JP2021104931A - Dibenzoazepine derivative having nitrogen-containing heterocycle - Google Patents

Abstract

To provide a dibenzoazepine derivative and a pharmaceutically acceptable salt thereof that are useful as a therapeutic and/or prophylactic agent for central nervous system diseases.SOLUTION: Provided is a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof. [Rings Q1 and Q2 are benzene or pyridine; Ra is hydrogen, C1-6 alkyl which may be substituted with ≤3 halogens; n = 0 to 2; m = 1 to 4; Rb is hydrogen, halogen, C1-6 alkyl which may be substituted with ≤3 halogens].SELECTED DRAWING: None

Description

The present invention is a dibenzoazepine derivative having a partially unsaturated nitrogen-containing heterocycle having _{a dopamine D 1} receptor antagonism, a dopamine D ₂ receptor antagonism, and a serotonin 5-HT _{2A receptor antagonism, or a pharmaceutical preparation thereof.} With respect to a pharmaceutically acceptable salt and a therapeutic and / or prophylactic agent for a central nervous system disease containing the derivative as an active ingredient.

Schizophrenia is a psychiatric disorder with an estimated number of patients of 45 million worldwide, with positive, negative and cognitive dysfunction as the main symptoms. Currently, as therapeutic agents for schizophrenia, antipsychotic drugs having dopamine D ₂ receptor (hereinafter, D ₂ receptor) antagonism and serotonin 5-HT _2A receptor (hereinafter, 5-HT _2A receptor) antagonism are available. Although it is used, it is known that about 30% of schizophrenia patients suffer from so-called treatment-resistant schizophrenia for which existing antipsychotic drugs are ineffective (non-patented). Document 1).

Under these circumstances, clozapine, an atypical antipsychotic, is known to be highly effective in patients with schizophrenia and is the only drug effective in patients with refractory schizophrenia. It has been reported (Non-Patent Document 1). However, it has been reported that 0.8% of patients taking clozapine cause agranulocytosis, which is a serious side effect, and blood monitoring is required at the time of taking the drug. In addition, side effects such as epilepsy, gastrointestinal disorders, sedation, weight gain, and salivation have also been reported, which make it difficult to continue treatment with clozapine (Non-Patent Documents 2 and 3). Therefore, the development of safer and more effective antipsychotics for patients with treatment-resistant schizophrenia is an urgent issue.

Clozapine, D ₂ receptor antagonism, in addition to the 5-HT _2A receptor antagonistic action, dopamine D ₁ receptor (hereinafter, D ₁ receptors) are known to have antagonistic action against. _{In addition, it has been reported that clozapine occupies D 2} receptor and D ₁ receptor at the same time and in the same proportion in PET studies for patients with schizophrenia (Non-Patent Documents 4, 5, and 6).

So far, 1-piperadino-1,2-dihydroindene derivatives have been reported as compounds having an antagonistic effect on the D ₁ receptor, the D ₂ receptor, and the 5-HT _{2A receptor (Patent Document 1).} .. The compound having an antagonism to D ₂ receptors and 5-HT _2A receptor, dibenzo Oki Se pins derivatives and dibenzo triazabenzocycloheptene derivatives have been reported (Non-Patent Document 7, Patent Documents 2 and 3) .. Furthermore, dibenzothiepine derivatives and dibenzoazepine derivatives have been reported to have antipsychotic effects (Patent Document 4, Non-Patent Document 8).
However, all of these compounds are different from the dibenzoazepine derivatives having a partially unsaturated nitrogen-containing heterocycle of the present invention. And, there is no disclosure about a dibenzoazepine derivative having a partially unsaturated nitrogen-containing heterocycle in these documents, and no suggestion is made.

Japanese Patent No. 3255416 UK Patent Application Publication No. 1184027 U.S. Pat. No. 3,479,356 UK Patent Application Publication No. 1163485

Pharmgenomics Pers Med. (2016) 9, 117-129. Lancet. (2013) 382, 951-962. Neurotherapeutics (2017) 14, 750-761. Journal of Neural Transmission (1998) 105, 181-191. The American Journal of Psychiatry (2004); 161 (9): 1620-1625. The American Journal of Psychiatry (1995) 152, 1444-1449. Journal of Medicinal Chemistry (1995) 38, 708-714. Arzneimittel-Forschung (1965), 15 (8), 841-3.

A subject of the present invention is a compound for use in the prevention or treatment of a central nervous system disease characterized by _{D 1} receptor antagonism, D ₂ receptor antagonism, and 5-HT _{2A receptor antagonism, or a pharmaceutical product thereof.} It is an object of the present invention to provide a pharmaceutically acceptable salt, a method for producing the same, a composition containing the compound, and the like.

We found _{that compounds having antagonism against D 1} receptor, D ₂ receptor, and 5-HT _2A receptor have strong efficacy against schizophrenia including treatment resistance and other psychiatric disorders. shows the idea of intensive research as a result, (sometimes abbreviated as needed hereinafter "the compound of the present invention".) the compound represented by the following formula (1) and a pharmaceutically acceptable salt thereof, D ₁ We have found that it has a strong antagonism against the receptor, D ₂ receptor, and 5-HT _{2A receptor, and have completed the present invention.}

［式中、環Ｑ^１及び環Ｑ^２は、それぞれ独立して、置換されていてもよいベンゼン環、または置換されていてもよいピリジン環を表し；
Ｒ^ａは、水素原子、または同種もしくは異種の１〜３個のハロゲン原子で置換されていてもよいＣ_１−６アルキルを表し；
ｎは、０、１または２を表し；
ｍは、１、２、３または４を表し；
Ｒ^ｂは、複数ある場合はそれぞれ独立して、水素原子、ハロゲン原子、または同種もしくは異種の１〜３個のハロゲン原子で置換されていてもよいＣ_１−６アルキルを表す]で表される化合物、またはその製薬学的に許容される塩。 That is, the present invention is as follows.
[Item 1] Equation (1):

[Wherein ring Q ¹ and ring Q ² are expressed independently, a benzene ring which may be substituted, or a pyridine ring optionally substituted;
^Ra _{represents a hydrogen atom or a C 1-6} alkyl optionally substituted with 1-3 halogen atoms of the same or different species;
n represents 0, 1 or 2;
m represents 1, 2, 3 or 4;
R ^b represents a _{C 1-6} alkyl which may be independently substituted with a hydrogen atom, a halogen atom, or 1 to 3 halogen atoms of the same kind or different kinds, if there are a plurality of them.] A compound, or a pharmaceutically acceptable salt thereof.

[Claim 2] cycloaddition Q ¹ and ring Q ² are each independently a benzene ring or a pyridine ring (the benzene ring or pyridine ring, in each case, 1 to 3 halogen atoms, cyano, same or different C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the _{same or heterogeneous, C 1-6} alkoxy optionally substituted with 1 to 3 halogen atoms of the same or heterogeneous, and 1-2 of the same or heterologous Item 2. The compound according to Item 1, which is substituted with 1 to 4 groups of the same type or different types selected from the group consisting of aminos which may be substituted with C _{1-6 alkyl, or a compound thereof.} Pharmaceutically acceptable salt.

[Claim 3] ring Q ¹ and ring Q ² are each independently a benzene ring (said ring, in each case, halogen atom, cyano, optionally substituted by 1 to 3 halogen atoms the same or different be C _1-6 alkyl, and the like, or one to three same or 1-4 groups of different selected from the group consisting of C _1-6 alkoxy optionally substituted by a halogen atom heterologous Item 2. The compound according to Item 1 or 2, or a pharmaceutically acceptable salt thereof.

[Item 4] The compound according to any one of Items 1 to 3, wherein n is 1, or a pharmaceutically acceptable salt thereof.

［式中、Ｒ^ａは、水素原子、または同種もしくは異種の１〜３個のハロゲン原子で置換されていてもよいＣ_１−６アルキルを表し；
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、およびＲ^８は、それぞれ独立して、水素原子、ハロゲン原子、シアノ、同種もしくは異種の１〜３個のハロゲン原子で置換されていてもよいＣ_１−６アルキル、同種もしくは異種の１〜３個のハロゲン原子で置換されていてもよいＣ_１−６アルコキシ、または同種もしくは異種の１〜２個のＣ_１−６アルキルで置換されていてもよいアミノを表し；
Ｒ^１１、Ｒ^１２、Ｒ^１３、およびＲ^１４は、それぞれ独立して、水素原子、ハロゲン原子、または同種もしくは異種の１〜３個のハロゲン原子で置換されていてもよいＣ_１−６アルキルを表す]で表される、項１に記載の化合物、またはその製薬学的に許容される塩。 [Item 5] Equation (1a):

[In the formula, ^Ra _{represents a hydrogen atom or a C 1-6} alkyl optionally substituted with 1-3 halogen atoms of the same or different species;
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are independently hydrogen atoms, halogen atoms, cyano, and 1 to 3 halogen atoms of the same or different species. in an optionally substituted C _1-6 alkyl, same or 1 to 3 halogen atoms which may be substituted with optionally C _1-6 alkoxy heterologous or of homologous or heterologous 1-2, C _{1- Represents} an amino that may be substituted with 6 alkyl;
R ¹¹ , R ¹² , R ¹³ and R ¹⁴ _{each independently contain a C 1-6} alkyl which may be substituted with a hydrogen atom, a halogen atom, or 1 to 3 halogen atoms of the same or different species. Represented], the compound according to Item 1, or a pharmaceutically acceptable salt thereof.

［式中、Ｒ^ａ、Ｒ^２、Ｒ^７、Ｒ^１３、およびＲ^１４は、項５と同義である]で表される、項５に記載の化合物、またはその製薬学的に許容される塩。 [Item 6] Equation (1b):

Item 5. The compound according to Item 5, or a pharmaceutically acceptable salt thereof, which is represented by [in the formula, ^Ra , R ² , R ⁷ , R ¹³ and R ^{14 are synonymous with Item 5].} ..

[Item 7] The compound according to Item 5 or 6, or a pharmaceutically acceptable salt thereof, wherein ^{R 13} is a C _{1-6 alkyl or a hydrogen atom.}

Salts [Claim 8] R ¹³ is methyl or hydrogen, A compound according to claim 5 or 6, or is a pharmaceutically acceptable.

[Item 9] The compound according to any one of Items 5 to 8, wherein ^{R 14 is a hydrogen atom, or a pharmaceutically acceptable salt thereof.}

［式中、Ｒ^ａ、Ｒ^２およびＲ^７は、項５と同義である]で表される、項５に記載の化合物、またはその製薬学的に許容される塩。 [Item 10] Equation (1b-1):

Item 2. The compound according to Item 5, or a pharmaceutically acceptable salt thereof, which is represented by [where ^Ra , R ² and R ^{7 are synonymous with Item 5].}

［式中、Ｒ^ａ、Ｒ^２およびＲ^７は、項５と同義である]で表される、項５に記載の化合物、またはその製薬学的に許容される塩。 [Item 11] Equation (1b-2):

Item 2. The compound according to Item 5, or a pharmaceutically acceptable salt thereof, which is represented by [where ^Ra , R ² and R ^{7 are synonymous with Item 5].}

[Item 12] _{C 1-6} ^{alkyl in which R 2} and R ⁷ may be independently substituted with hydrogen atom, halogen atom, 1 to 3 halogen atoms of the same kind or different kind, or the same kind or different kind. The compound according to any one of Items 5 to 11, which is a _{C 1-6} alkoxy optionally substituted with 1 to 3 halogen atoms of the above, or a pharmaceutically acceptable salt thereof.

