Field of the invention

The present invention relates to novel amidoalkylpiperazinyl derivatives of tricyclic heterocyclic systems having affinity to dopaminergic, serotoninergic and adrenergic receptors and to voltage-dependent sodium channels, pharmaceutical compositions containing the same and to the use thereof. The compounds may be useful for the treatment of diseases of the central nervous systemsuch as schizophrenia, bipolar affective disorder, depression, anxiety disorders, sleep disorders or Alzheimer disease.

State of art

CNS disorders are considered a global and growing medical problem. A number of people suffering from those diseases constantly grows, particularly in highly developed countries and intensively developing ones. Approximately 20% of population in highly developed societies may suffer from CNS disorders. In addition a cost of treatment of such disorders represents nearly 35% of total expenses spent for treatment of all medical diseases in seven countries considered the biggest pharmaceutical markets.

Among all psychiatric diseases, schizophrenia, bipolar affective disorder, depression, anxiety, sleep disorders and addictions are the major ones. Among many others, the main neurologic disorders are Alzheimer's disease, Parkinson's disease, epilepsy and different pain disorders.

Antipsychotic drugs, which are main treatment of schizophrenia, are divided into two main classes on the basis of their liability to induce neurological side effects after long- -term treatment. Typical antipsychotic drugs, such as chlorpromazine and haloperidol, induce after repeated administration various extrapyramidal side effects (EPS) including Parkinson-like symptoms and tardive dyskinesia. Repeated treatment with so called atypical antipsychotic drugs, such as clozapine, risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole, is associated with a lower incidence of neurological side effects. Typical antipsychotics reduce positive symptoms but do not reduce negative symptoms and cognitive dysfunctions. Plasma prolactin levels are increased in humans, and there is a gain in body weight, potentially leading to the development of metabolic syndrome. Atypical antipsychotic drugs effectively reduce positive symptoms and also to some extent negative symptoms and cognitive disturbances, while producing less serious EPS. Atypical antipsychotic drugs differ in their propensity to elevate plasma prolactin levels in humans. Typical antipsychotic drugs block dopamine D2 receptors in the meso- limbic and nigrostriatal system. This mechanism is responsible for the antipsychotic effect (reduction of positive symptoms) as well as induction of EPS. Clinical support for the dopamine hypothesis of antipsychotic drug action was provided by PET findings of high dopamine D2 receptor occupancy in the striatum of patients responding to different antipsychotic drug treatments. Patients with a good response show dopamine D2 receptor occupancy of more than 65% (Nord M, Farde L , CNS Neuroscience & Therapeutics. 2010; 17:97). The occurrence of EPS seems to be related to a higher occupancy of dopamine D2 receptors (above 80%). Atypical antipsychotics, also called second generation antipsychotic drugs, have clinical approvals for the treatment of psychosis and mania. Each drug has a unique pharmacodynamic and pharmacokinetic profile. Some of atypical antipsychotic drugs have additional antidepressant, anxiolytic or hypnotic profile (Schwartz T. L , Stahl S.M. , CNS Neurosci. Ther.; 17(2), 1 10-7, 201 1 ). Atypical antipsychotic drugs have in common a potent serotonin 5-HT2A receptor antagonism in relation to a weaker dopamine D2 receptor antagonism. This pharmacodynamic property is the basis of "atypicality" (Meltzer H.Y. , Neuropsychopharmacology; 1 , 193—6, 1989). Antagonism of 5-HT2A receptors likely allows more dopamine activity and neurotransmission to occur in the nigrostriatal system to avoid EPS. The same mechanism may allow small improvement in negative symptoms, and 5-HT2 antagonism in the tuberoinfundibular pathway may help to avoid hyperprolactinemia (Schwartz T. L , Stahl S.M. , CNS Neurosci. Ther. ; 17(2), 1 10-7, 201 1 ).

The atypical antipsychotics have not fulfilled the initial expectations of improved negative symptoms and cognitive dysfunctions in schizophrenia. Therefore, more molecular targets are presently under investigation for the development of new drugs for the treatment of schizophrenia (Gray, J. A., Roth B. L.; Schizophr. Bull. ; 33 (5, 1 100-19, 2007).

Dopaminergic D2 receptors are the primary biological target of antipsychotic therapy. It is a recognized fact that that blockade of these receptors in the mesolimbic system is responsible for the antipsychotic activity of neuroleptics, in particular for preventing the positive symptoms. All antipsychotic drugs currently used reveal at least moderate affinity for dopamine D2 receptors. However, blockade of these receptors in the nigrostriatal system, if not compensated by a partial agonism to these receptors or by affecting other receptors (5-HT2A, 5-HT1A, alfa2c), may be a cause of extrapyramidal disorders, such as drug-induced parkinsonism, and within tuberoinfundibular pathway - of hyperprolactinaemia (Miyamoto S. et al., Mol. Psychiatry; 10(1 ), 79-104, 2005).

Dopaminergic D3 receptors are localized in limbic cortex and thus a preferential blockade of these receptors offers locally selective antidopaminergic activity. This results in increased effectiveness in reducing positive symptoms of schizophrenia without blockade of extrapyramidal system and therefore reduces the risk of the main side effect such as pseudoparkinson's syndrome. Moreover, several preclinical data suggest that D3 dopamine receptor antagonism is more efficient in reducing the negative symptoms of schizophrenia and improves working memory.

Serotoninergic neurons interact with dopaminergic neurons. Antagonistic activity of antipsychotics against serotoninergic receptors 5-HT2A type can stimulate the release of dopamine in the extrapyramidal, tuberoinfundibular systems and prefrontal cortex but not in the limbic system, what can result in alleviation of undesirable extrapyramidal symptoms and hyperprolactinaemia induced by D2 receptor blockade and in increased effectiveness of the drug against some of the negative symptoms of schizophrenia, without increasing the positive symptoms. It is considered that high affinity for 5-HT2A receptors, higher than for D2 receptors, is one of the reasons of atypicality of the second -generation antipsychotics. Similar effects to those caused by the blockade of 5- HT2A receptors, are achieved by stimulation of serotonin receptor type 5-HT1A (aripiprazole, ziprasidone). It is assumed that stimulation of 5-HT1A receptors takes part in the antipsychotic effect in combination with D2 receptor blockade, especially in the safety profile of a drug as well as is beneficial in fighting mood and cognitive symptoms of schizophrenia (Kim D. et al. , Neurotherapeutics, 6(1 ), 78-85, 2009).

Serotoninergic receptors type 5-HT6 are exclusively localized in the central nervous system (CNS). Both the localization of the 5-HT6 receptors in limbic and cortical brain areas and relatively potent affinity and antagonistic activity of several antipsychotics (clozapine, olanzapine, sertindole) and antidepressants (mianserin, amitryptiline) at 5- HT6 receptors are suggestive of a potential role in pathophysiology and treatment of CNS disorders. Recent data in the literature indicate that blockade of 5-HT6 receptors may be implicated in a pro-cognitive effect due to the increase in cholinergic transmission, in antidepressant activity due to the increase in noradrenergic and dopaminergic one, as well as in anxiolytic effect. It is evident that the 5-HT6 receptor has emerged as a very interesting molecular target and antagonists of that receptor may serve as potential drugs in treatment of disorders characterized by cognitive impairments, such as Alzheimer's disease, schizophrenia, depression, anxiety (Liu K., Robichaud A. , Drug Development Research 70,145-168, 2009; Wesotowska, A; Nikiforuk, A, Neuropharmacology 52(5), 1274-83). Moreover, 5-HT6 receptor antagonists have been demonstrated to be active in reduction of food intake and body weight by clinically approved mechanism that is consistent with an enhancement of satiety. Hence, several compounds with 5-HT6 receptor antagonistic activity are currently being clinically evaluated for the treatment of obesity (Heal D. et al. , Pharmacology therapeutics, 1 17(2), 207- 231 , 2008).

Intensive research conducted since 1993 indicates that serotoninergic 5-HT7 receptors may play some role in the control of circadian rhythms, sleep, thermoregulation, cognitive processes, pain and migraine, as well as in neuronal excitability. Potent affinity and antagonistic activity of several antipsychotic and antidepressant drugs at 5-HT7 receptors suggest a potential role of these receptors in the pathophysiology of many neuro- psychiatric disorders. Taking account of the behavioral data presented in the literature, it has been established that selective 5-HT7 receptor antagonists produce antidepressant and anxiolytic activity in rats and mice (Wesotowska A. et al. , Neuropharmacology 51 , 578-586, 2006). Using mouse models of antipsychotic activity, Galici et al. showed that a selective 5-HT7 receptor antagonist SB-269970 may also evoke antipsychotic- like effects (Galici R. et al. , Behav. Pharmacol.; 19(2), 153-9, 2008).

Serotoninergic 5-HT2C and histaminergic H1 receptors localized in hypothalamus play an important role in food intake regulation. Blockade of both types of these receptors produced by antipsychotic drugs is most closely correlated with an increased risk of weight gain and diabetes. On the other hand, blockade of 5-HT2C receptors, mostly localized in cortical areas and in the hippocampus, striatum, septal nuclei, thalamic and midbrain nuclei, may produce beneficial antidepressant and pro-cognitive effects. In the substantia nigra, 5-HT2C receptors are co-localised with GABA, indicating that they yield indirect control of dopaminergic transmission. Consequently, the blockade of 5- HT2C receptors, together with the 5-HT2A receptor one, would potentiate the D2 receptor-mediated tonic inhibitory control of dopaminergic projection, with protective effect against extrapyramidal symptoms (Kim D. et al. , Neurotherapeutics, 6(1 ), 78-85, 2009). Histaminergic H1 receptor blockade produced by antipsychotic drugs may be implicated in sedative effect that is clinically beneficial in controlling arousal that accompanies the acute phase of psychosis. It seems that simultaneous reduction in affinity of new molecule for both types of these receptors may be an element that protects against excessive body weight. However, the total elimination of affinity for these receptors may not be necessary because of certain benefits of blockade of 5-HT2C and H1 receptors.

Blockade of alphal adrenergic receptors, despite potential peripheral adverse effects involving hypotension, may cause some central nervous system benefits involving decrease in the risk of extrapyramidal side effects caused be antipsychotics. This may be associated with interaction between noradrenergic and serotoninergic neurons (Horacek J. et al. , CNS Drugs, 20(5), 389-409, 2006).

Because of important role of cholinergic system in the cognitive processes, current research is focused on substances which can directly or indirectly potentiate the activity of cholinergic system. This includes substances which are agonists of selected subtypes of nicotinic or muscarinic receptors and antagonists of 5-HT6 receptors. On the other hand, potential procognitive effects evoked by interaction with the above receptors may be masked by cholinolytic activity. Thus, in the scope of interest are substances free of antagonistic properties against cholinergic receptors. Moreover this strategy allows elimination of many undesired peripheral autonomic effects like constipations, dry mouth or tachycardia (Miyamoto S. et al., Mol. Psychiatry; 10(1 ), 79- 104, 2005). In addition, it has been found that M3 muscarinic receptors are engaged in the control of insulin secretion, and their activation stimulates pancreas to secrete insulin. Hence, it can be expected that M3 receptors blockade may be unfavorable in terms of the risk of development of type II diabetes in patients treated with second generation antipsychotics (ex. olanzapine, clozapine, quetiapine). Recent research is focused on substances free of this undesired effect (Silvestre J.S. , Prous J., Methods Find. Exp. Clin. Pharmacol. ; 27(5), 289-304, 2005). Another serious side effects caused by antipsychotic drugs, e.g. sertindole, ziprasidone, are cardiac arrhythmias associated with delayed repolarization of cardiomyocytes. This condition appears on electrocardiograms (ECG) as prolonged corrected QT interval (QTc), what is most often evoked by substances which block hERG potassium channels. To prevent introduction to the developmental pipelines drugs with pro-arrhythmic potential, at a very early stage of research new substances are screened in vitro for their potency to block hERG potassium channels, using electrophysiological methods (Recanatini M. et al. , Med. Res. Rev. , 25(2), 133-66, 2005).

Despite the advances that have been made in the development of antidepressants, there are clearly still unmet clinical needs with respect to both efficacy and side effects. These needs range from efficacy in treatment resistant patients (about 30% ) to improved onset, to reductions in side effects such as sexual dysfunction, gastrointestinal events, sedation, weight gain. There are multiple approaches to improve current pharmacological means of modulating biogenic amines neurotransmission by either combining mechanisms or alternatively selectively stimulating/- blocking receptor subtypes that may trigger improved efficacy or fewer side effects. One of them is combination therapies that maintain the benefits associated with selective serotonin reuptake inhibitors (SSRIs) (blockers of serotonin transporter) but attempt to either improve efficacy or reduce side effects by adding additional mechanism involving blockade of 5-HT2A or 5-HT2C receptors (Millan M., Neurotherapeutics, 6(1 ), 53-77, 2009). 5-HT2A receptor antagonists administered alone may produce antidepressant activity and also co-administered with SSRIs augment their antidepressant effects. The mechanism for this interaction may be a further increase in extracellular serotonin levels produced when SSRIs are given with 5-HT2A antagonists. Moreover, blockade of 5-HT2A receptors is part of the pharmacological profile of antidepressant drugs such as mianserin and mirtazapine. Presynaptic 5-HT1A receptors are associated with the risk for depressive behavior and their blockade augments the effects of SSRIs. Postsynaptic 5-HT1A receptors are essential for producing the antidepressant effects of 5-HT1A receptor agonists and possibly SSRIs. Thus partial agonism of 5-HT1A receptors is a preferred feature for new molecules the more that this mechanism occurs in approved anxiolytic buspirone and antidepressant/anxiolytic tandospirone. Although introduction of new psychotropic drugs (among others neuroleptics, antidepressants, benzodiazepines, acetylcholinesterase inhibitors) since 50-thies of the XX century was an unquestioned breakthrough, therapy of neuropsychiatric disorders is still far from satisfactory both because of limited efficacy and wide spectrum of side effects evoked by available drugs. These disadvantages are a challenge for modern pharmacotherapy and there is a continuous effort to search for new, more effective psychotropic drugs.

From the state of art there are known certain alkylpiperazinyl derivatives of the tricyclic heterocyclic systems.

In EP1016664A compounds of the following general formula were disclosed, potentially useful i.a. for the treatment of schizophrenia.

Substituent R ³ in the compounds of the above general formula may be piperazine substituted at nitrogen atom by a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, acyl, alkoxycarbonyl and alkoxyalkyl.

WO95/17400 discloses compounds of the general formula presented below.

In the above compounds ring D may be cyclohexane or benzene, and ring E may be saturated or non-saturated 5- or 6-membered heterocycle. The above compounds were described as having activity of dopaminergic receptor D4 ligand that may be manifested in their potential usefulness in the treatment of anxiety and schizophrenia. In W096/18623 derivatives of the following formula were described.

Ring D in these compounds may be a 5-, 6- or 7-membered ring, saturated or non- saturated, homo- or heterocyclic. The above derivatives were described as showing selective affinity towards dopaminergic receptor D4 that may be manifested in their potential usefulness in the treatment of anxiety and schizophrenia.

In WO2007/022068 olanzapine analogs of the following formula and their use to modulate sleep were disclosed:

In US2006/094705 quetiapine analogs of the following formula for the treatment of sleep disorders were described:

Disclosure of the invention

The present invention relates to novel compounds, amidoalkylpiperazinyl derivatives of tricyclic heterocyclic systems, having the structure represented by the general formula (I):

wherein:

Z represents -NH- and X represents -S-, or Z represents -S- and X represents >C=C<; R ¹ represents H or -CH ₃ ;

R ⁶ and R ⁷ both represent H; n is an integer from 0 to 4, inclusive;

G represents a cyclic amide or imide moiety selected from the group consisting of G1 , G2, G3, G4, G5 and G6:

(G1 ) (G2) (G3)

(G4) (G5) ( ^G6 ) wherein:

Q represents H or -(d -C ₃ )alkyl;

L represents -CH ₂ - or >C=0;

represents a single bond or double bond;

R ² , R ³ , R ⁴ and R ⁵ independently from each other represent H, straight or branched - Ci -C ₅ -alkyl, -C ₃ -C ₆ -cycloalkyl, phenyl unsubstituted or substituted with halogen atom, or 5-membered heteroaryl having 1 heteroatom selected from the group consisting of N, 0 and S;

or R ² and R ³ together with a carbon atom, to which they are attached, form -C ₅ -C ₆ - cycloalkyl, which may be optionally fused with a benzene ring, and R ⁴ and R ⁵ , if present, represent H;

or R ² and R ⁴ together with carbon atoms, to which they are attached, form 6- membered saturated, non-saturated or aromatic hydrocarbon ring, and R ³ and R ⁵ , if present, represent H;

and optical isomers, geometric isomers, and pharmaceutically acceptable salts thereof.

One group of the compounds of the present invention are the compounds of formula (I ) as defined above, wherein G moiety represents G1 , wherein represents a single bond, L represents >C=0, and R ² , R ³ , R ⁴ and R ⁵ have the meanings as defined above for formula (I ).

In a particular variant of the compounds of the invention in G1 moiety, as defined above, R ² and R ³ are linked together to form together with a carbon atom to which they are attached, unsubstituted C ₅ -C ₆ -cycloalkyl, while R ⁴ and R ⁵ both represent H. Preferably, (G1 ) represents in this sub-group 2-azaspiro[4.4]nonan-1 ,3-dion-2-yl or 2- azaspiro[4.5]decan-1 ,3-dion-2-yl.

Further group of the compounds of the invention are the compounds of formula (I ) as defined above, wherein G moiety represents G6, wherein represents a double bond. Preferably, (G6) represents in this sub-group (1 /?,7S)-4-azatricyclo[5.2.1 .0 ² ' ⁶ ]dec- 8-en-3,5-dion-4-yl, (1 /?,2S,6/?,7S)-4-azatricyclo[5.2.1 .0 ^2,6 ]dec-8-en-3,5-dion-4-yl or (1 /?,2/?,6S,7S)-4-aza-tricyclo[5.2.1 .0 ² ' ⁶ ]dec-8-en-3,5-dion-4-yl.

Yet further group of the compounds of the invention are the compounds of formula (I ) as defined above, wherein G moiety represents G6, wherein represents a single bond. Preferably, (G6) represents in this sub-group 4-azatricyclo[5.2.1 .0 ² ' ⁶ ]decane-3,5- dion-4-yl or (1 /?,2S,6/?,7S)-4-azatricyclo[5.2.1 .0 ^2,6 ]decane-3,5-dion-4-yl.

Another group of the compounds of the invention are the compounds of formula (I) as defined above, wherein G moiety represents G2, wherein Q represents H, while R ² and R ³ have the meanings as defined above for formula (I ).

In a particular variant of the compounds of the invention in G2 moiety, as defined above, R ² represents straight or branched Ci -C ₅ -alkyl and R ³ represents phenyl. Preferably, in this sub-group G2 represents 5-methyl-5-phenylimidazolidine-2,4-dion-3-yl.

Yet another group of the compounds of the invention are the compounds of formula (I ) as defined above, wherein G moiety represents G3, wherein R ² and R ³ have the meanings as defined above for formula (I ).

In a particular variant of the compounds of the invention in G3 moiety, as defined above, R ² and R ³ represent straight or branched Ci -C ₅ -alkyl. Preferably, in his sub-group G3 represents 5,5-dimethyl-1 ,3-oxazolidine-2,4-dion-3-yl.

Yet further group of the compounds of the invention are the compounds of formula (I ) as defined above, wherein G moiety represents G4, wherein L represents >C=0, while R ² , R ³ , R ⁴ and R ⁵ have the meanings as defined above for formula (I).

Yet another group of the compounds of the invention are the compounds of formula (I ) as defined above, wherein G moiety represents G5. Further group of compounds of the invention are the compounds of formula (I) as defined above, wherein G moiety represents G1 , wherein represents a single bond, L represents -CH ₂ - and wherein R ² , R ³ , R ⁴ and R ⁵ have the meanings as defined above for formula (I).

