WO2014174745A1

WO2014174745A1 - Eg5 INHIBITOR

Info

Publication number: WO2014174745A1
Application number: PCT/JP2014/000982
Authority: WO
Inventors: 藤井　信孝; 浩章大野; 真也大石; 智起竹内; 章良浅井; 潤一澤田
Original assignee: 国立大学法人京都大学; 一般社団法人ファルマバレープロジェクト支援機構
Priority date: 2013-04-26
Filing date: 2014-02-25
Publication date: 2014-10-30
Also published as: JPWO2014174745A1

Abstract

Compared to a traditional Eg5 (KSP: kinesin spindle protein) inhibitor, this water-soluble polycyclic compound or a pharmacologically acceptable salt thereof has a greater solubility in an aqueous solvent and has Eg5 inhibitory activity that is equivalent to or greater than that of the traditional Eg5 inhibitor. Furthermore, due to these properties, the present invention has a remarkable growth inhibiting activity against various cancer cells and is very effective for the treatment of cancer, etc.

Description

Eg5 inhibitor

The present invention relates to an Eg5 inhibitor containing a water-soluble polycyclic compound as an active ingredient.

Eg5 (KSP: Kinesin Spindle Protein) is a kind of motor protein and plays an important role in cell division of cancer cells. That is, Eg5 is involved in centrosome separation / movement, spindle formation / maintenance, spindle pole formation, and the like, and controls the progression of cell division in the M phase (see, for example, Non-Patent Document 1). ). It is known that by inhibiting Eg5, cancer cells are arrested in the M phase and apoptosis is induced (see, for example, Non-Patent Document 2). Therefore, Eg5 inhibitors are expected as therapeutic agents for cell proliferative diseases such as cancer.

Conventionally, various Eg5 inhibitors including compounds having a skeleton similar to natural products have been known (Non-patent Document 3).

So far, the present inventors have found that the fused indole skeleton is a skeleton common to Eg5 inhibitory activity based on the similarity of skeletons of Eg5 inhibitors such as terpendole E and HR22C16, and their structure-activity relationship Through research, it was clarified that a compound having a carbazole skeleton is a structural element necessary for inhibition of Eg5 (Non-patent Document 4, Patent Document 1).

In addition, the present inventors have found that a compound in which a modified functional group such as a lactam ring possessed by a biphenyl-type inhibitor is imparted to a carbazole-type inhibitor exhibits a strong Eg5 inhibitory activity (Non-Patent Document). 5).

In addition, several groups have reported Eg5 inhibitors having a carbazole type structure. For example, a carbazole derivative represented by the following formula (A) (wherein X represents CF ₃ or S (O) _n R ₁ , Y represents NR ₁ R ₂ , NR ₁ COR ₂ , NR ₁ CONR ₂ R ₃ , NR ₁ CSNR ₂ R ₃ or NR ₁ (S) _n R ₂ , A and B represent carbon or nitrogen) have KSP inhibitory activity and are effective for treatment of cancer, etc. Is known (see, for example, Patent Document 2).

Further, it is known that tetrahydrocarboline compounds also have KSP inhibitory activity (see, for example, Patent Document 3).

Not only compounds having a carbazole type structure but also Eg5 inhibitors having the following biphenyl type structure have been reported (Non-Patent Documents 6 to 8).

In addition, Eg5 inhibitors having the following flavone or isoflavone structures (Non-Patent Document 9) and amine derivatives having a trimethylphenyl group as Eg5 inhibitors (Non-Patent Document 10) have been reported.

JP 2012-051804 A WO2006 / 005063 Publication Special table 2007-518822 gazette

Conventionally, an Eg5 inhibitor having a skeleton similar to a natural product has been poorly put into practical use because many compounds have insufficient activity from the viewpoint of practical use, the chemical structure is complicated, and chemical synthesis is not easy. In addition, although the Eg5 inhibitor having a biphenyl type structure or a carbazole type structure has strong Eg5 inhibitory activity, the solubility from the structure to an aqueous solvent is extremely poor, and thus has a serious problem in the course of drug administration. . An object of the present invention is to provide a water-soluble Eg5 inhibitor having sufficient cell growth inhibitory activity and easy chemical synthesis, an anticancer agent containing the Eg5 inhibitor, and the like.

The present inventors consider that the poor water solubility of Eg5 inhibitors having a carbazole-type structure reported so far is derived from the high planarity of the structure, and thus the carbon-carbon bond of the pyrrole ring in the central part is cleaved. The resulting polycyclic compound was prepared. It was found that the solubility of this skeletal compound in 50% aqueous ethanol solution and phosphate buffer was very large compared to the conventional carbazole type and biphenyl type.

Conventionally, from the structure-activity relationship studies of Eg5 inhibition by the present inventors and other groups, a fused indole skeleton or biphenyl skeleton containing a carbazole skeleton has been considered important for inhibiting Eg5 activity. Surprisingly, however, the present inventors are useful as an Eg5 inhibitor because the water-soluble polycyclic compound of the present invention has an Eg5 inhibitory activity equivalent to that of conventional carbazole type inhibitors. As a result, the present invention has been completed.

That is, the present invention
(1) Formula (I)

{Where,
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
X is NZ (wherein Z is hydrogen, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 or 4 carbon atoms, or a substituted or unsubstituted alkenyl group having 2 to 4 carbon atoms) Represents a group, a substituted or unsubstituted alkynyl group having 2 to 4 carbon atoms), O or S;
R ¹ and R ² are the same or different and each represents hydrogen, a halogen atom, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 or 4 carbon atoms, or 2 to 4 carbon atoms. A substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group having 2 to 4 carbon atoms, OZ ¹ (wherein Z ¹ is as defined above for Z), OCOZ ² (wherein Z ² is the same as Z NZ ³ COOZ ⁴ (wherein Z ³ and Z ⁴ are the same or different and have the same meaning as Z), S (O) _n Z ⁵ (wherein n is 0-3) Z ⁵ is as defined above for Z), SO ₂ NZ ⁶ Z ⁷ (wherein Z ⁶ and Z ⁷ are the same or different and have the same meaning as Z or Z ⁶ Z ⁷ together may form a substituted or unsubstituted nitrogen-containing heterocyclic group) COZ ⁸ (wherein, ^{Z 8} is the same meaning as Z), COOZ ⁹ (wherein, ^{Z 9} is the same meaning as ^Z), 10 ^{Z 11} (wherein ^{^CONZ, Z 10} and ^{Z 11} is Each having the same meaning as Z ⁶ and Z ⁷ ), NZ ¹² Z ¹³ (wherein Z ¹² and Z ¹³ are the same as Z ⁶ and Z ⁷ , respectively), a nitro group or a cyano group,
Q ¹ , Q ² , and Q ³ are the same or different and represent a nitrogen atom or —C (W) = (wherein W has the same meaning as R ¹ ),
Y ¹ , Y ² , Y ³ and Y ⁴ are the same or different and have the same meaning as R ¹ or an alkylene-COOZ ¹⁴ having 1 to 4 carbon atoms (wherein Z ¹⁴ has the same meaning as Z above). Y ¹ and Y ² , Y ² and Y ³ , Y ³ and Y ⁴ may form a 5- to 7-membered ring structure containing carbons to which each is bonded;
However, in the above compound, ab, cd, and ef are simultaneously a double bond, X is NH, R ¹ is trifluoromethyl, and Q ¹ , Q ² , and Q ³ are When it is CH and Y ¹ and Y ⁴ are hydrogen,
Excluding compounds in which Y ² is hydrogen and Y ³ is a nitro group, or Y ² and Y ³ are combined to form a δ-lactam structure in which Y ² -Y ³ is CH ₂ CH ₂ CONH}
Or a water-soluble polycyclic compound represented by
(2) The compound represented by the formula (I) is represented by the following formula (II)

(Where
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
R ¹ , R ² , X and Y ¹ to Y ⁴ are as defined above.
A water-soluble polycyclic compound or a salt thereof according to (1) above, which is a polycyclic compound represented by the formula:
(3) The compound represented by the formula (II) is represented by the following formula (III)

(Where
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
R ¹ , R ² , X and Y ¹ , Y ² are as defined above.
A water-soluble polycyclic compound or a salt thereof according to the above (2), which is a polycyclic compound represented by the formula:
(4) The compound represented by the formula (III) is represented by the following formula (IV)

(Where
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
R ¹ represents hydrogen, a halogen atom, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a hydroxyl group, a substituted or unsubstituted alkoxyl group having 1 to 4 carbon atoms, a formyl group, a carboxyl group, a sulfonic acid group, a nitro group, and Any one selected from cyano groups, and Y ¹ and Y ² are the same or different and each is hydrogen or fluorine)
A water-soluble polycyclic compound or a salt thereof according to the above (3), which is a polycyclic compound represented by the formula:
(5) The water-soluble polycyclic compound or a salt thereof according to any one of (1) to (4) above, wherein the bonds ab, cd, and ef are simultaneously double bonds ,
(6) R ¹ is a trifluoromethyl group, an ethyl group, an isopropyl group, a tert-butyl group, a trifluoromethoxy group or a nitro group, according to any one of (1) to (5) above A water-soluble polycyclic compound or a salt thereof,
(7) The compound represented by the formula (I) is represented by the following formula (V)

(Where
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
Y ¹ to Y ⁴ are as defined above,
(One or more of Q ¹ , Q ² , and Q ³ are nitrogen electrons)
A water-soluble polycyclic compound or a salt thereof according to (1) above, which is a polycyclic compound represented by the formula:
(8) The water-soluble polycyclic compound or a salt thereof according to the above (7), wherein the bonds ab, cd, and ef are simultaneously double bonds,
(9) Water-soluble polycyclic compounds represented by the formula (I) are represented by the formulas (I-3) to (I-25):

It is related with the water-soluble polycyclic compound or its salt as described in said (1) characterized by being any one of the water-soluble polycyclic compounds represented by these.

Furthermore, the present invention provides (10) Formula (I)

{Where,
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
X is NZ (wherein Z is hydrogen, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 or 4 carbon atoms, or a substituted or unsubstituted alkenyl group having 2 to 4 carbon atoms) Represents a group, a substituted or unsubstituted alkynyl group having 2 to 4 carbon atoms), O or S;
R ¹ and R ² are the same or different and each represents hydrogen, a halogen atom, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 or 4 carbon atoms, or 2 to 4 carbon atoms. A substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group having 2 to 4 carbon atoms, OZ ¹ (wherein Z ¹ is as defined above for Z), OCOZ ² (wherein Z ² is the same as Z NZ ³ COOZ ⁴ (wherein Z ³ and Z ⁴ are the same or different and have the same meaning as Z), S (O) _n Z ⁵ (wherein n is 0-3) Z ⁵ is as defined above for Z), SO ₂ NZ ⁶ Z ⁷ (wherein Z ⁶ and Z ⁷ are the same or different and have the same meaning as Z or Z ⁶ Z ⁷ together may form a substituted or unsubstituted nitrogen-containing heterocyclic group) COZ ⁸ (wherein, ^{Z 8} is the same meaning as Z), COOZ ⁹ (wherein, ^{Z 9} is the same meaning as ^Z), 10 ^{Z 11} (wherein ^{^CONZ, Z 10} and ^{Z 11} is Each having the same meaning as Z ⁶ and Z ⁷ ), NZ ¹² Z ¹³ (wherein Z ¹² and Z ¹³ are the same as Z ⁶ and Z ⁷ , respectively), a nitro group or a cyano group,
Q ¹ , Q ² , and Q ³ are the same or different and represent a nitrogen atom or —C (W) = (wherein W has the same meaning as R ¹ ),
Y ¹ , Y ² , Y ³ and Y ⁴ are the same or different and have the same meaning as R ¹ or an alkylene-COOZ ¹⁴ having 1 to 4 carbon atoms (wherein Z ¹⁴ has the same meaning as Z above). And Y ¹ and Y ² , Y ² and Y ³ , Y ³ and Y ⁴ may each form a 5- to 7-membered ring structure containing carbon bonded to each other}
An Eg5 inhibitor containing, as an active ingredient, a water-soluble polycyclic compound represented by or a pharmacologically acceptable salt thereof,

(11) The compound represented by the formula (I) is represented by the following formula (II)

(Where
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
R ¹ , R ² , X and Y ¹ to Y ⁴ are as defined above.
An Eg5 inhibitor according to (10), which is a polycyclic compound represented by:
(12) The compound represented by the formula (II) is represented by the following formula (III)

(Where
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
R ¹ , R ² , X and Y ¹ , Y ² are as defined above.
An Eg5 inhibitor according to the above (11), which is a polycyclic compound represented by:
(13) The compound represented by the formula (III) is represented by the following formula (IV)

(Where
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
R ¹ represents hydrogen, a halogen atom, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a hydroxyl group, a substituted or unsubstituted alkoxyl group having 1 to 4 carbon atoms, a formyl group, a carboxyl group, a sulfonic acid group, a nitro group, and Any one selected from cyano groups, and Y ¹ and Y ² are the same or different and each is hydrogen or fluorine)
An Eg5 inhibitor according to (12) above, which is a polycyclic compound represented by:
(14) The Eg5 inhibitor according to any one of (10) to (13) above, wherein the bonds ab, cd, and ef are simultaneously double bonds,
(15) Any one of (10) to (14) above, wherein R ¹ is a trifluoromethyl group, an ethyl group, an isopropyl group, a tert-butyl group, a trifluoromethoxy group, or a nitro group. Eg5 inhibitors,
(16) The compound represented by the formula (I) is represented by the following formula (V)

(Where
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
Y ¹ to Y ⁴ are as defined above,
1 or 2 of Q ¹ , Q ² , and Q ³ is a nitrogen electron)
An Eg5 inhibitor according to (10), which is a polycyclic compound represented by:
(17) The Eg5 inhibitor according to the above (16), wherein the bonds ab, cd, and ef are simultaneously double bonds,
(18) The water-soluble polycyclic compounds represented by the formula (I) are represented by the formulas (I-1) to (I-25):

The Eg5 inhibitor according to (10) above, which is any one of the water-soluble polycyclic compounds represented by: or a pharmacologically acceptable salt thereof,
(19) A pharmacologically acceptable salt of the water-soluble polycyclic compound represented by the formula (I) is represented by the following formula (VI):

{Where,
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
R ¹ , R ² , Q ¹ to Q ³ , Y ¹ to Y ⁴ and Z are as defined above,
L is synonymous with Z,
M is a halogen atom, Z ¹⁵ COO (wherein Z ¹⁵ is as defined above for Z), Z ¹⁶ SO ₃ (wherein Z ¹⁶ is as defined above for Z), BF ₄ and PF ₆ Any one selected from}
The Eg5 inhibitor according to any one of the above (10) to (18),
(20) The Eg5 inhibitor according to any one of (10) to (17) and (19), wherein the bonds ab, cd, and ef are double bonds.

