MXPA00002221A

MXPA00002221A - Fused thiophene compounds and medicinal use thereof

Info

Publication number: MXPA00002221A
Application number: MXPA/A/2000/002221A
Authority: MX
Inventors: Hiroshi Tanaka; Koji Seio; Toshiyuki Kohara; Kenji Hashimoto; Masatake Fujimura; Hideki Horiuchi; Hiroshi Yasumatsu; Koreichi Kimura
Original assignee: Yoshitomi Pharmaceutical Industries Ltd
Priority date: 1997-09-02
Filing date: 2000-03-02
Publication date: 2001-03-05

Abstract

Fused thiophene compounds represented by general formula (I), pharmaceutically acceptable salts thereof or hydrates of the same, wherein each symbol is as defined in the description. The compounds of general formula (I) are useful as novel antipsychotics which are efficacious against both of positive and negative symptoms of schizophrenia, exhibit little side effects such as extrapyramidal motility disturbance, and have little severe side effects such as granulocytopenia. These compounds are also useful as remedies for dementia of Alzheimer type and periodic psychosis.

Description

CONDENSED THIOPHENE COMPOUNDS AND THEIR PHARMACEUTICAL USE TO TECHNICAL FIELD The present invention relates to condensed thiophene compounds useful for the treatment of schizophrenia, Alzheimer's disease, manic-depressive illness and the like, to the pharmaceutical use thereof and to a synthetic intermediary thereof. 10 BACKGROUND TECHNIQUE Schizophrenia is a mental illness that has a high incidence of approximately 1% of the total population. In most of the In 15 cases, convalescence is lower and patients and their relatives are forced to suffer from a large problem over a long period. To avoid this, many studies have been made about the etiology of schizophrenia, the development of therapeutic drugs for it and the like. 20 The first hypothesis proposed about the etiology of schizophrenia was an hypothesis of excess dopamine. Based on this hypothesis several compounds have been developed that have an inhibitory action of the dopamine receptor as antipsychotic agents and have achieved certain therapeutic effects. Conditions of schizophrenia include positive symptoms that mainly show delirium, hallucination and the like, showing negative symptoms mainly social withdrawal, emotional numbing and the like, disorders of recognition function such as memory defects, learning disability and the like, and Similar. A so-called typical antipsychotic agent that focuses on the inhibition of the dopamine receptor is comparatively effective in positive symptoms, but ineffective against negative symptoms and disorders of recognition function. When a typical antipsychotic agent is used, extrapyramidal side effects (eg, dystonia, akathisia, dyskinesia and the like) are inevitably caused by the inhibitory action of the dopamine receptor. These difficulties suggest a limit in the development of an antipsychotic agent based solely on a so-called dopamine excess hypothesis. In an attempt to solve the aforementioned problems, antipsychotic agents, namely, serotonin-dopamine antagonist (SDA), which has an inhibitory action of the serotonin receptor as a major action, have been studied and developed in place of the inhibitory action of the dopamine receptor. The antipsychotic agents of SDA include risperidone, Seroquel and the like. However, the problems of poor effectiveness against negative symptoms and recognition function disorder or extrapyramidal side effects have not been completely overcome [American Journal of Psychiatry 151, 825 (1994)]. One of the etiological hypotheses of schizophrenia that have reached the hypothesis of excess dopamine and the hypothesis of serotonin / dopamine is a hypothesis of functional depression of the glutamic acid nerve [Trends in Neuroscience 13, 272 (1990)]. This hypothesis has been supported by the facts that (1) phencyclidine (PCP) which is an inhibitor of the NMDA receptor (N-methyl-D-aspartic acid) induces mental conditions in humans that are similar to schizophrenia with symptoms positive and negative symptoms [American Journal of Psychiatry 135, 1081 (1978), ibid. 148, 1301 (1991)], (2) the cerebral cortex of schizophrenic patients shows a lower reactivity of the glutamic acid nervous system [Neuroscience Letters 121, 77 (1991)], (3) the number of NMDA receptors also present in the glutamic acid nervous system shows a compensatory increase [Life Science 55, 1683 (1994)], (4) NMDA receptor agonists, such as glycine, D-cycloserine and the like, are effective in decreasing symptoms Negatives of Schizophrenia [British Journal of Psychiatry 169, 610 (1996), American Journal of Psychiatry 152, 1213 (1995), ibid. 151, 1234 (1994)] and the like. Clozapine and olanzapine are atypical antipsychotic agents characterized by their effectiveness against positive symptoms, as well as negative symptoms of schizophrenia [Psychopharmacology 63, 51 (1992), Neuropsychopharmacology 14, 111 (1996)]. These atypical antipsychotic agents suppress abnormal behaviors induced in laboratory animals [Psychopharmacology 120, 67 (1995), ibid, 129, 79 (1997), Pharmacology, Biochemistry and Behavior 47, 579 (1994)] and abnormal psychological function [Psychopharmacology 111 , 339 (1993), Journal of Pharmacology and Experimental Therapeutics 271, 787 (1994)] by functional depression of the glutamic acid nervous system by NMDA receptor inhibitors such as PCP and MK-801 (dizocilpine maleate), and its Inhibitory capacity is often stronger than that of typical antipsychotic agents. In other words, the clinical effects supepores of the atypical antipsychotic agent can be attributed to the decrease of functional nervous system depression of glutamic acid in addition to the inhibitory action of the dopamine receptor and the inhibitory action of the serotonin receptor. Abnormalities in neurophysiological function induced by an NMDA receptor inhibitor include neurotoxicity induced by NMDA receptor inhibitor [Archive of General Psychiatry 52, 998 (1995)] and neurotoxicity induced by MK-801 have been studied extensively. This neurotoxic action can be inhibited by several antipsychotic agents, in which the inhibitory action is stronger in clozapine and olanzapine, which are atypical antipsychotic agents, than in haloperidol and the like, which are typical antipsychotic agents [Schizophrenia Research 15, 57 (1995 ), ibid. 21, 33 (1996)]. Using this neurotoxic action induced by MK-801 as an indicator, we can look for an antipsychotic agent that has a diminishing action of functional nervous system depression of glutamic acid, which is one of the characteristics of clozapine and olanzapine. In addition, a neurotoxic action induced by MK-801 is also considered a model of recognition function disorder observed in several diseases such as Alzheimer's disease and the like [Brain Research - Brain Research Reviews, 20, 250-267 (1995)], and a compound capable of inhibiting this neurotoxicity is also effective as a therapeutic drug of Alzheimer's disease, manic-depressive diseases and the like. Meanwhile, the use of clozapine is limited, since it induces agranulocytosis, although it also shows superior antipsychotic action [New England Journal of Medicine 324, 746 (1991)]. The reduction of the possibility of side effects is also an important aspect in the development of an antipsychotic agent. Recently, a report has been documented that a cation radical generated as a metabolic intermediate of clozapine could be involved in the mechanism of agranulocytosis [CNS Drugs 7, 139 (1997)]. Therefore, it is significant to inhibit the generation of cation radical to avoid the appearance of agranulocytosis. There are several reports to date on the appropriate modification of the chemical structures of clozapine and olanzapine. For example, WO95 / 17400, W096 / 18621, W096 / 18623, W096 / 18629, WO96 / 18630 and W096 / 19479 describe a dibenzoxazepine compound, Japanese patents examined Publication Nos. 42-24513, 42-24514, 43- 27404, 45-20909, 45-6822, 46-29861, 48-34599 and 49-40236 and Japanese Unexamined Patent Publication No. 47-4425 describe a dibenzoxazepine or dibenzothiazepine compound, WO93 / 07143 discloses a pyridobenzoxazepine compound , Journal of Heterocyclic Cemistry 31, 1053 (1994) discloses a thienobenzoxazepine compound and Japanese Unexamined Patent Publication No. 63-8378 discloses a dibenzothiazepine compound. In addition, a benzothiophene compound is disclosed in, for example, Japanese Patents Not Examined Publication Nos. 52-87196 and 51-76296 with respect to a derivative of 1., 2,3,4-tetrahydrobenzothieno [2,3-b] [1,5] benzodiazepine. However, these compounds have remotely overcome the problems of effectiveness against negative symptoms and recognition function disorder, extrapyramidal side effects and the like, and activation of the nervous system function of glutamic acid of clozapine compounds has not been reported. and olanzapine that have chemical structures modified in an appropriate way.

BRIEF DESCRIPTION OF THE INVENTION The present inventors took note of the hypothesis of functional nervous system depression of glutamic acid, and carried out intensive studies in an attempt to develop a compound that would decrease positive symptoms, as well as the negative symptoms of schizophrenia and dementia. the recognition function, and which is free of serious side effects such as extrapyramidal disorders, agranulocytosis and the like. As a result, it has been found that the condensed thiophene compound of the formula (I) has an inhibitory action of the superior dopamine receptor and decreasing action of the depression of the glutamic acid nervous system function, shows anti-methamphetamine action, action anti-apomorphine, inhibitory action of the conditioned avoidance response, inhibitory action of MK-801-induced neurotoxicity, antagonistic action of MK-801 discrimination, generalization action of clozapine discrimination and the like in laboratory animals such as mouse , rat and the like, and is useful as an antipsychotic agent; that the compound shows fewer side effects in the extrapyramidal system, such as induction of catalepsy and the like; and that a reaction intermediate corresponding to the cation radical intermediate considered to be the cause of clozapine-induced agranulocytosis was not detected when the reaction intermediate was analyzed by an ESR spectrum, using oxidation of the compound of the formula (I ) by horseradish peroxidase as a model reaction of the metabolic reaction of this compound, which resulted in the conclusion of the present invention. Therefore, an object of the present invention is to provide a condensed thiophene compound useful as a therapeutic agent for schizophrenia and the like, and an important synthetic intermediate for it. The condensed thiophene compound of the formula (I) is also useful as a therapeutic agent for Alzheimer's disease and manic-depressive diseases. Accordingly, the present invention provides the following: (1) A condensed thiophene compound of the formula (I): wherein: Ra and Rb are the same or different and each is hydrogen, alkyl, cycloalkyl, acyl, alkenyl, aryl, heteroaryl, aralkyl, alkoxy, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, acyloxyalkyl, acylaminoalkyl, halogen, halide of alkyl or nitro, or Ra and Rb together can form a benzene ring or cyclohexene ring optionally having substituents R1 and R2, wherein R1 and R2 are the same or different and each is hydrogen, alkyl, alkoxy, hydroxyl or halogen; X is NH, O, S, SO, SO2 or N-R4, wherein R4 is alkyl, provided that when X is NH, Ra and Rb together form a benzene ring having optionally substituents R1 and R2, and when X whether S, SO or SO2, Ra and Rb together form a benzene ring or cyclohexene ring optionally having substituents R1 and R2; Ring A is a benzene ring having 1 to 4 same or different substituents thereon selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, halogen, alkyl halide, nitro, amino, monoalkylamino, dialkylamino, acylamino, hydroxyl and cyano, or a benzene ring without a substituent; and R3 is a group of the formula (1), formula (2), formula (3), formula (26), formula (27), formula (28), formula (29) or formula (30) (3) (1) (2) (27) (28) (29) (30) in the formula (1), formula (26), formula (27) and formula (30), R5, R6 and R7 are the same or different and each is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl, is already an integer of 2-4, in formula (2) and formula (28)R8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, acyl, alkoxycarbonyl or alkoxyalkyl, b is 1 or 2, as long as the combination of X is O and R8 is aralkyl is excluded and when X is O, the alkyl, hydroxyalkyl or alkoxyalkyl alkyl in R8 has 1 to 4 carbon atoms, in the formula (3) and formula (29), R9 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acyl, alkoxycarbonyl or alkoxyalkyl, or a pharmaceutically acceptable salt thereof or a hydrate thereof. (2) The condensed thiophene compound of (1) above, wherein formula (I) is formula (IA): wherein: X is NH, O, S, SO, S02 or N-R4, wherein R4 is alkyl; R1 and R2 are the same or different and each is hydrogen, alkyl, alkoxy, hydroxyl or halogen; Ring A is a benzene ring having 1 to 4 identical or different substituents thereon selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, halogen, alkyl halide, nitro, amino, monoalkylamino, dialkylamino, acylamino, hydroxyl and cyano, or a benzene ring without a substituent; Ring B is a benzene ring in which the bond shown by a dotted line and a solid line is a double bond, or a cyclohexane ring in which said bond is an individual bond, provided that when X is NH, the bond shown by a dotted line and a continuous line is not an individual link; and R3 is a group of the formula (1), formula (2), formula (3), formula (26), formula (27), formula (28), formula (29) or formula (30) (1) (2) (3) (27) (28) (29) (30) in the formula (1), formula (26), formula (27) and formula (30), R5, R6 and R7 are the same or different and each is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl, is already an integer of 2-4; in the formula (2) and formula (28), R8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, acyl, alkoxycarbonyl or alkoxyalkyl, b is 1 or 2; in the formula (3) and formula (29), R9 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acyl, alkoxycarbonyl or alkoxyalkyl, or a pharmaceutically acceptable salt thereof or a hydrate of it. (3) The condensed thiophene compound of (2) above, wherein ring B is a benzene ring in which the bond shown by a dotted line and a solid line is a double bond, or a pharmaceutically acceptable salt of the same or a hydrate thereof. (4) The condensed thiophene compound of (2) above, wherein X is NH, O or S, R1 and R2 are the same or different and each is hydrogen, halogen, alkoxy or alkyl, ring A is a benzene ring having 1 to 4 same or different substituents thereon selected from the group consisting of alkyl, alkoxy, halogen and alkyl halide, or a benzene ring without a substituent, ring B is a benzene ring in the that the bond shown by a dotted line and a solid line is a double bond, and R3 is a group of the formula (2) wherein R8 is hydroxyalkoxyalkyl, methyl or ethyl and b is 1, or a pharmaceutically acceptable salt thereof or a hydrate thereof. (5) The condensed thiophene compound of (2) above, wherein X is NH, R1 and R2 are the same or different and each is hydrogen, halogen, alkoxy or alkyl, ring A is a benzene ring which has 1 to 4 identical or different substituents thereon selected from the group consisting of alkyl, alkoxy, halogen and alkyl halide, or a benzene ring without a substituent, ring B is a benzene ring in which the bond shown by a dotted line and a continuous line is a double bond, and R3 is a group of the formula (2) wherein R8 is methyl or ethyl and b is 1, or a pharmaceutically acceptable salt thereof or a hydrate thereof. (6) The condensed thiophene compound of (2) above, which is a member selected from the group consisting of: 12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] ] [1,5] -benzodiazepine, 8-fluoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 8-methyl- 12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 8-chloro-12- (4-methylpiperazin-1-yl) -6H - [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 8-bromo-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2], 3-b] [1, 5] -benzodiazepine, 9-fluoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 9-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 9-chloro-12- (4-methylpiperazine-1 - il) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 9-bromo-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3 -b] [1, 5] -benzodiazepine, 9-methoxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 8, 9-difluoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 8,10-difluoro-12- (4-methylpiperaz) n-1 -yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 3-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothiene [2,3-b] [1, 5] -benzodiazepine, 8-fluoro-3-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1 , 5] -benzodiazepine, 2-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 8-fluoro-2-methyl -12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 3-methoxy-12- (4-met) ilpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 8-fluoro-3-methoxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepine, 8,9-dichloro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 7,8-dichloro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 3-bromo -8-fluoro-12- (4-methyl-piperazin-1-yl) -6H- [1] -benzothieno [2,3-b] [1,5] -benzodiazepine, 3-fluoro-12- (4-methyl-piperazin-1) -yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 3-chloro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2, 3-b] [1,5] -benzodiazepine, 1-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 4 -methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 3,8-difluoro-12- (4-methylpiperazine-1) -yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 3-fluoro-8-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepine and 12- (4-ethylpiperazin-1 -yl) -8-fluoro-6H- [1] benzothieno [2,3-b] [ 1,5] -benzodiazepine, or a pharmaceutically acceptable salt thereof or a hydrate thereof. (7) A pharmaceutical agent comprising a fused thiophene compound of the formula (IA) or a pharmaceutically acceptable salt thereof or a hydrate thereof, a pharmaceutical composition comprising said compound and a pharmaceutically acceptable additive, and an antipsychotic agent which comprises, as an active ingredient, a compound of the formula (IA). (8) A benzothiophene compound of the formula (HA) wherein X is NH, O, S, SO, SO2 or N-R4, wherein R4 is alkyl; R1 and R2 are the same or different and each is hydrogen, alkyl, alkoxy, hydroxyl or halogen; ring A is a benzene ring having 1 to 4 same or different substituents thereon selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, halogen, alkyl halide, nitro, amino, monoalkylamino, dialkylamino, acylamino, hydroxyl and cyano, or a benzene ring without a substituent; and ring B is a benzene ring in which the bond shown by a dotted line and a solid line is a double bond, or a cydohexane ring in which said bond is an individual bond, provided that when X is NH, the link shown by a dotted line and a continuous line is not an individual link, which is an important intermediary for the synthesis of the compound of the formula (IA). (9) The benzothiophene compound of (8) above, wherein X is NH, O or S; R1 and R2 are the same or different and each is hydrogen, halogen, alkoxy or alkyl; ring A is a benzene ring having 1 to 4 same or different substituents thereon selected from the group consisting of alkyl, alkoxy, halogen, hydoxyl and alkyl halide, or a benzene ring without a substituent; and ring B is a benzene ring in which the bond shown by a dotted line and a solid line is a double bond, or a cydohexane ring in which said bond is an individual bond, provided that when X is NH, the link shown by a dotted line and a continuous line is not an individual link. (10) The benzothiophene compound of (8) above, which is a member selected from the group consisting of 6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 8-fluoro-6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 8-chloro-6H- [1] benzothieno [2,3 -b] [1, 5] -benzodiazepin-12 (11H) -one, 8-bromo-6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one , 8-methyl-6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 9-fluoro-6H- [1] benzothieno [2,3-b] ] [1,5] -benzodiazepin-12 (11 H) -one, 8-chloro-6 H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 9-bromo-6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 9-methyl-6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 9-methoxy-6 H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 8 , 9-difluoro-6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 3-methyl-6H- [1] benzothieno [2,3-b] ] [1,5] -benzodiazepin-12 (11 H) -one, 8-fluoro-3-methyl-6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) ) -one, 3-methoxy-6H - [1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 8-fluoro-3-methoxy-6H- [1] benzothieno [2,3-b] [ 1, 5] -benzodiazepin-12 (11 H) -one, 2-methyl-6 H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 8- fluoro-2-methyl-6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 3,9-dimethyl-6H- [1] benzothieno [2, 3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 1, 2,3,4-tetrahydro- [1] benzothieno [2,3-b] [1, 5] -benzoxazepin- 12 (11 H) -one, 1, 2,3,4-tetrahydro-8-methyl- [1] benzothieno [2,3-b] [1,5] -benzoxazepin-12 (11 H) -one, 8- fluoro-1, 2,3,4-tetrahydro- [1] benzothieno [2,3-b] [1, 5] -benzoxazepin-12 (11 H) -one, [1] benzothieno [2,3-b] [1,5] -benzoxazepin-12 (11H) -one, 8-methyl- [1] benzothieno [2,3-b] [1,5] -benzoxazepin-12 (11 H) -one, 8-fluoro- [1] benzothieno [2,3-b] [1, 5] -benzoxazepin-12 (11 H) -one, 1, 2,3,4-tetrahydro- [1] benzothieno [2,3-b] [1 , 5] -benzothiazepin-12 (11 H) -one, 1, 2,3,4-tetrahydro-8-methyl- [1] benzothieno [2,3-b] [1,5] -benzothiazepin- 12 (11 H) -one, 8-fluoro-1, 2,3,4-tetrahydro- [1] benzothieno [2,3-b] [1, 5] -benzothiazepin-12 (11 H) -one, [1] benzothieno [2,3 -b] [1, 5] -benzothiazepin-12 (11 H) -one, 8-methyl- [1] benzothieno [2,3-b] [1,5] -benzothiazepin-12 (11 H) -one, 8-fluoro- [1] benzothieno [2,3-b] [1, 5] -benzothiazepin-12 (11 H) -one, 8,9-dichloro-6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 7,8-dichloro-6 H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one , 9-trifluoromethyl-6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11H) -one, 3-bromo-8-fluoro-6H- [1] benzothieno [2, 3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 6-methyl- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one , 3-fluoro-6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 3-chloro-6H- [1] benzothieno [2,3-b] ] [1,5] -benzodiazepin-12 (11 H) -one, 1-methyl-6 H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 4-methyl-6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 3,8-difiuoro-6H- [1] benzothieno [2,3-] b] [1, 5] -benzodiazepin-12 (11 H) -one and 3-fluoro-8-methyl-6H- [1] benzoti eno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one. (11) The condensed thiophene compound of (1) above, wherein formula (I) is formula (IB): wherein: Ra 'and Rb' are the same or different and each is hydrogen, alkyl, cycloalkyl, acyl, alkenyl, aryl, heteroaryl, aralkyl, alkoxy, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, acyloxyalkyl, acylaminoalkyl, halogen , alkyl halide or nitro, and Ring A is a benzene ring having 1 to 4 same or different substituents thereon selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, halogen, alkyl halide, nitro, amino , monoalkylamino, dialkylamino, acylamino, hydroxyl and cyano, or a benzene ring without a substituent; and R3 is a group of the formula (1), formula (2), formula (3), formula (26), formula (27), formula (28), formula (29) or formula (30) (1) (2) (3) (29) (30) in the formula (1), formula (26), formula (27) and formula (30), R5, R6 and R7 are the same or different and each is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl, is already an integer of 2-4, in formula (2) and formula (28), R8 is hydrogen, alkyl having 1 to 4 carbon atoms, cycloalkyl, hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acyl, alkoxycarbonyl or alkoxyalkyl, wherein the alkyl having 1 to 4 carbon atoms is substituted by alkoxy, and b is 1 or 2, in the formula (3) and formula (29), R9 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acyl, alkoxycarbonyl or alkoxyalkyl, or a pharmaceutically acceptable salt thereof. or a hydrate thereof. (12) The condensed thiophene compound of (11) above, wherein Ra 'and Rb' are the same or different and each is hydrogen or alkyl, ring A is a benzene ring having 1 to 4 substituents the same or different thereon selected from the group consisting of alkyl, alkoxy, halogen and alkyl halide, or a benzene ring without a substituent; and R3 is a group of the formula (2), wherein R8 is hydroxyalkoxyalkyl, methyl or ethyl and b is 1, or a pharmaceutically acceptable salt thereof or a hydrate thereof. (13) The condensed thiophene compound of (11) above, wherein Ra 'is alkyl, Rb' is hydrogen or alkyl, ring A is a benzene ring having a substituent thereon selected from the group consisting of alkyl , alkoxy and halogen, or a benzene ring without a substituent; and R3 is a group of the formula (2), wherein R8 is methyl and b is 1, or a pharmaceutically acceptable salt thereof or a hydrate thereof. (14) The benzothiophene compound of (11) above, which is a member selected from the group consisting of 2-methyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1, 5] -benzoxazepine, 2-ethyl-4- (4-methyl-piperazin-1-yl) -thieno [2,3-b] [1,5] -benzoxazepine, 2,8-dimethyl-4- (4-methyl-piperazin-1) -yl) thieno [2,3-b] [1,5] -benzoxazepine, 8-methoxy-2-methyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1, 5] ] -benzoxazepine, 2,6-dimethyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1,5] -benzoxazepine, 2,9-dimethyl-4- (4- methylpiperazin-1-yl) thieno [2,3-b] [1,5] -benzoxazepine, 2,3-dimethyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1, 5] -benzoxazepine, 8-chloro-2-methyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1,5] -benzoxazepine and 8-fIuoro-2-methyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1,5] -benzoxazepine or a pharmaceutically acceptable salt thereof or a hydrate thereof. (15) A pharmaceutical agent comprising a condensed thiophene compound of the formula (IB) or a pharmaceutically acceptable salt thereof or a hydrate thereof, a pharmaceutical composition comprising said compound and a pharmaceutically acceptable additive, and an antipsychotic agent which understands, as an active ingredient, a compound of the formula (IB). (16) A thienobenzoxazepinone compound of the formula (IIB) wherein Ra 'and Rb' are the same or different and each is hydrogen, alkyl, cycloalkyl, acyl, alkenyl, aryl, heteroaryl, aralkyl, alkoxy, hydroxyalkyl, aminoalkyl , monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, acyloxyalkyl, acylaminoalkyl, halogen, alkyl halide or nitro and ring A is a benzene ring having 1 to 4 same or different substituents thereon selected from the group consisting of alkyl, cycloalkyl, alkoxy , alkoxyalkyl, halogen, alkyl halide, nitro, amino, monoalkylamino, dialkylamino, acylamino, hydroxyl and cyano, or a benzene ring without a substituent, which is an important intermediate for the synthesis of the compound of the formula (IB). (17) The thienobenzoxazepinone compound of (16) above, wherein Ra 'and Rb' are the same or different and each is hydrogen or alkyl, ring A is a benzene ring having 1 to 4 equal substituents or different thereon selected from the group consisting of alkyl, alkoxy, halogen and alkyl halide, or a benzene ring without a substituent. (18) The thienobenzoxazepinone compound of (16) above, which is a member selected from the group consisting of: 2-methylthieno [2,3-b] [1,5] -benzoxazepin-4 (5H) -one, 2,3-dithmetol [2,3-b] [1,5] -benzoxazepin-4 (5H) -one, 2,8-dimethylthieno [2,3-b] [1,5] -benzoxazepin-4 (5H) -one, 8-chloro-2-methylthieno [2,3-b] [1, 5] -benzoxazepin-4 (5H) -one, 8-fluoro-2-methyl-tione [2,3-b] [1, 5] -benzoxazepin-4 (5H) -one, 8-methoxy-2-methyltiene [2,3-b] [1,5] -benzoxazepin-4 ( 5H) -one, 2,6-dimethylthieno [2,3-b] [1,5] -benzoxazepin-4 (5H) -one, 2,9-dimethylthieno [2,3-b] [1, 5] - benzoxazepin-4 (5H) -one and 2-ethylthieno [2,3-b] [1, 5] -benzoxazepin-4 (5H) -one.

DETAILED DESCRIPTION OF THE INVENTION In the present invention, each symbol used specifically means the following. Alkyl is alkyl having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl. Cycloalkyl is cycloalkyl having 3 to 6 carbon atoms, such as cyclopropyl, cyclohexyl and the like. Alkoxy is alkoxy having 1 to 5 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like. Aryl is phenyl or naphthyl, with preference given to phenyl. Heteroaryl is pyridyl, furyl, thienyl and the like.

Aralkyl is one in which aryl has been substituted by alkyl having 1 to 5 carbon atoms and is exemplified by benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl and the like. Hydroxyalkyl is hydroxyalkyl having 1 to 5 carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-hydroxypropyl, 4-hydroxybutyl, 1-hydroxy-1-methylethyl and the like. Hydroxyalkoxyalkyl is that in which the alkyl having 1 to 4 carbon atoms has been linked to hydroxyalkyl having 1 to 4 carbon atoms by means of an oxygen atom, and is exemplified by 2- (2-hydroxyethoxy) ethyl and Similar. Aminoalkyl is that in which alkyl having 1 to 5 carbon atoms has been replaced by amino, which is exemplified by aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 1-aminopropyl, 4-aminobutyl, 1- amino-1-methylethyl and the like. Monoalkylaminoalkyl is that in which the aminoalkyl nitrogen atom is substituted by an alkyl having 1 to 5 carbon atoms, which is exemplified by methylaminomethyl, N-methyl-2-aminoethyl, N-methyl-1-aminoethyl, N -methyl-3-aminopropyl, N-methyl-1-aminopropyl, N-methyl-4-aminobutyl, N-methyl-1-amino-1-methylethyl and the like. Dialkylaminoalkyl is that in which the aminoalkyl nitrogen atom has been replaced by two alkyls having 1 to 5 carbon atoms, which is exemplified by dimethylaminomethyl, N, N-dimethyl-2-aminoethyl, N, N-dimethyl- 1-aminoethyl, N, N-dimethyl-3-aminopropyl, N, N-dimethyl-1-aminopropyl, N, N-dimethyl-4-aminobutyl, N, N-dimethyl-1-amino-1-methylethyl and the like. Alkoxyalkyl is that in which alkyl having 1 to 5 carbon atoms has been substituted by alkoxy, such as methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl and the like. Halogen is fluorine, chlorine, bromine or iodine. Alkyl halide is that having 1 to 5 carbon atoms, such as fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl and the like. Monoalkylamino is amino substituted by an alkyl having 1 to carbon atoms, such as methylamino, ethylamino and the like. Dialkylamino is amino substituted by two alkyls having 1 to 5 carbon atoms, such as dimethylamino, diethylamino and the like. Acyl is one having 2 to 7 carbon atoms, such as acetyl, propanoyl, butanoyl, pivaloyl, benzoyl and the like. Acylamino is one in which amino or monoalkylamino is attached to acyl having 1 to 5 carbon atoms, such as acetylamino, N-acetyl-N-methylamino and the like. As used herein, acyl means having 2 to 5 carbon atoms, such as acetyl, propanoyl, butanoyl, pivaloyl and the like. Alkoxycarbonyl is that having 2 to 8 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, pentoxycarbonyl, and the like.

Ring B is preferably a benzene ring in which the bond shown by a dotted line and a solid line is a double bond. The group of the formula (1) as defined by R5, R6, R7 and the a-a-mentioned above is N- (N ', N'-dimethyl-2-aminoethyl) amino, N- (N', N'- dimethyl-2-aminoethyl) -N-methylamino and the like. The group of the formula (2) as defined by R8 and the integer b mentioned above is piperazinyl-1-yl, 4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1-yl, 4-propyl-piperazin-1-yl, 4-isopropyl-piperazin-1-yl, 4- [2- (2-hydroxyethoxy) -ethyl] -piperazin-1-yl , 4-methylhomopiperazin-1-yl and the like, preferably to 4-methylpiperazin-1-yl. The group of the formula (3) as defined by R9 mentioned above is 8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl and the like. The group of the formula (26) as defined by R5 and R6 mentioned above is amino, N, N-dimethylamino and the like. The group of formula (27) as defined by R5, R6, R7 and the integer a mentioned above is N'-N- (N ', N'-dimethyl-2-aminoethyl) amino oxide, N'-oxide of N- (N ', N'-dimethyl-2-aminoethyl) -N-methylamino and the like. The group of the formula (28) as defined by R8 and the integer b mentioned above is 4-methylpiperazin-4-oxid-1-yl and the like. The group of formula (29) as defined by R9 mentioned above is 8-methyl-3,8-diazabicyclo [3.2.1] octan-8-oxid-3-yl and the like.

