Heteroalicyclic Derivatives and Their Use in the Treatment of CNS Disorders - Patent application

Abstract

The present invention relates to heteroalicyclic compounds represented by the general formula (I), or their isotopes, stereoisomers, or pharma- ceutically acceptable salts. The present invention also describes methods for making such compounds, pharmaceutical compositions containing such compounds, and their use for the treatment or prevention of central nervous system related disorders. JPEG2025504406000073.jpg38170

Description

[Technical field]

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

[0002] The class of medicines primarily used to manage psychosis (including delusions, hallucinations, paranoia, or disorganized thinking) in schizophrenia and bipolar disorder is known as antipsychotics. They are divided into first-generation antipsychotics (or typical antipsychotics) and second-generation drugs (or atypical antipsychotics). Antipsychotics are most frequently used for various central nervous system (CNS) disorders such as schizophrenia, bipolar disorder, Tourette's syndrome, psychotic depression, treatment-resistant depression, agitation, or psychosis associated with dementia (https: / / www.ncbi.nlm.nih.gov / books / NBK519503 / ).

[0003] WO2006069993 is a 5-HT 1A WO1996006846 discloses arylpiperazine derivatives as 5-HT receptor subtype ligands for the treatment of central nervous system disorders. 1A Arylpiperazine derivatives are disclosed as ligands.

[0004] EP0453042 discloses novel 2,9-disubstituted-4H-pyrido-[1,2-a]pyrimidin-4-ones having dopamine and serotonin antagonist activity.

[0005] EP0464846 discloses imide derivatives having affinity for the dopamine D2 receptor. CN105367565 discloses piperazine (piperidine) cyclohexyl derivatives that bind to the dopamine D2 receptor, the dopamine D3 receptor, the serotonin 5-HT 1AReceptors and serotonin 5-HT 2A It is disclosed that it has affinity at the receptor.

[0006] M.L. Lopez-Rodriguez et al. 1A (Bioorg. Med. Chem. Lett. 9 (1999) 2339-2342) disclose (benzoimidazolyl)piperazine compounds as receptor ligands. O. Ichikawa et al. 2A and lurasidone, which has affinity for the 5-HT7 receptor (Neurochemistry International 61 (2012) 1133-1143).

[0007] The compounds of the present invention exhibit the desired heterogeneous nature of multiple pharmacological effects in order to have a broad therapeutic spectrum as a causative agent of schizophrenia, bipolar disorder, mood disorders and affective disorders.

[0008] Long-term use of antipsychotics is associated with side effects such as involuntary movement disorders, cognitive slowing, gynecomastia, metabolic syndrome, and tardive dyskinesia (TD). TD causes involuntary movements of the tongue, lips, face, trunk, and limbs that occur in patients long-term treated with antipsychotics. Antipsychotics are also associated with increased mortality in elderly people with dementia. Thus, there is an unmet need and scope to discover and develop novel antipsychotics with improved therapeutic target selectivity, acceptable tolerability and safety profile for the treatment of schizophrenia and other CNS-related disorders.

[0009] The aim of the present invention is to provide drugs that are active on the CNS and have a wider therapeutic freedom, minimal side effects and a very good safety margin compared to typical and atypical antipsychotics known in the literature. Intensive and thorough research aimed at achieving the above-mentioned aim has resulted in heteroalicyclic substituted piperazine and piperidine derivatives. These derivatives are antagonists of dopamine D2 receptors, 5-HT 1AReceptor antagonist, 5-HT 2A It exhibits activity as an antagonist of the 5-HT7 receptor and an antagonist of the 5-HT7 receptor, and further inhibits serotonin reuptake.

[0010] In addition to demonstrating efficacy in animal models of schizophrenia and related disorders, the heteroalicyclic substituted piperazine and piperidine compounds of the present invention also attenuate the associated cognitive deficits and exhibit a reduced tendency to induce side effects such as extrapyramidal side effects, involuntary movements and tardive dyskinesia. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] WO2006069993 [Patent Document 2] WO1996006846 [Patent Document 3] EP0453042 [Patent Document 4] EP0464846 [Patent Document 5] CN105367565 [Patent Document 6] WO2007113634 [Patent Document 7] WO2011061751 [Patent Document 8] WO2012019426 [Non-patent literature]

[0012] [Non-Patent Document 1] ML Lopez-Rodriguez et al., Bioorg. Med. Chem. Lett. 9 (1999)2339~2342 [Non-Patent Document 2] O. Ichikawa et al., Neurochemistry International 61 (2012) 1133~1143 [Non-Patent Document 3] J. Org. Chem. 2007, 72, 4254~4257

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-licensed Document 14

Non-licensed Document 15

[0013] In a first aspect, there is provided herein a heteroalicyclic piperazine or piperidine derivative represented by a compound of formula (I) or an isotope, stereoisomer, or pharma- ceutically acceptable salt thereof:

[0014] [ka]

[0015] [In the formula, HetAr is

[0016] [ka]

[0017] where X is hydrogen, halogen or alkoxy;

[0018] [ka]

[0019] represents the attachment point; P is -(CH2) b -or

[0020] [ka]

[0021] where b is an integer from 2 to 6; A is CH or N; n is 0 or 1, m is 0 or 1, Q is -CH2-, O, NH, N-Alkyl, -N(COR)-, or -N(COOR)-, where R is alkyl, alkoxyalkyl, cycloalkyl, or alkylaryl; B is hydrogen, halogen or alkoxy, with the proviso that Q is CH2, in which case B may be hydrogen, halogen or alkoxy.

[0022] In another aspect, the present invention relates to a process for the preparation of a compound of formula (I) or an isotope, stereoisomer, or a pharma- ceutically acceptable salt thereof.

[0023] In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or an isotope, stereoisomer, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. [Brief description of the drawings]

[0024] [Figure 1] FIG. 1 shows a reserpine-induced dihydroxyphenylalanine (DOPA) accumulation assay. [Diagram 2] FIG. 1 shows the regulation of dopamine levels in the prefrontal cortex. [Diagram 3] FIG. 1 shows regulation of norepinephrine levels in the prefrontal cortex. [Figure 4] FIG. 1 shows the regulation of dopamine levels in the striatum. [Diagram 5] FIG. 1 shows the effect on sleep / wakefulness. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] Unless otherwise stated, the following terms used in the specification and claims have the meanings set forth below.

[0026] The term "alkyl" as used herein refers to a branched or straight chain aliphatic hydrocarbon. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0027] The term "alkoxy" as used herein refers to an alkyl group attached to an oxygen atom. Examples of alkoxy include methoxy, ethoxy, propyloxy, and butyloxy.

[0028] The term "alkoxyalkyl" as used herein refers to an alkyl and alkoxy group as defined above linked through an oxygen atom. Examples of alkoxyalkyl include methoxymethyl, methoxyethyl, ethoxymethyl, ethoxypropyl, methoxypropyl, and the like.

[0029] The term "alkylaryl" as used herein refers to an alkyl, as defined above, to which an aryl group is attached. Examples of alkylaryl include benzyl, phenethyl, pyridylethyl, pyridylpropyl, and the like.

[0030] The term "cycloalkyl" as used herein refers to a saturated monocyclic hydrocarbon ring containing from 3 to 6 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0031] As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine. Preferably, the halogen is fluorine, chlorine or bromine.

[0032] The term "isotopes" as used herein refers to compounds of formula (I) where one or more atoms of the compound of formula (I) are replaced by their respective isotopes. For example, an isotope of hydrogen is 2 H (deuterium) and 3 H (tritium) and the carbon isotopes are 11 C. 14 C, and the isotopes of iodine are123 I, and the fluorine isotopes are 18 Contains F.

[0033] As used herein, the term "stereoisomer" refers to an isomer that differs in the spatial arrangement of the atoms of the compounds of formula (I). 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.

[0034] As used herein, the term "pharmaceutically acceptable salts" refers to salts of the active compounds described herein, i.e., compounds of formula (I), which are prepared by reaction with a suitable acid or acid derivative, depending on the particular substituents found on the compound.

[0035] The phrase "therapeutically effective amount" is defined as an amount of a compound of the present invention that (i) treats a particular disease, condition, or disorder described herein; (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.

[0036] 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 frogs, zebra fish, guinea pigs, elephants, camels, chimpanzees, and humans. More preferably, the patient is a human.

[0037] Embodiment Although the present invention encompasses all compounds described by the compounds of formula (I) without any limitation, preferred aspects and elements of the present invention are described herein in the form of the following embodiments.

[0038] In one embodiment, the present invention relates to a compound of formula (Ia) derived from a compound of formula (I):

[0039] [ka]

[0040] or its isotopes, stereoisomers, or pharma- ceutically acceptable salts. [wherein HetAr, A, P, Q and n are as defined in the first aspect].

[0041] In another embodiment, the present invention relates to a compound of formula (Ib) derived from a compound of formula (I):

[0042] [ka]

[0043] or its isotopes, stereoisomers, or pharma- ceutically acceptable salts. wherein B is hydrogen or halogen, n is 0 or 1, with the proviso that when n is 0 then B is hydrogen or halogen, and HetAr, A and P are as defined in the first aspect.

[0044] In some embodiments, the HetAr group is

[0045] [ka]

[0046] where X is hydrogen, alkoxy or halogen.

[0047] In some embodiments, the HetAr group is

[0048] [ka]

[0049] It is.

[0050] In some embodiments, the HetAr group is

[0051] [ka]

[0052] where X is hydrogen or halogen.

[0053] In some embodiments, the HetAr group is

[0054] [ka]

[0055] It is.

[0056] In some embodiments, the B group is hydrogen or halogen.

[0057] In another embodiment, preferred compounds of the invention are 2-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione oxalate; 2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione oxalate; 2-{4-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-{4-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-butyl}-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-{4-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-butyl}-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione oxalate; 2-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-6-fluoro-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-6-fluoro-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione oxalate; 3-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-hexahydro-1b,3-diaza-cyclopropa[a]indene-2,4-dione; 3-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-hexahydro-1b,3-diaza-cyclopropa[a]indene-2,4-dione oxalate; 2-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-hexahydro-pyrido[1,2-c]pyrimidine-1,3-dione; 2-{4-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-hexahydro-pyrido[1,2-c]pyrimidine-1,3-dione; 2-{4-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-hexahydro-pyrido[1,2-c]pyrimidine-1,3-dione fumarate; 2-{4-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-butyl}-hexahydro-pyrido[1,2-c]pyrimidine-1,3-dione; 2-{4-[4-(5-methoxy-1H-indol-3-yl)-piperidin-1-yl]-butyl}-hexahydro-pyrido[1,2-c]pyrimidine-1,3-dione; 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-tetrahydro-pyrimido[6,1-c][1,4]oxazine-6,8-dione; 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-tetrahydro-pyrimido[6,1-c][1,4]oxazine-6,8-dione oxalate; 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid benzyl ester; 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid benzyl ester fumarate; 7-{4-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid benzyl ester; 7-{4-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid benzyl ester fumarate; 2-[3-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-propyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-propyl}-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-{3-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-propyl}-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-ylmethyl)-cyclohexylmethyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-ylmethyl)-cyclohexylmethyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione oxalate; 2-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-ylmethyl]-cyclohexylmethyl}-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-ylmethyl]-cyclohexylmethyl}-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione oxalate; 7-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-ylmethyl)-cyclohexylmethyl]-tetrahydro-pyrimido[6,1-c][1,4]oxazine-6,8-dione; 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-hexahydro-pyrazino[1,2-c]pyrimidine-6,8-dione; 7-{4-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-hexahydro-pyrazino[1,2-c]pyrimidine-6,8-dione; 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid methyl ester; 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid methyl ester fumarate; 7-{4-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid methyl ester; 7-{4-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid methyl ester fumarate; 2-Acetyl-7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-hexahydro-pyrazino[1,2-c]pyrimidine-6,8-dione; 2-Acetyl-7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-hexahydro-pyrazino[1,2-c]pyrimidine-6,8-dione fumarate; 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-2-isopropyl-hexahydro-pyrazino[1,2-c]pyrimidine-6,8-dione; 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-2-isopropyl-hexahydro-pyrazino[1,2-c]pyrimidine-6,8-dione fumarate; 2-{4-[4-(benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-{4-[4-(benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione oxalate; 2-[3-(4-benzo[d]isoxazol-3-yl-piperidin-1-yl)-propyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; and 2-[3-(4-benzo[d]isoxazol-3-yl-piperidin-1-yl)-propyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione oxalate; or an isotope, stereoisomer, or pharma-ceutically acceptable salt thereof.

