HK1179878B - Composition containing tetracyclic compound - Google Patents

Description

Compositions containing tetracyclic compounds

Technical Field

The present invention relates to a composition of a tetracyclic compound having an ALK inhibitory activity, particularly to a composition for oral administration and the like.

Background

Anaplastic Lymphoma Kinase (ALK) is one of receptor type tyrosine kinases belonging to the insulin receptor family (non-patent document 1, non-patent document 2), and it has been reported that genetic abnormality of ALK leads to the production of abnormal Kinase fused with other genes.

As diseases accompanied by abnormality of ALK, for example, cancer metastasis (non-patent document 1, patent document 1), depression, cognitive dysfunction (non-patent document 2), and the like are known, and provision of an ALK inhibitor provides an effective therapeutic and prophylactic agent for these diseases.

The development of the above-mentioned pharmaceutical preparations as orally administrable dosage forms is desired, but the development of orally administrable preparations depends on the level of bioavailability of the drug. One of the factors affecting bioavailability is water solubility of the drug, and generally, when a poorly water-soluble or insoluble compound is orally administered, bioavailability is low. It is also important to improve the bioavailability and oral absorbability of the active ingredients to stably exert the drug effects of the active ingredients. Patent document 2 describes a composition containing a poorly water-soluble component such as a steroid, sodium lauryl sulfate, and an organic polymer, and wet granulating the mixture in the presence of water in order to improve the solubility and oral absorbability of the poorly water-soluble substance.

Hitherto, as ALK inhibitory substances, for example, tricyclic compounds (patent document 2) and the like have been reported. However, a tetracyclic compound represented by the following formula (I) or a salt thereof is not disclosed in any literature.

In addition, as a tetracyclic substance, ellipticine derivatives are known (non-patent document 3). The tetracyclic compounds used in the present invention have excellent ALK inhibitory activity, but further studies have been required for the development of orally administrable dosage forms due to their poorly water-soluble or insoluble nature.

Documents of the prior art

Patent document

Patent document 1: JP2009100783 (A)

Patent document 2: japanese laid-open patent publication No. 2008-280352

Non-patent document

Non-patent document 1: nature, volume 448, page 561 and 566, 2007

Non-patent document 2: neuropsychopharmacology, volume 33, page 685-

Non-patent document 3: current medical Chemistry: Anti-Cancer Agents, volume 4, No. 2, pages 149-172, 2004.

Disclosure of Invention

Technical problem to be solved by the invention

The present inventors have made extensive studies to solve the above problems, and as a result, have found that: the solubility of the poorly water-soluble or insoluble substance of formula (I) can be unexpectedly significantly improved by allowing the substance to coexist with a dissolution aid. The present inventors have further studied based on this finding, and have completed the present invention.

Means for solving the problems

Namely, the present invention is as follows.

A composition comprising a substance represented by the formula (I), a pharmaceutically acceptable carrier, and a dissolution aid,

[ solution 1]

In the formula (I), the compound is shown in the specification,

A¹、A²、A³、A⁴、A⁷、A⁸、A⁹and A¹⁰All being C, or A²、A³、A⁴、A⁷、A⁸Or A⁹Any one of the N is N (wherein, when the N is N, no substituent is contained), and the rest is C;

A⁵selected from NR⁵、O、S；

R¹And R¹⁰Each independently represents [ 1] a hydrogen atom, [ 2] a cyano group, [ 3] a halogen atom or [ 4] a 4-to 10-membered heterocycloalkyl group which may be substituted with a 4-to 10-membered heterocycloalkyl group;

R²selected from:

(1) a hydrogen atom, and a nitrogen atom,

（2）C_1-8an alkyl group, a carboxyl group,

（3）C_2-8an alkenyl group, which is a radical of an alkenyl group,

（4）C_2-8an alkynyl group,

(5) the cyano group(s),

(6) a halogen atom,

(7) can be covered with C_1-8Alkylsulfonyl substituted (C)_1-8Alkyl radical)_m2-an amino group,

m 2: 0 to 2, and

(8) a nitro group;

R³selected from:

(1) a hydrogen atom, and a nitrogen atom,

(2) can be substituted by [ 1] halogen atom, [ 2] hydroxy or [ 3] C_1-8Alkoxy-substituted C_1-8An alkyl group, a carboxyl group,

（3）C_6-10an aryl group, a heteroaryl group,

(4) the cyano group(s),

(5) can be covered with C_6-10Aryl substituted C_1-8An alkanoyl group, a carbonyl group,

(6) can be substituted by more than 1R^3ASubstituted (C)_1-8Alkyl radical)_m3a-an amino-carbonyl group,

R^3A：［1］C_6-10aryl, [ 2] C_1-8Alkoxy group, [ 3] 5-to 14-membered heteroaryl group, or [ 4] C_6-10An arylsulfonyl group having a structure represented by the general formula,

m3a：0～2，

(7) a hydroxyl carbonyl group, a carboxyl group,

(8) can be substituted by [ 1] hydroxy or [ 2] C_1-8Alkoxy-substituted C_1-8An alkoxycarbonyl group, a carbonyl group,

(9) a halogen atom,

(10) can be covered with C_6-10Aryl substituted (C)_1-8Alkyl radical)_m3b-an amino group,

m3b：0～2，

(11) can be covered by [ 1] C_6-10Aryl or [ 2] C_6-10Aryloxy substituted C_1-8Alkylcarbonyl (C)_0-8Alkyl) amino group(s),

(12) can be covered with C_1-8Alkyl substituted C_6-10Arylcarbonyl (C)_0-8Alkyl) amino, C_1-8The alkyl group may be substituted with a halogen atom,

(13) can be covered with C_6-10Aryl substituted (C)_1-8Alkyl radical)_m3c-aminocarbonyl (C)_0-8Alkyl) amino group(s),

m3c：0～2，

(14) the nitro group(s),

(15) a hydroxyl group(s),

(16) can be substituted by more than 1R^3BSubstituted C_1-8An alkoxy group,

R^3B: [1] hydroxy group, [ 2] C_1-8Alkoxy group, [ 3] C_6-10Aryl radical (C)_0-8Alkyl) aminocarbonyl, [ 4] (C)_1-8Alkyl radical)_m3d-Amino group, or [ 5] halogen atom,

m3d：0～2，

(17) a 4-to 10-membered heterocycloalkyl group,

(18) a 5-to 14-membered heteroaryloxy group,

(19) can be covered with C_6-10Aryl substituted (C)_1-8Alkyl radical)_m3e-aminocarbonyloxy

m3e：0～2，

(20) A 4-to 10-membered nitrogen-containing heterocycloalkyl carbonyl group,

(21) c which may be substituted by halogen atoms_1-8An alkyl-sulfonyloxy group, which is a sulfonyl group,

（22）C_1-8an alkylthio group is a group of one or more,

(23) can be covered with C_6-10Aryl substituted C_1-8An alkyl sulfonyl group, a carboxyl group,

(24) can be covered with C_1-8Alkyl-substituted 5-to 14-membered heteroarylC of the_1-8Alkyl groups may be substituted by C_1-8The substitution of alkoxy groups is carried out,

(25) can be covered with C_1-8Alkoxy-substituted C_1-8Alkoxycarbonyl (C)_0-8Alkyl) amino group(s),

(26) can be covered with C_1-8Alkyl substituted C_6-10Aryloxy carbonyl group (C)_0-8Alkyl) amino, C_1-8The alkyl group may be substituted with a halogen atom,

(27) can be substituted by more than 1R^3CSubstituted C_6-10Aryl radical (C)_0-8Alkyl) aminocarbonyl (C)_0-8Alkyl) amino group(s),

R^3C: [1] c which may be substituted by halogen atoms_1-8Alkyl, or [ 2] C_1-8An alkoxy group,

（28）C_3-8cycloalkyl (C)_0-8Alkyl) aminocarbonyloxy, and

(29) can be selected from [ 1] C_1-8Alkyl and [ 2] C_1-8C substituted by a substituent of the group consisting of alkoxy_6-10Aryl radical (C)_0-8Alkyl) aminocarbonyloxy;

R⁴selected from:

(1) a hydrogen atom, and a nitrogen atom,

(2) c which may be substituted by halogen atoms_1-8An alkyl group, a carboxyl group,

（3）C_2-8an alkenyl group, which is a radical of an alkenyl group,

（4）C_2-8an alkynyl group,

（5）C_3-8a cycloalkyl group,

(6) the cyano group(s),

(7) the amino-carbonyl group of the amino-carbonyl group,

（8）（C_1-8alkyl radical)_m4a-an amino-carbonyl group,

m4a：1～2，

(9) a hydroxyl carbonyl group, a carboxyl group,

（10）C_1-8an alkoxycarbonyl group, a carbonyl group,

(11) a halogen atom,

（12）（C_1-8alkyl radical)_m4b-an amino group,

m4b：0～2，

(13) a hydroxyl group, and

(14) c which may be substituted by hydroxy_1-8An alkoxy group;

R⁵selected from:

(1) a hydrogen atom, and a nitrogen atom,

(2) can be substituted by more than 1R^5ASubstituted C_1-8An alkyl group, a carboxyl group,

R^5A: [1] hydroxycarbonyl, [ 2] C_1-8Alkoxycarbonyl, [ 3] hydroxy, [ 4] C_1-8Alkoxy group, [ 5] (C)_1-8Alkyl radical)_m5-amino, [ 6] C_6-10Aryl group, or [ 7] C_1-8An alkylthio group is a group of one or more,

m5：0～2，

（3）C_2-8an alkenyl group, which is a radical of an alkenyl group,

（4）C_2-8an alkynyl group,

（5）C_3-8cycloalkyl radicals, and

（6）C_1-8an alkylsulfonyl group;

R⁶and R^{6 ’}Each independently selected from:

(1) c which may be substituted by halogen atoms_1-8An alkyl group, a carboxyl group,

（2）C_2-8alkenyl, and

（3）C_2-8an alkynyl group;

or with R⁶And R^{6 ’}The bonded carbon atoms together forming

（4）C_3-8Cycloalkyl radicals, or

(5) Can be covered with C_1-8Alkyl radical C_6-10Arylsulfonyl-substituted 4-to 10-membered heterocycloalkyl group, C_1-8Alkyl radical C_6-10Arylsulfonyl can be replaced by C_1-8Alkyl substitution;

R⁷selected from:

(1) a hydrogen atom, and a nitrogen atom,

(2) a halogen atom,

(3) can be substituted by more than 1R^7ASubstituted C_1-8An alkoxy group,

R^7A：［1］（C_1-8alkyl radical)_m7a-amino, [ 2] hydroxy, [ 3] optionally substituted by C_1-8An alkyl-substituted 4-to 10-membered heterocycloalkyl group,

m7a：0～2，

（4）C_1-8an alkyl sulfonyl group, a carboxyl group,

(5) nitro group, and

(6) a hydroxyl group;

R⁸selected from:

(1) a hydrogen atom, and a nitrogen atom,

(2) can be substituted by more than 1R^8ASubstituted C_1-8An alkyl group, a carboxyl group,

R^8A: [1] can be substituted by more than 1R^8A1Substituted 4-to 10-membered heterocycloalkyl group, [ 2] which may be substituted with a halogen atom_1-8Alkyl radical)_m8a-amino, or [ 3] hydroxy,

m8a：0～2，

R^8A1：［1］C_1-8alkyl group, [ 2] C_1-8Alkylsulfonyl, [ 3] (C)_1-8Alkyl radical)_m8b-aminosulfonyl, [ 4] oxo, [ 5] C_1-8Alkoxycarbonyl, or [ 6] C_1-8Alkoxycarbonyl (C)_0-8Alkyl) aminosulfonyl groups, and (C) aminosulfonyl groups,

m8b：0～2，

（3）C_2-8an alkenyl group, which is a radical of an alkenyl group,

(4) can be substituted by more than 1R^8BA substituted 4-to 10-membered heterocycloalkyl group,

R^8B：

<1>can be substituted by more than 1R^8B1Substituted C_1-8An alkyl group, a carboxyl group,

<2>　C_2-8an alkenyl group, which is a radical of an alkenyl group,

<3>　C_2-8an alkynyl group,

<4>can be substituted by [ 1] cyano or [ 2] C_1-8Alkyl substituted C_3-8A cycloalkyl group,

<5>can be substituted by more than 1R^8B2A substituted 4-to 10-membered heterocycloalkyl group,

<6>can be selected from [ 1] C_1-8Alkoxy and [ 2] C_3-8C substituted by a substituent of the group consisting of cycloalkyl_1-8An alkoxy group,

<7>　C_1-8an alkoxycarbonyl group, a carbonyl group,

<8>　C_1-8an alkyl sulfonyl group, a carboxyl group,

<9> 5-to 14-membered heteroarylsulfonyl group,

<10> the oxo group(s),

<11> the cyano group,

<12>can be substituted by more than 1R^8B3Substituted C_1-8An alkanoyl group, a carbonyl group,

<13>　C_3-8a cycloalkyl-carbonyl group,

<14>　（C_1-8alkyl radical)_m8c-an aminosulfonyl group,

<15>　C_1-8alkylsulfonyl (C)_0-8Alkyl) amino group(s),

<16>can be substituted by more than 1R^8B4Substituted (C)_1-8Alkyl radical)_m8d-an amino group,

<17> the hydroxyl group(s),

<18>　（C_1-8alkyl radical)_m8e-aminocarbonyl, or

<19>　C_1-8Alkoxycarbonyl (C)_0-8Alkyl) amino

m8c：0～2，

m8d：0～2，

m8e：0～2，

R^8B1：［1］C_3-8Cycloalkyl, [ 2] hydroxy, or [ 3] C_1-8An alkoxy group,

R^8B2: [1] halogen atom, [ 2] C_1-8Alkyl, [ 3] oxo, [ 4] hydroxy, or [ 5] deuterium,

R^8B3：（C_1-8alkyl radical)_m8f-an amino group,

m8f：0～2，

R^8B4：［1］C_3-8cycloalkyl, or [ 2] hydroxy,

(5) can be covered with C_1-8An alkyl-substituted 5-to 14-membered heteroaryl group,

(6) can be substituted by more than 1R^8CSubstituted (C)_1-8Alkyl radical)_m8g-an amino-carbonyl group,

m8g：0～2，

R^8C: [1] a hydroxyl group; [2] can be selected freely<1>（C_1-8Alkyl radical)_m8i-an aminosulfonyl group,<2>C_1-8an alkyl sulfonyl group, a carboxyl group,<3>C_1-8alkoxycarbonyl and<4>C_1-8alkoxycarbonyl (C)_0-8Alkyl) aminosulfonyl-substituted (C)_1-8Alkyl radical)_m8h-an amino group; [3] c_1-8An alkylsulfonyl group; or [ 4] C which may be substituted by hydroxy_1-8An alkoxy group,

m8h：0～2，

m8i：0～2，

(7) 4-10 membered heterocycloalkyl (C) which may be substituted by oxo_0-8Alkyl) aminocarbonyl group(s),

(8) can be substituted by more than 1R^8DA substituted 4-to 10-membered nitrogen-containing heterocycloalkyl carbonyl group,

R^8D: [1] can be substituted by more than 1R^8D1Substituted C_1-8Alkyl group, [ 2] hydroxy group, [ 3] C_1-8Alkylsulfonyl, or [ 4] C_1-8An alkoxycarbonyl group, a carbonyl group,

R^8D1: [1] hydroxy, or [ 2] C_1-8An alkoxy group,

(9) a hydroxyl carbonyl group, a carboxyl group,

(10) c which may be substituted by hydroxy_0-8Alkoxy (C)_0-8Alkyl) aminocarbonyl group(s),

(11) a halogen atom,

(12) can be substituted by more than 1R^8HSubstituted (C)_1-8Alkyl radical)_m8j-an amino group,

m8j：0～2，

R^8H: [1] hydroxy, or [ 2] 4-to 10-membered heterocycloalkyl,

(13) a hydroxyl group(s),

(14) can be substituted by more than 1R^8ESubstituted C_1-8An alkoxy group,

R^8E：

<1> the hydroxyl group(s),

<2> the halogen atom, and,

<3> a hydroxyl-carbonyl group, and,

<4>　C_1-8an alkoxycarbonyl group, a carbonyl group,

<5>can be substituted by more than 1R^8E1A substituted 4-to 10-membered nitrogen-containing heterocycloalkyl carbonyl group,

<6>can be substituted by more than 1R^8E2Substituted (C)_1-8Alkyl radical)_m8k1-an amino group,

m8k1：0～2，

<7>can be substituted by more than 1R^8E3A substituted 4-to 10-membered heterocycloalkyl group,

<8> 5-to 14-membered heteroaryl,

<9>can be substituted by more than 1R^8E6Substituted (C)_1-8Alkyl radical)_m8k2-an amino-carbonyl group,

m8k2：0～2，

<10>can be substituted by more than 1R^8E7Substituted C_1-8An alkoxy group,

<11>　C_1-8an alkylthio group is a group of one or more,

<12>　C_1-8an alkylsulfinyl group which is a substituent of a fatty acid,

<13>　C_1-8an alkyl sulfonyl group, a carboxyl group,

R^8E1：

<1>　C_1-8an alkoxycarbonyl group, a carbonyl group,

<2>　C_1-8an alkanoyl group, a carbonyl group,

<3>　C_1-8an alkyl sulfonyl group, a carboxyl group,

<4>　（C_1-8alkyl radical)_m8k3-an aminosulfonyl group,

m8k 3: 0 to 2, or

<5> 4-to 10-membered heterocycloalkyl group,

R^8E2：

<1> the hydroxyl group(s),

<2>c which may be substituted by halogen atoms_1-8An alkoxycarbonyl group, a carbonyl group,

<3>can be covered with C_1-8Alkyl substituted C_3-8Cycloalkyl radical, C_1-8The alkyl group may be substituted with a hydroxyl group,

<4>can be selected from [ 1] (C)_1-8Alkyl radical)_m8k4C substituted by a substituent of the group consisting of amino group and [ 2] halogen atom_1-8An alkanoyl group, a carbonyl group,

m8k4：0～2，

<5>　（C_1-8alkyl radical)_m8k5-an amino-carbonyl group,

m8k5：0～2，

<6>　C_1-8an alkyl sulfonyl group, a carboxyl group,

<7>can be covered with C_1-8An alkyl-substituted 4-to 10-membered nitrogen-containing heterocycloalkyl sulfonyl group,

<8>can be covered with C_1-8Alkoxycarbonyl substituted (C)_1-8Alkyl radical）_m8k6-an aminosulfonyl group,

m8k 6: 0 to 2, or

R^8E3：

<1>Can be selected from the group consisting of [ 1] hydroxy and [ 2] C_1-8C substituted by a substituent of the group consisting of alkylcarbonyloxy_1-8An alkyl group, a carboxyl group,

<2>　C_1-8an alkylcarbonyloxy group, a carbonyl group,

<3> the hydroxyl group(s),

<4>　C_3-8a cycloalkyl group,

<5>　C_1-8an alkoxy group,

<6>　C_1-8an alkoxycarbonyl group, a carbonyl group,

<7>　C_1-8an alkyl sulfonyl group, a carboxyl group,

<8>　（C_1-8alkyl radical)_m8k8-aminocarbonyl group

m8k8：0～2，

<9>C which may be substituted by hydroxy_1-8An alkanoyl group, a carbonyl group,

<10> oxo, or

<11>Can be selected from [ 1] C_1-8Alkanoyl group, [ 2] C_1-8Alkoxycarbonyl and [ 3] C_1-8A 4-to 10-membered heterocycloalkyl group substituted with a substituent selected from the group consisting of alkylsulfonyl,

R^8E6：

<1>　C_2-8an alkenylcarbonyloxy group, a carbonyl group,

<2> the hydroxyl group(s),

<3> the cyano group,

<4>optionally substituted by hydroxy(s) (iii)C_1-8Alkyl radical)_m8k9-amino group

m8k9：0～2，

<5>C which may be substituted by hydroxy_1-8An alkoxy group,

<6>　C_1-8an alkylcarbonyloxy group, a carbonyl group,

<7>can be covered with C_1-8Alkyl-substituted 4-to 10-membered heterocycloalkyl, or

<8> 5-to 14-membered heteroaryl,

R^8E7：

<1> hydroxy, or

<2>C which may be substituted by hydroxy_1-8An alkoxy group,

(15) can be substituted by more than 1R^8FA substituted 4-to 10-membered heterocycloalkyloxy group,

R^8F：

<1>can be substituted by more than 1R^8F1Substituted C_1-8An alkyl group, a carboxyl group,

<2>　C_3-8a cycloalkyl group,

<3>c which may be substituted by halogen atoms_1-8An alkanoyl group, a carbonyl group,

<4>　C_1-8an alkylcarbonyloxy group, a carbonyl group,

<5>　C_1-8an alkoxycarbonyl group, a carbonyl group,

<6>can be substituted by more than 1R^8F2A substituted 4-to 10-membered heterocycloalkyl group,

<7>　C_1-8an alkyl sulfonyl group, a carboxyl group,

<8> hydroxy, or

<9>　C_6-10An aryl group, a heteroaryl group,

R^8F1: [1] hydroxy group, [ 2] C_1-8Alkoxy group, or [ 3] halogen atom,

R^8F2: [1] 4-to 10-membered heterocycloalkyl group, [ 2] C_1-8Alkoxycarbonyl, or [ 3] C_1-8An alkyl sulfonyl group, a carboxyl group,

(16) a 5-to 14-membered heteroaryloxy group,

(17) a 4-to 10-membered heterocycloalkyl carbonyloxy group,

（18）（C_1-8alkyl radical)_m8l1-an amino-sulfonyloxy group,

m8l1：0～2，

(19) can be covered by [ 1] (C)_1-8Alkyl radical)_m8l2-amino, [ 2] hydroxy or [ 3] hydroxycarbonyl substituted C_1-8An alkylthio group is a group of one or more,

m8l2：0～2，

(20) can be substituted by more than 1R^8GSubstituted C_1-8An alkyl sulfonyl group, a carboxyl group,

R^8G: [1] hydroxycarbonyl, [ 2] hydroxy, or [ 3] (C)_1-8Alkyl radical)_m8l3-an amino group,

m8l3：0～2，

(21) can be covered with C_1-8An alkyl-substituted 4-to 10-membered nitrogen-containing heterocycloalkyl sulfonyloxy group,

（22）C_2-8alkenyloxy, and

(23) c which may be substituted by halogen atoms_1-8An alkylsulfonyloxy group;

R⁹selected from:

(1) a hydrogen atom, and a nitrogen atom,

(2) can be substituted by more than 1R^9ASubstituted C_1-8An alkyl group, a carboxyl group,

R^9A：［1］C_3-8cycloalkyl, [ 2] can be substituted by 1 or more R^9A1Substituted 4-to 10-membered heterocycloalkyl group, [ 3] hydroxy, [ 4] C_1-8Alkoxy, or [ 5] hydroxycarbonyl,

R^9A1：［1］C_1-8alkyl group, [ 2] C_3-8Cycloalkyl, or [ 3] 4-to 10-membered heterocycloalkyl,

(3) can be substituted by more than 1R^9BSubstituted C_2-8An alkenyl group, which is a radical of an alkenyl group,

R^9B：［1］（C_1-8alkyl radical)_m9a-amino, [ 2] can be substituted by more than 1R^9B1A substituted 4-to 10-membered heterocycloalkyl group,

R^9B1：［1］C_3-8cycloalkyl, or [ 2] 4-to 10-membered heterocycloalkyl,

m9a：0～2，

(4) can be substituted by more than 1R^9CSubstituted C_2-8An alkynyl group,

R^9C：［1］C_1-8alkoxy, [ 2] may be substituted by C_6-10Aryl substituted (C)_1-8Alkyl radical)_m9b-amino, [ 3] can be substituted by more than 1R^9C1Substituted 4-to 10-membered heterocycloalkyl group, [ 4] C_3-8Cycloalkyl, [ 5] hydroxy, [ 6] hydroxycarbonyl, or [ 7] C_1-8An alkyloxycarbonyl group,

m9b：0～2，

R^9C1：［1］C_3-8cycloalkyl group, [ 2] 4-to 10-membered heterocycloalkyl group, or [ 3] oxo group,

（5）C_3-8a cycloalkyl group,

(6) can be substituted by more than 1R^9DA substituted 4-to 10-membered heterocycloalkyl group,

R^9D: [1] can be substituted by 4-to 10-membered heterocycloalkylSubstituted C_1-8Alkyl group, [ 2] C_3-8Cycloalkyl, [ 3] 4-to 10-membered heterocycloalkyl, or [ 4] C_1-6Alkylsulfonyl, or [ 5] C_1-8An alkoxycarbonyl group, a carbonyl group,

(7) can be substituted by more than 1R^9ESubstituted C_6-10An aryl group, a heteroaryl group,

R^9E: [1] halogen atom, [ 2] hydroxy, [ 3] hydroxycarbonyl, or [ 4] C which may be substituted by hydroxy_1-8Alkyl, or [ 5] C_1-8An alkoxy group,

(8) can be covered with C_1-8An alkyl-substituted 5-to 14-membered heteroaryl group,

(9) the cyano group(s),

（10）C_1-8an alkanoyl group, a carbonyl group,

(11) can be covered with C_1-8An alkyl-substituted 4-to 10-membered nitrogen-containing heterocycloalkyl carbonyl group,

(12) a halogen atom,

(13) can be substituted by more than 1R^9FSubstituted (C)_1-8Alkyl radical)_m9c-an amino group,

m9c：0～2，

(14) can be covered (C)_1-8Alkyl radical)_m9d-amino-substituted C_1-8Alkylcarbonyl (C)_0-8Alkyl) amino group(s),

m9d：0～2，

（15）C_1-8alkylsulfonyl (C)_0-8Alkyl) amino group(s),

（16）（C_1-8alkyl radical)_m9e-aminosulfonyl (C)_0-8Alkyl) amino group(s),

m9e：0～2，

(17) the nitro group(s),

(18) a hydroxyl group(s),

(19) can be substituted by more than 1R^9GSubstituted C_1-8An alkoxy group,

R^9G: [1] hydroxy, [ 2] hydroxycarbonyl, [ 3] optionally substituted by C_1-8Alkoxy-substituted C_6-10Aryl, [ 4] (C)_1-8Alkyl radical)_m9g1-amino, [ 5] can be substituted by more than 1R^9G1Substituted C_1-8Alkoxy, [ 6] 5-to 14-membered heteroaryl, or [ 7] optionally substituted by C_1-8An alkyl-substituted 4-to 10-membered heterocycloalkyloxy group,

m9g1：0～2，

R^9G1：［1］C_1-8alkoxy, or [ 2] hydroxycarbonyl,

(20) can be substituted by [ 1] 4-to 10-membered heterocycloalkyl or [ 2] C_1-84-to 10-membered heterocycloalkyloxy substituted with alkoxycarbonyl,

(21) c which may be substituted by halogen atoms_1-8An alkyl-sulfonyloxy group, which is a sulfonyl group,

(22) can be covered (C)_1-8Alkyl radical)_m9f-amino-substituted C_1-8An alkylthio group is a group of one or more,

m9f：0～2，

(23) can be covered (C)_1-8Alkyl radical)_m9g-amino-substituted C_1-8An alkyl sulfonyl group, a carboxyl group,

m9g：0～2，

（24）（C_1-8alkyl radical)_m9h-an aminosulfonyl group,

m9h：0～2，

(25) can be covered with C_1-8An alkyl-substituted 4-to 10-membered nitrogen-containing heterocycloalkylsulfonyl group, and

(26) a hydroxycarbonyl group;

the composition according to [ 2] [ 1], wherein the dissolution aid is a surfactant;

the composition according to [ 3] or [ 2], wherein the surfactant is a nonionic or anionic surfactant;

the composition according to [ 4] [ 2] or [ 3], wherein the surfactant is selected from the group consisting of monoalkyl sulfates, polyoxyl (40) stearate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, castor oil polyoxyl (35), lauromacrogol, sodium dioctyl sulfosuccinate, sodium lauroyl sarcosinate, sodium dodecylbenzenesulfonate and mixtures thereof;

the composition according to [ 4-1 ] [ 2] or [ 3], wherein the surfactant is selected from the group consisting of monoalkyl sulfates, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, castor oil polyoxyl ester (35), dioctyl sodium sulfosuccinate, sodium lauroyl sarcosinate, sodium dodecylbenzenesulfonate and mixtures thereof;

the composition according to [ 4-2 ] [ 2] to [ 4], wherein the surfactant is selected from the group consisting of sodium lauryl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, and a mixture thereof;

the composition according to [ 4-3 ] [ 2] to [ 4], wherein the surfactant is a mixture of sodium lauryl sulfate and polyoxyethylene (105) polyoxypropylene (5) diol;

the composition according to [ 4-4 ] [ 2] to [ 4], wherein the surfactant is sodium lauryl sulfate;

the composition as described in [ 4-5 ] to [ 2] to [ 4-4 ], wherein the surfactant is contained in an amount of 0.5 to 25 parts by weight;

the composition as described in [ 4-6 ] [ 2] to [ 4-4 ], wherein the surfactant is contained in an amount of 1.5 to 15 parts by weight;

the composition according to [ 5] to [ 2] to [ 4-6 ], wherein the composition further comprises an organic polymer;

the composition according to [ 6] or [ 5], wherein the organic polymer is selected from the group consisting of a synthetic resin, a water-soluble polymer, a gastric-soluble polymer, an enteric-soluble polymer and a mixture thereof;

the composition according to [ 7] or [ 5], wherein the organic polymer is a synthetic resin;

[ 7-1 ] [ 6] the composition, wherein the water-soluble polymer is hydroxypropyl cellulose, hydroxypropyl methylcellulose, propylene glycol alginate, sodium caseinate, carboxyvinyl polymer, agar powder, guar gum, copovidone, hydroxyethyl methylcellulose, or polyvinyl alcohol, the gastric-soluble polymer is aminoalkyl methacrylate copolymer E or polyvinyl acetal diethylaminoacetate, and the enteric-soluble polymer is methacrylic acid copolymer LD, purified shellac, carboxymethyl ethylcellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, methacrylic acid copolymer S, casein, zeatin;