The group of the formula (30) as defined by R5 and R6 mentioned above is amino N-oxide, N, N-dimethylamino N-oxide and the like. The compound of the formula (I) is specifically a compound of the formula (I A) or a compound of the formula (IB). The compound of the formula (IA), a pharmaceutically acceptable salt thereof and hydrates thereof is preferably a condensed thiophene compound of the formula (IA) wherein: X is NH. O or S, R1 and R2 are the same or different and each is hydrogen, halogen, alkoxy or alkyl, ring A is a benzene ring having 1 to 4 same or different substituents thereon selected from the group consisting of alkyl, alkoxy, halogen and alkyl halide, or a benzene ring without a substituent, ring B is a benzene ring in which the bond shown by a dotted line and a solid line is a double bond, and R3 is a group of the formula (2) wherein R8 is hydroxyalkoxyalkyl, methyl or ethyl and b is 1, or a pharmaceutically acceptable salt thereof and hydrates thereof. More preferred is a fused thiophene compound of the formula (IA) wherein: X is NH, R1 and R2 are the same or different and each is hydrogen, halogen, alkoxy or alkyl, ring A is a benzene ring which has 1 to 4 identical or different substituents thereon selected from the group consisting of alkyl, alkoxy, halogen and alkyl halide, or a benzene ring without a substituent, ring B is a benzene ring in which the bond shown by a dotted line and a continuous line is a double bond, and R3 is a group of the formula (2) wherein R8 is methyl or ethyl and b is 1, or a pharmaceutically acceptable salt thereof or a hydrate thereof. Compounds of the formula (IA) that are preferred include the following compounds in which the number denotes the example number. (1) 12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, (2) 8-fluoro-12- (4-methylpiperazine- 1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, (6) 8-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepine, (7) 8-chloro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1 , 5] -benzodiazepine, (8) 8-bromo-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, (49) 9 -fluoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, (10) 9-methiM 2- (4-methylpiperazin-1) -yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, (11) 9-chloro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothiene [2,3-b] [1,5] -benzodiazepine, (12) 9-bromo-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepine, (13) 9-methoxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, (50) 8 , 9-difluoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, (15) 8,10-difluoro-12- ( 4-methylpiper azin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, (16) 3-methyl-12- (4-methylpiperazin-1-yl) -6H- [ 1] benzothieno [2,3-b] [1,5] -benzodiazepine, (17) 8-fluoro-3-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2, 3-b] [1, 5] -benzodiazepine, (18) 2-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1, 5] - benzodiazepine, (19) 8-fluoro-2-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, (20) 3 -methoxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, (21) 8-fluoro-3-methoxy-12- ( 4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, (22) 8,9-dichloro-12- (4-methylpiperazine-1-yl) ) -6H- [1] benzothien [2,3-b] [1, 5] -benzodiazepine, (23) 7,8-dichloro-12- (4-methylpiperazin-1-yl) -6H- [1 ] benzothieno [2,3-b] [1, 5] -benzodiazepine, (25) 3-bromo-8-fluoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3 -b] [1, 5] -benzodiazepine, (42) 3-fluoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine , (43) 3-c parrot-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, (45) 1-methyl-12- (4-methyl-piperazin-1-yl) -6H- [1] -benzothieno [2,3-b] [1,5] -benzodiazepine, (46) 4-methyl-12- (4-methyl-piperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, (47) 3,8-difluoro-12- (4-methyl-piperazin-1-yl) ) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, (48) 3-fluoro-8-methyl-12- (4-methylpiperazin-1-yl) -6H- [1 ] benzothieno [2,3-b] [1, 5] -benzodiazepine and (51) 12- (4-ethylpiperazin-1-yl) -8-fluoro-6H- [1] benzothieno [2,3-b] [ 1, 5] -benzodiazepine. The present invention also encompasses the pharmaceutically acceptable salts of the compounds mentioned above and the hydrates thereof. The compound of the formula (HA) is preferably a benzothiophene compound in which X is NH, O or S, R1 and R2 are the same or different and each is hydrogen, halogen, alkoxy or alkyl, ring A is a benzene ring having 1 to 4 same or different substituents thereon selected from the group consisting of alkyl, alkoxy, halogen and alkyl halide, or a benzene ring without a substituent, and ring B is a benzene ring in that the link shown by a dotted line and a solid line is a double bond, or a ring of cyclohexane in which said link is an individual bond, provided that when X is NH, the link shown by a dotted line and a line continue is not an individual link. Specific compounds of the formula (HA) include the following: 6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 8-fluoro-6H- [1 ] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 8-chloro-6 H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin- 12 (11 H) -one, 8-bromo-6 H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 8-methyl-6 H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 9-fluoro-6 H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 9-chloro-6 H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 9-bromo-6 H- [1] benzothiene [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 9-methyl-6 H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 ( 11 H) -one, 9-methoxy-6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 8,9-difluoro-6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 3-methyl-6 H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 8-fluoro-3-methyl-6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 3-methoxy-6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazep in-12 (11 H) -one, 8-fluoro-3-methoxy-6 H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 2-methyl -6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 8-fluoro-2-methyl-6H- [1] benzothieno [2,3-b] ] [1, 5] -benzodiazepin-12 (11 H) -one, 3,9-dimethyl-6 H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) - Ona, 1, 2,3,4-tetrahydro- [1] benzothieno [2,3-b] [1, 5] -benzoxazepin-12 (11 H) -one, 1, 2,3,4-tetrahydro-8 -methyl- [1] benzothieno [2,3-b] [1, 5] -benzoxazepin-12 (11 H) -one, 8-fluoro-1, 2,3,4-tetrahydro- [1] benzothieno [2] , 3-b] [1, 5] -benzoxazepin-12 (11 H) -one, [1] benzothieno [2,3-b] [1,5] -benzoxazepin-12 (11 H) -one, 8- methyl- [1] benzothieno [2,3-b] [1, 5] -benzoxazepin-12 (11 H) -one, 8-fluoro- [1] benzothieno [2,3-b] [1, 5] - benzoxazepin-12 (11 H) -one, 1, 2,3,4-tetrahydro- [1] benzothieno [2,3-b] [1, 5] -benzothiazepin-12 (11 H) -one, 1, 2 , 3,4-tetrahydro-8-methyl- [1] benzothieno [2,3-b] [1, 5] -benzothiazepin-12 (11 H) -one, 8-fluoro-1, 2,3,4- tetrahydro- [1] benzothieno [2,3-b] [1, 5] -benzothiazepin-12 (11 H) -one, [1] benzothieno [2, 3-b] [1, 5] -benzothiazepin-12 (11 H) -one, 8-methyl- [1] benzothieno [2,3-b] [1,5] -benzothiazepin-12 (11 H) -one , 8-fluoro- [1] benzothieno [2,3-b] [1, 5] -benzothiazepin-12 (11 H) -one, 8,9-dichloro-6H- [1] benzothieno [2,3-b] ] [1,5] -benzodiazepin-12 (11 H) -one, 7,8-dichloro-6 H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) - ona, 9-trifluoromethyl-6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 3-bromo-8-fluoro-6H- [1] benzothieno [ 2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 6-methyl- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 3-fluoro-6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 3-chloro-6H- [1] benzothieno [2,3 -b] [1, 5] -benzodiazepin-12 (11 H) -one, 1-methyl-6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 4-methyl-6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 3,8-difluoro-6H- [1] benzothieno [2,3-] b] [1, 5] -benzodiazepin-12 (11 H) -one and 3-fluoro-8-methyl-6 H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one. The compound of the formula (IB) is preferably a condensed thiophene compound in which Ra 'and Rb' are the same or different and each is hydrogen or alkyl, ring A is a benzene ring having 1 to 4 substituents equal or different thereon selected from the group consisting of alkyl, alkoxy, halogen and alkyl halide, or a benzene ring without a substituent; and R3 is a group of the formula (2), wherein R8 is hydroxyalkoxyalkyl, methyl or ethyl and b is 1, or a pharmaceutically acceptable salt thereof and hydrates thereof. More preferred is a fused thiophene compound of the formula (IB) wherein Ra 'is alkyl, Rb' is hydrogen or alkyl, ring A is a benzene ring having a substituent thereon selected from the group consisting of alkyl , alkoxy and halogen, or a benzene ring without a substituent; and R3 is a group of the formula (2), wherein R8 is methyl and b is 1, or a pharmaceutically acceptable salt thereof or a hydrate thereof. Preferred compounds of the formula (IB) include the following compounds in which the numbers in parentheses are the example numbers: (125) 2-methyl-4- (4-methylpiperazin-1-yl) thieno [2, 3-b] [1, 5] -benzoxazepine, (130) 2-ethyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1,5] -benzoxazepine, (138) 2 , 8-dimethyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1,5] -benzoxazepine, (142) 8-methoxy-2-methyl-4- (4-methylpiperazin- 1-yl) thieno [2,3-b] [1,5] -benzoxazepine, (143) 2,6-dimethyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1 , 5] -benzoxazepine, (145) 2,9-dimethyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1,5] -benzoxazepine, (144) 2,3-dimethyl -4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1, 5] -benzoxazepine, (146) 8-chloro-2-methyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1, 5] -benzoxazepine and (147) 8-fluoro-2-methyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1, 5] ] -benzoxazepine. The present invention also encompasses the pharmaceutically acceptable salts of the compounds mentioned above and the hydrates thereof. The compound of the formula (IIB) is preferably a thienobenzoxazepinone compound in which: Ra 'and Rb' are the same or different and each is hydrogen or alkyl and the ring A is a benzene ring having 1 to 4 substituents equal or different thereon selected from the group consisting of alkyl, alkoxy, halogen, hydroxyl and alkyl halide, or a benzene ring without a substituent. The compounds of the formula (I IB) that are preferred include the following compounds in which the numbers in parentheses are the example numbers: (98) 2-methylthieno [2,3-b] [1,5] -benzoxazepin- 4 (5H) -one, (101) 2,3-dimethyl-thieno [2,3-b] [1,5] -benzoxazepin-4 (5H) -one, (102) 2,8-dimethylthieno [2, 3-b] [1, 5] -benzoxazepin-4 (5H) -one, (105) 8-chloro-2-methylthieno [2,3-b] [1, 5] -benzoxazepin-4 (5H) -one , (106) 8-fluoro-2-methylthieno [2,3-b] [1,5] -benzoxazepin-4 (5H) -one, (107) 8-methoxy-2-methylthieno [2,3-b] [1, 5] -benzoxazepin-4 (5H) -one, (108) 2,6-Dimethylthieno [2,3-b] [1, 5J-benzoxazepin-4 (5H) -one, (109) 2,9-dimethylthieno [2,3-b] [1, 5] - benzoxazepin-4 (5H) -one and (116) 2-ethylthieno [2,3-b] [1,5] -benzoxazepin-4 (5H) -one. The pharmaceutically acceptable salt of the compound of the formula (I), particularly of the formula (IA) or formula (IB), includes salts with inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and salts with organic acid, such as acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, mentanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphor sulfonic acid, ascorbic acid, maleic acid, citric acid, tartaric acid, fumaric acid and the like. The compound of the formula (I), particularly of the formula (IA) or formula (IB) and the pharmaceutically acceptable salts thereof may exist in the form of hydrates or solvates, and their hydrates (1/2 hydrates, monohydrates, dihydrates, trihydrates and the like) and solvates are also encompassed in the present invention. When the compounds of the invention include an asymmetric atom, they may be obtained in the form of a racemic mixture or optically active compound. When the compounds of the invention include at least two asymmetric atoms, they can be obtained in the form of the respective diastereomers or mixtures thereof. The present invention also encompasses these mixtures and individual isomers. The present invention also encompasses stereoisomers. The synthetic methods of the compounds of the present invention are the following.

METHOD 1 Synthetic method of the compound of the formula (IA) A benzothiophene compound of the formula (HA) wherein each symbol is as defined above is maintained with a suitable chlorinating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride and the like, in a solvent that does not adversely affect the reaction, such as benzene, toluene, xylene , chloroform, 1,2-dichloroethane, and optionally mixed solvents thereof or without solvent, from room temperature to 170 ° C for 1 to 24 hours to give a compound of the formula (4A) where each symbol is like the one defined above. The compound of the formula (4A) obtained is maintained with a compound of the formula (5) H-R3 (5) wherein R3 is as defined above, with a solvent that does not adversely affect the reaction, such as benzene, toluene , xylene, chloroform, 1,2-dichloroethane, optionally mixed solvents thereof and the like or without solvent, from room temperature to 170 ° C for 1 to 24 hours to give a compound of the formula (IA).

METHOD 2 Synthetic method of the compound of the formula (IA) A benzothiophene compound of the formula (HA) is maintained with a suitable sulfurizing agent such as diphosphoric tetrasulphate, Lawesson's reagent and the like in a solvent that does not adversely affect the reaction, such as benzene, toluene, xylene, chloroform, 1, 2-dichloroethane, optionally mixed solvents thereof and the like or without solvent, from room temperature to 170 ° C for 1 to 24 hours to give a compound of the formula (7) where each symbol is like the one defined above. The compound of the formula (7) obtained is reacted with a suitable methylating agent such as methyl iodide, methyl bromide and the like in a solvent which does not adversely affect the reaction, such as tetrahydrofuran, N, N-dimethylformamide, acetonitrile , N-methylpyrrolidone, dichloromethane, chloroform, 1,2-dichloroethane, optionally mixed solvents thereof and the like in the presence of an organic base such as pyridine, triethylamine, diisopropylethylamine and the like or an inorganic base such as sodium hydride, carbonate potassium, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium alkoxide, butyl lithium and the like, or without a base to give a compound of the formula (8) where each symbol is like the one defined above. The compound of formula (7) or formula (8) obtained is maintained with a compound of formula (5) in a solvent that does not adversely affect the reaction, such as tetrahydrofuran, N, N-dimethylformamide, acetonitrile, N -methylpyrrolidone, dichloromethane, benzene, toluene, xylene, chloroform, 1,2-dichloroethane, optionally mixed solvents thereof and the like, or without solvent, from room temperature to 170 ° C for 1 to 24 hours to give a compound of the formula (IA).

METHOD 3 Synthetic method of the compound of the formula (IA) wherein X is NH, N- R4, O or 3 A benzothiophene compound of the formula (9) wherein R10 is alkyl, R11 is halogen and the other symbols are as defined above, maintained with a compound of the formula (10) wherein R12 is NH2, NH-R4, OH or SH and ring A is as defined above, in a solvent that does not adversely affect the reaction, such as N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran , ethanol, 1,4-dioxane, an optionally mixed solvent thereof and the like, or without a solvent, in the presence of an organic base such as pyridine, triethylamine, diisopropylethylamine and the like, or an inorganic base such as sodium hydride, carbonate of potassium, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium alkoxide, butyl lithium and the like, from -20 ° C to 170 ° C for 1 to 24 hours to give a compound of the formula (11) where each symbol is like the one defined above. A compound of the formula (11a) (11a) wherein R13 is hydrogen or alkyl and the other symbols are as defined above, which is a compound of the formula (11) wherein X is NH or N-R4, can also be synthesized by the following method. For example, a benzothiophene compound of the formula (12) where each symbol is like the one defined above, it is maintained with a compound of the formula (13) wherein R14 is halogen and ring A is as defined above, in a solvent that does not adversely affect the reaction, such as N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, ethanol, 1,4-dioxane , optionally mixed solvents thereof and the like, or without a solvent, in the presence of an organic base such as pyridine, triethylamine, diisopropylethylamine and the like, or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, hydroxide sodium, potassium hydroxide, potassium tert-butoxide, sodium alkoxide, butyl lithium and the like, from -20 ° C to 170 ° C for 1 to 24 hours to give the above-mentioned compound of the formula (11a).

In particular, of the compounds of the formula (11a), a compound in which R 13 is alkyl can also be obtained by keeping a compound wherein R 13 is hydrogen with an alkyl halide of the formula (6) which will be mentioned below, in a solvent that does not adversely affect the reaction, such as N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane, an optionally mixed solvent thereof and the like, or without solvent, in the presence of an organic base such as pyridine, triethylamine, diisopropylethylamine and the like, or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium alkoxide, butyllithium, lithium diisopropylamine and the like, from room temperature to 170 ° C for 1 to 24 hours. The compound of the formula (11) obtained is maintained with hydrogen of the normal pressure at 100 atmospheres, in a solvent that does not adversely affect the reaction, such as ethanol, methanol, ethyl acetate, dimethylformamide, acetic acid, water, a solvent optionally mixed thereof and the like, or without solvent, in the presence of a suitable metal catalyst such as palladium-carbon, palladium black, palladium hydroxide, Raney nickel, platinum oxide and the like, from room temperature to 150 ° C for 1 to 24 hours to give a compound of the formula (14) wherein each symbol is as defined above. The compound of the formula (14) can also be obtained by keeping a compound of the formula (11) with a suitable inorganic reagent such as iron, zinc, tin chloride (ll) and the like, in a solvent which does not adversely affect the reaction, such as ethanol, methanol, 1,4-dioxane, dimethylformamide, acetic acid, water, an optionally mixed solvent thereof and the like, or without a solvent, in the presence of a suitable acid such as hydrochloric acid, acetic acid and the like, de - 20 ° C to 150 ° C for 1 to 24 hours. In addition, the compounds of the formula (14), a compound wherein X is S or O, can also be obtained by keeping a compound of the formula (9) with a compound of the formula (25) wherein R16 is OH or SH and ring A is as defined above, in a solvent that does not adversely affect the reaction, such as N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, ethanol, 1, 4 - dioxane, an optionally mixed solvent thereof and the like, or without a solvent, in the presence of an organic base such as pyridine, triethylamine, diisopropylethylamine and the like, or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate , sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium alkoxide, butyl lithium and the like, from -20 ° C to 150 ° C for 1 to 24 hours. The compound of the formula (14) obtained is maintained with a compound of the formula (5) in a solvent that does not adversely affect the reaction, such as anisole, toluene, xylene, mesitylene, nitrobenzene, 1,2-dichloroethane, an optionally mixed solder thereof and the like, or without a solvent, in the presence of a suitable Lewis acid such as titanium tetrachloride, tin tetrachloride , aluminum chloride and the like, from room temperature to 170 ° C for 1 to 24 hours to give a compound of the formula (IA).

METHOD 4 A compound of the formula (lAa) where each symbol is like the one defined above, which is a compound of the formula (IA) where X is N-R4, can also be obtained by keeping a benzothiophene compound of the formula (Lab) wherein each symbol is as defined above, with an alkyl halide of the formula (6) Hal-R4 (6) wherein Hal is halogen and R4 is as defined above, in a solvent that does not adversely affect the reaction, such as N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane, an optionally mixed solvent thereof and the like, or without a solvent, in the presence of an organic base such as pyridine, triethylamine, diisopropylethylamine and the like, or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium alkoxide, butyl lithium and the like, of room temperature at 170 ° C for 1 to 24 hours.

METHOD 5 A compound of the formula (lAc) where c is 1 or 2 and the other symbols are as defined above, which is a compound of the formula (IA) where X is SO or S02, can also be obtained by keeping a benzothiophene compound of the formula (lAd) wherein each symbol is as defined above, with an oxidizing agent such as hydrogen peroxide, m-chloroperbenzoic acid, sodium periodate, sodium perbromate and the like, in a solvent that does not adversely affect the reaction, such as water, ethanol , acetic acid, formic acid, dichloromethane, chloroform, an optionally mixed solvent thereof and the like, or without solvent, from -78 ° C to 120 ° C for 1 to 24 hours.

METHOD 6 Synthetic method of the compound of the formula (HA) A compound of the formula (14) is maintained with an organic base such as pyridine, triethylamine, diisopropylethylamine and the like, or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium alkoxide, butyl lithium and the like, or a suitable Lewis acid such as titanium tetrachloride, tin tetrachloride, aluminum chloride, boron trifluoride and the like, or a suitable acid, such as acid sulfuric acid, phosphoric acid and the like, in a solvent that does not adversely affect the reaction, such as dichloromethane, chloroform, tetrahydrofuran, dimethyl sulfoxide, N, N-dimethylformamide, benzene, toluene, xylene, an optionally mixed solvent thereof and the like , from room temperature to 170 ° C for 1 to 24 hours to give a compound of the formula (HA). A compound of the formula (14) is maintained with a suitable inorganic base, such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like, in a solvent that does not adversely affect the reaction, such as methanol, ethanol, water, tetrahydrofuran, 1,4-dioxane, an optionally mixed solvent thereof and the like, from room temperature to 150 ° C for 1 to 24 hours to give a compound of the formula (15). where each symbol is like the one defined above. The compound of formula (15) obtained is maintained with a suitable condensing agent, such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-N'-3-dimethylaminopropylcarbodiimide, diethylphosphoryl azide, diphenylphosphoryl azide, in a solvent that does not adversely affect the reaction, such as benzene, toluene, xylene, hexane, ethyl acetate, diethyl ether, tetrahydrofuran, dioxane, chloroform, dichloromethane, 1,2-dichloroethane, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, pyridine, an optionally mixed solvent thereof and the like, from room temperature to 100 ° C for 10 minutes to 24 hours to give a compound of the formula (HA).

METHOD 7 Synthetic method of the compound of the formula (HA) A compound of the formula (16) wherein each symbol is as defined above, it is maintained with a suitable chlorinating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride and the like, in a solvent that does not adversely affect the reaction, such as benzene, toluene, xylene, chloroform, 1,2-dichloroethane, an optionally mixed solvent thereof and the like, or without solvent, from room temperature to 170 ° C for 1 to 24 hours to give a compound of the formula (17 ). where each symbol is like the one defined above. The compound of the formula (17) is maintained with a compound of the formula (18) wherein each symbol is as defined above, in a solvent that does not adversely affect the reaction, such as benzene, toluene, xylene, hexane, ethyl acetate, diethyl ether, tetrahydrofuran, dioxane, chloroform, dichloromethane, 1,2-dichloroethane , N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, pyridine, an optionally mixed solvent thereof and the like, or without a solvent, in the presence of an organic base, such as pyridine, triethylamine, diisopropylethylamine and the like, or an inorganic base, such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and the like of room temperature at 170 ° C for 10 minutes to 24 hours to give a compound of the formula (19) where each symbol is like the one defined above. A compound of the formula (19) can also be obtained by keeping a compound of the formula (16) with a compound of the formula (18) in a solvent that does not adversely affect the reaction, such as benzene, toluene, xylene, hexane, acetate of ethyl, diethyl ether, tetrahydrofuran, dioxane, chloroform, dichloromethane, 1,2-dichloroethane, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, pyridine, an optionally mixed solvent thereof and the like, and a suitable condensation, such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-N'-3-dimethylaminopropylcarbodiimide, diethylphosphoryl azide, diphenylphosphoryl azide and the like, from room temperature to 100 ° C for 10 minutes to 24 hours. The compound of formula (19) obtained is maintained in a solvent that does not adversely affect the reaction, such as in a solvent that does not adversely affect the reaction, such as methanol, ethanol, N, N-dimethylformamide, dimethyl sulfoxide, N -methylpyrrolidone, hexamethylphosphorus triamide, benzene, toluene, xylene, chloroform, dichloroethane and the like, an optionally mixed solvent thereof and the like, in the presence of an organic base, such as pyridine, triethylamine, diisopropylethylamine and the like, or an inorganic base , such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like at room temperature at 170 ° C for 10 minutes to 24 hours to give a compound of the formula (HA).

METHOD 8 A compound of the formula (HAa) wherein each symbol is as defined above, which is a compound of the formula (IIA) wherein X is SO or SO2, can be obtained by keeping a benzothiophene compound of the formula (HAb) wherein each symbol is as defined above, with oxidizing agent, such as hydrogen peroxide, m-chloroperbenzoic acid, sodium periodate, sodium perbromate and the like, in a solvent that does not adversely affect the reaction, such as water, ethanol , acetic acid, formic acid, dichloromethane, chloroform, an optionally mixed solvent thereof and the like, or without a solvent, from -78 ° C to 120 ° C for 1 to 24 hours.

METHOD 9 A compound of the formula (HAc) wherein each symbol is as defined above, which is a compound of the formula (IIA) wherein X is N-R4, can also be obtained, for example, by maintaining a benzothiophene compound of the formula (IIAd) wherein each symbol is as defined above, with an alkyl halide of the formula (6) in a solvent that does not adversely affect the reaction, such as N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, , 4-dioxane, an optionally mixed solvent thereof and the like, or without a solvent, in the presence of an organic base, such as pyridine, triethylamine, diisopropylethylamine and the like, or an inorganic base, such as sodium hydride, potassium carbonate , sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium alkoxide, butyl lithium, lithium diisopropylamide and the like at room temperature at 170 ° C for 1 to 24 hours.oVe METHOD 10 A compound of the formula (IIAe) where each symbol is as defined ab as long as a compound is excluded where X is NH, which is a compound of the formula (HA) where ring B is a benzene ring, can also be obtained by keeping a composed of 1, 2,3,4-tetrahydrobenzothiophene of the formula (IIAf) (FEIS) wherein each symbol is as defined ab with a suitable oxidizing agent such as sulfur, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, dichlorodicyano-p-benzoquinone, or a noble metal catalyst suitable as palladium coal, palladium hydroxide, palladium black, platinum oxide and the like, in a solvent which does not adversely affect the reaction, such as benzene, toluene, xylene, mesitylene, chloroform, carbon tetrachloride, 1, 4-dioxane and optionally mixed solvent thereof and the like, or with solvent from 0 ° C to 250 ° C for 1 to 48 hours.

METHOD 11 A compound of the formula (HAg) wherein each symbol is as defined ab which is a compound of the formula (HA) wherein the substituent on the A ring is amino, can be obtained by keeping a compound of the formula (IIAh) (IIAh) wherein each symbol is as defined ab which is a compound of the formula (HA) wherein a substituent on ring A is nitro, with hydrogen, in a solvent that does not adversely affect the reaction, such as methanol, ethanol, ethyl acetate, dioxane, benzene, toluene, xylene, diethyl ether, chloroform, 1, 2-dichloroethane and a solvent optionally mixing thereof and the like, using palladium-carbon, palladium hydroxide, platinum oxide and similar as a catalyst from 0 ° C to 100 ° C and from normal pressure to 100 atmospheres for 10 minutes to 24 hours.

METHOD 12 A compound of the formula (IlAi) wherein R15 is fluorine, chlorine, bromine, iodine or cyano and other symbols as defined ab which is a compound of formula (HA) wherein the substituent on ring A is cyano or halogen, can be obtained by diazotizing a compound of formula (IIag) in a solvent which does not adversely affect the reaction such as water, dilute hydrochloric acid and the like and using sodium nitrite and the like from -10 ° C to room temperature and keeping with fluoroboric acid, hydrogen-fluoride pyridine, sodium chloride, cuprous chloride, sodium bromide, cuprous bromide, sodium iodide, potassium iodide and the like of -10 ° C to 100 ° C.

METHOD 13 Synthetic method of the compound of the formula (IA) where X is NH and joins shown by the dotted line and the solid line in B is a double bond Using a benzyl cyanide compound of the formula (20) wherein each symbol is as defined ab as a starting material and in accordance with the method described in Japanese Unexamined Patent Publication No. 7-89965 to give a benzothiophene compound of the formula (21) where each symbol is like the one defined ab The compound of the formula (21) obtained is maintained with a compound of the formula (13) in a solvent that does not adversely affect the reaction, such as N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, ethanol, 1, 4-dioxane, a solvent optionally mixing thereof and the like, or without solvent, in the presence of an organic base such as pyridine, triethylamine, diisopropylethylamine and the like or inorganic base such as sodium hydride, potassium carbonate , sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium alkoxide, butyl lithium or the like of -50 ° C to 170 ° C for 1 to 24 hours to give a compound of the formula (22) 1 where each symbol is like the one defined ab The compound of the formula (22) obtained is maintained with a suitable reducing agent such as iron, zinc, tin chloride (ll) and the like, in a solvent that does not adversely affect the reaction such as ethanol, methanol, 1,4-dioxane, dimethylformamide, acetic acid, water and an optionally mixed solvent thereof and the like, in the presence of a suitable acid, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid and from -20 ° C to 150 ° C for 1 to 24 hours to give a compound of the formula (23) wherein each symbol is as defined above or a salt thereof with an organic acid, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like. A compound of the formula (23) can be obtained by keeping a compound of the formula (22) with hydrogen of the normal pressure at 100 atmospheres in a solvent that does not adversely affect the reaction, such as ethanol, methanol, ethyl acetate, dimethylformamide, acetic acid, water, an optionally mixed solvent thereof and the like or without a solvent, in the presence of a suitable metal catalyst, such as palladium-carbon, palladium black, palladium hydroxide, Raney nickel, platinum oxide and the like ambient temperature of 150 ° C for 1 to 24 hours, or maintaining a compound of the formula (24) wherein each symbol is as defined above, which is obtained by maintaining a suitable reducing agent, such as sodium hydrosulfite, iron, zinc, tin chloride (ll) and the like in the presence of hydrochloric acid, acetic acid and the like, or under neutral conditions of -20 ° C to 150 ° C for 1 to 24 hours is maintained in a solvent that does not adversely affect the reaction, such as benzene, toluene, xylene, dimethyl sulfoxide, N, N-dimethylformamide, 1, 4-dioxane, ethanol, methanol, acetic acid, water, an optionally mixed solvent thereof and the like, in the presence or absence of a suitable inorganic acid, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like, Ambient temperature of 180 ° C for 1 to 24 hours. The compound of the formula (23) obtained is maintained with a compound of the formula (1), (2), (3), (26), (27), (28), (29) or (30) in a solvent that does not adversely affect the reaction, such as benzene, toluene, xylene, dimethyl sulfoxide, N, N-dimethylformamide, an optionally mixed solvent thereof and the like, or without a solvent, in the presence of a suitable organic base, such as pyridine, triethylamine, diisopropylethylamine and the like, or inorganic base, such as potassium carbonate, sodium carbonate and the like, or in the absence of a base at room temperature of 180 ° C for 1 to 20 hours to give a compound of the formula ( IA) where X is NH and the bond shown by the dotted line and a continuous line in ring B is a double bond.

METHOD 14 Compounds of the formulas (lAe) and (lAf) (lAe) (lAf) where each symbol is like the one defined above, provided that when X is NH, the link shown by a dotted line and a continuous line is not an individual link, which are the compounds of the formula (IA) where R3 is Formula (2) or (3) and R8 or R9 is hydrogen, can also be obtained by keeping a compound wherein R3 is alkoxycarbonyl or acyl of the formula (2a), (2b), (3a) or (3b) (2a) (2b) (3a) (3b) wherein R17 is alkyl or aralkyl, R18 is alkyl or aryl, and b is as defined above, in a solvent that does not adversely affect the reaction, such as ethanol, methanol, 1,4-dioxane, tetrahydrofuran, benzene, toluene, water, an optionally mixed solvent thereof and the like, or without using a solvent, in the presence of an inorganic acid such as hydrochloric acid, sulfuric acid and the like or an organic acid such as acetic acid, trifluoroacetic acid, acid p-toluenesulfonic acid and the like from 0 ° C to 150 ° C for 1 to 18 hours. The compounds (Iae) and (IaF) can also be obtained by keeping the compounds of the formulas (2c) and (3c) (2c) (3c) wherein R22 is aryl and b is as defined above, with hydrogen at normal pressure at 100 atmospheres in a solvent that does not adversely affect the reaction, such as ethanol, methanol, ethyl acetate, dimethylformamide, acetic acid , water and an optionally mixed solvent thereof and the like, or without a solvent, in the presence of a suitable metal catalyst such as palladium-carbon, palladium black, palladium hydroxide, Raney nickel, platinum oxide and the like at room temperature of 150 ° C for 1 to 24 hours.

METHOD 15 Compounds of the formulas (lAg) and (lAh) (lAg) (lAh) wherein R8 'and R9 are each acyl or alkoxycarbonyl and other symbols are as defined above, provided that when X is NH and the bond shown by a dotted line and a solid line is not an individual bond , which are compounds of the formula (IA) wherein R3 is of the formula (2) or (3) and R8 or R9 is acyl or alkoxycarbonyl, can be obtained by keeping the compounds (IaE) and (IaF) (R8 or R9) is hydrogen) with a suitable acylating agent, such as acyl halide of the formula (31). Hal-CO-R19 (31) wherein Hal is halogen and R19 is alkyl or aryl, or an acid anhydride of the formula (32) wherein R19 is as defined above, or ester halide of the formula (33) Hal-COOR20 (33) wherein Hal is halogen and R20 is alkyl or aralkyl as an alkoxycarbonylating agent, in a solvent that does not adversely affect the reaction such as benzene, toluene, xylene , chloroform, 1,4-dioxane, tetrahydrofuran and an optionally mixed solvent thereof and the like, or without a solvent, in the presence of a basic reagent such as pyridine, triethylamine, N, N-dimethylaminopyridine, sodium hydride, potassium carbonate , sodium hydroxide, potassium tert-butoxide, sodium alkoxide, butyllithium, lithium diisopropylamine and the like, from -50 to 150 ° C for 10 minutes to 15 hours.

METHOD 16 Compounds of the formulas (lAi) and (lAj) (lAi) (lAj) wherein R8 and R9"are each alkyl, cycloalkyl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl and other symbols as defined above, provided that when X is NH, the bond shown by a dotted line and a solid line is not an individual bond, which are the compounds of the formula (IA) wherein R3 has the formula (2) or (3) and R8 or R9 is alkyl, cycloalkyl, aralkyl, hydroxyalkyl , hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl, can be obtained by keeping compounds (IaE) and (IaF) (R8 or R9 is hydrogen) with a suitable alkylating agent such as a compound of the formula (34) Hal-R21 (34) wherein Hal is halogen and R21 is alkyl, cycloalkyl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl in a solvent that does not adversely affect The reaction, such as benzene, toluene, xylene, chloroform, 1,4-dioxane, tetrahydrofuran and an optionally mixed solvent thereof and the like, or without a solvent, in the presence of a suitable basic reagent such as pyridine, triethylamine, N , N-dimethylaminopyridine, sodium hydride, potassium carbonate, sodium hydroxide, potassium tert-butoxide, sodium alkoxide, butyl lithium, lithium diisopropylamine and the like, from -50 to 200 ° C for 10 minutes to 24 hours .

METHOD 17 Of the compounds of the formula (IA), a compound may be obtained wherein R3 has the formula (27), (28), (29) or (30) keeping the compound (1), (2), (3) or (26) corresponding with a suitable oxidizing agent, such as aqueous hydrogen peroxide, m-chloroperbenzoic acid, tert-butyl hydroperoxide and the like in a solvent that does not adversely affect the reaction such as methylene chloride, chloroform, 1,2 dimethoxyethane, benzene, toluene, diethyl ether, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, water and an optionally mixed solvent thereof and the like of -30 to 130 ° C for 10 minutes to 12 hours.

METHOD 18 A compound of the formula (HA) wherein X is O, S, SO or SO2 and the bond shown by a dotted line and a continuous line in ring B is a double bond, can also be obtained by keeping a compound of the formula ( HA) where X is O, S, SO or SO2 and the bond shown with a dotted line and a continuous line on ring B is an individual bond, in a solvent that does not adversely affect the reaction, such as benzene, toluene, xylene, mesitylene, dichloromethane, chloroform, ethyl acetate, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, N, N-dimethylformamide, an optionally mixed solvent thereof and the like, in the presence of an oxidizing agent suitable, such as 2,3-dichloro-5,6-dicyan-1,4-benzoquinone, chloranil, manganese dioxide, nickel peroxide, palladium-carbon, lead tetraacetate and the like at room temperature at 200 ° C for 1 to 24 hours.

METHOD 19 Synthetic method of the compound of the formula (IB) A thienobenzoxazepinone compound of the formula (I IB) wherein each symbol is as defined above, it is maintained with an appropriate flavoring agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride and the like in a suitable solvent, such as a solvent that does not adversely affect the reaction ( example, benzene, toluene, xylene, chloroform, 1,2-dichloroethane and an optionally mixed solvent thereof and the like), or without solvent, from room temperature to 170 ° C for 1 to 24 hours to give a compound of the formula (4B). where each symbol is as defined above. Subsequently, a compound of the formula (4B) is maintained with a compound of the formula (5) H-R3 (5) wherein R3 is as defined above, in a suitable solvent, such as a solvent that does not adversely affect the reaction (for example, benzene, toluene, xylene, chloroform, 1,2-dichloroethane and an optionally mixed solvent thereof and the like), or without solvent, from room temperature to 170 ° C for 1 to 24 hours to give a composed of the formula (IB).

METHOD 20 Synthetic method of the compound of the formula (IBa) wherein W is an oxygen atom or nitrogen atom bonded with hydrogen or a C: -C5 alkyl, R23 and R24 are the same or different and each is hydrogen, C-? -C alkyl and the like, c is an integer from 0 to 4 and the other symbols are as defined above, which is a compound of formula (IB) (Ra 'is hydroxyalkyl, aminoalkyl or monoalkylaminoalkyl). For example, a compound of the formula (IBb) (Ra 'is acyloxyalkyl or acylaminoalkyl), which is synthesized according to the method wherein R25 is hydrogen or alkyl having 1 to 4 carbon atoms, and the like and other symbols are as defined above, maintained with a base such as sodium hydroxide, potassium hydroxide, ammonia and the like or an acid such as hydrochloric acid, hydrobromic acid, acetic acid, formic acid, sulfuric acid and the like, in water or in a solvent mixed with water and a suitable solvent, such as methanol, ethanol, pyridine, dioxane and the like of room temperature at 100 ° C. for 10 minutes to 24 hours to give a compound of the formula (IBa).

METHOD 21 Synthetic method of the compound of the formula (IBc) wherein each symbol is as defined above, which is a compound of formula (IB) wherein the substituent on ring A is acyloxy or monoalkylamino. For example, a compound of the formula (IBd) which is a compound of the formula (IB) wherein the substituent on ring A is acyloxy or acylamino (I Bd) where each symbol is as defined above, it is maintained with a base such as sodium hydroxide, potassium hydroxide, ammonia and the like or an acid such as hydrochloric acid, hydrobromic acid, acetic acid, formic acid, acid sulfuric and the like in water or a mixed solvent of water and a suitable solvent, such as methanol, ethanol, pyridine, dioxane and the like, from room temperature to 100 ° C for 10 minutes to 24 hours to give a compound of the formula ( IBc).