Furthermore, the present invention provides (21) a cell growth inhibitor or anticancer agent containing the Eg5 inhibitor according to any one of (10) to (20) as an active ingredient,
(22) A medicament comprising the water-soluble polycyclic compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (9) as an active ingredient,
(23) A pharmaceutical composition comprising the water-soluble polycyclic compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (9) above and a pharmaceutically acceptable carrier.

Other aspects of the invention relating to the Eg5 inhibitor include use of a water-soluble polycyclic compound represented by formula (I) or a pharmacologically acceptable salt thereof for the preparation of an Eg5 inhibitor, Eg5 The water-soluble polycyclic compound represented by the formula (I) for use as an inhibitor or a pharmacologically acceptable salt thereof can be mentioned. In addition, as another aspect of the invention relating to the anticancer agent, the use of the water-soluble polycyclic compound represented by the formula (I) or a pharmacologically acceptable salt thereof for the preparation of the anticancer agent, or use as an anticancer agent A water-soluble polycyclic compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, a water-soluble polycyclic compound represented by the formula (I) or a pharmacologically acceptable And a method for treating cancer in which a salt is administered to a subject.

The Eg5 inhibitor containing the water-soluble polycyclic compound of the present invention or a pharmacologically acceptable salt thereof has cell growth inhibitory activity and can be used as an anticancer agent or the like for various cancers.

The compound used as the Eg5 inhibitor of the present invention is preferably a bicyclic or higher water-soluble polycyclic compound, and as the compound, a compound represented by the following formula (I) (hereinafter, The compound is not particularly limited as long as it is referred to as compound (I), and the same applies to compounds of other formula numbers.

(Where
The bonds ab, cd, and ef are simultaneously or differently represented as a single bond or a double bond,
Q ¹ to Q ³ , R ¹ , R ² , X, Y ¹ to Y ⁴ and Z are as defined above)
The polycyclic compound represented by these is preferable.

In the above formula (I), the bonds ab, cd, and ef are the same or different and each represents a single bond or a double bond. The ring containing the bonds ab, cd, ef is a cyclohexane ring when all the bonds are simultaneously single bonds, and is a cyclohexene ring when any one is a double bond, When one of them is a single bond, it is a dihydrobenzene ring, and when all the bonds are simultaneously double bonds, it is a benzene ring.

In the above formula (I), X is NZ (wherein Z is hydrogen, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 or 4 carbon atoms, or 2 to 4 carbon atoms). Represents a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group having 2 to 4 carbon atoms), O or S.

The substituted or unsubstituted alkyl group having 1 to 4 carbon atoms is a linear or branched alkyl group, and specifically includes a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and an n-butyl group. , Isobutyl group, sec-butyl group, and tert-butyl group.

The substituted or unsubstituted cycloalkyl group having 3 or 4 carbon atoms is a 3- or 4-membered cycloalkyl group in which a saturated or partially unsaturated bond may exist, specifically, a cyclopropyl group, Examples thereof include a cyclopropenyl group, a cyclobutyl group, a cyclobutenyl group, a methylcyclopropyl group, and a methylcyclopropenyl group.

The substituted or unsubstituted alkenyl group having 2 to 4 carbon atoms is a linear or branched alkenyl group, and specifically includes a vinyl group, 1-propenyl group, allyl group, isopropenyl group, 1- Butenyl group, 2-butenyl group, 3-butenyl group, 1,3-butadienyl group, 1-ethylvinyl group, 1-methyl-1-propenyl group, 2-methyl-1-propenyl group, 2-methyl-2-propenyl group Groups.

The substituted or unsubstituted alkynyl group having 2 to 4 carbon atoms is a linear or branched alkynyl group, and specifically includes an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, Examples thereof include 2-butynyl group, 3-butynyl group, 1,3-butadiynyl group, and 1-methyl-2-propynyl group.

These alkyl group, cycloalkyl group, alkenyl group, and alkynyl group may be substituted, and examples of the substituent include a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, and a carboxyl group.

Here, the halogen atom means each atom of fluorine, chlorine, bromine and iodine.

The number of substitutions of these substituents may be the same or different, up to the maximum number of hydrogen atoms present in each group.

Z is preferably hydrogen, a methyl group, an ethyl group, an n-propyl group, a cyclopropyl group or an n-butyl group, more preferably hydrogen.

In the above formula (I), R ¹ and R ² are the same or different and each represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 or 4 carbon atoms. A substituted or unsubstituted alkenyl group having 2 to 4 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 4 carbon atoms, OZ ¹ , OCOZ ² , NZ ³ COOZ ⁴ , S (O) _n Z ⁵ (wherein n Represents an integer of 0 to 3), SO ₂ NZ ⁶ Z ⁷ , COZ ⁸ , COOZ ⁹ , CONZ ¹⁰ Z ¹¹ , NZ ¹² Z ¹³ , a nitro group or a cyano group.

In R ¹ and R ² , a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 or 4 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 4 carbon atoms, 2 carbon atoms ˜4 substituted or unsubstituted alkynyl groups and Z have the same meanings, and Z ¹ to Z ¹³ have the same meanings as Z. Z ⁶ and Z ⁷ _, Z ¹⁰ and Z ^11, and Z ¹² and Z ¹³ may be combined to form a substituted or unsubstituted nitrogen-containing heterocyclic group.

Specific examples of the nitrogen-containing heterocycle include a pyrrolidinyl group, pyrazolidinyl group, imidazolidinyl group, pyrazole group, imidazole group, oxazolidinyl group, isoxazolidinyl group, thiazolidinyl group, isothiazolidinyl group, piperidinyl group, Examples include a hexahydropyrazinyl group, a hexahydropyrimidinyl group, a piperazinyl group, a hexahydrotriazinyl group, an oxadinanyl group, a morpholino group, a thiadinanyl group, and a thiomorpholino group.

The alkyl group, cycloalkyl group, alkenyl group, alkynyl group, and alkylene group may be substituted with one or more substituents, and may be a halogen atom, OZ ²¹ , OCOZ ²² , NZ ²³ COOZ ²⁴ , S (O ) _N Z ²⁵ (n represents an integer of 0 to 3), SO ₂ NZ ²⁶ Z ²⁷ , COZ ²⁸ , COOZ ²⁹ , CONZ ³⁰ Z ³¹ , NZ ³² Z ³³ , a nitro group, a cyano group, or the like. The Here, Z ²¹ to Z ³¹ are the same or different and each represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an alkylene group or the like, and represents Z ²⁶ and Z ²⁷ , Z ³⁰ and Z ³¹ , Z ³² and Z ³³ may together form a nitrogen-containing heterocyclic group.

The number of substitutions of these substituents may be the same or different, and may be up to the number of hydrogen atoms present in each group, but is preferably 1 to 10, more preferably 1 to 6.

R ¹ or R ² includes hydrogen, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, trifluoromethyl group, hexafluoroisopropyl group, hydroxyl group, Methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy, acetoxy, methoxycarbonylamino, methylthio, formyl, acetyl, carboxyl, methoxycarbonyl, dimethylaminocarbonyl, amino Group, nitro group, more preferably hydrogen, methyl group, ethyl group, isopropyl group, tert-butyl group, trifluoromethyl group, hydroxyl group, methoxy group, trifluoromethoxy group, carboxyl group, methoxycarbonyl group, An amino group, a nitro group, Et to preferably an ethyl group, an isopropyl group, tert- butyl group, a trifluoromethyl group, a trifluoromethoxy group, a nitro group, and most preferably a trifluoromethyl group.

R ¹ or R ² may be a group shown above at the same time, but preferably one of them is hydrogen, preferably R ¹ is an ethyl group, isopropyl group, tert-butyl group, trifluoro When methyl, trifluoromethoxy or nitro and R ² is hydrogen, most preferably R ¹ is a trifluoromethyl group and R ² is hydrogen.

In the above formula (I), Q ¹ , Q ² , and Q ³ are the same or different and represent a nitrogen atom or —C (W) = (wherein W has the same meaning as R ¹ ). When Q ¹ to Q ³ are —C (W) ═, W is preferably hydrogen, a methyl group, or a trifluoromethyl group. Most preferred is hydrogen. When one or more of Q ¹ to Q ³ are nitrogen atoms, the compound (I) is more soluble in an aqueous solvent than the compound (I) in which all of Q ¹ to Q ³ are —C (W) ═ Increases nature. The combinations of Q ¹ to Q ³ include {Q ¹ / Q ² / Q ³ : N / CH / CH}, {Q ¹ / Q ² / Q ³ : CH / N / CH}, {Q ¹ / Q ² / Q ³ : CH / CH / N}, {Q ¹ / Q ² / Q ³ : N / N / CH}, {Q ¹ / Q ² / Q ³ : N / CH / N}, {Q ¹ / Q ² / Q ³ : CH / CH / -CH} or {Q ¹ / Q ² / Q ³ : C (CF ₃ ) / CH / CH}, preferably {Q ¹ / Q ² / Q ³ : N / CH / CH}, {Q ¹ / Q ² / Q ³ : CH / N / CH}, {Q ¹ / Q ² / Q ³ : CH / CH / N}, {Q ¹ / Q ² / Q ³ : N / CH / N}, or {Q ¹ / Q ² / Q ³ : CH / CH / CH}, most preferably {Q ¹ / Q ² / Q ³ : CH / CH / N} or {Q ¹ ^/ ^Q 2 / ^Q 3: CH It is CH / CH}.

In the above formula (I), Y ¹ , Y ² , Y ³ and Y ⁴ are the same or different and have the same meaning as R ¹ or alkylene-COOZ ¹⁴ having 1 to 4 carbon atoms. Here, Z ¹⁴ has the same meaning as Z. Y ¹ and Y ² , Y ² and Y ³ , Y ³ and Y ⁴ may form a 5- to 7-membered ring structure containing carbons to which each is bonded.

The alkylene group is a linear or branched divalent alkyl group having 2 to 4 carbon atoms, and specifically includes a methylene group, an ethylene group, a propylene group, a butylene group, a methylmethylene group, a dimethylmethylene group, Propylmethylene group, ethylmethylmethylene group, 1-methylethylene group, 2-methylethylene group, 1-ethylethylene group, 2-ethylethylene group, 1,1-dimethylethylene group, 1,2-dimethylmethylene group, 2 , 2-dimethylmethylene group, 1-methylbutylene group, 2-methylbutylene group, and 3-methylbutylene group.

These alkylene groups may be substituted, and examples of the substituent include a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, and a carboxyl group.

As Y ¹ , Y ² , Y ³ and Y ⁴ , hydrogen, halogen atom, hydroxyl group, amino group, urea group, tert-butoxycarbonylamino group, nitro group, carboxymethyl group, 2-carboxyethyl group, 1 -Hydroxy-2-carboxyethyl group, carboxymethoxy group, preferably hydrogen, fluorine atom, hydroxyl group, amino group, urea group, nitro group, 2-carboxyethyl group, 1-hydroxy-2-carboxyethyl group, carboxy It is a methoxy group, more preferably a hydrogen atom, a fluorine atom, an amino group, a urea group or a nitro group, most preferably a hydrogen atom or a fluorine atom.

In the case where Y ¹ , Y ² , Y ³ and Y ⁴ form a 5- to 7-membered ring structure containing carbon bonded to each other, the ring structure is a structure represented by the following formula (Y ^1-4 ). Yes:

(Wherein C ^A and C ^B are carbons to which Y ¹ , Y ² , Y ³ or Y ⁴ are bonded, and X ¹ , X ² and X ³ are any one selected from CH ₂ , NH, S and O) M is an integer of 0 to 2, and the broken line portion represents a single bond or a double bond, provided that when the broken line portion is a double bond, m is not 0 and X ¹ is CH Or N and not S and O.)
Preferably, the structure represented by the following chemical formula

More preferably, the bonds ab, cd, and ef are all double bonds, and Y ² and Y ³ form the ring structure, and more preferably, the bond a -B, cd and ef are all double bonds, and when Y ³ and Y ⁴ form the ring structure, Y ¹ and Y ² are the same or different, and each represents hydrogen or fluorine. In some cases, more preferably, the left segment of compound (I) has one of the following structures.

In addition, Y ¹ and Y ² , Y ² and Y ³ , Y ³ and Y ⁴ may be an aromatic ring containing carbon bonded to each other. The aromatic ring is not limited as long as the compound (I) is water-soluble, and examples thereof include a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, an oxazole ring, Examples thereof include an oxazole ring, a thiazole ring, an isothiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, and a triazine ring. Further, a naphthalene ring, an indole ring, an isoindole ring, a benzofuran ring, an isobenzofuran ring, a benzothiophene ring, an isobenzothiophene ring, a benzoxazole ring, a benzoisoxazole ring, and a benzothiazole ring, which are condensed with the aromatic ring. Benzoisothiazole ring, benzooxadiazole ring, benzothiadiazole ring, pyrrolopyridine ring, pyrrolopyrazine ring, quinoline ring, isoquinoline ring, cinnoline ring, quinazoline ring, quinoxaline ring and the like, or azulene.

When compound (I) has an asymmetric carbon atom, such compound includes all possible optical isomers, which may be in any ratio. For example, an optically active compound may be an enantiomer, a racemate, or an enantiomeric mixture in an arbitrary ratio, and when a plurality of asymmetric points are present, an optically active compound may be an arbitrary ratio of diastereomeric mixtures.