Salts [Claim 13] R ² is a hydrogen atom, a halogen atom or C _1-3 alkyl, A compound according to any one of claims 5-12, or is a pharmaceutically acceptable.

Salts [Claim 14] R ² is a hydrogen atom or a halogen atom A compound according to any one of claims 5-12, or is a pharmaceutically acceptable.

[Claim 15] R ² is a hydrogen atom, a fluorine atom or a chlorine atom, or a compound according to (1) or a pharmaceutically acceptable salt thereof, of claim 5-12.

[Claim 16] R ² is a chlorine atom, a compound or a pharmaceutically acceptable salt thereof, according to any one of claims 5-12.

[Item 17] R ⁷ _{is substituted with a halogen atom, C 1-6} alkyl which may be substituted with 1 to 3 halogen atoms of the same or different species, or 1 to 3 halogen atoms of the same or different species. Item 5. The compound according to any one of Items 5 to 16, which is a _{C 1-6} alkoxy which may be present, or a pharmaceutically acceptable salt thereof.

[Item 18] The compound according to any one of Items 5 to 16, wherein ^{R 7} _{is a C 1-6} alkyl substituted with a halogen atom, 1 to 3 halogen atoms of the same type or different types. , Or its pharmaceutically acceptable salt.

Salts [Claim 19] R ⁷ is a fluorine atom, a chlorine atom or a C _1-3 alkyl, A compound according to any one of claims 5 to 16, or being a pharmaceutically acceptable.

[Claim 20] R ⁷ is a fluorine atom, A compound according to any one of claims 5-16 or a pharmaceutically acceptable salt thereof.

[Claim 21] R ⁷ is a hydrogen atom A compound according to any one of claims 5-16 or a pharmaceutically acceptable salt thereof.

Item 22. The compound according to any one of Items 1 to 21, wherein ^Ra _{is a C 1-6} alkyl optionally substituted with 1 to 3 halogen atoms of the same or different species, or a compound thereof. Pharmaceutically acceptable salt.

[Claim 23] R ^a is substituted with 1 to 3 halogen atoms the same or different is also good C _1-3 alkyl, A compound according to any one of claims 1 to 21, or a, Pharmaceutically acceptable salt.

[Item 24] The compound according to any one of Items 1 to 21, wherein ^{Ra is methyl or ethyl, or a pharmaceutically acceptable salt thereof.}

[Item 25] The compound according to Item 1 or a pharmaceutically acceptable salt thereof selected from the following compound group:
2-Chloro-8-fluoro-10- (1-methyl-1,2,3,6-tetrahydropyridine-4-yl) -5H-dibenzo [b, f] azepine (Example 1),
8-Chloro-10-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-fluoro-5H-dibenzo [b, f] azepine (Example 8) ),
2-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridine-4-yl] -5H-dibenzo [b, f] azepine (Example 10),
2-Chloro-10-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridine-4-yl] -5H-dibenzo [b, f] azepine (Example 13),
2-Chloro-10-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridine-4-yl] -8-methyl-5H-dibenzo [b, f] azepine (Example 14) ),
8-Chloro-10-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-methyl-5H-dibenzo [b, f] azepine (Example 15) ),
2-Chloro-10- (1-ethyl-1,2,3,6-tetrahydropyridin-4-yl) -8-fluoro-5H-dibenzo [b, f] azepine (Example 22), and 10- [ (6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-fluoro-8-methyl-5H-dibenzo [b, f] azepine (Example 25).

[Item 26] The compound according to Item 1 or a pharmaceutically acceptable salt thereof selected from the following compound group:
2-Chloro-8-fluoro-10- (1-methyl-1,2,3,6-tetrahydropyridine-4-yl) -5H-dibenzo [b, f] azepine (Example 1),
2-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridine-4-yl] -5H-dibenzo [b, f] azepine (Example 10),
8-Chloro-10-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridine-4-yl] -2-methyl-5H-dibenzo [b, f] azepine (Example 15) ), And 2-chloro-10- (1-ethyl-1,2,3,6-tetrahydropyridin-4-yl) -8-fluoro-5H-dibenzo [b, f] azepine (Example 22).

[Item 27] The following compounds according to Item 1 or pharmaceutically acceptable salts thereof:
2-Chloro-8-fluoro-10- (1-methyl-1,2,3,6-tetrahydropyridine-4-yl) -5H-dibenzo [b, f] azepine (Example 1).

[Item 28] The following compounds according to Item 1 or pharmaceutically acceptable salts thereof:
2-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridine-4-yl] -5H-dibenzo [b, f] azepine (Example 10).

[Item 29] The following compounds according to Item 1 or pharmaceutically acceptable salts thereof:
8-Chloro-10-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-methyl-5H-dibenzo [b, f] azepine (Example 15) ).

[Item 30] The following compounds according to Item 1 or pharmaceutically acceptable salts thereof:
2-Chloro-10- (1-ethyl-1,2,3,6-tetrahydropyridin-4-yl) -8-fluoro-5H-dibenzo [b, f] azepine (Example 22).

[Item 31] A drug containing the compound according to any one of Items 1 to 30 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Item 32] A therapeutic agent for a central nervous system disease, which comprises the compound according to any one of Items 1 to 30 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Item 33] Behavioral and Psychological Symptoms of Dementia (BPSD) in which central nervous system diseases include schizophrenia, bipolar disorder, autism, ADHD, depression, anxiety disorder, sleep disorder, and dementia. ) Or the therapeutic agent according to Item 32, which is a psychological symptom of a neurodegenerative disease.

[Item 34] Central nervous system, which comprises administering to a patient in need of treatment a therapeutically effective amount of the compound according to any one of items 1 to 30, or a pharmaceutically acceptable salt thereof. A method for treating systemic diseases.

Item 35. Use of the compound according to any one of Items 1 to 30, or a pharmaceutically acceptable salt thereof, for producing a therapeutic agent for a central nervous system disease.

Item 36. The compound according to any one of Items 1 to 30, or a pharmaceutically acceptable salt thereof, for use in the treatment of central nervous system diseases.

[Item 37] The compound according to any one of Items 1 to 30, or a pharmaceutically acceptable salt thereof, and alipyrazole, olanzapine, quetiapine, risperidone, blonanserin, perospirone, paliperidone, ziprasidone, asenapine, iroperidone, A therapeutic agent for central nervous system diseases consisting in combination with at least one drug selected from the group consisting of sertindol, lurasidone and their pharmaceutically acceptable salts.

Item 38 At least one selected from the group consisting of alipyrazole, olanzapine, quetiapine, risperidone, blonanserin, perospirone, paliperidone, ziprasidone, asenapine, iroperidone, sertindol, lurasidone and their pharmaceutically acceptable salts. A therapeutic agent containing, as an active ingredient, the compound according to any one of Items 1 to 30, or a pharmaceutically acceptable salt thereof for treating central nervous system diseases in combination with a drug.

Since the compound of the present invention _{exhibits an antagonistic effect on the D 1} receptor, the D ₂ receptor, and the 5-HT _2A receptor, it is useful as a therapeutic agent and / or a preventive agent for central nervous system diseases. In addition, in a preferred embodiment, the amount of reactive metabolites produced, which contributes to agranulocytosis, is low, and high safety can be expected. _{In a more preferred embodiment, to histamine receptor, muscarinic receptor, serotonin 5-HT 2c} receptor (hereinafter, 5-HT _2c receptor) and the like, which are considered to be involved in side effects such as digestive disorders, sedation and weight gain. It has a weak antagonism and can be expected to be highly safe.

Hereinafter, the present invention will be described in detail. In the present specification, the number of carbons in the definition of "substituent" may be expressed _{as, for example, "C 1-6".} Specifically, the _{notation "C 1-6} alkyl" is synonymous with alkyl having 1 to 6 carbon atoms.

Specific examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferably, it is a fluorine atom or a chlorine atom.

"C _1-6 alkyl" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferably, it is "C _1-3 alkyl". Specific examples of "C _1-6 alkyl" include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, Examples thereof include 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.

_{"C 1-6} alkyl" moiety of the _{"C 1-6} alkoxy" has the same meaning as the _{"C 1-6} alkyl". Preferably, it is "C _1-3 alkoxy". Specific examples of "C _1-6 alkoxy" include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

Among the compound of the present invention represented by the formula ^{(1a), R a, R} 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 11, R 12, R 13, and in R ^14, but preferred are as follows, the technical scope of the present invention is not limited to the scope of the compounds listed below.

In the compound represented by the formula (1), the R ^b group may be substituted with any carbon atom on the nitrogen-containing monocycle as long as it can be substituted, and if possible, the same or different 2 on the same carbon atom. One ^Rb group may be substituted.
In the compound represented by formula (1), when the ring Q ¹ and / or ring Q ² is pyridine ring, four atoms indicated by an arrow in which they have shared with ring condensed ring is a carbon atom be.

Examples of the substituent in the "optionally substituted benzene ring" and the "optionally substituted pyridine ring" include, for example.
(A) Halogen atom,
(B) Cyano,
(C) C _1-6 alkyl (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C _{1-6 alkoxy),}
(D) C _1-6 alkoxy (the group may be substituted with 1-3 groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C _{1-6 alkoxy),}
(E) Phenyl (the group may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy),}
(F) 5- or 6-membered heteroaryl (the group is substituted with 1 to 4 groups of the same or different species selected from the group _{consisting of halogen atoms, C 1-6} alkyl, and C _{1-6 alkoxy.} May have been),
(G) Phenoxy (the group may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _{1-6 alkoxy),}
(H) Hydroxy,
(I) Amino (the group _{may be substituted with one or two C 1-6} alkyls of the same or different species), and (j) Aminocarbonyl (the amino may be one or two of the same or different species). It may be substituted with _{C 1-6 alkyl).}
Preferably, it may be substituted with a halogen atom, cyano, C _1-6 alkyl which may be substituted with 1 to 3 halogen atoms of the same or different type, and 1 to 3 halogen atoms of the same or different type. Examples include C _1-6 alkoxy, and aminos that may be substituted with _{one or two C 1-6 alkyls of the same or different species.
More preferably, it may be substituted with a halogen atom, a C 1-6} alkyl which may be substituted with 1 to 3 halogen atoms of the same or different type, and 1 to 3 halogen atoms of the same or different type. _Examples include C 1-6 alkoxy.

Preferred examples of ^Ra _{include C 1-6} alkyl which may be substituted with 1 to 3 halogen atoms of the same type or different types. It is more preferably C _1-3 alkyl, and even more preferably methyl. Another preferred ^{embodiment of Ra} is ethyl. Further, ^{as another aspect of Ra} , methyl deuterated (CD ₃ ) and ethyl deuterated (CD ₃ CD ₂ ) can be mentioned.

Preferred examples of R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁸ include hydrogen and halogen atoms. More preferably, it is a hydrogen atom.

Preferred as R ^2, a hydrogen atom, substituted with a halogen atom, the same or 1-3 C _1-6 alkyl optionally substituted by a halogen atom different, and the same or 1 to 3 halogen atoms heterologous Examples thereof include C _{1-6 alkoxy which may be used.} More preferably, a hydrogen atom and a halogen atom can be mentioned.

R ⁷ is preferably substituted with a hydrogen atom, a halogen atom, a C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different species, and 1 to 3 halogen atoms of the same or different species. Examples thereof include C _{1-6 alkoxy which may be used. More preferably, C 1-6} alkyl which may be substituted with a hydrogen atom, a halogen atom, and 1 to 3 halogen atoms of the same kind or different kinds can be mentioned.