[0058] In another aspect, the present invention relates to a method for treating or preventing a central nervous system disorder or condition selected from anxiety disorder, agitation, aggression, borderline personality disorder, schizophrenia, affective disorder, psychotic disorder, mood disorder, bipolar I disorder, bipolar II disorder, delirium, hysteria, dissociative disorder, sleep disorder, anhedonia, neuropsychiatric symptoms associated with dementia, amnesic disorder, cognitive disorder, cognitive deficit associated with schizophrenia, movement disorder, depressive disorder, drug dependence, drug addiction, autistic disorder, Tourette's syndrome and / or attention deficit hyperactivity disorder, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or an isotope, stereoisomer, or a pharmaceutically acceptable salt thereof.

[0059] In another aspect, the invention relates to a compound of formula (I) or an isotope, stereoisomer, or a pharma- ceutically acceptable salt thereof for use in the treatment of a central nervous system disorder or condition selected from anxiety disorders, agitation, aggression, borderline personality disorder, schizophrenia, affective disorders, psychotic disorders, mood disorders, bipolar I disorder, bipolar II disorder, delirium, hysteria, dissociative disorders, sleep disorders, anhedonia, neuropsychiatric symptoms associated with dementia, amnesic disorders, cognitive disorders, cognitive deficits associated with schizophrenia, movement disorders, depressive disorders, drug dependence, drug addiction, autistic disorders, Tourette's syndrome, and / or attention deficit hyperactivity disorder.

[0060] In another aspect, the invention relates to the use of a compound of formula (I) or an isotope, stereoisomer, or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a central nervous system disorder or condition selected from anxiety disorders, agitation, aggression, borderline personality disorder, schizophrenia, affective disorders, psychotic disorders, mood disorders, bipolar I disorder, bipolar II disorder, delirium, hysteria, dissociative disorders, sleep disorders, anhedonia, neuropsychiatric symptoms associated with dementia, amnesic disorders, cognitive disorders, cognitive deficits associated with schizophrenia, movement disorders, depressive disorders, drug dependence, drug addiction, autistic disorders, Tourette's syndrome, and / or attention deficit hyperactivity disorder.

[0061] In another aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or an isotope, stereoisomer, or a pharma- ceutically acceptable salt thereof for use in the treatment of a central nervous system disorder or condition selected from anxiety disorders, agitation, aggression, borderline personality disorder, schizophrenia, affective disorders, psychotic disorders, mood disorders, bipolar I disorder, bipolar II disorder, delirium, hysteria, dissociative disorders, sleep disorders, anhedonia, neuropsychiatric symptoms associated with dementia, amnesic disorders, cognitive disorders, cognitive deficits associated with schizophrenia, movement disorders, depressive disorders, drug dependence, drug addiction, autistic disorders, Tourette's syndrome, and / or attention deficit hyperactivity disorder.

[0062] In some embodiments, the anxiety disorder is selected from panic disorder with or without agoraphobia, agoraphobia without a history of panic disorder; specific phobias, such as specific animal phobias, social anxiety, and social phobia; obsessive-compulsive disorder; stress disorders, including post-traumatic stress disorder and acute stress disorder; and generalized anxiety disorder.

[0063] In some embodiments, the anhedonia is selected from iatrogenic anhedonia; anhedonia due to psychological or psychiatric causes; anhedonia associated with depression; anhedonia associated with schizophrenia.

[0064] In some embodiments, the neuropsychiatric symptoms associated with dementia are selected from lack of motivation / apathy, agitation, aggression, depression, anxiety, irritability / lability, moodiness, abnormal behavior, delusions, hallucinations, elation / euphoria, psychosis, disinhibition, sleep and nocturnal behavior disorders, appetite and eating disorders, or a combination thereof.

[0065] In some embodiments, the schizophrenia is refractory schizophrenia, treatment-refractory schizophrenia, or chronic schizophrenia.

[0066] In some embodiments, the psychotic disorder is selected from a psychotic mood disorder such as schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder with delusions or hallucinations, psychotic episode of anxiety, anxiety associated with psychosis, or severe major depressive disorder.

[0067] In some embodiments, the mood disorder is selected from a mood disorder associated with a psychotic disorder, such as acute manic-depressive illness associated with bipolar disorder; or a mood disorder associated with schizophrenia.

[0068] In some embodiments, the cognitive disorder is selected from senile dementia, Alzheimer's dementia, memory impairment, loss of executive function, vascular dementia, dementia due to HIV disease, dementia due to head trauma, dementia due to Parkinson's disease, dementia due to Huntington's disease, dementia due to Pick's disease, dementia due to Creutzfeldt-Jakob disease, or dementia due to multiple etiologies.

[0069] In some embodiments, the movement disorder is selected from akinesia, dyskinesia including familial paroxysmal dyskinesia, spasticity, Tourette's syndrome, Scott syndrome, PALSY syndrome, akinetic rigidity syndrome, medication-induced movement disorders, e.g., extrapyramidal movement disorders such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia, or medication-induced postural tremor.

[0070] In some embodiments, the depressive disorder is selected from major depression, single episode major depressive disorder, recurrent major depressive disorder, depressive neurotic and neurotic depression, or melancholic depression.

[0071] In some embodiments, the drug dependence and addiction is selected from dependence or addiction to alcohol, alcoholism, heroin, cocaine, benzodiazepines, nicotine, phenobarbital, stimulant addiction, narcotic drug addiction, and behavioral addictions such as gambling addiction.

[0072] In another embodiment, the present invention relates to a process for the preparation of the compounds of formula (I) described herein.

[0073] Testing Procedure: The schemes show a general method for the preparation of compounds of formula (I) where X is a halogen and HetAr, A, B, P, Q, n, and m are as defined above.

[0074] [ka]

[0075] Route-1: Preparation of compounds of formula (I) A mixture of intermediate-1, intermediate-2 and an inorganic base selected from K2CO3, KHCO3, Na2CO3, NaHCO3 or NaOH is stirred in the presence of a metal scavenger such as 18-crown-6 in a solvent selected from 1,4-dioxane, toluene, DMF or xylene and heated at 100-155°C, preferably 133-140°C until most of intermediate-1 is consumed or for 3-12 hours, preferably 6 hours. The desired product is isolated by standard isolation techniques such as filtration, trituration, aqueous / organic work-up or recrystallization to give the compound of formula (I).

[0076] Route-2: Preparation of compounds of formula (I) A mixture of intermediate-1, intermediate-3 and an inorganic base selected from K2CO3, KHCO3, Na2CO3, NaHCO3 or NaOH is stirred in a solvent selected from 1,4-dioxane, toluene, DMF or xylene in the presence of a metal scavenger such as 18-crown-6 and heated at 100-155°C, preferably 133-140°C until most of intermediate-1 is consumed or for 3-12 hours, preferably 6 hours. The desired product is isolated by standard isolation techniques such as filtration, trituration, aqueous / organic work-up or recrystallization to give the compound of formula (I).

[0077] Route-3: Preparation of compounds of formula (I) A suspension of intermediate-1, intermediate-4, and an inorganic base selected from K2CO3, KHCO3, Na2CO3, NaHCO3 or NaOH in a solvent selected from 1,4-dioxane, toluene, DMF or xylene, most preferably DMF, is stirred and heated at 100-155°C, preferably 150-155°C until most of intermediate-1 is consumed or for 12-16 hours, preferably 16 hours. The desired product is isolated by standard isolation techniques such as filtration, trituration, aqueous / organic work-up or recrystallization to provide a compound of formula (I).

[0078] Preparation of Pharmacologically Acceptable Salts of Compounds of Formula (I) The compound of formula (I) can be optionally converted into its pharmaceutically acceptable salt by reaction with a suitable acid or acid derivative.Suitable pharmaceutically acceptable salts are clear 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, fumaric acid, citric acid, malic acid, tartaric acid, benzoic acid, p-toluic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid or naphthalenesulfonic acid.

[0079] Preparation of stereoisomers of compounds of formula (I) Stereoisomers of compounds of formula (I) may be prepared in one or more of the conventional manners set out below. a. One or more of the reagents may be used in their optically active form. b. An optically pure catalyst or chiral ligand along with a metal catalyst may be employed in the reduction process. The metal catalyst may be rhodium, ruthenium, indium, etc. The chiral ligand may be a preferably chiral phosphine. c. Mixtures of stereoisomers may be resolved by conventional methods such as forming diastereomeric salts with chiral acids or chiral amines or chiral amino alcohols, or chiral amino acids. The resulting mixture of diastereomers may then be separated by methods such as fractional crystallization, chromatography, and the like, followed by an additional step of isolating the optically active products from the salts of the resolved materials. 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 may be employed may be tartaric acid, mandelic acid, lactic acid, camphorsulfonic acid, amino acids, etc. Chiral bases that may be employed may be cinchona alkaloids, brucine, or basic amino acids such as lysine, arginine, etc.

[0080] In another embodiment, suitable pharma- ceutically acceptable salts of the compounds of formula (I) include, but are not limited to, hydrochloride, hydrobromide, oxalate, fumarate, tartrate, maleate, and succinate salts.

[0081] In another embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. For use in therapy, the compounds of formula (I) or their stereoisomers and their pharma- ceutically acceptable salts are normally formulated into pharmaceutical compositions in accordance with standard pharmaceutical practice.

[0082] 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, flow agents, polymers, coating agents, solvents, cosolvents, preservatives, wetting agents, thickeners, antifoaming agents, sweeteners, flavoring agents, antioxidants, colorants, solubilizers, plasticizers, dispersants, etc. The excipient may be 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 saline, alcohols, e.g. ethanol, propanol or glycerol, sugar solutions such as glucose solutions or mannitol solutions, or a mixture of different excipients.

[0083] In yet another embodiment, the compounds of the present invention may be formulated in the form of pills, tablets, coated tablets, capsules, powders, granules, pellets, patches, implantable injections, films, liquids, semisolids, gels, aerosols, emulsions, elixirs, etc. Such pharmaceutical compositions and methods for their preparation are well known in the art.

[0084] In yet 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 of the broader ranges of 1 mg to 500 mg.

[0085] The dose of the active compound may vary depending on factors such as the age and weight of the patient, the nature and severity of the disease or disorder to be treated, and other such factors. Therefore, any reference to a therapeutically effective amount of the compounds of general formula (I), their stereoisomers and pharma- ceutically acceptable salts refers to the above factors.

[0086] 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 Boc: tert-Butyloxycarbonyl Bn: Benzyl C max :Maximum blood concentration Cbz: benzyloxycarbonyl CDCl3: Deuterated chloroform DCM: dichloromethane DIPEA: N,N-Diisopropylethylamine DMF: N,N-dimethylformamide DMAP: 4-Dimethylaminopyridine DMSO: Dimethyl sulfoxide DOI: 2,5-dimethoxy-4-iodoamphetamine EC 50 : Half maximum effective concentration EtOAc:Ethyl acetate EtOH: Ethanol h: time g: grams HCl: Hydrochloric acid H2O: Water K2CO3: Potassium carbonate KHCO3: Potassium bicarbonate KOH: Potassium hydroxide L: Liters LC-MS / MS: Liquid chromatography-mass spectrometry / mass spectrometry LiOH: Lithium hydroxide nM: nanomolar concentration mL: milliliter mmol: millimolar min : minute M: Molar concentration Mp: Melting point MgSO4: Magnesium sulfate NaHCO3: Sodium bicarbonate Na2CO3: Sodium carbonate NaOH: Sodium hydroxide Na2SO4: Sodium sulfate NH4Cl: Ammonium chloride rpm: Revolutions per minute rt: Room temperature (25℃~30℃) ROA: Route of administration THF: Tetrahydrofuran t 1 / 2 :Half-life μL: microliter μM: micromolar ng / mL: nanograms per milliliter im: intramuscular po : oral sc: subcutaneous EXAMPLES

[0087] 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.

