JP2020055752A - Dibenzo diazepine derivative - Google Patents

Abstract

To provide a dibenzo diazepine derivative useful for central nervous diseases.SOLUTION: The present invention provides a compound represented by formula (1) [ring Qand ring Qindependently represent a substituted/unsubstituted benzene ring or pyridine ring; Ris H or Calkyl substituted/unsubstituted with halogen; n is an integer of 0-2; m is an integer of 1-4; Rindependently represent H, a halogen atom or Calkyl substituted/unsubstituted with a halogen atom].SELECTED DRAWING: None

Description

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

Schizophrenia is reported to have an estimated 45 million patients worldwide and is a psychiatric disorder with positive symptoms, negative symptoms and cognitive dysfunction as major symptoms. At present, antipsychotics having dopamine D ₂ receptor (hereinafter referred to as D ₂ receptor) antagonism and serotonin 5-HT _2A receptor (hereinafter referred to as 5-HT _2A receptor) antagonism are used as therapeutic agents for schizophrenia. Although it is used, it is known that about 30% of schizophrenia patients suffer from so-called treatment-resistant schizophrenia, which is not effective with existing antipsychotics (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 drug effective in patients with refractory schizophrenia It has been reported (Non-Patent Document 1). However, it has been reported that 0.8% of patients taking clozapine cause severe agranulocytosis, which is a serious side effect, and blood monitoring is required when taking the drug. Therefore, development of an antipsychotic drug that is safer and effective for patients with refractory schizophrenia has become an urgent issue.

Clozapine is known to have an antagonistic action on dopamine D ₁ receptor (hereinafter, D ₁ receptor) in addition to dopamine D ₂ receptor antagonistic action and serotonin 5-HT _2A receptor antagonistic action. (Non-Patent Document 2).

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. Has a different chemical structure from the dibenzodiazepine derivative.
Patent Document 2 discloses a dibenzoxazepine derivative useful as an antipsychotic.

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

Pharmgenomics Pers Med. (2016) 9, 117-129. Am J Psychiatry. (2004); 161 (9): 1620-5.

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

The present inventors have reported that compounds having an antagonistic effect on D ₁ receptor, D ₂ receptor, and 5-HT _2A receptor have strong efficacy against schizophrenia and other mental disorders including treatment resistance. shows the idea of intensive research as a result, (sometimes abbreviated as needed hereinafter "the compound of the present invention".) the compound represented by the following formula (1) and a pharmaceutically acceptable salt thereof, D ₁ receptor, found to have a strong antagonistic effect on D ₂ receptors, and 5-HT _2A receptor, and have completed the present invention.

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

[In the formula, ring Q ¹ represents an optionally substituted benzene ring or an optionally substituted pyridine ring;
Ring Q ² are represent a benzene ring which may be substituted, or a pyridine ring optionally substituted;
R ^a represents a hydrogen atom or C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms;
n represents 0, 1 or 2;
m represents 1, 2, 3 or 4;
R ^b independently represents a hydrogen atom, a halogen atom, or a C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types, when there are a plurality of R ^b. A compound or a pharmaceutically acceptable salt thereof.

[2] ring Q ¹ is a benzene ring or a pyridine ring (the benzene ring or the pyridine ring may be a halogen atom, cyano, or a C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms; consists also an amino substituted with one to two C _1-6 alkyl also a C _1-6 alkoxy, and same or different optionally substituted with 1 to 3 halogen atoms the same or different Which may be substituted with 1 to 4 same or different groups selected from the group);
Ring Q ² is a benzene ring or a pyridine ring (the benzene ring or the pyridine ring may be a halogen atom, cyano, C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms, the same type or Selected from the group consisting of hetero-C _1-6 alkoxy optionally substituted with 1 to 3 halogen atoms, and amino optionally substituted with 1 or 2 homo- or hetero C _1-6 alkyl. Or a pharmaceutically acceptable salt thereof according to item 1, wherein the compound may be substituted with 1 to 4 same or different groups.

[3] ring Q ¹ is a benzene ring (the ring is a halogen atom, cyano, a C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms, and a same or different 1 Which may be substituted with 1 to 4 same or different groups selected from the group consisting of C _1-6 alkoxy optionally substituted with 3 halogen atoms);
Ring Q ² is a benzene ring (the ring is a halogen atom, cyano, C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms, and 1 to 3 same or different 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). A compound or a pharmaceutically acceptable salt thereof.

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

[5] Items 1 to 4 wherein, when R ^b is plural, each is independently a halogen atom or C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different kind. Or a pharmaceutically acceptable salt thereof.

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

[Wherein, ^Ra represents a hydrogen atom or C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms;
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, a cyano, 1 to 3 halogen atoms of the same or different kind in an optionally substituted C _1-6 alkyl, same or 1 to 3 halogen atoms which may be substituted with optionally C _1-6 alkoxy heterologous or of homologous or heterologous 1-2, C _{1- Represents} an amino optionally substituted with ₆ alkyl;
R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ each independently represent a hydrogen atom, a halogen atom, or a C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms. The compound according to item 1, or a pharmaceutically acceptable salt thereof, wherein

[7] Any one or more of R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ may be a halogen atom, or a C _1-6 alkyl which may be substituted with the same or different one to three halogen atoms. Item 7. The compound according to Item 6, or a pharmaceutically acceptable salt thereof.

［式中、Ｒ^ａ、Ｒ^２、Ｒ^７、Ｒ^１３、およびＲ^１４は、項６と同義である]で表される、項６に記載の化合物、またはその製薬学的に許容される塩。 [8] 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 salt thereof. .

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

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

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

［式中、Ｒ^ａ、Ｒ^２およびＲ^７は、項６と同義である]で表される、項６に記載の化合物、またはその製薬学的に許容される塩。 [12] Formula (1b-1):

[Wherein, R ^a , R ² and R ⁷ have the same meaning as in item 6,] or a pharmaceutically acceptable salt thereof according to item 6.

[13] The compound according to any one of items 1 to 12, wherein ^Ra is C _1-6 alkyl which may be substituted with the same or different 1 to 3 halogen atoms, or a pharmaceutical thereof. A biologically acceptable salt.

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

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

[16] at least one of R ² and R ⁷ is a halogen atom, cyano, C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms, or the same or different optionally substituted with 1 to 3 halogen atoms is also a C _1-6 alkoxy, a compound according to any one of claims 6-14 or a pharmaceutically acceptable salt thereof.

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

[18] The compound according to item 1, or a pharmaceutically acceptable salt thereof, selected from the following compound group:
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-lahydropyridin-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),
11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-ethoxy-8-methyl-5H-dibenzo [b, e] [1,4] diazepine (example 88), and 2-ethoxy-8-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 89).

