 mg, 4.61 mmol) was added over 4 hours under argon. After the reaction mixture was subsequently stirred at 90 ° C for 8 hours and cooled to room temperature, the solvent was evaporated under vacuum. The residue was purified by column chromatography using dichloromethane: methanol = 95: 5 as the eluent. Thus, the target product was obtained (188 mg, 74%). MS (ESI) m / z 278.1 (M + H) ⁺ .

Intermediate 24
1-bromo-8-chloro-5,6-dihydro-4 H -[1,2,4] triazolo [4,3- a ] [1] Methylbenzoazine-5-carboxylic acid

Let 8-chloro-5,6-dihydro-4 H -[1,2,4] triazolo [4,3- a ] [1] Benzoazine-5-carboxylic acid methyl ester (Intermediate 23) (187 mg, 0.67 mmol) was dissolved in THF (15 ml). N-Bromosuccinimide (120 mg, 0.68 mmol) was added and the resulting pale yellow solution was stirred at reflux temperature and irradiated by a RH-500 halogen lamp (Tracon Electric) for 60 minutes. At this time, the color of the solution was initially dark and then gradually faded. After cooling to room temperature, the solvent was evaporated under vacuum. The residue was purified by column chromatography (using cyclohexane: ethyl acetate = 1; 1 to 1: 4 as eluent). Thus, the target compound (226 mg, 94%) was obtained. MS (ESI) m / z 358.0 (M + H) ⁺ .

Intermediate 25
7-methyl-2- pendant thio-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid

Let 7-methyl-2- pendantoxy-2,3,4,5-tetrahydro-1 H Methyl-1-benzoacryl-4-carboxylic acid (100 mg, 0.43 mmol), which was prepared according to the method described in Intermediate 3, was dissolved in THF (10 ml), followed by the addition of a Lawson reaction (105 mg, 0.26 mmol) and the mixture was stirred at room temperature for 20 hours. The reaction mixture was first concentrated, and the residue was then added with saturated NaHCO ₃ The solution was stirred for 60 minutes. The precipitated product was filtered, washed with water and dried. Thus, the target product was obtained (80 mg, 75%). MS (ESI) m / z 250.2 (M + H) ⁺ .

Intermediate 26
7-methoxy-2- pendant thio-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid

According to the method described in Intermediate 25, from 7-methoxy-2- pendantoxy-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid (which was prepared according to the method described in Intermediate 3) was used to prepare the target product. MS (ESI) m / z 266.1 (M + H) ⁺ .

Intermediate 27
7-bromo-2- pendant thio-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid

According to the method described in Intermediate 25, from 7-bromo-2- pendantoxy-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid (which was prepared according to the method described in Intermediate 3) was used to prepare the target product. MS (ESI) m / z 316.0 (M + H) ⁺ .

Intermediate 28
7-bromo-2- (methylthio) -4,5-dihydro-3 H Methyl-1-benzoazine-4-carboxylic acid

According to the method described in Intermediate 22, from 7-bromo-2- pendant thio-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid (Intermediate 27) was used to prepare the target product. MS (ESI) m / z 330.1 (M + H) ⁺ .

Intermediate 29
1-bromo-8-chloro-5,6-dihydro-4 H -[1,2,4] triazolo [4,3- a ] [1] Benzacridin-5-carboxamide

a) 1-Bromo-8-chloro-5,6-dihydro-4 H -[1,2,4] triazolo [4,3- a ] [1] Benzacene-5-carboxylic acid

Let 1-bromo-8-chloro-5,6-dihydro-4 H -[1,2,4] triazolo [4,3- a ] [1] Methyl benzoazine-5-carboxylate (Intermediate 24) (631 mg, 1.77 mmol), THF (13 ml), methanol (6.5 ml), water (6.5 ml) and lithium hydroxide A mixture of hydrates (379 mg, 9.03 mmol) was stirred at room temperature for 2.5 hours, then the solvent was evaporated and the remaining aqueous solution was diluted with water (10 ml). The pH of the solution was adjusted to 5 with 1M hydrochloric acid, and the precipitated product was filtered and washed with water. The mother liquor was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting residue was combined with the filtered product to give the target compound (433 mg, 71%). MS (ESI) m / z 343.9 (M + H) ⁺ .

b) 1-bromo-8-chloro-5,6-dihydro-4 H -[1,2,4] triazolo [4,3- a ] [1] Benzacridin-5-carboxamide
P-Bromo-8-chloro-5,6-dihydro-4 H -[1,2,4] triazolo [4,3- a ] [1] Benzacene-5-carboxylic acid (Intermediate 29 step a)) (620 mg, 1.8 mmol), DMF (8 ml), HOBt (498 mg, 3.25 mmol), DIPEA ( 0.88 ml, 5.06 mmoles) and EDC (623 mg, 3.25 mmoles) in an ice-cold mixture was added ammonium chloride (290 mg, 5.48 mmoles) and the reaction mixture was stirred at 5 ° C for 0.5 hours and then Stir for another 20 hours at room temperature. After completion of the reaction, the mixture was diluted with water and brine and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and filtered and concentrated. The residue was crystallized from ethyl acetate to give the target compound (428 mg, 69%). MS (ESI) m / z 343.0 (M + H) ⁺ .

Intermediate 30
(5 s ,8 s ) -1-Pentoxy-2- (prop-2-yl) -2-azaspiro [4.5] decane-8-carboxylic acid methyl ester

with
Intermediate 31
(5 r ,8 r ) -1-Pentoxy-2- (prop-2-yl) -2-azaspiro [4.5] decane-8-carboxylic acid methyl ester

Let trans-1- (2-oxoethyl) cyclohexane-1,4-dicarboxylic acid dimethyl ester (WO 2011/143150 A1, (05.10.2011) SANOFI) (0.9 g, 4.0 mmol) ), 1,2-dichloroethane (40 ml), isopropylamine (316 µl, 3.71 mmol) and acetic acid (637 µl, 11.1 mmol) were cooled to 5 ° C and the reaction mixture was added with three Acetyloxyborohydride (2.36 g, 11.1 mmol), where the addition rate maintains the internal temperature below 5 ° C. After the addition was complete, the reaction mixture was allowed to stir at room temperature for 2 hours and then diluted with water. By adding 10% K ₂ CO ₃ The solution adjusted the pH of the mixture to 8, the phases were separated and the aqueous phase was extracted with dichloromethane. Let the combined organic phase undergo continuous 10% K ₂ CO ₃ The solution, water and brine were rinsed, dried over sodium sulfate and filtered and concentrated. The residue was dissolved in anhydrous THF (40 ml) and tertiary potassium butoxide (330 mg, 2.94 mmol) was added. The reaction mixture was allowed to stir at room temperature for 3 hours and then CO was added. ₂ The solid was neutralized. After adding water, the THF was evaporated and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and filtered and concentrated. The residue was purified by flash column chromatography (using a mixture of cyclohexane: ethyl acetate = 45: 55 as the eluent) to produce the first fraction (5 s ,8 s ) -1-Pentoxy-2- (prop-2-yl) -2-azaspiro [4.5] decane-8-carboxylic acid methyl ester (Intermediate 30) (56 mg, 6%) and Distillate (5 r ,8 r ) -1-Phenoxy-2- (prop-2-yl) -2-azaspiro [4.5] decane-8-carboxylic acid methyl ester (Intermediate 31) (172 mg, 19%). GC-MS (EI) m / z 253.

Intermediate 32
(5 r ,8 r ) -1-Pentoxy-2- (prop-2-yl) -2-azaspiro [4.5] decane-8-formamidine

According to the method described in step b) of intermediate 9, from (5 r ,8 r ) -1-Pentoxy-2- (prop-2-yl) -2-azaspiro [4.5] decane-8-carboxylic acid methyl ester (Intermediate 31) to prepare the target compound. GC-MS (EI) m / z 253.

Intermediate 33
4- (1-([tertiarybutyl (dimethyl) silyl] oxy} ethyl) -7-chloro-1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-one


a) 7-Chloro-2-sideoxy-2,3,4,5-tetrahydro-1 H -1-Benzazine-4-carboxylic acid

Let 7-chloro-2- pendantoxy-2,3,4,5-tetrahydro-1 H A mixture of methyl-1-benzoazine-4-carboxylate (Intermediate 3) (12.38 g, 48.8 mmol), methanol (55 ml) and 50% NaOH solution (12 ml) was stirred at room temperature 0.5 hours and then cooled to 0 ° C and 5% hydrochloric acid solution (105 ml) was added. After stirring for 10 minutes at 0 ° C, the precipitated product was filtered, washed with water and dried to give the target compound (11.1 g, 95%). MS (ESI) m / z 240.2 (M + H) ⁺ .

b) 7-chloro- N -Methoxy- N -Methyl-2- pendantoxy-2,3,4,5-tetrahydro-1 H -1-benzoazepine-4-carboxamide

According to the method described in step a) of Intermediate 9, from 7-chloro-2- pendantoxy-2,3,4,5-tetrahydro-1 H 1-Benzacne-4-carboxylic acid (Intermediate 33 step a)) and N-methoxymethylamine hydrochloride were used to prepare the target compound, which was used in the next step without further purification.

c) 4-Ethyl-7-chloro-1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-one

Order 7-chloro- under argon N -Methoxy- N -Methyl-2- pendantoxy-2,3,4,5-tetrahydro-1 H A mixture of -1-benzoazepine-4-carboxamidine (Intermediate 33 step b)) (2.5 g, 8.84 mmol) in anhydrous THF (100 ml) was cooled to -15 ° C and 3M methyl was added Diethyl ether solution of magnesium bromide (14.7 ml, 44.1 mmol). The reaction mixture was allowed to stir at -10 ° C to 0 ° C for 3 hours, and then by adding saturated NH ₄ The Cl solution was quenched and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered and concentrated. The residue was purified by flash column chromatography (using dichloromethane: methanol = 96: 4 as the eluent) to give the target compound (1.6 g, 76%). MS (ESI) m / z 238.2 (M + H) ⁺ .

d) 7-chloro-4- (1-hydroxyethyl) -1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-one

Let 4-ethenyl-7-chloro-1,3,4,5-tetrahydro-2 H -1-Benzacridin-2-one (Intermediate 33 step c)) (300 mg, 1.26 mmol), ethanol (50 ml), and NaBH ₄ The mixture (96 mg, 2.5 mmol) was stirred at room temperature for 0.5 hours, then quenched by the addition of a 1M solution of hydrochloric acid and the ethanol was evaporated. The aqueous phase was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (using dichloromethane: methanol = 95: 5 as the eluent) to give the target compound (235 mg, 78%) as a mixture of 63:37 non-mirror isomers. MS (ESI) m / z 240.2 (M + H) ⁺ .

e) 4- (1-([tertiary butyl (dimethyl) silyl] oxy} ethyl) -7-chloro-1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-one
Let 7-chloro-4- (1-hydroxyethyl) -1,3,4,5-tetrahydro-2 H -1-Benzacridin-2-one (Step d) of Intermediate 33) (665 mg, 2.77 mmol), DMF (5 ml), methylene chloride (50 ml), and 2,6-dimethylamine The stirred mixture of pyridine (0.8 ml, 6.94 millimoles) was cooled to 0 ° C and tributylmethane sulfonyl trifluoromethanesulfonate (792 mg, 3.0 millimoles) was added under argon. The reaction mixture was allowed to warm to room temperature and was stirred at this temperature for 16 hours. Evaporate the dichloromethane, add water (10 ml) and saturated NaHCO ₃ Solution (10 ml) and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered and concentrated. The residue was purified by flash column chromatography (using cyclohexane: ethyl acetate = 75: 25 as eluent). The first fraction is one of the non-mirro isomers (200 mg, 20%), the second fraction is a mixture of non-mirro isomers (191 mg, 19%) and the third fraction is the other non-mirro isomer (326 mg, 33%). MS (ESI) m / z 354.2 (M + H) ⁺ .

Intermediate 34
4- (1-([tertiarybutyl (dimethyl) silyl] oxy} ethyl) -7-chloro-1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-thione

According to the method described in Intermediate 4, from 4- (1-{[Tri-butyl (dimethyl) silyl] oxy} ethyl) -7-chloro-1,3,4,5-tetrahydro-2 H 1-Benzacridin-2-one (Intermediate 33 step e)) prepares the target compound, which is used in the next step without further purification. Use the same method for a mixture of non-image isomers (second fraction of step e) of intermediate 33) or independently non-image isomers (first and third fractions of step 33 of intermediate 33) .

Intermediate 35
4-methoxy-4-methylcyclohexanemethanehydrazine

a) Ethyl 4-hydroxy-4-methylcyclohexanecarboxylate

To a stirred solution of 2M trimethylaluminum in toluene (100 ml, 220 mmol) under argon was added 4-lanthoxycyclohexanecarboxylic acid ethyl ester (8.7 ml, 55 mmol) at -60 ° C over 2.5 hours. Ear) in toluene (50 ml). After the addition was completed, the mixture was allowed to stir at -60 ° C for 0.5 hours and then warmed to -20 ° C over 2 hours. While maintaining the internal temperature below 10 ° C, the reaction mixture was transferred to ethyl acetate (180 ml), water (425 ml), concentrated hydrochloric acid (75 ml), and crushed ice by intubation over 25 to 30 minutes. (100 g) of ice-cold mixture. The layers were separated and the organic phase was washed successively with water (400 ml) and brine (400 ml), dried over sodium sulfate, filtered and concentrated to give the target compound (5.44 g, 53%). in accordance with ¹ HNMR spectrum, the compound is a 28:72 mixture of cis and trans isomers. This mixture was used in the next step without further purification.

b) Ethyl 4-methoxy-4-methylcyclohexanecarboxylate

Under argon, a solution of 60% sodium hydride in mineral oil (2.16 g, 54 mmol), anhydrous THF (34 ml), tetrabutylammonium iodide (200 mg, 0.54 mmol), imidazole (49 mg , 0.72 millimolar) and a solution of methyl iodide (3.36 ml, 54 millimolar) at 20 to 25 ° C over 30 to 40 minutes. Ethyl 4-hydroxy-4-methylcyclohexanecarboxylic acid (intermediate Step a)) of 35 (3.36 g, 18 mmol) in anhydrous THF (21 ml). The reaction mixture was allowed to stir at room temperature for 3 hours, then cooled to 0 to 5 ° C and acetic acid (2.28 ml, 40 mmol) was added over 10 minutes. Allow the mixture to stir for 15 minutes, then pour into diethyl ether (280 ml) and saturated NaHCO ₃ A mixture of solutions (120 ml). The layers were separated and the organic phase was washed with brine, dried over sodium sulfate and filtered and concentrated. The residue was purified by column chromatography (using n-hexane: ethyl acetate = 85: 15 as the eluent) to give the target compound (2.3 g, 64%). in accordance with ¹ HNMR spectrum, the compound is a 21:79 mixture of cis and trans isomers.

c) 4-methoxy-4-methylcyclohexanemethanehydrazine
The subject compound was prepared from 4-methoxy-4-methylcyclohexanecarboxylic acid ethyl ester (intermediate 35 step b)) according to the method described in intermediate step 9). in accordance with ¹ HNMR spectrum, the compound is a 21:79 mixture of cis and trans isomers.

Intermediate 36
7-chloro-4- (fluoromethyl) -1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-one

a) 7-Chloro-4- (hydroxymethyl) -1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-one

Order 7-chloro-2-lanthoxy-2,3,4,5-tetrahydro-1 under argon H A stirred mixture of methyl-1-benzoazine-4-carboxylic acid methyl ester (Intermediate 3) (500 mg, 1.97 mmol), anhydrous diethyl ether (15 ml) and anhydrous THF (20 ml) was cooled to -40 ° C. A 1 M solution of lithium aluminum hydride in diethyl ether (4.33 ml, 4.33 mmol) was added. The reaction mixture was allowed to stir at -20 ° C for 1 hour and then warmed to 0 ° C and water was carefully added. The THF was evaporated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and filtered and concentrated to give the title compound (422 mg, 95%). MS (ESI) m / z 226.1 (M + H) ⁺ .

b) 7-chloro-4- (fluoromethyl) -1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-one
Order 7-chloro-4- (hydroxymethyl) -1,3,4,5-tetrahydro-2 under argon H A stirred mixture of -1-benzoazepine-2-one (Intermediate 36 step a)) (532 mg, 2.36 mmol) and anhydrous dichloromethane (50 ml) was cooled to -78 ° C and added dropwise (Diethylamino) sulfur trifluoride (950 mg, 5.89 mmol) in dichloromethane (1 ml). The reaction mixture was allowed to warm to 0 ° C over 4 hours, stirred at this temperature for 45 minutes and then saturated NaHCO was added. ₃ Solution. The layers were separated, the aqueous phase was extracted with dichloromethane, the combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse-phase flash column chromatography (using water (containing 0.1% trifluoroacetic acid): acetonitrile = 60:40 as the eluent) to give the target compound (222 mg, 41%). MS (ESI) m / z 228.1 (M + H) ⁺ .