METHOD 22 Synthetic method of the compound of the formula (IBe) wherein each symbol is as defined above, which is the compound of formula (IB) wherein the substituent on ring A is amino. A compound of the formula (IBf) (I Bf) where each symbol is as defined above, which is the compound of formula (IB) where the substituent on ring A is nitro, and which is synthesized according to method 19, is maintained with hydrogen in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., methanol, ethanol, ethyl acetate, dioxane, benzene, toluene, xylene, diethyl ether, chloroform, 1,2-dichloroethane, and a solvent optionally mixed thereof and the like), using palladium-activated carbon, palladium hydroxide, platinum oxide and the like as a catalyst, from 0 ° C to 100 ° C and from normal pressure to 100 atmospheres for 10 minutes to 24 hours to give a compound of the formula (IBe).

METHOD 23 Synthetic method of the compound of the formula (IIB) The 2-halogen-3-thiophenecarboxylic acid derivative of the formula (35) where Hal is halogen and the other symbols are as defined above, it is maintained with a suitable chlorinating agent, such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride and the like in a suitable solvent, such as a solvent that does not adversely affect the reaction (for example, benzene, toluene, xylene, chloroform, 1,2-dichloroethane and an optionally mixed solvent thereof and the like), or without a solvent, from room temperature to 170 ° C during 1 to 24 hours to give a compound of the formula (36) where each symbol is like the one defined above. The compound of the formula (36) obtained is maintained with a compound of the formula (37) wherein ring A is as defined above, in a suitable solvent such as a solvent that does not adversely affect the reaction (e.g., benzene, toluene, xylene, hexane, ethyl acetate, diethyl ether, tetrahydrofuran, dioxane, chloroform, dichloromethane, 1,2-dichloroethane, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, pyridine, an optionally mixed solvent thereof and the like), or without a solvent, in the presence of an organic base, such as pyridine, triethylamine, diisopropylethylamine and the like, or an inorganic base such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and similar, from room temperature to 170 ° C for 10 minutes to 24 hours to give a compound of the formula (38) where each symbol is like the one defined above. The compound of the formula (38) can also be obtained by keeping a compound of the formula (35) and a compound of the formula (37) in a suitable solvent, such as a solvent that does not adversely affect the reaction (for example, benzene, toluene, xylene, hexane, ethyl acetate, diethyl ether, tetrahydrofuran, dioxane, chloroform, dichloromethane, 1,2-dichloroethane, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, pyridine, an optionally mixed solvent thereof and the like), together with a suitable condensing agent, such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-N'-3-dimethylaminopropylcarbodiimide, diethylphosphoryl azide, diphenylphosphoryl azide and the like at room temperature at 100 ° C for 10 minutes at 24 hours. The compound of the formula (38) obtained is maintained in a suitable solvent, such as a solvent which does not adversely affect the reaction (for example, methanol, ethanol, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, hexamethylphosphorus triamide, benzene, toluene, xylene, chloroform, dichloroethane and the like, an optionally mixed solvent thereof and the like), in the presence of an organic base, such as pyridine, triethylamine, N, N-diisopropylethylamine and the like, or a inorganic base, such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like or metal alkoxide or sodium ethoxide, sodium methoxide, potassium tert-butoxide and the like, of the temperature atmosphere at 170 ° C for 10 minutes to 24 hours to give a compound of the formula (I IB).

METHOD 24 Synthetic method of the compound of the formula (IIBa) wherein R26 is alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, butyl and the like, and the other symbols are as defined above, which is a compound of the formula (HB) wherein Ra ' it is acyl and it is not formyl.

A compound of the formula (IIBb) which is a compound of the formula (110) wherein Ra 'is hydrogen and is synthesized according to the method where each symbol is like the one defined above, it is maintained with a compound of the formula (39) O R26- -C Hal (39) where each symbol is as defined above or a compound of the formula (40) wherein R26 is as defined above, in the presence of an aluminum chloride and the like in a suitable solvent, such as a solvent that does not adversely affect the reaction, (eg, nitrobenzene, hexane, chloroform, 1,2-dichloroethane and similar, an optionally mixed solvent thereof and the like), from 0 ° C to 100 ° C for 10 minutes to 24 hours to give a compound of the formula (IIBa).

METHOD 25 Synthetic method of the compound of the formula (HBc) wherein each symbol is as defined above, which is a compound of formula (IIB) wherein Ra 'is formyl. A compound of the formula (IIBc) can be obtained by keeping a compound of the formula (IIBb) with aluminum chloride and the like in a suitable solvent, such as a solvent that does not adversely affect the reaction (for example, nitrobenzene, hexane, chloroform, 1,2-dichloroethane and the like, an optionally mixed solvent thereof and the like) in the presence of dichloromethylmethyl ether and the like, from 0 ° C to 100 ° C for 10 minutes to 24 hours. In addition, a compound of the formula (II Be) can also be obtained by keeping a compound of the formula (IIBb) with N, N-dimethylformamide, N-methylformanilide, N-methylmorpholine, N, N-diisopropylformamide and the like, in a suitable solvent , such as a solvent that does not adversely affect the reaction (eg, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, hexamethylphosphorus triamide, benzene, toluene, xylene, chloroform, dichloroethane and the like, an optionally mixed solvent of the same and similar), or without solvent, in the presence of a halogenating agent such as phosphorus oxychloride, phosgene, oxalyl chloride, thionyl chloride and the like, from 0 ° C to 100 ° C for 10 minutes to 24 hours.

METHOD 26 Synthetic method of the compound of the formula (HBd) wherein each symbol is as defined above, which is a compound of formula (IIB) wherein Ra 'is hydroxyalkyl, aminoalkyl or monoalkylaminoalkyl. A compound of the formula (IIBe) (IIB where Ra 'is acyloxyalkyl or acylaminoalkyl) wherein each symbol is as defined above, synthesized according to method 36 that will be mentioned later, maintained with a base such as sodium hydroxide, potassium hydroxide, ammonia and the like, or an acid such as hydrochloric acid, hydrobromic acid, acetic acid, formic acid, sulfuric acid and the like, in a suitable solvent such as water and a mixed solvent of water and a suitable solvent (for example, methanol, ethanol, pyridine, dioxane and the like), of room temperature at 100 ° C for 10 minutes to 24 hours to give a compound of the formula (IIBd).

METHOD 27 Synthetic method of the compound of the formula (IIBf) wherein R27 and R28 are the same or different and each is alkyl having 1 to 4 carbon atoms, and the other symbols are as defined above, among the compounds of formula (IIB) wherein Ra 'is hydroxyalkyl . For example, a compound of the formula (IIBg) wherein each symbol is as defined above, it is maintained with an alkyl metal compound such as a compound of the formula (41) R28MgBr (41) wherein R28 is alkyl having 1 to 4 carbon atoms and the like, a suitable solvent, such as a solvent that does not adversely affect the reaction (for example, benzene, toluene, xylene, diethyl ether, tetrahydrofuran, chloroform, dichloroethane, an optionally mixed solvent thereof, and the like), from 0 ° C to 100 ° C. ° C for 10 minutes to 24 hours to give a compound of the formula (IIBf).

METHOD 28 Synthetic method of the compound of the formula (HBh) wherein each symbol is as defined above, among the compounds of the formula (IIB) wherein Ra 'is hydroxyalkyl. For example, a compound of the formula (HBi) (U Bi) wherein each symbol is as defined above, is maintained with sodium borohydride, lithium aluminum hydride and the like in a suitable solvent, such as a solvent that does not adversely affect the reaction (eg, methanol, ethanol, benzene, toluene , xylene, diethyl ether, tetrahydrofuran, chloroform, dichloroethane, an optionally mixed solvent thereof and the like), from 0 ° C to 100 ° C for 10 minutes to 24 hours to give a compound of the formula (IIBh).

METHOD 29 Synthetic method of the compound of the formula (HBi) wherein each symbol is as defined above, among the compounds of the formula (I IB) wherein Ra 'is hydroxyalkyl. For example, a compound of the formula (IIBc) is maintained with a compound of the formula (41) in a suitable solvent, such as a solvent that does not adversely affect the reaction (for example, benzene, toluene, xylene, diethyl ether, tetrahydrofuran, chloroform, dichloroethane, an optionally mixed solvent thereof and the like), from 0 ° C to 100 ° C for 10 minutes to 24 hours to give a compound of the formula (IIBj).

METHOD 30 Synthetic method of the compound of the formula (IIBk) wherein R29, R30 and R31 are the same or different and each is hydrogen or alkyl having 1 to 3 carbon atoms and the other symbols are as defined above, among the compounds of the formula (I IB) wherein Ra 'is alkenyl. Of the compounds of the formula (NB) wherein Ra 'is hydroxyalkyl, a compound of the formula (IIB1) wherein each symbol is as defined above, it is maintained in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., methanol, ethanol, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, triamide of hexamethylphosphorus, benzene, toluene, xylene, chloroform, dichloroethane and the like, an optionally mixed solvent thereof and the like), in the presence of an acid, such as hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, trichloroacetic acid and the like, from room temperature to 190 ° C to give a compound of the formula (IIBk).

METHOD 31 Synthetic method of the compound of the formula (IIBm) wherein each symbol is as defined above, among the compounds of the formula (IIB) wherein Ra 'is alkyl. A compound of the formula (UBi) is maintained with triethylsilane, lithium aluminum hydride and the like in a suitable solvent, such as a solvent that does not adversely affect the reaction (eg, trifluoroacetic acid, benzene, toluene, xylene, diethyl ether , chloroform, dichloroethane, an optionally mixed solvent thereof and the like), from 0 ° C to 100 ° C for 10 minutes to 24 hours to give a compound of the formula (IIBm).

METHOD 32 Synthetic method of the compound of the formula (HBn wherein R32 is alkyl having 2 to 5 carbon atoms and the other symbols are as defined above, which is a compound of the formula (IIB) wherein Ra 'is alkyl that is not methyl. A compound of the formula (IIBo) wherein R33 is alkenyl having 2 to 5 carbon atoms and the other symbols are as defined above, which is a compound of the formula (IIB) wherein Ra 'is alkenyl, is maintained with hydrogen in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., methanol, ethanol, ethyl acetate, dioxane, benzene, toluene, xylene, diethyl ether, chloroform, 1,2-dichloroethane, an optionally mixed solvent thereof, and the like) ), using palladium-activated carbon, palladium hydroxide, platinum oxide and the like as a catalyst, from 0 ° C to 100 ° C, and from the normal pressure to 100 atmospheres for 10 minutes to 24 hours to give a compound of the formula (IIBn).

METHOD 33 Synthetic method of the compound of the formula (HBp) wherein each symbol is as defined above, which is a compound of formula (IIB) wherein Ra 'is halogen. A compound of the formula (IIBb) is maintained with fluorine, chlorine, bromine, iodine, iodine monochloride, N-bromosuccinimide, N-iodosuccinimide and the like in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g. , acetic acid, methanol, ethanol, ethyl acetate, dioxane, benzene, toluene, xylene, diethyl ether, chloroform, 1,2-dichloroethane, an optionally mixed solvent thereof and the like) from room temperature to 100 ° C during 10 minutes to 24 hours to give a compound of the formula (IIBp).

METHOD 34 Synthetic method of the compound of the formula (IIBq) wherein Ar is aryl or heteroaryl and the other symbols are as defined above, which is a compound of the formula (IIB) wherein Ra 'is aryl or heteroaryl. A compound of the formula (IIBp) is maintained with a compound of the formula (42) Ar-Y (42) wherein Y is dihydroxyboron, diethylboryl, triethylstannyl, trimethylstannyl and the like and Ar is as defined above, and palladium tetrakistriphenylphosphine and the like, in a suitable solvent, such as a solvent which does not negatively affect the reaction (for example methanol, ethanol, ethyl acetate, dioxane, benzene, toluene, xylene, diethyl ether, chloroform, 1,2-dichloroethane, a optionally mixed solvent thereof and the like), at room temperature at 100 ° C for 10 minutes to 24 hours to give a compound of formula (IIBq).

METHOD 35 Synthetic method of compound of formula (IIBr) wherein R34 and R35 are the same or different and each is hydrogen or alkyl having 1 to 5 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl and the like and other symbols are as defined above, which is a compound of formula (I IB) wherein Ra 'is aminoalkyl, monoalkylaminoalkyl or dialkylaminoalkyl. Of the compounds of formula (IIB) wherein Ra 'is hydroxyalkyl, a compound of the formula (IIBs) where each symbol is as defined above and is maintained with a compound of the formula (43) wherein R36 is methyl, ethyl, trifluoromethyl, phenyl, 4-methylphenyl and the like and Hal is as defined above or a compound of the formula (44) wherein R, 36 is as defined above, in a suitable solvent, such as a solvent that does not negatively affect the reaction (for example benzene, toluene, xylene, chloroform, dichloroethane, pyridine, an optionally mixed solvent thereof, and the like) ), in the presence of an organic base, such as pyridine, triethylamine and the like, or an inorganic base, such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and the like, from room temperature to 170 ° C during 1 to 24 hours to give a compound of the formula (45) where each symbol is as defined above. The compound obtained from the formula (45) is maintained with a compound of the formula (46) wherein each symbol is as defined above, in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., methanol, ethanol, dioxane, benzene, toluene, xylene, diethyl ether, chloroform, dichloroethane, a solvent optionally mixed thereof and the like), from room temperature to 100 ° C for 10 minutes to 24 hours to give the compound of the formula (IIBr).

METHOD 36 Synthetic method of compound of formula (HBe) which is a compound of formula (HB) wherein Ra 'is acyloxyalkyl or acylaminoalkyl For example, the aforementioned compound of formula (IIBd), which is a compound of formula (IIB) wherein Ra 'is aminoalkyl or monoalkylaminoalkyl, is maintained with the aforementioned compound of formula (39) or (40), or ethyl formate, phenyl formate and the like, in a suitable solvent, such as a solvent which does not negatively affect the reaction (for example, benzene, toluene, xylene, chloroform, dichloroethane, pyridine, an optionally mixed solvent thereof and the like) ), from room temperature to 100 ° C from 10 minutes to 24 hours to produce the compound of formula (II Be).

METHOD 37 Synthetic method of the compound of formula (HBt) wherein each symbol is as defined above, which is a compound of formula (IIB) wherein Ra 'is nitrogen. For example, a compound of formula (IIBb) is reacted with a suitable nitrating reagent, such as concentrated nitric acid-concentrated sulfuric acid, acetyl nitrate, nitronium tetrafluoroborate and the like, from 0 ° C to 100 ° C for 10 minutes to 24 hours to produce the compound of formula (NBt).

METHOD 38 Synthetic method of the compound of formula (HBu) wherein each symbol is as defined above, which is composed of formula (IIB) wherein the substituent on ring A is amino.

A compound of formula (IIBv) which is a compound of formula (IIB) wherein the substituent on ring A is nitrogen wherein each symbol is as defined above, and is maintained with hydrogen in a suitable solvent, such as a solvent that does not negatively affect the reaction (e.g., methanol, ethanol, ethyl acetate, dioxane, benzene, toluene, xylene, diethyl ether, chloroform, 1,2-dichloroethane, an optionally mixed solvent thereof and the like), using palladium-activated carbon, palladium hydroxide, platinum oxide and the like as a catalyst, from 0 ° C to 100 ° C and normal pressure at 100 atmospheres from 10 minutes to 24 hours, to produce the compound of the formula (HBu).

METHOD 39 Synthetic method of the compound of formula (HBw) wherein Z is fluorine, chlorine, bromine, iodine or cyano and other symbols are as defined above, which is a compound of formula (IIB) wherein the substituent on ring A is cyano or halogen.

For example, a compound of the formula (II Bu) is diazotized in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., water, dilute hydrochloric acid, and the like) using sodium nitrite and the like of - 10 ° C at room temperature, and maintained with fluoroboric acid, hydrogen fluoride-pyridine, sodium chloride, cuprous chloride, sodium bromide, cuprous bromide, sodium iodide, potassium iodide and the like of -10 ° C to 100 ° C to give the compound of formula (IIBw). When the compound obtained according to the aforementioned method is to be purified as a salt of inorganic acid or organic acid, the following steps are followed. A compound of the formula (IA) or a compound of the formula (IB) is dissolved in a suitable solvent, such as methanol, ethanol, isopropyl alcohol, ethyl acetate, diethyl ether, diisopropyl ether, benzene, toluene, xylene, chloroform, methylene chloride and the like, an optionally mixed solvent thereof and the like, and inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like or organic acid such as acetic acid, acid are added. propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, ascorbic acid, maleic acid, citric acid, tartaric acid, fumaric acid and the like or a hydrate thereof . The resulting crystals were recrystallized from a suitable solvent, such as methanol, ethanol, isopropyl alcohol, ethyl acetate, diethyl ether, diisopropyl ether, benzene, toluene, xylene, chloroform, methylene chloride, dichloroethane and the like or a mixed solvent thereof to give a salt of an inorganic acid, organic acid, hydrate or solvate of a compound of the formula (IA) or a compound of the formula (IB). The compound obtained from the present invention can be purified by one or more selected methods of crystallization, chromatography, extraction and filtration. When the resulting purified compound is a racemate, a desired optically active compound can be separated, for example, by preparative recrystallization from an optically active acid, or by passing the compound through a column packed with optically active carrier. The stereoisomer can be isolated by recrystallization, column chromatography and the like. The compound of formula (I), particularly (IA) and (IB), of the present invention obtained in the aforementioned manner is useful as a novel antipsychotic agent which is effective for the symptoms of both positive and negative schizophrenia, which causes less side effects of extrapyramidal motor disorder and the like that causes less serious side effects such as agranulocytosis and the like. The compound of the invention (I), particularly (IA) and (IB), is useful as a therapeutic agent for Alzheimer's disease and manic-depressive illness. The compounds of the formulas (HA) and (I IB) are useful as important synthetic intermediates for the compounds of the formulas (IA) and (IB).

When the compound of the ula (I) is used as a pharmaceutical agent, the compound of the invention is mixed with a pharmaceutically acceptable carrier (eg, excipient, binder, disintegrant, corrective, concealer, emulsifier), diluent, solubilizer and the like to give a pharmaceutical composition by a conventional method, which is ulated into a tablet, capsule, granule, powder, syrup, suspension, solution, injection, infusion, deposition agent, suppository, and the like and administered orally or parenterally. When tablets are used oral administration, vehicles typically used include sucrose, lactose, mannitol, maltitol, dextran, corn starch and the like, typical lubricants such as magnesium stearate, preservatives such as parabens, sorbins and the like, antioxidants such as ascorbic acid, α-tocopherol, cysteine and the like, disintegrants, binders and the like. When administered orally as capsules, effective diluents include lactose and dried corn starch. A liquid oral use includes syrup, suspension, solution, emulsion and the like, which may typically comprise an inert diluent used in this field, such as water. In addition, sweeteners or flavors may also be understood. In the case of parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion and the like, the pH of the active ingredient solution is adjusted appropriately, regulated and sterilized. Examples of useful vehicle or solvent include distilled water, Ringer's solution, isotonic brine and the like. intravenous use, the total concentration of solution is adjusted to make the solution isotonic. Suppositories can be produced by mixing with a drug and a suitable non-irritating excipient such as those which are solid at normal temperature but become liquid at the temperature in the intestine and melt in the rectum to release the drug, such as cocoa butter , polyethylene glycols, and the like. The dose is determined depending on the age, body weight, time of administration, method of administration, combination of drugs, the level of condition of the patient who is going to undergo therapy and other factors. The compound of the present invention, optical isomers thereof and pharmaceutically acceptable salts thereof are slightly toxic and can be used safely. Although the daily dose varies depending on the conditions and the body weight of the patients, the type of compound, route of administration and the like, in the case of oral use, is around 0.01-300 mg / person / day, preferably 0.1 -100 mg / person / day, in the case of parenteral use conveniently about 0.01-50 mg / person / day, preferably 0.01-10 mg / person / day subcutaneous injection, intravenous injection, intramuscular injection and intrarectal injection. The present invention is explained in more detail below by the examples of synthesis of starting material, examples and experimental examples that do not limit the present invention in any aspect.

EXAMPLE 1 Synthesis of starting material Using cyclohexanone as starting material and following the method described in the publication [Archiv der Pharmazie (Weinheim), 317, 675 (1984)], ethyl 2-aminobenzo [b] thiophene-3-carboxylate was synthesized. 1 H- NMR (400 MHz, CDCl 3) d: 8.10 (d, J = 7.3 Hz, 1 H), 7.50 (d, J = 7.3 Hz, 1 H), 7.31 (t, J = 7.3 Hz, 1 H), 7.13 (t, J = 7.3 Hz, 1 H), 6.53 (br.s, 2H), 4.42 (q, J = 7.3 Hz, 2H), 1.46 (t, J = 7.3 Hz, 3H) EXAMPLE 2 Synthesis of starting material Using 3-methylcyclohexanone as a starting material and following the method described in the publication [Archiv der Pharmazie (Weinheim), 317, 675 (1984)], 2-amino-5-methylbenzo [b] thiophen-3-carboxylate was synthesized of methyl. 1 H-NMR (400 MHz, CDCl 3) d: 7.89 (s, 1H), 7.37 (d, J = 8.3 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 6.49 (br.s, 2H ), 3.95 (s, 3H), 2.43 (s, 3H).

EXAMPLE 3 Synthesis of starting material Using 4-methylcyclohexanone as a starting material and following the method described in the publication [Archiv der Pharmazie (Weinheim), 317, 675 (1984)], 2-amino-6-methylbenzo [b] thiophene-3-carboxylate was synthesized of ethyl.

Melting point: 126-128 ° C.

EXAMPLE 4 Synthesis of starting material (2 g) of ethyl 2-aminobenzo [b] thiophene-3-carboxylate and 2-fluoro-nitrobenzene (2 ml) were dissolved in N, N-dimethylformamide (150 ml) and heated to 60 ° C. Potassium carbonate (8 g) was added thereto and the mixture was stirred at 100 ° C for 18 hours. After cooling, the reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration. The crystals were washed with water and diisopropyl ether and dried at 60 ° C to produce ethyl 2- (2-nitroanilino) -benzo [b] thiophene-3-carboxylate (5.7 g). 1 H-NMR (400 MHz, CDCl 3) d: 12.2 (s, 1 H), 8.32 (d, J = 8.3 Hz, 1 H), 8.25 (d, J = 8.3 Hz, 1 H), 8.10 (d, J = 8.8 Hz, 1 H), 7.67-7.62 (m, 2H), 7.42 (t, J = 7.8 Hz, 1 H), 7.27 (m, 1 H), 7.16 (t, J = 7.8 Hz, 1 H ), 4.57 (q, J = 7.3 Hz, 2H), 1.52 (t, J = 7.3 Hz, 3H).

EXAMPLE 5 Synthesis of starting material Ethyl 2-aminobenzo [b] thiophene-3-carboxylate (69.3 g) and 2,4-difluoronitrobenzene (50 g) were dissolved in dimethyl sulfoxide (550 ml) and heated to 50 ° C. To the foregoing, potassium carbonate (63 g) was added and the mixture was stirred at 100 ° C for 70 minutes. After cooling, the reaction mixture was allowed to cool to 70 ° C and poured into water (2.5 L). The reaction mixture was allowed to settle and filtered. The orange crystals of the filtrate were washed with ethyl acetate to give ethyl 2- (5-fluoro-2-nitroanilino) benzo [b] thiophene-3-carboxylate (50.7 g). Melting point: 137-140 ° C. 1 H- NMR (400 MHz, CDCl 3) d: 12.40 (br.s, 1H), 8.33-8.29 (m, 2H), 7.79 (d, J = 7.8, 2.9 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.42 (dd, J = 8.3, 8.2 Hz, 1H), 7.29 (dd, J = 6.9, 8.3 Hz, 1H), 6.80-6.77 (m, 1H), 4.54 (q, J = 6.8 Hz , 2H), 1.49 (t, J = 6.8 Hz, 3H). IR (KBr): 3085, 2993, 1624, 1582, 1553, 1510, 1274, 1206, 1035 MS: m / e 360.

EXAMPLE 6 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using ethyl 2-aminobenzo [b] -thiophene-3-carboxylate (4.0 g), 2,4-dichloronitrobenzene (3.8 g) and dimethyl sulfoxide ( 55 ml), ethyl 2- (5-chloro-2-nitroanilino) benzo [b] thiophene-3-carboxylate (3.2 g) was obtained. 1 H NMR (400 MHz, CDCl 3) d: 12.27 (br.s, 1 H), 8.31 (d, J = 8.3 Hz, 1 H), 8.19 (d, J = 8.8 Hz, 1 H), 8.08 (s) , 1 H), 7.65 (d, J = 7.3 Hz, 1 H), 7.41 (dd, J = 7.3 Hz, 1 H), 7.28 (d, J = 7.8, 7.3 Hz, 1 H), 7.06 (d, 8.3 Hz, 1 H), 4.54 (q, J = 7.3 Hz, 2H), 1.49 (t, J = 7.3 Hz, 3H).

EXAMPLE 7 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using ethyl 2-aminobenzo [b] thiophene-3-carboxylate 2,4-dibromonitrobenzene and dimethyl sulfoxide, 2- (5-bromo-2- nitroanilino) benzo [b] thiophene-3-carboxylic acid ethyl ester.

EXAMPLE 8 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using ethyl 2-aminobenzo [b] thiophene-3-carboxylate 2,5-difluoronitrobenzene and dimethyl sulfoxide, 2- (4-fluoro-2 -nitroanilino) benzo [b] thiophene-3-carboxylic acid ethyl ester.

EXAMPLE 9 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using ethyl 2-aminobenzo [b] thiophene-3-carboxylate (4.0 g), 4-fluoro-3-nitrotoluene (3.3 g) and dimethyl sulfoxide (55 ml), ethyl 2- (4-methyl-2-nitroanilino) benzo [b] thiophene-3-carboxylate (6.5 g) was obtained. 1 H- NMR (400 MHz, CDCl 3) d: 12.06 (br.s 1 H), 8.27 (d, J = 8.3 Hz, 1 H), 8.01 (s, 1 H), 7.95 (d, J = 8.8 Hz, 1 H), 7.58 (d, J = 7.3 Hz, 1 H), 7.44 (d, J = 8.3 Hz, 1 H), 7.38 (dd, J = 8.8, 8.3 Hz, 1 H), 7.21 (d, J = 7.3 Hz, 1 H), 4.53 (q, J = 7.3 Hz, 2.40 (s, 3H), 1.49 (t, J = 7.3 Hz, 3H).

EXAMPLE 10 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using ethyl 2-aminobenzo [b] -thiophene-3-carboxylate, 2,4,5-trifluoronitrobenzene and dimethyl sulfoxide, 2- (4 Ethyl 5-difluoro-2-nitroanilino) benzo [b] thiophene-3-carboxylate.

EXAMPLE 11 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using ethyl 2-aminobenzo [b] thiophene-3-carboxylate, 2,4,6-trifluoronitrobenzene and dimethyl sulfoxide, 2- (3, Ethyl 5-difluoro-2-nitroanilino) benzo [b] thiophene-3-carboxylate.

EXAMPLE 12 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using ethyl 2-aminobenzo [b] thiophene-3-carboxylate, 2-fluoro-5-methoxynitrobenzene and dimethyl sulfoxide, 2- (4- ethyl methoxy-2-nitroanilino) benzo [b] thiophene-3-carboxylate.

EXAMPLE 13 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using ethyl 2-amino-6-methylbenzo [b] thiophene-3-carboxylate (4.5 g), 2,4-difluoronitrobenzene (3.1 g) and sulfoxide of dimethyl, ethyl 2- (5-fluoro-2-nitroanilino) -6-methylbenzo [b] thiophene-3-carboxylate (5.1 g) was obtained.

Melting point: 147-149 ° C.

EXAMPLE 14 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using methyl 2-amino-5-methylbenzo [b] thiophene-3-carboxylate, 2-fluoronitrobenzene and dimethyl sulfoxide, 2- (2- Nitroanilino-5-methyl-benzo [b] thiophene-3-carboxylic acid methyl ester.

EXAMPLE 15 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using methyl 2-amino-5-methylbenzo [b] thiophene-3-carboxylate (3.11 g), 2,4-difluoronitrobenzene (1.54 ml) and sulfoxide of dimethyl (30 ml), methyl 2- (5-fluoro-2-nitroanilino) -5-methylbenzo [b] thiophene-3-carboxylate was obtained. 1 H NMR (400 MHz, CDCl 3) d: 12.44 (br.s, 1 H), 8.34 (dd, J = 9.3, 3.4 Hz, 1 H), 8.14 (s, 1 H), 7.82 (d, J = 8.3 Hz, 1 H), 7.55 (d, J = 7.8 Hz, 1 H), 7.14 (d, J = 8.3 Hz, 1 H), 6.83-6.78 (m, 1 H), 4.09 (s, 3H), 2.49 (s, 3H).

EXAMPLE 16 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using ethyl 2-amino-6-methoxybenzo [b] thiophene-3-carboxylate, 2-fluoronitrobenzene and dimethyl sulfoxide, 6-methoxy-2 was obtained - ethyl (2-nitroanilino) benzo [b] thiophene-3-carboxylate.

EXAMPLE 17 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using ethyl 2-amino-6-methoxybenzo [b] thiophene-3-carboxylate, 2,4-fluoronitrobenzene and dimethyl sulfoxide, ethyl 2- (5-fluoro-2-nitroanilino) -6-methoxybenzo [b] thiophene-3-carboxylate was obtained.

EXAMPLE 18 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using ethyl 6-bromo-2-aminobenzo [b] thiophene-3-carboxylate (8.8 g), 2,4-difluoronitrobenzene (5.6 g) and sulfoxide of dimethyl (100 ml), ethyl 6-bromo-2- (5-fluoro-2-nitroanilino) benzo [b] thiophene-3-carboxylate (10 g) was obtained. 1 H NMR (400 MHz, CDCl 3) d: 12.35 (s, 1 H), 8.31 (dd, 1 H), 8.17 (d, J = 8.8 Hz, 1 H), 7.76-7.71 (m, 2H), 7.50 (d, J = 8.8 Hz, 1 H), 6.82 (dd, 1 H), 4.53 (q, J = 7.3 Hz, 2H), 1.48 (t, J = 7.3 Hz, 3H).

EXAMPLE 19 Synthesis of starting material Ethyl 2- (2-nitroanilino) benzo [b] thiophene-3-carboxylate (4.9 g) was dissolved in ethyl acetate (200 ml) and 10% palladium-carbon (0.5 g) was added. The mixture was stirred with hydrogen (60kg / cm2) at 60 ° C for 5 hours. The reaction mixture was cooled and the catalyst was filtered. The filtrate was evaporated under reduced pressure to give ethyl 2- (2-aminoanilino) benzo [b] thiophene-3-carboxylate (3.5g). 1 H NMR (400 MHz, CDCl 3) d: 9.61 (s, 1 H), 8.14 (d, J = 7.8 Hz), 7.47 (d, J = 7.8 Hz, 1 H), 7.33-7.35 (m, 2H) , 7.10-7.12 (m, 2H), 6.80-6.86 (m, 2H), 4.47 (q, J = 7.3 Hz, 2H), 3.88 (br.s, 2H), 1.50 (t, J = 7.3 Hz, 3H ).

EXAMPLE 20 Synthesis of starting material Ethyl 2- (5-fluoro-2-nitroanilino) benzo [b] thiophene-3-carboxylate (4.9 g) was dissolved in ethyl acetate (1000 ml) and 10% palladium-carbon (8.0 g) was added. The mixture was stirred with hydrogen (60kg / cm2) at 55 ° C for 5 hours. The reaction mixture was cooled and the catalyst was filtered. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform) to give ethyl 2- (2-amino-5-fluoroanilino) benzo [b] thiophene-3-carboxylate (24.5 g). melting point: 141 ° C-142 ° C 1 H-NMR (400 MHz, CDCl 3) d: 9.87 (s, 1 H), 8.14 (d, J = 8.8 Hz, 1 H), 7.50 (d, J = 7.3 Hz, 1 H), 7.31-7.35 (m, 2H), 7.19-7.11 (m, 2H), 6.75-6.85 (m, 2H), 3.69 (br.s, 2H), 4.45 (q, J = 7.3 Hz , 2H), 1.48 (t, J = 7.3 Hz, 3H). IR (KBr): 3417, 3353, 3234, 2994, 1633, 1605, 1551, 1479, 1384, 1235, 1039 cm'1. MS: m / e 330.

EXAMPLE 21 Synthesis of starting material Ethyl 2- (5-chloro-2-nitroanilino) benzo [b] thiophene-3-carboxylate (3.2 g) was suspended in ethanol (40 ml) and a solution obtained by dissolving tin chloride dihydrate (7.7 g) was added. in ethanol (50 ml) and 18% hydrochloric acid (50 ml) with stirring of the mixture. The mixture was stirred at 60 ° C for 2 hours and cooled to 30 ° C. Potassium carbonate was added until the reaction mixture was basified. After filtering through celite, the filtrate was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. After natural filtration, the solvent was evaporated under reduced pressure to give ethyl 2- (2-amino-5-chloroanilino) benzo [b] thiophene-3-carboxylate (2.6g). 1 H NMR (400 MHz, CDCl 3) d: 9.71 (s, 1 H), 8.14 (d, J = 8.3 Hz, 1 H), 7.51 (d, J = 7.3 Hz, 1 H), 7.38 (s, 1 H), 7.36 (t, J = 7.3 Hz, 1 H), 7.15 (dd, J = 7.8, 7.3 Hz, 1 H), 7.09 (d, J = 7.8 Hz, 1 H), 6.77 (d, J = 8.3 Hz, 1 H), 4.47 (q, J = 7.3 Hz, 2H), 3.88 (br. S, 2H), 1.50 (t, J = 7.3 Hz, 3H).

EXAMPLE 22 Synthesis of starting material In the same manner as in Example 19 of synthesis of starting material and using ethyl 2- (5-chloro-2-nitroanilino) benzo [b] thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg / cm2), ethyl 2- (2-amino-5-chloroanilino) benzo [b] thiophene-3-carboxylate was obtained.