Examples of the pharmacologically acceptable salt of compound (I) include acid addition salts, metal salts, ammonium salts, organic amine addition salts and the like, and acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid, boric acid and other inorganic acid salts, and organic acids such as formic acid, acetic acid, propionic acid, fumaric acid, malonic acid, succinic acid, maleic acid, tartaric acid, benzoic acid and other carboxylic acids, methanesulfone Examples thereof include acids, sulfonic acids such as p-toluenesulfonic acid, and amino acids such as glutamic acid and aspartic acid. As the metal salt, each alkali metal salt such as lithium, sodium, potassium, etc., each alkaline earth metal salt such as magnesium, calcium, etc., each metal salt such as aluminum, zinc, etc., as the ammonium salt, ammonium, tetramethylammonium, etc. Examples of the organic amine salt include salts of triethylamine, piperidine, morpholine, toluidine and the like.

As a pharmacologically acceptable salt of compound (I), an ammonium salt of compound (I) may be used.

(Where
The bonds ab, cd, and ef are simultaneously or differently represented as a single bond or a double bond,
Q ¹ to Q ³ , R ¹ , R ² , X, Y ¹ to Y ⁴ , Z, L, and M are as defined above.

In the ammonium salt of the compound (I) represented by the formula (V), L has the same meaning as Z.
M is selected from a halogen atom, Z ¹⁵ COO, Z ¹⁶ SO ₃ , BF ₄ and PF ₆ . Here, Z ¹⁵ and Z ¹⁶ are synonymous with Z.

In the compound (I) represented by the formula (V), the combination of L and M is not limited to these, but when M is a halogen atom, L is an alkyl group, a cycloalkyl group, an alkylene group, It is preferably an alkenyl group or an alkynyl group, and when M is Z ¹⁵ COO, Z ¹⁶ SO ₃ , BF ₄ or PF ₆ , L is preferably hydrogen.

In the compound (I) represented by the formula (V), L is hydrogen, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, preferably hydrogen, methyl group, An ethyl group, an n-propyl group and an n-butyl group; Most preferably, they are hydrogen and a methyl group.

In the compound (I) represented by the formula (V), M is fluorine, chlorine, bromine, iodine, CH ₃ COO, CF ₃ COO, CCl ₃ COO, CBr ₃ COO, CHBr ₂ COO, CH ₃ SO ₃ , CF ₃ SO ₃ , CCl ₃ SO ₃ , BF ₄ and PF ₆ , preferably chlorine, bromine, iodine, CH ₃ COO, CF ₃ COO, CCl ₃ COO, CH ₃ SO ₃ , CF ₃ SO ₃ , BF ₄ And PF ₆ , more preferably bromine, iodine, CH ₃ COO, CF ₃ COO, CCl ₃ COO, CH ₃ SO ₃ , BF ₄ and PF ₆ , and more preferably bromine, iodine, CH ₃ COO, CCl ₃ COO, CH ₃ SO ₃ , BF ₄ and PF ₆ .

Examples of the production method of the compound (I) used as the Eg5 inhibitor of the present invention will be described below. However, the production method is not limited to these methods, and some compounds are available as reagents.

Manufacturing method 1. Production of diarylamine Compound (IA) in which X is NZ among compounds (I) used in the present invention is a coupling reaction described in the literature (Chem. Comm. 2007, 4516-4518) or according to these reactions. Can be manufactured by the following manufacturing method.

(In the formula, E represents a leaving group, and R ¹ , R ² , Q ¹ to Q ⁴ , Y ¹ to Y ⁴ and Z are as defined above).

Examples of the leaving group in the definition of E include a halogen atom, a substituted or unsubstituted alkylsulfonyloxy group, a substituted or unsubstituted arylsulfonyloxy group, and the like. The halogen atom has the same meaning as described above. The alkylsulfonyloxy group is synonymous with the alkyl group, for example, an alkylsulfonyloxy group having 1 to 8 carbon atoms, and the arylsulfonyloxy group is synonymous with the aryl group. Examples thereof include an arylsulfonyloxy group having 6 to 14 carbon atoms, and examples of the substituent include a halogen atom, an alkyl group, and a nitro group, and the halogen atom and the alkyl group are as defined above. Specifically, alkylsulfonyloxy groups such as methanesulfonyloxy and trifluoromethanesulfonyloxy, and arylsulfonyloxy groups such as benzenesulfonyloxy and toluenesulfonyloxy can be exemplified.

Aryl compound (Ia) and amine compound (Ib) are combined with a suitable inert solvent such as halogenated hydrocarbons such as chloroform and dichloromethane, benzene, toluene and the like in the presence of a transition metal catalyst, a ligand and a base. Aromatic hydrocarbons, diethyl ether, tetrahydrofuran (THF), ether solvents such as 1,4-dioxane, N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), N-methylmorpholine, dimethyl sulfoxide ( Compound (IA) can be obtained by reacting in an aprotic polar solvent such as DMSO) or a mixed solvent thereof at a temperature between −78 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours. .

Examples of the transition metal of the transition metal catalyst include palladium, nickel, copper, and iron. Specific examples of the transition metal catalyst include tetrakis (triphenylphosphine) palladium (0), tetrakis (triphenylphosphine) nickel (0 ) And the like. These transition metal catalysts may be prepared in situ from the corresponding transition metal salt in the presence of a ligand. Examples of the ligand include triphenylphosphine, tributylphosphine, 1,1′-bis (diphenylphosphine). Fino) ferrocene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 1,3-bis (diphenylphosphino) propane, 4,5-bis (diphenylphosphino) -9,9- Examples thereof include dimethylxanthene, tricyclohexylphosphonium tetrafluoroborate, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, and transition metal salts such as palladium chloride, palladium acetate, palladium-carbon, Nickel chloride, copper chloride (I), copper iodide (I), copper oxide (I), iron chloride (II), iron chloride (III), etc. The transition metal catalyst is used in an amount of 5 to 10 mol% relative to compound (Ia), and the ligand is used in an amount of 5 to 20 mol% relative to compound (Ia).

Examples of the base include organic bases such as triethylamine, N-methylmorpholine, and pyridine, inorganic bases such as potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, sodium hydroxide, sodium hydride, sodium methoxide, potassium and metal alkoxides such as tert-butoxide.
If necessary, an organic acid such as pivalic acid may be added.
Compounds (Ia) and (Ib) are commercially available or can be produced by conventional methods.

In the above production method, the target compound (IA) can be produced even if the amine compound and the aryl compound are exchanged.

(Wherein E, R ¹ , R ² , Q ¹ to Q ⁴ , Y ¹ to Y ⁴ and Z are as defined above)

When the aryl compound (Ia) and the amine compound (Ib) are converted into the amine compound (Ic) and the aryl compound (Id), respectively, the compound (IA) can be produced by the method described above.

In addition, Z may be hydrogen during the coupling reaction, or Z may be introduced onto nitrogen after the coupling reaction. In particular,

(Wherein R ¹ , R ² , Q ¹ to Q ⁴ , Y ¹ to Y ⁴ and Z are as defined above, and E ¹ is as defined above)
The target compound (IA) can be produced by anionizing the secondary amine nitrogen with a base, followed by nucleophilic substitution with ZL ¹ .

Here, as the base, metal hydrides such as lithium hydride, sodium hydride and potassium hydride and organometallic compounds such as methyl lithium, n-butyl lithium, tert-butyl lithium and isopropyl magnesium bromide may be used. it can.

As a reaction solvent, an ether solvent such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, or an amide solvent such as N, N-dimethylformamide (DMF) or N, N-dimethylacetamide (DMA) is used. be able to. As reaction conditions, compound (I) can be obtained by reacting at a temperature between −78 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours.

Production method 2. Production of Ammonium Salt The ammonium salt (V) of the compound (I) can be produced by the following production method.

(Wherein Q ¹ to Q ³ , R ¹ , R ² , X, Y ¹ to Y ⁴ , Z, L and M are as defined above)

Ammonium salt (V) of compound (I) is a diarylamine represented by formula (IA), represented by LM, methyl bromide, methyl iodide, ethyl bromide, ethyl iodide, butyl bromide , Alkyl halides such as butyl iodide, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, tetrafluoroboric acid, hexafluorophosphoric acid, carboxylic acids such as acetic acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, It can be obtained by reacting sulfonic acid such as trifluoromethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid and the like.

Diarylamine (IA) and LM are suitable inert solvents, for example, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, diethyl ether, tetrahydrofuran (THF), 1,4- In an aprotic polar solvent such as ether solvents such as dioxane, N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), N-methylmorpholine, dimethylsulfoxide (DMSO), and the like, The compound (V) can be obtained by reacting at a temperature between 78 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours.

As a purification method of the compound (V), the compound (V) precipitated from an insoluble solvent can be collected by filtration. When LM is a volatile compound, the desired compound can be obtained by concentrating the reaction system under reduced pressure. These compounds may be used as they are, or may be used after purification using column chromatography, or may be used after recrystallization using an appropriate solvent.

Production method 3. Production of diaryl ether Compound (IB) in which X is O among compounds (I) used in the present invention is a coupling reaction described in the literature (Org. Lett. 13, 1552-1555 (2011)) or these According to the reaction of, it can manufacture according to the following manufacturing method.

(Wherein M ¹ has the same meaning as M, and Q ¹ to Q ⁴ , Y ¹ to Y ⁴ and Z have the same meanings as described above) or

Can be manufactured by.

M ¹ in the hypervalent iodine compound (Id) or (Ie) is any one selected from chlorine, bromine, CF ₃ SO ₃ , NO ₃ , BF ₄ and PF ₆ .

The phenol compound (Ic) or (If) and the hypervalent iodine compound (Id) or (Ie) are mixed with a suitable inert solvent such as a halogenated hydrocarbon such as chloroform or dichloromethane, benzene, toluene in the presence of a base. Aromatic hydrocarbons such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), N-methylmorpholine, dimethyl Compound (IB) can be obtained by reacting in an aprotic polar solvent such as sulfoxide (DMSO) or a mixed solvent thereof at a temperature between 0 ° C. and the boiling point of the solvent used for 5 minutes to 24 hours. it can.

Examples of the base include organic bases such as triethylamine, N-methylmorpholine, and pyridine, inorganic bases such as potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, sodium hydroxide, sodium hydride, sodium methoxide, potassium and metal alkoxides such as tert-butoxide.

In addition, the compounds (Ic), (Id), (Ie) and (If) are commercially available or can be produced by a conventional method. As a method for synthesizing a hypervalent iodine compound, it can be synthesized with reference to literature (J. Org. Chem. 73, 4602-4607 (2008)).

Manufacturing method 4. Production of Diaryl Sulfide Among the compounds (I) used in the present invention, the compound (IC) in which X is S is a coupling reaction described in the literature (Org. Lett. 4, 3517-3520 (2002)), or these compounds. According to the reaction, it can be produced by the following production method.

Aryl compound (Ig) and thiophenol compound (Ih) are combined with a suitable inert solvent such as halogenated hydrocarbons such as chloroform and dichloromethane, benzene, toluene and the like in the presence of a copper catalyst, a ligand and a base. Aromatic hydrocarbons, diethyl ether, tetrahydrofuran (THF), ether solvents such as 1,4-dioxane, N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), N-methylmorpholine, dimethyl sulfoxide ( Compound (IC) can be obtained by reacting in an aprotic polar solvent such as DMSO) or a mixed solvent thereof at a temperature between room temperature and the boiling point of the solvent used for 5 minutes to 48 hours.

The copper catalyst is not limited as long as it is a monovalent copper salt, but specific examples include copper (I) chloride, copper (I) iodide, copper (I) cyanide and the like. Specific examples of the ligand include ethylene glycol and 2,9-dimethyl-1,10-phenanthroline. The transition metal catalyst is used in an amount of 5 to 40 mol% relative to compound (Ig), and the ligand is used in an amount of 100 to 200 mol% relative to compound (Ig).

Examples of the base include organic bases such as triethylamine, N-methylmorpholine, and pyridine, inorganic bases such as potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, sodium hydroxide, sodium hydride, sodium methoxide, potassium and metal alkoxides such as tert-butoxide.
In addition, compound (Ig) and (Ih) can be obtained as a commercial item, or can be manufactured by a conventional method.

In the above production method, the target compound (IC) can be produced by replacing the thiophenol compound and the aryl compound in the same manner as in the production of the compound (IA).

(Wherein E, R ¹ , R ² , Q ¹ to Q ⁴ , Y ¹ to Y ⁴ and Z are as defined above).

In the above production method, when the defined group changes under the conditions of the implementation method or is inappropriate for carrying out the method, by using a method for introducing and removing a protective group commonly used in organic synthetic chemistry, etc. The target compound can be obtained. Such protecting groups are, Green & Wuts, "PROTECTIVE GROUPS in ORGANIC SYNTHESIS" 3 rd ed.John Wiley & Sons, referring to Inc., can be used. In addition, some compounds (I) can be further converted to other derivatives (I) as synthetic intermediates.

The intermediates and target compounds in the above production methods are isolated and purified by purification methods commonly used in organic synthetic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. be able to. In addition, the intermediate can be subjected to the next reaction without any particular purification.

When it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, it can be purified as it is, and if it is obtained in a free form, it can be dissolved in an appropriate organic solvent. Alternatively, the salt may be formed by suspending and adding an acid or a base by a usual method.

Further, Compound (I) and pharmacologically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts should also be used as the Eg5 inhibitor of the present invention. Can do.

Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually desirable to prepare various pharmaceutical preparations. It can be produced by a conventional method of pharmaceutics by mixing with one or two or more types of carriers that are acceptable.

Examples of administration routes include oral administration, inhalation administration, parenteral administration such as intravenous administration.

Examples of the dosage form include tablets, injections, etc. The tablets are mixed with various additives such as lactose, starch, magnesium stearate, hydroxypropyl cellulose, polyvinyl alcohol, surfactant, glycerin, etc. The inhalant may be produced according to a conventional method by adding, for example, lactose. An injection may be produced according to a conventional method by adding water, physiological saline, vegetable oil, solubilizer, preservative and the like.

The effective amount and frequency of administration of compound (I) or a pharmacologically acceptable salt thereof vary depending on the administration form, patient age, body weight, symptoms, etc., but usually 0.001 mg to 5 g per adult, preferably Is administered at a dose of 0.1 mg to 1 g, more preferably 1 mg to 500 mg, once a day or several times a day.