[19] A medicament comprising the compound according to any one of items 1 to 18 or a pharmaceutically acceptable salt thereof as an active ingredient.

[20] A therapeutic agent for central nervous system diseases, comprising the compound according to any one of items 1 to 18 or a pharmaceutically acceptable salt thereof as an active ingredient.

[21] Central nervous system diseases are schizophrenia, bipolar disorder, autism, ADHD, depression, anxiety disorder, sleep disorder, behavioral and psychological symptoms of dementia (BPSD (Behavioral and Psychological Symptoms of Dementia)) 21. The therapeutic agent according to item 20, which is a psychiatric symptom of a neurodegenerative disease.

[22] a central nervous system comprising administering to a patient in need of treatment a therapeutically effective amount of the compound according to any one of items 1 to 18 or a pharmaceutically acceptable salt thereof. A method for treating a disease.

[23] Use of the compound according to any one of items 1 to 18, or a pharmaceutically acceptable salt thereof, for producing a therapeutic agent for a central nervous system disease.

[24] The compound according to any one of items 1 to 18, or a pharmaceutically acceptable salt thereof, for use in treating a central nervous system disease.

[25] The compound according to any one of Items 1 to 18 or a pharmaceutically acceptable salt thereof, and aripyrazole, olanzapine, quetiapine, risperidone, blonanserin, perospirone, paliperidone, ziprasidone, asenapine, iloperidone, cell A therapeutic agent for a central nervous system disease, which is combined with at least one drug selected from the group consisting of tindole, lurasidone, and pharmaceutically acceptable salts thereof.

[26] at least one drug selected from the group consisting of aripyrazole, olanzapine, quetiapine, risperidone, blonanserin, elospirone, paliperidone, ziprasidone, asenapine, iloperidone, sertindole, lurasidone, and pharmaceutically acceptable salts thereof 19. A therapeutic agent comprising the compound according to any one of items 1 to 18 or a pharmaceutically acceptable salt thereof as an active ingredient, for treating a central nervous system disease in combination with the above.

The present invention compounds exhibit antagonism _{D 1} receptors, _{D 2} receptors, and against _{5-HT 2A} receptor. In addition, in a preferred embodiment, it has excellent brain localization, and also has low production of reactive metabolites. Therefore, the compound of the present invention is useful as a highly safe and excellent therapeutic and / or prophylactic agent for central nervous system diseases (eg, schizophrenia).

Hereinafter, the present invention will be described in detail. In this specification, the number of carbons in the definition of “substituent” may be described as, for example, “C _1-6 ”. Specifically, the notation “C _1-6 alkyl” has the same meaning as alkyl having 1 to 6 carbon atoms.

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

“C _1-6 alkyl” means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferably, it is “C _1-4 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, and 2-ethylbutyl.

The “C _1-6 alkyl” part of “C _1-6 alkoxy” has the same _{meaning as} the above “C _1-6 alkyl”. Preferably, it is " _C1-4 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), when the ring Q ¹ and / or the ring Q ² is a pyridine ring, the four atoms indicated by arrows shared by the rings 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) C _1-6 alkyl (the group may be substituted by 1 to 3 same or different groups selected from the group consisting of halogen atom, hydroxy, and C _1-6 alkoxy),
(C) C _1-6 alkoxy (the group may be substituted with 1 to 3 same or different groups selected from the group consisting of halogen atom, hydroxy, and C _1-6 alkoxy),
(D) cyano,
(E) phenyl (the group may be substituted with 1 to 4 same or different groups selected from the group consisting of a halogen atom, C _1-6 alkyl and C _1-6 alkoxy),
(F) 5- or 6-membered heteroaryl, wherein the group is substituted with 1 to 4 same or different groups selected from the group consisting of halogen atoms, C _1-6 alkyl, and C _1-6 alkoxy. May be done),
(G) phenoxy (the group may be substituted with 1 to 4 same or different groups selected from the group consisting of a halogen atom, C _1-6 alkyl and C _1-6 alkoxy),
(H) hydroxy,
(I) amino, wherein the group may be substituted with one or two same or different C _1-6 alkyl, and (j) aminocarbonyl, wherein the amino is one or two same or different C _1-6 alkyl).
Preferably, it may be substituted with a halogen atom, cyano, C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms, or substituted with 1 to 3 identical or different halogen atoms. C _1-6 alkoxy and amino optionally substituted with 1 to 2 same or different C _1-6 alkyl.
More preferably, it may be substituted with a halogen atom, C _1-6 alkyl which may be substituted with the same or different 1 to 3 halogen atoms, and may be substituted with 1 to 3 same or different halogen atoms. _C1-6 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 , and in R ^14, but preferred are as follows, the technical scope of the present invention is not limited to the scope of the compounds listed below.

^Ra is preferably C _1-6 alkyl which may be substituted with the same or different 1 to 3 halogen atoms. More preferably, it is C _1-3 alkyl; even more preferably it is methyl. Another embodiment of ^Ra includes methyl deuteride (CD3).

R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁸ preferably include 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, a cyano, a C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types, and 1 to 3 C _1-6 alkyls 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 which may be substituted with the same or different 1 to 3 halogen atoms, and may be substituted with 1 to 3 same or different halogen atoms. _C1-6 alkoxy is mentioned.

R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ are each independently a hydrogen atom, a halogen atom, or a C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms. However, at least one of R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ is a halogen atom, or a C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms. It is preferred 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 preferably include a hydrogen atom and C _1-6 alkyl. More preferably, it is a hydrogen atom.

Preferably, R ¹³ includes a hydrogen atom and C _1-6 alkyl. More preferably, it is C _1-4 alkyl; even more preferably it is methyl.

In another embodiment of R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ , R ¹¹ and R ¹² are a hydrogen atom; R ¹³ is C _1-6 alkyl; R ¹⁴ is a 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 a hydrogen atom; and R ¹³ is C _1-4 alkyl.

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

The compound represented by the formula (1) may have at least one asymmetric carbon atom. Therefore, the compounds of the present invention include not only racemic forms of the compound represented by the formula (1) but also optically active forms of these compounds.
Further, a deuterium conversion product obtained by converting 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 may be used. And the like are also included in the compounds of the present invention. Further, the compound of the present invention includes all forms of crystalline forms.
As the pharmaceutically acceptable salt, when the compound represented by the formula (1) has an acidic group, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth salts such as calcium salt and magnesium salt Metal salts; inorganic metal salts such as zinc salts; and 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 salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate; and acetate, propionate Organic such as succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, ascorbate, etc. Acid salts and the like.