Intermediate 37
7-chloro-4- (fluoromethyl) -1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-thione

According to the method described in Intermediate 4, from 7-chloro-4- (fluoromethyl) -1,3,4,5-tetrahydro-2 H 1-Benzacridin-2-one (step b) of intermediate 36) prepares the target compound, which is used in the next step without further purification.

Intermediate 38
7-fluoro-2-oxo-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid

a) 7-Fluoro-4- (hydroxyimino) -1,2,3,4-tetrahydronaphthalene-2-carboxylic acid methyl ester

Prepared according to the method described in Intermediate 2 from methyl 7-fluoro-4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (US5595872 (03.09.1993) Bristol-Myers Squibb Company) The target compound was used in the next step without further purification.

b) 7-fluoro-2-oxo-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid
Prepare the target compound from 7-fluoro-4- (hydroxyimino) -1,2,3,4-tetrahydronaphthalene-2-carboxylic acid methyl ester (Intermediate 38 step a)) according to the method described in Intermediate 3. Compound. MS (ESI) m / z 238.2 (M + H) ⁺ .

Intermediate 39
7-fluoro-2- pendant thio-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid

According to the method described in Intermediate 4, from 7-fluoro-2- pendantoxy-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid (Intermediate 38, step b)) prepared the target compound, which was used in the next step without further purification.

Intermediate 40
7-fluoro-4- (fluoromethyl) -1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-one

a) 7-Fluoro-4- (hydroxymethyl) -1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-one

According to the method described in step a) of Intermediate 36, from 7-fluoro-2- pendantoxy-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid (Intermediate 38, step b)) prepared the target compound, which was used in the next step without further purification.

b) 7-fluoro-4- (fluoromethyl) -1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-one
According to the method described in step b) of Intermediate 36, from 7-fluoro-4- (hydroxymethyl) -1,3,4,5-tetrahydro-2 H 1-Benzacridin-2-one (Intermediate 40, step a)) prepares the target compound, which is used in the next step without further purification.

Intermediate 41
7-fluoro-4- (fluoromethyl) -1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-thione

According to the method described in Intermediate 4, from 7-fluoro-4- (fluoromethyl) -1,3,4,5-tetrahydro-2 H 1-Benzacridin-2-one (Intermediate 40, step b)) prepares the target compound, which is used in the next step without further purification.

Intermediate 42
4- (fluoromethyl) -7-methyl-1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-one

a) 4- (hydroxymethyl) -7-methyl-1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-one

According to the method described in step a) of intermediate 36, from 7-methyl-2- pendantoxy-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid (prepared according to the method described in Intermediate 3) was used to prepare the target compound, which was used in the next step without further purification.

b) 4- (fluoromethyl) -7-methyl-1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-one
From 4- (hydroxymethyl) -7-methyl-1,3,4,5-tetrahydro-2 according to the method described in step b) of intermediate 36 H 1-Benzacridin-2-one (Intermediate 42 step a)) to prepare the target compound. MS (ESI) m / z 208.2 (M + H) ⁺ .

Intermediate 43
4- (fluoromethyl) -7-methyl-1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-thione

From 4- (fluoromethyl) -7-methyl-1,3,4,5-tetrahydro-2 according to the method described in Intermediate 4 H 1-Benzacridin-2-one (Intermediate 42 step b)) prepares the target compound, which is used in the next step without further purification.

Intermediate 44
7-fluoro-2- (methylthio) -4,5-dihydro-3 H Methyl-1-benzoazine-4-carboxylic acid

According to the method described in Intermediate 22, from 7-fluoro-2- pendant thio-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid (Intermediate 39) prepared the target compound. MS (ESI) m / z 268.1 (M + H) ⁺ .

Intermediate 45
7-chloro-4-methyl-2-oxo-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid

a) 7-Chloro-1- (4-methoxybenzyl) -2-oxo-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid

Let 7-chloro-2- pendantoxy-2,3,4,5-tetrahydro-1 H A stirred mixture of methyl-1-benzoacryl-4-carboxylate (Intermediate 3) (1.0 g, 3.94 mmol) in anhydrous DMF (10 ml) was cooled to 0 ° C and 60% hydrogenated under argon. A solution of sodium (205 mg, 5.12 mmol) in mineral oil. The mixture was allowed to stir at this temperature for 1 hour, then 4-methoxybenzyl chloride (0.8 ml, 5.9 mmol) was added and the reaction mixture was stirred at room temperature for 20 hours. After the reaction was completed, the mixture was diluted with water and brine, extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (using cyclohexane: ethyl acetate = 4: 1 as the eluent) to give the target compound (820 mg, 56%). MS (ESI) m / z 374.1 (M + H) ⁺ .

b) 7-Chloro-1- (4-methoxybenzyl) -4-methyl-2- pendantoxy-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid

Let 7-chloro-1- (4-methoxybenzyl) -2- pendantoxy-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid methyl ester (Intermediate 45, step a)) (600 mg, 1.61 mmol) was stirred in anhydrous THF (30 ml) and cooled to -70 ° C under argon. A 2.0 M solution of lithium diisopropylamide in THF / heptane / ethylbenzene (1.2 ml, 2.4 mmol) was added. The mixture was allowed to stir at this temperature for 2 hours, then methyl iodide (0.2 ml, 3.2 mmol) was added and the reaction mixture was allowed to warm to 0 ° C over 2 hours. After the reaction was completed, the mixture was quenched by the addition of saturated ammonium chloride, extracted with ethyl acetate, the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (using cyclohexane: ethyl acetate = 4: 1 as the eluent) to give the target compound (460 mg, 74%). MS (ESI) m / z 388.1 (M + H) ⁺ .

c) 7-chloro-4-methyl-2-oxo-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid
Let 7-chloro-1- (4-methoxybenzyl) -4-methyl-2- pendantoxy-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylate (Intermediate 45 step b)) (460 mg, 1.2 mmol), acetonitrile (20 ml), water (5 ml), and cerium (IV) ammonium nitrate (1.95 g, 3.56 mmol) was stirred at room temperature for 2 hours and then diluted with water. By adding saturated NaHCO ₃ The solution adjusted the pH of the mixture to 8 and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered and concentrated. The residue was purified by flash column chromatography (using cyclohexane: ethyl acetate = 4: 1 as the eluent) to give the target compound (190 mg, 60%). MS (ESI) m / z 268.1 (M + H) ⁺ .

Intermediate 46
7-chloro-4-methyl-2- pendant thio-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid

According to the method described in Intermediate 25, from 7-chloro-4-methyl-2- pendantoxy-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid (Intermediate 45, step c)) The title compound was prepared and used in the next step without further purification.

Intermediate 47
7-chloro-4-ethyl-2-oxo-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid


a) 7-Chloro-1- (4-methoxybenzyl) -4-ethyl-2- pendantoxy-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid

According to the method described in step b) of Intermediate 45, from 7-chloro-1- (4-methoxybenzyl) -2- pendantoxy-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid (Intermediate 45, step a)) and iodoethane prepared the target compound, which was used in the next step without further purification.

b) 7-chloro-4-ethyl-2-oxo-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid
According to the method described in step c) of intermediate 45, from 7-chloro-1- (4-methoxybenzyl) -4-ethyl-2- pendantoxy-2,3,4,5-tetrahydro -1 H Methyl-1-benzoazine-4-carboxylic acid (Intermediate 47, step a)) to prepare the target compound. MS (ESI) m / z 282.1 (M + H) ⁺ .

Intermediate 48
7-chloro-4-ethyl-2-sulfanyl-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid

According to the method described in Intermediate 25, from 7-chloro-4-ethyl-2- pendantoxy-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid (step b) of intermediate 47) prepared the target compound, which was used in the next step without further purification.

Intermediate 49
7-chloro-4-ethyl-2- (methylthio) -4,5-dihydro-3 H Methyl-1-benzoazine-4-carboxylic acid

According to the method described in Intermediate 22, from 7-chloro-4-ethyl-2- pendant thio-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid (Intermediate 48) prepared the title compound, which was used in the next step without further purification.

Intermediate 50
Tert-butyl 2-[(3,3-difluorocyclobutyl) carbonyl] hydrazine formate

The target compound was prepared from 3,3-difluorocyclobutanecarboxylic acid (Combi-Blocks Inc.) according to the method described in Intermediate 5. GC-MS (EI) m / z 250.1.

Intermediate 51
3,3-difluorocyclobutanemethanehydrazine

The title compound was prepared from tert-butyl 2-[(3,3-difluorocyclobutyl) carbonyl] hydrazinecarboxylic acid (intermediate 50) according to the method described in Intermediate 6. GC-MS (EI) m / z 150.1.

Intermediate 52
1-bromo-8-chloro-5,6-dihydro-4 H -[1,2,4] triazolo [4,3- a ] [1] Benzacridin-5-carbonitrile

Let 1-bromo-8-chloro-5,6-dihydro-4 H -[1,2,4] triazolo [4,3- a ] [1] Benzacridine-5-carboxamide (Intermediate 29 step b)) (155 mg, 0.45 mmol), anhydrous dichloromethane (77 ml), and triethylamine (400 µl, 2.86 The stirred solution was cooled to 0 ° C and trifluoroacetic anhydride (105 µl, 0.73 mmol) was added. The mixture was allowed to warm to room temperature and the reaction mixture was stirred at this temperature for 1 hour, then cooled to 0 ° C and triethylamine (400 µl, 2.86 mmol) and trifluoroacetic anhydride (105 µl, 0.73 millimolar). The mixture was allowed to stir at room temperature for 2.5 hours and then saturated NaHCO ₃ The solution was diluted. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water and brine, dried over sodium sulfate and filtered and concentrated. The residue was purified by column chromatography (using dichloromethane: methanol: ammonium hydroxide = 180: 10: 1 as eluent) to give the target compound (125 mg, 85%). MS (ESI) m / z 323.0 (M + H) ⁺ .

Intermediate 53
7-fluoro-4,4-dimethyl-1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-one

a) [1- (3-Fluorophenyl) -2-methylprop-2-yl] diethyl malonate

Slowly add 0.5M 3-fluorobenzylmagnesium chloride (Alfa Aesar) in 2-Me-THF (33 ml, 16.5 mmol) to (propan-2-yl) via a dropping funnel under argon over 4 hours ) A solution of diethyl malonate (Aldrich) (3.0 g, 15.0 mmol) in diethyl ether (150 ml). Stirring was then continued at room temperature for 18 hours. The reaction was then quenched with a 1M hydrochloric acid solution and extracted with ethyl acetate. The combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated. Thus, the target product was obtained as a yellow oil (4.30 g, 92.5%). MS (ESI) m / z 311.1 (M + H) ⁺ .

b) [1- (3-Fluorophenyl) -2-methylprop-2-yl] malonate

Let [1- (3-fluorophenyl) -2-methylprop-2-yl] diethyl malonate (4.30 g, 13.9 mmol), 2M aqueous NaOH (60 ml, 120 mmol) And ethanol (60 ml) solution was stirred overnight at 50 ° C. The organic solvent was removed under vacuum, the residue was acidified with 3M hydrochloric acid and extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated. Thus, the target product was obtained as a slightly brown oil (3.43 g, 97%). MS (ESI) m / z 255.1 (M + H) ⁺ .

c) 4- (3-fluorophenyl) -3,3-dimethylbutanoic acid

[1- (3-Fluorophenyl) -2-methylprop-2-yl] malonic acid (3.43 g, 13.5 mmol) was heated at 210 ° C until gas generation ceased and then cooled to room temperature . Thus, the target product was obtained as an oil (2.35 g, 83%). MS (ESI) m / z 211.1 (M + H) ⁺ .

d) 6-fluoro-3,3-dimethyl-3,4-dihydronaphthalene-1 (2H) -one

Concentrated sulfuric acid (8 ml) was added to 4- (3-fluorophenyl) -3,3-dimethylbutanoic acid (2.35 g, 11.2 mmol) and the resulting mixture was stirred at 40 ° C for 1 hour. It was then poured onto ice, extracted with ethyl acetate, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated. Thus, the target product was obtained as a slightly brown oil (1.51 g, 70%). MS (ESI) m / z 193.4 (M + H) ⁺ .

e) N- (6-fluoro-3,3-dimethyl-3,4-dihydronaphthalene-1 (2H) -subunit) hydroxylamine

Let 6-fluoro-3,3-dimethyl-3,4-dihydronaphthalene-1 (2H) -one (1.51 g, 7.86 mmol), hydroxylamine hydrochloride (Aldrich) (3.01 g, 43.3 A solution of sodium mol), anhydrous sodium acetate (Aldrich) (3.61 g, 44.0 mmol) and methanol (55 ml) were refluxed overnight. The solvent was then removed under vacuum, water and ethyl acetate were added, the layers were separated, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated. Thus, the target product was obtained as a beige solid (1.45 g, 89%). MS (ESI) m / z 208.1 (M + H) ⁺ .

f) 7-fluoro-4,4-dimethyl-1,3,4,5-tetrahydro-2H-1-benzoazepine-2-one
N- (6-fluoro-3,3-dimethyl-3,4-dihydronaphthalene-1 (2 H ) -Subunit) hydroxylamine (1.45 g, 7.00 mmol) was added to the polyphosphoric acid (15.0 g) and stirred at 130 ° C for 20 minutes. Ice was added to the reaction mixture and stirred for 10 minutes. It was then extracted with chloroform, dried over anhydrous sodium sulfate and filtered and concentrated. The residue was triturated with diethyl ether and the precipitate was collected by suction. Thus, the target product was obtained as white crystals (1.10 g, 76%). MS (ESI) m / z 208.2 (M + H) ⁺ .

Intermediate 54
7-fluoro-4- (prop-2-yl) -1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-one

The target product was prepared from diethyl 2- (2-methylpropylene) malonate (Combi Blocks) according to the method described in Intermediate 53. MS (ESI) m / z 222.1 (M + H) ⁺ .

Intermediate 55
1,5-dihydrospiro [1-benzoazine-4,1'-cyclopentane] -2 (3H) -one

a) (1-Benzylcyclopentyl) diethylmalonate

A 2M solution of benzyl magnesium chloride in THF (Aldrich) (12 ml, 24 mmol) was slowly added to the diethyl 2-cyclopentylmalonate (Lehnert, W. ., Tetrahedron 1973, 29 : 635-638) (5.0 g, 22.1 mmol) in diethyl ether (100 ml). Stirring was then continued at room temperature for 18 hours. The reaction was then quenched with a 1M hydrochloric acid solution and extracted with ethyl acetate. The combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated. Thus, the target product was obtained as an oil (5.62 g, 80%). MS (ESI) m / z 319.4 (M + H) ⁺ .
b) (1-Benzylcyclopentyl) malonic acid

Let (1-benzylcyclopentyl) diethyl malonate (Step a) of Intermediate 55) (5.62 g, 17.7 mmol), 2M aqueous NaOH (60 ml, 120 mmol) and ethanol ( 30 ml) of the solution was refluxed for 2 hours. The organic solvent was removed under vacuum, the residue was acidified with 3M hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated. Thus, the target product was obtained as an oil (3.52 g, 76%). MS (ESI) m / z 263.3 (M + H) ⁺ .

c) (1-Benzylcyclopentyl) acetic acid

(1-Benzylcyclopentyl) malonic acid (Step b) of Intermediate 55) (3.52 g, 13.4 mmol) was heated at 180 ° C until gas evolution ceased and then cooled to room temperature. Thus, the target product was obtained as an oil (2.90 g, 99%). MS (ESI) m / z 219.1 (M + H) ⁺ .

d) 1 ' H -Spiro [cyclopentane-1,2'-naphthalene] -4 '(3' H )-ketone

Concentrated sulfuric acid (Aldrich) (20 ml) was added to (1-benzylcyclopentyl) acetic acid (Step c) of Intermediate 55) (2.90 g, 13.3 mmol) and the resulting mixture was allowed to stand at 35 ° C. Stir for 1 hour. It was then poured onto ice and extracted with ethyl acetate. The combined organic phases were washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was placed in dichloromethane and filtered through a pad of silica to remove colored impurities. Thus, the target product was obtained as an oil (1.41 g, 53%). MS (ESI) m / z 201.2 (M + H) ⁺ .

e) N-1 ' H -Spiro [cyclopentane-1,2'-naphthalene] -4 '(3' H ) -Subunit hydroxylamine

Order 1 ' H -Spiro [cyclopentane-1,2'-naphthalene] -4 '(3' H ) -Ketone (step d)) of Intermediate 55) (1.41 g, 7.05 mmol), hydroxylamine hydrochloride (Aldrich) (1.95 g, 28 mmol), anhydrous sodium acetate (Aldrich) (2.30 g, 28 mmol) and methanol (40 ml) were refluxed for 2 hours. The solvent was then removed under vacuum, water and ethyl acetate were added, the layers were separated, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated. Thus, the target product was obtained as a beige solid (1.33 g, 88%). MS (ESI) m / z 216.1 (M + H) ⁺ .

f) 1,5-Dihydrospiro [1-benzoazine-4,1'-cyclopentane] -2 (3H) -one
Will N-1 ' H -Spiro [cyclopentane-1,2'-naphthalene] -4 '(3' H ) -Subunit hydroxyamine (Intermediate 55 step e)) (1.33 g, 6.19 mmol) was added to the polyphosphoric acid (20.0 g) and stirred at 110 ° C for 20 minutes. Ice was added to the reaction mixture and stirred for 10 minutes. It was then extracted with ethyl acetate, and the combined organic phases were washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (using cyclohexane: ethyl acetate = 2: 1 as eluent). Thus, the target product was obtained as white crystals (0.51 g, 38%). MS (ESI) m / z 216.1 (M + H) ⁺ .