The cell proliferative diseases treated with the Eg5 inhibitor of the present invention can be broadly classified into malignant tumors and benign tumors, and malignant tumors that are infiltrated and metastasize include malignant melanoma (melanoma) and skin. Cancer, lung cancer, tracheal and bronchial cancer, oral epithelial cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, colon cancer, liver and intrahepatic bile duct cancer, kidney cancer, pancreatic cancer, prostate Examples include cancer in which epithelial cells such as cancer, breast cancer, uterine cancer, ovarian cancer, and brain tumor have become malignant, and cancer and tumor in which supporting tissue constituent cells such as osteosarcoma and myoma have become malignant. . On the other hand, benign tumors that grow autonomously but grow only at the place of occurrence include those that originate from epithelial cells such as papillomas, adenomas, cystadenomas, fibromas, myxomas, lipomass. Examples thereof include those generated from non-epithelial cells such as chondroma, osteoma, rhabdomyosarcoma, leiomyoma, hemangioma and the like. The tissue in which malignant tumor or benign tumor is present is not particularly limited, but brain, eyeball, nasal passage, nasal cavity, trachea, bronchi, oral cavity, pharynx, esophagus, stomach, breast, colorectal, lung, ovary, central nervous system, Examples include liver, bladder, urethra, ureter, pancreas, cervical canal, abdominal cavity, anus, cervix, genital organs, kidney, prostate, muscle, bone, and hematopoietic cells.

Hereinafter, the present invention will be described more specifically by way of examples. However, the technical scope of the present invention is not limited to these examples.

General N-arylation for the preparation of diarylamine compounds

[Production Example 1]
6-((3- (trifluoromethyl) phenyl) amino) -3,4-dihydroquinolin-2 (1H) -one

Under an argon atmosphere, 6-bromo-3,4-dihydroquinolin-2 (1H) -one (800 mg, 3.54 mmol), 3- (trifluoromethoxy) aniline (482 μL, 3.89 mmol), Pd ₂ (dba ₃ ) CHCl ₃ (183 mg, 0.18 mmol), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (104 mg, 0.27 mmol) and sodium tert-butoxide (477 mg, 4.96 mmol) Toluene (7.0 mL) was added to the flask filled with. The mixture was stirred at 100 ° C. for 6 hours. After cooling, the reaction mixture was diluted with ethyl acetate and filtered through a pad of celite. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (hexane / ethyl acetate-1: 1) to obtain the desired product, 6-((3- (trifluoromethyl) phenyl) amino) -3, A pale yellow solid (292 mg, 68% yield) of 4-dihydroquinolin-2 (1H) -one was obtained.
mp 190-191 ° C;
IR (neat) cm ⁻¹ : 1652, 3045, 3317;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.45 (t, J = 7.4 Hz, 2H), 2.86 (t, J = 7.4 Hz, 2H), 6.85 (d, J = 8 0.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.97 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 7.16 (s) , 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 8.30 (s, 1H), 10.0 (s, 1H) ); ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 25.0, 30.4, 110.5, 114.0, 115.8, 117.6, 118.8, 119.7, 124.3 (q ), 124.7, 130.0 (q), 130.2, 133.2, 136.1, 145.9, 169.8;
Anal. _{_{_{calcd for C 16 H 13 F 3}}} N 2 O: C, 62.74; H, 4.28; N, 9.15. Found: C, 62.94; H, 4.36; N, 8.91.

[Production Example 2]
7-((3- (trifluoromethyl) phenyl) amino) -3,4-dihydroquinolin-2 (1H) -one

7-((3- (trifluoromethyl) phenyl) amino from 7-bromo-3,4-dihydroquinolin-2 (1H) -one and 3- (trifluoromethyl) aniline in the same manner as in Production Example 1 ) -3,4-dihydroquinolin-2 (1H) -one was obtained as a white solid (1.27 g, 63% yield).
mp 164-165 ° C;
IR (neat) cm ⁻¹ : 1675, 3219, 3338;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.44 (t, J = 7.4 Hz, 2H), 2.81 (t, J = 7.4 Hz, 2H), 6.67 (dd, J = 8 0.0, 2.3 Hz, 1H), 6.71 (d, J = 2.3 Hz, 1H), 7.05-7.08 (m, 2H), 7.24 (s, 1H), 7.27. (D, J = 8.0 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 8.48 (s, 1H), 10.0 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 24.2, 30.7, 105.1, 111.4, 112.0, 114.9, 116.4, 118.8, 124.3 (q), 129.6, 130.0 (q), 130.2, 139.1, 141.0, 144.8, 170.2;
Anal. _{_{_{calcd for C 16 H 13 F 3}}} N 2 O: C, 62.74; H, 4.28; N, 9.15. Found: C, 62.47; H, 3.98; N, 9.14.

[Production Example 3]
6- (Phenylamino) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 1, from 6-bromo-3,4-dihydroquinolin-2 (1H) -one and aniline to 6- (phenylamino) -3,4-dihydroquinolin-2 (1H) -one Of a white solid (57.5 mg, yield 20%) was obtained.
mp 156-158 ° C;
IR (neat) cm ⁻¹ : 1665, 3216, 3310;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.41 (t, J = 7.4 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H), 6.73 (t, J = 8 0.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.87 (dd, J = 8.0, 2.3 Hz, 1H), 6.91 (d, J = 2. 3 Hz, 1H), 6.95 (d, J = 8.0 Hz, 2H), 7.17 (t, J = 8.0 Hz, 2H), 7.88 (s, 1H), 9.90 (s, 1H).
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 25.1, 30.5, 115.4 (2C), 115.7, 117.1, 117.9, 118.6, 124.5, 129.1 ( 2C), 131.8, 137.6, 144.5, 169.7;
_{_{_{HRMS (FAB): calcd for C}}} 15 H 14 N 2 O (M +) 238.1106; found: 238.1099.

[Production Example 4]
6-((3-Ethylphenyl) amino) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 1, from 6-bromo-3,4-dihydroquinolin-2 (1H) -one and 3-ethylaniline to 6- (phenylamino) -3,4-dihydroquinoline-2 (1H ) -One white solid (57.5 mg, yield 20%) was obtained.
mp 179-181 ° C;
IR (neat) cm ⁻¹ : 1665, 3195, 3307;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.15 (t, J = 7.4 Hz, 3H), 2.41 (t, J = 7.4 Hz, 2H), 2.81 (t, J = 7 .4 Hz, 2H), 6.59 (d, J = 7.4 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H) 6.79 (s, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.89 (s, 1H), 7.07 (t, J = 7.4 Hz, 1H), 7 .82 (s, 1H), 9.90 (s, 1H).
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 15.6, 25.1, 28.3, 30.5, 112.8, 115.1, 115.6, 116.9, 117.8, 118.3 , 124.4, 129.0, 131.6, 137.8, 144.5, 144.6, 169.7;
_{_{_{HRMS (FAB): calcd for C}}} 17 H 18 N 2 O (M +) 266.1419; found: 266.1419.

[Production Example 5]
6-((3-Isopropylphenyl) amino) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 1, from 6-bromo-3,4-dihydroquinolin-2 (1H) -one and 3-isopropylaniline to 6- (phenylamino) -3,4-dihydroquinoline-2 (1H ) -One pale yellow solid (66.7 mg, 36% yield) was obtained.
mp 180-181 ° C;
IR (neat) cm ⁻¹ : 1667, 3192, 3311;
¹ H NMR (500 MHz, DMSO-d ₆ ); δ 1.17 (d, J = 6.9 Hz, 6H), 2.41 (t, J = 7.4 Hz, 2H), 2.74-2.83 ( m, 1H), 2.81 (t, J = 7.4 Hz, 2H), 6.63 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.82 (s, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.88 (s, 1H), 7. 08 (t, J = 8.0 Hz, 1H), 7.83 (s, 1H), 9.90 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ): δ 23.9 (2C), 25.1, 30.5, 33.5, 112.8, 113.9, 115.6, 116.8, 116.9 , 117.7, 124.4, 128.9, 131.6, 137.8, 144.4, 149.3, 169.7;
_{_{_{HRMS (FAB): calcd for C}}} 18 H 20 N 2 O (M +) 280.1576; found: 280.1569.

[Production Example 6]
6-((3-tert-Butylphenyl) amino) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 1, 6-((3-tert-butyl) was prepared from 6-amino-3,4-dihydroquinolin-2 (1H) -one and 1-bromo- (3-tert-butyl) benzene. A white solid (227 mg, 42% yield) of phenyl) amino) -3,4-dihydroquinolin-2 (1H) -one was obtained.
mp 151-152 ° C;
IR (neat) cm ⁻¹ : 1667, 3216, 3330;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.25 (s, 9H), 2.40 (t, J = 7.4 Hz, 2H), 2.81 (t, J = 7.4 Hz, 2H), 6.74 (d, J = 8.0 Hz, 1H), 6.77-6.81 (m, 2H), 6.87 (d, J = 8.0 Hz, 1H), 6.88 (s, 1H) ), 6.98 (s, 1H), 7.09 (t, J = 8.0 Hz, 1H), 7.84 (s, 1H), 9.89 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 25.1, 30.5, 31.1 (3C), 34.3, 112.4, 113.2, 115.6, 115.9, 116.5 117.5, 124.5, 128.7, 131.5, 138.0, 144.0, 151.5, 169.7;
Anal. _{_{_{calcd for C 19 H 22 N 2}}} O: C, 77.52; H, 7.53; N, 9.52. Found: C, 77.39; H, 7.48; N, 9.46.

[Production Example 7]
6-((3-Methoxyphenyl) amino) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 1, 6-((3-methoxyphenyl) amino) -3,4-dihydroquinoline is obtained from 6-bromo-3,4-dihydroquinolin-2 (1H) -one and 3-methoxyaniline. A light yellow solid (870 mg, 43% yield) of -2 (1H) -one was obtained.
mp 160-161 ° C;
IR (neat) cm ⁻¹ : 1664, 3214, 3325;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.41 (t, J = 7.4 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H), 3.69 (s, 3H), 6.32 (d, J = 8.0 Hz, 1H), 6.49 (s, 1H), 6.54 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 8.0 Hz) , 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.92 (s, 1H), 7.07 (t, J = 8.0 Hz, 1H), 7.91 (s, 1H) ), 9.93 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 25.1, 30.5, 54.7, 100.9, 104.0, 107.9, 115.7, 117.5, 118.4, 124.5 , 129.8, 132.0, 137.4, 145.9, 160.2, 169.7;
Anal. _{_{_{calcd for C 16 H 16 N 2}}} O 2: C, 71.62; H, 6.01; N, 10.44. Found: C, 71.86; H, 5.90; N, 10.38.

[Production Example 8]
6-((3- (trifluoromethoxy) phenyl) amino) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 1, 6-((3- (trifluoromethoxy) phenyl) amino from 6-bromo-3,4-dihydroquinolin-2 (1H) -one and 3- (trifluoromethoxy) aniline ) -3,4-dihydroquinolin-2 (1H) -one was obtained as a pale yellow solid (292 mg, 68% yield).
mp 160-162 ° C;
IR (neat) cm ⁻¹ : 1667, 3219, 3315;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.43 (t, J = 6.9 Hz, 2H), 2.85 (t, J = 6.9 Hz, 2H), 6.63 (d, J = 8 0.0 Hz, 1H), 6.79 (s, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.91-6.96 (m, 3H), 7.25 (t, J = 8.0 Hz, 1H), 8.25 (s, 1H), 9.99 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 25.0, 30.4, 106.3, 109.6, 113.1, 115.8, 118.7, 119.5, 120.1 (q), 124.7, 130.7, 133.1, 136.1, 146.9, 149.4, 169.8;
Anal. _{_{_{calcd for C 16 H 13 F 3}}} N 2 O 2: C, 59.63; H, 4.07; N, 8.69. Found: C, 59.51; H, 4.12; N, 8.59.

[Production Example 9]
3-Nitro-N- (3- (trifluoromethyl) phenyl) aniline

In the same manner as in Production Example 1, 3-nitro-N- (3- (trifluoromethyl) phenyl) aniline orange solid (365 mg) from 1-bromo-3- (trifluoromethyl) benzene and 3-nitroaniline Yield 97%).
mp 69-71 ° C;
IR (neat) cm ⁻¹ : 1526, 3379;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.27 (d, J = 7.4 Hz, 1H), 7.39 (s, 1H), 7.47 (d, J = 7.4 Hz, 1H), 7.53-7.57 (m, 3H), 7.70 (d, J = 7.4 Hz, 1H), 7.86 (s, 1H), 9.08 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 110.2, 113.7, 114.5, 117.2, 120.8, 122.6, 124.1 (q), 130.2 (q), 130 .6, 130.7, 142.8, 144.0, 148.7;
HRMS (FAB): m / z calcd for C 13 H 9 F 3 N 2 O 2 (M +) 282.0616; found: 282.0621.

[Production Example 10]
6-((3-Nitrophenyl) amino) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 1, 6-((3-nitrophenyl) amino) -3,4-dihydroquinoline is obtained from 6-bromo-3,4-dihydroquinolin-2 (1H) -one and 3-nitroaniline. A red-brown solid (70.7 mg, 28% yield) of -2 (1H) -one was obtained.
mp 243-244 ° C;
IR (neat) cm ⁻¹ : 1536, 1706, 3198, 3383;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.44 (t, J = 7.4 Hz, 2H), 2.86 (t, J = 7.4 Hz, 2H), 6.84 (d, J = 8 0.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 7.00 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.42 (t , J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 8.50 (s, 1H), 10.0 (s, 1H) ); ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 24.9, 30.3, 107.7, 112.1, 115.8, 119.3, 120.1, 120.3, 124.8, 130 4, 133.6, 135.5, 146.6, 148.8, 169.8;
Anal. _{_{_{calcd for C 15 H 13 N 3}}} O 3: C, 63.60; H, 4.63; N, 14.83. Found: C, 63.44; H, 4.59; N, 14.57.

[Production Example 11]
Methyl 3-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) amino) benzoate

In the same manner as in Production Example 1, 3-((2-oxo-1,2,3,4) was prepared from 6-bromo-3,4-dihydroquinolin-2 (1H) -one and methyl 3-aminobenzoate. A pale yellow solid (70.7 mg, 28% yield) of methyl tetrahydroquinolin-6-yl) amino) benzoate was obtained.
mp 169-171 ° C;
IR (neat) cm ⁻¹ : 1668, 1706, 3220, 3295;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.44 (t, J = 7.4 Hz, 2H), 2.85 (t, J = 7.4 Hz, 2H), 3.82 (s, 3H), 6.82 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.94 (s, 1H), 7.19-7.21 (m, 1H) ), 7.28-7.31 (m, 2H), 7.54 (s, 1H), 8.17 (s, 1H), 9.98 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 25.0, 30.4, 52.0, 115.2, 115.8, 118.2, 118.8, 119.1, 119.1, 124.6 , 129.5, 130.5, 132.7, 136.6, 145.3, 166.4, 169.8;
Anal. _{_{_{calcd for C 17 H 16 N 2}}} O 3: C, 68.91; H, 5.44; N, 9.45. Found: C, 68.67; H, 5.39; N, 9.64.