Another group of the compounds of the invention are the compounds of formula (I) as defined above, wherein G moiety represents G4, wherein L represents -CH ₂ - and wherein R ² , R ³ , R ⁴ and R ⁵ have the meanings as defined above for formula (I).

Another group of the compounds of the invention are the compounds of formula (I) as defined above, wherein Z represents -NH-, X represents -S-, and R ¹ represents -CH ₃ .

Further group of the compounds of the invention are the compounds of formula (I) as defined above, wherein Z represents -S-, X represents >C=C<, and R ¹ represents H.

Further group of the compounds of the invention are the compounds of formula (I) as defined above, wherein n is 1.

Another group of the compounds of the invention are the compounds of formula (I) as defined above, wherein n is 2.

The following specific compounds of formula (I) of the invention can be mentioned:

1 ) 1 -[2-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]ethyl]- pyrrolidine-2,5-dione,

2) 1 -[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]propyl]- pyrrolidine-2,5-dione,

3) 1 -[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]butyl]- pyrrolidine-2,5-dione,

4) 1 -[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]pyrrolidine-2,5-dione,

5) 1 -[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]pyrrolidine-2,5-dione,

6) 3-methyl-1 -[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]propyl]pyrrolidine-2,5-dione,

7) 3-methyl-1 -[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]butyl]pyrrolidine-2,5-dione,

8) 1 -[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-3-methyl-pyrrolidine- 2,5-dione,

9) 1 -[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-3-methyl-pyrrolidine- 2,5-dione, 10) 3,3-dimethyl-1 -[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin 1 -yl]propyl]pyrrolidine-2,5-dione,

11 ) 3,3-dimethyl-1 -[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin 1 -yl]butyl]pyrrolidine-2,5-dione,

12) 1 -[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-3,3-dimethyl- pyrrolidine-2,5-dione,

13) 1 -[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-3,3-dimethyl- pyrrolidine-2,5-dione,

14) 3,4-dimethyl-1 -[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin 1 -yl]propyl]pyrrolidine-2,5-dione,

15) 3,4-dimethyl-1 -[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin 1 -yl]butyl]pyrrolidine-2,5-dione,

16) 1 -[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-3,4-dimethyl- pyrrolidine-2,5-dione,

17) 1 -[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-3,4-dimethyl- pyrrolidine-2,5-dione,

18) 3-ethyl-3-methyl-1-[3-[4-(2-methyl-10H-thieno[2,3-b][1,5]ben zodiazepin-4- yl)piperazin-1-yl]propyl]pyrrolidine-2,5-dione,

19) 3-ethyl-3-methyl-1-[4-[4-(2-methyl-10H-thieno[2,3-b][1,5]ben zodiazepin-4- yl)piperazin-1-yl]butyl]pyrrolidine-2,5-dione,

20) 1 -[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-3-ethyl-3-methyl- pyrrolidine-2,5-dione,

21 ) 1 -[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-3-ethyl-3-methyl- pyrrolidine-2,5-dione,

22) 3,3-diethyl-1-[3-[4-(2-methyl-10H-thieno[2,3-b][1,5]benzodia zepin-4-yl)piperazin-1 yl]propyl]pyrrolidine-2,5-dione,

23) 3,3-diethyl-1-[4-[4-(2-methyl-10H-thieno[2,3-b][1,5]benzodia zepin-4-yl)piperazin-1 yl]butyl]pyrrolidine-2,5-dione,

24) 1 -[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-3,3-diethyl- pyrrolidine-2,5-dione,

25) 1 -[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-3,3-diethyl- pyrrolidine-2,5-dione,

26) 1 -[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-3-isobutyl-3-methyl- pyrrolidine-2,5-dione, 27) 3-methyl-1-[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]propyl]-3-phenyl-pyrrolidine-2,5-dione,

28) 3-methyl-1-[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]butyl]-3-phenyl-pyrrolidine-2,5-dione,

29) 1 -[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-3-methyl-3-phenyl- pyrrolidine-2,5-dione,

30) 1 -[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-3-methyl-3-phenyl- pyrrolidine-2,5-dione,

31 ) 1 -[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]propyl]- 3,3-diphenyl-pyrrolidine-2,5-dione,

32) 1 -[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]butyl]- 3,3-diphenyl-pyrrolidine-2,5-dione,

33) 1 -[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-3,3-diphenyl- pyrrolidine-2,5-dione,

34) 2-[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]propyl]- 2-azaspiro[4.4]nonane-1 ,3-dione,

35) 2-[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]butyl]-2- azaspiro[4.4]nonane-1 ,3-dione,

36) 2-[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-2-azaspiro[4.4]- nonane-1 ,3-dione,

37) 2-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-2-azaspiro[4.4]nonane- 1 ,3-dione,

43) 2-[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]propyl]- 2-azaspiro[4.5]decane-1 ,3-dione,

44) 2-[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]butyl]-2- azaspiro[4.5]decane-1 ,3-dione,

45) 2-[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-2-azaspiro[4.5]- decane-1 ,3-dione,

46) 2-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-2-azaspiro[4.5]- decane-1 ,3-dione,

47) 1 -[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]propyl]- spiro[pyrrolidine-3,2'-tetralin]-2,5-dione,

48) 1-[4-[4-(2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-yl)p iperazin-1-yl]butyl]- spiro[pyrrolidine-3,2'-tetralin]-2,5-dione, 49) 3-[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]spiro[pyrrolidine-3,2' tetralin]-2,5-dione,

50) 3-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]spiro[pyrrolidine-3,2'- tetralin]-2,5-dione,

51 ) 2-[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]propyl] 3a,4,5,6,7,7a-hexahydroisoindole-1 ,3-dione,

52) 2-[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]butyl]- 3a,4,5,6,7,7a-hexahydroisoindole-1 ,3-dione,

53) 2-[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-3a,4,5,6,7,7a- hexahyd roisoi ndole- 1 , 3 -dione,

54) 2-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-3a,4,5,6,7,7a- hexahydroisoindole-1 ,3-dione,

55) 2-[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]propyl] 4,5,6,7-tetrahydroisoindole-1 ,3-dione,

56) 2-[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]butyl]- 4,5,6,7-tetrahydroisoindole-1 ,3-dione,

57) 2-[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-4, 5,6,7- tetrahydroisoindole-1 ,3-dione,

58) 2-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-4,5,6,7- tetrahydroisoindole-1 ,3-dione,

59) 2-[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]propyl] 3a,4,7,7a-tetrahydroisoindole-1 ,3-dione,

60) 2-[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]butyl]- 3a,4,7,7a-tetrahydroisoindole-1 ,3-dione,

61 ) 2-[5-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]pentyl] 3a,4,7,7a-tetrahydroisoindole-1 ,3-dione,

62) 4-[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]propyl] (1/?,7S)-4-azatricyclo[5.2.1.0 ² ' ⁶ ]dec-8-en-3,5-dione,

63) 4-[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]butyl]- (1/?,7S)-4-azatricyclo[5.2.1.0 ² ' ⁶ ]dec-8-en-3,5-dione,

69) 4-[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]- (1/?,7S)-4- azatricyclo[5.2.1.0 ² ' ⁶ ]dec-8-en-3,5-dione,

70) 4-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]- (1/?,7S)-4- azatricyclo[5.2.1.0 ² ' ⁶ ]dec-8-en-3,5-dione, 76) 4-[5-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)pentyl]-(1/?,7S)-4- azatricyclo[5.2.1.0 ² ' ⁶ ]dec-8-en-3,5-dione,

77) 4-[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]butyl]- (1/?,2S,6/?,7S)-4-azatricyclo[5.2.1.0 ² ' ⁶ ]dec-8-en-3,5-dione,

78) 4-[4-[4-(2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-yl)p iperazin-1-yl]butyl]- (1/?,2/?,6S,7S)-4-azatricyclo[5.2.1.0 ² ' ⁶ ]dec-8-en-3,5-dione,

79) 2-[2-[4-(2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-yl)p iperazin-1-yl]ethyl]- isoindoline-1 ,3-dione,

80) 2-[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]propyl]- isoindoline-1 ,3-dione,

81) 2-[4-[4-(2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-yl)p iperazin-1-yl]butyl]- isoindoline-1 ,3-dione,

82) 2-[5-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]pentyl]- isoindoline-1 ,3-dione,

83) 2-[6-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]hexyl]- isoindoline-1 ,3-dione,

84) 2-[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]isoindoline-1 ,3-dione

85) 2-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]isoindoline-1 ,3-dione,

86) 2-[5-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)pentyl]isoindoline-1 ,3-dione

87) 5,5-dimethyl-3-[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazii 1 -yl]propyl]imidazolidine-2,4-dione,

88) 3-[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-5,5-dimethyl- imidazolidine-2,4-dione,

89) 3-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-5,5-dimethyl- imidazolidine-2,4-dione,

90) 5-ethyl-5-methyl-3-[3-[4-(2-methyl-10H-thieno[2,3-b][1,5]ben zodiazepin-4-yl)- piperazin-1 -yl]propyl]imidazolidine-2,4-dione,

91) 5-ethyl-5-methyl-3-[4-[4-(2-methyl-10H-thieno[2,3-b][1,5]ben zodiazepin-4-yl)- piperazin-1 -yl]butyl]imidazolidine-2,4-dione,

92) 3-[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-5-ethyl-5-methyl- imidazolidine-2,4-dione,

93) 3-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-5-ethyl-5-methyl- imidazolidine-2,4-dione,

94) 5,5-diethyl-3-[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin- yl]propyl]imidazolidine-2,4-dione, 95) 5,5-diethyl-3-[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 yl]butyl]imidazolidine-2,4-dione,

96) 3-[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-5,5-diethyl- imidazolidine-2,4-dione,

97) 3-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-5,5-diethyl- imidazolidine-2,4-dione,

98) 1 -[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-3-isopropyl-3-methyl- pyrrolidine-2,5-dione,

99) 5,5-diisopropyl-3-[3-[4-(2-methyl-10H-thieno[2,3-b][1,5]benz odiazepin-4-yl)- piperazin-1 -yl]propyl]imidazolidine-2,4-dione,

100) 3-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-5,5-diisopropyl- imidazolidine-2,4-dione,

101 ) 3-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-5-cyclopropyl-5- methyl-imidazolidine-2,4-dione,

101 ) 3-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-5,5-dicyclopropyl- imidazolidine-2,4-dione,

103) 5-methyl-3-[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]propyl]-5-phenyl-imidazolidine-2,4-dione,

104) 5-methyl-3-[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]butyl]-5-phenyl-imidazolidine-2,4-dione,

105) 5-methyl-3-[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl] -5-phenyl- imidazolidine-2,4-dione,

106) 5-methyl-3-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl] -5-phenyl- imidazolidine-2,4-dione,

107) 3-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-5-(4-chlorophenyl)-5- cyclopropyl-imidazolidine-2,4-dione,

108) 3-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]- 5-(2-furylo)-5- methyl-imidazolidine-2,4-dione,

109) 8-[3-[4-(2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-yl)p iperazin-1-yl]propyl] 6,8-diazaspiro[4.4]nonane-7,9-dione,

110) 8-[4-[4-(2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-yl)p iperazin-1-yl]butyl]- 6,8-diazaspiro[4.4]nonane-7,9-dione,

111) 7-[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-7,9-diaza- spiro[4.4]nonane-6,8-dione, 112) 7-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-7,9- diazaspiro[4.4]nonane-6,8-dione,

113) 3-[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]propyl] 1 ,3-diazaspiro[4.5]decane-2,4-dione,

114) 3-[4-[4-(2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-yl)p iperazin-1-yl]butyl]- 1 ,3-diazaspiro[4.5]decane-2,4-dione,

115) 2-[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-2,4-diazaspiro- [4.5]decane-1 ,3-dione,

116) 2-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-2,4-diazaspiro- [4.5]decane-1 ,3-dione,

117) 3-[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]propyl] spiro[imidazolidine-5,2'-tetralin]-2,4-dione,

118) 3-[4-[4-(2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-yl)p iperazin-1-yl]butyl]- spiro[imidazolidine-5,2'-tetralin]-2,4-dione,

119) 3-[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]spiro[imidazolidine- 5,2'-tetralin]-2,4-dione,

120) 3-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]spiro[imidazolidine- 5,2'-tetralin]-2,4-dione,

121 ) 1 -methyl-3-[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]propyl]imidazolidine-2,4-dione,

122) 1 -methyl-3-[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]butyl]imidazolidine-2,4-dione,

123) 3-[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-1 -methyl- imidazolidine-2,4-dione,

124) 3-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-1 -methyl- imidazolidine-2,4-dione,

125) 5,5-dimethyl-3-[3-[4-(2-methyl-10H-thieno[2,3-b][1,5]benzodi azepin-4- yl)piperazin-1-yl]propyl]oxazolidine-2,4-dione,

126) 5,5-dimethyl-3-[4-[4-(2-methyl-10H-thieno[2,3-b][1,5]benzodi azepin-4- yl)piperazin-1-yl]butyl]oxazolidine-2,4-dione,

127) 3-[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-5,5- dimethyloxazolidine-2,4-dione,

128) 3-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-5,5-dimethyl- oxazolidine-2,4-dione, 129) 1 -[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]propyl] piperidine-2,6-dione,

130) 1-[4-[4-(2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-yl)p iperazin-1-yl]- butyl]piperidine-2,6-dione,

131 ) 1 -[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]piperidine-2,6-dione

132) 1 -[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]piperidine-2,6-dione,

133) 4,4-dimethyl-1-[3-[4-(2-methyl-10H-thieno[2,3-b][1,5]benzodi azepin-4- yl)piperazin-1-yl]propyl]piperidine-2,6-dione,

134) 4,4-dimethyl-1-[4-[4-(2-methyl-10H-thieno[2,3-b][1,5]benzodi azepin-4- yl)piperazin-1-yl]butyl]piperidine-2,6-dione,

135) 1 -[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-4,4-dimethyl- piperidine-2,6-dione,

136) 1 -[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-4,4-dimethyl- piperidine-2,6-dione,

137) 4-ethyl-4-methyl-1-[4-[4-(2-methyl-10H-thieno[2,3-b][1,5]ben zodiazepin-4- yl)piperazin-1-yl]butyl]piperidine-2,6-dione,

138) 1 -[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-4-ethyl-4-methyl- piperidine-2,6-dione,

139) 8-[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]propyl] 8-azaspiro[4.5]decane-7,9-dione,

140) 8-[4-[4-(2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-yl)p iperazin-1-yl]butyl]-

8- azaspiro[4.5]decane-7,9-dione,

141 ) 8-[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-8- azaspiro[4.5]decane-7,9-dione,

142) 8-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-8- azaspiro[4.5]decane-7,9-dione,

143) 9-[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]propyl]

9- azaspiro[5.5]undecane-8,10-dione,

144) 9-[4-[4-(2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-yl)p iperazin-1-yl]butyl]- 9-azaspiro[5.5]undecane-8,10-dione,

145) 9-[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]-9- azaspiro[5.5]undecane-8,10-dione,

146) 9-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-9- azaspiro[5.5]undecane-8,10-dione, 147) 2-(4-(4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl)butyl)- 1 H-benzo[de]isoquinoline-1 ,3(2H)-dione,

148) 2-(5-(4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl)pentyl)- 1 H-benzo[de]isoquinoline-1 ,3(2H)-dione,

149) 2-[2-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)ethyl]-3a,4,7,7a-tetrahydro- 1 H-isoindole-1 ,3(2H)-dione,

150) 2-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]- 1 H-benzo[de]- isoquinoline-1 ,3(2H)-dione,

151 ) 1 -[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]propyl]pyrrolidin-2-one,

152) 1 -[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]butyl]pyrrolidin-2-one,

153) 1 -[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]pyrrolidin-2-one,

154) 1 -[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]pyrrolidin-2-one,

155) 1 -[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]propyl]piperidin-2-one,

156) 1 -[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]butyl]piperidin-2-one,

157) 1 -[3-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)propyl]piperidin-2-one,

158) 1 -[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]piperidin-2-one.

159) 4-[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]propyl]- 4-azatricyclo[5.2.1.0 ² ' ⁶ ]decane-3,5-dione,

160) 4-[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]butyl]-4- azatricyclo[5.2.1.0 ² ' ⁶ ]decane-3,5-dione,

161 ) 4-[4-(4-dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-4-azatricyclo- [5.2.1.0 ² ' ⁶ ]decane-3,5-dione,

162) 4-[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 -yl]butyl]- (1 /?,2S,6/?,7S)-4-azatricyclo[5.2.1 .0 ² ' ⁶ ]decane-3,5-dione,

and pharmaceutically acceptable salts thereof.

Amidoalkylpiperazinyl derivatives of tricyclic heterocyclic systems of the above formula (I) exhibit affinity to receptors which are recognized therapeutical targets in the treatment of CNS disorders, such as dopaminergic, in particular D2 and D3, sero- toninergic, in particular 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, adrenergic, in particular a1 , receptors. Moreover, compounds of formula (I) of the invention show ability to block voltage-dependent sodium channels Nav1.7 and have low affinity toward biological targets associated with adverse effects, such as potassium channel hERG or muscarinic receptors. Due to such a broad pharmacological profile, the compounds of the invention may be useful in medicine as medicaments, for the treatment and/or prevention of the central nervous system disorders such as schizophrenia, schizoaffective disorders, schizophreniform disorders, delusional syndromes and other psychotic conditions related and not related to taking psychoactive substances, affective disorder, bipolar disorder, mania, depression, anxiety disorders of various etiology, stress reactions, consciousness disorders, coma, delirium of alcoholic or other etiology, aggression, psychomotor agitation and other conduct disorders, sleep disorders of various etiology, withdrawal syndromes of various etiology, addiction, pain syndromes of various etiology, intoxication with psychoactive substances, cerebral circulatory disorders of various etiology, psychosomatic disorders of various etiology, conversion disorders, dissociative disorders, urination disorders, autism and other developmental disorders, including nocturia, stuttering, tics, cognitive disorders of various types, such as Alzheimer's disease, psychopathological symptoms and neurological disorders in the course of other diseases of the central and peripheral nervous systems.

Thus, the subject of the present invention are the compounds of formula (I) as defined above, for use as a medicament.

In the treatment of central nervous system disorders compounds of formula (I) may be administered in the form of a pharmaceutical composition or preparation containing it.

Thus, the subject of the present invention is also the pharmaceutical composition containing the compound or compounds of formula (I) as defined above as an active substance, in combination with pharmaceutically acceptable carrier(s) and /or excipient(s).

The subject of the invention is also a use of alkylpiperazinyl derivatives of tricyclic heterocyclic systems of the above formula (I) for the treatment of disorders of central nervous system.

The invention relates also to a method for the treatment of disorders of the central nervous system in mammals, including humans, comprising administration of a therapeutically effective amount of the compound of above formula (I) or the pharmaceutical composition containing the compound of formula (I) as defined above as an active substance.

Terms used in the description of the present invention have the following meanings. The terms „Ci -C ₅ -alkyl" and „CrC ₃ -alkyl" relate to a saturated, straight or branched hydrocarbon group, having indicated number of carbon atoms. „Ci -C ₅ -alkyl" encompasses„Ci -C2-alkyl", „Ci -C ₃ -alkyl", and„C ₁ -C ₄ -alkyl". Specific examples of groups encompassed by the term „Ci -C ₅ -alkyl" are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl and n-pentyl. „Ci -C ₃ -alkyl" encompasses„Ci -C2-alkyl", and specific examples are methyl, ethyl, n-propyl, and isopropyl.

The term„halogen atom" relates to a substituent selected from F, CI, Br and I.

The term„C ₃ -C ₆ -cycloalky relates to a saturated cyclic hydrocarbon group having from 3 to 6 carbon atoms, and encompasses „C ₄ -C6-cycloalkyl", „C ₅ -C6-cycloalkyl", and „C ₄ - C ₅ -cycloalkyl". Specific examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term ,,6-membered saturated, non-saturated or aromatic hydrocarbon ring" encompasses cyclohexane, cyclohexene, cyclohexadiene and benzene (cyclohexatriene) rings.