  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 combination of the following production methods and known synthesis methods.
Each of the compounds in the reaction formulas may form a salt, and examples of the salt include those similar to the salt of the compound represented by the formula (1). These reactions are merely examples, and the compounds of the present invention can be produced by other methods as appropriate based on the knowledge of those skilled in organic synthesis.

  In each of the production methods described below, even when the use of a protective group is not specifically specified, if a functional group requiring protection is present, the functional group is protected as necessary, After completion of the reaction or after performing a series of reactions, the desired product may be obtained by deprotection.

The introduction and elimination of the protecting group may be carried out by a method commonly used in organic synthetic chemistry (for example, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sunderland). , Inc., New York (1999)) or a method analogous thereto.
Examples of the amino-protecting group include tert-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl and the like.

[式中、環Ｑ^１、環Ｑ^２、Ｒ^ｂ、ｍ、およびｎは、前記〔１〕と同義であり；Ｒ^ａ１は同種または異種の１〜３個のハロゲン原子で置換されていてもよいＣ_１−６アルキルを表し；Ｘはハロゲンを表し；Ｐｒｏはアミノ基の保護基を表し；Ａはボロン酸またはボロン酸エステルを表す。] Manufacturing method 1
Among the compounds represented by the formula (1), the compounds represented by the formulas (1c) and (1d) are produced, for example, by the following method.

[In the formula, ring Q ¹ , ring Q ² , R ^b , m, and n have the same ^{meanings as in the} above [1]; and R ^a1 may be substituted with the same or different one to three halogen atoms. It represents 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 on compound (1-1) in a suitable inert solvent in the presence or absence of a base. It is manufactured by
As the compound (1-1), a commercially available compound or a compound produced by a known method (for example, WO 2007/047766) 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 and the like.
Examples of the inert solvent include toluene, dichloromethane and the like.
The reaction time is generally 5 minutes to 72 hours, preferably 30 minutes to 2 hours.
The reaction temperature is generally -78C to 200C, preferably 20C to 100C.

Step 1-2: Production Step of Compound (1d) Compound (1d) is obtained by coupling compound (1-2) with compound (1-3) in a suitable inert solvent in the presence of a palladium catalyst. 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 a compound produced by a known method (for example, International Publication WO2002 / 066470) can be used.
As the palladium catalyst, various palladium catalysts used in a usual manner can be used, and preferred is tetrakis (triphenylphosphine) palladium (0).
Examples of the base include potassium carbonate, cesium carbonate and the like.
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 the reaction can be performed, if necessary, under microwave irradiation.
The reaction time varies depending on the conditions such as the reaction temperature, the palladium catalyst used, the raw material, and the solvent, but is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.

Step 1-3: 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. You.
As the compound (1-4), those produced by Production Method 2 described later can be used.

Step 1-4: Step of Producing Compound (1c) Compound (1c) is prepared by converting the amino-protecting group Pro of compound (1-5) by 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: Step of Producing Compound (1d) Compound (1d) is also produced by reacting compound (1c) with various alkyl aldehydes in a suitable inert solvent in the presence of a reducing agent. .
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 generally 5 minutes to 48 hours, preferably 1 hour to 24 hours.
The reaction temperature is usually from -78C to 100C, preferably from 0C to 80C.

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 generally 5 minutes to 48 hours, preferably 1 hour to 24 hours.
The reaction temperature is usually from -78C to 100C, preferably from 0C to 80C.

[式中、Ｒ^ｂ、ｍ、およびｎは、前記〔１〕と同義であり；Ｘ^１はハロゲンまたはトリフラートを表し；Ｐｒｏはアミノ基の保護基を表し；Ａはボロン酸またはボロン酸エステルを表す。] Manufacturing method 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 in the above [1]; X ¹ represents a halogen or a triflate; Pro represents an amino-protecting group; A represents a boronic acid or a boronic ester; Represent. ]

Step 2-1: Step of producing compound (2-2) Compound (2-2) is produced by reacting compound (2-1) with a triflating agent in a suitable inert solvent in the presence of a base. Is done.
As the compound (2-1), a commercially available compound or a compound produced by a known method (for example, WO2012 / 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 usual manner can be used, and N-phenylbis (trifluoromethanesulfonimide) is preferable.
Examples of the inert solvent include THF and the like.
The reaction time is generally 5 minutes to 72 hours, preferably 30 minutes to 8 hours.
The reaction temperature is generally -78C to 200C, preferably -78C to 20C.

Step 2-2: Step of manufacturing compound (1-4) Compound (1-4) is obtained by coupling compound (2-2) with a boration reagent in a suitable inert solvent in the presence of a palladium catalyst. It is 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.
As the boration reagent, various boration reagents used in a usual manner can be used, and preferred is bis (pinacoleate) diborane.
As the palladium catalyst, various palladium catalysts used in a usual manner 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 the reaction can be performed, if necessary, under microwave irradiation.
The reaction time varies depending on the conditions such as the reaction temperature, the palladium catalyst used, the raw materials, and the solvent, but is usually 5 minutes to 72 hours, preferably 2 hours to 8 hours.

[式中、環Ｑ^１、環Ｑ^２、Ｒ^ｂ、およびｍは、前記〔１〕と同義であり；Ｒ^ａ１は同種または異種の１〜３個のハロゲン原子で置換されていてもよいＣ_１−６アルキルを表し；Ｘはハロゲンを表し；Ａはボロン酸またはボロン酸エステルを表す。] Manufacturing method 3
Among the compounds represented by the formula (1), the compound represented by the formula (1e) is produced, for example, by a method shown below.

[Wherein, ring Q ¹ , ring Q ² , R ^b and m have the same ^{meanings as in the} above [1]; R ^a1 is the same or different and may be substituted by 1 to 3 halogen atoms _1-6 alkyl; X is a halogen; a represents a boronic acid or boronic acid 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. You.
As the compound (3-1), a commercially available compound or a compound produced by a known method (for example, International Publication No. 2011/119518) can be used.

Step 3-2: Step of Producing Compound (1e) Compound (1e) was reacted with compound (3-2) and compound (3-3) in a suitable inert solvent to generate a quaternary ammonium cation. It is then produced by the action of a reducing agent.
Examples of the inert solvent include acetonitrile, THF, 1,4-dioxane and the like.
The reaction time of the alkylation step is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature in the alkylation step is from 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, and methanol.
The reaction time is generally 5 minutes to 48 hours, preferably 1 hour to 24 hours.
The reaction temperature is usually from -78C to 100C, preferably from -78C to 20C.

