Benzothiazole and benzisoxazole compounds for the treatment of psychiatric disorders - Patents.com

Abstract

The present invention relates to substituted heterocyclic compounds represented by the general formula (I) or their isotopic forms, stereoisomers or pharma- ceutically acceptable salts thereof. The present invention also describes methods for preparing such compounds, pharmaceutical compositions containing such compounds, and their use in the treatment of central nervous system disorders.

Description

[Technical field]

[0001] The present invention relates to substituted heterocyclic compounds represented by the general formula (I) or their isotopic forms, stereoisomers or pharma- ceutically acceptable salts thereof. The present invention also describes methods for making such compounds, pharmaceutical compositions containing such compounds, and their use in the treatment of central nervous system diseases or disorders. [Background technology]

[0002] Despite the number of different antipsychotic drugs on the market, psychiatric disorders such as schizophrenia and psychosis remain complex and difficult to treat. In clinical practice, the heterogeneity of individual patient responses, both in terms of efficacy and tolerability of different drugs, is sometimes surprising. This leads to the practice of switching from one drug to another to find the best fit and maximize adherence.

[0003] First-generation typical antipsychotics such as haloperidol (an antagonist of dopamine D2 receptors in the striatum) are very useful in controlling positive symptoms, but lack a consistent response to long-term efficacy on negative symptoms and cognitive impairment, and cause extrapyramidal side effects (EPS) that almost nullify treatment outcomes. Second-generation atypical antipsychotics, primarily clozapine, have provided a wide range of treatment outcomes by being effective on both positive and negative symptoms and by being less likely to cause extrapyramidal side effects. These new drugs appear to pose a risk of metabolic syndrome, including diabetes, weight gain, and hyperlipidemia.

[0004] Atypical antipsychotics such as iloperidone, ziprasidone, risperidone and paliperidone have antipsychotic efficacy and a lower risk of EPS than typical antipsychotics, but these drugs appear to be associated with variable degrees of metabolic adverse effects such as weight gain, impaired glucose metabolism, dyslipidemia, and in some cases more severe morbidity such as cardiovascular disease (Molecular Psychiatry (2008) 13, 27-35; J Clin Psychopharmacol. 2008 April;28(2 Suppl 1):S20-8).

[0005] WO2020156312 is a compound that inhibits D3 receptor agonist activity and 5-HT 2A Compounds having receptor inhibitory activity are disclosed.

[0006] WO2003074518 discloses D2 and 5-HT 1A Receptor ligands, especially D2 and 5-HT 1A The thiazole derivatives of formula (I) are disclosed as agonists of the receptor.

[0007] US6242448B1 is 5HT 1A Disclosed are 4-(arylpiperazin-1-yl)oxazole derivatives that are receptor subtype agonists and antagonists.

[0008] No. 5,958,923 discloses thiazole and thiadiazole compounds which are selective ligands for the dopamine D3 receptor and have low affinity for the D2 receptor.

[0009] US6090807 discloses heterocyclic compounds which are selective ligands for the dopamine D3 receptor and have low affinity for the D2 receptor.

[0010] WO2007026959 describes a compound that inhibits partial agonist activity of dopamine D2 receptors, serotonin 5-HT 2A The present invention discloses novel compounds which have receptor antagonist activity and adrenergic α1 receptor antagonist activity, and further have serotonin uptake inhibitory activity.

[0011] WO2012130183 is a method for the treatment of dopamine D2, D3, 5-HT 1A and 5-HT 2A Disclosed are [1,3,4]oxadiazole derivatives with high affinity to receptors for the treatment of psychoneurotic disorders.

[0012] JPH07258252 discloses thiazole compounds having binding affinity to dopamine D2 receptors, serotonin 5-HT2 receptors and adrenergic α1 receptors.

[0013] EP0512755A2 binds to 5-HT receptors to a much greater extent than it binds to α1 and D2 receptors. 1A The present invention discloses compounds that selectively bind to the 5-HT 1A It may exhibit receptor antagonist activity.

[0014] WO2004041793 relates to a method for detecting dopamine D2 receptors and serotonin 5-HT 2A Phenylalkyl and pyridylalkyl piperazine derivatives having activity as receptor antagonists are disclosed.

[0015] WO2002066469 discloses novel heterocyclic amide derivatives as dopamine D3 receptor modulators for the treatment of central nervous system disorders.

[0016] WO2001017993 discloses alkylpiperidinylbenzo[d]isoxazole derivatives which act on the central nervous system and mainly have psychotropic activity.

[0017] WO94 / 27996A1 discloses 1,2,5-thiazole derivatives which have high affinity for 5-HT2, dopamine D1 and D2 receptors or combinations thereof and are useful for treating CNS, cardiovascular and / or gastrointestinal disorders.

[0018] WO 97 / 47302 discloses tetrahydropiperidinylindoles and piperidinylindoles and benzothiazoles for the inhibition of serotonin reuptake in mammals.

[0019] WO97 / 40038 describes 5-HT 1A The present invention discloses piperidine and pyrrolidine derivatives which act as receptor antagonists and exhibit 5-HT reuptake inhibitory activity.

[0020] Xu et al. describe pyridine carboxamide compounds as potent multi-receptor antipsychotics. These compounds inhibit dopamine D2, serotonin 5-HT 1A and 5-HT 2A It has good activity at the α receptor and 1A , H1 and 5-HT 2C It showed low efficacy against the receptor (Bioorganic & Medicinal Chemistry Letters 28(2018)606~611). [Prior art documents] [Patent documents]

[0021] [Patent Document 1] WO2020156312 [Patent Document 2] WO2003074518 [Patent Document 3] US6242448B1 [Patent Document 4] US5958923 [Patent Document 5] US6090807 [Patent Document 6] WO2007026959 [Patent Document 7] WO2012130183 [Patent Document 8] JPH07258252 [Patent Document 9] EP0512755A2 [Patent Document 10] WO2004041793 [Patent Document 11] WO2002066469 [Patent Document 12] WO2001017993 [Patent Document 13] WO94 / 27996A1 [Patent Document 14] WO97 / 47302 [Patent Document 15] WO97 / 40038 [Non-patent literature]

[0022] [Non-Patent Document 1] Molecular Psychiatry(2008)13, 27~35; J Clin Psychopharmacol.April 2008;28(2 Suppl 1):S20-8 [Non-Patent Document 2] Bioorganic & Medicinal Chemistry Letters 28(2018)606~611 [Non-Patent Document 3] Aust NZJ Psychiatry 50(5)410~472 Summary of the Invention [Problem to be solved by the invention]

[0023] The prior art discloses typical and atypical antipsychotics acting on single or multiple targets, which are associated with side effects such as EPS, dyslipidemia, weight gain, diabetes and QT interval prolongation, and have no or limited effect on negative symptoms and cognitive impairment. In addition, high levels of non-adherence are observed in patients, mainly due to side effects such as movement disorders, metabolic side effects and cardiometabolic side effects. Poor symptom recovery and relapse were associated with poor treatment response (Aust NZJ Psychiatry 50(5)410-472). Thus, there is a need for the development of new antipsychotics with reduced side effects and improved tolerability and safety compared to known typical and atypical antipsychotics. [Means for solving the problem]

[0024] The present invention relates to 5-HT 1A The partial agonist activity of dopamine D2 and serotonin 5-HT receptor agonism can improve the negative symptoms and cognitive impairment of patients, and indirectly improve the positive symptoms and reduce EPS. 2A In addition to its receptor antagonist activity, 5-HT 1A Compounds that target receptor agonism are disclosed.

[0025] In a first aspect, the present invention provides a compound of formula (I)

[0026] [ka]

[0027] (In the formula, A is O or S; R is N or CH; Y is -CH2-, -O-, NH or -N(C 1~4 alkyl)-; n is an integer from 0 to 2, R1 is

[0028] [ka]

[0029] is selected from R 2a , R 2b , R 2c , R 2d and R 2e teeth

[0030] [ka]

[0031] are each independently selected from

[0032] [ka]

[0033] represents the attachment point, R3, at each occurrence, is hydrogen, -(C 1~4 ) alkyl or -(C 3~6 ) cycloalkyl; R4 is hydrogen, halogen, -(C 1~4 ) alkyl, -(C 3~6 ) cycloalkyl or hydroxy-(C 1~4 ) alkyl) or an isotopic form, stereoisomer or pharma- ceutically acceptable salt thereof.

[0034] In another aspect, the present invention relates to a process for the preparation of a compound of formula (I) or an isotopic form, stereoisomer or pharma- ceutically acceptable salt thereof.

[0035] In another aspect, the present invention relates to a method for treating a disease or disorder selected from schizophrenia, psychosis, bipolar disorder, mood disorder, depression, anxiety, sleep disorder, sexual disorder, withdrawal symptoms of drug addiction, attention deficit hyperactivity disorder, neuropsychiatric disorders associated with Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia and vascular dementia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or an isotopic form, stereoisomer or pharma- ceutically acceptable salt thereof.