The term ,,5-membered heteroaryl having 1 heteroatom selected from the group consisting of N, 0 and S" relates to a monocyclic heteroaromatic group having 4 carbon atoms and one heteroatom selected from a group consisting of N, 0 and S. This group is represented by pyrrolyl, thienyl and furyl.

The compounds of formula (I) can be prepared in a process presented in the following scheme:

The appropriate secondary amine of formula (II) or acid addition salt thereof, is subjected to N-alkylation reaction with the appropriate halogen derivative (III) in the presence of an excess of a base, for example potassium carbonate, optionally in the pre- sence of a catalytic amount of potassium iodide, at room temperature or at elevated temperature, to give a compound of formula (I ) of the invention. Reaction is carried out for example at the boiling point of a solvent, which is selected from the group consisting of acetone, acetonitrile, n-propanol, toluene or at room temperature in N, N-dime- thylformamide (DMF) as a solvent. Reaction time ranges usually from 12 to 48 hours.

The starting secondary amines (I I) are commercially available. If necessary, they can also be obtained by the methods described in the literature. Amine (I I ), wherein Z = N, X = S, R ¹ = CH ₃ (2-methyl-4-piperazin-1 -yl-10H-thieno[2,3-b] [1 ,5]benzodiazepine, N-desmethylolanzapine, 11- 1 ) may be obtained, for example by the method described in WO 2006/053870. Amine wherein Z = S, X = C = C, R ¹ = H (1 1 -piperazin-1 -yldibenzo- [b,f] [1 ,4]thiazepine, II-2) may be obtained by the method described in WO 2005/012274.

Starting compounds of formula (I I I ) can be obtained by the method presented on the following scheme:

Hal = CI or Br Hal = CI or Br

(IV) (V) (III)

For compounds of formula (V) with G moiety selected from G1 , G2, G3, G4, G5 and G6, wherein L in G1 and G4 represents C=0, i.e. cyclic imides, the appropriate dihalogeno- alkane of formula (IV) is subjected to a reaction with a compound of formula (V) in the presence of an excess of a base, for example potassium carbonate, optionally in the presence of a catalytic amount of potassium iodide, for example in a solvent selected from the group consisting of acetone and acetonitrile, at room temperature or at elevated temperature, for example at the boiling point of a solvent, to give a compound of formula (II I ). Progress of the reaction can be monitored by thin layer chromatography (TLC). Alternatively, in the above embodiment, the compounds of formula (I II ) can be prepared under conditions of phase transfer catalysis, as described in Kowalski P. et al. , J. Heterocycl. Chem. , 2008, 45, 209-214.

For compounds of formula (V) with G moiety selected from G1 and G4, wherein L is -CH ₂ -, i.e. lactams, appropriate dihalogenoalkan of formula (IV) is subjected to a reaction with a compound of formula (V) in the presence of an excess of a base, for example potassium hydroxide, and in the presence of a phase transfer catalyst, for example in tetrahydrofuran, at elevated temperature, at the boiling point of the solvent for instance, to give a compound of formula (III). Another method is reacting the corresponding dihalogenoalkan of formula (IV) with a compound of formula (V) in the presence of an excess of a base - sodium hydride, in anhydrous dimethylformamide, to obtain the compound of formula (III). Progress of the reaction can be monitored by thin layer chromatography (TLC).

Dihalogenoalkanes of formula (IV) are commercially available.

Derivatives of formula (V) are either known or commercially available compounds, or can be prepared from commercially available starting materials, by adapting and applying known methods.

For example, compounds of formula (V) with G moiety selected from: G1 , G4 and G6, wherein L in moieties G1 and G4 represents C=0, represented by the general formula (Va), are obtained either from the corresponding dicarboxylic acids (Via) or from commercially available acid anhydrides (Vlb), according to the following scheme:

(Vlb) m = 0 or 1 The above reaction is carried out by heating the appropriate dicarboxylic acid of formula (Via) or the acid anhydride of formula (VIb) with aqueous ammonia.

Appropriate dicarboxylic acids of formula (Via) and anhydrides of formula (VIb) are commercially available. If necessary, the compounds of formula (Via) can be prepared by methods described in literature, for example in Le Moal, H. , Bull. Soc. Chim. Fr. 1956, 1 , 418-424, and Le Moal, H. et al. , Bull. Soc. Chim. Fr. 1964, 579-584.

Derivatives (V), with G moiety representing G2 (hydantoin derivatives (Vc)), are obtained from appropriate ketones (IVc), according to the following scheme:

(IVc) (Vc)

Conditions for conducting the above process are described in literature (Godson L. H. et al. , J. Org. Chem. , 1960, 25, 1920-1924).

Preparation of exemplary compounds of formula (I) according to the invention and of the starting compounds of formulas (III) and (V) is described in detail in the experimental part.

Since the compounds of formula (I) have alkaline character (contain substituted piperazine moiety), they can form acid addition salts.

Salts with acids can be pharmaceutically acceptable, especially when they are intended to be an active ingredient in pharmaceutical composition. The present invention relates also to salts of the compounds of formula (I) with acids other than pharmaceutically acceptable ones, which may be useful for example as intermediates suitable for purification of the compounds of the invention. In practice, it is often desirable to isolate first the compound from a reaction mixture in the form of a salt which is not pharmaceutically acceptable to purify the compound, and then convert the salt into free base by treatment with alkaline agent and to isolate, and optionally convert into the salt again.

Acid addition salts can be formed with inorganic (mineral) or organic acids. In particular, hydrochloric, hydrobromic, hydroiodic, phosphoric, sulphuric, nitric, carbonic, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamic, aspargic, p-toluenesulphonic, benzenesulphonic, methanesulphonic, ethanesulphonic, naphthalenesulphonic such as 2-naphthalene- sulphonic, pamoic, xinafoic or hexanoic acids can be mentioned as examples of acids.

Acid addition salt can be prepared in a simple manner by reaction of the compound of formula (I) with suitable inorganic or organic acid, optionally in suitable solvent, such as organic solvent, to form a salt that is usually isolated, for example by crystallization and filtration. For example, compounds in the form of a free base can be converted into corresponding hydrochloride salts by reaction of a compound in a solution, for example in methanol, with stoichiometric amount of hydrochloric acid or with solution of hydrochloric acid in methanol, ethanol or diethyl ether, followed by evaporation of solvent(s). Alternatively, a solution of the compound in the form of a free base, for example in ethanol, may be saturated with gaseous hydrogen chloride, followed by filtering of the formed precipitate of (di-)hydrochloride salt.

The term„disorders of the central nervous system" should be understood as including disorders selected from schizophrenia, schizoaffective disorders, schizophreniform disorders, delusional syndromes and other psychotic conditions related and not related to taking psychoactive substances, affective disorder, bipolar disorder, mania, depression, anxiety disorders of various etiology, stress reactions, consciousness disorders, coma, delirium of alcoholic and other etiology, aggression, psychomotor agitation and other conduct disorders, sleep disorders of various etiology, withdrawal syndromes of various etiology, addiction, pain syndromes of various etiology, intoxication with psychoactive substances, cerebral circulatory disorders of various etiology, psychosomatic disorders of various etiology, conversion disorders, dissociative disorders, urination disorders, autism and other developmental disorders, including nocturia, stuttering, and tics, cognitive disorders of various types, like Alzheimer's disease, psychopathological symptoms and neurological disorders in the course of other diseases of the central and peripheral nervous systems.

In the treatment of the disorders mentioned above, compounds of formula (I) of the present invention can be administered as a chemical compound, but usually will be applied in the form of a pharmaceutical composition containing the compound of the present invention or its pharmaceutically acceptable salt as defined above as an active ingredient in combination with pharmaceutically acceptable carrier(s) and /or excipient(s). In the treatment of the above mentioned disorders the pharmaceutical compositions of the invention can be delivered by any route of administration, preferably oral or parenteral, and will have the form of a preparation for use in medicine, depending on the intended route of administration.

Compositions for oral administration may have the form of solid or liquid preparations. Solid preparations may be in the form, for example, tablets or capsules prepared in conventional manner using pharmaceutically acceptable inactive ingredients, such as binding agents (e.g. pregelatinized maize starch, polyvinylpyrrolidone or hyd roxy propyl - methylcellulose); fillers (e.g. lactose, sucrose, carboxymethylcellulose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. crospovidone, maize starch or sodium starch glycolate); wetting agents (e.g. sodium lauryl sulfate). The tablets may be coated using methods well known in the art with conventional coatings, delaying /controlling release coatings or enteric coatings. Liquid preparations for oral administration may have the form of e.g. solutions, syrups or suspensions, or may be prepared from a dry product suitable for reconstitution with water or other suitable carrier ex tempore. Such liquid preparations may be prepared by conventional methods with pharmaceutically acceptable inactive ingredients, such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia gum), nonaqueous matrix components (e.g. almond oil, oils esters, ethyl alcohol or fractionated vegetable oils) and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid). The preparations may also contain suitable buffering systems, flavouring and aroma agents, colourants and sweeteners.

Preparations for oral administration can be formulated according to methods well known to those skilled in the art to afford a controlled release of the active compound.

The parenteral route of administration comprises administration by intramuscular and intravenous injections and intravenous continuous infusions. Compositions for parenteral administration may be in the form of a dosage unit, e.g. in ampoules or in multidose containers with the addition of a preservative. The compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous media, and may contain pharmaceutically acceptable excipients, such as suspending agents, stabilizing and /or dispersing agents. Alternatively, the active ingredient may be in the form of a powder for reconstitution ex tempore in a suitable carrier, e.g. sterile pyrogen-free water. Method of treatment using compounds of this invention will be based on administration of a therapeutically effective amount of the compound of the invention, preferably in the form of a pharmaceutical composition, to a subject in need of such a treatment.

The proposed dose of the compounds of the invention will be comprised in the range from 1 to about 1000 mg per day, in a single dose or in divided doses. It will be apparent to those skilled in the art that selection of a dose required to achieve the desired biological effect will depend on several factors, such as the type of specific compound, the indication, route of administration, age and condition of a patient and the exact dose will be finally determined at the discretion of attending physician.

Example 1.

Procedure for preparation of starting materials of general formula (V)

a) for compounds of formula (V) with G moiety, wherein L represents C=0, E, if present, is different from O, NH or N-(d-C ₃ )alkyl (imide derivatives)

To the appropriate dicarboxylic acid (Via) or acid anhydride (VIb) (0.05 mol) 25% aqueous ammonia (equivalent to 0.05 mol ammonia) and distilled water (10 ml) were added. The mixture was placed in a sand bath and heated until the water evaporates, and then it was heated for 1 hour at 180°C. Crude products were purified by crystallization from methanol or 2-propanol.

According to the above procedure the following compounds were prepared:

pyrrolidine-2,5-dione (V-1 ) 3-methylpyrrolidine-2,5-dione (V-2)

3.3- dimethylpyrrolidine-2,5-dione (V-3)

3.4- dimethylpyrrolidine-2,5-dione (V-4)

3-ethyl-3-methylpyrrolidine-2,5-dione (V-5)

3,3-diethylpyrrolidine-2,5-dione (V-6)

3-methyl-3-(2-methylpropyl)pyrrolidine-2,5-dione (V-7)

3- methyl-3-phenylpyrrolidine-2,5-dione (V-8)

3.3- diphenylpyrrolidine-2,5-dione (V-9)

2-azaspiro[4.4]nonane-1 ,3-dione (V-10)

2- azaspiro[4.5]decane-1 ,3-dione (V-1 1 )

3.4- dihydro-1 /-/,2'/-/,5'/-/-spiro[naphthalene-2,3'-pyrrolidine] -2',5'-dione (V-12) hexahydro-1 H-isoindole-1 ,3(2H)-dione (V-1 3)

4,5,6,7-tetrahydro-1 H-isoindole-1 ,3(2H)-dione (V-14)

3a,4,7,7a-tetrahydro-1 H-isoindole-1 ,3(2H)-dione (V-1 5)

(1 /?,7S)-4-azatricyclo[5.2.1 .0 ^2,6 ]dec-8-ene-3,5-dione (V-16) commercially available (1 /?,2S,6/?,7S)-4-azatricyclo[5.2.1 .0 ² ' ⁶ ]dec-8-ene-3,5-dione (V-17)

(1 /?,2/?,6S,7S)-4-azatricyclo[5.2.1 .0 ² ' ⁶ ]dec-8-ene-3,5-dione (V-18)

1 H-isoindole-1 ,3(2H)-dione (V-19) commercially available

piperidine-2,6-dione (V-20)

4,4-dimethylpiperidine-2,6-dione (V-21 )

4- ethyl-4-methylpiperidine-2,6-dione (V-22)

8-azaspiro[4.5]decane-7,9-dione (V-23)

3- azaspiro[5.5]undecane-2,4-dione (V-24)

1 H-benzo[de]isoquinoline-1 ,3(2H)-dione (V-25) commercially available

4- azatricyclo[5.2.1 .0 ² ' ⁶ ]decane-3,5-dione (V-43) commercially available

(1 /?,2S,6/?,7S)-4-azatricyclo[5.2.1 .0 ^2,6 ]decane-3,5-dione (V-44) commercially available b) for compounds (V), wherein G represents G4 (hydantoin derivatives)

H

(IVc) (Vc) A mixture of the appropriate ketone (Vic) (0.0825 mol) and ammonium carbonate (0.26 mol) in 60% aqueous ethanol (1 37.5 ml) was heated in a flask equipped with reflux condenser. After heating the mixture to a temperature of 50° C, a solution of potassium cyanide (0.875 mol) in water (12.5 ml) was added dropwise during 20 min. The reaction mixture was heated for 24-30 hours, maintaining the temperature in a range 56-60° C. Then the mixture was heated for about 2 hours at 75-80° C to remove the excess of ammonium carbonate. The resulting mixture was then cooled and acidified using 16% sulfuric acid to pH 5-6. The resulting precipitate was filtered off, washed several times with water and crystallized from ethanol or a mixture of ethanol/water 7:3 or 9: 1 v/v.

According to the above procedure, the following compounds were prepared:

5,5-dimethylimidazolidine-2,4-dione (V-26)

5-ethyl-5-methylimidazolidine-2,4-dione (V-27)

5,5-diethylimidazolidine-2,4-dione (V-28)

5-methyl-5-(1 -methylethyl)imidazolidine-2,4-dione (V-29)

5,5-bis(1 -methylethyl)imidazolidine-2,4-dione (V-30)

5-cyclopropyl-5-methylimidazolidine-2,4-dione (V-31 )

5,5-dicyclopropylimidazolidine-2,4-dione (V-32)

5-methyl-5-phenylimidazolidine-2,4-dione (V-33)

5-(4-chlorophenyl)-5-cyclopropylimidazolidine-2,4-dione (V-34)

5-furan-2-yl-5-methylimidazolidine-2,4-dione (V-35)

1 ,3-diazaspiro[4.4]nonane-2,4-dione (V-36)

1 ,3-diazaspiro[4.5]decane-2,4-dione (V-37)

3',4'-dihydro-1 '/-/,2/-/,5/-/-spiro[imidazolidine-4,2'-naphthalene] -2,5-dione (V-38)

1 -methylimidazolidine-2,4-dione (V-39)

Compounds (V), as shown below, not belonging to any of the above groups, are commercially available:

5,5-dimethyl-1 ,3-oxazolidine-2,4-dione (V-40)

pyrrolidin-2-one (V-41 )

piperidin-2-one (V-42) Example 2.

Hal = CI or Br Hal = CI or Br

(IV) (V) (HI)

Dihalogenoalkanes of formula (IV), as listed below, used for the preparation of intermediates of formula (III) are commercially available:

1 -bromo-2-chloroethane (IV- 1 )

1.2- dibromoethane (IV-2)

1 -bromo-3-chloropropane (IV-3)

1.3- dibromopropane (IV-4)

1 -bromo-4-chlorobutane (IV-5)

1.4- dibromobutane (IV-6)

4-bromo-1 -chloropentane (IV-7)

1 -bromo-5-chloropentane (IV-12)

1.5- dibromopentane (IV-13)

1.6- dibromohexane (IV-14) a) Procedure for preparation of starting compounds of general formula (III) for compounds (V), wherein G moiety represents G1 , G2, G3, G4, G5 and G6, and wherein L in moieties G1 and G4 represents C=0

The appropriate compound of formula (V) (0.0178 mol), potassium carbonate (0.051 mol) and a catalytic amount of potassium iodide (0.3 g) were stirred while heating under reflux in acetone or acetonitrile (100 ml). After 60 minutes, the appropriate dihalogenoalkane (IV) (0.0195 mol) was added dropwise. Reaction progress was monitored by TLC. After spots originating from the substrate (V) disappeared, inorganic precipitate was filtered off while hot and the filtrate was concentrated under reduced pressure. Product (III) was purified using column chromatography with the solvent system ethyl acetate/n-hexane, 3:7, 4:6 or 8:2 v/v as eluent.

Structure of prepared compounds was confirmed by MS data and by ¹ H-NMR analysis.

According to the above procedure, the following compounds were prepared:

1 -(2-bromoethyl)pyrrolidine-2,5-dione (111-1 )

1 -(3-bromopropyl)pyrrolidine-2,5-dione (III-2)

1 -(4-chlorobutyl)pyrrolidine-2,5-dione (III-3)

1 -(3-chloropropyl)-3-methylpyrrolidine-2,5-dione (III-4)

1 -(4-chlorobutyl)-3-methylpyrrolidine-2,5-dione (III-5)

1 -(3-chloropropyl)-3,3-dimethylpyrrolidine-2,5-dione (III-6)

1 -(4-chlorobutyl)-3,3-dimethylpyrrolidine-2,5-dione (I II -7)

1 -(3-chloropropyl)-3,4-dimethylpyrrolidine-2,5-dione (III-8)

1 -(4-chlorobutyl)-3,4-dimethylpyrrolidine-2,5-dione (I II -9)

1 -(3-chloropropyl)-3-ethyl-3-methylpyrrolidine-2,5-dione (111-10)

1 -(4-chlorobutyl)-3-ethyl-3-methylpyrrolidine-2,5-dione (111-11 )

1 -(3-chloropropyl)-3,3-diethylpyrrolidine-2,5-dione (111-12)

1 -(4-chlorobutyl)-3,3-diethylpyrrolidine-2,5-dione (111-13)

1 -(4-chlorobutyl)-3-methyl-3-(2-methylpropyl)pyrrolidine-2,5- dione (111-14)

1 -(3-chloropropyl)-3-methyl-3-phenylpyrrolidine-2,5-dione (111-15)

1 -(4-chlorobutyl)-3-methyl-3-phenylpyrrolidine-2,5-dione (111-16)

1 -(3-chloropropyl)-3,3-diphenylpyrrolidine-2,5-dione (111-17)

1 -(4-chlorobutyl)-3,3-diphenylpyrrolidine-2,5-dione (111-18)

2-(3-chloropropyl)-2-azaspiro[4.4]nonane-1 ,3-dione (111-19)

2-(4-chlorobutyl)-2-azaspiro[4.4]nonane-1 ,3-dione (III -20 )

2-(3-chloropropyl)-2-azaspiro[4.5]decane-1 ,3-dione (III-26)

2-(4-chlorobutyl)-2-azaspiro[4.5]decane-1 ,3-dione (III-27)

1 '-(3-chloropropyl)-3,4-dihydro-1 /-/,2'/-/,5'/-/-spiro[naphthalene-2,3'-pyrrolidine]-2',5'-di one (III-28)

1 '-(4-chlorobutyl)-3,4-dihydro-1 /-/,2'/-/,5'/-/-spiro[naphthalene-2,3'-pyrrolidine]-2',5'-di one (III-29)

2-(3-chloropropyl)hexahydro-1 H-isoindole-1 ,3(2H)-dione (III-30)

2-(4-chlorobutyl)hexahydro-1 H-isoindole-1 ,3(2H)-dione (111-31 )

2-(3-chloropropyl)-4,5,6,7-tetrahydro-1 H-isoindole-1 ,3(2H)-dione (III- 32.)