EXAMPLE 23 Synthesis of starting material In the same manner as in Example 19 of synthesis of starting material and using ethyl 2- (5-bromo-2-nitroanilino) benzo [b] thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg / cm2), ethyl 2- (2-amino-5-bromoanilino) benzo [b] thiophene-3-carboxylate was obtained.

EXAMPLE 24 Synthesis of starting material In the same manner as in Example 19 of synthesis of starting material and using ethyl 2- (4-fluoro-2-nitroanilino) benzo [b] thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg / cm2), ethyl 2- (2-amino-4-fluoroanilino) benzo [b] thiophene-3-carboxylate was obtained.

EXAMPLE 25 Synthesis of starting material In the same manner as in Example 19 of synthesis of starting material and using ethyl 2- (4-methyl-2-nitroanilino) benzo [b] thiophene-3-carboxylate (6.5 g), ethyl acetate (140 ml) ), 10% palladium-carbon and hydrogen (500 mg, 60 atmospheres kg / cm2), ethyl 2- (2-amino-4-methylanilino) benzo [b] thiophen-3-carboxylate (3.7 g) was obtained. 1 H- NMR (400 MHz, CDCl 3) d: 9.46 (br.s, 1 H), 8.12 (d, J = 8.3 Hz, 1 H), 7.45 (d, J = 7.3 Hz, 1 H), 7.33 (dd) , J = 7.8, 7.3 Hz, 1 H), 7.18 (d, J = 8.3 Hz, 1 H), 7.10 (d, J = 7.8, 8.3 Hz, 1 H), 6.67 (s, 1 H), 6.63 ( d, J = 7.8 Hz, 1 H), 4.46 (q, J = 7.3 Hz, 2H), 3.83 (br. s, 2H), 1.56 (s, 3H), 1.26 (t, J = 7.3 Hz, 3H) .

EXAMPLE 26 Synthesis of starting material In the same manner as in Example 19 of synthesis of starting material and using ethyl 2- (4,5-difluoro-2-nitroanilino) benzo [b] thiophene-3-carboxylate, ethyl acetate, palladium-carbon 10% and hydrogen (60 atm kg / cm2), ethyl 2- (2-amino-4,5-difluoroanilino) benzo [b] thiophene-3-carboxylate was obtained.

EXAMPLE 27 Synthesis of starting material In the same manner as in Example 19 of synthesis of starting material and using ethyl 2- (3,5-difluoro-2-nitroanilino) benzo [b] thiophene-3-carboxylate, ethyl acetate, palladium-carbon 10% and hydrogen (60 atm kg / cm2), ethyl 2- (2-amino-3,5-difluoroanilino) benzo [b] thiophene-3-carboxylate was obtained.

EXAMPLE 28 Synthesis of starting material In the same manner as in Example 19 of synthesis of starting material and using ethyl 2- (4-methoxy-2-nitroanilino) benzo [b] thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg / cm2), ethyl 2- (2-amino-4-methoxyanilino) benzo [b] thiophene-3-carboxylate was obtained.

EXAMPLE 29 Synthesis of starting material In the same manner as in Example 19 of synthesis of starting material and using ethyl 2- (5-fluoro-2-nitroanilino) -6-methylbenzo [b] thiophene-3-carboxylate (1.9 g), ethyl acetate (200 ml), 10% palladium-carbon (0.4 g) and hydrogen (60 atm kg / cm2), 2- (2-amino-5-fluoroanilino) -6-methylbenzo [b] thiophen-3-carboxylate was obtained of ethyl (1.54 g). melting point: 174-175 ° C.

EXAMPLE 30 Synthesis of starting material In the same manner as in Example 19 of synthesis of starting material and using methyl 2- (5-fluoro-2-nitroanilino) -5-methylbenzo [b] thiophene-3-carboxylate, ethyl acetate, palladium-carbon to 10% and hydrogen (60 atm kg / cm2), methyl 2- (2-amino-5-fluoroanilino) -5-methylbenzo [b] thiophene-3-carboxylate was obtained.

EXAMPLE 31 Synthesis of starting material In the same manner as in Example 19 of synthesis of starting material and using methyl 2- (5-fIuoro-2-nitroanilino) -5-methylbenzo [b] thiophene-3-carboxylate (4.42 g), ethyl acetate (400 ml), 10% palladium-carbon and hydrogen (400 mg, 60 atm kg / cm2), 2- (2-amino-5-fluoroanilino) -5-methylbenzo [b] thiophene-3-carboxylate was obtained from methyl (1.82 g). 1 H NMR (400 MHz, CDCl 3) d: 9.84 (s, 1 H), 7.94 (s, 1 H), 7.40 (d, J = 7.8 Hz, 1 H), 7.19 (d, J = 9.3 Hz, 1 H), 6.98 (d, J = 8.3 Hz, 1 H), 6.86-6.77 (m, 2H), 4.01 (s, 3H), 3.69 (br.s, 2H), 2.45 (s, 3H).

EXAMPLE 32 Synthesis of starting material In the same manner as in Example 19 of synthesis of starting material and using ethyl 6-methoxy-2- (2-nitroanilino) benzo [b] thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg / cm2), ethyl 2- (2-aminanilino) -6-methoxy-benzo [b] thiophene-3-carboxylate was obtained.

EXAMPLE 33 Synthesis of starting material In the same manner as in Example 19 of synthesis of starting material and using ethyl 2- (5-fluoro-2-nitroanilino) -6-methoxybenzo [b] thiophene-3-carboxylate, ethyl acetate, palladium-carbon at 10% and hydrogen (60 atm kg / cm2), ethyl 2- (2-amino-5-fluoroanilino) -6-methoxybenzo [b] thiophene-3-carboxylate was obtained.

EXAMPLE 34 Synthesis of starting material In the same manner as in Example 21 of synthesis of starting material and using ethyl 6-bromo-2- (5-fluoro-2-nitroanilino) -benzo [b] thiophene-3-carboxylate (10 g), ethanol (80 ml), tin (II) chloride dihydrate (20.6 g), ethanol (80 ml) and 18% hydrochloric acid (80 ml), 6-bromo-2- (2-amino-5-fluoroanilino) was obtained ethyl benzo [b] thiophene-3-carboxylate (3.8 g). 1 H NMR (400 MHz, CDCl 3) d: 9.81 (s, 1 H), 7.98 (d, J = 8.8 Hz, 1 H), 7.60 (s, 1 H), 7.41 (d, J = 8.8 Hz, 1 H), 7.13 (d, J = 9.3 Hz, 1 H), 6.84-6.76 (m, 2 H), 4.44 (q, J = 7.3 Hz, 2 H), 3.75 (br. S, 2 H), 1.47 (t, J = 7.3 Hz, 3H).

EXAMPLE 35 Synthesis of starting material In addition, in the same manner as in Example 19 of synthesis of starting material and using ethyl 6-bromo-2- (5-fluoro-2-nitroanilino) benzo [b] thiophene-3-carboxylic acid ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg / cm2), ethyl 6-bromo-2- (2-amino-5-fluoroanilino) benzo [b] thiophene-3-carboxylate was obtained.

EXAMPLE 36 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using ethyl 2-aminobenzo [b] thiophene-3-carboxylate (6.0 g), 2,5-dichloronitrobenzene (5.8 g) and dimethyl sulfoxide (70 ml), crude crystals (9.5 g) of 2- (4-chloro-2-nitroanilino) -benzo [b] thiophene-3-carboxylate were obtained. ethyl. Without purification, in the same manner as in Example 21 of synthesis of starting material and using ethanol (100 ml), 18% hydrochloric acid (100 ml) and tin (II) chloride dihydrate (22.5 g), was obtained 2- (2-amino-4-chloroanilino) -benzo [b] thiophene-3-carboxylic acid ethyl ester (3.0 g). 1 H-NMR (400 MHz, CDCl 3) d: 9.51 (s, 1 H), 8.11 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1 H), 7.29 (dd, J = 7.3, 8.3 Hz, 1 H), 7.23 (d, J = 8.3 Hz, 1 H), 7.11 (dd, J = 7.3, 3.8 Hz, 1 H), 6.81 (s, 1 H), 6.75 (d, J = 8.3 Hz, 1 H), 4.45 (q, J = 7.3 Hz, 2H), 3.95 (br.s, 2H), 1.48 (t, J = 7.3 Hz, 3H).

EXAMPLE 37 Synthesis of starting material In the same manner as in Example 19 of synthesis of starting material and using ethyl 2- (4-chloro-2-nitroanilino) benzo [b] thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg / cm2), ethyl 2- (2-amino-4-chloroanilino) benzo [b] thiophene-3-carboxylate was obtained.

EXAMPLE 38 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using ethyl 2-aminobenzo [b] thiophene-3-carboxylate (6.0 g), 2,5-dibromonitrobenzene (8.5 g) and dimethyl sulfoxide (70 mi), crude crystals (7.3 g) of ethyl 2- (4-bromo-2-nitroanilino) -benzo [b] thiophene-3-carboxylate were obtained. Without purification, in the same manner as in Example 21 of synthesis of starting material and using ethanol (70 ml), 18% hydrochloric acid (70 ml) and tin (II) chloride dihydrate (15.7 g), Ethyl 2- (2-amino-4-bromoanilino) -benzo [b] thiophene-3-carboxylate (3.3 g). 1 H-NMR (400 MHz, CDCl 3) d: 9.52 (s, 1 H), 8.11 (d, 1 H), 7.46 (d, J = 8.3 Hz, 1 H), 7.31 (dd, 1 H), 7.18 ( d, J = 8.3 Hz, 1 H), 7.11 (dd, 1 H), 6.99 (s, 1 H), 6.90 (d, 1 H), 4.44 (q, J = 7.3 Hz, 2H), 3.94 (br .s, 2H), 1.48 (t, J = 7.3 Hz, 3H).

EXAMPLE 39 Synthesis of starting material In the same manner as in Example 19 of synthesis of starting material and using ethyl 2- (4-bromo-2-nitroanilino) benzo [b] thiophene-3-carboxylate, ethyl acetate, palladium-carbon 10% and hydrogen (60 atm kg / cm2), ethyl 2- (2-amino-4-bromoanilino) benzo [b] thiophene-3-carboxylate was obtained.

EXAMPLE 40 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using ethyl 2-aminobenzo [b] thiophene-3-carboxylate (3 g), 3-fluoro-4-nitrotoluene (2.1 g) and dimethyl sulfoxide (25 ml), 2- (5-methyl-2-nitroaniiino) benzo [b] thiophene-3-carboxylic acid ethyl ester (5.4 g) was obtained. Without purification, in the same manner as in Example 19 of synthesis of starting material and using 10% palladium-carbon (1.5 g), 2- (2-amino-5-methylanilino) benzo [b] thiophene was obtained. 3-ethyl carboxylate (1.6 g). 1 H-NMR (400 MHz, CDCl 3) d: 9.61 (s, 1 H), 8.14 (d, J = 7.8 Hz, 1 H), 7.47 (d, J = 7.8 Hz, 1 H), 7.32 (dd, J = 7.8, 7.8 Hz, 1 H), 7.13 (s, 1 H), 7.10 (dd, J = 7.8, 7.8 Hz, 1 H), 6.95 (d, J = 7.8 Hz, 1 H), 6.76 (d, J = 7.8 Hz, 1 H), 4.46 (q, J = 7.3 Hz, 2H), 3.73 (br.s, 2H), 2.28 (s, 3H), 1.50 (t, J = 7.3 Hz, 3H).

EXAMPLE 41 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using ethyl 2-amino-6-methylbenzo [b] thiophene-3-carboxylate (4.18 g), 2-fluoronitrobenzene (2.5 g) and dimethyl sulfoxide (50 ml), crude crystals (7.5 g) of ethyl 6-methyl-2- (2-nitroanilino) benzo [b] thiophene-3-carboxylate were obtained. Without purification, in the same manner as in Example 21 of synthesis of starting material and using ethanol (50 ml), 18% hydrochloric acid (70 ml) and tin (II) chloride dihydrate (16 g), was obtained 2- (2-aminoanilino) -6-methylbenzo [b] thiophen-3-carboxylic acid ethyl ester (3.7 g). 1 H-NMR (400 MHz, CDCl 3) d: 9.53 (br.s, 1 H), 7.99 (d, J = 8.3 Hz, 1 H), 7.32 (d, J = 7.8 Hz, 1 H), 7.25 (s) , 1 H), 7.13 (m, 2H), 6.83-6.80 (m, 2H), 4.44 (q, J = 7.3 Hz, 2H), 3.86 (br.s, 2H), 2.37 (s, 3H), 1.47 (t, J = 7.3 Hz, 3H).

EXAMPLE 42 Synthesis of starting material In the same manner as in Example 19 of synthesis of starting material and using ethyl 6-methyl-2- (2-nitroanilino) benzo [b] thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg / cm2), ethyl 2- (2-aminoanilino) -6-methylbenzo [b] thiophen-3-carboxylate was obtained.

EXAMPLE 43 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using ethyl 2-aminobenzo [b] thiophene-3-carboxylate (6.0 g), 2,4,5-trichloronitrobenzene (6.8 g) and dimethyl sulfoxide (70 ml), crude crystals (10.3 g) of ethyl 2- (4,5-dichloro-2-nitroanilino) benzo [b] thiophene-3-carboxylate were obtained. Without purification, in the same manner as in Example 21 of synthesis of starting material and using ethanol (100 ml), 18% hydrochloric acid (100 ml) and tin (II) chloride dihydrate (22.8 g), 2- was obtained (2-amino-4,5-dichloroanilino) benzo [b] thiophene-3-carboxylic acid ethyl ester (5.3 g). 1 H-NMR (400 MHz, CDCl 3) d: 9.33 (s, 1 H), 8.15 (d, J = 7.3 Hz, 1 H), 7.44 (d, J = 7.8 Hz, 1 H), 7.32 (dd, J = 7.8, 7.3 Hz, 1 H), 7.25 (d, J = 8.8 Hz, 1 H), 7.12 (d, J = 7.8, 7.3 Hz, 1 H), 6.69 (d, J = 8.8, 1 H), 4.47 (q, J = 7.3 Hz, 2H), 4.10 (br.s, 2H), 1.49 (t, J = 7.3 Hz, 3H).

EXAMPLE 44 Synthesis of starting material In the same manner as in Example 19 of synthesis of starting material and using ethyl 2- (4,5-dichloro-2-nitroanilino) benzo [b] thiophen-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg / cm2), ethyl 2- (2-amino-4,5-dichloroanilino) benzo [b] thiophene-3-carboxylate was obtained.

EXAMPLE 45 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using ethyl 2-aminobenzo [b] thiophene-3-carboxylate (6.6 g), 2,3,4-tridoronitrobenzene (7.0 g) and dimethyl sulfoxide (70 ml), crude crystals (12 g) of ethyl 2- (2,3-dichloro-6-nitroanilino) benzo [b] thiophene-3-carboxylate were obtained. Without purification, in the same manner as in Example 21 of synthesis of starting material and using ethanol (40 ml), 18% hydrochloric acid (60 ml) and tin (II) chloride dihydrate (24.6 g), Ethyl 2- (6-amino-2,3-dichloroanilino) benzo [b] thiophene-3-carboxylate (4.2 g).

EXAMPLE 46 Synthesis of starting material In the same manner as in Example 19 of synthesis of starting material and using ethyl 2- (2,3-dichloro-6-nitroanilino) benzo [b] thiophene-3-carboxylate, ethyl acetate, palladium-carbon 10% and hydrogen (60 atm kg / cm2), ethyl 2- (6-amino-2,3-dichloroanilino) benzo [b] thiophene-3-carboxylate was obtained.

EXAMPLE 47 Synthesis of starting material In the same manner as in Example 4 of synthesis of starting material and using ethyl 2-aminobenzo [b] thiophene-3-carboxylate (5.0 g), 4-fluoro-3-nitrobenzotrifluoride (5.1 g) and dimethyl sulfoxide (65 ml), ethyl 2- (2-nitro-4-trifluoromethylanilino) benzo [b] thiophene-3-carboxylate (12 g) was obtained. Without purification, in the same manner as in Example 21 of synthesis of starting material and using ethanol (50 ml), 18% hydrochloric acid (50 ml) and tin (II) chloride dihydrate (10.9 g), was obtained 2- (2-amino-4-trifluoromethylanilino) benzo [b] thiophene-3-carboxylic acid ethyl ester (2.8 g). 1 H-NMR (400 MHz, CDCl 3) d: 9.93 (br.s, 1 H), 8.16 (d, J = 8.3 Hz, 1H), 7.52 (m, 2H), 7.36 (dd, J = 7.3, 8.3 Hz, 1H), 7.17 (d, J = 7.3, 6.9 Hz, 1 H), 7.08 (m, 2H), 4.48 (q, J = 7.3 Hz, 2H), 4.08 (br.s, 2H), 1.51 ( t, J = 7.3 Hz, 3H).

EXAMPLE 48 Synthesis of starting material In the same manner as in Example 19 of synthesis of starting material and using ethyl 2- (2-amino-4-trifluoromethylanilino) benzo [b] thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg / cm2), ethyl 2- (2-amino-4-trifluoromethylanilino) benzo [b] thiophene-3-carboxylate was obtained.

EXAMPLE 49 Synthesis of starting material Ethyl 2- (2-nitroanilino) benzo [b] thiophene-3-carboxylate (6.0 g) was dissolved in N, N-dimethylformamide (120 ml) and the mixture was stirred at 0 ° C, during which time ter- potassium butoxide by portions (3.0 g). Methyl iodide (12.4 g) was added dropwise under cooling with ice and the mixture was stirred at 0 ° C for 5 minutes and warmed to room temperature. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. After natural filtration, the solvent was evaporated under reduced pressure, and the residue was separated by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give crude crystals (2.8 g) of 2- ( N-methyl-2-nitroanilino) benzo [b] thiophene-3-carboxylic acid ethyl ester. Without purification, the crystals were treated in the same manner as in Example 21 of the synthesis of starting material using ethanol (50 ml), 18% hydrochloric acid (50 ml) and tin (II) chloride dihydrate (12.6 g) to produce ethyl 2- (2-amino-N-methylanilino) benzo [b] thiophene-3-carboxylate (3.2 g). 1 H-NMR (400 MHz, CDCl 3) d: 8.07 (d, 1H), 7.49 (d, 1H), 7.30-7.24 (m, 2H), 7.13-7.08 (m, 2H), 6.79-6.74 (m, 2H ), 4.26 (q, J = 7.3 Hz, 2H), 4.10 (br.s, 2H), 3.36 (s, 3H), 1.33 (t, J = 7.3 Hz, 3H).

EXAMPLE 1 Ethyl 2- (2-aminoanilino) benzo [b] thiophene-3-carboxylate was dissolved (3.5 g) and 1-methylpiperazine (20 ml) in anisole (50 ml), titanium tetrachloride (3.1 ml) was added by dropping while stirring the mixture at room temperature. After the dropwise addition was complete, the mixture was stirred at 140 ° C for 20 hours. The reaction mixture was cooled to 80 ° C and poured into ice water. The resulting precipitate was filtered. The filtrate was extracted with ethyl acetate (900 mL), washed with saturated brine, and dried over MgSO. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) and the obtained oily substance was dissolved in ethyl acetate (50 ml), to which was added a solution (10 ml) of maleic acid ( 580 mg) in ethyl acetate. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate / methanol to give 12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [2-maleate] 1, 5] -benzodiazepine (1.14 g). Melting point 248-249 ° C (decomposition).

EXAMPLE 2 Ethyl 2- (2-amino-5-fluoroanilino) benzo [b] thiophene-3-carboxylate (24.5 g) and 1-methylpiperazine (135 ml) were dissolved in anisole (400 ml), and titanium tetrachloride ( 21 ml) by dripping at the same time that the mixture was stirred at room temperature. After the dropwise addition was complete, the mixture was stirred at 140 ° C for 17 hours. The reaction mixture was cooled to 80 ° C and poured into ice water. The resulting precipitate was filtered. The filtrate was extracted with ethyl acetate, washed with saturated brine, and dried over MgSO. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) and the obtained oily substance (17 g) was dissolved in ethyl acetate (400 ml). To the above was added a solution of maleic acid (5.9 g) in ethyl acetate and ethanol (20 ml). The precipitated crystals were collected by filtration and recrystallized from ethanol to give 1 -maleate of 8-fIuoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [ 1, 5] benzodiazepine (10.2 g). Melting point 225-227 ° C (decomposition). 1 H-NMR (400 MHz, DMSO-d 6) d: 8.35 (s, 1 H), 7.82 (d, J = 7.8 Hz, 1 H), 7.74 (br, 1 H), 7.37 (dd, J = 8.3, 6.8 Hz, 1 H), 7.25 (dd, J = 8.3, 6.8 Hz, 1 H), 6.89 (dd, 1H), 6.78 (dd, 1 H), 6.63 (dd, 1 H), 6.03 (s) , 2H), 2.5-4.5 (br.s, 8H), 2.82 (s, 3H). IR (KBr): 3435, 3283, 3060, 2837, 2614, 1616, 1580, 1463, 1387, 1353, 1152, 966, 865 cm "1 MS: m le 366. Analysis calculated for: C2oH? 9FN4SaC4H404: C, 59.74; H, 4.80; N, 11.61%. Found: C, 59.71; H, 4.82; N, 11.46%.

EXAMPLE 3 Alternatively, using 2 equivalents of maleic acid, dimaleate monohydrate was obtained from 8-fluoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine. Melting point 123-125 ° C (decomposition).

EXAMPLE 4 Alternatively, using fumaric acid instead of maleic acid, 1/2 fumarate of 8-fluoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [ 1, 5] benzodiazepine (494 mg). Melting point 193-195 ° C (decomposition).

EXAMPLE 5 Alternatively, using 2 equivalents of hydrochloric acid instead of maleic acid, 2-hydrochloride of 8-fluoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] was obtained [1, 5] benzodiazepine 3 hydrated. Melting point 268-270 ° C (decomposition).

EXAMPLE 6 In the same manner as in Example 1 and using ethyl 2- (2-amino-5-methylanilino) benzo [b] thiophene-3-carboxylate (1.6 g), 1-methylpiperazine (8 ml), anisole (25 ml) ), titanium tetrachloride (1.3 ml) and maleic acid (100 mg), 3/2 8-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno maleate was obtained [2,3 -b] [1,5] -benzodiazepine (166 mg). Melting point 198-201 ° C (decomposition).

EXAMPLE 7 In the same manner as in example 1 and using ethyl 2- (2-amino-5-chloroanilino) benzo [b] thiophene-3-carboxylate (2.6 g), 1-methylpiperazine (15 ml), anisole (50 ml) ), and titanium tetrachloride (2.3 ml), was obtained 8-chloro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine ( 363 mg). Melting point 87-90 ° C (decomposition).

EXAMPLE 8 In the same manner as in example 1 and using ethyl 2- (2-amino-5-bromoanilino) benzo [b] thiophene-3-carboxylate, 1-methylpiperazine, anisole, and titanium tetrachloride, 8-bromine was obtained -12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine.

EXAMPLE 9 In the same manner as in example 1 and using ethyl 2- (2-amino-4-fluoroanilino) benzo [b] thiophene-3-carboxylate, 1-methylpiperazine, anisole, and titanium tetrachloride, 9-fluoro was obtained -12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine.

EXAMPLE 10 In the same manner as in example 1 and using ethyl 2- (2-amino-4-methylanilino) benzo [b] thiophene-3-carboxylate (3.7 g), 1-methylpiperazine (19 ml), anisole (60 ml) ), and titanium tetrachloride (3.0 ml), there was obtained 9-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine ( 1.18 g).

Melting point: 184-186 ° C: Analysis calculated for: C2? H22N4S: C, 69.58; H, 6.12; N, 15.46%. Found: C, 69.45; H, 6.20; N, 15.11%.

EXAMPLE 11 In the same manner as in Example 1 and using ethyl 2- (2-amino-4-chloroaniino) benzo [b] thiophene-3-carboxylate (3.0 g), 1-methylpiperazine (17 ml), anisole (75 ml) ), titanium tetrachloride (2.9 ml) and maleic acid, 2 maleate of 9-chloro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepine 1/2 hydrated (1.37 g). Melting point: 105-107 ° C (decomposed): Analysis calculated for: C20H? 9N4S32C4H4O431 / 2H2O: C, 53.89; H, 4.52; N, 8.98%. Found: C, 53.94; H, 4.45; N, 9.00%.

EXAMPLE 12 In the same manner as in example 1 and using ethyl 2- (2-amino-4-bromoanilino) benzo [b] thiophene-3-carboxylate (3.3 g), 1-methylpiperazine (17 ml), anisole (75 ml) ), titanium tetrachloride (3.0 ml) and maleic acid, 2 maleate of 9-bromo-12- (4-metiipiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepine. Melting point: 113-114 ° C (decomposition) Analysis calculated for: C20H19BrN4S? 2C4H O4: C, 50.99; H, 4.13; N, 8.50%. Found: C, 50.73; H, 4.15; N, 8.60%.

EXAMPLE 13 In the same manner as in Example 1 and using ethyl 2- (2-amino-4-methoxy-anilino) benzo [b] thiophene-3-carboxylate, 1-methylpiperazine, anisole, and titanium tetrachloride, there was obtained -methoxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine.

EXAMPLE 14 In the same manner as in example 1 and using ethyl 2- (2-amino-4,5-difluoroanilino) benzo [b] thiophene-3-carboxylate, 1-methylpiperazine, anisole, and titanium tetrachloride, there was obtained , 9-difluoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine.

EXAMPLE 15 In the same manner as in example 1 and using ethyl 2- (2-amino-3,5-difluoroanilino) benzo [b] thiophene-3-carboxylate, 1-methylpiperazine, anisole, and titanium tetrachloride, there was obtained , 10-difluoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine.

EXAMPLE 16 In the same manner as in example 1 and using ethyl 2- (2-aminoanilino) -6-methylbenzo [b] thiophene-3-carboxylate (3.7 g), 1-methylpperazine (80 ml), anisole (16 ml) , and titanium tetrachloride (3 mL), was obtained 3-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine (1.4 g). 1 H-NMR (400 MHz, CDCl 3) d: 7.65 (d, J = 8.3 Hz, 1 H), 7.38 (s, 1 H), 7.12 (d, J = 8.3 Hz, 1 H), 7.03 (t, J = 7.8 Hz, 1 H), 6.97 (dd, J = 7.3, 7.8 Hz, 1 H), 6.86 (dd, J = 7.3, 5.9 Hz, 1 H), 6.64 (d, J = 7.8 Hz, 1 H), 5.10 (br.s, 1 H), 4.20-1.75 (m, 8H), 2.38 (s, 3H), 2.33 (s, 3H).

EXAMPLE 17 In the same manner as in Example 1 and using ethyl 2- (2-amino-5-fluoroanilino) -6-methylbenzo [b] thiophene-3-carboxylate, 1-methylpiperazine, anisole, titanium tetrachloride and hydrochloric acid, 2-hydrochloride of 8-fluoro-3-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine 3/2 hydrate was obtained. Melting point: 273-275 ° C (decomposition).

EXAMPLE 18 In the same manner as in Example 1 and using methyl 2- (2-aminoanilino) -5-methylbenzo [b] thiophene-3-carboxylate, 1-methylpiperazine, anisole, and titanium tetrachloride, 2-methyl- 12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine.

EXAMPLE 19 In the same manner as in example 1 and using methyl 2- (2-amino-5-fluoroanilino) -5-methylbenzo [b] thiophene-3-carboxylate (1.82 g), 1-methylpiperazine (9.7 ml), anisole (30ml), titanium tetrachloride (1.51ml) and maleic acid, 8-fluoro-2-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] was obtained. [1,5] -benzodiazepine. 1 Maleic acid 1/2 H20 (928 mg). Melting point: 199-201 ° C (decomposition) Analysis calculated for: C2? H2? FN4S «C4H4O4« 1 / 2H2O: C, 59.39; H, 5.18; N, 11.08%. Found: C, 59.49; H, 4.98; N, 11.04%.

EXAMPLE 20 In the same manner as in Example 1 and using ethyl 2- (2-aminoanilino) -5-methoxybenzo [b] thiophen-3-carboxylate, 1-methylpiperazine, anisole, and titanium tetrachloride, 3- was obtained methoxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine.

EXAMPLE 21 In the same manner as in Example 1 and using ethyl 2- (2-amino-5-fluoroanilino) -6-methoxybenzo [b] thiophene-3-carboxylate, 1-methylpiperazine, anisole, and titanium tetrachloride, 8-fluoro-3-methoxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine.

EXAMPLE 22 In the same manner as in example 1 and using ethyl 2- (2-amino-4,5-dichloroanilino) benzo [b] thiophene-3-carboxylate (5.3 g), 1-methylpiperazine (27 ml), anisole ( 120 ml), titanium tetrachloride (4.8 ml) and fumaric acid, there was obtained 1 fumarate of 8,9-dichloro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] ] [1,5] -benzodiazepine (571 mg). Melting point: 243-245 ° C (decomposition): Analysis calculated for: C2oH18CI2N4S * C4H O4: C, 54.04; H, 4.16; N, 10.50%. Found: C, 54.00; H, 4.10; N, 10.41%.

EXAMPLE 23 In the same manner as in example 1 and using ethyl 2- (6-amino-2,3-dichloroanilino) benzo [b] thiophene-3-carboxylate (4.2 g), 1-methylpiperazine (22 ml), anisole ( 100 ml), titanium tetrachloride (3.9 ml) and fumaric acid, there was obtained 1 fumarate of 7,8-dichloro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] ] [1,5] -benzodiazepine (660 mg). Melting point: 235-236 ° C (decomposition): Analysis calculated for: C20H18CI2N4S * C4H4O4: C, 54.04; H, 4.16; N, 10.50%. Found: C, 53.69; H, 4.19; N, 10.33%.

EXAMPLE 24 In the same manner as in example 1 and using ethyl 2- (2-amino-4-trifluoromethylanilino) benzo [b] thiophene-3-carboxylate (2.8 g), 1-methylpiperazine (15 ml), anisole (60 ml) ), titanium tetrachloride (2.5 ml) and maleic acid, 2 maleate of 12- (4-methylpiperazin-1-yl) -9-trifluoromethyl-6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepine (363 mg). Melting point: 128-129 ° C Analysis calculated for: C21Hi9F3N4S »2C4H4O4: C, 53.70; H, 4.20; N, 8.64%. Found: C, 53.56; H, 4.26; N, 8.56%.

EXAMPLE 25 In the same manner as in example 1 and using ethyl 6-bromo-2- (2-amino-5-fluoroanilino) benzo [b] thiophene-3-carboxylate (3.8 g), 1-methylpiperazine (16 ml), anisole (85 ml) and titanium tetrachloride (3.0 ml), 3-bromo-8-fluoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [ 1, 5] benzodiazepine (1.16 g). Melting point: 219-221 ° C Analysis calculated for: C20H? 8BrFN4S: C, 53.94; H, 4.07; N, 12.58%. Found: C, 53.72; H, 3.88; N, 12.41%.

EXAMPLE 26 In the same manner as in example 1 and using ethyl 2- (N-methyl-2-nitroanilino) benzo [b] thiophene-3-carboxylate (3.2 g), 1-methylpiperazine, anisole (80 ml) and tetrachloride of titanium (3.5 ml), 6-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine (166 mg) was obtained. Melting point: 88-90 ° C EXAMPLE 50 Synthesis of starting material To a solution of 2-aminobenzo [b] thiophene-3-carbonitrile (116 g), dimethylformamide (370 ml) and 2,4-difluoronitrile benzene (73 ml) was added powdered potassium carbonate (276 g) and the mixture was stirred at 55 ° C for 5.5 hours. The reaction mixture was stirred under ice-cooling for 30 minutes and water (1.9 L) was added. Additionally, the mixture was stirred for 30 minutes. The precipitated crystals were filtered by suction and washed with water (1.9 L) and dried in a drying box overnight to give crude crystals (198 g). The crude crystals obtained were suspended in ethyl acetate (700 ml) and the mixture was stirred under reflux with heating, at the same time that the water was removed for 2 hours. The reaction mixture was cooled and stirred at 20 ° C for 1 hour. The precipitated crystals were filtered by suction, washed with ethyl acetate (150 ml) and dried to give 2- (5-fluoro-2-nitroanilino) benzo [b] thiophene-3-carbonitrile (123 g) as red powder crystalline. Melting point 161 -163 ° C EXAMPLE 51 Synthesis of starting material To a solution of 2-amino-6-fluorobenzo [b] thiophene-3-carbonitrile (15 g), tetrahydrofuran (140 ml) and 2-fluoronitrobenzene (11.3 g) were added by portions to 60% sodium hydride (3.5 g) under cooling with ice and the mixture remained thus at 5 ° C for 30 minutes. The precipitated crystals were filtered by suction, washed with isopropyl ether (120 ml) and dried to give 6-fluoro-2- (2-nitroanilino) benzo [b] thiophene-3-carbonitrile (8.0 9). 1 H-NMR (400 MHz, CDCl 3) d: 10.13 (br.s, 1H), 8.28 (d, J = 8.3 Hz, 1 H), 7.75 (m, 1 H), 7.61-7.57 (m, 2H), 7.43 (m, 1 H), 7.25 (m, 1 H), 7.10 (m, 1 H).

EXAMPLE 52 Synthesis of starting material In the same manner as in Example 51 of synthesis of starting material and using 2-amino-6-chlorobenzo [b] thiophene-3-carbonitrile and 2-fluoronitrobenzene, 6-chloro-2- (2-nitroanilino) is obtained benzo [b] thiophene-3-carbonitrile.

EXAMPLE 53 Synthesis of starting material In the same manner as in Example 51 of synthesis of starting material and using 2-amino-6-methoxybenzo [b] thiophene-3-carbonitrile (5.2 g) and 2,4-difluoronitrobenzene (4.0 g), 6 was obtained. -methoxy-2- (5-fluoro-2-nitroanilino) benzo [b] thiophene-3-carbonitrile (2.5 g). H-NMR (400 MHz, CDCl 3) d: 10.04 (br.s, 1 H), 8.33 (m, 1 H), 7.74 (d, J = 8.8 Hz, 1 H), 7.23 (s, 1 H), 7.13 (d, J = 8.8 Hz, 1 H), 7.04 (d, J = 10.3 Hz, 1 H), 6.70 (m, 1H), 3.88 (s, 3H).