[0036] In another aspect, the present invention relates to a compound of formula (I) or an isotopic form, stereoisomer or a pharma- ceutically acceptable salt thereof for use in the treatment of a disease or disorder selected from schizophrenia, psychosis, bipolar disorder, mood disorder, depression, anxiety, sleep disorder, sexual disorder, withdrawal symptoms of drug dependency, attention deficit hyperactivity disorder, neuropsychiatric disorders associated with Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia and vascular dementia.

[0037] In another aspect, the present invention relates to the use of a compound of formula (I) or an isotopic form, stereoisomer or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease or disorder selected from schizophrenia, psychosis, bipolar disorder, mood disorder, depression, anxiety, sleep disorder, sexual disorder, withdrawal symptoms of drug dependence, attention deficit hyperactivity disorder, neuropsychiatric disorders associated with Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia and vascular dementia.

[0038] In another aspect, the present invention relates to a compound of formula (I) or an isotopic form, stereoisomer or pharma- ceutically acceptable salt thereof for use as a partial agonist of the dopamine D2 receptor, an antagonist of the 5-hydroxytryptamine 2A receptor and a partial agonist of the 5-hydroxytryptamine 1A receptor.

[0039] In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one of a compound of formula (I) or an isotopic form, stereoisomer, or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient or carrier. [Brief description of the drawings]

[0040] [Figure 1] FIG. 1 shows the effect of Example 2 on amphetamine-induced hyperlocomotion. [Diagram 2] FIG. 1 shows the effect of Example 2 in a rotarod assay. [Diagram 3] FIG. 1 shows the effect of Example 2 on 3-PPP and reserpine-induced DOPA levels in the striatum. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] Unless otherwise stated, the following terms used in the specification and claims have the meanings indicated:

[0042] As used herein, "-(C 1~4 The term "alkyl" refers to a branched or straight chain aliphatic hydrocarbon containing 1 to 4 carbon atoms. 1~4 ) Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0043] As used herein, "-(C 3~6 The term "cycloalkyl" refers to a saturated monocyclic hydrocarbon ring containing 3 to 6 carbon atoms. 3~6 ) Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0044] As used herein, “hydroxy-(C 1~4 The term "alkyl" refers to -(C)alkyl, as defined above, in which one or more hydrogen atoms of the same or different carbon atoms are replaced by a hydroxy group.1-4 ) alkyl. Hydroxy-(C 1~4 ) Examples of alkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl.

[0045] As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine. Preferably, the halogen is fluorine, chlorine or bromine.

[0046] As used herein, the term "isotopic forms" refers to compounds of formula (I) in which one or more atoms of the compound of formula (I) have been replaced by their respective isotopes. For example, isotopes of hydrogen include: 2 H (deuterium) and 3 H (tritium).

[0047] The term "stereoisomer" as used herein refers to an isomer of a compound of formula (I) that differs in the arrangement of their atoms in space. The compounds disclosed herein may exist as single stereoisomers, racemates, and / or mixtures of enantiomers and / or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the scope of the present invention.

[0048] The term "neuropsychiatric disorders" refers to a heterogeneous group of non-cognitive symptoms and behaviors occurring in patients with Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, and vascular dementia. Neuropsychiatric disorders include areas such as agitation / aggression, delusions and / or hallucinations, abnormal motor behavior, abnormal vocalizations, anxiety, elation / euphoria, irritability, depression / dysphoria, blunted affect, disinhibition, changes in sleep and nocturnal behavior, or appetite and feeding.

[0049] As used herein, the expression "pharmaceutically acceptable salts" refers to salts of active compounds, i.e., compounds of formula (I), which are prepared by reaction with a suitable acid or acid derivative, depending on the particular substituents found in the compounds described herein.

[0050] The term "therapeutically effective amount" is defined as an amount of a compound of the present invention that (i) treats a particular disease, condition or disorder, (ii) eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition or disorder described herein.

[0051] As used herein, the term "patient" refers to an animal. Preferably, the term "patient" refers to a mammal. The term mammal includes animals such as mice, rats, dogs, rabbits, pigs, monkeys, horses, pigeons, Xenopus laevis, zebrafish, guinea pigs, and humans. More preferably, the patient is a human.

[0052] Embodiment Although the present invention encompasses all compounds described by compounds of formula (I) without any limitation, preferred aspects and elements of the present invention are discussed herein in the form of the following embodiments.

[0053] In one embodiment, the present invention provides a compound of formula (Ia)

[0054] [ka]

[0055] (In the formula, n is an integer from 0 to 2, R1 is

[0056] [ka]

[0057] is selected from R 2a , R 2b , R 2c , R 2d and R 2e teeth

[0058] [ka]

[0059] are each independently selected from

[0060] [ka]

[0061] represents the attachment point, R3, for each occurrence, is hydrogen, -(C 1~4 ) alkyl or -(C 3~6 )cycloalkyl) or an isotopic form, stereoisomer or pharma- ceutically acceptable salt thereof.

[0062] In another embodiment, the present invention relates to a compound of formula (Ib)

[0063] [ka]

[0064] (In the formula, n is an integer from 0 to 2, R1 is

[0065] [ka]

[0066] is selected from R 2a , R 2b , R 2c , R 2d and R 2e teeth

[0067] [ka]

[0068] are each independently selected from

[0069] [ka]

[0070] represents the attachment point, R3, for each occurrence, is hydrogen, -(C 1~4 ) alkyl or -(C 3~6 )cycloalkyl) or an isotopic form, stereoisomer or pharma- ceutically acceptable salt thereof.

[0071] In some embodiments of the compound of Formula (1b), R1 is

[0072] [ka]

[0073] is selected from R 2a , R 2b , R 2c and R 2d teeth

[0074] [ka]

[0075] are each independently selected from R3 at each occurrence is hydrogen or -(C 1~4 ) alkyl.

[0076] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 3-(4-{3-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-(4-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-ethyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-(4-{3-[4-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-(4-{3-[5-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-(4-{3-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-(4-{3-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-{4-[3-(4-oxazol-5-yl-thiazol-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole; 3-(4-{3-[6-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyridin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-(4-{3-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyridin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-(4-{3-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyrazin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-{4-[3-(5-oxazol-5-yl-pyridin-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole; 6-Fluoro-3-(1-{3-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperidin-4-yl)-benzo[d]isoxazole; 6-Fluoro-3-(1-{3-[5-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperidin-4-yl)-benzo[d]isoxazole; 6-Fluoro-3-(1-{3-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-thiazol-2-yloxy]-propyl}-piperidin-4-yl)-benzo[d]isoxazole; 6-Fluoro-3-(1-{3-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-thiazol-2-yloxy]-propyl}-piperidin-4-yl)-benzo[d]isoxazole; 6-Fluoro-3-{1-[3-(4-oxazol-5-yl-thiazol-2-yloxy)-propyl]-piperidin-4-yl}-benzo[d]isoxazole; 6-Fluoro-3-{1-[3-(5-oxazol-5-yl-pyridin-2-yloxy)-propyl]-piperidin-4-yl}-benzo[d]isoxazole; 3-(4-{3-[6-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-(4-{3-[6-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyridin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-{4-[3-(4-[1,2,4]oxadiazol-3-yl-thiazol-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole; and 3-{4-[3-(6-[1,2,4]oxadiazol-3-yl-pyridin-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole is selected from the group consisting of:

[0077] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 3-(4-{3-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate 3-(4-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-ethyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-(4-{3-[4-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-(4-{3-[5-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-(4-{3-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-(4-{3-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-{4-[3-(4-oxazol-5-yl-thiazol-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole oxalate; 3-(4-{3-[6-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyridin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-(4-{3-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyridin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-(4-{3-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyrazin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-{4-[3-(5-oxazol-5-yl-pyridin-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole oxalate; 6-Fluoro-3-(1-{3-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperidin-4-yl)-benzo[d]isoxazole oxalate; 6-Fluoro-3-(1-{3-[5-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperidin-4-yl)-benzo[d]isoxazole oxalate; 6-Fluoro-3-(1-{3-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-thiazol-2-yloxy]-propyl}-piperidin-4-yl)-benzo[d]isoxazole oxalate; 6-Fluoro-3-(1-{3-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-thiazol-2-yloxy]-propyl}-piperidin-4-yl)-benzo[d]isoxazole oxalate; 6-Fluoro-3-{1-[3-(4-oxazol-5-yl-thiazol-2-yloxy)-propyl]-piperidin-4-yl}-benzo[d]isoxazole oxalate; 6-Fluoro-3-{1-[3-(5-oxazol-5-yl-pyridin-2-yloxy)-propyl]-piperidin-4-yl}-benzo[d]isoxazole oxalate; 3-(4-{3-[6-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-(4-{3-[6-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyridin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-{4-[3-(4-[1,2,4]oxadiazol-3-yl-thiazol-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole oxalate; and 3-{4-[3-(6-[1,2,4]oxadiazol-3-yl-pyridin-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole oxalate is selected from the group consisting of:

[0078] In another embodiment, the present invention relates to a process for the preparation of the compounds of formula (I) described herein.