[0088] Preparation of intermediates: Intermediate-1a: Preparation of (S)-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione

[0089] [ka]

[0090] Step-a: At about 0° C., a 1M THF solution of lithium aluminum hydride (791.6 mL) was added dropwise to a mixture of pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (165.0 g, 719.6 mmol). After stirring at about 0° C. for about 60 min, the mixture was quenched by adding EtOAc (360.0 mL), saturated aqueous NH4Cl solution (719.6 mL), and then 1N NaOH solution (719.6 mL). The suspension was stirred for 1 h and then filtered through cloth / paper. The filtrate was then separated into two layers, the organic layer was washed with brine solution, dried over anhydrous Na2SO4, and the solvent was removed under vacuum to give (S)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (126.0 g) in 87% yield. 1 H NMR (400 MHz, CDCl3): δ 4.80-4.72 (m, 1H), 4.01-3.92 (m, 1H), 3.68-3.54 (m, 2H), 3.50-3.40 (m, 1H), 3.37-3.28 (m, 1H), 2.08-1.50 (m, 1H), 1.90-1.75 (m, 3H), 1.47 (s, 9H); IR (film) υ 3428, 2971, 2880, 2376, 1683, 1407 cm -1 ; Mass (m / z): 202.1 (M+H) + .

[0091] Step-b: To a stirred mixture of step-a compound (200.0 g, 993.7 mmol) cooled at 0° C., triethylamine (278.9 mL, 1987.4 mmol) was added followed by methanesulfonyl chloride (97.5 mL, 1192.4 mmol). The reaction mass was stirred for 1 h and then quenched with water. The two layers were separated and the organic layer was washed again with water, dried over anhydrous Na2SO4 and the solvent was removed under vacuum to give (S)-2-(methanesulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (274.0 g) in 98% yield. 1H NMR (400 MHz, CDCl3): δ 4.35-4.28 (m, 2H), 4.05-3.95 (m, 1H), 3.40-3.30 (m, 2H), 3.00 (s, 3H), 2.10-1.80 (m, 4H), 1.46 (s, 9H); Mass (m / z): 280.0 (M+H) + .

[0092] Step-c: A solution of step-b compound (229.8 g, 822.6 mmol) and potassium cyanide (160.4 g, 2467.8 mmol) in DMSO (1.64 L) was stirred for about 7 hours at about 90° C. Standard extractive workup with EtOAc followed by solvent evaporation afforded (S)-2-cyanomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as an oil (137.1 g) in 79% yield. 1 H NMR (400 MHz, CDCl3): δ 4.05-3.96 (m, 1H), 3.50-3.35 (m, 2H), 2.88-2.80 (m, 0.5H), 2.78-2.65 (m, 2H), 2.60-2.52 (m, 0.5H), 2.22-2.12 (m, 1H), 2.08-1.80 (m, 3H), 1.46 (s, 9H). IR (film) υ 2975, 2885, 2248, 1693, 1462, 1397, 1254 cm -1 ; Mass (m / z): 211.2 (M+H) + .

[0093] Step-d: To a solution of step-c compound (0.50 g, 2.37 mmol) in isopropanol (4.8 mL) cooled at 0-5° C., dry HCl in isopropanol (3 M, 23.7 mL) was added over 15 minutes. The reaction mass was stirred at the same temperature for another hour, after which the temperature was gradually increased to reflux. Reflux was continued for 48 hours, followed by distillation of solvent and removal of traces of solvent under high vacuum at 50° C. to obtain (S)-2-pyrrolidin-2-yl-acetic acid isopropyl ester hydrochloride (0.42 g) as an off-white solid in 86% yield. 1H-NMR (DMSO-d6): δ 9.55 (bs, 1H), 9.38 (bs, 1H), 5.0-4.88 (m, 1H), 3.76-3.63 (m, 1H), 3.20-3.10 (m, 2H), 2.90 (dd, J = 7.6, 17.2 Hz, Mass (m / z): 172.0 (M+H) + .

[0094] Step-e: To a solution of step-d compound (100.3 g, 482.9 mmol) in a 1:1 mixture of THF and water (1932.0 mL) cooled at 0-5°C, NaHCO3 (386.3 g, 4829 mmol) was added. The reaction mixture was stirred for further 30 min and cyanogen bromide (61.4 g, 579.4 mmol) was added over 15 min. The reaction mass was stirred for further 2 h at the same temperature and then extracted multiple times with EtOAc. The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4 and the solvent was evaporated under vacuum to give (S)-(1-cyanopyrrolidin-2-yl)-acetic acid isopropyl ester (66.9 g) in 70.6% yield. 1 H-NMR (CDCl3): δ 5.10-5.0 (m, 1H), 4.02-3.94 (m, 1H), 3.01-2.88 (m, 2H), 2.78 (dd, J = 5.2, 16.0 Hz, 1H), 2.43 (dd, J = 8.4, 16.0 Hz, Mass (m / z): 197.1 (M+H) + .

[0095] Step-f: A solution of step-e compound (66.9 g, 340.9 mmol) in dibutyl phosphate (143.3 mL, 681.8 mmol) at room temperature was heated at 110° C. for 2 hours. The reaction mass was then cooled to room temperature and triturated with hexane multiple times, followed by trituration twice. The precipitated solid compound was then filtered through a Nutsche filter to obtain (S)-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione (45.1 g) in 85% yield. 1 H-NMR (CDCl3): δ 7.95 (bs, 1H), 3.82-3.72 (m, 1H), 3.70-3.60 (m, 1H), 3.56-3.47 (m, 1H), 2.80 (dd, J = 4.0, 16.4 Hz, 1H), 2.38 (dd, J = Mass (m / z): 154.9 (M+H) + .

[0096] Intermediate-1b: Preparation of 6-fluoro-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione

[0097] [ka]

[0098] Step-a: To a stirred solution of 4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.70 g, 3.0 mmol; prepared from 4-hydroxy-pyrrolidine-2-carboxylic acid by using the protocol reported in WO2007113634 A1) in DCM (6.0 mL) cooled at -30°C, triethylamine (0.5 mL, 3.6 mmol) and isobutyl chloroformate (0.47 mL, 3.6 mmol) were added. The reaction mass was stirred for further 15 min. The reaction mass was warmed to 0°C and then a freshly prepared solution of diazomethane (ca. 15-30 mmol) in diethyl ether was added. The reaction mixture was stirred for further 30 min at the same temperature. Excess diazomethane was quenched by adding methanol. The reaction mixture was diluted with additional diethyl ether and washed with saturated NaHCO3 aqueous solution. The organic layer was washed with brine solution, dried over anhydrous Na2SO4, and the solvent was removed under vacuum to give 2-(2-diazoacetyl)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (1.1 g) in 42% yield. Mass (m / z): 258.2 (M+H). + .

[0099] Step-b: To a stirred solution of step-a compound (1.1 g, 4.27 mmol) in methanol (17.0 mL) cooled at -30°C under nitrogen atmosphere, DIPEA (2.24 mL, 12.82 mmol) was added. After 10 min, silver benzoate (0.21 g, 0.85 mmol) was added and the reaction mass was allowed to warm to room temperature slowly. After 2 h, the reaction mass was filtered through cloth / paper bed and the filtrate was concentrated under vacuum to obtain crude mass. It was purified by silica gel column chromatography to obtain 4-fluoro-2-methoxycarbonylmethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.186 g) in 17% yield. 1H-NMR (CDCl3): δ 5.30-5.10 (m, 1H), 4.56-4.40 (m, 1H), 3.67 (s, 3H), 3.60-3.48 (m, 1H), 3.45-3.25 (m, 1H), 2.90-2.77 (m, 2H), 2.60-2.40 (m, 1H), 2.05-1.90 (m, 1H), 1.48 (s, 9H); Mass (m / z): 262.2 (M+H) + .

[0100] Step-c: To a stirred solution of step-b compound (0.186 g, 0.72 mmol) in methanol (1.5 mL) cooled at 0° C., dry HCl in methanol (3 M, 1.5 mL) was added. The reaction mass was gradually warmed to room temperature and stirred for 16 hours. The contents were removed under vacuum to give a gummy mass, which was triturated with diethyl ether to give (4-fluoro-pyrrolidin-2-yl)-acetic acid methyl ester hydrochloride as a solid (0.097 g) in 69% yield. 1 H-NMR (DMSO-d6): δ 9.66 (bs, 1H), 9.29 (bs, 1H), 5.50-5.30 (m, 1H), 4.02-3.90 (m, 1H), 3.66 (s, 3H), 3.60-3.45 (m, 1H), 3.45-3.30 (m, 1H), 2.90-2.75 (m, 2H), 2.60-2.45 (m, 1H), 2.05-1.88 (m, 1H); Mass (m / z): 162.1 (M+H) + .

[0101] Step-d: By following the procedure reported for step-e of preparation of intermediate-1a, step-c compound (97.0 mg) was converted to (1-cyano-4-fluoro-pyrrolidin-2-yl)-acetic acid methyl ester (73.0 mg) in 80% yield. 1H-NMR (CDCl3): δ 5.40-5.20 (m, 1H), 4.02-3.90 (m, 1H), 3.66 (s, 3H), 3.60-3.45 (m, 1H), 3.45-3.30 (m, 1H), 2.90-2.75 (m, 2H), 2.60-2.45 (m, 1H), 2.05-1.88 (m, 1H); Mass (m / z): 187.1 (M+H) + .

[0102] Step-e: By following the procedure reported for step-f of preparation of intermediate-1a, step-d compound (73.0 mg) was converted to 6-fluoro-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione (37.0 mg) in 55% yield. 1 H-NMR (CDCl3): δ 7.43 (bs, 1H), 5.36-5.18 (m, 1H), 4.17 (dd, J = 13.2, 19.6 Hz, 1H), 4.05-3.95 (m, 1H), 3.57 (dd, J = 3.6, 13.6 Hz, Mass (m / z): 173.1 (M+H) + .

[0103] Intermediate-1c: Preparation of hexahydro-1b,3-diaza-cyclopropa[a]indene-2,4-dione

[0104] [ka]

[0105] Step-a: 3-(methanesulfonyloxymethyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester was prepared from 3-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (prepared by following the protocol of WO2011061751) by following the procedure reported for step-b of the preparation of intermediate-1a. Mass (m / z): 292.1 (M+H) + .

[0106] Step-b: 3-Cyanomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester was prepared from step-a compound by following the procedure reported for step-c of intermediate-1a preparation. Mass (m / z): 223.1 (M+H). + .

[0107] Step-c: (2-Aza-bicyclo[3.1.0]hex-3-yl)-acetic acid isopropyl ester hydrochloride was prepared from step-b compound by following the procedure reported for step-d of intermediate-1a preparation. Mass (m / z): 184.1 (M+H). + .

[0108] Step-d: (2-Cyano-2-aza-bicyclo[3.1.0]hex-3-yl)-acetic acid isopropyl ester was prepared from step-c compound by following the procedure reported for step-e of preparation of intermediate-1a. Mass (m / z): 209.2 (M+H). + .

[0109] Step-e: Hexahydro-1b,3-diaza-cyclopropa[a]indene-2,4-dione was prepared from step-d compound by following the procedure reported for step-f of intermediate-1a preparation. Mass (m / z): 167.1 (M+H). + .

[0110] Intermediate-1d: Preparation of hexahydro-pyrido[1,2-c]pyrimidine-1,3-dione

[0111] [ka]

[0112] Step-a: 2-(2-Diazo-acetyl)-piperidine-1-carboxylic acid tert-butyl ester was prepared from commercially available piperidine-1,2-dicarboxylic acid 1-tert-butyl ester by following the procedure reported for step-a of the preparation of intermediate-1b. 1 H NMR (400 MHz, CDCl3): δ 5.42 (s, 1H), 4.85-4.75 (m, 1H), 4.20-3.92 (m, 1H), 2.95-2.72 (m, 1H), 2.35-2.22 (m, 1H), 1.70-1.60 (m, 4H), 1.55-1.50 (m, 1H), 1.48 (s, 9H); Mass (m / z): 254.2 (M+H) + .