EXAMPLE 54 Synthesis of starting material In the same manner as in Example 51 of synthesis of starting material and using 2-amino-4-methylbenzo [b] thiophene-3-carbonitrile (3.8 g), 2-chloronitrobenzene (3.5 g) and dimethyl sulfoxide (45 g) mi), 4-methyl-2- (2-nitroanilino) benzo [b] thiophene-3-carbonitrile (5.8 g) was obtained. 1 H-NMR (400 MHz, CDCl 3) d: 10.31 (br.s, 1 H), 8.28 (d, J = 8.3 Hz, 1 H), 7.66-7.52 (m, 3H), 7.27-7.11 (m, 2H ), 7.08 (d, J = 7.4 Hz, 1H), 2.81 (s, 3H).

EXAMPLE 55 Synthesis of starting material In the same manner as in Example 51 of synthesis of starting material and using 2-amino-7-methylbenzo [b] thiophene-3-carbonitrile and 2-fluoronitrobenzene, 7-methyl-2- (2-nitroanilino) was obtained benzo [b] thiophene-3-carbonitrile.

EXAMPLE 56 Synthesis of starting material In the same manner as in Example 51 of synthesis of starting material and using 2-amino-6-fluorobenzo [b] thiophene-3-carbonitrile (4.9 g) and 2,4-difluoronitrobenzene (4.1 g), 6 was obtained. -fluoro-2- (5-fluoro-2-nitroanilino) benzo [b] thiophen-3-carbonitrile (7.8 g). 1 H-NMR (400 MHz, CDCl 3) d: 10.23 (br.s, 1 H), 8.35 (dd, J = 9.3, 5.1 Hz, 1H), 7.81 (dd, J = 8.8, 4.9 Hz, 1H), 7.48. (d, J = 8.3 Hz, 1 H), 7.31-7.28 (m, 1H), 7.14 (d, J = 9.3 Hz, 1H), 6.76 (m, 1H).

EXAMPLE 57 Synthesis of starting material In the same manner as in Example 51 of synthesis of starting material and using 2-amino-6-fluorobenzo [b] thiophene-3-carbonitrile (5.0 g), 3-fluoro-4-nitrotoluene (4.7 g) and sulfoxide of dimethyl (55 ml), 6-fluoro-2- (5-methyl-2-nitroanilino) benzo [b] thiophene-3-carbonitrile (7.5 g) was obtained. 1 H-NMR (400 MHz, CDCl 3) d: 10.19 (br.s, 1 H), 8.17 (d, J = 8.8 Hz, 1H), 7.75 (m, 1H), 7.44 (d, J = 8.3 Hz, 1H ), 7.24-7.22 (m, 2H), 6.89 (d, J = 8.8 Hz, 1H), 2.41 (s, 3H).

EXAMPLE 58 Synthesis of starting material In the same manner as in Example 51 of synthesis of starting material and using 2-aminobenzo [b] thiophene-3-carbonitrile (4.0 g) and 2,5-difluoronitrobenzene (3.7 g), 2- (4-) fluoro-2-nitroanilino) -benzo [b] thiophene-3-carbonitrile (6.7 g). 1 H-NMR (400 MHz, CDCl 3) d: 9.94 (br.s, 1 H), 8.01 (m, 1 H), 7.79 (d, J = 7.9 Hz, 1 H), 7.71 (d, J = 8.3 Hz , 1 H), 7.62 (m, 1H), 7.50 (dd, J = 7.3, 8.3 Hz, 1 H), 7.42-7.35 (m, 2H).

EXAMPLE 59 Synthesis of starting material Sodium hydrosulfite (86%, 233 g) was suspended in dimethylformamide (240 ml) and the suspension was heated to 110 ° C. To this suspension was added dropwise at 110 ° C a solution of 2- (5-fluoro-2-nitroanilino) benzo [b] thiophene-3-carbonitrile (120 g), dimethylformamide (720 ml) and water (27.5 ml) , said solution had been heated to 65-70 ° C. The reaction mixture was stirred at 110 ° C for 1 hour and cooled to 20 ° C. Water (3.3 L) was added in 6 portions for 1 hour and the mixture was stirred at 20 ° C for 1.5 hours. The precipitated crystals were filtered by suction and washed with water (2 L) to give 2- (2-amino-5-fluoroanilino) benzo [b] thiophene-3-carbonitrile (158 g) as ocher crystals. Melting point 178-180 ° C (decomposition).

EXAMPLE 27 2- (2-Amino-5-fluoroanilino) benzo [b] thiophene-3-carbonitrile (155 g) was suspended in a mixture of methanol (250 ml) and water (200 ml) and 35% hydrochloric acid was added ( 42 mi) aqueous. The mixture was stirred under reflux with heating for 5.5 hours. The reaction mixture was cooled and stirred at 20 ° C for 1 hour. The precipitated crystals were filtered by suction, washed with water (500 ml) and isopropyl alcohol (200 ml) and dried in a drying box overnight to give 1-hydrochloride of 12-amino-8-fluoro-6H- [ 1] benzothien [2,3-b] [1,5] benzodiazepine (104 g) as yellow crystals. Melting point 213-216 ° C (decomposition) EXAMPLE 28 Tin (II) chloride (50 g) was dissolved in a solution of 18% hydrochloric acid (250 ml) heated to 50 ° C, and a suspension of 6-fluoro-2- (2-nitroanilino) was added. benzo [b] thiophene-3-carbonitrile (20 g) in ethanol (280 ml). The mixture was refluxed under heating for 4 hours. Then, the reaction mixture was cooled to 40 ° C and poured into water (1 L) and the mixture remained so for 30 minutes. The precipitated crystals were filtered by suction and washed with water (500 ml) to give 1-amino-3-fIuoro-6H- [1] benzothien [2,3-b] [1,5] benzodiazepine hydrochloride (15 g). 1 H-NMR (400 MHz, DMSO-d 6) d: 11.46 (s, 1 H), 9.92 (s, 1 H), 9.02 (s, 1 H), 9.00 (s, 1 H), 7.84 (d, J = 6.3 Hz, 1 H), 7.69 (m, 1 H), 7.31 (m 1 H), 7.20-6.98 (m, 4H).

EXAMPLE 29 In the same manner as in Example 28 and using 6-methoxy-2- (5-fluoro-2-nitroanilino) benzo [b] thiophene-3-carbonitrile, 1-hydrochloride of 12-amino-3-chloro-6H was obtained - [1] benzothien [2,3-b] [1,5] benzodiazepine.

EXAMPLE 30 In the same manner as in Example 28 and using 6-methoxy-2- (5-fluoro-2-nitroanilino) benzo [b] thiophene-3-carbonitrile (2.5 g), 1-amino-8-hydrochloride was obtained -fluoro-3-methoxy-6H- [1] benzothien [2,3-b] [1,5] benzodiazepine (2.1 g). 1 H-NMR (400 MHz, DMSO-d 6) d: 11.68 (br.s, 1 H), 10.02 (br.s, 1 H), 9.09 (br.s, 1 H), 9.01 (br.s, 1 H), 7.58 (d, J = 8.8 Hz, 1 H), 7.10-6.95 (m, 3H), 6.86 (d, J = 9.3 Hz, 1 H), 3.78 (s, 3H).

EXAMPLE 31 In the same manner as in Example 28 and using 4-methyl-2- (2-nitroanilino) benzo [b] thiophene-3-carbonitrile (2.5 g), 1-hydrochloride of 12-amino-1-methyl-6H was obtained - [1] benzothien [2,3-b] [1,5] benzodiazepine. 1 H-NMR (400 MHz, DMSO-d 6) d: 11.32 (s, 1 H), 10.02 (s, 1 H), 9.08 (s, 1 H), 9.08 (s, 1 H), 8.64 (s, 1 H), 7.71 (d, J = 7.3 Hz, 1 H), 7.27-7.15 (m, 2H), 7.02 (d, J = 7.3 Hz, 1 H), 2.36 (s, 3H).

EXAMPLE 32 In the same manner as in Example 28 and using 7-methyl-2- (2-nitroanilino) benzo [b] thiophene-3-carbonitrile, 1-hydrochloride of 12-amino-4-methyl-6H- [1] was obtained. benzothien [2,3-b] [1,5] benzodiazepine.

EXAMPLE 33 In the same manner as in example 28 and using 6-fluoro-2- (5-fIuoro-2-nitro-ylino) benzo [b] tofen-3-carbonitrile (7.8 g), 1-amino-3,8-difluoro-6H- [1] benzothien [2,3-b] [1,5] benzodiazepine hydrochloride (4.8 g). 1 H-NMR (400 MHz, DMSO-d 6) d: 11.51 (s, 1 H), 10.08 (s, 1 H), 9.05 (s, 2 H), 7.86 (d, J = 8.7 Hz, 1 H), 7.70 (m, 1 H), 7.32 (m, 1 H), 7.11 (m, 1 H), 7.00 (m, 1 H), 6.86 (d, J = 9.3 Hz, 1 H).

EXAMPLE 34 In the same manner as in Example 28 and using 6-fluoro-2- (5-methyl-2-nitroanilino) benzo [b] thiophen-3-carbontril (7.4 g), 1 hydrochloride of 12 was obtained. -amino-3-fluoro-6H- [1] benzothien [2,3-b] [1,5] benzodiazepine (8.5 g). 1 H-NMR (400 MHz, DMSO-d 6) d: 11.53 (br.s, 1 H), 9.92 (br.s, 1 H), 9.02 (br.s, 2H), 8.95 (br.s, 1H) , 7.84 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.30 (dd, J = 8.8, 9.3 Hz, 1 H), 6.96-6.91 (m, 2H), 6.79 (s, 1 H), 2.22 (s, 3H).

EXAMPLE 35 In the same manner as in Example 28 and using 2 (4-fluoro-2-nitroanilino) benzo [b] thiophene-3-carbonitrile (6.7 g), 1-hydrochloride of 12-amino-9-fluoro-6H- was obtained [1] benzothien [2,3-b] [1, 5] benzodiazepine (4.8 g). 1 H NMR (400 MHz, DMSO-d 6) d: 11.73 (s, 1 H), 10.06 (s, 1 H), 9.14 (s, 1 H), 9.11 (s, 1 H), 7.87 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.48 (dd, J = 8.3, 7.3 Hz, 1 H), 7.28 (dd, J = 7.8, 7.3 Hz, 1 H), 7.10-7.04 (m, 2H), 6.93 (dd, J = 9.3, 2.4 Hz, 1 H).

EXAMPLE 36 In the same manner as in Example 51 of synthesis of starting material and using 2-aminobenzo [b] thiophene-3-carbonitrile (5.0 g) and 2,4,5-trifluoronitrobenzene (5.1 g), crude crystals were obtained ( 8.7 g) of 2- (4,5-difluoro-2-nitroanilino) benzo [b] thiophen-3-carbonitrile. Without purification, in the same manner as in example 28 and using tin (II) chloride dihydrate (95 g), 18% hydrochloric acid (65 ml) and ethanol (120 ml), 1 12-amino hydrochloride was obtained -8,9-difluoro-6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine (7.7 g). 1 H-NMR (400 MHz, DMSO-d 6) d: 11.36 (br.s, 1 H), 9.97 (s, 1 H), 9.16 (br.s, 1 H), 9.09 (br.s, 1 H), 7.90 (d, J = 7.8 Hz, 1 H), 7.69 (d, J = 8.3 Hz, 1 H), 7.44 (t, J = 7.8 Hz, 1 H), 7.32 (dd, J = 7.8, 7.3 Hz, 1 H), 7.2 (dd, J = 7.9, 8.7 Hz, 1 H), 7.05 (t, J = 7.8 Hz, 1H).

EXAMPLE 37 To 12- (4-methylpiperazin-1-yl) -8-fluoro-6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine (63.5 g) was added ethanol (320 ml) and the mixture was heated for dissolution. Active carbon (1.9 g) was added for natural filtration and the mixture was washed with ethanol (220 ml). The solution was heated to 35 ° C and a solution of maleic acid (20.1 g) in an aqueous organic solution (95 ml, on natural filtration after dissolution) was added dropwise with stirring. The solution was stirred at 35 ° C for 1 hour, cooled and stirred at 20 ° C for 2 hours. The precipitated crystals were collected by filtration, washed with ethanol (130 ml) and dried at 50 ° C to produce 1-maleate of 12- (4-methylpiperazin-1-yl) -8-fluoro-6H- [1] benzothiene [2,3-b] [1,5] -benzodiazepine (50.5 g) as pale yellow crystals. Melting point 225-227 ° C (decomposition) The following salt compounds can be synthesized using a suitable organic or inorganic acid instead. of the maleic acid used in the aforementioned examples.

EXAMPLE 38 1 12- (4-Methylpiperazin-1-yl) -8-fluoro-6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine methanesulfonate. Melting point 303.5 ° C (decomposition). H-NMR (400 MHz, DMSO-d6) d: 9.64 (br.s 1 H), 8.36 (s, 1 H), 7.82 (d, 1 H), 7.38 (dd, 1 H), 7.25 (dd, 1 H), 6.89 (dd, 1 H), 6.79 (dd, 1 H), 6.62 (d, 1H), 3.10-3.60 (m, 8H), 2.85 (s, 3H), 2.30 (s, 3H). IR (KBr): 3246, 1618, 1518, 1385 crt? 1. MS: m / e 366. Analysis calculated for C20H? 9FN4S * CH4O3S: C, 54.53; H, 5.01; N, 12.11%. Found: C, 54.35; H, 5.04; N, 11.94%.

EXAMPLE 39 2- Nitrate of 12- (4-methylpiperazin-1-yl) -8-fluoro-6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine. Melting point 170 ° C (decomposed) 1 H NMR (400 MHz, DMSO-d 6) d: 9.78 (br.s, 1 H), 7.92 (d, 1 H), 7.58-7.77 (m, 1 H), 7.45 (dd, 1 H), 7.33 (dd, 1 H), 6.77-6.98 (m, 3H), 3.20-3.90 (m, 8H), 2.84 (s, 3H). IR (KBr): 3462, 3043, 1599, 1508 crt? 1. MS: m / e 366. Analysis calculated for C20H19FN4S »2HNO3» 0.5H2O: C, 47.90; H, 4.42; N, 16.76%. Found: C 47.89; H, 4.44; N, 16.75%.

EXAMPLE 40 1. 5 12- (4-Methylpiperazin-1-yl) -8-fluoro-6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine sulfate. Melting point 236-239 ° C. 1 H NMR (400 MHz, DMSO-d 6) d: 9.69 (br, 1 H), 7.87 (d, 1 H), 7.80- 7.86 (m, 1 H), 7.42 (dd, 1 H), 7.30 (dd, 1 H), 6.60-7.10 (m, 3H), 3.80-4.40 (m, 8H), 2.89 (s, 3H). IR (KBr): 3406, 2986, 1597, 1510 cm "1.

MS: m / e 366. Analysis calculated for C2oHi9FN4S »1.5H2S04« 1.5H20: C, 44.43; H, 4.66; N, 10.36%. Found: C, 44.45; H, 4.65; N, 10.31%.

EXAMPLE 41 2 Phosphate of 12- (4-methylpiperazin-1-yl) -8-fluoro-6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine. Melting point 189-192 ° C. 1 H NMR (400 MHz, DMSO-d 6) d: 8.29 (s, 1 H), 7.81 (d, 1 H), 7.71 (d, 1 H), 7.35 (dd, 1 H), 7.23 (dd, 1 H), 6.87 (dd, 3H), 6.70 (d, 1H), 6.56 (d, 1 H), 2.40-3.90 (m, 8H), 2.44 (s, 3H). IR (KBr): 3429, 2922, 1597, 1510 crrA MS: m / e 366. Analysis calculated for C20H19FN4S »2H3PO4» 1H2O: C, 41.38; H, 4.69; N, 9.65%. Found: C, 41.54; H, 5.11; N, 9.66%.

EXAMPLE 42 1-hydrochloride of 12-amino-3-fluoro-6H- [1] benzothieno [2,3-b] [1, 5] bendodiazepine (12 g) was dissolved in N-methylpiperazine (140 ml) and the mixture was stirred under reflux with heating for 3 hours. The reaction mixture was cooled to 40 ° C, extracted with ethyl acetate (250 ml) and washed with saturated brine (10 ml). The ethyl acetate layer was dried over magnesium sulfate. The solution was filtered naturally and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (ethyl acetate: methanol) to give crude crystals of 3-fluoro-12- (4-methylpiperazin-1-yl) -6H- [1] -benzothieno [2, 3-b] [1,5] benzodiazepine. The crude crystals obtained were dissolved in ethyl acetate (30 ml) and a solution of maleic acid (1.83 g) in ethanol (20 ml) was added. The precipitated crystals were collected by filtration and recrystallized from aqueous ethanol to give 1 maleate of 3-fluoro-12- (4-methylpiperazin-1-yl) -6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (2.82 g). Melting point 209 ° C.

Analysis calculated for C20H? 9FN4S * C4H4O4: C, 59.74; H, 4.80; N, 11 61%. Found: C, 59.66; H, 4.69; N, 11.56%.

EXAMPLE 43 In the same manner as in example 42 and using 1-hydrochloride of 12-amino-3-chloro-6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine and N-methylpiperazine, 3 was obtained. -chloro-12- (4-methyl-piperazin-1-yl) -6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine.

EXAMPLE 44 In the same manner as in example 42 and using 1-amino-8-fluoro-3-methoxy-6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine hydrochloride (1.6 g) , N-methylpipierazine (50 ml) and citric acid, crude crystals (1.0 g) of 8-fluoro-3-methoxy-12- (4-methylpiperazin-1-yl) -6H- [1] -benzothieno [2] were obtained. , 3-b] [1, 5] benzodiazepine. The crystals were dissolved in ethanol (10 ml) and a solution of citric acid (552 mg) in ethanol (10 ml) was added. The precipitated salt was recrystallized from a mixed solvent of ethyl acetate and ethanol to give 1-citrate of 5-fluoro-3-methoxy-12- (4-methylpiperazin-1-yl) -6H- [1] -benzothiene. [2,3-b] [1,5] benzodiazepine dihydrate (204 mg). Melting point 118-120 ° C. Analysis calculated for C20H19FN S »C6H807« 2H20: C, 51.92; H, 5.33; N, 8.97%. Found: C, 52.18; H, 5.19; N, 8.63%.

EXAMPLE 45 In the same manner as in example 42 and using 1-hydrochloride of 12-amino-1-methyl-6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine and N-methylpiperazine, 1-methyl-12- (4-methyl-piperazin-1-yl) -6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine.

EXAMPLE 46 In the same manner as in example 42 and using 1-hydrochloride of 12-amino-4-methyl-6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine and N-methylpiperazine, 4-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine.

EXAMPLE 47 In the same manner as in example 42 and using 1-hydrochloride of 12-amino-3,8-difluoro-6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (8.0 g), N-methylpiperazine (100 ml) and maleic acid, there was obtained 1-maleate of 3,8-difluoro-12- (4-methylpiperazin-1-yl) -6H- [1] -benzothieno [2,3-b] [ 1, 5] benzodiazepine (3.4 g). Melting point: 211-213 ° C Analysis calculated for C20H18FN4S »C4H4O4: C, 57.59; H, 4.43; N, 11.19%. Found: C, 57.58; H, 4.37; N, 11.10%.

EXAMPLE 48 In the same manner as in example 42 and using 1-hydrochloride of 12-amino-3-fluoro-8-methyl-6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (8.5 g ), N-methylpiperazine, (100 ml) and hydrochloric acid, 2-hydrochloride of 3-fluoro-8-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] -benzothieno [2, 3-b] [1, 5] benzodiazepine. Melting point 240-242 ° C (decomposition). 1 H NMR (400 MHz, DMSO-d 6) d: 11.82 (br.s 2 H), 11.09 (br.s, 1 H), 7.89-7.5 (m, 2 H), 7.33-7.26 (m, 2 H), 6.98- 6.96 (m, 2H), 4.79-2.87 (m, 11H), 2.24 (s, 3H).

EXAMPLE 49 In the same manner as in example 42 and using 1-hydrochloride of 12-amino-9-fluoro-6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (2.0 g), N- methylpiperazine (40 ml) and maleic acid, 2-maleate of 9-fluoro-12- (4-methylpiperazin-1-yl) -6H- [1] -benzothieno [2,3-b] [1,5] was obtained benzodiazepine (1 -2 g). Melting point 136-137 ° C. Analysis calculated for C20H? 9FN4S »2C4H404: C, 56.18; H, 4.55; N, 9.36%. Found: C 56.14; H, 4.58; N, 9.32%.

EXAMPLE 50 In the same manner as in example 42 and using 1-hydrochloride of 12-amino-8,9-difluoro-6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (4.0 g), N-methylpiperazine (40 ml) and maleic acid, there was obtained 1-maleate of 8,9-difluoro-12- (4-methylpiperazin-1-yl) -6H- [1] -benzothieno [2,3-b] [ 1, 5] benzodiazepine (924 mg). Melting point 144-146 ° C (decomposition). Analysis calculated for C20H18F2N4S * C H404: C, 57.59; H, 4.43; N, 11.19%. Found: C, 57.39; H, 4.44; N, 11.10%.

EXAMPLE 51 In the same manner as in example 42 and using 1-hydrochloride of 12-amino-8-fluoro-6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (1.3 g), N- ethylpiperazine (25 ml) and maleic acid, 1 -maleate of 12-12- (4-methylpiperazin-1-yl) -6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine was obtained ( 731 mg). Melting point 211-212 ° C. Analysis calculated for C2? H21FN4S »C4H4O4: C, 60.47; H, 5.07; N, 11.28%. Found: C, 60.30; H, 5.03; N, 11.18%.

EXAMPLE 52 In the same manner as in example 42 and using 1-hydrochloride of 12-amino-8-fluoro-6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (1.5 g), Nn- propylpiperazine (17 g), dimethyl sulfoxide (10 ml) and hydrochloric acid, crude crystals (850 mg) of 8-fluoro-12- (4-propipiperazin-1-yl) -6H- [1] -benzot were obtained Eno [2,3-b] [1, 5] benzodiazepine. The crude crystals were dissolved in ethyl acetate (12 ml) and a solution of 1-hydrochloric acid / 5.5 moles in ether was added to produce 2-hydrochloride of 8-fluoro-12- (4-methylpiperazin-1-yl) - 6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine 1.5 hydrated (757 mg). Melting point 215-217 ° C (decomposition). Analysis calculated for C 22 H 23 FN 4 S »2 HCl» 3 / 2H 2 O: C, 53.44; H, 5.71; N, 11.33%. Found: C ,. 53.33; H, 5.78; N, 11.14%.

EXAMPLE 53 In the same manner as in example 42 and using 1-hydrochloride of 12-amino-8-fluoro-6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (1.5 g), N- isopropylpiperazine (17 g), dimethyl sulfoxide (10 ml) and maleic acid, there was obtained 1 -maleate of 8-fluoro-12- (4-isopropylpiperazin-1-yl) -6H- [1] -benzothieno [2,3 -b] [1, 5] benzodiazepine (521 mg). Melting point 217 ° C. Analysis calculated for C 22 H 23 FN 4 S »C 4 H 4 O 4: C, 61.16; H, 5.33; N, 10.97%. Found: C, 61.03; H, 5.30; N, 10.91%.

EXAMPLE 54 In the same manner as in example 42 and using 1-hydrochloride of 12-amino-8-fluoro-6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (1.7 g), N- cyclopropylpiperazine (8.0 g), dimethyl sulfoxide (10 ml) and maleic acid, there was obtained 1 -maleate of 12- (4-cyclopropylpiperazin-1-yl) -8-fluoro-6H- [1] -benzothieno [2,3 -b] [1, 5] benzodiazepine (877 mg). Melting point 182-183 ° C. Analysis calculated for C22H21FN4S «C4H4O4: C, 61.40; H, 4.95; N, 11.02%. Found: C, 61.28; H, 4.88; N, 10.82%.

EXAMPLE 55 In the same manner as in example 42 and using 1-hydrochloride of 12-amino-8-fluoro-6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (1.3 g), N- (2-hydroxyethyl) piperazine (12.5 ml), dimethyl sulfoxide (5 ml) and maleic acid, 2-maleate of 8-fluoro-12- [4- (2-hydroxyethyl) piperazin-1-yl) -6H was obtained - [1] -benzothieno [2,3-b] [1,5] benzodiazepine 1-hydrated (1.18 g). Melting point 75-77 ° C. Analysis calculated for C2? H2? FN4OS »2C4H404« H20: C, 53.86; H, 4.83; N, 8.66%. Found: C, 53.80; H, 4.94; N, 8.67%.

EXAMPLE 56 In the same manner as in example 42 and using 1-hydrochloride of 12-amino-8-fluoro-6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (1.4 g), N- methylhomopiperazine (5.4 g), dimethyl sulfoxide (25 ml) and citric acid, 1 -citrate of 8-fluoro-12- (4-methylhomopiperazin-1-yl) -6H- [1] -benzothieno [2,3 -b] [1, 5] benzodiazepine 0.5 hydrated (455 mg). Melting point 98-100 ° C (decomposition). Analysis calculated for C21H2? FN4S «C6H8O7« 1 / 2H2O: C, 55.76; H, 5.20; N, 9.63%. Found: C, 55.48; H, 5.60; N, 9.64%.

EXAMPLE 57 In the same manner as in example 42 and using 1-hydrochloride of 12-amino-8-fluoro-6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (1.3 g), N, N, N'-trimethylethylenediamine (13 g), dimethyl sulfoxide (5 ml) and citric acid gave 1-8-fluoro-12- [N- (2-dimethylaminoethyl) N-methylamino] -6H- [1] -benzothieno [2,3-b] [1, 5] benzodiazepine 1 hydrate (289 mg). Melting point 72-74 ° C (decomposition). Analysis calculated for C20H19FN4S »C6H8O7« H ^ C, 53.97; H, 5.40; N, 9.68%. Found: C, 53.60; H, 5.27; N, 9.02%.

EXAMPLE 58 In the same manner as in example 42 and using 1-hydrochloride of 12-amino-8-fluoro-6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (1.6 g), 1- [2 (2-hydroxyethoxy) ethyl] piperazine (13 g) and dimethyl sulfoxide (5 ml), 8-fluoro-12- was obtained. { 4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl} -6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (422 mg). Melting point 198 ° C. Analysis calculated for C 23 H 25 FN 4 O 2 S: C, 62.71; H, 5.72; N, 12. 72%. Found: C, 62.63; H, 5.59; N, 12.57%.

EXAMPLE 59 In the same manner as in example 42 and using 1-hydrochloride of 12-amino-8-fluoro-6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (2.1 g), N- Benzylpiperazine (25 g), dimethyl sulfoxide (10 ml) and hydrochloric acid gave 2-hydrochloride of 8-fluoro-12- (4-benzylpiperazin-1-yl) -6H- [1] -benzothieno [2,3 -b] [1,5] benzodiazepine 1/4 hydrated (360 mg). Melting point 260-262 ° C.

EXAMPLE 60 In the same manner as in example 42 and using 1-hydrochloride of 12-amino-8-fluoro-6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (2.0 g), ter- butyl-1-piperazinecarboxylate (5.0 g) and dimethyl sulfoxide (15 ml) gave 8-fluoro-12- (4-tert-butoxycarbonylpiperazin-1-yl) -6H- [1] -benzothieno [2,3-] b] [1, 5] benzodiazepine (1.6 mg). 1 H-NMR (400 MHz, CDCl 3) d: 7.76 (d, J = 7.8 Hz, 1 H), 7.60 (d, J = 7.8 Hz, 1 H), 7.32 (dd, J = 7.4, 7.1 Hz, 1 H ) 7.22 (dd, J = 9.2, 8.3 Hz, 1 H) 6.97 (dd, J = 8.8, 2.9 Hz, 1 H) 6.70 (dd, J = 8.3, 2.8 Hz, 1 H), 6.42 (dd, J = 8.8, 2.9 Hz, 1 H), 5.18 (br.s, 1 H), 4.20-0.70 (m, 9H), 1.44 (s, 9H).

EXAMPLE 61 8-Fluoro-12- (4-tert-butoxycarbonylpiperazin-1-yl) -6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (1.6 g) was dissolved in trifluoroacetic acid (8 ml). ) and the mixture was stirred at room temperature for 3 hours. Trifluoroacetic acid was evaporated unreduced pressure. The residue was dissolved in ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate was added. The mixture was stirred at room temperature for 2 hours and the ethyl acetate layer was dried over magnesium sulfate. After the natural filtration, the solvent was evaporated and the residue was separated and purified by silica gel column chromatography (chloroform-methanol = 4: 1) to give 8-fluoro-12- (piperazin-1-yl) - 6H- [1] -benzothieno [2,3-b] [1, 5] benzodiazepine (1.7 g) which was treated with maleic acid to give 3/2 8-fIuoro-12- (piperazin-1-yl) maleate -6H- [1] -benzothieno [2,3-b] [1, 5] benzodiazepine 1/2 hydrate (347 mg). Melting point 141-143 ° C (decomposition). Analysis calculated for C? 9H? 7FN4S * 3 / 2C H40"1/2 H2O: C, 56.17; H, 4.34; N, 10.48%. Found: C, 56.30; H, 4.58; N, 10.08%.

EXAMPLE 62 8-Fluoro-3-methoxy-12- (4-methylpiperazin-1-yl) -6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (500 mg) was dissolved in dichloromethane (15 mg). mi) and ethanedithiol (2.10 ml) and aluminum chloride (2.51 g) were added. The mixture was stirred at room temperature for 2 hours. Water (50 ml) was added to the reaction mixture and an aqueous solution of sodium hydroxide was added until alkalinity was reached. The mixture was extracted with chloroform, washed with water and saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvent was evaporated unreduced pressure and the residue was separated by silica gel column chromatography (chloroform-methanol = 5: 1) and recrystallized from ethyl acetate to give 8-fluoro-3-hydroxy-12- (4-methylpiperazin-1-yl) -6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (251 mg). 1 H-NMR (400 MHz, CDCl 3) d: 7.59 (d, 1 H), 7.01 (d, 1 H), 6.96 (d, 1 H) 6.83 (dd, 1 H), 6.68 (m, 1 H), 6.41 (dd, 1 H), 5.09 (br.s, 1 H), 4.00-2.00 (m, 8H), 2.34 (s, 3H).

EXAMPLE 63 8-Fluoro-12- (piperazin-1-yl) -6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine (260 mg) was dissolved in toluene (5 ml) and acid was added anhydrous acetic acid (230 mg) and triethylamine (375 mg). The mixture was stirred at 80 ° C for minutes. The reaction mixture was allowed to cool to room temperature and was extracted with chloroform, washed with water and dried over anhydrous magnesium sulfate, after the natural filtration, the solvent was evaporated unreduced pressure and the residue was recrystallized at room temperature. from methanol to give 8-fluoro-12- (4-acetylpiperazin-1-yl) -6H- [1] -benzothieno [2,3-b] [1,5] benzodiazepine 1/4 hydrated (97 mg ). Melting point > 290 ° C. Analysis calculated for C2iH19FN4OS »1/4 H20: C, 63.22; H, 4.93; N, 14.04%. Found: C, 62.97; H, 4.67; N, 13.75%.

EXAMPLE 64 To a solution of 8-fluoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine (100 mg) in ethanol (2 ml) was added 30% aqueous hydrogen peroxide solution (0.1 ml) and the mixture was stirred at room temperature for 3 hours and then allowed to stand for one day. The suspension obtained was filtered and the solvent was evaporated unreduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to give 8-fluoro-12- (4-methylpiperazin-4-oxide-1-yl) -6H- [1] benzothiene. [2, 3-b] [1,5] benzodiazepine (50 mg) as a yellow oily substance. 1 H-NMR (400 MHz, CDCl 3) d 3.00-3.80 (8 H, m, CH 2 X 4), 3.25 (3 H, s, CH 3), 6.46 (1 H, dd, J = 2.9, 8.8 Hz, Ar H), 6.74 (1H, ddd, J = 2.4, 2.9 8.3 Hz, ArH), 6.97 (1H, dd, J = 2.9, 8.8 Hz, ArH), 7.24 (1H, d, J = 7.4 Hz, ArH, 7.37 (1 H, dd, J = 7.3, 7.8 Hz, ArH), 7.63 (1H, d, J = 8.3 Hz, ArH), 7.72 (1 H, d, J = 8.3 Hz, ArH) MS: m / e 383 (M + 1).

EXAMPLE 65 In the same manner as in example 62 and using 8-fluoro-1-methoxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine , dichloromethane, ethanedithiol and aluminum chloride gave 8-fluoro-1-hydroxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothien [2,3-b] [1,5 ] benzodiazepine.

EXAMPLE 66 In the same manner as in example 62 and using 8-fluoro-2-methoxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine , dichloromethane, ethanedithiol and aluminum chloride gave 8-fluoro-2-hydroxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine.

EXAMPLE 67 In the same manner as in example 62 and using 8-fluoro-4-methoxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine , dichloromethane, ethanedithiol and aluminum chloride gave 8-fluoro-4-hydroxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine.

EXAMPLE 68 In the same manner as in example 62 and using 8-fluoro-7-methoxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] benzod Azepine, dichloromethane, ethanediol and aluminum chloride was obtained 8-fluoro-7-hydroxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine.

EXAMPLE 69 In the same manner as in example 62 and using 8-fluoro-9-methoxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine , dichloromethane, ethanedithiol and aluminum chloride gave 8-fluoro-9-hydroxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine.

EXAMPLE 70 In the same manner as in example 62 and using 8-fluoro-10-methoxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine , dichloromethane, ethanedithiol and aluminum chloride gave 8-fluoro-10-hydroxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine.

EXAMPLE 71 3-Fluoro-8-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine was dissolved in carbon tetrachloride and reacted with 2,2'-azobis (isobutylonitrile) in the presence of N-chlorosuccinamide to give 8-chloromethyl-3-fluro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] ] [1, 5] benzodiazepine.