2-(4-chlorobutyl)-4,5,6,7-tetrahydro-1 H-isoindole-1 ,3(2H)-dione ( 111 - 33 ) 2-(2-bromoethyl)-3a,4,7,7a-tetrahydro-1 H-isoindole-1 ,3(2H)-dione (III-86) 2-(3-bromopropyl)-3a,4,7,7a-tetrahydro-1 H-isoindole-1 ,3(2H)-dione (III- 3-4) 2-(4-bromobutyl)-3a,4,7,7a-tetrahydro-1 H-isoindole-1 , 3(2H)-dione (III-35) 2-(5-bromopentyl)-3a, 4, 7, 7a-tetrahydro-1 H-isoindole-1 ,3(2H)-dione (III-36) 4-(3-chloropropyl)-4-azatricyclo[5.2.1.0 ² ' ⁶ ]dec-8-en-3,5-dione (III-37)

4-(4-chlorobutyl)-4-azatricyclo[5.2.1 .0 ² ' ⁶ ]dec-8-en-3,5-dione (III-38)

4-(3-bromopropyl)-4-azatricyclo[5.2.1.0 ² ' ⁶ ]decane-3,5-dione (III-93)

4-(4-bromobutyl)-4-azatricyclo[5.2.1 .0 ² ' ⁶ ]decane-3,5-dione (III-94)

(1 /?,2S,6/?,7S)-4-(4-bromobutyl)-4-azatricyclo[5.2.1.0 ² ' ⁶ ]decane-3,5-dione (III-95)

4-(5-chloropentyl)-4-azatricyclo[5.2.1 .0 ² ' ⁶ ]dec-8-en-3,5-dione (III-44)

(1 /?,2S,6/?,7S)-4-(4-chlorobutyl)-4-azatricyclo[5.2.1.0 ² ' ⁶ ]dec-8-en-3,5-dione (III-45) (1 /?,2/?,6S,7S)-4-(4-chlorobutyl)-4-azatricyclo[5.2.1.0 ² ' ⁶ ]dec-8-en-3,5-dione (III-46) 2-(2-bromoethyl)-1 H-isoindole-1 , 3(2H)-dione (III-47) commercially available 2-(3-chloropropyl)-1 H-isoindole-1 , 3(2H)-dione (III-48)

2-(4-bromobutyl)-1 H-isoindole-1 ,3(2H)-dione (III-49) commercially available 2-(5-bromopentyl)-1 H-isoindole-1 , 3(2H)-dione (II I -50)

2- (6-bromohexyl)-1 H-isoindole-1 , 3(2H)-dione (111-51 )

3- (3-bromopropyl)-5,5-dimethylimidazolidine-2,4-dione (II I -52)

3-(4-chlorobutyl)-5,5-dimethylimidazolidine-2,4-dione (II I -53)

3-(3-chloropropyl)-5-ethyl-5-methylimidazolidine-2,4-dion e (III- 5-4)

3-(4-chlorobutyl)-5-ethyl-5-methylimidazolidine-2,4-dione (II I -55)

3-(3-chloropropyl)-5,5-diethylimidazolidine-2,4-dione (III-56)

3-(4-chlorobutyl)-5,5-diethylimidazolidine-2,4-dione (III-57)

3-(4-chlorobutyl)-5-methyl-5-(1 -methylethyl)imidazolidine-2,4-dione (II I -58) 3-(3-chloropropyl)-5,5-bis(1 -methylethyl)imidazolidine-2,4-dione (II I -59)

3-(4-chlorobutyl)-5,5-bis(1 -methylethyl)imidazolidine-2,4-dione (II I -60)

3-(4-chlorobutyl)-5-cyclopropyl-5-methylimidazolidine-2,4 -dione (111-61 )

3-(4-chlorobutyl)-5,5-dicyclopropylimidazolidine-2,4-dion e (II I -62)

3-(3-chloropropyl)-5-methyl-5-phenylimidazolidine-2,4-dio ne (III-63)

3-(4-chlorobutyl)-5-methyl-5-phenylimidazolidine-2,4-dion e (III- 6-4)

3-(4-chlorobutyl)-5-(4-chlorophenyl)-5-cyclopropylimidazo lidine-2,4-dione (II I -65) 3-(4-chlorobutyl)-5-furan-2-ylo-5-methylimidazolidine-2,4-di one (II I -66)

3-(3-chloropropyl)-1 ,3-diazaspiro[4.4]nonane-2,4-dione (II I -67)

3-(4-chlorobutyl)-1 ,3-diazaspiro[4.4]nonane-2,4-dione (II I -68) 3-(3-chloropropyl)-1 ,3-diazaspiro[4.5]decane-2,4-dione (I II -69)

3-(4-chlorobutyl)-1 ,3-diazaspiro[4.5]decane-2,4-dione (II I -70)

1 -(3-chloropropyl)-3^4'-dihydro-1 ^,2H,5H-spi o[imidazolidine-4,2'-naphthalene]-2,5- dione (111-71 )

1 -(4-chlorobutyl)-3^4'-dihydro-1 ^,2H,5H-spi o[imidazolidine-4,2'-naphthalene]-2,5- dione (111 -72)

3-(3-chloropropyl)-1 -methylimidazolidine-2,4-dione (I II -73)

3-(4-chlorobutyl)-1 -methylimidazolidine-2,4-dione (II I -74)

3-(3-chloropropyl)-5,5-dimethyl-1 ,3-oxazolidine-2,4-dione (II I -75)

3-(4-chlorobutyl)-5,5-dimethyl-1 ,3-oxazolidine-2,4-dione (II I -76)

1 -(3-chloropropyl)piperidine-2,6-dione (III-77)

1 -(4-chlorobutyl)piperidine-2,6-dione (III-78)

1 -(3-chloropropyl)-4,4-dimethylpiperidine-2,6-dione (II I -79)

1 -(4-chlorobutyl)-4,4-dimethylpiperidine-2,6-dione (I II -80)

1 -(4-chlorobutyl)-4-ethyl-4-methylpiperidine-2,6-dione (111-81 )

8-(3-chloropropyl)-8-azaspiro[4.5]decane-7,9-dione (II I -82)

8-(4-chlorobutyl)-8-azaspiro[4.5]decane-7,9-dione (III -S3 )

3-(3-chloropropyl)-3-azaspiro[5.5]undecane-2,4-dione (III-84)

3-(4-chlorobutyl)-3-azaspiro[5.5]undecane-2,4-dione (III-85)

2-(4-bromobutyl)-1 H-benzo[de]isoquinoline-1 ,3(2H)-dione (III-87)

2-(5-bromopentyl)-1 H-benzo[de]isoquinoline-1 ,3(2H)-dione (III- SS ) b) Procedure for preparation of starting compounds of general formula (III) for compounds (V), wherein G moiety represents G1 or G4, and wherein L in moieties G1 and G4 represents CH ₂ (lactams)

b1 ) for compounds of formula (V) which are pyrrolidin-2-one derivatives

Potassium hydroxide (0.033 mol) was ground and suspended in 300 ml of THF, then TBAB (3.9 mmol) was added and the resulting mixture was stirred for 10 min. The mixture was then heated to reflux and within one hour the appropriate pyrrolidin-2-one (0.03 mol) in 5 ml of THF, and then dihalogenoderivative (IV) (0.03 mol) dissolved in 5 ml THF were added dropwise. Heating and stirring were continued for 3 hours. The reaction was monitored by TLC. After reaction was completed, the mixture was cooled, inorganic solid was filtered off and the filtrate was concentrated under reduced pressure. The oily residue was purified by column chromatography (ethyl acetate/n-hexane: 9/1 , v/v). Structure of prepared compounds was confirmed by MS data and by ¹ H-NMR analysis. According to the above procedure, the following compounds were prepared:

1 -(3-chloropropyl)pyrrolidin-2-one (III-89)

1 -(4-chlorobutyl)pyrrolidin-2-one (III-90)

b2) for compounds of formula (V) being piperidin-2-one derivatives

To the solution of an appropriate piperidin-2-one (0.02 mol) in DMF (30 ml) under nitrogen NaH (0.021 mol) was added portionwise while stirring. The mixture was then heated in an oil bath to 80°C and stirring was continued for 1 hour. After cooling to room temperature, dihalogenoderivative of formula (IV) (0.1 mol) dissolved in 10 ml of DMF was added to the mixture, which was then left for a further 48 hours under stirring. Subsequently, to the mixture 100 ml of chloroform was added and after cooling the precipitate of inorganic salts was filtered off. Organic filtrate was concentrated under reduced pressure. The oily residue was dissolved in chloroform and washed successively with water, sodium bicarbonate solution and finally with a solution of sodium chloride. Chloroform layer was dried over anhydrous sodium sulfate and concentrated. The oily residue was purified by column chromatography (ethyl acetate/methanol 8/2 v/v).

Structure of prepared compounds was confirmed by MS data and by ¹ H-NMR analysis. According to the above procedure, the following compounds were prepared:

1 -(3-bromopropyl)piperidin-2-one (111-91 )

1 -(4-chlorobutyl)piperidin-2-one (III-92)

Example 3.

General procedure for the preparation of compounds (I) of the invention

(II) (IN) (I) A mixture of appropriate secondary amine of formula (II) (0.67 mmol), the appropriate halogenoderivative of formula (III) (0.8 mmol) and potassium carbonate (2 mmol) was heated at reflux in a solvent (acetone, acetonitrile, n-propanol or toluene (10 ml)) for 12-24 hours or stirred at room temperature in N,N'-dimethylformamide (10 ml) for 15-48 hours. The progress of N-alkylation reaction was monitored by TLC. After the reaction was completed, inorganic solid was filtered off, the filtrate was concentrated under reduced pressure and the crude product was purified either by crystallization or by column chromatography. The structure of the compounds was analyzed by mass spectrometry and proton nuclear magnetic resonance. Yield of the products ranged from 50 to 70% and purity thereof determined by HPLC was higher than 95%.

Following the general procedure described above and starting from the appropriate intermediate compounds: amine of formula (II) and halogenoderivative of formula (III), following compounds of the invention were obtained.

Compound 1. 1 -[2-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]ethyl]pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111-1 ). MS: 424[M+H ⁺ ].

Compound 2. 1 -[3-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]propyl]pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -2). MS: 438[M+H ⁺ ].

Compound 3. 1 -[4-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]butyl]pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -3). MS: 452[M+H ⁺ ].

Compound 4. 1 -[3-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]pyrrolidine- 2,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111 -2). MS: 436[M+H ⁺ ].

Compound 5. 1 -[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]pyrrolidine- 2,5-dione The title compound was prepared starting from the secondary amine (11-2) and halogenoderivative (111 -3).

¹ H NMR (300 MHz) CDCl ₃ : δ 1 .30-1 .66 (m, 4Η), 2.37-2.53 (m, 6Η), 2.68 (s, 4Η), 3.45-3.55 (m, 6Η), 6.87 (td, 1 Η), 7.06 (dd, 1 Η), 7.13-7.19 (m, 1 Η), 7.26-7.39 (m, 4Η), 7.48-7.53 (m, 1 Η). MS: 450[M+H ⁺ ].

Compound 6. 3-Methyl-1 -[3-[4-(2-methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)- piperazin-1 -yl]propyl]pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -4).

¹ H NMR (300 MHz) CDCl ₃ : 1 .25-1 .82 (m, 7H), 2.30 (d, 3H), 2.31 -2.95 (m, 7H), 3.50-3.66 (m, 6H), 5.01 (brs, 1 H), 6.29 (d, 1 H), 6.61 (dd, 1 H), 6.84-7.06 (m, 3H). MS: 452[M+H ⁺ ].

Compound 7. 3-Methyl-1 -[4-[4-(2-methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4- yl)piperazin-1 -yl]butyl]pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -5).

¹ H NMR (300 MHz) CDCl ₃ : 1 .18-1 .66 (m, 9H), 2.31 (d, 3H), 2.33-2.95 (m, 7H), 3.47-3.54 (m, 6H), 4.96 (brs, 1 H), 6.29 (d, 1 H), 6.60 (dd, 1 H), 6.87 (td, 1 H), 6.93-7.06 (m, 2H).

MS: 467[M+H ⁺ ].

Compound 8. 1 -[3-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-3-methyl- pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111 -4). MS: 450[M+H ⁺ ].

Compound 9. 1 -[4-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-3-methyl- pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III-5). MS: 463[M+H ⁺ ].

Compound 10. 3,3-Dimethyl-1 -[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4- yl)piperazin-1 -yl]propyl]pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -6). MS: 466[M+H ⁺ ]. Compound 1 1. 3, 3- Dimethyl- 1 -[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4- yl)piperazin-1 -yl]butyl]pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III-7). MS: 481 [M+H ⁺ ].

Compound 12. 1 -[3-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-3,3- dimethyl-pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111 -6). MS: 464[M+H ⁺ ].

Compound 13. 1 -[4-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-3,3- dimethyl-pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111 -7). MS: 478[M+H ⁺ ].

Compound 14. 3,4-Dimethyl-1 -[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4- yl)piperazin-1 -yl]propyl]pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -8).

¹ H NMR (300 MHz) CDCl ₃ : 1 .22-1 .82 (m, 8H), 2.30 (d, 3H), 2.36-2.91 (m, 8H), 3.55-3.64 (m, 6H), 5.06 (brs, 1 H), 6.27 (d, 1 H), 6.61 (d, 1 H), 6.87 (td, 1 H), 6.93-7.02 (m, 2H).

MS: 466[M+H ⁺ ].

Compound 15. 3,4-Dimethyl-1 -[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4- yl)piperazin-1 -yl]butyl]pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -9).

¹ H NMR (300 MHz) CDCl ₃ : δ 1 .21 -1 .66 (m, 10H), 2.30 (d, 3H), 2.37-2.53 (m, 6H), 3.48- 3.53 (m. 8H), 4.95 (brs, 1 H), 6.29 (d, 1 H), 6.59 (dd, 1 H), 6.84-7.04 (m, 3H). MS: 480[M+H ⁺ ].

Compound 16. 1 -[3-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-3,4- dimethyl-pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III-8). MS: 463[M+H ⁺ ]. Compound 17. 1 -[4-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-3,4- dimethyl-pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111 -9). MS: 478[M+H ⁺ ].

Compound 18. 3-Ethyl-3-methyl-1 -[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzo- diazepin-4-yl)piperazin-1 -yl]propyl]pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111-10).

¹ H NMR (300 MHz) CDCl ₃ : 0.87 (t, 3H), 1 .24. -81 (m, 7H), 2.30 (d, 3H), 2.37-2.63 (m, 8H), 3.52-3.58 (m, 6H), 5.03 (brs, 1 H), 6.28 (d, 1 H), 6.60 (dd, 1 H), 6.86 (td, 1 H), 6.93-7.04 (m, 2H). MS: 480[M+H ⁺ ].

Compound 19. 3-Ethyl-3-methyl-1 -[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzo- diazepin-4-yl)piperazin-1 -yl]butyl]pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111-1 1 ).

¹ H NMR (300 MHz) CDCl ₃ : 0.86 (t, 3H), 1 .28 (s, 3H), 1 .42-1 .76 (m, 6H), 2.31 (d, 3H), 2.36-2.64 (m, 8H), 3.48-3.53 (m, 6H), 4.95 (brs, 1 H), 6.29 (d, 1 H), 6.60 (dd, 1 H), 6.87 (td, 1 H), 6.93-7.01 (m, 2H). MS: 495[M+H ⁺ ].

Compound 20. 1 -[3-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-3-ethyl-3- methyl-pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111-10).

¹ H NMR (300 MHz) CDCl ₃ : δ 0.85 (t, 3H), 1 .27 (s, 3H), 1 .45-1 .75 (m, 6H), 2.35-2.52 (m, 8H), 3.43-3.52 (m, 6H), 6.88 (td, 1 H), 7.06 (dd, 1 H), 7.1 1 -7.19 (m, 1 H), 7.24-7.34 (m, 3H), 7.38 (dd, 1 H), 7.46-7.52 (m, 1 H). MS: 478[M+H ⁺ ].

Compound 21. 1 -[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-3-ethyl-3- methyl-pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111-1 1 ). MS: 492[M+H ⁺ ].

Compound 22. 3,3-Diethyl-1 -[3-[4-(2-methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)- piperazin-1 -yl]propyl]pyrrolidine-2,5-dione The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111-12). MS: 495[M+H ⁺ ].

Compound 23. 3,3-Diethyl-1 -[4-[4-(2-methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)- piperazin-1 -yl]butyl]pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111-13).

¹ H NMR (300 MHz) CDCl ₃ : δ 0.89 (t, 6H), 1 .52-1 .82 (m, 8H), 2.31 (d, 3H), 2.42-2.52 (m, 8H), 3.48-3.53 (m, 6H), 4.92 (brs, 1 H), 6.28 (d, 1 H), 6.59 (dd, 1 H), 6.87 (td, 1 H), 6.93- 7.04 (m, 2H). MS: 509[M+H ⁺ ].

Compound 24. 1 -[3-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-3,3- diethyl-pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111-12). MS: 492[M+H ⁺ ].

Compound 25. 1 -[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-3, 3-diethyl- pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111-13).

¹ H NMR (300 MHz) CDCl ₃ : δ 0.84 (t, 6H, Hz), 1 .46-1 .78 (m, 8H), 2.36-2.52 (m, 8H), 3.43- 3.52 (m, 6H), 6.86 (td, 1 H), 7.06 (dd, 1 H), 7.1 1 -7.20 (m, 1 H), 7.23-7.34 (m, 3H), 7.38 (dd, 1 H), 7.46-7.52 (m, 1 H). MS: 506[M+H ⁺ ].

Compound 26. 1 -[4-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-3-isobutyl- 3-methyl-pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111-14). MS: 520[M+H ⁺ ].

Compound 27. 3-Methyl-1 -[3-[4-(2-methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)- piperazin-1 -yl]propyl]-3-phenyl-pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111-15). MS: 529[M+H ⁺ ].

Compound 28. 3-Methyl-1 -[4-[4-(2-methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)- piperazin-1 -yl]butyl]-3-phenyl-pyrrolidine-2,5-dione The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111-16). MS: 543[M+H ⁺ ].

Compound 29. 1 -[3-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-3-methyl- 3-phenyl-pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111-15). MS: 525[M+H ⁺ ].

Compound 30. 1 -[4-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-3-methyl-3- phenyl-pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111-16). MS: 539[M+H ⁺ ].

Compound 31. 1 -[3-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]propyl]-3,3-diphenyl-pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111-17). MS: 590[M+H ⁺ ].

Compound 32. 1 -[4-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]butyl]-3,3-diphenyl-pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111-18). MS: 604[M+H ⁺ ].

Compound 33. 1 -[4-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-3,3- diphenyl-pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111-18). MS: 602[M+H ⁺ ].

Compound 34. 2-[3-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]propyl]-2-azaspiro[4.4]nonane-1 ,3-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111-19). ¹ H NMR (300 MHz) DMSO: δ 1 .63-1 .95 (m, 18H), 2.30 (s, 3H), 2.63 (s, 2H), 3.09-3.85 (m, 12H), 6.65 (s, 1 H), 6.97 (d, 1 H, J=7.18 Hz), 7.12 (d, 1 H, J=7.18 Hz), 7.19-7.24 (m, 2H), 9.25 (brs, 1 H), 1 1 .35 (brs, 1 H, HCl), 1 1 .62 (brs, 1 H, HCl) (as dihydrochloride). MS: 493[M+H ⁺ ].

Compound 35. 2-[4-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]butyl]-2-azaspiro[4.4]nonane-1 ,3-dione The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -20). MS: 507[M+H ⁺ ].