[Production Example 12]
6-((4- (Trifluoromethyl) phenyl) amino) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 1, from 6-bromo-3,4-dihydroquinolin-2 (1H) -one and 4- (trifluoromethyl) aniline, 6-((4- (trifluoromethyl) phenyl) A pale yellow solid (122 mg, 30% yield) of amino) -3,4-dihydroquinolin-2 (1H) -one was obtained.
mp 293-294 ° C;
IR (neat) cm ⁻¹ : 1650, 3320;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.43 (t, J = 7.4 Hz, 2H), 2.86 (t, J = 7.4 Hz, 2H), 6.83 (d, J = 8 .6 Hz, 1H), 6.97 (dd, J = 8.6, 2.3 Hz, 1H), 699-7.02 (m, 3H), 7.46 (d, J = 8.6 Hz, 2H), 8.46 (s, 1H), 10.0 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 25.0, 30.4, 113.6 (2C), 115.8, 117.5 (q), 119.5, 120.2, 124.6, 125 0.0 (q), 126.5 (2C), 133.5, 135.5, 148.6, 169.8;
_{HRMS (FAB): m / z} calcd for C 16 H 13 F 3 N 2 O (M +) 306.0980; found: 306.0982.

[Production Example 13]
6-((2- (trifluoromethyl) phenyl) amino) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 1, from 6-bromo-3,4-dihydroquinolin-2 (1H) -one and 2- (trifluoromethyl) aniline, 6-((2- (trifluoromethyl) phenyl) A pale yellow solid (104 mg, 26% yield) of amino) -3,4-dihydroquinolin-2 (1H) -one was obtained.
mp 167-169 ° C;
IR (neat) cm ⁻¹ : 1671, 3205, 3440;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.42 (t, J = 7.4 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H), 6.79 (d, J = 8 .0 Hz, 1H), 6.91 (dd, J = 8.0, 2.3 Hz, 1H), 6.93-6.97 (m, 2H), 7.11 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 10.0 (s, 1H) ;
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 24.9, 30.4, 115.7, 116.6 (q), 118.6, 119.3, 120.0, 120.8, 124.5 ( q), 124.5, 126.7, 133.2, 133.4, 136.8, 143.3, 169.8;
_{HRMS (FAB): m / z} calcd for C 16 H 13 F 3 N 2 O (M +) 306.0980; found: 306.0982.

[Production Example 14]
7-((3- (trifluoromethyl) phenyl) amino) -2H-benzo [b] [1,4] oxazin-3 (4H) -one

In the same manner as in Production Example 1, from 7-amino-2H-benzo [b] [1,4] oxazin-3 (4H) -one and 3- (trifluoromethyl) aniline, 7-((3- (tri A white solid (43.6 mg, 46% yield) of fluoromethyl) phenyl) amino) -2H-1,4-benzoxazin-3 (4H) -one was obtained.
mp 117-118 ° C;
IR (neat) cm ⁻¹ : 1688, 3224, 3335;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 4.55 (s, 2H), 6.71 (d, J = 1.7 Hz, 1H), 6.75 (dd, J = 8.0, 1.7 Hz) , 1H), 6.85 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.23 (dd, J = 8.0, 1.7 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 8.40 (s, 1H), 10.6 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 66.8, 107.2, 110.9, 113.1, 114.7, 116.4, 118.3, 121.5, 124.3 (q), 130.0 (q), 130.3, 137.4, 143.9, 145.1, 164.2;
Anal. _{_{_{calcd for C 15 H 11 F 3}}} N 2 O 2: C, 58.45; H, 3.60; N, 9.09. Found: C, 58.21; H, 3.35; N, 9.02.

[Production Example 15]
7-((3- (trifluoromethyl) phenyl) amino) -2H-benzo [b] [1,4] thiazin-3 (4H) -one

From 7-bromo-2H-benzo [b] [1,4] thiazin-3 (4H) -one and 3- (trifluoromethyl) aniline in the same manner as in Production Example 1, 7-((3- (tri A pale yellow solid (303 mg, 65% yield) of fluoromethyl) phenyl) amino) -2H-benzo [b] [1,4] thiazin-3 (4H) -one was obtained.
mp 166-167 ° C;
IR (neat) cm ⁻¹ : 1678, 3076, 3194;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.46 (s, 2H), 6.94 (d, J = 8.6 Hz, 1H), 6.99 (dd, J = 8.6, 2.3 Hz) ), 7.04-7.07 (m, 2H), 7.17 (s, 1H), 7.23 (d, J = 8.6 Hz, 1H), 7.41 (t, J = 8.6 Hz) , 1H), 8.43 (s, 1H), 10.47 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 29.0, 111.2, 114.8, 117.5, 118.0, 118.1, 118.3, 120.2, 124.2 (q), 130.0 (q), 130.3, 131.8, 137.1, 145.0, 164.7;
_{HRMS (FAB): m / z} calcd for C 15 H 11 F 3 N 2 OS (M +) 324.0544; found: 324.0545.

[Production Example 16]
6-((3- (trifluoromethyl) phenyl) amino) -oxindole

A yellow solid of 20-((3- (trifluoromethyl) phenyl) amino) -oxindole was prepared from 5-bromoindoline-2-one and 3- (trifluoromethyl) aniline in the same manner as in Production Example 1. 0.5 mg, 6% yield).
mp 147-150 ° C;
IR (neat) cm ⁻¹ : 1700, 3209, 3330;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.47 (s, 2H), 6.79 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 2H), 7.03 (s, 1H), 7.09 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 8. 22 (s, 1H), 10.27 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 36.1, 109.6, 110.0, 113.7, 117.2, 118.0, 120.0, 124.3 (q), 127.0, 129.9 (q), 130.1, 135.4, 138.9, 146.4, 176.1;
_{HRMS (FAB): m / z} calcd for C 15 H 11 F 3 N 2 O (M +) 292.0823; found: 292.0822.

[Production Example 17]
6-((3- (trifluoromethyl) phenyl) amino) benzo [d] oxazol-2 (3H) -one

From 6-bromobenzo [d] oxazol-2 (3H) -one and 3- (trifluoromethyl) aniline in the same manner as in Production Example 1, 6-((3- (trifluoromethyl) phenyl) amino) benzo [ d] A white solid (59.3 mg, 22% yield) of oxazol-2 (3H) -one was obtained.
mp 162-164 ° C;
IR (neat) cm ⁻¹ : 1756, 3258, 3350;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 6.93 (dd, J = 8.0, 1.7 Hz, 1H), 7.03-7.07 (m, 2H), 7.10 (d, J = 1.7 Hz, 1H), 7.17 (d, J = 1.7 Hz, 1H), 7.22 (dd, J = 8.0, 1.7 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 8.45 (s, 1H), 11.5 (br, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 102.3, 110.2, 110.6, 114.6, 115.5, 118.0, 124.3 (q), 125.1, 130.0 ( q), 130.3, 136.6, 144.0, 145.6, 154.6;
Anal. _{_{_{calcd for C 14 H 9 F 3}}} N 2 O 2: C, 57.15; H, 3.08; N, 9.52. Found: C, 57.22; H, 3.32; N, 9.43.

[Production Example 18]
6-((3- (trifluoromethyl) phenyl) amino) benzo [d] thiazol-2 (3H) -one

From 6-bromobenzo [d] thiazol-2 (3H) -one and 3- (trifluoromethyl) aniline in the same manner as in Production Example 1, 6-((3- (trifluoromethyl) phenyl) amino) benzo [ d] A yellow solid (9.1 mg, 5% yield) of thiazol-2 (3H) -one was obtained.
mp 129-130 ° C;
IR (neat) cm ⁻¹ : 1670, 3348;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.02-7.09 (m, 3H), 7.15 (s, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7. 36-7.41 (m, 2H), 8.42 (s, 1H), 11.7 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 110.7, 112.2, 114.0, 114.5, 117.8, 118.9, 124.3 (q), 124.4, 130.0 ( q), 130.2, 131.3, 137.0, 145.6, 169.8;
HRMS (FAB): m / z calcd for C 14 H 9 F 3 N 2 OS (M +) 310.0388; found: 310.0392.

[Production Example 19]
6-((3- (trifluoromethyl) phenyl) amino) -2H-benzo [b] [1,4] xazin-3 (4H) -one

From 6-bromo-2H-benzo [b] [1,4] oxazin-3 (4H) -one and 3- (trifluoromethyl) aniline in the same manner as in Production Example 1, 7-((3- (tri Obtained as a pale yellow solid (23.1 mg, 43% yield) of fluoromethyl) phenyl) amino) -2H-1,4-benzoxazin-3 (4H) -one.
mp 167-168 ° C;
IR (neat) cm ⁻¹ : 1695, 3215, 3341;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 4.53 (s, 2H), 6.68 (dd, J = 8.0, 2.3 Hz, 1H), 6.74 (d, J = 2.3 Hz) , 1H), 6.90 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 7.19 (d, J = 8.0 Hz, 1 H), 7.39 (t, J = 8.0 Hz, 1 H), 8.39 (s, 1 H), 10.7 (s, 1 H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 66.8, 107.0, 110.6, 113.9, 114.5, 116.8, 118.1, 124.3 (q), 128.0, 130.0 (q), 130.3, 136.6, 138.2, 145.4, 165.1;
_{HRMS (FAB): m / z} calcd for C 15 H 11 F 3 N 2 O 2 (M +) 308.0773; found: 308.0776.

[Production Example 20]
6-((6- (Trifluoromethyl) pyridin-2-yl) amino) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 1, from 6-amino-3,4-dihydroquinolin-2 (1H) -one and 2-bromo-6- (trifluoromethyl) pyridine, 6-((6- (trifluoro A white solid (294 mg, 67% yield) of methyl) pyridin-2-yl) amino) -3,4-dihydroquinolin-2 (1H) -one was obtained.
mp 202-204 ° C;
IR (neat) cm ⁻¹ : 16663, 3202, 3306;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.46 (t, J = 7.4 Hz, 2H), 2.86 (t, J = 7.4 Hz, 2H), 6.83 (d, J = 8 0.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.43 (dd, J = 8.0, 2. 3 Hz, 1 H), 7.50 (d, J = 2.3 Hz, 1 H), 7.73 (t, J = 8.0 Hz, 1 H), 9.33 (s, 1 H), 10.0 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 25.3, 30.5, 109.8, 113.8, 115.2, 117.8, 118.7, 121.8 (q), 123.9, 132.8, 135.1, 138.4, 144.3 (q), 156.0, 169.8;
Anal. _{_{_{calcd for C 15 H 12 F 3}}} N 3 O: C, 58.63; H, 3.94; N, 13.68. Found: C, 58.81; H, 4.01; N, 13.59.

[Production Example 21]
6-((4- (Trifluoromethyl) pyridin-2-yl) amino) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 1, from 6-amino-3,4-dihydroquinolin-2 (1H) -one and 2-bromo-4- (trifluoromethyl) pyridine, 6-((6- (trifluoro A white solid (154 mg, 54% yield) of methyl) pyridin-2-yl) amino) -3,4-dihydroquinolin-2 (1H) -one was obtained.
mp 177-178 ° C;
IR (neat) cm ⁻¹ : 1667, 3224;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.43 (t, J = 7.9 Hz, 2H), 2.86 (t, J = 7.9 Hz, 2H), 6.80 (d, J = 8 .7 Hz, 1 H), 6.93 (d, J = 5.5 Hz, 1 H), 7.01 (s, 1 H), 7.37 (dd, J = 8.7, 2.3 Hz, 1 H), 7 .47 (d, J = 2.3 Hz, 1H), 8.32 (d, J = 5.5 Hz, 1H), 9.27 (s, 1H), 9.96 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 25.2, 30.4, 105.7, 108.1, 115.2, 118.1, 118.9, 123.1 (q), 123.9, 132.9, 135.0, 137.5 (q), 149.4, 156.5, 169.8;
Anal. _{_{_{calcd for C 15 H 12 F 3}}} N 3 O: C, 58.63; H, 3.94; N, 13.68. Found: C, 58.61; H, 3.80; N, 13.45.

[Production Example 22]
6-((5- (trifluoromethyl) pyridin-3-yl) amino) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 1, from 6-amino-3,4-dihydroquinolin-2 (1H) -one and 3-bromo-5- (trifluoromethyl) pyridine, 6-((5- (trifluoro A white solid (124 mg, 29% yield) of methyl) pyridin-3-yl) amino) -3,4-dihydroquinolin-2 (1H) -one was obtained.
mp 213-215 ° C;
IR (neat) cm ⁻¹ : 1669, 3202, 3291;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.44 (t, J = 7.4 Hz, 2H), 2.86 (t, J = 7.4 Hz, 2H), 6.85 (d, J = 8 .6 Hz, 1H), 6.98-7.01 (m, 2H), 7.42 (s, 1H), 8.23 (s, 1H), 8.47 (s, 1H), 8.53 ( s, 2H), 10.0 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 24.9, 30.3, 115.4, 115.9, 119.3, 120.1, 123.8 (q), 124.9, 125.4 ( q), 133.9, 134.5, 134.8, 140.6, 141.8, 169.9;
Anal. _{_{_{calcd for C 15 H 12 F 3}}} N 3 O: C, 58.63; H, 3.94; N, 13.68. Found: C, 58.58; H, 3.83; N, 13.65.