EXAMPLE 72 12-amino-8-fluoro-6H- [1] benzothieno [2,3-b] [1,5] benzodiazepine hydrochloride (102 g) was suspended in toluene (600 ml), and the mixture was stirred at reflux with Warm up for 3 hours to remove the water. The mixture was cooled to 70 ° C under a nitrogen atmosphere, and N-methylpiperazine (300 ml) was added. The mixture was stirred under heating under a nitrogen atmosphere until the inner temperature reached 120 ° C while at the same time the toluene was removed for 1.5 hours. The mixture was heated under a nitrogen atmosphere at 120 ° C for 2.5 hours and cooled to 25 ° C under a nitrogen atmosphere. Ethyl acetate (600 ml) and water (450 ml) were added to the reaction mixture for extraction and the obtained ethyl acetate layer was washed three times with water (300 ml). After verifying that the pH of the wash water was between 7-8, the solvent was concentrated under reduced pressure. Acetonitrile (100 ml) was added and the mixture was concentrated azeotropically to dryness under reduced pressure. Acetonitrile (300 ml) was added to the residue and the mixture was heated to solution. The solution was cooled and stirred at -10 ° C - -5 ° C for 2.5 hours to allow the precipitation of crystals. The precipitated crystals were filtered by suction and washed with acetonitrile (100 ml), and then dried to give 8-fluoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3- b] [1, 5] benzodiazepine (65.5 g). Melting point 167-169 ° C.

EXAMPLE 73 Using an equivalent amount of hydrochloric acid in place of maleic acid in Example 2, 8-fluoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] monohydrochloride was obtained [1,5] benzodiazepine. Melting point 310.3 ° C. MS: m / e 366, Calculated Analysis for C20H? 9FN4S «HCI: C, 59.62; H, 5.00; N, 13.91%. Found: C, 59.43; H, 5.02; N, 13.88%.

EXAMPLE 60 Synthesis of starting material 2-Bromo-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylic acid (6 g) was suspended in thionyl chloride (30 ml) and the mixture was stirred under reflux with heating for 75 minutes. The thionyl chloride was evaporated under reduced pressure and the residue was dissolved in toluene (50 ml). This solution in toluene was added dropwise to a solution of 2-aminophenol (2.5 g) in pyridine (50 ml) under cooling with ice. The mixture was stirred at room temperature for 2 hours and the completion of the reaction was confirmed by thin layer chromatography. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The mixture was washed with dilute hydrochloric acid and saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. The solvents were evaporated under reduced pressure. Di-isopropyl ether was added to the residue and the mixture was filtered to give 2-bromo-4,5,6,7-tetrahydro-N- (2-hydroxyphenyl) -benzo [b] thiophene-3-carboxamide (.3 g. ). 1 H-NMR (400 MHz, CDCl 3) d 8.65 (br, 1 H), 7.94 (br, 1 H), 7.15- 7.19 (m, 2H), 7.06 (d, J = 8.3 Hz, 1 H), 6.91 (m, 1 H), 2.75-2.78 (m, 2H), 2.67-2.70 (m.2H), 1.77-1.86 (m, 4H) EXAMPLE 61 Synthesis of starting material In the same manner as in example 60 of synthesis of the starting material and using 2-bromo-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylic acid (6 g), thionyl chloride (30 ml) ), 2-amino-5-methylphenol (3.14 g), was obtained 2-bromo-4,5,6,7-tetrahydro-N- (2-hydroxy-4-methylphenyl) -benzo [b] thiophene-3 carboxamide (5.8 g). 1 H-NMR (400 MHz, DMSO-d 6) d 9.66 (s, 1 H 9, 9.33 (br, 1 H), 7.62 (d, J = 8.3 Hz, 1 H), 6.71 (s, 1 H), 6.62 ( d, J = 8.3 Hz, 1 H), 2.66-2.50 (m, 4H), 2.22 (s, 3H), 1.76-1.72 (m, 4H).

EXAMPLE 62 Synthesis of starting material In the same manner as in example 60 of synthesis of the starting material and using 2-bromo-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylic acid, thionyl chloride and 2-amino-5- fluorophenol, 2-bromo-4,5,6,7-tetrahydro-N- (4-fluro-2-hydroxyphenyl) -benzo [b] thiophene-3-carboxamide was obtained.

EXAMPLE 63 Synthesis of starting material In the same manner as in example 60 of synthesis of the starting material and using 2-bromo-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylic acid, thionyl chloride, 2-aminothiophenol, was obtained 2-bromo-4, 5,6,7-tetrahydro-N- (2-mercapto-phenyl) -benzo [b] thiophene-3-carboxamide.

EXAMPLE 64 Synthesis of starting material In the same manner as in example 60 of synthesis of the starting material and using 2-bromo-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylic acid, thionyl chloride and 2-amino-5- methylthiophene, 2-bromo-4,5,6,7-tetrahydro-N- (2-mercapto-4-methylphenyl) -benzo [b] thiophene-3-carboxamide was obtained.

EXAMPLE 65 Synthesis of starting material In the same manner as in example 60 of synthesis of the starting material and using 2-bromo-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylic acid, thionyl chloride, 2-amino-5- fIuotothiophenol, 2-bromo-4,5,6,7-tetrahydro-N- (4-fluoro-2-mercapto-phenyl) -benzo [b] thiophene-3-carboxamide was obtained.

EXAMPLE 74 To a solution of 2-bromo-4,5,6,7-tetrahydro-N- (2-hydroxyphenyl) -benzo [b] thiophene-3-carboxamide (5.3 g) in dimethyl sulfoxide (50 ml) was added carbonate of potassium (4.2 g) and the mixture was stirred at 140 ° C for 4 hours. The completion of the reaction was confirmed by thin layer chromatography. The mixture was cooled to room temperature and the reaction mixture was poured into water (300 ml). After neutralizing with hydrochloric acid, the mixture was extracted twice with chloroform and washed with saturated brine.

The organic layer was dried with magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography with silica gel (chloroform) to give 1,4-tetrahydro [1] benzothieno [2,3-b] [1,5] benzoxazepin-12 (11 H) -one ( 2.1 g). 1 H NMR (400 MHz, DMSO-d 6) d: 7.81 (br, 1 H), 7.10-7.17 (m, 3H), 6.98 (d, J = 8.3 Hz, 1 H), 2.75-2.78 (m, 2H), 2.58-2.61 (m, 2H), 1.73-1.83 (m, 4H).

EXAMPLE 75 In the same manner as in example 18 and using 2-bromo-4,5,6,7-tetrahydro-N- (2-hydroxy-4-methylphenyl) -benzo [b] thiophene-3-carboxamide (5.8 g) , dimethyl sulfoxide (80 ml) and potassium carbonate (4.7 g), 1, 2,3,4-tetrahydro-8-methyl [1] benzothieno [2,3-b] [1,5] benzoxazepin- was obtained. 12 (11 H) -one (1 -87 g). H-NMR (400 MHz, DMSO-d6) d: 10.03 (s, 1 H), 7.03-6.99 (m, 3H9, 2.62-2.56 (m, 4H9, 2.25 (s, 3H), 1.73-1.67 (m, 4H).

EXAMPLE 76 In the same manner as in Example 74 and using 2-bromo-4,5,6,7-tetrahydro-N- (4-fluoro-2-hydroxyphenyl) -benzo [b] thiophene-3-carboxamide, sulfoxide of dimethyl and potassium carbonate, 8-fluro-1, 2,3,4-tetrahydro- [1] benzothieno [2,3-b] [1,5] benzoxazepin-12 (11 H) -one was obtained.

EXAMPLE 77 1, 2,3,4-tetrahydro- [1] benzothieno [2,3-b] [1,5] benzoxazepin-12 (11 H) -one (1.5 g) and dichlorodicyn-p-benzoquinone (2.6 g) were dissolved. ) in benzene (45 ml) and the mixture was stirred under reflux with heating for 12 hours. The reaction mixture was evaporated under reduced pressure to remove the solvent, and the residue was added to a chloroform / water mixture. The organic layer was washed with water and dried with magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform) to give [1] benzothieno [2,3-b] [1,5] benzoxazepin-12 (11 H) -one (1.25 g) Melting point 240-242 ° C.

EXAMPLE 78 In the same manner as in example 77 and using 1, 2,3,4-tetrahydro-8-methyl- [1] benzothieno [2,3-b] [1,5] benzoxazepin-12 (11 H) -one (1.87 g), dicrodiodic-p-benzoquinone (3.1 g) and benzene (55 ml), 8-methyl- [1] benzothieno [2,3-b] [1,5] benzoxazepin-12 (11 H) was obtained -one (1.5 g). 1 H-NMR (400 MHz, DMSO-d 6) d: 10.26 (s, 1 H), 8.25 (d, J = 8.3 Hz, 1 H), 7.89 (d, J = 7.8 Hz <1 H), 7.43-7.38 (m, 2H), 7.14-7.06 (m, 2H9, 7.10 (s, 1 H9, 2.09 (s, 3H) EXAMPLE 79 In the same manner as in example 77 and using 8-fluoro-1, 2,3,4-tetrahydro- [1] benzothieno [2,3-b] [1,5] benzoxazepin-12 (11 H) -one dichlorodicyano-p-benzoquinone and benzene, 8-fluoro- [1] benzothieno [2,3-b] [1,5] benzoxazepine-12 (11 H) -one was obtained.

EXAMPLE 80 [1] Benzothieno [2,3-b] [1,5] benzoxazepin-12 (11 H) -one (0.7 g) was suspended in phosphorus oxychloride (5 ml) and N, N-dimethylaniline (0.17 ml) was added. ). The mixture was stirred at reflux with heating for 1 hour. The solvent was azeotropically evaporated with toluene under reduced pressure, and 1-methylpiperazine (10 mL) was added to the residue with ice cooling, and the mixture was stirred under reflux with heating for 40 minutes. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure.

Chloroform was added to the residue and the mixture was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform: methanol = 100: 1). The obtained oily substance was dissolved in ethyl acetate, and a solution of fumaric acid (135 mg) in ethanol was added. The obtained crystals were recrystallized with ethyl acetate / ethanol to give 12- (4-methylpiperazin-1-yl) - [1] benzothieno [2,3-b] [1,5] benzoxazepine-1/2 fumarate (264 mg ). Melting point 240-242 ° C.

EXAMPLE 81 In the same manner as in Example 80 and using 8-methyl- [1] benzothieno [2,3-b] [1,5] benzoxazepin-12 (11 H) -one (1.5 g), phosphorus oxychloride (15.3) mi), N, N-dimethylaniline (380 mg), 1-methylpiperazine (25 ml) and fumaric acid (176 mg), gave 8-methyl-12- (4-methylpiperazin-1-yl) - [1] benzothiene. [2,3-b] [1,5] benzoxazepine-1/2 fumarate 1/4 hydrate (221 mg). Melting point 140-141 ° C (ethanol / water) EXAMPLE 82 In the same manner as in Example 80 and using 8-fluoro- [1] benzothieno [2,3-b] [1,5] benzoxazepin-12 (11 H) -one, phosphorus oxychloride, N, N-dimethylaniline and 1-methylpiperazine, 8-fluoro-12- (4-methylpiperazin-1-yl) - [1] benzothieno [1,3-b] [1,5] benzoxazepine was obtained EXAMPLE 83 In the same manner as in Example 80 and using 1, 2,3,4-tetrahydro- [1] benzothieno [2,3-b] [1,5] benzoxazepin-12 (11 H) -one, (0.6 g ), phosphorus oxychloride (5 ml) N, N-dimethylaniline (0.14 ml), 1-methylpiperazine (10 ml) and fumaric acid (260 mg), fumarate of 1, 2,3,4-tetrahydro-12- was obtained (4-methylpiperazin-1-yl) - [1] benzothieno [2,3-b] [1,5] benzoxazepine (575 mg).

Melting point 247-249 ° C (ethanol / water).

EXAMPLE 84 In the same manner as in example 80 and using 1, 2,3,4-tetrahydro-8-methyl- [1] benzothieno [2,3-b] [1,5] benzoxazepin-12 (11 H) -one , phosphorus oxychloride, N, N-dimethylaniline and 1-methylpiperazine, was obtained 1, 2,3,4-tetrahydro-8-methyl-12 (4-methylpiperazin-1-yl) - [1] benzothieno [2,3-b] [1,5] benzoxazepine EXAMPLE 85 In the same manner as in Example 80 and using 8-fluoro-1, 2,3,4-tetrahydro- [1] benzothieno [2,3-b] [1, 5] benzoxazepin-12 (11 H) -one , phosphorus oxychloride, N, N-dimethylaniline and 1-methylpiperazine, 8-fluoro-1, 2,3,4-tetrahydro-12- (4-methylpiperazin-1-yl) - [1] benzothieno [2, 3-b] [1, 5] benzoxazepine.

EXAMPLE 66 Synthesis of starting material 2-Aminobenzenetiol (1.1 g) was dissolved in N, N, -dimethylformamide (25 ml) and 60% sodium hydride (360 mg) was added. The mixture was stirred at room temperature for 20 minutes. To the mixture was added ethyl 2-bromo-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate (2.6 g), and the mixture was stirred at 140 ° C for 1.5 hours and allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate (300 ml), washed with water (200 ml) and dried with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the obtained crude crystals were washed with isopropyl ether and filtered to give ethyl 2- (2-aminobenzothio) -4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate (1.4 g). 1 H-NMR (400 Hz, CDCl 3) d: 7.50 (d, J = 7.4 Hz, 1 H), 7.28 (m, 1 H), 6.80 (m, 2H), 4.43 (br, s, 2H), 4.38 (q, J = 7.3 Hz, 2H), 2.78 (m, 2H), 2.52 (m, 2H), 1.73-1.60 ( m, 4H), 1.41 (t, 3H).

EXAMPLE 86 Ethyl 2- (2-aminobenzothio) -4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate (1.4 g) was dissolved in N, N-dimethylformamide (20 ml) and hydride was added. 60% sodium (170 mg). The mixture was stirred at 80 ° C for 1.5 hours and 110 ° C for 45 minutes. The reaction mixture was allowed to cool and poured into water (300 ml), followed by acidification with 35% hydrochloric acid. Filtration of precipitated crystals gave 1, 2,3,4-tetrahydro [1] benzothieno [2,3-b] [1,5] benzothiazepin-12 (11 H) -one (1.3 g). 1 H-NMR (400 Hz, CDCl 3) d: 8.54 (br, s, 1 H), 7.79 (d, 1 H), 7.64-7.45 (m, 3 H), 3.27-2.82 (m, 4 H), 2.36-1.57 (m, 4H9.) Alternatively, in the same manner as in example 18 and using 2-bromo-4,5,6,7-tetrahydro-N- (2-mercapto-phenyl) -benzo [b] thiophene-3. carboxamide, methyl sulfoxide and potassium carbonate, 1, 2,3,4-tetrahydro [1] benzothieno [2,3-b] [1,5] benzothiazepin-12 (11 H) -one was obtained.

EXAMPLE 87 In the same manner as in example 18 and using 2-bromo-4,5,6,7-tetrahydro-N- (2-mercapto-4-methylphenyl) -benzo [b] thiophene-3-carboxamide, dimethyl sulfoxide and potassium carbonate, 1, 2,3,4-tetrahydro-8-methyl- [1] benzothieno [2,3-b] [1,5] benzothiazepin-12 (11H) -one, (1.87 g) was obtained. . 7 EXAMPLE 88 In the same manner as in Example 74 and using 2-bromo-4,5,6,7-tetrahydro-N- (4-fluro-2-mercapto-phenyl) -benzo [b] thiophene-3-carboxamide, dimethyl sulfoxide and potassium carbonate, 8-fluoro-1, 2,3,4-tetrahydro- [1] benzothieno [2,3-b] [1,5] benzothiazepin-12 (11 H) -one was obtained.

EXAMPLE 89 In the same manner as in example 77 and using 1, 2,3,4-tetrahydro- [1] benzothieno [2,3-b] [1,5] benzothiazepin-12 (11 H) -one (1.2 g) , dichlorodicyano-p-benzoquinone (2.1 g) and toluene (20 ml), [1] benzothieno [2,3-b] [1,5] benzothiazepin-12 (11 H) -one (500 mg) was obtained. 1 H-NMR (400 MHz, DMSO-d 6) d: 10.77 (br, s, 1 H), 8.10 (d, J = 8.3 Hz, 1 H), 7.96 (d, J = 6.4 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.42 (m, 3H), 7.31 (d, J = 8.4 Hz, 1 H), 7.19 (dd, J = 7.4, 7.8 Hz, 1 H).

EXAMPLE 90 In the same manner as in example 77 and using 1, 2,3,4-tetrahydro-8-methyl- [1] benzothieno [2,3-b] [1,5] benzothiazepin-12 (11 H) -one , dichlorodicyano-p-benzoquinone and benzene, 8-methyl- [1] -benzothieno [2,3-b] [1,5] benzothiazepin-12 (11 H) -one was obtained.

EXAMPLE 91 In the same manner as in example 77 and using 8-fluoro-1, 2,3,4-tetrahydro- [1] benzothieno [2,3-b] [1,5] benzothiazepin-12 (11 H) -one , dichlorodicyano-p-benzoquinone and benzene, 8-fluro- [1] -benzothieno [2,3-b] [1,5] benzothiazepin-12 (11 H) -one was obtained.

EXAMPLE 92 In the same manner as in example 80 and using [1] benzothieno [2,3-b] [1,5] benzothiazepin-12 (11 H) -one (500 mg), phosphorus oxychloride (6.3 g), N , N-dimethylaniline (109 mg) and 1-methylpiperazine (5 ml), was obtained 12- (4-methylpiperazine-1-yl) - [1] -benzothieno [2,3-b] [1,5] benzothiazepin- 12 (11 H) -one (278 mg). 1 H-NMR (400 MHz, CDCl 3) d: 7.87 (d, J = 7.8 Hz, 1 H), 7.70 (d, J = 7.8 Hz, 1 H), 7.38-7.29 (m, 3H), 7.20 (dd, J = 7.3, 7.8 Hz, 1 H), 7.07 (d, J = 8.3 Hz, 1 H), 6.91 (dd, J = 8.3, 8.5 Hz, 1 H), 4.11-3.84 (m, 2H), 3.24- 3.06 (m, 2H), 2.76 (m, 1 H), 2.50-2.30 (m, 3H), 2.33 (s, 3H).

EXAMPLE 93 In the same manner as in Example 80 and using 8-methyl- [1] benzothieno [2,3-b] [1,5] benzothiazepin-12 (11H) -one, phosphorus oxychloride, N, N-dimethylaniline, 1-methylpiperazine, 8-methyl-12- (4-methylpiperazine-1-yl) - [1] -benzothieno [2,3-b] [1,5] benzothiazepine was obtained.

EXAMPLE 94 In the same manner as in Example 80 and using 8-fluoro- [1] benzothieno [2,3-b] [1,5] benzothiazepin-12 (11 H) -one, phosphorus oxychloride, N, N- dimethylaniline and 1-methylpiperazine, there was obtained 8-fluoro-12- (4-methylpiperazin-1-yl) - [1] -benzothione [2,3-b] [1,5] benzothiazene.

EXAMPLE 95 In the same manner as in example 80 and using 1, 2,3,4-tetrahydro- [1] benzothieno [2,3-b] [1,5] benzothiazepin-12 (11 H) -one, phosphorus oxychloride , N, N-dimethylaniline and 1-methylpiperazine, 1, 2,3,4-tetrahydro-12- (4-methylpiperazine-1-yl) - [1] -benzothieno [2,3-b] [1, 5] benzothiazepine.

EXAMPLE 96 In the same manner as in example 80 and using 1, 2,3,4-tetrahydro-8-methyl- [1] benzothieno [2,3-b] [1,5] benzothiazepine-12 (11 H) -one , phosphorus oxychloride, N, N-dimethylaniline and 1-methylpiperazine, there was obtained 1, 2,3,4-tetrahydro-8-metii-12- (4-methylpiperazin-1-yl) - [1] -benzothieno [2 , 3-b] [1, 5] benzothiazepine.

EXAMPLE 97 In the same manner as in Example 80 and using 8-fluoro-1, 2,3,4-tetrahydro- [1] benzothieno [2,3-b] [1,5] benzothiazepin-12 (11 H) -one , phosphorus oxychloride, N, N-dimethylaniline and 1-methylpiperazine, there was obtained 8-fluoro-1, 2,3,4-tetrahydro-12- (4-methylpiperazin-1-yl) - [1] -benzothieno [2 , 3-b] [1, 5] benzothiazepine.

EXAMPLE 67 Synthesis of starting material 2-Bromo-5-methyl-3-thiophenecarboxylic acid (5 g) was suspended in thionyl chloride (20 ml) and the mixture was stirred at reflux with heating for 75 minutes. The thionyl chloride was evaporated under reduced pressure and the residue was dissolved in toluene (5 ml). This solution in toluene was added dropwise to a solution of 2-aminophenol (3.7 g) in pyridine (30 ml) at 0 ° C. The mixture was stirred at room temperature for 6 hours and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate. This solution was washed with dilute hydrochloric acid and saturated aqueous sodium bicarbonate solution and dried with sodium sulfate. The solvent was evaporated under reduced pressure and di-isopropyl ether was added to the residue. The precipitated crystals were collected by filtration and washed with hexane to give N- (2-hydroxyphenyl) -2-bromo-5-methyl-3-thiophenecarboxamide (5.5 g). 1 H-NMR (400 MHz, CDCl 3) d: 2.45 (3 H, s, CH 3), 6.92 (1 H, t, Ar H), 7.06 (1 H, d, Ar H), 7.16 (3 H, m, Ar H of thiophene ring) , 8.53, 8.63 (1 H, 1 H, br, br, NH, OH) EXAMPLE 68 Synthesis of starting material 2-Bromo-3-thiophenecarboxylic acid (30 g) was suspended in thionyl chloride (35 ml) and the mixture was stirred at reflux with heating for 1 hour. The thionyl chloride was evaporated under reduced pressure and the residue was dissolved in toluene (10 ml). This solution in toluene was added dropwise to a solution of 2-aminophenol (19 g) in pyridine (100 ml) at 0 ° C. The mixture was stirred at room temperature for 20 minutes and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate. This solution was washed with dilute hydrochloric acid and saturated aqueous sodium bicarbonate solution and the precipitated crystals were collected by filtration to give N- (2-hydroxyphenyl) -2-bromo-3-thiophenecarboxamide (10 g). 1 H-NMR (400 MHz, CDCl 3) d: 6.82 (1 H, t, J = 7.8 Hz, Ar H), 6.91 (1 H, d, J = 8.3 Hz, Ar H), 7.00 (1 H, t, J = 7.8 ArH), 7.40 (1 H, d, J = 5.3 Hz, H of the thiophene ring), 7.68 (1 H, d, J = 5.9 Hz, H of the thiophene ring), 7.81 (1 H, d, J = 7.8 Hz, ArH), 7.81 (1 H, d, J = 7.8 Hz, ArH), 9.30 (1 H, br.NH or OH), 9.87 (1 H, br, NH or OH) EXAMPLE 69 Synthesis of starting material 2-Bromo-5-methyl-3-thiophenecarboxylic acid (3 g) was suspended in thionyl chloride (15 ml) and the mixture was stirred under reflux with heating for 40 minutes. The thionyl chloride was evaporated under reduced pressure and the residue was dissolved in toluene (5 ml). This solution in toluene was added dropwise to a solution of 2-amino-4-fluorophenol (1.7 g) in pyridine (20 ml) at 0 ° C. The mixture was stirred at room temperature for 1.5 hours and the solvent was evaporated under reduced pressure. Water-ethyl acetate was added to the residue. The precipitated crystals were collected by filtration to give N- (3-fluoro-6-hydroxyphenyl) -2-bromo-5-methyl-3-thiophenecarboxamide (2.1 g). The filtrate was extracted three times with ethyl acetate and the obtained organic layer was washed with water. The organic layer was dried with sodium sulfate and the solvent was evaporated under reduced pressure. To the residue was added ethyl acetate and the precipitated crystals were collected by filtration to give N- (3-fluoro-6-hydroxyphenyl) -2-bromo-5-methyl-3-thiophenecarboxamide (1.3 g). Melting point 210-212 ° C.

EXAMPLE 70 Synthesis of starting material 2-Bromo-4,5-dimethyl-3-thiophenecarboxylic acid (2.9 g) was suspended in thionyl chloride (15 ml) and the mixture was stirred at reflux with heating for 65 minutes. The thionyl chloride was evaporated under reduced pressure and the residue was dissolved in toluene (25 ml). This solution in toluene was added dropwise to a solution of 2-aminophenol (1.5 g) in pyridine (30 ml) at 0 ° C. The mixture was stirred at room temperature for 1.5 hours and the solvent was evaporated under reduced pressure. To the residue was added ethyl acetate and the mixture was washed with dilute hydrochloric acid, and water and saturated brine. The organic layer was dried with magnesium sulfate and the solvent was evaporated under reduced pressure. Di-isopropyl ether was added to the residue and the precipitated crystals were collected by filtration to give N- (2-hydroxyphenyl) -2-bromo-4,5-dimethyl-3-thiophenecarboxamide (3.3 g). 1 H-NMR (400 MHz, CDCl 3) d: 2.20 (3 H, s, CH 3), 2.33 (3 H, s, CH 3), 6.90 (2 H, m, Ar H), 7.03 (1 H, m, Ar H), 7.87 ( 1 H, m, ArH).

EXAMPLE 71 Synthesis of starting material 2-Bromo-5-methyl-3-thiophenecarboxylic acid (3 g) was suspended in thionyl chloride (15 ml) and the mixture was stirred under reflux with heating for 70 minutes. The thionyl chloride was evaporated under reduced pressure and the residue was dissolved in toluene (20 ml). This solution in toluene was added dropwise to a solution of 2-amino-5-methylphenol (1.7 g) in pyridine (20 ml) at 0 ° C. The mixture was stirred at room temperature for 2 hours and the solvent was evaporated under reduced pressure. After this, dilute hydrochloric acid-ethyl acetate was added. The precipitated crystals were collected by filtration to give N- (2-hydroxy-4-methylphenyl) -2-bromo-5-methyl-3-thiophenecarboxamide (3.3 g). Melting point 210-212 ° C.

EXAMPLE 72 Synthesis of starting material 2-Bromo-5-methyl-3-thiophenecarboxylic acid (2 g) was suspended in thionyl chloride (10 ml) and the mixture was stirred under reflux with heating for 50 minutes. The thionyl chloride was evaporated under reduced pressure and the residue was dissolved in toluene (20 ml). This solution in toluene was added dropwise to a solution of 2-amino-4-methylphenol (1.1 g) in pyridine (20 ml) at 0 ° C. The mixture was stirred at room temperature for 2.5 hours and the solvent was evaporated under reduced pressure. After this, ethyl acetate-di-isopropyl ether was added. The precipitated crystals were collected by filtration to give N- (2-hydroxy-5-methylphenyl) -2-bromo-5-methyl-3-thiophenecarboxamide (2.6 g). Melting point 173-175 ° C.

EXAMPLE 73 Synthesis of starting material 2-Bromo-5-methyl-3-thiophenecarboxylic acid (3.5 g) was suspended in thionyl chloride (17 ml) and the mixture was stirred under reflux with heating for 1 hour. Thionyl chloride was evaporated under reduced pressure and the residue was dissolved in toluene (20 ml). This solution in toluene was added dropwise to a solution of 2-amino-4-chlorophenol (2.3 g) in pyridine (35 ml) at 0 ° C. The mixture was stirred at room temperature for 1.5 hours and the solvent was evaporated under reduced pressure. To the residue was added ethyl acetate-di-isopropyl ether and the precipitated crystals were collected by filtration and washed with dilute hydrochloric acid and then with di-isopropyl ether to give N- (3-chloro-6-hydroxyphenyl) -2- Bromo-5-methyl-3-thiophenecarboxamide (4.1 g). Melting point: 232-235 ° C.

EXAMPLE 74 Synthesis of starting material 2-Bromo-5-methyl-3-thiophenecarboxylic acid (4.6 g) was suspended in thionyl chloride (15 ml) and the mixture was stirred under reflux with heating for 35 minutes. The thionyl chloride was evaporated under reduced pressure and the residue was dissolved in toluene (20 ml). This solution in toluene was added dropwise to a solution of 2-amino-5-chlorophenol (3.0 g) in pyridine (15 ml) at 0 ° C. The mixture was stirred at room temperature for one hour and poured into dilute hydrochloric acid-ethyl acetate. The precipitated crystals were collected by filtration to give N- (4-chloro-2-hydroxyphenyl) -2-bromo-5-methyl-3-thiophenecarboxamide (3.4 g). 1 H-NMR (400 MHz, CD 3 OD) d: 2.42 (3 H, s, CH 3), 6.87 (1 H, d, J = 8.8 Hz, Ar H), 6.90 (1 H, s, H of the thiophene ring), 7.12 (1 H, s, ArH), 7.84 (1 H, d, J = 8.8 Hz, ArH), 9.23 (1 H, br, NH or OH), 10.48 (1 H, br, NH or OH).

EXAMPLE 75 Synthesis of starting material 2-Bromo-5-methyl-3-thiophenecarbonyl chloride (2.6 g), prepared in the same manner as indicated above from 2-bromo-5-methyl-3-thiophenecarboxylic acid and thionyl chloride, was suspended in toluene ( 20 mi). This solution in toluene was added dropwise to a solution of 2-amino-5-methoxyphenol (2.0 g) in pyridine (50 ml) at 0 ° C. The mixture was stirred at room temperature for 2.5 hours and the solvent was evaporated under reduced pressure. The precipitated crystals were collected by filtration and washed with dilute hydrochloric acid and diesisopropyl ether to give N- (2-hydroxy-4-, methoxyphenyl) -2-bromo-5-methyl-3-thiophenecarboxamide (2.1 g). Melting point 183-184 ° C EXAMPLE 76 Synthesis of starting material 2-Bromo-5-methyl-3-thiophenecarbonyl chloride (2.6 g), prepared in the same manner as indicated above from 2-bromo-5-methyl-3-thiophenecarboxylic acid and thionyl chloride, was suspended in toluene ( 20 mi). This solution in toluene was added dropwise to a solution of 2-amino-3-methylphenol (1.4 g) in pyridine (30 ml) at 0 ° C. The mixture was stirred at room temperature for 3 hours and di-isopropyl ether-ethyl acetate was added. The solvent was evaporated under reduced pressure. The precipitated crystals were collected by filtration and washed with dilute hydrochloric acid and di-isopropyl ether to give N- (2-hydroxy-6-methylphenyl) -2-bromo-5-methyl-3-thiophenecarboxamide (3.0 g) . Melting point 164-167 ° C.

EXAMPLE 77 Synthesis of starting material In the same manner as in example 67 of synthesis of starting material and using 2-bromo-5-methyl-3-thiophenecarboxylic acid, thionyl chloride and 2-amino-5-fluorophenol, N- (4-fluoro) was obtained. -2-hydroxyphenyl) -2-bromo-5-methyl-3-thiophenecarboxamide.

EXAMPLE 78 Synthesis of starting material In the same manner as in Example 67 of synthesis of starting material and using 2-bromo-5-methyl-3-thiophenecarboxylic acid, thionyl chloride and 2-amino-6-methylphenol, N- (2-hydroxy) was obtained 3-methylphenyl) -2-bromo-5-methyl-3-thiophenecarboxamide.

EXAMPLE 79 Synthesis of starting material In the same manner as in Example 67 of synthesis of starting material and using 2-bromo-5-methyl-3-thiophenecarboxylic acid, thionyl chloride and 2-amino-5-nitrophenol, N- (2-hydroxy) was obtained -4-nitrophenyl) -2-bromo-5-methyl-3-thiophenecarboxamide EXAMPLE 80 Synthesis of starting material In the same manner as in Example 67 of synthesis of starting material and using 2-bromo-5-methyl-3-thiophenecarboxylic acid, thionyl chloride and 2-amino-4-nitrophenol, N- (2-hydroxy) was obtained -5-nitrophenyl) -2-bromo-5-methyl-3-thiophenecarboxamide.

EXAMPLE 81 Synthesis of starting material 2-Bromo-5-methyl-3-thiophenecarboxylic acid (2.52 g) was suspended in thionyl chloride (12 mL), the mixture was stirred at 60 ° C for 70 minutes. The thionyl chloride was evaporated under reduced pressure and the residue was dissolved in toluene (20 ml). This solution in toluene was added dropwise to a solution of 2-amino-6-methoxyphenol hydrochloride (2.0 g) in pyridine (42 ml) at 0 ° C. The mixture was stirred at room temperature for 2 hours and the solvent was evaporated under reduced pressure. Ethyl acetate-d-isopropyl ether was added to the residue. The precipitated crystals were collected by filtration and washed with 0.5N hydrochloric acid., di-isopropyl ether and hexane to give N- (2-hydroxy-3-methoxyphenyl) -2-bromo-5-methyl-3-thiophenecarboxamide (3.46 g). Melting point: 169-172 ° C. 1 H-NMR (400 MHz, CDCl 3) d: 2.41 (3 H, s, CH 3), 3.89 (3 H, s, CH 3), 6.27 (1 H, s, OH), 6.68 (1 H, d, J = 8.3 Hz , ArH), 6.86 (1 H, dd, J = 8.3 Hz, ArH), 7.09 (1 H, s, H of the thiophene ring), 8.62 (1 H, br, s, NH). MS: m / e 342.

EXAMPLE 98 To a solution of N- (2-hydroxyphenyl) -2-bromo-5-methyl-3-thiophenecarboxamide (15 g) in dimethyl sulfoxide (100 ml) was added potassium carbonate (13 g), and the mixture was stirred at 140 ° C for 1.5 hours. The reaction system was cooled to room temperature and the reaction mixture was poured into water (800 ml). After neutralizing with hydrochloric acid, the mixture was extracted twice with chloroform and washed with water and with saturated aqueous sodium bicarbonate solution. The organic layer was dried with sodium sulfate and the solvent was evaporated under reduced pressure. Chloroform was added to the residue and the crystals were collected by filtration to give 2-methylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (3.3 g). 1 H-NMR (400 MHz, DMSO-d 6) d: 2.31 (1 H, s, CH 3), 6.72 (1 H, s, H of the thiophene ring), 7.09-7.23 (4 H, m, Ar H), 10.12 ( 1 H, br, NH).

EXAMPLE 99 To a solution of N- (2-hydroxyphenyl) -2-bromo-3-thiophenecarboxamide (16 g) in dimethyl sulfoxide (160 ml) was added potassium carbonate (15 g) and the mixture was stirred at 150-160 °. C for 25 minutes. The reaction system was cooled to room temperature and the reaction mixture was poured into water-ethyl acetate. The crystals were collected by filtration and washed with water and di-isopropyl ether to give thieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (5.3 g). 1 H-NMR (400 MHz, DMSO-d 6) d: 7.02 (2H, s, H of the thiophene ring), 7.12-7.26 (4H, m, ArH), 10.20 (1 H, br, NH).