[0079] Experimental procedure Scheme 1 shows a general method for the preparation of compounds of formula (I) where X is halogen, Y is O, and A, R, R1, R4 and n are as defined in the first aspect.

[0080] [ka]

[0081] Step 1: Preparation of Compound of Formula (2) The compound of formula (2) was prepared by reacting the compound of formula (1) with the compound of formula (a) in the presence of a solvent selected from acetonitrile, THF or DMF using a base such as K2CO3, CS2CO3 or Na2CO3 at a temperature ranging from RT to 80°C for 2 to 16 hours, preferably 6 hours.

[0082] Step 2: Preparation of Compounds of Formula (I) The compound of formula (I) was prepared by reacting the compound of formula (2) with the compound of formula (3) in a solvent selected from THF, DMF, DMSO, diethyl ether or 1,4-dioxane using a base such as sodium hydroxide, potassium hydroxide, potassium tert-butoxide or sodium tert-butoxide at a temperature ranging from 0° C. to reflux temperature for 2 to 16 hours, preferably 6 hours.

[0083] Scheme 2 shows a general method for the preparation of compounds of formula (I) where X is halogen, Y is O, and A, R, R1, R4 and n are as defined in the first aspect.

[0084] [ka]

[0085] Step 1: Preparation of a compound of formula (4) Compounds of formula (4) were obtained by reacting compound of formula (1) with compound of formula (b) in the presence of a base such as K2CO3, CS2CO3, Na2CO3, KOH or NaOH and a solvent selected from THF, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, acetonitrile, HO or a combination of one or two of the above solvents at a temperature ranging from RT to 90°C, preferably at RT, for 2 to 16 hours.

[0086] Step 2: Preparation of Compounds of Formula (I) The compound of formula (I) was obtained by reacting the compound of formula (4) with the compound of formula (5) in a solvent selected from THF, DMF, DMSO, diethyl ether or 1,4-dioxane using a base such as sodium hydroxide, potassium hydroxide or sodium tert-butoxide at a temperature ranging from 0° C. to reflux temperature for 2 to 16 hours, preferably 6 hours.

[0087] Scheme 3 shows a general method for the preparation of compounds of formula (I) wherein the hydrogen atom of R1 is replaced by [1,2,4]oxadiazole, Y is O, and A, R, R1, R4 and n are as defined in the first aspect.

[0088] [ka]

[0089] Step 1: Preparation of compound of formula (7) Compounds of formula (7) were obtained by reacting compound of formula (2) with compound of formula (6) using a base such as K2CO3, CS2CO3, Na2CO3, KOH or NaOH and a solvent selected from THF, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, acetonitrile, HO or a combination of one or two of the above solvents at a temperature ranging from RT to 90°C, preferably at RT, for 2 to 16 hours, preferably 6 hours.

[0090] Step 2: Preparation of compound of formula (8) The compound of formula (8) was obtained by reacting the compound of formula (7) with hydroxylamine hydrochloride using a base such as K2CO3 or CS2CO3 in a solvent selected from ethanol, methanol or isopropanol at a temperature ranging from RT to 85°C for 2 to 12 hours, preferably 4 hours.

[0091] Step 3: Preparation of Compounds of Formula (I) Compounds of formula (I) in which the hydrogen atom of R1 is replaced by [1,2,4]-oxadiazole were obtained by reacting compound of formula (8) with triethyl orthoformate using a base such as K2CO3 or CS2CO3 in a solvent such as methanol, ethanol or isopropanol at a temperature ranging from RT to 85°C for 2 to 12 hours, preferably 4 hours.

[0092] Preparation of Pharmacologically Acceptable Salts of Compounds of Formula (I) The compound of formula (I) can be optionally converted into its pharma- ceutically acceptable salt by reaction with a suitable acid or acid derivative.Suitable pharma- ceutically acceptable salts will be apparent to those skilled in the art.Salts are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or organic acids, such as oxalic acid, succinic acid, maleic acid, acetic acid, citric acid, malic acid, tartaric acid, benzoic acid, p-toluic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid or naphthalenesulfonic acid.

[0093] Preparation of stereoisomers of compounds of formula (I) Stereoisomers of compounds of formula (I) may be prepared by one or more conventional methods as set out below: a. One or more of the reagents may be used in its optically active form. b. An optically pure catalyst or chiral ligand along with a metal catalyst may be used in the reduction process. The metal catalyst may be rhodium, ruthenium, indium, etc. The chiral ligand may preferably be a chiral phosphine. c. The mixture of stereoisomers may be resolved by conventional methods such as forming diastereomeric salts with chiral acids, chiral amines, chiral amino alcohols, or chiral amino acids. The resulting mixture of diastereomers may then be separated by methods such as fractional recrystallization, chromatography, and the like, followed by an additional step of isolating the optically active products from the resolved material salts. d. Mixtures of stereoisomers may be resolved by conventional methods such as microbial resolution, which resolves diastereomeric salts formed with chiral acids or chiral bases. Chiral acids that can be used may be tartaric acid, mandelic acid, lactic acid, camphorsulfonic acid, amino acids, etc. Chiral bases that can be used may be cinchona alkaloids, brucine or basic amino acids such as lysine, arginine, etc.

[0094] In another embodiment, suitable pharma- ceutically acceptable salts of the compounds of formula (I) include, but are not limited to, hydrochloride, hydrobromide, oxalate, tartrate, maleate, and succinate salts.

[0095] In another embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I) or an isotopic form, stereoisomer or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient or carrier. For use in therapy, the compounds of formula (I) or their stereoisomers and pharma- ceutically acceptable salts thereof are typically formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice.

[0096] The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharma- ceutically acceptable excipients, such as diluents, disintegrants, binders, lubricants, glidants, polymers, coating agents, solvents, cosolvents, preservatives, wetting agents, thickeners, antifoaming agents, sweeteners, flavoring agents, antioxidants, colorants, solubilizers, plasticizers, dispersants, and the like. The excipients are selected from microcrystalline cellulose, mannitol, lactose, pregelatinized starch, sodium starch glycolate, corn starch or derivatives thereof, povidone, crospovidone, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, talc, colloidal silicon dioxide, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oils, gum arabic, magnesia, glucose, fats, waxes, natural or hardened oils, water, physiological sodium chloride solution, alcohols such as ethanol, propanol or glycerol, sugar solutions such as glucose or mannitol solutions, etc., or mixtures of different excipients.

[0097] In another embodiment, the compounds of the present invention may be formulated into the form of pills, tablets, coated tablets, capsules, powders, granules, pellets, patches, implants, films, liquids, semisolids, gels, aerosols, emulsions, elixirs, etc. Such pharmaceutical compositions and methods for preparing the same are well known in the art.

[0098] In another embodiment, the pharmaceutical composition of the present invention contains 1-90% by weight, 5-75% by weight, or 10-60% by weight of the compound of the present invention or a pharma- ceutically acceptable salt thereof. The amount of the compound or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition can range from about 1 mg to about 500 mg, about 5 mg to about 400 mg, about 5 mg to about 250 mg, about 7 mg to about 150 mg, or any range within a broader range of 1 mg to 500 mg.

[0099] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or an isotopic form, stereoisomer or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient for use in the treatment of a disease or disorder selected from schizophrenia, psychosis, bipolar disorder, mood disorder, depression, anxiety, sleep disorder, sexual disorder, withdrawal symptoms of drug addiction, attention deficit hyperactivity disorder, neuropsychiatric disorders associated with Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia and vascular dementia.

[0100] In another embodiment, the present invention relates to a method for treating a disease or disorder selected from schizophrenia, psychosis, bipolar disorder, mood disorder, depression, anxiety, sleep disorder, sexual disorder, withdrawal symptoms of drug addiction, attention deficit hyperactivity disorder, neuropsychiatric disorders associated with Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia and vascular dementia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or an isotopic form, stereoisomer or pharma- ceutically acceptable salt thereof.

[0101] In another embodiment, the present invention relates to a compound of formula (I) or an isotopic form, stereoisomer or a pharma- ceutically acceptable salt thereof for use in the treatment of a disease or disorder selected from schizophrenia, psychosis, bipolar disorder, mood disorder, depression, anxiety, sleep disorder, sexual disorder, withdrawal symptoms of drug addiction, attention deficit hyperactivity disorder, neuropsychiatric disorders associated with Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia and vascular dementia.

[0102] In another embodiment, the present invention relates to the use of a compound of formula (I) or an isotopic form, stereoisomer or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease or disorder selected from schizophrenia, psychosis, bipolar disorder, mood disorder, depression, anxiety, sleep disorder, sexual disorder, withdrawal symptoms of drug addiction, attention deficit hyperactivity disorder, neuropsychiatric disorders associated with Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia and vascular dementia.