[ 7-2 ] [ 6] the composition, wherein the water-soluble polymer is propylene glycol alginate, sodium caseinate, carboxyvinyl polymer, agar powder, guar gum, copovidone, hydroxyethyl methylcellulose, or polyvinyl alcohol, the stomach-soluble polymer is aminoalkyl methacrylate copolymer E or polyvinyl acetal diethylaminoacetate, and the enteric polymer is methacrylic acid copolymer LD, carboxymethyl ethylcellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, methacrylic acid copolymer S, casein, zein;

the composition according to [ 7-3 ] [ 6], wherein the organic polymer is selected from the group consisting of casein, sodium caseinate, sodium polystyrene sulfonate, polyvinyl acetal diethylaminoacetate, carboxymethylethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylic acid copolymer S, and a mixture thereof;

[ 7-4 ] [ 5] to [ 7-3 ], wherein the surfactant is sodium lauryl sulfate, and the organic polymer is sodium polystyrene sulfonate;

the composition according to [ 7-5 ] [ 5] to [ 7-3 ], wherein the surfactant is a mixture of sodium lauryl sulfate and polyoxyethylene (105) polyoxypropylene (5) diol, and the organic polymer is selected from sodium polystyrene sulfonate;

[ 7-6 ] [ 7] wherein the synthetic resin is sodium polystyrene sulfonate or a vinyl acetate resin;

the composition according to [ 7-7 ] [ 5] to [ 7-6 ], wherein the organic polymer is contained in an amount of 1 to 20 parts by weight;

the composition according to [ 7-8 ] [ 5] to [ 7-6 ], wherein the organic polymer is contained in an amount of 2 to 10 parts by weight;

the composition as described in [ 8] to [ 7-5 ], which further comprises 1 or more than 1 selected from the following additive groups A,

additive A: citric acid, fumaric acid, DL-malic acid, adipic acid, succinic acid, tartaric acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, tartaric acid, lactic acid, citric acid, lactic,

Maleic acid, sulfuric acid, phosphoric acid, sodium dehydroacetate, sodium stearyl fumarate,

L-ascorbyl stearate, L-aspartic acid, skim milk powder, aluminum lactate, ascorbyl palmitate, aluminum sulfate, monocalcium phosphate, or acetyltryptophan;

[ 8-2 ] [ 8] wherein the additive group A is citric acid, fumaric acid, DL-malic acid, adipic acid, succinic acid, tartaric acid, lactic acid, maleic acid, phosphoric acid, sodium dehydroacetate, sodium stearyl fumarate, L-ascorbyl stearate, L-aspartic acid, skim milk powder, or calcium dihydrogen phosphate;

[ 8-3 ] [ 8] wherein the additive selected from the additive group A is sodium dehydroacetate or skim milk powder;

[ 8-4 ] [ 8] to [ 8-3 ], wherein the total content of 1 or more than 1 additive selected from the additive group A is 1 to 20 parts by weight;

the composition described in [ 9] to [ 8-4 ], wherein the aforementioned substance has a solubility in water of less than 100. mu.g/mL at 25 ℃;

the composition according to [ 9-1 ] or [ 1], wherein the dissolution aid is selected from the group consisting of,

group (2):

citric acid, sodium stearyl fumarate, methacrylic acid copolymer LD, sodium lauryl sulfate, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbyl stearate, L-aspartic acid, adipic acid, aminoalkyl methacrylate copolymer E, propylene glycol alginate, casein, sodium caseinate, carboxyvinyl polymer, carboxymethyl ethyl cellulose, agar powder, guar gum, succinic acid, copovidone, cellulose acetate phthalate, tartaric acid, sodium dioctyl sulfosuccinate, zein, skim milk powder, sorbitan trioleate, lactic acid, aluminum lactate, ascorbyl palmitate, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, castor oil poly (35) alkoxide, Sodium polystyrene sulfonate, polyvinyl acetal diethylamino acetate, polyvinyl alcohol, maleic acid, methacrylic acid copolymer S, sulfuric acid, aluminum sulfate, phosphoric acid, monocalcium phosphate, sodium dodecylbenzenesulfonate, vinylpyrrolidone-rich vinyl acetate copolymer, sodium lauroyl sarcosinate, acetyltryptophan, sodium methyl sulfate, sodium ethyl sulfate, sodium butyl sulfate, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate;

the composition according to [ 9-2 ] [ 1], wherein the dissolution aid is selected from the group consisting of,

group (2):

citric acid, methacrylic acid copolymer LD, sodium lauryl sulfate, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbic acid stearate, L-aspartic acid, adipic acid, propylene glycol alginate, casein, sodium caseinate, carboxymethylethylcellulose, succinic acid, copovidone, dioctyl sodium sulfosuccinate, lactic acid, aluminum lactate, ascorbyl palmitate, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, polyoxyethylene hydrogenated castor oil 60, castor oil polyoxyl ester (35), sodium polystyrene sulfonate, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, methacrylic acid copolymer S, sulfuric acid, aluminum sulfate, sodium dodecylbenzene sulfonate, vinyl pyrrolidone vinylacetate copolymer, acetyl tryptophan, sodium decyl sulfate, sodium tetradecyl sulfate, sodium dodecyl sulfate, sodium lauryl sulfate, sodium laurylsulfate, sodium laurylsulfonate, sodium lauryl sulfate, sodium lauryl, Sodium stearyl sulfate;

the composition according to [ 9-3 ] or [ 1], wherein the dissolution aid is selected from the group consisting of,

group (2):

citric acid, methacrylic acid copolymer LD, sodium lauryl sulfate, sodium dehydroacetate, fumaric acid, DL-malic acid, L-aspartic acid, adipic acid, propylene glycol alginate, sodium caseinate, carboxymethyl ethyl cellulose, succinic acid, copovidone, dioctyl sodium sulfosuccinate, lactic acid, aluminum lactate, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, sodium polystyrene sulfonate, polyvinyl acetal diethylaminoacetate, methacrylic acid copolymer S, sulfuric acid, aluminum sulfate, vinyl pyrrolidone vinyl acetate copolymer, decyl sodium sulfate;

[ 9-4 ] [ 1] wherein the solubility of the substance of formula (I) is improved by using a dissolution aid selected from the group consisting of,

group (2):

citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium stearyl fumarate, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, refined shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbyl stearate, L-aspartic acid, adipic acid, aminoalkyl methacrylate copolymer E, propylene glycol alginate, casein, sodium caseinate, carboxyvinyl polymer, carboxymethylethylcellulose, agar powder, guar gum, succinic acid, copovidone, cellulose acetate phthalate, tartaric acid, dioctyl sodium sulfosuccinate, zein, skim milk powder, sorbitan trioleate, lactic acid, aluminum lactate, ascorbyl palmitate, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, polyoxyethylene (105) polyoxypropylene (5) glycol, sodium lauryl sulfate, sodium caseinate, carboxyvinyl polymer, carboxymethyl ethylcellulose, agar powder, guar gum, succinic acid, copovidone, cellulose acetate, tartaric acid, dioctyl sodium sulfosuccinate, zein, skim milk powder, sorbitan, Polyoxyethylene hydrogenated castor oil 60, castor oil polyoxyl ester (35), sodium polystyrene sulfonate, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, maleic acid, methacrylic acid copolymer S, sulfuric acid, aluminum sulfate, phosphoric acid, monocalcium phosphate, sodium dodecylbenzenesulfonate, vinylpyrrolidone, a seeding vinyl acetate copolymer, sodium lauroyl sarcosinate, acetyl tryptophan, sodium methyl sulfate, sodium ethyl sulfate, sodium butyl sulfate, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate;

[ 9-5 ] [ 1] wherein the solubility of the substance of formula (I) is improved by using a dissolution aid selected from the group consisting of,

group (2):

citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, refined shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbyl stearate, L-aspartic acid, adipic acid, propylene glycol alginate, casein, sodium caseinate, carboxymethylethyl cellulose, succinic acid, copovidone, sodium dioctyl sulfosuccinate, lactic acid, aluminum lactate, ascorbyl palmitate, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, polyoxyethylene hydrogenated castor oil 60, castor oil polyoxyl ester (35), sodium polystyrene sulfonate, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, methacrylic acid copolymer S, sulfuric acid, aluminum sulfate, sodium dodecylbenzene sulfonate, vinyl pyrrolidone vinyl acetate copolymer, sodium lauryl sulfate, sodium caseinate, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbic acid stearate, L-aspartic acid, propylene glycol alginate, casein, sodium caseinate, acetyl tryptophan, sodium decyl sulfate, sodium tetradecyl sulfate, sodium octadecyl sulfate;

[ 9-6 ] [ 1] wherein the solubility of the substance of formula (I) is improved by using a dissolution aid selected from the group consisting of,

group (2):

citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, refined shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-aspartic acid, adipic acid, propylene glycol alginate, sodium caseinate, carboxymethyl ethylcellulose, succinic acid, copovidone, dioctyl sodium sulfosuccinate, lactic acid, aluminum lactate, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, sodium polystyrene sulfonate, polyvinyl acetal diethylaminoacetate, methacrylic acid copolymer S, sulfuric acid, aluminum sulfate, vinyl pyrrolidone vinylacetate copolymer, decyl sodium sulfate;

[ 10] to [ 1] to [ 9-3 ], wherein, for the aforementioned substances, A¹～A⁴、A⁶And A⁷Is a carbon atom, A⁵Is NH, R³Is cyano, R⁶，R^{6 ’}Are both methyl;

[ 10-1 ] to [ 1] of the composition, wherein, for the foregoing, A is¹～A⁴、A⁶And A⁷Is a carbon atom, A⁵Is NH, R³Is cyano, R⁸Is 4-to 10-membered heterocycloalkyl or may be substituted by C_3-8Cycloalkyl-substituted 4-to 10-membered heterocycloalkyl;

the composition according to any one of [ 11] to [ 9-6 ], wherein the substance is selected from the group consisting of:

9- (4-isopropyl-piperazin-1-yl) -6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

6, 6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-9-prop-1-ynyl-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-cyclopropylethynyl-6, 6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

6, 6-dimethyl-8- (1-oxetan-3-yl-piperidin-4-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-bromo-6, 6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-bromo-8- (4-cyclopropyl-piperazin-1-yl) -6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-chloro-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

8- (4-cyclobutyl-piperazin-1-yl) -6, 6-dimethyl-11-oxo-9-prop-1-ynyl-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

6, 6, 9-trimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-ethyl-6, 6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-ethyl-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-ethynyl-6, 6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

8- (4-cyclobutyl-piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-ethynyl-6, 6-dimethyl-11-oxo-8- (4-pyrrolidin-1-yl-piperidin-1-yl) -6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

6, 6-dimethyl-11-oxo-8- (4-pyrrolidin-1-yl-piperidin-1-yl) -6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

8- (4-cyclobutyl-piperazin-1-yl) -9-ethynyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

8- (4-cyclobutyl-piperazin-1-yl) -6, 6-dimethyl-11-oxo-9-propyl-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

8- (1-isopropyl-piperidin-4-yl) -6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

8- (4-isopropyl-piperazin-1-yl) -6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

8- (4-cyclobutyl-piperazin-1-yl) -9-cyclopropyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

8- (2-tert-butylamino-ethoxy) -6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-ethynyl-8- (4-methanesulfonyl-piperazin-1-yl) -6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-bromo-8- (4-cyclobutyl-piperazin-1-yl) -6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

6, 6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-9-propyl-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile; and 9-ethynyl-6, 6-dimethyl-8-morpholin-4-yl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

the composition according to any one of [ 11-1 ] [ 1] to [ 8], wherein the aforementioned substance is selected from the group consisting of (i) 6, 6-dimethyl-8- (1-oxetan-3-yl-piperidin-4-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile, (ii) 8- (4-cyclobutyl-piperazin-1-yl) -9-cyclopropyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile, (iii) 8- (4-cyclobutyl-piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile, and (iv) 9-ethyl-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

the composition as described in [ 11-2 ] to [ 11-1 ], wherein the content of the above-mentioned substance is 1 to 50 parts by weight;

the composition as described in [ 11-3 ] to [ 11-1 ], wherein the content of the above-mentioned substance is 3 to 30 parts by weight;

[ 11-4 ] to [ 2] to [ 8], wherein the weight ratio of the foregoing to the surfactant is 1: 0.01-1: 25;

[ 11-5 ] to [ 2] or [ 8] wherein the weight ratio of the above-mentioned substance to the surfactant is 1:0.05 to 1: 1;

the composition according to [ 11-6 ] [ 9] to [ 11-5 ], wherein the weight ratio of the substance to the organic polymer is 1:0.02 to 1: 20;

the composition according to [ 11-7 ] [ 9] to [ 11-6 ], wherein the weight ratio of the substance to the organic polymer is 1:0.25 to 1: 1;

[ 11-8 ] [ 8] to [ 11-7 ] wherein the weight ratio of the aforementioned substance to the total amount of 1 or more than 1 additive selected from the additive group A is 1:0.02 to 1: 20.

The present invention further includes the following embodiments.

A pharmaceutical preparation comprising the composition described in [ 1] to [ 11-8 ];

the pharmaceutical preparation described in [ 13] [ 12], which is an orally administrable preparation;

the pharmaceutical preparation according to [ 14] [ 12], wherein the preparation for oral administration is a solid preparation; and

the pharmaceutical preparation according to [ 15] [ 13], wherein the preparation for oral administration is a tablet, capsule, granule, powder, pill, aqueous or non-aqueous solution or suspension for oral administration;

[ 16-1 ] A dissolution aid for a substance represented by the formula (I), which comprises a substance selected from the group consisting of,

group (2):

citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium stearyl fumarate, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, refined shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbyl stearate, L-aspartic acid, adipic acid, aminoalkyl methacrylate copolymer E, propylene glycol alginate, casein, sodium caseinate, carboxyvinyl polymer, carboxymethylethylcellulose, agar powder, guar gum, succinic acid, copovidone, cellulose acetate phthalate, tartaric acid, dioctyl sodium sulfosuccinate, zein, skim milk powder, sorbitan trioleate, lactic acid, aluminum lactate, ascorbyl palmitate, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, polyoxyethylene (105) polyoxypropylene (5) glycol, sodium lauryl sulfate, sodium caseinate, carboxyvinyl polymer, carboxymethyl ethylcellulose, agar powder, guar gum, succinic acid, copovidone, cellulose acetate, tartaric acid, dioctyl sodium sulfosuccinate, zein, skim milk powder, sorbitan, Polyoxyethylene hydrogenated castor oil 60, castor oil polyoxyl ester (35), sodium polystyrene sulfonate, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, maleic acid, methacrylic acid copolymer S, sulfuric acid, aluminum sulfate, phosphoric acid, monocalcium phosphate, sodium dodecylbenzenesulfonate, vinylpyrrolidone, a seeding vinyl acetate copolymer, sodium lauroyl sarcosinate, acetyl tryptophan, sodium methyl sulfate, sodium ethyl sulfate, sodium butyl sulfate, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate;

[ 16-2 ] A dissolution aid for a substance represented by the formula (I), which comprises a substance selected from the group consisting of,

group (2):

citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, refined shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbyl stearate, L-aspartic acid, adipic acid, propylene glycol alginate, casein, sodium caseinate, carboxymethylethyl cellulose, succinic acid, copovidone, sodium dioctyl sulfosuccinate, lactic acid, aluminum lactate, ascorbyl palmitate, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, polyoxyethylene hydrogenated castor oil 60, castor oil polyoxyl ester (35), sodium polystyrene sulfonate, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, methacrylic acid copolymer S, sulfuric acid, aluminum sulfate, sodium dodecylbenzene sulfonate, vinyl pyrrolidone vinyl acetate copolymer, sodium lauryl sulfate, sodium caseinate, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbic acid stearate, L-aspartic acid, propylene glycol alginate, casein, sodium caseinate, acetyl tryptophan, sodium decyl sulfate, sodium tetradecyl sulfate, sodium octadecyl sulfate;

[ 16-3 ] A dissolution aid for a substance represented by the formula (I), which comprises a substance selected from the group consisting of,

group (2):

citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, refined shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-aspartic acid, adipic acid, propylene glycol alginate, sodium caseinate, carboxymethyl ethylcellulose, succinic acid, copovidone, dioctyl sodium sulfosuccinate, lactic acid, aluminum lactate, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, sodium polystyrene sulfonate, polyvinyl acetal diethylaminoacetate, methacrylic acid copolymer S, sulfuric acid, aluminum sulfate, vinyl pyrrolidone vinylacetate interpolymer, and decyl sodium sulfate.

Effects of the invention

The composition of the present invention can improve the solubility, oral absorbability and/or absorbability in blood of a poorly water-soluble or insoluble tetracyclic compound having an ALK inhibitory action, which is useful as a prophylactic and/or therapeutic agent for cancer, depression, cognitive dysfunction.

Drawings

FIG. 1 is a graph showing a comparison of the effect of the amount of sodium lauryl sulfate added on the solubility of Compound F6-20.

FIG. 2 is a graph showing the effect of various cellulose polymers on the solubility of hydrochloride salt of compound F6-20.

FIG. 3 is a graph showing the effect of the amount of hydroxypropylcellulose added on the solubility of hydrochloride salt of compound F6-20.

FIG. 4 is a graph showing the solubility of compound F6-20 hydrochloride in the case where sodium lauryl sulfate and hydroxypropyl cellulose were blended.

FIG. 5 is a graph showing a comparison of the effect of the production method on the solubility of hydrochloride salt of Compound F6-20.

FIG. 6 is a graph showing a comparison of the effect of the amount of sodium lauryl sulfate added on the solubility of Compound F6-20 methanesulfonate salt.

FIG. 7 is a graph showing the solubility of Compound F6-20 mesylate in the presence of sodium lauryl sulfate and hydroxypropyl cellulose.

FIG. 8 is a graph showing the effect of SLS and polyvinylpyrrolidone on the solubility of the hydrochloride salt crystals of Compound B4-8.

FIG. 9 is a graph showing the effect of SLS and polyvinylpyrrolidone on the solubility of compound B4-8 mesylate salt crystals.

FIG. 10 is a graph showing the effect of SLS and HPC on the solubility of Compound B4-8 sulfate salt crystals.

FIG. 11 is a graph showing the effect of SLS and HPC on the solubility of compound B4-8L-tartrate crystals.

FIG. 12 is a graph showing the effect of SLS and HPC on the solubility of phosphate crystals of Compound B4-8.

FIG. 13 is a graph showing the effect of polyoxyethylene (105) polyoxypropylene (5) diol on the solubility of the hydrochloride salt crystals of Compound F6-4.

FIG. 14 is a graph showing the effect of polyoxyethylene (105) polyoxypropylene (5) diol on the solubility of compound F6-4 mesylate salt crystals.

FIG. 15 is a graph showing the effect of SLS on the solubility of the hydrochloride salt crystals of Compound F6-17.

FIG. 16 is a graph showing the effect of SLS on the solubility of crystals of Compound F6-17 mesylate.

FIG. 17 is a graph showing the effect of SLS and polyvinylpyrrolidone on the solubility of a crystalline form of compound F6-17 methanesulfonate.

FIG. 18 is a graph showing the effect of SLS on the solubility of compound F6-17 maleate crystals.

FIG. 19 is a graph showing the effect of SLS and polyvinylpyrrolidone on the solubility of the crystals of Compound F6-17L-tartrate.

FIG. 20 is a graph showing the effect of SLS on the solubility of compound F6-17 citrate crystals.

FIG. 21 is a graph showing the effect of SLS on the solubility of compound F6-17 malate salt crystals.

FIG. 22 is a graph showing the effect of SLS on the solubility of the hydrochloride salt crystals of Compound F5-46.

FIG. 23 is a graph showing the effect of SLS on the solubility of crystals of Compound F5-46 mesylate.

FIG. 24 is a graph showing the effect of SLS on the solubility of the hydrochloride salt crystals of Compound F5-51.

FIG. 25 is a graph showing the effect of SLS on the solubility of crystals of Compound F5-51 mesylate.

FIG. 26 is a graph showing the effect of SLS, polyoxyethylene (105) polyoxypropylene (5) diol and poly (sodium 4-styrenesulfonate) on the solubility of the hydrochloride crystals of Compound F6-20.

FIG. 27 is a graph showing the effect of the combination of SLS and polyoxyethylene (105) polyoxypropylene (5) diol on the solubility of the hydrochloride salt crystals of Compound F6-20.

FIG. 28 is a graph showing the effect of SLS in combination with poly (sodium 4-styrenesulfonate) on the solubility of the hydrochloride crystals of Compound F6-20.

FIG. 29 is a graph showing the effect of a combination of SLS, polyoxyethylene (105) polyoxypropylene (5) diol and poly (sodium 4-styrenesulfonate) on the solubility of the hydrochloride salt crystals of Compound F6-20.

FIG. 30 is a graph showing the effect of SLS content on the solubility of a crystalline hydrochloride preparation of Compound F6-20 containing polyoxyethylene (105) polyoxypropylene (5) diol and sodium poly (4-styrenesulfonate).

Detailed Description

In this specification, the term "pharmaceutically acceptable carrier" means one or more suitable solid or liquid excipient diluents or encapsulating materials, and is a substance suitable for administration to a mammal. In the present specification, the term "acceptable" means that the components of the composition can be mixed with the subject compound by a method that does not mutually generate a reaction such as a substantial decrease in the pharmaceutical effectiveness of the composition under ordinary use conditions. For a pharmaceutically acceptable carrier to be suitable for administration to a subject to be treated, preferably an animal, more preferably a mammal, it must, without doubt, be of sufficiently high purity and sufficiently low toxicity.

The "dissolution aid" used in the present invention includes surfactants, organic polymers, pH adjusters, and the like, and specifically, those shown in table 2 described below. Preferred examples thereof include: casein, sodium caseinate, skim milk powder, sodium lauryl sulfate (hereinafter, also referred to as SLS), dioctyl sodium sulfosuccinate, polyoxyl (40) stearate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, castor oil polyoxyl (35), lauroyl sarcosinate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, sodium methylsulfate, sodium ethylsulfate, sodium butylsulfate, sodium octylsulfate, sodium decylsulfate, sodium dodecylbenzenesulfonate, and the like.

In the present invention, the dissolution assistant may be used in combination of 2 or more kinds at an appropriate ratio.

Surfactants are particularly preferred.

In the present invention, when 2 or more dissolution aids are used in combination, the combination of the dissolution aids is preferably a combination of sodium lauryl sulfate and polyoxyethylene (105) polyoxypropylene (5) diol or a combination of sodium lauryl sulfate and sodium polystyrene sulfonate, and particularly preferably a combination of sodium lauryl sulfate, sodium polystyrene sulfonate, and polyoxyethylene (105) polyoxypropylene (5) diol.

The sodium polystyrene sulfonate includes, for example, a substance having CAS (Chemical abstracts) registration number 9080-79-9 (defined in the fifteenth edition of Japanese pharmacopoeia, which is a sodium-type cation exchange resin prepared by bonding a copolymer of styrene and divinylbenzene with a sulfonic acid group), or poly (sodium 4-styrenesulfonate) [ a homopolymer formed by polymerizing sodium 4-vinylbenzenesulfonate having CAS registration number 25704-18-1 to form a polymer ], and preferably poly (sodium 4-styrenesulfonate).

The "surfactant" refers to a substance having both a hydrophilic group and a hydrophobic group in a molecule. The surfactant includes ionic surfactants and nonionic surfactants.

The ionic surfactant means an ionic surfactant which is ionized to form ions (atoms or atom groups having charges) when dissolved in water. Ionic surfactants are further classified into anionic surfactants, cationic surfactants, and amphoteric surfactants according to the charge of the generated ions. In the present invention, a nonionic surfactant and an anionic surfactant are preferable.

Examples of the nonionic surfactant include: sorbitan fatty acid ester (C)_{12 ～ 18}) POE sorbitan fatty acid ester (C)_{12 ～ 18}) Sugar ester type surfactants such as sucrose fatty acid esters; POE fatty acid ester (C)_{12 ～ 18}) POE resinates, POE fatty acid diesters (C)_{12 ～ 18}) And the like fatty acid ester type; POE alkyl ether (C)_{12 ～ 18}) An iso-alcohol type; POE alkyl (C)_{8 ～ 12}) Phenyl ether, POE dialkyl (C)_{8 ～ 12}) Phenyl ether, POE alkyl (C)_{8 ～ 12}) Alkylphenol surfactants such as phenyl ether formaldehyde condensates; polyoxyethylene seed-polyoxypropylene Block polymers, alkyl radicals (C)_{12 ～ 18}) Polyoxyethylene seed, polyoxypropylene block polymer ether and like polyOxyethylene, polyoxypropylene block polymer type surfactants; POE alkylamine (C)_{12 ～ 18}) POE fatty amide (C)_{12 ～ 18}) Of the alkylamine type; a bisphenol surfactant such as POE fatty acid bisphenyl ether; polyaromatic surfactants such as POA benzylphenyl (or phenylphenyl) ether, POA styrylphenyl (or phenylphenyl) ether and the like; POE ether and ester type silicon and fluorine type surfactants; POE castor oil, POE hydrogenated castor oil, and other vegetable oil type surfactants. Preferred examples thereof include: polyoxyl (40) stearate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, castor oil polyoxyl (35), lauromacrogol and the like.

Examples of the anionic surfactant include: alkyl sulfates (C)_{12 ～ 18}，Na，NH₄Alkanolamine), POE alkyl ether sulfate (C)_{12 ～ 18}，Na，NH₄Alkanolamine), POE alkylphenyl ether sulfate (C)_{12 ～ 18}，NH₄Alkanolamine, Ca), POE benzyl (or styryl) phenyl (or phenylphenyl) ether sulfate (Na, NH)₄Alkanolamine), polyoxyethylene, polyoxypropylene block polymer sulfate (Na, NH)₄Alkanolamine), etc.; paraffin (paraffin) sulfonate (C)_{12 ～ 22}Na, Ca, alkanolamine), AOS (C)_{14 ～ 16}Na, alkanolamine), dialkyl succinate sulfonate (C)_{8 ～ 12}Na, Ca, Mg), alkylbenzenesulfonate (C)₁₂，Na，Ca，Mg，NH₄Alkyl amines, alkanols, amines, cyclohexylamines), mono-or dialkyl radicals (C)_{3 ～ 6}) Naphthalenesulfonates (Na, NH)₄Alkanolamine, Ca, Mg), naphthalene sulfonate, and condensate (Na, NH) of formaldehyde₄) Alkyl (C)_{8 ～ 12}) Diphenyl ether disulfonate (Na, NH)₄) Lignosulfonates (Na, Ca),POE alkyl (C)_{8 ～ 12}) Phenyl ether sulfonate (Na), POE alkyl (C)_{12 ～ 18}) Sulfonate surfactants such as ether sulfosuccinic acid half-ester (Na); fatty acid salt (C)_{12 ～ 18}，Na，K，NH₄Alkanolamine), N-methyl-fatty acid sarcosinate (C)_{12 ～ 18}Carboxylic acid type surfactants such as Na), resinates (Na, K), etc.; POE alkyl (C)_{12 ～ 18}) Ether phosphates (Na, alkanolamines), POE mono-or dialkyl (C)_{8 ～ 12}) Phenyl ether phosphate (Na, alkanolamine), POE benzyl (or styryl) phenyl (or phenylphenyl) ether phosphate (Na, alkanolamine), polyoxyethylene, seeding and polyoxypropylene block polymer (Na, alkanolamine), phosphatidylcholine, seeding and phosphatidylethanolamine imine (lecithin), alkyl (C)_{8 ～ 12}) Phosphate type surfactants such as phosphates. Preferred examples thereof include: and monoalkyl sulfates such as sodium lauryl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, and sodium octadecyl sulfate, sodium dioctyl sulfosuccinate, sodium lauroyl sarcosinate, and sodium dodecylbenzenesulfonate.

The organic polymer is a substance mainly having carbon as a skeleton and having a molecular weight of 1 ten thousand or more. The organic polymer includes proteins derived from animals and plants, polysaccharides, synthetic resins, and the like.

Specific examples of the organic polymer include: polysaccharides such as hydroxypropyl cellulose (hereinafter, also referred to as HPC), hydroxypropyl methylcellulose, propylene glycol alginate, agar powder, guar gum, zein, and hydroxyethyl methylcellulose, synthetic resins such as carboxyvinyl polymers, polyvinyl alcohol, or vinyl acetate resins, and sodium polystyrene sulfonate, and phosphoproteins such as casein and sodium caseinate.

Among organic polymers, those having a solubility in water of 1g/100g or more are called water-soluble polymers. Specific examples thereof include: hydroxypropyl cellulose, hydroxypropyl methylcellulose, propylene glycol alginate, sodium caseinate, carboxyvinyl polymer, agar powder, guar gum, copovidone, hydroxyethyl methylcellulose, polyvinyl alcohol, and the like.

Among organic polymers, those which dissolve in an acidic condition of gastric juice at pH1.2 to 3.5 are called gastric-soluble polymers, and those which dissolve rapidly in the intestine at pH6 to 8 are called enteric-soluble polymers. Examples of the stomach-soluble polymer include aminoalkyl methacrylate copolymer E and polyvinylacetal diethylaminoacetate, and examples of the intestine-soluble polymer include methacrylic acid copolymer LD (emulsion), methacrylic acid copolymer S, purified shellac, carboxymethylethylcellulose, cellulose acetate phthalate (cellulose acetate), hydroxypropylmethylcellulose acetate succinate, casein, and zeatin.

The pH adjuster means a substance that increases the solubility of a poorly soluble substance by adjusting the pH of a solution by adding an acid agent or an alkali agent. The pH adjuster may be appropriately selected depending on the nature of the substance to be dissolved, and for example, in the case of a basic poorly soluble substance, the solubility may sometimes be improved by adjusting the pH to acidic by adding an acid agent.

Examples of the pH adjuster include adipic acid, citric acid, trisodium citrate, gluconic acid, sodium gluconate, glucono-lactone, potassium gluconate, succinic acid, monosodium succinate, disodium succinate, sodium acetate, L-tartaric acid, potassium L-tartrate, sodium L-tartrate, DL-tartaric acid, potassium DL-tartrate, sodium hydrogen carbonate, potassium carbonate (anhydrous), sodium carbonate, carbon dioxide, lactic acid, sodium lactate, glacial acetic acid, disodium dihydrogen pyrophosphate, fumaric acid, monosodium fumarate, DL-malic acid, sodium DL-malate, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, and disodium hydrogen phosphate.

Preferred examples of the acid include acids such as adipic acid, citric acid, gluconic acid, glucono-lactone, succinic acid, L-tartaric acid, DL-tartaric acid, carbon dioxide, lactic acid, glacial acetic acid, fumaric acid, DL-malic acid, and phosphoric acid.

The preparation of the present invention is particularly preferably a preparation containing a dissolution aid selected from casein, sodium caseinate, skim milk powder, sodium lauryl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate and sodium octadecyl sulfate.