Compound 36. 2-[3-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-2- azaspiro[4.4]nonane-1 ,3-dione The title compound was prepared starting from the secondary amine (II-2) and halogenoderivative (111-19). MS: 490[M+H ⁺ ].

Compound 37. 2-[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-2-azaspiro- [4.4]nonane-1 ,3-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111 -20).

¹ H NMR (300 MHz) DMSO: δ 1 .49-2.06 (m, 12H), 2.62 (s, 2H), 3.10-4.12 (m, 12H), 7.05 (t,

I H, J=7.43 Hz), 7.19 (d, 1 H, J=7.95 Hz), 7.29 (t, 1 H, J=6.92 Hz), 7.45-7.64 (m, 5H),

I I .48 (brs, 1 H, HCl)(as hydrochloride). MS: 504[M+H ⁺ ].

Compound 43. 2-[3-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]propyl]-2-azaspiro[4.5]decane-1 ,3-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -26). MS: 507[M+H ⁺ ].

Compound 44. 2-[4-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]butyl]-2-azaspiro[4.5]decane-1 ,3-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -27). MS: 520[M+H ⁺ ].

Compound 45. 2-[3-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-2- azaspiro[4.5]decane-1 ,3-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111 -26). MS: 504[M+H ⁺ ].

Compound 46. 2-[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-2-azaspiro- [4.5]decane-1 ,3-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111 -27). MS: 518[M+H ⁺ ].

Compound 47. 1 -[3-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]propyl]spiro[pyrrolidine-3,2'-tetralin]-2,5-dione The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -28). MS: 555[M+H ⁺ ].

Compound 48. 1 -[4-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]butyl]spiro[pyrrolidine-3,2'-tetralin]-2,5-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -29). MS: 569[M+H ⁺ ].

Compound 49. 3-[3-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]spiro- [pyrrolidine-3,2'-tetralin]-2,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111 -28).

¹ H NMR (300 MHz) CDCl ₃ : δ 1 .79-1 .84 (m, 3H), 2.16-2.25 (m, 2H), 2.40-2.61 (m, 9H), 2.84-3.04 (m, 2H), 3.29 (d, 1 H), 3.44-3.64 (m, 5H), 6.85-6.90 (m, 1 H), 7.04-7.17 (m, 6H), 7.26-7.40 (m, 4H), 7.49-7.52 (m, 1 H). MS: 552[M+H ⁺ ].

Compound 50. 3-[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]spiro- [pyrrolidine-3,2'-tetralin]-2,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111 -29). MS: 566[M+H ⁺ ].

Compound 51. 2-[3-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]propyl]-3a,4,5,6,7,7a-hexahydroisoindole-1 ,3-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -30). MS: 493[M+H ⁺ ].

Compound 52. 2-[4-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]butyl]- 3a,4,5,6,7,7a-hexahydroisoindole-1 ,3-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111-31 ). MS: 507[M+H ⁺ ].

Compound 53. 2-[3-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]- 3a,4,5,6,7,7a-hexahydroisoindole-1 ,3-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111 -30). MS: 490[M+H ⁺ ]. Compound 54. 2-[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]- 3a,4,5,6,7,7a-hexahydroisoindole-1 ,3-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111-31 ).

¹ H NMR (300 MHz) DMSO: δ 1 .26-1 .34 (m, 4H), 1 .51 -1 .58 (m, 4H), 1 .69 (br s, 4H), 2.91 - 2.94 (m, 2H), 3.10 (br s, 3H), 3.26 (br s, 1 H), 3.35-3.41 (m, 2H), 3.43-4.51 (m, 6H), 7.05-7.09 (t, 1 H), 7.20-7.23 (m, 1 H), 7.27-7.32 (m, 1 H), 7.46-7.64 (m, 5H), 1 1 .55 (brs, 1 H, HCl) as hydrochloride. MS: 504[M+H ⁺ ].

Compound 55. 2-[3-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]propyl]-4,5,6,7-tetrahydroisoindole-1 ,3-dioneThe title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III-32). MS: 491 [M+H ⁺ ].

Compound 56. 2-[4-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]butyl]-4,5,6,7-tetrahydroisoindole-1 ,3-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -33). MS: 505[M+H ⁺ ].

Compound 57. 2-[3-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-4, 5,6,7- tetrahydroisoindole-1 ,3-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111 -32). MS: 488[M+H ⁺ ].

Compound 58. 2-[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-4, 5,6,7- tetrahydroisoindole-1 ,3-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111 -33). MS: 502[M+H ⁺ ].

Compound 59. 2-[3-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]propyl]-3a,4,7,7a-tetrahydroisoindole-1 ,3-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -34). MS: 490[M+H ⁺ ].

Compound 60. 2-[4-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]butyl]-3a,4,7,7a-tetrahydroisoindole-1 ,3-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -35). MS: 504[M+H ⁺ ]. Compound 61. 2-[5-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]pentyl]-3a,4,7,7a-tetrahydroisoindole-1 ,3-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -36). MS: 518[M+H ⁺ ].

Compound 62. 4-[3-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]propyl]-(1 /?,7S)-4-azatricyclo[5.2.1 .0 ^2,6 ]dec-8-ene-3,5-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III-37). MS: 503[M+H ⁺ ].

Compound 63. 4-[4-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]butyl]-(1 /?,7S)-4-azatricyclo[5.2.1 .0 ² ' ⁶ ]dec-8-ene-3,5-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III-38). ¹ H NMR (300 MHz) DMSO: δ 1 .37-1 .62 (m, 6H), 2.30 (s, 3H),

3.07- 3.85 (m, 16H), 6.10-6.1 1 (m, 2H), 6.65 (s, 1 H), 6.99 (d, 1 H, J=7.95 Hz), 7.12 (d, 1 H, J=7.43 Hz), 7.20-7.25 (m, 2H), 9.32 (brs, 1 H), 1 1 .42 (brs, 1 H, HCl), 1 1 .78 (brs, 1 H, HCl). (as dihydrochloride). MS: 516[M+H ⁺ ].

Compound 69. 4-[3-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-(1 /?, 7S)-4- azatricyclo[5.2.1 .0 ² ' ⁶ ]dec-8-ene-3,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -37).

¹ H NMR (300 MHz) CDCl ₃ : δ 1 .42-1 .75 (m, 6H), 2.33-2.50 (m, 6H), 3.22-3.53 (m, 8H),

6.08- 6.12 (m, 2H), 6.87 (td, 1 H), 7.06 (dd, 1 H), 7.16 (td, 1 H), 7.24-7.40 (m, 4H), 7.48- 7.52 (m, 1 H). MS: 500[M+H ⁺ ].

Compound 70. 4-[4-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-(1 /?,7S)-4- azatricyclo[5.2.1 .0 ² ' ⁶ ]dec-8-ene-3,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -38).

¹ H NMR (300 MHz) DMSO: δ 1 .35-1 .60 (m, 6H), 3.07-3.55 (m, 16H), 6.08-6.10 (m, 2H), 6.99 (t, 1 H, J=6.92 Hz), 7.09 (d, 1 H, J=7.69 Hz), 7.25 (t, 1 H, J=6.92 Hz), 7.41 -7.61 (m, 5H), 10.99 (brs, 1 H). (as hydrochloride). MS: 514[M+H ⁺ ].

Compound 76. 4-[5-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)pentyl]-(1 /?, 7S)-4- azatricyclo[5.2.1 .0 ² ' ⁶ ]dec-8-ene-3,5-dione The title compound was prepared starting from the secondary amine (11-2) and halogenoderivative (111-44). MS: 527[M+H ⁺ ].

Compound 77. 4-[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]butyl]-(1/?,2S,6/?,7S)-4-azatricyclo[5.2.1.0 ² ' ⁶ ]dec-8-ene-3,5-dione

The title compound was prepared starting from the secondary amine (11-1) and halogenoderivative (III-45).

¹ H NMR (300 MHz, CDCl ₃ ) δ: 1.36-1.43 (m, 2H), 1.49-1.63 (m, 4H), 2.29 (d, 3H, J=0.77 Hz), 2.69-2.87 (m, 2H), 3.06-3.3.42 (m, 16H), 6.10-6.11 (m, 2H), 6.66 (s, 1H), 7.0-7.28 (m, 4H), 9.41 (brs, 1H), 11.52 (brs, 1H), 11.89 (brs, 1H) (as dihydrochloride). MS: 516[M+H ⁺ ].

Compound 78. 4-[4-[4-(2-Methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]butyl]-(1/?,2/?,6S,7S)-4-azatricyclo[5.2.1.0 ² ' ⁶ ]dec-8-ene-3,5-dione

The title compound was prepared starting from the secondary amine (11-1) and halogenoderivative (III-46).

¹ H NMR (300 MHz, CDCl ₃ ) δ: 1.10-1.14 (m, 1H), 1.34-1.38 (m, 1H), 1.48-1.55 (m, 2H), 1.71-1.89 (m, 2H), 2.29 (d, 3H, J=0.77 Hz), 2.69-2.87 (m, 2H), 3.08-3.3.42 (m, 14H), 6.29-6.30 (m, 2H), 6.67 (d, 1H, J=0.77 Hz), 7.02-7.26 (m, 4H), 9.41 (brs, 1H), 11.54 (brs, 1H), 11.85 (brs, 1H) (as dihydrochloride). MS: 516[M+H ⁺ ].

Compound 79. 2-[2-[4-(2-Methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]ethyl]isoindoline-1 ,3-dione

The title compound was prepared starting from the secondary amine (11-1) and halogenoderivative (111 -47). MS: 472[M+H ⁺ ].

Compound 80. 2-[3-[4-(2-Methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]propyl]isoindoline-1 ,3-dione

The title compound was prepared starting from the secondary amine (11-1) and halogenoderivative (III-48). MS: 486[M+H ⁺ ].

Compound 81. 2-[4-[4-(2-Methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]butyl]isoindoline-1 ,3-dione

The title compound was prepared starting from the secondary amine (11-1) and halogenoderivative (III-49). MS: 500[M+H ⁺ ].

Compound 82. 2-[5-[4-(2-Methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]pentyl]isoindoline-1 ,3-dione The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -50). MS: 514[M+H ⁺ ].

Compound 83. 2-[6-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin-1 - yl]hexyl]isoindoline-1 ,3-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -51 ). MS: 528[M+H ⁺ ].

Compound 84. 2-[3-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]isoindoline- 1 ,3-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -48). MS: 483[M+H ⁺ ].

Compound 85. 2-[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]isoindoline- 1 ,3-dione The title compound was prepared starting from the secondary amine (II-2) and halogenoderivative (III -49). MS: 497[M+H ⁺ ].

Compound 86. 2-[5-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)pentyl]isoindoline- 1 ,3-dione The title compound was prepared starting from the secondary amine (II-2) and halogenoderivative (III -50). MS: 51 1 [M+H ⁺ ].

Compound 87. 5,5-Dimethyl-3-[3-[4-(2-methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4- yl)piperazin-1 -yl]propyl]imidazolidine-2,4-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -52). MS: 467[M+H ⁺ ].

Compound 88. 3-[3-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-5,5- dimethyl-imidazolidine-2,4-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -52). MS: 465[M+H ⁺ ].

Compound 89. 3-[4-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-5,5- dimethyl-imidazolidine-2,4-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -53). MS: 426[M+H ⁺ ].

Compound 90. 5-Ethyl-5-methyl-3-[3-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzo- diazepin-4-yl)piperazin-1 -yl]propyl]imidazolidine-2,4-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -54). MS: 482[M+H ⁺ ]. Compound 91. 5-Ethyl-5-methyl-3-[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzo- diazepin-4-yl)piperazin-1 -yl]butyl]imidazolidine-2,4-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -55). MS: 496[M+H ⁺ ].

Compound 92. 3-[3-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-5-ethyl-5- methyl-imidazolidine-2,4-dione The title compound was prepared starting from the secondary amine (II-2) and halogenoderivative (III-54).

¹ H NMR (CDCl ₃ ) δ 0.83-0.89 (t, 3H, J = 7.44 Hz), 1 .39 (s, 3H), 1 .59-1 .79 (m, 2H), 1 .81 - 1 .88 (m, 2H), 2.42-2.49 (m, 6H), 3.48-3.54 (m, 6H), 5.43 (s, 1 H), 6.84-6.89 (m, 1 H), 7.05-7.08 (m, 1 H), 7.1 3-7.19 (m, 1 H), 7.24-7.39 (m, 4H), 7.48-7.51 (m, 1 H). MS: 479[M+H ⁺ ].

Compound 93. 3-[4-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-5-ethyl-5- methyl-imidazolidine-2,4-dione The title compound was prepared starting from the secondary amine (II-2) and halogenoderivative (III-55).

¹ H NMR (CDCI ₃ ) δ 0.83-0.88 (t, 3H, J = 7.44 Hz), 1 .39 (s, 3H), 1 .49-1 .59 (m, 2H), 1 .62- 1 .79 (m, 4H), 2.38-2.53 (m, 6H), 3.49-3.55 (m, 6H), 5.46 (s, 1 H, NH), 6.84-6.89 (m, 1 H), 7.05-7.08 (m, 1 H), 7.1 3-7.19 (m, 1 H), 7.25-7.39 (m, 4H), 7.49-7.52 (m, 1 H). MS: 493[M+H ⁺ ].

Compound 94. 5,5-Diethyl-3-[3-[4-(2-methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)- piperazin-1 -yl]propyl]imidazolidine-2,4-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -56).

¹ H NMR (CDCI ₃ ) δ 0.83-0.88 (t, 6H, J = 3.0 Hz), 1 .58-1 .62 (m, 2H), 1 .79-1 .91 (m, 4H), 2.31 (s, 3H), 2.41 -2.45 (t, 2H, J = 7,37 Hz), 2.50-2.53 (t, 4H, J = 4,87 Hz) 3.48-3.59 (m, 6H), 5.02 (s, 1 H), 5.18 (s, 1 H), 6.28 (d, 1 H), 6.59-6.62 (d, 1 H), 6.84-7.05 (m, 3H).

MS: 496[M+H ⁺ ].

Compound 95. 5,5-Diethyl-3-[4-[4-(2-methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)- piperazin-1 -yl]butyl]imidazolidine-2,4-dione The title compound was prepared starting from the secondary amine (11 -1 ) and halogenoderivative (III-57).

¹ H NMR (CDCI ₃ ) δ 0.83-0.88 (t, 6H, J = 7.44 Hz), 1 .49-1 .64 (m, 4H), 1 .67-1 .90 (m, 4H), 2.31 (s, 3H), 2.39-2.44 (t, 2H, J = 7.44), 2.49-2.53 (t, 4H, J = 4.87 Hz) 3.48-354 (m, 6H), 5.06 (s, 1 H), 5.41 (s, 1 H), 6.28 (d, 1 H), 6.60-6.63 (d, 1 H), 6.83-7.04 (m, 3H).

MS: 510[M+H ⁺ ]. Compound 96. 3-[3-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-5,5- diethyl-imidazolidine-2,4-dioneThe title compound was prepared starting from the secondary amine (II-2) and halogenoderivative (III-56).

¹ H NMR (CDCl ₃ ) δ 0.82-0.87 (m, 6H), 1 .59-1 .69 (m, 2H), 1 .76-1 .88 (m, 4H), 2.39-2.49 (m, 6H), 3.53-3.67 (m, 6H), 5.59 (s, 1 H), 6.84-6.89 (m, 1 H), 7.05-7.08 (m, 1 H), 7.13-7.19 (m, 1 H), 7.26-7.39 (m, 4H), 7.48-751 (m, 1 H). MS: 493[M+H ⁺ ].

Compound 97. 3-[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-5, 5-diethyl- imidazolidine-2,4-dioneThe title compound was prepared starting from the secondary amine (II-2) and halogenoderivative (III-57).

¹ H NMR (CDCI ₃ ) δ 0.82-0.87 (t, 6H, J = 7.44 Hz), 1 .49-1 .59 (m, 2H), 1 .62-1 .78 (m, 4H), 1 .80-1 .89 (m, 2H), 2.38-2.52 (m, 6H), 3.48-3.53 (m, 6H), 5.45 (s, 1 H), 6.84-6.89 (m, 1 H), 7.05-7.08 (m, 1 H), 7.13-7.19 (m, 1 H), 7.25-7.39 (m, 4H), 7.48-7.52 (m, 1 H).

MS: 507[M+H ⁺ ].

Compound 98. 1 -[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-3-isopropyl-

3- methyl-pyrrolidine-2,5-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -58). MS: 507[M+H ⁺ ].

Compound 99. 5,5-Diisopropyl-3-[3-[4-(2-methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-

4- yl)piperazin-1 -yl]propyl]imidazolidine-2,4-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -59).

¹ H NMR (CDCI ₃ ) δ 0,82-0,87 (m, 3H), 1 ,18-1 ,26 (m, 3H), 1 ,61 -1 ,69 (m, 2H), 2,30 (s, 3H), 2,40-2,68 ( m, 6H), 3,44-3,73 ( m, 8H), 4,97 (s, 1 H), 5,36 (s, 1 H), 6,28 (s, 1 H), 6,58-6,61 (dd, 1 H, J = 8,9 Hz), 6,84-7,04 (m, 3H). MS: 523[M+H ⁺ ].

Compound 100. 3-[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-5,5- diisopropyl-imidazolidine-2,4-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -60) .

¹ H NMR (CDCI ₃ ) δ 0,82-0,97 (m, 8H), 1 ,22-1 ,28 (m, 4H), 2,13-2,18 (m,2H), 2,4-2,6 (m, 6H), 3,43-3,73 ( m, 6H) 4,86 (s, 1 H), 6,84-6,89 (m, 1 H), 7,05-7,08 (m, 1 H), 7,13-7,19 (m, 1 H), 7,24-7,39 (m, 4H), 7,48-7,51 (m, 1 H). MS: 534[M+H ⁺ ]. Compound 101. 3-[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-5- cyclopropyl-5-methyl-imidazolidine-2,4-dioneThe title compound was prepared starting from the secondary amine (II -2) and halogenoderivative (111-61 ). MS: 604[M+H ⁺ ].

Compound 102. 3-[4-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-5,5- dicyclopropyl-imidazolidine-2,4-dioneThe title compound was prepared starting from the secondary amine (II -2) and halogenoderivative (III-62). MS: 531 [M+H ⁺ ].

Compound 103. 5-Methyl-3-[3-[4-(2-methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4- yl)piperazin-1 -yl]propyl]-5-phenyl-imidazolidine-2,4-dioneThe title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III-63).

¹ H NMR (CDCl ₃ ) δ 1 .83-1.90 (m, 5H), 2.30 (s, 3H), 2.39-2.47 (m, 6H), 3.44-3.61 (m, 6H), 4.93 (s, 1 H), 5.52 (s, 1 H), 6.27 (s, 1 H), 6.58-6.61 (d, 1 H), 6.86-7.00 (m, 3H), 7.23 - 7.50 (m, 5H). MS: 530[M+H ⁺ ].

Compound 104. 5-Methyl-3-[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)- piperazin-1 -yl]butyl]-5-phenyl-imidazolidine-2,4-dioneThe title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III-64). MS: 543[M+H ⁺ ].

Compound 105. 5-Methyl-3-[3-(4-dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]- 5-phenyl-imidazolidine-2,4-dioneThe title compound was prepared starting from the secondary amine (II-2) and halogenoderivative (III-63). MS: 525[M+H ⁺ ].

Compound 106. 5-Methyl-3-[4-(4-dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]- 5-phenyl-imidazolidine-2,4-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -64). MS: 540[M+H ⁺ ].

Compound 107. 3-[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-5-(4- chlorophenyl)-5-cyclopropyl-imidazolidine-2,4-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -65).

¹ H NMR (CDCI ₃ ) δ 0.27-0.32 (m, 1 H), 0.56-0.69 (m, 3H), 1 .18-1 .26 (m, 1 H), 1 .43-1 .53 (m, 2H), 1 .59-1 .67 (m, 2H), 2.36-2.49 (m, 6H), 3.44-3.55 (m, 6H), 5.99 (s, 1 H), 6.84-6.90 (m, 1 H), 7.05-7.08 (m, 1 H), 7.14-7.19 (m, 1 H), 7.25-7.40 (m, 7H), 7.48-7.53 (m, 2H). MS: 600[M+H ⁺ ].