[0103] The dosage of the active compounds of the present invention may vary depending on factors such as the age and weight of the patient, the nature and severity of the disease to be treated, and other such factors. Therefore, any reference to a therapeutically effective amount of a compound of formula (I), or its isotopes, stereoisomers, and pharma- ceutically acceptable salts, refers to the factors mentioned above.

[0104] The following abbreviations are used herein: 5-HT 1A :5-hydroxytryptamine 1A receptor 5-HT 2A :5-hydroxytryptamine 2A receptor AUC: Area under the curve C max :Maximum concentration CaCl2: Calcium chloride CDCl3: Deuterated chloroform CHCl3: Chloroform DOPA: Dihydroxyphenylalanine DCM: dichloromethane DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide EC 50 : Half maximum effective concentration EDTA: Ethylenediaminetetraacetic acid EtOAc: ethyl acetate EtOH: Ethanol g: grams h: time H2O: Water ip: intraperitoneal K2CO3: Potassium carbonate KCl: Potassium chloride KOH: Potassium hydroxide LC-MS / MS: Liquid chromatography-mass spectrometry / mass spectrometry mL: milliliter mmol: millimolar min:minutes MeOH: Methanol MgSO4: Magnesium sulfate NaH: Sodium hydroxide NaCl: Sodium chloride NaHCO3: Sodium bicarbonate Na2SO4: Sodium sulfate NH4OH: Ammonium hydroxide po: oral POCl3: Phosphoryl chloride RT: Room temperature (25℃~30℃) SERT: Serotonin reuptake transporter THF: tetrahydrofuran TosMIC: Toluenesulfonylmethyl isocyanide t 1 / 2 :Half-life EXAMPLES

[0105] The compounds of the present invention were prepared according to the following experimental procedures using appropriate materials and conditions. The following examples are provided by way of illustration only and are not intended to limit the scope of the present invention.

[0106] Preparation of intermediates Intermediate 1a: 3-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-propan-1-ol To a stirred solution of 3-piperazin-1-yl-benzo[d]isothiazole (10 g, 45.6 mmol), K2CO3 (18.9 g, 137 mmol) and acetonitrile (100 mL) was added 1-bromo-3-propanol (19 g, 137 mmol) at RT. The reaction mixture was heated at 70-80 °C for 6 h. It was cooled to RT and poured into water and kept under stirring for 30 min during which time a solid precipitated. The solid was filtered, washed with n-hexane and dried under vacuum to give intermediate 1a. Yield 10.13 g; 1 H NMR (400 MHz, DMSO-d6): δ 1.59-1.66 (m, 2H), 2.41-2.42 (m, 2H), 2.50-2.59 (m, 4H), 3.40-3.48 (m, 6H), 4.45 (bs, 1H), 7.41-7.45 (dd, J = 7.6 Hz, 1H), 7.53-7.57 (dd, J = 7.2 Hz, 1H), 8.03-8.06 (m, 2H); Mass (m / z): 278.1 (M+H) + .

[0107] Intermediate 1b: 2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethanol Intermediate 1b was prepared by reacting 3-piperazin-1-yl-benzo[d]isothiazole with 2-bromo-ethanol following the same procedure as in the preparation of intermediate 1a with some minor variations. Yield 9.04g; 1 H NMR (400 MHz, DMSO-d6): δ 2.67-2.69 (m, 4H), 2.72-2.76 (m, 2H), 3.43-3.45 (m, 4H), 3.72-3.75 (m, 2H) 4.48 (bs, 1H), 7.15-7.45 (dd, Mass (m / z): 264.3 (M+H) + .

[0108] Intermediate 1c: 3-[4-(3-chloro-propyl)-piperazin-1-yl]-benzo[d]isothiazole To a stirred suspension of 3-piperazin-1-yl-benzo[d]isothiazole (10 g, 45.6 mmol), KOH (7.6 g, 137 mmol) and THF:water (1:1, 100 mL) was added 1-bromo-3-chloropropane (19.6 g, 137 mmol) at RT and stirred at RT for 16 h. The resulting mixture was extracted with EtOAc (200 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the solvent was evaporated in vacuum. The resulting residue was purified by column chromatography (silica gel, 15% EtOAc / petroleum ether) to give intermediate 1c. Yield 9.68 g; 1 H NMR (400 MHz, DMSO-d6): δ 1.91-1.94 (m, 2H), 2.48-2.50 (m, 2H), 2.58-2.60 (m, 4H), 3.43-3.45 (m, 4H), 3.68-3.72 (m, 2H), 7.41-7.45 (dd, J = 7.6 Hz, 1H), 7.53-7.57 (dd, J = 7.2 Hz, 1H), 8.03-8.06 (m, 2H); Mass (m / z): 296.2 (M+H) + .

[0109] Intermediate 1d: 3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-propan-1-ol Intermediate 1d was prepared from 6-fluoro-3-piperidin-4-yl-benzo[d]isoxazole following the same procedure as in the preparation of intermediate 1a with some minor variations; yield 8.24 g; 1H NMR (400 MHz, DMSO-d6): δ 1.78-1.83 (m, 2H), 2.00-2.03 (m, 2H), 2.21-2.27 (m, 2H), 2.68-2.71 (m, 1H), 2.98-3.01 (m, 2H), 3.11-3.17 (m, 2H), 3.69-3.73 (m, 2H), 4.53-4.62 (m, 2H), 4.48 (bs, 1H), 7.21-7.26 (m, 1H), 7.45-7.47 (m, 1H), 7.79 (s, 1H); Mass (m / z): 279.2 (M+H) + .

[0110] Intermediate 1e: 3-[1-(3-chloro-propyl)-piperidin-4-yl]-6-fluoro-benzo[d]isoxazole Intermediate 1e was prepared from 6-fluoro-3-piperidin-4-yl-benzo[d]isoxazole following the same procedure as in the preparation of intermediate 1c with some minor variations; yield 7.9 g; 1 H NMR (400 MHz, DMSO-d6): δ 1.78-1.83 (m, 2H), 2.00-2.03 (m, 2H), 2.21-2.27 (m, 2H), 2.68-2.71 (m, 1H), 2.98-3.01 (m, 2H), 3.11-3.17 (m, 2H), 3.69-3.73 (m, 2H), 4.53-4.62 (m, 2H), 7.21-7.26 (m, 1H), 7.45-7.47 (m, 1H), 7.79 (s, 1H); Mass (m / z): 297.2, 299.2 (M+H) + .

[0111] Intermediate 2a: 3-(2-bromo-thiazol-4-yl)-5-methyl-[1,2,4]-oxadiazole Step a: Sulfuric acid (14.27 g, 145.6 mmol) was added slowly to a stirred mixture of 2-bromo-thiazole-4-carboxylic acid (10.0 g, 48.5 mmol) and methanol (100 mL) at about 0° C. and further stirred at reflux temperature for 6 h. The reaction mixture was cooled to RT, poured into water and maintained under stirring for 30 min during which a solid precipitated. The solid was filtered, washed with water and dried under vacuum to give methyl 2-bromo-thiazole-4-carboxylate. Yield 6.98 g; 1 H NMR (400 MHz, DMSO-d6): δ 3.89 (s, 3H), 8.55 (s, 1H); Mass (m / z): 223.1, 225.1 (M+H) + .

[0112] Step b: To a stirred mixture of methyl 2-bromo-thiazole-4-carboxylate (5.0 g, 22.5 mmol) and EtOAc (25 mL) was added NH4OH (25 mL) at RT and stirred for further 3 h. The reaction mixture was extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the solvent was evaporated in vacuum to give 2-bromo-thiazole-4-carboxamide as a solid. Yield 3.60 g; mass (m / z): 208.2, 210.2 (M+H). + .

[0113] Step c: To a stirred mixture of 2-bromo-thiazole-4-carboxamide (3.5 g, 17 mmol) and DMF (20 mL), POCl3 (2.6 g, 17 mmol) was added dropwise and stirred at 60 °C for 1 h. The reaction mixture was poured into water and neutralized with saturated NaHCO3 solution. The mixture was extracted with EtOAc (100 mL x 3), and the combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuum. The residue was purified by column chromatography (silica gel, 15% EtOAc / petroleum ether) to give 2-bromo-thiazole-4-carbonitrile as a solid. Yield 2.2 g; 1 H NMR (400 MHz, DMSO-d6): δ 8.72 (s, 1H).

[0114] Step d: To a stirred mixture of 2-bromo-thiazole-4-carbonitrile (2.0 g, 10.6 mmol), K2CO3 (2.95 g, 21.27 mmol) and ethanol (20 mL) was added hydroxylamine hydrochloride (1.5 g, 21.27 mmol) at RT and stirred at 80°C-85°C for 4 h. The mixture was concentrated and diluted with water. The mixture was extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the solvent was evaporated in vacuum to give 2-bromo-N-hydroxythiazole-4-carboxamidine as a solid, which was used as such in the next step. Yield 1.5 g.

