JPWO2020071550A1 - CDK8 Inhibitors and Their Applications - Google Patents

Abstract

To provide a novel CDK8 inhibitor. In the present invention, the general formula (I): [each symbol in the formula is as described in the specification. ], A pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound as an active ingredient. According to the present invention, the above-mentioned compound has CDK8 inhibitory activity, and is useful as a prophylactic / therapeutic agent for CDK8-related diseases, bone metabolism-related diseases such as osteoporosis, and cell proliferation diseases such as cancer. Can be provided.

Description

The present invention relates to a compound having cyclin-dependent kinase (CDK) 8 inhibitory activity or a pharmaceutically acceptable salt thereof. Furthermore, the present invention relates to compounds useful for the prevention and / or treatment of CDK8-related diseases, bone metabolism-related diseases such as osteoporosis, and cell proliferation diseases such as cancer, or pharmaceutically acceptable salts thereof.

CDK is a kinase that is activated by forming a complex with a cyclin protein, and is known as a factor involved in cell cycle and transcriptional regulation. In particular, it is known that CDK2, CDK4 and CDK6 are mainly involved in the cell cycle, and CDK7, CDK8 and CDK9 are mainly involved in transcription. Among them, CDK8 forms a complex with cyclin C, MED12, and MED13, and acts as a kinase that mainly controls transcription by controlling phosphorylation of the C-terminal domain of RNA polymerase II (non-patent literature). 1).
CDK8 is an oncogene in some colorectal cancer cells, and in colorectal cancer patients, the expression of CDK8 is enhanced, which activates β-catenin signal and positively regulates cell proliferation. It has been reported (Non-Patent Document 2). Furthermore, CDK8 is known to be involved in the maintenance of undifferentiated cancer cells and epithelial-mesenchymal transition.
In addition, it has been reported that the CDK8 inhibitor Cyclin A suppresses the growth of various cancer cells and has a particularly remarkable effect on leukemia cells (Non-Patent Document 3).
Non-Patent Document 4 discloses that a compound that inhibits CDK8 is useful for the treatment or prevention of cancer, and Patent Documents 1 to 6 disclose CDK inhibitors having an anticancer activity.

The compound of the present invention is also useful for diseases related to bone metabolism such as osteoporosis. As therapeutic agents for osteoporosis, there are bone resorption inhibitors that suppress the activity of osteoclasts and bone formation promoters that activate osteoblasts. As the bone resorption inhibitor, calcitonin, bisphosphonate, estrogen receptor modulator and the like are used. However, while these treatments prevent further loss of bone mass, they cannot reconstruct lost bone. On the other hand, human PTH (1-34) is used as a bone formation-promoting agent, and can be used for increasing bone mass and bone density and reconstructing bone structure. However, the period of use is limited to one and a half to two years, and long-term subcutaneous injection is required, making it difficult for patients to comply with it.

Therefore, it is desired to develop an orally administrable bone formation promoter having a high clinical effect. Recently, a benzothiepine derivative having alkaline phosphatase-inducing activity (Patent Documents 7 and 8), an N-quinolylanthranic acid derivative (Patent Document 9), a triazolopyridazine derivative (Patent Document 10), and a thienopyridine derivative (Patent Document 11). ), [5,6] Heterocyclic compounds (Patent Document 12) and aromatic compounds (Patent Document 13) have been reported to be useful for promoting bone formation and treating diseases related to bone metabolism. However, its clinical usefulness is unknown.

U.S. Patent Application Publication No. 2012/0071477 WO2007 / 133772 WO2013 / 116786 WO2014 / 072435 WO2015 / 159937 WO2015 / 159938 US636521 US6632807 Japanese Unexamined Patent Publication No. 9-188665 US7173033 Japanese Unexamined Patent Publication No. 2007-131617 WO2011 / 136264 WO2015 / 030189

A. D. Clark et al., Crit Rev Biochem Mol Biol., 50 (5), 393-426 (2015) R. Firestein et al., Nature 455, 547-551 (2008) H. E. Pelish et al., Nature 526, 273-276 (2015) T. Rzymski et al., Biochim. Biophys. Acta, Volume 1845, 1617-1629 (2015)

An object of the present invention is to provide a preventive and / or therapeutic agent for a CDK8-inhibiting action, a disease related to CDK8, a disease related to bone metabolism such as osteoporosis, and a cell proliferative disease such as cancer. be. Furthermore, it is to provide a compound which is highly safe and can be orally administered, and a pharmaceutically acceptable salt.

As a result of diligent studies under such circumstances, the present inventors showed a strong inhibitory effect on CDK8, and found diseases related to CDK8, diseases related to bone metabolism such as osteoporosis, and cell proliferative diseases such as cancer. We have found an excellent compound of the present invention that can be a prophylactic and / or therapeutic agent, and have completed the present invention.

That is, the present invention
[1] General formula (I):

[In the formula, each substituent is defined as follows.
Ring A:

(R ⁴ :
C _1-6 alkylcarbonyl group, C _1-6 alkylthiocarbonyl group, carbamoyl group, C _1-6 alkoxycarbonyl group or carboxy group,
R ⁵ :
Hydrogen atom, C _1-6 alkyl group or halogen atom,
R ⁶ :
C _1-6 alkyl group, halogen atom, amino group, hydroxy C _1-6 alkyl group, carboxy C _1-6 alkyl group or hydrogen atom (provided that T is = CH- and U is = N-),
R ⁷ :
Hydrogen atom or C _1-6 alkyl group,
R ⁸ :
Hydrogen atom, C _1-6 alkyl group or C _1-6 alkyl carbonyl group,
R ⁹ :
Hydrogen atom or C _1-6 alkyl group),
R ¹ :
Hydrogen atom, halogen atom, cyano group, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 alkyl sulfanyl group, C _1-6 alkyl carbonyl group, carbamoyl group or heterocyclic group,
T and U:
If either T or U is = N-, the other is = CR ^2- ,
Both T and U = CR ^2- ,
R ² :
Hydrogen atom, halogen atom, C _1-6 alkyl group or C _1-6 alkoxy group,
R ³ :
−BDEG
(B:
C _6-14 arylene group, C _3-8 cycloalkenylene group, -heterocycle-or-saturated heterocycle-,
D:
Single bond, -O (CH ₂ ) _n -,-(CH ₂ ) _n O- or -saturated heterocycle-,
n:
An integer of any one selected from 1 to 4,
E:
Single bond, -O-, -N (R ¹⁰ )-, -CO- or -CONH-,
R ¹⁰ :
_{A hydrogen atom, a C 1-6} alkyl group which may be substituted with any group selected from the substituent group α,
G:
Hydrogen atom, C _{1-6 alkyl group may be substituted with any group selected from the substituent group α, C 3} which may be substituted with any group selected from the substituent group α _-8 Cycloalkyl group, C _6-14 aryl group which may be substituted with any group selected from the substituent group α, or any group selected from the substituent group α Saturated heterocyclic groups, which may be substituted with a good heterocyclic group or any group selected from the substituent group α,
Substituent group α:
Heterocyclic group, saturated heterocyclic group, halogen atom, cyano group, C _1-6 alkylcarbonyl group, C _1-6 alkylcarbonyloxy group, C _1-6 alkylcarbonylamino group, C _1-6 alkoxycarbonyl group, C _1-6 alkoxy C _1-6 alkyl group, hydroxy C _1-6 alkyl group, hydroxy C _1-6 alkoxy group, C _1-6 alkylsulfonyl group, C _1-6 alkylsulfonylamino group, aminosulfonylamino group, carboxy Group, carboxy C _1-6 alkylcarbonyloxy group, carbamoyl group, hydroxy group, C _1-6 alkoxy group, C _1-6 alkyl group, C _3-8 cycloalkyl group, amino group, amino C _1-6 alkylcarbonyl Oxy group, mono or di-C _1-6 alkylamino group, 4-hydroxy tetrahydrofuran-3-yloxy group, mono or di-C _1-6 alkylphosphono group,

(N is an integer of any one selected from 1 to 4))] (hereinafter, may be referred to as “Compound (I)”) or a pharmaceutically acceptable salt thereof.
[2] Ring A

The compound according to [1] or a pharmaceutically acceptable salt thereof, wherein R ⁴ is an acetyl group, a carbamoyl group or a carboxy group, and R ^{5 is a methyl group.}
[3] Ring A

The compound according to [1] or a pharmaceutically acceptable salt thereof, wherein R ⁷ is a methyl group and R ^{9 is a hydrogen atom.}
[4] Ring A

The compound according to [1] or a pharmaceutically acceptable salt thereof, wherein R ^{7 is a methyl group.}
[5] Ring A

The compound according to [1] or a pharmaceutically acceptable salt thereof.
[6] Ring A

The compound according to [1] or a pharmaceutically acceptable salt thereof.
[7] Ring A

, And the salt R ⁶ is chlorine, a methyl group or a carboxymethyl group, that is acceptable compound or a medicament according to [1].
[8] ^{The compound according to any one of [1] to [7], wherein R 1} is a cyano group, a methoxy group, a methylsulfanyl group, an acetyl group, a carbamoyl group or an imidazolyl group, or a pharmaceutically acceptable compound thereof. Salt.
[9] The compound according to any one of [1] to [8], wherein T is = CH- and U is = N-, or a pharmaceutically acceptable salt thereof.
[10] In any one of [1] to [8], where T is = CH-, U is = CR ^2- , and R ² is a hydrogen atom, a fluorine atom or a methoxy group. The compound described or a pharmaceutically acceptable salt thereof.
[11] B is

The compound according to any one of [1] to [10] or a pharmaceutically acceptable salt thereof.
[12] B is

The compound according to any one of [1] to [10] or a pharmaceutically acceptable salt thereof.
[13] The compound according to any one of [1] to [12], wherein D is a single bond, −O (CH ₂ ) _{n − or − saturated heterocycle −, and n is 2.} Pharmaceutically acceptable salt.
[14] The compound according to any one of [1] to [13] or a pharmaceutically acceptable salt thereof, wherein E is a single bond or —O—.
[15] G is a hydroxy group, an amino group, a carboxy group, an aminosulfonylamino group, a diethylphosphono group or

The compound according to any one of [1] to [14], which is a C _1-6 alkyl group, a phenyl group, a tetrahydropyranyl group, a tethydrofuranyl group, a piperazinyl group or a morpholinyl group substituted with. Or its pharmaceutically acceptable salt.
[16] Any compound selected from the compound group described below or a pharmaceutically acceptable salt thereof.
(1) 3-Acetyl-5,6-dimethoxy-2-methyl-1- [4- (morpholine-4-yl) phenyl] indole

(2) 3-Acetyl-5,6-dimethoxy-2-methyl-1-{4- [3- (2-oxo-2λ ^5- [1,3,2] dioxaphosphinan-2-yl) propoxy ] Phenyl} indole

(3) 3-Acetyl-1-{4- [3- (2-Hydroxyethoxy) azetidine-1-yl] phenyl} -6-methoxy-2-methylindole

(4) 3-Acetyl-1-{4- [4- (3-aminopropyl) piperidine-1-yl] phenyl} -5,6-dimethoxy-2-methylindole

(5) 3-Acetyl-6-methoxy-2-methyl-1- [4- (4- (morpholine-4-yl) butoxy) phenyl] indole hydrochloride

(6) 3-Acetyl-5-Fluoro-6-Methoxy-2-methyl-1- (1-phenylpiperidine-4-yl) indole

(7) 3- {1- [4- (3-Acetyl-5,6-dimethoxy-2-methylindole-1-yl) phenyl] piperidin-4-yl} propionic acid

(8) 1- [4- (4-Acetylpiperazin-1-yl) phenyl] -5,6-dimethoxy-2-methylindole-3-carboxamide

(9) 1- {4- [4- (2-Hydroxyethoxy) piperidine-1-yl] phenyl} -6-methoxy-2-methyl-1H-pyrrolo [3,2-c] pyridine-3-carboxamide

[17] Any compound selected from the compound group described below or a pharmaceutically acceptable salt thereof.
(1) 2- {1- [4- (6-Methoxy-2-methylimidazole [4,5-c] pyridin-1-yl) phenyl] azetidine-3-yloxy} ethanol

(2) Diethyl (1- (4- (5-fluoro-6-methoxy-2-methyl-1H-benzo [d] imidazol-1-yl) phenyl) azetidine-3-yloxy) methylphosphonate

[18] The compounds described below or pharmaceutically acceptable salts thereof.
(1) 4- {4- [3- (2-Hydroxyethoxy) azetidine-1-yl] phenyl} -6-methoxy-1-methyl-1H- [1,7] naphthididine-2-one

[19] The compound described below or a pharmaceutically acceptable salt thereof.
(1) 7-Methoxy-1- [4- (3- (morpholine-4-yl) azetidine-1-yl) phenyl] -1H-quinoline-4-one dihydrochloride

[20] The compound described below or a pharmaceutically acceptable salt thereof.
(1) 2-oxo-4- {4- [2- (tetrahydropyran-4-yloxy) ethoxy] phenyl} -2H-chromen-6-carboxamide

[21] Any compound selected from the compound group described below or a pharmaceutically acceptable salt thereof.
(1) 1- {4- [3- (2-Hydroxyethoxy) azetidine-1-yl] phenyl} -7-methoxy-4-methyl-1,4-dihydro-2H-pyrido [3,4-b] Pyrazine-3-on

(2) 1-{4- [3- (2-Sulfamoylaminoethoxy) azetidine-1-yl] phenyl} -7-methoxy-4-methyl-1,4-dihydro-2H-pyrido [3,4 -b] Pyrazine-3-on

[22] Any compound selected from the compound group described below or a pharmaceutically acceptable salt thereof.
(1) 8- {4- [2- (Tetrahydropyran-4-yloxy) ethoxy] phenyl} naphthalene-2-carboxamide

(2) 3- {4- [2- (Tetrahydropyran-4-yloxy) ethoxy] phenyl} benzo [b] thiophene-5-carboxamide

[23] A pharmaceutical composition containing the compound according to any one of [1] to [22] or a pharmaceutically acceptable salt thereof as an active ingredient.
[24] A CDK8 inhibitor containing the compound according to any one of [1] to [22] or a pharmaceutically acceptable salt thereof as an active ingredient.
[25] A pharmaceutical composition containing the compound according to any one of [1] to [22] or a pharmaceutically acceptable salt thereof, which is used for preventing or treating a disease related to CDK8, as an active ingredient. thing.
[26] A drug containing the compound according to any one of [1] to [22] or a pharmaceutically acceptable salt thereof as an active ingredient, which is used for preventing or treating a disease related to bone metabolism. Composition.
[27] A pharmaceutical composition containing, as an active ingredient, the compound according to any one of [1] to [22] or a pharmaceutically acceptable salt thereof, which is used for preventing or treating cancer.

Compound (I) of the present invention has excellent inhibitory activity against CDK8. Therefore, the drug containing the compound (I) of the present invention as an active ingredient can be used as a CDK8 inhibitor, and also has a CDK8-related disease, a bone metabolism-related disease such as osteoporosis, and cells such as cancer. It is useful as a prophylactic and / or therapeutic agent for proliferative diseases.

Definitions of terms and symbols used herein will be described below.
As used herein, the term "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

As used herein, the term "C _1-6 alkyl group" means a linear or branched monovalent saturated hydrocarbon group having 1 to 6 carbon atoms. Examples of the "C _1-6 alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 4-methylpentyl, hexyl and the like. Be done.

As used herein, "C _3-8 cycloalkyl group" means a monovalent group derived from a saturated hydrocarbon ring having 3 to 8 carbon atoms. Moreover, the said "C _3-8 cycloalkyl group" may be crosslinked. Examples of the "C _3-8 cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

In the present specification, the "C _1-6 alkoxy group" means a group in which the "C _1-6 alkyl group" is bonded to an oxygen atom, that is, a linear or branched alkoxy group having 1 to 6 carbon atoms. do. Examples of the "C _1-6 alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like. Can be mentioned.

As used herein, the "C _1-6 alkylcarbonyl group" means a monovalent group in which the _{"C 1-6 alkyl group" is bonded to a carbonyl.} Examples of the "C _1-6 alkylcarbonyl group" include acetyl, propionyl, butyryl, isobutyryl, pentanoyl, isopentanoyl, 1-methylbutyryl, pivaloyl, hexanoyl, isohexanoyl, 3,3-dimethylbutyryl, 1 -Ethylbutyryl, 4-methylhexanoyl, heptanoyl and the like can be mentioned.

In the present specification, _{"C 1-6} alkoxy _{C 1-6} alkyl group" means the _{"C 1-6} alkyl group" in the monovalent radical _{"C 1-6} alkoxy group" is bonded. Examples of the "C _1-6 alkoxy C _1-6 alkyl group" include methoxymethyl, 2-methoxyethyl, ethoxymethyl, 2-ethoxyethyl, 3-ethoxypropyl, 2-propoxyethyl, and 2-isopropoxyethyl. , 2-Butoxyethyl, 2-Isobutoxyethyl, sec-Butoxymethyl, tert-Butoxymethyl, 2-Pentyloxyethyl, Isopentyloxymethyl, 2-Neopentyloxyethyl, 2-Hexyloxyethyl and the like. ..

As used herein, the "C _1-6 alkyl thiocarbonyl group" means a monovalent group in which the _{"C 1-6 alkyl group" is bonded to thiocarbonyl.} Examples of the "C _1-6 alkylthiocarbonyl group" include methylthiocarbonyl, ethylthiocarbonyl, propylthiocarbonyl, butylthiocarbonyl, isobutylthiocarbonyl, pentylthiocarbonyl, 3,3-dimethylbutylthiocarbonyl and 1-ethyl. Examples thereof include butylthiocarbonyl and hexylthiocarbonyl.

As used herein, the "C _1-6 alkylcarbonyloxy group" means a monovalent group in which the "C _{1-6 alkylcarbonyl group" is bonded to an oxygen atom.} Examples of the "C _1-6 alkylcarbonyloxy group" include acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, isopentanoyloxy, 1-methylbutyryloxy, pivaloyloxy and hexanoyloxy. , Isohexanoyloxy, 3,3-dimethylbutylyloxy, 1-ethylbutyryloxy, 4-methylhexanoyloxy, heptanoyloxy and the like.

As used herein, the "C _1-6 alkylcarbonylamino group" means a monovalent group in which the "C _{1-6 alkylcarbonyl group" is bonded to a nitrogen atom.} Examples of the "C _1-6 alkylcarbonylamino group" include methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino, and tert-butylcarbonyl. Examples thereof include amino, pentylcarbonylamino, isopentylcarbonylamino, neopentylcarbonylamino, 1-ethylpropylcarbonylamino, hexylcarbonylamino and the like.

In the present specification, the "C _1-6 alkylsulfonyl group" is a group in which the "C _1-6 alkyl group" is bonded to a sulfonyl group, that is, a linear or branched alkylsulfonyl group having 1-6 carbon atoms. Means. Examples of the "C _1-6 alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, and the like. Examples thereof include neopentylsulfonyl, 1-ethylpropylsulfonyl, and hexylsulfonyl.

As used herein, the "C _1-6 alkylsulfonylamino group" means a monovalent group in which the _{"C 1-6 alkylsulfonyl group" is bonded to a nitrogen atom.} Examples of the "C _1-6 alkylsulfonylamino group" include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino, and tert-butylsulfonyl. Examples thereof include amino, pentylsulfonylamino, isopentylsulfonylamino, neopentylsulfonylamino, 1-ethylpropylsulfonylamino, hexylsulfonylamino and the like.

In the present specification, the "C _1-6 alkyl sulfanyl group" is a group in which the "C _1-6 alkyl group" is bonded to a sulfur atom, that is, a linear or branched alkyl sulfanyl group having 1-6 carbon atoms. Means. Examples of the "C _1-6 alkyl sulfanyl group" include methyl sulfanyl, ethyl sulfanyl, propyl sulfanyl, isopropyl sulfanyl, butyl sulfanyl, isobutyl sulfanyl, sec-butyl sulfanyl, tert-butyl sulfanyl, pentyl sulfanyl, and isopentyl sulfanyl. Examples thereof include neopentyl sulfanyl, 1-ethylpropyl sulfanyl, hexyl sulfanyl and the like.

As used herein, "C _3-8 cycloalkyl group" means a monovalent group derived from a saturated hydrocarbon ring having 3-8 carbon atoms. Moreover, the said "C _3-8 cycloalkyl group" may be crosslinked. Examples of the "C _3-8 cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [1,1,1] pentyl and the like.

In the present specification, the "amino C _1-6 alkylcarbonyloxy group" means a group in which an amino group is bonded to the _{"C 1-6 alkylcarbonyloxy group".} Examples of the "amino C _1-6 alkylcarbonyloxy" include aminoacetyloxy, aminopropionyloxy, aminobutyryloxy, aminoisobutyryloxy, aminopentanoyloxy, aminoisopentanoyloxy, and amino-1-. Methylbutyryloxy, Aminopivaloyloxy, Aminohexanoyloxy, Aminoisohexanoyloxy, Amino-3,3-Dimethylbutyryloxy, Amino-1-ethylbutyryloxy, Amino-4-methylhexanoyloxy , Aminoheptanoyloxy and the like.

In the present specification, the "mono or di-C _1-6 alkylamino group" is a _{group in which one or two of the "C 1-6} alkyl groups" are bonded to a nitrogen atom, that is, the number of carbon atoms is 1-6. Means a linear or branched alkylamino group of. Examples of the "mono or di-C _1-6 alkylamino group" include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino and pentylamino. Examples thereof include isopentylamino, neopentylamino, 1-ethylpropylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino and methylethylamino.

In the present specification, the "C _1-6 alkoxycarbonyl group" is a group in which the "C _1-6 alkoxy group" is bonded to carbonyl, that is, a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms. means. Examples of the "C _1-6 alkoxycarbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and iso. Examples thereof include pentyloxycarbonyl, neopentyloxycarbonyl, 1-ethylpropyloxycarbonyl, hexyloxycarbonyl and the like.

As used herein, a "C _{3-8 cycloalkenylene group" is a C 3-8} cycloalkenyl derived from a hydrocarbon ring having one or more carbon-carbon double bonds and 3-8 carbon atoms. It means a divalent group derived from a group. Examples of the C _3-8 cycloalkenyl group include 3-cyclobutenyl, 3-cyclopentenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclooctenyl, 3-cyclooctenyl and the like. Be done.

As used herein, the "C _6-14 aryl group" means an aromatic hydrocarbon group having 6-14 carbon atoms. Examples of the "C _6-14 aryl group" include phenyl, naphthyl (eg, 1-naphthyl, 2-naphthyl), acenaphthylenyl, azulenyl, anthryl, phenanthryl and the like.