[0113] Step-b: 2-Methoxycarbonylmethyl-piperidine-1-carboxylic acid tert-butyl ester was prepared from step-a compound by following the procedure reported for step-b of preparation of intermediate-1b. 1 H NMR (400 MHz, CDCl3): δ 4.76-4.62 (m, 1H), 4.10-3.90 (m, 1H), 3.66 (s, 3H), 2.85-2.70 (m, 1H), 2.65-2.49 (m, 2H), 1.75-1.60 (m, 4H), 1.55-1.35 (m, 11H); Mass (m / z): 258.2 (M+H) + .

[0114] Step-c: Piperidin-2-yl-acetic acid methyl ester hydrochloride was prepared from step-b compound by following the procedure reported for step-c of preparation of intermediate-1b. 1H NMR (400 MHz, DMSO-d6): δ 9.09 (bs, 2H), 3.64 (s, 3H), 3.43-3.30 (m, 1H), 3.27-3.19 (m, 1H), 2.95-2.80 (m, 2H), 2.68 (dd, J = 8.0, Mass (m / z): 157.9 (M+H) + .

[0115] Step-d: (1-Cyano-piperidin-2-yl)-acetic acid methyl ester was prepared from step-c compound by following the procedure reported for step-d of preparation of intermediate-1b. 1 H NMR (400 MHz, CDCl3): δ 3.72 (s, 3H), 3.48-3.38 (m, 2H), 3.15-3.04 (m, 1H), 2.86 (dd, J = 6.4, 16.0 Hz, 1H), 2.55 (dd, J = 7.2, 16.0 Hz, 1H), 1.88-1.75 (m, 2H), 1.70-1.62 (m, 2H), 1.56-1.36 (m, 2H); Mass (m / z): 183.1 (M+H) + .

[0116] Step-e: Hexahydro-pyrido[1,2-c]pyrimidine-1,3-dione was prepared from step-d compound by following the procedure reported for step-e of preparation of intermediate-1b. 1 H NMR (400 MHz, DMSO-d6): δ 10.18 (bs, 1H), 4.12-4.05 (m, 1H), 3.43-3.30 (m, 1H), 2.70-2.58 (m, 2H), 2.41 (dd, J = 8.8, 16.8 Hz, 1H), 1.78-1.68 (m, 2H), 1.68-1.62 (m, 1H), 1.45-1.25 (m, 2H), 1.25-1.13 (m, 1H); Mass (m / z): 169.0 (M+H)+ .

[0117] Intermediate-1e: Preparation of tetrahydro-pyrimido[6,1-c][1,4]oxazine-6,8-dione

[0118] [ka]

[0119] Step-a: To a stirred solution of morpholine-3,4-dicarboxylic acid 4-(9H-fluoren-9-ylmethyl) ester 3-methyl ester (1.9 g, 5.17 mmol; prepared according to the procedure reported in J. Org. Chem. 2007, 72, 4254-4257) in methanol (21.0 mL) at room temperature, 10% Pd-C (palladium on carbon 0.9 g) was added and the reaction mass was stirred for 16 h under nitrogen atmosphere. The reaction mass was filtered through cloth / paper bed, the filtrate was evaporated under vacuum and the crude product thus obtained was purified by silica gel column chromatography to obtain morpholine-3-carboxylic acid methyl ester (0.67 g) in 90% yield. 1 H NMR (400 MHz, CDCl3): δ 4.01 (dd, J = 3.2, 11.2 Hz, 1H), 3.80-3.72 (m, 2H), 3.75 (s, 3H), 3.65-3.56 (m, 2H), 3.08-3.02 (m, 1H), 2.91-2.83 (m, 1H); Mass (m / z): 146.1 (M+H) + .

[0120] Step-b: To a stirred solution of step-a compound (0.64 g, 4.45 mmol) in DCM (18.0 mL) cooled at 0° C., triethylamine (2.40 mL, 17.80 mmol), DMAP (54.0 mg, 0.44 mmol), and Boc anhydride (2.26 mL, 9.78 mmol) were added. The reaction mass was gradually warmed to room temperature and stirred for 16 h. The volatiles were removed under vacuum and the crude product was purified by silica gel column chromatography to give morpholine-3,4-dicarboxylic acid 4-tert-butyl ester 3-methyl ester (0.75 g) in 69% yield. 1 H NMR (400 MHz, CDCl3): δ 4.61-4.56 (m, 0.5H), 4.45-4.30 (m, 1.5H), 3.95-3.72 (m, 1.5H), 3.77 (s, 3H), 3.70-3.60 (m, 1.5H), 3.54-3.41 (m, 1H), 3.38-3.28 (m, 0.5H), 3.25-3.13 (m, 0.5H), 1.48 (s, 4.5H), 1.44 (s, 4.5H); Mass (m / z): 268.1 (M+Na) + .

[0121] Step-c: To a stirred solution of step-b compound (0.75 g, 3.05 mmol) in a mixture of THF and water (1:1, 12 mL) at room temperature, LiOH.H2O (0.16 g, 3.66 mmol) was added. The reaction mass was stirred for 2 h and then diluted with diethyl ether and water. The two layers were separated and the aqueous layer was acidified to pH 2 using concentrated HCl and extracted with EtOAc. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and the solvent was removed under vacuum to give morpholine-3,4-dicarboxylic acid 4-tert-butyl ester (0.64 g) in 90% yield. 1H NMR (400 MHz, DMSO-d6): δ 12.99 (bs, 1H), 4.34 (dd, J = 2.4, 20.4 Hz, 1H), 4.18 (dd, J = 12.0, 15.2 Hz, 1H), 3.86-3.72 (m, 1H), 3.60-3.50 (m, 2H), 3.40-3.34 (m, 1H), 3.05-2.95 (m, 1H), 1.40 (s, 4H), 1.36 (s, 5H); Mass (m / z): 254.3 (M+Na) + .

[0122] Step-d: Step-c compound (0.64 g, 2.77 mmol) was converted to 3-(2-diazo-acetyl)-morpholine-4-carboxylic acid tert-butyl ester in quantitative yield by following the procedure reported for step-a of intermediate-1b preparation. Mass (m / z): 278.3 (M+Na). + .

[0123] Step-e: Step-d compound (0.90 g, 3.5 mmol) was converted to 3-methoxycarbonylmethyl-morpholine-4-carboxylic acid tert-butyl ester (0.15 g) in 17% yield by following the procedure reported for step-b of preparation of intermediate-1b. Mass (m / z): 260.2 (M+H). + .

[0124] Step-f: Step-e compound (0.15 g, 0.58 mmol) was converted to morpholin-3-yl-acetic acid methyl ester hydrochloride (0.11 g) in quantitative yield by following the procedure reported for step-c of preparation of intermediate-1b. 1 H NMR (400 MHz, DMSO-d6): δ 9.47 (bs, 1H), 9.28 (bs, 1H), 3.96-3.85 (m, 2H), 3.72-3.65 (m, 1H), 3.64 (s, 3H), 3.60-3.35 (m, 2H), 3.30-3.06 (m, 2H), 2.76-2.60 (m, 2H); Mass (m / z): 160.2(M+H) + .

[0125] Step-g: Step-f compound (0.1 g, 0.6 mmol) was converted to (4-cyano-morpholin-3-yl)-acetic acid methyl ester (0.07 g) in 59% yield by following the procedure reported for step-d of preparation of intermediate-1b. Mass (m / z): 185.1 (M+H). + .

[0126] Step-h: Step-g compound (0.07 g, 0.37 mmol) was converted to tetrahydro-pyrimido[6,1-c][1,4]oxazine-6,8-dione (24.0 mg) in 38% yield by following the procedure reported for step-e of preparation of intermediate-1b. 1 H NMR (400 MHz, CDCl3): δ 7.49 (bs, 1H), 4.10-4.01 (m, 2H), 4.0-3.93 (m, 1H), 3.68-3.52 (m, 2H), 3.21 (t, J = 11.2 Hz, 1H), 3.07-2.98 (m, 1H), 2.65 (dd, J = 4.8, 16.8 Hz, 1H), 2.39 (dd, J = 12.4, 16.8 Hz, 1H); Mass (m / z): 171.1 (M+H) + .

[0127] Intermediate-1f: Preparation of 6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid benzyl ester

[0128] [ka]

[0129] Step-a: Cbz protection of commercially available S-piperazine-2-carboxylic acid was carried out by following the procedure reported in WO2012019426, followed by Boc protection as reported in Tetrahedron Letters 1989, 30, 5129-5132 to obtain piperazine-1,2,4-tricarboxylic acid 4-benzyl ester 1-tert-butyl ester. The above obtained compound was converted to 2-(2-diazo-acetyl)-piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester by following the procedure reported for step-a of preparation of intermediate-1b. 1 H NMR (400 MHz, CDCl3): δ 7.40-7.30 (m, 5H), 5.50-5.36 (m, 1H), 5.20-5.08 (m, 2H), 4.70-4.50 (m, 2H), 4.08-3.85 (m, 2H), 3.25-3.08 (m, 2H), 3.06-2.95 (m, 1H), 1.47 (s, 9H); Mass (m / z): 389.1 (M+H) + .

[0130] Step-b: The compound of step-a was converted to 2-Methoxycarbonylmethyl-piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester by following the procedure reported for step-b of preparation of intermediate-1b. 1 H NMR (400 MHz, CDCl3): δ 7.40-7.30 (m, 5H), 5.20-5.06 (m, 2H), 4.70-4.52 (m, 1H), 4.15-4.05 (m, 2H), 3.98-3.85 (m, 1H), 3.70-3.52 (m, 3H), 3.13-2.80 (m, 3H), 2.62-2.42 (m, 2H), 1.48 (s, 9H); Mass (m / z): 393.2 (M+H) + .

[0131] Step-c: The compound of step-b was converted to 3-Methoxycarbonylmethyl-piperazine-1-carboxylic acid benzyl ester hydrochloride by following the procedure reported for step-c of preparation of intermediate-1b. 1 H NMR (400 MHz, CDCl3): δ 7.40-7.30 (m, 5H), 5.20-5.10 (m, 2H), 4.30-4.15 (m, 1H), 3.73 (s, 3H), 3.60-3.05 (m, 6H), 2.96-2.86 (m, 1H), 2.70-2.58 (m, 1H); Mass (m / z): 293.1 (M+H) + .

[0132] Step-d: The compound of step-c was converted to 4-cyano-3-methoxycarbonylmethyl-piperazine-1-carboxylic acid benzyl ester by following the procedure reported for step-d of preparation of intermediate-1b. 1 H NMR (400 MHz, CDCl3): δ 7.40-7.30 (m, 5H), 5.20-5.08 (m, 2H), 3.95-3.82 (m, 1H), 3.80-3.40 (m, 5H), 3.50-3.40 (m, 1H), 3.40-3.32 (m, 1H), 3.30-3.15 (m, 2H), 2.81 (dd, J = 6.4, 16.8 Hz, 1H), 2.61 (dd, J = 7.2, 16.8 Hz, 1H); Mass (m / z): 318.2(M+H) + .

[0133] Step-e: The compound of step-d was converted to 6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid benzyl ester by following the procedure reported for step-e of preparation of intermediate-1b. 1H NMR (400 MHz, DMSO-d6): δ 10.35 (bs, 1H), 7.40-7.38 (m, 5H), 5.10 (s, 2H), 4.10-3.96 (m, 3H), 3.60-3.50 (m, 1H), 3.05-2.85 (m, 1H), 2.85-2.62 (m, 3H), 2.50-2.38 (m, 1H); Mass (m / z): 304.3 (M+H) + .