Preferred examples of R ¹¹ , R ¹² and R ¹⁴ _{include hydrogen atoms and C 1-6} alkyls which may be substituted with 1 to 3 halogen atoms of the same or different species. More preferably, a hydrogen atom or a C _1-3 alkyl can be mentioned. Most preferably, it is a hydrogen atom.

Preferred examples of R ¹³ _{include hydrogen atoms and C 1-6} alkyls which may be substituted with 1 to 3 halogen atoms of the same type or different types. More preferably, it is a hydrogen atom or a C _1-3 alkyl. More preferably, it is a hydrogen atom or methyl.

In another embodiment of ^{R 11} , R ¹² , R ¹³ and R ^{14 , R 11} and R ¹² are hydrogen atoms, R ¹³ is a C _1-6 alkyl and R ¹⁴ is a hydrogen atom or C _1-. It is _{6 alkyl.}

In another aspect of ^{R 11} , R ¹² , R ¹³ and R ^{14 , R 11} , R ¹² and R ¹⁴ are hydrogen atoms and R ¹³ is a C _1-3 alkyl.

Another aspect of ^{R 11, R 12, R 13} , and ^{R 14, R 11, R 12} , R 13 and ^{R 14} are hydrogen atoms.

Among the compounds of the present invention represented by the formula (1b-1), ^Ra , R ² and R ⁷ which are preferable are as follows, but the technical scope of the present invention is the range of the compounds listed below. It is not limited.

Preferred examples of ^Ra _{include C 1-6} alkyl which may be substituted with 1 to 3 halogen atoms of the same type or different types. It is more preferably C _1-3 alkyl, and even more preferably methyl. Another preferred ^{embodiment of Ra} is ethyl. Further, ^{as another aspect of Ra} , methyl deuterated (CD ₃ ) and ethyl deuterated (CD ₃ CD ₂ ) can be mentioned.

A hydrogen atom or a halogen atom is preferably used as ^{R 2.}

Preferred as R ⁷ _{is C 1-6} alkyl which may be substituted with a hydrogen atom, a halogen atom, or 1 to 3 halogen atoms of the same kind or different kinds.

Among the compounds of the present invention represented by the formula (1b-2), ^Ra , R ² and R ⁷ which are preferable are as follows, but the technical scope of the present invention is the range of the compounds listed below. It is not limited.

Preferred examples of ^Ra _{include C 1-6} alkyl which may be substituted with 1 to 3 halogen atoms of the same type or different types. It is more preferably C _1-3 alkyl, and even more preferably methyl. Another preferred ^{embodiment of Ra} is ethyl. Further, ^{as another aspect of Ra} , methyl deuterated (CD ₃ ) and ethyl deuterated (CD ₃ CD ₂ ) can be mentioned.

A hydrogen atom or a halogen atom is preferably used as ^{R 2.} Halogen atoms are more preferred, fluorine or chloro is more preferred, and chloro is most preferred.

Preferred as R ⁷ _{is C 1-6} alkoxy which may be substituted with a halogen atom, 1 to 3 halogen atoms of the same type or different types. A halogen atom is more preferable, fluorine or chloro is more preferable, and fluorine is most preferable.

The compound represented by the formula (1) may exist as a tautomer. Therefore, the compound of the present invention also includes tautomers of the compound represented by the formula (1).

The compound represented by the formula (1) may have at least one asymmetric carbon atom. Therefore, the compound of the present invention includes not only the racemic compound of the compound represented by the formula (1) but also the optically active compound of these compounds.
Also included in either one or deuterium converter which converts the two or more ^{1 H 2} to ^H (D) compounds represented by the formula (1) of the compound represented by formula (1) ..

Since the compound represented by the formula (1) and the pharmaceutically acceptable salt thereof may exist in the form of a hydrate and / or a solvate, these hydrates or ethanol solvates. And other solvates are also included in the compounds of the present invention. Furthermore, the compounds of the present invention also include those in crystalline form in all aspects.
As a pharmaceutically acceptable salt, when the compound represented by the formula (1) has an acidic group, for example, an alkali metal salt such as a sodium salt or a potassium salt; an alkaline soil such as a calcium salt or a magnesium salt. Kind of metal salt; Inorganic metal salt such as zinc salt; Organic base salt such as triethylamine, triethanolamine, trihydroxymethylaminomethane, amino acid and the like.
When the compound represented by the formula (1) has a basic group, for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate; and acetate, propionate. , Succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, ascorbate and other organics Examples include acid salts.

Hereinafter, a method for producing a compound represented by the formula (1) in the present invention will be described with reference to an example, but the present invention is not limited thereto.

Production Method The compound of the present invention is synthesized by a method combining the production methods shown below and a known synthesis method.
The compounds in the reaction formula include the case where each compound forms a salt, and examples of the salt include the same salts as those of the compound represented by the formula (1). It should be noted that these reactions are merely examples, and the compound of the present invention can be produced by other methods as appropriate based on the knowledge of a person who is proficient in organic synthesis.

In each of the production methods described below, even if the use of a protecting group is not specifically specified, if a functional group that requires protection exists, the functional group is protected as necessary. The desired product may be obtained by deprotecting after completion of the reaction or after performing a series of reactions.

The introduction and elimination of protecting groups is a method commonly used in synthetic organic chemistry (eg, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons. , Inc., the method described in New York (1999), etc.) or a method similar thereto.
Examples of the amino-protecting group include tert-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl and the like.

[式中、環Ｑ^１、環Ｑ^２、Ｒ^ｂ、ｍ、およびｎは、前記〔項１〕と同義であり；Ｒ^ａ１は同種または異種の１〜３個のハロゲン原子で置換されていてもよいＣ_１−６アルキルを表し；Ｘはハロゲンまたはトリフラート（トリフルオロメタンスルホニルオキシ）を表し；ＰｒｏおよびＰｒｏ’はアミノ基の保護基を表し；Ａはボロン酸またはボロン酸エステルを表す。] Manufacturing method 1
Among the compounds represented by the formula (1), the compound represented by the formula (1c) is produced, for example, by the method shown below.

[In the formula, ring Q ¹ , ring Q ² , R ^b , m, and n are synonymous with [Item 1] above; R ^a1 is substituted with 1 to 3 halogen atoms of the same or different species. May represent a C _1-6 alkyl; X represents a halogen or triflate (trifluoromethanesulfonyloxy); Pro and Pro'represent a protecting group for an amino group; A represents a boronic acid or a boronic acid ester. ]

Step 1-1: Production of compound (1-2) Compound (1-2) is subjected to base-presence or absence in a suitable inert solvent, and compound (1-1) is trifurated or halogenated. Manufactured by the action of an agent. As the compound (1-1), those produced by a known method (for example, Tetrahedron Letters, 2001, 42 (3), 385-389) can be used. Examples of the base include sodium hydride, lithium diisopropylamide and the like. Examples of the inert solvent include tetrahydrofuran, toluene, dichloromethane and the like. Examples of the triflate reagent include trifluoromethanesulfonic anhydride, N, N-bis (trifluoromethylsulfonyl) aniline and the like. Examples of the halogenating agent include phosphorus oxychloride and phosphorus pentachloride. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 2 hours. The reaction temperature is usually −78 ° C. to 200 ° C., preferably −78 ° C. to 80 ° C.

Step 1-2: Production step of compound (1-4) Compound (1-4) is prepared by cupping compound (1-2) and compound (1-3) in a suitable inert solvent in the presence of a palladium catalyst. Manufactured by ringing. This step can be performed in the presence of base and / or phosphorus ligands, if desired. As the compound (1-3), a commercially available compound or a compound produced by a known method (for example, International Publication No. 2002/066470) can be used. Further, those manufactured by the manufacturing method 5 described later can be used. As the palladium catalyst, various palladium catalysts used in a conventional method can be used, and tetrakis (triphenylphosphine) palladium (0) and the like are preferable. Examples of the base include potassium carbonate, cesium carbonate and the like. Examples of the phosphorus ligand include triphenylphosphine and bis (diphenylphosphino) methane. Examples of the inert solvent include 1,4-dioxane, tetrahydrofuran, water and a mixed solvent thereof. The reaction temperature is usually 0 ° C. to 200 ° C., preferably 20 ° C. to 150 ° C., and can be carried out under microwave irradiation if necessary. The reaction time varies depending on the conditions such as the reaction temperature, the palladium catalyst used, the raw material, and the solvent, but is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.

Step 1-3: Production Step of Compound (1c) Compound (1c) uses a known method (eg, Protective Group in Organic Synthesis 3rd Edition (Theodora W)) to remove the protecting group Pro of the amino group of compound (1-4). Manufactured by deprotection by Green, Peter GM Wuts, John Wiley & Sons Inc, 1999).

Step 1-4: Production step of compound (1-6) Compound (1-6) is produced from compound (1-2) and compound (1-5) according to the method described in step 1-2. NS. As the compound (1-5), a commercially available compound or a compound produced by a known method (for example, International Publication No. 2002/066470) can be used. Further, those manufactured by the manufacturing method 3 described later can be used.

Step 1-5: Preparation of Compound (1-7) Compound (1-7) uses a known method (eg, Protective Group in Organic Synthesis) to remove the protecting group Pro'of the amino group of compound (1-6). Manufactured by deprotection in Edition 3 (Theodora W. Green, Peter GM Wuts, John Wiley & Sons Inc, 1999).

Step 1-6: Production of Compound (1-4) Compound (1-4) is prepared by reacting compound (1-7) with various aldehydes in the presence of a reducing agent in a suitable inert solvent. Is also manufactured. Examples of the reducing agent include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like. Examples of the inert solvent include toluene, THF, dichloroethane, methanol and the like. The reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually −78 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.

Compound (1-4) is also produced by reacting compound (1-7) with various alkyl halides in the presence of a base in a suitable inert solvent. Examples of the base include potassium carbonate, cesium carbonate, sodium hydride, lithium diisopropylamide and the like. Examples of the inert solvent include DMF, dimethyl sulfoxide, THF, 1,4-dioxane and the like. The reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually −78 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.

[式中、環Ｑ^１、環Ｑ^２は、前記〔項１〕と同義であり；Ｘ_１はハロゲンを表し；Ｐｒｏはアミノ基の保護基を表す。] Manufacturing method 2
Among the compounds represented by the formula (1-2), the compound represented by the formula (1-2a) is also produced, for example, by the method shown below.

[In the formula, ring Q ¹ and ring Q ² are synonymous with [Item 1] above; X ₁ represents a halogen; Pro represents a protecting group for an amino group. ]

Step 2-1: Production step of compound (2-2) Compound (2-2) is subjected to the presence or absence of an acid in a suitable inert solvent, and compound (2-1) is halogenated with bromine, chlorine or the like. Manufactured by the action of an agent. As the compound (2-1), a compound produced by a known method (for example, Bioorganic & Medicinal Chemistry, 22 (3), 1077-1088; 2014) can be used. Examples of the acid include acetic acid and the like. Examples of the inert solvent include chloroform, dichloromethane and the like. Examples of the halogenating agent include bromine and chlorine. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 2 hours. The reaction temperature is usually −78 ° C. to 200 ° C., preferably 0 ° C. to 80 ° C.

Step 2-2: Production Step of Compound (1-2a) Compound (1-2a) is produced by allowing a base to act on compound (2-2) in a suitable inert solvent. Examples of the base include 1,8-diazabicyclo [5.4.0] -7-undecene, potassium carbonate and the like. Examples of the inert solvent include THF, acetonitrile, dichloromethane and the like. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 2 hours. The reaction temperature is usually −78 ° C. to 200 ° C., preferably 0 ° C. to 80 ° C.