Intermediate 56
4- (prop-2-yl) -1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-one

The target product was prepared from diethyl 2- (2-methylpropylene) malonate (Combi Blocks) according to the method described in Intermediate 53. MS (ESI) m / z 204.1 (M + H) ⁺ .

Intermediate 57
1,5-dihydrospiro [1-benzoazine-4,4'-ethylene oxide] -2 (3 H )-ketone

According to the method described in Intermediate 53, from tetrahydro-4 H -Piperan-4-ylidene malonate (Griffiths et al., HeIv Chim Acta 1991, 74 (2): 09-314) Prepare the target product. MS (ESI) m / z 232.2 (M + H) ⁺ .

Intermediate 58
1,4 ', 5,5'-tetrahydrospiro [1-benzoazine-4,3'-furan] -2 (3 H )-ketone

According to the method described in Intermediate 53, from dihydrofuran-3 (2H) -diylmalonate (Griffiths et al., HeIv Chim Acta 1991, 74 (2): 09-314) Prepare the target product. MS (ESI) m / z 218.2 (M + H) ⁺ .
Intermediate 59
1,5,5 ', 6'-tetrahydro-4' H -Spiro [1-benzoazine-4,3'-piperan] -2 (3 H )-ketone

According to the method described in Intermediate 53, from dihydro-2H-piperan-3 (4H) -diylmalonate (Griffiths et al., HeIv Chim Acta 1991, 74 2): 09-314) Prepare the target product. MS (ESI) m / z 232.1 (M + H) ⁺ .

Intermediate 60
7-bromo-1,5-dihydrospiro [1-benzoazine-4,1'-cyclopentane] -2 (3 H )-ketone

P-1,5-Dihydrospiro [1-benzoazine-4,1'-cyclopentane] -2 (3 H ) -Ketone (Intermediate 55) (0.51 g, 2.37 mmol), acetic acid (10 ml) and water (2 ml) was slowly added to the solution of Aldrich (0.121 ml, 2.37 mmol) in acetic acid (3 ml) solution. After stirring the reaction mixture at room temperature for 1 hour, it was poured onto ice, and the precipitate was filtered by suction and dried. Thus, the target product was obtained as beige crystals (0.50 g, 72%). MS (ESI) m / z 294.2 & 296.1 (M + H) ⁺ .

Intermediate 61
7-bromo-4- (prop-2-yl) -1,3,4,5-tetrahydro-2 H -1-benzoazepine-2-one

From 4- (prop-2-yl) -1,3,4,5-tetrahydro-2 according to the method described in Intermediate 60 H 1-Benzacridin-2-one (Intermediate 56) prepared the target product. MS (ESI) m / z 282.1 & 284.1 (M + H) ⁺ .

Intermediate 62
7-bromo-1,5-dihydrospiro [1-benzoazine-4,4'-ethylene oxide] -2 (3 H )-ketone

According to the method described in Intermediate 60, from 1,5-Dihydrospiro [1-benzoazine-4,4'-ethylene oxide] -2 (3 H ) -One (Intermediate 57) to prepare the target product. MS (ESI) m / z 310.1 & 312.1 (M + H) ⁺ .

Intermediate 63
7-bromo-1,5-dihydrospiro [1-benzoazine-4,3'-tetrahydrofuran] -2 (3 H )-ketone

According to the method described in intermediate 60, from 1,4 ', 5,5'-tetrahydrospiro [1-benzoazine-4,3'-furan] -2 (3 H ) -One (Intermediate 58) to prepare the target product. MS (ESI) m / z 296.2 & 298.2 (M + H) ⁺ .

Intermediate 64
7-chloro-1,5-dihydrospiro [1-benzoazine-4,4'-ethylene oxide] -2 (3 H )-ketone

P-1,5-Dihydrospiro [1-benzoazine-4,4'-ethylene oxide] -2 (3 H ) -Ketone (Intermediate 57) (0.73 g, 3.16 mmol) in DMF (20 ml) was added with N-chlorosuccinimide (0.59 g, 4.42 mmol). After stirring the reaction mixture at room temperature for 1 hour, it was poured onto ice, and the precipitate was filtered by suction and dried. Thus, the target product was obtained as yellow crystals (0.58 g, 69%). MS (ESI) m / z 266.1 (M + H) ⁺ .

Intermediate 65
7-chloro-1,5-dihydrospiro [1-benzoazine-4,3'-ethylene oxide] -2 (3 H )-ketone

According to the method described in Intermediate 64, from 1,5,5 ', 6'-tetrahydro-4' H -Spiro [1-benzoazine-4,3'-piperan] -2 (3 H ) -One (Intermediate 59) to prepare the target product. MS (ESI) m / z 266.2 (M + H) ⁺ .

Intermediate 66
7-chloro-1,5-dihydrospiro [1-benzoazine-4,3'-tetrahydrofuran] -2 (3 H )-ketone

According to the method described in Intermediate 64, from 1,4 ', 5,5'-tetrahydrospiro [1-benzoazine-4,3'-furan] -2 (3 H ) -One (Intermediate 58) to prepare the target product. MS (ESI) m / z 252.2 (M + H) ⁺ .

Intermediate 67
Trans-4- (pyridin-2-ylamino) cyclohexanemethylhydrazine

a) Methyl trans-4- (pyridin-2-ylamino) cyclohexanecarboxylate

Let trans-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride (1.5 g, 7.745 mmol), 2-fluoropyridine (4 ml, 46.5 mmol) and DIPEA (1.35 ml, 7.75 mmol) The mixture) was stirred in a pressure-resistant glass reactor at 125 ° C. for 20 hours and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (20 ml), washed with water (2 x 30 ml) and saturated NaCl solution (2 x 30 ml), and the organic phase was dried over anhydrous sodium sulfate and filtered and concentrated to produce The target compound (325 mg, 18%). MS (ESI) m / z 235.1 (M + H) ⁺ .

b) trans-4- (pyridin-2-ylamino) cyclohexanemethylhydrazine
The title compound was prepared from trans-4- (pyridin-2-ylamino) cyclohexanecarboxylic acid methyl ester (intermediate 67 step a)) according to the method described in intermediate step 9) without further purification. Purified and used in the next step.

Example 1
8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Methylbenzoazine-5-carboxylic acid

Let 7-chloro-2- pendant thio-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid (Intermediate 4) (92 mg, 0.34 mmol), trans-4- (pyridin-2-yloxy) cyclohexanemethanehydrazine (WO2010 / 060836 A1 (03.06.2010) A solution of F. HOFFMANN-LA ROCHE AG.) (96.5 mg, 0.41 mmol) and xylene (10 ml) was stirred at reflux temperature for 3 days. The reaction mixture was concentrated and the residue was purified by column chromatography using dichloromethane: methanol = 20: 1 as the eluent. Thus, the target product was obtained (68 mg, 44.0%). MS (ESI) m / z 454.2 (M + H) ⁺ .

Example 2
8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Benzacene-5-carboxylic acid

Let 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Methyl benzoazine-5-carboxylic acid (Example 1) (0.85 g, 1.88 mmol) was dissolved in methanol (60 ml), followed by the addition of a 2M NaOH solution (20 ml) and the mixture was Stir overnight. Methanol was evaporated from the reaction mixture, the pH of the aqueous phase was adjusted to 3 with 1M hydrochloric acid solution, and then extracted with ethyl acetate. The combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate and filtered and concentrated. Thus, the target product was obtained (0.83 g, 99.9%). MS (ESI) m / z 439.1 (M + H) ⁺ .

Example 3
8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Benzacridin-5-carboxamide

Let 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzacridine-5-carboxylic acid (Example 2) (0.4 g, 0.91 mmol), HOBt (0.25 g, 1.64 mmol) and EDC (0.314 g, 1.64 mmol) were dissolved In anhydrous DMF (3 ml). The reaction mixture was cooled in an ice water bath and ammonium chloride (0.146 g, 2.73 mmol) and DIPEA (0.443 ml, 2.55 mmol) were added under argon. The reaction mixture was allowed to stir at 0 ° C for 2 hours and then overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Thus, the target product was obtained (0.34 g, 85.4%). MS (ESI) m / z 438.2 (M + H) ⁺ .

Example 4
8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Benzacridin-5-carbonitrile

Let 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzoazine-5-carboxamide (Example 3) (0.26 g, 0.60 mmol) was dissolved in pyridine (4.4 ml). It was then cooled to 5 ° C and phosphonium chloride (56 μl, 0.60 mmol) was added to the reaction mixture. The mixture was allowed to stir overnight at room temperature. The reaction mixture was then concentrated, water was added to the residue and the pH of the aqueous phase was adjusted to 9 with a 1M NaOH solution. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate and filtered and concentrated. The residue was purified by column chromatography using dichloromethane: methanol = 20: 1 as the eluent. Thus, the target product was obtained (0.177 g, 70.2%). MS (ESI) m / z 420.2 (M + H) ⁺ .

Example 5
8-chloro-N, N-dimethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] Zolo [4,3-a] [1] benzoazine-5-carboxamide

According to the method described in Example 3, from 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] Triazolo [4,3-a] [1] benzoazine-5-carboxylic acid (Example 2) and dimethylamine (2M THF solution) were used to prepare the target product. MS (ESI) m / z 466.2 (M + H) ⁺ .

Example 6
(5S) -8-chloro-N, N-dimethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazepine-5-carboxamide

with
Example 7
(5R) -8-chloro-N, N-dimethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazepine-5-carboxamide

By chiral preparative HPLC (CHIRALPAK IA (containing preparative 20 μm stationary phase) 2.5 x 20 cm; F = 15 ml / min; eluent: n-hexane: EtOH = 75: 25 + 0.3% diethylamine; Isocratic; temperature = 25 ℃), self-racemic 8-chloro-N, N-dimethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6- Dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine-5-carboxamide (Example 5) was used to prepare the target product. The residence time of the first eluted compound was 11.3 minutes; = -8.3˚ (c = 0.1; methanol); the residence time of the second eluting compound is 19.7 minutes; = + 4.9˚ (c = 0.1; methanol). The absolute configuration of these compounds has not been determined.

Example 8
8-chloro-N- (prop-2-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazine-5-carboxamide

According to the method described in Example 3, from 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] Triazolo [4,3-a] [1] benzoazine-5-carboxylic acid (Example 2) and isopropylamine were used to prepare the target product. MS (ESI) m / z 480.2 (M + H) ⁺ .

Example 9
{8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzacridin-5-yl} (pyrrolidin-1-yl) methanone

According to the method described in Example 3, from 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] Triazolo [4,3-a] [1] benzoazine-5-carboxylic acid (Example 2) and pyrrolidine were used to prepare the target product. MS (ESI) m / z 492.2 (M + H) ⁺ .

Example 10
{8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzacridin-5-yl} (morpholin-4-yl) methanone

According to the method described in Example 3, from 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] Triazolo [4,3-a] [1] benzoazine-5-carboxylic acid (Example 2) and morpholine prepared the target product. MS (ESI) m / z 508.2 (M + H) ⁺ .

Example 11
{8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzacridin-5-yl} (1,1-dioxythiomorpholin-4-yl) methanone

According to the method described in Example 3, from 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] Triazolo [4,3-a] [1] benzoazine-5-carboxylic acid (Example 2) and thiomorpholine-1,1-dioxide were used to prepare the target product. MS (ESI) m / z 556.2 (M + H) ⁺ .

Example 12
{8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzacridin-5-yl} methanol

Let 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Methyl benzoazine-5-carboxylate (Example 1) (1.11 g, 2.51 mmol) was dissolved in a mixture of anhydrous diethyl ether (60 ml) and anhydrous dichloromethane (60 ml) and Allow the solution to cool to -20 ° C. To the mixture was added dropwise a 1 M lithium aluminum hydride diethyl ether solution (5.5 ml) and stirred at -20 ° C for 20 minutes. The reaction mixture was carefully added with water and then diethyl ether was evaporated under vacuum. The aqueous phase was then extracted with ethyl acetate. The combined organic phases were washed with saturated NaCl solution, dried over anhydrous sodium sulfate and filtered and concentrated under vacuum. Thus, the target product was obtained (0.955 g, 85.4%). MS (ESI) m / z 425.2 (M + H) ⁺ .

Example 13
{(5R) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazepine-5-yl} methanol

with
Example 14
{(5S) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazepine-5-yl} methanol

By chiral preparative HPLC (CHIRALPAK IC (containing preparative 20 μm stationary phase) 2.5 x 20 cm; F = 15 ml / min; eluent: n-hexane: EtOH = 75: 25; isocratic; temperature = 25 ℃), self-racemic {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] Zolo [4,3-a] [1] benzoazin-5-yl} methanol (Example 12) prepared the target product. The first eluting compound (retention time 7.0 minutes) is {(5R) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H -[1,2,4] triazolo [4,3-a] [1] benzoazin-5-yl} methanol (Example 13); = + 11.9 ° (c = 0.1; chloroform); the second elutable compound (retention time: 7.8 minutes) is {(5S) -8-chloro-1- [trans-4- (pyridin-2-yloxy) Cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazin-5-yl} methanol (Example 14); = -11.1˚ (c = 0.1; chloroform). By the VCD method and the ¹ H NMR spectroscopy determined the absolute configuration of these compounds.

Example 15
8-chloro-5- (methoxymethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazine

Let {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] Benzacridin-5-yl} methanol (Example 12) (70 mg, 0.16 mmol) was dissolved in anhydrous THF (2 ml) and the solution was then cooled to -5 ° C. A 60% sodium hydride (13 mg, 0.32 mmol) oil dispersion was added and stirred under cooling for 90 minutes, and then methyl iodide (12 μl, 0.2 mmol) was added to the reaction mixture and the mixture was stirred at room temperature. Stir for 2 hours. Subsequently, methyl iodide (12 μl, 0.2 mmol) was added again and the mixture was heated at 40 ° C. for 2 hours. The reaction was diluted with water (30 ml) and then extracted with ethyl acetate. The combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate and filtered and concentrated. The residue was purified by column chromatography using dichloromethane: methanol = 50: 1 as the eluent. Thus, the target product was obtained (20 mg, 28%). MS (ESI) m / z 439.2 (M + H) ⁺ .

Example 16
Morpholine-4-carboxylic acid {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazole Benzo [4,3-a] [1] benzoazin-5-yl} methyl ester

a) Methanesulfonic acid {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] Benzacridin-5-yl} methyl ester

Let {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] Benzacridin-5-yl} methanol (Example 12) (0.855 g, 2.01 mmol) was dissolved in anhydrous dichloromethane (80 ml) and then cooled to 0 ° C. Triethylamine (0.785 ml, 5.63 mmol), methanesulfonyl chloride (0.258 ml, 3.38 mmol) and DMAP (34 mg, 0.28 mmol) were added. The reaction mixture was allowed to stir at 0 ° C for 1 hour and then overnight at room temperature. Pass the reaction mixture over saturated NaHCO ₃ The solution was rinsed and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate and filtered and concentrated. Thus, the target product was obtained (1.0 g, 99%). MS (ESI) m / z 503.1 (M + H) ⁺ .

b) Morpholine-4-carboxylic acid {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] Triazolo [4,3-a] [1] benzoazin-5-yl} methyl ester
Let methanesulfonic acid {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazino-5-yl} methyl ester (step a) of Example 16) (0.053 g, 0.106 mmol) was dissolved in anhydrous DMF (5 ml). Triethylamine (0.030 ml, 0.212 mmol), cesium carbonate (0.038 g, 0.117 mmol) and morpholine (0.050 ml, 0.573 mmol) were added and the mixture was stirred at 100 ° C for 2 days. The reaction mixture was then cooled, water was added and extracted with ethyl acetate. The combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate and filtered and concentrated. The residue was purified by column chromatography using dichloromethane: methanol = 20: 1 as the eluent. Thus, the target product was obtained (0.013 g, 23.0%). MS (ESI) m / z 538.2 (M + H) ⁺ .