[0134] Intermediate-2a: Preparation of 8-benzo[d]isothiazol-3-yl-8-aza-5-azonia-spiro[4.5]decane bromide

[0135] [ka]

[0136] A mixture of 3-piperazin-1-yl-benzo[d]isothiazole (50.0 g, 227.98 mmol), 1,4-dibromobutane (60.5 g, 280.42 mmol), anhydrous K2CO3 (75.5 g, 547.15 mmol), and 18-crown-6 (0.6 g, 2.27 mmol) in EtOH (912 mL) was heated to reflux with stirring for 8 h. The hot reaction mixture was filtered and the filtrate was concentrated under vacuum to approximately 1 / 3 of its original volume, refiltered, and cooled. The crystalline precipitate was collected and dried under vacuum at 100 °C to give 58.9 g (73%) of the title compound. Mp: 258-259 °C; 1 H NMR (400 MHz, DMSO-d6): δ 8.20 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 3.86-3.80 (m, 4H), 3.78-3.65 (m, 8H), 2.20-2.08 (m, 4H); Mass (m / z): 274.3 (M) + .

[0137] Intermediates-2b-2e were prepared from 1-benzo[b]thiophen-4-yl-piperazine, 5-fluoro-4-piperidin-4-yl-1H-indole, 6-fluoro-4-piperidin-4-yl-benzo[d]isoxazole, and 5-methoxy-3-piperidin-4-yl-1H-indole using the procedure described for Intermediate-2a with some minor modifications.

[0138] [Table 1A]

[0139] [Table 1B]

[0140] Intermediate-3a: Preparation of Intermediate-3a

[0141] [ka]

[0142] Step-a: To a stirred solution of commercially available (R,R)-trans-1,2-cyclohexanedimethanol (3.0 g, 20.8 mmol) in DCM (83.0 mL) cooled at 0° C., triethylamine (10.1 mL, 72.9 mmol) and methanesulfonyl chloride (4.4 mL, 57.2 mmol) were added. The reaction mixture was gradually warmed to room temperature and the mixture was stirred for 6 h. After completion of the reaction, the reaction mass was diluted with water and the two layers were separated. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and the solvent was removed under vacuum to obtain (1R,2R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane as a solid (5.5 g) in 90% yield. 1H-NMR (CDCl3): δ 4.32-4.25 (m, 2H), 4.21-4.16 (m, 2H), 3.0 (s, 6H), 1.86-1.75 (m, 4H), 1.73-1.68 (m, 1H), 1.63-1.52 (m, 1H), 1.35-1.20 (m, 4H); Mass (m / z): 323.0 (M+Na) + .

[0143] Step-b: To a stirred solution of commercially available 3-piperazin-1-yl-benzo[d]isothiazole (1.0 g, 4.56 mmol) in toluene (20.0 mL) at room temperature, the solid (1R,2R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane (13.7 g, 45.6 mmol) obtained in step-a above was added and the reaction mass was stirred under reflux for 3 hours. The reaction mass was then cooled to room temperature and the volatiles were removed under vacuum. The crude reaction mass was triturated with diethyl ether and the solid obtained was dried under vacuum to give intermediate 3a (0.98 g) in quantitative yield. 1 H-NMR (DMSO-d6): δ 8.20 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 4.0-3.92 (m, Mass (m / z): 328.1(M) + .

[0144] Intermediate-3b: Preparation of Intermediate-3b

[0145] [ka]

[0146] By following the procedure reported for step-b of the preparation of intermediate-3a, intermediate-3b was prepared in quantitative yield by reacting 6-fluoro-3-piperidin-4-yl-benzo[d]isoxazole and (1R,2R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane. 1 H-NMR (DMSO-d6): δ 8.11 (dd, J = 5.6, 8.8 Hz, 1H), 7.75 (dd, J = 1.2, 9.2 Hz, 1H), 7.37 (dd, J = 1.2, 9.2 Hz, 1H), 4.03-3.97 (m, 1H), 3.88-3.82 (m, 1H), 3.78-3.70 (m, 1H), 3.65-3.50 (m, 5H), 3.34 (s, 3H), 2.40-2.23 (m, 4H), 2.20-2.08 (m, 1H), 1.95-1.75 (m, 6H), 1.30-1.10 (m, 4H); Mass (m / z): 329.1 (M) + .

[0147] Preparation of Intermediate-4a: 3-[4-(3-chloro-propyl)-piperazin-1-yl]-benzo[d]isothiazole

[0148] [ka]

[0149] To a stirred suspension of commercially available 3-piperazin-1-yl-benzo[d]isothiazole (10.0 g, 45.6 mmol), KOH flakes (7.6 g, 137.0 mmol) and a 1:1 mixture of THF and water (100.0 mL) was added 1-bromo-3-chloropropane (19.6 g, 137.0 mmol) at room temperature. The mixture was stirred for 16 h and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine solution, dried over anhydrous Na2SO4 and the solvent was evaporated under vacuum. The resulting residue was purified by silica gel column chromatography to give intermediate-4a (9.68 g) in 72% yield. 1H NMR (400 MHz, DMSO-d6): δ 8.06-8.03 (m, 2H), 7.53 (dd, J = 7.2 Hz, 1H), 7.41 (dd, J = 7.6 Hz, 1H), 3.72-3.68 (m, 2H), 3.45-3.43 (m, 4H), 2.60-2.56 (m, 4H), 2.52-2.46 (m, 2H), 1.96-1.90 (m, 2H); Mass (m / z): 296.1, 298.1 (M+H) + .

[0150] Using a similar procedure described in the preparation of Intermediate-4a with some minor modifications, Intermediates-4b, 4c and 4d were prepared.

[0151] Preparation of Intermediate-4b: 3-[1-(3-chloro-propyl)-piperidin-4-yl]-6-fluoro-benzo[d]isoxazole

[0152] [ka]

[0153] Yield: 7.9g (62%); 1 H NMR (400 MHz, DMSO-d6): δ 7.79 (s, 1H), 7.47-7.45 (m, 1H), 7.26-7.21 (m, 1H), 4.63-4.53 (m, 2H), 3.75-3.65 (m, 2H), 3.19-3.11 mass (m / z): 297.2, 299.2 (M+H) + .

[0154] Preparation of Intermediate-4c: 3-[1-(3-chloro-propyl)-piperidin-4-yl]-5-fluoro-1H-indole

[0155] [ka]

[0156] Yield: 2.3g (65%); 1 H NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 7.43 (dd, J = 2, 10.4 Hz, 1H), 7.36 (dd, J = 4.8, 8.8 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 6.94 (dt, J = 2.4, 9.2 Hz, 1H), 4.62 (t, J = 7.6 Hz, 2H), 3.75-3.65 (m, 2H), 3.19-3.11 (m, 2H), 3.03-2.95 (m, 2H), 2.74-2.63 (m, 1H), 2.29-2.21 (m, 2H), 2.07-2.01 (m, 2H), 1.85-1.78 (m, 2H); Mass (m / z): 295.2, 297.2 (M+H) + .

[0157] Preparation of Intermediate-4d: 3-[1-(3-chloro-propyl)-piperidin-4-yl]-benzo[d]isoxazole

[0158] [ka]

[0159] Yield: 0.3g (44%); 1H NMR (400 MHz, DMSO-d6): δ 8.07 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 4.65-4.55 (m, 2H), 3.75-3.65 (m, 2H), 3.20-3.10 (m, 2H), 3.05-2.95 (m, 2H), 2.75-2.65 (m, 1H), 2.30-2.20 (m, 2H), 2.08-2.0 (m, 2H), 1.85-1.75 (m, 2H); Mass (m / z): 279.2, 281.2 (M+H) + .

[0160] Example 1 2-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione

[0161] [ka]

[0162] A mixture of intermediate-2a (114.0 g, 321.78 mmol), intermediate-1a (45.1 g, 292.5 mmol), anhydrous K2CO3 (80.7 g, 585.0 mmol), and 18-crown-6 (0.77 g, 2.92 mmol) in xylene (1170 mL) was stirred and heated to reflux for 3 h. The hot mixture was filtered through cloth / paper and the cloth / paper was washed with EtOAc. The combined organic layer was washed with water and brine solution. The organic layer thus obtained was dried over anhydrous Na2SO4 and the solvent was removed under vacuum. The crude product was triturated with pentane followed by 3% EtOAc in hexane to obtain the above titled compound (87.2 g) in 69.7% yield. 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 3.88-3.79 (m, 1H), 3.78-3.61 (m, 2H), 3.59-3.48 (m, 5H), 2.86 (dd, J = 4.0, 16.0 Hz, 1H), 2.70-2.63 (m, 4H), 2.49-2.42 (m, 4H), 2.43 (dd, J = 14.0, 16.0Hz, 1H), 2.31-2.23 (m, 1H), 2.12-2.02 (m, 1H), 1.96-1.81 (m, 1H), 1.68-1.51 (m, 4H); Mass (m / z): 428.1 (M+H) + .

[0163] Example 2 2-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione oxalate

[0164] [ka]

[0165] Example 1 (87.0 g) was converted to the oxalate salt by treatment with 1 equivalent of oxalic acid in isopropanol for 12 hours to give Example 2 (112.3 g) in quantitative yield. 1H NMR (400 MHz, DMSO-d6): δ 8.11 (d, J = 7.6 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 3.73-3.55 (m, 7H), 3.49-3.42 (m, 1H), 3.41-3.32 (m, 1H), 3.23-3.09 (m, 4H), 2.97-2.87 (m, 2H), 2.74 (dd, J = 4.0, 16.0 Hz, 1H), 2.59 (dd, J = 14.0, 16.0 Hz, 1H), 2.19-2.11 (m, 1H), 2.0-1.91 (m, 1H), 1.86-1.71 (m, 1H), 1.65-1.45 (m, 5H); Mass (m / z): 428.2 (M+H) + ; HPLC purity: 99.6%.

[0166] Using the procedures described for the preparation of Example-1 and Example-2 with some minor changes, the following Examples 3 to 22 were prepared by using the appropriate intermediates (the fumarate salts of the compounds were prepared by reacting with fumaric acid using the procedure of Example 2).

[0167] [Table 2A]

[0168] [Table 2B]

[0169] [Table 2C]

[0170] [Table 2D]

[0171] [Table 2E]

[0172] [Table 2F]

[0173] [Table 2G]

[0174] [Table 2H]

[0175] (Example 23) 2-[3-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-propyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione

[0176] [ka]

[0177] A mixture of intermediate-1a (1.54 g, 10.0 mmol), intermediate-4a (2.95 g, 10.0 mmol) and K2CO3 (2.76 g, 20.0 mol) in DMF (20 mL) was stirred at 80-100 °C for 16 h. The reaction mixture was cooled to room temperature, poured into water (200 mL) and extracted with EtOAc. The organic phase was washed once with brine solution, dried over MgSO4 and evaporated under vacuum. The residue was further purified by flash column chromatography to give the above titled compound (2.12 g) in 52% yield. 1H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 3.95-3.85 (m, 1H), 3.82-3.75 (m, 1H), 3.74-3.62 (m, 1H), 3.62-3.55 (m, 4H), 3.55-3.48 (m, 1H), 2.86 (dd, J = 4.0, 16.0 Hz, 1H), 2.75-2.68 (m, 4H), 2.53 (t, J = 7.6 Hz, Mass (m / z): 414.1 (M+H) + .

[0178] Examples 24 and 25 were prepared using the procedure of Example 23 using the appropriate intermediates with some minor modifications.

[0179] [Table 3]

[0180] (Example 26) 2-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-ylmethyl)-cyclohexylmethyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione

[0181] [ka]

[0182] A mixture of intermediate-3a (114.0 g, 321.78 mmol), intermediate-1a (45.1 g, 292.5 mmol), anhydrous K2CO3 (80.7 g, 585.0 mmol), and 18-crown-6 (0.77 g, 2.92 mmol) in xylene (1170 mL) was stirred and heated to reflux for 3 h. The hot mixture was filtered through filter cloth / paper and the filter cloth / paper was washed with EtOAc. The filtrate was washed with water and brine solution. The organic layer thus obtained was dried over anhydrous Na2SO4 and the solvent was removed under vacuum. The crude product was triturated with pentane followed by 3% EtOAc in hexane to obtain the above titled compound (87.2 g) in 69.7% yield. 1 H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 4.15-4.0 (m, 1H), 3.80-3.60 (m, 4H), 3.58-3.48 (m, 5H), 2.88-2.76 (m, 1H), 2.70-2.56 (m, 4H), 2.45-2.33 (m, 1H), 2.32-2.20 (m, 2H), 2.15-2.02 (m, 1H), 1.98-1.83 (m, 2H), 1.70-1.48 (m, 5H), 1.45-1.35 (m, 1H), 1.30-0.95 (m, 4H); Mass (m / z): 482.2 (M+H) + ; HPLC purity: 92.01%.