[式中、Ｒ^ｂ、ｍ、およびｎは、前記〔項１〕と同義であり；Ｘ^２はハロゲンまたはトリフラート（トリフルオロメタンスルホニルオキシ）を表し；Ｐｒｏ’はアミノ基の保護基を表し；Ａはボロン酸またはボロン酸エステルを表す。] Manufacturing method 3
The compound represented by the formula (1-5) is produced, for example, by the method shown below.

[In the formula, R ^b , m, and n are synonymous with [Item 1] above; X ² represents halogen or triflate (trifluoromethanesulfonyloxy); Pro'represents an amino protecting group; A Represents boronic acid or boronic acid ester. ]

Step 3-1: Production of compound (3-2) Compound (3-2) is subjected to the presence or absence of a base in a suitable inert solvent, and the compound (3-1) is triflated or halogenated. Manufactured by the action of an agent. As the compound (3-1), a commercially available compound or a compound produced by a known method (for example, International Publication No. 2012/142668) can be used. Examples of the base include lithium diisopropylamide, sodium bis (trimethylsilyl) amide, triethylamine and the like. As the triflate agent, various triflate agents used in a conventional method can be used, and examples thereof include N-phenylbis (trifluoromethanesulfonimide) and the like. As the halogenating agent, various halogenating agents used in a conventional method can be used, and examples thereof include phosphorus oxychloride and phosphorus pentachloride. Examples of the inert solvent include THF, dichloroethane and the like. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 8 hours. The reaction temperature is usually −78 ° C. to 200 ° C., preferably −78 ° C. to 80 ° C.

Step 3-2: Production of Compound (1-5) Compound (1-5) is prepared by coupling compound (3-2) with a boring reagent in the presence of a palladium catalyst in a suitable inert solvent. Manufactured by. This step can be performed in the presence of base and / or phosphorus ligands, if desired. Examples of the base include potassium acetate. Examples of the phosphorus ligand include triphenylphosphine and bis (diphenylphosphino) methane. As the boring reagent, various boring reagents used in a conventional method can be used, and examples thereof include bis (pinacholate) diborane and the like. As the palladium catalyst, various palladium catalysts used in a conventional method can be used, and examples thereof include 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride. Examples of the inert solvent include 1,4-dioxane, THF and the like. The reaction temperature is usually 0 ° C. to 200 ° C., preferably 50 ° C. to 120 ° C., and can be carried out under microwave irradiation if necessary. The reaction time varies depending on the conditions such as the reaction temperature, the palladium catalyst used, the raw material, and the solvent, but is usually 5 minutes to 72 hours, preferably 2 hours to 8 hours.

[式中、環Ｑ^１、環Ｑ^２、Ｒ^ｂ、およびｍは、前記〔項１〕と同義であり；Ｒ^ａ１は同種または異種の１〜３個のハロゲン原子で置換されていてもよいＣ_１−６アルキルを表し；Ｘはハロゲンまたはトリフラート（トリフルオロメタンスルホニルオキシ）を表し；Ｘ^３はハロゲンを表し；Ａはボロン酸またはボロン酸エステルを表し；Ｐｒｏはアミノ基の保護基を表す。] Manufacturing method 4
Among the compounds represented by the formula (1), the compound represented by the formula (1d) is produced, for example, by the method shown below.

[In the formula, ring Q ¹ , ring Q ² , R ^b , and m are synonymous with [Item 1] above; R ^a1 may be substituted with 1 to 3 halogen atoms of the same or different species. C _1-6 alkyl represents; X represents halogen or triflate (trifluoromethanesulfonyloxy); X ³ represents halogen; A represents boronic acid or boronic acid ester; Pro represents a protective group for the amino group. ]

Step 4-1: Production step of compound (4-2) Compound (4-2) is produced from compound (1-2) and compound (4-1) according to the method described in step 1-2. NS. As the compound (4-1), a commercially available compound or a compound produced by a known method (for example, International Publication No. 2011/119518) can be used.

Step 4-2: Production step of compound (4-4) Compound (4-4) is a reducing agent after reacting compound (4-2) with compound (4-3) in an appropriate inert solvent. Manufactured by the action of. Examples of the inert solvent include acetonitrile, THF, 1,4-dioxane and the like. The reaction time of the alkylation step is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature of the alkylation step is 0 ° C to 100 ° C.

Examples of the reducing agent used in the subsequent reduction reaction step include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like. Examples of the solvent used include toluene, THF, dichloroethane, methanol and the like. The reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually −78 ° C. to 100 ° C., preferably −78 ° C. to 20 ° C.

Step 4-3: Preparation of Compound (1d) Compound (1d) uses a known method (eg, Protective Group in Organic Synthesis 3rd Edition (Theodora W)) to use the protecting group Pro of the amino group of compound (4-4). Manufactured by deprotection by Green, Peter GM Wuts, John Wiley & Sons Inc, 1999).

[式中、Ｒ^ｂ、ｍ、およびｎは、前記〔項１〕と同義であり；Ｒ^ａ１は同種または異種の１〜３個のハロゲン原子で置換されていてもよいＣ_１−６アルキルを表し；Ｘ^２はハロゲンまたはトリフラート（トリフルオロメタンスルホニルオキシ）を表し；Ｐｒｏ’はアミノ基の保護基を表し；Ａはボロン酸またはボロン酸エステルを表す。] Manufacturing method 5
The compound represented by the formula (1-3) is also produced, for example, by the method shown below.

[In the formula, R ^b , m, and n are synonymous with [Item 1] above; Ra ¹ _{is a C 1-6} alkyl optionally substituted with 1-3 halogen atoms of the same or different species. Representation; X ² represents halogen or triflate (trifluoromethanesulfonyloxy); Pro'represents an amino protecting group; A represents boronic acid or boronic acid ester. ]

Step 5-1: Preparation of Compound (5-1) Compound (5-1) uses a known method (for example, Protective Group in Organic Synthesis) to use the protecting group Pro'of the amino group of compound (3-2). Manufactured by deprotection in 3rd edition (Theodora W. Green, Peter GM Wuts, John Wiley & Sons Inc, 1999).

Step 5-2: Production of compound (5-2) Compound (5-2) is prepared by reacting compound (5-1) with various aldehydes in the presence of a reducing agent in a suitable inert solvent. Manufactured. Examples of the reducing agent include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like. Examples of the inert solvent include toluene, THF, dichloroethane, methanol and the like. The reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually −78 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.

Compound (5-2) is also produced by reacting compound (5-1) with various alkyl halides in the presence of a base in a suitable inert solvent. Examples of the base include potassium carbonate, cesium carbonate, sodium hydride, lithium diisopropylamide and the like. Examples of the inert solvent include DMF, dimethyl sulfoxide, THF, 1,4-dioxane and the like. The reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually −78 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.

Step 5-3: Production of Compound (1-3) Compound (1-3) is prepared by coupling compound (5-2) with a boring reagent in the presence of a palladium catalyst in a suitable inert solvent. Manufactured by. This step can be performed in the presence of base and / or phosphorus ligands, if desired. Examples of the base include potassium acetate. Examples of the phosphorus ligand include triphenylphosphine and bis (diphenylphosphino) methane. As the boring reagent, various boring reagents used in a conventional method can be used, and examples thereof include bis (pinacholate) diborane and the like. As the palladium catalyst, various palladium catalysts used in a conventional method can be used, and examples thereof include 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride. Examples of the inert solvent include 1,4-dioxane, THF and the like. The reaction temperature is usually 0 ° C. to 200 ° C., preferably 50 ° C. to 120 ° C., and can be carried out under microwave irradiation if necessary. The reaction time varies depending on the conditions such as the reaction temperature, the palladium catalyst used, the raw material, and the solvent, but is usually 5 minutes to 72 hours, preferably 2 hours to 8 hours.

By carrying out the above production methods in an appropriate combination, the compound of the present invention having a desired substituent at a desired position can be obtained. Isolation and purification of intermediates and products in the above production method may be carried out by appropriately combining methods used in ordinary organic synthesis, such as filtration, extraction, washing, drying, concentration, crystallization, and various types of chromatography. can. Further, the intermediate can be subjected to the next reaction without any particular purification.

Depending on the reaction conditions and the like, the raw material compound or intermediate in the above production method may exist in the form of a salt such as hydrochloride, but can be used as it is or in a free form. When the raw material compound or intermediate is obtained in the form of a salt and the raw material compound or intermediate is to be used or obtained in free form, they are dissolved or suspended in a suitable solvent, for example, a base such as an aqueous sodium hydrogen carbonate solution. It can be converted to a free form by neutralizing with or the like.

Among the compounds represented by the formula (1) or pharmaceutically acceptable salts thereof are tautomers such as keto-enol, positional isomers, geometric isomers or optical isomers. All possible isomers, including these, and mixtures in any proportion of the isomers are also included in the invention.
Further, the optical isomer can be separated by carrying out a known separation step such as a method using an optically active column or a fractional crystallization method in an appropriate step of the above-mentioned production method. An optically active substance can also be used as a starting material.

When it is desired to obtain the salt of the compound represented by the formula (1), if the salt of the compound represented by the formula (1) can be obtained, it may be purified as it is, and the compound represented by the formula (1) can be obtained. When obtained in the free form, the compound represented by the formula (1) may be dissolved or suspended in an appropriate solvent, and an acid or a base may be added to form a salt. In addition, compound (1) or a pharmaceutically acceptable salt thereof may exist in the form of a solvate with water or various solvents, and these solvates are also included in the present invention.

As used herein, the term "treatment-resistant schizophrenia" refers to schizophrenia in which sufficient improvement is not observed even when two or more antipsychotic drugs are administered in a sufficient amount for a sufficient period of time. According to the Japanese guidelines for schizophrenia drugs, two or more antipsychotic drugs are administered at 600 mg / day or more in terms of chlorpromazine for 4 weeks or more, and the Global Assessment of Functioning (GAF) is 41 points or more. It is defined that it has never been in a corresponding state.

Is effective for treatment resistant schizophrenia clozapine, D ₂ receptor antagonism, in addition to the 5-HT _2A receptor antagonistic action, are known to have antagonistic action against D ₁ receptor ( Non-Patent Documents 4, 5, 6). _{The compound of the present invention, which has an antagonistic effect on the D 1} receptor, the D ₂ receptor, and the 5-HT _2A receptor as well as clozapine, can be expected to be effective for treatment-resistant schizophrenia.

In addition, since the compound of the present invention _{exhibits an antagonistic effect on the D 2} receptor and the 5-HT _2A receptor, schizophrenia, bipolar disorder, autism, ADHD, depression, anxiety disorder, sleep disorder, etc. It is expected to be effective for behavioral and psychological symptoms of dementia (BPSD (Behavioral and Psychological Symptoms of Dementia)) and psychological symptoms of neurodegenerative diseases.

Although there is no general animal model that mimics treatment-resistant schizophrenia, treatment of schizophrenia is performed by conducting a rat methanephrenia-induced hypermotility test (Test Example 6), which is a model of positive symptoms of schizophrenia. By finding a drug and _{confirming that it has an antagonistic effect on the above-mentioned D 1} receptor and D ₂ receptor, it is considered possible to search for a drug effective for treatment-resistant schizophrenia.

After a pharmaceutical compound is taken into the body, its chemical structure is changed by undergoing metabolism, and a highly reactive intermediate, that is, a reactive metabolite, is produced, and toxicity (non-granulopathy, hepatotoxicity, allergy, etc.) Tissue necrosis, mutagenicity, carcinogenicity, etc.) may be expressed. One of the tests for simply evaluating the risk of toxicity due to this reactive metabolite is a glutathione trapping test using dansylated glutathione (dGSH). The higher the value of dGSH co-binding amount, the higher the above-mentioned toxicity risk when exposed to the whole body.