Example 17
(4-fluorophenyl) carbamic acid {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazin-5-yl} methyl ester

Let {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] Benzacridin-5-yl} methanol (Example 12) (40 mg, 0.09 mmol) was dissolved in anhydrous THF (3 ml), cooled to 5 ° C and introduced with argon Triethylamine (24 μl, 0.17 mmol) was added. A solution of 4-fluorophenyl isocyanate (14 mg, 0.10 mmol) in anhydrous THF (1 ml) was added to the reaction mixture. The reaction did not occur even at reflux temperature and was therefore concentrated. The product was dissolved in acetonitrile (5 ml) and an oil dispersion of 60% sodium hydride (4 mg, 0.09 mmol) was added. The reaction mixture was allowed to stir overnight at room temperature and then concentrated. The residue was purified by column chromatography using dichloromethane: methanol = 20: 1 as the eluent. Thus, the target product was obtained (35 mg, 66%). MS (ESI) m / z 562.2 (M + H) ⁺ .

Example 18
5- (azidomethyl) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazine

Methanesulfonic acid {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazin-5-yl} methyl ester (step a) of Example 16) (0.418 g, 0.83 mmol), anhydrous DMF (10 ml), and sodium azide (0.162 g, 2.49 mmol) was filled into a pressure-resistant glass reactor and then stirred at 80 ° C. for 4 hours. The reaction mixture was then added with water and extracted with ethyl acetate. The combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate and filtered and concentrated. The residue was purified by column chromatography using dichloromethane: methanol = 20: 1 as the eluent. Thus, the target product was obtained (0.26 g, 69.5%). MS (ESI) m / z 450.2 (M + H) ⁺ .

Example 19
1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazin-5-yl} methylamine

Let 5- (azidomethyl) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2, 4] Triazolo [4,3-a] [1] benzoazine (Example 18) (0.242 g, 0.54 mmol) was dissolved in THF (20 ml) and then water (1 ml) and three Phenylphosphine (0.423 g, 1.61 mmol). The reaction mixture was allowed to stir overnight under argon and room temperature, then concentrated and the residue was purified by column chromatography using dichloromethane: methanol: ammonium hydroxide = 10: 1: 0.1 as the eluent. Thus, the target product was obtained (0.183 g, 80%). MS (ESI) m / z 424.2 (M + H) ⁺ .

Example 20
8-chloro-5- (morpholin-4-ylmethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazine

Methanesulfonic acid {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazine-5-yl} methyl ester (step a) of Example 16) (100 mg, 0.20 mmol), anhydrous DMF (3 ml), DIPEA (0.42 ml , 2.39 mmoles) and morpholine (0.21 ml, 2.39 mmoles) were filled into a pressure-resistant glass reactor and then stirred at 110 ° C. for 1 day. The reaction mixture was then cooled, water was added and extracted with ethyl acetate. The combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate and filtered and concentrated. The residue was purified by column chromatography using dichloromethane: methanol = 50: 1 as the eluent. Thus, the target product was obtained (59 mg, 60%). MS (ESI) m / z 494.2 (M + H) ⁺ .

Example 21
1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazepine-5-yl} -N, N-dimethylmethylamine

According to the method described in Example 20, from methanesulfonic acid {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazin-5-yl} methyl ester (step a) of Example 16) and dimethylamine (2M THF solution) to prepare the target product. MS (ESI) m / z 452,2 (M + H) ⁺ .

Example 22
N-({8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4 , 3-a] [1] benzoazin-5-yl} methyl) propan-2-amine

Let 1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4 , 3-a] [1] Benzacridin-5-yl} methylamine (Example 19) (50 mg, 0.12 mmol) was dissolved in 1,2-dichloroethane (5 ml) and subsequently added Acetic acid (14 µl, 0.25 millimoles), acetone (45 µl, 0.61 millimoles), and sodium triacetoxyborohydride (77 mg, 0.37 millimoles). The reaction mixture was allowed to stir at room temperature for 1 day and then water was added. The pH of the aqueous phase was adjusted to 9 with a 1M NaOH solution and the organic phase was separated. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography using dichloromethane: methanol: ammonium hydroxide = 10: 1: 0.1 as the eluent. Thus, the target product was obtained (46 mg, 83.6%). MS (ESI) m / z 466.2 (M + H) ⁺ .

Example 23
8-chloro-1- [1- (pyrimidin-2-yl) tetrahydroazepine-3-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Methylbenzoazine-5-carboxylic acid

According to the method described in Example 1, from 1- (Pyrimidin-2-yl) tetrahydroazepine-3-formamidine (Intermediate 13) prepared the target product. MS (ESI) m / z 411.1 (M + H) ⁺ .

Example 24
8-chloro-1- [trans-4- (dimethylamino) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [ 1] Methyl benzoazine-5-carboxylate

According to the method described in Example 1, from 7-chloro-2- pendant thio-2,3,4,5-tetrahydro-1H-1-benzoazine-4-carboxylic acid methyl ester (intermediate 4) and The trans-4- (dimethylamino) cyclohexanemethylhydrazine (Intermediate 11) prepared the target product. MS (ESI) m / z 403.2 (M + H) ⁺ .

Example 25
8-chloro-1- [trans-4- (trifluoromethyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1 ] Methyl benzoazine-5-carboxylate

According to the method described in Example 1, from 7-chloro-2- pendant thio-2,3,4,5-tetrahydro-1H-1-benzoazine-4-carboxylic acid methyl ester (intermediate 4) and Trans-4- (trifluoromethyl) cyclohexanemethanehydrazine (Intermediate 6) prepared the target product. MS (ESI) m / z 428.1 (M + H) ⁺ .

Example 26
8-chloro-1- [trans-4- (morpholin-4-yl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] Methyl benzoazine-5-carboxylate

According to the method described in Example 1, from 7-chloro-2- pendant thio-2,3,4,5-tetrahydro-1H-1-benzoazine-4-carboxylic acid methyl ester (intermediate 4) and The trans-4- (morpholin-4-yl) cyclohexanemethanehydrazine (Intermediate 12) prepared the target product. MS (ESI) m / z 445.2 (M + H) ⁺ .

Example 27
{1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1 ] Benzacridin-5-yl} methanol

Let {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] Benzacridin-5-yl} methanol (Example 12) (63 mg, 0.15 mmol) was dissolved in ethanol (15 ml) and then 10% Pd / C (65 mg) was added To solution and hydrogenation at room temperature. After the reaction was completed, the catalyst was removed by filtration, rinsed with ethanol and the filtrate was concentrated. The residue was purified by column chromatography using dichloromethane: methanol: ammonium hydroxide = 10: 1: 0.1 as the eluent. Thus, the target product was obtained (23 mg, 39%). MS (ESI) m / z 391.2 (M + H) ⁺ .

Example 28
8-chloro-1- [trans-4- (pyrrolidin-1-ylcarbonyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Methylbenzoazine-5-carboxylic acid

Let 7-chloro-2- pendant thio-2,3,4,5-tetrahydro-1H-1-benzoazine-4-carboxylic acid methyl ester (Intermediate 4) (56.8 mg, 0.21 mmol) A solution of trans-4- (pyrrolidin-1-ylcarbonyl) cyclohexanemethylhydrazine (Intermediate 9) (75.6 mg, 0.32 mmol) and n-butanol (2 ml) was refluxed for 28 hours and The reaction mixture was then concentrated under vacuum. The residue was purified by column chromatography (using dichloromethane: methanol = 9: 1 as eluent). Thus, the target product was obtained (29.6 mg, 31%). MS (ESI) m / z 457.2 (M + H) ⁺ .

Example 29
{8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzacridin-5-yl} acetonitrile

Let methanesulfonic acid {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazine-5-yl} methyl ester (step a) of Example 16) (100 mg, 0.20 mmol), anhydrous DMF (10 ml), and sodium cyanide ( 25 mg, 0.52 mmol) in a pressure-resistant glass reactor and stirred at 80 ° C. for 5 hours. Water was then added to the reaction mixture and extracted with ethyl acetate. The combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate and filtered and concentrated. The residue was purified by column chromatography using dichloromethane: methanol = 20: 1 as the eluent. Thus, the target product was obtained (62 mg, 71.8%). MS (ESI) m / z 434.2 (M + H) ⁺ .

Example 30
8-chloro-5-[(4-methylpiperazin-1-yl) methyl] -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro -4H- [1,2,4] triazolo [4,3-a] [1] benzoazine

According to the method described in Example 20, from methanesulfonic acid {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazin-5-yl} methyl ester (step a) of Example 16) and 1-methyl-piperazine to prepare the target product. MS (ESI) m / z 507.2 (M + H) ⁺ .

Example 31
8-chloro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] tris Zolo [4,3-a] [1] benzoazine

Let methanesulfonic acid {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] Benzacridin-5-yl} methyl ester (step a) of Example 16) (100 mg, 0.20 mmol) and a 1M solution of tetrabutylammonium fluoride in THF ( 1 ml) was stirred overnight under argon and reflux temperature. The reaction mixture was then added with water and extracted with ethyl acetate. The combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate and filtered and concentrated. The residue was subjected to preparative HPLC (Kinetex EVO C18; 5 μm load; 150 x 21.2 mm; F = 20 ml / min; eluent: A: water; B: acetonitrile, gradient: B% 15 → 70; temperature = 40 ° C). Thus, the target product was obtained (21 mg, 24.7%). MS (ESI) m / z 427.2 (M + H) ⁺ .

Example 32
8-chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5, 6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine

Let 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzoazine-5-carboxylic acid (Example 2) (50 mg, 0.11 mmol), HOBt (21 mg, 0.13 mmol), EDC (26 mg, 0.13 mmol) and A mixture of DMF (1 ml) was stirred under argon and room temperature for 15 minutes and then N-hydroxyacetamidine (10 mg, 0.13 mmol) and additional DMF (1 ml) were added. The reaction mixture was allowed to stir overnight at 100 ° C. The reaction mixture was then cooled to room temperature, water was added and extracted with ethyl acetate. The combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate and filtered and concentrated. The residue was purified by column chromatography using dichloromethane: methanol = 50: 1 as the eluent. Thus, the target product was obtained (29 mg, 53.7%). MS (ESI) m / z 477.2 (M + H) ⁺ .

Example 33
8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5- (2H-tetrazol-5-yl) -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazine

Let 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzoazine-5-carbonitrile (Example 4) (90 mg, 0.21 mmol), DMF (2.5 ml), sodium azide (133 mg, 2.04 mmol) and chloride A mixture of ammonium (111 mg, 2.08 mmol) was placed in a pressure resistant glass reactor and stirred at 115 ° C for 4 hours. The reaction mixture was allowed to cool, water was added and extracted with ethyl acetate. The combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate and filtered and concentrated. The residue was purified by column chromatography (using dichloromethane: methanol = 3: 1 as eluent). Thus, the target product was obtained (54 mg, 54.5%). MS (ESI) m / z 463.2 (M + H) ⁺ .

Example 34
N-({8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4 , 3-a] [1] benzoazepine-5-yl} methyl) tetrahydro-2H-piperan-4-amine

According to the method described in Example 22, from 1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazin-5-yl} methylamine (Example 19) and tetrahydro-4 H -Piperan-4-one to prepare the target product. MS (ESI) m / z 508.2 (M + H) ⁺ .

Example 35
N, N-dimethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -8- (trifluoromethyl) -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazepine-5-amine

According to the method described in Example 22, from 1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazin-5-yl} methylamine (Example 19) and 4,4-difluorocyclohexanone to prepare the target product. MS (ESI) m / z 542.2 (M + H) ⁺ .

Example 36
8-Chloro-1- [trans-3-methyl-2-oxo-1-oxa-3-azaspiro [4.5] dec-8-yl] -5,6-dihydro-4H- [1,2,4] Triazolo [4,3-a] [1] benzoazine-5-carboxylic acid methyl ester

According to the method described in Example 1, from 7-chloro-2- pendant thio-2,3,4,5-tetrahydro-1H-1-benzoazine-4-carboxylic acid methyl ester (intermediate 4) and (Trans) -3-methyl-2-oxo-1-oxan-3-azaspiro [4.5] decane-8-formamidine (Intermediate 17) The title product was prepared. MS (ESI) m / z 445.2 (M + H) ⁺ .

Example 37
N-({8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4 , 3-a] [1] benzoazepine-5-yl} methyl) acetamide

Let 1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4 , 3-a] [1] benzoazin-5-yl} methylamine (Example 19) (45 mg, 0.12 mmol) was dissolved in pyridine (5 ml) and then acetic anhydride (0.10 ml, 1.06 Mol). The reaction mixture was allowed to stir at room temperature for 4 hours and then concentrated. The residue was dissolved in water. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated. Thus, the target product was obtained (44 mg, 89.0%). MS (ESI) m / z 466.2 (M + H) ⁺ .

Example 38
N-({8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4 , 3-a] [1] benzoazepine-5-yl} methyl) oxetan-3-amine

According to the method described in Example 22, from 1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazin-5-yl} methylamine (Example 19) and 3-oxetanone to prepare the target product. MS (ESI) m / z 480.2 (M + H) ⁺ .

Example 39
8-chloro-1- [trans-4- (morpholin-4-ylcarbonyl) cyclohexyl] -5,6-dihydro-4 H -[1,2,4] triazolo [4,3- a ] [1] Methylbenzoazine-5-carboxylic acid

According to the method described in Example 28, from the Trans-4- (morpholin-1-ylcarbonyl) cyclohexanemethanehydrazine (Intermediate 10) prepared the target product. MS (ESI) m / z 473.2 (M + H) ⁺ .

Example 40
8-chloro-1- [cis-3-methyl-2-oxo-1-oxa-3-azaspiro [4.5] dec-8-yl] -5,6-dihydro-4H- [1,2,4] Triazolo [4,3-a] [1] benzoazine-5-carboxylic acid methyl ester

According to the method described in Example 1, from 7-chloro-2- pendant thio-2,3,4,5-tetrahydro-1H-1-benzoazine-4-carboxylic acid methyl ester (intermediate 4) and (Cis) -3-methyl-2-oxo-1-oxa-3-azaspiro [4.5] decane-8-formamidine (Intermediate 18) The title product was prepared. MS (ESI) m / z 445.2 (M + H) ⁺ .

Example 41
8-chloro-1- [1- (pyridin-2-yl) tetrahydroazepine-3-yl] -5,6-dihydro-4 H -[1,2,4] triazolo [4,3- a ] [1] Methylbenzoazine-5-carboxylic acid

According to the method described in Example 28, starting from 7-chloro-2- pendant thio-2,3,4,5-tetrahydro-1H-1-benzoazine-4-carboxylic acid methyl ester (Intermediate 4) and 1- (Pyridin-2-yl) tetrahydroazepine-3-formamidine (Intermediate 14) prepared the target product. MS (ESI) m / z 410.1 (M + H) ⁺ .

Example 42
1- [trans-4- (tetrahydroazepine-1-ylcarbonyl) cyclohexyl] -8-chloro-5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] Benzacne-5-carboxylic acid methyl ester

According to the method described in Example 1, from 7-chloro-2- pendant thio-2,3,4,5-tetrahydro-1H-1-benzoazine-4-carboxylic acid methyl ester (intermediate 4) and Trans-4- (tetrahydroacryl-1-ylcarbonyl) cyclohexanemethanehydrazine (Intermediate 19) prepared the target product. MS (ESI) m / z 443.2 (M + H) ⁺ .

Example 43
8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5- (pyrrolidin-1-ylmethyl) -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazine

According to the method described in Example 20, from methanesulfonic acid {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazin-5-yl} methyl ester (step a) of Example 16) and pyrrolidine to prepare the target product. MS (ESI) m / z 478.2 (M + H) ⁺ .

Example 44
N-({8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4 , 3-a] [1] benzoazin-5-yl} methyl) -2-methyl-N- (2-methylpropyl) propan-1-amine

According to the method described in Example 22, from 1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazin-5-yl} methylamine (Example 19) and 2-methylpropanal to prepare the target product. MS (ESI) m / z 536.3 (M + H) ⁺ .

Example 45
8-chloro-1- [trans-4- (piperidin-1-ylcarbonyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Methylbenzoazine-5-carboxylic acid

According to the method described in Example 28, starting from 7-chloro-2- pendant thio-2,3,4,5-tetrahydro-1H-1-benzoazine-4-carboxylic acid methyl ester (Intermediate 4) and Trans-4- (piperidin-1-ylcarbonyl) cyclohexanemethanehydrazine (Intermediate 20) prepared the target product. MS (ESI) m / z 471.2 (M + H) ⁺ .

Example 46
1- (trans-4-{[4- (tertiary butoxycarbonyl) piperazin-1-yl] carbonyl} cyclohexyl) -8-chloro-5,6-dihydro-4H- [1,2, 4] Triazolo [4,3-a] [1] benzoazine-5-carboxylic acid methyl ester

According to the method described in Example 28, starting from 7-chloro-2- pendant thio-2,3,4,5-tetrahydro-1H-1-benzoazine-4-carboxylic acid methyl ester (Intermediate 4) and 4-{[trans-4- (hydrazinocarbonyl) cyclohexyl] carbonyl] piperazine-1-carboxylic acid tert-butyl ester (Intermediate 21) The target product was prepared. MS (ESI) m / z 572.2 (M + H) ⁺ .