[Production Example 23]
6-((4- (Trifluoromethyl) pyrimidin-2-yl) amino) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 1, from 6-bromo-3,4-dihydroquinolin-2 (1H) -one and 2-amino- (trifluoromethyl) pyrimidine, 6-((5- (trifluoromethyl) A white solid (75.3 mg, 21% yield) of pyridin-3-yl) amino) -3,4-dihydroquinolin-2 (1H) -one was obtained.
mp 230-231 ° C;
IR (neat) cm ⁻¹ : 1646, 3390;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.44 (t, J = 7.4 Hz, 2H), 2.85 (t, J = 7.4 Hz, 2H), 6.81 (d, J = 8 .6 Hz, 1H), 7.18 (d, J = 5.2 Hz, 1H), 7.46 (dd, J = 8.6, 1.7 Hz, 1H), 7.51 (d, J = 1. 7 Hz, 1 H), 8.75 (d, J = 5.2 Hz, 1 H), 9.99 (s, 1 H), 10.0 (s, 1 H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 25.2, 30.4, 106.6, 115.0, 118.7, 119.5, 120.6 (q), 123.7, 133.5, 133.8, 154.6 (q), 160.0, 161.6, 169.9;
_{HRMS (FAB): m / z} calcd for C 14 H 11 F 3 N 4 O (M +) 308.0885; found: 308.0880.

[Production Example 24]
6-((6- (Trifluoromethyl) pyrazin-2-yl) amino) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 1, from 6-bromo-3,4-dihydroquinolin-2 (1H) -one and 6- (trifluoromethyl) pyrazin-2-amine, 6-((5- (trifluoro A white solid (75.3 mg, 21% yield) of methyl) pyrazin-2-yl) amino) -3,4-dihydroquinolin-2 (1H) -one was obtained.
mp 273-275 ° C;
IR (neat) cm ⁻¹ : 1662, 3399;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.44 (t, J = 7.4 Hz, 2H), 2.86 (t, J = 7.4 Hz, 2H), 6.84 (d, J = 8 .6 Hz, 1H), 7.45 (dd, J = 8.6, 2.3 Hz, 1H), 7.49 (d, J = 2.3 Hz, 1H), 8.29 (s, 1H), 8 .41 (s, 1H), 9.90 (s, 1H), 10.0 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 25.2, 30.4, 115.3, 118.0, 118.8, 121.5 (q), 124.1, 128.4, 133.6 133.8, 138.5 (q), 139.2, 151.5, 169.8;
_{HRMS (FAB): m / z} calcd for C 14 H 11 F 3 N 4 O (M +) 308.0885; found: 308.0891.

[Production Example 25]
7-((4- (trifluoromethyl) pyridin-2-yl) amino) -2H-benzo [b] [1,4] thiazin-3 (4H) -one

In the same manner as in Production Example 1, from 7-bromo-2H-benzo [b] [1,4] thiazin-3 (4H) -one and 6-amino-4- (trifluoromethyl) pyridine, 7- ( A white solid (48.5 mg, 12% yield) of (4- (trifluoromethyl) pyridin-2-yl) amino) -2H-benzo [b] [1,4] thiazin-3 (4H) -one Obtained.
mp 217-218 ° C;
IR (neat) cm ⁻¹ : 1688, 3194;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.45 (s, 2H), 6.92 (d, J = 8.6 Hz, 1H), 6.99 (d, J = 5.2 Hz, 1H), 7.03 (s, 1H), 7.33 (dd, J = 8.6, 1.7 Hz, 1H), 7.81 (d, J = 1.7 Hz, 1H), 8.37 (d, J = 5.2 Hz, 1H), 9.43 (s, 1H), 10.44 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 29.1, 106.2, 108.6, 117.1, 117.5, 117.7, 119.3, 123.0 (q), 131.7, 135.9, 137.6 (q), 149.3, 156.1, 164.8;
_{HRMS (FAB): m / z} calcd for C 14 H 10 F 3 N 3 OS (M +) 325.0497; found: 325.0497.

[Production Example 26]
7-((4- (trifluoromethyl) pyridin-2-yl) amino) -1,3,4,5-tetrahydro-2H-benzazepin-2-one

In the same manner as in Production Example 1, from 7-bromo-1,3,4,5-tetrahydro-2H-benzazepin-2-one and 2-amino-4- (trifluoromethyl) pyridine, 7-((4 A pale yellow solid (16.7 mg, 18% yield) of-(trifluoromethyl) pyridin-2-yl) amino) -1,3,4,5-tetrahydro-2H-benzazepin-2-one was obtained.
mp 185-187 ° C;
IR (neat) cm ⁻¹ : 1688, 2936;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.09-2.16 (m, 4H), 2.67 (t, J = 6.9 Hz, 2H), 6.92 (d, J = 8.0 Hz) , 1H), 6.98 (d, J = 5.2 Hz, 1H), 7.07 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H) ), 8.37 (d, J = 5.2 Hz, 1H), 9.36 (s, 1H), 9.42 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 27.8, 30.1, 32.7, 106.0, 108.4, 117.4, 119.6, 121.9, 122.0, 123.0 (Q), 132.7, 134.1, 137.4, 137.5 (q), 149.3, 156.3, 173.1;
_{HRMS (FAB): m / z} calcd for C 16 H 14 F 3 N 3 O (M +) 321.1089; found: 321.1092.

[Production Example 27]
6-((3,5-bis (trifluoromethyl) phenyl) amino) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 1, from 6-bromo-3,4-dihydroquinolin-2 (1H) -one and 3,5-bis (trifluoromethyl) aniline, 6-((3,5-bis ( A white solid (144 mg, yield 58%) of trifluoromethyl) phenyl) amino) -3,4-dihydroquinolin-2 (1H) -one was obtained.
mp 180-182 ° C;
IR (neat) cm ⁻¹ : 1664, 3229, 3314;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.44 (t, J = 7.4 Hz, 2H), 2.87 (t, J = 7.4 Hz, 2H), 6.87 (d, J = 8 .6 Hz, 1H), 7.00 (s, 1H), 7.01 (d, J = 8.6 Hz, 1H), 7.22 (s, 1H), 7.33 (s, 2H), 8. 72 (s, 1H), 10.1 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 24.9, 30.3, 109.5, 112.9 (2C), 116.0, 120.3, 121.2, 123.4 (q, 2C) 125.0, 131.2 (q, 2C), 134.4, 134.5, 147.4, 169.9;
_{_{_{HRMS (FAB): calcd for C}}} 17 H 12 F 6 N 2 O (M +) 374.0854; found: 374.0847.

[Production Example 28]
8-Fluoro-6-((3- (trifluoromethyl) phenyl) amino) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 1, from 6-bromo-8-fluoro-3,4-dihydroquinolin-2 (1H) -one and 3- (trifluoromethyl) aniline, 8-fluoro-6-(((3 A white solid (275 mg, 69% yield) of-(trifluoromethyl) phenyl) amino) -3,4-dihydroquinolin-2 (1H) -one was obtained.
mp 166-167 ° C;
IR (neat) cm ⁻¹ : 1670, 3216, 3355;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.46 (t, J = 7.4 Hz, 2H), 2.90 (t, J = 7.4 Hz, 2H), 6.81 (s, 1H), 6.82 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 7.28 (d, J = 8.0 Hz) , 1H), 7.42 (t, J = 8.0 Hz, 1H), 8.48 (s, 1H), 9.97 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 25.2, 30.5, 104.2 (d), 111.6, 113.8, 115.1, 118.6, 120.2 (d), 124 .2 (q), 127.8, 130.0 (q), 130.4, 136.9 (d), 144.7, 149.7 (d), 169.5;
Anal. _{_{_{calcd for C 16 H 12 F 4}}} N 2 O: C, 59.26; H, 3.73; N, 8.64. Found: C, 59.05; H, 3.64; N, 8.40.

[Production Example 29]
7-Fluoro-6-((3- (trifluoromethyl) phenyl) amino) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 1, from 6-bromo-7-fluoro-3,4-dihydroquinolin-2 (1H) -one and 3- (trifluoromethyl) aniline, 7-fluoro-6-(((3 A white solid (246 mg, 62% yield) of-(trifluoromethyl) phenyl) amino) -3,4-dihydroquinolin-2 (1H) -one was obtained.
mp 179-180 ° C;
IR (neat) cm ⁻¹ : 1679, 3301;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.46 (t, J = 7.4 Hz, 2H), 2.85 (t, J = 7.4 Hz, 2H), 6.76 (d, J = 11 .5 Hz, 1H), 6.97-7.02 (m, 3H), 7.14 (d, J = 8.6 Hz, 1H), 7.36 (t, J = 8.6 Hz, 1H), 8 .11 (s, 1H), 10.12 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 24.2, 30.2, 103.1 (d), 110.0, 114.0, 117.3, 120.1, 122.2 (d), 124 0.0, 124.3 (q), 129.8 (q), 130.0, 135.3 (d), 146.2, 154.5 (d), 169.9;
Anal. _{_{_{calcd for C 16 H 12 F 4}}} N 2 O: C, 59.26; H, 3.73; N, 8.64. Found: C, 59.11; H, 3.79; N, 8.62.

[Production Example 30]
7-((3- (trifluoromethyl) phenyl) amino) -1,3,4,5-tetrahydro-2H-benzazepin-2-one

In the same manner as in Production Example 1, from 7-bromo-1,3,4,5-tetrahydro-2H-benzazepin-2-one and 3- (trifluoromethyl) aniline, 7-((3- (trifluoro A pale yellow solid (55.4 mg, 83% yield) of methyl) phenyl) amino) -1,3,4,5-tetrahydro-2H-benzazepin-2-one was obtained.
mp 140-141 ° C;
IR (neat) cm ⁻¹ : 1657, 3194, 3300;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.07-2.12 (m, 2H), 2.16 (t, J = 6.8 Hz, 2H), 2.65 (t, J = 6.8 Hz) , 2H), 6.91 (d, J = 8.0 Hz, 1H), 6.99-7.02 (m, 2H), 7.05 (d, J = 8.0 Hz, 1H), 7.22. (S, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 8.44 (s, 1H), 9.35 (s , 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 27.7, 30.0, 32.7, 111.2, 114.7, 117.2, 118.4, 119.8, 122.6, 124.3 (Q), 130.0 (q), 130.3, 132.7, 134.9, 138.6, 145.0, 173.1;
_{HRMS (FAB): m / z} calcd for C 17 H 15 F 3 N 2 O (M +) 320.1136; found: 320.1144.

Molecular transformation using N-arylation compound as a synthetic intermediate

[Production Example 31]
6-((3- (trifluoromethyl) phenyl) amino) -3,4-dihydroquinoline-2 (1H) -thione

A solution of 6-((3- (trifluoromethyl) phenyl) amino) -3,4-dihydroquinolin-2 (1H) -one (50.0 mg, 0.16 mmol) prepared in Preparation Example 1 in toluene (1. 0 mL) was added Lawesson's reagent (33.0 mg, 0.08 mmol) with stirring in an argon atmosphere. After stirring the reaction for 30 minutes at 110 ° C., the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (hexane / ethyl acetate-3: 1) to give the desired product, 6-((3- (trifluoromethyl) phenyl) amino) -3,4-dihydroquinoline-2 (1H ) -Thione yellow solid (51.4 mg, 100% yield) was obtained.
mp 195-196 ° C;
IR (neat) cm ⁻¹ : 1499, 3361;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.77 (t, J = 8.0 Hz, 2H), 2.90 (t, J = 8.0 Hz, 2H), 6.97 (s, 1H), 6.98 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.20 (s) , 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 8.49 (s, 1H), 12.1 (s, 1H) ); ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 24.0, 38.9, 111.4, 114.9, 117.0, 117.3, 118.3, 118.5, 124.3 (q ), 126.6, 130.0 (q), 130.3, 131.3, 138.3, 144.9, 197.3;
_{HRMS (FAB): m / z} calcd for C 16 H 13 F 3 N 2 S (M +) 322.0752; found: 322.0758.

[Production Example 32]
7-((3- (trifluoromethyl) phenyl) amino) -quinolin-2 (1H) -one

In a flask, 7-((3- (trifluoromethyl) phenyl) amino) -3,4-dihydroquinolin-2 (1H) -one (80.0 mg, 0.26 mmol) prepared in Preparation Example 2 and palladium acetate ( 22.4 mg, 0.10 mmol) was added and acetic acid (1.0 mL) was added after attaching an oxygen balloon. After reacting for 2 hours, it was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (hexane / ethyl acetate-1: 3-1: 5) to give white 7-((3- (trifluoromethyl) phenyl) amino) -quinolin-2 (1H) -one. An individual (34.1 mg, 43% yield) was obtained.
mp 177-179 ° C;
IR (neat) cm ⁻¹ : 1655, 3452;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 6.24 (d, J = 9.2 Hz, 1H), 6.88 (dd, J = 8.0, 2.3 Hz, 1H), 7.06 (d , J = 2.3 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7 50-7.53 (m, 2H), 7.75 (d, J = 9.2 Hz, 1H), 8.99 (s, 1H), 11.5 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 99.7, 112.3, 113.1, 113.5, 116.7, 117.7, 121.0, 124.1 (q), 129.0, 130.0 (q), 130.4, 139.8, 140.5, 142.9, 144.5, 162.2;
_{HRMS (FAB): m / z} calcd for C 16 H 11 F 3 N 2 O [M + H] + 305.0902; found: 305.0905.

[Production Example 33]
6-((3-Hydroxyphenyl) amino) -3,4-dihydroquinolin-2 (1H) -one

A dichloromethane suspension (5 mL) of 6-((3-methoxyphenyl) amino) -3,4-dihydroquinolin-2 (1H) -one (500 mg, 1.86 mmol) prepared in Preparation Example 7 was −78 ° C. And 1M boron tribromide in dichloromethane (7.45 mL, 7.45 mmol) was added. After stirring at −78 ° C. for 30 minutes, the cold bath was removed and the reaction mixture was stirred for 18 hours. The reaction was then quenched with 12 mL water and dichloromethane was removed under reduced pressure. The aqueous solution was neutralized by adding aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (hexane / ethyl acetate-1: 3), and the desired 6-((3-hydroxyphenyl) amino) -3,4-dihydroquinolin-2 (1H) -one was obtained. Brown needle crystals (232 mg, 49% yield) were obtained.
mp 213-214 ° C;
IR (neat) cm ⁻¹ : 1651, 3222, 3321;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.41 (t, J = 7.4 Hz, 2H), 2.81 (t, J = 7.4 Hz, 2H), 6.15 (d, J = 8 0.0 Hz, 1H), 6.38 (d, J = 8.0 Hz, 1H), 6.39 (s, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.85 (d , J = 8.0 Hz, 1H), 6.89 (s, 1H), 6.94 (t, J = 8.0 Hz, 1H), 7.77 (s, 1H), 9.07 (s, 1H) ), 9.89 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 25.1, 30.5, 102.2, 106.0, 106.6, 115.6, 117.4, 118.2, 124.4, 129.7 131.7, 137.7, 145.8, 158.1, 169.7;
Anal. _{_{_{calcd for C 15 H 14 N 2}}} O 2: C, 70.85; H, 5.55; N, 11.02. Found: C, 71.11; H, 5.59; N, 10.89.