EXAMPLE 100 To a solution of N- (3-fluoro-6-hydroxyphenyl) -2-bromo-3-thiophenecarboxamide (3.3 g) in dimethyl sulfoxide (100 ml) was added potassium carbonate (2.8 g), and the mixture was stirred at 140 ° C for 1 hour. The reaction system was cooled to room temperature and the reaction mixture was poured diluted hydrochloric acid with ice cooling. The precipitated crystals were collected by filtration, dissolved in chloroform, washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform: methanol = 99.5: 0.5). The solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue and the precipitated crystals were collected by filtration to give 7-fluoro-2-methylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (350 mg). Melting point: 274-275 ° C.

EXAMPLE 101 To a solution of N- (2-hydroxyphenyl) -2-bromo-4,5-d-methyl-3-thiophenecarboxamide (3.3 g) in dimethyl sulfoxide (50 ml) was added potassium carbonate (2.8 g), and the mixture was stirred at 160-170 ° C for 20 minutes. The reaction system was cooled to room temperature and the reaction mixture was poured into water-ethyl acetate. The insoluble matter was filtered and the filtrate was extracted with ethyl acetate, washed with water and dried with magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 2,3-dimethylthieno [2,3-b] [1, 5] benzoxazepin-4 (5H) -one (1.4 g). 1 H-NMR (400 MHz, DMSO-d 6) d: 2.13 (3 H, s, CH 3), 2.21 (3 H, s, CH 3), 7.11-7.22 (4 H, m, Ar H), 10.17 (1 H, br, NH ).

EXAMPLE 102 To a solution of N- (2-hydroxy-4-methylphenyl) -2-bromo-3-thiophenecarboxamide (3.4 g) in dimethyl sulfoxide (30 mL) was added potassium carbonate (2.9 g) and the mixture was stirred at room temperature. 140-150 ° C for 1 hour. The reaction system was cooled to room temperature and the reaction mixture was poured into water. The precipitated crystals were collected by filtration, washed with water and purified by column chromatography with silica gel (chloroform) to give 2,8-dimethylinethane [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.4 g) .di-isopropyl ether to give thieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.2 g). Melting point: 211 -215 ° C.

EXAMPLE 103 To a solution of N- (2-hydroxy-5-methylphenyl) -2-bromo-3-thiophenecarboxamide (2.9 g) in dimethyl sulfoxide (24 ml) was added potassium carbonate (2.4 g) and the mixture was stirred at 140-150 ° C for 2 hours. The reaction system was cooled to room temperature and the reaction mixture was poured into ice water. The precipitated crystals were collected by filtration. The filtrate was extracted twice with chloroform and the organic layer was dried with magnesium sulfate. The solvent was evaporated under reduced pressure. The residue and the aforementioned crystals were combined and purified by column chromatography with silica gel (chloroform: methanol = 20: 1). The solid obtained was collected by filtration from hexane to give 2, 7-dimethylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one d -0 g). Melting point: 175-179 ° C.

EXAMPLE 104 To a solution of N- (3-chloro-6-hydroxyphenyl) -2-bromo-3-thiophenecarboxamide (4.1 g) in dimethyl sulfoxide (33 ml) was added potassium carbonate (3.3 g) and the mixture was stirred at room temperature. 140-150 ° C for 75 minutes. The reaction system was cooled to room temperature and the reaction mixture was poured into ice water. The precipitated crystals were collected by filtration. The filtrate was extracted twice with chloroform, the organic layer was dried with magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue and the above-mentioned crystals were combined and purified by column chromatography with silica gel (chloroform: methanol = 20: 1, hexane: ethyl acetate = 1: ethyl acetate: methanol = 20: 1). The solid obtained was collected by filtration from hexane: ethyl acetate to give 7-chloro-2-methylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (660 mg). Melting point: 250-253 ° C.

EXAMPLE 105 The similar reaction is carried out using N- (4-chloro-2-hydroxyphenyl) -bromo-5-methyl-3-thiophenecarboxamide and potassium carbonate to give 8-chloro-methylthieno [2,3-b] [1, 5] benzoxazepin-4 (5H) -one.

EXAMPLE 106 The similar reaction is performed using N- (4-fluoro-2-hydroxyphenyl) -bromo-5-methyl-3-thiophenecarboxamide and potassium carbonate to give 8-fluoro-methylthieno [2,3-b] [1, 5] benzoxazepin-4 (5H) -one.

EXAMPLE 107 To a solution of N- (2-hydroxy-4-methoxyphenyl) -2-bromo-5-methyl-3-thiophenecarboxamide (2.1 g) in dimethyl sulfoxide (17 ml) was added potassium carbonate (1.7 g) and the The mixture was stirred at 145 ° C for 2 hours. The reaction system was cooled to room temperature and the reaction mixture was poured into ice water. The precipitated crystals were collected by filtration and the obtained crystals were purified by column chromatography with silica gel (chloroform: methanol = 20: 0-20: 1). The solid obtained was collected by filtration from di-isopropyl ether-ethyl acetate-methanol to give 8-methoxy-2-methylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one ( 530 mg). 1 H NMR (400 MHz, DMSO-d 6) d: 2.13 (3 H, s, CH 3), 3.72 (3 H, s, OCH3), 6.52 (1 H, s, H of the thiophene ring), 6.70-7.07 (2H, m, ArH), 7.28 (1 H, d, ArH), 10.25 (1 H, br, NH).

EXAMPLE 108 To a solution of N- (2-hydroxy-6-methylphenyl) -2-bromo-5-methyl-3-thiophenecarboxamide (3.0 g) in dimethyl sulfoxide (25 ml) was added potassium carbonate (2.5 g) and the mixture it was stirred at 145 ° C for 2 hours. The reaction system was cooled to room temperature and the reaction mixture was poured into ice water. The precipitated crystals were collected by filtration and the filtrate was extracted with chloroform, washed twice with water and dried with sodium sulfate. The solvent was evaporated under reduced pressure and the residue and crystals obtained above were purified by column chromatography with silica gel (chloroform: methanol = 20: 0-20: 1). The solid obtained was collected by filtration from di-isopropyl ether-hexane to give 2,6-dimethylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (700 mg). Melting point: 198-200 ° C.

EXAMPLE 109 In the same manner as in example 98 and using N- (2-hydroxy-3-methylphenyl) -2-bromo-5-methyl-3-thiophenecarboxamide and potassium carbonate, there is obtained 2,9-dimethylthieno [2,3 -b] [1, 5] benzoxazepin-4 (5H) -one.

EXAMPLE 110 Thieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (2 g) was suspended in acetic acid (30 ml) and a solution of bromine (1.5 g) in acetic acid (10 g) was added. mi), drop by drop, in a period of 30 minutes. The mixture was stirred at room temperature for 35 minutes and poured into water. The precipitated crystals were collected by filtration and washed with water and di-isopropyl ether to give 2-bromothieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (2.2 g). 1 H-NMR (400 MHz, DMSO-d 6) d: 7.12-7.16 (3H, m, ArH, H of the thiophene ring), 7.20-7.26 (2H, m, ArH), 10.29 (1 H, br, NH) .

EXAMPLE 111 2-Bromothieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.0 g) was suspended in 2M sodium carbonate (8 ml) -toluene (8 ml) -ethanol (8 ml) and fenium borate (620 mg) and tetrakisphenylphosphine palladium (390 mg) were added. The mixture was stirred under reflux with heating for 80 minutes. The reaction system was cooled to room temperature and diisopropyl ether and ethyl acetate were added. The precipitated crystals were collected by filtration and the crystals obtained were washed with ethyl acetate and water to give 2-phenylthieno [2]., 3-b] [1, 5] benzoxazepin-4 (5H) -one (830 mg). 1 H-NMR (400 MHz, DMSO-d 6) d: 7.18-7.46 (8H, m, ArH), 7.65 (2H, m, ArH), 10.34 (1 H, br, NH).

EXAMPLE 112 Thieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (5 g) was suspended in 1,2-dichloroethane (50 ml) and acetyl chloride (2.2 g) was added. To this reaction system aluminum chloride was added in portions (15 g) under cooling with ice and the mixture was stirred at room temperature for 10 minutes. The reaction system was poured on ice. Chloroform was added and the mixture was stirred for 15 minutes. The precipitated crystals were collected by filtration to give 2-acetylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (5.2 g). 1 H-NMR (400 MHz, CDCl 3) d: 2.50 (3 H, s, CH 3), 6.97 (1 H, d, Ar H), 7. 17-7.20 (3H, m, ArH), 7.80 (1 H, s, H of the thiophene ring).

EXAMPLE 113 Thieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.5 g) was suspended in 1,2-dichloroethane (20 ml) and propionyl chloride (770 mg) was added. To this reaction system aluminum chloride was added in portions (4.7 g) under cooling with ice. The insoluble matter was filtered and the filtrate was poured into ice water and chloroform was added. The aqueous layer was extracted twice with chloroform and the combined organic layer was dried with sodium sulfate. The solvent was evaporated under reduced pressure and the precipitated crystals were collected by filtration to give 2-propionyl-thieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.4 g). Melting point: 205-210 ° C (decomposition).

EXAMPLE 114 Thieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.5 g) was suspended in 1,2-dichloroethane (20 ml) and butyryl chloride (880 mg) was added. To this reaction system aluminum chloride was added in portions (4.6 g) under cooling with ice. The mixture was stirred at room temperature for 45 minutes. The insoluble matter was filtered and the filtrate was poured into ice water and chloroform was added. The organic layer was washed with water and dried with sodium sulfate. The solvent was evaporated under reduced pressure and water-ethanol was added. The precipitated crystals were collected by filtration. The crystals obtained were washed with chloroform-di-isopropyl ether to give 2-butyryl-thieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.2 g). 1 H-NMR (400 MHz, DMSO-d 6) d: 0.89 (3 H, t, J = 7.3 Hz, CH 3), 1.59 (2 H, m, CH 2), 2.90 (2 H, t, J = 7.3 Hz, CH 2), 7.14-7.31 (4H, m, ArH), 7.93 (1 H, s, H of the thiophene ring), 10.41 (1 H, br, NH).

EXAMPLE 115 Thieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.9 g) was suspended in methylene chloride (20 ml) and dichloromethylmethyl ether (4.0 g) was added to this reaction system. aluminum chloride was added in portions (4.6 g) under cooling with ice and the mixture was stirred for 15 minutes. The reaction mixture was poured into ice water-chloroform and the mixture was stirred at room temperature for 20 minutes. The aqueous layer was extracted 5 times with chloroform and the combined organic layer was dried with sodium sulfate. The solvent was evaporated under reduced pressure and di-isopropyl ether was added to the residue. The precipitated crystals were collected by filtration to give 2-formylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.2 g). 1 H-NMR (400 MHz, DMSO-d 6) d: 7.14-7.33 (4H, m, ArH), 8.08 (1 H, s, H of the thiophene ring), 9.81 (1 H, s, HC = 0), 10.45 (1 H, br, NH).

EXAMPLE 116 2-Acetylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.5 g) was dissolved in trifluoroacetic acid (20 ml) and triethylsilane (2 g) was added. The mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in chloroform. The mixture was washed with water and saturated aqueous sodium bicarbonate solution and dried with sodium sulfate. The solvent was evaporated under reduced pressure. To the residue chloroform and ethyl acetate were added and the precipitated crystals were collected by filtration, the crystals obtained were washed with di-isopropyl ether to give 2-ethylthieno [2,3-b] [1,5] benzoxazepin-4 (5H ) -one (1.1 g). 1 H-NMR (400 MHz, CDCl 3) d: 1.26 (3 H, t, J = 7.3 Hz, CH 3), 2. 69 (2H, q, J = 7.0 Hz, 16.1 Hz, CH2), 6.82 (1H, s, H of the thiophene ring) 6.93 (1 H, d, J = 7.8 Hz, ArH), 7.10-7.18 (3H, m, ArH).

EXAMPLE 117 2-Propionyl-thieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.2 g) was dissolved in trifluoroacetic acid (20 ml) and triethylsilane (2 g) was added. The mixture was stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in chloroform. The mixture was washed with water and saturated aqueous sodium bicarbonate solution and dried with sodium sulfate. The solvent was evaporated under reduced pressure. Chloroform and ethyl acetate were added to the residue and the precipitated crystals were collected by filtration. The crystals obtained were washed with di-isopropyl ether to give 2-propylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (930 mg). H-NMR (400 MHz, CDCl 3) d: 0.94 (3 H, t, J = 7.3 Hz, CH 3), 1.61 (2 H, m, CH 2), 2.60 (2 H, t, J = 7.3 Hz, CH 2), 6.79 ( 1 H, s, H of the thiophene ring) 6.91 (1H, d, J = 7.3 Hz, ArH), 7.08-7.15 (3H, m, ArH), 7.34 (br, NH).

EXAMPLE 118 2-Butyrylieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.1 g) was dissolved in trifluoroacetic acid (20 ml) and triethylsilane (1.3 g) was added. The mixture was stirred at room temperature for 72 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in chloroform. The mixture was washed with water and saturated aqueous sodium bicarbonate solution and dried with sodium sulfate. The solvent was evaporated under reduced pressure. Chloroform and ethyl acetate were added to the residue and the precipitated crystals were collected by filtration. The obtained crystals were washed with di-isopropyl ether to give 2-butylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (600 mg). 1 H-NMR (400 MHz, DMSO-d 6) d: 0.87 (3 H, t, J = 7.3 Hz, CH 3), 1. 30 (2H, m, CH2), 1.52 (2H, m, CH2), 2.65 (2H, t, J = 7.80 Hz, CH2), 6.74 (1H, s, H of the thiophene ring), 7.11-7.23 ( 4H, m, ArH), 10.14 (1 H, br, NH).

EXAMPLE 119 2-Acetylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.8 g) was dissolved in ether (15 mL) and 20 equivalent amounts of methyl magnesium iodide were added under cooling with ice. The mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into 1M hydrochloric acid under cooling with ice and the insoluble material was filtered. The resulting mixture was extracted twice with chloroform, the chloroform layer was dried with sodium sulfate and the solvent was evaporated under reduced pressure. The residue was suspended in toluene and a catalytic amount of p-toluenesulfonic acid was added. The mixture was stirred under reflux with heating for 20 minutes. The reaction system was cooled to room temperature and the mixture was washed with saturated aqueous sodium bicarbonate solution. The solvent was evaporated under reduced pressure and di-isopropyl ether was added to the residue. The precipitated crystals were collected by filtration to give 2-isopropenylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (800 mg). 1 H-NMR (400 MHz, DMSO-d 6) d: 2.04 (3H, s, CH 3), 5.00 (1 H, s, olefin), 5.22 (1 H, s, olefin), 7.00 (1 H, s, H of the thiophene ring), 7.14-7.27 (4H, m, ArH), 10.25 (1 H, br, NH).

EXAMPLE 120 2-Isopropenyl-thieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (780 mg) was suspended in dioxane (40 ml) and 10% palladium on activated charcoal (100 mg) was added. ). Hydrogen was sealed in the mixture and this was stirred at 40 ° C, 50 atm for 7.5 hours. The catalyst was filtered and the solvent was evaporated under reduced pressure to give 2-isopropylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (600 mg). 1 H-NMR (400 MHz, DMSO-d 6) d: 1.21 (6H, d, J = 6.8 Hz, CH 3), 3.01 (1 H, m, CH), 6.75 (1 H, s, H of the thiophene ring) , 7.10-7.23 (4H, m, ArH), 10.15 (1 H, br, NH).

EXAMPLE 121 2-Formylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.6 g) was suspended in methanol (30 mL) and sodium borohydride (480 mg) was added. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water and extracted 3 times with chloroform. The organic layer was dried with sodium sulfate and the solvent was evaporated under reduced pressure. Chloroform and diisopropyl ether were added to the residue and the precipitated crystals were collected by filtration to give 2-hydroxymethyl-thieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.0 g). 1 H-NMR (400 MHz, DMSO-d 6) d: 1.21 (6H, d, J = 6.8 Hz, CH 3), 3.01 (1 H, m, CH), 6.75 (1 H, s, H of the thiophene ring) , 7.10-7.23 (4H, m, ArH), 10.14 (1 H, br, NH).

EXAMPLE 122 2-Hydroxymethyl-thieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.0 g) was dissolved in methylene chloride (10 ml) and triethylamine (450 mg) and methanesulfonyl chloride ( 500 mg). The mixture was stirred at room temperature for 15 minutes and the solvent was evaporated under reduced pressure. After this 2M dimethylamine / methanol was added and the mixture was stirred at room temperature for 14 hours. The solvent was evaporated under reduced pressure and chloroform was added to the residue. After washing with water, the aqueous layer was extracted twice with chloroform. The organic layer was dried with sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography with silica gel (ethyl acetate) to give 2- (N, N-dimethylaminomethyl) thieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one ( 500 mg). 1 H-NMR (400 MHz, DMSO-d 6) d: 1.98 (6H, s, CH 3), 3.46 (2H, s, CH 2), 6.87 (1H, s, H of the thiophene ring), 7.12-7.25 (4H, m, ArH), 10.15 (1 H, br, NH).

EXAMPLE 123 In the same manner as in example 98 and using N- (2-hydroxy-4-nitrophenyl) -2-bromo-5-methyl-3-thiophenecarboxamide and potassium carbonate, 2-methyl-8-nitrothieno is obtained [ 2,3-b] [1, 5] benzoxazepin-4 (5H) -one.

EXAMPLE 124 In the same manner as in example 98 and using N- (2-hydroxy-5-nitrophenyl) -2-bromo-5-methyl-3-thiophenecarboxamide and potassium carbonate, 2-methyl-7-nitrothieno [2 is obtained , 3-b] [1, 5] benzoxazepin-4 (5H) -one.

EXAMPLE 125 2-Methylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.0 g) was suspended in phosphorus oxychloride (6.4ml) and N, N-dimethylaniline (240 mg) was added. The mixture was stirred under reflux with heating for 1 hour. The solvent was completely evaporated azeotropically with toluene under reduced pressure, and 1-methylpiperazine (25 ml) was added to the residue. The mixture was stirred under reflux with heating for 40 minutes. The reaction system was cooled to room temperature and the solvent was evaporated under reduced pressure. Chloroform was added to the residue and the mixture was washed with water and saturated brine and dried with sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform: methanol = 100: 1). The obtained compound was recrystallized with di-isopropyl ether to give 2-methyl-4- (4-methylpiperazin-1-yl) - [1] thieno [2,3-b] [1,5] benzoxazepine (520 mg). Melting point: 132-133 ° C.

EXAMPLE 126 Thieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.2 g) was suspended in phosphorus oxychloride (8.5 ml) and N, N-dimethylaniline (310 mg) was added. The mixture was stirred under reflux with heating for 1 hour and the solvent was completely evaporated azeotropically with toluene under reduced pressure. 1-Methylpiperazine (25 ml) was added to the residue and the mixture was stirred under reflux with heating for 30 minutes. The reaction system was cooled to room temperature and the solvent was evaporated under reduced pressure. Chloroform was added to the residue and the mixture was washed with water and saturated brine and dried with sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (chloroform: methanol = 100: 1.5). The obtained compound was converted to fumarate, which was recrystallized with ethyl acetate to give fumarate of 4- (4-methylpiperazin-1-yl) - [1] thieno [2,3-b] [1, 5] Benzoxazepine (650 mg). Melting point: 200-202 ° C.

EXAMPLE 127 2-Bromothieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (800 mg) was suspended in phosphorus oxychloride (5 ml) and N, N-dimethylaniline (155 mg) was added. The mixture was stirred under reflux with heating for 1 hour and the solvent was completely evaporated azeotropically with toluene under reduced pressure. 1-Methiipiperazine (10 ml) was added to the residue and the mixture was stirred under reflux with heating for 30 minutes and then under reflux with heating for 5 minutes. The reaction system was cooled to room temperature and the solvent was evaporated under reduced pressure. Chloroform was added to the residue and the mixture was washed with water and saturated brine and dried with sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform: methanol = 100: 1). The obtained compound was recrystallized with di-isopropyl ether-ethyl acetate to give 2-bromo-4- (4-methylpiperazin-1-yl) -thieno [2,3-b] [1,5] benzoxazepine (300 mg) . Melting point: 150-151 ° C.

EXAMPLE 128 2-Acetylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.2 g) was suspended in phosphorus oxychloride (7 ml) and N, N-dimethylaniline (280 mg) was added. The mixture was stirred under reflux with heating for 1.5 hours. The solvent was completely evaporated azeotropically with toluene under reduced pressure. 1-Methylpiperazine (20 ml) was added to the residue and the mixture was stirred at 80 ° C for 15 minutes. The reaction system was cooled to room temperature and the solvent was evaporated under reduced pressure. Chloroform was added to the residue and the mixture was washed with water and saturated brine and dried with sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform: methanol = 100: 0.5). The obtained compound was recrystallized with di-isopropyl ether-ethyl acetate to give 2-acetyl-4- (4-methyl-piperazin-1-yl) -thieno [2,3-b] [1,5] benzoxazepine (80 mg) . Melting point: 143-144 ° C.

EXAMPLE 129 2-Phenylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.2 g) was suspended in phosphorus oxychloride (6.5 ml) and N, N-dimethylaniline (250 mg) was added. The mixture was stirred under reflux with heating for 1 hour. The solvent was completely evaporated azeotropically with toluene under reduced pressure and 1-methylpiperazine (20 ml) was added to the residue. The mixture was stirred under reflux with heating for 1 hour. The reaction system was cooled to room temperature and the solvent was evaporated under reduced pressure. To the residue-chloroform was added and the mixture was washed with water and saturated brine and dried with sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform: methanol = 100: 1). The obtained compound was recrystallized from ethyl acetate to give 4- (4-methylpiperazin-1-yl) -2-phenylthieno [2,3-b] [1,5] benzoxazepine (620 mg). Melting point: 163-164 ° C.

EXAMPLE 130 2-Ethylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.1 g) was suspended in phosphorus oxychloride (7 ml) and N, N-dimethylaniline (270 mg) was added. The mixture was stirred under reflux with heating for 3 hours and the solvent was completely evaporated azeotropically with toluene under reduced pressure. 1-Methylpiperazine (13 ml) was added to the residue and the mixture was stirred under reflux with heating for 1 hour. The reaction system was cooled to room temperature and the solvent was evaporated under reduced pressure. To the residue was added ethyl acetate and the mixture was washed with water and saturated brine and dried with sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform: methanol = 100: 1). The obtained compound was recrystallized with ethyl acetate-ethanol as maleate to give 2-ethyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1,5] benzoxazepine dimaleate (630 mg) .

Melting point: 154-156 ° C.

EXAMPLE 131 2-Propylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one was suspended (910 mg) in phosphorus oxychloride (6 ml) and N, N-dimethylaniline (220 mg) was added. The mixture was stirred under reflux with heating for 1 hour. The solvent was completely evaporated azeotropically with toluene under reduced pressure, and 1-methylpiperazine (10 ml) was added to the residue. The mixture was stirred under reflux with heating for 40 minutes. The reaction system was cooled to room temperature and the solvent was evaporated under reduced pressure. To the residue was added ethyl acetate and the mixture was washed with water and saturated brine and dried with sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform: methanol = 100: 1). The obtained compound was recrystallized with ethyl acetate as a maleate to give 4- (4-methylpiperazin-1-yl) -2-propylthieno [2,3-b] [1,5] benzoxazepine (550 mg). Melting point: 175-177 ° C.

EXAMPLE 132 2-Isopropylthieno [2,3-b] [1 was suspended, 5] benzoxazepin-4 (5H) -one (550 mg) in phosphorus oxychloride (3 ml) and N, N-dimethylaniline (120 mg) was added. The mixture was stirred under reflux with heating for 50 minutes. The solvent was completely evaporated azeotropically with toluene under reduced pressure and 1-methylpiperazine (6 ml) was added to the residue. The mixture was stirred under reflux with heating for 50 minutes. The reaction system was cooled to room temperature and the solvent was evaporated under reduced pressure. To the residue was added ethyl acetate and the mixture was washed with water and saturated brine and dried with sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform). The obtained compound was recrystallized with ethyl acetate-ethanol as maleate to give 2-isopropyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1,5] benzoxazepine dimaieate ( 280 mg). Melting point: 170-172 ° C.

EXAMPLE 133 2-Butyl thieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (580 mg) was suspended in phosphorus oxychloride (4 ml) and N, N-dimethylaniline (130 mg) was added. The mixture was stirred under reflux with heating for 1 hour. The solvent was completely evaporated azeotropically with toluene under reduced pressure and 1-methylpiperazine (6 ml) was added to the residue. The mixture was stirred under reflux with heating for 2 hours. The reaction system was cooled to room temperature and the solvent was evaporated under reduced pressure. Chloroform was added to the residue and the mixture was washed with water and saturated brine and dried with sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform: methanol = 100: 1). The obtained compound was recrystallized with ethyl acetate-ethanol as fumarate to give 2-butyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1,5] benzoxazepine fumarate (320 mg) . Melting point: 202-204 ° C.

EXAMPLE 134 2- (N, N-dimethylaminomethyl) thieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (500 mg) was suspended in phosphorus oxychloride (3 mL) and N, N was added. -dimethylaniline (110 mg). The mixture was stirred under reflux with heating for 1 hour. The solvent was completely evaporated azeotropically with toluene under reduced pressure and 1-methylpiperazine (6 ml) was added to the residue. The mixture was stirred under reflux with heating for 1 hour. The reaction system was cooled to room temperature and the solvent was evaporated under reduced pressure. Chloroform was added to the residue and the mixture was washed with water and saturated brine and dried with sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform: methanol = 100: 1). The obtained compound was recrystallized with ethyl acetate-ethanol as fumarate to give 2- (N, N-dimethylaminomethyl) -4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1 V fumarate] , 5] benzoxazepine 1/5 hydrate (71 mg). Melting point: 188-189 ° C.

EXAMPLE 135 2-Methylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (800 mg) was suspended in phosphorus oxychloride (5 ml) and N, N-dimethylaniline (218 mg) was added. The mixture was stirred under reflux with heating for 1 hour. The solvent was completely evaporated azeotropically with toluene under reduced pressure and 1-methylhomopiperazine (10 ml) was added to the residue. The mixture was stirred at 150 ° C for 1 hour. The reaction system was cooled to room temperature and chloroform was added. The mixture was washed with water and saturated brine and dried with sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform). The obtained compound was recrystallized from acetonitrile as hydrochloride to give 2-methyl-4- (4-methylhomopiperazin-1-yl) thieno [2,3-b] [1, 5] benzoxazepine 3/4 hydrate hydrochloride (270 mg). Melting point: 243-245 ° C.

EXAMPLE 136 2-Methylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (600 mg) was suspended in phosphorus oxychloride (4 ml) and N, N-dimethylaniline (160 mg) was added. The mixture was stirred under reflux with heating for 30 minutes. The solvent was completely azeotroped with toluene under reduced pressure and toluene (10 mL) and 1- [2- (2-hydroxyethoxy) ethyl] piperazine (2.5 mL) were added to the residue. The mixture was stirred under reflux with heating for 1 hour. The reaction system was cooled to room temperature and chloroform was added. The mixture was washed with water and saturated brine and dried with sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform: methanol = 100: 1). The obtained compound was recrystallized with hexane-ethyl acetate to give 4- [4- (2- (2-hydroxyethoxy) ethyl] piperazin-1-yl] -2-methylthieno [2,3-b] [1,5 ] benzoxazepine (350 mg) Melting point: 111-112 ° C.

EXAMPLE 137 7-Fluoro-2-methylthieno [2] was suspended, 3-b] [1,5] benzoxazepin-4 (5H) -one (500 mg) in phosphorus oxychloride (5 ml) and N, N-dimethylaniline (240 mg) was added. The mixture was stirred under reflux with heating for 1.5 hours. The solvent was completely evaporated azeotropically with toluene under reduced pressure and 1-methylpiperazine (6 ml) was added to the residue. The mixture was stirred under reflux with heating for 1 hour. The reaction system was cooled to room temperature and ethyl acetate was added. The mixture was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform: methanol = 100: 1). The obtained compound was recrystallized with ethyl acetate-ethanol as maleic acid to give 7-fluoro-2-methyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] dimaleate [1,5] benzoxazepine (450 mg). Melting point: 137-139 ° C.

EXAMPLE 138 2,8-Dimethylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1 g) was suspended in phosphorus oxychloride (6 ml) and N, N-dimethylaniline (220 mg) was added. ). The mixture was stirred under reflux with heating for 2.5 hours. The solvent was completely evaporated azeotropically with toluene under reduced pressure and 1-methylpiperazine (14 ml) was added to the residue. The mixture was stirred under reflux with heating for 2.5 hours and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1 -20: 1) and the obtained compound was recrystallized with di-isopropyl ether-hexane to give 2,8-dimethyl4- (4-methylpiperazine. -1-yl) thieno [2,3-b] [1,5] benzoxazepine (310 mg). Melting point: 149-150 ° C.

EXAMPLE 139 2,7-Dimethylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1 g) was suspended in phosphorus oxychloride (6 ml) and N, N-dimethylaniline (220 mg) was added. ). The mixture was stirred under reflux with heating for 2 hours. The solvent was completely evaporated azeotropically with toluene under reduced pressure and 1-methylpiperazine (14 ml) was added to the residue. The mixture was stirred under reflux with heating for 3.5 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform: methanol = 50: 1-20: 1) and the obtained compound was recrystallized with di-isopropyl ether-hexane to give 2, 7-Dimethyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1,5] benzoxazepine (330 mg). Melting point: 146-148 ° C.

EXAMPLE 140 2-Methylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.2 g) was suspended in phosphorus oxychloride (8 ml). N, N-dimethylaniline (280 mg) was added and the mixture was refluxed with heating for 3 hours. The solvent was completely evaporated azeotropically with toluene under reduced pressure. To the residue was added 1- (2-hydroxyethyl) piperazine (15 ml) and the mixture was stirred at 140-150 ° C for 2 hours. The reaction mixture was purified by column chromatography with silica gel (chloroform: methanol = 50: 1, ethyl acetate). The obtained compound was subsequently recrystallized from ethyl acetate-hexane to give 4- [4- (2-hydroxyethyl) piperazin-1-yl] -2-methylthieno [2,3-b] [1,5] benzoxazepine (210 mg ). Melting point: 87-89 ° C.

EXAMPLE 141 7-Chloro-2-methylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (600 mg) was suspended in phosphorus oxychloride (4 mL). N, N-Dimethylaniline (130 mg) was added and the mixture was stirred under reflux with stirring for 4.5 hours. The solvent was completely evaporated azeotropically with toluene under reduced pressure. To the residue was added 1-methylpiperazine (10 mL) and the mixture was stirred under reflux with stirring for 2 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform: methanol = 20: 1). The obtained compound was converted to fumarate, which was recrystallized with ethyl acetate-methanol to give 7-chloro-2-methyl-4- (4-methyl-piperazin-1-yl) t-ene [2,3-b] fumarate. ] [1,5] benzoxazepine (250 mg). Melting point: 227-228 ° C.

EXAMPLE 142 8-Methoxy-2-methylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (530 mg) was suspended in phosphorus oxychloride (3 mL). N, N-dimethylaniline (120 mg) was added and the mixture was stirred under reflux with heating for 1.5 hours. The solvent was completely evaporated azeotropically with toluene under reduced pressure and 1-methylpiperazine (9 ml) was added to the residue. The mixture was stirred under reflux with heating for 2 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform: methanol = 50: 1). The obtained compound was converted to fumarate, which was recrystallized with ethyl acetate-hexane-methanol to give 8-methoxy-2-methyl-4- (4-methyl-piperazin-1-yl) thieno fumarate [2,3-b] ] [1,5] benzoxazepine (330 mg). Melting point: 219-222 ° C (decomposition).

EXAMPLE 143 2,6-Dimethylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (860 mg) was suspended in phosphorus oxychloride (5 ml). N, N-dimethylaniline (190 mg) was added and the mixture was stirred under reflux with heating for 1.5 hours. The solvent was completely evaporated azeotropically with toluene under reduced pressure and 1-methylpiperazine (14 ml) was added to the residue. The mixture was stirred under reflux with heating for 1.5 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform: methanol = 50: 1-20: 1). The obtained compound was recrystallized from hexane to give 2,6-dimethyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1,5] benzoxazepine (490 mg). Melting point: 114-117 ° C.

EXAMPLE 144 2,3-Dimethylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.4 g) was suspended in phosphorus oxychloride (14 ml). N, N-dimethylaniline (340 mg) was added and the mixture was stirred under reflux with heating for 2.5 hours. The solvent was completely evaporated azeotropically with toluene under reduced pressure and 1-methylpiperazine (20 ml) was added to the residue. The mixture was stirred under reflux with heating for 1 hour. The reaction system was cooled to room temperature. Ethyl acetate was added and the mixture was washed with water and saturated brine and dried with sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (chloroform: methanol = 9: 1). The obtained compound was converted to fumarate, which was recrystallized with ethanol to give 1/2 fumarate of 2,3-dimethyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1, 5 ] benzoxazepine. 1 H NMR (400 MHz, DMSO-d 6) d 2.03 (3 H, s, CH 3), 2.21 (3 H, s, CH 3), 2.26 (3 H, s, CH 3), 2.35-3.80 (8 H, br, CH 2) , 6.61 (1 H, s, fumaric acid), 6.97-7.11 (4H, m, ArH).

EXAMPLE 145 In the same manner as in example 125 and using 2,9-dimethylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one, phosphorus oxychloride, N, N-dimethylaniline and 1-methylpiperazine, obtained 2,9-dimethyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1,5] benzoxazepine.

EXAMPLE 146 In the same manner as in example 125 and using 8-chloro-2-methylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one, phosphorus oxychloride, N, N-dimethylaniline and methylpiperazine, 8-chloro-2-methyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1,5] benzoxazepine was obtained.

EXAMPLE 147 In the same manner as in example 125 and using 8-fluoro-2-methylthieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one, phosphorus oxychloride, N, N-dimethylaniline and -methylpiperazine, 8-fluoro-2-methyl-4- (4-methylpiperazin-1 -yl) thieno [2,3-b] [1,5] benzoxazepine was obtained.

EXAMPLE 148 In the same manner as in example 125 and using 2-methy1-8-nitrothieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one, phosphorus oxychloride, N, N-dimethylaniline and 1-methylpiperazine, 2-methyl-4- (4-methylpiperazin-1-yl) -8-nitrothieno [2,3-b] [1,5] benzoxazepine was obtained.