Example 47
8-chloro-1- [trans-4- (piperazin-1-ylcarbonyl) cyclohexyl] -5,6-dihydro-4 H -[1,2,4] triazolo [4,3- a ] [1] Benzacne-5-carboxylic acid methyl ester hydrochloride

Let 1- (trans-4-{[4- (tertiary butoxycarbonyl) piperazin-1-yl] carbonyl} cyclohexyl) -8-chloro-5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazine-5-carboxylic acid methyl ester (Example 46) (41 mg, 0.07 mmol) was dissolved in ethyl acetate (1 ml) and To the solution was added a 2.5 M solution of hydrochloric acid in ethyl acetate (1 ml). The reaction mixture was allowed to stir at room temperature for 1 hour and then diethyl ether was added. The precipitated product was filtered and washed with diethyl ether. Thus, the target product was obtained (30.5 mg, 84%). MS (ESI) m / z 472.2 (M + H) ⁺ .

Example 48
8-methoxy-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] Benzacne-5-carboxylic acid methyl ester

According to the method described in Example 1, from 7-methoxy-2- pendant thio-2,3,4,5-tetrahydro-1H-1-benzoazine-4-carboxylic acid methyl ester (Intermediate 26 ) Preparation of the target compound. MS (ESI) m / z 449.3 (M + H) ⁺ .

Example 49
8-methyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Methylbenzoazine-5-carboxylic acid

According to the method described in Example 1, from 7-methyl-2- pendant thio-2,3,4,5-tetrahydro-1H-1-benzoazine-4-carboxylic acid methyl ester (Intermediate 25) Prepare the target compound. MS (ESI) m / z 433.2 (M + H) ⁺ .

Example 50
8-chloro-N- (4-fluorophenyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazine-5-carboxamide

P-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzoazine-5-carboxylic acid (Example 2) (100 mg, 0.23 mmol), DMF (15 ml), HOBt (84 mg, 0.55 mmol), DIPEA (151 µl, 0.87 mmoles) and EDC (105 mg, 0.55 mmoles) in an ice-cold mixture was added 4-fluoroaniline (25 mg, 0.23 mmoles) and the reaction mixture was stirred at 5 ° C for 0.5 hours and then at room temperature After stirring for another 20 hours. After completion of the reaction, the mixture was diluted with water and brine and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and filtered and concentrated. The residue was purified by flash column chromatography (using dichloromethane: methanol = 95: 5 as the eluent) to give the target compound (105 mg, 87%). MS (ESI) m / z 532.1 (M + H) ⁺ .

Example 51
8-bromo-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Methylbenzoazine-5-carboxylic acid

Prepared according to the method described in Example 1 from 7-bromo-2- pendant thio-2,3,4,5-tetrahydro-1H-1-benzoazine-4-carboxylic acid methyl ester (Intermediate 27) Underlying compound. MS (ESI) m / z 499.1 (M + H) ⁺ .

Example 52
1- (1,4'-bipiperidin-1'-yl) -8-chloro-5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1 ] Benzacridin-5-carboxamide

Let 1-bromo-8-chloro-5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazepine-5-carboxamide (middle Body 29) (34 mg, 0.1 mmol), cyclobutane (0.3 ml) and 4-piperidinepiperidine (218 mg, 1.3 mmol) were stirred at 180 ° C for 3 hours and then cooled To room temperature. The reaction mixture was diluted with dichloromethane and washed with brine, and the organic phase was dried over sodium sulfate and filtered and concentrated. The residue was purified by flash column chromatography (using dichloromethane: methanol: ammonium hydroxide = 9: 1: 0.1 as the eluent) to give the target compound (13 mg, 30%). MS (ESI) m / z 429.2 (M + H) ⁺ .

Example 53
8-chloro-1-[(5r, 8r) -1-oxo-2- (prop-2-yl) -2-azaspiro [4.5] dec-8-yl] -5,6-dihydro -4H- [1,2,4] triazolo [4,3-a] [1] benzoazine-5-carboxylic acid methyl ester

According to the method described in Example 28, from the (5r, 8r) -1-Pentoxy-2- (prop-2-yl) -2-azaspiro [4.5] decane-8-formamidine (Intermediate 32) The title compound was prepared. MS (ESI) m / z 471.2 (M + H) ⁺ .

Example 54
1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazepine-5-yl} ethanol

a) 5- (1-{[Tri-butyl (dimethyl) silyl] oxy} ethyl) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl ] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine

According to the method described in Example 1, from 4- (1-{[tertiary butyl (dimethyl) silyl] oxy} ethyl) -7-chloro-1,3,4,5-tetrahydro-2H -1-Benzazine-2-thione (Intermediate 34) prepared the target compound. The product was a 55:45 mixture of non-mirromeric isomers. MS (ESI) m / z 553.2 (M + H) ⁺ .

b) 1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazepine-5-yl} ethanol
Let 5- (1-{[tertiary butyl (dimethyl) silyl] oxy} ethyl) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine (step a) of Example 54) (222 mg, 0.4 mmol Ear) and anhydrous THF (40 ml) was cooled to 0 ° C and 1M tetrabutylammonium fluoride (0.8 ml, 0.8 mmol) in THF was added and the reaction mixture was stirred at room temperature for 20 hours and It was then concentrated. Water was added to the residue and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered and concentrated. The residue was purified by flash column chromatography (using dichloromethane: methanol = 9: 1 as the eluent) to give the target compound (172 mg, 98%). The product is a 54:46 mixture of non-mirromeric isomers. MS (ESI) m / z 439.1 (M + H) ⁺ .

Example 55
1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazin-5-yl} ethanone

Let 1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4 , 3-a] [1] Benzacridin-5-yl} ethanol (Example 54) (142 mg, 0.32 mmol) and dichloromethane (10 ml) were stirred and cooled to 0 ° C and added to Stewart-Martin iodine (206 mg, 0.48 mmol). The reaction mixture was allowed to stir at room temperature for 3 hours and then filtered. The filtrate was diluted with water, the layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and filtered and concentrated. The residue was purified by flash column chromatography (using dichloromethane: methanol = 95: 5 as the eluent) to give the target compound (111 mg, 79%). MS (ESI) m / z 437.2 (M + H) ⁺ .

Example 56
8-chloro-5- (fluoromethyl) -1- (trans-4-methoxy-4-methylcyclohexyl) -5,6-dihydro-4H- [1,2,4] triazole Ac [4,3-a] [1] benzoacene

According to the method described in Example 1, from 7-chloro-4- (fluoromethyl) -1,3,4,5-tetrahydro-2H-1-benzoazine-2-thione (Intermediate 37) And 4-methoxy-4-methylcyclohexanemethanehydrazine (Intermediate 35, step c)) to prepare the target compound. MS (ESI) m / z 378.2 (M + H) ⁺ .

Example 57
1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazin-5-yl} -N- (2-methoxyethyl) ethylamine

Let 1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4 , 3-a] [1] benzoazin-5-yl} ethanone (Example 55) (30 mg, 0.07 mmol), 1,2-dichloromethane (5 ml), 2-methoxy Ethylamine (24 µl, 0.275 mmol), acetic acid (30 µl), and NaBH (OAc) ₃ (29 mg, 0.137 mmol) was stirred at room temperature for 4 hours and then concentrated. The pH of the residue was adjusted to 9 by adding 1M NaOH and the mixture was then extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and filtered and concentrated. The residue was purified by flash column chromatography (using dichloromethane: methanol = 97: 3 as the eluent) to give the target compound (12 mg, 35%). The product was a 58:42 mixture of non-mirromeric isomers. MS (ESI) m / z 496.3 (M + H) ⁺ .

Example 58
8-fluoro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Methylbenzoazine-5-carboxylic acid

According to the method described in Example 1, from 7-fluoro-2- pendant thio-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid (Intermediate 39) prepared the target compound. MS (ESI) m / z 437.4 (M + H) ⁺ .

Example 59
8-chloro-5- (fluoromethyl) -1- [trans-4- (trifluoromethyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazine

According to the method described in Example 1, from 7-chloro-4- (fluoromethyl) -1,3,4,5-tetrahydro-2H-1-benzoazine-2-thione (Intermediate 37) And trans-4- (trifluoromethyl) cyclohexanemethanehydrazine (Intermediate 6) to prepare the target compound. MS (ESI) m / z 402.3 (M + H) ⁺ .

Example 60
5- (fluoromethyl) -1- (trans-4-methoxy-4-methylcyclohexyl) -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazine

According to the method described in Example 27, from 8-chloro-5- (fluoromethyl) -1- (trans-4-methoxy-4-methylcyclohexyl) -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine (Example 56) The target compound was prepared. MS (ESI) m / z 344.3 (M + H) ⁺ .

Example 61
{8-fluoro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzacridin-5-yl} methanol

According to the method described in Example 12, from 8-fluoro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] Triazolo [4,3-a] [1] benzoazine-5-carboxylic acid methyl ester (Example 58) prepared the target compound. MS (ESI) m / z 409.3 (M + H) ⁺ .

Example 62
8-fluoro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] tris Zolo [4,3-a] [1] benzoazine

According to the method described in Example 1, from 7-fluoro-4- (fluoromethyl) -1,3,4,5-tetrahydro-2H-1-benzoazine-2-thione (intermediate 41) Prepare the target compound. MS (ESI) m / z 411.3 (M + H) ⁺ .

Example 63
Cis- (racemic) -1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2, 4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol

with
Example 64
Trans- (racemic) -1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2, 4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol

a) 5- [cis- (Meth) -1-{[tertiary butyl (dimethyl) silyl] oxy} ethyl] -8-chloro-1- [trans-4- (pyridine- 2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine and 5- [trans- (Racemic) -1-{[tertiary butyl (dimethyl) silyl] oxy} ethyl] -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl ] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine

According to the method described in Example 1, from 4- (1-{[tertiary butyl (dimethyl) silyl] oxy} ethyl) -7-chloro-1,3,4,5-tetrahydro-2H The isolated single non-mirror isomer of 1-benzoazepin-2-thione (Intermediate 34) prepared the target compound. The products are single non-mirromeric isomers but their configuration has not been determined. MS (ESI) m / z 553.3 (M + H) ⁺ .

b) cis- (racemic) -1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol and trans- (racemic) -1- {8-chloro-1- [trans-4 -(Pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazepine-5- Methyl} ethanol
According to the method described in step b) of Example 54, from 5- [cis- (racemic) -1-{[tertiary butyl (dimethyl) silyl] oxy} ethyl] -8-chloro- 1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] Benzacridine and 5- [trans- (racemic) -1-{[tertiary butyl (dimethyl) silyl] oxy} ethyl] -8-chloro-1- [trans-4- (Pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine (Example 63 And step a)) of 64 to prepare the target compound. The products are single non-mirromeric isomers but their configuration has not been determined. MS (ESI) m / z 439.4 (M + H) ⁺ .

Example 65
(1R) -1-{(5R) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2, 4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol

with
Example 66
(1S) -1-{(5S) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2, 4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol

with
Example 67
(1S) -1-{(5R) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2, 4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol

with
Example 68
(1R) -1-{(5S) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2, 4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol

By chiral preparative HPLC (CHIRALPAK IG preparative 20 µm stationary phase; 5 x 30 cm; F = 50 ml / min; eluent: n-heptane: isopropanol = 8: 2; isocratic; temperature = 25 ° C), from the isolated non-image isomer: cis- (racemic) -1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl]- 5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol and trans- (racemic) -1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzacridin-5-yl} ethanol (Examples 63 and 64) gave the target compound. Separation of one of the racemic mixtures produces 2 compounds: the first elutable compound (T _r 13.9 minutes) = + 14˚ (c = 0.1; chloroform) and the second eluting compound (T _r 16.7 minutes) = -12˚ (c = 0.1; chloroform). Separation of the other of the racemic mixtures yields another 2 compounds: the first elutable compound (T _r 19.0 minutes) = + 21˚ (c = 0.1; chloroform) and the second eluting compound (T _r 21.5 minutes) = -16˚ (c = 0.1; chloroform). The absolute configuration of these compounds has not been determined.

Example 69
5- (fluoromethyl) -8-methyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] Triazolo [4,3-a] [1] benzoazine

According to the method described in Example 1, from 4- (fluoromethyl) -7-methyl-1,3,4,5-tetrahydro-2H-1-benzoazine-2-thione (Intermediate 43 ) Preparation of the target compound. MS (ESI) m / z 407.3 (M + H) ⁺ .

Example 70
(5S) -8-chloro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazine

with
Example 71
(5R) -8-chloro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazine

By chiral preparative HPLC (CHIRALPAK IG preparative 20 µm stationary phase; 5 x 30 cm; F = 50 ml / min; eluent: tertiary butyl methyl ether: methylene chloride: EtOH = 90: 8: 2 Isocratic; temperature = 25 ℃), self-racemic 8-chloro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6 -Dihydro-4H- [1,2,4] triazolo [4,3- a ] [1] Benzoazine (Example 31) gave the target compound. The first eluted compound (retention time 20.2 minutes) is (5S) -8-chloro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5 , 6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine (Example 70), = + 6.3 ° (c = 0.1; dichloromethane); and the second elutable compound (retention time 22.9 minutes) is (5R) -8-chloro-5- (fluoromethyl) -1- [trans- 4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazepine (implementation Example 71), = -8.9 ° (c = 0.1; dichloromethane). The configuration of these compounds was determined by the VCD method.

Example 72
8-fluoro-1- [trans-4- (trifluoromethyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1 ] Methyl benzoazine-5-carboxylate

Let 7-fluoro-2- (methylthio) -4,5-dihydro-3H-1-benzoazine-4-carboxylic acid methyl ester (Intermediate 44) (270 mg, 0.1 mmol), 1 , 4-dioxane (20 ml), trans-4- (trifluoromethyl) cyclohexanemethanehydrazine (Intermediate 6) (210 mg, 0.1 mmol) and concentrated hydrochloric acid (10 µl The mixture) was refluxed for 1 hour and then concentrated. The residue was purified by flash column chromatography (using dichloromethane: methanol = 95: 5 as the eluent) to give the target compound (145 mg, 35%). MS (ESI) m / z 412.1 (M + H) ⁺ .

Example 73
8-chloro-1- [4- (2,3-dimethylphenyl) piperazin-1-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] Benzacene-5-carboxamide

According to the method described in Example 52, 5-Carboxamidamine (Intermediate 29) and 1- (2,3-dimethylphenyl) piperazine were used to prepare the target compounds. MS (ESI) m / z 451.2 (M + H) ⁺ .

Example 74
{8-fluoro-1- [trans-4- (trifluoromethyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [ 1] Benzacridin-5-yl} methanol

According to the method described in Example 12, from 8-fluoro-1- [trans-4- (trifluoromethyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] Benzacne-5-carboxylic acid methyl ester (Example 72) The target compound was prepared. MS (ESI) m / z 384.2 (M + H) ⁺ .

Example 75
{8-chloro-5-methyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazepine-5-yl} methanol

a) 8-Chloro-5-methyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazole Benzo [4,3-a] [1] benzoazine-5-carboxylic acid methyl ester

According to the method described in Example 1, from 7-chloro-4-methyl-2- pendant thio-2,3,4,5-tetrahydro-1H-1-benzoazine-4-carboxylic acid methyl ester ( Intermediate 46) The target compound was prepared. MS (ESI) m / z 467.1 (M + H) ⁺ .

b) {8-chloro-5-methyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] tri Zolo [4,3-a] [1] benzoazepine-5-yl} methanol
According to the method described in Example 12, from 8-chloro-5-methyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1 , 2,4] triazolo [4,3-a] [1] benzoazine-5-carboxylic acid methyl ester (step a) of Example 75) to prepare the target compound. MS (ESI) m / z 439.1 (M + H) ⁺ .

Example 76
{8-chloro-5-ethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazepine-5-yl} methanol

a) 8-Chloro-5-ethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazole Benzo [4,3-a] [1] benzoazine-5-carboxylic acid methyl ester

According to the method described in Example 72, from 7-chloro-4-ethyl-2- (methylthio) -4,5-dihydro-3H-1-benzoazine-4-carboxylic acid methyl ester (intermediate 49) Prepare the target compound. MS (ESI) m / z 481.2 (M + H) ⁺ .

b) {8-chloro-5-ethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] tri Zolo [4,3-a] [1] benzoazepine-5-yl} methanol
According to the method described in Example 12, from 8-chloro-5-ethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1 , 2,4] triazolo [4,3-a] [1] benzoazine-5-carboxylic acid methyl ester (step a) of Example 76) to prepare the target compound. MS (ESI) m / z 453.2 (M + H) ⁺ .