[Production Example 34]
6-((3-Aminophenyl) amino) -3,4-dihydroquinolin-2 (1H) -one

To the acetic acid solution (2.2 mL) of 6-((3-nitrophenyl) amino) -3,4-dihydroquinolin-2 (1H) -one (62.0 mg, 0.22 mmol) prepared in Preparation Example 10 at room temperature Zinc powder (102 mg, 1.56 mmol) was gradually added. The reaction was carried out at room temperature for 1 hour, then filtered through a pad of celite, and the pad was washed with acetic acid. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The organic solvent was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (hexane / ethyl acetate-1: 8) to obtain the desired 6-((3-aminophenyl) amino) -3,4-dihydro A pale yellow solid (41.6 mg, 75% yield) of quinolin-2 (1H) -one was obtained.
mp 196-198 ° C;
IR (neat) cm ⁻¹ : 1662, 3221, 3344;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.40 (t, J = 7.4 Hz, 2H), 2.80 (t, J = 7.4 Hz, 2H), 4.93 (br, 2H), 6.00 (d, J = 8.0 Hz, 1H), 6.15 (d, J = 8.0 Hz, 1H), 6.24 (s, 1H), 6.72 (d, J = 8.0 Hz) , 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.86 (s, 1H), 7.58 (s, 1H) ), 9.87 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 25.2, 30.5, 101.4, 104.5, 105.7, 115.5, 116.9, 117.7, 124.3, 129.3 131.2, 138.3, 145.0, 149.2, 169.6;
_{_{_{HRMS (FAB): calcd for C}}} 15 H 15 N 3 O (M +) 253.1215; found: 253.1213.

[Production Example 35]
3-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) amino) benzoic acid

Methyl 3-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) amino) benzoate (400 mg, 1.35 mmol) prepared in Preparation Example 11 in methanol / water (3: 1 v / V) The solution (5.2 mL) was cooled to 0 ° C., lithium hydroxide monohydrate (170 mg, 4.05 mmol) was added to the solution, and then the reaction was warmed to 50 ° C. After 1 hour, the reaction solution was adjusted to pH 2 or lower using 1M hydrochloric acid, and ethyl acetate and saturated brine were added. The aqueous layer was extracted with ethyl acetate, and the extracted organic layers were combined, washed with saturated brine, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to obtain a white solid (366 mg, yield 96%) of 3-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) amino) benzoic acid. It was.
mp 259-261 ° C;
IR (neat) cm ⁻¹ : 1656, 1684, 3203, 3326;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.43 (t, J = 7.4 Hz, 2H), 2.85 (t, J = 7.4 Hz, 2H), 6.81 (d, J = 8 0.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.94 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.27-7 .31 (m, 2H), 7.53 (s, 1H), 8.12 (s, 1H), 9.98 (s, 1H), 12.8 (br, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 25.1, 30.4, 115.5, 115.8, 118.1, 118.9, 119.0, 119.2, 124.6, 129.3 131.7, 132.6, 136.9, 145.2, 167.6, 169.8;
HRMS (FAB): m / z calcd for C ₁₆ H ₁₄ N ₂ O ₃ (M ⁺ ) 282.1004; found: 282.11.

[Production Example 36]
1- (3-((3- (trifluoromethyl) phenyl) amino) phenyl) urea

While stirring a solution of N ^1- (3- (trifluoromethyl) phenyl) benzene-1,3-diamine (80.0 mg, 0.32 mmol in AcOH (4.0 mL)), potassium cyanate (77.2 mg, 0 .95 mmol) and water (80.0 μL) were added, and the mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure, and the residue was subjected to silica gel flash chromatography (chloroform / methanol-20: 1-10: 1). ) To give a yellow oil (31.9 mg, 34% yield) of 1- (3-((3- (trifluoromethyl) phenyl) amino) phenyl) urea.
IR (neat) cm ⁻¹ : 1661, 3225, 3351;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 5.82 (br, 2H), 6.66 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.30 (d, J = 8.0 Hz) , 1H), 7.41 (s, 1H), 7.42 (t, J = 8.0 Hz, 1H), 8.50 (br, 2H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 107.4, 110.7, 110.9, 111.5, 118.8, 118.9, 124.2 (q), 129.3, 129.8 ( q), 130.1, 141.5, 142.2, 144.6, 155.8;
_{HRMS (FAB): m / z} calcd for C 14 H 12 F 3 N 3 O (M +) 295.0932; found: 295.0926.

[Production Example 37]
1- (4-((3- (trifluoromethyl) phenyl) amino) phenyl) urea

In the same manner as in Production Example 29, N ^1- (3- (trifluoromethyl) phenyl) benzene-1,4-diamine to 1- (4-((3- (trifluoromethyl) phenyl) amino) phenyl) A white solid of urea (109 mg, 37% yield) was obtained. ;
mp 165-166 ° C;
IR (neat) cm ⁻¹ : 1660, 3217, 3331, 3445;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 5.80 (br, 2H), 6.98 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.6 Hz, 2H), 7.13 (s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 8.6 Hz) , 2H), 8.28 (br, 1H), 8.44 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 110.0, 113.8, 117.5, 119.2 (2C), 120.7 (2C), 124.4 (q), 130.0 (q) 130.2, 135.2, 135.4, 146.1, 156.1;
_{HRMS (FAB): m / z} calcd for C 14 H 12 F 3 N 3 O (M +) 295.0932; found: 295.0932.

General etherification for the preparation of diaryl ether compounds

[Production Example 38]
6-((3- (trifluoromethyl) phenoxy) -3,4-dihydroquinolin-2 (1H) -one

To a suspension of tert-butoxypotassium (60.5 mg, 0.54 mmol) in dimethylformamide (DMF) (2.1 mL) at 0 ° C., 6-hydroxy-3,4-dihydroquinolin-2 (1H) -one (80 0.0 mg, 0.49 mmol) was added and stirred at that temperature for 15 minutes. Bis (3-trifluoromethylphenyl) iodonium tetrafluoroborate (259 mg, 0.51 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at 40 ° C. for 1 hour. The reaction was cooled to 0 ° C., quenched with water, extracted with chloroform, and the organic layer was washed with saturated brine and dried over sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (hexane / ethyl acetate-1: 1) to obtain the desired product, 6-((3- (trifluoromethyl) phenoxy) -3,4. A white solid (39.9 mg, 27% yield) of -dihydroquinolin-2 (1H) -one was obtained.
mp 158-159 ° C;
IR (neat) cm ⁻¹ : 1681, 3203;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.44 (t, J = 7.4 Hz, 2H), 2.87 (t, J = 7.4 Hz, 2H), 6.91 (s, 2H), 6.99 (s, 1H), 7.20-7.23 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H) ), 10.1 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 24.7, 30.0, 113.6, 116.3, 118.7, 119.1, 119.5, 121.0, 123.7 (q), 125.7, 130.6 (q), 131.2, 135.3, 149.6, 158.4, 169.9;
HRMS (FAB): m / z calcd for C ₁₆ H ₁₂ F ₃ NO ₂ (M ⁺ ) 307.0820; found: 307.0826.

General thioetherification for the preparation of diaryl sulfide compounds

[Production Example 39]
6-((4- (trifluoromethyl) phenyl) thio) -3,4-dihydroquinolin-2 (1H) -one

Under an argon atmosphere, 6-mercapto-3,4-dihydroquinolin-2 (1H) -one (40.0 mg, 0.22 mmol), 4-trifluoromethyliodobenzene (32.3 μL, 0.22 mmol), iodine A flask charged with copper (I) chloride (8.5 mg, 0.05 mmol), ethylene glycol (24.9 μL, 0.45 mmol) and potassium carbonate (77.0 mg, 0.56 mmol) was isopropanol (1.0 mL). Was added. The mixture was stirred at 80 ° C. for 12 hours. After cooling, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (hexane / ethyl acetate-3: 2) to obtain the target product 6-6-((4- (trifluoromethyl) phenyl) thio)- A white solid (10.8 mg, 15% yield) of 3,4-dihydroquinolin-2 (1H) -one was obtained.
mp 158-159 ° C;
IR (neat) cm ⁻¹ : 1646, 3406;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.48 (t, J = 7.4 Hz, 2H), 2.92 (t, J = 7.4 Hz, 2H), 6.97 (d, J = 8 0.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 1H), 7.
41 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 10.3 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 24.4, 30.0, 116.5, 121.7, 124.2 (q), 125.5, 125.8 (q), 125.9 (2C ), 126.5 (2C), 134.0, 134.3, 139.8, 144.5, 170.2; HRMS (FAB): m / z calcd for C ₁₆ H ₁₂ F ₃ NOS (M ⁺ ) 323.0592; found: 323.0596.

[Production Example 40]
6-((3- (trifluoromethyl) phenyl) thio) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 32, 6-((3- (trifluoromethyl) phenyl) thio) from 6-mercapto-3,4-dihydroquinolin-2 (1H) -one and 3-trifluoromethyliodobenzene A white solid (6.2 mg, 7% yield) of -3,4-dihydroquinolin-2 (1H) -one was obtained.
mp 102-104 ° C;
IR (neat) cm ⁻¹ : 1676, 3387;
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.53 (t, J = 7.4 Hz, 2H), 2.96 (t, J = 7.4 Hz, 2H), 7.00 (d, J = 8 0.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.42-7.45 (m, 2H), 7.49 (s, 1H), 7.58-7.59 (M, 2H), 10.3 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 24.4, 30.0, 116.4, 122.4, 122.6, 123.0, 123.7 (q), 125.4, 129.9 ( q), 130.3, 131.0, 133.5, 133.7, 139.5, 140.1, 170.1;
HRMS (FAB): m / z calcd for C ₁₆ H ₁₂ F ₃ NOS (M ⁺ ) 323.0592; found: 323.0591.

[Comparative Production Example 1]
6-([1,1′-biphenyl] -3-ylamino) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 1, from 6-bromo-3,4-dihydroquinolin-2 (1H) -one and 3-aminobiphenyl to 6-([1,1′-biphenyl] -3-ylamino)- A yellow solid (375 mg, 86% yield) of 3,4-dihydroquinolin-2 (1H) -one was obtained.
mp 143-145 ° C;
IR (neat) cm ⁻¹ : 1666, 3218, 3316;
¹ HNMR (500 MHz, DMSO-d ₆ ) δ 2.42 (t, J = 7.4 Hz, 2H), 2.84 (t, J = 7.4 Hz, 2H), 6.79 (d, J = 8. 0 Hz, 1H), 6.96-6.98 (m, 3H), 7.00 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H) ), 8.02 (s, 1H), 9.94 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 25.1, 30.5, 113.7, 114.2, 115.7, 117.2, 117.4, 118.3, 124.6, 126.5 ( 2C), 127.3, 128.8 (2C), 129.7, 132.0, 137.4, 140.7, 141.3, 145.1, 169.7;
Anal. _{_{_{calcd for C 21 H 18 N 2}}} O: C, 80.23; H, 5.77; N, 8.91. Found: C, 80.29; H, 5.71; N, 8.72.

[Comparative Production Example 2]
6-((3-Phenoxyphenyl) amino) -3,4-dihydroquinolin-2 (1H) -one

In the same manner as in Production Example 1, from 6-bromo-3,4-dihydroquinolin-2 (1H) -one and 3-phenoxyaniline to 6-((3-phenoxyphenyl) amino) -3,4-dihydro A white solid (175 mg, 48% yield) of quinolin-2 (1H) -one was obtained.
mp 130-132 ° C;
IR (neat) cm ⁻¹ : 1661, 3204, 3309;
¹ HNMR (500 MHz, DMSO-d ₆ ) δ 2.41 (t, J = 6.9 Hz, 2H), 2.81 (t, J = 6.9 Hz, 2H), 6.36 (dd, J = 8. 0, 2.3 Hz, 1H), 6.54 (t, J = 2.3 Hz, 1H), 6.72 (dd, J = 8.0, 2.3 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.88 (dd, J = 8.0, 2.3 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 7.03 (d, J = 8.0 Hz, 2H), 7.12 (t, J = 8.0 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.38 (t, J = 8.0 Hz, 2H) ), 8.05 (s, 1H), 9.95 (s, 1H);
¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 25.1, 30.4, 104.7, 108.3, 110.0, 115.7, 117.9, 118.7, 118.8 (2C), 123 3, 124.5, 129.9 (2C), 130.4, 132.3, 136.9, 146.4, 156.5, 157.8, 169.7;
HRMS (FAB): m / z calcd for C ₂₁ H ₁₈ N ₂ O ₂ (M ⁺ ) 330.1368; found: 330.1374.

Solubility test of compounds in aqueous solvents

The compound of the present invention and the comparative compound were dissolved in an equal volume mixture of ethanol and 1/15 M phosphate buffer (pH 7.4) and 1/15 M phosphate buffer (pH 7.4) to determine solubility. . As comparative compounds, carbazole type compounds and biphenyl type compounds described in the literature were used.

The solubility was determined by the following method and shown in Table 1.
1) A certain amount of compound was measured in a vial, a solvent was added, and the mixture was stirred at 25 ° C. for 48 hours.
2) The undissolved compound was collected by filtration.
3) m-cresol was added as an internal standard to the collected compound to prepare a DMF solution.
4) The ratio of compound to m-cresol was determined by HPLC analysis.
5) From the above ratio, the correct solubility of the compound was determined using a calibration curve.

From the solubility shown in Table 1, it was found that the compound of the present invention has a large solubility in an aqueous solvent as compared with a conventionally known Eg5 inhibitor. In particular, it has been clarified that the compound having a pyridine ring greatly increases the solubility. In addition, the compound having a pyrazine ring and a pyrimidine ring has substantially the same solubility in a mixed solution of ethanol and 1 / 15M phosphate buffer as in a conventional compound, but the compound has a solubility in 1 / 15M phosphate buffer. It can be seen that the solubility is remarkably improved as compared with the conventional compounds.

