WO2018139471A1

WO2018139471A1 - Dibenzodiazepine derivative

Info

Publication number: WO2018139471A1
Application number: PCT/JP2018/002058
Authority: WO
Inventors: 渡辺　仁; 磯部　義明
Original assignee: 大日本住友製薬株式会社
Priority date: 2017-01-25
Filing date: 2018-01-24
Publication date: 2018-08-02
Also published as: TW201831462A

Abstract

The present invention relates to a dibenzodiazepine derivative represented by formula (1), which is useful as a therapeutic and/or prophylactic agent for central nervous system diseases, and a pharmaceutically acceptable salt thereof. (In the formula, each of ring Q¹ and ring Q² independently represents an optionally substituted benzene ring or an optionally substituted pyridine ring; R^a represents a hydrogen atom or a C_1-6 alkyl group which may be substituted by 1-3 same or different halogen atoms; n represents 0, 1 or 2; m represents 1, 2, 3 or 4; and if a plurality of R^b moieties are present, each one of the R^b moieties independently represents a hydrogen atom, a halogen atom, or a C_1-6 alkyl group which may be substituted by 1-3 same or different halogen atoms.)

Description

Dibenzodiazepine derivatives

The present invention relates to a dibenzodiazepine derivative having a dopamine D ₁ receptor antagonistic action, a dopamine D ₂ receptor antagonistic action, and a serotonin 5-HT _2A receptor antagonistic action, or a pharmaceutically acceptable salt thereof, and a derivative thereof. The present invention relates to an agent for treating and / or preventing central nervous system diseases as an active ingredient.

Schizophrenia is a psychiatric disorder that is reported to have an estimated 45 million patients worldwide, with positive symptoms, negative symptoms, and cognitive impairment as main symptoms. Currently, antipsychotics having dopamine D ₂ receptor (hereinafter referred to as D ₂ receptor) antagonistic action and serotonin 5-HT _2A receptor (hereinafter referred to as 5-HT _2A receptor) antagonistic action as therapeutic drugs for schizophrenia Although it is used, it is known that about 30% of schizophrenic patients suffer from so-called treatment-resistant schizophrenia that is not effective with existing antipsychotic drugs (non-patented) Reference 1).

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

Clozapine, dopamine D ₂ receptor antagonistic action, in addition to the serotonin 5-HT _2A receptor antagonistic action, dopamine D ₁ receptor (hereinafter, D ₁ receptors) are known to have antagonistic action against . Clozapine has been reported to occupy the D ₂ receptor and the D ₁ receptor simultaneously and in a similar ratio in the PET test for schizophrenic patients (Non-Patent Documents 4, 5, and 6).

Patent Document 1 discloses a 1-piperazino-1,2-dihydroindene derivative as a substance having an antagonistic action on D ₁ receptor, D ₂ receptor, and 5-HT _2A receptor. The dibenzodiazepine derivative has a different chemical structure in both the basic skeleton and the side chain.
Patent Document 2 discloses a dibenzoxazepine derivative useful as an antipsychotic drug, but the basic skeleton has a different chemical structure from the dibenzodiazepine derivative of the present invention.

Japanese Patent No. 3255416 U.S. Pat. No. 4,221,714

An object of the present invention is to provide 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 to provide a salt that is chemically acceptable, a method for producing the same, a composition containing the compound, and the like.

The present inventors have shown that a compound having an antagonistic action on the D ₁ receptor, D ₂ receptor, and 5-HT _2A receptor has a strong medicinal effect on schizophrenia and other psychiatric disorders including treatment resistance. As a result of diligent research, the compound represented by the following formula (1) and a pharmaceutically acceptable salt thereof (hereinafter sometimes abbreviated as “the compound of the present invention” as necessary) are D _1. It has been found that it has a strong antagonistic action on the receptor, D ₂ receptor, and 5-HT _2A receptor, and has completed the present invention.

That is, the present invention is as follows.
[Claim 1] Formula (1):

[Wherein, ring Q ¹ represents an optionally substituted benzene ring or an optionally substituted pyridine ring;
Ring Q ² represents an optionally substituted benzene ring or an optionally substituted pyridine ring;
R ^a represents a hydrogen atom or C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types;
n represents 0, 1 or 2;
m represents 1, 2, 3 or 4;
Each of R ^b independently represents a hydrogen atom, a halogen atom, or C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types]. A compound, or a pharmaceutically acceptable salt thereof.

[Claim 2] The ring Q ¹ is a benzene ring or a pyridine ring (the benzene ring or pyridine ring is optionally substituted by a halogen atom, cyano, the same or different 1 to 3 halogen atoms, C _1-6 From alkyl, C _1-6 alkoxy optionally substituted with 1 to 3 halogen atoms of the same or different types, and amino optionally substituted with 1 to 2 C _1-6 alkyls of the same or different types Optionally substituted with 1 to 4 groups of the same or different types selected from the group consisting of:
Ring Q ² is a benzene ring or a pyridine ring (wherein the benzene ring or pyridine ring is a C _1-6 alkyl which may be substituted with 1 to 3 halogen atoms, the same or different halogen atoms, the same or different Selected from the group consisting of C _1-6 alkoxy optionally substituted with 1 to 3 different halogen atoms and amino optionally substituted with 1 or 2 same or different C _1-6 alkyl Or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein the compound is optionally substituted with 1 to 4 groups of the same or different types.

[Claim 3] The ring Q ¹ is a benzene ring (the ring is a halogen atom, cyano, a C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms, and the same or different Optionally substituted with 1 to 4 groups of the same or different types selected from the group consisting of C _1-6 alkoxy optionally substituted with 1 to 3 halogen atoms;
Ring Q ² is a benzene ring (the ring is a halogen atom, cyano, C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different species, and 1 to 3 of the same or different species) Item 1 or 2 which may be substituted with the same or different 1 to 4 groups selected from the group consisting of C _1-6 alkoxy optionally substituted with a halogen atom of A compound, 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.

[Claim 5] When there are a plurality of R ^{b s} , each R ^b is independently a halogen atom, or C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types. 5. The compound according to any one of 4 or a pharmaceutically acceptable salt thereof.

[Item 6] Formula (1a):

[Wherein R ^a represents a hydrogen atom, or C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types;
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each independently a hydrogen atom, a halogen atom, cyano, the same or different, 1 to 3 halogen atoms C _1-6 alkyl optionally substituted with 1 to 3 C _1-6 alkoxy optionally substituted with 1 to 3 halogen atoms of the same or different type, or 1 to 2 C _{1-of the} same or different type _Represents an amino optionally substituted with ₆ alkyls;
R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ each independently represent a hydrogen atom, a halogen atom, or C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types. The compound according to Item 1, or a pharmaceutically acceptable salt thereof.

[Claim 7] ^{^{^{R 11, R 12, R 13}}} , and any one or more of the ^{R 14} is a halogen atom or an optionally substituted with 1 to 3 halogen atoms same or different, _{C 1-6} Item 7. The compound according to Item 6, which is alkyl, or a pharmaceutically acceptable salt thereof.

[Section 8] Formula (1b):

[Wherein R ^a , R ² , R ⁷ , R ¹³ , and R ¹⁴ are as defined in item 6], or a pharmaceutically acceptable salt thereof .

[Item 9] The compound according to any one of Items 6 to 8, or a pharmaceutically acceptable salt thereof, wherein R ¹³ is C _1-6 alkyl.

[Item 10] The compound according to any one of Items 6 to 8, or a pharmaceutically acceptable salt thereof, wherein R ¹³ is methyl.

[Item 11] The compound according to any one of Items 6 to 10, or a pharmaceutically acceptable salt thereof, wherein R ¹⁴ is a hydrogen atom.

[Item 12] Formula (1b-1):

[Wherein R ^a , R ² and R ⁷ are as defined in item 6], or a pharmaceutically acceptable salt thereof.

[Item 13] The compound according to any one of Items 1 to 12, wherein R ^a is C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types, or A pharmaceutically acceptable salt.

[Item 14] The compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R ^a is methyl.

[Item 15] R ² and R ⁷ are each independently a hydrogen atom, a halogen atom, cyano, a C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different kinds, or the same Or the compound according to any one of Items 6 to 14, or a pharmaceutically acceptable salt thereof, which is C _1-6 alkoxy optionally substituted with 1 to 3 different halogen atoms.

Any one or more of [Claim 16] R ² and R ⁷ is halogen atom, cyano, same or different 1 to 3 C _1-6 alkyl optionally substituted by a halogen atom or a same or different, Item 15. The compound according to any one of Items 6 to 14, or a pharmaceutically acceptable salt thereof, which is C _1-6 alkoxy optionally substituted with 1 to 3 halogen atoms.

[Item 17] R ² is a hydrogen atom, a fluorine atom, a chlorine atom, C _1-3 alkyl, or C _1-3 alkoxy;
R ⁷ may be substituted with a hydrogen atom, a fluorine atom, a chlorine atom, cyano, C _1-3 alkyl optionally substituted with 1 to 3 fluorine atoms, or 1 to 3 fluorine atoms C _1-6 alkoxy,
Item 15. The compound according to any one of Items 6 to 14, or a pharmaceutically acceptable salt thereof.