[0115] Step e: To a stirred mixture of 2-bromo-N-hydroxy-thiazole-4-carboxamidine (1.5 g, 6.8 mmol) and methanol (7.5 mL), triethyl orthoacetate (7.5 mL) was added at RT and stirred at 80° C. for 4 h. The mixture was concentrated to give an oily mass. The crude residue was purified by column chromatography (silica gel, 15% EtOAc / petroleum ether) to give intermediate 2a as a solid. Yield 1.06 g; 1 H NMR (400 MHz, DMSO-d6): δ 2.66 (s, 3H), 8.41 (s, 1H); Mass (m / z): 246.1, 248.1 (M+H) + .

[0116] Intermediate 2b: 2-chloro-5-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyridine 6-Chloronicotinonitrile was reacted with hydroxylamine hydrochloride according to the same procedure as set forth in the preparation of intermediate 2a, step d, to give 6-chloro-N-hydroxy-nicotinamidine, which was further treated with triethyl orthoacetate according to the same procedure as set forth in the preparation of intermediate 2a, step e, to give intermediate 2b. Yield 2.40 g; Mass (m / z): 196.1, 198.1 (M+H). + .

[0117] Intermediate 2c: 2-chloro-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyridine 6-Chloro-pyridine-2-carbonitrile was reacted with hydroxylamine hydrochloride according to the same procedure as set forth in the preparation of intermediate 2a, step d, to give 6-chloro-N-hydroxy-pyridine-2-carboxamidine, which was further treated with triethyl orthoformate according to the same procedure as set forth in the preparation of intermediate 2a, step e, to give intermediate 2c. Yield 2.60 g; Mass (m / z): 196.1, 198.1 (M+H). + .

[0118] Intermediate 2d: 2-chloro-5-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyrazine 5-Chloro-pyrazine-2-carbonitrile was reacted with hydroxylamine hydrochloride according to the same procedure as set forth in the preparation of intermediate 2a step d to give 5-chloro-N-hydroxy-pyrazine-2-carboxamidine, which was further treated with triethyl orthoformate according to the same procedure as set forth in the preparation of intermediate 2a step e to give intermediate 2d. Yield 2.50 g; Mass (m / z): 197.1, 199.1 (M+H). + .

[0119] Intermediate 2e: 5-(2-bromo-thiazol-4-yl)-oxazole To a stirred mixture of 2-bromo-thiazole-4-carbaldehyde (5 g, 26 mmol), K2CO3 (7.2 g, 52 mmol) and methanol (30 mL) was added TosMIC (10 g, 52 mmol) at RT and stirred at reflux temperature for 4 h. The mixture was concentrated, diluted with water and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the solvent was evaporated in vacuum. The residue was purified by column chromatography (silica gel, 15% EtOAc / petroleum ether) to give intermediate 2e. Yield 4.5 g; mass (m / z): 231.2, 233.2 (M+H). + .

[0120] Intermediate 2f: 2-chloro-5-oxazol-5-yl-pyridine 6-Chloro-pyridine-3-carbaldehyde was reacted according to the same procedure as mentioned in the preparation of intermediate 2e with some minor variations. Yield 4.8 g; Mass (m / z): 181.3, 183.1 (M+H). + .

[0121] Intermediate 2g: 2-(2-bromo-thiazol-4-yl)-5-methyl-[1,3,4]oxadiazole Step a: To a mixture of 2-bromo-thiazole-4-carboxylic acid (5 g, 24.03 mmol) and 1,4-dioxane (20 mL), 1,1'-carbonyldiimidazole (4.67 g, 28.8 mmol) was added at RT and stirred at 50 °C for 30 min. Then, hydrazine hydrate (1.44 g, 28.84 mmol) was added at 50 °C and stirred at 50 °C for 1 h. The mixture was concentrated, diluted with water, and extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuum. The residue was purified by column chromatography (silica gel, 30% EtOAc / petroleum ether) to give 2-bromo-thiazole-4-carboxylic acid hydrazide. Yield 2.5 g; 1 H NMR (400 MHz, CDCl3): δ 4.06 (bs, 2H), 7.26 (bs, 1H), 7.90 (s, 1H); Mass (m / z): 222.0, 224.1 (M+H) + .

[0122] Step b: To a mixture of 2-bromo-thiazole-4-carboxylic acid hydrazide (6.5 g, 29.27 mmol), acetic acid (7.9 g, 131.75 mmol) and toluene (35 mL), phosphorus oxychloride (6.7 g, 43.91 mmol) was added at RT and stirred at 100° C. for 2 h. The mixture was concentrated, diluted with water and neutralized with NH4OH, during which a solid precipitated. The solid was filtered, washed with water and dried in vacuum to give intermediate 2g. Yield 3 g; 1H NMR (400 MHz, CDCl3): δ 2.62 (s, 3H), 8.10 (s, 1H); Mass (m / z): 246.1, 248.1 (M+H) + .

[0123] Intermediate 2h: 2-(2-bromo-thiazol-4-yl)-5-cyclopropyl-[1,3,4]oxadiazole The compound of step a of intermediate 2g was reacted with cyclopropyl carboxylate and phosphorus oxychloride in toluene according to the same conditions as those mentioned in the preparation of step b of intermediate 2g to give intermediate 2h. Yield 3.0 g; mass (m / z): 272.3, 274.3 (M+H). + .

[0124] Intermediate 2i: 2-(2-bromo-thiazol-5-yl)-5-methyl-[1,3,4]oxadiazole 2-Bromo-thiazole-5-carboxylic acid was reacted according to the same procedure as set forth in step a of intermediate 2g to give 2-bromo-thiazole-5-carboxylic acid hydrazide, which was further reacted according to the same procedure as set forth in step b of intermediate 2g to give intermediate 2i. Yield 3.2 g; Mass (m / z): 246.2, 248.1 (M+H). + .

[0125] Intermediate 2j: 5-(2-bromo-thiazol-4-yl)-3-methyl-[1,2,4]oxadiazole Step a: To a mixture of acetonitrile (8 g, 95 mmol), sodium hydroxide (8.4 g, 218 mmol), ethanol (25 mL) and water (25 mL), hydroxylamine hydrochloride (14 g, 204 mmol) was added at RT and stirred at reflux for 24 h. The reaction mixture was cooled to RT, concentrated in vacuo, diluted with ethanol and filtered. The filtrate was concentrated to give N-hydroxy-acetamidine. Yield 2.2 g; mass (m / z): 75.3 (M+H). + .

[0126] Step b: To a mixture of N-hydroxy-acetamidine (2.1 g, 28 mmol), propylphosphonic anhydride solution (50% by weight in ethyl acetate) (10.9 g, 34 mmol), triethylamine (11.6 g, 115 mmol) and EtOAc (20 mL) was added 2-bromo-thiazole-4-carboxylic acid (5 g, 23.9 mmol) at RT and stirred at reflux temperature for 8 h. The reaction mixture was cooled to RT, diluted with cold water and extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the solvent was evaporated in vacuum. The residue was purified by column chromatography (silica gel, 30% EtOAc / petroleum ether) to give intermediate 2j as a solid. Yield 1.0 g; mass (m / z): 246.2, 248.2 (M+H). + .

[0127] Intermediate 2k: 6-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyridin-2-ol Intermediate 2k was prepared by reacting the N-hydroxy-acetamidine obtained above with 6-hydroxy-pyridine-2-carboxylic acid according to the preparation of intermediate 2j step b. Yield 0.76 g; mass (m / z): 178 (M+H). + .

[0128] Intermediate 2l: 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyridin-2-ol Intermediate 2l was prepared by reacting N-hydroxy-acetamidine obtained above with 6-hydroxy-nicotinic acid according to the preparation of intermediate 2j in step b. Yield 0.5 g; mass (m / z): 178.2 (M+H). + .

[0129] Intermediate 2m: 6-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-ol To a mixture of 6-hydroxy-pyridine-2-carboxylic acid (2 g, 17 mmol), propylphosphonic anhydride solution (50% by weight in ethyl acetate) (6.8 g, 21.44 mmol), triethylamine (7.2 g, 71.5 mmol) and EtOAc (10 mL) was added acetohydrazine (1.27 g, 14.3 mmol) at RT and stirred at reflux temperature for 8 h. The reaction mixture was cooled to RT, diluted with cold water and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and the solvent was evaporated in vacuum. The residue was purified by column chromatography (silica gel, 1.5% MeOH / DCM) to give intermediate 2m. Yield 0.62 g; mass (m / z): 178.2 (M+H). + .