As used herein, "C _6-14 arylene group" means a divalent group derived from _{a C 6-14} aryl group derived from an aromatic hydrocarbon group having 6-14 carbon atoms. Examples of the "C _6-14 aryl group" include phenyl, naphthyl (eg, 1-naphthyl, 2-naphthyl), acenaphthylenyl, azulenyl, anthryl, phenanthryl and the like.

In the present specification, the "hydroxy C _1-6 alkyl group" is a _{group in which one hydroxy group is bonded to the "C 1-6} alkyl group", and is, for example, a 1-hydroxymethyl group or a 1-hydroxyethyl group. Groups, 1-hydroxypropyl groups, 2-hydroxyethyl groups, 3-hydroxypropyl groups and the like can be mentioned.

In the present specification, the "hydroxy C _1-6 alkoxy group" is a _{group in which one hydroxy group is bonded to the "C 1-6} alkoxy group", and is, for example, a 1-hydroxymethoxy group or a 1-hydroxyethoxy group. Groups, 1-hydroxypropoxy groups, 2-hydroxyethoxy groups, 3-hydroxypropoxy groups and the like can be mentioned.

In the present specification, the "carboxy C _1-6 alkyl group" means a group in which a carboxy group is bonded to the _{"C 1-6 alkyl group".} Examples of the "carboxyC _1-6 alkyl group" include carboxymethyl, carboxyethyl, carboxypropyl, carboxyisopropyl, carboxybutyl, carboxyisobutyl, carboxy-sec-butyl, carboxy-tert-butyl, carboxypentyl, and carboxyiso. Examples thereof include pentyl, carboxyneopentyl, carboxy-1-ethylpropyl, carboxyhexyl and the like.

In the present specification, the "carboxy C _1-6 alkylcarbonyloxy group" means a group in which a carboxy group is bonded to the _{"C 1-6 alkylcarbonyloxy group".} Examples of the "carboxy C _1-6 alkylcarbonyloxy" include carboxyacetyloxy, carboxypropionyloxy, carboxybutylyloxy, carboxyisobutyryloxy, carboxypentanoyloxy, carboxyisopentanoyloxy, and carboxy-1- Methylbutyryloxy, carboxypivaloyloxy, carboxyhexanoyloxy, carboxyisohexanoyloxy, carboxy-3,3-dimethylbutylyloxy, carboxy-1-ethylbutyryloxy, carboxy-4-methylhexanoyloxy , Carboxyheptanoyloxy and the like.

As used herein, the "heterocyclic group" is a monovalent monocyclic aromatic heterocyclic group containing at least one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, and a condensed aromatic. It means a heterocyclic group. Examples of the monocyclic aromatic heterocyclic group include a 5- or 6-membered monocyclic aromatic heterocyclic group, for example, frill, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, Examples thereof include thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and the like. Examples of the fused aromatic heterocyclic group include bicyclic or tricyclic condensed aromatic heterocyclic groups, for example, indolyl, isoindrill, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, and the like. Quinoline, isoquinolyl, benzoxazinyl, benzothiazinyl, flo [2,3-b] pyridyl, thieno [2,3-b] pyridyl, naphthilidinyl, imidazolepyridyl, oxazolopyridyl, thiazolopyridyl, quinolyl, carbazolyl, dibenzo Examples include thiophenyl.

As used herein, a "saturated heterocyclic group" is a saturated 5-7-membered heterocyclic group containing 1-3 sulfur, oxygen or / / nitrogen atoms, eg, tetrahydropyranyl, tetrahydrofuranyl, oxo. Tetrahydrofuranyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazoridinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, 1, Examples thereof include 4-dioxanyl and 1,1-dioxohexahydrothiopyranyl.

In the present specification, "-heterocyclic group-" indicates a divalent group derived from the heterocycle, and examples of the monocyclic aromatic heterocycle of the heterocycle include furan, thiophene, pyrrole, imidazole, and pyrazole. , Oxazole, isoxazole, thiazole, triazole, tetrazole, thiaziazole, oxaziazole, pyridine, pyridazine, pyrimidine and the like. Examples of the fused aromatic heterocycle include indolin, isoindolin, indazoline, benzofuran, benzothiophene, benzimidazole, benzoxazole, benzothiazole, quinoline, isoquinoline, benzoxazine, benzothiazine, flo [2,3-b] pyridine, and the like. Examples thereof include thieno [2,3-b] pyridine, naphthylidine, imidazopyridine, oxazolopyridine, thiazolopyridine, quinoline, carbazole, dibenzothiophene and the like.

In the present specification, "-saturated heterocyclic group-" indicates a divalent group derived from the saturated heterocycle, and examples of the saturated heterocycle include azetidine, tetrahydropyrrane, tetrahydrofuran, morpholine, thiomorpholine, 1-. Examples thereof include oxothiomorpholine, 1,1-dioxothiomorpholine, pyrrolidine, pyrrolidine, imidazolidine, pyrazolidine, piperazine, piperazine, oxazolidine, isoxazolidine, thiazolidine and the like.

"May be substituted" is either non-replacement or substitution of 1-3. In the case of 2 or 3 substitutions, each substituent may be the same or different.

As used herein, the term "the pharmaceutically acceptable salt" refers to a salt that can be used as a medicine. In the compound of the present invention, when it has an acidic group or a basic group, it can be made into a basic salt or an acidic salt by reacting with a base or an acid, and thus the salt thereof is shown.
The pharmaceutically acceptable "basic salt" of the compound (I) of the present invention is preferably an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt; an alkaline soil such as a magnesium salt or a calcium salt. Metal salts; organic base salts such as N-methylmorpholin salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidin salt, pyridine salt, 4-pyrrolidinopyridine salt, picolin salt or It is an amino acid salt such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, asparaginate salt, and is preferably an alkali metal salt.

The pharmaceutically acceptable "acidic salt" of the compound (I) of the present invention is preferably hydrogen halide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide. Inorganic acid salts such as acid salts, nitrates, perchlorates, sulfates, phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate , Allyl sulfonates such as p-toluene sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc. Organic acid salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamates, asparaginates, most preferably hydrohalogenates (particularly hydrochlorides). ..

As used herein, the term "prevention" means, for example, a patient who does not develop the disease or symptom that is expected to be at high risk of developing the disease or symptoms due to some factor related to the disease or symptom, or who is aware that the disease or symptom has developed. The compound of the present invention ( I) is to administer a drug containing.
"Treatment" is the cure of an illness or symptom.

The definition of each symbol in the formula (I) will be described in detail below.
R ¹ contains a hydrogen atom, a halogen atom, a cyano group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkyl sulfanyl group, a C _1-6 alkyl carbonyl group, a carbamoyl group or a heterocyclic group. show.
R ¹ is preferably a halogen atom (eg, chlorine atom), a cyano group, a C _1-6 alkoxy group (eg, methoxy), a C _1-6 alkyl sulfanyl group (eg, methyl sulfanyl), a C _1-6 alkyl. It is a carbonyl group (eg, acetyl), a carbamoyl group or a heterocyclic group (eg, imidazolyl, furyl, pyridyl), more preferably a cyano group, a methoxy group, a methylsulfanyl group, an acetyl group, a carbamoyl group or an imidazolyl group. ..

When one of T and U is = N−, the other indicates = CR ² −, or both T and U ^{indicate = CR 2} −.
For T and U, T is preferably = CR ^2- and U is = N-, or both T and U are = CR ^2- , and more preferably T is = CH. -, U is = N-, or T is = CH-, U is = CR ^2- , and R ² is a hydrogen atom, a fluorine atom or a methoxy group.

R ² represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group.
R ² is preferably a hydrogen atom, a halogen atom (eg, fluorine atom), a C _1-6 alkyl group (eg, methyl) or a C _1-6 alkoxy group (eg, methoxy), and more preferably hydrogen. It is an atom, a hydrogen atom or a methoxy group.
Ring A is

Is shown.
R ³ represents -BD-EG [in the formula, B represents a C _6-14 arylene group, a C _3-8 cycloalkenylene group, a-heterocycle-or a-saturated heterocycle-, and D is. Indicates a single bond, -O (CH ₂ ) _n -,-(CH ₂ ) _n O- or -saturated heterocycle-, where n represents an integer of any one selected from 1-4, where E is. It exhibits a single bond, -O-, -N (R ¹⁰ )-, -CO- or -CONH-, even if R ¹⁰ is substituted with a hydrogen atom or any group selected from the substituent group α. It represents a good C _{1-6 alkyl group, where G is selected from the C 1-6} alkyl group, substituent group α, which may be substituted with any group selected from the hydrogen atom, substituent group α. C _{3-8 cycloalkyl group optionally substituted with any group, C 6-14} aryl group optionally substituted with any group selected from substituent group α, from substituent group α A heterocyclic group which may be substituted with any of the selected groups or a saturated heterocyclic group which may be substituted with any of the groups selected from the substituent group α, wherein the substituent group α is Heterocyclic group, saturated heterocyclic group, halogen atom, cyano group, C _1-6 alkylcarbonyl group, C _1-6 alkylcarbonyloxy group, C _1-6 alkylcarbonylamino group, C _1-6 alkoxycarbonyl group, C _1-6 alkoxy C _1-6 alkyl group, hydroxy C _1-6 alkyl group, hydroxy C _1-6 alkoxy group, C _1-6 alkylsulfonyl group, C _1-6 alkylsulfonylamino group, aminosulfonylamino group, carboxy Group, carboxy C _1-6 alkylcarbonyloxy group, carbamoyl group, hydroxy group, C _1-6 alkoxy group, C _1-6 alkyl group, C _3-8 cycloalkyl group, amino group, amino C _1-6 alkylcarbonyl Oxy group, mono or di-C _1-6 alkylamino group, 4-hydroxy tetrahydrofuran-3-yloxy group, mono or di-C _1-6 alkylphosphono group,

(N represents an integer of any one selected from 1 to 4). ] Is shown.
B is preferably a C _6-14 arylene group (eg, phenylene), a C _3-8 cycloalkenylene group (eg, cyclohexenylene), a-heterocycle- (eg, pyridinediyl) or a-saturated heterocycle- (eg, pyridinediyl). For example, piperidine diyl), more preferably

And even more preferably

Is.
D is preferably a single bond, −O (CH ₂ ) _n − (n is 1, 2, 3 or 4), − (CH ₂ ) _n O − (n is 1). Or a -saturated heterocycle- (eg, azetidinediyl, pyrrolidinediyl, piperidinediyl, piperazindiyl, tetrahydropyridinediyl), more preferably a single bond, -O (CH _{2 ) n-} (n is 2). ) Or-Saturated heterocycle- (eg, azetidinediyl, pyrrolidinediyl, piperidinediyl, piperazindiyl, tetrahydropyridinediyl).
E is preferably a single bond, −O−, −N (R ¹⁰ ) − (where R ¹⁰ _{is a C 1-6} alkyl group optionally substituted with a hydrogen atom or a hydroxy group (eg, methyl, ethyl). ), -CO- or -CONH-, more preferably a single bond or -O-.

G is preferably (1) a heterocyclic group (eg, oxazolyl, imidazolyl, tetrazolyl), a saturated heterocyclic group (eg, tetrahydrofuryl, piperazinyl, morpholinyl, tetrahydropyranyl, 1,4-dioxanyl), a halogen atom (eg, tetrahydrofuryl, piperazinyl, morpholinyl), halogen atom (eg, tetrahydrofuryl, piperazinyl, morpholinyl), halogen atom (eg, tetrahydrofuryl, piperazinyl, morpholinyl). For example, fluorine atom), C _1-6 alkylcarbonyloxy group (eg, methylcarbonyloxy), C _1-6 alkylcarbonylamino group (eg, methylcarbonylamino), C _1-6 alkoxycarbonyl group (eg, ethoxycarbonyl) ), Hydroxy C _1-6 alkoxy group (eg, hydroxyethoxy), aminosulfonylamino group, carboxy group, carboxy C _1-6 alkylcarbonyloxy group (eg, carboxyethylcarbonyloxy), carbamoyl group, hydroxy group, C _{1 -6} alkoxy groups (eg, methoxy, ethoxy, isopropoxy, tert-butoxy), C _3-8 cycloalkyl groups (eg, cyclopropyl), amino groups, amino C _1-6 alkylcarbonyloxy groups (eg, aminomethyl) Carbonyloxy), mono or di-C _1-6 alkylamino groups (eg, dimethylamino), 4-hydroxy tetrahydrofuran-3-yloxy groups, mono or di-C _1-6 alkylphosphono groups (eg, diethylphosphono). ),and

_{(N indicates 3) C 1-6} alkyl groups optionally substituted with any group selected from (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isopentyl). ), (2) C _3-8 cycloalkyl groups optionally substituted with hydroxy groups (eg, cyclopropyl, cyclopentyl), (3) C _6-14 aryls optionally substituted with carboxy groups (eg, eg. (Phenyl), (4) C _1-6 alkoxy C _1-6 alkyl group (eg, methoxymethyl) and hydroxy C _1-6 alkyl group (eg, hydroxymethyl) substituted with any group selected from May be heterocyclic groups (eg, imidazolyl, oxazolyl, pyridyl) or (5) saturated heterocyclic groups (eg, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl), halogen atoms (eg, fluorine atoms), cyano groups, C. _1-6 alkylcarbonyl group (eg, methylcarbonyl), C _1-6 alkylcarbonylamino group (eg, methylcarbonylamino), hydroxy C _1-6 alkyl group (eg, hydroxymethyl), C _1-6 alkylsulfonyl group (Eg, methylsulfonyl), C _1-6 alkylsulfonylamino group (eg, methylsulfonylamino), carboxy group, carbamoyl group, hydroxy group, C _1-6 alkoxy group (eg, methoxy, ethoxy), C _1-6 A saturated heterocyclic group optionally substituted with an alkyl group (eg, methyl), an amino group, and _{any group selected from a mono or di-C 1-6} alkylamino group (eg, dimethylamino, diethylamino). (For example, azetidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, dihydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, oxopyrrolidinyl, oxopiperidinyl, oxothiomorpholinyl, dioxothiomorpholinyl, 1, 4-Dioxanyl, sulfolanyl), more preferably (1) hydroxy group, amino group, carboxy group, aminosulfonylamino group, diethylphosphono group or

_{C 1-6} alkyl groups substituted with (eg, methyl, ethyl, propyl, butyl, isobutyl, isopentyl), (2) phenyl group, (3) tetrahydropyranyl group, (4) tethydrofuranyl group, ( 5) piperazinyl group or (6) morpholinyl group.

R ⁴ represents a C _1-6 alkylcarbonyl group, a C _1-6 alkylthiocarbonyl group, a carbamoyl group, a C _1-6 alkoxycarbonyl group or a carboxy group.
R ⁴ is _{preferably, C 1-6} alkylcarbonyl group (e.g., _{acetyl), C 1-6} alkyl thio group (e.g., methylthiocarbonyl), a carbamoyl _{group, C 1-6} alkoxycarbonyl group (e.g., methoxycarbonyl, It is an ethoxycarbonyl) or a carboxy group.

R ⁵ represents a hydrogen atom, a C _1-6 alkyl group or a halogen atom.
R ⁵ is preferably a hydrogen atom, a C _1-6 alkyl group (eg, methyl) or a halogen atom (eg, chlorine atom).

R ⁶ is a C _1-6 alkyl group, a halogen atom, an amino group, a hydroxy C _1-6 alkyl group, a carboxy C _1-6 alkyl group or a hydrogen atom (where T is = CH− and U is = N−. If) is shown.
R ⁶ is preferably a C _1-6 alkyl group (eg, methyl), a halogen atom (eg, a chlorine atom), an amino group, a hydroxy C _1-6 alkyl group (eg, hydroxyethyl), a carboxy C _1-6. It is an alkyl group (eg, carboxymethyl) or a hydrogen atom (where T is = CH− and U is = N−).

R ⁷ represents a hydrogen atom or a C _1-6 alkyl group.
R ⁷ is preferably a hydrogen atom or a C _1-6 alkyl group (eg, methyl, ethyl).

R ⁸ represents a hydrogen atom, a C _1-6 alkyl group or a C _1-6 alkyl carbonyl group.
R ⁸ is preferably a hydrogen atom or a C _1-6 alkylcarbonyl group (eg, methylcarbonyl, ethylcarbonyl).

R ⁹ represents a hydrogen atom or a C _1-6 alkyl group.
R ⁹ is preferably a hydrogen atom or a C _1-6 alkyl group (eg, methyl).

In a preferred embodiment of the invention
(1) Ring A is

R ⁴ is an acetyl group, a carbamoyl group or a carboxy group, and R ⁵ is a methyl group;
(2) Ring A is

R ⁷ is a methyl group and R ⁹ is a hydrogen atom;
(3) Ring A is

In and, ^{R 7} is a methyl group;
(4) Ring A is

Is;
(5) Ring A is

Or (6) Ring A is

And a, R ⁶ is chlorine, methyl or carboxymethyl groups.

Preferable examples of compound (I) include the following compounds.
[Compound I-1]
R ¹ is a halogen atom (eg, chlorine atom), cyano group, C _1-6 alkoxy group (eg, methoxy, isopropoxy), C _1-6 alkyl sulfanyl group (eg, methyl sulfanyl), C _1-6 alkyl. A carbonyl group (eg, acetyl), a carbamoyl group or a heterocyclic group (eg, imidazolyl, frill, pyridyl);
T and U have T = CR ² − and U = N −, or both T and U have = CR ² −;
R ² is a hydrogen atom, a halogen atom (e.g., fluorine _atom), be _{C 1-6} alkyl group (e.g., methyl) or _{C 1-6} alkoxy group (e.g., methoxy);
Ring A is

Is;
R ³ is -BD-EG;
B is a C _6-14 arylene group (eg, phenylene), a C _3-8 cycloalkenylene group (eg, cyclohexenylene), a-heterocycle- (eg, pyridinediyl) or a-saturated heterocycle- (eg, pi). Perizinzyl);
D is single bond, -O (CH ₂ ) _n- (n is 1, 2, 3 or 4),-(CH ₂ ) _n O- (n is 1) or -saturated Heterocycle- (eg, azetidinediyl, pyrrolidinediyl, piperidinediyl, piperazindiyl, tetrahydropyridinediyl);
E is a single bond, -O-, -N (R ¹⁰ )-(R ¹⁰ _{is a C 1-6} alkyl group (eg, methyl, ethyl) that may be substituted with a hydrogen atom or a hydroxy group. ), -CO- or -CONH-;
G is (1) heterocyclic group (eg, oxazolyl, imidazolyl, tetrazolyl), saturated heterocyclic group (eg, tetrahydrofuryl, piperazinyl, morpholinyl, tetrahydropyranyl, 1,4-dioxanyl), halogen atom (eg, fluorine). Atomic), C _1-6 alkylcarbonyloxy group (eg, methylcarbonyloxy), C _1-6 alkylcarbonylamino group (eg, methylcarbonylamino), C _1-6 alkoxycarbonyl group (eg, ethoxycarbonyl), hydroxy C _1-6 alkoxy group (eg, hydroxyethoxy), aminosulfonylamino group, carboxy group, carboxy C _1-6 alkylcarbonyloxy group (eg, carboxyethylcarbonyloxy), carbamoyl group, hydroxy group, C _1-6 alkoxy Groups (eg, methoxy, ethoxy, isopropoxy, tert-butoxy), C _3-8 cycloalkyl groups (eg, cyclopropyl), amino groups, amino C _1-6 alkylcarbonyloxy groups (eg, aminomethylcarbonyloxy) , Mono or di-C _1-6 alkylamino groups (eg, dimethylamino), 4-hydroxy tetrahydrofuran-3-yloxy groups, mono or di-C _1-6 alkylphosphono groups (eg, diethylphosphono), and

_{A C 1-6} alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isopentyl) which may be substituted with any group selected from (n indicates 3). ), (2) C _3-8 cycloalkyl groups optionally substituted with hydroxy groups (eg, cyclopropyl, cyclopentyl), (3) C _6-14 aryls optionally substituted with carboxy groups (eg, eg. Substituted with any group selected from (phenyl), (4) C _1-6 alkoxy C _1-6 alkyl groups (eg, methoxymethyl) and hydroxy C _1-6 alkyl groups (eg, hydroxymethyl). May be heterocyclic groups (eg, imidazolyl, oxazolyl, pyridyl) or (5) saturated heterocyclic groups (eg, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl), halogen atoms (eg, fluorine atoms), cyano groups, C. _1-6 alkylcarbonyl group (eg, methylcarbonyl), C _1-6 alkylcarbonylamino group (eg, methylcarbonylamino), hydroxy C _1-6 alkyl group (eg, hydroxymethyl), C _1-6 alkylsulfonyl group (Eg, methylsulfonyl), C _1-6 alkylsulfonylamino group (eg, methylsulfonylamino), carboxy group, carbamoyl group, hydroxy group, C _1-6 alkoxy group (eg, methoxy, ethoxy), C _1-6 Saturated heterocyclic groups optionally substituted with any group selected from alkyl groups (eg, methyl), amino groups, and mono or di-C _{1-6 alkylamino groups (eg, dimethylamino, diethylamino).} (For example, azetidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, dihydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, oxopyrrolidinyl, oxopiperidinyl, oxothiomorpholinyl, dioxothiomorpholinyl, 1, 4-Dioxanyl, sulfolanyl);
R ⁴ is a C _1-6 alkylcarbonyl group (eg, acetyl), C _1-6 alkylthiocarbonyl group (eg, methylthiocarbonyl), carbamoyl group, C _1-6 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl). Or a carboxy group;
R ⁵ is a hydrogen atom, C _1-6 alkyl group (eg, methyl) or halogen atom (eg, chlorine atom);
R ⁶ is a C _1-6 alkyl group (eg, methyl), a halogen atom (eg, chlorine atom), an amino group, a hydroxy C _1-6 alkyl group (eg, hydroxyethyl) or a carboxy C _1-6 alkyl group (eg, hydroxyethyl). For example, carboxymethyl);
R ⁷ is a hydrogen atom or C _1-6 alkyl group (eg, methyl, ethyl);
R ⁸ is a hydrogen atom or a C _1-6 alkylcarbonyl group (eg, methylcarbonyl, ethylcarbonyl);
R ⁹ is a hydrogen atom or a C _1-6 alkyl group (eg, methyl);
Compound (I).