[Item 18] The compound according to item 1 or a pharmaceutically acceptable salt thereof selected from the following group of compounds:
11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -8-methyl-2- (trifluoromethyl) -5H-dibenzo [b, e] [ 1,4] diazepine (Example 32),
8-Methyl-11-[(6S) -6-methyl-1- ( ² H ₃ ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -2- (trifluoromethyl) -5H- Dibenzo [b, e] [1,4] diazepine (Example 33),
8-chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2- (trifluoromethoxy) -5H-dibenzo [b, e] [ 1,4] diazepine (Example 38),
8-chloro-11-[(6S) -6-methyl-1- ( ² H ₃ ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -2- (trifluoromethoxy) -5H- Dibenzo [b, e] [1,4] diazepine (Example 39),
8-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-ethyl-5H-dibenzo [b, e] [1,4] Diazepine (Example 45),
8-chloro-2-ethyl-11-[(6S) -6-methyl-1- ( ² H ₃ ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, e] [1,4] diazepine (Example 46),
11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-ethyl-8-fluoro-5H-dibenzo [b, e] [1,4] Diazepine (Example 49),
2-Ethyl-8-fluoro-11-[(6S) -6-methyl-1- ( ² H ₃ ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, e] [1,4] diazepine (Example 50),
2-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -8-fluoro-5H-dibenzo [b, e] [1,4] Diazepine (Example 57),
2-Chloro-8-fluoro-11-[(6S) -6-methyl-1- ( ² H ₃ ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, e] [1,4] diazepine (Example 58),
8-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-methyl-5H-dibenzo [b, e] [1,4] Diazepine (Example 65),
8-chloro-2-methyl-11-[(6S) -6-methyl-1- ( ² H ₃ ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, e] [1,4] diazepine (Example 66),
8-chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-methoxy-5H-dibenzo [b, e] [1,4] Diazepine (Example 72),
8-chloro-2-methoxy-11-[(6S) -6-methyl-1- ( ² H ₃ ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, e] [1,4] diazepine (Example 73),
8-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-ethoxy-5H-dibenzo [b, e] [1,4] Diazepine (Example 88) and 8-chloro-2-ethoxy-11-[(6S) -6-methyl-1- ( ² H ₃ ) methyl-1,2,3,6-tetrahydropyridin-4-yl ] -5H-Dibenzo [b, e] [1,4] diazepine (Example 89).

[Item 19] The compound according to item 1 or a pharmaceutically acceptable salt thereof selected from the following group of compounds:
11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -8-methyl-2- (trifluoromethyl) -5H-dibenzo [b, e] [ 1,4] diazepine (Example 32),
8-Methyl-11-[(6S) -6-methyl-1- ( ² H ₃ ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -2- (trifluoromethyl) -5H- Dibenzo [b, e] [1,4] diazepine (Example 33),
8-chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2- (trifluoromethoxy) -5H-dibenzo [b, e] [ 1,4] diazepine (Example 38),
8-chloro-11-[(6S) -6-methyl-1- ( ² H ₃ ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -2- (trifluoromethoxy) -5H- Dibenzo [b, e] [1,4] diazepine (Example 39),
8-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-ethyl-5H-dibenzo [b, e] [1,4] Diazepine (Example 45),
8-chloro-2-ethyl-11-[(6S) -6-methyl-1- ( ² H ₃ ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, e] [1,4] diazepine (Example 46),
11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-ethyl-8-fluoro-5H-dibenzo [b, e] [1,4] Diazepine (Example 49),
2-Ethyl-8-fluoro-11-[(6S) -6-methyl-1- ( ² H ₃ ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, e] [1,4] diazepine (Example 50),
8-chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-methoxy-5H-dibenzo [b, e] [1,4] Diazepine (Example 72),
8-chloro-2-methoxy-11-[(6S) -6-methyl-1- ( ² H ₃ ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, e] [1,4] diazepine (Example 73),
8-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-ethoxy-5H-dibenzo [b, e] [1,4] Diazepine (Example 88) and 8-chloro-2-ethoxy-11-[(6S) -6-methyl-1- ( ² H ₃ ) methyl-1,2,3,6-tetrahydropyridin-4-yl ] -5H-Dibenzo [b, e] [1,4] diazepine (Example 89).

[Item 20] The compound according to item 1 or a pharmaceutically acceptable salt thereof selected from the following group of compounds:
11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -8-methyl-2- (trifluoromethyl) -5H-dibenzo [b, e] [ 1,4] diazepine (Example 32),
8-Methyl-11-[(6S) -6-methyl-1- ( ² H ₃ ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -2- (trifluoromethyl) -5H- Dibenzo [b, e] [1,4] diazepine (Example 33),
8-chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2- (trifluoromethoxy) -5H-dibenzo [b, e] [ 1,4] diazepine (Example 38),
8-chloro-11-[(6S) -6-methyl-1- ( ² H ₃ ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -2- (trifluoromethoxy) -5H- Dibenzo [b, e] [1,4] diazepine (Example 39),
8-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-ethyl-5H-dibenzo [b, e] [1,4] Diazepine (Example 45),
8-chloro-2-ethyl-11-[(6S) -6-methyl-1- ( ² H ₃ ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, e] [1,4] diazepine (Example 46),
8-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-ethoxy-5H-dibenzo [b, e] [1,4] Diazepine (Example 88) and 8-chloro-2-ethoxy-11-[(6S) -6-methyl-1- ( ² H ₃ ) methyl-1,2,3,6-tetrahydropyridin-4-yl ] -5H-Dibenzo [b, e] [1,4] diazepine (Example 89).

[Item 21] A pharmaceutical comprising the compound according to any one of items 1 to 20 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Item 22] A therapeutic agent for central nervous system diseases, comprising the compound according to any one of items 1 to 20 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Claim 23] Central nervous system disease is schizophrenia, bipolar disorder, autism, ADHD, depression, anxiety disorder, sleep disorder, behavioral and psychological symptoms of dementia (BPSD (Behavioral and Psychological Symptoms of Dementia) Item 23. The therapeutic agent according to Item 22, which is a psychiatric symptom of a neurodegenerative disease.

[Item 24] A central nervous system comprising administering to a patient in need of treatment a therapeutically effective amount of a compound according to any one of items 1 to 20, or a pharmaceutically acceptable salt thereof. For treating systemic diseases.

[Item 25] Use of the compound according to any one of Items 1 to 20 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for a central nervous system disease.

[Item 26] The compound according to any one of items 1 to 20 or a pharmaceutically acceptable salt thereof for use in the treatment of a central nervous system disease.

[Item 27] The compound according to any one of Items 1 to 20 or a pharmaceutically acceptable salt thereof, and aripyrazole, olanzapine, quetiapine, risperidone, blonanserin, perospirone, paliperidone, ziprasidone, asenapine, iloperidone, A therapeutic agent for central nervous system diseases, comprising a combination of at least one drug selected from the group consisting of sertindole, lurasidone, and pharmaceutically acceptable salts thereof.

[Item 28] At least one selected from the group consisting of aripyrazole, olanzapine, quetiapine, risperidone, blonanserin, perospirone, paliperidone, ziprasidone, asenapine, iloperidone, sertindole, lurasidone, and pharmaceutically acceptable salts thereof. Item 21. A therapeutic agent comprising the compound according to any one of Items 1 to 20 or a pharmaceutically acceptable salt thereof as an active ingredient for treating a central nervous system disease in combination with a drug.

The compound of the present invention exhibits an antagonistic action on the D ₁ receptor, D ₂ receptor, and 5-HT _2A receptor. In addition, in a preferred embodiment, the ability to migrate to the brain is excellent, and the amount of reactive metabolites that are responsible for agranulocytosis is also low. In a more preferred embodiment, histamine receptor, muscarinic receptor, serotonin 5-HT _2c receptor (hereinafter referred to as 5-HT _2c receptor) and the like which are related to side effects such as digestive disorders, sedation, weight gain, etc. Antagonism is weak. Therefore, the compound of the present invention is useful as a highly safe and excellent therapeutic agent and / or preventive agent for central nervous system diseases (for example, schizophrenia).

The present invention is described in detail below. In the present specification, the number of carbons in the definition of “substituent” may be expressed as “C _1-6 ”, for example. Specifically, the expression “C _1-6 alkyl” is synonymous with alkyl having 1 to 6 carbons.

Specific examples of “halogen atom” include fluorine atom, chlorine atom, bromine atom or iodine atom. Preferably, they are a fluorine atom and a chlorine atom.

“C _1-6 alkyl” means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferred is “C _1-4 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.

The “C _1-6 alkyl” part of “C _1-6 alkoxy” has the same _{meaning as} the above “C _1-6 alkyl”. Preferred is “C _1-4 alkoxy”. Specific examples of “C _1-6 alkoxy” include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

In the compound represented by the formula (1), the R ^b group may be substituted with any carbon atom on the nitrogen-containing monocycle if possible, and the same or different 2 on the same carbon atom if possible. One R ^b group may be substituted.
In the compound represented by formula (1), when ring Q ¹ and / or ring Q ² is a pyridine ring, the four atoms indicated by the arrows shared by the ring to which they are condensed are carbon atoms. is there.

Examples of the substituent in the “optionally substituted benzene ring” and the “optionally substituted pyridine ring” include, for example,
(A) a halogen atom,
(B) cyano,
(C) C _1-6 alkyl (the group may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of halogen atoms, hydroxy, and C _1-6 alkoxy),
(D) C _1-6 alkoxy (the group may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of halogen atoms, hydroxy, and C _1-6 alkoxy),
(E) phenyl (the group may be substituted with 1 to 4 groups of the same or different types selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _1-6 alkoxy),
(F) 5-membered or 6-membered heteroaryl (the group is substituted with 1 to 4 groups of the same or different types selected from the group consisting of a halogen atom, C _1-6 alkyl, and C _1-6 alkoxy) May be)
(G) Phenoxy (the group may be substituted with 1 to 4 groups of the same or different types 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 the same or different 1-2 C _1-6 alkyl), and (j) aminocarbonyl (wherein the amino is the same or different 1-2 And may be substituted with C _1-6 alkyl).
Preferably, C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different halogen atom, cyano, optionally substituted with 1 to 3 halogen atoms of the same or different type C _1-6 alkoxy, and amino optionally substituted with the same or different 1-2 C _1-6 alkyl.
More preferably, it may be substituted with a halogen atom, C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms, and 1 or 3 halogen atoms of the same or different. C _1-6 alkoxy is mentioned.

Among the compounds 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 , Preferred examples of R ¹⁴ and R ¹⁴ are as follows, but the technical scope of the present invention is not limited to the following compounds.

R ^a is preferably C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types. More preferred is C _1-3 alkyl; even more preferred is methyl. Another example of R ^a is deuterated methyl (CD ₃ ).

R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁸ are preferably a hydrogen atom and a halogen atom. More preferably, it is a hydrogen atom.

R ² and R ⁷ are preferably a hydrogen atom, a halogen atom, cyano, a C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types, and 1 to 3 of the same or different types And C _1-6 alkoxy optionally substituted with a halogen atom. More preferably, it may be substituted with a halogen atom, C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms, and 1 or 3 halogen atoms of the same or different. C _1-6 alkoxy is mentioned.

R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ are each independently a hydrogen atom, a halogen atom, or C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types And any one or more of R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ is a halogen atom, or a C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types It is preferable that More preferably, any one or more of R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ is C _1-6 alkyl.