[0130] Example 1 3-(4-{3-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole

[0131] [ka]

[0132] To a stirred suspension of 3-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-propan-1-ol (5 g, 18 mmol, intermediate 1a) in THF (25 mL) was added NaH (2.16 g, 90 mmol) at 0-10 °C to give a clear solution, which was further stirred at RT for 30 min. 2-(2-Bromo-thiazol-4-yl)-5-methyl-[1,3,4]oxadiazole (5.32 g, 21.6 mmol, intermediate 2g) was added to the reaction mixture at RT and heated at reflux for 6 h. After cooling, the reaction mixture was poured into water and extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the solvent was evaporated in vacuum. The residue was purified by column chromatography (silica gel, 2% MeOH / DCM) to give Example 1. Yield 2.84g;1 H NMR (400 MHz, DMSO-d6): δ 2.19-2.02 (m, 2H), 2.50 (s, 3H), 2.55-2.58 (m, 2H), 2.63 (m, 4H), 3.4 (m, 4H), 4.52-4.56 (m, 2H), 7.41-7.45 (m, 1H), 7.54-7.57 (m, 1H), 7.88 (s, 1H), 8.04-8.06 (m, 2H); Mass (m / z): 443.1 (M+H) + .

[0133] Example 2 3-(4-{3-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate

[0134] [ka]

[0135] To a solution of Example 1 (1 mmol) in methanol (20 mL) was added oxalic acid (1 mmol). The mixture was stirred at 25° C.-30° C. for 1 h and concentrated in vacuum to give a solid. The solid was washed with diethyl ether and dried in vacuum to give Example 2. 1 H NMR (400 MHz, CD3OD): δ 2.35 (m, 2H), 2.62 (s, 3H), 3.33-3.50 (m, 6H), 3.78 (m, 4H), 4.69-4.72 (m, 2H), 7.46-7.50 (m, 1H), 7.56-7.60 (m, 1H), 7.78 (s, 1H), 7.96-7.98 (d, J = 8 Hz, 1H), 8.06-8.08 (d, J = 8 Hz, 1H); Mass (m / z): 443.1 (M+H) + .

[0136] Examples 3-34 were prepared according to the procedures of Examples 1 and 2 using the appropriate intermediates with some minor variations.

[0137]

Table 1A

[0138]

Table 1B

[0139]

Table 1C

[0140]

Table 1D

[0141]

Table 1E

[0142]

Table 1F

[0143]

Table 1G

[0144]

Table 1H

[0145]

Table 1I

[0146]

Table 1J

[0147] [Table 1K]

[0148] [Table 1L]

[0149] Example 35 3-(4-{3-[6-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-yloxy]propyl}-piperazin-1-yl)-benzo[d]isothiazole

[0150] [ka]

[0151] To a mixture of intermediate 2m (2 g, 11.28 mmol) and acetonitrile (20 mL), K2CO3 (4.67 g, 33.8 mmol) and intermediate 1c (4 g, 13.56 mmol) were added at RT and stirred at reflux temperature for 6 h. The reaction mixture was poured into water and the mixture was extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by column chromatography (silica gel, 4% MeOH / DCM) to give the title compound. Yield 1.2 g. 1 H NMR (400 MHz, DMSO-d6): δ 2.25 (m, 2H), 2.45 (s, 3H), 3.40 (m, 2H), 3.50 (m, 4H), 3.77 (m, 4H), 4.52 (m, 2H), 7.08-7.11 (d, J = 8 Mass (m / z): 437.2 (M+H) + .

[0152] (Example 36) 3-(4-{3-[6-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate

[0153] [ka]

[0154] Example 35 was converted to Example 36 using the similar procedure given in the preparation of Example 2. Yield: 1.3 g; 1 H NMR (400 MHz, CD3OD): δ 2.36 (m, 2H), 2.48 (s, 3H), 3.44 (m, 2H), 3.57 (m, 4H), 3.83 (m, 4H), 4.63 (m, 2H), 7.10-7.12 (d, J = 8 Hz, Mass (m / z): 437.2 (M+H) + .

[0155] (Example 37) 3-(4-{3-[6-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyridin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole

[0156] [ka]

[0157] Example 37 was prepared by reacting intermediate 1c and intermediate 2k using the same procedure as given in the preparation of example 35. Yield: 1.2 g; 1H NMR (400 MHz, DMSO-d6): δ 2.25 (m, 2H), 2.45 (s, 3H), 3.40 (m, 2H), 3.51 (m, 4H), 3.80 (m, 4H), 4.59 (m, 2H), 7.05-7.10 (d, J = 8 Mass (m / z): 437.2 (M+H) + .

[0158] (Example 38) 3-(4-{3-[6-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyridin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate

[0159] [ka]

[0160] Example 37 was converted to Example 38 using the similar procedure given in the preparation of Example 2. Yield: 1.2 g; 1 H NMR (400 MHz, CD3OD): δ 2.36 (m, 2H), 2.48 (s, 3H), 3.44 (m, 2H), 3.57 (m, 4H), 3.83 (m, 4H), 4.63 (m, 2H), 7.10-7.12 (d, J = 8 Hz, Mass (m / z): 437.2 (M+H) + .

[0161] (Example 39) 3-{4-[3-(4-[1,2,4]oxadiazol-3-yl-thiazol-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole

[0162] [ka]

[0163] Step a: To a stirred suspension of intermediate 1a (1 g, 3.6 mmol) and THF (10 mL) was added NaH (0.17 g, 7.2 mmol) at 0 °C followed by 2-bromo-thiazole-4-carbonitrile (0.8 g, 5.4 mmol) at 0 °C. The reaction mixture was brought to RT and stirred at reflux temperature for 6 h. The reaction mixture was poured into water and extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the solvent was evaporated in vacuum. The residue was purified by column chromatography (silica gel, 2% methanol in dichloromethane) to give 2-[3-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-propoxy]-thiazole-4-carbonitrile. Yield 1.05 g; mass (m / z): 386.1 (M+H). + .

[0164] Step b: To a mixture of 2-[3-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-propoxy]-thiazole-4-carbonitrile (1 g, 2.6 mmol), K2CO3 (0.71 g, 5.2 mmol) and ethanol (10 mL) was added hydroxylamine hydrochloride (0.36 g, 5.2 mmol) at RT. The reaction mixture was stirred at reflux for 4 h, cooled to RT and evaporated in vacuum. The residue thus obtained was poured into water and extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the solvent was evaporated in vacuum. The residue was purified by column chromatography (silica gel, 2% methanol in dichloromethane) to give 2-[3-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-propoxy]-N-hydroxy-thiazole-4-carboxamidine, which was carried on to the next step without further purification. Yield 0.79 g.

[0165] Step c: To a mixture of 2-[3-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-propoxy]-N-hydroxy-thiazole-4-carboxamidine (0.7 g, 1.6 mmol) and methanol (7 mL), triethyl orthoformate (7 mL) was added at RT, stirred at reflux temperature for 4 h, and evaporated. The residue was purified by column chromatography (1% methanol in chloroform) to give Example 39. Yield 0.5 g. 1 H NMR (400 MHz, DMSO-d6): δ 2.00-2.31 (m, 2H), 3.29-3.56 (m, 2H), 3.55-3.62 (m, 4H), 3.77-3.80 (m, 4H) 4.65-4.70 (m, 2H), 7.40-7.49 (dd, J = 7.6 Hz, 1H), 7.50-7.59 (dd, J = 7.2 Hz, 1H), 7.78 (s, 1H ), 7.90-7.92 (d, J = 8.0 Hz, 1H), 8.00-8.01 (d, J = 8.0 Hz, 1H), 9.26 (s, 1H); Mass (m / z): 428.9 (M+H) + .

[0166] (Example 40) 3-{4-[3-(4-[1,2,4]oxadiazol-3-yl-thiazol-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole oxalate

[0167] [ka]

[0168] Example 39 was converted to Example 40 using the similar procedure given in the preparation of Example 2. Yield: 0.5 g; 1H NMR (400 MHz, CD3OD): δ 2.12-2.42 (m, 2H), 3.32-3.62 (m, 2H), 3.63-3.70 (m, 4H), 3.85-3.89 (m, 4H) 4.70-4.71 (m, 2H), 7.47-7.51 (dd, J = 7.6 Hz, 1H), 7.57-7.61 (dd, J = 7.2 Hz, 1H), 7.80 (s, 1H ), 7.96-7.98 (d, J = 8.0 Hz, 1H), 8.07-8.09 (d, J = 8.0 Hz, 1H), 9.30 (s, 1H); Mass (m / z): 428.9 (M+H) + .

[0169] (Example 41) 3-{4-[3-(6-[1,2,4]oxadiazol-3-yl-pyridin-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole

[0170] [ka]

[0171] Example 41 was prepared by reacting intermediate 1a and 6-chloropyridine-2-carbonitrile using the same procedure as given in the preparation of example 39. Yield: 0.28 g; 1 H NMR (400 MHz, DMSO-d6): δ 2.20 (m, 2H), 3. 35 (m, 2H), 3.41 (m, 4H), 3.70 (m, 4H), 4.45 (m, 2H), 7.08-7.10 (d, J = 8 Hz, 1H), 7.41-7.43 (m, 1H), 7.55-7.59 (m, 1H), 7.85-7.96 (m, 3H), 8.00 (d, J = 8 Hz, 1H), 9.05 (s, 1H); Mass (m / z): 423.0 (M+H) + .