[Compound I-2]
R ¹ is a C _1-6 alkoxy group (eg, methoxy) or a carbamoyl group;
T and U have T = CR ² − and U = N −, or both T and U have = CR ² −;
R ² is hydrogen atom, a halogen atom (e.g., fluorine atom) or a _{C 1-6} alkoxy group (e.g., methoxy);
Ring A is

Is;
R ³ is -BD-EG;
B is a C _6-14 arylene group (eg, phenylene) or-saturated heterocycle- (eg, piperidinediyl);
D is a single bond, -O (CH ₂ ) _n- (n is 1, 2, 3 or 4) or -saturated heterocycle- (eg, azetidinediyl, piperidinediyl);
E is a single bond or -O-;
G is (1) a saturated heterocyclic group (eg, morpholinyl), an aminosulfonylamino group, a carboxy group, a hydroxy group, an amino group, a mono or di-C _1-6 alkylphosphono group (eg, diethylphosphono), and

_{(N indicates 3) C 1-6} alkyl groups (eg, methyl, ethyl, propyl, butyl), which may be substituted with any group selected from _{(2) C 6-14} aryl. It is a saturated heterocyclic group (eg, piperazinyl, tetrahydropyranyl, morpholinyl) which may be substituted with (eg, phenyl) or (3) C _{1-6 alkylcarbonyl group (eg, methylcarbonyl);}
R ⁴ is _located at _{C 1-6} alkylcarbonyl group (e.g., acetyl) or a carbamoyl group;
R ⁵ is a hydrogen atom or a C _1-6 alkyl group (eg, methyl);
R ⁶ is a C _1-6 alkyl group (eg, methyl);
R ⁷ is a C _1-6 alkyl group (eg, methyl);
R ⁹ is a hydrogen atom;
Compound (I).

[Compound I-3]
R ¹ is a C _1-6 alkoxy group (eg, methoxy), a carbamoyl group or a heterocyclic group (eg, imidazolyl);
T and U have T = CR ² − and U = N −, or both T and U have = CR ² −;
R ² is hydrogen atom, a halogen atom (e.g., fluorine atom) or a _{C 1-6} alkoxy group (e.g., methoxy);
Ring A is

Is;
R ³ is -BD-EG;
B is a C _6-14 arylene group (eg, phenylene) or-saturated heterocycle- (eg, piperidinediyl);
D is single bond, -O (CH ₂ ) _n- (n is 1, 2, 3 or 4),-(CH ₂ ) _n O- (n is 1) or -saturated Heterocycle- (eg, azetidinediyl, pyrrolidinediyl, piperidinediyl, piperazindiyl);
E is a single bond, -O- or -CO-;
G is (1) a saturated heterocyclic group (eg, morpholinyl), an aminosulfonylamino group, a carboxy group, a hydroxy group, an amino group, a mono or di-C _1-6 alkylphosphono group (eg, diethylphosphono), and

_{(N indicates 3) C 1-6} alkyl groups (eg, methyl, ethyl, propyl, butyl), which may be substituted with any group selected from _{(2) C 6-14} aryl. Substituted with any group selected from (eg, phenyl) or (3) C _1-6 alkylcarbonyl group (eg, methylcarbonyl), carboxy group, C _1-6 alkyl group (eg, methyl) and amino group. Saturated heterocyclic groups that may be (eg, piperazinyl, piperidinyl, tetrahydropyranyl, morpholinyl);
R ⁴ _{is, C 1-6} alkylcarbonyl group (e.g., _{acetyl), C 1-6} alkyl thio group (e.g., methylthiocarbonyl) be or carbamoyl group;
R ⁵ is a hydrogen atom or a C _1-6 alkyl group (eg, methyl);
R ⁶ is a hydrogen atom or a C _1-6 alkyl group (eg, methyl);
R ⁷ is a C _1-6 alkyl group (eg, methyl);
R ⁹ is a hydrogen atom;
Compound (I).

Preferred specific examples of the compound (I) include, for example, the compounds of Examples 1 to 21 and Examples 22 to 375 shown in Table 1-1 to 1-71 below (hereinafter, also referred to as compounds 1 to 375). Among them,
(1) 3-Acetyl-5,6-dimethoxy-2-methyl-1- [4- (morpholine-4-yl) phenyl] indole

(Compound 1),
(2) 3-Acetyl-5,6-dimethoxy-2-methyl-1-{4- [3- (2-oxo-2λ ^5- [1,3,2] dioxaphosphinan-2-yl) propoxy ] Phenyl} indole

(Compound 38),
(3) 3-Acetyl-1-{4- [3- (2-Hydroxyethoxy) azetidine-1-yl] phenyl} -6-methoxy-2-methylindole

(Compound 63),
(4) 2- {1- [4- (6-Methoxy-2-methylimidazole [4,5-c] pyridin-1-yl) phenyl] azetidine-3-yloxy} ethanol

(Compound 19),
(5) 4- {4- [3- (2-Hydroxyethoxy) azetidine-1-yl] phenyl} -6-methoxy-1-methyl-1H- [1,7] naphthididine-2-one

(Compound 10),
(6) 7-Methoxy-1- [4- (3- (morpholine-4-yl) azetidine-1-yl) phenyl] -1H-quinoline-4-one dihydrochloride

(Compound 20),
(7) 2-oxo-4- {4- [2- (tetrahydropyran-4-yloxy) ethoxy] phenyl} -2H-chromen-6-carboxamide

(Compound 163),
(8) 1-{4- [3- (2-Hydroxyethoxy) azetidine-1-yl] phenyl} -7-methoxy-4-methyl-1,4-dihydro-2H-pyrazine [3,4-b] Pyrazine-3-on

(Compound 120),
(9) 1-{4- [3- (2-Sulfamoylaminoethoxy) azetidine-1-yl] phenyl} -7-methoxy-4-methyl-1,4-dihydro-2H-pyrido [3,4 -b] Pyrazine-3-on

(Compound 149),
(10) 8- {4- [2- (Tetrahydropyran-4-yloxy) ethoxy] phenyl} naphthalene-2-carboxamide

(Compound 21),
(11) 3-Acetyl-1-{4- [4- (3-aminopropyl) piperidine-1-yl] phenyl} -5,6-dimethoxy-2-methylindole

(Compound 31),
(12) 3-Acetyl-6-Methoxy-2-methyl-1- [4- (4- (morpholine-4-yl) butoxy) phenyl] indole hydrochloride

(Compound 6),
(13) 3-Acetyl-5-Fluoro-6-Methoxy-2-methyl-1- (1-phenylpiperidine-4-yl) indole

(Compound 78),
(14) 3- {1- [4- (3-Acetyl-5,6-dimethoxy-2-methylindole-1-yl) phenyl] piperidin-4-yl} propionic acid

(Compound 28),
(15) 1- [4- (4-Acetylpiperazin-1-yl) phenyl] -5,6-dimethoxy-2-methylindole-3-carboxamide

(Compound 48),
(16) 1- {4- [4- (2-Hydroxyethoxy) piperidine-1-yl] phenyl} -6-methoxy-2-methyl-1H-pyrrolo [3,2-c] pyridine-3-carboxamide

(Compound 8),
(17) Diethyl (1- (4- (5-fluoro-6-methoxy-2-methyl-1H-benzo [d] imidazol-1-yl) phenyl) azetidine-3-yloxy) methylphosphonate

(Compound 112), and (18) 3- {4- [2- (tetrahydropyran-4-yloxy) ethoxy] phenyl} benzo [b] thiophene-5-carboxamide

(Compound 14) is preferred.

(Method for producing compound (I) of the present invention)
The compound (I) of the present invention can be produced by applying various known production methods by utilizing its characteristics based on the basic skeleton or the type of substituent. Known methods include, for example, the methods described in "ORGANIC FUNCTIONAL GROUP PREPARATIONS", 2nd Edition, ACADEMIC PRESS, INC., 1989, "Comprehensive Organic Transformations", VCH Publishers Inc., 1989 and the like.
At that time, depending on the type of the functional group, it is effective in terms of manufacturing technology to protect the functional group with an appropriate protecting group at the stage of the raw material or the intermediate, or to replace it with a group that can be easily converted to the functional group. In some cases.
Such functional groups include, for example, amino groups, hydroxyl groups, carboxyl groups and the like, and their protecting groups include, for example, TW Greene and PG Wuts, "Protective Groups in Organic Synthesis (3rd Edition, 1999)". ”, And may be appropriately selected and used according to these reaction conditions. According to such a method, a desired compound can be obtained by introducing the substituent, carrying out the reaction, and then removing the protecting group or converting to a desired group, if necessary.
Further, the prodrug of the compound of the present invention is produced by introducing a specific group at the stage of a raw material or an intermediate, or by carrying out a reaction using the obtained compound of the present invention, similarly to the above-mentioned protecting group. can. The reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration, hydrogenation and the like.
The method for producing the compound of the present invention will be described below. However, the manufacturing method is not limited to the following methods.
If the specific production method is not described, the raw material compound in each reaction can be easily obtained and used on the market, or can be produced according to a method known per se or a method similar thereto. ..

(Manufacturing method A)
In the production method A, the A ring of the compound (I) of the present invention is formed by coupling the compound (a-1) and the compound (a-2).

This is a method for producing an intermediate compound (a-3) of the compound.
The compound (a-1) used in this production method can be produced by a method known per se.

In the above scheme, R ¹ , R ³ , R ⁵ , T and U have the same meaning as above, and X indicates a leaving group such as a halogen atom or a trifluoromethanesulfonyloxy group.

StepA is a base such as an inorganic carbonate or phosphate (eg, potassium carbonate, cesium carbonate, tripotassium phosphate), a copper compound (eg, CuBr, CuI) and a ligand (eg, N, N'-dimethylethylenediamine, This is a nucleophilic substitution reaction using 1,2-diaminocyclohexane, trans-N, N'-dimethylcyclohexane-1,2-diamine, etc.), in which compound (a-1) and compound (a-) are used in an inert solvent. This is a step of producing an intermediate compound (a-3) of the compound (I) of the present invention from 2).

The amount of compound (a-2) used in Step A is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound (a-1). The amount of the inorganic carbonate or phosphate used is usually 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (a-1). The amount of the copper compound used is generally 0.01 to 0.3 equivalents, preferably 0.05 to 0.1 equivalents, relative to compound (a-1). The amount of the ligand used is generally 0.01 to 0.3 equivalents, preferably 0.01 to 0.15 equivalents, relative to compound (a-1).

The inert solvent used is, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; aromatic hydrocarbons such as benzene, toluene, or xylene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane. Or ethers such as 1,2-dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide. Or with halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene or trifluoromethylbenzene, or mixtures thereof. be.

The reaction temperature varies depending on the starting compound or the solvent used, but is usually from 0 ° C. to the reflux temperature of the reaction mixture, preferably from room temperature to the reflux temperature of the reaction mixture.
The reaction time varies depending on the starting compound, the solvent used or the reaction temperature, but is usually 30 minutes to 72 hours, preferably 30 minutes to 24 hours.

(Manufacturing method B)
In the production method B, the A ring of the compound (I) of the present invention is used.

R ⁴ is a method for producing a compound (b-2) which is a C _1-6 lower alkylcarbonyl group, and compound (b-1) is added to the intermediate compound (a-3) obtained in the production method A. Is a method for producing the compound of the present invention (b-2).

In the above scheme, R ¹ , R ³ , R ⁵ , T and U have the same meaning as above, and R ¹¹ indicates C _1-6 lower alkyl.

Step B is a step of producing the compound (b-2) of the present invention from the compound (a-3) and the compound (b-1) in the presence of titanium (IV) chloride in an inert solvent.
Examples of the inert solvent used include those mentioned above.

The amount of compound (b-1) used in Step B is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound (a-3). The amount of titanium (IV) chloride used is usually 1 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to compound (a-3).

The reaction temperature varies depending on the raw material compound or the solvent used, but is usually 0 ° C. to 50 ° C., preferably 0 ° C. to room temperature.
The reaction time varies depending on the starting compound, the solvent used or the reaction temperature, but is usually 30 minutes to 24 hours, preferably 30 minutes to 2 hours.

(Manufacturing method C)
In the production method C, the A ring of the compound (I) of the present invention is used.

R ⁴ is a method for producing a compound (c-2) which is a carbamoyl group, and is a compound (c) obtained by reacting the intermediate compound (a-3) obtained in the production method A with chlorosulfonyl isocyanate. This is a method for obtaining the compound of the present invention (c-2) from -1).

In the above scheme, R ¹ , R ³ , R ⁵ , T and U have the same meaning as above.

Step C1 is a step of reacting compound (a-3) with chlorosulfonyl isocyanate in an inert solvent to produce intermediate compound (c-1).
Step C2 is a step of producing the compound (c-2) of the present invention by removing the chlorosulfonyl group of the intermediate compound (c-1) with acetic acid or the like.
Examples of the inert solvent used include those mentioned above.

The amount of chlorosulfonyl isocyanate used in Step C1 is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound (a-3).
The reaction temperature varies depending on the raw material compound or the solvent used, but is usually 0 ° C. to 50 ° C., preferably 0 ° C. to room temperature.
The reaction time varies depending on the starting compound, the solvent used or the reaction temperature, but is usually 30 minutes to 24 hours, preferably 30 minutes to 2 hours.

(Manufacturing method D)
In the production method D, the A ring of the compound (I) of the present invention is used.

R ⁴ is a method for producing the compound (c-2) which is a carbamoyl group, and the iodide of the intermediate compound (a-3) obtained in the production method A and the intermediate compound (d-1). This is a method for obtaining the compound (c-2) of the present invention by cyanation and hydrolysis of the cyano group of the intermediate compound (d-2).

In the above scheme, R ¹ , R ³ , R ⁵ , T and U have the same meaning as above.

Step D1 is a step of reacting compound (a-3) with an iodizing agent such as N-iodosuccinimide in an inert solvent to produce intermediate compound (d-1).
In StepD2, in the presence of catalysts such as tris (dibenzylideneacetone) dipalladium (0) and 1,1'-bis (diphenylphosphino) ferrocene in an inert solvent, compound (d-1) was added to copper cyanate and the like. This is a step of producing the intermediate compound (d-2) by reacting with the cyanating agent of.
StepD3 is a step of subjecting the cyano group of the compound (d-2) to a hydrolysis reaction in an inert solvent to convert it into a carbamoyl group to produce the compound (c-2) of the present invention. The hydrolysis reaction of the cyano group can be carried out according to a method known per se.
Examples of the inert solvent used include those mentioned above.

The amount of an iodizing agent such as N-iodosuccinimide used in Step D1 is usually 1 to 2 equivalents, preferably 1 to 1.1 equivalents, relative to compound (a-3).
The reaction temperature varies depending on the raw material compound or the solvent used, but is usually 0 ° C. to 50 ° C., preferably 0 ° C. to room temperature.
The reaction time varies depending on the starting compound, the solvent used or the reaction temperature, but is usually 30 minutes to 24 hours, preferably 30 minutes to 2 hours.

The amount of the cyanating agent such as copper cyanide used in Step D2 is usually 1 to 5 equivalents, preferably 1 to 4 equivalents, relative to compound (d-1). The amount of catalysts used, such as tris (dibenzylideneacetone) dipalladium (0) and 1,1'-bis (diphenylphosphino) ferrocene, is usually 0.01-0.5 relative to compound (d-1). Equivalent, preferably 0.01-0.2 equivalent.
The reaction temperature varies depending on the raw material compound or the solvent used, but is usually 0 ° C. to 50 ° C., preferably 0 ° C. to room temperature.
The reaction time varies depending on the starting compound, the solvent used or the reaction temperature, but is usually 30 minutes to 24 hours, preferably 30 minutes to 10 hours.

(Manufacturing method E)
In the production method E, the A ring of the compound (I) of the present invention is formed by coupling the compound (e-1) and the compound (e-2).

This is a method for producing the compound of the present invention (e-3).
The compound (e-1) used in this production method can be produced by a method known per se.

In the above scheme, R ¹ , R ³ , R ⁵ , T, U and X have the same meaning as above, and Z indicates -N (R ⁸ )-, oxygen atom or sulfur atom.

In Step E, the compound (e-1) and the compound (e-2) are subjected to a coupling reaction using an organometallic catalyst in an inert solvent in the presence of a base to produce the compound (e-3) of the present invention. It is a process to do. In addition, this reaction may be carried out in the presence of a phosphine ligand, if necessary.
Examples of the inert solvent used include those mentioned above.

Examples of the base include inorganic carbonates or phosphates (for example, potassium carbonate, cesium carbonate, tripotassium phosphate) and the like.
Examples of the organometallic catalyst include palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), and dichlorobis (triphenylphosphine) palladium (II).
Phosphine ligands include 2,2'-bis (diphenylphosphine) -1,1'-binaphthyl (BINAP), tris (2-methylphenyl) phosphine, 1,1'-bis (diphenylphosphine) ferrocene, 2 -Dicyclohexylphosphine-2', 6'-dimethoxybiphenyl, 2-dicyclohexylphosphine-2', 4, 6'-triisopropylbiphenyl and the like can be mentioned.

The reaction conditions such as the reaction temperature and the reaction time vary depending on the reaction reagent used, the reaction solvent, and the like, but usually the reaction temperature is −30 ° C. to 150 ° C. and the reaction time is 30 minutes to 20 hours.

(Manufacturing method F)
In the production method F, the A ring of the compound (I) of the present invention is formed by coupling the compound (f-1) and the compound (e-2).

This is a method for producing the compound of the present invention (f-2).
The compound (f-1) used in this production method can be produced by a method known per se.

In the above scheme, R ¹ , R ³ , R ⁷ , T, U and X have the same meaning as above.

In Step F, the compound (f-1) and the compound (e-2) are subjected to a coupling reaction using an organometallic catalyst in an inert solvent in the presence of a base to produce the compound (f-2) of the present invention. This step can be performed under the same conditions as the reaction of Step E described in Production Method E.

(Manufacturing method G)
In the production method G, the A ring of the compound (I) of the present invention is formed by coupling the compound (g-1) and the compound (e-2).

This is a method for producing the compound of the present invention (g-2).
The compound (g-1) used in this production method can be produced by a method known per se.

In the above scheme, R ¹ , R ³ , T, U and X have the same meaning as above.

StepG produces the compound (g-2) of the present invention by subjecting the compound (g-1) and the compound (e-2) to a coupling reaction using an organometallic catalyst in the presence of a base in an inert solvent. This step can be performed under the same conditions as the reaction of Step E described in Production Method E.

(Manufacturing method H)
In the production method H, the A ring of the compound (I) of the present invention is formed by coupling the compound (h-1) and the compound (a-2).

This is a method for producing the compound of the present invention (h-2).
The compound (h-1) used in this production method can be produced by a method known per se.

In the above scheme, R ¹ , R ³ , T, U and X have the same meaning as above.

StepH refers to bases such as inorganic carbonates or phosphates (eg potassium carbonate, cesium carbonate, tripotassium phosphate), copper compounds (eg CuBr, CuI) and ligands (eg N, N'-dimethylethylenediamine, It is a nucleophilic substitution reaction using 1,2-diaminocyclohexane, trans-N, N'-dimethylcyclohexane-1,2-diamine, etc.), and is a compound (h-1) and compound (a-) in an inert solvent. This is a step of producing the compound (h-2) of the present invention from 2), and can be carried out under the same conditions as the reaction of Step A described in Production Method A.

(Manufacturing method I)
In the production method I, the compound (i-1) is reacted with the compound (a-2), the nitro group is reduced by a method known per se, and the amino group of the obtained compound (i-3) is converted to chloroacetyl chloride. After amidation, the compound (i-5) is subjected to a ring-closing reaction, and the obtained compound (i-5) is reacted with the compound (i-6) to form the A ring of the compound (I) of the present invention.

This is a method for producing the compound of the present invention (i-7).

In the above scheme, R ¹ , R ³ , R ⁷ , R ⁹ , T, U and X have the same meaning as above.

Step I1 is a step of producing compound (i-2) by subjecting compound (i-1) and compound (a-2) to a coupling reaction using an organometallic catalyst in the presence of a base in an inert solvent. Is. Further, this reaction may be carried out in the presence of a phosphine ligand, if necessary, and can be carried out under the same conditions as the reaction of Step E described in Production Method E.
StepI2 is a step of reducing the nitro group of compound (i-2) to an amino group by a method known per se to produce compound (i-3).
Step I3 is a step of producing compound (i-4) by reacting the amino group of compound (i-3) with chloroacetyl chloride in the presence of a base such as triethylamine in an inert solvent.
Step I4 is a step of producing compound (i-5) by intramolecularly closing the ring of compound (i-4) in an inert solvent in the presence of a base such as sodium hydride.
Step I5 is a step of producing the compound (i-7) of the present invention by reacting the compound (i-5) with the compound (i-6) in the presence of a base such as sodium hydride in an inert solvent.
Examples of the inert solvent used include those mentioned above.

The amount of chloroacetyl chloride used in Step I3 is usually 1 to 2 equivalents, preferably 1 to 1.2 equivalents, relative to compound (i-3). The amount of the base used is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound (i-3). The reaction conditions such as the reaction temperature and the reaction time vary depending on the reaction reagent used, the reaction solvent, and the like, but the reaction temperature is usually −30 ° C. to 50 ° C., and the reaction time is 30 minutes to 5 hours.
The amount of the base used in Step I4 is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound (i-4). The reaction conditions such as the reaction temperature and the reaction time vary depending on the reaction reagent used, the reaction solvent, and the like, but the reaction temperature is usually −30 ° C. to 50 ° C., and the reaction time is 30 minutes to 5 hours.
The amount of compound (i-6) used in Step I5 is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound (i-5). The reaction conditions such as the reaction temperature and the reaction time vary depending on the reaction reagent used, the reaction solvent, and the like, but the reaction temperature is usually −30 ° C. to 50 ° C., and the reaction time is 30 minutes to 5 hours.

(Manufacturing method J)
In the production method J, the compound (j-3) obtained from the reaction of the compound (j-1) and the compound (j-2) is reacted with the compound (a-2), or the compound (i) obtained by the production method I is reacted. The compound (j-4) of the present invention is obtained by reacting -4) with the compound (j-2) to obtain the compound (j-4), and subjecting the compound (j-4) to a ring-closing reaction by a method known per se. A ring

This is a method for producing the compound of the present invention (j-5).

In the above scheme, R ¹ , R ³ , R ⁶ , T, U and X have the same meaning as above.