By "orally administrable formulation" is meant a formulation that can be administered orally. By oral administration is meant that the formulation is swallowed by passage into the gastrointestinal tract and the active ingredient is absorbed primarily from the intestinal tract.

The oral administration preparation specifically comprises: solid preparation and liquid preparation such as tablet, capsule, solution, powder, lozenge, chewable agent, granule, gel, pellicle, spray, etc.

Examples of the liquid preparation include: suspensions, solutions, syrups, elixirs and the like. Such formulations can be used as fillers in soft or hard capsules, and typically, as carriers, there can be used, for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose, or suitable oils, and 1 or more emulsifying agents and/or suspending agents. In addition, a liquid preparation can also be prepared by dissolving a solid, for example, a packaged drug in water or the like.

In the present specification, "hardly water-soluble or insoluble" means, for example, that the solubility in water at 25 ℃ is less than 100. mu.g/mL, preferably less than 10. mu.g/mL or the like. The solubility can be measured according to a conventional method.

In the present specification, "improved aqueous solubility" refers to an increase in solubility of FaSSIF as a fasting human small intestine-mimicking fluid. Specifically, the solubility was significantly increased (p < 0.05) in the T-test in comparison with the comparative examples. By "significantly improved water solubility" is meant that the solubility is significantly increased (p < 0.01) by the same significant differential test. By "particularly significantly improved water solubility" is meant that the solubility is significantly increased (p < 0.001) by the same significant differential test.

In the present specification, "ALK" means "Anaplastic Lymphoma Kinase, Anaplastic Lymphoma Kinase", which is a receptor-type tyrosine Kinase belonging to the insulin receptor family.

In the specification of the present application, "substance" represented by formula (I) or a specific chemical name means a compound represented by a prescribed structure, a salt thereof, or a solvate or prodrug thereof.

In the specification of the present application, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like. In the present invention, when a halogen atom is a substituent of an aromatic carbocyclic ring, an aromatic heterocyclic ring or the like, preferable examples of the halogen atom include fluorine, chlorine atom and bromine atom. In the present invention, when a halogen atom is a substituent of an alkyl group or a group (alkoxy group, alkenyl group, unsaturated carbocyclic ring, unsaturated heterocyclic ring, etc.) partially containing an alkyl group, a preferable halogen atom is a fluorine atom. Specific examples thereof include: trifluoromethyl, pentafluoroethyl, pentafluoropropyl, nonafluorobutyl, trifluoromethoxy, pentafluoroethoxy, pentafluoropropoxy, nonafluorobutoxy, trifluoroacetyl, pentafluoropropionyl, pentafluorobutyryl, nonafluorovaleryl, and the like.

“C_1-8The alkyl group is a 1-valent group derived by removing any 1 hydrogen atom from a linear or branched aliphatic hydrocarbon having 1 to 8 carbon atoms. Specific examples thereof include: methyl, ethyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2, 3-dimethylpropyl, hexyl, 2, 3-dimethylhexyl, 1-dimethylpentyl, heptyl, octyl and the like. Preferably C_1-6Alkyl, more preferably C_1-5Alkyl, more preferably C_1-4Alkyl, more preferably C_1-3An alkyl group.

"optionally substituted C_1-8Alkyl "means the aforementioned C unsubstituted_1-8An alkyl group, or a group in which 1 or more hydrogen atoms in the alkyl group are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Further, the alkyl group may be substituted with a cyclic substituent through a spiro bond. Preferably can be coveredC substituted with a predetermined substituent 1 to 3_1-8An alkyl group.

“C_2-8The alkenyl group is a 1-valent group having at least 1 double bond (2 adjacent SP2 carbon atoms) in a linear or branched aliphatic hydrocarbon group having 2 to 8 carbon atoms. As C_2-8Specific examples of the alkenyl group include: vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis, trans), 3-butenyl, pentenyl, hexenyl, and the like. Preferably C_2-6Alkenyl, more preferably C_2-5Alkenyl, more preferably C_2-4Alkenyl, more preferably C_2-3An alkenyl group.

"optionally substituted C_2-8Alkenyl "means unsubstituted the aforementioned C_2-8An alkenyl group or a group in which 1 or more hydrogen atoms in the alkenyl group are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Further, the single bond part of the carbon atom may be substituted with a cyclic substituent through a spiro bond. Preferably C which may be substituted by a predetermined substituent(s) 1 to 3_2-8An alkenyl group. More preferably to C_2-6Alkenyl and C_2-5Alkenyl is 1 to 3 substituents to C_2-3The alkenyl group is a 1-2 substituent.

“C_2-8The alkynyl group refers to a group having a valence of 1 having at least 1 triple bond (2 adjacent SP carbon atoms) in a linear or branched aliphatic hydrocarbon group having 2 to 8 carbon atoms. Specific examples thereof include: ethynyl, 1-propynyl, propargyl, 3-butynyl, and the like. Preferably, C is mentioned_2-6Alkynyl, more preferably C_2-5Alkynyl, more preferably C_2-4Alkynyl, further preferably C_2-3Alkynyl.

"optionally substituted C_2-8Alkynyl "means unsubstituted the aforementioned C_2-8An alkynyl group or a group in which 1 or more hydrogen atoms in the alkynyl group are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Further, the single bond part of the carbon atom may be substituted with a cyclic substituent through a spiro bond. Preferably it is made ofC substituted with a predetermined substituent 1 to 3_2-8Alkynyl. More preferably to C_2-6Alkynyl and C_2-5Alkynyl is 1-3 substituents to C_2-3The alkynyl group is a 1-2 substituent.

“C_3-8Cycloalkyl "means a cyclic aliphatic hydrocarbon group, and preferably C is mentioned_3-6A cycloalkyl group. Specific examples thereof include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Preferably C_3-6A cycloalkyl group.

"optionally substituted C_3-8Cycloalkyl "means unsubstituted the aforementioned C_3-8Cycloalkyl, or C mentioned above_3-8A cycloalkyl group in which 1 or more hydrogen atoms are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Preferably C which may be substituted by a predetermined substituent(s) 1 to 3_3-8A cycloalkyl group.

The term "4-to 10-membered heterocycloalkyl group" means a saturated or partially unsaturated heterocyclic group containing 1 to 3 hetero atoms selected from O, S and N and having 4 to 10 ring-constituting atoms. The heterocycloalkyl group can be monocyclic, or 2-or spiro-heterocyclic. Specific examples thereof include: oxetanyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidino, pyrrolidinyl, piperidino, piperidinyl, piperazino, piperazinyl, morpholino, morpholinyl, tetrahydrothiopyranyl, thiomorpholinyl, imidazolidinyl, 1, 3-dioxazinyl, tetrahydropyranyl, 1, 3-dioxazinyl, 1, 2, 3, 6-tetrahydropyridinyl, 1-oxa-8-aza-spiro [ 4.5 ] decyl, 1, 4-dioxa-8-aza-spiro [ 4, 5] decyl, and the like. Preferably 4-to 8-membered heterocycloalkyl group, more preferably 4-to 6-membered heterocycloalkyl group.

The "optionally substituted 4-to 10-membered heterocycloalkyl group" means the optionally substituted 4-to 10-membered heterocycloalkyl group or a group in which 1 or more hydrogen atoms in the heterocycloalkyl group are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Further, the alkyl moiety may also be substituted with a cyclic substituent by a spiro bond. Preferably a 4-to 10-membered heterocycloalkyl group which may be substituted by the specified substituent(s) 1 to 4. More preferably, 1-4 substituents are used for 4-to 8-membered heterocycloalkyl groups, and 1-3 substituents are used for 4-to 6-membered heterocycloalkyl groups. When the substituent is an oxo group, 2 oxo groups may be bonded to the same sulfur atom. In the case of forming a quaternary ammonium salt, 2 alkyl groups may be bonded to the nitrogen atom.

“C_6-10Aryl "means an aromatic hydrocarbon ring having a valence of 1. As C_6-10Specific examples of the aryl group include phenyl, 1-naphthyl and 2-naphthyl groups.

"optionally substituted C_6-10Aryl "means the aforementioned C unsubstituted_6-10Aryl, or C as aforementioned_6-10A group in which 1 or more hydrogen atoms of the aryl group are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Preferably C which may be substituted by a predetermined substituent(s) 1 to 3_6-10And (4) an aryl group.

"5-to 14-membered heteroaryl" means a group constituting an aromatic ring containing 1 or more heteroatoms in 5 to 14 atoms constituting the ring. The ring may be a monocyclic ring, or a 2-ring heteroaryl group fused to a benzene ring or a monocyclic heteroaromatic ring. Specific examples thereof include: furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzooxadiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imidazopyridinyl, and the like. Preferably 5-6 membered heteroaryl.

The "optionally substituted 5-to 14-membered heteroaryl" refers to an unsubstituted 5-to 14-membered ring heteroaryl or a group in which 1 or more hydrogen atoms in a heteroaryl group are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Preferably a 5-to 14-membered heteroaryl group which may be substituted by a predetermined substituent(s) 1-3. Further, it is preferable that the 5-to 6-membered heteroaryl group is a 1-to 3-substituent or a 1-to 2-substituent.

“C_1-8Alkanoyl "means C_1-8alkyl-C (O) -radical, C_1-8Alkyl groups are as previously described. Specific examples thereof include: acetyl, propionyl, butyryl, isobutyryl, valeryl, tert-butylcarbonyl, hexanoyl and the like. Preferably C_1-6Alkanoyl, more preferably C_1-3An alkanoyl group.

"optionally substituted C_1-8Alkanoyl "means unsubstituted or substituted C_1-8An alkanoyl group or a group in which 1 or more hydrogen atoms in the alkanoyl group are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Preferably C which may be substituted by a predetermined substituent(s) 1 to 3_1-8An alkanoyl group. Further preferred is p-C_1-6Alkanoyl and C_1-3Alkanoyl is 1-2 substituent.

“C_3-8Cycloalkylcarbonyl "means C_3-8cycloalkyl-C (O) -yl, C_3-8Cycloalkyl groups are as previously described. Specific examples thereof include: cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl and the like.

The "4-to 10-membered heterocycloalkylcarbonyl group" means a 4-to 10-membered heterocycloalkyl-CO-yl group having the aforementioned 4-to 10-membered heterocycloalkyl group.

“C_3-8Cycloalkyl (C)_0-8Alkyl) aminocarbonyloxy "means C_3-8cycloalkyl-NHC (O) O-group or C_3-8cycloalkyl-N (C)_1-8Alkyl) C (O) O-radical, C_3-8Cycloalkyl groups are as previously described. Specific examples thereof include: cyclopropylaminocarbonyloxy, cyclobutylaminocarbonyloxy, cyclopentylaminocarbonyloxy, cyclohexylaminocarbonyloxy, cyclopropyl (N-methyl) aminocarbonyloxy, and cyclobutyl (N-methyl) aminocarbonyloxy, and the like.

“（C_1-8Alkyl radical)_x-aminocarbonyl "(wherein x represents a symbol defined in the claims) means NH₂A radical of (C), (O) or (C)_1-8Alkyl) -N-C (O) -yl or (C)_1-8Alkyl radical)₂-N-C (O) -group. Specific examples thereof include: n-methylaminocarbonyl group, N-ethylaminocarbonyl group, N-N-butylaminocarbonyl group, N-dimethylaminocarbonyl group and the like.

"optionally substituted (C)_1-8Alkyl radical)_x-aminocarbonyl "means unsubstituted (C)_1-8Alkyl radical)_xAminocarbonyl group, or a group in which at least 1 or more hydrogen atoms of a nitrogen atom or an alkyl moiety are substituted with a predetermined substituent. In the case of polysubstitution, the substituents may be the same or different.

“C_6-10Aryl radical (C)_0-8Alkyl) aminocarbonyl "means C_6-10Aryl NHC (O) -yl or C_6-10Aryl radical N (C)_1-8Alkyl) C (O) -group. Specific examples thereof include a phenyl-NHC (O) -group, a phenyl- (N-methyl) -aminocarbonyl group and the like. C_6-10Aryl and C_1-8Alkyl groups are as previously described. Specific examples thereof include a phenylaminocarbonyl group and a phenyl (N-methyl) aminocarbonyl group.

"4-to 10-membered nitrogen-containing heterocycloalkyl carbonyl" means a carbonyl group to which a 4-to 10-membered nitrogen-containing heterocycloalkyl group is bonded. Here, the 4-to 10-membered nitrogen-containing heterocycloalkyl group (4-to 10-membered nitrogen-containing heterocycloalkyl group) means a heterocycloalkyl group containing at least 1 nitrogen atom as a hetero atom and composed of 4 to 10 ring-constituting atoms, and is preferably bonded to a carbonyl group through a nitrogen atom in the heterocycloalkyl ring. Specific examples of such heterocycloalkyl groups include pyrrolidinyl, imidazolidinyl, morpholino, piperazino, piperidino, and the like. Examples of the 4-to 10-membered nitrogen-containing heterocycloalkyl carbonyl group include a pyrrolidinylcarbonyl group, a piperidinocarbonyl group, a piperazinocarbonyl group, and a morpholinocarbonyl group.

The "4-to 10-membered nitrogen-containing heterocycloalkylcarbonyl group which may be substituted" means an unsubstituted 4-to 10-membered nitrogen-containing heterocycloalkylcarbonyl group in which 1 or more hydrogen atoms of a heterocycloalkyl moiety are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Further, the heterocycloalkyl moiety may also be substituted with a cyclic substituent through a spiro bond. Preferably a 4-to 10-membered nitrogen-containing heterocycloalkyl carbonyl group which may be substituted by a predetermined substituent(s) 1 to 3.

"4-to 10-membered heterocycloalkyl (C)_0-8Alkyl) aminocarbonyl "means a 4-to 10-membered heterocycloalkyl NHC (O) -yl or a 4-to 10-membered heterocycloalkyl N (C)_1-8Alkyl) C (O) -group. Specific examples thereof include: oxetan-3-yl-amido and (1, 1-dioxo-tetrahydrothiophen-3-yl) amido, and the like.

The "4-to 10-membered heterocycloalkylaminocarbonyl group which may be substituted with 1 or more oxo groups" means the aforementioned 4-to 10-membered heterocycloalkylaminocarbonyl group which is unsubstituted, or a group in which 1 or more oxo groups are substituted with a heterocycloalkyl moiety.

“C_6-10Arylsulfonyl "means C_6-10aryl-S (O)₂A radical, C_6-10Aryl groups are as previously described. Specific examples thereof include phenylsulfonyl and the like.

"5-to 14-membered heteroarylsulfonyl" means 5-to 14-membered heteroaryl-S (O)₂-yl, 5-to 14-membered heteroaryl as hereinbefore described. Specific examples thereof include an imidazole sulfonyl group and the like.

“C_1-8Alkyl radical C_6-10Arylsulfonyl "means C_1-8alkyl-C_6-10aryl-S (O)₂A radical, C_1-8Alkyl and C_6-10Aryl groups are as previously described. Specific examples thereof include 4-methyl-phenylsulfonyl and the like.

“（C_1-8Alkyl radical)_x-amino "(wherein x represents a symbol defined in the claims) means amino, NH (C)_1-8Alkyl) radical, or NH (C)_1-8Alkyl radical)₂And (4) a base. Specific examples thereof include: amino, methylamino, ethylamino, butylamino, isopropylamino, dimethylamino, diethylamino, and the like. Preferably C_1-3An alkylamino group.

"optionally substituted (C)_1-8Alkyl radical)_x-amino "means unsubstituted (C)_1-8Alkyl radical)_xAn amino group or a group in which at least 1 hydrogen atom of a nitrogen atom or an alkyl moiety is substituted with a predetermined substituent. When a plurality of substituents are present, each substituent may be the same or different.

“C_1-8Alkylcarbonyl (C)_0-8Alkyl) amino "means C_1-8alkyl-C (O) -NH-group, or C_1-8alkyl-C (O) -N (C)_1-8Alkyl) -radical, C_1-8Alkyl groups are as previously described. Specific examples thereof include methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino and butylcarbonylamino.

"optionally substituted C_1-8Alkylcarbonyl (C)_0-8Alkyl) amino "means the aforementioned C unsubstituted_1-8Alkylcarbonyl (C)_0-8Alkyl) amino, or C_1-8Alkylcarbonyl (C)_0-8Alkyl) amino group, wherein 1 or more hydrogen atoms of the alkyl moiety at the terminal of the amino group are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Further, the alkyl moiety may also be substituted with a cyclic substituent by a spiro bond. Preferably C which may be substituted by a predetermined substituent(s) 1 to 3_1-8Alkylcarbonyl (C)_0-8Alkyl) amino.

“C_6-10Arylcarbonyl (C)_0-8Alkyl) amino "means C_6-10aryl-C (O) -NH-yl, or C_6-10aryl-C (O) -N (C)_1-8Alkyl) -radical, C_6-10Aryl and C_1-8Alkyl groups are as previously described. Specific examples thereof include phenylcarbonylamino group and the like.

"optionally substituted C_6-10Arylcarbonyl (C)_0-8Alkyl) amino "means the aforementioned C unsubstituted_6-10Arylcarbonyl (C)_0-8Alkyl) amino, or C_6-10Arylcarbonyl (C)_0-8Alkyl) amino group, wherein 1 or more hydrogen atoms of the aryl moiety of the amino group are substituted with a predetermined substituent. Utensil for cleaning buttockWhen there are 2 or more substituents, each substituent may be the same or different. Preferably C which may be substituted by a predetermined substituent(s) 1 to 3_6-10Arylcarbonyl (C)_0-8Alkyl) amino.

“（C_1-8Alkyl radical)_x-aminocarbonyl (C)_0-8Alkyl) amino "(wherein x represents a symbol defined in the claims) means NH₂C (O) NH-group, (C)_1-8Alkyl) NHC (O) NH-group, NH₂C（O）N（C_1-8Alkyl) -radical, or (C)_1-8Alkyl) NHC (O) N (C)_1-8Alkyl) -radical, C_1-8Alkyl groups are as previously described. Specific examples thereof include aminocarbonyl- (N-methyl) amino group and (N-methyl) aminocarbonyl- (N' -methyl) amino group.

"optionally substituted (C)_1-8Alkyl radical)_x-aminocarbonyl (C)_0-8Alkyl) amino "means unsubstituted (C)_1-8Alkyl radical)_x-aminocarbonyl (C)_0-8Alkyl) amino, or (C) wherein at least 1 hydrogen atom of the nitrogen atom or alkyl moiety is substituted by a specified substituent_1-8Alkyl radical)_x-aminocarbonyl (C)_0-8Alkyl) amino. Preferably (C) which may be substituted by phenyl_1-8Alkyl radical)_x-aminocarbonyl (C)_0-8Alkyl) amino.

“（C_1-8Alkyl radical)_xAminosulfonyl (C)_0-8Alkyl) amino "(wherein x represents a symbol defined in the claims) means NH₂S（O）₂NH radical, NH (C)_1-8Alkyl) -S (O)₂NH radical, or N (C)_1-8Alkyl radical)₂-S（O）₂NH radical, NH₂S（O）₂N（C_1-8Alkyl) -radical, NH (C)_1-8Alkyl) -S (O)₂（C_1-8Alkyl) N-yl, or N (C)_1-8Alkyl radical)₂-S（O）₂（C_1-8Alkyl) N-radical, C_1-8Alkyl groups are as previously described. Specific examples thereof include methylaminosulfonylamino group and dimethylaminomethylsulfonylamino group.

“C_1-8Alkoxy "means C_1-8alkyl-O-group. Specific examples thereof include: methoxy group, ethoxy group, 1-propoxy group, 2-propoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, 1-pentyloxy group, 2-pentyloxy group, 3-pentyloxy group, 2-methyl-1-butyloxy group, 3-methyl-1-butyloxy group, 2-methyl-2-butyloxy group, 3-methyl-2-butyloxy group, 2-dimethyl-1-propyloxy group, 1-hexyloxy group, 2-hexyloxy group, 3-hexyloxy group, 2-methyl-1-pentyloxy group, 3-methyl-1-pentyloxy group, 4-methyl-1-pentyloxy group, 2-methyl-2-pentyloxy group, n-butyloxy group, 3-methyl-2-pentyloxy, 4-methyl-2-pentyloxy, 2-methyl-3-pentyloxy, 3-methyl-3-pentyloxy, 2, 3-dimethyl-1-butyloxy, 3-dimethyl-1-butyloxy, 2-dimethyl-1-butyloxy, 2-ethyl-1-butyloxy, 3-dimethyl-2-butyloxy, 2, 3-dimethyl-2-butyloxy, 1-methyl-cyclopropylmethoxy, and the like. Preferably C_1-6Alkoxy, more preferably C_1-5Alkoxy, more preferably C_1-4Alkoxy, more preferably C_1-3An alkoxy group.

"optionally substituted C_1-8Alkoxy "means unsubstituted C_1-8An alkoxy group or a group in which 1 or more hydrogen atoms in the alkyl moiety are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Further, the alkyl moiety may also be substituted with a cyclic substituent by a spiro bond. Preferably C which may be substituted by a predetermined substituent(s) 1 to 3_1-8An alkoxy group. More preferably to C_1-6Alkoxy and C_1-4Alkoxy is a1 to 3 substituent, to C_1-3The alkoxy group is a 1-2 substituent.

“C_1-8Alkoxycarbonyl "means C_1-8alkyl-O-C (O) -radical, C_1-8Alkyl groups are as previously described. Specific examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl and isopropoxycarbonyl. Preferably C_1-6Alkoxycarbonyl, more preferably C_1-3An alkoxycarbonyl group.

"optionally substituted C_1-8Alkoxycarbonyl "means unsubstituted the aforementioned C_1-8Alkoxycarbonyl, or C_1-8A group in which 1 or more hydrogen atoms in the alkoxycarbonyl group are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Further, the alkyl moiety of the alkoxycarbonyl group may be substituted with a cyclic substituent by a spiro bond. Preferably C which may be substituted by a predetermined substituent(s) 1 to 3_1-8An alkoxycarbonyl group.

“C_0-8Alkoxy (C)_0-8Alkyl) aminocarbonyl "means HO-NH-C (O) -group, C_1-8alkyl-NH-C (O) -radical, HO-N (C)_1-8Alkyl) -C (O) -yl, or C_1-8alkyl-N (C)_1-8Alkyl) -C (O) -radical, C_1-8Alkoxy and C_1-8Alkyl groups are as previously described. Specific examples thereof include a methoxyaminocarbonyl group, an ethoxyaminocarbonyl group, an n-propoxylaminocarbonyl group, an isopropoxyaminocarbonyl group and the like. Preferably C_1-6Alkoxyaminocarbonyl, more preferably C_1-3An alkoxyaminocarbonyl group.

"optionally substituted C_0-8Alkoxy (C)_0-8Alkyl) aminocarbonyl "means the aforementioned hydroxyaminocarbonyl, or C, unsubstituted_1-8Alkoxyaminocarbonyl, hydroxy (C)_1-8Alkyl) aminocarbonyl, or C_1-8Alkoxy (C)_1-8Alkyl) aminocarbonyl group in which 1 or more hydrogen atoms in the alkyl moiety are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Further, the alkyl moiety may also be substituted with a cyclic substituent by a spiro bond. Preferably C which may be substituted by a predetermined substituent(s) 1 to 3_1-8An alkoxyaminocarbonyl group.

"4-to 10-membered heterocycloalkyloxy" means a 4-to 10-membered heterocycloalkyl-O-group having the aforementioned 4-to 10-membered heterocycloalkyl group.

The "4-to 10-membered heterocycloalkyloxy group which may be substituted" means the 4-to 10-membered heterocycloalkyloxy group which is unsubstituted, or a group in which 1 or more hydrogen atoms of the heterocycloalkyloxy group are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Further, the heterocycloalkyl moiety may also be substituted with a cyclic substituent through a spiro bond. Preferably a 4-to 10-membered heterocycloalkyloxy group which may be substituted with the specified substituent 1-3.

“C_6-10Aryloxy "means C_6-10aryl-O-radicals, C_6-10Aryl groups are as previously described.

The "5-to 14-membered heteroaryloxy" means a 5-to 14-membered heteroaryl-O-group having the aforementioned 5-to 14-membered heteroaryl group. Specific examples thereof include pyrimidinyloxy group and the like.

“C_1-8Alkylcarbonyloxy "means C_1-8alkyl-C (O) -O-group having the aforementioned C_1-8An alkyl group. Specific examples thereof include methylcarbonyloxy group, ethylcarbonyloxy group, propylcarbonyloxy group and the like.

“C_2-8Alkenylcarbonyloxy "means C_2-8alkenyl-C (O) -O-group, and having the aforementioned C_2-8An alkenyl group. Specific examples thereof include 2-methyl-2-butenyloxy and the like.

The "4-to 10-membered heterocycloalkyl carbonyloxy" means a 4-to 10-membered heterocycloalkyl-C (O) -O-group having the aforementioned 4-to 10-membered heterocycloalkyl group.

“（C_1-8Alkyl radical)_x-aminocarbonyloxy "(wherein x represents a symbol defined in the claims) means NHC (O) -O-yl, N (C)_1-8Alkyl) C (O) -O-group, or N (C)_1-8Alkyl radical)₂C (O) -O-group. Specific examples thereof include: methylamino-carbonyloxy, ethylamino-carbonyloxy, and propylamino-carbonyloxy, and the like.

"optionally substituted (C)_1-8Alkyl radical)_xBy-aminocarbonyloxy "is meant unsubstituted (C)_1-8Alkyl radical)_xAminocarbonyloxy, or on the nitrogen atom or alkyl part toA group in which 1 or less hydrogen atom is substituted with a predetermined substituent. In the case of polysubstitution, the substituents may be the same or different.

The "4-to 10-membered nitrogen-containing heterocycloalkyl sulfonyl group" means the aforementioned 4-to 10-membered nitrogen-containing heterocycloalkyl-S (O)₂-a radical. Specific examples thereof include morpholino-sulfonyl group and the like.

The "4-to 10-membered nitrogen-containing heterocycloalkylsulfonyl group which may be substituted" means the 4-to 10-membered nitrogen-containing heterocycloalkylsulfonyl group which is unsubstituted, or a group in which 1 or more hydrogen atoms of the 4-to 10-membered nitrogen-containing heterocycloalkyi group are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Preferably a 4-to 10-membered nitrogen-containing heterocycloalkylsulfonyl group which may be substituted by the specified substituent 1-3.

The term "4-to 10-membered nitrogen-containing heterocycloalkyl sulfonyloxy" means the aforementioned 4-to 10-membered nitrogen-containing heterocycloalkyl-S (O)₂-O-group. Specific examples thereof include morpholino-sulfonyloxy and piperazino-sulfonyloxy.

The "optionally substituted 4-to 10-membered nitrogen-containing heterocycloalkylsulfonyloxy group" means the aforementioned 4-to 10-membered nitrogen-containing heterocycloalkylsulfonyloxy group which is unsubstituted, or a group in which 1 or more hydrogen atoms of a 4-to 10-membered nitrogen-containing heterocycloalkyi moiety are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Preferably a 4-to 10-membered nitrogen-containing heterocycloalkyl sulfonyloxy group which may be substituted with a predetermined substituent(s) 1 to 3.

“C_1-8Alkylsulfonyloxy "means C_1-8alkyl-S (O)₂-O-group, C_1-8Alkyl groups are as previously described.

"optionally substituted C_1-8Alkylsulfonyloxy "means unsubstituted the aforementioned C_1-8An alkylsulfonyloxy group or a group in which 1 or more hydrogen atoms of an alkyl moiety are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Further, the alkyl moiety may also be cyclized by a spiro bondSubstituted by substituent(s). Preferably C which may be substituted by a predetermined substituent(s) 1 to 3_1-8An alkylsulfonyloxy group. Specific examples thereof include a trifluoromethylsulfonyloxy group.

“（C_1-8Alkyl radical)_x-aminosulfonyloxy "(wherein x represents a symbol defined in the claims) means NH₂S（O）₂O-radical, N (C)_1-8Alkyl) S (O)₂O-radical, or N (C)_1-8Alkyl radical)₂S（O）₂An O-group. Specific examples thereof include an N-methylaminosulfonyloxy group and the like.

“C_1-8Alkylthio "means C_1-8alkyl-S-yl, C_1-8Alkyl groups are as previously described. For example, there are included methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, isobutylthio, tert-butylthio, n-pentylthio, 3-methylbutylthio, 2-methylbutylthio, 1-ethylpropylthio, n-hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, 3-ethylbutylthio, 2-ethylbutylthio and the like. Preferably C_1-6Alkylthio, more preferably C_1-3An alkylthio group.

Optionally substituted C_1-8Alkylthio "means unsubstituted C_1-8Alkylthio groups or groups in which 1 or more hydrogen atoms in the alkyl moiety are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Further, the alkyl moiety may also be substituted with a cyclic substituent by a spiro bond. Preferably C which may be substituted by a predetermined substituent(s) 1 to 3_1-8An alkylthio group.

“C_1-8Alkylsulfonyl "means C_1-8alkyl-S (O)₂A radical, C_1-8Alkyl groups are as previously described. Specific examples thereof include methylsulfonyl group, ethylsulfonyl group, and n-propylsulfonyl group. Preferably C_1-6Alkylsulfonyl, more preferably C_1-3An alkylsulfonyl group.

“C_1-8Alkylsulfinyl "means C_1-8alkyl-S (O) -radical, C_1-8Alkyl groups are as previously described. Specific examples thereof include methylsulfinyl, ethylsulfinyl and n-propylsulfinyl. Preferably C_1-6Alkylsulfinyl, more preferably C_1-3An alkylsulfinyl group.

"optionally substituted C_1-8Alkylsulfonyl "means unsubstituted C_1-8An alkylsulfonyl group or a group in which 1 or more hydrogen atoms of an alkyl moiety are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Preferably C which may be substituted by a predetermined substituent(s) 1 to 3_1-8An alkylsulfonyl group.

"optionally substituted C_1-8Alkylsulfinyl "means unsubstituted the aforementioned C_1-8Alkylsulfinyl or a group in which 1 or more hydrogen atoms of an alkyl moiety are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Preferably C which may be substituted by a predetermined substituent(s) 1 to 3_1-8An alkylsulfinyl group.

"4-to 10-membered heterocycloalkylsulfonyl" means 4-to 10-membered heterocycloalkyl-S (O)₂A group having the aforementioned 4-to 10-membered heterocycloalkyl group.