[0183] Example 27 2-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-ylmethyl)-cyclohexylmethyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione oxalate

[0184] [ka]

[0185] Example-27 was prepared from Example-26 by following the procedure described for Example-2 with minor changes. 1 H NMR (400 MHz, DMSO-d6): δ 8.10 (d, J = 6.8 Hz, 1H), 8.09 (d, J = 7.2 Hz, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 3.88-3.72 (m, 2H), 3.70-3.50 (m, 4H), 3.50-3.26 (m, 4H), 3.15-2.95 (m, 4H), 2.76-2.62 (m, 1H), 2.62-2.30 (m, 3H), 2.20-2.08 (m, 1H), 2.0-1.90 (m, 2H), 1.86-1.70 (m, 1H), 1.65-1.40 (m, 5H), 1.30-0.90 (m, 4H); Mass (m / z): 482.2 (M+H) + ; HPLC purity: 98.3%.

[0186] Examples 28-30 were prepared using the procedures of Example 26 and Example 2 using the appropriate intermediates with some minor modifications.

[0187] [Table 4A]

[0188] [Table 4B]

[0189] (Example 31) 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-hexahydro-pyrazino[1,2-c]pyrimidine-6,8-dione

[0190] [ka]

[0191] To a stirred solution of Example-19 (300 mg, 0.52 mmol) in EtOAc (4.8 mL) was added Pd-C (10%, 60 mg). The reaction mass was degassed with nitrogen followed by hydrogen. A hydrogen filled balloon was fixed to the reaction flask using a two-pronged adapter to maintain positive hydrogen pressure in the reaction. The reaction mass was continued until the starting material was completely consumed. The hydrogen atmosphere was removed and the reaction mass was purged with nitrogen gas and filtered through a filter cloth / paper pad to remove the catalyst. The filtrate was evaporated to dryness to obtain a crude mass. It was triturated with a few small amounts of hexane to obtain the title compound (235 mg) in quantitative yield. 1 H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 4.20-3.90 (m, 3H), 3.90-3.72 (m, 1H), 3.60-3.55 (m, 4H), 3.52-3.42 (m, 1H), 3.08-2.86 (m, 2H), 2.80-2.68 (m, 4H), 2.68-2.62 (m, 4H), 2.52-2.40 (m, 2H), 1.63-1.52 (m, 4H); Mass (m / z): 443.3 (M+H) + .

[0192] Example 32 7-{4-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-hexahydro-pyrazino[1,2-c]pyrimidine-6,8-dione

[0193] [ka]

[0194] Example-32 was prepared from Example-21 using the procedure of Example-31 with minor changes. 1H NMR (400 MHz, CDCl3): δ 8.10-8.02 (m, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.36 (dd, J = 8.0, 9.2 Hz, 1H), 4.25-4.15 (m, 2H), 4.15-3.95 (m, 3H), 3.95-3.75 (m, 2H), 3.60-3.50 (m, 2H), 3.10-2.90 (m, 5H), 2.86-2.77 (m, 1H), 2.77-2.65 (m, 1H), 2.60-2.50 (m, 1H), 2.25-2.05 (m, 3H), 1.97-1.80 (m, 2H), 1.80-1.68 (m, 4H); Mass (m / z): 444.4 (M+H) + .

[0195] (Example 33) 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid methyl ester

[0196] [ka]

[0197] To a stirred solution of Example-31 (50.0 mg, 0.11 mmol) in DCM (1.0 mL) cooled at 0° C., triethylamine (0.03 mL, 0.22 mmol) was added followed by methyl chloroformate (0.02 mL, 0.2 mmol). The reaction mixture was stirred at the same temperature for another 1 h and then quenched by addition of NaHCO3 aqueous solution. The reaction mass was extracted with EtOAc, the combined organic layer was washed with brine solution, dried over anhydrous Na2SO4, and the solvent was removed under vacuum to obtain a crude mass. It was purified by silica gel column chromatography to obtain the above titled compound (50 mg) in 90% yield. 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 4.30-4.10 (m, 3H), 3.95-3.45 (m, 11H), 3.10-2.88 (m, 3H), 2.85-2.60 (m, 5H), 2.60-2.40 (m, 2H), 1.70-1.55 (m, 2H), 1.38-1.20 (m, 2H); Mass (m / z): 501.3 (M+H) + ; HPLC purity: 91.61%.

[0198] (Example 34) 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid methyl ester fumarate

[0199] [ka]

[0200] Example-33 was converted to its fumarate salt by treatment with fumaric acid in isopropanol to give the above titled compound. 1 H NMR (400 MHz, DMSO-d6): δ 8.07 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 6.62 (s, 2H), 4.05-3.93 (m, 3H), 3.95-3.45 (m, 10H), 3.10-2.88 (m, 2H), 2.85-2.60 (m, 5H), 2.60-2.40 (m, 2H), 1.70-1.55 (m, 4H), 1.35-1.22 (m, 2H); Mass (m / z): 501.3 (M+H) + ; HPLC purity: 92.01%.

[0201] Examples 35-38 were prepared by following the procedures reported for Examples 33 and 34 with some minor modifications.

[0202] [Table 5A]

[0203] [Table 5B]

[0204] (Example 39) 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-2-isopropyl-hexahydro-pyrazino[1,2-c]pyrimidine-6,8-dione

[0205] [ka]

[0206] To a stirred solution of Example-31 (44.0 mg, 0.1 mmol) in DCM (1.0 mL) cooled at 0° C., K2CO3 (28.0 mg, 0.2 mmol) was added followed by 2-iodopropane (26.0 mg, 0.15 mmol). The reaction mixture was gradually warmed to room temperature and stirred for another 1 h before being quenched by addition of NaHCO3 aqueous solution. The reaction mass was extracted with EtOAc, the combined organic layers were washed with brine solution, dried over anhydrous Na2SO4 and the solvent was removed under vacuum to obtain a crude mass. It was purified by silica gel column chromatography to give the above titled compound (38 mg) in 82% yield. 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 4.20-3.90 (m, 3H), 3.90-3.72 (m, 4H), 3.60-3.55 (m, 4H), 3.52-3.42 (m, 1H), 3.08-2.86 (m, 2H), 2.80-2.68 (m, 2H), 2.68-2.62 (m, 4H), 2.52-2.40 (m, 2H), 1.73-1.54 (m, 4H), 1.05 (d, J = 6.4 Hz, 6H); Mass (m / z): 485.5 (M+H) + .

[0207] (Example 40) 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-2-isopropyl-hexahydro-pyrazino[1,2-c]pyrimidine-6,8-dione fumarate

[0208] [ka]

[0209] Example-39 was converted to its fumarate salt by treatment with fumaric acid in isopropanol to give the above titled compound. 1H NMR (400 MHz, DMSO-d6): δ 8.06 (d, J = 8.4 Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 6.62 (s, 2H), 4.10-3.90 (m, 3H), 3.90-3.72 (m, 2H), 3.60-3.55 (m, 4H), 3.52-3.42 (m, 1H), 3.08-2.86 (m, 2H), 2.80-2.68 (m, 2H), 2.68-2.62 (m, 4H), 2.52-2.40 (m, 2H), 1.77-1.53 ​​(m, 4H), 1.04 (d, J = 6.0 Hz, 6H); Mass (m / z): 485.4 (M+H) + .

[0210] The following Examples 41 and 42 were prepared by using the procedures described for the preparation of Examples-1 and -2, respectively, using the appropriate intermediates with some minor changes, and Examples 43 and 44 were prepared using the procedures for the preparation of Examples 23 and -2, respectively, using the appropriate intermediates with some minor changes.

[0211] [Table 6A]

[0212] [Table 6B]

[0213] (Example 45) Determination of in vitro binding affinity at multiple receptors i) 5-HT 1A K at the receptor i Decision The compounds were tested according to the following procedure. Materials and Methods: Receptor source: recombinant mammalian cells (HEK293-EBNA) Radioligand: 3H]-8-hydroxyDPAT (200Ci / mmol) Final ligand concentration: 0.8 nM Non-specific determinant: 0.1mM U92016A Reference compound: U92016A Positive control: U92016A Incubation conditions: The reaction was carried out at room temperature for 2 hours in a buffer containing 50 mM Tris-HCl, 0.5 mM EDTA, 10 mM MgSO4, 0.1% ascorbic acid (pH 7.4). The reaction was terminated by rapid vacuum filtration through glass fiber filters. Test compounds and cloned human 5-HT 1A To confirm any interaction with the receptor binding sites, the radioactivity trapped on the filters was determined and compared with control values. Reference: British Journal of Pharmacology, 2000, 130, 1108 - 1114.

[0214] ii) 5-HT 2A K at the receptor i Decision The compounds were tested according to the following procedure. 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 room temperature for 1 hour 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 through glass fiber filters. Test compounds and cloned human 5-HT 2ATo confirm any interaction with the receptor binding sites, the radioactivity trapped on the filters was determined and compared with control values. Reference: J Biomol Screen, 2000, 5(4), 269~278.

[0215] iii) K at the SERT receptor i Decision The compounds were tested according to the following procedure. 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 room temperature for 3 hours in a buffer (pH 7.4) containing 50 mM Tris-HCl, 150 mM NaCl, 5 mM KCl and scintillation proximity assay (SPA) beads (0.1 mg / well). To confirm any interaction of test compounds with the cloned human SERT receptor binding site, the radioactivity in proximity to the SPA beads was determined by scintillation proximity assay and compared to control values. References: Journal of Pharmacology and Experimental Therapeutics, 1987, 242 (1), 364~371.

[0216] iv) D 2S K at the receptor i Decision The compounds were tested according to the following procedure. 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 at room temperature for 2 hours 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 through glass fiber filters. Test compounds and cloned human dopamine D 2S To confirm any interaction with the receptor binding sites, the radioactivity trapped on the filters was determined and compared with control values. Reference: Neuropsychopharmacology, 2010, 35, 806~817.

[0217] [Table 7]

[0218] (Example 46) In vitro functional activity a) 5-HT 2A K at the receptor b Determining the value: Recombinant human 5-HT 2A A stable CHO cell line expressing the receptor and the pCRE-Luc reporter system was used in the cell-based assay. The assay provides a non-radioactive based method to determine the binding of compounds to GPCRs. This specific assay measures the level of intracellular cAMP, which is modulated by receptor activation or inhibition. The recombinant cells carry a luciferase reporter gene under the control of a cAMP response element.

[0219] The cells were grown in Hams F12 medium containing 10% fetal bovine serum (FBS) in 96-well clear bottom white plates. Cells were serum starved overnight before adding compounds or standard agonists. Increasing concentrations of test compounds were added to the cells along with 1 μM serotonin in Opti-MEM medium. Incubation continued for 4 hours at 37°C in a CO2 incubator. The medium was removed and cells were washed with phosphate buffered saline. Cells were lysed and luciferase activity was measured in a luminometer. Luminescence units were plotted against compound concentration using GraphPad Prism software. Compound EC 50 The K value was defined as the concentration required to reduce luciferase activity by 50%. b Values ​​indicate the concentration of agonist used in the assay and its EC 50 The values ​​were calculated by inputting them into the same software. References: Scientific Reports, 2015, 5, 8060 and Journal of biological chemistry, 2002, 277, 11441~11449. Results: Example 2 shows that recombinant human 5-HT1C was detected in a pCRE-Luc-based reporter gene assay. 2A It exhibited antagonist activity at the receptor but no detectable agonist activity. b The values ​​are summarized in the table below.

[0220] [Table 8]

[0221] b)D 2S K at the receptor b Determining the value: Recombinant human D 2SA stable CHO cell line expressing the receptor and the pCRE-Luc reporter system was used in the cell-based assay. The assay provides a non-radioactive based method to determine the binding of compounds to GPCRs. This specific assay measures the level of intracellular cAMP, which is modulated by receptor activation or inhibition. The recombinant cells carry a luciferase reporter gene under the control of a cAMP response element.