Compound 108. 3-[4-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]- 5-(2- furyl)-5-methyl-imidazolidine-2,4-dioneThe title compound was prepared starting from the secondary amine (II -2) and halogenoderivative (III-66). ¹ H NMR (CDCl ₃ ) δ 1 .42-1 .55 (m, 2H), 1 .63-1 .74 (m, 2H), 1 .78 (m, 2H), 2.38-2.52 (m, 6H), 3.47-3.59 (m, 6H), 5.64 (s, 1 H), 6.33-6.37 (m, 2H), 6.84-6.90 (m, 1 H), 7.05-7.08 (m, 1 H), 7.14-7.19 (m, 1 H), 7.25-7.40 (m, 5H), 7.49-7.52 (m, 1 H). MS: 530[M+H ⁺ ].

Compound 109. 8-[3-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl]propyl]-6,8-diazaspiro[4.4]nonane-7,9-dioneThe title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III-67).

¹ H NMR (CDCI ₃ ) δ 1 .75-1.92 (m, 8H), 2.15-2.21 (m, 2H), 2.30 (s, 3H), 2.41 -2.53 (m, 6H), 2.51 -2.60 (m, 6H), 4.96 (s, 1 H), 5.36 (s, 1 H), 6.28 (s, 1 H), 6.58-6.61 (dd, 1 H, J = 8.89), 6.84-7.04 (m, 3H). MS: 494[M+H ⁺ ].

Compound 1 10. 8-[4-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl]butyl]-6,8-diazaspiro[4.4]nonane-7,9-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -68). MS: 508[M+H ⁺ ].

Compound 1 1 1. 7-[3-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-7,9- diazaspiro[4.4]nonane-6,8-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -67). MS: 491 [M+H ⁺ ].

Compound 1 12. 7-[4-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-7,9- diazaspiro[4.4]nonane-6,8-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -68).

¹ H NMR (CDCI ₃ ) δ 1 .48-1 .56 (m, 2H), 1 .62-1 .91 (br m, 8H), 2.1 1 -2.17 (m, 2H), 2.33-2.53 (m, 6H), 3.47-3.54 (m, 6H), 6.06 (s, 1 H), 6.84-6.90 (m, 1 H), 7.05-7.08 (m, 1 H), 7.13- 7.19 (m, 1 H), 7.26-7.39 (m, 4H), 7.48-7.51 (m, 1 H). MS: 504[M+H ⁺ ].

Compound 1 13. 3-[3-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl]propyl]-1 ,3-diazaspiro[4.5]decane-2,4-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -69).

MS: 508[M+H ⁺ ].

Compound 1 14. 3-[4-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl]butyl]-1 ,3-diazaspiro[4.5]decane-2,4-dione The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -70). MS: 522[M+H ⁺ ].

Compound 1 15. 2-[3-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-2,4- diazaspiro[4.5]decane-1 ,3-dioneThe title compound was prepared starting from the secondary amine (II-2) and halogenoderivative (III-69). MS: 505[M+H ⁺ ].

Compound 1 16. 2-[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-2,4- diazaspiro[4.5]decane-1 ,3-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -70). MS: 519[M+H ⁺ ].

Compound 1 17. 3-[3-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl]propyl]spiro[imidazolidine-5,2'-tetralin]-2,4-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -71 ).

¹ H NMR (300 MHz) DMSO: δ 1 .68-1 .81 (m, 2H), 1 .91 -2.18, (m, 2H), 2.25 (s, 3H), 2.29- 2.34 (m, 2H), 2.41 -2.48 (m, 2H), 2.48-2.49 (m, 2H), 2.72-2.78 (d, 1 H), 2.88-2.93 (m, 2H), 3.10-3.16 (d, 1 H), 3.39-3.44 (m, 2H), 6.32-6.33 (d, 1 H), 6.65-6.68 (t, 1 H), 6.75- 6.85 (m, 3H), 7.27-7.32 (m, 1 H), 7.09-7.12 (m, 4H), 7.58 (s, 1 H), 8.58 (s, 1 H). MS: 555[M+H ⁺ ].

Compound 1 18. 3-[4-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl]butyl]spiro[imidazolidine-5,2'-tetralin]-2,4-dioneThe title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III-72). MS: 569[M+H ⁺ ].

Compound 1 19. 3-[3-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]spiro- [imidazolidine-5,2'-tetralin]-2,4-dioneThe title compound was prepared starting from the secondary amine (II -2) and halogenoderivative (111-71 ). MS: 553[M+H ⁺ ].

Compound 120. 3-[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]spiro- [imidazolidine-5,2'-tetralin]-2,4-dioneThe title compound was prepared starting from the secondary amine (II -2) and halogenoderivative (III-72). MS: 567[M+H ⁺ ].

Compound 121. 1 -Methyl-3-[3-[4-(2-methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)- piperazin-1 -yl]propyl]imidazolidine-2,4-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III - 73 ) . ¹ H NMR (CDCl ₃ ) δ 1 .81 -1 ,86 (m, 2H), 2.30 (s, 3H), 2.42-2.51 (m, 6H), 2.99 (s, 3H), 3.47- 3.50 (t, 4H, J = 4.53 Hz) 3.56-3.61 (t, 2H, J = 7.05 Hz), 3.84 (s, 2H), 5.04 (s, 1 H), 6.27 (d, 1 H), 6.58-6.62 (d, 1 H), 6.83-7.04 (m, 3H). MS: 534[M+H ⁺ ].

Compound 122. 1 -Methyl-3-[4-[4-(2-methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4- yl)piperazin-1 -yl]butyl]imidazolidine-2,4-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -74).

¹ H NMR (CDCI ₃ ) δ 1 .51 -1 .69 (m, 4H), 2.30 (s, 3H), 2.39-2.45 (t, 2H, J = 7.44), 2.52-2.55 (t, 4H, J = 4.87) 3.51 -3.85 (m, 6H), 2.99 (s, 2H), 5.17 (s, 1 H), 6.28 (d, 1 H), 6.61 -6.64 (d, 1 H), 6.84-706 (m, 3H). MS: 468[M+H ⁺ ].

Compound 123. 3-[3-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-1 - methyl-imidazolidine-2,4-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -73).

¹ H NMR (CDCI ₃ ) δ 1 .75-1.87 (m, 2H), 2.42-2.53 (m, 6H), 2.98 (s, 3H), 3.48-3.60 (m, 6H), 3.84 (s, 2H), 6.84-6.90 (m, 1 H), 7.05-7.08 (m, 1 H), 7.13-7.19 (m, 1 H), 7.26-7.39 (m, 4H), 7.48-7.51 (m, 1 H). MS: 451 [M+H ⁺ ].

Compound 124. 3-[4-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-1 -methyl- imidazolidine-2,4-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -74).

¹ H NMR (CDCI ₃ ) δ 1 .48-1.56 (m, 2H), 1 .61 -1 .68 (m, 2H), 2.37-2.53 (m, 6H), 2.98 (s, 3H), 3.48-3.55 (m, 6H), 3.84 (s, 2H), 6.84-6.90 (m, 1 H), 7.05-7.08 (m, 1 H), 7.13-7.19 (m, 1 H), 7.26-7.39 (m, 4H), 7.48-7.52 (m, 1 H). MS: 465[M+H ⁺ ].

Compound 125. 5,5-Dimethyl-3-[3-[4-(2-methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4- yl)piperazin-1 -yl]propyl]oxazolidine-2,4-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -75). MS: 468[M+H ⁺ ].

Compound 126. 5,5-Dimethyl-3-[4-[4-(2-methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4- yl)piperazin-1 -yl]butyl]oxazolidine-2,4-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -76). MS: 483[M+H ⁺ ]. Compound 127. 3-[3-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-5,5- dimethyl-oxazolidine-2,4-dioneThe title compound was prepared starting from the secondary amine (II-2) and halogenoderivative (III-75).

¹ H NMR (300 MHz) CDCl ₃ : δ 1 .56 (s, 6H), 1 .83-1 .85 (m, 2H), 2.40-2.48 (m, 4H), 3.46-3.64 (m, 8H), 6.87 (td, 1 H), 7.07 (dd, 1 H), 7.14-7.19 (m, 1 H), 7.26-7.40 (m, 4H), 7.49-7.52 (m, 1 H). MS: 466[M+H ⁺ ].

Compound 128. 3-[4-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-5,5- dimethyl-oxazolidine-2,4-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -76). MS: 480[M+H ⁺ ].

Compound 129. 1 -[3-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl]propyl]piperidine-2,6-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -77). MS: 452[M+H ⁺ ].

Compound 130. 1 -[4-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl]butyl]piperidine-2,6-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -78). MS: 467[M+H ⁺ ].

Compound 131. 1 -[3-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]piperi- dine-2,6-dioneThe title compound was prepared starting from the secondary amine (II- 2) and halogenoderivative (III -77). MS: 449[M+H ⁺ ].

Compound 132. 1 -[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]piperidine- 2,6-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -78).

¹ H NMR (CDCl ₃ ) δ: 1 .51 -1 .53 (m, 4H), 1 .87-1 .96 (m, 2H), 2.33-2.54 (m, 6H), 2.60-2.65 (m, 4H), 3.52 (br s, 4H), 3.75-3.79 (m, 2H), 6.84-6.89 (td, 1 H), 7.05-7.08 (dd, 1 H), 7.13- 7.19 (td, 1 H), 7.25-7.29 (m, 2H), 7.30-7.35 (m, 1 H), 7.36-7.39 (dd, 1 H), 7.47-7.51 (m, 1 H). MS: 464[M+H ⁺ ].

Compound 133. 4,4-Dimethyl-1 -[3-[4-(2-methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4- yl)piperazin-1 -yl]propyl]piperidine-2,6-dione The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -79). MS: 481 [M+H ⁺ ].

Compound 134. 4,4-Dimethyl-1 -[4-[4-(2-methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4- yl)piperazin-1 -yl]butyl]piperidine-2,6-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -SO) .

¹ H NMR (CDCl ₃ ) δ: 1 .09 (s, 6H), 1.32-1 .87 (m, 8H), 2.31 (s, 3H), 2.56 (s, 4H), 3.15 (br s, 4H), 3.77 (m, 2H), 4.27 (m, 2H), 6.34 (s, 1 H), 7.03-7.17 (m, 3H), 7.47-7.50 (d, 1 H).

MS: 495[M+H ⁺ ].

Compound 135. 1 -[3-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-4,4- dimethyl-piperidine-2,6-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (II I -79). MS: 478[M+H ⁺ ].

Compound 136. 1 -[4-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-4,4- dimethyl-piperidine-2,6-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -SO). MS: 491 [M+H ⁺ ].

Compound 137. 4-Ethyl-4-methyl-1 -[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzo- diazepin-4-yl)piperazin-1 -yl]butyl]piperidine-2,6-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -81 ).

¹ H NMR (CDCI ₃ ) δ: 0.86-0.92 (m, 4H), 1 .00 (s, 3H), 1 .27-1 .41 (m, 2H), 1 .52-1 .55 (m, 4H), 2.30-2.31 (dd, 3H), 2.40-2.41 (m, 2H), 2.47-2.54 (m, 7H), 3.48-3.51 (m, 4H), 3.75-3.80 (t, 2H), 4.97 (s, 1 H), 6.28-6.29 (d, 1 H), 6.58-6.61 (dd, 1 H), 6.83-6.89 (td, 1 H), 6.93-7.03 (m, 2H). MS: 509[M+H ⁺ ].

Compound 138. 1 -[4-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-4-ethyl-4- methyl-piperidine-2,6-dioneThe title compound was prepared starting from the secondary amine (II-2) and halogenoderivative (111-81 ). MS: 506[M+H ⁺ ].

Compound 139. 8-[3-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl]propyl]-8-azaspiro[4.5]decane-7,9-dioneThe title compound was prepared starting from the secondary amine (11 -1 ) and halogenoderivative (III-82). ¹ H NMR (CDCl ₃ ) δ: 1 .47-1 .51 (m, 4H), 1 .68-1 .79 (m, 6H), 2.29-2.30 (d, 3H), 2.41 -2.46 (t, 2H), (br s, 4H), 2.58 (s, 4H), 3.52 (br s, 4H), 3.80-3.85 (t, 2H, J = 7.44 Hz), 6.27-6.28 (d, 1 H), 6.59-6.62 (dd, 1 H), 6.83-6.89 (td, 1 H, J = 1 .8 Hz, J = 7.2 Hz), 6.93-7.04 (m, 2H). MS: 507[M+H ⁺ ].

Compound 140. 8-[4-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl]butyl]-8-azaspiro[4.5]decane-7,9-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -83).

¹ H NMR (CDCI ₃ ) δ: 1 .47-1 .54 (m, 8H), 1 .66-1 .73 (m, 4H), 2.30-2.36 (d, 3H), 2.40-2.42 (m, 2H), 2.49-.252 (t, 4H), 2.55 (s, 4H), 3.49-3.51 (m, 4H), 3.75-3.79 (t, 2H), 6.28-6.29 (d, 1 H), 6.58-6.61 (dd, 1 H, J = 1 .3 Hz, J = 7.7 Hz), 6.83-6.88 (td, 1 H, J = 1 .89 Hz, J = 7.2 Hz), 6.93-7.03 (m, 2H). MS: 520[M+H ⁺ ].

Compound 141. 8-[3-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-8- azaspiro[4.5]decane-7,9-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III-82). MS: 504[M+H ⁺ ].

Compound 142. 8-[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-8- azaspiro[4.5]decane-7,9-dioneThe title compound was prepared starting from the secondary amine (II-2) and halogenoderivative (III-83).

¹ H NMR (CDCI ₃ ) δ: 1 .47-1 .54 (m, 8H), 1 .66-1 .73 (m, 4H), 2.30-2.36 (d, 3H), 2.40-2.42 (m, 2H), 2.49-.252 (t, 4H), 2.55 (s, 4H), 3.49-3.51 (m, 4H), 3.75-3.79 (t, 2H), 6.84-6.89 (td, 1 H), 7.05-7.08 (dd, 1 H), 7.13-7.18 (td, 1 H), 7.26-7.28 (m, 2H), 7.29-7.34 (m, 1 H), 7.36-7.39 (dd, 1 H), 7.48-7.51 (m, 1 H). MS: 518[M+H ⁺ ].

Compound 143. 9-[3-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl]propyl]-9-azaspiro[5.5]undecane-8,10-dioneThe title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III-84). MS: 521 [M+H ⁺ ].

Compound 144. 9-[4-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl]butyl]-9-azaspiro[5.5]undecane-8,10-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -85). MS: 535[M+H ⁺ ].

Compound 145. 9-[3-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]-9- azaspiro[5.5]undecane-8,10-dione The title compound was prepared starting from the secondary amine (11-2) and halogenoderivative (111 -84). MS: 518[M+H ⁺ ].

Compound 146. 9-[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]-9- azaspiro[5.5]undecane-8,10-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111 -85).

¹ H NMR (CDCl ₃ ) δ: 1 .24-1 .52 (m, 14H), 2.36-2.47 (m, 4H), 2.52 (m, 6H), 3.51 (br s, 4H), 3.72-3.77 (m, 2H), 6.83-6.88 (td, 1 H), 7.04-7.07 (dd, 1 H), 7.12-7.18 (td, 1 H), 7.26-7.28 (m, 2H), 7.29-7.33 (m, 1 H), 7.35-7.38 (dd, 1 H), 7.47-7.50 (m, 1 H). MS: 532[M+H ⁺ ].

Compound 147. 2-(4-(4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl)butyl)-1 H-benzo[de]isoquinoline-1 ,3(2H)-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -87). MS: 550[M+H ⁺ ].

Compound 148. 2-(5-(4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl)pentyl)-1 H-benzo[de]isoquinoline-1 ,3(2H)-dione

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -88). MS: 564[M+H ⁺ ].

Compound 149. 2-[2-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)ethyl]-3a, 4, 7, 7a- tetrahydro 1 H-isoindole-1 ,3(2H)-dione The title compound was prepared starting from the secondary amine (I I-2) and halogenoderivative (III-86). MS: 473[M+H ⁺ ].

Compound 150. 2-[4-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]- 1 H- benzo[de]isoquinoline-1 ,3(2H)-dione

The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -87). MS: 547[M+H ⁺ ].

Compound 151. 1 -[3-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl]propyl]pyrrolidin-2-oneThe title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III-89). MS: 424[M+H ⁺ ].

Compound 152. 1 -[4-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl]butyl]pyrrolidin-2-one The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III-90). ¹ H NMR (CDCl ₃ ) δ 1 .99-2.04 (m, 4H), 2.30-2.53 (m, 9H), 3.28-3.32 (t, J = 6.9 Hz, 2H), 3.35-3.40 (t, J = 6.7 Hz, 2H), 3.48-3.73(m, 4H), 4.2-4.23 (m, 2H), 4.95 (s, 1 H); 6.28 (s, 1 H); 6.59-6.61 (d, 1 H); 6.85-7.03 (m, 2H), 7.24-7.26 (m, 1 H). MS: 438[M+H ⁺ ].

Compound 153. 1 -[3-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]pyrroli- din-2-one The title compound was prepared starting from the secondary amine (II-2) and halogenoderivative (III -89). MS: 421 [M+H ⁺ ].

Compound 154. 1 -[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]pyrrolidin- 2-one The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -90). MS: 435[M+H ⁺ ].

Compound 155. 1 -[3-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl]propyl]piperidin-2-one

The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (111 -91 ). MS: 438[M+H ⁺ ].

Compound 156. 1 -[4-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl]butyl]piperidin-2-one The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -92 ) .

¹ H NMR (CDCI ₃ ) δ 1 .2-1 .41 (m, 4H); 1 .55-1 .8 (m, 4H); 2.3 (s, 3H); 2.36-2.38 (t, J=6.5Hz, 2H); 2.41 -2.46 (t, J=6.5Hz, 2H); 2.54-2.60 (m, 4H); 3.24-3.26 (t, J=6.7Hz, 2H); 3.35-3.4 (t, J=6.3Hz, 2H); 3.44-3.53 (m; 4H); 5.29 (s, 1 H); 6.28 (s, 1 H); 6.59-6.61 (d, 1 H); 6.8- 7.03 (m, 3H). MS: 452[M+H ⁺ ].

Compound 157. 1 -[3-(4-Dibenzo[b,f][1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)propyl]piperidin- 2-one The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (111 -91 ). MS: 435[M+H ⁺ ].

Compound 158. 1 -[4-(4-Dibenzo[b,f] [1 ,4]thiazepin-1 1 -ylpiperazin-1 -yl)butyl]piperidin- 2-one The title compound was prepared starting from the secondary amine (I I -2) and halogenoderivative (III -92). MS: 449[M+H ⁺ ].

Compound 159. 4-[3-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl]propyl]-4-azatricyclo[5.2.1 .0 ² ' ⁶ ]decane-3,5-dione The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative ( 111 -93 ) . MS: 504[M+H ⁺ ].

Compound 160. 4-[4-[4-(2-Methyl-10H-thieno[2,3-b] [1 ,5]benzodiazepin-4-yl)piperazin- 1 -yl]butyl]-4-azatricyclo[5.2.1 .0 ² ' ⁶ ]decane-3,5-dione The title compound was prepared starting from the secondary amine (11-1 ) and halogenoderivative (III -9-4) . ¹ H NMR (300 MHz, CDCl ₃ ) δ: 1.03-1.07 (m, 2H), 1.47-1.73 (m, 8H), 2.30 (s, 3H), 2.47- 2.49 (m, 2H), 3.10-3.54 (m, 14H), 6.66 (s, 1H), 6.99-7.08 (m, 1H), 7.10-7.19 (m, 1H), 7.22-7.28 (m, 2H), 9.34 (brs, 1H, NH), 11.78 (brs, 1H), 11.92 (brs, 1H) (as ^hydrochloride) MS: 518[M+H ⁺ ].