The "4-to 10-membered heterocycloalkylsulfonyl group which may be substituted" means the 4-to 10-membered heterocycloalkylsulfonyl group which is unsubstituted, or a group in which 1 or more hydrogen atoms of the heterocycloalkyl moiety are substituted with a predetermined substituent. When 2 or more substituents are present, the substituents may be the same or different. Further, the heterocycloalkyl moiety may also be substituted with a cyclic substituent through a spiro bond. Preferably a 4-to 10-membered heterocycloalkylsulfonyl group which may be substituted by the specified substituent 1-3.

“（C_1-8Alkyl radical)_x-aminosulfonyl "(wherein x represents a symbol defined in the claims) means NH₂-S（O）₂-radical, C_1-8alkylamino-S (O)₂A radical or (C)_1-8Alkyl radical)₂amino-S (O)₂A radical, C_1-8Alkyl groups are as previously described. Specific examples thereof include aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.

"optionally substituted (C)_1-8Alkyl radical)_xThe "aminosulfonyl" refers to an unsubstituted aminosulfonyl group or a group wherein at least 1 hydrogen atom on a nitrogen atom or on an alkyl moiety is substituted with a specified substituent. In the case of polysubstitution, the substituents may be the same or different.

“C_1-8Alkoxycarbonyl (C)_0-8Alkyl) amino "means C_1-8alkoxy-C (O) -NH, or C_1-8alkoxy-C (O) -N (C)_1-8Alkyl) radical, C_1-8Alkoxy and C_1-8Alkyl groups are as previously described. Specific examples thereof include a methoxycarbamoyl group, an N-ethylcarbonyl-N-methylamino group and the like.

"optionally substituted C_1-8Alkoxycarbonyl (C)_0-8Alkyl) amino "means the aforementioned C unsubstituted_1-8Alkoxycarbonyl (C)_0-8Alkyl) amino, or C in which at least 1 hydrogen atom on the nitrogen atom or on the alkyl moiety may be substituted by a defined substituent_1-8Alkoxycarbonyl (C)_0-8Alkyl) amino. Preferably C substituted with 1 to 3 substituents_1-8Alkoxycarbonyl (C)_0-8Alkyl) amino.

“C_1-8Alkoxycarbonyl (C)_0-8Alkyl) aminosulfonyl "means C_1-8alkoxy-C (O) -NHS (O)₂A radical, or C_1-8alkoxy-C (O) -N (C)_1-8Alkyl) S (O)₂A radical, C_1-8Alkoxy and C_1-8Alkyl groups are as previously described. Specific examples thereof include methoxycarbonylaminosulfonyl and ethoxycarbonyl-N-methylaminosulfonyl.

“C_6-10Aryloxy carbonyl group (C)_0-8Alkyl) amino "means C_6-10Aryl radicals-O-C (O) -NH group, or C_6-10aryl-O-C (O) -N (C)_1-8Alkyl) radical, C_6-10Aryl and C_1-8Alkyl groups are as previously described. Specific examples thereof include a phenyloxycarbonylamino group and an N-methyl-N-phenyloxycarbonylamino group.

"optionally substituted C_6-10Aryloxy carbonyl group (C)_0-8Alkyl) amino "means the aforementioned C unsubstituted_6-10Aryloxy carbonyl group (C)_0-8Alkyl) amino, or C wherein at least 1 hydrogen atom on the nitrogen atom or on the alkyl moiety is substituted by a specified substituent_6-10Aryloxy carbonyl group (C)_0-8Alkyl) amino. When 2 or more substituents are present, the substituents may be the same or different. Preferably C which may be substituted by a predetermined substituent(s) 1 to 3_6-10Aryloxy carbonyl group (C)_0-8Alkyl) amino.

“C_6-10Aryl radical (C)_0-8Alkyl) aminocarbonyl (C)_0-8Alkyl) amino "means C_6-10aryl-NH-C (O) -NH radical, C_6-10aryl-N (C)_1-8Alkyl) -C (O) -NH, or C_6-10aryl-N (C)_1-8Alkyl) -C (O) -N (C)_1-8Alkyl) radical, C_6-10Aryl and C_1-8Alkyl groups are as previously described. Specific examples thereof include a phenylaminocarbonylamino group, a phenylaminocarbonyl (N-methyl) amino group and the like.

"optionally substituted C_6-10Aryl radical (C)_0-8Alkyl) aminocarbonyl (C)_0-8Alkyl) amino "means the aforementioned C unsubstituted_6-10Aryl radical (C)_0-8Alkyl) aminocarbonyl (C)_0-8Alkyl) amino, or C wherein at least 1 hydrogen atom on the nitrogen atom or on the alkyl moiety is substituted by a specified substituent_6-10Aryl radical (C)_0-8Alkyl) aminocarbonyl (C)_0-8Alkyl) amino. When 2 or more substituents are present, the substituents may be the same or different. Preferably C which may be substituted by a predetermined substituent(s) 1 to 3_6-10Aryl radical (C)_0-8Alkyl) aminocarbonyl (C)_0-8Alkyl) amino.

“C_6-10Aryl radical (C)_0-8Alkyl) aminocarbonyloxy "means C_6-10aryl-NH-C (O) -O-radical, or C_6-10aryl-N (C)_1-8Alkyl) -C (O) -O-radical, C_6-10Aryl and C_1-8Alkyl groups are as previously described. Specific examples thereof include a phenylaminocarbonyloxy group and a phenyl (N-methyl) aminocarbonyloxy group.

"optionally substituted C_6-10Aryl radical (C)_0-8Alkyl) aminocarbonyloxy "means the aforementioned C unsubstituted_6-10Aryl radical (C)_0-8Alkyl) aminocarbonyloxy, or C wherein at least 1 hydrogen atom on the nitrogen atom or on the alkyl moiety is substituted by a defined substituent_6-10Aryl radical (C)_0-8Alkyl) aminocarbonyloxy. When 2 or more substituents are present, the substituents may be the same or different. Preferably C which may be substituted by a predetermined substituent(s) 1 to 3_6-10Aryl radical (C)_0-8Alkyl) aminocarbonyloxy.

“C_1-8Alkylsulfonyl (C)_0-8Alkyl) amino "means C_1-8alkyl-S (O)₂-NH-group or C_1-8alkyl-S (O)₂-N（C_1-8Alkyl) -radical, C_1-8Alkyl groups are as previously described. Specific examples thereof include methylsulfonylamino, ethylsulfonylamino and methylsulfonyl (N-methyl) amino.

“C_2-8Alkenyloxy "means C_2-8alkenyl-O-radicals, C_2-8Alkenyl groups are as previously described. As C_2-8Specific examples of the alkenyloxy group include a vinyloxy group, an allyloxy group and the like.

As a preferred example of the substance represented by the formula (I), A is mentioned¹～A⁴And A⁶～A⁷Is a carbon atom, R³Is cyano, A⁵A substance that is NH.

A further preferred example of the substance represented by the formula (I) is A¹～A⁴And A⁶～A⁷Is a carbon atom, R³Is cyano, A⁵Is NH, R⁸Is 4-to 10-membered heterocycloalkyl or may be substituted by C_3-8A 4-to 10-membered heterocycloalkyl group substituted with a cycloalkyl group.

Specific examples of the substance represented by the formula (I) are preferably selected from the following:

9- (4-isopropyl-piperazin-1-yl) -6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

6, 6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-9-prop-1-ynyl-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-cyclopropylethynyl-6, 6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

6, 6-dimethyl-8- (1-oxetan-3-yl-piperidin-4-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-bromo-6, 6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-bromo-8- (4-cyclopropyl-piperazin-1-yl) -6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-chloro-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

8- (4-cyclobutyl-piperazin-1-yl) -6, 6-dimethyl-11-oxo-9-prop-1-ynyl-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

6, 6, 9-trimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-ethyl-6, 6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-ethyl-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-ethynyl-6, 6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

8- (4-cyclobutyl-piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-ethynyl-6, 6-dimethyl-11-oxo-8- (4-pyrrolidin-1-yl-piperidin-1-yl) -6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

6, 6-dimethyl-11-oxo-8- (4-pyrrolidin-1-yl-piperidin-1-yl) -6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

8- (4-cyclobutyl-piperazin-1-yl) -9-ethynyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

8- (4-cyclobutyl-piperazin-1-yl) -6, 6-dimethyl-11-oxo-9-propyl-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

8- (1-isopropyl-piperidin-4-yl) -6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

8- (4-isopropyl-piperazin-1-yl) -6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

8- (4-cyclobutyl-piperazin-1-yl) -9-cyclopropyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

8- (2-tert-butylamino-ethoxy) -6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-ethynyl-8- (4-methanesulfonyl-piperazin-1-yl) -6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

9-bromo-8- (4-cyclobutyl-piperazin-1-yl) -6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;

6, 6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-9-propyl-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile; and

9-ethynyl-6, 6-dimethyl-8-morpholin-4-yl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile.

More preferred specific examples of the substance represented by the formula (I) include: (i) 6, 6-dimethyl-8- (1-oxetan-3-yl-piperidin-4-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile, (ii) 8- (4-cyclobutyl-piperazin-1-yl) -9-cyclopropyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile, (iii) 8- (4-cyclobutyl-piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile, and pharmaceutically acceptable salts thereof, Or (iv) 9-ethyl-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile or a salt thereof.

(method for producing substance used in the present invention)

Representative manufacturing method

The substance represented by the formula (I) according to the present invention can be produced, for example, by the following method, but the method for producing the compound used in the present invention is not limited thereto. The order of the reaction steps such as introduction of a substituent may be changed as necessary. The compounds used in the present invention are novel compounds which are not described in the literature, but can be produced by a known chemical method. The starting compound used in the production may be a commercially available product or may be produced by a conventional method as needed.

The reaction steps are shown belowIn the formula, A¹～A¹⁰And R¹～R¹⁰As defined in formula (I). PR¹～PR¹⁰Each being R in the definition of formula (I)¹～R¹⁰The same definition, or represents a group convertible to R by functional group modification or deprotection¹～R¹⁰A group of (1).

Other abbreviations used in the following equations have the meanings that are understood by those skilled in the art.

Manufacturing method I

Construction of A in formula (I)⁵Is N, R⁵One of the methods for the skeleton in the case of H.

[ solution 2]

(wherein P represents a protecting group as described above, and when a defined group is subjected to an undesired chemical conversion under the conditions for carrying out the method in the production method described below, a desired compound can be produced by protecting or deprotecting the functional group using an appropriate protecting group.)

Step I-1

Alkylation step of the cyclic ketone derivative Ia. For this step, the cyclic ketone Ia can be reacted with a compound corresponding to R in the presence of a base⁶And R^{6 ‘}The alkylation of the reagent(s) can be carried out, for example, by referring to Journal of the American Chemical Society, 115 (23), 10628-36; 1993. organic Letters, 9 (24), 5027-5029; 2007, and the like. The reaction may be carried out in a solvent in the presence or absence of a catalyst under reaction conditions ranging from-20 ℃ to the boiling point of the solvent. R⁶And R^{6 ‘}The reaction sequence for different radicals other than hydrogen atom can be arbitrarily selected, and separation and purification can be performed in stages,the reaction may also be carried out continuously.

Examples of the alkylating reagent include alkyl halides such as MeI, ethyl iodide, 2-iodopropane, 1, 4-dibromobutane and 1, 1' -oxybis (2-bromoethane), and sulfonic acid esters such as dimethyl sulfuric acid, methyl methanesulfonate, methyl toluenesulfonate and methyl trifluoromethanesulfonate, and preferably alkyl halides such as MeI. Examples of the catalyst include transfer catalysts such as tetrabutylammonium chloride and tetrabutylammonium hydrogen sulfate, and tetrabutylammonium hydrogen sulfate is preferable. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride and calcium hydride, and organic bases such as t-BuOK, t-BuONa, pyridine, TEA (trifluoroacetic acid), DIPEA (N, N-diisopropylethylamine), LDA (lithium diisopropylamide), LiHMDS (lithium hexamethyldisilazide), and N-BuLi, and potassium hydroxide, potassium tert-butoxide and sodium tert-butoxide are preferable. Examples of the solvent include toluene, xylene, N-hexane, cyclohexane, DMF (N, N-dimethylformamide), DMA (N, N-dimethylacetamide), EtOAc, DMSO (dimethyl sulfoxide), dichloromethane, carbon tetrachloride, THF (tetrahydrofuran), dioxane, acetonitrile, and the like, water, methanol, ethanol, and the like, and a mixture thereof, and water-THF mixed solvent and THF are preferable.

Step I-2

Synthesis of carbazole skeleton Id by Fischer method. This step is usually carried out by reacting the cyclic ketone Ib in a solvent or with the acid itself as a solvent in the presence of the hydrazine compound Ic and an acid under reaction conditions of from 0 ℃ to the boiling point of the solvent, and for example, reference may be made to "Journal of Heterocyclic Chemistry, 28 (2), 321-3; 1991. bioorganic & Medicinal Chemistry Letters (2008), 18 (24), 6479-. In addition, when the reaction rate is low, a zinc chloride catalyst or the like can be used, for example, under the conditions described in "Organic Letters (2006), 8 (3), 367-. The reaction is composed of a phenylhydrazone production process and a sigma shift rearrangement process, and may be separated and purified at each stage or may be carried out continuously. In this step, depending on the structure of the arylhydrazine of the starting material, a mixture of positional isomers may be obtained as a reaction product. These positional isomers may be used separately or as a mixture in a subsequent step.

Examples of the acid used in the reaction include formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, TFA, hydrochloric acid, sulfuric acid, pyridinium p-toluenesulfonate, and the like, and acetic acid, sulfuric acid, and TFA are preferable. Examples of the solvent include: toluene, xylene, NMP (N-methylpyrrolidone), DMF, DMA, DMSO, sulfolane, dioxane, DME (dimethoxyethane), TFE (trifluoroethanol), diethylene glycol, triethylene glycol, and the like, and mixtures thereof.

Step I-3

A step of oxidation at the benzyl position at the 11-position of the carbazole skeleton Id. The step is carried out by reacting an oxidizing agent with a substrate in a solvent in the presence or absence of a catalyst under reaction conditions of-20 ℃ to the boiling point of the solvent. As the reaction conditions, for example, "Journal of Medicinal Chemistry, 51 (13), 3814-3824; 2008 ", and the like.

As the oxidizing agent and the catalyst used in the reaction, there may be used either singly or in combination: peracids such as DDQ and mCPBA, permanganate such as cerium (IV) ammonium nitrate (CAN), potassium permanganate, barium permanganate, and the like, sodium chlorite, hydrogen peroxide, N-hydroxyphthalimide, and the like, and DDQ (2, 3-dichloro-5, 6-dicyano-p-benzoquinone) and N-hydroxyphthalimide are preferable. Examples of the solvent used in the reaction include water, t-butanol, acetonitrile, THF, dichloromethane, ethyl acetate, and a mixture thereof, and THF is preferred.

In the present invention, as the salt of the compound represented by the formula (I), for example, there are included: sulfonates such as hydrochloride, hydrobromide, hydroiodide, phosphate, phosphonate, sulfate, methanesulfonate and p-toluenesulfonate, carboxylates such as acetate, citrate, malate, tartrate, succinate and salicylate, or alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salts and calcium salts; ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts and tetraalkylammonium salts.

Preferably, the hydrochloride and the methanesulfonate are mentioned, and more preferably, the hydrochloride is mentioned.

These salts are produced by bringing the compound into contact with an acid or a base which can be used for the production of a pharmaceutical.

In the present invention, the compound represented by the formula (I) or a salt thereof may be an anhydride or may form a solvate such as a hydrate. As used herein, "solvation" refers to the phenomenon in which solute molecules or ions strongly attract adjacent solvent molecules in solution to form a molecular group, and for example, if the solvent is water, it is referred to as hydration. The solvate may be either a hydrate or a non-hydrate. As the non-hydrate, an alcohol (e.g., methanol, ethanol, n-propanol), dimethylformamide, or the like can be used.

In addition, in the compounds of the invention and their salts, several tautomeric forms may be present, such as, for example, the enol and imine forms, the ketone and enamine forms, and mixtures thereof. Tautomers exist in solution as mixtures of tautomeric combinations. In solid form, typically, one tautomer predominates. Although one tautomer is sometimes described, the present invention includes all tautomers of the compounds of the present invention.

Included in the present invention are all stereoisomers (e.g., enantiomers, diastereomers (including cis and trans geometric isomers)), racemates of the foregoing isomers, and other mixtures of the compounds of formula (I). For example, formula (I) may have more than 1 point of asymmetry for the compounds of the present invention, including racemic mixtures, diastereomeric mixtures, and enantiomers of such compounds.

When the compound of the present invention is obtained in a free form, it can be converted into a state of a salt which the compound can form, or a hydrate or solvate thereof, according to a conventional method.

When the compound of the present invention is obtained as a salt, hydrate, or solvate of the compound, the compound can be converted into a free form of the compound according to a conventional method.

In addition, the substances used in the present invention also include prodrugs of the compounds of the formula (I). Here, "prodrug" means a derivative of the compound of formula (I) which is converted into the compound of formula (I) or a pharmaceutically acceptable salt thereof by enzymatic or non-enzymatic decomposition under physiological conditions after administration. A prodrug is a substance that is inactive when administered to a patient, but is present in vivo as a compound of formula (I) that is converted to activity.

For example, a prodrug is converted to the desired drug form upon reaching a particular pH, or by the action of an enzyme. A typical prodrug is a compound that generates a free acid in vivo, and is a compound having a hydrolyzable ester residue. Such hydrolyzable ester residues include, for example, the following residues, but are not limited thereto: a residue of a carboxyl moiety having a free hydrogen (e.g., a free hydrogen in a carboxyl group when Y in formula (I) has the carboxyl group) substituted with: c_1-4Alkyl radical, C_2-7An alkanoyloxymethyl group, a 1- (alkanoyloxy) ethyl group having 4 to 9 carbon atoms, a 1-methyl-1- (alkanoyloxy) -ethyl group having 5 to 10 carbon atoms, an alkoxycarbonyloxymethyl group having 3 to 6 carbon atoms, a 1- (alkoxycarbonyloxy) ethyl group having 4 to 7 carbon atoms, a 1-methyl-1- (alkoxycarbonyloxy) ethyl group having 5 to 8 carbon atoms, an N- (alkoxycarbonyl) aminomethyl group having 3 to 9 carbon atoms, a 1- (N- (alkoxycarbonyl) amino) ethyl group having 4 to 10 carbon atoms, a 3-phthalidyl group, a 4-crotonolactone group, a γ -butyrolactone-4-yl group, a di-N, N- (C)_1-2) Alkylamino radical (C)_2-3) Alkyl (e.g. N, N-dimethylaminoethyl), carbamoyl- (C)_1-2) Alkyl, N-di (C)_1-2) Alkylcarbamoyl-, (C_1-2) Alkyl, piperidino (C)_2-3) Alkyl, pyrrolidino (C)_2-3) Alkyl, or morpholino (C)_2-3) An alkyl group.

The preparation of the present invention can be produced by a known method using additives such as an excipient, a lubricant, a coating agent, a binder, a disintegrant, a stabilizer, a flavoring agent, and a diluent.

Examples of the excipient include: starches such as corn starch, potato starch, flour starch, rice starch, partially gelatinized starch, and porous starch; sugars or sugar alcohols such as lactose hydrate, fructose, glucose, mannitol, and sorbitol; anhydrous calcium hydrogen phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate, and the like. Preferred excipients include: starch such as starch, potato starch, and corn starch, lactose hydrate, crystalline cellulose, and anhydrous calcium hydrogen phosphate.

The formulation of the present invention preferably uses lactose hydrate and crystalline cellulose as excipients. The amount of lactose hydrate used is preferably 5 to 60 parts by weight, and more preferably 10 to 50 parts by weight, per 100 parts by weight of the preparation. The amount of crystalline cellulose used is preferably 5 to 60 parts by weight, and more preferably 10 to 50 parts by weight, per 100 parts by weight of the preparation.

Examples of the disintegrant include: the same compounds as the above excipients, and chemically modified starches such as croscarmellose sodium, sodium starch glycolate and crosslinked polyvinylpyrrolidone, and seeds and celluloses. Specific examples of the disintegrant include: sodium starch glycolate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substitution hydroxypropyl cellulose, hydroxypropyl starch, and the like. The amount of the disintegrant used is preferably 0.5 to 25 parts by weight, more preferably 1 to 15 parts by weight, per 100 parts by weight of the preparation.

Examples of the binder include: polyvinylpyrrolidone, polyethylene glycol and the same compounds as the aforementioned excipients. Specific examples of the binder include: hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone (polyvinylpyrrolidone), acacia powder, and the like. The amount of the binder is preferably 0.1 to 50 parts by weight, more preferably 0.5 to 40 parts by weight, per 100 parts by weight of the preparation.

Suitable examples of the lubricant include, for example: magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, etc.

Examples of the surfactant or emulsifier include: polysorbate 80, polyoxyl (40) stearate, lauromacrogol, and the like.

The colorant may be any colorant as long as it is acceptable for addition to a pharmaceutical product, and examples thereof include: edible pigment such as edible yellow No. 5 (sunset yellow, American edible yellow No. 6), edible red No. 2, edible blue No. 2, etc., edible lake pigment, ferric oxide, etc.

Examples of the stabilizer include: parabens such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol, and phenyl ethanol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.

Examples of the taste corrigent include commonly used sweeteners, souring agents, and perfumes.

The fluidizing agent is used for improving the fluidity of the mixed powder or the granules, and typical examples thereof include talc, light anhydrous silicic acid as silica, and hydrated silica. Here, the light anhydrous silicic acid may be mainly composed of a water-containing silicon dioxide (SiO 2 seed) (n represents an integer) (h 2O), and specific examples thereof include: サイリシア 320 (trade name, fuji シリシア chemical strain)), アエロジル 200 (trade name, japanese アエロジル (strain)), and the like.

As suitable examples of preservatives, there may be used, for example: parabens, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like.

As suitable examples of antioxidants, there may be used, for example: sulfites, ascorbic acid, and the like.

The above additives may be used by mixing 2 or more kinds thereof at an appropriate ratio.

As a solvent for producing a solution, ethanol, phenol, chlorocresol, pure water, distilled water, or the like can be used.

The solid preparation of the present invention can be produced by a widely used production method by mixing the substance used in the present invention with a dissolution aid and a pharmaceutically acceptable carrier. The production method is preferably as follows.

1) The solid preparation of the present invention is produced by mixing the substance used in the present invention with additives selected from the additive group a, excipients, disintegrants, lubricants and the like, and then filling the mixture into capsules or compression molding the mixture.

2) The substance used in the present invention is mixed with additives selected from the additive group a, such as an additive, an excipient, and a binder, and then granulated while adding or spraying a solvent (e.g., pure water, ethanol, or a mixture thereof). The solid preparation of the present invention is produced by adding an appropriate amount of a lubricant, a disintegrant if necessary, or the like to the obtained granulated product, mixing the mixture, and then filling the mixture in a capsule or compression molding the mixture.

3) The substance used in the present invention is mixed with additives selected from the additive group a, excipients, and the like, and then granulated while adding or spraying a solution obtained by dispersing or dissolving a binder and, if necessary, other additives in a solvent (for example, pure water, ethanol, or a mixture thereof). The solid preparation of the present invention is produced by adding an appropriate amount of a lubricant to the obtained granules, mixing the mixture with a disintegrant or the like as needed, and filling the mixture into a capsule or compression-molding the mixture.

Sugar-coated tablets or film-coated tablets can be obtained from the tablets by further using an appropriate coating agent.

As the sugar coating base, for example, sugar or sugar alcohol such as white sugar or erythritol can be used, and further, 1 or 2 or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like can be used in combination.

Examples of the coating agent include: ethyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, paraffin wax and the like.

Examples of enteric film coating bases include: cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; acrylic polymers such as methacrylic acid copolymer L [ オイドラギット L (trade name), エボニックデグサ Co., Ltd ], methacrylic acid copolymer LD [ オイドラギット L-30D55 (trade name), エボニックデグサ Co., Ltd ], methacrylic acid copolymer S [ オイドラギット S (trade name), エボニックデグサ Co., Ltd ]; shellac and the like.

Examples of the sustained-release film-coating base include: cellulose polymers such as ethyl cellulose; acrylic polymers such as aminoalkyl methacrylate copolymers RS [ オイドラギット RS (trade name), エボニックデグサ society ], ethyl acrylate and seeded methyl methacrylate copolymer suspensions [ オイドラギット NE (trade name), エボニックデグサ society ]; cellulose acetate, and the like.

The coating base may be used by mixing 2 or more thereof at an appropriate ratio.

The coating agent may contain a water-soluble substance or a plasticizer for adjusting the dissolution rate, if necessary. The water-soluble substance may be 1 or more selected from water-soluble polymers such as hydroxypropyl methylcellulose, sugar alcohols such as mannitol, sugars such as white sugar and anhydrous maltose, surfactants such as sucrose fatty acid ester, polyoxyethylene polyoxypropylene glycol, polysorbate, and sodium lauryl sulfate. As the plasticizer, 1 or more selected from the group consisting of acetyl monoglyceride, triethyl citrate, triacetin, dibutyl sebacate, dimethyl sebacate, medium-chain fatty acid triglyceride, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, dibutyl adipate, oleic acid, oleyl alcohol, and the like can be used.

In addition, as a method for coating a tablet with the coating layer, a general method can be used, and examples thereof include: pan coating, flow coating, rotary coating, and flow rotary coating. The coating solution used in this method can be obtained by mixing the coating base with the talc and a solvent (preferably ethanol or a mixture of ethanol and water). The solid content concentration of the coating liquid is preferably in the range of 5 to 15 mass% based on the total mass of the coating liquid.

These methods comprise the step of administering to a patient in need of such treatment or suffering from such a disease or condition a pharmaceutically effective amount of a pharmaceutical composition containing the disclosed agents for use in the invention.

The substance used in the present invention has an excellent ALK inhibitory activity, is excellent in stability in vivo and solubility in water, and is useful as a prophylactic or therapeutic agent (particularly a therapeutic agent) for proliferative diseases. In addition, the compound of the present invention or a pharmaceutically acceptable salt thereof is useful as a prophylactic or therapeutic agent (particularly, a therapeutic agent) for the following diseases: leukemia (acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphatic leukemia, chronic lymphatic leukemia, etc.), malignant lymphoma (Hodgkin's lymphoma, non-Hodgkin's lymphoma, etc.), brain tumor, neuroblastoma, glioma, thyroid cancer, myelodysplastic syndrome, head and neck cancer, esophageal cancer, gastric cancer, colorectal cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer, liver cancer, gallbladder cancer, skin cancer, malignant melanoma, kidney cancer, nephroureteral cancer, bladder cancer, ovarian cancer, uterine cancer, testicular cancer, and pre-malignant adenocarcinoma. Further, the compounds of the present invention are useful as a prophylactic or therapeutic agent (particularly a therapeutic agent) for infiltration of solid tumors and seed transfer. Further, the substance used in the present invention is also effective as a prophylactic or therapeutic agent for other diseases associated with ALK, for example, depression and cognitive dysfunction.

When the pharmaceutical composition of the present invention is used as an ALK inhibitor, a therapeutic or prophylactic agent for proliferative diseases, or for the treatment of depression or cognitive dysfunction, examples of the administration method include: oral administration, rectal administration, non-oral administration (intravenous administration, intramuscular administration, subcutaneous administration), intracisternal administration, intravaginal administration, intraperitoneal administration, intravesical administration, topical administration (drops, powders, ointments, gels or creams) administration, and inhalation administration (oral or nasal spray), and the like. Examples of administration methods include: tablets, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions, and non-oral solutions filled in containers suitable for subdivision into individual dosage amounts. In addition, the mode of administration is also suitable for various administration methods including subcutaneous implantation of such controlled release formulations.

Oral administration using tablets, capsules, granules, powders, pills and the like is preferred.

The above-mentioned preparation can be produced by a known method using additives such as an excipient, a lubricant (coating agent), a binder, a disintegrant, a stabilizer, a flavoring agent, and a diluent.

When the pharmaceutical composition of the present invention is used as an ALK inhibitor, or a therapeutic or prophylactic agent for a proliferative disease, or for the treatment of depression or cognitive dysfunction, the amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to be used varies depending on the symptoms, age, body weight, relative health state, presence of other administration, administration method, and the like.

When the pharmaceutical composition of the present invention is used as an ALK inhibitor, or a therapeutic or prophylactic agent for proliferative diseases, or for the treatment of depression or cognitive dysfunction, the amount of the compound of the present invention or a salt or solvate thereof to be used varies depending on the symptoms, age, body weight, relative health state, presence of other administration, administration method, and the like. For example, in a case of oral preparations, the amount of the compound of the present invention represented by formula (I) as an active ingredient is preferably 0.001 to 1000mg per 1kg body weight per day, more preferably 0.01 to 300mg per 1kg body weight per day, and the amount of the compound used per day is preferably in the range of 1 to 800mg for an adult patient of normal body weight. In the case of a non-oral preparation, the amount is preferably 0.001 to 1000mg per 1kg body weight per day, more preferably 0.01 to 300mg per 1kg body weight. It is desirable to administer it 1 or several times a day, corresponding to symptoms.

The pharmaceutical composition of the present invention may be combined with other chemotherapeutic agents, hormonal therapy agents, immunotherapy agents, molecular targeting drugs, and the like.