R ¹¹ , R ¹² , and R ¹⁴ are preferably a hydrogen atom and C _1-6 alkyl. More preferably, it is a hydrogen atom.

R ¹³ preferably includes a hydrogen atom and C _1-6 alkyl. More preferred is C _1-4 alkyl; even more preferred is 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 C _1-6 alkyl; R ¹⁴ is hydrogen atom, or C _1-6 alkyl.

In another embodiment of R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ , R ¹¹ , R ¹² , and R ¹⁴ are hydrogen atoms; R ¹³ is C _1-4 alkyl.

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

The compound represented by formula (1) may have at least one asymmetric carbon atom. Accordingly, the compound of the present invention includes not only the racemic form of the compound represented by the formula (1) but also optically active forms of these compounds.
In addition, a deuterium converter obtained by converting any one or two or more ¹ H of the compound represented by the formula (1) into ² H (D) is also included in the compound represented by the formula (1). .

Since the compound represented by the formula (1) and a pharmaceutically acceptable salt thereof may exist in the form of a hydrate and / or a solvate, these hydrates or ethanol solvates. Solvates such as are also included in the compounds of the present invention. Further, the compounds of the present invention include all forms of crystal forms.
As the pharmaceutically acceptable salt, when the compound represented by the formula (1) has an acidic group, for example, an alkali metal salt such as sodium salt or potassium salt; an alkaline earth such as calcium salt or magnesium salt; Metal salts; inorganic metal salts such as zinc salts; organic base salts such as triethylamine, triethanolamine, trihydroxymethylaminomethane, and amino acids.
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 Organics such as succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, ascorbate Examples include acid salts.

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

Production Method The compound of the present invention is synthesized by a method combining the following production method and a known synthesis method.
The compounds in the reaction formula also include the case where each forms a salt, and examples of the salt include the same salts as the salt of the compound represented by the formula (1). These reactions are merely examples, and the compounds of the present invention can also be produced by other methods as appropriate based on the knowledge of those skilled in organic synthesis.

In each production method described below, even when the use of a protective group is not specifically stated, if a functional group that requires protection is present, the functional group is protected as necessary, The desired product may be obtained by deprotection after completion of the reaction or after a series of reactions.

The introduction and removal of protecting groups can be accomplished by methods commonly used in organic synthetic chemistry (eg, TW Greene and PMGM Wuts, “Protective Groups in Organic Synthesis”, 3rd Ed., John Wiley and Sons). , Inc., New York (1999)) or a similar method.
Examples of the amino-protecting group include tert-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl and the like.

Manufacturing method 1
Among the compounds represented by the formula (1), the compounds represented by the formulas (1c) and (1d) are produced, for example, by the method shown below.

[Wherein, ring Q ¹ , ring Q ² , R ^b , m and n are as defined above in [Item 1]; and R ^a1 is substituted with 1 to 3 halogen atoms of the same or different species It represents also a C _1-6 alkyl; X is a halogen; Pro represents a protecting group of amino group; a represents a boronic acid or boronic acid ester. ]

Step 1-1: Production Step of Compound (1-2) Compound (1-2) is reacted with a halogenating reagent in compound (1-1) in the presence or absence of a base in a suitable inert solvent. It is manufactured by.
As the compound (1-1), a commercially available compound or one produced by a known method (for example, International Publication No. 2007/047776) can be used.
Examples of the halogenating reagent include 1-chloro-N, N, 2-trimethylpropenylamine, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, phosphorus pentachloride and the like.
Examples of the base include N, N-dimethylaniline.
Examples of the inert solvent include toluene, 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 20 ° C. to 100 ° C.

Step 1-2: Production Step of Compound (1d) Compound (1d) is prepared by coupling compound (1-2) and compound (1-3) in the presence of a palladium catalyst in a suitable inert solvent. Manufactured. This step can be performed in the presence of a base and / or a phosphorus ligand as necessary.
As the compound (1-3), a commercially available compound or one produced by a known method (for example, International Publication No. WO 2002/066470) can be used. Moreover, what was manufactured by the postscript manufacturing method 4 can be used.
As the palladium catalyst, various palladium catalysts used in a conventional method can be used, and tetrakis (triphenylphosphine) palladium (0) is preferable.
Examples of the base include potassium carbonate and cesium carbonate.
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 performed under microwave irradiation as necessary.
While the reaction time varies depending on the reaction temperature, the palladium catalyst used, the raw materials, the solvent and the like, it is generally 5 minutes to 72 hours, preferably 30 minutes to 24 hours.

Step 1-3: Step of producing compound (1-5) Compound (1-5) is produced from compound (1-2) and compound (1-4) according to the method described in step 1-2. The
As the compound (1-4), one produced by the production method 2 described later can be used.

Step 1-4: Step of Producing Compound (1c) Compound (1c) is obtained by reacting the protecting group Pro of the amino group of compound (1-5) with a known method (for example, Protective Group in Organic Synthesis 3rd Edition (Theodora W Green, Peter GM Wuts, published by John Wiley & Sons Inc, 1999).

Step 1-5: Production Step of Compound (1d) Compound (1d) can also be produced by reacting compound (1c) with various alkyl aldehydes in the presence of a reducing agent in a suitable inert solvent. .
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 (1d) can also be produced by reacting compound (1c) with various alkyl halides in a suitable inert solvent in the presence of a base.
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.

Manufacturing method 2
The compound represented by the formula (1-4) is produced, for example, by the method shown below.

[Wherein, R ^b , m and n are as defined above in [Item 1]; X ¹ represents halogen or triflate (trifluoromethanesulfonyloxy); Pro represents an amino-protecting group; Represents boronic acid or boronic ester. ]

Step 2-1: Step of producing compound (2-2) Compound (2-2) is produced by reacting compound (2-1) with a triflating agent in the presence of a base in a suitable inert solvent. Is done.
As the compound (2-1), a commercially available compound or one produced by a known method (for example, International Publication No. 2012/142668) can be used.
Examples of the base include lithium diisopropylamide or sodium bis (trimethylsilyl) amide.
As the triflating agent, various triflating agents used in a conventional method can be used, and preferably N-phenylbis (trifluoromethanesulfonimide) is used.
Examples of the inert solvent include THF.
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 20 ° C.

Step 2-2: Production Step of Compound (1-4) Compound (1-4) is obtained by coupling compound (2-2) and a boronation reagent in the presence of a palladium catalyst in a suitable inert solvent. Manufactured by. This step can be performed in the presence of a base and / or a phosphorus ligand as necessary.
Examples of the base include potassium acetate.
Examples of the phosphorus ligand include triphenylphosphine and bis (diphenylphosphino) methane.
As the boronation reagent, various boronation reagents used in a conventional method can be used, and bis (pinacolate) diborane is preferable.
As the palladium catalyst, various palladium catalysts used in a conventional method can be used, and preferably 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride is used.
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 performed under microwave irradiation as necessary.
While the reaction time varies depending on the reaction temperature, the palladium catalyst used, the raw materials, the solvent and the like, it is generally 5 minutes to 72 hours, preferably 2 hours to 8 hours.

Production method 3
Among the compounds represented by the formula (1), the compound represented by the formula (1e) is produced, for example, by the method shown below.

[Wherein ring Q ^1, ring Q ^2, R ^b, and m is the [claim 1] in the above formula; R ^a1 is optionally substituted by 1 to 3 halogen atoms the same or different Represents C _1-6 alkyl; X represents halogen; A represents boronic acid or boronic ester. ]

Step 3-1: Production Step of Compound (3-2) Compound (3-2) is produced from compound (1-2) and compound (3-1) according to the method described in Step 1-2. The
As the compound (3-1), a commercially available compound or one produced by a known method (for example, International Publication No. 2011/119518) can be used.

Step 3-2: Production Step of Compound (1e) Compound (1e) was reacted with compound (3-2) and compound (3-3) in a suitable inert solvent to form a quaternary ammonium cation. Thereafter, it is produced by acting a reducing agent.
Examples of the inert solvent include acetonitrile, THF, 1,4-dioxane and the like.
The reaction time in the alkylation step is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature in 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.

Manufacturing method 4
The compound represented by the formula (1-3) is also produced, for example, by the method shown below.

[Wherein R ^b , m and n are as defined above in [Item 1]; R ^a1 represents C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types; X ¹ represents halogen or triflate; Pro represents an amino-protecting group; A represents boronic acid or a boronic ester. ]

Step 4-1: Production Step of Compound (4-1) The compound (4-1) is prepared by reacting the protecting group Pro of the amino group of the compound (2-2) with a known method (for example, Protective Group in Organic Synthesis 3). It is manufactured by deprotection in a plate (Theodora W. Green, by Peter GM Wuts, published by John Wiley & Sons Inc, 1999).

Step 4-2: Production Step of Compound (4-2) Compound (4-2) is obtained by reacting compound (4-1) with various alkyl aldehydes in the presence of a reducing agent in a suitable inert solvent. Can also be 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 (4-2) can also be produced by reacting compound (4-1) with various alkyl halides in a suitable inert solvent in the presence of a base.
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 4-3: Production Step of Compound (1-3) Compound (1-3) is obtained by coupling compound (4-2) and a boronation reagent in the presence of a palladium catalyst in a suitable inert solvent. Manufactured by. This step can be performed in the presence of a base and / or a phosphorus ligand as necessary.
Examples of the base include potassium acetate.
Examples of the phosphorus ligand include triphenylphosphine and bis (diphenylphosphino) methane.
As the boronation reagent, various boronation reagents used in a conventional method can be used, and bis (pinacolate) diborane is preferable.
As the palladium catalyst, various palladium catalysts used in a conventional method can be used, and preferably 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride is used.
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 performed under microwave irradiation as necessary.
While the reaction time varies depending on the reaction temperature, the palladium catalyst used, the raw materials, the solvent and the like, it is generally 5 minutes to 72 hours, preferably 2 hours to 8 hours.

The compound of the present invention having a desired substituent at a desired position can be obtained by appropriately combining the above production methods. Isolation and purification of intermediates and products in the above production method may be performed by appropriately combining methods used in ordinary organic synthesis, for example, filtration, extraction, washing, drying, concentration, crystallization, various chromatography, and the like. it can. In addition, the intermediate can be subjected to the next reaction without any particular purification.