It has been reported that agranulocytosis observed in clozapine is partly due to the production of reactive metabolites (see The Journal of Pharmacology and Experimental Therapeutics, 1997, 283 (3) 1375-1382, etc.).
When a dansylated glutathione (dGSH) trapping test was performed on the compound of the present invention, it was surprisingly found that the compound of the present invention had an extremely low value of the dGSH covalent bond amount and the production of reactive metabolites was significantly reduced. (Test Example 2). From this, it is expected that the compound of the present invention has a low risk of agranulocytosis and can be safely administered for a long period of time.

It has been reported that side effects such as digestive disorders, sedation, and weight gain observed with clozapine are partly due _{to antagonism of histamine receptor, muscarine receptor, 5-HT2c} receptor, etc. (Molecular Psychiatry (2008) ) 13, 27-35; Prim Care Companion J Clin Psychiatry. 2004, 6 (suppl 2): 3-7; CNS Drugs. 2013 Jun; 27 (6): 423-34; J Clin Psychiatry 2004, 6 (Suppl 2) ): 20-23; Clin Psychopharmacol Neurosci. 2012 Aug; 10 (2): 71-77 etc.).
When the antagonist activity evaluation test for these receptors was performed on the compound of the present invention, it was surprisingly found that the antagonist action on these receptors was low in a more preferable embodiment of the compound of the present invention (Test Example 3). From this, in a more preferable embodiment of the compound of the present invention, it is expected that the risk of digestive disorders, sedation, weight gain and the like is low, and that the compound can be safely administered.

In the present invention, "prevention" is an act of administering the active ingredient of the present invention to a healthy person who has not developed a disease, for example, for the purpose of preventing the onset of a disease. be. "Treatment" is an act of administering the active ingredient of the present invention to a person (patient) who has been diagnosed as having a disease by a doctor.

The compound of the present invention can be formulated and administered directly or by using an appropriate dosage form by oral administration or parenteral administration. Dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, poultices and the like. The pharmaceutical product is produced by a known method using pharmaceutically acceptable additives.
Additives include excipients, disintegrants, binders, fluidizers, lubricants, coatings, solubilizers, solubilizers, thickeners, dispersants, stabilizers, and sweeteners, depending on the purpose. , Perfume and the like can be used. Specifically, for example, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, stearate. Examples thereof include magnesium acid, stearyl sodium fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.

As the administration route, it is desirable to use the most effective route for treatment, and oral administration or parenteral administration such as intravenous, application, inhalation and eye drops can be mentioned, but oral administration is preferable. Examples of the administration form include tablets, injections and the like, but tablets are preferable. The dose and frequency of administration of these pharmaceutical compositions vary depending on the administration form, the patient's disease and symptoms, the age and weight of the patient, etc., and cannot be unconditionally specified, but are usually effective for adults per day. The amount of the component is in the range of about 0.0001 to about 5000 mg, preferably in the range of about 0.001 to about 1000 mg, more preferably in the range of about 0.1 to about 500 mg, and particularly preferably in the range of about 1 to about 300 mg. It can be administered once or several times a day, preferably divided into 1 to 3 times a day.

The compound of the present invention can be used in combination with other drugs for the purpose of enhancing its effect and / or reducing side effects. For example, it can be used in combination with antipsychotics such as aripyrazole, olanzapine, quetiapine, risperidone, blonanserin, perospirone, paliperidone, ziprasidone, asenapine, iroperidone, sertindol, lurasidone or a pharmaceutically acceptable salt thereof. Hereinafter, a drug that can be used in combination with the compound of the present invention is abbreviated as a concomitant drug.

The administration period of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or at different times. Further, it may be a mixture of the compound of the present invention and a concomitant drug. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration target, administration route, target disease, symptom, combination and the like. For example, when the administration target is a human, 0.01 to 100 parts by weight of the concomitant drug may be used with respect to 1 part by weight of the compound of the present invention. In addition, for the purpose of suppressing the side effects, it can be used in combination with drugs (combined drugs) such as antiemetics, sleep-inducing agents, and anticonvulsants.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples and Test Examples, but the present invention is not limited thereto. The compound names shown in the following reference examples and examples do not necessarily follow the IUPAC nomenclature.

In order to simplify the description of the specification, the following abbreviations may be used in Reference Examples, Examples and Test Examples.
Me: Methyl Et: Ethyl DMF: N, N-Dimethylformamide DMSO: Dimethyl sulfoxide THF: Tetrahydrofuran TFA: Trifluoroacetic acid

As symbols used in NMR, s is a single line, d is a double line, dd is a double line, t is a triple line, td is a triple line double line, q is a quadruple line, and m. Is a multiple line, br is a wide range, brs is a wide single line, brm is a wide multiple line, and J is a coupling constant.

High performance liquid chromatography mass spectrometer; LCMS measurement condition is as follows, the observed value of mass spectrometry [MS (m / z)] a [M + ^{H] +} or [M-H] ^- a, the retention time Is indicated by Rt (minutes).
Measurement conditions (1)
Detection device: ACQUITY® SQ deteceter (Waters)
HPLC: ACQUITY UPLC® system
Column: Waters ACQUITY UPLC® BEH C18 (1.7 μm, 2.1 mm X 30 mm)
Flow velocity: 0.80 mL / min
Measurement wavelength: 254 nm
Moving layer: Solution A 0.05% aqueous formic acid solution Solution B acetonitrile Time program:
Step time (minutes)
1 0.0-1.3 Solution A: Solution B = 90: 10-5: 95
2 1.3-1.5 Solution A: Solution B = 90:10

Measurement conditions (2)
Detection device: ACQUITY® SQ deteceter (Waters)
HPLC: ACQUITY UPLC® system
Column: Waters ACQUITY UPLC® BEH C18 (1.7 μm, 2.1 mm X 30 mm)
Flow velocity: 0.75 mL / min
Measurement wavelength: 254 nm
Moving layer: Solution A 0.05% aqueous formic acid solution Solution B acetonitrile Time program:
Step time (minutes)
1 0.0-1.3 Solution A: Solution B = 90:10 to 1:99
2 1.3-1.5 Solution A: Solution B = 1:99
3 1.5-2.0 Solution A: Solution B = 90:10

Measurement conditions (3)
Detection device: LCMS-2020 (Shimadzu)
Column: Phenomenex Kinetex (1.7 μm, C18, 50 mm X 2.10 mm)
Flow velocity: 0.50 mL / min
Measurement wavelength: 220, 254 nm
Moving layer: Solution A 0.05% TFA aqueous solution Solution B acetonitrile Column temperature: 40 ° C
Time program:
Step time (minutes)
1 0.0 Solution A: Solution B = 90:10
2 0.0-1.9 Solution A: Solution B = 90: 10-10: 99
3 1.9-3.0 Solution A: Solution B = 90:10

Reference example 1
2-Chloro-8-fluoro-5-[(4-Methoxyphenyl) methyl] -5,11-dihydro-10H-dibenzo [b, f] azepine-10-one

a) Preparation of 2-bromo-N, N-diethyl-5-fluorobenzamide (Compound W1) Oxalyl chloride (2.2 mL) in a chloroform (114 mL) solution of 2-bromo-5-fluorobenzoic acid (5.0 g). ) And a few drops of DMF were added and stirred at room temperature for 1 hour. Diethylamine (11.8 mL) was added to the reaction solution at 0 ° C., and the mixture was further stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The obtained organic layer was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent of the organic layer after drying under reduced pressure, the compound W1 (6.3 g) was obtained by purification by silica gel column chromatography (eluting solvent; hexane / ethyl acetate).
LC-MS ([M + H] ⁺ / Rt (min)): 275 / 0.77 Measurement conditions (1)

b) Preparation of 2- (4-chloro-2-methylanilino) -N, N-diethyl-5-fluorobenzamide (Compound W2) 4-Chloro-2 in a toluene (76 mL) solution of compound W1 (6.3 g). -Methylaniline (4.2 g), palladium acetate (0.26 g), 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (1.4 g) and sodium t-butoxide (3.3 g) Was added, and the mixture was stirred at 80 ° C. for 4 hours. The reaction mixture was cooled, filtered through Celite, washed with ethyl acetate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent; hexane / ethyl acetate) to obtain compound W2 (7.6 g).
LC-MS ([M + H] ⁺ / Rt (min)): 335 / 1.13 Measurement conditions (1)

c) Production of 2-{(4-chloro-2-methylphenyl) [(4-methoxyphenyl) methyl] amino} -N, N-diethyl-5-fluorobenzamide (Compound W3) Compound W2 (7.6 g) 4-Methoxybenzyl chloride (4.0 mL) and sodium hydride (60% mineral oil dispersion) (1.2 g) were added to a solution of DMF (76 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent of the organic layer after drying under reduced pressure, the compound W3 (8.0 g) was obtained by purification by silica gel column chromatography (eluting solvent; hexane / ethyl acetate).
LC-MS ([M + H] ⁺ / Rt (min)): 455 / 1.24 Measurement conditions (1)

d) Production of 2-chloro-8-fluoro-5-[(4-methoxyphenyl) methyl] -5,11-dihydro-10H-dibenzo [b, f] azepine-10-one (Reference Example 1) Compound W3 To a solution of (8.0 g) in THF (88 mL) was added a 1.1 mol / L lithium diisoproamide-THF solution (40 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent of the organic layer after drying was evaporated under reduced pressure and then purified by silica gel column chromatography (eluting solvent; hexane / ethyl acetate) to give the title compound (6.0 g).
LC-MS ([M + H] ⁺ / Rt (min)): 382 / 1.17 Measurement conditions (1)

Reference examples 2-11
The compounds shown in the table below were obtained using the corresponding raw material compounds according to the method described in Reference Example 1.

Reference example 12
2,8-dimethyl-5H-dibenzo [b, f] azepine

a) Preparation of 5-methyl-1- (4-methylphenyl) -1H-indole (Compound W4) 1-iodo-4- in a solution of 5-methyl-1H-indole (0.26 g) in DMF (4 mL). Methylbenzene (0.65 g), cesium carbonate (1.3 g) and copper (I) iodide (0.42 g) were added, and the mixture was stirred at 100 ° C. for 12 hours and cooled. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent of the organic layer after drying under reduced pressure, the compound W4 (0.44 g) was obtained by purification by silica gel column chromatography (eluting solvent; hexane / ethyl acetate).
LC-MS ([M + H] ⁺ / Rt (min)): 222 / 1.42 Measurement conditions (2)

b) Production of 2,8-dimethyl-5H-dibenzo [b, f] azepine (Reference Example 12) Polyphosphoric acid (3 g) was added to compound W4 (0.44 g), stirred at 110 ° C. for 24 hours, and cooled. did. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The obtained organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent of the organic layer after drying was evaporated under reduced pressure and then purified by silica gel column chromatography (eluting solvent; hexane / ethyl acetate) to give the title compound (0.14 g).
LC-MS ([M + H] ⁺ / Rt (min)): 222 / 1.29 Measurement conditions (2)

Reference example 13
The compounds shown in the table below were obtained using the corresponding raw material compounds according to the method described in Reference Example 12.