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

  Depending on the reaction conditions and the like, some of the starting compounds or intermediates in the above-mentioned production methods may exist in the form of a salt such as a hydrochloride, but they 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 free form, these are dissolved or suspended in an appropriate solvent and, for example, a base such as aqueous sodium hydrogen carbonate solution is used. It can be converted to a free form by neutralizing with, for example.

Some of the compounds represented by the formula (1) or pharmaceutically acceptable salts thereof include tautomers such as keto enols, isomers such as positional isomers, geometric isomers and optical isomers. May exist, but all possible isomers, including these, and mixtures of the isomers in any ratio are included in the present invention.
In addition, the optical isomer 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 above-mentioned production method. Further, an optically active substance can be used as a starting material.

  When it is desired to obtain a salt of the compound represented by the formula (1), when a salt of the compound represented by the formula (1) is obtained, the compound may be purified as it is. When it is 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 a base may be added to form a salt. The compound (1) or a pharmaceutically acceptable salt thereof may exist in the form of a solvate with water or various solvents, and such solvates are also included in the present invention.

  As used herein, “treatment-resistant schizophrenia” refers to schizophrenia in which sufficient improvement is not observed even when two or more antipsychotics are administered in a sufficient amount for a sufficient period of time. According to the Japanese schizophrenia drug guidelines, two or more antipsychotics are administered at chlorpromazine equivalent of 600 mg / day or more for 4 weeks or more, and the global assessment of functioning (GAF) score is 41 points or more. It is defined as having never reached a corresponding state.

Is effective for treatment resistant schizophrenia clozapine, D ₂ receptor antagonism, in addition to the 5-HT _2A receptor antagonistic action, are known to have antagonistic action against D ₁ receptor ( Non-patent document 2). Clozapine as well as D ₁ receptors, the compounds of the invention having antagonism D ₂ receptors, and 5-HT _2A receptor can be expected to be effective in treatment-resistant schizophrenia.

The compounds of the present invention because they exhibit antagonism against _{D 2} receptors and _{5-HT 2A} receptor, schizophrenia, bipolar disorder, autism, ADHD, depression, anxiety disorders, sleep disorders, It is also expected to be effective for behavioral and psychological symptoms of dementia (BPSD (Behavioral and Psychological Symptoms of Dementia)) and mental symptoms of neurodegenerative diseases.

Although there is no general animal model that mimics treatment-resistant schizophrenia, treatment of schizophrenia can be achieved by conducting a rat methamphetamine-induced hyperactivity test (Test Example 5), which is a model of a positive symptom of schizophrenia. It can be found medicine is considered possible to search for treatment-resistant schizophrenia also enabled drugs by confirming that it has an antagonistic action on D ₁ receptor and D ₂ receptor described above.

  After a drug compound is taken into a living body, it undergoes metabolism and changes its chemical structure, producing highly reactive intermediates, ie, reactive metabolites, and causing toxicity (agranulocytosis, hepatotoxicity, allergy, Tissue necrosis, mutagenicity, carcinogenicity, etc.). As one of the tests for simply evaluating the toxicity risk due to this reactive metabolite, there is a glutathione trapping test using dansylated glutathione (dGSH). The higher the value of the amount of dGSH covalently bound, the higher the above-mentioned toxicity risk when exposed systemically.

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

  In the present invention, the term "prevention" refers to an act of administering the active ingredient of the present invention to a healthy individual who has not developed a disease, for example, to prevent 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 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 an appropriate 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 pharmaceutically acceptable additives.
Additives include excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, and sweeteners, depending on the purpose. , Fragrance and the like can be used. Specifically, for example, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, stearin And magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc and the like.

  As the administration route, it is desirable to use the one that is most effective in the treatment. Oral administration or parenteral administration such as intravenous, application, inhalation, and eye drops can be mentioned, and oral administration is preferred. Examples of the administration form include a tablet and an injection, but a tablet is preferable. The dose and frequency of administration of these pharmaceutical compositions vary depending on the form of administration, the disease and symptoms of the patient, the age and weight of the patient, and cannot be specified unconditionally, but are generally effective for adults per day. Component amounts range 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, and particularly preferably from about 1 to about 300 mg. It can be administered once or several times a day, preferably once to three 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 drug such as aripyrazole, olanzapine, quetiapine, risperidone, blonanserin, perospirone, paliperidone, ziprasidone, asenapine, iloperidone, sertindole, lurasidone or a pharmaceutically acceptable salt thereof. Hereinafter, drugs that can be used in combination with the compound of the present invention are abbreviated as concomitant drugs.

  The administration period of the compound of the present invention and the concomitant drug is not limited, and they may be administered to a subject at the same time or may be administered at a time interval. Further, the compound of the present invention and a concomitant drug may be used as a mixture. The dose of the concomitant drug can be appropriately determined 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. In addition, for the purpose of suppressing the side effects, it can be used in combination with a drug (concomitant drug) such as an antiemetic, a sleep inducer, and an anticonvulsant.

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

In order to simplify the description of the specification, the following abbreviations may be used in Reference Examples, Examples, and Test Examples.
Me: methyl Et: ethyl DMF: N, N-dimethylformamide DMSO: dimethylsulfoxide THF: tetrahydrofuran TFA: trifluoroacetic acid

  As symbols used for NMR, s is a singlet, d is a doublet, dd is a doublet of a doublet, t is a triplet, td is a doublet of a triplet, q is a quadruple, m Is a multiplet, br is a wide, brs is a wide singlet, brm is a wide multiplet, and J is a coupling constant.

High-performance liquid chromatography mass spectrometer; LCMS measurement conditions are as follows, and the observed mass spectrometry value [MS (m / z)] is expressed as [M + H] ⁺ or [MH] ⁻ , and the retention time Is denoted by Rt (minutes).
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: A solution 0.05% formic acid aqueous solution B solution Acetonitrile time program:
Step time (min)
1 0.0-1.3 Solution A: Solution B = 90: 10 to 1:99
2 1.3-1.5 Solution A: Solution B = 1: 99
3 1.5-2.0 Solution A: Solution B = 90: 10

Measurement conditions (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: 0.80 mL / min
Measurement wavelength: 254 nm
Moving layer: A solution 0.05% formic acid aqueous solution B solution Acetonitrile time program:
Step time (min)
1 0.0-1.3 Solution A: Solution B = 90: 10 to 5:95
2 1.3-1.5 Solution A: Solution B = 90: 10