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

Among the compounds represented by the formula (1) or a pharmaceutically acceptable salt thereof, there are tautomers such as keto enol, isomers such as positional isomer, geometric isomer or optical isomer. May be present, but all possible isomers including these and mixtures in any ratio of the isomers are also encompassed by the present invention.
In addition, optical isomers can be separated by performing a known separation step such as a method using an optically active column or a fractional crystallization method in an appropriate step of the production method. An optically active substance can also be used as a starting material.

When it is desired to obtain a salt of the compound represented by the formula (1), the salt of the compound represented by the formula (1) may be purified as it is, and the compound represented by the formula (1) When obtained in a free form, the compound represented by the formula (1) may be dissolved or suspended in a suitable solvent, and an acid or 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 encompassed in the present invention.

As used herein, “treatment refractory schizophrenia” refers to schizophrenia in which two or more types of antipsychotic drugs are not sufficiently improved even when administered in sufficient amounts for a sufficient period. According to Japan's Schizophrenia Drug Guidelines, two or more antipsychotic drugs are administered at a dose of 600 mg / day or more in chlorpromazine for 4 weeks or more, resulting in an overall function assessment (Global Assessment of Functioning: GAF) of 41 or more. It is defined that the corresponding state has never been reached.

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 having an antagonistic action on the D ₁ receptor, D ₂ receptor, and 5-HT _2A receptor similarly to clozapine can be expected to be effective for treatment-resistant schizophrenia.

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

Although there is no general animal model that mimics treatment-resistant schizophrenia, the rat methamphetamine-induced hyperactivity test (Test Example 5), which is a model of positive symptoms of schizophrenia, is conducted to treat schizophrenia. It is considered that a drug effective for treatment-resistant schizophrenia can be searched by finding a drug and confirming that it has an antagonistic action on the aforementioned D ₁ receptor and D ₂ receptor.

After the pharmaceutical compound is taken into the living body, it undergoes metabolism to change its chemical structure, producing a highly reactive intermediate, that is, a reactive metabolite, which is toxic (agranulocytosis, hepatotoxicity, allergy, Tissue necrosis, mutagenicity, carcinogenicity, etc.) may occur. One of the tests for easily evaluating the toxicity risk due to this reactive metabolite is a glutathione trapping test using dansylated glutathione (dGSH). The higher the dGSH covalent bond value, the higher the toxicity risk when exposed to whole body.

It has been reported that agranulocytosis observed in clozapine is due to the formation of reactive metabolites (see The Journal of Pharmacology and Experimental Therapeutics, 1997, 283 (3) 1375-1382).
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 has an extremely low dGSH covalent bond value, and the production of reactive metabolites is significantly reduced. (Test Example 2). From this, it is expected that the compound of the present invention has a low risk such as agranulocytosis and can be safely administered over 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 receptors, muscarinic receptors, 5-HT _2c receptors, 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 compound of the present invention was subjected to an antagonistic activity evaluation test for these receptors, it was surprisingly found that in a more preferred embodiment of the compound of the present invention, the antagonistic action against these receptors was low (Test Example 8). From this, in a more preferred embodiment of the compound of the present invention, it is expected that the risk of digestive disorders, sedation, weight gain, etc. is low, and it can be administered safely.

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 the disease. is there. “Treatment” is an act of administering the active ingredient of the present invention to a person (patient) diagnosed as having developed a disease by a doctor.

The compound of the present invention can be formulated and administered by oral administration or parenteral administration, directly or using a suitable dosage form. Examples of the dosage form include, but are not limited to, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, and cataplasms. The preparation is produced by a known method using a pharmaceutically acceptable additive.
Additives are excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners depending on the purpose. Perfumes 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, hydroxypropyl methylcellulose, polyvinyl alcohol, stearin Examples include magnesium acid, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.

As the administration route, it is desirable to use the most effective treatment, and oral or parenteral such as intravenous, application, inhalation and instillation can be mentioned, but oral administration is preferable. Examples of the dosage form include tablets and injections, and tablets are preferred. The dosage and frequency of administration of these pharmaceutical compositions vary depending on the dosage form, the patient's disease and symptoms, the patient's age and weight, etc., and cannot be generally specified, but are usually effective for adults per day The amount of ingredients ranges from about 0.0001 to about 5000 mg, preferably from about 0.001 to about 1000 mg, more preferably from about 0.1 to about 500 mg, particularly preferably from about 1 to about 300 mg. It can be administered once or several times a day, preferably 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 an antipsychotic such as aripirazole, olanzapine, quetiapine, risperidone, bronanserin, perospirone, paliperidone, ziprasidone, asenapine, iloperidone, sertindole, 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 simultaneously to the administration subject or may be administered with a time difference. Moreover, it is good also as a mixture of this invention compound and a concomitant drug. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention. Moreover, it can be used in combination with drugs (concomitant drugs) such as antiemetics, sleep-inducing agents, and anticonvulsants for the purpose of suppressing the side effects.

Hereinafter, the present invention will be described more specifically with reference examples, examples and test examples, but the present invention is not limited thereto. In addition, the compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature.

In order to simplify the description, 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

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

High-performance liquid chromatograph / mass spectrometer; LCMS measurement conditions are as follows, and the observed mass spectrometry value [MS (m / z)] is [M + H] ⁺ or [M−H] ⁻ , and the retention time Is represented by Rt (min).
Measurement conditions (1)
Detector: ACQUITY (registered trademark) SQ deteceter (Waters)
HPLC: ACQUITY UPLC (registered trademark) system
Column: Waters ACQUITY UPLC® BEH C18 (1.7 μm, 2.1 mm X 30 mm)
Flow rate: 0.75 mL / min
Measurement wavelength: 254 nm
Moving layer: Liquid A 0.05% formic acid aqueous solution Liquid B Acetonitrile time program:
Step time (minutes)
1 0.0-1.3 Liquid A: Liquid B = 90: 10 to 1:99
2 1.3-1.5 Liquid A: Liquid B = 1: 99
3 1.5-2.0 Liquid A: Liquid B = 90: 10

Measurement conditions (2)
Detector: ACQUITY (registered trademark) SQ deteceter (Waters)
HPLC: ACQUITY UPLC (registered trademark) system
Column: Waters ACQUITY UPLC® BEH C18 (1.7 μm, 2.1 mm X 30 mm)
Flow rate: 0.80mL / min
Measurement wavelength: 254 nm
Moving layer: Liquid A 0.05% formic acid aqueous solution Liquid B Acetonitrile time program:
Step time (minutes)
1 0.0-1.3 Liquid A: Liquid B = 90: 10 to 5:95
2 1.3-1.5 Liquid A: Liquid B = 90: 10

Measurement conditions (3)
MS detector: LCMS-IT-TOF
HPLC: Shimadzu Nexera X2 LC 30AD
Column: Kinetex 1.7μ C18 100A New column 50 X 2.1 mm
Flow rate: 1.2 mL / min
Measurement wavelength: 254 nm
Moving bed: A liquid; 0.1% formic acid aqueous solution B liquid; Acetonitrile time program:
Step time (minutes)
1 0.01-1.40 Liquid A: Liquid B = 90: 10 to 5:95
2 1.40-1.60 Liquid A: Liquid B = 5: 95
3 1.61-2.00 Liquid A: Liquid B = 99: 1

Measurement conditions (4)
Detector: LCMS-2020 (Shimadzu)
Column: Phenomenex Kinetex (1.7 μm, C18, 50 mm X 2.10 mm)
Flow rate: 0.50 mL / min
Measurement wavelength: 220, 254 nm
Moving bed: Liquid A 0.05% TFA aqueous solution Liquid B Acetonitrile column temperature: 40 ° C
Time program:
Step time (minutes)
1 0.0 Liquid A: Liquid B = 90: 10
2 0.0-1.9 Liquid A: Liquid B = 90: 10 to 1:99
3 1.9-3.0 Liquid A: Liquid B = 90: 10

Reference example 1
8-Chloro-2-fluoro-5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one

a) Preparation of 2-[(4-chloro-2-nitrophenyl) amino] -5-fluorobenzoic acid (Compound W1) 4-Chloro-1-fluoro-2-nitrobenzene (5.0 g) in DMF (29 mL) To the solution were added 2-amino-5-fluorobenzoic acid (4.4 g) and cesium carbonate (28 g), and the mixture was stirred at 120 ° C. overnight. Water was added to the reaction solution at 0 ° C., and the pH was adjusted to 5 with 1 mol / L hydrochloric acid, followed by extraction 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 Compound W1 (8.8 g).
LC-MS ([M + H] ⁺ / Rt (min)): 311 / 1.18 Measurement conditions (1)

b) Preparation of 2-[(2-amino-4-chlorophenyl) amino] -5-fluorobenzoic acid (Compound W2) Compound W1 (8.8 g) in THF / MeOH / H ₂ O (3: 2: 1) (300 mL) To the solution was added ammonium chloride (15 g) and iron (16 g), and the mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was cooled, filtered through Celite, washed with methanol, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to liquid separation extraction with ethyl acetate-water, and the obtained organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound W2 (8.0 g).
LC-MS ([M + H] ⁺ / Rt (min)): 281 / 1.06 Measurement conditions (1)

c) Preparation of 8-chloro-2-fluoro-5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one (Reference Example 1) DMF of Compound W2 (8.0 g) To the (143 mL) solution were added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (6.0 g) and 1-hydroxybenzotriazole (4.2 g), 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, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with chloroform (20 mL) to give the title compound (3 g).
LC-MS ([M + H] ⁺ / Rt (min)): 263 / 0.93 Measurement conditions (1)

Reference examples 2-8
According to the method described in Reference Example 1, using the corresponding starting material compounds, the compounds shown in the table below were obtained.

LC-MS in the above table was measured using measurement condition (1).

Reference Example 9
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-{[(tri Preparation of fluoromethyl) sulfonyl] oxy} -3,6-dihydropyridine-1 (2H) -carboxylate (Substance A) 1- (tert-Butoxycarbonyl) -2-methylpiperidin-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, a 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. The solvent of the organic layer after drying was distilled off under reduced pressure, and then purified by silica gel column chromatography (elution solvent; chloroform / methanol) and NH ₂ silica gel column chromatography (elution solvent; hexane / ethyl acetate) to obtain substance A ( 1.7 g, a mixture of isomers).
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- (4,4,5,5-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 (reference example) 9) Preparation of substance A (1.7 g) in THF (50 mL) was added bis (pinacolate) 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 celite filtration. Water was added to the filtrate and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over sodium sulfate. After the solvent of the organic layer after drying was distilled off under reduced pressure, the compound of Reference Example 9 (1.2 g, mixture of isomers) was obtained by purification by silica gel column chromatography (elution solvent; hexane / ethyl acetate). It was.
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 10-12
According to the method described in Reference Example 9, the corresponding raw material compounds were used to obtain the compounds shown in the following table (mixture of isomers).