Reference example 14
tert-Butyl 6-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate and tert- Butyl 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate

a) tert-Butyl 6-methyl-4-{[(trifluoromethyl) sulfonyl] oxy} -3,6-dihydropyridine-1 (2H) -carboxylate and tert-butyl 2-methyl-4-{[(trifluoromethyl) Fluoromethyl) sulfonyl] oxy} -3,6-dihydropyridine-1 (2H) -carboxylate (substance A) of 1- (tert-butoxycarbonyl) -2-methylpiperidine-4-one (1.1 g) A 1.5 mol / L lithium diisoproamide-THF solution (4.0 mL) was added dropwise to the THF solution (10 mL) at −78 ° C. After stirring at −78 ° C. for 10 minutes, a THF solution (5 mL) of N-phenylbis (trifluoromethanesulfonimide) (2.1 g) was added dropwise. After stirring at room temperature for 4 hours, saturated aqueous ammonium chloride solution was added at 0 ° C., and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. After distilling off the solvent of the organic layer after drying under reduced pressure, the _{substance A (eluting solvent; chloroform / methanol) and NH 2} silica gel column chromatography (eluting solvent; hexane / ethyl acetate) are used for purification. 1.7 g, a mixture of isomers) was obtained.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 5.73, 5.69 (s, 1H, isomer ratio = 1: 1), 4.65-4.23 (m, 2H), 3.64-2.52 (m, 2H), 2.21-2.02 (m, 1H), 1.45 (s, 9H), 1.23, 1.16 (ds, 3H, J = 6.8 Hz, isomer ratio = 1: 1).

b) tert-Butyl 6-methyl-4- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate and tert-Butyl 2-methyl-4- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate (reference example) Production of 14) In THF solution (50 mL) of substance A (1.7 g), bis (pinacholate) diborane (1.4 g), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride (0) .73 g) and potassium acetate (1.5 g) were added. After stirring at 80 ° C. for 2 hours, the mixture was cooled to room temperature and the precipitate was removed by filtration through Celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. The solvent of the organic layer after drying was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography (eluting solvent; hexane / ethyl acetate) to obtain Reference Example 14 (1.2 g, a mixture of isomers).
LC-MS ([M + H] ⁺ / Rt (min)): 324 / 1.37 Measurement conditions (1)
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 5.73, 5.69 (s, 1H, isomer ratio = 1: 1), 4.43-4.16 (m, 2H), 3.61-2.37 (m, 2H), 2.13-2.01 (m, 1H), 1.44 (s, 9H), 1.24 (s, 12H), 1.16, 1.03 (d, 3H, J = 6.8Hz, isomer ratio = 1: 1).

Reference examples 15 to 17
The compounds (mixtures of isomers) shown in the table below were obtained using the corresponding raw material compounds according to the method described in Reference Example 14.

Reference example 18
(6S) -1,6-dimethyl-4- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2,3,6-tetrahydropyridine hydrochloride

a) tert-butyl (6S) -6-methyl-4-[(trifluoromethanesulfonyl) oxy] -3,6-dihydropyridine-1 (2H) -carboxylate and tert-butyl (2S) -2-methyl-4 -[(Trifluoromethanesulfonyl) oxy] -3,6-dihydropyridine-1 (2H) -carboxylate (substance B) production tert-butyl (2S) -2-methyl-4-oxopiperidine-1-carboxylate ( To a 10 g) THF solution (117 mL) was added dropwise a 1.1 mol / L lithium diisoproamide-THF solution (56 mL) at 0 ° C. After stirring at 0 ° C. for 10 minutes, N-phenylbis (trifluoromethanesulfonimide) (22 g) was added at −78 ° C. After stirring at −78 ° C. for 10 minutes, the mixture was further stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added at room temperature, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. After distilling off the solvent of the organic layer after drying under reduced pressure, the substance B (18 g, a mixture of isomers) was obtained by purification by silica gel column chromatography (eluting solvent; hexane / ethyl acetate).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 5.73, 5.69 (s, 1H, isomer ratio = 1: 1), 4.65-4.24 (m, 2H), 3.64-2.52 (m, 2H), 2.21- 2.02 (m, 1H), 1.45 (s, 9H), 1.21, 1.16 (d, 3H, J = 6.8 Hz, isomer ratio = 1: 1).

b) (6S) -6-methyl-1,2,3,6-tetrahydropyridine-4-yltrifluoromethanesulfonate and (2S) -2-methyl-1,2,3,6-tetrahydropyridine-4- Production of Iltrifluoromethanesulfonate (Substance C) A 4 mol / L hydrogen chloride-ethyl acetate solution (61 mL) was added to an ethyl acetate solution (98 mL) of substance B (17 g). After stirring at room temperature for 3 hours, the solvent was distilled off under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added to the obtained crude product, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. The solvent of the organic layer after drying was distilled off under reduced pressure to obtain a substance C (14 g, a mixture of isomers).
LC-MS ([M + H] ⁺ / Rt (min)): 246 / 0.76 Measurement conditions (3)

c) Production of (6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yltrifluoromethanesulfonate (Compound W5) 0 in a methanol solution (163 mL) of substance C (12 g). A 37% aqueous formaldehyde solution (11 mL) and sodium triacetoxyborohydride (21 g) were added at ° C. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added to the obtained crude product, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. After distilling off the solvent of the organic layer after drying under reduced pressure, the compound was purified by silica gel column chromatography (eluting solvent; chloroform / ethyl acetate) and NH ₂ silica gel column chromatography (eluting solvent; chloroform / ethyl acetate). W5 (3.9 g) was obtained.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 5.60 (s, 1H), 2.94-2.92 (m, 2H), 2.61-2.53 (m, 2H), 2.32-2.25 (m, 1H), 2.36 (s , 3H), 1.18 (d, 3H, J = 6.7 Hz).

d) (6S) -1,6-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2,3,6-tetrahydropyridin hydrochloride Production of salt (Reference Example 18) Bis (pinacholate) diborane (4.3 g), 1,1'-bis (diphenylphosphino) ferrocene-in a THF solution (51 mL) of compound W5 (3.9 g) at room temperature. Palladium (II) dichloride (0.62 g) and potassium acetate (4.5 g) were added. After stirring at 80 ° C. for 1 hour, the mixture was cooled to room temperature. After removing the precipitate by filtration through Celite, the solvent was distilled off under reduced pressure. Diethyl ether was added to the crude product, and the precipitate was removed by filtration through Celite again, and then the solvent was distilled off under reduced pressure. The obtained crude product (6.5 g) was dissolved in diethyl ether (40 mL), and a 4 mol / L hydrogen chloride-ethyl acetate solution (4.0 mL) was added. Reference Example 18 (3.5 g) was obtained by filtering the precipitated solid and washing with hexane.
LC-MS ([M + H] ⁺ / Rt (min)): 238 / 1.25 Measurement conditions (3)

Example 1
2-Chloro-8-fluoro-10- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, f] azepine

a) Production of 2-chloro-8-fluoro-5-[(4-methoxyphenyl) methyl] -5H-dibenzo [b, f] azepine-10-yltrifluoromethanesulfonate (Compound W6) Compound of Reference Example 1. To a solution of (5.2 g) in THF (50 mL) was added a 1.1 mol / L lithium diisoproamide-THF solution (16 mL) at −78 ° C., and the mixture was stirred for 10 minutes. A solution of N-phenylbis (trifluoromethanesulfonimide) (6.3 g) in THF (20 mL) was added at −78 ° C., and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent of the organic layer after drying under reduced pressure, the compound W6 (3.7 g) was obtained by purification by silica gel column chromatography (eluting solvent; hexane / ethyl acetate).
LC-MS ([M + H] ⁺ / Rt (min)): 514 / 1.36 Measurement conditions (1)

b) 2-Chloro-8-fluoro-5-[(4-methoxyphenyl) methyl] -10- (1-methyl-1,2,3,6-tetrahydropyridine-4-yl) -5H-dibenzo [b) , F] Production of Azepine (Compound W7) 1-Methyl-4- (4,5,5-tetramethyl-1) in a THF / water (4/1) (100 mL) solution of Compound W6 (3.7 g) , 3,2-Dioxaboran-2-yl) -1,2,3,6-tetrahydropyridine (1.9 g), potassium carbonate (3.0 g) and tetrakis (triphenylphosphine) palladium (0) (1.7 g) ) Was added. After stirring for 1 hour under heating under reflux, the mixture was cooled. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent of the organic layer after drying under reduced pressure _{, the compound W7 (1.3 g) was obtained by purification by NH 2} silica gel column chromatography (eluting solvent; hexane / ethyl acetate).
LC-MS ([M + H] ⁺ / Rt (min)): 461 / 0.87 Measurement conditions (1)

c) Preparation compound of 2-chloro-8-fluoro-10- (1-methyl-1,2,3,6-tetrahydropyridine-4-yl) -5H-dibenzo [b, f] azepine (Example 1) Trifluoroacetic acid (10 mL) was added to W7 (1.3 g). After stirring at 80 ° C. for 1 hour, the mixture was cooled to 0 ° C. Saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the mixture was extracted with chloroform. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. The solvent of the organic layer after drying was evaporated under reduced pressure, _{purified by NH 2} silica gel column chromatography (eluting solvent; hexane / ethyl acetate), and recrystallized from diethyl ether and hexane to give the title compound (0. 57 g) was obtained.
LC-MS ([M + H] ⁺ / Rt (min)): 341 / 0.67 Measurement conditions (1)
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.04-6.98 (m, 2H), 6.87-6.78 (m, 2H), 6.66-6.64 (m, 1H), 6.58-6.55 (m, 2H), 5.82 -5.81 (m, 1H), 4.97 (s, 1H), 3.10-3.09 (m, 2H), 2.61-2.54 (m, 2H), 2.41 (s, 3H), 2.37-2.36 (m, 2H).

Examples 2-16
The compounds of Examples 2 to 16 were obtained by using the corresponding reference example compounds and raw material compounds according to the method described in Example 1.

Example 17
2-Chloro-11- (1-ethyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, f] azepine

a) Production of 8-chloro-5-[(4-methoxyphenyl) methyl] -5H-dibenzo [b, f] azepine-10-yltrifluoromethanesulfonate (Compound W8) Compound (1.0 g) of Reference Example 5. ) Was added to a 1.1 mol / L lithium diisoproamide-THF solution (3.3 mL) at −78 ° C., and the mixture was stirred for 10 minutes. A solution of N-phenylbis (trifluoromethanesulfonimide) (1.3 g) in THF (5 mL) was added at −78 ° C., and the mixture was stirred at 0 ° C. for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent of the organic layer after drying under reduced pressure, the compound W8 (0.5 g) was obtained by purification by silica gel column chromatography (eluting solvent; hexane / ethyl acetate).
LC-MS ([M + H] ⁺ / Rt (min)): 496 / 1.35 Measurement conditions (1)

b) 2-Chloro-5-[(4-methoxyphenyl) methyl] -11- (pyridin-4-yl) -5H-dibenzo [b, f] Azepine (Compound W9) Production Compound W8 (0.30 g) 4-Pyridylboronic acid (74 mg), potassium carbonate (0.25 g) and tetrakis (triphenylphosphine) palladium (0) (0.14 g) were added to a solution of THF / water (4/1) (10 mL). After stirring for 1 hour under heating under reflux, the mixture was cooled. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent of the organic layer after drying under reduced pressure _{, the compound W9 (0.22 g) was obtained by purification by NH 2} silica gel column chromatography (eluting solvent; hexane / ethyl acetate).
LC-MS ([M + H] ⁺ / Rt (min)): 425 / 1.03 Measurement conditions (1)

c) Preparation of 2-chloro-11- (pyridin-4-yl) -5H-dibenzo [b, f] azepine (compound W10) Trifluoroacetic acid (2 mL) was added to compound W9 (70 mg). After stirring at 80 ° C. for 1 hour, the mixture was cooled to 0 ° C. Saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the mixture was extracted with chloroform. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. After distilling off the solvent of the organic layer after drying under reduced pressure _{, the compound W10 (40 mg) was obtained by purification by NH 2} silica gel column chromatography (eluting solvent; hexane / ethyl acetate).
LC-MS ([M + H] ⁺ / Rt (min)): 305 / 0.70 Measurement conditions (1)

d) Preparation of 2-chloro-11- (1-ethyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, f] azepine (Example 17) Compound W10 (20 mg) Ethyl iodide (0.14 mL) was added to a solution of acetonitrile (0.59 mL). After stirring at 70 ° C. for 1 hour, the reaction solution was concentrated. The obtained residue was dissolved in methanol (2 mL), and sodium borohydride (11 mg) was added at 0 ° C. After stirring at room temperature for 30 minutes, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent of the organic layer after drying was evaporated under reduced pressure and then _{purified by NH 2} silica gel column chromatography (eluting solvent; hexane / ethyl acetate) to give the title compound (15 mg).
LC-MS ([M + H] ⁺ / Rt (min)): 337 / 0.58 Measurement conditions (1)
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.09-7.04 (m, 3H), 7.02-6.99 (m, 1H), 6.93-6.89 (m, 1H), 6.67-6.62 (m, 3H), 5.82 -5.80 (m, 1H), 5.03 (s, 1H), 3.15-3.13 (m, 2H), 2.66-2.61 (m, 2H), 2.55-2.49 (m, 2H), 2.38-2.34 (m, 2H) , 1.14 (t, 3H, J = 7.2 Hz).