Compound 161. 4-[4-(4-Dibenzo[b,f][1 ,4]thiazepin-11 -ylpiperazin-1 -yl)butyl]-4-aza- tricyclo-[5.2.1.0 ² ' ⁶ ]decane-3,5-dione The title compound was prepared starting from the secondary amine (II-2) and halogenoderivative (III-94).

¹ H NMR (300 MHz, CDCl ₃ ) δ: 1.03-1.11 (m, 2H), 1.47-1.73 (m, 6H), 1.71-1.83 (m, 2H), 2.47-2.49 (m, 2H), 3.06-3.68 (m, 14H), 7.09-7.11 (m, 1H), 7.24-7.32 (m, 2H), 7.47-7.66 (m, 5H), (brs, 1H) (as hydrochloride) MS: 515[M+H ⁺ ].

Compound 162. 4-[4-[4-(2-methyl-10H-thieno[2,3-b][1 ,5]benzodiazepin-4-yl)piperazin- 1-yl]butyl]-(1/?,2S,6/?,7S)-4-azatricyclo[5.2.1.0 ^2,6 ]decane-3,5-dione The title compound was prepared starting from the secondary amine (11-1) and halogenoderivative (III-95).

¹ H NMR (300 MHz, CDCl ₃ ) δ: 1.03-1.06 (m, 2H), 1.46-1.74 (m, 8H), 2.29 (s, 3H), 2.47- 2.49 (m, 2H), 3.10-3.92 (m, 14H), 6.66 (s, 1H), 7.09-7.24 (m, 4H), 9.43 (brs, 1H), 11.56 (brs, 1H), 11.91 (brs, 1H). (as dihydrochloride) MS: 518[M+H ⁺ ].

Example 4.

In Vitro Pharmacology: Binding Assays

The affinity of compounds of the present invention to dopaminergic, serotoninergic, adrenergic, muscarinic, histaminergic H1 and sigma receptors was tested using the methods as described below, by measuring their binding to these receptors using radioreceptors methods. Moreover, ability of the compounds of the invention to block sodium channel Nav1.7 and potassium channel hERG was tested.

The specific ligand binding to the receptors is defined as the difference between the total binding and the non-specific binding determined in the presence of the excess of unlabelled ligand.

The results are expressed as a percent of control specific binding ((measured specific binding/control specific binding) x 100). The compounds were tested for their affinity to receptors at a concentration of 1 ^χ 10 ^"6 M, and for ability to block of channels at a concentration of 1 ^χ 10 M.

Conditions and methodology of in vitro tests are given by reference to the literature.

Affinity for dopaminergic receptors D2 and D3

Tests were performed on the following biological material: D2 receptor: human recombinant (Invitrogen, GeneBLAzer® D2-Gqo5 CHO-K1 DA), according to methodology described in Bryan L. Roth. Assay Protocol Bok. University of North Carolina At Chapel Hill. National Institute of Mental Health. Psychoactive Drug Screening Program. Available on-line at 31 .08.2008: http: //pdsp.med.unc.edu/UNC- CH%20Protocol%20Bok.pdf;

D3 receptor: human recombinant D3 receptors (Membrane Target Systems™ human dopamine D3 Receptor, PerkinElmer), according to the methodology described in Missale et al. (1998), Physiol. Rev. , 78: 189-225.

Experimental conditions for tests are given in Table 1 , and results of tests for representative compounds are given in Table 2.

Table 1 : Experimental conditions for testing the affinity for dc )paminergic receptors

D2 D3

Radioligand [3H]methylspiperone [3H]methylspiperone

Concentration ok. 0.5 nM 0.3 nM

Kd about 0.4 nM 0.1 nM

Non-specific binding haloperidol (1 μΜ) (+)-butaclamol (1 μΜ)

Incubation 60 min, 30° C 60 min, 24° C

Table 2: Results for representative compounds of the invention

Compound No. D2 [%] D3 [%] Compound No. D2 [%] D3 [%]

2 55 29 92 45 52

4 37 56 93 88 92

5 43 81 94 73 41

6 51 66 95 100 100

7 79 85 96 42 40

8 54 40 97 94 98

9 69 80 98 90 97 Compound No. D2 [%] D3 [%] Compound No. D2 [%] D3 [%] 1 95 92 99 68 76 2 10 36 100 81 94 3 78 97 101 85 92 4 38 51 102 83 95 5 84 84 103 92 84 6 90 86 104 97 89 7 64 51 105 23 45 8 82 62 106 63 72 9 100 98 107 57 87 0 39 53 108 95 92 1 92 97 109 48 61 2 70 58 110 83 97 3 96 96 111 42 64 4 48 56 112 72 97 5 74 92 113 74 75 6 77 84 114 99 95 7 91 77 115 38 65 8 100 97 116 71 98 9 62 31 117 87 90 0 67 77 118 100 96 1 82 58 119 0 24 2 82 61 120 51 94 3 20 50 121 41 30 Compound No. D2 [%] D3 [%] Compound No. D2 [%] D3 [%] 4 88 85 122 86 89 5 100 100 123 16 25 6 40 70 124 62 81 7 99 101 125 50 49 3 84 81 126 100 97 4 99 100 127 20 40 5 60 74 128 79 92 6 84 97 129 66 61 7 85 41 130 97 95 8 99 100 131 20 46 9 10 27 132 76 85 0 45 94 133 61 60 1 85 76 134 100 100 2 100 95 135 34 62 3 57 66 137 100 97 4 100 85 138 95 97 5 86 63 139 92 87 6 92 97 140 100 96 7 40 38 141 61 84 8 76 93 142 100 96 9 80 76 143 92 83 0 80 96 144 100 98 1 93 93 145 67 67 Compound No. D2 [%] D3 [%] Compound No. D2 [%] D3 [%]

62 87 87 146 84 97

63 101 100 147 92 90

69 78 87 148 88 64

70 100 100 149 38 46

76 95 92 150 38 82

77 103 104 151 0 30

78 102 105 152 75 91

80 77 75 153 0 52

82 96 97 154 50 85

83 95 92 155 0 0

84 2 30 156 100 97

85 91 88 157 0 0

86 80 75 158 63 95

88 18 88 160 98 98

89 29 90 161 97 98

90 71 55 162 97 98

91 98 100

Affinity for serotoninergic receptors 5-HT1A, 5-HT2A, 5-HT6 and 5-HT7

Tests were performed on the following biological material:

5-HT1A receptor: rat hippocampus, according to the methodology described in Borsini et al. (1995), Naunyn.Sch. Arch. Pharmacol. 352: 276-282;

5-HT2A receptor: human recombinant (Membrane Target Systems™ Human Serotonin 5- HT2A Receptor, PerkinElmer), according to the methodology described in Bryan L. Roth. Assay Protocol Bok. University of North Carolina At Chapel Hill. National Institute of Mental Health. Psychoactive Drug Screening Program. Available on-line at 31 .08.2008: http: //pdsp.med.unc.edu/UNC-CH%20Protocol%20Bok.pdf;

5-HT6 receptor: human recombinant (Membrane Target Systems™ human Serotonin 5- HT6 Receptor, PerkinElmer), according to the methodology described in Bryan L. Roth. Assay Protocol Bok. University of North Carolina At Chapel Hill. National Institute of Mental Health. Psychoactive Drug Screening Program. Available on-line at 31 .08.2008: http: //pdsp.med.unc.edu/UNC-CH%20Protocol%20Bok.pdf;

5-HT7 receptor: human recombinant (Membrane Target Systems™ human Serotonin 5- HT7 Receptor, PerkinElmer), according to the methodology described in Bryan L. Roth. Assay Protocol Bok. University of North Carolina At Chapel Hill. National Institute of Mental Health. Psychoactive Drug Screening Program. Available on-line at 31 .08.2008: http: //pdsp.med.unc.edu/UNC-CH%20Protocol%20Bok.pdf.

Experimental conditions for tests are given in Table 3, and results of tests for representative compounds are given in Table 4.

Table 3: Experimental conditions for testing the affinity for serotoninergic receptors

Table 4: Results for representative compounds of the invention

Compound No. 5-HT1A [%] 5-HT2A [%] 5-HT6 [%] 5-HT7 [%]

2 30 96 82 93

4 81 82 16 79

5 88 81 25 88

6 90 65 0 90

7 44 100 82 90

8 19 83 62 74 Compound No. 5-HT1A [%] 5-HT2A [%] 5-HT6 [%] 5-HT7 [%]

9 96 99 45 93

1 1 65 99 87 79

12 30 5 14 52

13 99 87 45 85

14 95 69 0 88

15 92 85 28 96

16 31 90 62 87

17 10 90 63 71

18 47 100 80 88

19 73 100 88 93

20 92 100 21 89

21 99 100 67 93

22 54 100 85 87

23 88 100 86 91

24 97 98 31 93

25 100 96 62 98

26 98 80 12 93

27 34 97 97 95

28 46 98 84 98

29 72 83 0 88

30 94 83 30 100

31 67 90 73 83

32 0 84 65 92

33 49 38 9 95

34 61 98 93 67

35 63 95 88 88

36 91 84 43 81

37 100 100 41 96

43 10 96 80 74

44 64 99 91 92 Compound No. 5-HT1A [%] 5-HT2A [%] 5-HT6 [%] 5-HT7 [%]

45 80 79 27 83

46 93 91 55 88

47 22 96 92 94

48 38 100 98 92

49 51 71 0 78

50 62 87 57 96

51 59 93 83 78

52 73 93 89 93

53 95 89 35 91

54 58 96 52 100

55 59 100 88 89

56 79 93 90 81

57 66 76 35 82

58 92 89 40 92

59 62 87 70 88

60 53 6 94 75

61 46 95 80 82

62 33 98 72 77

63 89 100 99 93

69 98 100 30 92

70 99 100 49 97

76 93 100 16 96

77 92 101 95 94

78 89 102 97 95

80 78 101 87 86

82 84 48 91 97

83 91 100 96 97

84 82 84 33 86

85 95 90 42 85

86 95 93 25 87 Compound No. 5-HT1A [%] 5-HT2A [%] 5-HT6 [%] 5-HT7 [%]

88 61 22 0 74

89 91 82 0 93

90 52 100 69 82

91 62 97 100 91

92 98 93 22 98

93 96 93 37 95

94 40 100 66 86

95 62 100 100 95

96 93 96 24 100

97 99 84 68 99

98 83 90 43 97

99 89 89 59 95

100 93 90 63 98

101 100 94 49 93

102 100 79 70 93

103 40 88 97 97

104 34 87 96 97

105 82 100 42 97

106 89 88 54 94

107 75 84 94 97

108 94 99 47 99

109 38 89 93 94

1 10 24 70 82 78

1 1 1 80 89 53 95

1 12 92 92 55 91

1 13 29 93 94 92

1 14 50 98 97 92

1 15 83 86 31 87

1 16 84 92 67 94

1 17 14 96 99 95 Compound No. 5-HT1A [%] 5-HT2A [%] 5-HT6 [%] 5-HT7 [%]

1 18 59 92 95 90

1 19 70 92 27 90

120 89 91 69 90

121 0 87 43 85

122 56 93 91 88

123 73 67 0 93

124 95 86 0 96

125 6 93 55 62

126 39 100 93 85

127 94 98 24 91

128 100 99 64 93

129 31 93 90 84

130 58 89 75 88

131 79 71 17 86

132 92 77 38 91

133 34 100 90 82

134 56 91 80 92

135 87 85 54 84

137 80 100 96 97

138 93 100 66 93

139 33 100 93 94

140 78 100 92 90

141 94 100 56 94

142 100 99 60 94

143 34 100 95 93

144 89 100 90 98

145 91 84 70 94

146 99 100 64 94

147 55 97 82 93

148 21 98 91 86 Compound No. 5-HT1A [%] 5-HT2A [%] 5-HT6 [%] 5-HT7 [%]

149 32 89 24 81

150 37 63 0 83

151 1 39 10 13

152 35 89 73 75

153 39 78 0 82

154 97 61 37 87

155 12 45 15 24

156 84 99 92 83

157 0 15 5 12

158 94 51 15 93

160 94 101 97 75

161 100 101 61 98

162 94 99 97 99

Affinity for a1 adrenergic receptors

Tests were performed on receptors from rat cerebral cortex, according to the procedure of Leopoldo M. et al. (2002), J. Med. Chem. , (26):5727-35.

Experimental conditions are given in Table 5, and results for representative compounds are given in Table 6.

Table 5: Experimental conditions for testing the affinity for adrenergic receptors

Tabela 6: Results for representative compounds of the invention

Compound No. a1 [%] Compound No. a1 [%] Compound No. a1 [%]

2 88 54 94 1 15 97

4 97 55 99 1 16 100 Compound No. a1 [%] Compound No. a1 [%] Compound No. a1 [%]

5 100 56 100 1 17 98

6 98 57 93 1 18 100

7 100 58 100 1 19 82

8 95 59 97 120 99

9 100 60 100 121 95

1 1 99 61 100 122 100

12 74 62 92 123 98

13 100 63 102 124 100

14 97 69 98 125 95

16 100 77 100 127 98

17 92 78 100 128 100

18 99 82 100 129 97

19 100 83 99 130 100

20 97 84 94 131 98

21 100 85 100 132 94

22 98 86 100 133 98

23 100 88 95 134 100

24 99 89 88 135 96

25 99 90 98 137 100

26 98 91 100 138 100

27 98 92 99 139 98

28 100 93 100 140 100

29 92 94 98 141 97 Compound No. a1 [%] Compound No. a1 [%] Compound No. a1 [%]

30 100 95 100 142 100

31 88 96 98 143 97

32 98 97 100 144 100

33 90 98 100 145 94

34 87 99 99 146 100

35 100 100 100 147 98

36 90 101 100 148 95

37 100 102 100 149 81

43 94 103 92 150 96

44 100 104 94 151 79

45 85 105 96 152 99

46 100 106 100 153 94

47 89 107 98 154 98

48 100 108 100 155 51

49 78 109 98 156 100

50 97 1 10 100 157 58

51 99 1 1 1 98 158 98

52 94 1 12 100 160 97

53 97 1 13 98 161 96

54 94 1 14 95 162 100

Affinity for muscarinic receptors

Tests were performed on the following biological material: Non-selective affinity: rat cerebral cortex, according to the methodology described in Richards, M.H. (1990), Brit. J. Pharmacol. , 99: 753-761 ;

M3 receptor: human recombinant, (CHO cells), according to the methodology described in Peralta et al. (1987), Embo. J., 6: 3923-3929.

Experimental conditions are given in Table 7, and results for representative compounds are presented in Tables 8 and 9.

Table 7: Experimental conditions for testing the affinity for muscarinic receptors: nonselective affinity for muscarinic and for M3 muscarinic receptor

Table 8: Results for representative compounds of the invention

Compound No. M non-sel. Compound No. M non-sel. Compound No. M non-sel.

[¾] [¾] [¾]

2 -14 54 13 1 15 80

4 76 55 60 1 16 84

5 44 56 76 1 17 33

6 67 57 87 1 18 67

7 22 58 81 1 19 80

8 66 59 2 120 85

9 53 60 43 121 -5

1 1 35 61 70 122 20

12 78 62 43 123 57

13 54 63 32 124 53

14 56 69 92 125 17

15 34 70 63 126 29 Compound No. M non-sel. Compound No. M non-sel. Compound No. M non-sel. [%] [%] [¾]

17 70 76 81 127 70

18 26 82 71 128 59

19 39 83 91 129 29

20 72 84 78 130 30

21 66 85 89 131 62

22 46 86 79 132 41

23 46 88 77 133 51

24 78 89 -12 134 43

25 73 90 -1 135 85

26 45 91 21 137 40

27 24 92 64 138 65

28 70 93 63 139 66

29 79 94 9 140 35

30 76 95 44 141 92

31 5 96 63 142 56

32 26 97 79 143 71

33 20 98 52 144 43

34 43 99 56 145 90

35 38 100 83 146 49

36 84 101 33 147 80

37 63 102 48 148 61

43 40 103 29 150 75

44 34 104 36 151 24

45 85 105 79 152 39

46 70 106 65 153 43

47 50 107 75 154 61

48 69 108 73 155 3

49 85 1 10 23 156 76

50 75 1 1 1 82 157 14 Compound No. M non-sel. Compound No. M non-sel. Compound No. M non-sel.

[%] [%] [¾]

51 46 1 12 59

52 45 1 1 3 33

53 93 1 14 29

Table 9: Results for representative compounds

Ability to block Nav1 .7 sodium channel

Ability to block Nav1 .7 sodium channels was determined using the electrophysiological method and cloned Nav1 .7 sodium channels (SCN9A gene, expressed in CHO cells) as biological material. The blockade in an inactivated state is defined as a reduction in the amplitude of the current of a test pulse (TP12*) resulting from conditioning action of depolarizing pulse, preceding the TP12. Blockade in an inactivated state is calculated according to the formula:

%Blockade (inactivated state) = (1 - (l _T pi2, TA / ITPI2, TA control) 100%

where l _T pi2, TA, control and l _T pi2, TA are Na ⁺ peak currents induced by TP12, in the control and test samples, respectively. Nav1 .7 channel blockade was measured using standard of stimulating voltage as shown in the chart below.

Voltage protocol parameters are given in the table below. The pulse pattern is repeated twice: before and 5 minutes after the addition of the test sample and the peak-current amplitudes are measured at the test pulses 12.

Voltage protocol parameters for Nav1.7 channels

Table 10. Results of tests for ability to block Nav1 .7 sodium channels for representative compounds of the invention

Ability to block hERG potassium channel

Ability to block hERG potassium channels was determined using the electrophysiological method and cloned hERG potassium channels (KCNH2 gene, expressed in CHO cells) as biological material. The effects were evaluated using lonWorksTM Quattro system (MDS- AT).

hERG current was elicited using a pulse pattern with fixed amplitudes (conditioning prepulse: -80 mV for 25 ms; test pulse: +40 mV for 80 ms) from a holding potential of 0 mV. hERG current was measured as a difference between the peak current at 1 ms after the test step to +40 mV and the steady-state current at the end of the step to +40 mV.

Data acquisition and analyses were performed using the lonWorks QuattroTM system operation software (version 2.0.2; Molecular Devices Corporation, Union City, CA). Data were corrected for leak current. The hERG block was calculated as: % Block = (1 - I TA / IControl) x 100%, where IControl and ITA were the currents elicited by the test pulse in control and in the presence of a test compound, respectively.

Table 1 1 : Results for representative compounds of the invention

Results of in vitro tests as presented above show that compounds of the invention display high affinity for D2, D3, 5-HT1A, 5-HT2A, 5-HT6, 5-HT7 and alphal receptors. This confirms their potential usefulness in the treatment of diseases associated with disturbances in dopaminergic, serotoninergic and noradrenergic transmission, e.g. psychoses, depression as well as anxiety disorders etc. It should be stressed that some of the compounds possess simultaneously high affinity for D2, 5-HT2A and 5-HT1 A and/or 5-HT6 and/or 5-HT7 receptors, as well as ability to block voltage-dependent Nav1 .7 sodium channels. Such a pharmacological profile suggests possible efficacy in the treatment of psychoses as well as antidepressant, precognitive and mood stabilizing activity. At the same time compounds of the invention possess weak affinity for muscarinic receptors, in particular M3 receptor. This may potentially contribute to lack of or reduced side effects such as vegetative disorders or diabetogenic effect, what distinguishes them from the compounds currently used to treat the above-mentioned diseases, particularly fro olanzapine or quetiapine.

Example 5.