LC-MS in the above table was measured using measurement condition (1).

Reference Examples 13-29
According to the method described in Reference Example 1, using the corresponding starting material compounds, the compounds shown in the table below were obtained.

LC-MS in the above table was measured using measurement condition (2).

Reference Example 30
8-Methyl-2- (trifluoromethyl) -5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one

a) Preparation of 4-methyl-2-nitrophenyl trifluoromethanesulfonate (Compound W3) A solution of 4-methyl-2-nitrophenol (2.0 g) in chloroform (26 mL) was cooled to 0 ° C. and triethylamine (5. 4 mL) and trifluoromethanesulfonic anhydride (2.4 mL) were added, and the mixture was stirred at 0 ° C. for 1 hour. Sodium bicarbonate water was added to the reaction solution at 0 ° C., 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 distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane / ethyl acetate) to obtain the title compound (3.4 g).
LC-MS ([MH] ^- / Rt (min)): 283 / 0.99 Measurement conditions (2)

b) Preparation of methyl 2-[(4-methyl-2-nitrophenyl) amino] -5- (trifluoromethyl) benzoate (Compound W4) 2-Amino-into a solution of Compound W3 (2.0 g) in toluene (68 mL) Add methyl 5- (trifluoromethyl) benzoate (1.5 g), potassium carbonate (0.95 g), triphenylphosphine (0.36 g) and tetrakis (triphenylphosphine) palladium (0) (0.79 g) The mixture was stirred for 2 hours with heating under reflux. The reaction solution was returned to room temperature, water 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 dried organic layer was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate) to obtain the title compound (2.0 g).
LC-MS ([M + H] ⁺ / Rt (min)): 355 / 1.21 Measurement conditions (2)

c) Preparation of methyl 2-[(2-amino-4-methylphenyl) amino] -5- (trifluoromethyl) benzoate (Compound W5) Compound W4 (2.0 g) in THF / MeOH / H ₂ O (3 : 2: 1) (30 mL) was added ammonium chloride (3.6 g) and iron (1.9 g), and the mixture was stirred with heating under reflux for 1 hour. The reaction mixture was cooled, filtered through celite, and washed with ethyl acetate. The obtained filtrate was subjected to separation / extraction with ethyl acetate-water, and then the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.8 g) as a crude product.
LC-MS ([M + H] ⁺ / Rt (min)): 325 / 1.17 Measurement conditions (2)

d) 2 - [(2-amino-4-methylphenyl) amino] -5- _(THF / H 2 O for the preparation of compound of trifluoromethyl) benzoic acid (Compound W6) W5 (1.8g) (1 : 1 ) (30 mL), lithium hydroxide (1.6 g) was added, and the mixture was stirred with heating under reflux for 2 hours. The reaction mixture was cooled, water was added at 0 ° C., the pH was adjusted to 5 with 1 mol / L hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.6 g) as a crude product.
LC-MS ([M + H] ⁺ / Rt (min)): 311 / 0.98 Measurement conditions (2)

e) Preparation of 8-methyl-2- (trifluoromethyl) -5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one Compound D6 (1.6 g) in DMF ( 23 mL) solution was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.4 g) and 1-hydroxybenzotriazole (1.0 g), and the mixture was stirred at room temperature for 1 hour. 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. The solvent of the organic layer after drying was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate) to obtain the title compound (0.41 g).
LC-MS ([M + H] ⁺ / Rt (min)): 293 / 0.89 Measurement conditions (2)

Reference Examples 31 and 32
According to the method described in Reference Example 30, the corresponding raw material compounds were used to obtain the compounds shown in the following table.

LC-MS in the above table was measured using measurement condition (2).

Reference Example 33
8-Chloro-11-oxo-10,11-dihydro-5H-dibenzo [b, e] [1,4] diazepine-2-carbonitrile

a) Preparation of 2-[(4-chloro-2-nitrophenyl) amino] -5-cyanobenzoic acid (Compound W7) 4-chloro-1-fluoro-2-nitrobenzene (0.50 g) in DMF (2. 8 mL) solution was added methyl 2-amino-5-cyanobenzoate (0.50 g) and cesium carbonate (2.8 g), and the mixture was stirred at 120 ° C. for 4 hours. The reaction mixture was cooled, water was added at 0 ° C., the pH was adjusted to 5 with 1 mol / L hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over sodium sulfate. The title compound (0.90 g) was obtained as a crude product by evaporating the solvent of the organic layer after drying under reduced pressure.
LC-MS ([MH] ^- / Rt (min)): 316 / 0.87 Measurement conditions (2)

b) Preparation of 2-[(2-amino-4-chlorophenyl) amino] -5-cyanobenzoic acid (Compound W8) Compound W7 (0.90 g) in THF / MeOH / H ₂ O (3: 2: 1) (30 mL) To the solution was added ammonium chloride (1.5 g) and iron (0.73 g), and the mixture was stirred with heating under reflux for 1 hour. The reaction mixture was cooled, filtered through celite, and washed with ethyl acetate. The obtained filtrate was subjected to separation / extraction with ethyl acetate-water, and then the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.82 g) as a crude product.
LC-MS ([M + H] ⁺ / Rt (min)): 288 / 0.84 Measurement conditions (2)

c) Preparation of 8-chloro-11-oxo-10,11-dihydro-5H-dibenzo [b, e] [1,4] diazepine-2-carbonitrile Compound W8 (0.82 g) in DMF (14 mL) To the mixture were added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.60 g) and 1-hydroxybenzotriazole (0.42 g), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with chloroform (5 mL) to give the title compound (0.25 g).
LC-MS ([M + H] ⁺ / Rt (min)): 270 / 0.71 Measurement conditions (2)

Reference Example 34
(6S) -1,6-Dimethyl-4- (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 Preparation of — [(trifluoromethanesulfonyl) oxy] -3,6-dihydropyridine-1 (2H) -carboxylate (Substance C) tert-Butyl (2S) -2-methyl-4-oxopiperidine-1-carboxylate ( To a THF solution (117 mL) of 10 g), a 1.1 mol / L lithium diisoproamide-THF solution (56 mL) was added dropwise 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. 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. The solvent of the organic layer after drying was distilled off under reduced pressure, and then purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to obtain substance C (18 g, mixture of isomers).
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-tetrahydropyridin-4-yl trifluoromethanesulfonate and (2S) -2-methyl-1,2,3,6-tetrahydropyridine-4- Preparation of yl trifluoromethanesulfonate (substance D) To a solution of substance C (17 g) in ethyl acetate (98 mL) was added a 4 mol / L hydrogen chloride-ethyl acetate solution (61 mL). 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 substance D (14 g, mixture of isomers).
LC-MS ([M + H] ⁺ / Rt (min)): 246 / 0.76 Measurement conditions (4)

c) Preparation of (6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (Compound W11) To a methanol solution (163 mL) of substance D (12 g), 0 At 37 ° C., 37% aqueous formaldehyde solution (11 mL) and sodium triacetoxyborohydride (21 g) were added. 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 the solvent of the organic layer after drying was distilled off under reduced pressure, the compound was purified by silica gel column chromatography (elution solvent; chloroform / ethyl acetate) and NH ₂ silica gel column chromatography (elution solvent; chloroform / ethyl acetate). W11 (3.9 g) was obtained.
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-tetrahydropyridine hydrochloride Preparation of Salt (Reference Example 34) To a solution of compound W11 (3.9 g) in THF (51 mL) at room temperature, bis (pinacolate) diborane (4.3 g), 1,1′-bis (diphenylphosphino) ferrocene- 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 Celite filtration, the solvent was distilled off under reduced pressure. Diethyl ether was added to the crude product, the precipitate was again removed by Celite filtration, and the solvent was evaporated 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. The precipitated solid was filtered and washed with hexane to obtain Reference Example 34 (3.5 g).
LC-MS ([M + H] ⁺ / Rt (min)): 238 / 1.25 Measurement conditions (4)

Example 1
8-Chloro-2-fluoro-11- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, e] [1,4] diazepine

a) Preparation of 8,11-dichloro-2-fluoro-5H-dibenzo [b, e] [1,4] diazepine (Compound W9) N in a solution of the compound of Reference Example 1 (1.0 g) in toluene (20 mL) , N-dimethylaniline (2.3 g) and phosphorus oxychloride (1.8 g) were added. The mixture was stirred at 95 ° C. for 2 hours and then cooled. THF and saturated aqueous sodium hydrogen carbonate solution were 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 sodium sulfate. After the solvent of the dried organic layer was distilled off under reduced pressure, N, N-dimethylaniline was removed by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to obtain Compound W9 (0.9 g).

b) 8-chloro-2-fluoro-11- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, e] [1,4] diazepine (Examples) 1) Preparation 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane in a solution of compound W9 (0.9 g) in THF / water (4/1) (50 mL) -2-yl) -1,2,3,6-tetrahydropyridine (1.0 g), potassium carbonate (1.6 g) and tetrakis (triphenylphosphine) palladium (0) (0.88 g) were added. The mixture was stirred at 75 ° C. for 1 hour and then 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 sodium sulfate. After the solvent of the organic layer after drying was distilled off under reduced pressure, the title compound was purified by silica gel column chromatography (elution solvent; chloroform / methanol) and NH ₂ silica gel column chromatography (elution solvent; hexane / ethyl acetate). (0.70 g) was obtained.
LC-MS ([M + H] ⁺ / Rt (min)): 342 / 0.67 Measurement conditions (1)
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.20 (d, 1H, J = 2.4 Hz), 7.00-6.92 (m, 3H), 6.72-6.68 (m, 1H), 6.61 (d, 1H, J = 8.0 Hz), 6.09-6.05 (m, 1H), 4.78 (s, 1H), 3.15-3.11 (m, 2H), 2.74-2.70 (m, 2H), 2.64 (t, 2H, J = 5.2 Hz) , 2.40 (s, 3H).