Examples 18-24
Compounds of Examples 18 to 24 were obtained using the corresponding reference example compounds and raw material compounds according to the method described in Example 17.

Example 25
10-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-fluoro-8-methyl-5H-dibenzo [b, f] azepine

a) 2-Fluoro-8-methyl-10-[(6S) -6-methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, f] azepine and 2-fluoro -8-Methyl-10-[(2S) -2-methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, f] Azepine (substance D) Production Reference Example 4 And using the compound of Reference Example 15, substance D (mixture of isomers) was obtained according to the method described in Example 1.
LC-MS ([M + H] ⁺ / Rt (min)): 321 / 0.60 Measurement conditions (1)

b) 10-[(6S) -1,6-dimethyl-1,6,3,6-tetrahydropyridine-4-yl] -2-fluoro-8-methyl-5H-dibenzo [b, f] azepine (implemented) Example 25) Production A 37% formaldehyde solution (0.30 g) and a molecular sieve 4A (0.80 g) were added to a solution of substance D (0.23 g) in methanol (7 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was ice-cooled and sodium borohydride (0.27 g) was added. The mixture was stirred at 0 ° C. for 1 hour, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. The solvent of the organic layer after drying was evaporated under reduced pressure and then _{purified by NH 2} silica gel column chromatography (eluting solvent; hexane / ethyl acetate) to give the title compound (69 mg).
LC-MS ([M + H] ⁺ / Rt (min)): 335 / 0.67 Measurement conditions (1)
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 6.98 (dd, 1H, J = 7.9, 1.2 Hz), 6.91 (d, 1H, J = 1.2 Hz), 6.79-6.73 (m, 2H), 6.65 ( d, 1H, J = 7.9 Hz), 6.63-6.60 (m, 2H), 5.65-5.64 (m, 1H), 4.97 (s, 1H), 2.95-2.86 (m, 2H), 2.59-2.45 (m, 2H), 2.43 (s, 3H), 2.22 (s, 3H), 2.20-2.15 (m, 1H), 1.24 (d, 3H, J = 6.7 Hz).

Example 26
2,8-Dimethyl-10- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, f] azepine

a) Production of 2,8-dimethyl-5H-dibenzo [b, f] azepine-5-carbonyl chloride (Compound W11) Triethylamine (0.18 mL) in a chloroform (8 mL) solution of the compound (0.14 g) of Reference Example 12 ) Was added, the mixture was cooled to 0 ° C., and a solution of triphosgene (0.19 g) in chloroform (4 mL) was added. After stirring at room temperature for 2 hours, water was added to the reaction solution and the mixture was extracted with chloroform. The obtained organic layer was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent of the organic layer after drying under reduced pressure, the compound W11 (0.15 g) was obtained by washing with diethyl ether.
LC-MS ([M + H] ⁺ / Rt (min)): 284 / 1.32 Measurement conditions (2)

b) Production of 10,11-dibromo-2,8-dimethyl-10,11-dihydro-5H-dibenzo [b, f] azepine-5-carbonyl chloride (Compound W12) Acetic acid (0. Bromine (17 μL) was added to the 28 mL) solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ° C., saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent of the organic layer after drying was distilled off under reduced pressure to obtain compound W12 (0.13 g).
LC-MS ([M + H] ⁺ / Rt (min)): 443 / 1.32 Measurement conditions (2)

c) Production of 2,8-dimethyl-10- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, f] azepine (Example 26) Compound W12 ( To a solution of 0.13 g) in THF (1.3 mL) was added 1,8-diazabicyclo [5.4.0] -7-undecene (0.13 g), and the mixture was stirred at room temperature for 30 minutes. In the reaction solution, 1-methyl-4- (4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) -1,2,3,6-tetrahydropyridine (94 mg), carbonate. Potassium (0.19 g) and tetrakis (triphenylphosphine) palladium (0) (65 mg) were added. After stirring for 1 hour under heating under reflux, the mixture was cooled. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent of the organic layer after drying under reduced pressure _{, the title compound was purified by NH 2} silica gel column chromatography (eluting solvent; hexane / ethyl acetate) and silica gel column chromatography (eluting solvent; chloroform / methanol). (10 mg) was obtained.
LC-MS ([M + H] ⁺ / Rt (min)): 317 / 0.74 Measurement conditions (2)

Examples 27 and 28
Compounds of Examples 27 and 28 were obtained using the corresponding reference example compounds and raw material compounds according to the method described in Example 26.

Test Examples The results of the pharmacological test of the compound of the present invention will be shown below, and the pharmacological action of the compound will be described, but the present invention is not limited to these test examples.

Test Example 1: human _{D 1} receptor, human _{D 2} receptor antagonist activity evaluation test human _{D 1} receptor for human _{5-HT 2A} receptor, human _{D 2} receptors, human 5-HT _The antagonist activity against the 2A receptor was measured using the intracellular calcium concentration as an index. After transient expression of each receptor for equolin and Gα16 protein in CHO-K1 cells (Chinese hamster ovary), the cells were seeded on a 384-well plate and cultured overnight at 37 ° C. _{in a CO 2 incubator.} After adding serenterazine, using FDSS (manufactured by Hamamatsu Photonics), after adding the DMSO suspension of the compound of the present invention, dopamine (final concentration 100 nmol / L) or serotonin (final concentration 30 nmol / L) is added to emit light. Changes in volume were measured.
For the antagonist activity, the inhibition rate at 1 μmol / L of the compound of the present invention was calculated when the luminescence amount of the well to which only DMSO was added was 100% inhibited and the luminescence amount of the well to which only dopamine or serotonin was added was 0% inhibition. .. In addition, those listed in the table below represent the inhibition rate at the stated concentration (for example, those listed as 58 @ 0.1 μmol / L have an inhibition rate at 0.1 μmol / L. It shows that it was 58%). In addition, clozapine was used as a comparative substance as a comparative example. The results are shown in the table below.

Test Example 2: Dansylated glutathione (dGSH) trapping assay The compound of the present invention was metabolized in hepatic microsomes, and reactive metabolites that react with dansylated glutathione (dGSH) were detected and quantified from the metabolites produced. The metabolic reaction was measured using a screening robot (manufactured by Tecan), and the concentration of metabolite-dGSH conjugate was measured using a fluorescence detection UPLC system (manufactured by Waters).

(Solution preparation)
The compound of the present invention was dissolved in DMSO to prepare a 10 mmol / L test substance solution. In addition, clozapine was used as a comparative substance as a comparative example.
A microsome solution was prepared by mixing 7.6 mL of potassium phosphate buffer (500 mmol / L, pH 7.4), 1.9 mL of human liver microsomes (manufactured by Xenotech, 20 mg protein / mL), and 1.27 mL of pure water. ..
A microsome (dGSH (−)) solution was prepared by adding 0.67 mL of pure water to 3.78 mL of the microsome solution.
1.14 mL of dGSH solution (20 mmol / L) was added to 6.48 mL of microsome solution to prepare a microsome (dGSH (+)) solution.
A cofactor solution was prepared by dissolving 80.9 mg of NADPH in 30 mL of pure water.
A reaction terminator was prepared by dissolving 33 mg of Tris (2-carboxyethyl) phosphin (TECP) in 115 mL of methanol.

(reaction)
12 μL of the test substance solution was mixed with 388 μL of pure water, and 50 μL each was dispensed into 6 wells on a 96-well plate. The above 6 wells were divided into 3 groups of 2 wells each, and were designated as a "reaction group", a "unreacted group" and a "dGSH non-added group", respectively.
A microsome (dGSH (+)) solution was added to the “reaction group” and the “unreacted group”, and 50 μL of the microsome (dGSH (−)) solution was added to the “dGSH non-added group”.
A cofactor solution was added to the "reaction group" and the "dGSH non-added group", and 50 μL of pure water was added to the "unreacted group".
After incubating at 37 ° C. for 60 minutes, the reaction was stopped by adding 450 μL of the reaction terminator solution. Add pure water to the "reaction group" and "dGSH-unadded group", add 50 μL of cofactor solution to the "unreacted group", cool the plate at -20 ° C for 1 hour, and then centrifuge (4000 rpm, 10 minutes). went. The supernatant was collected on a separate plate and used for analysis.

(analysis)
Using a fluorescence detection UPLC system (manufactured by Waters Corp.), the "reaction group", "unreacted group" and "dGSH unadded group" were analyzed under the following conditions.
Column: Waters ACQUITY UPLC® BEH C18 (1.7 μm, 2.1 mm x 10 mm)
Elution solvent: Solution A 0.2% formic acid / 40% methanol
Solution B 0.2% formic acid / methanol gradient: Solution B, 0% (0 min) → 83.3% (9.33 min) → 83.3% (10.63 min) → 0% (10.64 min) ) → 0% (13 min)
Since the fluorescence intensity changes depending on the organic solvent composition, the correction was made with the organic solvent composition at the time of elution.
The metabolite-dGSH conjugate concentration of the "reaction group" was calculated by subtracting the fluorescence peaks detected in the "unreacted group" and the "dGSH non-added group" from the fluorescence peaks detected in the "reaction group". By measuring the metabolite-dGSH conjugate concentration of the "reaction group", the risk of the reactive metabolite of the test substance can be assessed.

The table below shows the results of the metabolite-dGSH conjugate concentration of clozapine and the "reaction group" of the compounds of the present invention.

Test Example 3: Human-type 5-HT _2C receptor, histamine H ₁ receptor (hereinafter, H ₁ receptor), Muscarin M ₁ receptor (hereinafter, M ₁ receptor), Muscarin M ₂ receptor (hereinafter, hereinafter, M 2 receptor) Antagonist activity evaluation test against M ₂ receptor), Muscarin M ₃ receptor (hereinafter M ₃ receptor) and Muscarin M ₄ receptor (hereinafter M ₄ receptor) Human type 5-HT _2C receptor, H ₁ The antagonistic activity on the receptor, M ₁ receptor, M ₂ receptor, M ₃ receptor and M ₄ receptor was measured using the intracellular calcium concentration as an index. After transiently expressing equolin, Gα16 protein and each receptor in CHO-K1 cells (Chinese hamster ovary), the cells were seeded on a 384-well plate and cultured overnight at 37 ° C. _{in a CO 2 incubator.} After adding coelenterazine, using FDSS (manufactured by Hamamatsu Photonics), a DMSO suspension of the compound of the present invention was added, and then the corresponding ligand shown in the table below was added, and the change in the amount of luminescence was measured. The table below shows the ligands used to evaluate the antagonist activity of each receptor and their concentrations.