StepJ1 is a step of reacting compound (j-1) with compound (j-2) in an inert solvent to amidate the amino group of compound (j-1) to produce compound (j-3). be. This reaction may be carried out in the presence of bases such as triethylamine, pyridine, 4-dimethylaminopyridine and potassium carbonate, if necessary.
In StepJ2, compound (j-3) and compound (a-2) are subjected to a coupling reaction using an organometallic catalyst in an inert solvent in the presence of a base to produce compound (j-4). It is a process. Further, this reaction may be carried out in the presence of a phosphine ligand, if necessary, and can be carried out under the same conditions as the reaction of Step E described in Production Method E.
StepJ3 is a step of producing the compound (j-4) by reacting the compound (i-4) obtained by the production method I with the compound (j-2) in an inert solvent. It can be carried out under the same conditions as the reaction of Step J1.
StepJ4 is a step of producing the compound (j-5) of the present invention by intramolecularly closing the compound (j-4) in an inert solvent by a method known per se.
Examples of the inert solvent used include those mentioned above.

In StepJ1, the compound (j-2) is not only in the form of a free acid, but also a salt (for example, a salt with sodium, potassium, calcium, triethylamine, pyridine, etc.) or a reactive derivative (for example, acid chloride, acid bromide, etc.). Acid halide; Acid anhydride; Substituted phosphoric acid such as dialkyl phosphate, mixed acid anhydride with alkyl carbonate such as monoethyl carbonate; Active amide which is an amide with imidazole, etc .; Cyanomethyl ester, 4-nitrophenyl ester, etc. Is subjected to the reaction as an active ester) or the like.

When the compound (j-2) is used in the state of a free acid or a salt in Step J1, the reaction is preferably carried out in the presence of a condensing agent, and the condensing agent is, for example, N, N'-dicyclohexylcarbodiimide. N, N'-di-substituted carbodiimides such as 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, N-cyclohexyl-N'-morpholinoethyl carbodiimide, N-cyclohexyl-N'-(4-diethylamino). Carbodiimide compounds such as cyclohexyl) carbodiimide; azolide compounds such as N, N'-carbonyldiimidazole and N, N'-thionyldiimidazole are used. When the above condensing agent is used, it is considered that the reaction proceeds via the reactive derivative of compound (j-2).

The amount of compound (j-2) used in Step J1 is usually 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (j-1). The amount of the base used is usually 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (j-1).
The reaction conditions such as the reaction temperature and the reaction time vary depending on the reaction reagent used, the reaction solvent, and the like, but usually the reaction temperature is −30 ° C. to 100 ° C., and the reaction time is 30 minutes to 20 hours.

(Manufacturing method K)
In the production method K, the A ring of the compound (I) of the present invention is formed by coupling the compound (k-1) and the compound (e-2).

This is a method for producing the compound of the present invention (k-2).
The compound (k-1) used in this production method can be produced by a method known per se.

In the above scheme, R ¹ , R ³ , T, U and X have the same meaning as above.

Examples of the inert solvent used include those mentioned above.

StepK produces the compound (k-2) of the present invention by subjecting the compound (k-1) and the compound (e-2) to a coupling reaction using an organometallic catalyst in the presence of a base in an inert solvent. This step can be performed under the same conditions as the reaction of Step E described in Production Method E.

The compound (I) of the present invention produced by the above method is purified to an arbitrary purity by subject to conventional purification means such as concentration, extraction, chromatography, reprecipitation, recrystallization and the like. Can be done. Further, if necessary, the salt can be obtained as a pharmaceutically acceptable salt by treating with an acid, a base or the like in an appropriate solvent. Further, compound (I) of the present invention or a pharmaceutically acceptable salt thereof is left in the air, treated with water, a hydrated solvent or other solvent (for example, alcohol), or recrystallized. As a result, water (or solvent) may be absorbed and adsorbed water (or adsorbed solvent) may be attached to form a hydrate (or solvent). It also includes such various hydrates, solvates and polymorphic compounds.

The compound (I) of the present invention or a pharmaceutically acceptable salt thereof is a geometric isomer such as a cis isomer or a trans isomer, or an optically isomer such as a t-form or a d-form or l-form, depending on the type and combination of substituents. Various isomers such as isomers may exist, but the compound (I) of the present invention is all isomers, steric isomers and mixtures of these isomers and steric isomers in any ratio unless otherwise specified. Also includes. These optical isomers and mixtures of isomers can be isolated by known partitioning means (see, eg, "Enantiomers, Racemates and Resolution, John Wiley And Sons, Inc." by J. Jacques et al.). The isomer can also be produced by asymmetric synthesis. The compounds (I) of the present invention, the label body, i.e., the compounds of the present invention (I) 1 or 2 or more atoms isotopes constituting the ^{(e.g., 2 H, 3 H, 13} C, 14 C, ^{Compounds substituted with 35} S etc.) are also included.

The present invention also includes so-called prodrugs, which are pharmaceutically acceptable, of the compound (I) of the present invention. A pharmaceutically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxy group, etc. of the compound (I) of the present invention by hydrolysis or under physiological conditions. The groups that form such prodrugs include Prog. Med., Vol. 5, pp. 2157-2161, 1985, and "Pharmaceutical Development" (Hirokawa Shoten, 1990), Vol. 7, Molecular Design 163-198. It is the basis described on the page. More specifically, as the prodrug, when the compound (I) of the present invention has an amino group, the amino group is acylated, alkylated, or phosphorylated (for example, the amino group thereof). Eikosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation , A tert-butylated compound, etc.), etc., and when the compound (I) of the present invention has a hydroxyl group, the hydroxyl group is acylated, alkylated, phosphorylated, or boroinated. Examples thereof include an oxidized compound (for example, a compound whose hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.) and the like. .. When the compound (I) of the present invention has a carboxy group, the compound in which the carboxy group is esterified or amidated (for example, the carboxy group is ethyl esterified, phenyl esterified, or carboxymethyl ester). , Dimethylaminomethyl esterification, pivaloyloxymethyl esterification, 1-ethoxycarbonyloxyethyl esterification, 1-cyclohexyloxycarbonyloxyethyl esterification, amidated or methylamided compounds, etc.) Can be mentioned.

The compound (I) of the present invention or a pharmaceutically acceptable salt thereof has cyclin-dependent kinase (CDK) 8 inhibitory activity, and mammals (humans, horses, cows, dogs, cats, rats, mice, hamsters, etc.) ), It is useful as a prophylactic / therapeutic agent for CDK8-related diseases, bone metabolism-related diseases such as osteoporosis, and cell-proliferative diseases such as cancer. That is, the compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be, for example, osteoporosis, osteodysplasia, chondropathy, fibroosteitis (hyperparathyroidism), osteomalacia, page. It can be used as a prophylactic and therapeutic agent for et's disease, rheumatoid arthritis, osteomalacia, cancer, autoimmune disease, inflammatory disease and the like. In that case, the compound (I) of the present invention may be used as it is or by blending a pharmaceutically acceptable carrier, orally or parenterally to a mammal (preferably human) as a medicine (that is, a pharmaceutical composition). Can be administered.

Cancers to which the compound (I) of the present invention is applied include, for example, colon cancer (eg, colon cancer, rectal cancer, anal cancer, familial colon cancer, hereditary non-polyposis colon cancer, gastrointestinal stromal tumor). Pulmonary cancer (eg, non-small cell lung cancer, small cell lung cancer, malignant mesoderma), mesopharyngoma, pancreatic cancer (eg, pancreatic duct cancer, pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (eg, papillary) Adenocarcinoma, mucinous adenocarcinoma, squamous epithelial cancer), duodenal cancer, small intestinal cancer, breast cancer (eg, invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer), ovarian cancer (eg, epithelial ovarian cancer) , Extragonal embryonic cell tumor, ovarian embryonic cell tumor, low-grade ovarian tumor), testicular tumor, prostate cancer (eg, hormone-dependent prostate cancer, hormone-independent prostate cancer, castration-resistant prostate cancer), liver Cancer (eg, hepatocellular carcinoma, primary liver cancer, extrahepatic bile duct cancer), thyroid cancer (eg, thyroid medullary cancer), kidney cancer (eg, renal cell cancer, metastatic epithelial cancer of the renal pelvis and urinary tract), uterine cancer (Example, endometrial cancer, cervical cancer, uterine body cancer, uterine sarcoma), gestational chorionic villus cancer, brain tumor (eg, medullary cell tumor, glioma, pineapple stellate cell tumor, hairy cell type Star cell tumor, diffuse stell cell tumor, degenerative stell cell tumor, pituitary adenoma), retinoblastoma, skin cancer (eg, basal cell tumor, malignant melanoma), sarcoma (eg, rhizome myoma, Smooth muscle tumor, soft sarcoma, spindle cell sarcoma), malignant bone tumor, bladder cancer, hematological cancer (eg, multiple myeloma, leukemia (eg, acute myeloid leukemia), malignant lymphoma, Hodgkin's disease, chronic myeloproliferative disorder ), Cancer of unknown primary, etc.
Among them, the compound (I) of the present invention contains breast cancer, pancreatic cancer, bladder cancer, prostate cancer, esophageal cancer, gastric cancer, uterine cancer, ovarian cancer, brain tumor, colon cancer (eg, colon cancer, rectal cancer), and hematological cancer (eg, colon cancer, rectal cancer). It is effective against at least one cancer selected from the group consisting of eg, acute myeloid leukemia, multiple myeloma), liver cancer (eg, hepatocellular carcinoma), skin cancer, lung cancer and thyroid cancer.

The pharmaceutical product of the present invention can be produced by a known production method generally used in the field of pharmaceutical technology (eg, the method described in the Japanese Pharmacopoeia). In addition, the medicament of the present invention includes excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, emulsifiers, and colorants commonly used in the pharmaceutical field, if necessary. , Preservatives, fragrances, flavoring agents, stabilizers, thickeners and other additives can be appropriately contained.
Examples of the pharmaceutically acceptable carrier described above include these additives.

For example, tablets can be produced using excipients, binders, disintegrants, lubricants and the like, and pills and granules can be produced using excipients, binders, disintegrants and the like. Can be done. Further, powders and capsules can be produced using excipients and the like, syrups can be produced using sweeteners and the like, and emulsions or suspending agents can be produced using suspending agents, surfactants, emulsifiers and the like.

Examples of excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, citrus powder, mannitol, sodium hydrogen carbonate, calcium phosphate, calcium sulfate.
Examples of the binder include 5 to 10% by weight starch paste solution, 10 to 20% by weight Arabic rubber solution or gelatin solution, 1 to 5% by weight tragant solution, carboxymethyl cellulose solution, sodium alginate solution, and glycerin.
Examples of disintegrants include starch and calcium carbonate.
Examples of lubricants include magnesium stearate, stearic acid, calcium stearate, and purified talc.
Examples of sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, and simple syrup.
Examples of surfactants include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and polyoxyl 40 stearate.
Examples of suspending agents include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose and bentonite.
Examples of emulsifiers include gum arabic, tragant, gelatin and polysorbate 80.

For example, when the medicament of the present invention is a tablet, the tablet can be added to the compound of the present invention according to a method known per se, for example, an excipient (eg, lactose, sucrose, starch), a disintegrant (eg, starch, carbonate). Calcium), binders (eg starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose) or lubricants (eg talc, magnesium stearate, polyethylene glycol 6000) are added and compression molded, then required It can be produced by coating by a method known per se for the purpose of taste masking, enteric or persistent. Examples of the coating agent used for coating include hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, and hydroxymethyl cellulose acetate succinate. Eudragit (Roam, Germany, methacrylic acid / acrylic acid copolymer) and dyes (eg, Bengala, titanium dioxide) are used.

In addition to intravenous injections, the injections include subcutaneous injections, intradermal injections, intramuscular injections, intraperitoneal injections, drip injections and the like.

Such injections are prepared by a method known per se, that is, by dissolving, suspending or emulsifying compound (I) of the present invention in a sterile aqueous or oily solution. Examples of the aqueous solution include physiological saline, an isotonic solution containing glucose and other auxiliary agents (eg, D-sorbitol, D-mannitol, sodium chloride) and the like. The aqueous solution contains suitable solubilizers such as alcohols (eg ethanol), polyalcohols (eg propylene glycol, polyethylene glycol), nonionic surfactants (eg polysorbate 80, HCO-50). You may. Examples of the oily liquid include sesame oil and soybean oil. The oily liquid may contain a suitable dissolution aid. Examples of the solubilizing agent include benzyl benzoate and benzyl alcohol. In addition, the injection includes a buffer (eg, phosphate buffer, sodium acetate buffer), a soothing agent (eg, benzalkonium chloride, prokine hydrochloride), and a stabilizer (eg, human serum albumin, polyethylene glycol). , Preservatives (eg, benzyl alcohol, phenol) and the like may be blended. The prepared injection solution is usually filled in an ampoule.

In addition to the above, a preferable preparation can be appropriately prepared by using a conventional method.

The content of the additive in the pharmaceutical product of the present invention varies depending on the form of the preparation, but is usually about 1 to about 99.9% by weight, preferably about 10 to about 90% by weight, based on the entire preparation. be.

The dose of the compound of the present invention or a pharmaceutically acceptable salt thereof varies depending on the administration subject, symptoms, and other factors, but for example, when orally administered to an adult (body weight of about 60 kg), the daily dose is administered. As the compound of the present invention, it is about 1 to about 1000 mg, preferably about 3 to about 300 mg, more preferably about 10 to about 200 mg, and it is desirable to administer these in one or several divided doses.

In addition, when the compound of the present invention or a pharmaceutically acceptable salt thereof is used as an anticancer agent, it can be used in combination with another agent, for example, an existing anticancer agent, as long as its efficacy is not impaired. At this time, the administration time is not limited, and these may be administered to the administration subject at the same time or may be administered at different times. The dose can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of the compound of the present invention or a pharmaceutically acceptable salt thereof and the concomitant drug can be appropriately selected according to the administration target, administration route, target disease, symptom, combination and the like.

Examples of existing anticancer agents include chemotherapeutic agents, hormonal therapeutic agents, immunotherapeutic agents, molecular targeted agents, immune checkpoint inhibitors (anti-PD-1 antibody, anti-PD-L1 antibody) and the like.
As the "chemotherapeutic agent", for example, an alkylating agent, an antimetabolite, an anticancer antibiotic, a plant-derived anticancer agent and the like are used.
Examples of the "alkylating agent" include nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, and melphalan. Faran, dacarbazine, lanimustine, bendamustine, procarbazine, sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamstine hydrochloride Pydium, fotemustine, prednimustine, pumitepa, ribomustine, temozolomid, treosfamide, trophosphamide, diostatinstimalamare, adzelesin, cisplatin, bizelesin, and their DDS preparations are used.

Examples of the "antimetabolite" include mercaptopurine, 6-mercaptopurine riboside, thioinosin, methotrexate, pemetrexed, enocitabine, cytarabine, cytarabine octofusphate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, etc.). UFT, doxiflulysine, carmofur, galositabin, emitefur, capecitabine), aminopterin, nerzarabin, leucovorin calcium, tabloid, butocin, forinate calcium, levofolinate calcium, cladribine, clofarabine, nerarabine, emitefur, fludarabin Statins, pyritrexim, idoxyuridine, mitoguazone, cytarabine, and DDS preparations thereof and the like are used.

Examples of the "anticancer antibiotic" include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, acralubicin hydrochloride, pyrarubicin hydrochloride, and epirubicin hydrochloride. , Neocartinostatin, myslamycin, zarcomycin, cartinophylline, mittane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and DDS preparations thereof and the like are used.

As the "plant-derived anticancer agent", for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine, and DDS preparations thereof and the like are used.

Examples of the "hormone therapeutic agent" include phosfestol, diethylstilbestrol, chlorotrianisen, medroxyprogesterone acetate, megestrol acetate, chlormaginone acetate, ciproterone acetate, dannazole, allylestradiol, guestlinone, mepartricin, and the like. Laroxyphene, olmeroxyphene, revolmeroxyphene, anti-estrogen (eg tamoxifen citrate, tremiphen citrate), pills, mepitiostane, testrolactone, aminoglutetiimide, LH-RH agonists (eg goseleline acetate, busererin) , Leuprorelin), droroxyfen, epithiostanol, ethinyl estradiol sulfonate, aromatase inhibitors (eg, fadrosole hydrochloride, anastrosol, retrosol, exemethan, borozol, formestan), antiandrogens (eg, flutamide, Bicalutamide, niltamide), 5α-reductase inhibitors (eg, finasteride, epristeride), corticohormonal agents (eg, dexamethasone, prednisolone, betamethasone, triamsinolone), androgen synthesis inhibitors (eg, avirateron), retinoid and retinoid metabolism Drugs that delay the disease (eg, riarozole) are used.

"Immunotherapeutic agents" include biological reaction modifiers (eg, schizophyllan, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, phosphotoxin, BCG vaccine, etc. Corinebacterium parbum, levamisol, polysaccharide K, procodazole, anti-CTLA4 antibody) and the like are used.

"Molecular-targeted drugs" include, for example, trastuzumab, ibritsumomab, alemtuzumab, axitinib, bebashizumab, afatinib, osimertinib, voltezomib, bostinib, calfilzomib, cetuximab, dasatinib, denosumab, edretimib Ozogamycin, imatinib, ipilimumab, lapatinib, renalidemid, nirotinib, nimotuzumab, olaparib, panitzumumab, pazopanib, pertuzumab, rituximab, ofatumumab, mogamurizumab, ofatumumab, mogamurizumab, brentsumumab Salidamide, trastuzumab, trastuzumab emtansine, tretinoin, bandetanib, bolinostat, cabozantinib, tramethinib, dabrafenib, crizotinib, alektinib, cetuximab, luxoritinib, seritinib, luxoritinib, seritinib, luxoritinib, ibrutinib, parvosirib

As the "immune checkpoint inhibitor", for example, ipilimumab, tremelimumab, nivolumab, pembrolizumab, avelumab, atezolizumab, durvalumab and the like are used.

The present invention will be described in detail with reference to the following examples, but the present invention is not limited to the following examples. In addition, the reagents and materials used are commercially available unless otherwise specified.

Example 1

(1a) 1- (4,5-dimethoxy-2-nitrophenyl) propan-2-one

Dissolve 1.00 g (5.2 mmol) of 1- (4,5-dimethoxyphenyl) propan-2-one in 10 mL of chloroform and add 0.94 mL (10 mmol) of concentrated nitrate (P = 69%) at -5 ° C for 1 hour. The mixture was added dropwise, and the mixture was stirred under ice-cooling for 1 hour. After adding 30 mL of water and extracting with chloroform, the chloroform layer was washed with saturated brine and dried (Na ₂ SO ₄ ). Chloroform was distilled off under reduced pressure to obtain 1.22 g (yield: 99%) of a yellow powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.34 (3H, s), 3.95 (3H, s), 3.96 (3H, s), 4.08 (2H, s), 6.64 (1H, s), 7.74 ( 1H, s).

(1b) 5,6-dimethoxy-2-methyl-1H-indole

100 mg of 10% Pd-C was suspended in 10 mL of benzene, 1.22 g (5.10 mmol) of the compound prepared in Example 1 (1a) was added, and catalytic hydrogenation was carried out at 0.3 MPa at room temperature for 16.5 hours. After filtering Pd-C, benzene was distilled off under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 10: 1 → 3: 1, V / V) to obtain 300 mg (yield: 31%) of a reddish brown powder of the title compound. ..
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.40 (3H, s), 3.89 (3H, s), 3.90 (3H, s), 6.09-6.10 (1H, m), 6.82 (1H, s), 6.98 (1H, s), 7.60-7.75 (1H, br).

(1c) 5,6-dimethoxy-2-methyl-1- [4- (morpholine-4-yl) phenyl] -1H-indole

Compound 992 mg (5.19 mmol) prepared in Example 1 (1b) was dissolved in 7 mL of toluene, 4- (4-iodophenyl) morpholine 1.50 g (5.19 mmol), trans-N, N'-dimethylcyclohexane-. Add 0.12 mL (0.78 mmol) of 1,2-diamine, 49 mg (0.26 mmol) of copper iodide and 2.20 g (10.4 mmol) of ground tripotassium phosphate, bubbling nitrogen for 10 minutes, and then at 110 ° C. under a nitrogen stream. Stirred for 13.5 hours. 50 mL of water was added, the aqueous layer was extracted with 50 mL of ethyl acetate, the organic layer was washed with saturated brine and dried (Na ₂ SO ₄ ). The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 10: 1 → 5: 1 → 3: 1, V / V), and the title compound was slightly yellowed. A white powder of 1.07 g (yield: 58%) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.23 (3H, s), 3.25-3.27 (4H, m), 3.78 (3H, s), 3.88-3.95 (7H, m), 6.24 (1H, s) ), 7.01-7.04 (3H, m), 7.22-7.24 (2H, m).

(1) 3-Acetyl-5,6-dimethoxy-2-methyl-1- [4- (morpholine-4-yl) phenyl] -1H-indole

1.07 g (3.04 mmol) of the compound prepared in Example 1 (1c) was dissolved in 10 mL of methylene chloride, and under ice-cooling, 0.32 mL (4.6 mmol) of acetyl chloride and 0.50 mL (4.6 mmol) of titanium chloride (IV) were dissolved. Was sequentially added dropwise, and the mixture was stirred at the same temperature for 1 hour. 20 mL of water and 20 mL of ethyl acetate were added, and the mixture was stirred for 30 minutes, the precipitate was collected by filtration, and washed successively with water and ethyl acetate. The obtained powder was dissolved by heating in 25 mL of methylene chloride, 20 mL of ethyl acetate was added, and the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with methylene chloride-ethyl acetate (1: 3) to give 435 mg (yield: 36%) of white crystalline powder of the title compound.
IR ν (ATR) cm ^-1 : 1618, 1514, 1120, 869.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.52 (3H, s), 2.65 (3H, s), 3.28-3.30 (4H, m), 3.77 (3H, s), 3.90-3.93 (7H, m) ), 3.98 (3H, s), 6.47 (1H, s), 7.05 (2H, m), 7.20 (2H, m), 7.69 (1H, s).
MS m / z: 395 [M + H] ⁺ , 417 [M + Na] ⁺ .