Examples 2 to 6
In accordance with the method described in Example 1, the compounds of Examples 2 to 6 were obtained using the compounds of the corresponding reference examples and the raw material compounds.

LC-MS in the above table was measured using measurement condition (1).

Example 7 and Example 8
8-chloro-2-fluoro-11- (6-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, e] [1,4] diazepine (Example 7)
8-chloro-2-fluoro-11- (2-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, e] [1,4] diazepine (Example 8)

a) tert-Butyl 4- (8-chloro-2-fluoro-5H-dibenzo [b, e] [1,4] diazepin-11-yl) -6-methyl-3,6-dihydropyridine-1 (2H) -Carboxylate and tert-butyl 4- (8-chloro-2-fluoro-5H-dibenzo [b, e] [1,4] diazepin-11-yl) -2-methyl-3,6-dihydropyridine-1 ( 2H) -Carboxylate (Substance B) Preparation of Compound W9 (1.1 g) in THF / water (4/1) (50 mL) solution of the compound of Reference Example 9 (mixture of isomers) (1.3 g), Potassium carbonate (1.7 g) and tetrakis (triphenylphosphine) palladium (0) (0.92 g) were added. The mixture was stirred at 75 ° C. for 1 hour and then 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 sodium sulfate. The solvent of the organic layer after drying was distilled off under reduced pressure, and then purified by silica gel column chromatography (elution solvent; hexane / ethyl acetate) to obtain substance B (1.0 g, mixture of isomers).
LC-MS ([M + H] ⁺ / Rt (min)): 442 / 1.45 Measurement conditions (1)

b) 8-chloro-2-fluoro-11- (6-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, e] [1,4] diazepine (Examples) 7) and 8-chloro-2-fluoro-11- (2-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, e] [1,4] diazepine Preparation of Example 8) Trifluoroacetic acid (1 mL) was added to a solution of substance B (0.17 g) in dichloromethane (4 mL), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the ice-cooled reaction mixture, and the mixture was extracted with chloroform. The obtained organic layer was washed with saturated brine, and dried over sodium sulfate. After the solvent of the organic layer after drying was distilled off under reduced pressure, the resulting residue was subjected to reverse phase purification on an ODS column (0.05% aqueous trifluoroacetic acid: acetonitrile), and TFA was separated by chloroform-saturated aqueous sodium bicarbonate solution. By freeing the salt, the compound of Example 7 (10 mg) and the compound of Example 8 (10 mg) were obtained.
8-chloro-2-fluoro-11- (6-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, e] [1,4] diazepine (Example 7) :
LC-MS ([M + H] ⁺ / Rt (min)): 342 / 0.73 Measurement conditions (1)
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.19 (d, 1H, J = 2.3 Hz), 7.00-6.89 (m, 3H), 6.73-6.70 (m, 1H), 6.62 (d, 1H, 8.3 Hz), 5.98 (s, 1H), 4.80 (s, 1H), 3.64-3.62 (m, 1H), 3.28-3.23 (m, 1H), 2.98-2.91 (m, 1H), 2.61-2.46 (m, 2H), 1.19 (d, 3H, J = 6.9 Hz).
8-chloro-2-fluoro-11- (2-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, e] [1,4] diazepine (Example 8) :
LC-MS ([M + H] ⁺ / Rt (min)): 342 / 0.75 Measurement conditions (1)
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.20 (d, 1H, J = 2.3 Hz), 7.01-6.89 (m, 3H), 6.73-6.69 (m, 1H), 6.61 (d, 1H, J = 8.7 Hz), 6.12 (s, 1H), 4.79 (s, 1H), 3.65-3.62 (m, 2H), 2.98-2.89 (m, 1H), 2.84-2.79 (m, 1H), 2.16-2.06 ( m, 1H), 1.25 (d, 3H, J = 6.4 Hz).

Examples 9 to 16
In accordance with the methods described in Example 7 and Example 8, the compounds of Examples 9 to 16 were obtained using the compounds and starting compounds of the corresponding reference examples.

LC-MS in the above table was measured using measurement condition (1).

Example 17 and Example 18
8-chloro-11- (1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl) -2-fluoro-5H-dibenzo [b, e] [1,4] diazepine (Examples) 17)
8-chloro-11- (1,2-dimethyl-1,2,3,6-tetrahydropyridin-4-yl) -2-fluoro-5H-dibenzo [b, e] [1,4] diazepine (Examples) 18)

To a (1.0 g) methanol (20 mL) solution of the mixture of Example 7 and Example 8 (1: 1), 37% formaldehyde solution (0.73 g) and magnesium sulfate (5.0 g) were added, and at 50 ° C. Stir for 1 hour. The reaction solution was ice-cooled and sodium borohydride (0.68 g) was gradually added. The mixture was stirred at room temperature for 1 hour, and solids were removed by celite filtration. Water was added to the filtrate and 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, NH ₂ silica gel column chromatography; purified by (eluent hexane / ethyl acetate), the compound of Example 17 (0.20 g) and Example 18 Compound (0.20 g) was obtained.
8-chloro-11- (1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl) -2-fluoro-5H-dibenzo [b, e] [1,4] diazepine (Examples) 17):
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.20 (d, 1H, J = 2.3 Hz), 7.01-6.89 (m, 3H), 6.72-6.69 (m, 1H), 6.61 (d, 1H, J = 8.7 Hz), 5.87 (s, 1H), 4.78 (s, 1H), 3.01-2.88 (m, 2H), 2.73-2.43 (m, 3H), 2.41 (s, 3H), 1.19 (d, 3H, J = 6.8 Hz).
LC-MS ([M + H] ⁺ / Rt (min)): 356 / 0.71 Measurement conditions (1)
8-chloro-11- (1,2-dimethyl-1,2,3,6-tetrahydropyridin-4-yl) -2-fluoro-5H-dibenzo [b, e] [1,4] diazepine (Examples) 18):
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.20 (d, 1H, J = 2.8 Hz), 7.00-6.92 (m, 3H), 6.72-6.68 (m, 1H), 6.61 (d, 1H, J = 8.7 Hz), 6.05 (s, 1H), 4.77 (s, 1H), 3.49-3.39 (m, 2H), 3.06-2.22 (m, 3H), 2.36 (s, 3H), 1.18 (d, 3H, J = 4.8 Hz).
LC-MS ([M + H] ⁺ / Rt (min)): 356 / 0.73 Measurement conditions (1)

Examples 19-21
According to the methods described in Example 17 and Example 18, the compounds of Examples 19 to 21 were obtained using the compounds and starting compounds of the corresponding reference examples.

LC-MS in the above table was measured using measurement condition (1).

Example 22
8-Chloro-2-fluoro-11- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, e] [1,4] diazepine

a) Preparation of 8-chloro-2-fluoro-11- (pyridin-4-yl) -5H-dibenzo [b, e] [1,4] diazepine (W10) Compound W9 (107 mg) in THF / water (4 / 1) To the (5 mL) solution was added pyridine-4-boronic acid (94 mg), potassium carbonate (0.16 g) and tetrakis (triphenylphosphine) palladium (0) (88 mg). After stirring at 75 ° C. for 1 hour. Water was added to the ice-cooled reaction mixture, 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 the residue was purified by silica gel column chromatography (elution solvent; chloroform / methanol) and NH ₂ silica gel column chromatography (elution solvent; hexane / ethyl acetate) to give compound W10. (45 mg) was obtained.
LC-MS ([M + H ] + / Rt (min)): 324 / 1.03 Measurement conditions (1)

b) 8-chloro-2-fluoro-11- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, e] [1,4] diazepine (Examples) 22) Preparation Methyl iodide (59 mg) was added to a solution of compound W10 (15 mg) in acetonitrile (0.42 mL). After stirring at 60 ° C. for 1 hour, the reaction solution was concentrated. The obtained residue was dissolved in methanol (0.20 mL), and sodium borohydride (16 mg) was added at 0 ° C. After stirring at room temperature for 1 hour, 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 sodium sulfate. After the solvent of the organic layer after drying was distilled off under reduced pressure, the title compound was purified by silica gel column chromatography (elution solvent; chloroform / methanol) and NH ₂ silica gel column chromatography (elution solvent; hexane / ethyl acetate). (10 mg) was obtained.
LC-MS ([M + H] ⁺ / Rt (min)): 342 / 0.67 Measurement conditions (1)
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.20 (d, 1H, J = 2.4 Hz), 7.00-6.92 (m, 3H), 6.72-6.68 (m, 1H), 6.61 (d, 1H, J = 8.0 Hz), 6.09-6.05 (m, 1H), 4.78 (s, 1H), 3.15-3.11 (m, 2H), 2.74-2.70 (m, 2H), 2.64 (t, 2H, J = 5.2 Hz) , 2.40 (s, 3H).

Examples 23-31
According to the method described in Example 22, the compounds of Examples 23 to 31 were obtained using the compounds of the corresponding reference examples and raw material compounds.

LC-MS in the above table was measured using measurement condition (1).

Examples 32-89
According to the methods described in Example 1, Example 7 and Example 8, Example 17 and Example 18, the compounds of Examples 32 to 89 were obtained using the compounds and starting compounds of the corresponding reference examples.

Test Examples The pharmacological test results of the compounds of the present invention are shown below and the pharmacological actions of the compounds are described. However, 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. Aequorin and Gα16 protein and their respective receptors were transiently expressed in CHO-K1 cells (Chinese hamster ovary), seeded in 384-well plates, and cultured overnight at 37 ° C. in a CO ₂ incubator. After adding coelenterazine, using FDSS (manufactured by Hamamatsu Photonics), adding a DMSO suspension of the compound of the present invention, then adding dopamine (final concentration 100 nmol / L) or serotonin (final concentration 30 nmol / L), and emitting light The change in quantity was 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 wells added only with DMSO was inhibited by 100%, and the luminescence amount of wells added only with dopamine or serotonin was inhibited by 0%. . Moreover, what has described the density | concentration in the following table represents the inhibition rate in the described density | concentration (For example, what is described as 58@0.1 micromol / L has the inhibition rate in 0.1 micromol / L. It represents 58%). In addition, it was set as the comparative example using the clozapine as a comparison object substance. 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 liver microsomes, and reactive metabolites that react with dansylated glutathione (dGSH) were detected and quantified from the metabolites generated. The metabolic reaction was measured using a screening robot (manufactured by Tecan), and the metabolite-dGSH conjugate concentration 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, it was set as the comparative example using the clozapine as a comparison object substance.
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 microsome (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 stopping solution was prepared by dissolving 33 mg of Tris (2-carboxyethyl) phosphine (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 in a 96-well plate. The 6 wells were divided into 3 groups of 2 wells, which were designated as “reaction group”, “unreacted group” and “dGSH non-added group”, respectively.
The 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-addition group”.
The cofactor solution was added to the “reaction group” and “dGSH non-addition group”, and 50 μL of pure water was added to the “non-reaction group”.
After incubation at 37 ° C. for 60 minutes, 450 μL of reaction stop solution was added to stop the reaction. Purified water was added to the “reaction group” and “dGSH non-added group”, and 50 μL of cofactor solution was added to the “unreacted group”. The plate was cooled at −20 ° C. for 1 hour, and then centrifuged (4000 rpm, 10 minutes) went. The supernatant was collected on a separate plate and subjected to analysis.