[0172] (Example 42) 3-{4-[3-(6-[1,2,4]oxadiazol-3-yl-pyridin-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole oxalate

[0173] [ka]

[0174] Example 41 was converted to Example 42 using the similar procedure given in the preparation of Example 2. Yield: 0.3 g; 1 H NMR (400 MHz, CD3OD): δ 2.29-2.33 (m, 2H), 3.32-3.36 (m, 4H), 3.48-3.50 (m, 6H), 4.23-4.26 (m, 2H), 6.72-6.75 (m, 1H ), 7.47-7.51 (dd, J = 8.0 Hz, 1H), 7.57-7.61 (dd, J = 7.6 Hz, 1H), 7.96-7.98 (d, J = 8.0 Hz, 1H), 8.05-8.07 (d, J = 8.0 Hz, 1H), 8.13-8.16 (m, 1H), 8.49-8.50 (m, 1H), 9.30 (s, 1H); Mass (m / z): 423.0 (M+H) + .

[0175] (Example 43) 5-HT 1A Receptor K i Determining Values Materials and Methods Receptor source: recombinant mammalian cells (HEK293-EBNA) Radioligand: 3 H]-8-hydroxyDPAT (200Ci / mmol) Final ligand concentration: 0.8 nM Non-specific determinant: 0.1mM U92016A Reference compound: U92016A Positive control: U92016A Incubation conditions: Reactions were carried out for 2 h at RT in a buffer containing 50 mM Tris-HCl, 0.5 mM EDTA, 10 mM MgSO4, 0.1% ascorbic acid, pH 7.4. Reactions were terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped on the filters was determined and the concentration of test compounds and cloned human 5-HT 1A Comparisons were made with control values ​​to identify any interactions with the receptor binding sites.

[0176] (Example 44) 5-HT 2A Receptor K i Determining Values Materials and Methods Receptor source: Recombinant mammalian cells (CHO-K1) Radioligand: 3 H]-Ketanserin (41.9 Ci / mmol) Final ligand concentration: 1.25 nM Nonspecific determinant: 0.1 mM 1-naphthylpiperazine (1-NP) Reference compound: 1-naphthylpiperazine (1-NP) Positive control: 1-naphthylpiperazine (1-NP) Incubation conditions: The reaction was carried out at RT for 1 h in a buffer containing 50 mM Tris-HCl, 4 mM CaCl2, 0.1% ascorbic acid, pH 7.4. The reaction was terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped on the filters was determined and the test compounds and cloned human 5-HT 2A Comparisons were made with control values ​​to identify any interactions with the receptor binding sites.

[0177] (Example 45) D 2S Receptor K i Determining Values Materials and Methods Receptor source: Recombinant mammalian cells (CHO-K1) Radioligand: 3 H]-raclopride (80.8 Ci / mmol) Final ligand concentration: 4 nM Nonspecific determinant: 0.1 mM haloperidol Reference compound: Haloperidol Positive control: haloperidol Incubation conditions: Reactions were carried out for 2 h at RT in a buffer containing 50 mM Tris-HCl, 120 mM NaCl, 5 mM KCl, 5 mM MgCl2, 1 mM EDTA, pH 7.4. Reactions were terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped on the filters was determined and assayed for the presence of test compounds and cloned human dopamine D 2S Comparisons were made with control values ​​to identify any interactions with the receptor binding sites.

[0178] (Example 46) K of SERT receptor i Determining Values Materials and Methods Receptor source: Recombinant mammalian cells (HEK293) Radioligand: 3 H]-Citalopram (80.8 Ci / mmol) Final ligand concentration: 2nM Nonspecific determinant: 0.1 mM venlafaxine Reference compound: Venlafaxine Positive control: venlafaxine Incubation conditions: Reactions were carried out at RT for 3 hours in a buffer containing 50 mM Tris-HCl, 150 mM NaCl, 5 mM KCl and scintillation proximity assay (SPA) beads (0.1 mg / well), pH 7.4. Radioactivity in proximity to the SPA beads was determined by scintillation proximity assay and compared to control values ​​to confirm any interaction of the test compound with the cloned human SERT receptor binding site.

[0179] (Example 47) Adrenaline alpha 1B Receptor K i Determining Values Materials and Methods Receptor source: recombinant mammalian cells (Chem-1) Radioligand: 3 H]-Prazosin (77.4 Ci / mmol) Final ligand concentration: 1 nM Non-specific determinant: 0.1mM prazosin Reference compound: Prazosin Positive control: prazosin Incubation conditions: Reactions were carried out at RT for 1 h in a buffer containing 67 mM Tris-HCl, 67 μM EDTA, 13 mM EDTA, pH 7.4. Reactions were terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped on the filters was determined and assayed for the presence of test compounds and cloned human adrenaline alpha. 1B Comparisons were made with control values ​​to identify any interactions with the receptor binding sites.

[0180] (Example 48) K of histamine H1 receptor i Determining Values Materials and Methods Receptor source: Recombinant mammalian cells (CHO-K1) Radioligand: 3 H]-pyrilamine (20.7 Ci / mmol) Final ligand concentration: 2nM Non-specific determinant: 0.1mM pyrilamine Reference compound: Pyrilamine Positive control: pyrilamine Incubation conditions: Reactions were carried out in a buffer containing 67 mM Tris-HCl and SPA beads (0.1 mg / well), pH 7.4, for 1 h at 37° C. Radioactivity in proximity to the SPA beads was determined by scintillation proximity assay and compared to control values ​​to confirm any interaction of the test compound with the cloned human histamine H1 receptor binding site.

[0181] [Table 2]

[0182] (Example 49) Rodent Pharmacokinetic Studies Male Wistar rats (250±50 grams) were used as experimental animals. Animals were individually housed in polypropylene cages. Two days before the study, male Wistar rats were anesthetized with isoflurane for surgical placement of intravenous catheters. Rats were randomized to oral (3 mg / kg and 10 mL / kg dose volumes) and intravenous (1 mg / kg and 2.0 mL / kg dose volumes) dosing (n=3 / group) and fasted overnight before oral dosing (po). However, rats assigned to intravenous dosing were provided with food and water ad libitum.

[0183] Intravenous formulations were prepared using 5% Pharmasolve+45% propylene glycol+50% PEG400 as the vehicle. Oral formulations were prepared using 0.25% Tween80+99.75% 1% (w / v) hydroxyethylcellulose solution as the vehicle. Dose formulations were prepared fresh on the day of dosing.

[0184] After dosing of the animals, at each time point, 200 μL blood samples were taken intravenously and supplemented with an equivalent volume of saline. The collected blood samples were transferred to labeled Eppendorf tubes containing 10 μL of sodium heparin (1000 IU / mL) as anticoagulant. Typically, blood samples were taken at the following time points: 0.08, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after dosing. Blood was centrifuged at 4000 revolutions per minute (rpm) for 10 minutes. Plasma was separated and stored frozen at -80°C until analysis. Test compound concentrations were quantified in plasma with a calibration range of approximately 1-2000 ng / mL in plasma by a qualified LC-MS / MS method using suitable extraction techniques. Study samples were analyzed with calibration samples in the batch and quality control samples powdered into the batch.

[0185] Pharmacokinetic parameter C max , AUC 0-t , t 1 / 2, clearance and bioavailability (F) were calculated using the Phoenix WinNonlin version 8.1 software package using standard non-compartmental models.

[0186] [Table 3]

[0187] (Example 50) Rodent brain penetration studies Male Wistar rats (260±40 g) were used as experimental animals. Three animals were housed in each cage. The animals were provided with water and food ad libitum throughout the experiment and were maintained on a 12-h light / dark cycle.

[0188] Brain penetration was determined individually in rats. One day before dosing, male Wistar rats were acclimated and randomly grouped according to their body weight. At each time point (0.50, 1 and 2 hours), n=3 animals were used.

[0189] Test compounds were suitably preformulated and administered orally at 3mg / kg (free base equivalent). Blood samples were removed via cardiac puncture using isoflurane anesthesia. Animals were sacrificed and brain tissue was harvested. Plasma was separated and brain samples were homogenized and stored frozen at -20°C until analysis. Concentrations of test compounds in plasma and brain were determined using LC-MS / MS methods.

[0190] Test compounds were quantified in plasma and brain homogenates with a calibration range of approximately 1-2000 ng / mL by a qualified LC-MS / MS method using suitable extraction techniques. Study samples were analyzed with in-batch calibration samples and quality control samples interspersed among the batches. Brain-to-plasma ratios (C brain / C plasma ) was calculated.