Example 2

(2a) Ethyl 1-phenylpiperidine-4-carboxylate

Iodobenzene 20.4 g (100 mmol), ethyl piperidine-4-carboxylate 23 mL (0.15 mol), copper iodide 1.90 g (9.98 mmol), 2-acetylcyclohexanone 2.6 mL (20 mmol) and cesium carbonate 48.9 g (150) mmol) was suspended in 50 mL of N, N-dimethylformamide and stirred at 60 ° C. for 37 hours. After allowing to cool, the mixture was poured into 500 mL of ice water, 200 mL of diisopropyl ether was added, and the insoluble material was filtered off. The two layers were separated, the aqueous layer was extracted with 200 mL of diisopropyl ether, the diisopropyl ether layers were combined, washed with 200 mL of water, and diisopropyl ether was distilled off under reduced pressure. 50 mL of diisopropyl ether was added to the residue, 200 mL of 1 M hydrochloric acid was added under ice-cooling, and the insoluble material was filtered off. The two layers were separated, the diisopropyl ether layer was extracted with 40 mL of 1M hydrochloric acid, the aqueous layers were combined, and the mixture was neutralized with 20 g of baking soda. Extraction was performed twice with 200 mL and 100 mL of diisopropyl ether, the diisopropyl ether layers were combined, washed with saturated brine, and dried (Na ₂ SO ₄ ). Diisopropyl ether was distilled off under reduced pressure to obtain 17.1 g (yield: 73%) of reddish brown oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.27 (3H, t, J = 7.1 Hz), 1.82-1.98 (2H, m), 1.99-2.09 (2H, m), 2.39-2.50 (1H, m) ), 2.79 (2H, td, J = 12.4, 2.7 Hz), 3.65 (2H, dt, J = 12.4, 3.4 Hz), 4.16 (2H, q, J = 7.1 Hz), 6.82-6.87 (1H, m) , 6.92-6.97 (2H, m), 7.21-7.28 (2H, m).

(2b) Ethyl 1- (4-iodophenyl) piperidine-4-carboxylate

10.4 g (44.6 mmol) of the compound prepared in Example 2 (2a) was dissolved in 100 mL of methylene chloride, 40 mL of water and 5.6 g (67 mmol) of baking soda were added, and then 13.6 g (53.6 mmol) of iodine was added at room temperature. ) Was added in portions over 1 hour, and the mixture was further stirred at the same temperature for 1 hour. The methylene chloride layer was separated, washed sequentially with 5% sodium thiosulfate water, water, and saturated brine, dried (Na ₂ SO ₄ ), and then methylene chloride was distilled off under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 20: 1 → 10: 1, V / V), and the solvent of the target fraction was distilled off under reduced pressure to obtain a yellow powder of the title compound. 13.6 g (yield: 35%) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.27 (3H, t, J = 7.2 Hz), 1.80-1.94 (2H, m), 1.94-2.09 (2H, m), 2.39-2.50 (1H, m) ), 2.73-2.88 (2H, m), 3.65 (2H, dt, J = 12.9, 3.6 Hz), 4.15 (2H, q, J = 7.2 Hz), 6.63-6.75 (2H, m), 7.46-7.54 ( 2H, m).

(2c) Ethyl 1- [4- (5-fluoro-6-methoxy-2-methylindole-1-yl) phenyl] piperidine-4-carboxylate

Compound 837 mg (2.33 mmol) prepared in Example 2 (2b), 5-fluoro-6-methoxy-2-methylindole 347 mg (1.94 mmol), copper iodide 18 mg (0.095 mmol), trans-N, 0.046 mL (0.29 mmol) of N'-dimethylcyclohexane-1,2-diamine and 906 mg (4.27 mmol) of tripotassium phosphate were suspended in 2 mL of toluene, and the mixture was stirred at 80 ° C. for 12 hours under a nitrogen stream. After allowing to cool, 20 mL of water and 30 mL of ethyl acetate were added, the insoluble material was filtered off, and the two layers were separated. The ethyl acetate layer was washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and ethyl acetate was distilled off under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate, 10: 1 → 6: 1, V / V), and the solvent for the target fraction was distilled off under reduced pressure. After adding 1 mL of diisopropyl ether to the residue and stirring, 10 mL of n-hexane was added, and the precipitate was collected by filtration to obtain 273 mg (yield: 34%) of a slightly yellow powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.29 (3H, t, J = 7.2 Hz), 1.86-2.00 (2H, m), 2.04-2.14 (2H, m), 2.22 (3H, s), 2.45-2.55 (1H, m), 2.87-2.97 (2H, m), 3.70-3.81 (2H, m), 3.79 (3H, s), 4.18 (2H, q, J = 7.2 Hz), 6.24 (1H, m) s), 6.59 (1H, d, J = 7.1 Hz), 7.02-7.08 (2H, m), 7.17-7.24 (3H, m).

(2d) Ethyl 1- [4- (2-acetyl-5-fluoro-6-methoxy-2-methylindole-1-yl) phenyl] piperidine-4-carboxylate

Compound 265 mg (0.646 mmol) prepared in Example 2 (2c) was dissolved in 3 mL of methylene chloride, and 0.070 mL (0.98 mmol) of acetyl chloride and 0.11 mL (1.0 mmol) of titanium (IV) chloride were sequentially added under ice-cooling. In addition, the mixture was stirred at the same temperature for 30 minutes. 20 mL of ice water and 20 mL of methylene chloride were added, and the mixture was stirred for 30 minutes, and then the two layers were separated. The methylene chloride layer was washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and methylene chloride was distilled off under reduced pressure. The residue was purified by column chromatography (toluene: ethyl acetate, 10: 1 → 5: 1, V / V), and the solvent for the target fraction was evaporated under reduced pressure. 5 mL of diethyl ether was added to the obtained residue, and the mixture was stirred and collected by filtration to give 174 mg (yield: 60%) of a white powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.29 (3H, t, J = 7.1 Hz), 1.86-2.00 (2H, m), 2.04-2.14 (2H, m), 2.48-2.58 (1H, m) ), 2.52 (3H, s), 2.64 (3H, s), 2.90-3.03 (2H, m), 3.75-3.83 (2H, m), 3.79 (3H, s), 4.18 (2H, q, J = 7.1) Hz), 6.53 (1H, d, J = 7.3 Hz), 7.03-7.09 (2H, m), 7.12-7.18 (2H, m), 7.79 (1H, d, J = 12.2 Hz).

(2) 1- [4- (2-Acetyl-5-fluoro-6-methoxy-2-methylindole-1-yl) phenyl] piperidine-4-carboxylic acid

Compound 166 mg (0.367 mmol) prepared in Example 2 (2d) was dissolved in 4 mL of a mixture of methylene chloride-methanol (1: 1), and 5.0 M sodium hydroxide water 0.37 mL (1.8 mmol) was added at room temperature. In addition, the mixture was stirred at the same temperature for 13 hours. The solvent was evaporated under reduced pressure, 5 mL of ethyl acetate was added to the residue, and the mixture was extracted with 15 mL of water. After adding 5 mL of ethyl acetate to the aqueous layer and adjusting the pH to 4 or less with citric acid, the precipitate was collected by filtration to obtain 110 mg (yield: 70%) of a white powder of the title compound.
IR ν (ATR) cm ^-1 ; 1724, 1707, 1579, 1510, 1489, 1192, 931, 733.
^{1 1} H-NMR (DMSO-d6, 400 MHz) δ: 1.60-1.73 (2H, m), 1.89-2.00 (2H, m), 2.42-2.50 (1H, m), 2.46 (3H, s), 2.55 ( 3H, s), 2.83-2.93 (2H, m), 3.71 (3H, s), 3.73-3.83 (2H, m), 6.57 (1H, d, J = 7.3 Hz), 7.10-7.17 (2H, m) , 7.22-7.28 (2H, m), 7.86 (1H, d, J = 12.4 Hz), 12.05-12.40 (1H, br).
MS m / z: 425 [M + H] ⁺ , 423 [MH] ^- .

Example 3

(3a) 8-Phenyl-1,4-dioxa-8-azaspiro [4,5] decane

3.80 g (12.5 mmol) of tris (2-methylphenyl) phosphine and 1.11 g (6.24 mmol) of palladium (II) chloride were suspended in 50 mL of toluene and stirred for 30 minutes under a nitrogen stream. Toluene 650 mL, 1,4-dioxa-8-azaspiro [4.5] decane 22.3 g (156 mmol), sodium tert-butoxide 22.5 g (234 mmol) and bromobenzene 19.7 mL (187 mmol) were added sequentially under a nitrogen stream. The mixture was stirred at 100 ° C. for 20 hours. After allowing to cool, 650 mL of saturated brine and 300 mL of ethyl acetate were added, and the insoluble material was filtered off. The ethyl acetate layer was separated, dried (Na ₂ SO ₄ ), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 10: 1 → 5: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 33.3 g (yield: 98%) of a light orange oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.80-1.88 (4H, m), 3.28-3.36 (4H, m), 3.99 (4H, s), 6.79-6.87 (1H, m), 6.91-6.98 (2H, m), 7.20-7.29 (2H, m).

(3b) 4- [2- (tert-Butyldimethylsilanyloxy) ethoxy] -1-phenylpiperidine

17.6 g (132 mmol) of aluminum chloride was dissolved in 200 mL of diethyl ether, and the mixture was stirred at −78 ° C. for 30 minutes. A 33 mL suspension of diethyl ether of 1.26 g (33.1 mmol) of lithium aluminum hydride was added, and the mixture was stirred at the same temperature for 30 minutes. A 66 mL solution of 14.5 g (66.1 mmol) of the compound prepared in Example 3 (3a) was added dropwise, and the mixture was stirred at room temperature for 2 hours. 200 mL of water was added dropwise to the reaction solution under ice-cooling, 7.44 g of sodium hydroxide was added, and the mixture was extracted with diethyl ether. The diethyl ether layer was washed with saturated brine and dried (Na ₂ SO ₄ ), and then diethyl ether was distilled off under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 2: 1 → 1: 1 → 1: 2, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 15.3 g of a brown oil of 2- (1-phenylpiperidine-4-yloxy) ethanol.
Dissolve 15.3 g of 2- (1-phenylpiperidine-4-yloxy) ethanol in 75 mL of N, N-dimethylformamide, add 8.99 g (132 mmol) of imidazole and 9.96 g (66.1 mmol) of tert-butyldimethylchlorosilane. The mixture was stirred at room temperature for 2.5 hours. 300 mL of water was added to the reaction mixture, and the mixture was extracted with 300 mL of diethyl ether. The diethyl ether layer was washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and then diethyl ether was distilled off under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 20: 1 → 10: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 17.7 g (yield: 80%) of a light orange oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 0.08 (6H, s), 0.90 (9H, s), 1.66-1.78 (2H, m), 1.94-2.06 (2H, m), 2.87-2.97 (2H) , m), 3.46-3.56 (3H, m), 3.56 (2H, t, J = 5.6 Hz), 3.76 (2H, t, J = 5.6 Hz), 6.78-6.87 (1H, m), 6.90-6.98 ( 2H, m), 7.20-7.28 (2H, m).

(3c) 4- [2- (tert-butyldimethylsilanyloxy) ethoxy] -1- (4-iodophenyl) piperidine

After dissolving 17.7 g (52.7 mmol) of the compound prepared in Example 3 (3b) in 350 mL of methylene chloride-water (4: 3), 6.65 g (79.1 mmol) of baking soda was added, and 13.4 g (52.7) of iodine under ice cooling was added. mmol) was added in portions, and the mixture was stirred at room temperature for 2.5 hours. Further, 2.68 g (10.5 mmol) of iodine under ice-cooling was added in portions, and the mixture was stirred at room temperature for 2 hours. 200 mL of water was added to the reaction mixture, and the mixture was extracted with 200 mL of methylene chloride. The methylene chloride layer was washed successively with 5% sodium thiosulfate, water and saturated brine, dried (Na ₂ SO ₄ ), and then methylene chloride was distilled off under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 20: 1 → 10: 1, V / V), and the solvent for the target fraction was evaporated under reduced pressure. The obtained residue was purified again by column chromatography (n-hexane: ethyl acetate, 10: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 22.4 g (yield: 92%) of a pale pink powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 0.07 (6H, s), 0.90 (9H, s), 1.64-1.76 (2H, m), 1.90-2.02 (2H, m), 2.87-2.97 (2H) , m), 3.41-3.54 (3H, m), 3.55 (2H, t, J = 5.4 Hz), 3.76 (2H, t, J = 5.4 Hz), 6.65-6.72 (2H, m), 7.44-7.51 ( 2H, m).

(3d) 1-(4- [4- (2-tert-butyldimethylsilanyloxy) ethoxy] piperidine-1-yl} phenyl) -5,6-dimethoxy-2-methylindole

Compound 22.4 g (48.5 mmol) prepared in Example 3 (3c), compound 10.2 g (53.4 mmol) prepared in Example 1 (1b), copper iodide 509 mg (2.67 mmol), trans-N, N'. -Suspended 1.26 mL (8.01 mmol) of dimethylcyclohexane-1,2-diamine and 23.8 g (112 mmol) of tripotassium phosphate in 70 mL of toluene, bubbling nitrogen for 10 minutes at room temperature, and bringing to 110 ° C. under a nitrogen stream. Stirred for 22 hours. After allowing to cool, 150 mL of water and 150 mL of ethyl acetate were added to the reaction solution, the insoluble material was filtered off, and the two layers were separated. The ethyl acetate layer was washed successively with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 5: 1 → 4: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 13.8 g (yield: 54%) of a white powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 0.09 (6H, s), 0.91 (9H, s), 1.71-1.83 (2H, m), 1.97-2.11 (2H, m), 2.22 (3H, s) ), 2.99-3.10 (2H, m), 3.53-3.66 (5H, m), 3.75-3.82 (2H, m), 3.78 (3H, s), 3.91 (3H, s), 6.23 (1H, s), 6.57 (1H, s), 7.00-7.07 (2H, m), 7.01 (1H, s), 7.15-7.22 (2H, m).

(3e) 3-Acetyl-1-(4- [4- (2-tert-butyldimethylsilanyloxy) ethoxy] piperidine-1-yl} phenyl) -5,6-dimethoxy-2-methylindole

13.8 g (26.3 mmol) of the compound prepared in Example 3 (3d) was dissolved in 140 mL of methylene chloride, and 2.81 mL (39.5 mmol) of acetyl chloride and 4.33 mL (39.5 mmol) of titanium (IV) chloride were sequentially added under ice-cooling. In addition, the mixture was stirred at the same temperature for 1.5 hours. 300 mL of water was added to the reaction mixture, and the mixture was extracted with 200 mL of methylene chloride. The methylene chloride layer was washed with saturated brine and dried (Na ₂ SO ₄ ), and then methylene chloride was distilled off under reduced pressure. The obtained residue was purified by column chromatography (toluene: ethyl acetate, 2: 1 → 1: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 3.00 g (yield: 20%) of a pale yellow foamy powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 0.91 (9H, s), 1.71-1.84 (2H, m), 1.98-2.11 (2H, m), 2.51 (3H, s), 2.65 (3H, s) ), 3.03-3.15 (2H, m), 3.54-3.68 (5H, m), 3.77 (3H, s), 3.77-3.83 (2H, m), 3.98 (3H, s), 6.48 (1H, s), 7.02-7.09 (2H, m), 7.11-7.17 (2H, m), 7.69 (1H, s).

(3) 3-Acetyl-1-{4- [4- (2-Hydroxyethoxy) piperidine-1-yl] phenyl} -5,6-dimethoxy-2-methylindole

3.00 g (5.29 mmol) of the compound prepared in Example 3 (3e) was dissolved in 30 mL of tetrahydrofuran, and 6.35 mL (6.4 mmol) of a 1.0 M tetra-n-butylammonium tetrahydrofuran tetrahydrofuran solution was added under ice-cooling to the same temperature. Was stirred for 1.5 hours. 100 mL of water was added to the reaction mixture, and the mixture was extracted with 100 mL of ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried (Na ₂ SO ₄ ), and then ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate). The solvent of the target fraction was distilled off under reduced pressure, diisopropyl ether was added, and the mixture was collected by filtration to obtain 1.64 g (yield: 68%) of a pale yellow foamy powder of the title compound.
IR ν (ATR) cm ^-1 ; 3494, 1630, 1610.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.73-1.88 (2H, m), 1.99-2.15 (3H, m), 2.51 (3H, s), 2.65 (3H, s), 3.06-3.18 (2H) , m), 3.55-3.70 (5H, m), 3.73-3.83 (2H, m), 3.78 (3H, s), 3.98 (3H, s), 6.48 (1H, s), 7.03-7.09 (2H, m) ), 7.12-7.18 (2H, m), 7.68 (1H, s).
MS m / z: 453 [M + H] ⁺ , 475 [M + Na] ⁺ .

Example 4

(4a) Benzyl 4- (4-iodophenyl) piperazin-1-carboxylate

Dissolve 2.0 g (6.9 mmol) of 1- (4-iodophenyl) piperazin in 10 mL of N, N-dimethylformamide, and add 1.09 mL (7.63 mmol) of benzyl chloroformate and 1.16 mL (8.33 mmol) of triethylamine under ice-cooling. In addition, the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The ethyl acetate layer was washed successively with 5% citric acid water, water and saturated brine, and dried (Na ₂ SO ₄ ). Ethyl acetate was distilled off under reduced pressure, n-hexane was added to the obtained residue, and the mixture was collected by filtration to give 2.36 g (yield: 81%) of a light brown powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 3.06-3.20 (4H, m), 3.61-3.70 (4H, m), 5.16 (2H, s), 6.66-6.68 (2H, m), 7.30-7.40 (5H, m), 7.51-7.53 (2H, m).

(4b) Benzyl [4- (5,6-dimethoxy-2-methylindole-1-yl) phenyl] piperazin-1-carboxylate

Compound 2.36 g (5.59 mmol) prepared in Example 4 (4a) was dissolved in 10 mL of toluene, and compound 1.07 g (5.59 mmol) prepared in Example 1 (1b), copper iodide 54 mg (0.28 mmol). Add 2.49 g (11.7 mmol) of crushed tripotassium phosphate and 0.13 mL (0.84 mmol) of trans-N, N'-dimethylcyclohexane-1,2-diamine, bubbling with nitrogen for 10 minutes, and then 110 ° C. under a nitrogen atmosphere. Was stirred for 20 hours. Ethyl acetate and water were added, and the insoluble material was filtered off with Celite. The two layers were separated, and the organic layer was washed with saturated brine and dried (Na ₂ SO ₄ ). The solvent was evaporated under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate: chloroform, 1:20, n-hexane: ethyl acetate, 1: 2, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 1.78 g (yield: 66%) of a white powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.22 (3H, s), 3.20-3.32 (4H, m), 3.68-3.78 (4H, m), 3.77 (3H, s), 3.92 (3H, s) ), 5.18 (2H, s), 6.24 (1H, s), 6.56 (1H, s), 7.00-7.09 (3H, m), 7.20-7.30 (2H, m), 7.32-7.42 (5H, m).

(4c) Benzyl 4- [3-acetyl-4- (5,6-dimethoxy-2-methylindole-1-yl) phenyl] piperazin-1-carboxylate

1.78 g (3.67 mmol) of the compound prepared in Example 4 (4b) was dissolved in 20 mL of methylene chloride, and 0.39 mL (5.5 mmol) of acetyl chloride and 0.61 mL (5.5 mmol) of titanium (IV) chloride were sequentially added under ice-cooling. In addition, the mixture was stirred at the same temperature for 1 hour. Water and chloroform were added to the reaction solution, the two layers were separated, the chloroform layer was washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and then chloroform was distilled off under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 1 → 1: 2, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 580 mg (yield: 30%) of a white powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.51 (3H, s), 2.65 (3H, s), 3.25-3.35 (4H, m), 3.68-3.74 (4H, m), 3.76 (3H, s) ), 3.98 (3H, s), 5.18 (2H, s), 6.46 (1H, s), 7.03-7.07 (2H, m), 7.17-7.21 (2H, m), 7.32-7.40 (5H, m), 7.68 (1H, s).

(4d) 1- [3-Acetyl-4- (5,6-dimethoxy-2-methylindole-1-yl) phenyl] piperazin

Suspend 100 mg of 10% Pd-C in 30 mL of methylene chloride-methanol (1: 2), add 580 mg (1.10 mmol) of the compound prepared in Example 4 (4c), and add 580 mg (1.10 mmol) at room temperature at 0.40 MPa for 17 hours. Contact hydrogenation was added. After filtering Pd-C, the solvent was evaporated under reduced pressure, diisopropyl ether was added to the obtained residue, and the mixture was collected by filtration to give 170 mg (yield: 85%) of a pale yellow powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.51 (3H, s), 2.65 (3H, s), 3.17-3.28 (4H, m), 3.37-3.47 (4H, m), 3.78 (3H, s) ), 3.98 (3H, s), 6.46 (1H, s), 7.06-7.08 (2H, m), 7.19-7.21 (2H, m), 7.68 (1H, s, indole C4-H).

(4) 3-Acetyl-1-{4- [4- (3-Hydroxypropyl) piperazine-1-yl] phenyl} -5,6-dimethoxy-2-methylindole

Compound 555 mg (1.41 mmol) prepared in Example 4 (4d) was suspended in 5 mL of N, N-dimethylformamide, potassium carbonate 390 mg (2.82 mmol) and 3-bromo-1-propanol 196 mg (1.41 mmol). ) Was added, and the mixture was stirred at 60 ° C. for 24 hours. After allowing to cool, water was added, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed successively with water and saturated brine, and dried (Na ₂ SO ₄ ). Ethyl acetate was distilled off under reduced pressure, the residue was purified by column chromatography (methylene chloride: methanol, 10: 1, V / V), and the solvent for the target fraction was distilled off under reduced pressure. The obtained residue was dissolved by heating in ethyl acetate, diisopropyl ether was added, and the precipitate was collected by filtration to obtain 477 mg (yield: 74%) of a white powder of the title compound.
IR ν (ATR) cm ^-1 ; 1628, 1516, 1475, 1232, 1134, 1043, 818, 768
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.78-1.89 (2H, m), 2.52 (3H, s), 2.66 (3H, s), 2.69-2.78 (6H, m), 3.30-3.42 (4H) , m), 3.78 (3H, s), 3.86 (2H, t), 3.99 (3H, s), 6.41 (1H, s), 7.02-7.07 (2H, m), 7.16-7.21 (2H, m), 7.70 (1H, s).
MS m / z: 452 [M + H] ⁺ .

Example 5

(5a) 1- [4- (tert-butyldimethylsilanyloxy) phenyl] -6-methoxy-2-methylindole

6-methoxy-2-methylindole 3.85 g (23.9 mmol), tert-butyl- (4-iodophenoxy) dimethylsilane 8.00 g (23.9 mmol), copper iodide 229 mg (1.20 mmol), trans-N, N' -Dimethylcyclohexane-1,2-diamine 0.57 mL (3.6 mmol) and tripotassium phosphate 10.7 g (50.2 mmol) were suspended in 27 mL of toluene, nitrogen was bubbled at room temperature for 10 minutes, and the temperature was 110 ° C. under a nitrogen atmosphere. Stirred for 18 hours. After allowing to cool, 80 mL of water was added to the reaction solution, and the mixture was extracted with 80 mL of ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and then ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 50: 1 → 20: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 4.38 g (yield: 50%) of a pale yellow powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 0.27 (6H, s), 1.03 (9H, s), 2.22 (3H, s), 3.74 (3H, s), 6.28 (1H, s), 6.54 ( 1H, d, J = 2.2 Hz), 6.75 (1H, dd, J = 8.3, 2.2 Hz), 6.93-7.00 (2H, m), 7.13-7.21 (2H, m), 7.41 (1H, d, J = 8.3 Hz).