Examples of the "chemotherapeutic agent" include: alkylating agents, platinum agents, metabolic antagonists, topoisomerase inhibitors, anticancer antibiotics, plant-derived anticancer agents, and the like. Examples of the "alkylating agent" include: nitrogen mustard, mechlorethamine hydrochloride-N-oxide, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carboquone, prasuzulene sulfonate, busulfan, nimustine hydrochloride, dibromomannitol, melphalan, dacarbazine, ranimustine, estramustine sodium phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, ethodridine, hexamethylmelamine, amtemustine, dibromospiro ammonium hydrochloride (dibromopidium hydrochloride), fotemustine, prednimustine, purepidopepidopepidine, bendamustine hydrochloride, temozolomide, busulfan, cyclophosphamide chloride, stastine, carboquone, aldesynin, sittemustine (cytin), bizelesin, and the like. Examples of the "platinum preparation" include: carboplatin, cisplatin, miriplatin, nedaplatin, oxaliplatin, and the like. Examples of the "metabolic antagonist" include: mercaptopurine, 6-mercaptopurine nucleosides, thioinosine, methotrexate, enocitabine, cytarabine octadecylphosphate, cyclocytidine hydrochloride, 5-FU series agents (e.g., fluorouracil, tegafur, UFT, fluorouracil deoxynucleoside, carmofur, galocidine, epetifur, etc.), aminopterin, leucovorin calcium, thioguanine, butocine (butocin), calcium folinate, calcium levofolinate, cladribine, ethimidifluoride, fludarabine, gemcitabine, hydroxyurea, pentostatin, pyridoxine, idoxuridine, mitoguazone, thiazolfurin, amostine, etc. Examples of the topoisomerase I inhibitor (e.g., irinotecan, topotecan, etc.), the topoisomerase II inhibitor (e.g., Sobuzoxan, etc.), and the "anticancer antibiotic" include: anthracycline anticancer drugs (doxorubicin hydrochloride, daunorubicin hydrochloride, doxorubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, etc.), actinomycin D, actinomycin C, mitomycin C, tryptomycin A3, bleomycin hydrochloride, bleomycin sulfate, pelomycin sulfate, neocarzinostatin, mithramycin, sarcomycin, carzinostat, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, etc. Examples of the "plant-derived anticancer agent" include: vinca alkaloids are anticancer drugs (vinblastine sulfate, vincristine sulfate, vindesine sulfate, etc.), taxane anticancer drugs (paclitaxel, docetaxel, etc.), etoposide phosphate, teniposide, vinorelbine, etc.

Examples of the "hormone therapy preparation" include: examples of the adrenocortical hormone-based drug include dexamethasone, prednisolone, betamethasone, and triamcinolone acetonide, and prednisolone is preferable.

Examples of the "immunotherapy preparation (BRM)" include: streptolysin preparation, coriolus versicolor polysaccharide K, sisofilan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, lymphotoxin, BCG vaccine, corynebacterium parvum, levamisole, polysaccharide K, propiconazole and the like.

The "molecular targeting drug" contains a "drug inhibiting the action of a cell growth factor and its receptor", and the "cell growth factor" may be any substance that promotes cell growth, and generally, a peptide having a molecular weight of 20000 or less and a factor that acts at a low concentration by binding to a receptor are exemplified by: (1) EGF (epidermal growth factor) or a substance having substantially the same activity as it [ e.g., EGF, human epidermal growth factor (HER 2 ligand), etc. ], (2) insulin or a substance having substantially the same activity as it [ e.g., insulin, IGF (insulin-stimulating factor, insulin-like growth factor) -1, IGF-2, etc. ], (3) FGF (fibroblast growth factor ) or a substance having substantially the same activity as it [ e.g., acidic FGF, basic FGF, KGF (keratinocytic growth factor, keratinocyte growth factor), FGF-10, etc. ], (4) VEGF (vascular endothelial growth factor), (5) other cell proliferation factor [ e.g., CSF (collagen, erythropoietin stimulating factor), EPO (erythropoietin, interleukin-2), interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGF β (transformingrowth factor β), HGF (hepatocyte growth factor), and the like).

The "receptor for a cell growth factor" may be any receptor having a binding ability to the cell growth factor, and specific examples thereof include: EGF receptor, human epidermal growth factor receptor (HER 2), insulin receptor, IGF receptor, FGF receptor-1 or FGF receptor-2, HGF receptor (c-met), VEGF receptor, SCF receptor (c-kit), and the like. Examples of the "agent for inhibiting the action of a cell growth factor" include: trastuzumab (HER 2 antibody), GLEEVEC (c-kit, abl inhibitor), Iressa (EGF receptor inhibitor), etc.

In addition, the present invention also includes a drug which inhibits the action of a plurality of cell growth factors with one drug, or a drug which blocks intracellular information generated by cell growth factors.

In addition to the above agents, L-asparaginase, aceglutamide, procarbazine hydrochloride, protoporphyrins, seeds and cobalt complexes, mercury hematoporphyrins, seeds and sodium, differentiation inducers (e.g., retinoids, vitamin D agents, etc.), angiogenesis inhibitors, α -blockers (e.g., tamsulosin hydrochloride, etc.), and the like can be used.

Of the above, preferred examples of the concomitant drug include platinum complexes (e.g., carboplatin, cisplatin, oxaliplatin, etc.), taxane drugs (e.g., paclitaxel, docetaxel), topoisomerase I inhibitors (e.g., irinotecan, topotecan, etc.), vinorelbine, gemcitabine, anticancer drugs (e.g., mitomycin C), and molecular targeting drugs (e.g., VEGF inhibitors). In addition, the composition can be used in combination with therapy using these agents. For example, combinations of cisplatin and vinblastine and mitomycin C, cisplatin and vinorelbine, cisplatin and paclitaxel, cisplatin and gemcitabine, carboplatin and paclitaxel, and the like can be used in combination therapy.

The solid preparation of the present invention and the concomitant agent may be administered at any time, and they may be administered simultaneously with the subject or with a time difference therebetween. In addition, the solid preparation and the concomitant agent of the present invention may be prepared as a single preparation containing them and administered to a subject. For example, there are a combination therapy of multiple doses in which multiple drugs are combined for drip injection over 3 to 6 months, or a method of taking an oral preparation over about 2 years.

In addition, preoperative adjuvant therapy such as "chemotherapy" may be performed before the operation is performed in order to suppress already scattered cancer cells, prevent recurrence due to metastasis, or reduce the range of the operation.

Furthermore, only local treatment such as surgery and radiation is insufficient, and postoperative adjuvant therapy such as "chemotherapy" may be performed to suppress the development of residual cancer cells and prevent recurrence due to metastasis.

Furthermore, the combined anticancer agent acts on both cancer cells and normal cells, and is shown as a side effect. Representative side effects are: nausea, vomiting, inappetence, stomatitis, diarrhea, constipation, taste abnormalities, reduction of leukocytes, seeds, red cells, seeds, and platelets due to damage to the digestive tract mucosa, reduction of seeds, red cells, seeds, and platelets, and reduction of immunity, which are caused by damage to the digestive tract mucosa, may be used in combination with a side effect-reducing agent for suppressing these side effects. Examples thereof include: an antiemetic agent (e.g., granisetron hydrochloride) effective for suppressing nausea, a drug (e.g., erythropoietin, G-CSF, GM-CSF) effective for promoting recovery from bone marrow damage, and the like.

The dose of the concomitant agent to be administered can be appropriately selected based on the clinically usable dose. The mixing ratio of the solid preparation of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, the administration route, the disease, symptom, combination, and the like of the subject. For example, when the subject to be administered is a human, 0.01 to 100 parts by weight of the concomitant agent can be used relative to 1 part by weight of the solid preparation.

[ examples ]

The present invention will be described in further detail below with reference to reference examples, examples and test examples, but the present invention is not limited thereto.

NMR analysis was carried out using JNM-EX270 (270 MHz) manufactured by JEOL, JNM-GSX400 (400 MHz) manufactured by Varian, and NMR data are expressed in ppm (parts per million) (), and reference is made to the deuterium lock signal from the sample solvent.

Mass spectra were obtained using JMS-DX303 manufactured by JEOL, or JMS-SX/SX102A manufactured by the same society.

Mass spectrum data (LC-MS) including high performance liquid chromatography were obtained using "マイクロマス (Micromass)" (ZMD, Micromass) including 996-600E gradient high performance liquid chromatography manufactured by Waters, or "マイクロマス (Micromass)" including 2525 gradient high performance liquid chromatography manufactured by Waters (ZQ, Micromass).

The conditions for high performance liquid chromatography used were those shown in the following table.

[ Table 1]

TABLE 1

The commercially available reagent was used without further purification. The room temperature is about 20-25 ℃. All non-aqueous reactions were carried out in anhydrous solvents under nitrogen or argon atmosphere. Concentration under reduced pressure or solvent distillation removal use a rotary evaporator.

An example of producing the substance represented by the formula (I) used in the present invention will be described below.

(reference example 1)

Compound J2

6- Methoxy radical -1 ， 1- Dimethyl group -3 ， 4- Dihydro -1H- Naphthalene -2- Ketones

[ solution 3]

By the same conditions as the synthesis method of the compound B1 (7-methoxy-3, 4-dihydro-1H-naphthalen-2-one was converted to (Compound A1, 209g, 1.18 mol), tetrabutylammonium hydrogen sulfate (40 g, 0.118 mol) and methyl iodide (162 g, 2.60 mol) were suspended in THF (500 ml) at room temperature, 50% aqueous potassium hydroxide (400 g) was added over 5 minutes while stirring, the internal temperature rose sharply and reflux occurred, after the internal temperature rose, stirring was continued for 45 minutes, the reaction solution was diluted with 1L of distilled water, and extracted twice with 1.5L of CPME, the combined organic layers were washed (1L of × 3) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting crude product was recrystallized from 1LMeOH and 500ml of distilled water to give compound B1 as colorless needle crystals (1)7- Methoxy radical -1 、 1- Dimethyl group -3 、 4- Dihydro -1H- Naphthalene -2- Ketones)(177 g, 73%)) the title compound was synthesized from 6-methoxy-3, 4-dihydro-1H-naphthalen-2-one and iodomethane.

LCMS：　m/z　205　［M＋H］^＋

HPLC retention time: score 1.54 (analytical conditions S).

(reference example 2)

Compound J3-1

9- Methoxy radical -6 ， 6- Dimethyl group -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 4]

By the same conditions as those for the synthesis of compound E2-1 (6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydro-1H-naphthalen-2-one (7.89 g, 27.85 mmol) and 3-hydrazino-benzonitrile (4.45 g, 1.2 equiv.) were dissolved in TFA (250 mL), stirred at 100 ℃ for 2 hours, after TFA was removed by concentration under reduced pressure, saturated NaHC was added to the residueO₃The aqueous solution (500 mL) was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. After the drying agent was filtered off, ethyl acetate was added to the residue obtained by concentration under reduced pressure, and the mixture was stirred at room temperature, and the precipitated solid was filtered. Concentrating the filtrate under reduced pressure to obtain the compound E2-29- Bromine compound -8- Methoxy radical -6 ， 6- Dimethyl group -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -1- Carbonitrile)Compound E2-1 (c)9- Bromine compound -8- Methoxy radical -6 ， 6- Dimethyl group -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Carbonitrile)(yellow-white powder, 2.65 g)) from compound J2 and 3-hydrazino-benzonitrile the title compound was synthesized.

LCMS：　m/z　303　［M＋H］^＋

HPLC retention time: score 2.73 (analytical conditions S).

(reference example 3)

Compound J3-2

9- Methoxy radical -6 ， 6- Dimethyl group -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -1- Nitrile (A) to methyl cyanide

[ solution 5]

Compound J3-2 was obtained as a by-product in the synthesis of compound J3-1.

LCMS：　m/z　303　［M＋H］^＋

HPLC retention time: score 2.67 (analytical conditions S).

Production example 1

Compound J4

9- Methoxy radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 6]

The title compound was synthesized from compound J3-1, J3-2 (mixture) by the same conditions as the synthesis method of compound a 4.¹H-NMR(DMSO-D₆) : 12.79 (1H, s),8.33 (1H, d, J = 8.2 Hz), 8.02 (1H, s), 7.81 (1H, d, J = 8.6 Hz), 7.69 (1H, d,J = 3.0 Hz), 7.63 (1H, dd, J = 8.3, 1.4 Hz), 7.28 (1H, dd, J = 8.7, 3.0 Hz),3.87 (3H, s), 1.74 (6H, s).

LCMS: m/z 317 [M+H]⁺

HPLC retention time: and 2.25 points (analysis condition S).

Production example 2

Compound J5

9- Hydroxy radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 7]

The title compound was synthesized from compound J4 under the same conditions as the synthesis method of compound a 6.

¹H-NMR(DMSO-D₆) : 12.75 (1H, s),9.77 (1H, s), 8.32 (1H, dd, J = 8.2, 0.7 Hz), 8.01 (1H, s), 7.68 (1H, d, J = 8.6Hz), 7.62 (1H, dd, J = 8.2, 1.4 Hz), 7.58 (1H, d, J = 2.8 Hz), 7.10 (1H, dd, J= 8.6, 2.8 Hz), 1.72 (6H, s).

LCMS: m/z 303 [M+H]⁺

HPLC retention time: score 1.75 (analytical conditions S).

(production example 3)

Compound J6

Trifluoro benzene radical - Methanesulfonic acid 3- Cyano radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -9- Esters of phenyl or naphthyl

[ solution 8]

The title compound was synthesized from compound J5 under the same conditions as the synthesis method of compound B1.

¹H-NMR(DMSO-D₆) : 12.95 (1H, s),8.31 (1H, d, J = 8.2 Hz), 8.15 (2H,m), 8.05 (1H, s), 7.87 (1H, dd, J = 9.0, 2.7Hz), 7.65 (1H, d, J = 8.2 Hz), 1.80 (6H, s).

LCMS: m/z 435 [M+H]⁺

HPLC retention time: score 2.75 (analytical conditions S).

Production example 4

Compound J7-4

9- （ 4- Isopropyl group - Piperazine derivatives -1- Base) -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 9]

By the same conditions as the synthesis method of compound B2-10 (trifluoro-methanesulfonic acid 3-cyano-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ B ] carbazol-8-yl ester (compound B1, 30mg, 0.069 mmol) was dissolved in 1, 4-dioxane (1 mL), thiomorpholine 1, 1-dioxide (19 mg, 2 equivalents), Pd, and the like were added₂dba₃(6.3 mg, 0.1 equiv.), BINAP (8.6 mg, 0.2 equiv.), K₃PO₄(29 mg, 2 equivalents), stirred at 100 ℃ for a whole day and night. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. Filtering off the drying agent, and purifying the residue obtained by concentration under reduced pressure by silica gel column chromatography (ethyl acetate/hexane) to obtain compound B2-10 (8- （ 1 ， 1- Dioxothiomorpholino) -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide) (white powder, 2.1mg, 7%)) from compound J6 and 1-isopropyl-piperazine the title compound was synthesized.

¹H-NMR(270MHz、DMSO-d₆) : 12.80 (1H, s), 8.33 (1H, d, J = 7.6 Hz), 8.02 (1H, s),7.66 (3H, m), 7.33 (1H, d, J = 8.2 Hz), 3.21 (4H, br), 2.66 (5H, m), 1.72 (6H,s), 1.02 (6H, d, J = 6.3 Hz).

LCMS: m/z 413 [M+H]⁺

HPLC retention time: score 1.38 (analytical conditions S).

(reference example 4)

Compound A27- Methoxy radical -1 、 1- Dimethyl group -3 、 4- Dihydro -1H- Naphthalene -2- Ketones

[ solution 10]

7-methoxy-3, 4-dihydro-1H-naphthalen-2-one (Compound A1, 209g, 1.18 mol), tetrabutylammonium hydrogensulfate (40 g, 0.118 mol) and iodomethane (162 g, 2.60 mol) were suspended in THF (500 ml) at room temperature, and a 50% aqueous solution of potassium hydroxide (400 g) was added over 5 minutes while stirring. The internal temperature sharply increased and reflux occurred, and after the internal temperature stopped increasing, stirring was continued for 45 minutes, and the reaction solution was diluted with 1L of distilled water and extracted twice with 1.5L of CPME. The combined organic layers were washed (distilled water 1L. times.3) and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The resulting crude product was recrystallized from MeOH 1L and distilled water 500ml to obtain the title compound (177 g, 73%) as colorless needle crystals.

¹H-NMR(400MHz,CDCl₃) : 1.43 (6 H, s),2.65 (2H, t, 12Hz),3.02 (2H, t, 12Hz), 3.79 (3H, s), 6.74 (1H, m),6.87 (1H,m),7.24 (1H, m).

LCMS: m/z 205 [M+H]⁺。

(reference example 5)

Compound A3-1, compound A3-2

3- Bromine compound -8- Methoxy radical -6 ， 6- Dimethyl group -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole

1- Bromine compound -8- Methoxy radical -6 ， 6- Dimethyl group -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole

[ solution 11]

7-methoxy-1, 1-dimethyl-3, 4-dihydro-1H-naphthalen-2-one (Compound A2, 66.2g, 324 mmol) and 3-bromophenylhydrazine hydrochloride (71.0 g, 318 mmol) were dissolved in AcOH (350 ml) and stirred at reflux for 6H. The reaction solvent was distilled off under reduced pressure to obtain a crude product as a mixture of the title compounds A3-1, A3-2.

Production example 5

Compound A4

3- Bromine compound -8- Methoxy radical -6 、 6- Dimethyl group -5 、 6- Dihydrobenzo [ alpha ], [ alpha b Carbazole -11- Ketones

[ solution 12]

The crude product (mixture of A3-1 and A3-2) obtained above was dissolved in a mixed solvent of THF (450 ml) and distilled water (50 ml), and DDQ (115 g, 509 mmol) was added in one portion and stirred at room temperature for 1 hour. The reaction mixture was diluted with CPME 3L, and the organic layer was washed successively with 1L of 0.5N aqueous sodium hydroxide solution 3 times, 1L of distilled water 2 times, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to 500ml, and the precipitated product was collected by filtration and washed with a small amount of CPME to obtain the title compound (48 g, 40%) as yellow crystals.

¹H-NMR(400MHz,DMSO-d₆) : 1.73 (6 H, s),3.90 (3H, s), 7.06-7.09 (1H, m), 7.32-7.38 (2H, m), 7.65-7.66 (1H, m),8.09-8.17 (2H, m),12.32 (1H, br.s).

LCMS: m/z 370、372 [M+H]⁺。

(production example 6)

Compound A5-2

8- Methoxy radical -6 、 6- Dimethyl group -11- Oxo radical -6 、 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 13]

3-bromo-8-methoxy-6, 6-dimethyl-5, 6-dihydrobenzo [ b ] carbazol-11-one (Compound A4, 10.45g, 28.2 mmol) and cuprous cyanide (5.0 g, 50.2 mmol) were dissolved in NMP (100 ml) and stirred at 170 ℃ for 17 hours. The reaction mixture was suspended in 500mL of ethyl acetate and 200mL of distilled water, and insoluble matter was removed by filtration through Celite and washed with ethyl acetate (300 mL. times.2). The organic layer was washed with 200mL of an aqueous solution of sodium salt of EDTA2 in that order 1 time, and with 200mL of saturated brine 2 times, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the product was washed with a small amount of CPME in suspension to give the title compound as colorless crystals (6.58 g, 73%).

¹H-NMR(400MHz,DMSO-d₆) : 1.71 (6 H, s),3.89 (3H, s), 7.07-7.09 (1H, m), 7.34 (1H, s), 7.58-7.60 (1H, m), 7.99 (1H, s),8.14-8.16 (1H, m),8.30-8.32 (1H, m), 12.32 (1H, br.s),

LCMS: m/z 317 [M+H]⁺

HPLC retention time: score 2.56 (analytical conditions U).

Production example 7

Compound A6

8- Hydroxy radical -6 、 6- Dimethyl group -11- Oxo radical -6 、 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 14]

8-methoxy-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (Compound A5-2, 6.58g, 20.8 mmol) was dissolved in pyridine hydrochloride (25.0 g), and stirred at 170 ℃ for 13 hours. The reaction mixture was partitioned with 400mL of ethyl acetate and 400mL of distilled water, and the aqueous layer was further extracted 1 time with 400mL of ethyl acetate. The combined organic layers were washed 2 times with 100mL of distilled water and 1 time with 100mL of saturated brine in this order, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the product was washed with a small amount of CPME in suspension to give the title compound as colorless crystals (5.91 g, 93%).

¹H-NMR(400MHz,DMSO-d₆) : 1.73 (6 H, s),6.87-6.90 (1H, m), 7.11 (1H, s), 7.57-7.59 (1H, m), 7.97 (1H, s), 8.04-8.06(1H, m),8.29-8.31 (1H, m), 10.27 (1H, s), 12.66 (1H, br.s),

LCMS: m/z 303 [M+H]⁺。

Production example 8

Compound B1

Trifluoro benzene radical - Methanesulfonic acid 3- Cyano radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -8- Esters of phenyl or naphthyl

[ solution 15]

8-hydroxy-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (Compound A6, 550mg, 0.189 mmol) was dissolved in pyridine (18 mL), trifluoromethanesulfonic anhydride (0.758 mL, 3 equivalents) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into water, extracted with dichloromethane, and the organic layer was dried over magnesium sulfate. After the drying agent was filtered off, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the objective compound (white powder, 641mg, 81%).

¹H-NMR(400MHz、DMSO-d₆) :12.89 (1H, br. s), 8.36 (1H, d, J = 8.8 Hz), 8.31 (1H, dd, J = 8.1, 0.7 Hz),8.11 (1H, d, J = 2.3 Hz), 8.04 (1H, dd, J = 1.5, 0.7 Hz), 7.65-7.60 (2H,m).1.76 (6H,s)

LCMS: m/z 435 [M+H]⁺

HPLC retention time: score 3.10 (analytical conditions U).

Production example 9

Compound B2-22-1

4- （ 3- Cyano radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -8- Base) -3 ， 6- Dihydro -2H- Pyridine compound -1- (iv) Carboxylic acid tert-butyl ester

[ solution 16]

To trifluoro-methanesulfonic acid 3-cyano-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ B ] carbazol-8-yl ester (compound B1, 7.80g, 18.0 mmol), tert-butyl 4- (4, 4, 5, 5-tetramethyl- [ 1, 3, 2] dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylate (6.11 g, 19.8mmol, 1.1 equiv.), Pd (PPh)₃）₂Cl₂(630 mg, 0.898mmol, 0.05 equiv.) and sodium carbonate (5.71 g, 53.9mmol, 3.0 equiv.) were added DME (125 ml) and water (25 ml). The pressure was reduced while ultrasonic wave was applied thereto, and then nitrogen was filled. This operation was repeated 5 times to carry out degassing. After stirring at 80 ℃ for 2 hours under nitrogen, it was cooled to room temperature and water (250 ml) was added and the mixture was further stirred for 30 minutes. The precipitate was collected by filtration and washed with water (50 ml). Further with CH₃CN (50 ml) gave the title compound as a crude product (grey powder, 7.54g, 90%).

LCMS：　m/z　468　［M＋H］^＋

HPLC retention time: score 2.90 (analytical conditions S).

Production example 10

Compound B3-13-1

4- （ 3- Cyano radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -8- Base) - Piperidine derivatives -1- (iv) Carboxylic acid tert-butyl ester

[ solution 17]

Tert-butyl 4- (3-cyano-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ B ] carbazol-8-yl) -3, 6-dihydro-2H-pyridine-1-carboxylate (compound B2-22-1, 16.2g, 34.6 mmol)Dissolved in THF (800 ml) and methanol (230 ml), 10wt% Pd/C (3.2 g) was added, and the mixture was stirred under a hydrogen atmosphere for 19 hours. The solid was filtered through celite, and the filtrate was dissolved in 400ml of a mixed solvent of THF/methanol 4/1, followed by concentration under reduced pressure. Dissolving the residue in 400ml ethyl acetate, adding 1% -N-acetylcysteine aqueous solution and saturated NaHCO₃The aqueous solution was washed with saturated brine. The organic layer was dried over sodium sulfate, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (white powder, 14.0g, 86%) as a crude product.

LCMS：　m/z　470　［M＋H］^＋

HPLC retention time: and 2.88 points (analysis condition S).

Production example 11

Compound B3-13-2

6 ， 6- Dimethyl group -11- Oxo radical -8- Piperidine derivatives -4- Base of -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 18]

After adding THF (0.5 mL) or TFA (0.5 mL) to tert-butyl 4- (3-cyano-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazol-8-yloxy) -piperidine-1-carboxylate (Compound A7-1, 35mg, 0.072 mmol) under the same conditions as the method for synthesizing Compound A8-1, the mixture was stirred at room temperature until Compound A7-1 disappeared, the reaction mixture was concentrated under reduced pressure, and the residue was purified by using anion exchange resin PL Stratospheres^TMDesalting of PL-HCO3 MP gave compound A8-1 (37 mg, 76%)), and the title compound was synthesized from compound B3-13-1.

LCMS：　m/z　370　［M＋H］^＋

HPLC retention time: score 1.30 (analytical conditions S).

Production example 12

Compound B4-8

6 ， 6- Dimethyl group -8- （ 1- Oxetanes -3- Base of - Piperidine derivatives -4- Base) -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 19]

Under the same conditions as the synthesis method of compound B3-32 (to compound B2-29:8- formyl radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanideMorpholine (6. mu.l, 1.5 equiv.) and sodium triacetoxyborohydride (81 mg, 2.0 equiv.) were added to a solution of (30 mg, 0.095 mmol) in THF (1 ml), and the mixture was stirred at room temperature for 1 hour. Filtering the reaction solution to remove insoluble substances, and purifying the residue obtained by concentrating under reduced pressure by high performance liquid chromatography to obtain compound B3-32 (6 ， 6- Dimethyl group -8- Morpholine -4- Radical methyl -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Carbonitrile)(19 mg, 50%)) was synthesized from compound B3-13-2 and oxetan-3-one.

¹H-NMR(400MHz, DMSO-d₆) : 12.74 (1H, s),8.32 (1H, d, 7.9Hz), 8.13 (1H, d, 7.9Hz), 8.00 (1H, s), 7.74 (1H, s), 7.61 (1H,d, 9.8Hz), 7.40 (1H, d, 7.9Hz), 4.56 (2H, t, 6.7Hz), 4.46 (2H, t, 6.1Hz),3.46-3.39 (1H, m), 2.85-2.82 (2H, m), 2.71-2.64 (1H, m), 1.92-1.86 (2H, m),1.82-1.79 (4H, m), 1.77 (6H, s)

LCMS: m/z 426 [M+H]⁺

HPLC retention time: score 1.53 (analysis condition S).

Compound B4-8 sulfate

6, 6-dimethyl-8- (1-oxetan-3-yl-piperidin-4-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile was dissolved in a mixture of DMA (5 parts by volume) and 2N sulfuric acid (1.4 parts by volume) at 80 ℃. After cooling to room temperature, acetone (15 parts by volume) was added dropwise, and the precipitated solid was filtered and dried to obtain 6, 6-dimethyl-8- (1-oxetan-3-yl-piperidin-4-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile sulfate.

¹H-NMR(400MHz, DMSO-d₆) : 12.81 (1H, s),10.26 (1H、br.s)、8.33(1H, d, 8.3Hz), 8.21 (1H, d, 8.3Hz), 8.04 (1H, s), 7.75 (1H, s), 7.63 (1H, d,8.3Hz), 7.41 (1H, d, 8.3Hz), 4.85-4.70 (4H, m), 4.50-4.40 (1H, br.s),3.60-3.00(6H, br.m), 2.20-2.10 (2H, m), 2.05-1.90 (2H, m), 1.79 (6H, s)

LCMS: m/z 426 [M+H]⁺。

B4-8 hydrochloride

B4-8 was dissolved in 5 parts by volume of dimethyl sulfoxide and 0.41 part by volume of aqueous hydrochloric acid (6N), and the solution was freeze-dried. To the lyophilized product was added a mixture of 3.7 parts by volume of water and 1.3 parts by volume of acetonitrile. After stirring at room temperature for a whole day and night, the precipitated crystals were filtered and dried to obtain B4-8 monohydrochloride.

B4-8 methanesulfonic acid salt

B4-8 was dissolved in 4 parts by volume of dimethyl sulfoxide and 1.2 parts by volume of a methanesulfonic acid aqueous solution (2N), and the solution was freeze-dried. To the lyophilized product were added 0.1 part by volume of water and 5 parts by volume of ethyl acetate. After stirring at room temperature for a whole day and night, the precipitated crystals were filtered and dried to obtain B4-8-methanesulfonate.

B4-8L-tartrate salt

B4-8 and 0.81 times the weight of L-tartaric acid were dissolved in 10 parts by volume of tetrahydrofuran and 2 parts by volume of water at 80 ℃. To the solution, 30 parts by volume of ethanol was added. After stirring at room temperature for a whole day and night, the precipitated crystals were filtered and dried to obtain B4-80.5L-tartrate. The obtained B4-80.5L-tartrate was pulverized by a jet mill.

B4-8 phosphate

B4-8 was dissolved in N, N parts by volume of dimethylacetamide and 5.9 parts by volume of an aqueous phosphoric acid solution (2N) under heating and refluxing. To the solution, 43 parts by volume of ethanol was added. After stirring at room temperature for a whole day and night, the precipitated crystals were filtered and dried to obtain B4-8-monophosphate. The obtained B4-8-monophosphate was pulverized with a jet mill.

Production example 13

Compound F5-22

6 ， 6- Dimethyl group -8- （ 4- Oxetanes -3- Base of - Piperazine derivatives -1- Base) -11- Oxo radical -9- C3 -1- Alkynyl radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 20]

By reacting with the compound E4-2-1 (9-bromo-8-methoxy-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (compound E3-1-1, compound E3-1, compound E-2-1, compound E-b-methyl-6, compound E-b-methyl-5,50mg, 0.13 mmol), bis (acetonitrile) dichloropalladium (II) (1.64 mg, 0.05 equiv.), XPhos (9.05 mg, 0.15 equiv.), cesium carbonate (185 mg, 4.5 equiv.), 3-methyl-1-butyn-1-ol (18.6. mu.l, 1.5 equiv.) were dissolved in acetonitrile and stirred at 85 ℃ for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. After the drying agent was filtered off, the residue obtained by concentration under reduced pressure was purified by HPLC to obtain Compound E4-2-1 (I)9- （ 3- Hydroxy radical -3- Methyl radical - T-shirt -1- Alkynyl) -8- Methoxy radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide) (brown solid, 21.3mg, 42%)) the title compound was synthesized from compound F4-3 and propyne under the same conditions.

¹H-NMR(400MHz, CD₃OD) : 8.37 (1H, d, J= 8.2 Hz), 8.18 (1H, s), 7.84 (1H, s), 7.53 (1H, d, J = 8.2 Hz), 7.19 (1H, s),4.70-4.77 (2H, m), 4.62-4.68 (2H, m), 3.57-3.63 (1H, m), 3.38-3.45 (4H, m),2.54-2.61 (4H, m), 2.10 (3H, s), 1.79 (6H, s)

LCMS: m/z 465 [M+H]⁺

HPLC retention time: score 1.90 (analytical conditions U).

Production example 14

Compound F5-25

9- Cyclopropyl ethynyl group -6 ， 6- Dimethyl group -8- （ 4- Oxetanes -3- Base of - Piperazine derivatives -1- Base) -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 21]

The title compound was synthesized from compound F4-3 and ethynylcyclopropane under the same conditions as the synthesis of compound E4-2-1.