EXAMPLE 149 In the same manner as in example 125 and using 2-methyl-7-nitrothieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one, phosphorus oxychloride, N, N-dimethylaniline and -methylpiperazine, 2-methyl-4- (4-methylpiperazin-1-yl) -7-nitrothieno [2,3-b] [1,5] benzoxazepine was obtained.

EXAMPLE 150 A solution of N- (2-hydroxy-3-methoxyphenyl) -2-bromo-5-methyl-3-thiophenecarboxamide (2.30 g) and sodium methoxide (549 mg) in N. N-dimethylformamide (12 ml) was stirred under reflux with heating for 19 hours. The reaction system was cooled to room temperature and the reaction mixture was poured into water (50 ml). The mixture was neutralized with hydrochloric acid, extracted twice with chloroform and washed with water. The organic layer was dried with sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent hexane: ethyl acetate = 1: 1) to give 2-methyl-9-methoxythieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.87 mg). Melting point: 160-164 ° C. 1 H-NMR (400 MHz, DMSO-d 6) d: 2.3 (3 H, s, CH 3), 3.81 (3 H, s, CH 3), 6.71 (1 H, s, H of the thiophene ring), 6.72 (1 H, d, J = 8.3 Hz, ArH), 6.86 (1 H, d, J = 8.3 Hz, ArH), 7.10 (1 H, dd, J = 8.3, 8.3 Hz), 10.09 (1 H, br, s, NH ). MS: m / e 261.

EXAMPLE 151 2-Methyl-9-methoxy-tieno [2,3-b] [1,5] benzoxazepin-4 (5H) -one (1.58 g) was suspended in phosphorus oxychloride (13 ml). N, N-dimethylaniline (330 mg) was added and the mixture was stirred under reflux with heating for 2 hours. The solvent was completely evaporated azeotropically with toluene under reduced pressure. To the residue was added 1-methylpiperazine (20 mL) and the mixture was stirred under reflux with heating for 3 hours. The reaction system was cooled to room temperature and solvent was evaporated under reduced pressure. Chloroform was added to the residue and the mixture was washed with water and saturated brine and dried with sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography with silica gel (chloroform: methanol = 100: 1) to give 2-methyl-9-methoxy-4- (4-methyl-piperazin-1-yl) thieno [2,3-b] [1, 5] benzoxazepine (1.90 g) as a liquid. The obtained liquid (350 mg) and fumaric acid (77 mg) were dissolved in methanol (20 ml) and the solvent was evaporated under reduced pressure. The obtained residue was washed with hot ethyl acetate to give 2-methyl-9-methoxy-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1,5] benzoxazepine fumarate (240 mg. ). Melting point: 239-241 ° C. 1 H-NMR (400 MHz, DMSO-d 6) d: 2.28 (3 H, s, CH 3), 2.33 (3 H, s, CH 3), 2.50-4.50 (8 H, br.s, CH 2 X 4), 3.78 (3 H, s, CH3), 6.51 (1 H, s, H of the thiophene ring), 6.58 (1 H, d, J = 7.8 Hz, ArH), 6.60 (2H, s, fumaric acid), 6.74 (1 H, d , J = 8.3 Hz, ArH), 6.98 (1 H, dd, J = 7.8 Hz, 8.3 Hz, ArH). MS: m / e 343. Cal analysis. for C18H2? N3O2S »C H4O4» 0.2H2O: C, 57.06; H, 5.53; N, 9.07%. Found: C, 57.06; H, 5.51; N, 9.08%.

EXAMPLE 152 2-Methyl [2,3-b] [1,5] benzoxazepin-4-one (370 mg) was dissolved in phosphorus oxychloride (7.3 g) and N, N-dimethylaniline (73 mg) was added. The mixture was stirred under reflux with heating for 40 minutes. The phosphorus oxychloride was completely evaporated azeotropically with toluene under reduced pressure. The residue was dissolved in toluene and the mixture was washed twice with saturated aqueous sodium bicarbonate solution. The organic layer was washed with sodium sulfate and the solvent was evaporated under reduced pressure. The residue was dissolved in acetonitrile (10 ml) and thereafter 8-methyl-3,8-diazabicyclo [3.2.1] octane dihydrochloride (240 mg) and diisopropylethylamine (470 mg) were added. The mixture was stirred under reflux with heating for 4.5 hours. 8-Methyl-3,8-3,8-diazabicyclo [3.2.1] octane dihydrochloride (240 mg) and diisopropylethylamine (470 mg) were added and 12 hours later 8-methyl-3,8-3 dihydrochloride was added , 8-diazabicyclo [3.2.1] octane (240 mg) and diisopropylethylamine (470 mg). The mixture was stirred for 6 hours. The reaction system was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate and washed three times with water. The organic layer was dried with sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the obtained compound was recrystallized from di-isopropyl ether to give 2-methyl-4- (8-methyl-3,8-diazabicyclo [3.2.1] octane-3-. il) thieno [2,3-b] [1,5] benzoxazepine (300 mg). Melting point: 156-159 ° C. 1 H-NMR (400 MHz, CDCl 3) d: 1.80 (2H, m), 2.01 (2H, m), 2.33 (3H, s), 2.35 (3H, s), 3.17 (4H.m), 4.00 (2H, m), 6.29 (1 H, s), 6.95-7.08 (4H, m).

EXAMPLE 153 Potassium tert-butoxide (718 mg) was suspended in 1,2-dimethoxyethane (35 ml) and the mixture was refluxed with heating. After this, 2- (2-aminoanilino) benzo [b] thiophene-3-carboxylic acid ethyl ester (1.0 g) dissolved in 1,2-dimethoxyethane (35 ml) was added dropwise in a period of 15 minutes. After 30 minutes, potassium tert-butoxide (359 mg) was added and the mixture was refluxed with heating for 1 hour. After the reaction is complete, the reaction is allowed to cool to room temperature and poured into 0.5N hydrochloric acid. The mixed solution was extracted 3 times with chloroform and washed with water and dried with magnesium sulfate. The solution was filtered and the solvent was evaporated under reduced pressure. The crude precipitated crystals were washed with ethyl acetate and di-isopropyl ether to give 6H- [1] benzothieno [2,3-b] [1,5] benzoxazepin-12 (11 H) -one (300 mg). 1 H-NMR (400 MHz, CDCl 3) d: 7.10-7.18 (3H, m), 7.36-7.44 (2H, m), 7.51 (1H, d, J = 8.8 Hz), 7.68 (1 H, m), 7.88 (1 H, d = 7.8 Hz), 7.97 (1 H, d = 7.8 Hz), 11.47 (1 H, br.s).

EXAMPLE 154 In the same manner as in example 153 and using potassium tert-butoxide and ethyl 2- (2-aminoanilino) -5-fluorobenzo [b] thiophene-3-carboxylate, 8-fluoro-6H- [1] was obtained. benzothieno [2,3-b] [1,5] benzoxazepin-12 (11H) -one. Melting point: 249-250 ° C. MS: m / e = 284. 1 H-NMR (270 MHz, CDCl 3) d: 11.54 (1 H, brs), 7.97-8.00 (1 H, m), 7.88-7.92 (1 H, m), 7.73 (1 H, s), 7.36-7.47 (3H, m), 7.10-7.18 (1 H, m), 6.96-7.04 (1 H, m).

EXAMPLE OF FORMULATION 1 Of the compounds of the present invention, a compound (50 mg) of the formula (I) is completely mixed with lactose (80 mg), corn starch (45 mg) and hydroxypropyl cellulose (3 mg) in a mixer. The mixed product is passed through a 200 mesh screen, dried at 50 ° C and passed through a 24 mesh screen. The product is combined with talc (3 mg) and magnesium stearate (1 mg) and tablets weighing 200 mg are obtained using a punch with a diameter of 9 mm. The tablets obtained can be coated with sugar or film as needed.

EXPERIMENTAL EXAMPLE 1 effects against neurotoxicity induced with MK-801 The compounds of the invention or vehicle (0.5% hydroxypropylcellulose, 2 ml / kg) were administered orally to female SD rats (approximately 9-12 weeks of age). One hour later, they were administered subcutaneously with MK-801 (0.5 mg / kg, 1 ml / kg) dissolved in distilled water. Four hours after the administration of MK-801, the rats were anesthetized with pentobarbital and exsanguinated with saline, which was followed by perfusion / fixation of the brain with formalin solution. Their brains were removed quickly after decapitation, and were subsequently fixed in the same formalin solution.

The brains were embedded in paraffin and cut into crown sections through the posterior cingulate cortex. The brain sections were stained with hematoxylin / eosin (HE). The number of vacuolated cells was counted by light microscopy and calculated as% of the vehicle-treated group. The inhibitory actions against neurotoxicity induced by MK-801 will be determined by the potentials to avoid the vacuolar reaction of the nerve cell by the administration of MK-801, which is expressed as% of the vehicle-treated group. As a result of the test, it indicated that the compounds of the formula (I) of the present invention suppressed the neurotoxicity induced with MK-801, in which 50% of the amount effective to inhibit the neurotoxicity induced with MK-801 it was not greater than 10 mg / kg.

EXPERIMENTAL EXAMPLE 2 Inhibitory action against methamphetamine-induced hyperactivity Groups of 15 male ddY mice (20-30 g, 4 weeks old) were used. These were administered orally with the test compounds. One hour later, they were administered methamphetamine in saline at 1 mg / kg subcutaneously and the mice were immediately placed in the test box (internal size: 25 X 15 X 14 (height) cm) each adapted with a pair of infrared beams. Interruptions of infrared beams were counted in a period of 30 minutes, from 10 minutes to 40 minutes after the start of observation, and used as an index of hyperactivity induced by methamphetamine. The ED50 values of the test compounds were calculated to suppress hyperactivity. As a result of the test, it indicated that the compounds of the formula (I) of this invention suppressed the hyperactivity induced by methamphetamine, wherein 50% of the amount effective to suppress methamphetamine-induced hyperactivity was not greater than 10 mg / kg.

EXPERIMENTAL EXAMPLE 3 Discrimination test driven by clozapine After reducing body weight with free access to the diet by up to 80%, limiting their diet, the rats were placed in a Skinner box equipped with two levers. In this, the rats were trained to press consecutively 10 times any of the right or left levers for reward reinforcement with supplied pellet. Subsequently, the rats were injected with clozapine or saline intraperitoneally in a random alternation sequence once per day (one session), where the administration of drug or saline did not occur for more than three consecutive days. When clozapine was administered at 5 mg / kg, one of the levers was paired with the reward and when saline was administered, the other lever was paired with the reward, which made the rats acquire the ability to discriminate. After acquiring the discrimination ability, the compound of the present invention was administered to confirm the generalization against clozapine. As a result of the test, it indicated that the compounds of the formula (I) of this invention were generalized to the discrimination stimulus to clozapine.

EXPERIMENTAL EXAMPLE 4 Discrimination test driven by MK-801 After reducing body weight with free access to the diet by up to 80%, limiting their diet, the rats were placed in a Skinner box equipped with two levers. In this, the rats were trained to press consecutively 10 times any of the right or left levers for reward reinforcement with supplied pellet. Subsequently, the rats were injected with MK-801 or saline intraperitoneally in a random alternation sequence once per day (one session), where the administration of drug or saline was not given for more than three consecutive days. . When MK-801 was administered at 0.1 mg / kg, one of the levers was paired with the reward and when saline was administered, the other lever was paired with the reward, which made the rats acquire the ability to discriminate . After acquiring the discrimination ability, the compound of the present invention was administered to confirm antagonism against discrimination to MK-801. As a result of the test, it indicated that the compounds of the formula (I) of this invention had antagonistic activity against the effect of the discrimination stimulus to MK-801.

EXPERIMENTAL EXAMPLE 5 Anti-apomorphine action Groups of 15 male ddY mice (20-30 g, 4 weeks old) were used. These were administered orally with the compounds of the present invention. One hour later, they were administered an aqueous solution of apomorphine in ascorbic acid at 0.5 mg / kg subcutaneously and the mice were immediately placed in the test box (internal size: 25 X 15 X 14 (height) cm) each adapted with a pair of infrared beams. The interruptions of the infrared beams immediately after the start of the observation until 30 minutes later were used as an index of hyperactivity induced by apomorphine. The compounds of the formula (I) of this invention suppressed the hyperactivity induced by apomorphine, wherein 50% of the amount effective to suppress the hyperactivity induced by apomorphine was not greater than 10 mg / kg.

EXPERIMENTAL EXAMPLE 6 Conditioned avoidance response inhibitory action Male Wistar rats (250-400 g, 14-25 weeks of age) were placed in the test box (30 X 30 X 35 (height) cm) equipped with a pole (diameter 2.5 cm) at its center and with grid in the floor and were given 5 seconds of sound stimulus (conditioned stimulus) and then 10 seconds of electric shock (CA 400v, 0.06 mA), which forced them to learn to avoid electric shock by climbing the pole during the sound stimulus. Each session consisted of 10 conditioned stimulus sequences and electric shocks at 2 minute intervals. Rats (10 per group) that stably showed at least 80% avoidance response were used for the study of the inhibitory action of the avoidance response conditioned by the compound of the present invention. The conditional avoidance response was determined at 1, 3, 5 and 24 hours after the administration of the compounds of the present invention, determining each time and 50% effective dose to inhibit the avoidance response conditioned by the compounds of the present invention. As a result of the test, 50% of the amount effective to inhibit the avoidance response conditioned by the compounds of the formula (I) of this invention was not greater than 20 mg / kg.

EXPERIMENTAL EXAMPLE 7 Induction of catalepsy Groups of 8 male ddY mice (20-30 g, 4 weeks old) were used for the test. These were administered with the test compounds and the time during which the mice were able to keep their front legs on a bar fixed horizontally at 4 cm in height with a body posture at an angle of 45 ° (catalepsy time) was measured. up to a maximum of 30 seconds to 1, 3, 5 and 7 hours after administration. The strength of the induction of catalepsy by the test compounds was determined by totaling the time to the points of the fourth determination at each dose (value of the sum) and regressively determined the dose that achieved the average time of 10 seconds, based on which of the values of DE10s was calculated. As a result of the test, the DEIOS value of the compounds of the formula (I) of this invention was not less than 100 mg / kg.

EXPERIMENTAL EXAMPLE 8 Analysis of intermediate in the oxidation with horseradish peroxidase A solution (10 μl) of the compounds of the invention 16 mM in dimethyl sulfoxide, a solution (100 μl) of 5 mM diethylenetriaminpentaacetic acid in phosphate buffer (50 mM, pH 7.4), a solution (100 μl) were mixed. ) of 100 mM glutathione in phosphate buffer (50 mM, pH 7.4), 50 mM phosphate buffer (750 μL) and 5,5-dimethyl-1-pyrroline N-oxide (1.1 μL), and added a solution (50 μl) of 0.5 mg / ml horseradish peroxidase in phosphate buffer (50 mM, pH 7.4). The mixture was incubated at 25 ° C for 4.5 minutes. The reaction mixture was subjected to ESR spectroscopy. As a result, it indicated that the compounds of the formula (I) of this invention did not produce cationic radical intermediate during the oxidation with horseradish peroxidase. From the experimental examples mentioned above, it is suggested that the compounds of the formula (I) of the present invention, particularly, the compounds of the formulas (IA) and (IB), showed anti-methamphetamine activity, anti-apomorphine activity , suppression of the conditioned avoidance response, suppression of neurotoxicity induced by MK-801, discrimination antagonism to MK-801 and generalization of clozapine discrimination in test animals such as mice and rats and are useful as antipsychotics. It is further suggested that these cause fewer side effects on the extrapyramidal system such as induction of catalepsy. It was further demonstrated that the compounds of the formula (I) of this invention do not produce a reaction intermediate corresponding to the cationic radical intermediate, which is possibly involved in agranulocytosis induced by clozapine, when the reaction intermediary thereof was analyzed using oxidation with horseradish peroxidase analyzed by ESR spectroscopy as a model reaction of the metabolism of the compounds of the invention. The compounds of formula (I) of the present invention, particularly, the compounds of formulas (IA) and (IB), are effective for both positive and negative symptoms of schizophrenia, are associated with fewer side effects such as motor disorder Extrapyramidal and the like are less associated with serious side effects such as agranulocytosis and are useful as novel antipsychotic agents. These agents are also useful as therapeutic agents for Alzheimer's disease and manic-depressive conditions. In addition, the compounds of the formulas (HA) and (IIB) are useful as important synthetic intermediates of the compounds of the formulas (I A) and (IB), respectively. This application is based on Requests Nos. 236700/1997, 277771/1997 and 165725/1998 filed in Japan, the contents of which are incorporated herein by reference.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A condensed thiophene compound of the formula (I): wherein: Ra and Rb are the same or different and each is hydrogen, alkyl, cycloalkyl, acyl, alkenyl, aryl, heteroaryl, aralkyl, alkoxy, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, acyloxyalkyl, acylaminoalkyl, halogen, halide of alkyl or nitro, or Ra and Rb together can form a benzene ring or cyclohexene ring optionally having substituents R1 and R2, wherein R1 and R2 are the same or different and each is hydrogen, alkyl, alkoxy, hydroxyl or halogen; X is NH, O, S, SO, S02 or N-R4, wherein R4 is alkyl, provided that when X is NH, Ra and Rb together form a benzene ring having optionally substituents R1 and R2, and when X whether S, SO or S02, Ra and Rb together form a benzene ring or cyclohexene ring optionally having substituents R1 and R2; ring A is a benzene ring having 1 to 4 same or different substituents thereon selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, halogen, alkyl halide, nitro, amino, monoalkylamino, dialkylamino, acylamino, hydroxyl and cyano, or a benzene ring without a substituent; and R3 is a group of the formula (1), formula (2), formula (3), formula (26), formula (27), formula (28), formula (29) or formula (30) (3) (1) (2) (29) (30) in the formula (1), formula (26), formula (27) and formula (30), R5, R6 and R7 are the same or different and each is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl, is already an integer of 2-4, in formula (2) and formula (28), R8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl , monoalkylaminoalkyl, acyl, alkoxycarbonyl or alkoxyalkyl, b is 1 or 2, provided that the combination of X is O and R8 is aralkyl is excluded and when X is O, the alkyl, hydroxyalkyl or alkoxyalkyl alkyl in R8 has 1 to 4 carbon atoms, in the formula (3) and formula (29), R9 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acyl, alkoxycarbonyl or alkoxyalkyl, or a pharmaceutically acceptable salt thereof or a hydrate thereof.

2. The condensed thiophene compound according to claim 1, further characterized in that formula (I) is formula (IA): wherein: X is NH, O, S, SO, S02 or N-R4, wherein R4 is alkyl; R1 and R2 are the same or different and each is hydrogen, alkyl, alkoxy, hydroxyl or halogen; ring A is a benzene ring having 1 to 4 same or different substituents thereon selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, halogen, alkyl halide, nitro, amino, monoalkylamino, dialkylamino, acylamino, hydroxyl and cyano, or a benzene ring without a substituent; ring B is a benzene ring in which the bond shown by a dotted line and a solid line is a double bond, or a cydohexane ring in which said bond is an individual bond, provided that when X is NH, the link shown by a dotted line and a continuous line is not an individual link; and R3 is a group of the formula (1), formula (2), formula (3), formula (26), formula (27), formula (28), formula (29) or formula (30) (3) (1) (2) (29) (30) in the formula (1), formula (26), formula (27) and formula (30), R5, R6 and R7 are the same or different and each is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoacylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl, is already an integer of 2-4; in the formula (2) and formula (28), R8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, acyl, alkoxycarbonyl or alkoxyalkyl, b is 1 or 2; in the formula (3) and formula (29), R9 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acyl, alkoxycarbonyl or alkoxyalkyl, or a pharmaceutically acceptable salt thereof or a hydrate of it.

3. The condensed thiophene compound according to claim 2, further characterized in that ring B is a benzene ring in which the bond shown by a dotted line and a solid line is a double bond, or a pharmaceutically acceptable salt of the same or a hydrate thereof.

4. The condensed thiophene compound according to claim 2, further characterized in that X is NH, O or S, R1 and R2 are the same or different and each is hydrogen, halogen, alkoxy or alkyl, ring A is a benzene ring having 1 to 4 same or different substituents thereon selected from the group consisting of alkyl, alkoxy, halogen and alkyl halide, or a benzene ring without a substituent, ring B is a benzene ring in wherein the bond shown by a dotted line and a solid line is a double bond, and R3 is a group of the formula (2) wherein R8 is hydroxyalkoxyalkyl, methyl or ethyl and b is 1, or a pharmaceutically acceptable salt thereof or a hydrate of it.

5. The condensed thiophene compound according to claim 2, further characterized in that X is NH, R1 and R2 are the same or different and each is hydrogen, halogen, alkoxy or alkyl, ring A is a benzene ring having 1 to 4 identical or different substituents thereon selected from the group consisting of alkyl, alkoxy, halogen and alkyl halide, or a benzene ring without a substituent, ring B is a benzene ring in which the bond shown by a dotted line and a solid line is a double bond, and R3 is a group of the formula (2) wherein R8 is methyl or ethyl and b is 1, or a pharmaceutically acceptable salt thereof or a hydrate thereof.

6. The condensed thiophene compound according to claim 2, which is a member selected from the group consisting of: 12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3- b] [1, 5] -benzodiazepine, 8-fluoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 8-methyl -12- (4-methyl-piperazin-1-yl) -6H- [1] -benzothieno [2,3-b] [1,5] -benzodiazepine, 8-chloro-12- (4-methyl-piperazin-1-yl) - 6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 8-bromo-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 9-fluoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 9-methyl-12 - (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 9-chloro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 9-bromo-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1 , 5] -benzodiazepine, 9-methoxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 8,9-difluoro- 12- (4-methylpiperazin-1-yl) -6H- [1] be nzothieno [2,3-b] [1, 5] -benzodiazepine, 8,10-difluoro-12- (4-methiipiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1 , 5] -benzodiazepine, 3-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 8-fluoro-3-methyl -12- (4-methyl-piperazin-1-yl) -6H- [1] -benzothieno [2,3-b] [1,5] -benzodiazepine, 2-methyl-12- (4-methyl-piperazin-1-yl) - 6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 8-fluoro-2-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2, 3-b] [1,5] -benzodiazepine, 3-methoxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 8 -fluoro-3-methoxy-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 8,9-dichloro-12- (4 -methylpiperazin-1-yl) -6H- [1] benzothieno [2, 3-b] [1, 5] -benzodiazepine, 7,8-dichloro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] - benzodiazepine, 3-bromo-8-fluoro-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 3-fluoro-12- ( 4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 3-chloro-12- (4-methylpiperazin-1-yl) -6H- [1 ] benzothieno [2,3-b] [1, 5] -benzodiazepine, 1-methyl-12- (4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1, 5 ] -benzodiazepine, 4-methyl-12- (4-methyl-piperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepine, 3,8-difluoro-12- ( 4-methylpiperazin-1-yl) -6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepine, 3-fluoro-8-methyl-12- (4-methyl-piperazin-1-yl) ) -6H- [1] benzothien [2,3-b] [1, 5] -benzodiazepine and 12- (4-ethylpiperazin-1-yl) -8-fluoro-6H- [1] benzothieno [2, 3-b] [1, 5] -benzodiazepine, or a pharmaceutically acceptable salt thereof or a hydrate thereof.

7. A pharmaceutical agent comprising a condensed thiophene compound according to claim 2, a pharmaceutically acceptable salt thereof or a hydrate thereof.

8. The pharmaceutical agent according to claim 7, which is an antipsychotic agent.

9. - A pharmaceutical composition comprising a condensed thiophene compound according to claim 2, a pharmaceutically acceptable salt thereof or a hydrate thereof, and a pharmaceutically acceptable additive.

10. A benzothiophene compound of the formula (HA) wherein X is NH, O, S, SO, S02 or N-R4, wherein R4 is alkyl; R1 and R2 are the same or different and each is hydrogen, alkyl, alkoxy, hydroxyl or halogen; Ring A is a benzene ring having 1 to 4 identical or different substituents thereon selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, halogen, alkyl halide, nitro, amino, monoalkylamino, dialkylamino, acylamino , hydroxyl and cyano, or a benzene ring without a substituent; and ring B is a benzene ring in which the bond shown by a dotted line and a solid line is a double bond, or a cydohexane ring in which said bond is an individual bond, provided that when X is NH, the link shown by a dotted line and a continuous line is not an individual link.

11. The benzothiophene compound according to claim 10, further characterized in that X is NH, O or S; R1 and R2 are the same or different and each is hydrogen, halogen, alkoxy or alkyl; ring A is a benzene ring having 1 to 4 same or different substituents thereon selected from the group consisting of alkyl, alkoxy, halogen, hydoxyl and alkyl halide, or a benzene ring without a substituent; and ring B is a benzene ring in which the bond shown by a dotted line and a solid line is a double bond, or a cydohexane ring in which said bond is an individual bond, provided that when X is NH, the link shown by a dotted line and a continuous line is not an individual link.

12. The benzothiophene compound according to claim 10, which is a member selected from the group consisting of 6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H ) -one, 8-fluoro-6H- [1] benzothieno [2,3-b?] [1,5] -benzodiazepin-12 (11 H) -one, 8-chloro-6H- [1] benzothieno [2 , 3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 8-bromo-6 H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H ) -one, 8-methyl-6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 9-fluoro-6H- [1] benzothieno [2, 3-b »] [1, 5] -benzodiazepin-12 (11 H) -one, 8-chloro-6 H- [1] benzothieno [2,3-b?] [1,5] -benzodiazepin-12 (11 H) -one, 9-bromo-6H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 9-methyl-6H- [1] benzothieno [2 , 3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 9-methoxy-6 H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H ) -one, 8,9-difluoro-6H- [1] benzothieno [2,3-b [1,5] -benzodiazepin-12 (11 H) -one, 3-methyl-6H- [1] benzothieno [2 , 3-b?] [1, 5] -benzodiazepin-12 (11 H) -one, 8-fluoro-3-methyl-6H- [1] benzothieno [2,3-b?] [1,5] - benzo diazepin-12 (11 H) -one, 3-methoxy-6H-1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 8-fluoro-3-methoxy- 6H-1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 2-methyl-6H-1] benzothieno [2,3-b] [1,5] - benzodiazepin-12 (11 H) -one, 8-fluoro-2-methyl-6H-1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 3.9- dimethyl-6H-1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 1, 2,3,4-tetrahydro-1] benzothieno [2,3-b] [1,5] -benzoxazepin-12 (11 H) -one, 1, 2,3,4-tetrahydro-8-methyl- [1] benzothieno [2,3-b] [1,5] -benzoxazepin-12 (11 H) -one, 8-fluoro-1, 2,3,4-ehydro- [1] benzothieno [2,3-b] [1,5] -benzoxazepin-12 (11 H) -one, 1] benzothiene [2,3-b] [1, 5] -benzoxazepin-12 (11 H) -one, 8-methyl 1] benzothieno [2,3-b] [1, 5] -benzoxazepin-12 (11 H) -one, 8-fluoro 1] benzothieno [2,3-b] [1, 5] -benzoxazepin-12 (11 H) -one, 1, 2,3,4-tetrahydro 1] benzothieno [2,3-b] [1, 5] -benzothiazepin-12 (11 H) -one, 1, 2,3,4-tetrahydro-8 methyl- [1] benzothieno [2,3-b] [1, 5] -benzothiazepin-12 (11 H) -one, 8-fluoro-1, 2,3,4: etrahydro- [1] benzothieno [2,3-b] [1,5] -benzothiazepin-12 (11 H) -one, 1] benzothieno [2,3-b] [1, 5] -benzothiazepin-12 (11 H) -one, 8-methyl-1] benzothieno [2,3-b] [1, 5] -benzothiazepin-12 (11 H) -one, 8-fluoro-1] benzothieno [2,3-b] [1,5] -benzothiazepin-12 (11 H) -one, 8,9-dichloro-6H-1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 7,8-dichloro -6H-1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 9-trifluoromethyl-6H-1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 3-bromo-8-fluoro-6H-1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 6-methyl - 1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 3-fluoro-6H- ^ benzothienop.S-blfl.dJ-benzodiazepin- ^ HHJ-ona, 3 -chloro-6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one, 1-methyl-6H- [1] benzothieno [2,3-b] [ 1, 5] -benzodiazepin-12 (11 H) -one, 4-methyl-6 H- [1] benzothieno [2,3-b] [1,5] -benzodiazepin-12 (11 H) -one, 3, 8-difluoro-6H- [1] benzothieno [2,3-b] [1, 5] -benzodiazepin-12 (11 H) -one and 3-fluoro-8-metii-6H- [1] benzothieno [2, 3-b] [1, 5] -benzodiazepin-12 (11 H) -one.

13. The condensed thiophene compound according to claim 1, further characterized in that formula (I) is formula (IB) wherein: Ra 'and Rb' are the same or different and each is hydrogen, alkyl, cycloalkyl, acyl, alkenyl, aryl, heteroaryl, aralkyl, alkoxy, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, acyloxyalkyl, acylaminoalkyl, halogen , alkyl halide or nitro, and ring A is a benzene ring having 1 to 4 same or different substituents thereon selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, halogen, alkyl halide, nitro, amino, monoalkylamino, dialkylamino, acylamino, hydroxyl and cyano, or a benzene ring without a substituent; and R3 is a group of the formula (1), formula (2), formula (3), formula (26), formula (27), formula (28), formula (29) or formula (30) (3) ( 1) (2) (26) (27) (28) (29) (30) in the formula (1), formula (26), formula (27) and formula (30), R5, R6 and R7 are the same or different and each is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl, is already an integer of 2-4, in formula (2) and formula (28), R8 is hydrogen, alkyl having 1 to 4 carbon atoms, cycloalkyl, hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acyl, alkoxycarbonyl or alkoxyalkyl, wherein the alkyl having 1 to 4 carbon atoms is substituted by alkoxy, and b is 1 or 2, in the formula (3) and formula (29), R9 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acyl, alkoxycarbonium or alkoxyalkyl, or a pharmaceutically acceptable salt thereof. or a hydrate thereof.

14. The condensed thiophene compound according to claim 13, further characterized in that Ra 'and Rb' are the same or different and each is hydrogen or alkyl, ring A is a benzene ring having 1 to 4 substituents equal or different thereon selected from the group consisting of alkyl, alkoxy, halogen and alkyl halide, or a benzene ring without a substituent; and R3 is a group of the formula (2), wherein R8 is hydroxyalkoxyalkyl, methyl or ethyl and b is 1, or a pharmaceutically acceptable salt thereof or a hydrate thereof.

15. The condensed thiophene compound according to claim 13, further characterized in that Ra 'is alkyl, Rb' is hydrogen or alkyl, ring A is a benzene ring having a substituent thereon selected from the group consisting of of alkyl, alkoxy and halogen, or a benzene ring without a substituent; and R3 is a group of the formula (2), wherein R8 is methyl and b is 1, or a pharmaceutically acceptable salt thereof or a hydrate thereof.

16. The condensed thiophene compound according to claim 13, which is a member selected from the group consisting of 2-methyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1,5] -benzoxazepine, 2-ethyl-4- (4-methylpiperazin-1 -yl) thieno [2,3-b] [1,5] -benzoxazepine, 2,8-dimethyl-4- (4- methylpiperazin-1-yl) thieno [2,3-b] [1,5] -benzoxazepine, 8-methoxy-2-methyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [ 1, 5] -benzoxazepine, 2,6-dimethyl-4- (4-methylpiperazin-1 -yl) thieno [2,3-b] [1,5] -benzoxazepine, 2,9-dimethyl-4- (4 -methylpiperazin-1 -yl) thieno [2,3-b] [1,5] -benzoxazepine, 2,3-dimethyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1 , 5] -benzoxazepine, 8-chloro-2-methyl-4- (4-methylpiperazin-1-yl) thieno [2,3-b] [1,5] -benzoxazepine and 8-fluoro-2-methyl-4 - (4-methylpiperazin-1-yl) thieno [2,3-b] [1,5] -benzoxazepine a pharmaceutically acceptable salt thereof or a hydrate thereof.

17. A pharmaceutical agent comprising a condensed thiophene compound according to claim 13, a pharmaceutically acceptable salt thereof or a hydrate thereof.

18. The pharmaceutical agent according to claim 17, which is an antipsychotic agent.

19. A pharmaceutical composition comprising a condensed thiophene compound according to claim 13, a pharmaceutically acceptable salt thereof or a hydrate thereof, and a pharmaceutically acceptable additive.

20. A thienobenzoxazepinone compound of the formula (IIB) wherein Ra 'and Rb' are the same or different and each is hydrogen, alkyl, cycloalkyl, acyl, alkenyl, aryl, heteroaryl, aralkyl, alkoxy, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, acyloxyalkyl, acylaminoalkyl, halogen, alkyl halide or nitro and ring A is a benzene ring having 1 to 4 same or different substituents thereon selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, halogen, alkyl halide, nitro, amino, monoalkylamino, dialkylamino, acylamino, hydroxyl and cyano, or a benzene ring without a substituent.

21. The thienobenzoxazepinone compound according to claim 20, further characterized in that Ra 'and Rb' are the same or different and each is hydrogen or alkyl, ring A is a benzene ring having 1 to 4 substituents. or different or different therefrom selected from the group consisting of alkyl, alkoxy, halogen and alkyl halide, or a benzene ring without a substituent.

22. The thienobenzoxazepinone compound according to claim 20, which is a member selected from the group consisting of: 2-methylthieno [2,3-b] [1,5] -benzoxazepin-4 (5H) -one , 2,3-dimethylthieno [2,3-b] [1,5] -benzoxazepin-4 (5H) -one, 2,8-dimethylthieno [2,3-b] [1,5] -benzoxazepin-4 ( 5H) -one, 8-chloro-2-methylthieno [2,3-b] [1,5] -benzoxazepin-4 (5H) -one, 8-fluoro-2-methylthieno [2,3-b] [1 , 5] -benzoxazepin-4 (5H) -one, 8-methoxy-2-methylthieno [2,3-b] [1,5] -benzoxazepin-4 (5H) -one, 2,6-dimethylthieno [2 , 3-b] [1, 5] -benzoxazepin-4 (5H) -one, 2,9-dimethylthieno [2,3-b] [1, 5] -benzoxazepin-4 (5H) -one and 2-ethyl-tiene [2,3-b] [1, 5] -benzoxazepin-4 (5H) -one.