[0222] The cells were grown in Hams F12 medium containing 10% fetal bovine serum (FBS) in 96-well clear bottom white plates. Cells were serum starved overnight before adding compounds or standard agonists. Increasing concentrations of test compounds were added to the cells along with 0.3 μM dopamine and 1 μM forskolin in Opti-MEM medium. Incubation continued for 4 hours at 37° C. in a CO2 incubator. The medium was removed and the cells were washed with phosphate buffered saline. Cells were lysed and luciferase activity was measured in a luminometer. Luminescence units were plotted against compound concentration using GraphPad Prism software. Compound EC 50 The K value was defined as the concentration required to reduce luciferase activity by 50%. b Values ​​indicate the concentration of agonist used in the assay and its EC 50 The values ​​were calculated by inputting them into the same software. Reference: European Journal of Pharmacology, 2005, 515, 10~19. Results: Examples 2 and 4 show that the pCRE-Luc-based reporter gene assay detects human recombinant D 2S It exhibited antagonist activity at the receptor but no detectable agonist activity. b The values ​​are summarized in the table below.

[0223] [Table 9]

[0224] c) 5-HT 1A K at the receptor b Determining the value: Recombinant human 5-HT 1A A stable CHO cell line expressing the receptor and the pCRE-Luc reporter system was used in the cell-based assay. The assay provides a non-radioactive based method to determine the binding of compounds to GPCRs. This specific assay measures the level of intracellular cAMP, which is modulated by receptor activation or inhibition. The recombinant cells carry a luciferase reporter gene under the control of a cAMP response element.

[0225] The cells were grown in Hams F12 medium containing 10% fetal bovine serum (FBS) in 96-well clear bottom white plates. Cells were serum starved overnight before adding compounds or standard agonists. Increasing concentrations of test compounds were added to the cells along with 1 μM U92016A and 1 μM forskolin in Opti-MEM medium. Incubation continued for 4 hours at 37°C in a CO2 incubator. The medium was removed and cells were washed with phosphate buffered saline. Cells were lysed and luciferase activity was measured in a luminometer. Luminescence units were plotted against compound concentration using GraphPad Prism software. Compound EC 50 The K value was defined as the concentration required to reduce luciferase activity by 50%. b Values ​​indicate the concentration of agonist used in the assay and its EC 50 The values ​​were calculated by inputting them into the same software. References:Scientific Reports, 2015, 5, 8060 and Journal of biological chemistry, 1990, 265, 5825~5832. Results: Example 2 shows that recombinant human 5-HT1C was detected in a pCRE-Luc-based reporter gene assay. 1A It exhibited antagonist activity at the receptor but no detectable agonist activity. b The values ​​are summarized in the table below.

[0226] [Table 10]

[0227] d) K at the 5-HT7 receptor b Determining the value: A stable CHO cell line expressing recombinant rat 5-HT7 receptor and pCRE-Luc reporter system was used in the cell-based assay. The assay provides a non-radioactive based method to determine the binding of compounds to GPCRs. This specific assay measures the level of intracellular cAMP, which is modulated by receptor activation or inhibition. The recombinant cells carry a luciferase reporter gene under the control of a cAMP response element.

[0228] The cells were grown in Hams F12 medium containing 10% fetal bovine serum (FBS) in 96-well clear bottom white plates. Cells were serum starved overnight before adding compounds or standard agonists. Increasing concentrations of test compounds were added to the cells along with 1 μM serotonin in Opti-MEM medium. Incubation continued for 4 hours at 37°C in a CO2 incubator. The medium was removed and cells were washed with phosphate buffered saline. Cells were lysed and luciferase activity was measured in a luminometer. Luminescence units were plotted against compound concentration using GraphPad Prism software. Compound EC 50 The K value was defined as the concentration required to reduce luciferase activity by 50%. b Values ​​indicate the concentration of agonist used in the assay and its EC 50 The values ​​were calculated by inputting them into the same software. References: Scientific Reports, 2015, 5, 8060; British Journal of Pharmacology, 2004, 143, 404-410; and Bioorganic & Medicinal Chemistry Letters, 2004, 14, 4245-4248. Results: Examples 2, 9, 11 and 18 exhibited antagonist activity but no detectable agonist activity against the recombinant rat 5-HT7 receptor in the pCRE-Luc-based reporter gene assay. b The values ​​are summarized in the table below.

[0229] [Table 11]

[0230] (Example 47) Pharmacokinetic studies in rodents Male Wistar rats (260±50 g) were used as experimental animals. Animals were individually housed in polypropylene cages. Two days before the study, male Wistar rats were anesthetized with isoflurane and surgically placed with a jugular catheter. Rats were randomly assigned (n=3 / group) to receive oral (3 mg / kg) or intravenous (1 mg / kg) treatment and were orally (po) dosed after an overnight fast. However, rats assigned to the intravenous treatment had free access to food and water.

[0231] At the designated time points, blood samples were collected from the jugular vein and replenished with an equal volume of saline. Collected blood was transferred into labeled Eppendorf tubes containing 10 μL of heparin as an anticoagulant. Blood samples were typically collected at 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing. Blood samples were centrifuged at 4000 rpm for 10 minutes. Plasma was separated and stored frozen at -80°C until analysis. Concentrations of test compounds in plasma were quantified by a qualified LC-MS / MS method using a suitable extraction technique. Test compounds were quantified in plasma with a calibration range of approximately 1-1000 ng / mL. Test samples were analyzed using calibration samples within the batch and quality control samples across batches.

[0232] Pharmacokinetic parameter C max , AUC t , t 1 / 2, clearance and bioavailability (F) were calculated using standard non-compartmental models by using the Phoenix WinNonlin 6.0.4 version software package.

[0233] [Table 12A]

[0234] [Table 12B]

[0235] (Example 48) Rodent Brain Penetration Test Male Wistar rats (260±40 g) were used as experimental animals. Three animals were housed in each cage. The animals had free access to water and food throughout the experiment and were maintained on a 12-h light / dark cycle.

[0236] Brain permeability was determined separately in rats. One day before dosing, Wistar male rats were acclimated and randomly divided into groups according to body weight. n=3 animals were used for each time point (0.50, 1 and 2 hours).

[0237] Test compounds were suitably preformulated and administered orally at 3 mg / kg (free base equivalent). Blood samples were taken by cardiac puncture under isoflurane anesthesia. Animals were sacrificed and brain tissue was harvested. Plasma was separated and brain samples were homogenized. Plasma and brain homogenates were stored frozen at -20°C until analysis. LC-MS / MS methods were used to determine the concentrations of test compounds in plasma and brain.

[0238] Test compounds in plasma and brain homogenates were quantified by a qualified LC-MS / MS method using suitable extraction techniques with a calibration range of 1-500 ng / mL. Test samples were analyzed using in-batch calibration samples and cross-batch quality control samples. Brain-to-plasma ratios (C 脳 / C 血漿) range was calculated.

[0239] [Table 13]

[0240] (Example 49) Amphetamine-induced hyperlocomotion Male Sprague Dawley rats weighing 230-280 g were used. Rats were weighed and randomized according to body weight. The next day, rats were brought to the experimental room 1 h before testing. In the morning period, rats were habituated to the open field area for 15 min. Test compound / vehicle and amphetamine / vehicle were administered 30 min before the trial. After a post-administration interval, rats were placed in the open field and locomotor activity was recorded for 15 min. Amphetamine-induced hyperlocomotion models the positive symptoms of schizophrenia.

[0241] [Table 14]

[0242] (Example 50) Forced swimming test Swiss male albino mice with body weights ranging from 30 to 40 g were used. Mice were administered vehicle or test compounds. Thirty minutes after treatment, animals were individually placed inside a Plexiglas cylinder (40 cm high x 17 cm wide) for 6 minutes. The depth of the water (24±1°C) was maintained at 18 cm. The immobility of the mice during the last 4 minutes of the 6-minute trial was recorded. The forced swim test evaluates the antidepressant-like effects of the test compounds.

[0243] [Table 15]

[0244] (Example 51) MK-801-induced amnesia in the novel object recognition task (NORT) Male Wistar rats weighing 230-280 g were used. Rats were weighed and randomized according to body weight. On day 1, animals were allowed to habituate to the arena for 45 min. On day 2, animals were administered vehicle (WFI) or test compound 30 min before trial-1, and MK-801 0.03 mg / kg was administered intraperitoneally 20 min before trial-1. Trial-1 was a 3 min familiarization task in the arena with two silver flasks of similar type and dimensions. After a 90 min intertrial interval, animals were subjected to a recognition task in the arena with one silver bottle and one purple bottle for 3 min. The time spent by rats with familiar or novel objects was described and analyzed. MK-801-induced amnesia in the novel object recognition task models cognitive deficits associated with schizophrenia.

[0245] [Table 16]

[0246] (Example 52) DOI-induced head twitch response On day 1, male Wistar rats (220-250 g) were habituated to the cylinder for 15 min. On day 2, rats were brought to the experimental room 30 min before the experiment. All animals were administered the respective formulation, i.e., vehicle or test compound, 30 min before DOI or vehicle administration. Immediately after DOI or vehicle administration, animals were kept in the cylinder for 10 min and head twitches were scored. 5-HT 2A Compounds acting as antagonists attenuate DOI-induced head twitches.

[0247] [Table 17]

[0248] (Example 53) Resident-Intruder Task CD1 male mice weighing 20-35 g (residents) and 15-25 g (intruders) were used. Resident mice were individually habituated to ovariectomized female mice in their respective cages, and intruders were socialized for 1 week. Female mice were given a single subcutaneous dose of β-estradiol at 0.2 mg / kg during habituation. On days 1 and 2, intruders were exposed to resident mice in the resident's home cage for 10 min, and the duration of aggression was measured. During this exposure, the female mice were removed from the cage. On the fourth day after the first exposure, animals were randomized based on their duration of aggression and administered the respective treatment. Test compounds and vehicle were administered 30 min before the trial. After a post-administration interval, resident mice were exposed to the same intruders for 10 min, and the duration of aggression was recorded. The resident-intruder task models aggressive behavior.

[0249] [Table 18]

[0250] (Example 54) Reserpine-induced dihydroxyphenylalanine (DOPA) accumulation assay in rat striatum Reserpine (5.0mg / kg, subcutaneous) was injected, and then the rats were fasted for 18 hours before sacrifice. Example-2 / Vehicle and apomorphine (dopamine receptor agonist, 0.1mg / kg, subcutaneous) were administered 1.0 hour and 0.6 hour before sacrifice, respectively. NSD-1015 (DOPA decarboxylase inhibitor, 100mg / kg, subcutaneous) was injected 0.5 hour before sacrifice. Each rat was sacrificed, and the striatum was dissected from the whole brain in ice. Each striatum was weighed and homogenized individually in a buffer containing 0.01N hydrochloric acid and 0.2mg / mL L-cysteine. DOPA in the supernatant was quantified using HPLC coupled to an electrochemical detector.

[0251] Example-2 (10 mg / kg, subcutaneous administration) did not alter the DOPA levels increased by reserpine, suggesting its non-agonistic nature at the dopamine receptor. On the other hand, apomorphine, a dopamine receptor agonist, caused a significant decrease in reserpine-induced DOPA accumulation (Figure 1). However, pretreatment with Example-2 blocked the effect of apomorphine. The results of this in vivo profiling assay suggest that Example-2 acts as a dopamine receptor antagonist in vivo.

[0252] (Example 55) Regulation of dopamine and norepinephrine levels in the prefrontal cortex and striatum of male Wistar rats Male Wistar rats (body weight 240-300 g) were anesthetized with isoflurane and stereotactically implanted with microdialysis guide cannulas into the prefrontal cortex (PFC; AP: +3.2 mm, ML: -0.5 mm, DV: -1.0 mm) or striatum (AP -0.2 mm, ML -3.0 mm, DV -3.0 mm). Coordinates were taken from the bregma and perpendicular to the skull according to the rat brain atlas (Paxinos and Watson 2004). Rats were allowed to recover individually in round-bottom Plexiglas bowls with free access to food and water for 4 days.