Example 77
(5S) -8-fluoro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazine

with
Example 78
(5R) -8-fluoro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazine

By chiral preparative HPLC (CHIRALPAK IA preparative 20 µm stationary phase; 2.5 x 20 cm; F = 15 ml / min; eluent: tertiary butyl methyl ether: dichloromethane = 75: 25; isocratic; Temperature = 25 ℃), self-racemic 8-fluoro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro- 4H- [1,2,4] triazolo [4,3-a] [1] benzoazine (Example 62) gave the target compound. First eluting compound (T _r 16.6 minutes) = + 9 ° (c = 0.1; dichloromethane) and the second eluting compound (T _r 19.0 minutes) = -10 ° (c = 0.1; dichloromethane). The absolute configuration of these compounds has not been determined.

Example 79
8-chloro-1- [4- (3-chlorophenyl) piperazin-1-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] Benzacene-5-carboxamide

According to the method described in Example 52, from 1-bromo-8-chloro-5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine 5-Carboxamidamine (Intermediate 29) and 1- (3-chlorophenyl) piperazine were used to prepare the target compounds. MS (ESI) m / z 457.2 (M + H) ⁺ .

Example 80
8-chloro-1- [4- (pyridin-2-yl) piperazin-1-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] Benzacene-5-carboxamide

According to the method described in Example 52, from 1-bromo-8-chloro-5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine 5-Carboxamidamine (Intermediate 29) and 1- (pyridin-2-yl) piperazine prepared the target compounds. MS (ESI) m / z 424.2 (M + H) ⁺ .

Example 81
8-chloro-1- [4- (pyridin-2-yloxy) piperidin-1-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzacene-5-carboxamide

According to the method described in Example 52, from 1-bromo-8-chloro-5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine 5-Carboxamidamine (Intermediate 29) and 2- (piperidin-4-yloxy) pyridine prepared the target compounds. MS (ESI) m / z 439.2 (M + H) ⁺ .

Example 82
5-[(benzyloxy) methyl] -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazine

Let {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] Benzacridin-5-yl} methanol (Example 12) (100 mg, 0.24 mmol) in anhydrous DMF (3 ml), the mixture was cooled to 0 ° C and added under argon to 60 % Sodium hydride (24 mg, 0.59 mmol) in mineral oil. The mixture was allowed to stir at this temperature for 0.5 hours, then benzyl bromide (70 µl, 0.59 mmol) and tetrabutylammonium iodide (27 mg, 0.07 mmol) were added and the reaction mixture was allowed to pass at room temperature. Stir for 3 hours. After the reaction was completed, the mixture was diluted with saturated ammonium chloride solution, extracted with ethyl acetate, and the combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (using dichloromethane: methanol = 95: 5 as the eluent) to give the target compound (44 mg, 36%). MS (ESI) m / z 515.2 (M + H) ⁺ .

Example 83
8-chloro-1- (3,3-difluorocyclobutyl) -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine甲酯 -5-carboxylic acid methyl ester

According to the method described in Example 1, from 7-chloro-2- pendant thio-2,3,4,5-tetrahydro-1H-1-benzoazine-4-carboxylic acid methyl ester (intermediate 4) and 3,3-Difluorocyclobutanemethanehydrazine (Intermediate 51) prepared the target compound. MS (ESI) m / z 368.1 (M + H) ⁺ .

Example 84
8-chloro-1- [trans-4- (piperidin-1-ylmethyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Methylbenzoazine-5-carboxylic acid

According to the method described in Example 1, from 7-chloro-2- pendant thio-2,3,4,5-tetrahydro-1H-1-benzoazine-4-carboxylic acid methyl ester (intermediate 4) and Trans-4- (piperidin-1-ylmethyl) cyclohexanemethylhydrazine (Intermediate 8) prepared the title compound. MS (ESI) m / z 457.3 (M + H) ⁺ .

Example 85
{8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzacridin-5-yl} methyl acetate

Let {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] benzoazepine-5-yl} methanol (Example 12) (100 mg, 0.24 mmol), dichloromethane (5 ml), pyridine (57 µl, 0.7 mmol), A mixture of acetic anhydride (67 µl, 0.7 mmol) and DMAP (3 mg, 0.02 mmol) was stirred at room temperature for 20 hours, then diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and filtered and concentrated. The residue was purified by flash column chromatography (using dichloromethane: methanol = 97: 3 as the eluent) to give the target compound (38 mg, 35%). MS (ESI) m / z 467.1 (M + H) ⁺ .

Example 86
8-chloro-1- (1'H, 3H-spiro [2-benzofuran-1,4'-piperidine] -1'-yl) -5,6-dihydro-4H- [1,2, 4] triazolo [4,3-a] [1] benzoazine-5-carboxamide

According to the method described in Example 52, from 1-bromo-8-chloro-5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine 5-Carboxamidamine (Intermediate 29) and 3H-spiro [2-benzofuran-1,4'-piperidine] (Combi-Blocks) prepared the target compound. MS (ESI) m / z 450.2 (M + H) ⁺ .

Example 87
8-chloro-N- (pyridin-2-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazine-5-carboxamide

P-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] A stirred solution of benzoazine-5-carboxylic acid (Example 2) (361 mg, 0.82 mmol) in dichloromethane (25 ml) was added chloramphenicol (446 µl, 5.3 mmol) And DMF (50 µl). The reaction mixture was allowed to stir at room temperature for 30 minutes and then concentrated. The residue was dissolved in pyridine (5 ml) and 2-aminopyridine (155 mg, 1.64 mmol) was added. The resulting reaction mixture was stirred at room temperature for 2 hours, then concentrated and the residue was subjected to preparative HPLC (KINETEX EVO 5 µm stationary phase; 150 x 21.2 mm; F = 20 ml / min; eluate: ( Water + 0.1% trifluoroacetic acid): (methanol: acetonitrile = 2: 1) = 52: 48; isocratic; temperature = 40 ° C) was purified to give the target compound (12.7 mg, 3%). MS (ESI) m / z 515.2 (M + H) ⁺ .

Example 88
8-chloro-1- (1'H, 3H-spiro [2-benzofuran-1,4'-piperidine] -1'-yl) -5,6-dihydro-4H- [1,2, 4] triazolo [4,3-a] [1] benzoazine-5-carbonitrile

Let 8-chloro-1- (1'H, 3H-spiro [2-benzofuran-1,4'-piperidine] -1'-yl) -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazepine-5-carboxamide (Example 86) (78.6 mg, 0.175 mmol), anhydrous dichloromethane (30 ml), and A stirred solution of triethylamine (153 µl, 1.1 mmol) was cooled to 0 ° C and trifluoroacetic anhydride (40 µl, 0.28 mmol) was added. The mixture was allowed to warm to room temperature and the reaction mixture was stirred at this temperature for 1 hour. Triethylamine (153 µl, 1.1 mmol) and trifluoroacetic anhydride (40 µl, 0.28 mmol) were then added. . The mixture was allowed to stir overnight at room temperature, then triethylamine (153 µl, 1.1 mmol) and trifluoroacetic anhydride (80 µl, 0.56 mmol) were added and stirring was continued overnight at room temperature. Pass the reaction mixture over saturated NaHCO ₃ The solution was diluted, the phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water and brine, dried over sodium sulfate and filtered and concentrated. The residue was purified by column chromatography (using dichloromethane: methanol: ammonium hydroxide = 180: 10: 1 as the eluent) to give the target compound (11.5 mg, 15%). MS (ESI) m / z 432.1 (M + H) ⁺ .

Example 89
8-chloro-1- [4- (2,3-dimethylphenyl) piperazin-1-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazine-5-carbonitrile

Let 1-bromo-8-chloro-5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine-5-carbonitrile (Intermediate 52 ) (100 mg, 0.31 mmol) and 1- (2,3-dimethylphenyl) piperazine (412 mg, 2.16 mmol) under argon and 180 ° C with stirring for 4 hours and then Cool to room temperature. The residue was purified by column chromatography (using dichloromethane: methanol: ammonium hydroxide = 180: 10: 1 as eluent) and crystallized from diethyl ether to give the title compound (28 mg, 21%). MS (ESI) m / z 433.1 (M + H) ⁺ .

Example 90
8-chloro-1- [4- (pyridin-2-yl) piperazin-1-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] Benazine-5-nitrile

According to the method described in Example 89, from 1-bromo-8-chloro-5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine -5-Nitrile (Intermediate 52) and 1- (pyridin-2-yl) piperazine prepared the target compounds. MS (ESI) m / z 406.1 (M + H) ⁺ .

Example 91
8-fluoro-5,5-dimethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] tris Zolo [4,3-a] [1] benzoazine

a) 7-Fluoro-4,4-dimethyl-1,3,4,5-tetrahydro-2H-1-benzoazine-2-thione

P-Fluoro-4,4-dimethyl-1,3,4,5-tetrahydro-2H-1-benzoazepine-2-one (Intermediate 53) (1.10 g, 5.31 mmol) And a solution of pyridine (10 ml) was added to Lawson's reagent (2.79 g, 6.90 mmol) and the reaction mixture was refluxed for 2 hours. The solvent was then removed in vacuo and the residue was subjected to saturated NaHCO ₃ Triturate and collect the precipitate by filtration. Thus, the target product (1.00 g, 84%) was obtained, which was used without further purification.

b) 7-fluoro-4,4-dimethyl-2- (methylthio) -4,5-dihydro-3H-1-benzoazepine

P-Fluoro-4,4-dimethyl-1,3,4,5-tetrahydro-2H-1-benzoazepine-2-thione (step a) of Example 91) (0.40 g, 1.68 mmol, potassium carbonate (6.60 g, 4.78 mmol) and acetone (30 ml) was added to methyl iodide (0.297 ml, 4.78 mmol) and the reaction mixture was stirred at 40 ° C for 1 hour. After evaporation of the solvent, water and ethyl acetate were added to the residue, the layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with a saturated NaCl solution, dried over anhydrous sodium sulfate and filtered and concentrated. Thus, the target product (0.40 g, 99%) was obtained, which was used without further purification.

c) 8-fluoro-5,5-dimethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazine
7-fluoro-4,4-dimethyl-2- (methylthio) -4,5-dihydro-3H-1-benzoazine (step b) of Example 91) (0.30 g, 1.26 Mol), trans-4- (pyridin-2-yloxy) cyclohexanemethylhydrazine (WO2010 / 060836 A1 (2010.06.03) F. HOFFMANN-LA ROCHE AG.) A mixture of mol) and 1,4-dioxane (20 ml) was added with concentrated hydrochloric acid (0.010 ml) and the reaction mixture was refluxed for 3 hours. After the solvent was evaporated, the residue was purified by column chromatography using dichloromethane: methanol = 20: 1 as the eluent. Thus, the target product was obtained (0.108 mg, 21%). MS (ESI) m / z 407.2 (M + H) ⁺ .

Example 92
8-fluoro-5- (prop-2-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazine

According to the method described in Example 91, starting from 7-fluoro-4- (prop-2-yl) -1,3,4,5-tetrahydro-2H-1-benzoazin-2-one (Intermediate 54 ) Preparation of the target product. MS (ESI) m / z 421.2 (M + H) ⁺ .

Example 93
8'-bromo-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -4'H, 6'H-spiro [cyclopentane-1,5'-[1,2 , 4] triazolo [4,3-a] [1] benzoazine]

Prepared from 7-bromo-1,5-dihydrospiro [1-benzoazine-4,1'-cyclopentane] -2 (3H) -one (intermediate 60) according to the method described in Example 91 Underlying products. MS (ESI) m / z 493.1 and 495.1 (M + H) ⁺ .

Example 94
8-bromo-5- (prop-2-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazine

According to the method described in Example 91, from 7-bromo-4- (prop-2-yl) -1,3,4,5-tetrahydro-2H-1-benzoazin-2-one (Intermediate 61 ) Preparation of the target product. MS (ESI) m / z 481.1 and 483.1 (M + H) ⁺ .

Example 95
8'-bromo-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -2,3,5,6-tetrahydro-4'H, 6'H-spiro [piperan -4,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazepine]

a) 7-bromo-2-methoxy-3,5-dihydrospiro [1-benzoazine-4,4'-ethylene oxide]

Let 7-bromo-1,5-dihydrospiro [1-benzoazine-4,4'-ethylene oxide] -2 (3 H ) -Ketone (Intermediate 62) (0.193 g, 062 mmol), trimethyloxonium tetrafluoroborate (0.183 g, 1.24 mmol), potassium carbonate (0.343 g, 2.48 mmol) and dichloride A mixture of methane (30 ml) was stirred at room temperature for 3 hours. The reaction mixture was then filtered and the filtrate was concentrated. Thus, the target product was obtained (0.190 g, 98%), which was used without further purification.

b) 8'-bromo-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -2,3,5,6-tetrahydro-4'H, 6'H-spiro [ Piperan-4,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazepine]
7-bromo-2-methoxy-3,5-dihydrospiro [1-benzoazine-4,4'-ethylene oxide] (0.190 g, 0.62 mmol), trans-4 -(Pyridin-2-yloxy) cyclohexanemethylhydrazine (WO2010 / 060836 A1 (03.06.2010) F. HOFFMANN-LA ROCHE AG.) (0.161 g, 0.68 mmol) and 1,4-bis A mixture of oxane (20 ml) was added with trifluoroacetic acid (0.010 ml) and the reaction mixture was refluxed for 3 hours. After the solvent was evaporated, the residue was purified by column chromatography using dichloromethane: methanol = 20: 1 as the eluent. Thus, the target product was obtained (0.144 mg, 45%). MS (ESI) m / z 509.2 and 511.2 (M + H) ⁺ .

Example 96
8-fluoro-5,5-dimethyl-1- [trans-4- (trifluoromethyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazine

According to the method described in step c) of Example 91, from 7-fluoro-4,4-dimethyl-2- (methylthio) -4,5-dihydro-3H-1-benzoazine (implemented Step b)) of Example 91 and trans-4- (trifluoromethyl) cyclohexanemethanehydrazine (Intermediate 6) prepared the target product. MS (ESI) m / z 382.2 (M + H) ⁺ .

Example 97
(5R) -8-bromo-5- (prop-2-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1 , 2,4] triazolo [4,3-a] [1] benzoazine

with
Example 98
(5S) -8-bromo-5- (prop-2-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1 , 2,4] triazolo [4,3-a] [1] benzoazine

By chiral preparative HPLC (CHIRALPAK IC preparative 20 μm stationary phase; 2.5 x 20 cm; F = 20 ml / min; eluent: tertiary butyl methyl ether: dichloromethane: ethanol = 85: 13: 2 Isocratic; temperature = 25 ℃), self-racemic 8-bromo-5- (prop-2-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5 , 6-Dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine (Example 94) The target product was prepared. By analytical HPLC (CHIRALPAK IA 5 μm stationary phase; 250 x 4.6 mm; F = 1 ml / min; eluent: tertiary butyl methyl ether: dichloromethane: ethanol = 85: 10: 5; isocratic; Temperature = 35 ° C) Determination of retention time: 15.0 minutes for the first eluate; = -5.0˚ (c = 0.1; dichloromethane); MS (ESI) m / z 481.2 and 483.2 (M + H) ⁺ ; The second eluate is 18.5 minutes; = + 10.0˚ (c = 0.1; dichloromethane); MS (ESI) m / z 481.2 and 483.2 (M + H) ⁺ . The absolute configuration of these compounds has not been determined.

Example 99
8'-bromo-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -4,5-dihydro-4'H, 6'H-spiro [furan-3,5' -[1,2,4] triazolo [4,3-a] [1] benzoazine]

The titled product was prepared from 7-bromo-1,5-dihydrospiro [1-benzoazine-4,3'-tetrahydrofuran] -2 (3H) -one (intermediate 63) according to the method described in Example 95 . MS (ESI) m / z 495.1 and 497.2 (M + H) ⁺ .

Example 100
8'-chloro-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -2,3,5,6-tetrahydro-4'H, 6'H-spiro [piperan -4,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazepine]

Following the method described in Example 95, Prepare the target product. MS (ESI) m / z 465.2 (M + H) ⁺ .

Example 101
8'-chloro-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H, 4'H, 6'H-spiro [piperan-3 , 5 '-[1,2,4] triazolo [4,3-a] [1] benzoazepine]

According to the method described in Example 95, from 7-Chloro-1,5-dihydrospiro [1-benzoazine-4,3'-oxirane] -2 (3H) -one (Intermediate 65) Prepare the target product. MS (ESI) m / z 465.3 (M + H) ⁺ .
Example 102
8'-Chloro-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -4,5-dihydro-4'H, 6'H-spiro [furan-3,5' -[1,2,4] triazolo [4,3-a] [1] benzoazine]

The title product was prepared according to the method described in Example 95 from 7-chloro-1,5-dihydrospiro [1-benzoazine-4,3'-tetrahydrofuran] -2 (3H) -one (intermediate 66) . MS (ESI) m / z 451.2 (M + H) ⁺ .
Example 103
8'-chloro-1 '-[trans-4- (trifluoromethyl) cyclohexyl] -2,3,5,6-tetrahydro-4'H, 6'H-spiro [piperan-4, 5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine]

According to the method described in Example 91, from 7-Chloro-1,5-dihydrospiro [1-benzoazine-4,4'-ethylene oxide] -2 (3H) -one (Intermediate 64) And trans-4- (trifluoromethyl) cyclohexanemethanehydrazine (Intermediate 6) to prepare the target product. MS (ESI) m / z 440.2 (M + H) ⁺ .