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

ａ）２−［（４−クロロ−２−ニトロフェニル）アミノ］−５−フルオロ安息香酸（化合物Ｗ１）の製造
４−クロロ−１−フルオロ−２−ニトロベンゼン（５．０ｇ）のＤＭＦ（２９ｍＬ）溶液に、２−アミノ−５−フルオロ安息香酸（４．４ｇ）および炭酸セシウム（２８ｇ）を加え、１２０℃にて一晩撹拌した。反応液に０℃にて水を加え、１ｍｏｌ／Ｌの塩酸でｐＨ５に調整した後、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。乾燥後の有機層の溶媒を減圧留去することにより、化合物Ｗ１（８．８ｇ）を得た。
LC-MS ([M+H]⁺/Rt (min)): 311/1.18 測定条件（１） 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) DMF (29 mL) of 4-chloro-1-fluoro-2-nitrobenzene (5.0 g) 2-Amino-5-fluorobenzoic acid (4.4 g) and cesium carbonate (28 g) were added to the solution, and the mixture was stirred at 120 ° C overnight. Water was added to the reaction solution at 0 ° C., adjusted to pH 5 with 1 mol / L hydrochloric acid, and extracted with ethyl acetate. The obtained organic layer was washed with a saturated saline solution and dried over sodium sulfate. The solvent of the dried organic layer 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) 2 - [(2-Amino-4-chlorophenyl) _{amino] -5- THF / MeOH / H 2} O fluorobenzoic acid (Compound W2) of Compound W1 (8.8g) (3: 2 : 1) (300 mL), ammonium chloride (15 g) and iron (16 g) were added to the solution, and the mixture was stirred at 80 ° C. for 2 hours. After cooling, the reaction solution was filtered through celite, washed with methanol, and then the solvent was distilled off under reduced pressure. After the obtained residue was subjected to liquid separation extraction with ethyl acetate-water, the obtained organic layer was washed with saturated saline. 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) (143 mL), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (6.0 g) and 1-hydroxybenzotriazole (4.2 g) were added to the solution, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off 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)

上表中のＬＣ−ＭＳは、測定条件（１）を用いて測定した。


















Reference Examples 2 to 8
According to the method described in Reference Example 1, and using the corresponding starting compounds, the compounds shown in the following table were obtained.

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

ａ）ｔｅｒｔ−ブチル ６−メチル−４−｛［（トリフルオロメチル）スルフォニル］オキシ｝−３，６−ジヒドロピリジン−１（２Ｈ）−カルボキシレート及びｔｅｒｔ−ブチル ２−メチル−４−｛［（トリフルオロメチル）スルフォニル］オキシ｝−３，６−ジヒドロピリジン−１（２Ｈ）−カルボキシレート（物質Ａ）の製造
１−（ｔｅｒｔ−ブトキシカルボニル）−２−メチルピペリジン−４−オン（１．１ｇ）のＴＨＦ溶液（１０ｍＬ）に−７８℃で１．５ｍｏｌ／Ｌのリチウムジイソプロアミド−ＴＨＦ溶液（４．０ｍＬ）を滴下した。−７８℃で１０分間撹拌した後、Ｎ−フェニルビス（トリフルオロメタンスルホンイミド）（２．１ｇ）のＴＨＦ溶液（５ｍＬ）を滴下した。室温で４時間撹拌した後、０℃にて飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。乾燥後の有機層の溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム／メタノール）及びＮＨ_２シリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン／酢酸エチル）で精製することにより物質Ａ（１．７ｇ、異性体の混合物）を得た。
¹H-NMR (400 MHz, CDCl₃)δ: 6.44, 6.36(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 (s, 3H, J = 6.8 Hz, isomer ratio=1:1). 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 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 solution of ammonium chloride was added at 0 ° C, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated saline solution and dried over sodium sulfate. After evaporating the solvent of the dried organic layer under reduced pressure, the substance A (purified by silica gel column chromatography (elution solvent; chloroform / methanol) and NH ₂ silica gel column chromatography (elution solvent: hexane / ethyl acetate) was purified. 1.7 g, a mixture of isomers) were obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.44, 6.36 (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 (s, 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) Preparation of 9) In a THF solution (50 mL) of substance A (1.7 g), bis (pinacoleate) diborane (1.4 g), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride (0 g) were added. .73 mmol) and potassium acetate (1.5 g). 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 a saturated saline solution and dried over sodium sulfate. After evaporating the solvent of the dried organic layer under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to obtain the compound of Reference Example 9 (1.2 g, mixture of isomers). 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 (s, 3H, J = 6.8Hz, isomer ratio = 1: 1).

上表中のＬＣ−ＭＳは、測定条件（１）を用いて測定した。














Reference Examples 10 to 12
Compounds (mixtures of isomers) shown in the following table were obtained according to the method described in Reference Example 9 and using the corresponding starting compounds.

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

上表中のＬＣ−ＭＳは、測定条件（２）を用いて測定した。













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

LC-MS in the above table was measured using the 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) was used. ) And trifluoromethanesulfonic anhydride (2.4 mL) were added, and the mixture was stirred at 0 ° C for 1 hour. Aqueous sodium bicarbonate was added to the reaction solution at 0 ° C., and the mixture was extracted with chloroform. The obtained organic layer was washed with saturated saline and dried over magnesium sulfate. After evaporating the solvent of the dried organic layer under reduced pressure, 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) A solution of compound W3 (2.0 g) in toluene (68 mL) was treated with 2-amino- Methyl 5- (trifluoromethyl) benzoate (1.5 g), potassium carbonate (0.95 g), triphenylphosphine (0.36 g) and tetrakis (triphenylphosphine) palladium (0) (0.79 g) were added. The mixture was stirred under reflux for 2 hours. 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 saline and dried over magnesium sulfate. After evaporating the solvent of the dried organic layer under reduced pressure, 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) Methyl 2 - [(2-amino-4-methylphenyl) _{amino] -5- (THF / MeOH / H} 2 O (3 for the preparation of compound of trifluoromethyl) benzoate (Compound W5) W4 (2.0 g) : 2: 1) (30 mL), ammonium chloride (3.6 g) and iron (1.9 g) were added, and the mixture was stirred with heating under reflux for 1 hour. After cooling, the reaction solution was filtered through celite and washed with ethyl acetate. After separating and extracting the obtained filtrate with ethyl acetate-water, the organic layer was washed with saturated saline. 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) solution, lithium hydroxide (1.6 g) was added, and the mixture was stirred under reflux for 2 hours. After cooling the reaction solution, 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 a saturated saline solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 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 DMF of compound W6 (1.6 g) ( 23 mL) solution, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.4 g) and 1-hydroxybenzotriazole (1.0 g) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over magnesium sulfate. After evaporating the solvent of the dried organic layer under reduced pressure, the residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate) to obtain the title compound (0.41 g).
LC-MS ([M + H] ⁺ / Rt (min)): 293 / 0.89 Measurement conditions (2)

上表中のＬＣ−ＭＳは、測定条件（２）を用いて測定した。











Reference Examples 31 and 32
According to the method described in Reference Example 30 and using the corresponding starting compounds, the compounds shown in the following table were obtained.