Effect on contractions in isolated guinea pig ileum induced by carbachol

Ileum was prepared from guinea-pigs fasted for 24 h before experiment and immediately placed into Krebs solution (NaCl 120 mM, KCl 5.6 mM, MgCl ₂ 2.2 mM, CaCl ₂ 2.4 mM, NaHC0 ₃ 19 mM, glucose 10 mM) at 37° C, pH 7.4, with constant oxygenation with carbogen mixture (95% of 0 ₂ and 5% of C0 ₂ ). The ileum was cut into 2-3 cm segments, the segments were placed in thermostated 30 ml cells of apparatus for the study of isolated organs IOBS 99 (Biopac Systems, COMMAT Ltd. , Turkey), filled with the nutrient fluid of the composition as described above. The ileum was fixed with hooks to the handle in the cell and to the force-displacement transducer (FDT 10-A). The preparation was maintained at a temperature 37° C and with constant oxygenation. An initial load was 0.5 g. Once mounted, preparations were allowed to stabilize for 30 min.

Concentration-response curves were constructed according to the method of van Rossum (Van Rossum, J.M. (1963) Arch. Int. Pharmacodyn., 1963, 143, 299-330). After calibration period a concentration-response curve for carbachol (0.01 - 3 μΜ) was constructed. Following the control curve, tissues were washed and after 60 min. concentration-response curve was constructed again for histamine in the presence of one of 3 to 4 test compounds concentrations. Tissues were incubated with one of the concentrations of tested compounds for 30 min. Experiment was repeated 4-7 times for each concentration of test compound. Only carbachol and one concentration of the potential antagonist (test compound) were tested in each piece of tissue. Experiments were repeated three to eight times. All compounds were added to water bath at volume not exceeding 5% of bath volume (1 .5 ml). All responses were recorded using software MP-35 Data Acquisition Unit.

Concentration-response curves were analysed using GraphPad Prism 4.0 (GraphPad Software Inc. , San Diego, CA, USA). Contractile responses to carbachol (in the presence or absence of tested compounds) are expressed as a percentage of maximal carbachol effect (Emax = 100%). Concentration-response curves in the presence of test compounds were compared to control curves. If test compound was tested in only one concentration or if slope of Schild equation was significantly different from 1 , the antagonistic activity was was estimated as pK _B value with the following equation:

pK _B = pB _x + log (CR- 1)

wherein:

CR (concentration ratio) - the ratio of EC ₅₀ of agonist in the presence of antagonist in concentration B _x to EC ₅₀ of agonist,

pB _x - the negative logarithm of antagonist concentration, which shifts concentration - response curve to right without reducing the maximal response.

Table 12: Results for representative compounds of the invention

not calculable (compound does not reveal blocking activity on muscarinic receptors) These results indicate a lack of anticholinergic effect in the concentration range associated with potential therapeutic effects of test compound.

Example 6.

Antipsychotic activity in mice

Potential antipsychotic activity was tested for the representative compound 63 as hydrochloride in mouse model of psychosis, involving the induction of locomotor hyperactivity by administering psychotomimetic substance - d-amphetamine. The ability of a test compound to remove that effect is a measure of potential antipsychotic activity.

Animals

Male CD-1 mice were group-housed for 2-3 day period in polycarbonate Makrolon type 3 cages (dimensions 26.5 x 15 x 42 cm) in an environmentally controlled, experimental room (ambient temperature 22-20° C; relative humidity 50-60%; 12:12 light:dark cycle, lights on at 8:00), in groups of 15. Standard laboratory food (Ssniff M-Z) and filtered water were freely available. On the day before experiments the equipment produced "white noise" was turned on for 30 minutes and mice were weighted exact to 1 g. Animals were assigned randomly to treatment groups. All the experiments were performed by two observers unaware of the treatment applied between 9:00 and 1 :00 on separate groups of animals. Mice were used only once and were killed immediately after the experiment.

d -Amphetamine-induced locomotor hyperactivity

The locomotor activity was recorded with an Opto M3 multi-channel activity monitor (MultiDevice Software v.1.3, Columbus Instruments). The mice were individually placed in plastic cages (22 x 12 x 13 cm) for 30 minutes habituation period, and then the crossings of each channel (ambulation) were counted during 1 h with data recording every 5 minutes. The cages were cleaned up with 70% ethanol after each mouse. Drugs were administered to 10 mice per treatment group. Test compounds were given 30 minutes before the experiment. d-Amphetamine was administered 30 minutes before the test.

Test compounds

Test compounds were prepared as a suspension in 1% aqueous solution of Tween 80, and d-amphetamine was dissolved in distilled water immediately before administration. An injection volume of 10 ml/kg was used and all compounds were administered intraperitoneal^ (i.p.), except d-amphetamine that was given subcutaneously (s.c). Statistical analysis

All the data are expressed as the mean ± SEM. The statistical significance of effects was evaluated using separate two-way analysis of variance (ANOVA) with comparison between individual groups by the Tukey's test; confidence intervals p<0.05, p<0.01 and p<0.001 were considered statistically significant.

Table 13. Results of d-amphetamine-induced locomotor hyperactivity test (MED. = Minimum Effective Dose) for representative compounds of the invention

Example 7.

Activity testing in rats

Animals

Animals for these tests were prepared as follows:

Drug-naive male Wistar rats (Charles River, Sulzfeld, Germany) weighing 250-400 g were housed in polycarbonate Makrolon cages (380 x 200 x 590 mm) in an environmentally controlled, experimental room (ambient temperature 21 -23°C ; relative humidity 50- 60%; 12:12 light:dark cycle, lights on at 7:00 a.m.), in groups of 4. Tap water and standard lab chow (Labofeed H, WPIK, Kcynia, Poland) was available ad libitum.

The animals were delivered to the Animal Research Unit of the Department of Pharmacology, Institute of Psychiatry and Neurology2 weeks before the start of experimental procedures. During these 2 weeks all the rats were repeatedly getting used to the presence of the experimenter (handling), and to injections of saline.

On the day before experiments rats were weighted exact to 1 g. Animals were assigned randomly to treatment groups. All the experiments were performed on separate groups of animals, between 9:00 and 15:00. Tested compound was administered intraperitoneally (i.p.) in an injection volume of 2 ml/kg in at least 3 selected doses. Control groups received an appropriate vehiculum.

All animals were used only once and were killed immediately after the experiment. d-Amphetamine- or dizocilpine (MK-801 )-induced locomotor hyperactivity in rats d -Amphetamine-induced locomotor hyperactivity

Within 24 h prior to testing, rats were habituated to experimental conditions. For this purpose rats in home cages were transferred to the experimental room for 60 min., while maintaining the lighting and the "white noise" characteristic for the experiment (see below). The test was conducted in a soundproof experimental room illuminated with scattered light of intensity about 20 lux and equipped with a source of white noise of intensity about 65 dB. The test of locomotor activity was conducted in a metal, octagonal arena having a diameter of 80 cm. The black floor of the arena was surrounded by a black wall of a height of 30 cm. Rats were placed individually into the central sector. Animal activity was monitored for 30 min. using the system that tracks the movement and behavior (Videomot, TSE, Hamburg, Germany), and which recorded the travelled distance (cm).

To induce locomotor hyperactivity amphetamine was administered intraperitoneally to animals (1 mg/kg in a volume of 1 ml / kg) 15 min. before the test. The test compound was administered 60 min. before the test. Cages were cleaned using 70% ethanol after examination of each rat.

Dizocilpine (MK-801 Hnduced locomotor hyperactivity

Dizocilpine (MK-801 )-induced locomotor hyperactivity was tested in the same manner as for amphetamine-induced locomotor hyperactivity. Dizocilpine (0.3 mg/kg in a volume of 1 ml/kg) was administered 15 min. before the test. The tested parameter was the distance travelled by animals (cm/ 30 min. ).

Compounds

Compound 63 as hydrochloride was dissolved in water for injection immediately before administration and administered intraperitoneally in an injection volume of 2 ml/kg 60 min. before the test. Dizocilpine and d-amphethamine were dissolved in saline immediately before administration and injected intraperitoneally in an injection volume of 1 ml/kg 15 min. before the test.

Statistical analysis

All the data are expressed as the mean ± SEM. The statistical significance of effects was evaluated using separate one-way analysis of variance (ANOVA) with post hoc comparison between individual groups by Newman-Keuls' test. Values p<0.05 were considered statistically significant.

Blocking of apomorphine-induced stereotyped behaviour in rats

Evaluation of stereotyped behaviour

Within 24 h prior to testing, rats were additionally habituated to experimental conditions. For this purpose rats in home cages were transferred to the experimental room and placed in observation cages for 20 min., while maintaining the lighting and the "white noise" characteristic for the experiment performed one day later.

Stereotyped behaviour was observed 20 min. after apomorphine injection (s.c.) in dosage of 0.6 mg/kg. and placed in the observation cages. Immediately after apomorfine injection, the animals were placed in glass observation cages (dimensions 25x25x40 cm) with fresh bedding on the floor. The experimenter observed each rat for 5 min., from 20 to 25 min. after administration of apomorphine. Parameter studied was the total time (s) of stereotyped sniffing or chewing/licking.

Test compounds

Compound 63 as hydrochloride was dissolved in water for injection immediately before administration and administered intraperitoneally in an injection volume of 2 ml/kg 60 min. before the test. Apomorphine was dissolved in saline immediately before administration and injected subcutaneously in an injection volume of 1 ml/kg 20 min. before the test.

Statistical analysis

All the data are expressed as the mean ± SEM. The statistical significance of effects was evaluated using Kruskal-Wallis test with comparison between individual groups by Mann- Whitney test. Values p<0.05 were considered statistically significant.

Blocking of 2,5-dimethoxy-4-iodoamphetamine(DOI)-induced head twitches in rats Evaluation of head twitches

Animals were placed in glass observation cages (dimensions: 25x25x40 cm) immediately after subcutaneous injection of DOI in dosis 2,5 mg/kg. Five minutes later, behaviour was observed for further 5 min. (5-10 min. after injection of DOI) and characteristic head twitches were counted (n/5 min.).

Test compounds Compound 63 as hydrochloride was dissolved in water for injection immediately before administration and administered intraperitoneally in an injection volume of 2 ml/kg 60 min. before the test. DOI was dissolved in saline immediately before administration and injected intraperitoneally in an injection volume of 1 ml/kg 5 min. before the test. Statistical analysis

All the data are expressed as the mean ± SEM. The statistical significance of effects was evaluated using Kruskal-Wallis test with comparison between individual groups by Mann- Whitney test. Values p<0.05 were considered statistically significant.

Blocking of conditioned avoidance response (CAR)

Evaluation of avoidance response

The apparatus for evaluation of avoidance response consisted of six identical stainless steel boxes (PACS-30, Columbus Instruments, USA). Each box was 22.8 cm wide, 48.3 cm long and 27.6 cm high and was divided into two equal-sized compartments, separated by a sliding door and equipped with light source and audio generator. An infrared-type beam assembly was used for detecting subject transfers. Each chamber floor was composed of stainless steel grid wired for application of a scrambled electric foot shock (0,5 mA).

Rats trained to avoid the foot shock were placed in the experimental chambers for a 3 min. habituation period followed by 50 CAR trials presented on a 15-s variable interval (VI) schedule. Each trial consisted of a 10 s warning tone and stimulus light (conditioned stimulus) followed by 10 s electric shock (0.5 mA). If during the initial 10 s of the trial an animal crossed through the sliding door, the tone and light were terminated, no shock was applied, and the response was considered as "an avoidance response". If the animal crossed through the sliding door, after a foot shock was initiated, the response was considered as "an escape response". If the animal did not cross the sliding door the response was considered as "none". If a response was made during an intertrial interval, it was punished with 0.5 s shock (0.5 mA). A stable demonstration of >80% of correct avoidance responses after 14-18 training sessions was a criterion for inclusion in subsequent drug tests.

Each drug was tested at different doses in the same group of eight animals (within- subject design). Test compound or vehiculum, were administered i.p. 60 minutes before the start of the test session consisting of 30 avoidance tests. Further test sessions were performed every 7 days (wash-out). Two CAR sessions consisting of 30 avoidance tests without test compound administration were conducted during the wash-out in order to maintain stable conditioned responding. The main parameter studied was the number of normal, conditioned avoidance responses (n/30).

Avoidances, escapes, and "none" responses were analyzed with the aid of a one-way analysis of variance (ANOVA). The Newman-Keuls test was used for individual post hoc comparisons.

Test compounds

Compound 63 as hydrochloride was dissolved in water for injection immediately before administration and administered intraperitoneally in an injection volume of 2 ml/kg 60 min. before the test session.

Statistical analysis

All the data are expressed as the mean ± SEM. The statistical significance of effects was evaluated using separate one-way analysis of variance (ANOVA) with post hoc comparison between individual groups by Newman-Keuls' test. Values p<0.05 were considered statistically significant.

Increased mobility in the Porsolt forced swim test

Evaluation of immobility in the Porsolt forced swim test

The animals were individually subjected to two experimental trials during which they were forced to swim in a cylinder (40 cm high, 18 cm in diameter) filled with water (25° C) to a height of 15 cm. A video camera was mounted 50 cm above the cylinder. The first (habituation) and second (test) trial lasted 15 and 5 minutes, respectively. There was a 24-h interval between the trials. The total duration of immobility (s) was measured during the second trial by a trained observer located in a separate room.

Test compounds

Compound 63 as hydrochloride was dissolved in water for injection immediately before administration and administered intraperitoneally in an injection volume of 2 ml/kg 60 min. before the test.

Statistical analysis

All the data are expressed as the mean ± SEM. The statistical significance of effects was evaluated using separate one-way analysis of variance (ANOVA) with post hoc comparison between individual groups by Newman-Keuls' test. Values p<0.05 were considered statistically significant. Reversal of amphetamine or dizocilpine (MK-801 )-induced PPI deficits Evaluation of prepulse inhibition (PPI)

The PPI apparatus consisted of eight soundproof chambers (SR-LAB, San Diego Instruments, San Diego, CA, USA). Each chamber consisted of a Plexiglas cylinder (8,9 cm diameter ^χ 20 cm long) resting on a Plexiglas frame in a sound attenuated, ventilated enclosure. Background noise and acoustic stimuli were presented via a loudspeaker mounted 24 cm above the animal. Startle responses, reflecting the motion of animals in the cylinder following the acoustic stimulus, were detected by a piezoelectric transducer mounted below the frame. The application of stimuli and response recording were controlled by the SR-LAB software. Test sessions started with a 5-minutes acclimatization period. Throughout the whole session, the chamber light was on, and the background white noise was set at 70 dB. The test session included 3 initial startling stimuli (intensity: 120 dB, duration: 40ms) to accustom the rat to the experimental procedure. The initial stimuli were followed by 60 trials (6 x 10 trials) presented in a random order:

- 10 background trials (B) which involved a presentation of a sham stimulus (intensity: 70 dB, duration: 40 ms),

- two types (2 x 1 0) of prepulse trials (PP) which included only a prepulse stimuli (84 dB or 90 dB, 20 ms),

- 10 pulse trials (P) which included only a pulse startling stimulus (120 dB, 40 ms),

- two types (2 x 10) of prepulse-and-pulse trials (PP-P) which involved a prepulse (84 dB or 90 dB, 20 ms) followed 100 ms later by a 120-dB, 40 ms. pulse stimulus (P).

The average inter-trial interval was 22.5 s (range: 1 5-30 s). This interval was randomized by the SR-LAB software. Startle responses were measured for 100 ms after the onset of the last trial stimulus. For each type of stimulation, startle amplitudes were averaged across the 10 trials. The magnitude of PPI was calculated as a percent inhibition of the startle amplitude in the pulse trial (treated as 100%) according to the formula: [(startle amplitude in P trials - startle amplitude in PP-P trials) / startle amplitude in P trials] ^χ 100%. Startle responses to the 3 initial stimuli of intensity of 120 dB were excluded from the statistical analyses. Reversal of the amphetamine-induced PPI deficits

Amphetamine (6 mg/kg) was administered intraperitoneally 15 min. before the start of PPI-session. Test compound was administered intraperitoneally 60 min. before the session.

Reversal of the dizocilpine (MK-801 )-induced PPI deficits

Dizocilpine (0.6 mg/kg) was administered intraperitoneally 15 min. before the start of PPI-session. Test compound was administered intraperitoneally 60 min. before the session.

Mean acoustic startle response, mean percentage of inhibition of acoustic startle response preceded by prepulse stimuli (separately for prepulse stimuli of 84 dB and 90 dB) were the tested parameters.

Test compound

Compound 63 as hydrochloride was dissolved in water for injection immediately before administration and administered intraperitoneally in an injection volume of 2 ml/kg 60 min. before the test. Dizocilpine and amphetamine were dissolved in saline immediately before administration and administered intraperitoneally in an injection volume of 1 ml/kg 15 min. before the session.

Statistical analysis

All the data are expressed as the mean ± SEM. The statistical significance of effects was evaluated using separate one-way analysis of variance (ANOVA) with post hoc comparison between individual groups by Newman-Keuls' test. Values p<0.05 were considered statistically significant.

Conflict test (Vogel test) in rats

24 Hours before the right experiment animals were habituated to test conditions. For this purpose rats in home cages were transferred to the experimental room for 15 min., while maintaining the lighting and the "white noise", characteristic for the experiment.

Anxiety Monitoring System "Vogel test" produced by TSE Systems was used. It consisted of a polycarbonate cage (dimensions 26.5 x 15 x 42 cm), equipped with a grid floor made from stainless steel bars and a drinking bottle containing tap water. Experimental chambers (two) were connected to PC software by control chassis and a device that generates electric shocks. The experiment lasted 3 days. On the first day of the experiment, the rats were placed individually in the experimental cage equipped with a drin- king bottle and were adapted to the test chamber for 10 min. After the adaptation period, the animals were deprived of water for 24 h and were then placed in the test chamber for another 10-min adaptation period during which they had free access to the drinking bottle. Afterwards, rats were allowed a 1 hour free-drinking session in their home cage. After another 24-h water deprivation period, the rats after administration of the test compound were placed in the test chamber. Recording data started immediately after the first lick and every 20 licks rats were punished with an electric shock (0.5 mA, lasting 1 s). The impulses were released via the spout of the drinking bottle. If a rat was drinking when an impulse was released, it received a shock. The number of licks and the number of shocks received throughout a 5-min experimental session were recorded automatically.

Table 14. Results of behavioral tests in rats for the representative compound (MED. = Minimum Effective Dose)

Results of behavioral tests described in Examples 6 and 7 show broad spectrum of antipsychotic activity for Compound 63 according to the invention, in all procedures used to measure the antipsychotic activity, at doses that cause no adverse effects. It is noteworthy that the compound was active in models utilizing psychotomimetic substances affecting either dopaminergic (d-amphetamine, apomorphine), serotoninergic (DOI) or glutamatergic transmission (dizocilpine) as well as in specific conditioning procedure (active avoidance response). The test compound was active in procedures indicative of efficacy in either positive symptoms of schizophrenia, such as: d-amphetamine and dizocilpine-induced hyperlocomotion, stereotyped behaviour induced by apomorphine and DOI -induced "head twitches" and active avoidance response, as well as in procedures assessing ability to treat attention deficits and information filtering (dimensions of cognitive deficits), underlying the pathomechanism of schizophrenia - reversal of amphetamine or dizocilpine-induced prepulse inhibition deficits.

Activity in these latter tests is of a special value due to the identity of the modeled disorders in animals and those occuring in humans, and therefore their relatively high translatability on clinical effects, and also due to the low efficiency in removing this type of disturbance by the currently available antipsychotic drugs, especially at doses that cause no adverse effects (Porsolt R. D et al. , J. Pharmacol. Exp. Ther., 333(3), 632- 8, 2010).

Moreover the test compound was active in well established models for detecting substances with potential antidepressant activity, i.e. forced swim test (Porsolt) in rats as well as potential anxiolytic activity, i.e. conflict drinking test (Vogel) in rats. Such a wide pharmacological activity, beyond the purely antipsychotic effects is a particularly desirable feature of modern antipsychotic drug, considering complexity of clinical conditions associated with schizophrenia, including depression and anxiety.