Synthesis Example 104
(3R) -8'-bromo-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -4,5-dihydro-4'H, 6'H-spiro [furan- 3,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazepine]

with
Example 105
(3S) -8'-bromo-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -4,5-dihydro-4'H, 6'H-spiro [furan- 3,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazepine]

By chiral preparative HPLC (CHIRALPAK IG preparative 20 μm stationary phase; 5 x 30 cm; F = 50 ml / min; eluent: n-heptane: ethanol = 6: 4; isocratic; temperature = 25 ℃ ), Self-racemic 8'-bromo-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -4,5-dihydro-4'H, 6'H-spiro [ Furan-3,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine] (Example 99) The target product was prepared. Determination of retention time by analytical HPLC (CHIRALPAK IG 5 μm stationary phase; 250 x 4.6 mm; F = 1 ml / min; eluent: n-heptane: ethanol = 6: 4; isocratic; temperature = 25 ° C) : The first eluate is 18.6 minutes; = + 10.0˚ (c = 0.11; CHCl ₃ ); MS (ESI) m / z 495.2 and 497.2 (M + H) ⁺ ; The second lysate is 23.0 minutes; = -3.8˚ (c = 0.105; CHCl ₃ ); MS (ESI) m / z 495.2 and 497.2 (M + H) ⁺ . The absolute configuration of these compounds has not been determined.

Example 106
(3S) -8'-chloro-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H, 4'H, 6'H-spiro [ Piperan-3,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazepine]

with
Example 107
(3R) -8'-chloro-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H, 4'H, 6'H-spiro [ Piperan-3,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazepine]

By chiral preparative HPLC (CHIRALPAK IG preparative 20 μm stationary phase; 5 x 30 cm; F = 50 ml / min; eluent: n-heptane: ethanol = 6: 4; isocratic; temperature = 25 ℃ ), Self-racemic 8'-chloro-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H, 4'H, 6'H- Spiro [piperan-3,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine] (Example 101) prepared the target product. Determination of retention time by analytical HPLC (CHIRALPAK IG 5 μm stationary phase; 250 x 4.6 mm; F = 1 ml / min; eluent: n-heptane: ethanol = 6: 4; isocratic; temperature = 25 ° C) : The first eluate is 20.2 minutes; = + 19.0˚ (c = 0.11; CHCl ₃ ); MS (ESI) m / z 465.2 (M + H) ⁺ ; The second lysate is 26.5 minutes; = -7.6˚ (c = 0.105; CHCl ₃ ); MS (ESI) m / z 465.2 (M + H) ⁺ . The absolute configuration of these compounds has not been determined.

Example 108
8-fluoro-1- (trans-4-methoxy-4-methylcyclohexyl) -5,5-dimethyl-5,6-dihydro-4H- [1,2,4] triazole Ac [4,3-a] [1] benzoacene

with
Example 109
8-fluoro-1- (cis-4-methoxy-4-methylcyclohexyl) -5,5-dimethyl-5,6-dihydro-4H- [1,2,4] triazole Ac [4,3-a] [1] benzoacene

P-Fluoro-4,4-dimethyl-2- (methylthio) -4,5-dihydro-3H-1-benzoazine (step b) of Example 91) (0.15 g, 0.63 Mmol), 4-methoxy-4-methylcyclohexane-1-methylhydrazine (Intermediate 35 step c)) (0.18 g, 0.95 mmol) and 1,4-dioxane (20 ml) of the mixture was added concentrated hydrochloric acid (0.010 ml) and the reaction mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was subjected to preparative HPLC (Chromolith preparative RP18 column; 100 × 25 mm; 25 ml / min; A: water + 0.1% trifluoroacetic acid; B: acetonitrile + 0.1% trifluoroacetic acid; Gradient: 0 to 12 minutes; B: 0 to 49%; 12 to 24 minutes; B: 49 to 90%; temperature = 40 ° C). By analytical HPLC (Chromolith performance RP18 column; 100 × 4.6 mm; 1 ml / min; eluent: A: water + 0.1% trifluoroacetic acid; B: acetonitrile + 0.1% trifluoroacetic acid; gradient: 0 to 10 minutes; B: 0 to 90%; 10 to 15 minutes; B: 90%; temperature = 40 ° C) Determination of retention time: first eluate 8.62 minutes; trans isomer; 0.088 g (39%) ; MS (ESI) m / z 358.3 (M + H) ⁺ ; Second eluate 8.95 minutes; cis isomer; 0.021 g (9%); MS (ESI) m / z 358.2 (M + H) ⁺ .

Example 110
8'-Chloro-1 '-(trans-4-methoxy-4-methylcyclohexyl) -2,3,5,6-tetrahydro-4'H, 6'H-spiro [piperan- 4,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine]

with
Example 111
8'-Chloro-1 '-(cis-4-methoxy-4-methylcyclohexyl) -2,3,5,6-tetrahydro-4'H, 6'H-spiro [piperan- 4,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine]

a) 7-Chloro-2-methoxy-3,5-dihydrospiro [1-benzoazine-4,4'-ethylene oxide]

Let 7-chloro-1,5-dihydrospiro [1-benzoazine-4,4'-ethylene oxide] -2 (3H) -one (intermediate 54) (0.35 g, 1.32 mmol) ), A mixture of trimethyloxonium tetrafluoroborate (0.583 g, 3.95 mmol), potassium carbonate (0.73 g, 5.27 mmol) and dichloromethane (25 ml) were stirred at room temperature for 3 hours. The reaction mixture was then filtered and the organic phase was concentrated. Thus, the target product (0.35 g, 98%) was obtained, which was used in the next reaction step without further purification and characterization.

b) 8'-Chloro-1 '-(4-methoxy-4-methylcyclohexyl) -2,3,5,6-tetrahydro-4'H, 6'H-spiro [piperan-4 , 5 '-[1,2,4] triazolo [4,3-a] [1] benzoazepine]
P-Chloro-2-methoxy-3,5-dihydrospiro [1-benzoazine-4,4'-ethylene oxide] (0.35 g, 1.31 mmol), 4-methoxy A mixture of methyl-4-methylcyclohexane-1-formamidine (Intermediate 35 step c)) (0.74 g, 3.95 mmol) and 1,4-dioxane (20 ml) was added to trifluoro Acetic acid (0.030 ml) and the reaction mixture was stirred overnight at 75 ° C. After evaporation of the solvent, the residue was subjected to preparative HPLC (Kinetex EVO column; 5 μm load; 150 × 21.2 mm; 20 ml / min; eluate: 20 mmol / L (NH ₄ ) ₂ CO ₃ : Acetonitrile = 65:35; isocratic; temperature = 40 ° C). By analytical HPLC (Kinetex EVO column; 5 μm load; 150 × 4.6 mm; 1 ml / min; eluent: 20 mmol / L (NH ₄ ) ₂ CO ₃ : Acetonitrile = 65: 35; isocratic; temperature = 40 ° C) measurement retention time: first eluate 5.53 minutes; trans isomer; 0.056 g (10%); MS (ESI) m / z 416.2 ( M + H) ⁺ ; Second eluate system 8.06 minutes; cis isomer; 0.016 g (3%); MS (ESI) m / z 416.3 (M + H) ⁺ .

Synthesis Example 112
8-chloro-1- [trans-4- (pyridin-2-ylamino) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Methylbenzoazine-5-carboxylic acid

According to the method described in Example 1, from 7-chloro-2- pendant thio-2,3,4,5-tetrahydro-1 H Methyl-1-benzoazine-4-carboxylic acid methyl ester (Intermediate 4) and trans-4- (pyridin-2-ylamino) cyclohexanemethylhydrazine (Intermediate 67) were used to prepare the target product. MS (ESI) m / z 452.1 (M + H) ⁺ .
The following formulation examples illustrate representative pharmaceutical compositions of the present invention. However, the present invention is not limited to the following pharmaceutical composition.

Claims (53)