LC-MS in the above table was measured using the 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, methyl 2-amino-5-cyanobenzoate (0.50 g) and cesium carbonate (2.8 g) were added, and the mixture was stirred at 120 ° C for 4 hours. After cooling the reaction solution, 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 a saturated saline solution and dried over sodium sulfate. The solvent of the dried organic layer was distilled off under reduced pressure to obtain the title compound (0.90 g) as a crude product.
LC-MS ([MH] ^- / Rt (min)): 316 / 0.87 Measurement conditions (2)

b) 2 - [(2-Amino-4-chlorophenyl) _{amino] -5- THF / MeOH / H 2} O of cyanobenzoic acid (compound W8) of Compound W7 (0.90g) (3: 2 : 1) (30 mL), ammonium chloride (1.5 g) and iron (0.73 g) were added to the solution, and the mixture was stirred under reflux for 1 hour. After cooling, the reaction solution was filtered through celite and washed with ethyl acetate. After separating and extracting the obtained filtrate with ethyl acetate-water, the organic layer was washed with saturated saline. 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 A solution of compound W8 (0.82 g) in DMF (14 mL) To the mixture, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.60 g) and 1-hydroxybenzotriazole (0.42 g) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off 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)

ａ）８，１１−ジクロロ−２−フルオロ−５Ｈ−ジベンゾ［ｂ，ｅ］［１，４］ジアゼピン（化合物Ｗ９）の製造
参考例１の化合物（１．０ｇ）のトルエン（２０ｍＬ）溶液にＮ，Ｎ−ジメチルアニリン（２．３ｇ）およびオキシ塩化リン（１．８ｇ）を加えた。９５℃で２時間撹拌した後、冷却した。反応液にＴＨＦ、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。乾燥後の有機層の溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン／酢酸エチル）にてＮ，Ｎ−ジメチルアニリンを除去し、化合物Ｗ９（０．９ｇ）を得た。 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) A solution of the compound of Reference Example 1 (1.0 g) in toluene (20 mL) was added with N. , N-dimethylaniline (2.3 g) and phosphorus oxychloride (1.8 g) were added. After stirring at 95 ° C. for 2 hours, the mixture was cooled. THF and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated saline solution and dried over sodium sulfate. After evaporating the solvent of the dried organic layer 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 (Example Preparation of 1) 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane was added to 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). After stirring at 75 ° C. for 1 hour, the mixture was cooled. Water was added to the reaction solution, which was extracted with ethyl acetate. The obtained organic layer was washed with a saturated saline solution and dried over sodium sulfate. After evaporating the solvent of the dried organic layer 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).
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).

上表中のＬＣ−ＭＳは、測定条件（１）を用いて測定した。







Examples 2 to 6
According to the method described in Example 1, the compounds of Examples 2 to 6 were obtained using the corresponding reference example compound and starting compound.

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

ａ）ｔｅｒｔ−ブチル ４−（８−クロロ−２−フルオロ−５Ｈ−ジベンゾ［ｂ，e］［１，４］ジアゼピン−１１−イル）−６−メチル−３，６−ジヒドロピリジン−１（２Ｈ）−カルボキシレート及びｔｅｒｔ−ブチル ４−（８−クロロ−２−フルオロ−５Ｈ−ジベンゾ［ｂ，e］［１，４］ジアゼピン−１１−イル）−２−メチル−３，６−ジヒドロピリジン−１（２Ｈ）−カルボキシレート（物質Ｂ）の製造
化合物Ｗ９（１．１ｇ）のＴＨＦ／水（４／１）（５０ｍＬ）溶液に、参考例９の化合物（異性体の混合物）（１．３ｇ）、炭酸カリウム（１．７ｇ）及びテトラキス（トリフェニルホスフィン）パラジウム（０）（０．９２ｇ）を加えた。７５℃で１時間撹拌した後冷却し、反応液に水を加え酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。乾燥後の有機層の溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン／酢酸エチル）で精製することにより、物質Ｂ（１．０ｇ、異性体の混合物）を得た。
LC-MS ([M+H]^＋/Rt (min))： 442/1.45 測定条件（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 ( Preparation of 2H) -carboxylate (substance B) In a solution of compound W9 (1.1 g) in THF / water (4/1) (50 mL), 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. After stirring at 75 ° C. for 1 hour and cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated saline solution and dried over sodium sulfate. After evaporating the solvent of the dried organic layer under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to obtain substance B (1.0 g, a 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 (Example 7) and 8-chloro-2-fluoro-11- (2-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, e] [1,4] diazepine (implemented Preparation of Example 8) To a solution of substance B (0.17 g) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the ice-cooled reaction solution, and the mixture was extracted with chloroform. The obtained organic layer was washed with a saturated saline solution and dried over sodium sulfate. After evaporating the solvent of the dried organic layer under reduced pressure, the obtained residue was subjected to reverse phase purification using an ODS column (0.05% trifluoroacetic acid aqueous solution: acetonitrile), and TFA was separated by chloroform-saturated aqueous sodium hydrogen carbonate. By making the salt free, 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).

上表中のＬＣ−ＭＳは、測定条件（１）を用いて測定した。
Examples 9 to 16
The compounds of Examples 9 to 16 were obtained according to the methods described in Example 7 and Example 8, using the corresponding reference example compounds and starting compounds.