(analysis)
Using a fluorescence detection UPLC system (manufactured by Waters), “reaction group”, “unreacted group” and “dGSH non-added group” were analyzed under the following conditions.
Column: Waters ACQUITY UPLC® BEH C18 (1.7 μm, 2.1 mm X 10 mm)
Elution solvent: Liquid A 0.2% formic acid / 40% methanol Liquid B 0.2% formic acid / methanol Gradient: Liquid 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 varies depending on the organic solvent composition, correction was performed with the organic solvent composition during elution.
The metabolite-dGSH conjugate concentration in the “reaction group” was calculated by subtracting the fluorescence peaks detected in the “unreacted group” and “dGSH non-added group” from the fluorescence peak detected in the “reaction group”. By measuring the concentration of the “reaction group” metabolite-dGSH conjugate, the risk of the reactive metabolite of the test substance can be evaluated.

The results of the metabolite-dGSH conjugate concentrations of the “reaction group” of clozapine and the compound of the present invention are shown in the table below.

Also, based on the analysis result of Test Example 2, the concentration of dGSH conjugate in the “unreacted group” is subtracted from the fluorescence peak detected in the “unreacted group” from the fluorescence peak detected in the “dGSH non-added group”. Was calculated. By measuring the concentration of the dGSH conjugate in the “unreacted group”, it is possible to evaluate the covalent binding property of the test substance that is considered to be related to cytotoxicity or immunotoxicity.
The result of the dGSH conjugate concentration of the “unreacted group” of the compound of the present invention is shown in the table below.

Test Example 3: Human Liver Microsome Metabolic Stability Test In this test, the stability of a test substance against human liver microsomal metabolism can be evaluated. Human liver microsomal metabolic stability (MS) of the compound of the present invention was evaluated by the following method. Human liver microsomes manufactured by Xenontech were used. Human liver microsomes, NADPH, and a test substance were mixed in 125 mmol / L phosphate buffer (pH 7.4) to the following concentrations and incubated at 37 ° C. for 30 minutes.
Human liver microsome: 0.1 mg / mL
NAPDH: 3.2 mmol / L,
Test substance: 0.1 μmol / L
The residual rate of the test substance in the sample after 30 minutes was measured by LC-MS, and the stability of the test substance against human liver microsome metabolism was calculated from the following formula.
Stability against human liver microsomal metabolism (mL / min / mg protein) = -LN (residual rate) /30/0.1
The results are shown in the table below.

Test Example 4: Rat Brain Translocation Test In this test, the brain translocation of the compound of the present invention can be evaluated. The SD compound 7-week-old rat is subcutaneously administered with the compound of the present invention in 0.01 mol / L hydrochloric acid aqueous solution, and plasma and brain are collected 1 hour after the administration, and the plasma and brain are collected by LC-MS. Drug concentration was measured.
Serum and brain protein binding rates of the compounds of the present invention were measured using equilibrium dialysis.
By fitting the plasma and brain compound concentrations and serum and brain protein binding rates obtained by the above test to the following equations, Kp, uu, brain (brain / plasma non-binding drug concentration ratio) Can be calculated.
Kp, uu, brain = (Brain compound concentration × (100−protein binding rate in brain (%)) / 100) / (plasma compound concentration × (100−protein binding rate in serum (%)) / 100)
The results are shown in the table below.

Test Example 5: Evaluation for Positive Symptoms by Rat Methamphetamine-Induced Momentum Increase Test The motility enhancement effect by methamphetamine administration to rats is used as an evaluation system for positive symptoms of schizophrenia, and the inhibitory action when the present compound is administered Can be evaluated. After the compound of the present invention is administered to 6-10 week old rats, the amount of exercise for 90 minutes is measured immediately after methamphetamine administration. SuperMex (Muromachi Machine Co., Ltd.) is used for the measurement. The inhibition rate when the momentum of the solvent administration group is 100% is calculated.

Test Example 6: 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 an evaluation scale for psychiatric symptoms of schizophrenia. After administering the compound of the present invention for 6 to 24 weeks, the effectiveness is evaluated using the above-mentioned evaluation scale.

Test Example 7: Cyano Trapping 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 with radioactive potassium cyanide (K ¹⁴ CN). Human liver microsomes manufactured by Xenontech are used, and the reaction is performed at 37 ° C. for 60 minutes under the following concentration conditions.
Concentration conditions / phosphate buffer solution (pH 7.4): 100 mM
・ Human liver microsomes: 1 mg / mL
・ K ¹⁴ CN: 0.1 mM
Test substance: 50 μM
NADPH: 0 mM or 1 mM
Reactive metabolites that react with K ¹⁴ CN are collected by solid phase extraction, and the radioactivity concentration is measured using a liquid scintillation counter. The production clearance of the reactive metabolite is calculated by subtracting the measurement value obtained under the condition where NADPH is not added from the measurement value obtained under the condition where NADPH is added.

Test Example 8: Human type 5-HT _2C receptor, human type histamine H ₁ receptor (hereinafter referred to as H ₁ receptor), human type muscarinic M ₁ receptor (hereinafter referred to as M ₁ receptor), human type muscarinic M ₂ receptor (hereinafter, _{M 2} receptors), human muscarinic _{M 3} receptor (hereinafter, _{M 3} receptors) and human muscarinic _{M 4} receptor (hereinafter, _{M 4} receptor) antagonist activity evaluation test human against 5 -Intracellular calcium concentration for antagonist activity against HT _2C receptor, human H ₁ receptor, human M ₁ receptor, human M ₂ receptor, human M ₃ receptor and human M ₄ receptor Was used as an index. Aequorin, Gα16 protein and each receptor were transiently expressed in CHO-K1 cells (Chinese hamster ovary), seeded in a 384-well plate, and cultured overnight at 37 ° C. in a CO ₂ incubator. After adding coelenterazine, a DMSO suspension of the compound of the present invention was added using FDSS (manufactured by Hamamatsu Photonics), and then the corresponding ligands shown in the table below were added, and the change in the amount of luminescence was measured. The following table shows the ligands used for evaluating the antagonist activity of each receptor and the concentrations used.

Antagonist activity is defined as 100% inhibition of luminescence in wells to which only DMSO has been added, and 0% inhibition of luminescence in wells to which only the corresponding ligand has been added. The inhibition rate in the case of was calculated.

Test Example 9: Human type 5-HT _2A receptor, human type D ₁ receptor, human type D ₂ receptor, human type 5-HT _2C receptor, human type H ₁ receptor, human type M ₁ receptor, Evaluation of binding activity to human type M ₂ receptor, human type M ₃ receptor and human type M ₄ receptor In this test, human type 5-HT _2A receptor, human type D ₁ receptor, human type of the compound of the present invention were used. Binding to D ₂ receptor, human 5-HT _2C receptor, human H ₁ receptor, human M ₁ receptor, human M ₂ receptor, human M ₃ receptor and human M ₄ receptor Affinity can be measured. Using a CHO cell membrane fraction or CHO-K1 cell membrane fraction in which these receptors are expressed, in a binding evaluation test, a test compound dissolved in DMSO, various receptor membrane samples diluted with a buffer, and these receptors RI (Radio Isotope) labeled ligands are mixed and incubated at room temperature for 30 or 60 minutes, respectively. As RI labeled ligand for a receptor, can be appropriately selected by the test conditions, for the 5-HT _2A receptor [3H] Ketanserin, for the _{D 2} receptor [3H] spiperone, for D ₁ receptor may be used [3H] SCH23390. Non-specific binding to the receptor is determined by competitive binding test in the presence of Mianserin for 5-HT _2A receptor, Dopamine for D ₂ receptor, SCH 23390 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 saturation binding test, and the substrate concentration, and use it as the binding affinity. To do. In addition, regarding binding affinity for human type 5-HT _2C receptor, human type H ₁ receptor, human type M ₁ receptor, human type M ₂ receptor, human type M ₃ receptor and human type M ₄ receptor Can also be measured according to the above method. The RI-labeled ligand for these receptors can be appropriately selected depending on the test conditions and the like. For example, for human type 5-HT _2C receptor, [3H] Mesulegene, human type H ₁ receptor against it is [3H] Pyrilamine, human _{M 1} receptor, human _{M 2} receptor, for the human _{M 3} receptor and human _{M 4} receptor be used [3H] N-Methylscopolamine etc. it can. Further, non-specific binding to these receptors is Mianserin for the human 5-HT _2C receptor, Pyrilamine for the human H ₁ receptor, human M ₁ receptor, human M ₂ For the receptor, human M ₃ receptor, and human M ₄ receptor, it is determined by a competitive binding test in the presence of Atropine or the like.

Since the compound of the present invention exhibits an antagonistic action on dopamine D ₁ receptor, dopamine D ₂ receptor, and serotonin 5-HT _2A receptor, it is useful as a therapeutic and / or prophylactic agent for central nervous system diseases. is there.