A compound of general formula (I), Wherein ring A is a cycloalkyl or heterocyclic group; if ring B is present, Y is -O-, -C (O)-, -CH _2- , -NH- or a bond; or, if ring B is not present, Y-N (C _1-4 alkyl) ₂ , C (O) OC _1-4 alkyl, C _1-4 alkyl optionally substituted with halogen, C _1-4 alkoxy or halogen; ring B is optionally substituted aryl, heterocyclyl or heteroaryl; or BYA-bonded represents 3H -spiro [2-benzofuran-1,4'-piperidine-1'-yl]; or R ¹ is hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ or CN; R ² is hydrogen or C _1-4 alkyl; R ³ is (CH ₂ ) _n R ⁴ , C (O) R ⁵ or C _1-4 alkyl optionally substituted by R ⁶ ; or R ^{2 in} combination with R ³ represents-(CH ₂ ) _p -O- (CH ₂ ) _q - _or- (CH ₂ ) _r- ; R ⁴ is CN, azide or Cy ¹ ; R ⁵ is C _1-4 alkyl, C _1-4 alkoxy, OH or NR ⁷ R ⁸ ; R ⁶ is OR ⁹ , NR ¹⁰ R ¹¹ , pendant oxy, -O (CH ₂ ) ₂ O- or one or more halogens; R ⁷ and R ^{8 are} independently hydrogen, C _1-4 alkyl or Cy ² , or R ⁷ and R ^{8 are} with them The linked N together form a heterocyclic ring; R ⁹ is hydrogen, C _1-4 alkyl optionally substituted with NH ₂ or optionally substituted aryl, Si (CH ₃ ) ₃ or C (O) R ¹² R ¹⁰ and R ^{11 are} independently hydrogen, C _1-4 alkyl optionally substituted with C _1-4 alkoxy, Cy ³ or C (O) R ¹³ , or R ¹⁰ and R ^{11 are} connected to each other And N together form an optionally substituted heterocyclic ring; R ¹² is C _1-5 alkyl or NR ¹⁴ R ¹⁵ ; R ¹³ is C _1-4 alkyl, Cy ¹ or NR ¹⁶ R ¹⁷ ; R ¹⁴ and R ^{15 is} independently hydrogen or optionally substituted aryl, or R ¹⁴ and R ¹⁵ together with the N to which they are attached form an optionally substituted hetero Rings; R ¹⁶ and R ¹⁷ are C _1-4 alkyl, or R ¹⁶ and R ¹⁷ together with the N to which they are attached form an optionally substituted heterocyclic ring; Cy ¹ is an optionally substituted heteroaryl Cy ² is optionally substituted aryl or heteroaryl; Cy ³ is optionally substituted cycloalkyl or heteroaryl; X is C _1-4 alkyl, aryl or heteroaryl; Z is C _1-4 alkyl; n is 0 or 1; p is 1, 2 or 3; q is 1, 2 or 3; r is 4, 5 or 6; and / or their salts and / or Geometric isomers and / or their stereoisomers and / or their mirror isomers and / or their racemates and / or their non-image isomers and / or their Bioactive metabolites and / or their prodrugs and / or their solvates and / or their hydrates and / or their polymorphs. A compound as claimed in claim 1, wherein R ¹ is hydrogen, fluorine, chlorine, bromine, methyl, methoxy, CF ₃ or CN. A compound as claimed in claim 1, wherein ring A is a 3 to 6 membered saturated carbocyclic ring, or a 4 to 7 membered saturated heterocyclic ring containing 1 or 2 N; ring B is optionally substituted 6 or 5 membered monocyclic Aryl, 6 to 10 membered aromatic carbocyclic rings or 4 to 7 membered saturated monocyclic, bicyclic, fused and / or bridged heterocyclic rings containing 1, 2 or 3 heteroatoms selected from O, S or N; Or BYA-binding represents 3H -spiro [2-benzofuran-1,4'-piperidine-1'-yl]; or X is isopropyl; Z is methyl. A compound according to any one of claims 1 to 3, wherein ring B is optionally substituted 6-membered monoheteroaryl, phenyl, or a group containing 1 or 2 heteroatoms selected from O, S or N 4 to 6 membered saturated monocyclic heterocyclic ring. The compound according to any one of claims 1 to 3, wherein if ring B is present, Y is -O-, -C (O)-, -CH _2- , -NH- or a single bond. The compound according to any one of claims 1 to 3, wherein ring A is a 4- to 6-membered saturated carbocyclic group, or via ring nitrogen and Y or the 5,6-dihydro-4 H- [1,2,4 ] Triazolo [4,3-a] [1] Benzazepine nucleus is connected by a triazole ring containing 1 or 2 N 4 to 7 membered saturated heterocyclic ring. The compound according to any one of claims 1 to 3, wherein ring A is cyclohexyl, Y is -O-, ring B is pyridin-2-yl and R ¹ is chlorine. A compound according to any one of claims 1 to 3, wherein ring A is azetidine, piperidine or piperazine, Y is -O- or a single bond, and ring B is pyridine, pyrimidine or piperidine, And R ¹ is chlorine. A compound according to any one of claims 1 to 3, wherein Y is -N (C _1-4 alkyl) ₂ , C (O) OC _1-4 alkyl, optionally substituted C _1-4 with halogen Alkyl, C _1-4 alkoxy or halogen, and ring B is absent. A compound as claimed in claim 3, wherein ring A is a 4- to 6-membered saturated carbocyclic group. A compound as claimed in claim 10, wherein Y is selected from the group consisting of -N (C _1-4 alkyl) ₂ , C (O) OC _1-4 alkyl, optionally substituted C _1-4 alkyl, C _{One of 1-4} alkoxy and halogen. A compound as claimed in claim 10, wherein Y is selected from the group consisting of C _1-4 alkyl, C _1-4 alkoxy, and halogen optionally substituted with halogen. A compound as claimed in claim 1, wherein R ² is hydrogen or C _1-4 alkyl, and R ³ is (CH ₂ ) _n R ⁴ . A compound as claimed in claim 13, wherein R ² is hydrogen, R ³ is (CH ₂ ) _n R ⁴ , R ⁴ is CN, azido or optionally substituted with C _1-4 alkyl containing 2 N and 1 O or 4 N 5-membered monoheteroaryl. A compound as claimed in claim 1, wherein R ² is hydrogen or C _1-4 alkyl, and R ³ is C (O) R ⁵ . A compound as claimed in claim 15 wherein R ² is hydrogen. A compound as claimed in claim 15, wherein R ⁵ is methyl, methoxy, OH or NR ⁷ R ⁸ , wherein R ⁷ and R ^{8 are} independently hydrogen, methyl, ethyl or isopropyl. The compound of 1, wherein R ² system hydrogen or C _1-4 alkyl, and R ³ is optionally substituted with R ⁶ lines of C _1-4 alkyl substituted with request entry. A compound as claimed in claim 18, wherein R ² is hydrogen or C _1-4 alkyl, and R ³ is C _1-4 alkyl. A compound as claimed in claim 19, wherein R ² is hydrogen or C _1-3 alkyl, and R ³ is C _1-3 alkyl. A compound as claimed in claim 18, wherein R ³ is a single or multiple branched C _1-4 alkyl substituted with R ⁶ . A compound as claimed in claim 21, wherein R ³ is -CH ₂ R ⁶ or -CH (R ⁶ ) CH ₃ . A compound as claimed in claim 21, wherein R ² is hydrogen and R ⁶ is OR ⁹ . A compound as claimed in claim 23, wherein R ⁹ is hydrogen, optionally substituted C _1-4 alkyl, or C (O) R ¹² , wherein R ¹² is methyl. A compound as claimed in claim 21, wherein R ² is C _1-4 alkyl and R ⁶ is OR ⁹ . A compound as claimed in claim 24, wherein R ² is methyl or ethyl and R ⁹ is hydrogen. A compound as claimed in claim 21, wherein R ² is hydrogen and R ⁶ is NR ¹⁰ R ¹¹ . A compound as claimed in claim 27, wherein R ¹⁰ and R ^{11 are} independently hydrogen, C _1-4 alkyl, optionally substituted with C _1-4 alkoxy, Cy ³ or C (O) R ¹³ , or R ¹⁶ And R ¹⁷ together with the N to which they are attached form an optionally substituted heterocyclic ring. A compound as claimed in claim 21, wherein R ² is C _1-4 alkyl and R ⁶ is NR ¹⁰ R ¹¹ . A compound as claimed in claim 21, wherein R ² is hydrogen and R ⁶ is one or more halogens. The compound of claim 30, wherein the halogen is fluorine. A compound as claimed in claim 21, wherein R ² is C _1-4 alkyl and R ⁶ is one or more halogens. A compound as claimed in claim 21, wherein R ⁶ is pendant oxygen or -O (CH ₂ ) ₂ O-. The compound according to any one of claims 13, 15 and 18, wherein the 5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazepine The absolute configuration of the carbon at position 5 of the nucleus (R). The compound according to any one of claims 13, 15 and 18, wherein the 5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazepine The absolute configuration of the carbon at the 5th position of the nucleus (S). A compound as claimed in claim 1, wherein R ² and R ^{3 are} combined to represent-(CH ₂ ) _p -O- (CH ₂ ) _q- , wherein p is 1, 2 or 3, and q is 1, 2 or 3. A compound as claimed in claim 35, wherein the sum of p and q is 3 or 4. A compound as claimed in claim 1, wherein R ² and R ^{3 in} combination represent-(CH ₂ ) _r- , wherein r is 4, 5 or 6. The compound of claim 1, wherein the compound is selected from: 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Methyl benzoazine-5-carboxylic acid; 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Benzacene-5-carboxylic acid; 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Benzacene-5-carboxamide; 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Benzacene-5-carbonitrile; 8-chloro-N, N-dimethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] Zolo [4,3-a] [1] benzoazine-5-carboxamide; (5S) -8-chloro-N, N-dimethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazepine-5-carboxamide; (5R) -8-chloro-N, N-dimethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazepine-5-carboxamide; 8-chloro-N- (prop-2-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazepine-5-carboxamide; {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzacridin-5-yl} (pyrrolidin-1-yl) methanone; {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzacridin-5-yl} (morpholin-4-yl) methanone; {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzacridin-5-yl} (1,1-dioxythiomorpholin-4-yl) methanone; {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzacridin-5-yl} methanol; {(5S) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazepine-5-yl} methanol; {(5R) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazepine-5-yl} methanol; 8-chloro-5- (methoxymethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazine; Morpholine-4-carboxylic acid {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazole Benzo [4,3-a] [1] benzoazin-5-yl} methyl ester; (4-fluorophenyl) carbamic acid {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazin-5-yl} methyl ester; 5- (azidomethyl) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazine; 1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazin-5-yl} methylamine; 8-chloro-5- (morpholin-4-ylmethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazine; 1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazin-5-yl} -N, N-dimethylmethylamine; N-({8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4 , 3-a] [1] benzoazepine-5-yl} methyl) propan-2-amine; 8-chloro-1- [1- (pyrimidin-2-yl) tetrahydroazepine-3-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Methylbenzoazine-5-carboxylic acid; 8-chloro-1- [trans-4- (dimethylamino) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [ 1] methyl benzoazine-5-carboxylic acid; 8-chloro-1- [trans-4- (trifluoromethyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1 ] Methyl benzoazine-5-carboxylic acid; 8-chloro-1- [trans-4- (morpholin-4-yl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] methyl benzoazine-5-carboxylic acid; {1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1 ] Benzacridin-5-yl} methanol; 8-chloro-1- [trans-4- (pyrrolidin-1-ylcarbonyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Methyl benzoazine-5-carboxylic acid; {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] benzoazin-5-yl} acetonitrile; 8-chloro-5-[(4-methylpiperazin-1-yl) methyl] -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro -4H- [1,2,4] triazolo [4,3-a] [1] benzoazine; 8-chloro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] tris Zolo [4,3-a] [1] benzoazine; 8-chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5, 6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine; 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5- (2H-tetrazol-5-yl) -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazine; N-({8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4 , 3-a] [1] benzoazin-5-yl} methyl) tetrahydro-2H-piperan-4-amine; N, N-dimethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -8- (trifluoromethyl) -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazepine-5-amine; 8-Chloro-1- [trans-3-methyl-2-oxo-1-oxa-3-azaspiro [4.5] dec-8-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine-5-carboxylic acid methyl ester; N-({8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4 , 3-a] [1] benzoazepine-5-yl} methyl) acetamide; N-({8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4 , 3-a] [1] benzoazepin-5-yl} methyl) oxetan-3-amine; 8-chloro-1- [trans-4- (morpholin-4-ylcarbonyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Methyl benzoazine-5-carboxylic acid; 8-chloro-1- [cis-3-methyl-2-oxo-1-oxa-3-azaspiro [4.5] dec-8-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine-5-carboxylic acid methyl ester; 8-chloro-1- [1- (pyridin-2-yl) tetrahydroazepine-3-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Methylbenzoazine-5-carboxylic acid; 1- [trans-4- (tetrahydroazepine-1-ylcarbonyl) cyclohexyl] -8-chloro-5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] methyl benzoazine-5-carboxylic acid; 8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5- (pyrrolidin-1-ylmethyl) -5,6-dihydro-4H- [1, 2,4] triazolo [4,3-a] [1] benzoazine; N-({8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4 , 3-a] [1] benzoazin-5-yl} methyl) -2-methyl-N- (2-methylpropyl) propan-1-amine; 8-chloro-1- [trans-4- (piperidin-1-ylcarbonyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Methyl benzoazine-5-carboxylic acid; 1- (trans-4-{[4- (tertiary butoxycarbonyl) piperazin-1-yl] carbonyl} cyclohexyl) -8-chloro-5,6-dihydro-4H- [1,2, 4] triazolo [4,3-a] [1] benzoazine-5-carboxylic acid methyl ester; 8-chloro-1- [trans-4- (piperazin-1-ylcarbonyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Benzoazine-5-carboxylic acid methyl ester hydrochloride; 8-methoxy-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] methyl benzoazine-5-carboxylic acid; 8-methyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Methylbenzoazine-5-carboxylic acid; 8-chloro-N- (4-fluorophenyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazepine-5-carboxamide; 8-bromo-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Methyl benzoazine-5-carboxylic acid; 1- (1,4'-bipiperidin-1'-yl) -8-chloro-5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1 ] Benzoazepine-5-carboxamide; 8-chloro-1-[(5r, 8r) -1-oxo-2- (prop-2-yl) -2-azaspiro [4.5] dec-8-yl] -5,6-dihydro -4H- [1,2,4] triazolo [4,3-a] [1] benzoazine-5-carboxylic acid methyl ester; 1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazepine-5-yl} ethanol; 1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazin-5-yl} ethanone; 8-chloro-5- (fluoromethyl) -1- (trans-4-methoxy-4-methylcyclohexyl) -5,6-dihydro-4H- [1,2,4] triazole Ac [4,3-a] [1] benzoazine; 1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazin-5-yl} -N- (2-methoxyethyl) ethylamine; 8-fluoro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Methyl benzoazine-5-carboxylic acid; 8-chloro-5- (fluoromethyl) -1- [trans-4- (trifluoromethyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazine; 5- (fluoromethyl) -1- (trans-4-methoxy-4-methylcyclohexyl) -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazine; {8-fluoro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzacridin-5-yl} methanol; 8-fluoro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] tris Zolo [4,3-a] [1] benzoazine; Cis- (racemic) -1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2, 4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol; Trans- (racemic) -1- {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2, 4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol; (1R) -1-{(5R) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2, 4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol; (1S) -1-{(5S) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2, 4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol; (1S) -1-{(5R) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2, 4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol; (1R) -1-{(5S) -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2, 4] triazolo [4,3-a] [1] benzoazin-5-yl} ethanol; 5- (fluoromethyl) -8-methyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] Triazolo [4,3-a] [1] benzoazine; (5S) -8-chloro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazine; (5R) -8-chloro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazine; 8-fluoro-1- [trans-4- (trifluoromethyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1 ] Methyl benzoazine-5-carboxylic acid; 8-chloro-1- [4- (2,3-dimethylphenyl) piperazin-1-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazine-5-carboxamide; {8-fluoro-1- [trans-4- (trifluoromethyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [ 1] benzoazepine-5-yl} methanol; {8-chloro-5-methyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazepine-5-yl} methanol; {8-chloro-5-ethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazepine-5-yl} methanol; (5S) -8-fluoro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazine; (5R) -8-fluoro-5- (fluoromethyl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazine; 8-chloro-1- [4- (3-chlorophenyl) piperazin-1-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] Benzacene-5-carboxamide; 8-chloro-1- [4- (pyridin-2-yl) piperazin-1-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] Benzacene-5-carboxamide; 8-chloro-1- [4- (pyridin-2-yloxy) piperidin-1-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Benzacridin-5-carboxamide; 5-[(benzyloxy) methyl] -8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2 , 4] triazolo [4,3-a] [1] benzoazine; 8-chloro-1- (3,3-difluorocyclobutyl) -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] benzoazine呯 -5-carboxylic acid methyl ester; 8-chloro-1- [trans-4- (piperidin-1-ylmethyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3- a] [1] Methylbenzoazine-5-carboxylic acid; Acetic acid {8-chloro-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3 -a] [1] benzoazin-5-yl} methyl ester; 8-chloro-1- (1'H, 3H-spiro [2-benzofuran-1,4'-piperidine] -1'-yl) -5,6-dihydro-4H- [1,2, 4] triazolo [4,3-a] [1] benzoazine-5-carboxamide; 8-chloro-N- (pyridin-2-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazepine-5-carboxamide; 8-chloro-1- (1'H, 3H-spiro [2-benzofuran-1,4'-piperidine] -1'-yl) -5,6-dihydro-4H- [1,2, 4] triazolo [4,3-a] [1] benzoazine-5-carbonitrile; 8-chloro-1- [4- (2,3-dimethylphenyl) piperazin-1-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4, 3-a] [1] benzoazine-5-carbonitrile; 8-chloro-1- [4- (pyridin-2-yl) piperazin-1-yl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1] Benazine-5-carbonitrile; 8-fluoro-5,5-dimethyl-1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4] tris Zolo [4,3-a] [1] benzoazine; 8-fluoro-5- (prop-2-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazine; 8'-bromo-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -4'H, 6'H-spiro [cyclopentane-1,5'-[1,2 , 4] triazolo [4,3-a] [1] benzoazine]; 8-bromo-5- (prop-2-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1,2,4 ] Triazolo [4,3-a] [1] benzoazine; 8'-bromo-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -2,3,5,6-tetrahydro-4'H, 6'H-spiro [piperan -4,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine]; 8-fluoro-5,5-dimethyl-1- [trans-4- (trifluoromethyl) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [ 4,3-a] [1] benzoazine; (5R) -8-bromo-5- (prop-2-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1 , 2,4] triazolo [4,3-a] [1] benzoazine; (5S) -8-bromo-5- (prop-2-yl) -1- [trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H- [1 , 2,4] triazolo [4,3-a] [1] benzoazine; 8'-bromo-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -4,5-dihydro-4'H, 6'H-spiro [furan-3,5' -[1,2,4] triazolo [4,3-a] [1] benzoazine]; 8'-chloro-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -2,3,5,6-tetrahydro-4'H, 6'H-spiro [piperan -4,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine]; 8'-chloro-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H, 4'H, 6'H-spiro [piperan-3 , 5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine]; 8'-Chloro-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -4,5-dihydro-4'H, 6'H-spiro [furan-3,5' -[1,2,4] triazolo [4,3-a] [1] benzoazine]; 8'-chloro-1 '-[trans-4- (trifluoromethyl) cyclohexyl] -2,3,5,6-tetrahydro-4'H, 6'H-spiro [piperan-4, 5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine]; (3R) -8'-bromo-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -4,5-dihydro-4'H, 6'H-spiro [furan- 3,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine]; (3S) -8'-bromo-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -4,5-dihydro-4'H, 6'H-spiro [furan- 3,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine]; (3S) -8'-chloro-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H, 4'H, 6'H-spiro [ Piperan-3,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine]; (3R) -8'-chloro-1 '-[trans-4- (pyridin-2-yloxy) cyclohexyl] -5,6-dihydro-4H, 4'H, 6'H-spiro [ Piperan-3,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine]; 8-fluoro-1- (trans-4-methoxy-4-methylcyclohexyl) -5,5-dimethyl-5,6-dihydro-4H- [1,2,4] triazole Ac [4,3-a] [1] benzoazine; 8-fluoro-1- (cis-4-methoxy-4-methylcyclohexyl) -5,5-dimethyl-5,6-dihydro-4H- [1,2,4] triazole Ac [4,3-a] [1] benzoazine; 8'-Chloro-1 '-(trans-4-methoxy-4-methylcyclohexyl) -2,3,5,6-tetrahydro-4'H, 6'H-spiro [piperan- 4,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine]; 8'-Chloro-1 '-(cis-4-methoxy-4-methylcyclohexyl) -2,3,5,6-tetrahydro-4'H, 6'H-spiro [piperan- 4,5 '-[1,2,4] triazolo [4,3-a] [1] benzoazine]; and 8-chloro-1- [trans-4- (pyridin-2-ylamino) cyclohexyl] -5,6-dihydro-4H- [1,2,4] triazolo [4,3-a ] [1] Methyl benzoazine-5-carboxylic acid. A pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (I) as claimed in claim 1 and / or their salts and / or their geometric isomers and / or their stereoisomers and / Or their mirror image isomers and / or their racemates and / or their non-image mirror isomers and / or their bioactive metabolites and / or their prodrugs and / or their Etc. solvates and / or their hydrates and / or their polymorphs serve as active substances and pharmaceutically acceptable excipients. A combination composition comprising a therapeutically effective amount of a compound of general formula (I) as claimed in claim 1 and / or their salts and / or their geometric isomers and / or their stereoisomers and / Or their mirror image isomers and / or their racemates and / or their non-image mirror isomers and / or their bioactive metabolites and / or their prodrugs and / or their Etc. solvates and / or their hydrates and / or their polymorphs and one or more other active substances. The composition of claim 41, wherein the one or more other active substances are selected from the group consisting of a psychoblocker, a psychostimulant, an antihypertensive agent, an antispasmodic agent, an antiepileptic drug or other agents. A composition according to any one of claims 40 to 42, for use in the treatment and / or prevention of diseases or conditions associated with central and / or peripheral antagonistic effects of the V1a receptor. A method for preparing a medicinal composition having V1a receptor antagonist activity, the medicinal composition comprising a therapeutically effective amount of a compound of the general formula (I) according to any one of claims 1 to 39 and / or their salts, and / Or their geometric isomers and / or their stereoisomers and / or their mirror isomers and / or their racemates and / or their non-mirro isomers and / Or their biologically active metabolites and / or their prodrugs and / or their solvates and / or their hydrates and / or their polymorphs as active substances and pharmaceutically acceptable excipient. Compounds of general formula (I) as claimed in claim 1, and / or their salts and / or their geometric isomers and / or their stereoisomers and / or their mirror isomers and / Or their racemates and / or their non-image isomers and / or their biologically active metabolites and / or their prodrugs and / or their solvates and / or their Hydrates and / or their polymorphs are used to treat and / or prevent diseases or conditions associated with central and / or peripheral antagonistic effects of the V1a receptor. The compound according to claim 45, wherein the disease or condition related to the central and / or peripheral antagonist of the Via receptor is selected from a variety of pathological symptoms of female sex organs, persistent symptoms of blood pressure control, and Symptoms caused by proper secretion, anxiety, depression, aggressive behavior, central nervous system disease (wherein one of the symptoms of the disease and / or multiple symptoms may be related to anxiety, depression or aggressive behavior or show a combination of the aforementioned three diseases Disease (autism group disorder, obsessive-compulsive disorder, many different types of Down's syndrome and post-traumatic stress disorder)), aggressive behavior disorder and / or irritability, hyperactivity disorder, cognitive impairment or other neuropsychiatric disorders. A compound of general formula (I) as claimed in claim 1 and / or their salts and / or their geometric isomers and / or their stereoisomers and / or their mirror isomers and / Or their racemates and / or their non-image isomers and / or their biologically active metabolites and / or their prodrugs and / or their solvates and / or their Hydrates and / or their polymorphs for use in the manufacture of a medicament for the treatment and / or prevention of diseases or conditions associated with central and / or peripheral antagonistic effects of the Via receptor. The use according to claim 47, wherein the disease or condition related to the central and / or peripheral antagonistic action of the V1a receptor is selected from a variety of pathological symptoms of female sex organs, persistent symptoms of blood pressure control, and Symptoms caused by proper secretion, anxiety, depression, aggressive behavior, central nervous system disease (wherein one of the symptoms of the disease and / or multiple symptoms may be related to anxiety, depression or aggressive behavior or show a combination of the aforementioned three diseases Disease (autism group disorder, obsessive-compulsive disorder, many different types of Down's syndrome and post-traumatic stress disorder)), aggressive behavior disorder and / or irritability, hyperactivity disorder, cognitive impairment or other neuropsychiatric disorders. A compound of formula (III-a), Wherein R ¹ is chlorine, bromine, fluorine, methyl or methoxy. A compound of formula (X), Wherein R ¹ is chlorine, bromine, fluorine, methyl or methoxy. A compound of formula (XLII), which is 1-bromo-8-chloro-5,6-dihydro-4 H- [1,2,4] triazolo [4,3- a ] [1] benzoazine甲酯 -5-carboxylic acid methyl ester . A compound of formula (LI), Wherein R ¹ is as defined by the general formula (I), R ² and R ³ together form-(CH ₂ ) _p -O- (CH ₂ ) _q - _or- (CH ₂ ) _r- . A compound of formula (LIV), Wherein R ¹ is chlorine, fluorine or methyl.