The antagonist activity inhibits the luminescence amount of the well to which only DMSO is added by 100% and the luminescence amount of the well to which only the corresponding ligand is added by 0%, and the concentration of the compound of the present invention is 1 μmol / L or 0.1 μmol / L. The inhibition rate in the case of was calculated.

Test Example 4: Human-type 5-HT _2A receptor, D ₁ receptor, D ₂ receptor, 5-HT _2C receptor, H ₁ receptor, M ₁ receptor, M ₂ receptor, M ₃ receptor the binding activity evaluation this test and for the _{M 4} receptor, _{5-HT 2A} receptor of the human forms of the present compounds, _{D 1} receptors, _{D 2} receptors, _{5-HT 2C} receptor, _{H 1} receptor, M _The binding affinity for 1 receptor, M ₂ receptor, M ₃ receptor and M ₄ receptor can be measured. Using the CHO cell membrane fraction expressing these receptors or the CHO-K1 cell membrane fraction, etc., in the binding evaluation test, the test compound dissolved in DMSO, various receptor membrane specimens diluted with a buffer solution, and these receptors RI (Radio Isotope) -labeled ligands are mixed and incubated at room temperature for 30 or 60 minutes, respectively. The RI-labeled ligand for the receptor can be appropriately selected depending on the test conditions and the like, but [3H] Ketanserin for the _{5-HT 2A} receptor and [3H] Spiperone for _{the D 2 receptor.} [3H] SCH233390 can be used for the D _{1 receptor.} Non-specific binding to the receptor is a competitive binding test in the presence of Mianserin for _{5-HT 2A} receptor, Dopamine for _{D 2 receptor, SCH23390 for D 1 receptor, etc.} More demanded. After measuring the radioactivity bound to the receptor using a liquid scintillation counter, calculate the 50% inhibitory concentration, evaluate the Ki value from the dissociation constant calculated from the saturated binding test, and the substrate concentration, and use it as the binding affinity. do. Other, _{5-HT 2C} receptor human, _{H 1} receptor, _{M 1} receptor, _{M 2} receptors, also for binding affinity for _{M 3} receptor and _{M 4} receptors, measured according to the above method can do. These include RI labeled ligands for the receptor, but can be appropriately selected depending on such as the test conditions, for example, for a _{5-HT 2C} receptor human [3H] Mesulergine, _{H 1} receptor of human [3H] Pyrilamine can be used for the body, [3H] N-Mepyrscopolamine and the like can be used for _{the human M 1} receptor, M ₂ receptor, M ₃ receptor and M _{4 receptor.} Furthermore, non-specific binding to these receptors, Mianserin for _{5-HT 2C} receptor of human type, Pyrilamine for _{H 1} receptor human, human _{M 1} receptor, M _{For 2} receptors, M ₃ receptors and M ₄ receptors, it is obtained from a competitive binding test in the presence of Atropine or the like.

Test Example 5: Cyanotrapping Assay In this test, reactive metabolites that cannot be captured by dansylated glutathione can be detected. Reactive metabolites are detected and quantified by metabolizing the compound of the present invention in human liver microsomes ^{and reacting it with radioactive potassium cyanide (K 14 CN).} Human liver microsomes manufactured by Xenontech are used, and the reaction is carried out at 37 ° C. for 60 minutes under the following concentration conditions.
Concentration conditions-Phosphate buffer (pH 7.4): 100 mmol / L
・ Human liver microsomes: 1 mg / mL
・ K ¹⁴ CN: 0.1 mmol / L
-Test substance: 50 μmol / L · NADPH: Reactive ^{metabolites that react with 0 mmol / L or 1 mmol / L K 14} CN are separated by solid-phase extraction, and the radioactivity concentration is measured using a liquid scintillation counter. The clearance for the production of reactive metabolites is calculated by subtracting the measured value obtained under the condition where NADPH is not added from the measured value obtained under the condition where NADPH is added.

Test Example 6: Evaluation of Positive Symptoms by Rat Methamphetamine-Induced Momentum Enhancement Test The momentum-enhancing effect of methamphetamine administration to rats is used as an evaluation system for positive symptoms of schizophrenia, and the inhibitory effect when the compound of the present invention is administered. Can be evaluated. After administering the compound of the present invention to 6-10 week old rats, the amount of exercise for 90 minutes immediately after the administration of methamphetamine is measured. SuperMex (Muromachi Machinery Co., Ltd.) is used for the measurement. The suppression rate when the momentum of the solvent-administered group is 100% is calculated.

Test Example 7: Evaluation of efficacy for schizophrenia patients In clinical practice, PANSS (Positive and Negative Syndrome Scale), CGI-S (Clinical Global Impression Severity Scale), etc. are used as evaluation scales for psychiatric symptoms of schizophrenia. After administration of the compound of the present invention for 6 to 24 weeks, the efficacy is evaluated using the above evaluation scale.

Since the compound of the present invention _{exhibits antagonism against dopamine D 1} receptor, dopamine D ₂ receptor, and serotonin 5-HT _2A receptor, it is useful as a therapeutic agent and / or a preventive agent for central nervous system diseases. be.

Claims (22)

Equation (1):

[Wherein ring Q ¹ and ring Q ² are expressed independently, a benzene ring which may be substituted, or a pyridine ring optionally substituted;
^Ra _{represents a hydrogen atom or a C 1-6} alkyl optionally substituted with 1-3 halogen atoms of the same or different species;
n represents 0, 1 or 2;
m represents 1, 2, 3 or 4;
R ^b represents a _{C 1-6} alkyl which may be independently substituted with a hydrogen atom, a halogen atom, or 1 to 3 halogen atoms of the same kind or different kinds, if there are a plurality of them.] A compound, or a pharmaceutically acceptable salt thereof. Ring Q ¹ and ring Q ² are each independently a benzene ring or a pyridine ring (the benzene ring or pyridine ring, in each case, halogen atom, cyano, with 1 to 3 halogen atoms the same or different C _{1-6 alkyl optionally substituted, C 1-6} alkoxy optionally substituted with 1-3 halogen atoms of the same or heterogeneous, and 1-2 C _{1-6 of the same or heterologous.} The compound according to claim 1, or the pharmaceutically of the compound thereof, which is substituted with 1 to 4 groups of the same type or different types selected from the group consisting of aminos which may be substituted with alkyl. Tolerant salt. The compound according to claim 1 or 2, wherein n is 1, or a pharmaceutically acceptable salt thereof. Equation (1a):

[In the formula, ^Ra _{represents a hydrogen atom or a C 1-6} alkyl optionally substituted with 1-3 halogen atoms of the same or different species;
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are independently hydrogen atoms, halogen atoms, cyano, and 1 to 3 halogen atoms of the same or different species. in an optionally substituted C _1-6 alkyl, same or 1 to 3 halogen atoms which may be substituted with optionally C _1-6 alkoxy heterologous or of homologous or heterologous 1-2, C _{1- Represents} an amino that may be substituted with 6 alkyl;
R ¹¹ , R ¹² , R ¹³ and R ¹⁴ _{each independently contain a C 1-6} alkyl which may be substituted with a hydrogen atom, a halogen atom, or 1 to 3 halogen atoms of the same or different species. Represented], the compound according to claim 1, or a pharmaceutically acceptable salt thereof. Equation (1b):

^{Wherein, R a, R 2, R} 7, R 13, and ^{R 14} are as defined in claim 4] represented by the acceptable compound, or a pharmaceutically according to claim 4 salt. The compound according to claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein R ¹³ is a C _{1-6 alkyl or a hydrogen atom.} The compound according to any one of claims 4 to 6, wherein R ^{14 is a hydrogen atom, or a pharmaceutically acceptable salt thereof.} Equation (1b-1):

The compound according to claim 4, or a pharmaceutically acceptable salt thereof, which is represented by [where ^Ra , R ² and R ^{7 are synonymous with claim 4].} Equation (1b-2):

The compound according to claim 4, or a pharmaceutically acceptable salt thereof, which is represented by [where ^Ra , R ² and R ^{7 are synonymous with Item 4].} R ² and R ⁷ are independently substituted with hydrogen atoms, halogen atoms, 1 to 3 halogen atoms of the _{same type or different types, C 1-6} alkyl, or 1 to 3 of the same type or different types. The compound according to any one of claims 4 to 9, which is a _{C 1-6} alkoxy optionally substituted with a single halogen atom, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 4 to 10, or a pharmaceutically acceptable salt thereof, wherein R ² is a hydrogen atom, a halogen atom or a C _{1-3 alkyl.} R ⁷ _{may be substituted with a halogen atom, C 1-6} alkyl which may be substituted with 1 to 3 halogen atoms of the same or different type, or 1 to 3 halogen atoms of the same or different type. The compound according to any one of claims 4 to 11, which is C _{1-6 alkoxy, or a pharmaceutically acceptable salt thereof.} The compound according to any one of claims 1 to 12, or a pharmaceutical product thereof, wherein ^Ra _{is a C 1-6} alkyl optionally substituted with 1 to 3 halogen atoms of the same kind or different kinds. Allowable salt. The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following compound group:
2-Chloro-8-fluoro-10- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, f] azepine,
8-Chloro-10-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-fluoro-5H-dibenzo [b, f] azepine,
2-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridine-4-yl] -5H-dibenzo [b, f] azepine,
2-Chloro-10-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridine-4-yl] -5H-dibenzo [b, f] azepine,
2-Chloro-10-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridine-4-yl] -8-methyl-5H-dibenzo [b, f] azepine,
8-Chloro-10-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-methyl-5H-dibenzo [b, f] azepine,
2-Chloro-10- (1-ethyl-1,2,3,6-tetrahydropyridin-4-yl) -8-fluoro-5H-dibenzo [b, f] azepine, and 10-[(6S) -1 , 6-Dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-fluoro-8-methyl-5H-dibenzo [b, f] azepine. A medicament containing the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic agent for a central nervous system disease, which comprises the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient. Central nervous system disorders include schizophrenia, bipolar disorder, autism, ADHD, depression, anxiety disorders, sleep disorders, dementia behavioral and psychological symptoms (BPSD (Behavioral and Psychological Symptoms of Dementia)) or neurodegeneration The therapeutic agent according to claim 16, which is a psychological symptom of a disease. Central nervous system diseases comprising administering to a patient in need of treatment a therapeutically effective amount of the compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof. A method for treatment. Use of the compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for producing a therapeutic agent for a central nervous system disease. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use in the treatment of central nervous system diseases. The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and alipyrazole, olanzapine, quetiapine, risperidone, blonanserin, perospirone, paliperidone, ziprasidone, asenapine, iroperidone, sertindol. , A therapeutic agent for central nervous system diseases consisting in combination with at least one drug selected from the group consisting of lurasidone and their pharmaceutically acceptable salts. In combination with at least one drug selected from the group consisting of alipyrazole, olanzapine, quetiapine, risperidone, blonanserin, perospirone, paliperidone, ziprasidone, asenapine, iroperidone, sertindol, lurasidone and their pharmaceutically acceptable salts. A therapeutic agent containing the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient for treating central nervous system diseases.