Claims

Formula (1):

[Wherein, ring Q 1 represents an optionally substituted benzene ring or an optionally substituted pyridine ring;
Ring Q 2 represents an optionally substituted benzene ring or an optionally substituted pyridine ring;
R a represents a hydrogen atom or C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types;
n represents 0, 1 or 2;
m represents 1, 2, 3 or 4;
Each of R b independently represents a hydrogen atom, a halogen atom, or C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types]. A compound, or a pharmaceutically acceptable salt thereof.
Ring Q 1 is a benzene ring or a pyridine ring (wherein the benzene ring or pyridine ring is a C 1-6 alkyl which may be substituted with 1 to 3 halogen atoms, the same or different halogen atoms, the same or different Selected from the group consisting of C 1-6 alkoxy optionally substituted with 1 to 3 different halogen atoms and amino optionally substituted with 1 or 2 same or different C 1-6 alkyl Optionally substituted with 1 to 4 groups of the same or different types;
Ring Q 2 is a benzene ring or a pyridine ring (wherein the benzene ring or pyridine ring is a C 1-6 alkyl which may be substituted with 1 to 3 halogen atoms, the same or different halogen atoms, the same or different Selected from the group consisting of C 1-6 alkoxy optionally substituted with 1 to 3 different halogen atoms and amino optionally substituted with 1 or 2 same or different C 1-6 alkyl Or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, which may be substituted with 1 to 4 groups of the same or different types.
Ring Q 1 is a benzene ring (the ring is a halogen atom, cyano, C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different species, and 1 to 3 of the same or different species) And optionally substituted with 1 to 4 groups of the same or different types selected from the group consisting of C 1-6 alkoxy optionally substituted with halogen atoms;
Ring Q 2 is a benzene ring (the ring is a halogen atom, cyano, C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different species, and 1 to 3 of the same or different species) The optionally substituted 1 to 4 groups of the same or different groups selected from the group consisting of C 1-6 alkoxy optionally substituted with a halogen atom of claim 1 or 2. Or a pharmaceutically acceptable salt thereof.
The compound according to any one of claims 1 to 3, wherein n is 1, or a pharmaceutically acceptable salt thereof.
5. When there are a plurality of R b s , they are each independently a halogen atom, or C 1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms. Or a pharmaceutically acceptable salt thereof.
Formula (1a):

[Wherein R a represents a hydrogen atom, or C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently a hydrogen atom, a halogen atom, cyano, the same or different, 1 to 3 halogen atoms C 1-6 alkyl optionally substituted with 1 to 3 C 1-6 alkoxy optionally substituted with 1 to 3 halogen atoms of the same or different type, or 1 to 2 C 1-of the same or different type Represents an amino optionally substituted with 6 alkyls;
R 11 , R 12 , R 13 , and R 14 each independently represent a hydrogen atom, a halogen atom, or C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, represented by:
Any one or more of R 11 , R 12 , R 13 , and R 14 is a halogen atom, or C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types. The compound according to claim 6, or a pharmaceutically acceptable salt thereof.
Formula (1b):

[Wherein R a , R 2 , R 7 , R 13 , and R 14 have the same meaning as in item 6], or a pharmaceutically acceptable compound thereof salt.
The compound according to any one of claims 6 to 8, or a pharmaceutically acceptable salt thereof, wherein R 13 is C 1-6 alkyl.
The compound according to any one of claims 6 to 8, or a pharmaceutically acceptable salt thereof, wherein R 13 is methyl.
The compound according to any one of claims 6 to 10, or a pharmaceutically acceptable salt thereof, wherein R 14 is a hydrogen atom.
Formula (1b-1):

The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R a , R 2 and R 7 are as defined in item 6.
The compound according to any one of claims 1 to 12, wherein R a is C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms, which are the same or different, or a pharmaceutically acceptable salt thereof. Acceptable salt.
R a is methyl, compound or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 12.
R 2 and R 7 are each independently a hydrogen atom, a halogen atom, cyano, a C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different kinds, or the same or different 1 The compound according to any one of claims 6 to 14, or a pharmaceutically acceptable salt thereof, which is C 1-6 alkoxy optionally substituted with ~ 3 halogen atoms.
Any one or more of R 2 and R 7 is a halogen atom, cyano, C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms, or the same or different 1-3 The compound according to any one of claims 6 to 14, or a pharmaceutically acceptable salt thereof, which is C 1-6 alkoxy optionally substituted by one halogen atom.
R 2 is a hydrogen atom, a fluorine atom, a chlorine atom, C 1-3 alkyl, or C 1-3 alkoxy;
R 7 may be substituted with a hydrogen atom, a fluorine atom, a chlorine atom, cyano, C 1-3 alkyl optionally substituted with 1 to 3 fluorine atoms, or 1 to 3 fluorine atoms C 1-6 alkoxy,
The compound according to any one of claims 6 to 14, or a pharmaceutically acceptable salt thereof.
The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following group of compounds:
11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -8-methyl-2- (trifluoromethyl) -5H-dibenzo [b, e] [ 1,4] diazepine,
8-Methyl-11-[(6S) -6-methyl-1- ( 2 H 3 ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -2- (trifluoromethyl) -5H- Dibenzo [b, e] [1,4] diazepine,
8-chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2- (trifluoromethoxy) -5H-dibenzo [b, e] [ 1,4] diazepine,
8-chloro-11-[(6S) -6-methyl-1- ( 2 H 3 ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -2- (trifluoromethoxy) -5H- Dibenzo [b, e] [1,4] diazepine,
8-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-ethyl-5H-dibenzo [b, e] [1,4] Diazepine,
8-chloro-2-ethyl-11-[(6S) -6-methyl-1- ( 2 H 3 ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, e] [1,4] diazepine,
11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-ethyl-8-fluoro-5H-dibenzo [b, e] [1,4] Diazepine,
2-Ethyl-8-fluoro-11-[(6S) -6-methyl-1- ( 2 H 3 ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, e] [1,4] diazepine,
2-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -8-fluoro-5H-dibenzo [b, e] [1,4] Diazepine,
2-Chloro-8-fluoro-11-[(6S) -6-methyl-1- ( 2 H 3 ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, e] [1,4] diazepine,
8-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-methyl-5H-dibenzo [b, e] [1,4] Diazepine,
8-chloro-2-methyl-11-[(6S) -6-methyl-1- ( 2 H 3 ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, e] [1,4] diazepine,
8-chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-methoxy-5H-dibenzo [b, e] [1,4] Diazepine,
8-chloro-2-methoxy-11-[(6S) -6-methyl-1- ( 2 H 3 ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, e] [1,4] diazepine,
8-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-ethoxy-5H-dibenzo [b, e] [1,4] Diazepine and 8-chloro-2-ethoxy-11-[(6S) -6-methyl-1- ( 2 H 3 ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [B, e] [1,4] diazepine.
The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following group of compounds:
11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -8-methyl-2- (trifluoromethyl) -5H-dibenzo [b, e] [ 1,4] diazepine,
8-Methyl-11-[(6S) -6-methyl-1- ( 2 H 3 ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -2- (trifluoromethyl) -5H- Dibenzo [b, e] [1,4] diazepine,
8-chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2- (trifluoromethoxy) -5H-dibenzo [b, e] [ 1,4] diazepine,
8-chloro-11-[(6S) -6-methyl-1- ( 2 H 3 ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -2- (trifluoromethoxy) -5H- Dibenzo [b, e] [1,4] diazepine,
8-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-ethyl-5H-dibenzo [b, e] [1,4] Diazepine,
8-chloro-2-ethyl-11-[(6S) -6-methyl-1- ( 2 H 3 ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, e] [1,4] diazepine,
11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-ethyl-8-fluoro-5H-dibenzo [b, e] [1,4] Diazepine,
2-Ethyl-8-fluoro-11-[(6S) -6-methyl-1- ( 2 H 3 ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, e] [1,4] diazepine,
8-chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-methoxy-5H-dibenzo [b, e] [1,4] Diazepine,
8-chloro-2-methoxy-11-[(6S) -6-methyl-1- ( 2 H 3 ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, e] [1,4] diazepine,
8-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-ethoxy-5H-dibenzo [b, e] [1,4] Diazepine and 8-chloro-2-ethoxy-11-[(6S) -6-methyl-1- ( 2 H 3 ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [B, e] [1,4] diazepine.
The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following group of compounds:
11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -8-methyl-2- (trifluoromethyl) -5H-dibenzo [b, e] [ 1,4] diazepine,
8-Methyl-11-[(6S) -6-methyl-1- ( 2 H 3 ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -2- (trifluoromethyl) -5H- Dibenzo [b, e] [1,4] diazepine,
8-chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2- (trifluoromethoxy) -5H-dibenzo [b, e] [ 1,4] diazepine,
8-chloro-11-[(6S) -6-methyl-1- ( 2 H 3 ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -2- (trifluoromethoxy) -5H- Dibenzo [b, e] [1,4] diazepine,
8-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-ethyl-5H-dibenzo [b, e] [1,4] Diazepine,
8-chloro-2-ethyl-11-[(6S) -6-methyl-1- ( 2 H 3 ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [b, e] [1,4] diazepine,
8-Chloro-11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-ethoxy-5H-dibenzo [b, e] [1,4] Diazepine and 8-chloro-2-ethoxy-11-[(6S) -6-methyl-1- ( 2 H 3 ) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H-dibenzo [B, e] [1,4] diazepine.
A pharmaceutical comprising the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof as an active ingredient.
A therapeutic agent for central nervous system diseases comprising the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof as an active ingredient.
Central nervous system disease is schizophrenia, bipolar disorder, autism, ADHD, depression, anxiety disorder, sleep disorder, behavioral and psychological symptoms of dementia (BPSD (Behavioral and Psychological Symptoms of Dementia)) or neurodegeneration The therapeutic agent according to claim 22, which is a psychiatric symptom of a disease.
A central nervous system disease comprising administering to a patient in need of treatment a therapeutically effective amount of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof. How to treat.
Use of the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for central nervous system diseases.
The compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof for use in the treatment of a central nervous system disease.
The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and aripyrazole, olanzapine, quetiapine, risperidone, blonanserin, perospirone, paliperidone, ziprasidone, asenapine, iloperidone, sertindole A therapeutic agent for central nervous system diseases, comprising a combination of at least one drug selected from the group consisting of lurasidone and pharmaceutically acceptable salts thereof.
Used in combination with at least one drug selected from the group consisting of aripiprazole, olanzapine, quetiapine, risperidone, bronanserin, perospirone, paliperidone, ziprasidone, asenapine, iloperidone, sertindole, lurasidone, and pharmaceutically acceptable salts thereof. A therapeutic agent comprising, as an active ingredient, the compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for treating central nervous system diseases.