(5b) 3-Acetyl-1- [4- (tert-butyldimethylsilanyloxy) phenyl] -6-methoxy-2-methylindole

4.36 g (11.9 mmol) of the compound prepared in Example 5 (5a) was dissolved in 44 mL of methylene chloride, and 1.27 mL (17.8 mmol) of acetyl chloride and 1.95 mL (17.8 mmol) of titanium (IV) chloride were sequentially added under ice-cooling. In addition, the mixture was stirred at the same temperature for 5 hours. The reaction mixture was washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), methylene chloride was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (n-hexane: ethyl acetate, 1:10). → Purified by 1: 5, V / V). The solvent of the target fraction was distilled off under reduced pressure, diisopropyl ether was added to the obtained residue, and the mixture was collected by filtration to obtain 1.30 g (yield: 27%) of a white powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 0.29 (6H, s), 1.03 (9H, s), 2.53 (3H, s), 2.68 (3H, s), 3.75 (3H, s), 6.47 ( 1H, d, J = 2.4 Hz), 6.91 (1H, dd, J = 8.8, 2.4 Hz), 6.97-7.04 (2H, m), 7.12-7.19 (2H, m), 7.93 (1H, d, J = 8.8 Hz).

(5c) 3-Acetyl-1- (4-Hydroxyphenyl) -6-methoxy-2-methylindole

1.29 g (3.15 mmol) of the compound prepared in Example 5 (5b) is dissolved in 13 mL of tetrahydrofuran, 1.0 M tetra-n-butylammonium fluoride tetrahydrofuran solution 3.47 mL (3.5 mmol) is added under ice-cooling, and the temperature is the same. Was stirred for 1 hour. 30 mL of water was added to the reaction mixture, and the mixture was extracted with 30 mL of ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried (Na ₂ SO ₄ ), and then ethyl acetate was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue and collected by filtration to obtain 900 mg (yield: 97%) of a pale pink powder of the title compound.
¹ H-NMR (DMSO-d6, 400 MHz) δ: 2.45 (3H, s), 2.56 (3H, s), 3.66 (3H, s), 6.39 (1H, d, J = 2.2 Hz), 6.85 (1H) , dd, J = 8.8, 2.2 Hz), 6.94-7.01 (2H, m), 7.17-7.23 (2H, m), 7.96 (1H, d, J = 8.8 Hz).

(5) 3-Acetyl-6-Methoxy-2-methyl-1-{4- [3- (2-oxo-2λ ^5- [1,3,2] dioxaphosphinan-2-yl) propoxy] phenyl } Indole

400 mg (1.35 mmol) of the compound prepared in Example 5 (5c) was dissolved in 4.0 mL of N, N-dimethylformamide, potassium carbonate 281 mg (2.03 mmol), potassium iodide 45 mg (0.27 mmol) and 2-. (3-Bromopropyl)-[1,3,2] dioxaphosphinan 2-oxide 362 mg (1.49 mmol) was added, and the mixture was stirred at room temperature for 4 hours and at 60 ° C. for 3.5 hours. 20 mL of water was added to the reaction mixture, and the mixture was stirred for 30 minutes, the precipitate was collected by filtration, 100 mL of water was added, and the mixture was extracted with 200 mL of ethyl acetate-tetrahydrofuran (1: 1). The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: chloroform: methanol, 1: 0: 0 → 0: 20: 1, V / V). After distilling off the solvent of the target fraction under reduced pressure, diisopropyl ether was added to the obtained residue and collected by filtration to obtain 455 mg (yield: 86%) of a white powder of the title compound.
IR ν (ATR) cm ^-1 : 1624
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.94-2.30 (6H, m), 2.52 (3H, s), 2.68 (3H, s), 3.75 (3H, s), 4.14 (2H, t, J) = 5.6 Hz), 4.21-4.35 (2H, m), 4.52-4.66 (2H, m), 6.46 (1H, d, J = 2.4 Hz), 6.91 (1H, dd, J = 7.3, 2.4 Hz), 7.02 -7.11 (2H, m), 7.17-7.25 (2H, m), 7.93 (1H, d, J = 8.8 Hz).
MS m / z: 458 [M + H] ⁺ , 480 [M + Na] ⁺ .

Example 6

(6a) 4- [4- (3-Acetyl-6-methoxy-2-methylindole-1-yl) phenoxy] butyl acetate

500 mg (1.69 mmol) of the compound prepared in Example 5 (5c) was dissolved in 5.0 mL of N, N-dimethylformamide, potassium carbonate 351 mg (2.54 mmol), potassium iodide 56 mg (0.34 mmol) and 4-. 0.36 mL (2.5 mmol) of chlorobutyl acetate was added, and the mixture was stirred at 60 ° C. for 17 hours. 30 mL of water was added to the reaction solution, and the mixture was stirred for 30 minutes, the precipitate was collected by filtration, and washed successively with water and diisopropyl ether. The obtained powder was purified by column chromatography (n-hexane: ethyl acetate, 2: 1 → 1: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 586 mg (yield: 85%) of a pale yellow powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.83-1.99 (4H, m), 2.08 (3H, s), 2.52 (3H, s), 2.68 (3H, s), 3.74 (3H, s), 4.08 (2H, t, J = 5.6 Hz), 4.18 (2H, t, J = 6.4 Hz), 6.46 (1H, d, J = 2.4 Hz), 6.91 (1H, dd, J = 8.8, 2.4 Hz), 7.02-7.09 (2H, m), 7.17-7.24 (2H, m), 7.93 (1H, d, J = 8.8 Hz).

(6b) 3-Acetyl-1- [4- (4-Hydroxybutoxy) phenyl] -6-methoxy-2-methylindole

578 mg (1.41 mmol) of the compound prepared in Example 6 (6a) was dissolved in 6.0 mL of methylene chloride-methanol (1: 1), 1.41 mL (7.1 mmol) of 5.0 M sodium hydroxide water was added, and the mixture was added at room temperature. Stirred for 1 hour. The solvent was distilled off under reduced pressure, 20 mL of water was added, and the mixture was stirred for 30 minutes. The precipitate was collected by filtration to give 483 mg (yield: 93%) of a white powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.57 (1H, t, J = 5.4 Hz), 1.77-1.87 (2H, m), 1.91-2.01 (2H, m), 2.52 (3H, s), 2.68 (3H, s), 3.74 (3H, s), 3.75-3.82 (2H, m), 4.10 (2H, t, J = 6.1 Hz), 6.46 (1H, d, J = 2.4 Hz), 6.91 (1H) , dd, J = 8.8, 2.4 Hz), 7.02-7.10 (2H, m), 7.17-7.24 (2H, m), 7.93 (1H, d, J = 8.8 Hz).

(6c) 4- [4- (3-Acetyl-6-methoxy-2-methylindole-1-yl) phenoxy] butyl methanesulfonate

478 mg (1.30 mmol) of the compound prepared in Example 6 (6b) was dissolved in 5.0 mL of methylene chloride, 0.54 mL (3.9 mmol) of triethylamine under ice cooling, and then 0.15 mL (2.0 mmol) of methanesulfonyl chloride were added thereto. The mixture was stirred at warm temperature for 1 hour. 30 mL of water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The methylene chloride layer was washed with saturated brine and dried (Na ₂ SO ₄ ), and then methylene chloride was distilled off under reduced pressure to obtain 552 mg (yield: 95%) of a pale yellow powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.94-2.10 (4H, m), 2.52 (3H, s), 2.68 (3H, s), 3.04 (3H, s), 3.74 (3H, s), 4.10 (2H, t, J = 5.4 Hz), 4.36 (2H, t, J = 5.8 Hz), 6.46 (1H, d, J = 2.4 Hz), 6.91 (1H, dd, J = 8.8, 2.4 Hz), 7.02-7.10 (2H, m), 7.18-7.25 (2H, m), 7.93 (1H, d, J = 8.8 Hz).

(6d) 3-Acetyl-6-Methoxy-2-methyl-1- [4- (4- (morpholine-4-yl) butoxy) phenyl] indole

544 mg (1.22 mmol) of the compound prepared in Example 6 (6c) was dissolved in 5.5 mL of N, N-dimethylformamide, 0.21 mL (2.4 mmol) of morpholine and 337 mg (2.44 mmol) of potassium carbonate were added, and 60 ° C. Was stirred for 16 hours. 30 mL of water was added to the reaction mixture, and the mixture was extracted with 30 mL of ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried (Na ₂ SO ₄ ), and then ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 1 → 0: 1, chloroform: methanol, 20: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 478 mg (yield: 90%) of pale yellow oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.68-1.79 (2H, m), 1.84-1.94 (2H, m), 2.41-2.51 (6H, m), 2.52 (3H, s), 2.68 (3H) , s), 3.70-3.76 (4H, m), 3.74 (3H, s), 4.07 (2H, t, J = 6.4 Hz), 6.46 (1H, d, J = 2.4 Hz), 6.91 (1H, dd, J = 8.8, 2.4 Hz), 7.02-7.09 (2H, m), 7.16-7.24 (2H, m), 7.93 (1H, d, J = 8.8 Hz).

(6) 3-Acetyl-6-methoxy-2-methyl-1- [4- (4- (morpholine-4-yl) butoxy) phenyl] indole hydrochloride

470 mg (1.08 mmol) of the compound prepared in Example 6 (6d) was dissolved in 10 mL of methanol, 0.25 mL (2.2 mmol) of an 8.6 M hydrogen chloride isopropanol solution was added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. .. The solvent was evaporated under reduced pressure, ethyl acetate was added to the obtained residue, and the insoluble material was collected by filtration. The obtained powder was dissolved by heating in 30 mL of ethanol, 150 mL of diethyl ether was added, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration to give 343 mg (yield: 67%) of a pale pink powder of the title compound.
IR ν (ATR) cm ^-1 : 1622
^{1 1} H-NMR (DMSO-d6, 400 MHz) δ: 1.77-2.00 (4H, m), 2.46 (3H, s), 2.57 (3H, s), 2.98-3.13 (2H, m), 3.13-3.23 ( 2H, m), 3.40-3.50 (2H, m), 3.66 (3H, s), 3.75-3.87 (2H, m), 3.90-4.05 (2H, m), 4.12 (2H, t, J = 5.8 Hz) , 6.38 (1H, d, J = 2.4 Hz), 6.87 (1H, dd, J = 8.8, 2.4 Hz), 7.14-7.21 (2H, m), 7.33-7.41 (2H, m), 7.97 (1H, d) , J = 8.8 Hz), 10.67-10.87 (1H, br).
MS m / z: 438 [M + H] ⁺ .

Example 7

(7a) 5-Bromo-2-methoxypyridine

Dissolve 60.8 g (0.560 mol) of 2-methoxypyridine in 300 mL of methylene chloride, add 50.5 g (0.620 mol) of sodium acetate, and add 28.7 mL (0.620 mol) of bromine at -10 ° C over 45 minutes. After stirring at the same temperature for 1 hour, the mixture was stirred at room temperature for 12 hours. After filtering the insoluble material, the filtrate was adjusted to pH 8 or higher with 5.0 M sodium hydroxide water, and the two layers were separated. The organic layer was washed with water and then dried (Na ₂ SO ₄ ). The solvent was evaporated under reduced pressure, and the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 1:20 → 1:10, V / V). The solvent of the target fraction was evaporated under reduced pressure to give 84.5 g (yield: 80%) of a colorless oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 6.65 (1H, d, J = 8.8 Hz), 7.63 (1H, dd, J = 8.8, 2.7 Hz), 8.19 (1H, d, J = 2.7 Hz) ..

(7b) 5-Bromo-2-methoxypyridin-N-oxide

84.5 g (0.450 mol) of the compound prepared in Example 7 (7a) was dissolved in 500 mL of chloroform, and 101 g (0.450 mol) of m-chloroperbenzoic acid (P = 77%) was added under ice-cooling to room temperature. Was stirred for 19 hours. After the reaction solution was dried (Na ₂ SO ₄ ), chloroform was distilled off under reduced pressure, and the residue was subjected to column chromatography (chloroform: ethyl acetate, 1: 0 → 1: 1, chloroform: methanol, 10: 1, V / V. ). The solvent of the target fraction was distilled off under reduced pressure to obtain 43.9 g (yield: 48%) of a white powder of the title compound.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 4.07 (3H, s), 6.78 (1H, d, J = 9.0 Hz), 7.38 (1H, d, J = 9.0 Hz), 8.38-8.42 (1H, s) m).

(7c) 5-Bromo-2-methoxy-4-nitropyridine

Under ice-cooling, 43.9 g (0.220 mol) of the compound prepared in Example 7 (7b) was added in portions to 80 mL of concentrated sulfuric acid, and 101 mL (2.20 mol) of fuming nitric acid was added dropwise. The temperature of the reaction solution was gradually raised, and the mixture was stirred at 80 ° C. for 3 days. The reaction mixture was poured into ice water, neutralized with potassium carbonate, extracted with chloroform, and dried (Na ₂ SO ₄ ). The solvent was distilled off under reduced pressure to obtain 30.0 g (yield: 60%) of a yellow powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 3.99 (3H, s), 7.11 (1H, s), 8.45 (1H, s).

(7d) Bis-tert-butyl (5-bromo-2-methoxypyridin-4-yl) carbamate

26.3 g (0.113 mol) of the compound prepared in Example 7 (7c) was dissolved in 100 mL of acetic acid, 30.7 g (0.550 mol) of iron was added, and the mixture was stirred at 80 ° C. for 1 hour. The insoluble material was filtered off with Celite, water was added to the filtrate, and the mixture was neutralized with potassium carbonate. After extraction with ethyl acetate twice, the organic layers were combined, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 100 mL of tetrahydrofuran, 33.9 mL (0.148 mol) of di-tert-butyl dicarbonate and 552 mg (4.90 mmol) of N, N-dimethylaminopyridine were added, and the mixture was heated under reflux for 1 hour. Tetrahydrofuran was evaporated under reduced pressure, ethyl acetate was added, the _{mixture was washed successively with water and saturated brine, dried (Na 2} SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 10: 1 → 3: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 18.2 g (yield: 40%) of a white powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.42 (18H, s), 3.94 (3H, s), 6.65 (1H, s), 8.28 (1H, s).

(7e) Bis-tert-butyl [2-methoxy-5- (2-oxopropyl) pyridin-4-yl] carbamate

Under a nitrogen atmosphere, 9.0 g (22 mmol) of the compound prepared in Example 7 (7d) was dissolved in 35 mL of toluene, isopropenyl acetate 3.69 mL (33.5 mmol), palladium acetate 250 mg (1.12 mmol), Tris (2). -Methylphenyl) phosphine 678 mg (2.23 mmol) and tributyltin methoxyde 9.63 mL (33.5 mmol) were added, and the mixture was stirred at 80 ° C. for 20 hours. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 10: 1 → 5: 1 → 3: 1, V / V). The solvent of the target fraction was evaporated under reduced pressure to give 1.40 g (yield: 17%) of a colorless oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.42 (18H, s), 2.15 (3H, s), 3.51 (2H, s), 3.95 (3H, s), 6.56 (1H, s), 8.06 ( 1H, s).

(7f) 6-Methoxy-2-methyl-1H-pyrrolo [3,2-c] pyridine

1.40 g (3.68 mmol) of the compound prepared in Example 7 (7e) was dissolved in 10 mL of trifluoroacetic acid at room temperature, and the mixture was stirred at the same temperature for 1 hour. Trifluoroacetic acid was distilled off under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogen carbonate. After extraction with chloroform twice, the organic layers were combined, dried (Na ₂ SO ₄ ), and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 3: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 460 mg (yield: 77%) of a white powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.42 (3H, s), 3.89 (3H, s), 6.20 (1H, s), 6.65 (1H, s), 8.30 (1H, s), 9.27- 9.50 (1H, br).

(7g) 1- (4- {4- [2- (tert-butyldimethylsilanyloxy) ethoxy] piperidine-1-yl} phenyl) -6-methoxy-2-methyl-1H-pyrrolo [3,2- c] Pyridine

Compound 450 mg (2.77 mmol) prepared in Example 7 (7f) was dissolved in 5 mL of toluene, and compound 1.54 g (3.32 mmol) prepared in Example 3 (3c), copper iodide 27 mg (0.14 mmol). Add 1.23 g (5.82 mmol) of crushed tripotassium phosphate and 0.066 mL (0.42 mmol) of trans-N, N'-dimethylcyclohexane-1,2-diamine, bubbling nitrogen for 10 minutes, and then 100 ° C. under a nitrogen atmosphere. Was stirred for 28 hours. 27 mg (0.14 mmol) of copper iodide and 0.066 mL (0.42 mmol) of trans-N, N'-dimethylcyclohexane-1,2-diamine were added, and the mixture was further stirred for 13 hours. Ethyl acetate and water were added, and the insoluble material was filtered off with Celite. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 10: 1 → 6: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 210 mg (yield: 15%) of a brown oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 0.09 (6H, s), 0.91 (9H, s), 1.70-1.83 (2H, m), 2.00-2.10 (2H, m), 2.22 (3H, s) ), 2.97-3.10 (2H, m), 3.55-3.65 (5H, m), 3.78 (2H, t, J = 5.4 Hz), 3.91 (3H, s), 6.31 (1H, s), 6.35 (1H, 1H, s), 7.00-7.02 (2H, m), 7.13-7.15 (2H, m), 8.36 (1H, s).

(7h) 2- {1- [4- (6-Methoxy-2-methyl-1H-pyrrolo [3,2-c] pyridin-1-yl) phenyl] piperidine-4-yloxy} ethyl acetate

210 mg (0.42 mmol) of the compound prepared in Example 7 (7 g) was dissolved in 2 mL of tetrahydrofuran, 1.3 mL (1.3 mmol) of a 1.0 M tetra-n-butylammonium tetrahydrofuran tetrahydrofuran solution was added under ice-cooling, and the temperature was the same. After stirring for 30 minutes, 0.63 mL (0.63 mmol) of a 1.0 M tetra-n-butylammonium tetrahydrofuran solution was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained colorless oil was dissolved in 2 mL of methylene chloride, 0.18 mL (1.3 mmol) of triethylamine and 60 μL (0.84 mmol) of acetyl chloride were added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 3: 1 → 1: 1, V / V). The solvent of the target fraction was evaporated under reduced pressure to give 125 mg (yield: 71%) of a colorless oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.72-1.86 (2H, m), 2.00-2.08 (2H, m), 2.10 (3H, s), 2.22 (3H, s), 3.00-3.10 (2H) , m), 3.50-3.66 (3H, m), 3.69-3.78 (2H, m), 3.91 (3H, s), 4.24-4.30 (2H, m), 6.31 (1H, s), 6.35 (1H, s) ), 7.00-7.03 (2H, m), 7.14-7.16 (2H, m), 8.37 (1H, s).

(7i) 2- {1- [4- (3-Acetyl-6-methoxy-2-methyl-1H-pyrrolo [3,2-c] pyridin-1-yl) phenyl] piperidine-4-yloxy} ethyl acetate

60 mg (0.45 mmol) of pulverized aluminum chloride was suspended in 1 mL of methylene chloride, 39 μL (0.54 mmol) of acetyl chloride was added under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. A solution of 76 mg (0.18 mmol) of the compound prepared in Example 7 (7h) in 1 mL of methylene chloride was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Methylene chloride and water were added to the reaction mixture, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate. The two layers were separated and the methylene chloride layer was dried (Na ₂ SO ₄ ). The solvent was distilled off under reduced pressure to obtain 42 mg (yield: 50%) of a brown oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.73-1.85 (2H, m), 2.00-2.08 (2H, m), 2.04 (3H, s), 2.53 (3H, s), 2.69 (3H, s) ), 3.04-3.14 (2H, m), 3.54-3.66 (3H, m), 3.72 (2H, t, J = 5.1 Hz), 3.94 (3H, s), 4.20-4.30 (2H, m), 6.33 ( 1H, s), 7.02-7.04 (2H, m), 7.10-7.12 (2H, m), 8.87 (1H, s).

(7) 2- {1- [4- (3-Acetyl-6-methoxy-2-methyl-1H-pyrrolo [3,2-c] pyridin-1-yl) phenyl] piperidine-4-yloxy} ethanol

40 mg (0.086 mmol) of the compound prepared in Example 7 (7i) was dissolved in 1 mL of a mixed solution of methylene chloride-methanol (1: 1), and at room temperature, 86 μL (0.43 mmol) of 5.0 M sodium hydroxide water was added. In addition, the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, the mixture was extracted with methylene chloride, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue and collected by filtration to give 20 mg (yield: 56%) of a white powder of the title compound.
IR ν (ATR) cm ^-1 : 3350-3100, 1635
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.75-1.83 (2H, m), 2.03-2.11 (2H, m), 2.54 (3H, s), 2.69 (3H, s), 3.05-3.15 (2H) , m), 3.57-3.69 (5H, m), 3.73 (2H, m), 3.94 (3H, s), 6.33 (1H, s), 7.03-7.05 (2H, m), 7.11-7.13 (2H, m) ), 8.88 (1H, s).
MS m / z: 424 [M + H] ⁺ , 446 [M + Na] ⁺ .

Example 8

(8a) 1-(4- {4- [2- (tert-butyldimethylsilanyloxy) ethoxy] piperidine-1-yl} phenyl) -3-iodo-6-methoxy-2-methyl-1H-pyrrolo [ 3,2-c] pyridine

3.03 g (6.11 mmol) of the compound prepared in Example 7 (7 g) was dissolved in 30 mL of tetrahydrofuran, 1.51 g (6.72 mmol) of N-iodosuccinimide was added, and the mixture was stirred at room temperature for 40 minutes. 100 mL of 5% sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 4: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 3.52 g (yield: 93%) of a slightly yellow powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 0.09 (6H, s), 0.91 (9H, s), 1.70-1.84 (2H, m), 1.97-2.09 (2H, m), 2.26 (3H, s) ), 3.00-3.12 (2H, m), 3.53-3.64 (5H, m), 3.73-3.82 (2H, m), 3.92 (3H, s), 6.29 (1H, s), 6.98-7.04 (2H, m) ), 7.08-7.14 (2H, m), 8.20 (1H, s).