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

実施例７および実施例８（１：１）の混合物の（１．０ｇ）メタノール（２０ｍＬ）溶液に、３７％ホルムアルデヒド液（０．７３ｇ）および硫酸マグネシウム（５．０ｇ）を加え、５０℃で１時間撹拌した。反応液を氷冷し、水素化ホウ素ナトリウム（０．６８ｇ）を徐々に加えた。室温で１時間撹拌し、セライトろ過により固形物を取り除いた。ろ液に水を加え、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。乾燥後の有機層の溶媒を減圧留去した後、ＮＨ_２シリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン／酢酸エチル）で精製することにより、実施例１７の化合物（０．２０ｇ）および実施例１８の化合物（０．２０ｇ）を得た。
８−クロロ−１１−（１，６−ジメチル−１，２，３，６−テトラヒドロピリジン−４−イル）−２−フルオロ−５Ｈ−ジベンゾ［ｂ，e］［１，４］ジアゼピン（実施例１７）：
¹H-NMR (400 MHz, CDCl₃)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 測定条件（１）
８−クロロ−１１−（１，２−ジメチル−１，２，３，６−テトラヒドロピリジン−４−イル）−２−フルオロ−５Ｈ−ジベンゾ［ｂ，e］［１，４］ジアゼピン（実施例１８）：
¹H-NMR (400 MHz, CDCl₃)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 測定条件（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 (Example 17)
8-chloro-11- (1,2-dimethyl-1,2,3,6-tetrahydropyridin-4-yl) -2-fluoro-5H-dibenzo [b, e] [1,4] diazepine (Example 18)

To a solution of the mixture of Example 7 and Example 8 (1: 1) in (1.0 g) in methanol (20 mL) was added a 37% formaldehyde solution (0.73 g) and magnesium sulfate (5.0 g). Stir for 1 hour. The reaction solution was cooled with ice, and sodium borohydride (0.68 g) was gradually added. The mixture was stirred at room temperature for 1 hour, and solid matter was removed by celite filtration. Water was added to the filtrate and extracted with ethyl acetate. The obtained organic layer was washed with a saturated saline solution and dried over sodium sulfate. After evaporating the solvent of the dried organic layer under reduced pressure, the residue was purified by NH ₂ silica gel column chromatography (eluent: hexane / ethyl acetate) to give the compound of Example 17 (0.20 g) and the compound of Example 18. The 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 (Example 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 (Example 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)

上表中のＬＣ−ＭＳは、測定条件（１）を用いて測定した。 Examples 19 to 21
The compounds of Examples 19 to 21 were obtained according to the methods described in Example 17 and Example 18 using the corresponding reference example compounds and starting compounds.

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

ａ）８−クロロ−２−フルオロ−１１−（ピリジン−４−イル）−５Ｈ−ジベンゾ［ｂ，ｅ］［１，４］ジアゼピン（Ｗ１０）の製造
化合物Ｗ９（１０７ｍｇ）のＴＨＦ／水（４／１）（５ｍＬ）溶液に、ピリジン−４−ボロン酸（９４ｍｇ）、炭酸カリウム（０．１６ｇ）及びテトラキス（トリフェニルホスフィン）パラジウム（０）（８８ｍｇ）を加えた。７５℃で１時間撹拌した後。氷冷した反応液に水を加え、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。乾燥後の有機層の溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム／メタノール）及びＮＨ_２シリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン／酢酸エチル）で精製することにより、化合物Ｗ１０（４５ｍｇ）を得た。
LC-MS ([M+H]⁺/Rt (min)): 342/0.73 測定条件（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) (5 mL) solution, pyridine-4-boronic acid (94 mg), potassium carbonate (0.16 g) and tetrakis (triphenylphosphine) palladium (0) (88 mg) were added. After stirring at 75 ° C. for 1 hour. Water was added to the ice-cooled reaction solution, and extracted with ethyl acetate. The obtained organic layer was washed with a saturated saline solution and dried over sodium sulfate. After evaporating the solvent of the dried organic layer under reduced pressure, the compound W10 was purified by silica gel column chromatography (elution solvent: chloroform / methanol) and NH ₂ silica gel column chromatography (elution solvent: hexane / ethyl acetate). (45 mg) was obtained.
LC-MS ([M + H] ⁺ / Rt (min)): 342 / 0.73 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 (Example Preparation of 22) To a solution of compound W10 (15 mg) in acetonitrile (0.42 mL) was added methyl iodide (59 mg). 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, 0.42 mmol) was added at 0 ° C. After stirring at room temperature for 1 hour, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated saline solution and dried over sodium sulfate. After evaporating the solvent of the dried organic layer 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.

上表中のＬＣ−ＭＳは、測定条件（１）を用いて測定した。 Examples 23 to 31
The compounds of Examples 23 to 31 were obtained according to the method described in Example 22 and using the corresponding compounds of Reference Examples and starting compounds.

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

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

Test Examples The pharmacological test results of the compound of the present invention will be shown below, and the pharmacological action of the compound will be 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 2A} receptor antagonist activity was measured using the intracellular calcium concentration as an index. After transiently expressing aequorin, Gα16 protein, and each receptor in CHO-K1 cells (Chinese hamster ovary), the cells were seeded in a 384-well plate and cultured overnight at 37 ° C. in a CO 2 incubator. After the addition of coelenterazine, a DMSO suspension of the compound of the present invention was added using FDSS (manufactured by Hamamatsu Photonics), and then dopamine (final concentration 100 nmol / L) or serotonin (final concentration 30 nmol / L) was added to emit light. The change in volume 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 of wells to which only DMSO was added was 100% inhibited and the luminescence of wells to which only dopamine or serotonin was added was 0% inhibition. . In the table below, the concentration is described, and the inhibition rate at the described concentration is shown (for example, when 58＠0.1 μmol / L, the inhibition rate at 0.1 μmol / L is shown). 58%). 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 a reactive metabolite reacting with dansylated glutathione (dGSH) was detected and quantified from the generated metabolite. 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. 7.6 mL of potassium phosphate buffer (500 mmol / L, pH 7.4), 1.9 mL of human liver microsome (manufactured by Xenotech, 20 mg protein / mL), and 1.27 mL of pure water were mixed to prepare a microsome solution. . 0.67 mL of pure water was added to 3.78 mL of the microsome solution to prepare a microsome (dGSH (-)) solution. 1.14 mL of a dGSH solution (20 mmol / L) was added to 6.48 mL of the 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 termination 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 the mixture was dispensed into a 96-well plate at 50 μL per 6 wells. The above 6 wells were divided into 3 groups of 2 wells, which were referred to as “reaction group”, “unreacted group”, and “dGSH-free group”, respectively. The microsome (dGSH (+)) solution was added to the “reaction group” and the “unreacted group”, and 50 μL of the microsome (dGSH (−)) was added to the “dGSH non-addition group”. The cofactor solution was added to the “reaction group” and the “dGSH-free group”, and 50 μL of pure water was added to the “unreacted group”. After incubating at 37 ° C. for 60 minutes, the reaction was stopped by adding 450 μL of a reaction stop solution. Pure water was added to the “reaction group” and “dGSH-free group”, and the cofactor solution was added to the “unreacted group” at 50 μL. went. The supernatant was collected on another plate and used for analysis.