[0191] [Table 4]

[0192] (Example 51) Amphetamine-induced open-field assay Male Wistar rats weighing 230-250 g were used. The rats' weights were recorded. The rats were randomized according to their weights. The animals were brought to the experimental room 1 h before acclimation to the experimental conditions. The open field was a black arena measuring 51 x 51 x 51 cm surrounded by black plastic walls of the same dimensions. The rats were allowed to habituate to the open field arena for 15 min. The animals were administered the respective treatment (vehicle or Example 2) 60 min before testing. After 30 min, the animals were challenged with amphetamine (2.5 mg / kg, ip) or vehicle. The animals were then placed in the open field arena and the distance traveled by the mice was tracked for 15 min using Videomot software. The data were analyzed using GraphPad prism.

[0193] Results: Rats treated with Example 2 at all doses (3, 10, 30 mg / kg, po) showed a significant decrease in locomotor activity when compared to the group treated with amphetamine (2.5 mg / kg, ip). Example 2 antagonized the effect of amphetamine on locomotor activity in rats. The results suggest that Example 2 may have potential utility for the treatment of schizophrenia (Figure 1).

[0194] (Example 52) Rat rotarod assay The possible effect of Example 2 on motor enhancement was investigated using the rotarod test. 20 hours before the test, rats were trained to remain on the rotating rod (4 rpm) of the rotarod apparatus (TSE Systems; GmHb, Germany). The animals that successfully stayed on the rotating rod for 60 seconds (out of 4 trials per animal) were selected for further study. The animals that did not complete the 60-second stay in the 4 choices were rejected from the test. A single test was performed the next day. The animals that could stay on the rotating rod for 60 seconds were selected for further study. The animals were administered Example 2 or vehicle 60 minutes before the test. The latency to fall off the rotating rod was recorded.

[0195] Results: No significant effects on motor coordination were observed at doses of 3 and 10 mg / kg, suggesting a separation between doses leading to efficacy and doses leading to side effects (Figure 2).

[0196] (Example 53) Reserpine-induced DOPA accumulation Male Wistar rats were pretreated with reserpine (5 mg / kg, sc) approximately 18 hours before sacrifice and then fasted until sacrifice. Example 2 (3 mg / kg, po) and (3-(3-hydroxyphenyl)-Nn-propylpiperidine (3-PPP); 30 mg / kg, sc) were administered 1.16 hours and 1 hour before sacrifice, respectively. Haloperidol (0.5 mg / kg, sc) was used as a positive control and was dosed in a separate group of animals 10 minutes before 3-PPP. 3-Hydroxybenzylhydrazine dihydrochloride (NSD-1015; 100 mg / kg, sc) was then administered 0.5 hours before sacrifice. Each rat was sacrificed, the brain was removed, and the striatum was then isolated. The tissues were immediately weighed and homogenized by an ultrasonic homogenizer in 0.1 N perchloric acid while cooling on ice. The homogenate was centrifuged at 20,000 g for 15 min at 4° C. The supernatant was assayed for dihydroxyphenylalanine (DOPA) levels using HPLC-ECD.

[0197] Results: Treatment with reserpine resulted in an increase of approximately 194% in DOPA levels in the striatum. However, 3-PPP, a dopamine receptor agonist, reversed reserpine-induced DOPA accumulation by 77%. Pretreatment with Example 2 blocked the effect of 3-PPP by 25%. Results from the current study indicate that Example 2 can behave as an in vivo partial agonist of the dopamine D2 receptor (Figure 3).

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, A is O or S; R is N or CH; Y is -CH 2 -, -O-, NH or -N(C 1～4 alkyl)-; n is an integer from 0 to 2, R 1 teeth 【Chemistry 2】 is selected from R 2a , R 2b , R 2c , R 2d and R 2e teeth 【Chemistry 3】 are each independently selected from 【Chemistry 4】 represents the attachment point, R 3 For each occurrence, hydrogen, -(C 1～4 ) alkyl or -(C 3～6 ) cycloalkyl; R 4 is hydrogen, halogen, -(C 1～4 ) alkyl, -(C 3～6 ) cycloalkyl or hydroxy-(C 1～4 ) alkyl or an isotopic form, stereoisomer or pharma- ceutically acceptable salt thereof.

2. below 3-(4-{3-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-(4-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-ethyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-(4-{3-[4-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-(4-{3-[5-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-(4-{3-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-(4-{3-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-{4-[3-(4-oxazol-5-yl-thiazol-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole; 3-(4-{3-[6-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyridin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-(4-{3-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyridin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-(4-{3-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyrazin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-{4-[3-(5-oxazol-5-yl-pyridin-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole; 6-Fluoro-3-(1-{3-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperidin-4-yl)-benzo[d]isoxazole; 6-Fluoro-3-(1-{3-[5-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperidin-4-yl)-benzo[d]isoxazole; 6-Fluoro-3-(1-{3-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-thiazol-2-yloxy]-propyl}-piperidin-4-yl)-benzo[d]isoxazole; 6-Fluoro-3-(1-{3-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-thiazol-2-yloxy]-propyl}-piperidin-4-yl)-benzo[d]isoxazole; 6-Fluoro-3-{1-[3-(4-oxazol-5-yl-thiazol-2-yloxy)-propyl]-piperidin-4-yl}-benzo[d]isoxazole; 6-Fluoro-3-{1-[3-(5-oxazol-5-yl-pyridin-2-yloxy)-propyl]-piperidin-4-yl}-benzo[d]isoxazole; 3-(4-{3-[6-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-(4-{3-[6-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyridin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole; 3-{4-[3-(4-[1,2,4]oxadiazol-3-yl-thiazol-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole; and 3-{4-[3-(6-[1,2,4]oxadiazol-3-yl-pyridin-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole 2. The compound of formula (I) according to claim 1, selected from:

3. below 3-(4-{3-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-(4-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-ethyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-(4-{3-[4-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-(4-{3-[5-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-(4-{3-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-(4-{3-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-thiazol-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-{4-[3-(4-oxazol-5-yl-thiazol-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole oxalate; 3-(4-{3-[6-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyridin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-(4-{3-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyridin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-(4-{3-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyrazin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-{4-[3-(5-oxazol-5-yl-pyridin-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole oxalate; 6-Fluoro-3-(1-{3-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperidin-4-yl)-benzo[d]isoxazole oxalate; 6-Fluoro-3-(1-{3-[5-(5-methyl-[1,3,4]oxadiazol-2-yl)-thiazol-2-yloxy]-propyl}-piperidin-4-yl)-benzo[d]isoxazole oxalate; 6-Fluoro-3-(1-{3-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-thiazol-2-yloxy]-propyl}-piperidin-4-yl)-benzo[d]isoxazole oxalate; 6-Fluoro-3-(1-{3-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-thiazol-2-yloxy]-propyl}-piperidin-4-yl)-benzo[d]isoxazole oxalate; 6-Fluoro-3-{1-[3-(4-oxazol-5-yl-thiazol-2-yloxy)-propyl]-piperidin-4-yl}-benzo[d]isoxazole oxalate; 6-Fluoro-3-{1-[3-(5-oxazol-5-yl-pyridin-2-yloxy)-propyl]-piperidin-4-yl}-benzo[d]isoxazole oxalate; 3-(4-{3-[6-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-(4-{3-[6-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyridin-2-yloxy]-propyl}-piperazin-1-yl)-benzo[d]isothiazole oxalate; 3-{4-[3-(4-[1,2,4]oxadiazol-3-yl-thiazol-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole oxalate; and 3-{4-[3-(6-[1,2,4]oxadiazol-3-yl-pyridin-2-yloxy)-propyl]-piperazin-1-yl}-benzo[d]isothiazole oxalate 2. The compound of formula (I) according to claim 1, selected from:

4. 4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a stereoisomer or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 3, and a pharma- ceutically acceptable excipient or carrier.

5. 5. The pharmaceutical composition of claim 4 for use in the treatment of a disease or disorder selected from schizophrenia, psychosis, bipolar disorder, mood disorder, depression, anxiety, sleep disorder, sexual disorder, withdrawal symptoms of drug addiction, attention deficit hyperactivity disorder, neuropsychiatric disorders associated with Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia and vascular dementia.

6. 4. A method for treating a disease or disorder selected from schizophrenia, psychosis, bipolar disorder, mood disorder, depression, anxiety, sleep disorder, sexual disorder, withdrawal symptoms of drug addiction, attention deficit hyperactivity disorder, neuropsychiatric disorders associated with Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia and vascular dementia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or an isotopic form, stereoisomer or pharma- ceutically acceptable salt thereof according to any one of claims 1 to 3.

7. 4. Use of a compound of formula (I) or an isotopic form, stereoisomer or pharma- ceutically acceptable salt thereof according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment of a disease or disorder selected from schizophrenia, psychosis, bipolar disorder, mood disorder, depression, anxiety, sleep disorder, sexual disorder, withdrawal symptoms of drug dependence, attention deficit hyperactivity disorder, neuropsychiatric disorders associated with Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia and vascular dementia.

Images