(8b) 1-(4- {4- [2- (tert-butyldimethylsilanyloxy) ethoxy] piperidine-1-yl} phenyl) -6-methoxy-2-methyl-1H-pyrrolo [3,2- c] Pyridine-3-carbonitrile

Compound 3.49 g (5.61 mmol) prepared in Example 8 (8a), copper (I) cyanide (I) 1.76 g (19.6 mmol), tris (dibenzylideneacetone) dipalladium (0) 257 mg (0.281 mmol), 1, 544 mg (0.982 mmol) of 1'-bis (diphenylphosphino) ferrocene was suspended in 60 mL of 1,4-dioxane, heated under reflux for 15 hours, and stirred at room temperature for 7 hours. The insoluble material was filtered off with Celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 4: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 2.27 g (yield: 78%) of a yellow powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 0.09 (6H, s), 0.91 (9H, s), 1.70-1.83 (2H, m), 1.97-2.09 (2H, m), 2.39 (3H, s) ), 3.03-3.15 (2H, m), 3.55-3.66 (5H, m), 3.73-3.82 (2H, m), 3.93 (3H, s), 6.36 (1H, s), 6.98-7.07 (2H, m) ), 7.08-7.15 (2H, m), 8.51 (1H, s).

(8) 1- {4- [4- (2-Hydroxyethoxy) piperidine-1-yl] phenyl} -6-methoxy-2-methyl-1H-pyrrolo [3,2-c] pyridine-3-carboxamide

Under ice-cooling, 15 mL of concentrated sulfuric acid was added to 1.92 g (3.69 mmol) of the compound prepared in Example 8 (8b), and the mixture was stirred at room temperature for 3 hours. Under ice-cooling, 100 mL of water was added to the reaction solution, neutralized with 5.0 M sodium hydroxide water, and extracted 13 times with chloroform. The organic layers were combined, washed with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate and then dissolved in 8 mL of 10% hydrochloric acid. Toluene (8 mL) was added, and the mixture was neutralized with 5.0 M sodium hydroxide water with stirring, and the precipitate was collected by filtration to obtain 754 mg (yield: 48%) of a slightly yellow powder of the title compound.
IR ν (ATR) cm ^-1 : 1641, 1513, 1352, 1144
^{1 1} H-NMR (DMSO-d6, 400 MHz) δ: 1.88-2.03 (2H, m), 2.38 (3H, s), 2.95-3.07 (2H, m), 3.44-3.56 (5H, m), 3.58- 3.69 (2H, m), 3.82 (3H, s), 6.18 (1H, s), 7.07-7.15 (2H, m), 7.16-7.25 (2H, m), 8.65 (1H, s).
MS m / z: 425 [M + H] ⁺ , 447 [M + Na] ⁺ , 423 [MH] ^- .

Example 9

(9a) 4-Hydroxy-6,7-dimethoxy-1-methyl-1H-quinoline-2-one

8.86 g (57.8 mmol) of 3,4-dimethoxyaniline was dissolved in 100 mL of tetrahydrofuran, 14.0 mL (60.9 mmol) of di-tert-butyl dicarbonate was added, and the mixture was heated under reflux for 1.5 hours. The solvent was distilled off under reduced pressure, n-hexane was added, and the solvent was distilled off again under reduced pressure. Diisopropyl ether was added to the obtained residue and collected by filtration to obtain 10.3 g of a brown powder containing tert-butyl (3,4-dimethoxyphenyl) carbamate.
Dissolve 10.3 g of the obtained powder in 100 mL of N, N-dimethylformamide, add 1.94 g (49 mmol) of sodium hydride (P = 60%) in portions at 0 ° C, and stir at the same temperature for 15 minutes. After that, 3.78 mL (60.7 mmol) of methyl iodide was added, and the mixture was stirred at the same temperature for 40 minutes and at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers are combined, washed sequentially with water and saturated brine, dried (Na ₂ SO ₄ ), and then the solvent is distilled off under reduced pressure to obtain a residue containing tert-butyl (3,4-dimethoxyphenyl) methylcarbamate. rice field.
30 mL of the obtained residue was added, and 15.3 mL (0.13 mol) of an 8.6 M hydrogen chloride isopropanol solution was added under ice-cooling, and the mixture was stirred at the same temperature for 20 minutes. The reaction mixture is poured into 1.2 L of ice water, neutralized with potassium carbonate, extracted twice with ethyl acetate, combined with organic layers, washed with saturated brine, dried (Na ₂ SO ₄ ), and then reduced in pressure. The lower solvent was distilled off to obtain a residue containing (3,4-dimethoxyphenyl) methylamine.
To the obtained residue was added 8.43 g (81.0 mmol) of malonic acid and 35.0 mL (378 mmol) of phosphorus oxychloride, and the mixture was stirred at 90 ° C. for 2 hours. The reaction mixture was poured into ice water, 130 mL of 5.0 M sodium hydroxide water was added, neutralized with potassium carbonate, and extracted twice with ethyl acetate and three times with chloroform. The organic layers were combined, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the obtained residue and collected by filtration to obtain 1.96 g (yield: 14%) of a reddish brown powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 3.53 (3H, s), 3.80 (3H, s), 3.91 (3H, s), 5.75 (1H, s), 6.90 (1H, s), 7.27 ( 1H, s), 11.14 (1H, s).

(9b) 4-Chloro-6,7-dimethoxy-1-methyl-1H-quinoline-2-one

To 948 mg (4.03 mmol) of the compound prepared in Example 9 (9a) was added 3 5.63 mL (60.5 mmol) of phosphorus oxychloride, and the mixture was stirred at 90 ° C. for 2 hours. 100 mL of water was added to the reaction mixture, the pH was adjusted to 11 or higher with potassium carbonate, and the mixture was extracted twice with ethyl acetate and twice with chloroform. The organic layers were combined, washed with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the obtained residue and collected by filtration to obtain 815 mg (yield: 80%) of a reddish brown powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 3.71 (3H, s), 3.98 (3H, s), 4.03 (3H, s), 6.77 (1H, s), 6.78 (1H, s), 7.36 ( 1H, s).

(9c) 1-Phenyl-3- [2- (Tetrahydropyran-2-yloxy) ethoxy] Azetidine

Dissolve 20.0 g (83.6 mmol) of benzhydryl azetidine-3-ol in 150 mL of dimethylformamide, add 5.02 g (125 mmol) of sodium hydride (P = 60%) in portions under ice-cooling, and then add at the same temperature. Was stirred. 18.9 mL (125 mmol) of 2- (2-bromoethoxy) tetrahydropyran was added dropwise, and the mixture was stirred at 60 ° C. for 30 minutes. Sodium hydride (P = 60%) of 2.00 g (50 mmol) was added, and the mixture was further stirred for 12 hours and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate, 6: 1 → 3: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 23.8 g of a light brown oil of 1-benzhydryl-3- [2- (tetrahydropyran-2-yloxy) ethoxy] azetidine (yield: 77%). ..
Suspend 0.90 g of Pd (OH) _2- C in 200 mL of methanol, add 17.7 g (48.2 mmol) of 1-benzhydryl-3- [2- (tetrahydropyran-2-yloxy) ethoxy] azetidine, room temperature, 0.3 MPa. Contact hydrogenation was added for 46 hours. After filtering Pd (OH) _2- C, the solvent was distilled off under reduced pressure. To the obtained residue was added 7.0 mL (63 mmol) of phenyl iodide, 918 mg (4.82 mmol) of copper iodide, 1.11 g (9.64 mmol) of L-proline, 13.3 g (96.2 mmol) of potassium carbonate and 24 mL of dimethyl sulfoxide. After bubbling nitrogen for 1 minute, the mixture was stirred at 70 ° C. for 19 hours under a nitrogen atmosphere. After allowing to cool, the reaction solution was poured into 120 mL of water and extracted twice with 100 mL of ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate, 5: 1 → 2: 1, V / V). The solvent of the target fraction was evaporated under reduced pressure to give 7.8 g (yield: 55%) of a yellow oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.40-1.90 (6H, m), 3.47-3.67 (4H, m), 3.69-3.78 (2H, m), 3.82-3.92 (2H, m), 4.08 -4.16 (2H, m), 4.47-4.55 (1H, m), 4.62-4.68 (1H, m), 6.44-6.52 (2H, m), 6.70-6.78 (1H, m), 7.16-7.26 (2H, m) m).

(9d) 1- (4-iodophenyl) -3- [2- (tetrahydropyran-2-yloxy) ethoxy] azetidine

7.8 g (28 mmol) of the compound prepared in Example 9 (9c) was dissolved in 40 mL of methylene chloride, 3.5 g (42 mmol) of baking soda and 40 mL of water were added, and 7.46 g (29.4 mmol) of iodine was added at room temperature. After the divided addition over 1 hour, the mixture was further stirred for 1.5 hours. 40 mL of 5% sodium thiosulfate water was added, and the mixture was stirred for 30 minutes, and then methylene chloride was distilled off under reduced pressure. The residue was extracted with 200 mL of ethyl acetate, and the organic layer was washed successively with 5% sodium thiosulfate solution and saturated brine, and dried (Na ₂ SO ₄ ). The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (n-hexane: ethyl acetate, 4: 1 → 2: 1, V / V). The solvent of the target fraction was evaporated under reduced pressure to give 10.34 g (yield: 92%) of a yellow oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.40-1.90 (6H, m), 3.47-3.65 (4H, m), 3.68-3.75 (2H, m), 3.83-3.91 (2H, m), 4.07 (2H, t, J = 7.1 Hz), 4.44-4.52 (1H, m), 4.60-4.65 (1H, m), 6.20-6.25 (2H, m), 7.43-7.47 (2H, m).

(9e) 1- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3- [2- (tetrahydropyran-2-yloxy) ethoxy] Azetidine

Compound 2.50 g (6.20 mmol) prepared in Example 9 (9d), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct 101 mg (0.124 mmol), 4,4, Suspend 1,35 mL (9.30 mmol) of 5,5-tetramethyl-1,3,2-dioxaborolane in 20 mL of 1,4-dioxane, add 4.32 mL (31.0 mmol) of triethylamine, and at 80 ° C. under a nitrogen atmosphere. Stirred for 40 minutes. 100 mL of water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 10: 1 → 5: 1, V / V). The solvent of the target fraction was evaporated under reduced pressure to give 1.83 g (yield: 73%) of a slightly yellow oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.29-1.78 (18H, m), 3.46-3.54 (1H, m), 3.55-3.66 (3H, m), 3.73-3.81 (2H, m), 3.82 -3.91 (2H, m), 4.08-4.17 (2H, m), 4.46-4.54 (1H, m), 4.59-4.65 (1H, m), 6.37-6.45 (2H, m).

(9f) 6,7-Dimethoxy-1-methyl-4- (4- {3- [2- (tetrahydropyran-2-yloxy) ethoxy] azetidine-1-yl} phenyl) -1H-quinoline-2-one

Compound 200 mg (0.788 mmol) prepared in Example 9 (9b), compound 381 mg (0.946 mmol) prepared in Example 9 (9e), tetrakis (triphenylphosphine) palladium (0) 92 mg (0.079 mmol). , 515 mg (1.58 mmol) of cesium carbonate was suspended in 8 mL of 1,4-dioxane, and the mixture was stirred at 80 ° C. for 16 hours under a nitrogen atmosphere. 80 mL of water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: ethyl acetate, 1: 1 → 1: 2 → 1: 3, V / V). The solvent of the target fraction was evaporated under reduced pressure to give 123 mg (yield: 32%) of a brown oil of the title compound.

(9) 4- {4- [3- (2-Hydroxyethoxy) azetidine-1-yl] phenyl} -6,7-dimethoxy-1-methylquinoline-2 (1H) -one

123 mg (0.294 mmol) of the compound prepared in Example 9 (9f) was dissolved in 2.5 mL of methanol, 86 μL (0.75 mmol) of an 8.6 M hydrogen chloride isopropanol solution was added under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. .. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, 50 mL of water was added, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: methanol, 100: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 23 mg (yield: 23%) of a yellow powder of the title compound.
IR ν (ATR) cm ^-1 : 1635, 1041
^{1 1} H-NMR (DMSO-d6, 400 MHz) δ: 3.41-3.47 (2H, m), 3.49-3.56 (2H, m), 3.63-3.73 (8H, m), 3.95 (3H, s), 4.09- 4.18 (2H, m), 4.43-4.52 (1H, m), 4.60-4.75 (1H, br), 6.28 (1H, s), 6.54-6.61 (2H, m), 7.03 (1H, s), 7.04 ( 1H, s), 7.29-7.37 (2H, m).
MS m / z: 411 [M + H] ⁺ , 433 [M + Na] ⁺ , 409 [MH] ^- .

Example 10

(10a) 5-tert-Butyloxycarbonylamino-2-methoxyisonicotinic acid

10.0 g (80.6 mmol) of 5-amino-2-methoxypyridine was dissolved in 100 mL of tetrahydrofuran, 18.5 mL (80.6 mmol) of di-tert-butyl dicarbonate was added, and the mixture was heated under reflux for 2 hours. Tetrahydrofuran was distilled off under reduced pressure, and the residue was purified by column chromatography (n-hexane: ethyl acetate, 2: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain a light brown oil (18.2 g, yield: quantitative) of tert-butyl (6-methoxypyridin-3-yl) carbamate.
5.00 g (22.3 mmol) of tert-butyl (6-methoxypyridin-3-yl) carbamate was dissolved in 120 mL of dehydrated diethyl ether, and 10 mL (67 mmol) of N, N, N, N-tetramethylethylenediamine was added. At -78 ° C, 26 mL (67 mmol) of a 2.6 M n-butyllithium n-hexane solution was added dropwise. After stirring at -20 ° C for 2 hours, the temperature was slowly raised to 0 ° C while blowing carbon dioxide gas at -78 ° C. Water was added to the reaction solution, the two layers were separated, and the aqueous layer was washed with diethyl ether. 13 mL of concentrated hydrochloric acid was added to the aqueous layer, and the precipitate was collected by filtration and washed with water to obtain 2.94 g (yield: 49%) of a slightly yellow powder of the title compound.
¹ H-NMR (DMSO-d6, 400 MHz) δ: 1.45 (9H, s), 3.84 (3H, s), 7.12 (1H, s), 8.67 (1H, s), 9.40 (1H, s).

(10b) Methyl 2-methoxy-5-methylaminoisonicotinate

6.30 g (23.5 mmol) of the compound prepared in Example 10 (10a) was dissolved in 50 mL of N, N-dimethylformamide, and sodium hydride (P = 60%) 2.82 g (71 mmol) was added under ice-cooling. After stirring at the same temperature for 10 minutes, 7.3 mL (120 mmol) of methyl iodide was added, and the mixture was stirred at room temperature for 30 minutes. 5% water citrate was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried (Na ₂ SO ₄ ). The solvent was distilled off under reduced pressure to obtain 8.19 g (yield: quantitative) of a brown oil of methyl 5- (tert-butoxycarbonylmethylamino) -2-methoxyisonicotinate.
Methyl 5- (tert-butoxycarbonylmethylamino) -2-methoxyisonicotinate 8.19 g (23.5 mmol) was dissolved in 20 mL of formic acid, and 8.6 M hydrogen chloride isopropanol solution 8.2 mL (71 mmol) was added under ice-cooling. In addition, the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into cold water, neutralized with potassium carbonate, extracted twice with ethyl acetate, the organic layers were combined, and dried (Na ₂ SO ₄ ). The solvent was evaporated under reduced pressure, diisopropyl ether was added to the residue, and the mixture was collected by filtration to give 2.50 g of a yellow powder of the title compound. The solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography (n-hexane: ethyl acetate, 5: 1, V / V) to obtain 2.02 g of yellow powder of the title compound. .. (Total yield: 98%)
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.93 (3H, m), 3.88 (3H, m), 3.89 (3H, m), 7.18 (1H, s), 7.74 (1H, m).

(10c) Methyl 5-[(2-ethoxycarbonylacetyl) Methylamino] -2-methoxyisonicotinate

4.52 g (23.0 mmol) of the compound prepared in Example 10 (10b) was dissolved in 40 mL of methylene chloride, and under ice-cooling, 4.17 mL (29.9 mmol) of triethylamine and 3.24 mL (25.3 mmol) of ethylmalonyl chloride were added. After stirring at warm temperature for 30 minutes, 0.64 mL (4.6 mmol) of triethylamine and 0.29 mL (2.3 mmol) of ethylmalonyl chloride were added, and the mixture was further stirred at the same temperature for 30 minutes. The reaction mixture was washed successively with water and saturated brine, and dried (Na ₂ SO ₄ ). The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (n-hexane: methanol, 9: 1 → 3: 7, V / V). The solvent of the target fraction was distilled off under reduced pressure, and 5.37 g of the yellow oil of the title compound (yield: 75).
%) Was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.23 (3H, t, J = 7.3 Hz), 3.11 (2H, s), 3.20 (3H, m), 3.91 (3H, m), 3.99 (3H, m) m), 4.12 (2H, q, J = 7.3 Hz), 7.24 (1H, s), 8.15 (1H, m).

(10d) 4-Hydroxy-6-methoxy-1-methyl-1H- [1,7] diazanaphthalene-2-one

5.37 g (17.3 mmol) of the compound prepared in Example 10 (10c) was suspended in 50 mL of ethanol, 2.36 g (34.6 mmol) of sodium ethoxide was added in portions at room temperature, and then 40 mL of ethanol was added at the same temperature. Was stirred for 1.5 hours. The reaction mixture was poured into 10% aqueous citric acid, ethyl acetate was added, the insoluble material was collected by filtration, and ethyl 4-hydroxy-6-methoxy-1-methyl-2-oxo-1,2-dihydro- [1 , 7] 1.80 g of yellow powder of naphthylidine-3-carboxylate was obtained. The filtrate was extracted twice with ethyl acetate, the organic layers were combined, washed successively with water and saturated brine, and dried (Na ₂ SO ₄ ). The solvent was distilled off under reduced pressure to obtain 2.94 g of a yellow powder of ethyl 4-hydroxy-6-methoxy-1-methyl-2-oxo-1,2-dihydro- [1,7] naphthylidine-3-carboxylate. rice field. (Total yield 99%)
Ethyl 4-hydroxy-6-methoxy-1-methyl-2-oxo-1,2-dihydro- [1,7] diazanaphthalene-3-carboxylate 4.73 g (17.0 mmol) with 40 mL of concentrated hydrochloric acid and 40 of trifluoroacetic acid mL was added, and the mixture was stirred at 80 ° C. for 13 hours. The solvent was evaporated under reduced pressure, the obtained residue was neutralized with saturated aqueous sodium hydrogen carbonate, and the precipitated powder was collected by filtration to give 1.80 g of a yellow powder of the title compound. The filtrate was extracted twice with ethyl acetate, the organic layers were combined, washed successively with water and saturated brine, and dried (Na ₂ SO ₄ ). The solvent was distilled off under reduced pressure to obtain 2.94 g of a yellow powder of the title compound. (Total yield: 99%)
^{1 1} H-NMR (DMSO-d6, 400 MHz) δ: 3.54 (3H, s), 3.89 (3H, s), 5.96 (1H, s), 7.08 (1H, s), 8.44 (1H, s), 11.61 (1H, s).

(10e) 4-Chloro-6-methoxy-1-methyl-1H- [1,7] diazanaphthalene-2-one

964 mg (4.68 mmol) of compound prepared in Example 10 (10d) was suspended in 6.54 mL (70.1 mmol) of phosphorus oxychloride and stirred at 90 ° C. for 1 hr. After allowing to cool, 100 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and then chloroform. The organic layers were combined, washed with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: methanol, 50: 1, V / V). After distilling off the solvent of the target fraction under reduced pressure, diisopropyl ether was added to the residue and collected by filtration to obtain 754 mg (yield: 72%) of a pale yellow powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 3.71 (3H, s), 4.00 (3H, s), 7.00 (1H, s), 7.24 (1H, s), 8.38 (1H, s).

(10) 4- {4- [3- (2-Hydroxyethoxy) azetidine-1-yl] phenyl} -6-methoxy-1-methyl-1H- [1,7] naphthididine-2-one

200 mg (0.890 mmol) of the compound prepared in Example 10 (10e) and 432 mg (1.07 mmol) of the compound prepared in Example 9 (9e) were suspended in 4.0 mL of N, N-dimethylformamide and tripotassium phosphate. 567 mg (2.67 mmol) and 103 mg (0.089 mmol) of tetrakis (triphenylphosphine) palladium (0) were added, and the mixture was stirred at 90 ° C. for 80 minutes under a nitrogen atmosphere. After allowing to cool, 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 2: 1 → 1: 1 → 0: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 480 mg of a brown oil.
480 mg of the obtained oil was dissolved in 2.4 mL of 6.0 M hydrochloric acid, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: methanol, 1: 0 → 50: 1, V / V). The solvent of the target fraction was evaporated under reduced pressure, diisopropyl ether was added to the residue, and the mixture was collected by filtration to give 242 mg (yield: 71%) of a yellow powder of the title compound.
IR ν (ATR) cm ^-1 : 3556, 1639, 1610
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.85-2.20 (1H, br), 3.55-3.62 (2H, m), 3.75 (3H, s), 3.76-3.82 (2H, m), 3.83 (2H) , dd, J = 8.3, 4.4 Hz), 3.94 (3H, s), 4.14-4.24 (2H, m), 4.47-4.57 (1H, m), 6.50-6.59 (2H, m), 6.74 (1H, s) ), 6.98 (1H, s), 7.23-7.32 (2H, m), 8.38 (1H, s).
MS m / z: 382 [M + H] ⁺ , 404 [M + Na] ⁺ , 380 [MH] ^- .

Example 11

(11a) 4-Hydroxy-6-methoxy-2H-chromen-2-one

Dissolve 5.00 g (30.1 mmol) of 1- (2-hydroxy-5-methoxyphenyl) etanone in 50 mL of toluene, add 5.5 mL (45 mmol) of diethyl carbonate and 5.10 g (45.5 mmol) of potassium tert-butoxide, and room temperature. After stirring at 60 ° C. for 2 hours, 5.5 mL (45 mmol) of diethyl carbonate and 5.10 g (45.5 mmol) of potassium tert-butoxide were added, and the mixture was further stirred at 60 ° C. for 6 hours. 17 mL (0.10 mol) of 6.0 M hydrochloric acid and 50 mL of water were added to the reaction solution under ice-cooling, and the precipitate was collected by filtration. The obtained powder was washed successively with water, methanol and diethyl ether to obtain 4.75 g (yield: 82%) of a light brown powder of the title compound.
^{1 1} H-NMR (DMSO-d6, 400 MHz) δ: 3.80 (3H, s), 5.60 (1H, s), 7.18-7.23 (2H, m), 7.29 (1H, d, J = 8.5 Hz), 12.42 -12.61 (1H, br).