¹H-NMR(270MHz, DMSO-d₆) : 12.74 (1 H,br.s), 8.32-8.29 (1 H, d, 8.08 Hz), 8.05 (1 H, s), 8.00 (1 H, s),7.62-7.58 (1 H, m), 7.21 (1 H, s), 4.62-4.57 (2 H, m), 4.51-4.47 (2 H, m),3.53-3.48 (1 H, m), 3.34 (4 H, m), 2.46 (4 H, m), 1.76 (6 H, s), 1.64-1.58 (1H, m), 0.97-0.89 (2 H, m), 0.76-0.70 (2 H, m)

LCMS: m/z 491 [M+H]⁺。

(reference example 6)

Compound E1

6- Bromine compound -7- Methoxy radical -1 ， 1- Dimethyl group -3 ， 4- Dihydro -1H- Naphthalene -2- Ketones

[ solution 22]

7-methoxy-1, 1-dimethyl-3, 4-dihydro-1H-naphthalen-2-one (Compound A2, 2.0g, 9.791 mmol) was dissolved in CH₃CN (40 mL), NBS (1.92 g, 1.1 eq) was added and stirred at room temperature for 2.5 hours. The reaction mixture was poured into water (40 mL), and the precipitated solid was collected by filtration to give the title compound (white powder, 2.55g, 92%).

¹H-NMR(270MHz、CDCl₃) : 7.36 (1H, s), 6.84 (1H, s), 3.91 (3H, s), 3.02 (2H, t,J = 6.8 Hz), 2.66 (2H, t, J = 6.8 Hz), 1.42 (6H, s).

LCMS: m/z 283、285 [M+H]⁺

HPLC retention time: score 2.67 (analytical conditions S).

(reference example 7)

Compound E2-1

9- Bromine compound -8- Methoxy radical -6 ， 6- Dimethyl group -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 23]

6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydro-1H-naphthalen-2-one (compound E1, 7.89g, 27.85 mmol) and 3-hydrazino-benzonitrile (4.45 g, 1.2 equiv.) were dissolved in TFA (250 mL) and stirred at 100 ℃ for 2H. After TFA was removed by concentration under reduced pressure, saturated NaHCO was added to the residue₃The aqueous solution (500 mL) was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. After the drying agent was filtered off, ethyl acetate was added to the residue obtained by concentration under reduced pressure, followed by stirring at room temperature and filtration of the precipitated solid (compound E2-2). The filtrate was concentrated under reduced pressure, whereby the title compound (yellow-white powder, 2.65 g) was obtained as a mixture with E2-2.

LCMS：　m/z　381、383　［M＋H］^＋

HPLC retention time: score 3.03 (analytical conditions S).

Production example 15

Compound E3-1

9- Bromine compound -8- Methoxy radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 24]

The title compound was synthesized from compound E2-1 under the same conditions as the synthesis of compound a 4.

¹H-NMR(270MHz、DMSO-D₆) : 12.82 (1H, s), 8.30 (2H, s+d), 8.03 (1H, s), 7.61 (1H,dd, J = 8.2, 1.4 Hz), 7.49 (1H, s), 4.04 (3H, s), 1.81 (6H, s).

LCMS: m/z 395、397 [M+H]⁺

HPLC retention time: score 2.77 (analytical conditions S).

Production example 16

Compound E3-2

9- Bromine compound -8- Hydroxy radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide[ solution 25]]

9-bromo-8-methoxy-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (compound E3-1-1, 1.0g, 2.53 mmol) was dissolved in NMP (10 mL), NaOMe (683 mg, 5 equiv.) and 1-dodecanethiol (3.0 mL, 5 equiv.) were added, and stirring was carried out at 160 ℃ for 1 hour. The reaction mixture was poured into a 0.5N aqueous hydrochloric acid solution, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. After the drying agent was filtered off, the mixture was concentrated under reduced pressure, MeOH was added to the obtained residue, and the remaining solid was dissolved by filtration, whereby the title compound (yellow powder, 1.88g, 65%) was obtained.

¹H-NMR(400MHz、DMSO-d₆) : 12.77 (1H, s), 11.13 (1H, d, J = 2.4 Hz), 8.31 (1H, dd,J = 7.9, 2.4 Hz), 8.25 (1H, d, J = 3.0 Hz), 8.01 (1H, s), 7.61 (1H, d, J = 7.9Hz), 7.28 (1H, d, J = 2.4 Hz), 1.74 (6H, s).

LCMS: m/z 381,383 [M+H]⁺

HPLC retention time: score 2.40 (analytical conditions S).

Production example 17

Compound F2

Trifluoro benzene radical - Methanesulfonic acid 9- Bromine compound -3- Cyano radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -8- Esters of phenyl or naphthyl

[ solution 26]

The title compound was synthesized from compound E3-2 by the same conditions as the synthesis method of compound B1.

¹H-NMR(270MHz、DMSO-d₆) : 12.99 (1H, s), 8.51 (1H, s), 8.31 (1H, dd, J = 8.2, 0.7Hz), 8.17 (1H, s), 8.07 (1H, s), 7.67 (1 H, dd, J = 8.2, 1.4 Hz), 1.81 (6H, s).

LCMS: m/z 513,515 [M+H]⁺

HPLC retention time: score 3.13 (analytical conditions S).

Production example 18

Compound F3-9

9- Bromine compound -6 ， 6- Dimethyl group -11- Oxo radical -8- Piperazine derivatives -1- Base of -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 27]

Compound B2-1 (compound B2-1 (R) was obtained by dissolving trifluoro-methanesulfonic acid 3-cyano-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ B ] carbazol-8-yl ester (compound B1, 40mg, 0.0921 mmol) in NMP (1 ml) under the same conditions as the synthesis method of compound B2-1, adding 1-isopropylpiperazine (236 mg, 20 equivalents), stirring at 120 ℃ for 3 hours, cooling to room temperature, and purifying by HPLC8- （ 4- Isopropyl group - Piperazine derivatives -1- Base) -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide) (white powder, 12.8mg, 34%)), the title compound was synthesized from compound F2 and piperazine.

1H-NMR(DMSO-D₆) : 8.30-8.24 (2H,m), 8.00 (1H, s), 7.63-7.58 (1H, m), 7.37 (1H, s), 3.10-3.01 (4H, m), 2.91-2.85(4H,m), 1.76 (6H, s)

LCMS: m/z 449、451 [M+H]⁺

HPLC retention time: score 1.45 (analytical conditions S).

Production example 19

Compound F4-3

9- Bromine compound -6 ， 6- Two-agentBase of -8- （ 4- Oxetanes -3- Base of - Piperazine derivatives -1- Base) -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 28]

The title compound was synthesized from compound F3-9 and 1-oxetan-3-one by the same conditions as for compound B3-32.

¹H-NMR(270MHz、DMSO-d₆) : 12.83 (1H, br.s), 8.31-8.32 (1H, m), 8.27-8.29 (1H, m),8.01-8.04 (1H, m), 7.59-7.64 (1H, m), 7.48 (1H, s), 4.59 (2H, dd, J = 6.3, 6.3Hz), 4.48 (2H, dd, J = 6.3, 6.3 Hz), 3.52 (1H, t, J = 6.3 Hz), 3.12-3.25 (4H,m), 2.44-2.54 (4H, m), 1.78 (6H, s).

LCMS: m/z 505、507 [M+H]⁺

HPLC retention time: score 1.45 (analytical conditions S).

Hydrochloride salt of Compound F4-3

9-bromo-6, 6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile was dissolved by adding DMSO and 6N hydrochloric acid 1.05 equivalents. After freeze-drying, crystallization was carried out by 25% aqueous ethanol to obtain 9-bromo-6, 6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile monohydrochloride.

¹H-NMR(270MHz、DMSO-d₆) : 12.91 (1H、br.s)、11.70(1H、br.s)、8.32-8.29(2H, m)、8.04(1H,s),7.64-7.62(1H, m)、7.52(1H、s)、4.89-4.62(4H,br.m)、3.66-3.39(1H、m)、3.31-3.05(8H, br.m)、1.81(6H、s)

LCMS: m/z 505、507 [M+H]⁺。

Production example 20

Compound F4-9

9- Bromine compound -8- （ 4- Cyclopropyl group - Piperazine derivatives -1- Base) -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 29]

The title compound was synthesized from compound F3-9 and (1-ethoxy-cyclopropoxy) trimethylsilane by the same conditions as for compound B3-32.

¹H-NMR(270MHz、DMSO-D₆) : 8.22-8.30 (2H, m), 8.00 (1H, s), 7.56 (1H, d, J = 7.9Hz), 7.43 (1H, s), 3.30(1H, d, J = 5.8 Hz), 3.11 (4H, s), 2.75 (4H, s), 1.75(6H, s), 0.47 (2H, d, J = 5.8 Hz), 0.34 (2H, d, J = 5.8 Hz)

LCMS: m/z 489,491 [M+H]⁺

HPLC retention time: score 1.68 (analytical conditions S).

(reference example 8)

Compound I1-1

6- Chlorine -7- Methoxy radical -1 ， 1- Dimethyl group -3 ， 4- Dihydro -1H- Naphthalene -2- Ketones

[ solution 30]

7-methoxy-1, 1-dimethyl-3, 4-dihydro-1H-naphthalen-2-one (Compound A2, 3.37g, 16.5 mmol) was dissolved in CH₃CN (82 mL), NCS (2.42 g, 1.1 equiv) was added thereto, and the mixture was stirred at 90 ℃ for 1.5 hours. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. After the drying agent was removed, the residue was concentrated under reduced pressure to obtain the objective compound (yellow oily substance, 4.45 g).

¹H-NMR(400MHz, CDCl₃) : 7.16 (1H, s),6.85 (1H, s), 3.90 (3H, s), 3.00 (2H, t, J = 6.8 Hz), 2.65 (2H, t, J = 6.8 Hz),1.42 (6H, s).

LCMS: m/z 239 [M+H]⁺

HPLC retention time: score 2.80 (analytical conditions U).

(reference example 9)

Compound I1-2

9- Chlorine -8- Methoxy radical -6 ， 6- Dimethyl group -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 31]

6-chloro-7-methoxy-1, 1-dimethyl-3, 4-dihydro-1H-naphthalen-2-one (compound I1-1, 4.45g, 16.5 mmol) and 3-hydrazinobenzonitrile (2.63 g, 1.2 eq) were dissolved in TFA (91 mL) and stirred at 90 ℃ for 3H. After TFA was removed by concentration under reduced pressure, saturated NaHCO was added to the residue₃The aqueous solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. Filtering to remove desiccant, and reducing pressureEthyl acetate was added to the residue obtained by concentration, and the mixture was stirred at room temperature, and the precipitated solid was filtered. The filtrate was concentrated under reduced pressure, whereby the objective compound (red powder, 6.46 g) was obtained as a mixture with I1-3.

Production example 21

Compound I3

9- Chlorine -8- Methoxy radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 32]

The title compound was synthesized from compound I1-2 by the same conditions as the synthesis method of compound a 4.

¹H-NMR(400MHz, DMSO-d₆) : 12.79 (1H, s),8.27-8.31 (1H, m), 8.12 (1H, s), 8.00-8.02 (1H, m), 7.58-7.63 (1H, m), 7.51(1H, s), 4.03 (3H, s), 1.80 (6H, s).

LCMS: m/z 351 [M+H]⁺

HPLC retention time: score 2.87 (analytical conditions U).

Production example 22

Compound I4

9- Chlorine -8- Hydroxy radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 33]

Compound E3-2 (Compound E3-2) (10 mL) was prepared by dissolving 9-bromo-8-methoxy-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (Compound E3-1-1, 1.0g, 2.53 mmol) in NMP (10 mL), adding NaOMe (683 mg, 5 equiv.), 1-dodecanethiol (3.0 mL, 5 equiv.), stirring at 160 ℃ for 1 hour, injecting the reaction mixture into 0.5N aqueous hydrochloric acid, extracting with ethyl acetate, washing the organic layer with saturated brine, drying with sodium sulfate, filtering off the drying agent, concentrating under reduced pressure, adding MeOH to the resulting residue, and filtering off the remaining solid to obtain9- Bromine compound -8- Hydroxy radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide) (yellow powder, 1.88g, 65%)), the title compound was synthesized from compound I3.

LCMS：　m/z　337　［M＋H］^＋

HPLC retention time: score 2.47 (analytical conditions U).

Production example 23

Compound I5

Trifluoro benzene radical - Methanesulfonic acid 9- Chlorine -3- Cyano radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -8- Esters of phenyl or naphthyl

[ chemical 34]

The title compound was synthesized from compound I4 under the same conditions as the synthesis method of compound B1.

LCMS：　m/z　469　［M＋H］^＋

HPLC retention time: score 3.40 (analytical conditions U).

Production example 24

Compound I6-4

9- Chlorine -6 ， 6- Dimethyl group -8- （ 4- Morpholine -4- Base of - Piperidine derivatives -1- Base) -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 35]

The title compound was synthesized from compound I5 and 4-piperidin-4-yl-morpholine by the same conditions as the synthesis of compound B2-1.

¹H-NMR(400MHz, DMSO-d₆) : 12.75 (1H, s),8.28 (1H, d, 8.0 Hz), 8.07 (1H, s), 8.00 (1H, s), 7.59 (1H, d, 8.0 Hz), 7.41(1H, s), 3.55-3.62 (4H, m), 3.47-3.56 (4H, m), 2.75-2.86 (2H, m), 2.45-2.55(4H, m), 2.28-2.39 (1H, m), 1.86-1.96 (2H, m), 1.76 (6H, s), 1.52-1.66 (2H, m)

LCMS: m/z 489 [M+H]⁺

HPLC retention time: score 1.97 (analytical conditions U).

Production example 25

Compound F5-44

8- （ 4- Cyclobutyl radical - Piperazine derivatives -1- Base) -6 ， 6- Dimethyl group -11- Oxo radical -9- C3 -1- Alkynyl radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 36]

The title compound was synthesized from compound F4-10 under the same conditions as the synthesis method of compound E4-2-1, in a propyne gas atmosphere.

¹H-NMR(400MHz, DMSO-d₆) : 12.71 (1 H,s),8.30 (1 H, d, 7.9 Hz), 8.06 (1 H, s),8.00 (1 H, s), 7.59 (1 H, d, 7.9 Hz), 7.20(1 H, s), 2.75-2.83 (1 H, m), 2.40-2.48 (4 H, m), 2.11 (3 H, s), 1.97-2.06 (2H, m), 1.76 (6 H, s), 1.62-1.71 (2 H, m)

LCMS: m/z 463 [M+H]⁺

HPLC retention time: and 2.80 points (analysis condition W).

[ example 282 ]

Production example 26

Compound F3-11

9- Bromine compound -6 ， 6- Dimethyl group -8- （ 4- Morpholine -4- Base of - Piperidine derivatives -1- Base) -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 37]

The title compound was synthesized from compound F2 and 4-piperidin-4-ylmorpholine by the same conditions as the synthesis method of compound B2-1.

1H-NMR　（DMSO-D₆）　：　8.30-8.24　（2H，　m），　8.00　（1H，　s），　7.59　（1H，　d，　J　＝　8.2　Hz），　7.42　（1H，　s），　3.66-3.45　（6H，　m），　2.80　（2H，　t，　J　＝　11.1　Hz），　2.38-2.28　（1H，　m），　1.96-1.87　（2H，　m），　1.75　（6H，　s），　1.66-1.56　（2H，　m）

LCMS：　m/z　533、535　［M＋H］^＋

HPLC retention time: score 1.53 (analysis condition S).

(production example 27)

Compound F5-51

6 ， 6 ， 9- Trimethyl -8- （ 4- Morpholine -4- Base of - Piperidine derivatives -1- Base) -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 38]

By the same conditions as the synthesis method of the compound F5-47 (under a nitrogen atmosphere, trimethylboroxine (12 mg, 0.1 equivalent), tetrakis (triphenylphosphine) palladium (39 mg, 0.2 equivalent), potassium carbonate (41 mg, 3.0 equivalent) were added to a solution of 9-bromo-8- (4-cyclobutyl-piperazin-1-yl) -6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (compound F4-10, 50mg, 0.099 mmol) in N, N-dimethylformamide (1.5 ml),stirred at 100 ℃ for 24 hours. After completion of the reaction, distilled water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. Filtering off the drying agent, concentrating under reduced pressure, and purifying the obtained residue with silica gel column chromatography (ethyl acetate/methanol) to obtain compound F5-47 (8- （ 4- Cyclobutyl radical - Piperazine derivatives -1- Base) -6 ， 6 ， 9- Trimethyl -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide) (25 mg, 58%)) was synthesized from compound F3-11.

¹H-NMR(270MHz, DMSO-d₆) : 12.70 (1 H,br.s), 8.33-8.30 (1 H, d, 8.08 Hz), 8.00 (1 H, s), 7.95 (1 H, s),7.61-7.58 (1 H, m), 7.28 (1 H, s), , 3.60 (4 H, m), 3.32-3.26 (2 H, m),2.79-2.69 (2 H, m), 2.32 (3 H, s), 1.95-1.90 (2 H, m), 1.74 (6 H, s), 1.65-1.52(2 H, m),

LCMS: m/z 469 [M+H]⁺。

Methanesulfonic acid salt of Compound F5-51

6, 6, 9-trimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile was dissolved by adding DMSO and 1.05 equivalents of 2N methanesulfonic acid. After freeze drying, the mixture is crystallized by ethanol to obtain 6, 6, 9-trimethyl-8- (4-morpholine-4-yl-piperidine-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-formonitrile mesylate.

¹H-NMR(270MHz, DMSO-d₆) : 12.72(1H、br.s)、9.60(1H、br.s)、8.33-8.31(1H、d、9.8Hz)、8.01(1H、s)、7.99(1H、s)、7.61-7.59(1H、m)、7.31 (1H、s)、4.07-4.04 (2H、m)、3.73-3.67(2H、m)、 3.55-3.40(8H、m)、3.32-3.26(1H、m)、2.70-2.60(2H、m)、2.34(3H、s)、2.30(3H、s)、1.95-1.90 (2 H、m)、1.75(6H、s)

LCMS: m/z 469 [M+H]⁺。

F5-51 hydrochloride

F5-51 was dissolved in 5 parts by volume of dimethyl sulfoxide and 0.37 part by volume of hydrochloric acid (6N), and the solution was freeze-dried. To the lyophilized product, 5 parts by volume of ethanol was added. The precipitated crystals were collected by filtration and dried to obtain F5-51 hydrochloride.

Production example 28

Compound F6-4

9- Ethyl radical -6 ， 6- Dimethyl group -8- （ 4- Oxetanes -3- Base of - Piperazine derivatives -1- Base) -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 39]

The title compound was synthesized from compound F5-16 by the same conditions as the synthesis method of compound B3-13-1.

¹H-NMR(400MHz、DMSO-d₆) : 12.70 (1H, br. s), 8.29 (1H, d, 8.0 Hz), 8.03-7.94 (2H,m), 7.59-7.55 (1H, m), 7.38 (1H, s), 4.59-4.47 (4H, m), 3.53-5.47 (1H, m),3.03-2.97 (2H, m), 2.73-2.62 (2H, m), 1.74 (6H, s), 1.29-1.98 (3H, m)LCMS: m/z455 [M+H]⁺

HPLC retention time: score 1.92 (analytical conditions U).

Hydrochloride salt of Compound F6-4

9-Ethyl-6, 6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile was dissolved by adding DMSO and 6N hydrochloric acid 1.05 equivalents. After freeze-drying, crystallization was carried out by 25% aqueous ethanol to obtain 9-ethyl-6, 6-dimethyl-8- (4-oxetan-3-yl-piperazin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile monohydrochloride.

¹H-NMR(270MHz、DMSO-d₆) : 12.83 (1H、br.s)、11.59(1H、br.s)、8.33-8.31(1H、m)、8.09(1H、s),8.02(1H、s)、7.63-7.61(1H、m)、7.39(1H、s)、4.91-4.60(4H,br.m)、3.58-3.40(1H、m)、3.31-3.05(8H, br.m)、2.73(2H、q、、J=7.3)、1.81(6H、s)、1.29(3H、t、J=7.3)

LCMS: m/z 455 [M+H]⁺。

F6-4 methanesulfonic acid salt

F6-4 was dissolved in 5 parts by volume of dimethyl sulfoxide and 1.2 parts by volume of a methanesulfonic acid aqueous solution (2N), and the solution was freeze-dried. To the freeze-dried product was added a mixture of 3.8 parts by volume of water and 1.3 parts by volume of ethanol. The precipitated crystal was filtered and dried to obtain F6-4 methanesulfonate.

Production example 29

Compound F5-49

9- Ethynyl group -6 ， 6- Dimethyl group -8- （ 4- Morpholine -4- Base of - Piperidine derivatives -1- Base) -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 40]

The title compound was synthesized from compound F3-11 under the same conditions as the synthesis method of compound F5-43.

LCMS：　m/z　479　［M＋H］^＋

HPLC retention time: score 1.90 (analytical conditions U).

Production example 30

Compound F6-20

9- Ethyl radical -6 ， 6- Dimethyl group -8- （ 4- Morpholine -4- Base of - Piperidine derivatives -1- Base) -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 41]

The title compound was synthesized from compound F5-49 by the same conditions as the synthesis method of compound B3-13-1.

¹H-NMR(400MHz、DMSO-D₆) : 12.70 (1H, s), 8.32 (1H, d, J = 7.9 Hz), 8.04 (1H, s),8.00 (1H, s), 7.61 (1H, d, J = 8.5 Hz), 7.34 (1H, s), 3.64-3.57 (4H, m),3.27-3.18(2H, m), 2.82-2.66 (4H, m), 2.39-2.28 (1H,m), 1.96-1.87 (2H, m), 1.76(6H, s), 1.69-1.53 (2H, m), 1.29 (3H, t, J = 7.3 Hz)

LCMS: m/z 483 [M+H]⁺

HPLC retention time: score 1.98 (analytical conditions U).

Hydrochloride salt of Compound F6-20

9-ethyl-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile was dissolved in a mixture of 10 parts by volume of methyl ethyl ketone, 4 parts by volume of water and 3 parts by volume of acetic acid at 60 ℃.1 part by volume of hydrochloric acid (2N) was added dropwise to the solution. Stirring the mixture for 30 minutes at 60 ℃, dropwise adding 25 volume parts of ethanol, filtering the precipitated solid, and drying to obtain 9-ethyl-6, 6-dimethyl-8- (4-morpholine-4-yl-piperidine-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-formonitrile monohydrochloride. The obtained 9-ethyl-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile monohydrochloride was pulverized with a jet mill.

¹H-NMR(400MHz、DMSO-D₆) : 12.78(1H,s)、10.57(1H、br.s)、8.30(1H、J = 8.4 Hz)、8.05(1H,s)、7.99(1H,s)、7.59(1H、d、J = 7.9 Hz)、7.36(1H、s)、4.02-3.99(2H、m)、3.84-3.78(2H、m)、3.51-3.48(2H、m)、3.15-3.13(1H、s)、2.83-2.73(2H、s)、2.71-2.67(2H、s)、2.23-2.20(2H、m)、1.94-1.83(2H、m)、1.75(6H,s)、1.27(3H、t、J = 7.5 Hz)

FABMS: m/z 483 [M+H]⁺。

F6-20 methanesulfonic acid salt

F6-20 was dissolved in 33 parts by volume of dimethylacetamide at 90 ℃. To the solution were added 1.2 parts by volume of methanesulfonic acid aqueous solution (2N) and 168 parts by volume of ethyl acetate, and the mixture was stirred for 4 hours. The precipitated crystals were filtered and dried to obtain F6-20-monomethanesulfonate salt. The obtained F6-20-methanesulfonate was pulverized with a jet mill.

Production example 31

Compound F5-16

9- Ethynyl group -6 ， 6- Dimethyl group -8- （ 4- Oxetanes -3- Base of - Piperazine derivatives -1- Base) -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 42]

The title compound was synthesized from compound F4-3 under the same conditions as the synthesis of compound F5-43.

¹H-NMR(270MHz、DMSO-D₆) : 12.77 (1H, br.s), 8.31 (1H, d, J = 8.2 Hz), 8.16 (1H,s), 8.02 (1H, s), 7.61 (1H, dd, J = 8.2, 1.3 Hz), 7.27 (1H, s), 4.59 (2H, dd, J= 6.6, 6.6 Hz), 4.51 (1H, s), 4.49 (2H, dd, J = 6.6, 6.6 Hz), 3.51 (1H, t, J =6.6 Hz), 3.35-3.43 (4H, m), 2.43-2.50 (4H, s), 1.78 (6H, s).

LCMS: m/z 451 [M+H]⁺

HPLC retention time: score 1.40 (analytical conditions S).

Production example 32

Compound F6-17

8- （ 4- Cyclobutyl radical - Piperazine derivatives -1- Base) -9- Ethyl radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 43]

The title compound was synthesized from compound F5-43 by the same conditions as the synthesis method of compound B3-13-1.

¹H-NMR(400MHz, DMSO-d₆) : 12.80 (1 H,s),8.32 (1 H, d, 7.9 Hz), 8.10 (1 H, s),8.02 (1 H, s), 7.62 (1 H, d, 7.9 Hz), 7.38(1 H, s), 3.78-3.88 (1 H, m), 3.79-3.89 (1 H, m), 3.48-3.54 (2 H, m), 3.40-3.47(2 H, m), 3.30-3.39 (2 H, m), 3.02-3.24 (4 H, m), 2.73 (2 H, q, 7.3 Hz),2.30-2.41 (2 H, m), 2.17-2.26 (2 H, m), 1.71-1.86 (8 H, m), 1.29 (3 H, t, 7.3Hz)

LCMS: m/z 453 [M+H]⁺

HPLC retention time: score 2.76 (analytical conditions W).

Methanesulfonic acid salt of Compound F6-17

8- (4-cyclobutyl-piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile was dissolved in 6 parts by volume of DMF at room temperature, and 1.05 equivalents of methanesulfonic acid aqueous solution (2M) was added dropwise. The solution was added dropwise to 60 parts by volume of acetonitrile, and the precipitated solid was filtered and dried to obtain 8- (4-cyclobutyl-piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile monomethanesulfonate.

¹H-NMR(400MHz、DMSO-D₆) : 12.75(1H,s)、8.31(1H、J = 8.4 Hz)、8.07(1H,s)、8.01(1H,s)、7.59(1H、d、J = 7.9 Hz)、7.38(1H、s)、3.58-2.84(10H、m)、2.71(2H、q、J = 7.5 Hz)、2.34(3H、s)、2.20-2.04(4H、m)、1.76-1.68(8H,m)、1.26(3H、t、J = 7.5 Hz)

FABMS: m/z 453 [M+H]⁺。

F6-17 hydrochloride

F6-17 was dissolved in 5 parts by volume of dimethyl sulfoxide and 0.39 part by volume of hydrochloric acid (6N), and the solution was freeze-dried. To the freeze-dried product was added a mixture of 4.0 parts by volume of water and 1.3 parts by volume of ethanol. The precipitated crystals were collected by filtration and dried to obtain F6-17 hydrochloride.

F6-17 maleate

Maleic acid was added in an amount of 0.38 times by weight to F6-17, and the mixture was dissolved in 10 parts by volume of dimethylacetamide at 80 ℃. The solution was cooled to room temperature, and a mixture of 5.8 parts by volume of acetone and 5.8 parts by volume of water was added dropwise thereto, followed by stirring at room temperature. Further, 3.5 parts by volume of water was added dropwise thereto, and the precipitated crystals were filtered and dried to obtain F6-17 maleate.

F6-17L-tartrate salt

L-tartaric acid was added in an amount of 0.51 times by weight to F6-17, and the resulting mixture was dissolved in 6 parts by volume of dimethylacetamide at 80 ℃. The solution was cooled to room temperature, and 37 parts by volume of acetonitrile was added dropwise. After stirring at room temperature for a whole day and night, the precipitated crystals were filtered and dried to obtain F6-17 tartrate. The resulting F6-17 tartrate salt was pulverized with a jet mill.

F6-17 citrate salt

Citric acid was added in an amount of 0.50 times by weight to F6-17, and the resulting mixture was dissolved in 6 parts by volume of dimethylacetamide at 80 ℃. The solution was cooled to room temperature, and 12 parts by volume of acetonitrile was added dropwise. The precipitated crystals were filtered and dried to obtain F6-17 citrate. The resulting F6-17 citrate was pulverized with a jet mill.

F6-17 malate salt

L-malic acid in an amount of 0.46 times by weight was added to F6-17, and the resulting mixture was dissolved in 8 parts by volume of dimethylacetamide at 80 ℃. The solution was cooled to room temperature, and 62 parts by volume of acetonitrile was added dropwise. The precipitated crystals were filtered and dried to obtain F6-17 malate.

Production example 33

Compound F3-2

9- Bromine compound -6 ， 6- Dimethyl group -11- Oxo radical -8- （ 4- Pyrrolidine as a therapeutic agent -1- Base of - Piperidine derivatives -1- Base) -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 44]

The title compound was synthesized from compound F2 and 4-pyrrolidin-1-yl-piperidine by the same conditions as compound B2-1.

LCMS：　m/z　517，519　［M＋H］^＋

HPLC retention time: score 1.70 (analytical conditions S).

Production example 34

Compound F5-4

9- Ethynyl group -6 ， 6- Dimethyl group -11- Oxo radical -8- （ 4- Pyrrolidine as a therapeutic agent -1- Base of - Piperidine derivatives -1- Base) -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 45]

By dissolving 9- (3-hydroxy-3-methyl-but-1-ynyl) -8-methoxy-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (compound E4-2-1, 21.3mg, 0.05 mmol), sodium hydride (3.2 mg, 1.5 equivalents) in THF with compounds E4-2-1, E4-2-2 (compound E4-2-2 (compound E) and E3-2 (compound E) and THF), stirring at 50 ℃ until a reaction mixture, adding water to the reaction mixture, concentrating under reduced pressure, and purifying the resulting residue by HPLC, compound E4-2 (compound E) is obtained9- Ethynyl group -8- Methoxy radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide) (brown solid, 9.6mg, 31%)) the title compound was synthesized from compound F3-2 under the same conditions.