(analysis)
Using a fluorescence detection UPLC system (manufactured by Waters), the metabolite-dGSH conjugate concentration of the “reaction group” and the dGSH conjugate concentration of the “unreacted group” were measured under the following conditions.
Column: Waters ACQUITY UPLC BEHC18 1.7 μm 2.1 × 10 mm
Elution solvent: A, 0.2% formic acid / 40% methanol; B, 0.2% formic acid / methanol gradient: B, 0% (0 min) → 83.3% (9.33 min) → 83.3% (10.63 min) → 0% (10.64 min) → 0% (13 min)
Since the fluorescence intensity changes depending on the composition of the organic solvent, the correction was performed with the composition of the organic solvent at the time of elution.

ND: Not detected(検出限界未満)










The results of the metabolite-dGSH conjugate concentration of the “reaction group” are shown in the table below.

ND: Not detected (below detection limit)

ND: Not detected(検出限界未満) The results of the concentration of the dGSH-bound compound in the “unreacted group” are shown in the table below.

ND: Not detected (below detection limit)

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

Test Example 4: Rat brain migration test In this test, the brain migration of the compound of the present invention can be evaluated. To a 7-week-old SD rat, the compound of the present invention was subcutaneously administered with a 0.01 mol / L aqueous hydrochloric acid solution, and one hour after the administration, plasma and brain were collected, and plasma and brain were obtained by LC-MS. The drug concentration was measured.
The serum and brain protein binding rates of the compound of the present invention were measured using an equilibrium dialysis method.
By applying the plasma and brain compound concentrations and the serum and brain protein binding ratios obtained by the above test to the following formula, Kp, uu, and brain (brain / plasma unbound drug concentration ratio) are calculated. Can be calculated.
Kp, uu, brain = (compound concentration in brain × (100−protein binding ratio in brain (%)) / 100) / (plasma compound concentration × (100−protein binding ratio in serum (%)) / 100)
The results are shown in the table below.

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

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

INDUSTRIAL APPLICABILITY The compound of the present invention has an antagonistic effect on dopamine D ₁ receptor, dopamine D ₂ receptor and serotonin 5-HT _2A receptor, and thus is useful as a therapeutic and / or prophylactic agent for central nervous system diseases. is there.

Claims (20)

Equation (1):

[In the formula, ring Q ¹ represents an optionally substituted benzene ring or an optionally substituted pyridine ring;
Ring Q ² are represent a benzene ring which may be substituted, or a pyridine ring optionally substituted;
R ^a represents a hydrogen atom or C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms;
n represents 0, 1 or 2;
m represents 1, 2, 3 or 4;
R ^b independently represents a hydrogen atom, a halogen atom, or a C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types, when there are a plurality of R ^b. A compound or a pharmaceutically acceptable salt thereof. Ring Q ¹ is a benzene ring or a pyridine ring (the benzene ring or the pyridine ring may be a halogen atom, a cyano, a C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms, Selected from the group consisting of hetero-C _1-6 alkoxy optionally substituted with 1 to 3 halogen atoms, and amino optionally substituted with 1 or 2 homo- or hetero C _1-6 alkyl. Which may be substituted with the same or different 1 to 4 groups described above);
Ring Q ² is a benzene ring or a pyridine ring (the benzene ring or the pyridine ring may be a halogen atom, cyano, C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms, the same type or Selected from the group consisting of hetero-C _1-6 alkoxy optionally substituted with 1 to 3 halogen atoms, and amino optionally substituted with 1 or 2 homo- or hetero C _1-6 alkyl. Or a pharmaceutically acceptable salt thereof, wherein the compound may be substituted with 1 to 4 same or different groups. 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 type, and 1 to 3 of the same or different type; May be substituted with 1 to 4 same or different groups selected from the group consisting of C _1-6 alkoxy optionally substituted with a halogen atom);
Ring Q ² is a benzene ring (the ring is a halogen atom, cyano, C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms, and 1 to 3 same or different Or the same or different 1 to 4 groups selected from the group consisting of C _1-6 alkoxy optionally substituted with a halogen atom). 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. Any one of claims 1 to 4, wherein, when R ^b is plural, each is independently a halogen atom or C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different kind. Or a pharmaceutically acceptable salt thereof. Formula (1a):

[Wherein, ^Ra represents a hydrogen atom or C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms;
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, a cyano, 1 to 3 halogen atoms of the same or different kind in an optionally substituted C _1-6 alkyl, same or 1 to 3 halogen atoms which may be substituted with optionally C _1-6 alkoxy heterologous or of homologous or heterologous 1-2, C _{1- Represents} an amino optionally substituted with ₆ alkyl;
R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ each independently represent a hydrogen atom, a halogen atom, or a C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms. The compound according to claim 1, which is represented by the following formula: or a pharmaceutically acceptable salt thereof. 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 the same or different 1 to 3 halogen atoms, A 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 meanings as in claim 6], or a pharmaceutically acceptable compound thereof. Salt. The compound according to any one of claims 6 to 8, wherein R ¹³ is C _1-6 alkyl, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 6 to 8, wherein R ¹³ is methyl, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 6 to 10, wherein R ¹⁴ is a hydrogen atom, or a pharmaceutically acceptable salt thereof. Formula (1b-1):

[Wherein, R ^a , R ² and R ⁷ have the same meaning as in claim 6], or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 12, wherein R ^a is C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms, or a pharmaceutically acceptable salt thereof. Acceptable salts. The compound according to any one of claims 1 to 12, wherein ^Ra is methyl, or a pharmaceutically acceptable salt thereof. R ² and R ⁷ are each independently a hydrogen atom, a halogen atom, a C _1-6 alkyl _optionally substituted with the same or different 1 to 3 halogen atoms, 1 to 3 same or different 1 is a halogen a C _1-6 alkoxy optionally substituted by atoms or cyano, a compound or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 6-14. At least one of R ² and R ⁷ may be substituted with a halogen atom, cyano, C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different type, or C _1-6 alkyl of the same or different type; a halogen atoms C _1-6 alkoxy optionally substituted by a compound or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 6-14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the following compound group:
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-lahydropyridin-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,
11-[(6S) -1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -2-ethoxy-8-methyl-5H-dibenzo [b, e] [1,4] diazepine, and 2-ethoxy-8-methyl -11 - [(6S) -6- methyl ^-1- (2 _{H 3)} methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H- dibenzo [B, e] [1,4] diazepine.   A medicament comprising the compound according to any one of claims 1 to 17 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 17 or a pharmaceutically acceptable salt thereof as an active ingredient.   If the central nervous system disease is schizophrenia, bipolar disorder, autism, ADHD, depression, anxiety disorder, sleep disorder, dementia behavioral and psychological symptoms (BPSD) or neurodegeneration 20. The therapeutic agent according to claim 19, which is a psychiatric symptom of the disease.