Eg5 inhibitory activity: ATPase inhibition test of Eg5

Measurement of KSP ATPase activity was carried out on a 96-well plate in a buffer containing a KSP motor domain (38 nM) and a microtubule (350 nM) in which the C-terminal expressed in E. coli was fixed with a histidine tag. Thereafter, a DMSO solution of the compound of the present invention prepared to have various concentrations was added, and preincubated at 25 ° C. for 30 minutes. ATP hydrolysis reaction was started by adding ATP, and the reaction was performed at 25 ° C. for 15 minutes. Kinase-Glo Plus reagent (Promega) was added to each well to stop the reaction. In order to quantitate ATP consumption, it measured using the ATP measuring method by luciferase. The test was performed at least three times under each condition, and the concentration (IC ₅₀ ) that inhibits ATP hydrolysis by 50% was determined from the average value and standard deviation of the inhibition rate under each condition. The results are shown in Table 2.

From the results shown in Table 2, it can be seen that the compound of the present invention has Eg5 inhibitory activity equivalent to or higher than that of conventional Eg5 inhibitors.

Cytotoxicity test against human alveolar basal epithelial adenocarcinoma cells (A549 cells)

Human alveolar basal epithelial adenocarcinoma cells (A549 cells) were cultured in Dulbecco's modified Eagle medium (DMEM) containing 10% fetal bovine serum (FBS) at a density of 500 cells / well in a 96-well plate. The cells were cultured for 6 hours in a constant temperature room at 37 ° C. filled with 5% CO ₂ . To each well, a DMEM solution containing 10% FBS of a test sample (prepared from a DMSO solution) prepared to have various concentrations was added, and the culture was continued. The number of viable cells after culturing for 3 days was measured using a cell proliferation test kit (Promega) by MTS method, and the cell proliferation score was calculated according to the following formula.
Cell proliferation score (%) = 100 × MS / MD
MS: Absorbance by MTS reagent when sample is added MD: Absorbance by MTS reagent when only solvent for sample dissolution is added

Cytotoxicity test against human colon adenocarcinoma cells (HCT-116 cells)

Human colon adenocarcinoma cells (HCT-116 cells) were cultured in McCoy's 5A Medium containing 10% fetal bovine serum (FBS) as a culture medium in a 96-well plate at a density of 5000 cells / well and 5% CO _The cells were cultured in a thermostatic chamber filled with ₂ at 37 ° C. for 6 hours. To each well, a DMEM solution containing 10% FBS of a test sample (prepared from a DMSO solution) prepared to have various concentrations was added, and the culture was continued. The number of viable cells after culturing for 3 days was measured using a cell proliferation test kit (Promega) by MTS method, and the cell proliferation score was calculated according to the following formula.
Cell proliferation score (%) = 100 × MS / MD
MS: Absorbance by MTS reagent when sample is added MD: Absorbance by MTS reagent when only solvent for sample dissolution is added

Cytotoxicity test for human breast cancer cells (MCF-7 cells)

Human breast adenocarcinoma cells (MCF-7 cells) were cultured in Eagle's minimal essential medium (EMEM) containing 10% fetal bovine serum (FBS) at a density of 5000 cells / well in a 96-well plate. The cells were cultured for 6 hours in a constant temperature room at 37 ° C filled with 5% CO ₂ . To each well, a DMEM solution containing 10% FBS of a test sample (prepared from a DMSO solution) prepared to have various concentrations was added, and the culture was continued. The number of viable cells after culturing for 3 days was measured using a cell proliferation test kit (Promega) by MTS method, and the cell proliferation score was calculated according to the following formula.
Cell proliferation score (%) = 100 × MS / MD
MS: Absorbance by MTS reagent when sample is added MD: Absorbance by MTS reagent when only solvent for sample dissolution is added

The results of Examples 3 to 5 are shown in Table 3.

From the above results, the Eg5 inhibitor of the present invention has a greater solubility in an aqueous solvent than the conventional Eg5 inhibitor, and has an Eg5 inhibitory activity equal to or higher than that of the conventional Eg5 inhibitor. Have. Furthermore, it has a remarkable growth inhibitory activity against various cancer cells due to the above characteristics, and is very effective in treating cancer and the like.

The present invention can be suitably used in the fields of an Eg5 inhibitor and an anticancer agent containing the Eg5 inhibitor.

Claims

Formula (I)

{Where,
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
X is NZ (wherein Z is hydrogen, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 or 4 carbon atoms, or a substituted or unsubstituted alkenyl group having 2 to 4 carbon atoms) Represents a group, a substituted or unsubstituted alkynyl group having 2 to 4 carbon atoms), O or S;
R 1 and R 2 are the same or different and each represents hydrogen, a halogen atom, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 or 4 carbon atoms, or 2 to 4 carbon atoms. A substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group having 2 to 4 carbon atoms, OZ 1 (wherein Z 1 is as defined above for Z), OCOZ 2 (wherein Z 2 is the same as Z NZ 3 COOZ 4 (wherein Z 3 and Z 4 are the same or different and have the same meaning as Z), S (O) n Z 5 (wherein n is 0-3) Z 5 is as defined above for Z), SO 2 NZ 6 Z 7 (wherein Z 6 and Z 7 are the same or different and have the same meaning as Z or Z 6 Z 7 together may form a substituted or unsubstituted nitrogen-containing heterocyclic group) COZ 8 (wherein, Z 8 is the same meaning as Z), COOZ 9 (wherein, Z 9 is the same meaning as Z), 10 Z 11 (wherein CONZ, Z 10 and Z 11 is Each having the same meaning as Z 6 and Z 7 ), NZ 12 Z 13 (wherein Z 12 and Z 13 are the same as Z 6 and Z 7 , respectively), a nitro group or a cyano group,
Q 1 , Q 2 , and Q 3 are the same or different and represent a nitrogen atom or —C (W) = (wherein W has the same meaning as R 1 ),
Y 1 , Y 2 , Y 3 and Y 4 are the same or different and have the same meaning as R 1 or an alkylene-COOZ 14 having 1 to 4 carbon atoms (wherein Z 14 has the same meaning as Z above). Y 1 and Y 2 , Y 2 and Y 3 , Y 3 and Y 4 may form a 5- to 7-membered ring structure containing carbons to which each is bonded;
However, in the above compound, ab, cd, and ef are simultaneously a double bond, X is NH, R 1 is trifluoromethyl, and Q 1 , Q 2 , and Q 3 are When it is CH and Y 1 and Y 4 are hydrogen,
Excluding compounds in which Y 2 is hydrogen and Y 3 is a nitro group, or Y 2 and Y 3 are combined to form a δ-lactam structure in which Y 2 -Y 3 is CH 2 CH 2 CONH}
Or a salt thereof.
The compound represented by the formula (I) is represented by the following formula (II)

(Where
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
R 1 , R 2 , X and Y 1 to Y 4 are as defined above.
The water-soluble polycyclic compound or a salt thereof according to claim 1, wherein the water-soluble polycyclic compound is represented by the formula:
The compound represented by the formula (II) is represented by the following formula (III)

(Where
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
R 1 , R 2 , X and Y 1 , Y 2 are as defined above.
The water-soluble polycyclic compound or a salt thereof according to claim 2, wherein the water-soluble polycyclic compound is represented by the formula:
The compound represented by the formula (III) is represented by the following formula (IV)

(Where
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
R 1 represents hydrogen, a halogen atom, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a hydroxyl group, a substituted or unsubstituted alkoxyl group having 1 to 4 carbon atoms, a formyl group, a carboxyl group, a sulfonic acid group, a nitro group, and Any one selected from cyano groups, and Y 1 and Y 2 are the same or different and each is hydrogen or fluorine)
The water-soluble polycyclic compound or a salt thereof according to claim 3, wherein the water-soluble polycyclic compound is a polycyclic compound represented by the formula:
The water-soluble polycyclic compound or a salt thereof according to any one of claims 1 to 4, wherein the bonds ab, cd, and ef are simultaneously double bonds.
6. The water-soluble polycyclic compound according to claim 1 , wherein R 1 is a trifluoromethyl group, an ethyl group, an isopropyl group, a tert-butyl group, a trifluoromethoxy group or a nitro group. Or a salt thereof.
The compound represented by the formula (I) is represented by the following formula (V)

(Where
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
Y 1 to Y 4 are as defined above,
(One or more of Q 1 , Q 2 , and Q 3 are nitrogen electrons)
The water-soluble polycyclic compound or a salt thereof according to claim 1, wherein the water-soluble polycyclic compound is represented by the formula:
The water-soluble polycyclic compound or a salt thereof according to claim 7, wherein the bonds ab, cd, and ef are simultaneously double bonds.
Water-soluble polycyclic compounds represented by the formula (I) are represented by the formulas (I-3) to (I-25):

The water-soluble polycyclic compound or a salt thereof according to claim 1, wherein the water-soluble polycyclic compound is represented by any one of the following formulas:
Formula (I)

{Where,
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
X is NZ (wherein Z is hydrogen, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 or 4 carbon atoms, or a substituted or unsubstituted alkenyl group having 2 to 4 carbon atoms) Represents a group, a substituted or unsubstituted alkynyl group having 2 to 4 carbon atoms), O or S;
R 1 and R 2 are the same or different and each represents hydrogen, a halogen atom, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 or 4 carbon atoms, or 2 to 4 carbon atoms. A substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group having 2 to 4 carbon atoms, OZ 1 (wherein Z 1 is as defined above for Z), OCOZ 2 (wherein Z 2 is the same as Z NZ 3 COOZ 4 (wherein Z 3 and Z 4 are the same or different and have the same meaning as Z), S (O) n Z 5 (wherein n is 0-3) Z 5 is as defined above for Z), SO 2 NZ 6 Z 7 (wherein Z 6 and Z 7 are the same or different and have the same meaning as Z or Z 6 Z 7 together may form a substituted or unsubstituted nitrogen-containing heterocyclic group) COZ 8 (wherein, Z 8 is the same meaning as Z), COOZ 9 (wherein, Z 9 is the same meaning as Z), 10 Z 11 (wherein CONZ, Z 10 and Z 11 is Each having the same meaning as Z 6 and Z 7 ), NZ 12 Z 13 (wherein Z 12 and Z 13 are the same as Z 6 and Z 7 , respectively), a nitro group or a cyano group,
Q 1 , Q 2 , and Q 3 are the same or different and represent a nitrogen atom or —C (W) = (wherein W has the same meaning as R 1 ),
Y 1 , Y 2 , Y 3 and Y 4 are the same or different and have the same meaning as R 1 or an alkylene-COOZ 14 having 1 to 4 carbon atoms (wherein Z 14 has the same meaning as Z above). And Y 1 and Y 2 , Y 2 and Y 3 , Y 3 and Y 4 may each form a 5- to 7-membered ring structure containing carbon bonded to each other}
The Eg5 inhibitor which contains the water-soluble polycyclic compound represented by these, or its pharmacologically acceptable salt as an active ingredient.
The compound represented by the formula (I) is represented by the following formula (II)

(Where
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
R 1 , R 2 , X and Y 1 to Y 4 are as defined above.
The Eg5 inhibitor according to claim 10, which is a polycyclic compound represented by the formula:
The compound represented by the formula (II) is represented by the following formula (III)

(Where
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
R 1 , R 2 , X and Y 1 , Y 2 are as defined above.
The Eg5 inhibitor according to claim 11, which is a polycyclic compound represented by the formula:
The compound represented by the formula (III) is represented by the following formula (IV)

(Where
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
R 1 represents hydrogen, a halogen atom, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a hydroxyl group, a substituted or unsubstituted alkoxyl group having 1 to 4 carbon atoms, a formyl group, a carboxyl group, a sulfonic acid group, a nitro group, and Any one selected from cyano groups, and Y 1 and Y 2 are the same or different and each is hydrogen or fluorine)
The Eg5 inhibitor according to claim 12, which is a polycyclic compound represented by the formula:
The Eg5 inhibitor according to any one of claims 10 to 13, wherein the bonds ab, cd, and ef are simultaneously double bonds.
The Eg5 inhibitor according to any one of claims 10 to 14, wherein R 1 is a trifluoromethyl group, an ethyl group, an isopropyl group, a tert-butyl group, a trifluoromethoxy group, or a nitro group.
The compound represented by the formula (I) is represented by the following formula (V)

(Where
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
Y 1 to Y 4 are as defined above,
1 or 2 of Q 1 , Q 2 , and Q 3 is a nitrogen electron)
The Eg5 inhibitor according to claim 10, which is a polycyclic compound represented by the formula:
The Eg5 inhibitor according to claim 16, wherein the bonds ab, cd, and ef are simultaneously double bonds.
Water-soluble polycyclic compounds represented by the formula (I) are represented by the formulas (I-1) to (I-25):

The Eg5 inhibitor according to claim 10, which is any one of water-soluble polycyclic compounds represented by the formula: or a pharmacologically acceptable salt thereof.
A pharmacologically acceptable salt of the water-soluble polycyclic compound represented by the formula (I) is represented by the following formula (VI):

{Where,
The bonds ab, cd, and ef each represent a single bond or a double bond at the same time or different from each other;
R 1 , R 2 , Q 1 to Q 3 , Y 1 to Y 4 and Z are as defined above,
L is synonymous with Z,
M is a halogen atom, Z 15 COO (wherein Z 15 is as defined above for Z), Z 16 SO 3 (wherein Z 16 is as defined above for Z), BF 4 and PF 6 Any one selected from}
The Eg5 inhibitor according to any one of claims 10 to 18, wherein
The Eg5 inhibitor according to any one of claims 10 to 17 and 19, wherein the bonds ab, cd and ef are double bonds.
A cell growth inhibitor or anticancer agent comprising the Eg5 inhibitor according to any one of claims 10 to 20 as an active ingredient.
A pharmaceutical comprising the water-soluble polycyclic compound according to any one of claims 1 to 9 or a pharmacologically acceptable salt thereof as an active ingredient.
A pharmaceutical composition comprising the water-soluble polycyclic compound according to any one of claims 1 to 9 or a pharmacologically acceptable salt thereof and a pharmaceutically acceptable carrier.