[0253] After 4 days of postoperative recovery, rats were connected to a dual quartz-lined two-channel liquid swivel (Instech, UK) on a counterbalanced lever arm, allowing unrestricted movement of the animals. 16 hours before the start of the study, a pre-equilibrated microdialysis probe (4 mm dialysis membrane) was inserted through the induction cannula into the PFC or striatum. On the day of the study, the probe was perfused with artificial cerebrospinal fluid at a flow rate of 1.5 μL / min and maintained for 2 hours of stabilization. Four basal samples were collected at 30-minute intervals before treatment with Example-2 (3 or 10 mg / kg, orally administered) or vehicle. After an additional 4 hours of treatment, dialysate samples were collected and stored below -50°C before analysis.

[0254] Dopamine and norepinephrine levels in the dialysate were quantified using an LC-MS / MS method.

[0255] Microdialysis data were plotted as % change from mean dialysate basal concentration, with the average of the four pre-dose values ​​defined as 100%. Percentage changes in neurotransmitter levels were analyzed using two-way ANOVA (time and treatment) followed by Bonferroni post-hoc tests. Statistical significance was determined at a p-value of less than 0.05.

[0256] Treatment with Example-2 increased cortical dopamine levels in the prefrontal cortex with mean maximum increases of 326±24% and 458±91% at 3 mg / kg and 10 mg / kg, subcutaneous, respectively (FIG. 2).

[0257] Treatment with Example-2 increased cortical norepinephrine levels in the prefrontal cortex with mean maximum increases of 187±30% and 368±99% at 3 mg / kg and 10 mg / kg, subcutaneous, respectively (FIG. 3).

[0258] Treatment with Example-2 showed no changes in dopamine levels in the striatum (Figure 4).

[0259] The results of these studies indicate that Example-2 produces a significant increase in dopamine and norepinephrine in the prefrontal cortex and does not increase dopamine levels in the striatum, suggesting that it may have utility in the treatment of neuropsychiatric disorders without the tendency to induce psychostimulants.

[0260] (Example 56) Effects on sleep / wake profiles in male Wistar rats Male Wistar rats were anesthetized with isoflurane (Baxter India Private Limited; induction 4% in oxygen; maintenance 2%) and secured in a stereotaxic frame (Stoelting, Illinois, USA) for surgery. An incision was made to expose the bregma, from which coordinates were obtained. A telemetry transmitter (model F40-EET; DSI, St. Paul, MN, USA) was implanted in the rat's intraperitoneal cavity and the leads were threaded subcutaneously to the skull. For EEG recordings, a pair of electrodes was implanted epidurally in the frontal cortical region at the coordinates AP +3.2 mm, ML ±3.0 mm (Paxinos and Watson 2004) using stainless steel screws (CMA Microdialysis, Stockholm, Sweden), and the electrodes were fixed to the skull with dental acrylic cement (Dentalon® Plus). A second set of lead wires was implanted in the nuchal muscles of the neck to record electromyograms (EMG). After a minimum of 3 weeks of post-operative recovery, animals were acclimated to handling procedures and mock-treated for 3 days prior to experimental day 1.

[0261] One hour before light-off, the transmitter was switched on using a magnet and the animal was transferred onto the receiver with its home cage. Recordings were performed using Ponemah (Version 5.2; DSI, St. Paul, MN, USA) software. Animals were treated with vehicle or Example-2 (10 mg / kg, orally) 15 min before light-off in a crossover design with a one-week washout period between treatments. Recordings continued overnight after treatment. EEG and EMG were collected as primary signals and sampled at 500 Hz, while temperature and activity were sampled at 250 Hz. Data were stored for offline analysis using NeuroScore software (Version 3.0; DSI, St. Paul, MN, USA).

[0262] The amount of time spent awake was determined every 30 min and comparisons between treatments were made using Bonferroni post hoc tests.

[0263] Treatment with Example-2 (10 mg / kg, oral administration) did not result in any change (%) in wakefulness time in male Wistar rats (Figure 5), suggesting that Example-2 may not result in sleep-related side effects within the therapeutically effective dose range.

[0264] (Example 57) Tardive dyskinesia test Rats weighing 200-230 g were acclimated to a Plexiglas observation cage (30 x 20 x 30 cm) equipped with a mirror for 5 min. After acclimation, rats' basal empty chewing movements (VCM) and tongue protrusions (TP) were quantified manually for 5 min. Rats were randomized based on basal readings. Rats received a single dose of sesame oil (vehicle treatment) or haloperidol decanoate (38 mg / kg, intramuscular, positive control). Example-2, 10 mg / kg (5 mg, twice daily) was administered orally for 4 weeks. VCM and TP were scored weekly for 4 weeks. Tardive dyskinesia is a side effect of antipsychotic drugs.

[0265] [Table 19]

[0266] (Example 58) Rotarod test Male Wistar rats weighing 200-280 g were used. Rats were weighed and randomized according to body weight. Animals were habituated four times on the rotating rod (4 rpm). Animals that successfully stayed on the rotating rod for 60 seconds (out of four trials per animal) were selected for further study. Animals that did not complete the 60-second trial within four choices were excluded from the study. A single trial was performed the next day. Animals that were able to stay on the rotating rod for 60 seconds were selected for further study. Animals were administered the test compound or vehicle 60 minutes before the trial. The latency to fall off the rotating rod was recorded. The rotarod test evaluates the effect of test compounds on motor function.

[0267] [Table 20]

Claims

1. A compound of formula (I), 【Chemistry 1】 or its isotopes, stereoisomers, or pharma- ceutically acceptable salts [In the formula, HetAr is 【Chemistry 2】 where X is hydrogen, halogen or alkoxy; 【Chemistry 3】 represents the attachment point; P is -(CH 2 ) b -or 【Chemistry 4】 where b is an integer from 2 to 6; A is CH or N; n is 0 or 1, m is 0 or 1, Q is -CH 2 -, O, NH, N-alkyl, -N(COR)-, or -N(COOR)-, where R is alkyl, alkoxyalkyl, cycloalkyl, or alkylaryl; B is hydrogen, halogen or alkoxy, provided that Q is CH 2 with the proviso that in that case B may be hydrogen, halogen or alkoxy.

2. The compound is 2-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione oxalate; 2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione oxalate; 2-{4-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-{4-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-butyl}-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-{4-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-butyl}-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione oxalate; 2-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-6-fluoro-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-6-fluoro-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione oxalate; 3-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-hexahydro-1b,3-diaza-cyclopropa[a]indene-2,4-dione; 3-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-hexahydro-1b,3-diaza-cyclopropa[a]indene-2,4-dione oxalate; 2-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-hexahydro-pyrido[1,2-c]pyrimidine-1,3-dione; 2-{4-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-hexahydro-pyrido[1,2-c]pyrimidine-1,3-dione; 2-{4-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-hexahydro-pyrido[1,2-c]pyrimidine-1,3-dione fumarate; 2-{4-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-butyl}-hexahydro-pyrido[1,2-c]pyrimidine-1,3-dione; 2-{4-[4-(5-methoxy-1H-indol-3-yl)-piperidin-1-yl]-butyl}-hexahydro-pyrido[1,2-c]pyrimidine-1,3-dione; 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-tetrahydro-pyrimido[6,1-c][1,4]oxazine-6,8-dione; 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-tetrahydro-pyrimido[6,1-c][1,4]oxazine-6,8-dione oxalate; 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid benzyl ester; 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid benzyl ester fumarate; 7-{4-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid benzyl ester; 7-{4-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid benzyl ester fumarate; 2-[3-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-propyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-propyl}-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-{3-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-propyl}-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-ylmethyl)-cyclohexylmethyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-ylmethyl)-cyclohexylmethyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione oxalate; 2-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-ylmethyl]-cyclohexylmethyl}-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-ylmethyl]-cyclohexylmethyl}-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione oxalate; 7-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-ylmethyl)-cyclohexylmethyl]-tetrahydro-pyrimido[6,1-c][1,4]oxazine-6,8-dione; 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-hexahydro-pyrazino[1,2-c]pyrimidine-6,8-dione; 7-{4-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-hexahydro-pyrazino[1,2-c]pyrimidine-6,8-dione; 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid methyl ester; 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid methyl ester fumarate; 7-{4-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid methyl ester; 7-{4-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-6,8-dioxo-octahydro-pyrazino[1,2-c]pyrimidine-2-carboxylic acid methyl ester fumarate; 2-Acetyl-7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-hexahydro-pyrazino[1,2-c]pyrimidine-6,8-dione; 2-Acetyl-7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-hexahydro-pyrazino[1,2-c]pyrimidine-6,8-dione fumarate; 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-2-isopropyl-hexahydro-pyrazino[1,2-c]pyrimidine-6,8-dione; 7-[4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-2-isopropyl-hexahydro-pyrazino[1,2-c]pyrimidine-6,8-dione fumarate; 2-{4-[4-(benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; 2-{4-[4-(benzo[d]isoxazol-3-yl)-piperidin-1-yl]-butyl}-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione oxalate; 2-[3-(4-benzo[d]isoxazol-3-yl-piperidin-1-yl)-propyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione; and 2-[3-(4-benzo[d]isoxazol-3-yl-piperidin-1-yl)-propyl]-tetrahydro-pyrrolo[1,2-c]pyrimidine-1,3-dione oxalate 2. The compound of formula (I) according to claim 1, or an isotope, stereoisomer, or pharma- ceutically acceptable salt thereof, selected from:

3. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or 2, or an isotope, stereoisomer, or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

4. 4. The pharmaceutical composition according to claim 3 for use in the treatment of a central nervous system disorder or condition selected from anxiety disorder, agitation, aggression, borderline personality disorder, schizophrenia, affective disorder, psychotic disorder, mood disorder, bipolar I disorder, bipolar II disorder, delirium, hysteria, dissociative disorder, sleep disorder, anhedonia, neuropsychiatric symptoms associated with dementia, amnesic disorder, cognitive disorder, cognitive deficit associated with schizophrenia, movement disorder, depressive disorder, drug dependence, drug addiction, autistic disorder, Tourette's syndrome and / or attention deficit hyperactivity disorder.

5. 10. A method for treating or preventing a central nervous system disorder or condition selected from anxiety disorder, agitation, aggression, borderline personality disorder, schizophrenia, affective disorder, psychotic disorder, mood disorder, bipolar I disorder, bipolar II disorder, delirium, hysteria, dissociative disorder, sleep disorder, anhedonia, neuropsychiatric symptoms associated with dementia, amnesic disorder, cognitive impairment, cognitive deficit associated with schizophrenia, movement disorder, depressive disorder, drug dependence, drug addiction, autistic disorder, Tourette's syndrome and / or attention deficit hyperactivity disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) according to claim 1 or 2 or an isotope, stereoisomer or a pharmaceutically acceptable salt thereof.

6. 3. Use of a compound of formula (I) or an isotope, stereoisomer, or a pharma- ceutically acceptable salt thereof according to claim 1 or 2 for the manufacture of a medicament for the treatment of a central nervous system disorder or condition selected from the group consisting of anxiety disorder, agitation, aggression, borderline personality disorder, schizophrenia, affective disorder, psychotic disorder, mood disorder, bipolar I disorder, bipolar II disorder, delirium, hysteria, dissociative disorder, sleep disorder, anhedonia, neuropsychiatric symptoms associated with dementia, amnesic disorder, cognitive impairment, cognitive deficit associated with schizophrenia, movement disorder, depressive disorder, drug dependence, drug addiction, autistic disorder, Tourette's syndrome, and / or attention deficit hyperactivity disorder.

7. 3. The compound of formula (I) or an isotope, stereoisomer, or a pharma- ceutically acceptable salt thereof as claimed in claim 1 or 2 for use in the treatment of a central nervous system disorder or condition selected from anxiety disorder, agitation, aggression, borderline personality disorder, schizophrenia, affective disorder, psychotic disorder, mood disorder, bipolar I disorder, bipolar II disorder, delirium, hysteria, dissociative disorder, sleep disorder, anhedonia, neuropsychiatric symptoms associated with dementia, amnesic disorder, cognitive impairment, cognitive deficit associated with schizophrenia, movement disorder, depressive disorder, drug dependence, drug addiction, autistic disorder, Tourette's syndrome, and / or attention deficit hyperactivity disorder.

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