¹H-NMR(270MHz、DMSO-D₆) : 8.29 (1H, d, J = 8.2 Hz), 8.14 (1H, s), 8.00 (1H, s),7.58 (1H, dd, J = 8.1, 1.3 Hz), 7.24 (1H, s), 4.50 (1H, s), 3.70-3.83 (2H, m),3.34-3.48 (1H, m), 2.83-2.98 (2H, m), 2.45-2.58 (2H, m), 2.10-2.23 (2H, m),1.90-2.03 (2H, m), 1.76 (6H, s), 1.51-1.74 (6H, m).

LCMS: m/z 463 [M+H]⁺

HPLC retention time: score 1.60 (analytical conditions S).

Production example 35

Compound B2-4

6 ， 6- Dimethyl group -11- Oxo radical -8- （ 4- Pyrrolidine as a therapeutic agent -1- Base of - Piperidine derivatives -1- Base) -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 46]

The title compound was synthesized from compound B1 and 4-pyrrolidin-1-yl-piperidine by the same conditions as the synthesis of compound B2-1.

¹H-NMR(270MHz, DMSO-d₆) : 8.30 (1H, d,8.1Hz), 8.01 (1H, d, 8.7Hz), 7.97 (1H, s), 7.56 (1H, d, 8.6Hz), 7.20 (1H, s),3.94-3.90 (2H, m), 3.30-3.28 (4H, m), 2.95 (2H, t, 11.8Hz), 2.24-2.20 (1H, m),1.95-1.91 (2H, m), 1.75 (6H, s), 1.70-1.66 (4H, m), 1.54-1.52 (2H, m)

LCMS: m/z 439 [M+H]⁺。

Production example 36

Compound F5-43

8- （ 4- Cyclobutyl radical - Piperazine derivatives -1- Base) -9- Ethynyl group -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 47]

To a suspension of 9-bromo-8- (4-cyclobutyl-piperazin-1-yl) -6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (compound F4-10, 200mg, 0.397 mmol) in MeCN (8 ml) under a nitrogen atmosphere were added ethynyl triisopropylsilane (268 mg, 3.0 equivalents), 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl (Xphos) (39 mg, 0.2 equivalents), Pd (CH) (CH-1-yl)₃CN）₂Cl₂(11 mg, 0.1 equiv.) and cesium carbonate (518 mg, 4.0 equiv.) were stirred under reflux with heating until the reaction was complete. After completion of the reaction, distilled water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give 8- (4-cyclobutyl-piperazin-1-yl) -6, 6-dimethyl-11-oxo-9- [ (triisopropylsilyl) -ethynyl ] -6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (179 mg, 74%).

To a solution of the obtained compound (179 mg, 0.295 mmol) in THF (6 ml) was added a 1M THF solution of tetrabutylammonium fluoride (710. mu.l), and the mixture was stirred until the reaction was completed. After completion of the reaction, ethyl acetate was poured into the reaction mixture, which was washed with distilled water and dried over sodium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was washed with a mixed solvent of ethanol and distilled water to give the title compound (67 mg, 92%).

¹H-NMR(400MHz, DMSO-d₆) : 12.85 (1 H,s),8.31 (1 H, d, 7.9 Hz), 8.20 (1 H, s),8.03 (1 H, s), 7.62 (1 H, d, 7.9 Hz), 7.35(1 H, s), 4.62 (1 H, s), 3.94-4.03 (2 H, m), 3.79-3.89 (1H, m), 3.48-3.54 (2H, m), 3.27-3.38 (2 H, m), 2.96-3.16 (2 H, m), 2.30-2.41 (2 H, m), 2.16-2.26 (2H, m), 1.72-1.85 (8 H, m)

LCMS: m/z 449 [M+H]⁺

HPLC retention time: score 2.69 (analytical conditions W).

Production example 37

Compound F6-18

8- （ 4- Cyclobutyl radical - Piperazine derivatives -1- Base) -6 ， 6- Dimethyl group -11- Oxo radical -9- Propyl radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 48]

The title compound was synthesized from compound F5-44 by the same conditions as the synthesis method of compound B3-13-1.

¹H-NMR(400MHz, DMSO-d₆) : 12.69 (1 H,s),8.31 (1 H, d, 7.9 Hz), 8.01 (1 H, s),7.99 (1 H, s), 7.60 (1 H, d, 7.9 Hz), 7.39(1 H, s), 2.92-3.02 (4 H, m), 2.75-2.84 (1 H, m), 2.65 (2 H, t, 7.3 Hz),2.38-2.48 (4 H, m), 1.96-2.06 (2 H, m), 1.78-1.87 (2 H, m), 1.75 (6 H, s),1.62-1.73 (4 H, m), 0.97 (3 H, t, 7.3 Hz)

LCMS: m/z 467 [M+H]⁺

HPLC retention time: score 2.96 (analytical conditions W).

Production example 38

Compound B4-7

8- （ 1- Isopropyl group - Piperidine derivatives -4- Base) -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 49]

The title compound was synthesized from compound B3-13-2 and acetone under the same conditions as the synthesis of compound B3-32.

¹H-NMR(400MHz, DMSO-d₆) : 12.77 (1H, s),8.32 (1H, d, 7.9Hz), 8.13 (1H, d, 7.9Hz), 8.01 (1H, s), 7.73 (1H, s), 7.61 (1H,d, 9.1Hz), 7.39 (1H, d, 9.8Hz), 2.93 (2H, d, 11.0Hz), 2.77-2.71 (1H, m), 2.67-2.62 (1H, m), 2.25 (2H, t, 10.1Hz), 1.80-1.73 (10H, m), 1.02 (6H, d, 6.7 Hz)

LCMS: m/z 412 [M+H]⁺

HPLC retention time: score 1.60 (analytical conditions S).

Production example 39

Compound B2-1

8- （ 4- Isopropyl group - Piperazine derivatives -1- Base) -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 50]

Trifluoro-methanesulfonic acid 3-cyano-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ B ] carbazol-8-yl ester (compound B1, 40mg, 0.0921 mmol) was dissolved in NMP (1 ml) and 1-isopropylpiperazine (236 mg, 20 equivalents) was added. It was stirred at 120 ℃ for 3 hours. After cooling to room temperature, purification was performed by HPLC to obtain the objective compound (white powder, 12.8mg, 34%).

¹H-NMR(270MHz, DMSO-d₆) : 8.30 (1H, d,8.1Hz), 8.03 (1H, d, 8.6Hz), 7.98 (1H, s), 7.56 (1H, d, 8.6Hz), 7.21 (1H, s),7.04 (1H, d, 9.1Hz), 3.40-3.37 (4H, m), 2.73-2.65 (1H, m), 2.61-2.58 (4H, m),1.75 (6H, s), 1.02 (6H, d, 6.6Hz)

LCMS: m/z 413 [M+H]⁺。

Production example 40

Compound F3-10

4- （ 9- Bromine compound -3- Cyano radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -8- Base) - Piperazine derivatives -1- (iv) Carboxylic acid tert-butyl ester

[ solution 51]

The title compound was synthesized from compound F2 and tert-butyl piperazine-1-carboxylate by the same conditions as the synthesis method of compound B2-1.

LCMS：　m/z　549、　551　［M＋H］^＋

HPLC retention time: 4.61 points (analysis condition W).

Production example 41

Compound F5-15-1

4- （ 3- Cyano radical -9- Cyclopropyl group -6 、 6- Dimethyl group -11- Oxo radical -6 、 11- Dihydro -5H- Benzo [ 2] b Carbazole -8- Base) - Piperazine derivatives -1- (iv) Carboxylic acid tert-butyl ester

[ solution 52]

By the same conditions as the synthesis method of the compound E4-7-1 (at 9-bromo-8-methoxy-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (compound E3-1-1, 300mg, 0.759 mmol), tert-butyl 4- (4, 4, 5, 5-tetramethyl- [ 1, 3, 2] dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylate (282 mg, 0.911mmol, 1.2 equivalents), Pd (PPh)₃）₂Cl₂DME (5 ml) and water (1 ml) were added (26.6 mg, 0.0379mmol, 0.05 equiv.) and sodium carbonate (241 mg, 2.28mmol, 3.0 equiv.). The pressure was reduced while ultrasonic wave was applied thereto, and then nitrogen was filled. This operation was repeated 5 times to carry out degassing. Stirring was carried out for 80 minutes at 80 ℃ under nitrogen atmosphere. Adding Pd (PPh)₃）₂Cl₂(26.6 mg, 0.0379mmol, 0.05 eq.) and further stirred at 80 ℃ for 20 min. After cooling to room temperature, water and ethyl acetate were added, and insoluble matter was filtered off through celite. The organic layer was dried over sodium sulfate, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give compound E4-7-1 (crude product)4- （ 3- Cyano radical -8- Methoxy radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b CarbazateAzole -9- Base) -3 ， 6- Dihydro -2H- Pyridine compound -1- (iv) Carboxylic acid tert-butyl ester) (grey powder)), the title compound was synthesized from compound F3-10 and potassium cyclopropyltrifluoroborate.

¹H-NMR(400MHz, DMSO-d₆) : 8.55(1H、s)、 8.28-8.25(1H、 m)、 7.98-7.95(1H、 m)、 7.62(1H、 s)、 7.32(1H、 s)、 3.56-3.53(4h、 m)、3.09-3.07(4H、 m)、 2.22-2.18(1H、 m)、 1.73(6H、 br s)、 1.44(9H、 s)、 1.08-1.05(2H、 m)、 0.77-0.76(2H、m)

LCMS: m/z 511 [M+H]⁺

HPLC retention time: 4.50 points (analysis condition W).

Production example 42

Compound F5-15-2

9- Cyclopropyl group -6 、 6- Dimethyl group -11- Oxo radical -8- Piperazine derivatives -1- Base of -6 、 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ Hua 53]

The title compound was synthesized from the compound F5-15-1 by the same conditions as the synthesis method of the compound A8-1.

LCMS：　m/z　411　［M＋H］^＋

HPLC retention time: score 2.67 (analytical conditions W).

Production example 43

Compound F5-46

8- （ 4- Cyclobutyl radical - Piperazine derivatives -1- Base) -9- Cyclopropyl group -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 54]

The title compound was synthesized from compound F5-15-2 and cyclobutanone by the same method as that for the synthesis of compound B3-32.

¹H-NMR(400MHz, DMSO-d₆):8.23(1H, d,8Hz)、 7.92(1H, br.s)、 7.59(1H, s)、7.47(1H, br.d, 8Hz), 7.28(1H, s), 3.12(4H, br.s)、2.80(1H, dddd, 8,8,8,8Hz)、 2.20-2.13(1H,m)、 2.01(2H, br.s), 1.86-1.68(10H, m),1.05(2H, d, 8Hz), 0.76(2H, d, 4Hz)

LCMS: m/z 465 [M+H]⁺

HPLC retention time: score 2.79 (analytical conditions W).

Hydrochloride salt of Compound F5-46

8- (4-cyclobutyl-piperazin-1-yl) -9-cyclopropyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile was dissolved by adding 1.05 equivalents of DMSO and 6N hydrochloric acid. After freeze-drying, crystallization was carried out with 25% aqueous ethanol to obtain 8- (4-cyclobutyl-piperazin-1-yl) -9-cyclopropyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile monohydrochloride.

¹H-NMR(400MHz, DMSO-d₆):12.81(1H,s)、10.64(1H、br.s)、8.32-8.29(1H, m)、8.01(1H,s),7.67(1H、s)、7.61-7.60(1H、m)、7.33(1H、s)、4.00-3.39(6H、m)、3.28-3.02(3H、m)、2.45-2.05(5H、m)、1.83-1.77(8H、m)、1.09-1.07(2H、m)、0.81-0.80(2H、m)

LCMS: m/z 465 [M+H]⁺。

F5-46 methanesulfonic acid salt

F5-46 was dissolved in 5 parts by volume of dimethyl sulfoxide and 1.1 parts by volume of a methanesulfonic acid aqueous solution (2N), and the solution was freeze-dried. To the lyophilized product was added 5 parts by volume of benzyl alcohol. The precipitated crystals were filtered and dried to obtain F5-46-monomethanesulfonate salt.

Production example 44

Compound A7-24

8- （ 2- Bromine compound - Ethoxy group) -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 55]

By the same conditions as for compound A7-1 (8-hydroxy-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (compound A6, 30mg, 0.099 mmol) was dissolved in THF (1 mL), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (40 mg, 2 equivalents), triphenylphosphine (52 mg, 2 equivalents), diisopropyl azodicarboxylate (43. mu.L, 2 equivalents) were added in this order, stirring at room temperature for 4 hr, adding the reaction solution into water, extracting with ethyl acetate, washing the organic layer with saturated sodium chloride solution, drying with sodium sulfate, filtering to remove the drying agent, the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give compound A7-1 (.4- （ 3- Cyano radical -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -8- Oxy radical) - Piperidine derivatives -1- (iv) Carboxylic acid tert-butyl ester) (37 mg, 76%)) from compound a6 with 2-bromoethanol.

¹H-NMR(270MHz、DMSO-d₆) :12.75 (1H, br.s), 8.32 (1H, d, J = 8.2 Hz), 8.17 (1H, d, J = 8.6 Hz), 8.01 (1H,s), 7.61 (1H, dd, J = 8.2, 1.4 Hz), 7.40 (1H, d, J = 2.2 Hz), 7.12 (1H, dd, J =8.6, 2.2 Hz), 4.50 (2H, t, J = 5.3 Hz), 3.88 (2H, t, J = 5.3 Hz), 1.77 (6H, s).

LCMS: m/z 409、411 [M+H]⁺

HPLC retention time: score 2.48 (analytical conditions S).

Production example 45

Compound A8-10

8- （ 2- Tert-butylamino group - Ethoxy group) -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 56]

The reaction mixture was poured into water, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the drying agent, concentrated under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (ethyl acetate/hexane) to obtain a compound a7-17 (8-hydroxy-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (compound a6, 25mg, 0.083 mmol) was dissolved in N, N-dimethylacetamide (1 mL), 2-chloroethyldiethylamine (16 mg, 1.1 equiv) and cesium carbonate (54 mg, 2 equiv.) were added in this order, and the mixture was stirred at 100 ℃ for 4 hoursCompound A7-17 (8- （ 2- Diethylamino group - Ethoxy group) -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide) (11 mg, 32%)) was synthesized from compound A7-24 and tert-butylamine.

¹H-NMR(400MHz,DMSO-d₆) : 12.71 (1 H,s), 8.32 (1 H, d, 7.9 Hz), 8.15 (1 H, d, 9.1 Hz),8.07 (1 d, 1.8 Hz), 7.60 (1 H,dd, 1.8, 7.9 Hz), 7.35 (1 H, d, 2.4 Hz),7.09 (1 H, dd, 2.4, 9.1 Hz), 4.16 (2 H,t, 6.1 Hz), 2.91 (2 H, t, 6.1 Hz), 1.77 (6 H, s), 1.08 (9 H, s)

LCMS: m/z 402 [M+H]⁺

HPLC retention time: score 2.55 (analytical conditions W).

Production example 46

Compound F3-3

9- Bromine compound -8- （ 4- Mesyl radical - Piperazine derivatives -1- Base) -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 57]

The title compound was synthesized from compound F2 and 1-methanesulfonylpiperazine by the same conditions as the synthesis method of compound B2-1.

LCMS：　m/z　527，529　［M＋H］^＋

HPLC retention time: score 2.48 (analytical conditions S).

Production example 47

Compound F5-1

9- Ethynyl group -8- （ 4- Mesyl radical - Piperazine derivatives -1- Base) -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 58]

The title compound was synthesized from compound F3-3 under the same conditions as the synthesis of compound F5-43.¹H-NMR (270MHz、DMSO-D₆) :12.78 (1H, s), 8.31 (1H, dd, J = 8.1, 0.7 Hz), 8.19 (1H, s), 8.02 (1H, dd, J =1.4, 0.7 Hz), 7.61 (1H, dd, J = 8.2, 1.4 Hz), 7.33 (1H, s), 4.55 (1H, s), 3.43(4H, br), 2.98 (3H, s), 1.79 (6H, s).LCMS: m/z 473 [M+H]⁺

HPLC retention time: score 2.27 (analytical conditions S).

Production example 48

Compound F4-10

9- Bromine compound -8- （ 4- Cyclobutyl radical - Piperazine derivatives -1- Base) -6 ， 6- Dimethyl group -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ chemical 59]

The title compound was synthesized from compound F3-9 and cyclobutanone by the same method as that for the synthesis of compound B3-32.

¹H-NMR(400MHz, DMSO-d₆) : 8.23-8.29 (2H, m), 8.00 (1 H, s),7.55 (1 H, d, 7.9 Hz), 7.45 (1 H, s), 4.04-4.15 (1 H, m),3.10-3.20 (4 H, m), 2.39-2.48 (4 H, m), 1.97-2.06 (2 H, m), 1.78-1.88 (2 H, m),1.77 (6 H, s), 1.61-1.72 (2 H, m)LCMS: m/z 503, 505 [M+H]⁺

HPLC retention time: and 2.78 points (analysis condition W).

Production example 49

Compound F6-8

6 ， 6- Dimethyl group -8- （ 4- Oxetanes -3- Base of - Piperazine derivatives -1- Base) -11- Oxo radical -9- Propyl radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 60]

The title compound was synthesized from compound F5-22 by the same conditions as the synthesis method of compound B3-13-1.

¹H-NMR(270mHz DMSO-D₆) : 12.75 (1H, s),8.30 (1H, d, J = 8.2 Hz), 8.01-7.97 (2H, m), 7.59 (1H, d, J = 7.1 Hz), 7.38(1H, s), 4.51 (4H, dt, J = 27.7, 6.3 Hz), 3.55-3.49 (1H, m), 3.02-2.96 (4H, m),2.63 (2H, t, J = 7.3 Hz), 2.47-2.41 (4H, m), 1.73 (6H, s), 1.70-1.61 (2H, m),0.94 (3H, t, J = 7.4 Hz).

LCMS: m/z 469 [M+H]⁺

HPLC retention time: score 1.57 (analytical conditions S).

Production example 50

Compound F3-4

9- Bromine compound -6 ， 6- Dimethyl group -8- Morpholine -4- Base of -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 61]

The title compound was synthesized from compound F2 and morpholine by the same conditions as the synthesis of compound B2-1.

LCMS：　m/z　450，452　［M＋H］^＋

HPLC retention time: score 2.65 (analytical conditions S).

Production example 51

Compound F5-5

9- Ethynyl group -6 ， 6- Dimethyl group -8- Morpholine -4- Base of -11- Oxo radical -6 ， 11- Dihydro -5H- Benzo [ 2] b Carbazole -3- Nitrile (A) to methyl cyanide

[ solution 62]

The title compound was synthesized from compound F3-4 by the same conditions as the synthesis methods for compounds E4-2-1 and E4-2-2.

¹H-NMR(400MHz、DMSO-d₆) : 12.82 (1H, s), 8.31 (1H, d, J = 7.9 Hz), 8.18 (1H, s),8.02 (1H, s), 7.61 (1H, d, J = 7.9 Hz), 7.28 (1H, s), 4.53 (1H, s), 3.80 (4H,s), 3.36 (4H, s), 1.79 (6H, s).

LCMS: m/z 396 [M+H]⁺

HPLC retention time: score 2.32 (analytical conditions S).

Examples 1 to 269: ultra small scale dissolution test

(raw materials)

As a starting drug substance of compound F6-20 (free form), the one produced by the method described in production example 30 was used. The formulation additives used are those shown in Table 2.

(preparation of composition)

In examples 1 to 269, compound F6-20 was dissolved in DMSO at a concentration of 0.5mg/mL, hydrochloric acid equivalent to compound F6-20 was added to the resulting solution, and each dissolution aid was dissolved or dispersed in a solvent shown in table 2 to obtain a solution or dispersion, so that the weight ratio to compound F6-20 was 100%, and the solution or dispersion was freeze-dried to obtain a mixture of compound F6-20 and each dissolution aid.

Comparative example 1

Comparative example 1 was obtained by dissolving compound F6-20 in DMSO at a concentration of 0.5mg/mL, adding hydrochloric acid equivalent to compound F6-20 to the resulting solution, and freeze-drying the resulting solution.

(test example 1)

In Nos. 1 to 269 and comparative example 1, FaSSIF (fasted intestinal fluid) as a solution of human small intestine model was added (E.Galia et al pharm. Res.15:698Y705 (1998)), and after stirring at a stirring speed of 200rpm for 10 minutes and 240 minutes using a stirrer (Bio Shaker, TAITEC Co., Ltd.), the concentration was measured by high performance liquid chromatography (UFLC, Shimadzu corporation).

As shown in Table 3, citric acid (example 6), hydroxypropyl cellulose (example 16), hydroxypropylmethyl cellulose (example 17), sodium stearyl fumarate (example 18), methacrylic acid copolymer LD (example 22), methyl cellulose (example 23), sodium lauryl sulfate (example 24), polyoxyl stearate (example 40) ester (example 38), purified shellac (example 39), sodium dehydroacetate (example 44), fumaric acid (example 46), DL-malic acid (example 57), L-ascorbyl stearate (example 58), L-aspartic acid (example 59), adipic acid (example 66), aminoalkyl methacrylate copolymer E (example 67), propylene glycol alginate (example 73), casein (example 81), sodium caseinate (example 82), Carboxyvinyl polymer (example 85), carboxymethylethylcellulose (example 86), agar powder (example 88), guar gum (example 90), succinic acid (example 106), copovidone (example 107), cellulose acetate phthalate (example 112), tartaric acid (example 113), dioctyl sodium sulfosuccinate (example 117), zeatin (example 128), skim milk powder (example 136), sorbitan trioleate (example 147), lactic acid (example 148), aluminum lactate (example 149), ascorbyl palmitate (example 152), hydroxyethyl methylcellulose (example 154), hydroxypropyl methylcellulose acetate succinate (example 156), polyoxyethylene (105) polyoxypropylene (5) diol (example 176), polyoxyethylene hydrogenated castor oil 60 (example 182), Castor oil polyhydrocarbyloxyester (35) (example 185), poly (sodium 4-styrenesulfonate) (example 186), polyvinylacetal diethylaminoacetate (example 190), polyvinyl alcohol (example 191), maleic acid (example 200), methacrylic acid copolymer S (example 206), lauromacrogol (example 216), sulfuric acid (example 219), aluminum sulfate (example 220), phosphoric acid (example 223), monocalcium phosphate (example 230), sodium dodecylbenzenesulfonate (example 240), vinylpyrrolidone vinylacetate copolymer (example 241), sodium lauroyl sarcosinate (example 245), acetyltryptophan (example 253), sodium methylsulfate (example 260), sodium ethylsulfate (example 261), sodium butylsulfate (example 262), sodium octylsulfate (example 263), The solubility of compound F6-20 was significantly increased in sodium decyl sulfate (example 264), sodium tetradecyl sulfate (example 265), sodium hexadecyl sulfate (example 266), and sodium octadecyl sulfate (example 267).

Among them, the effects are found in citric acid (example 6), hydroxypropyl cellulose (example 16), hydroxypropylmethyl cellulose (example 17), methacrylic acid copolymer LD (example 22), methyl cellulose (example 23), sodium lauryl sulfate (example 24), purified shellac (example 39), sodium dehydroacetate (example 44), fumaric acid (example 46), DL-malic acid (example 57), L-ascorbyl stearate (example 58), L-aspartic acid (example 59), adipic acid (example 66), propylene glycol alginate (example 73), casein (example 81), sodium caseinate (example 82), carboxymethylethylcellulose (example 86), succinic acid (example 106), copovidone (example 107), sodium dioctyl sulfosuccinate (example 117), Lactic acid (example 148), aluminum lactate (example 149), ascorbyl palmitate (example 152), hydroxyethyl methylcellulose (example 154), hydroxypropyl methylcellulose acetate succinate (example 156), polyoxyethylene hydrogenated castor oil 60 (example 182), castor oil polyoxyl ester (35) (example 185), poly (sodium 4-styrenesulfonate) (example 186), polyvinyl acetal diethylaminoacetate (example 190), polyvinyl alcohol (example 191), methacrylic acid copolymer S (example 206), lauromacrogol (example 216), sulfuric acid (example 219), aluminum sulfate (example 220), sodium dodecylbenzenesulfonate (example 240), vinylpyrrolidone/vinyl acetate copolymer (example 241), acetyl tryptophan (example 253), sodium decyl sulfate (example 264), and sodium dodecyl sulfate (example 264), Sodium tetradecyl sulfate (example 265) and sodium octadecyl sulfate (example 267).

Among them, the effects are found in citric acid (example 6), hydroxypropyl cellulose (example 16), hydroxypropyl methylcellulose (example 17), methacrylic acid copolymer LD (example 22), methylcellulose (example 23), sodium lauryl sulfate (example 24), purified shellac (example 39), sodium dehydroacetate (example 44), fumaric acid (example 46), DL-malic acid (example 57), L-aspartic acid (example 59), adipic acid (example 66), propylene glycol alginate (example 73), sodium caseinate (example 82), carboxymethyl ethylcellulose (example 86), succinic acid (example 106), copovidone (example 107), sodium dioctyl sulfosuccinate (example 117), lactic acid (example 148), aluminum lactate (example 149), hydroxyethyl methylcellulose (example 154), Hydroxypropyl methylcellulose acetate succinate (example 156), poly (sodium 4-styrenesulfonate) (example 186), polyvinyl acetal diethylaminoacetate (example 190), methacrylic acid copolymer S (example 206), sulfuric acid (example 219), aluminum sulfate (example 220), vinylpyrrolidone seeding vinyl acetate copolymer (example 241), and sodium decyl sulfate (example 264) are particularly significant.

(examples 270 to 281)

(raw materials)

Compound F6-20 hydrochloride crystals were obtained according to the conventional method (for example, the method shown in preparation example 30).

Examples 270 to 281 were prepared by a dry method using hydrochloride crystals of compound F6-20 and an agate mortar according to the formulation shown in tables 4 to 8. Sodium lauryl sulfate used was a product that passed through a 100 mesh screen. Comparative example 2 was prepared by mixing crystalline hydrochloride salt of compound F6-20 with lactose in a weight ratio of 1: 9.

Test example 2 (small-scale dissolution test) (R. Takano et al, pharm. Res. 23: 1144. 1156 (2006)) the small-scale dissolution test was carried out by using a small-scale dissolution tester (Vankel Technologies, Inc.) to evaluate the solubility in FaSSIF at 37 ℃ and 50rpm of the blade rotation. For each test sample, the concentration of compound F6-20 in the test solution after 5,10, 15, 20, 25, 30, 45, 60, 120, 240 minutes was measured by high performance liquid chromatography.

Examples 270 to 272

The influence of the amount of SLS added on the solubility of the hydrochloride salt crystals of the compound F6-20 was examined by using examples 270 to 272 shown in Table 4 and comparative example 2. As a result, as is clear from FIG. 1, the solubility of compound F6-20 improved depending on the amount of sodium lauryl sulfate added.

[ Table 4]

TABLE 4

	Example 270	Example 271	Example 272
				Compound F6-20 hydrochloride	20.0%	20.0%	20.0%
Lactose hydrate	60.0%	75.0%	79.0%
				Sodium lauryl sulfate	20.0%	5.0%	1.0%

Examples 273 to 275

The influence of various cellulose polymers on the solubility of the hydrochloride salt crystals of the compound F6-20 was examined by using examples 273 to 275 shown in Table 5 and comparative example 2. As a result, as shown in FIG. 2, it was revealed that the solubility-improving effect of compound F6-20 in HPC was the most excellent even in a small amount among the cellulose-based polymers.

[ Table 5]

TABLE 5

	Example 273	Example 274	Example 275
				Compound F6-20 hydrochloride	21.5%	21.5%	21.5%
Lactose hydrate	67.5%	67.5%	67.5%
				Sodium lauryl sulfate	1.0%	1.0%	1.0%
Low substitution degree hydroxypropyl cellulose	5.0%	5.0%	5.0%
				Methyl cellulose	5.0%	0.0%	0.0%
Hydroxypropyl methylcellulose	0.0%	5.0%	0.0%
				Hydroxypropyl cellulose	0.0%	0.0%	5.0%

(examples 276 to 278)

The influence of the amount of HPC added on the solubility of the hydrochloride salt crystals of compound F6-20 was examined using examples 276 to 278 shown in Table 6 and comparative example 2 described above. As a result, as is clear from FIG. 3, examples 276 to 278 showed higher solubility than comparative example 2. Thus, the solubility-improving effect was exhibited by adding HPC to the compound F6-20 in a range of at least 25 to 100 wt.%.

[ Table 6]

TABLE 6

	Example 276	Example 277	Example 278
				Compound F6-20 hydrochloride	21.5%	21.5%	21.5%
Lactose hydrate	68.5%	63.5%	53.5%
				Low substitution degree hydroxypropyl cellulose	5.0%	5.0%	5.0%
Hydroxypropyl cellulose	5.0%	10.0%	20.0%

(embodiment 279)

The solubility of the hydrochloride salt crystals of compound F6-20 when SLS and HPC were blended was investigated using example 279 shown in Table 7. As a result, as clearly shown in fig. 4, the solubility was higher than that of example 276 only containing HPC, and thus higher than that of example 270 only containing SLS was maintained.

[ Table 7]

TABLE 7

	Example 279
		Compound F6-20 hydrochloride	21.5%
Lactose hydrate	48.5%
		Sodium lauryl sulfate	20.0%
Low substitution degree hydroxypropyl cellulose	5.0%
		Hydroxypropyl cellulose	5.0%

Example 280 to 281

The influence of the differences in the production methods on the elution property of the hydrochloride salt crystals of the compound F6-20 was examined by using examples 280 to 281 shown in Table 8 and comparative example 2. In the dry method, the components of the formula are mixed by an agate mortar. The wet granulated product was obtained by mixing a dissolution assistant other than magnesium stearate and compound F6-20 in a mortar, adding water dropwise, extruding the wet powder through a 850 μm-mesh sieve, granulating, drying at 60 ℃ for 3hr, and granulating again through a 850 μm-mesh sieve. As a result, as is clear from FIG. 5, there was no great difference in the elution properties of the hydrochloride crystal of Compound F6-20 between the production methods. Thus, the effect of improving the solubility of the SLS and the polymer on the surface is not dependent on the production method.

[ Table 8]

TABLE 8

	Example 280	Example 281
			Compound F6-20 hydrochloride	20.0%	20.0%
Lactose hydrate	41.5%	41.5%
			Crystalline cellulose	20.0%	20.0%
Croscarmellose sodium	3.0%	3.0%
			Hydroxypropyl cellulose	5.0%	5.0%
Sodium lauryl sulfate	10.0%	10.0%
			Magnesium stearate	0.5%	0.5%
Method for producing	Dry type	Wet granulation

(examples 282 to 284)

Examples 282 to 284 and comparative example 3 were prepared by a dry method using compound F6-20 mesylate salt crystals according to the formulation shown in Table 9 and using an agate mortar. Comparative example 3 was prepared by mixing crystalline mesylate salt of compound F6-20 with lactose in a weight ratio of 1: 9.

The effect of the addition amount of SLS on the solubility of Compound F6-20 mesylate was investigated, and the results are clearly shown in FIG. 6, where the solubility of Compound F6-20 mesylate was improved depending on the addition amount of sodium lauryl sulfate.

[ Table 9]

TABLE 9

	Example 282	Example 283	Example 284
				Compound F6-20 methanesulfonic acid salt	20.0%	20.0%	20.0%
Lactose hydrate	60.0%	75.0%	79.0%
				Sodium lauryl sulfate	20.0%	5.0%	1.0%

(example 285)

The solubility of the crystals of compound F6-20 mesylate when SLS and HPC were blended was examined using example 285 shown in Table 10 and comparative example 3. The results are clear from FIG. 7, showing high solubility by combining SLS and HPC.

[ Table 10]

Watch 10

	Example 285
		Compound F6-20 methanesulfonic acid salt	24.0%
Lactose hydrate	46.0%
		Sodium lauryl sulfate	20.0%
Low substitution degree hydroxypropyl cellulose	5.0%
		Hydroxypropyl cellulose	5.0%

(examples 286 to 298)

In comparative example 4 and examples 286 to 298, the effect of various dissolution aids on the solubility of compound B4-8 (production example 12) was examined in the same manner as in examples 1 to 269. The results are shown in Table 11.

[ Table 11]

TABLE 11 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound B4-8

(embodiment 299 to 311)

In comparative example 5 and examples 299 to 311, the effect of various dissolution aids on the solubility of the compound F4-3 (production example 19) was examined in the same manner as in examples 1 to 269. The results are shown in Table 12.

[ Table 12]

TABLE 12 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound F4-3

(examples 312 to 324)

In comparative example 6 and examples 312 to 324, the effect of various dissolution aids on the solubility of the compound F4-9 (production example 20) was examined in the same manner as in examples 1 to 269. The results are shown in Table 13.

[ Table 13]

TABLE 13 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound F4-9

(examples 325 to 337)

In comparative example 7 and examples 325 to 337, the effect of various dissolution aids on the solubility of the compound F6-4 (production example 28) was examined in the same manner as in examples 1 to 269. The results are shown in Table 14.

[ Table 14]

TABLE 14 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound F6-4

(examples 338 to 350)

In comparative example 8 and examples 338 to 350, the effect of various dissolution aids on the solubility of the compound F5-43 (production example 36) was examined in the same manner as in examples 1 to 269. The results are shown in Table 15.

[ Table 15]

TABLE 15 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound F5-43

(examples 351 to 363)

In comparative example 9 and examples 351 to 363, the effect of various dissolution aids on the solubility of the compound F6-17 (production example 32) was examined in the same manner as in examples 1 to 269. The results are shown in Table 16.

[ Table 16]

TABLE 16 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound F6-17

(examples 364 to 376)

In comparative example 10 and examples 364 to 376, the effect of various dissolution aids on the solubility of the compound F5-46 (production example 43) was examined in the same manner as in examples 1 to 269. The results are shown in Table 17.

[ Table 17]

TABLE 17 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound F5-46

(examples 377 to 389)

In comparative example 11 and examples 377 to 389, the effect of various dissolution aids on the solubility of compound F6-18 (production example 37) was examined in the same manner as in examples 1 to 269. The results are shown in Table 18.

[ Table 18]

TABLE 18 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound F6-18

(examples 390 to 402)

In comparative example 12 and examples 390 to 402, the effect of various dissolution aids on the solubility of the compound F5-51 (production example 27) was examined in the same manner as in examples 1 to 269. The results are shown in Table 19.

[ Table 19]

TABLE 19 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound F5-51

(examples 403 to 415)

In comparative example 13 and examples 403 to 415, the effect of various dissolution aids on the solubility of compound I6-4 (production example 24) was examined in the same manner as in examples 1 to 269. The results are shown in Table 20.

[ Table 20]

TABLE 20 Effect of various dissolution aids on the solubility of the hydrochloride salt of Compound I6-4

(examples 416 to 418)

The effects of SLS and polyvinylpyrrolidone on the solubility of the hydrochloride salt crystals of Compound B4-8 were investigated using small-scale dissolution tests using examples 416 to 418 shown in Table 21. Comparative example 14 was prepared by mixing crystalline hydrochloride salt of compound B4-8 with lactose in a weight ratio of 1: 9. The results are shown in FIG. 8.

[ Table 21]

TABLE 21

	Example 416	Example 417	Example 418
				Compound B4-8 hydrochloride	10.0%	10.0%	10.0%
Lactose hydrate	80.0%	80.0%	70.0%
				Polyvinyl pyrrolidone	0.0%	10.0%	10.0%
Sodium lauryl sulfate	10.0%	0.0%	10.0%

(examples 419 to 421)

Using examples 419 to 421 shown in table 22, the effect of SLS and polyvinylpyrrolidone on the solubility of compound B4-8 mesylate salt crystals was investigated using a small-scale dissolution test. Comparative example 15 was prepared by mixing compound B4-8 mesylate crystals with lactose in a weight ratio of 1: 9. The results are shown in FIG. 9.

[ Table 22]

TABLE 22

	Example 419	Example 420	Example 421
				Compound B4-8 methanesulfonic acid salt	10.0%	10.0%	10.0%
Lactose hydrate	80.0%	80.0%	70.0%
				Polyvinyl pyrrolidone	0.0%	10.0%	10.0%
Sodium lauryl sulfate	10.0%	0.0%	10.0%

(examples 422 to 424)

The effect of SLS and HPC on the solubility of Compound B4-8 sulfate crystals was investigated using small-scale dissolution tests using examples 422-424 shown in Table 23. Comparative example 16 was prepared by mixing the compound B4-8 sulfate crystal with lactose in a weight ratio of 1: 9. The results are shown in FIG. 10.

[ Table 23]

TABLE 23

	Example 422	Example 423	Example 424
				Compound B4-8 sulfate	24.6%	24.6%	24.6%
Lactose hydrate	55.4%	70.4%	50.4%
				Sodium lauryl sulfate	20.0%	0.0%	20.0%
Hydroxypropyl cellulose	0.0%	5.0%	5.0%

(examples 425 to 427)

The effect of SLS and HPC on the solubility of the compound B4-8L-tartrate crystals was investigated using examples 425 to 427 shown in Table 24 using a small scale dissolution test. Comparative example 17 was prepared by mixing the compound B4-8L-tartrate crystals with lactose in a weight ratio of 1: 9. The results are shown in FIG. 11.

[ Table 24]

Watch 24

	Example 425	Example 426	Example 427
				Compound B4-8L-tartrate	24.4%	24.4%	24.4%
Lactose hydrate	55.6%	70.6%	50.6%
				Sodium lauryl sulfate	20.0%	0.0%	20.0%
Hydroxypropyl cellulose	0.0%	5.0%	5.0%

(examples 428 to 429)

Using examples 428 to 429 shown in Table 25, the effect of SLS and HPC on the solubility of compound B4-8L-phosphate crystals was investigated using a small scale dissolution test. Comparative example 18 was prepared by mixing phosphate crystals of compound B4-8 with lactose in a weight ratio of 1: 9. The results are shown in FIG. 12.

[ Table 25]

TABLE 25

	Example 428	Example 429
			Compound B4-8 phosphate	26.3%	26.3%
Lactose hydrate	53.7%	48.7%
			Sodium lauryl sulfate	20.0%	20.0%
Hydroxypropyl cellulose	0.0%	5.0%

(example 430)

Using example 430 shown in table 26, the effect of polyoxyethylene (105) polyoxypropylene (5) diol on the solubility of compound F6-4 hydrochloride crystals was investigated using a small scale dissolution test. Comparative example 19 was prepared by mixing crystalline hydrochloride of compound F6-4 with lactose in a weight ratio of 1: 9. The results are shown in FIG. 13.

[ Table 26]

Watch 26

	Example 430
		Compound F6-4 hydrochloride	8.3%
Lactose hydrate	83.3%
		Polyoxyethylene (105) polyoxypropylene (5) diol	8.3%

Example 431

Using example 431 shown in table 27, the effect of polyoxyethylene (105) polyoxypropylene (5) diol on the solubility of compound F6-4 mesylate salt crystals was investigated by a small-scale dissolution test. Comparative example 20 was prepared by mixing compound F6-4 mesylate salt crystals with lactose in a weight ratio of 1: 9. The results are shown in FIG. 14.

[ Table 27]

Watch 27

	Example 431
		Compound F6-4 methanesulfonic acid salt	8.3%
Lactose hydrate	83.3%
		Polyoxyethylene (105) polyoxypropylene (5) diol	8.3%

(example 432)

Using example 432 shown in table 28, the effect of SLS on the solubility of compound F6-17 hydrochloride salt crystals was investigated using a small scale dissolution test. Comparative example 21 was prepared by mixing crystalline hydrochloride of compound F6-17 with lactose in a weight ratio of 1: 9. The results are shown in FIG. 15.

[ Table 28]

Watch 28

	Example 432
		Compound F6-17 hydrochloride	8.3%
Lactose hydrate	83.3%
		Sodium lauryl sulfate	8.3%

Example 433 to 435

Using examples 433 to 435 shown in Table 29, the effect of SLS on the solubility of compound F6-17 mesylate salt crystals was investigated using a small-scale dissolution test. Comparative example 22 was prepared by mixing compound F6-17 mesylate salt crystals with lactose in a weight ratio of 1: 9. The results are shown in FIG. 16.

[ Table 29]

Watch 29

	Example 433	Example 434	Example 435
				Compound F6-17 methanesulfonic acid salt	20.0%	20.0%	20.0%
Lactose hydrate	60.0%	75.0%	79.0%
				Sodium lauryl sulfate	20.0%	5.0%	1.0%

(examples 436 to 437)

The effects of SLS and polyvinylpyrrolidone on the solubility of crystals of the mesylate salt of Compound F6-17 were investigated by a small-scale dissolution test using examples 436 to 437 shown in Table 30 and comparative example 22 described above. The results are shown in FIG. 17.

[ Table 30]

Watch 30

	Example 436	Example 437
			Compound F6-17 methanesulfonic acid salt	24.2%	24.2%
Lactose hydrate	70.8%	50.8%
			Sodium lauryl sulfate	0.0%	20.0%
Polyvinyl pyrrolidone	5.0%	5.0%

(example 438)

Using example 438 shown in Table 31, the effect of SLS on the solubility of compound F6-17 maleate salt crystals was investigated using a small scale dissolution test. Comparative example 23 was prepared by mixing compound F6-17 maleate crystals with lactose in a weight ratio of 1: 9. The results are shown in FIG. 18.

[ Table 31]

Watch 31

	Example 438
		Compound F6-17 maleate	8.3%
Lactose hydrate	83.3%
		Sodium lauryl sulfate	8.3%

(examples 439 to 440)

Using examples 439 to 440 shown in Table 32, the effect of SLS and polyvinylpyrrolidone on the solubility of the crystalline compound F6-17L-tartrate was investigated by a small-scale dissolution test. Comparative example 24 was prepared by mixing compound F6-17L-tartrate crystals with lactose in a weight ratio of 1: 9. The results are shown in FIG. 19.

[ Table 32]

Watch 32

	Example 439	Example 440
			Compound F6-17L-tartrate	26.6%	26.6%
Lactose hydrate	53.4%	48.4%
			Sodium lauryl sulfate	20.0%	20.0%
Polyvinyl pyrrolidone	0.0%	5.0%

(examples 441 to 443)

The effect of SLS on the solubility of compound F6-17 citrate crystals was investigated using small-scale dissolution tests using examples 441 to 443 shown in Table 33. Comparative example 25 was prepared by mixing compound F6-17 citrate crystals with lactose in a weight ratio of 1: 9. The results are shown in FIG. 20.

[ Table 33]

Watch 33

	Example 441	Example 442	Example 443
				Compound F6-17 citrate	24.1%	24.1%	24.1%
Lactose hydrate	55.9%	70.9%	74.9%
				Sodium lauryl sulfate	20.0%	5.0%	1.0%

(examples 444 to 446)

The effect of SLS on the solubility of compound F6-17 malate crystal was investigated using examples 444-446 shown in Table 34 using a small scale dissolution test. Comparative example 26 was prepared by mixing compound F6-17 malate crystals with lactose in a weight ratio of 1: 9. The results are shown in FIG. 21.

[ Table 34]

Watch 34

	Example 444	Example 445	Example 446
				Compound F6-17 malate salt	25.9%	25.9%	25.9%
Lactose hydrate	54.1%	69.1%	73.1%
				Sodium lauryl sulfate	20.0%	5.0%	1.0%

(example 447)

Using example 447 shown in table 35, the effect of SLS on the solubility of the crystalline hydrochloride salt of compound F5-46 was investigated using a small scale dissolution test. Comparative example 27 was prepared by mixing crystalline hydrochloride of compound F5-46 with lactose in a weight ratio of 1: 9. The results are shown in FIG. 22.

[ Table 35]

Watch 35

	Example 447
		Compound F5-46 hydrochloride	8.3%
Lactose hydrate	83.3%
		Sodium lauryl sulfate	8.3%

Example 448

Using example 448 shown in Table 36, the effect of SLS on the solubility of crystals of compound F5-46 mesylate was investigated using a small scale dissolution test. Comparative example 28 was prepared by mixing compound F5-46 mesylate crystals with lactose in a weight ratio of 1: 9. The results are shown in FIG. 23.

[ Table 36]

Watch 36

	Example 448
		Compound F5-46 methanesulfonic acid salt	8.3%
Lactose hydrate	83.3%
		Sodium lauryl sulfate	8.3%

(example 449)

Using example 449 shown in table 37, the effect of SLS on the solubility of the hydrochloride salt crystals of compound F5-51 was investigated using a small scale dissolution test. Comparative example 29 was prepared by mixing crystalline hydrochloride of compound F5-51 with lactose in a weight ratio of 1: 9. The results are shown in FIG. 24.

[ Table 37]

Watch 37

	Example 449
		Compound F5-51 hydrochloride	8.3%
Lactose hydrate	83.3%
		Sodium lauryl sulfate	8.3%

Example 450

Using example 450 shown in Table 38, the effect of SLS on the solubility of crystals of compound F5-51 mesylate was investigated using a small scale dissolution test. Comparative example 30 was prepared by mixing compound F5-51 mesylate crystals with lactose in a weight ratio of 1: 9. The results are shown in FIG. 25.

[ Table 38]

Watch 38

	Example 450
		Compound F5-51 methanesulfonic acid salt	8.3%
Lactose hydrate	83.3%
		Sodium lauryl sulfate	8.3%

(preparation example of preparation)

Each of the components (excluding the lubricant) shown in tables 39 to 41 was put into a high-speed stirring mixer-granulator and premixed. This mixture was sprayed with pure water, stirred and granulated, and then vacuum-dried to obtain a dry powder. The dried powder was granulated by a granulator, and the obtained granulated powder and the lubricant were mixed by a V-type mixer to obtain a blended powder. The mixed powder was filled into capsules to prepare capsules containing 20mg of the active ingredient per 1 capsule.

[ Table 39]

Watch 39

[ Table 40]

Watch 40

[ Table 41]

Table 41

(examples 451 to 453)

Examples 451 to 453 were prepared by a dry method using hydrochloride crystals of compound F6-20 and an agate mortar according to the formulation shown in Table 42. Comparative example 31 was prepared by mixing crystalline hydrochloride salt of compound F6-20 with lactose.

The effects of SLS, polyoxyethylene (105) polyoxypropylene (5) glycol, and poly (sodium 4-styrenesulfonate) on the solubility of the hydrochloride crystals of compound F6-20 were investigated, and as a result, as clearly shown in fig. 26, the solubility of the hydrochloride crystals of compound F6-20 was improved by the addition of SLS, sodium poly (4-styrenesulfonate). It was also found that the initial solubility of the hydrochloride crystal of F6-20 was improved by the addition of polyoxyethylene (105) polyoxypropylene (5) diol.

The poly (sodium 4-styrenesulfonate) was manufactured under the reference numeral 243051 from Sigma.

[ Table 42]

Watch 42

	Example 451	Example 452	Example 453
				Hydrochloride crystal of compound F6-20	10.8%	10.8%	10.8%
Lactose hydrate	79.2%	79.2%	79.2%
				Sodium lauryl sulfate	10.0%	0.0%	0.0%
Polyoxyethylene (105) polyoxypropylene (5) diol	0.0%	10.0%	0.0%
				Poly (4-styrene sulfonic acid sodium salt)	0.0%	0.0%	10.0%
Total of	100.0%	100.0%	100.0%

Examples 454 to 457

The effect of the combination of SLS and polyoxyethylene (105) polyoxypropylene (5) diol on the solubility of the hydrochloride crystals of compound F6-20 was examined using examples 454 to 457 shown in Table 43. As a result, as clearly shown in fig. 27, the solubility-improving effect of the hydrochloride crystals of compound F6-20 by SLS was further improved in the early stage by blending at least 1% of polyoxyethylene (105) polyoxypropylene (5) diol in the preparation.

[ Table 43]

Watch 43

	Example 454	Example 455	Example 456	Example 457
					Hydrochloride crystal of compound F6-20	10.8%	10.8%	10.8%	10.8%
Lactose hydrate	84.2%	83.2%	81.7%	74.2%
					Sodium lauryl sulfate	5.0%	5.0%	5.0%	5.0%
Polyoxyethylene (105) polyoxypropylene (5) diol	0.0%	1.0%	2.5%	10.0%
					Total of	100.0%	100.0%	100.0%	100.0%

(examples 458 to 460)

Using examples 458-460 shown in Table 44, the effect of SLS in combination with poly (sodium 4-styrenesulfonate) on the solubility of the hydrochloride salt crystals of Compound F6-20 was investigated. As a result, as clearly shown in fig. 28, the solubility-improving effect of the hydrochloride crystals of compound F6-20 by SLS was further improved depending on the compounding amount of poly (sodium 4-styrenesulfonate).

The poly (sodium 4-styrenesulfonate) was manufactured under the reference numeral 243051 from Sigma.

[ Table 44]

Watch 44

	Example 458	Example 459	Example 460
				Hydrochloride crystal of compound F6-20	10.8%	10.8%	10.8%
Lactose hydrate	83.2%	81.7%	74.2%
				Sodium lauryl sulfate	5.0%	5.0%	5.0%
Poly (4-styrene sulfonic acid sodium salt)	1.0%	2.5%	10.0%
				Total of	100.0%	100.0%	100.0%

(embodiment 461 to 465)

The effect of the combination of SLS, polyoxyethylene (105) polyoxypropylene (5) diol and poly (sodium 4-styrenesulfonate) on the solubility of the hydrochloride crystal of Compound F6-20 was examined using examples 461 to 465 shown in Table 45. As a result, as clearly shown in fig. 29, the solubility of the hydrochloride crystal of compound F6-20 was improved by the combination of SLS, polyoxyethylene (105) polyoxypropylene (5) diol, and poly (sodium 4-styrenesulfonate).

The poly (sodium 4-styrenesulfonate) was manufactured under the reference numeral 243051 from Sigma.

[ Table 45]

TABLE 45

(examples 466 to 467)

Using examples 466 to 467 shown in Table 46, the effect of the SLS amount on the solubility of the hydrochloride crystalline preparation of Compound F6-20 containing polyoxyethylene (105) polyoxypropylene (5) diol and poly (sodium 4-styrenesulfonate) was examined. As a result, as clearly shown in fig. 30, even if SLS was reduced to half amount, the solubility of the hydrochloride crystalline formulation of compound F6-20 containing polyoxyethylene (105) polyoxypropylene (5) diol and poly (sodium 4-styrenesulfonate) was not changed.

The poly (sodium 4-styrenesulfonate) was manufactured under the reference numeral 243051 from Sigma.

[ Table 46]

TABLE 46

	Example 466	Example 467
			Hydrochloride crystal of compound F6-20	16.5%	16.5%
Lactose hydrate	27.3%	31.2%
			Crystalline cellulose	20.0%	20.0%
Starch sodium glycolate	6.0%	6.0%
			Hydroxypropyl cellulose	5.0%	5.0%
Sodium lauryl sulfate	7.7%	3.8%
			Polyoxyethylene (105) polyoxypropylene (5) diol	1.5%	1.5%
Poly (4-styrene sulfonic acid sodium salt)	15.4%	15.4%
			Magnesium stearate	0.5%	0.5%
Total of	100.0%	100.0%

Claims (22)

1. A composition comprising 9-ethyl-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile or a salt thereof, a pharmaceutically acceptable carrier, and a surfactant,

wherein the weight ratio of 9-ethyl-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile or a salt thereof and the surfactant is 1: 0.01 to 1: 25.

2. the composition of claim 1, wherein the surfactant is a nonionic or anionic surfactant.

3. The composition of claim 2, wherein the surfactant is selected from the group consisting of monoalkyl sulfates, polyoxyl (40) stearate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, castor oil polyoxyl ester (35), lauromacrogol, dioctyl sodium sulfosuccinate, sodium lauroyl sarcosinate, sodium dodecyl benzene sulfonate, and mixtures thereof.

4. The composition according to claim 2 or 3, wherein the composition further contains an organic polymer.

5. The composition of claim 4, wherein the organic polymer is selected from the group consisting of synthetic resins, water-soluble polymers, gastric-soluble polymers, enteric-soluble polymers, and mixtures thereof.

6. The composition according to claim 5, wherein the water-soluble polymer is hydroxypropyl cellulose, hydroxypropyl methylcellulose, propylene glycol alginate, sodium caseinate, carboxyvinyl polymer, agar powder, guar gum, copovidone, hydroxyethyl methylcellulose, or polyvinyl alcohol, the gastric-soluble polymer is aminoalkyl methacrylate copolymer E or polyvinyl acetal diethylaminoacetate, and the enteric-soluble polymer is methacrylic acid copolymer LD, purified shellac, carboxymethyl ethylcellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, methacrylic acid copolymer S, casein, or zeatin.

7. The composition of claim 5, wherein the weight ratio of 9-ethyl-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile or a salt thereof to organic polymer is 1:0.02 to 1: 20.

8. the composition of claim 6, wherein the weight ratio of 9-ethyl-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile or a salt thereof to organic polymer is 1:0.02 to 1: 20.

9. the composition according to claim 4, wherein the organic polymer is a synthetic resin.

10. The composition according to claim 6, wherein the composition further comprises 1 or more than 1 additive selected from the following additive group A,

additive A: citric acid, fumaric acid, DL-malic acid, adipic acid, succinic acid, tartaric acid, lactic acid, maleic acid, sulfuric acid, phosphoric acid, sodium dehydroacetate, sodium stearyl fumarate, L-ascorbyl stearate, L-aspartic acid, skim milk powder, aluminum lactate, ascorbyl palmitate, aluminum sulfate, monocalcium phosphate, or acetyltryptophan.

11. The composition of claim 1, wherein the weight ratio of 9-ethyl-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile or a salt thereof and the surfactant is 1:0.05 to 1: 1.

12. the composition of claim 4, wherein the weight ratio of 9-ethyl-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile or a salt thereof to the organic polymer is 1:0.02 to 1: 20.

13. the composition of claim 1, wherein the pharmaceutically acceptable carrier is corn starch, potato starch, flour starch, rice starch, gelatinized starch, porous starch; lactose hydrate, fructose, glucose, mannitol, sorbitol; anhydrous calcium hydrogen phosphate, crystalline cellulose, precipitated calcium carbonate or calcium silicate.

14. The composition of claim 13, wherein the gelatinized starch is a partially gelatinized starch.

15. An oral administration preparation containing the composition of any one of claims 1 to 14.

16. A composition comprising 9-ethyl-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile or a salt thereof, a pharmaceutically acceptable carrier, and a dissolution aid,

wherein the content of the 9-ethyl-6, 6-dimethyl-8- (4-morpholine-4-yl-piperidine-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile or a salt thereof is 1-50 parts by weight,

the dissolution aid is selected from the group consisting of,

group (2):

citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium stearyl fumarate, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, polyoxyl (40) stearate, refined shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbyl stearate, L-aspartic acid, adipic acid, aminoalkyl methacrylate copolymer E, propylene glycol alginate, casein, sodium caseinate, carboxyvinyl polymer, carboxymethyl ethyl cellulose, agar powder, guar gum, succinic acid, copovidone, cellulose acetate phthalate, tartaric acid, dioctyl sodium sulfosuccinate, zein, skim milk powder, sorbitan trioleate, lactic acid, aluminum lactate, ascorbyl palmitate, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, sodium stearyl fumarate, sodium lauryl sulfate, sodium caseinate, carboxymethyl cellulose, guar gum, succinic acid, copovidone, cellulose acetate, sodium lauryl sulfate, sodium sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) diol, polyoxyethylene hydrogenated castor oil 60, castor oil polyoxyl (35), poly (sodium 4-styrenesulfonate), polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, maleic acid, methacrylic acid copolymer S, lauromacrogol, sulfuric acid, aluminum sulfate, phosphoric acid, calcium dihydrogen phosphate, sodium dodecylbenzenesulfonate, vinyl pyrrolidone seed vinyl acetate copolymer, sodium lauroyl sarcosinate, acetyl tryptophan, sodium methylsulfate, sodium ethylsulfate, sodium butylsulfate, sodium octylsulfate, sodium decylsulfate, sodium tetradecylsulfate, sodium hexadecylsulfate, and sodium octadecylsulfate.

17. A composition comprising 9-ethyl-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile or a salt thereof, a pharmaceutically acceptable carrier, and a dissolution aid,

wherein the dissolution aid is selected from the group consisting of,

group (2):

citric acid, sodium stearyl fumarate, methacrylic acid copolymer LD, sodium lauryl sulfate, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbyl stearate, L-aspartic acid, adipic acid, aminoalkyl methacrylate copolymer E, propylene glycol alginate, casein, sodium caseinate, carboxyvinyl polymer, carboxymethyl ethyl cellulose, agar powder, guar gum, succinic acid, copovidone, cellulose acetate phthalate, tartaric acid, sodium dioctyl sulfosuccinate, zein, skim milk powder, sorbitan trioleate, lactic acid, aluminum lactate, ascorbyl palmitate, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, castor oil poly (35) alkoxide, Poly (sodium 4-styrenesulfonate), polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, maleic acid, methacrylic acid copolymer S, sulfuric acid, aluminum sulfate, monocalcium phosphate, sodium dodecylbenzenesulfonate, vinyl pyrrolidone seed vinyl acetate copolymer, sodium lauroyl sarcosinate, acetyl tryptophan, sodium methyl sulfate, sodium ethyl sulfate, sodium butyl sulfate, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, and sodium octadecyl sulfate.

18. The composition of claim 16, wherein the dissolution aid is selected from the group consisting of,

group (2):

citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, refined shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbyl stearate, L-aspartic acid, adipic acid, propylene glycol alginate, casein, sodium caseinate, carboxymethylethyl cellulose, succinic acid, copovidone, dioctyl sodium sulfosuccinate, lactic acid, aluminum lactate, ascorbyl palmitate, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, polyoxyethylene hydrogenated castor oil 60, castor oil polyoxyl ester (35), sodium polystyrene sulfonate, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, methacrylic acid copolymer S, lauroyl alcohol, sulfuric acid, aluminum sulfate, sodium dodecylbenzenesulfonate, vinyl pyrrolidone vinylacetate copolymer, vinyl acetate copolymer, sodium lauryl sulfate, sodium caseinate, sodium lauryl sulfate, sodium dehydroacetate, sodium lauryl sulfate, sodium caseinate, sodium lauryl sulfate, sodium lauryl, Acetyl tryptophan, sodium decyl sulfate, sodium tetradecyl sulfate, and sodium octadecyl sulfate.

19. The composition of claim 17, wherein the dissolution aid is selected from the group consisting of,

group (2):

citric acid, methacrylic acid copolymer LD, sodium lauryl sulfate, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbic acid stearate, L-aspartic acid, adipic acid, propylene glycol alginate, casein, sodium caseinate, carboxymethylethylcellulose, succinic acid, copovidone, dioctyl sodium sulfosuccinate, lactic acid, aluminum lactate, ascorbyl palmitate, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, polyoxyethylene hydrogenated castor oil 60, castor oil polyoxyl ester (35), sodium polystyrene sulfonate, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, methacrylic acid copolymer S, sulfuric acid, aluminum sulfate, sodium dodecylbenzene sulfonate, vinyl pyrrolidone vinylacetate copolymer, acetyl tryptophan, sodium decyl sulfate, sodium tetradecyl sulfate, sodium dodecyl sulfate, sodium lauryl sulfate, sodium laurylsulfate, sodium laurylsulfonate, sodium lauryl sulfate, sodium lauryl, And sodium stearyl sulfate.

20. The composition of claim 16, wherein the dissolution aid is selected from the group consisting of,

group (2):

citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, refined shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-aspartic acid, adipic acid, propylene glycol alginate, sodium caseinate, carboxymethyl ethylcellulose, succinic acid, copovidone, dioctyl sodium sulfosuccinate, lactic acid, aluminum lactate, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, sodium polystyrene sulfonate, polyvinyl acetal diethylaminoacetate, methacrylic acid copolymer S, sulfuric acid, aluminum sulfate, vinyl pyrrolidone vinylacetate copolymer, and decyl sodium sulfate.

21. The composition of claim 17, wherein the dissolution aid is selected from the group consisting of,

group (2):

citric acid, methacrylic acid copolymer LD, sodium lauryl sulfate, sodium dehydroacetate, fumaric acid, DL-malic acid, L-aspartic acid, adipic acid, propylene glycol alginate, sodium caseinate, carboxymethyl ethyl cellulose, succinic acid, copovidone, dioctyl sodium sulfosuccinate, lactic acid, aluminum lactate, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, sodium polystyrene sulfonate, polyvinyl acetal diethylaminoacetate, methacrylic acid copolymer S, sulfuric acid, aluminum sulfate, vinyl pyrrolidone vinyl acetate copolymer, and sodium decyl sulfate.

22. The composition of any one of claims 16-21, wherein the composition further comprises an organic polymer, wherein the organic polymer is a vinyl acetate resin.