(11b) 4-Chloro-6-methoxy-2H-chromen-2-one

4.64 g (24.1 mmol) of the compound prepared in Example 11 (11a) was suspended in 80 mL of chloroform, 19.0 g (72.4 mmol) of triphenylphosphine and 7.2 mL (72 mmol) of carbon tetrachloride were added, and the mixture was heated under reflux for 2 hours. bottom. After allowing to cool, the reaction mixture was concentrated to dryness under reduced pressure, and the obtained residue was purified by column chromatography (n-hexane: chloroform, 1: 1 → 0: 1, V / V). After distilling off the solvent of the target fraction under reduced pressure, the residue was washed successively with 100 mL of methanol and 20 mL of diisopropyl ether to obtain 2.61 g (yield: 51%) of a light brown powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 3.89 (3H, s), 6.61 (1H, s), 7.18 (1H, dd, J = 9.0, 2.9 Hz), 7.27 (1H, d, J = 2.9) Hz), 7.29 (1H, d, J = 9.0 Hz).

(11c) 6-Methoxy-4- (4- {3- [2- (tetrahydropyran-2-yloxy) ethoxy] azetidine-1-yl} phenyl) -2H-chromen-2-one

Compound 415 mg (1.03 mmol) prepared in Example 9 (9e) was dissolved in 4 mL of N, N-dimethylformamide, and compound 217 mg (1.03 mmol) prepared in Example 11 (11b), tripotassium phosphate. 656 mg (3.09 mmol) and tetrakis (triphenylphosphine) palladium (0) 119 mg (0.103 mmol) were added, and the mixture was stirred at 90 ° C. for 1 hour under a nitrogen atmosphere. After allowing to cool, the reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, and dried (Na ₂ SO ₄ ). The solvent was evaporated under reduced pressure, and the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 9: 1 → 1: 4, V / V). After distilling off the solvent of the target fraction under reduced pressure, the residue was washed successively with 100 mL of methanol and 20 mL of diisopropyl ether to obtain 250 mg (yield: 54%) of a brown oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.50-1.92 (6H, m), 3.48-3.55 (1H, m), 3.59-3.71 (3H, m), 3.76 (3H, s), 3.83-3.93 (4H, m), 4.17-4.22 (2H, m), 4.52-4.58 (1H, m), 4.62-4.66 (1H, m), 6.31 (1H, s), 6.52-6.57 (2H, m), 7.07 -7.12 (2H, m), 7.30-7.36 (3H, m).

(11) 4- {4- [3- (2-Hydroxyethoxy) azetidine-1-yl] phenyl} -6-methoxy-2H-chromen-2-one

245 mg (0.543 mmol) of the compound prepared in Example 11 (11c) was suspended in 4 mL of methanol, 1 mL of tetrahydrofuran and 8.6 M hydrogen chloride isopropanol solution 0.19 mL (1.6 mmol) were added under ice-cooling, and the temperature was the same. Stirred for 0.5 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture to adjust the pH to 8-9, methanol was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted twice with chloroform. The organic layers were combined, dried (Na ₂ SO ₄ ), the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (chloroform: methanol, 1: 0 → 93: 7, V / V). The solvent of the target fraction was evaporated under reduced pressure, and the residue was purified again by column chromatography (n-hexane: ethyl acetate, 1: 1 → 1: 3 → 0: 1, V / V). The solvent of the target fraction was evaporated under reduced pressure, 5 mL of diisopropyl ether was added to the residue, and the mixture was collected by filtration to give 99 mg (yield: 50%) of a pale yellow powder of the title compound.
IRν (ATR) cm ^-1 : 3465, 1709, 1685
^{1 1} H-NMR (DMSO-d6, 400 MHz) δ: 3.43-3.48 (2H, m), 3.50-3.56 (2H, m), 3.70-3.75 (5H, m), 4.13-4.19 (2H, m), 4.45-4.52 (1H, m), 4.63-4.70 (1H, br), 6.30 (1H, s), 6.56-6.61 (2H, m), 7.04 (1H, d, J = 2.9 Hz), 7.26 (1H, s) dd, J = 9.0, 2.9 Hz), 7.40-7.46 (3H, m).
MS m / z: 368 [M + H] ⁺ , 366 [MH] ^- .

Example 12

(12a) 4- (1-Benz Hydrill Azetidine-3-yl) Morpholine

5.00 g (20.9 mmol) of 1-benzhydryl azetidine-3-ol was dissolved in 40 mL of methylene chloride, and 4.38 mL (31.4 mmol) of triethylamine and 1.94 mL (25.1 mmol) of methanesulfonyl chloride were added under ice-cooling. The mixture was stirred at warm temperature for 30 minutes. 200 mL of water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure.
The obtained residue was dissolved in 40 mL of N, N-dimethylformamide, 3.65 mL (41.8 mmol) of morpholine and 5.78 g (41.8 mmol) of potassium carbonate were added, and the mixture was stirred at 70 ° C. for 20 hours and at room temperature for 42 hours. .. 200 mL of water was added to the reaction solution, the mixture was extracted twice with ethyl acetate, the organic layers were combined, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. .. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 3: 1, V / V), and the solvent of the target fraction was distilled off under reduced pressure to obtain 5.51 g of a pale yellow oil of the title compound. (Yield: 85%) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.26-2.33 (4H, m), 2.87-3.02 (3H, m), 3.36-3.43 (2H, m), 3.68-3.73 (4H, m), 4.41 (1H, s), 7.16-7.43 (10H, m).

(12b) 4- [1- (4-Nitrophenyl) Azetidine-3-yl] Morpholine

To 100 mL of methanol, 800 mg of 20% Pd (OH) _2- C (wet.) And 5.50 g (17.8 mmol) of the compound prepared in Example 12 (12a) were added under an argon atmosphere, and 0.4 MPa was added at room temperature for 3.5 hours. Contact hydrogenation was added. Pd (OH) _2- C was filtered off with Celite, and the solvent was distilled off under reduced pressure.
The obtained residue and 1.27 g (23.1 mmol) of 1-fluoro-4-nitrobenzene were dissolved in 30 mL of N, N-dimethylformamide, 3.69 g (26.7 mmol) of potassium carbonate was added, and the mixture was stirred at 70 ° C. for 12 hours. .. 200 mL of water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue and collected by filtration to obtain 3.10 g (yield: 66%) of a yellow powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.41-2.52 (4H, m), 3.35-3.41 (1H, m), 3.72-3.81 (4H, m), 3.86-3.92 (2H, m), 4.07 -4.11 (2H, m), 6.29-6.33 (2H, m), 8.08-8.12 (2H, m).

(12c) (2-Methoxy-5-nitropyridin-4-yl)-[4- (3- (morpholine-4-yl) azetidine-1-yl) phenyl] amine

To 80 mL of a mixed solution of methanol-tetrahydrofuran (7: 1 _{), add 230 mg of 10% Pd (OH) 2-} C (wet.) Under an argon atmosphere and 1.40 g (5.32 mmol) of the compound prepared in Example 12 (12b). , 0.4 MPa was contact hydrogenated for 35 minutes. Pd (OH) _2- C was filtered off with Celite, and the solvent was distilled off under reduced pressure.
Dissolve the obtained residue and 1.20 g (6.38 mmol) of 4-chloro-2-methoxy-5-nitropyridine in 15 mL of N, N-dimethylformamide, add 1.85 mL (10.6 mmol) of diisopropylethylamine, and bring to 70 ° C. Stirred for 3.5 hours. 150 mL of water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: ethyl acetate, 1: 0 → 1: 2, V / V), the solvent for the target fraction was distilled off under reduced pressure, and 1.81 g of the orange powder of the title compound was distilled off. (Yield: 88%) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.41-2.52 (4H, m), 3.30-3.39 (1H, m), 3.72-3.81 (6H, m), 3.90 (3H, s), 4.07 -4.11 (2H, m), 6.06 (1H, s), 6.45-6.50 (2H, m), 7.04-7.09 (2H, m), 9.02 (1H, s), 9.27 (1H, s).

(12) 7-Methoxy-4-methyl-1- [4- (3- (morpholine-4-yl) azetidine-1-yl) phenyl] -1,4-dihydro-2H-pyrido [3,4-b ] Pyrazine-3-on

To 100 mL of a mixed solution of methanol-tetrahydrofuran (9: 1), 250 mg of 10% Pd-C under an argon atmosphere and 1.78 g (4.62 mmol) of the compound prepared in Example 12 (12c) were added, and 0.4 MPa at room temperature 45. Contact hydrogenation was added for minutes. Pd-C was filtered off with Celite, and the solvent was distilled off under reduced pressure.
The obtained residue is dissolved in 10 mL of tetrahydrofuran (dehydrated), 966 μL (6.93 mmol) of triethylamine and 368 μL (4.62 mmol) of chloroacetyl chloride are sequentially added under ice-cooling, and the mixture is stirred at the same temperature for 1 hour, and then 644 μL of triethylamine (644 μL). 4.62 mmol) and 200 μL (2.51 mmol) of chloroacetyl chloride were sequentially added, and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for another 30 minutes. 20 mL of ethyl acetate and 100 mL of water were added to the reaction mixture, the two layers were separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure.
The obtained residue was dissolved in 10 mL of N, N-dimethylformamide, 408 mg (10 mmol) of sodium hydride (P = 60%) was added under ice-cooling, and the mixture was stirred at the same temperature for 80 minutes. 40 mL of ethyl acetate and 100 mL of water were added, the two layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure.
The obtained residue is dissolved in 10 mL of N, N-dimethylformamide (dehydrated), 222 mg (5.5 mmol) of sodium hydride (P = 60%) is added under ice-cooling, and the mixture is stirred at the same temperature for 15 minutes. , 288 μL (4.62 mmol) of methyl iodide was added, and the mixture was stirred at the same temperature for 30 minutes. 20 mL of ethyl acetate and 100 mL of water were added to the reaction mixture, the two layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: methanol, 1: 0 → 98: 2, V / V), and the solvent for the target fraction was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue and collected by filtration to obtain 715 mg (yield: 38%) of a white powder of the title compound.
IRν (ATR) cm ^-1 : 1676
^{1 1} H-NMR (DMSO-d6, 400 MHz) δ: 2.30-2.40 (4H, m), 3.26-3.31 (1H, m), 3.32 (3H, s), 3.58-3.67 (6H, m), 3.69 ( 3H, s), 3.90-3.97 (2H, m), 4.21 (2H, s), 5.51 (1H, s), 6.48-6.53 (2H, m), 7.12-7.16 (2H, m), 7.72 (1H, s) s).
MS m / z: 410 [M + H] ⁺ .

Example 13

(13a) 6-iodo-1-methyl-1H-benzo [d] [1,3] oxazine-2,4-dione

25.0 g (0.165 mol) of 2-methylaminobenzoic acid was suspended in a mixed solution of 150 mL of acetic acid and 300 mL of water, 42.0 g (0.165 mol) of iodine was added in portions, and the mixture was stirred at room temperature for 3 days. The precipitate was collected by filtration and washed with water to obtain 37.7 g of a black-purple powder containing 5-iodo-2-methylaminobenzoic acid.
Suspend 37.7 g of the obtained black-purple powder in 400 mL of water, add 14.5 g (0.137 mol) of sodium carbonate, add a solution of 13.5 g (45.5 mmol) of triphosgene in 65 mL of toluene under ice-cooling, and bring to the same temperature. Stirred for 2 hours. The precipitate was collected by filtration, and the obtained powder was washed successively with 150 mL of water, 150 mL of a mixed solution of ethanol-diethyl ether (1: 1), and then 50 mL of diethyl ether, and 17.3 g of brown powder of the title compound (yield). Rate: 35%) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 3.43 (3H, s), 7.26 (1H, d, J = 8.8 Hz), 8.13 (1H, dd, J = 8.8, 1.7 Hz), 8.20 (1H, 1H, d, J = 1.7 Hz).

(13b) 4-Chloro-1-methyl-2-oxo-1,2-dihydroquinoline-6-carbonitrile

Dissolve 40 mL (0.26 mol) of diethyl malonate in 150 mL of N, N-dimethylformamide, add 2.74 g (69 mmol) of sodium hydride (P = 60%) in portions, and stir at room temperature for 10 minutes. A solution of 17.3 g (57.1 mmol) of compound (3) prepared in Example 13 (13a) in 50 mL of N, N-dimethylformamide was added dropwise, and the mixture was stirred at 120 ° C. for 2.5 hours. After allowing to cool, 200 mL of ethyl acetate was added to the reaction solution, the insoluble material was collected by filtration, the obtained powder was dissolved in 4.5 L of water, and the pH of the solution was adjusted to 2-3 with 6.0 M hydrochloric acid. The precipitate was collected by filtration and washed with water, a mixed solution of ethanol-diethyl ether (1: 1), and then with diethyl ether to obtain 14.8 g of a light gray powder.
14.8 g of the obtained light gray powder was suspended in 100 mL of trifluoroacetic acid, 100 mL of concentrated hydrochloric acid was added, and the mixture was stirred at 80 ° C. for 24 hours. The reaction solution is concentrated to dryness under reduced pressure, water is added to the residue, the insoluble material is collected by filtration, and then washed sequentially with 100 mL of water, 50 mL of a mixed solution of ethanol-diethyl ether (1: 1), and then 50 mL of diisopropyl ether. And 12.4 g of light gray powder was obtained.
12.4 g of the obtained light gray powder was dissolved in 150 mL of N, N-dimethylformamide, 9.32 g (79.4 mmol) of zinc disianide and 4.59 g (3.97 mmol) of tetrakis (triphenylphosphine) palladium (0) were added, and nitrogen was added. The mixture was stirred at 90 ° C. for 2.5 hours in an atmosphere. After allowing to cool, 100 mL of tetrahydrofuran was added to the reaction solution, the insoluble material was filtered through Celite, 900 mL of water was added to the filtrate, and the precipitate was collected by filtration. Add 2 L of a mixed solution of methanol-tetrahydrofuran (1: 5) to the obtained powder, filter out the insoluble material, concentrate and dry the filtrate under reduced pressure, add 30 mL of ethyl acetate to the residue, and filter out the insoluble material. I took it. The obtained powder was washed successively with 5 mL of ethyl acetate and 5 mL of chloroform to obtain 7.25 g of a light brown powder.
To 7.25 g of the obtained light brown powder, 70 mL of phosphorus oxychloride was added, and the mixture was stirred at 90 ° C. for 6 hours. The reaction mixture was concentrated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with water, 10% potassium carbonate water was added, and the precipitate was filtered off with Celite. The two layers of the filtrate were separated, the organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified twice by column chromatography (chloroform: n-hexane, 1: 1 → 1: 0, V / V), the solvent for the target fraction was distilled off under reduced pressure, and ethyl acetate was added to the residue. -10 mL of a mixed solution of diethyl ether (1: 3) was added, and the insoluble material was collected by filtration. The obtained powder was washed with diethyl ether to obtain 1.27 g (yield: 10%) of a white powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 3.75 (3H, s), 6.98 (1H, s), 7.47 (1H, d, J = 8.8 Hz), 7.86 (1H, dd, J = 8.8, 2.0) Hz), 8.33 (1H, d, J = 2.0 Hz).

(13c) 4,4,5,5-Tetramethyl-2- [4- (2-phenoxyethoxy) phenyl] [1,3,2] dioxaborolane

1.00 g (4.54 mmol) of 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenol was dissolved in 20 mL of N, N-dimethylformamide and (2- 1.37 g (6.81 mmol) of bromoethoxy) benzene and 2.22 g (6.81 mmol) of cesium carbonate were added, and the mixture was stirred at 90 ° C. for 3 hours. After allowing to cool, the reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 0 → 7: 3, V / V), the solvent of the target fraction was distilled off under reduced pressure, and 1.54 g of white powder of the title compound ( Yield: Quantitative) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.33 (12H, s), 4.30-4.37 (4H, m), 6.92-6.70 (5H, m), 7.29 (2H, t, J = 7.6 Hz), 7.73-7.78 (2H, m).

(13d) 1-Methyl-2-oxo-4- [4- (2-phenoxyethoxy) phenyl] -1,2-dihydroquinoline-6-carbonitrile

200 mg (0.915 mmol) of compound prepared in Example 13 (13b) and 342 mg (1.01 mmol) of compound prepared in Example 13 (13c) were dissolved in 4 mL of N, N-dimethylformamide and tripotassium phosphate 583. Mg (2.75 mmol) and tetrakis (triphenylphosphine) palladium (0) 106 mg (0.917 mmol) were added, and the mixture was stirred at 90 ° C. for 2 hours under a nitrogen atmosphere. After allowing to cool, the reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. After purifying the residue by column chromatography (chloroform: ethyl acetate, 1: 0 → 3: 2, V / V), the solvent of the target fraction was distilled off under reduced pressure, and 1 mL of methanol and 10 mL of diethyl ether were added to the residue. Was added, and the mixture was stirred at room temperature for 1 hour. The insoluble material was collected by filtration to give 333 mg (yield: 92%) of a white powder of the title compound.
^{1 1} H-NMR (DMSO-d6, 400 MHz) δ: 3.69 (3H, s), 4.34-4.38 (2H, m), 4.40-4.45 (2H, m), 6.62 (1H, s), 6.93-7.02 ( 3H, m), 7.16-7.20 (2H, m), 7.29-7.34 (2H, m), 7.43-7.47 (2H, m), 7.78 (1H, d, J = 9.0 Hz), 7.82 (1H, d, J = 2.0 Hz), 8.06 (1H, dd, J = 9.0, 2.0 Hz).

(13) 1-Methyl-2-oxo-4- [4- (2-phenoxyethoxy) phenyl] -1,2-dihydroquinoline-6-carboxamide

Compound (5) prepared in Example 13 (13d) was added with a solution of 68 mg (0.49 mmol) of potassium carbonate and 4 mL of dimethyl sulfoxide of 130 mg (1.2 mmol) of 30% hydrogen peroxide solution to 325 mg (0.820 mmol). , Stirred at room temperature for 3.5 hours. 30 mL of water was added to the reaction solution, and the precipitate was collected by filtration and washed with 5 mL of ethanol to obtain 310 mg of white powder. To 310 mg of the obtained white powder, 15 mL of ethanol was added, and the mixture was heated under reflux for 15 minutes, allowed to cool to room temperature, and the insoluble material was collected by filtration. The obtained powder was washed with 10 mL of ethanol to obtain 260 mg (yield: 77%) of a gray powder of the title compound.
IR ν (ATR) cm ^-1 : 3272, 3182, 1651
^{1 1} H-NMR (DMSO-d6, 400 MHz) δ: 3.70 (3H, s), 4.33-4.39 (2H, m), 4.39-4.46 (2H, m), 6.53 (1H, s), 6.93-7.04 ( 3H, m), 7.15-7.20 (2H, m), 7.29-7.34 (2H, m), 7.37-7.42 (1H, br), 7.41-7.46 (2H, m), 7.66 (1H, d, J = 8.8) Hz), 8.02-8.09 (2H, m), 8.14 (1H, dd, J = 8.8, 1.5 Hz).
MS m / z: 437 [M + Na] ⁺ , 413 [MH] ^- .

Example 14

(14a) 2- (Tetrahydropyran-4-yloxy) Ethanol

1.37 g (36.0 mmol) of lithium aluminum hydride is suspended in 20 mL of tetrahydrofuran, a solution of 2.00 g (20.0 mmol) of 4-oxotetrahydropyran in 10 mL of tetrahydrofuran is added dropwise under ice-cooling, and the mixture is stirred at the same temperature for 40 minutes. bottom. 1.5 mL of water, 1.5 mL of 5.0 M sodium hydroxide water, and 1.5 mL of water were sequentially added to the reaction solution, and the insoluble material was filtered off. After drying the filtrate (Na ₂ SO ₄ ), the solvent was distilled off under reduced pressure to obtain 1.81 g (yield: 89%) of a colorless oil of tetrahydropyran-4-ol.
Dissolve 375 mg (3.67 mmol) of tetrahydropyran-4-ol in 2.5 mL of N, N-dimethylformamide, add 190 mg (4.75 mmol) of sodium hydride (P = 60%) under ice-cooling, and at room temperature 15 Stir for minutes. 1.0 g (4.8 mmol) of 2- (2-bromoethoxy) tetrahydropyran was added, and the mixture was stirred at 60 ° C. for 3 hours and at room temperature for 2 days. Ethyl acetate was added, and the mixture was washed successively with water and then saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 10: 1 → 2: 1, V / V), and the solvent of the target fraction was distilled off under reduced pressure to obtain 1- (tetrahydropyran). A colorless oil of -4-yloxy) -2- (tetrahydropyran-2-yloxy) ethane was obtained in an amount of 190 mg (yield: 22%).
Dissolve 180 mg (0.782 mmol) of 1- (tetrahydropyran-4-yloxy) -2- (tetrahydropyran-2-yloxy) ethane in 2.0 mL of methanol, and add 0.27 mL (2.3 mmol) of 8.6 M hydrogen chloride isopropanol solution. , Stirred for 15 minutes at room temperature. The solvent was evaporated under reduced pressure to give 110 mg (yield: 96%) of a colorless oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.54-1.66 (2H, m), 1.84 (1H, s), 1.86-1.97 (2H, m), 3.39-3.49 (2H, m), 3.49-3.57 (1H, m), 3.59 (2H, t, J = 4.9 Hz), 3.74 (2H, t, J = 4.9 Hz), 3.91-3.99 (2H, m).

(14b) 4- {2- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenoxy] ethoxy} tetrahydropyran

1.37 g (9.37 mmol) of the compound prepared in Example 14 (14a) was dissolved in 25 mL of methylene chloride, 1.96 mL (14.1 mmol) of triethylamine and 0.94 mL (12 mmol) of methanesulfonyl chloride were added under ice-cooling, and the mixture was brought to room temperature. Stir for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers are combined, washed with saturated brine, dried (Na ₂ SO ₄ ), the solvent is evaporated under reduced pressure, and a pale yellow oil of 2- (tetrahydropyran-2-yloxy) ethyl methanesulfonate is 2.10 g. Got
2.10 g (9.37 mmol) of 2- (tetrahydropyran-2-yloxy) ethyl methanesulfonate was dissolved in 20 mL of N, N-dimethylformamide and 4- (4,4,5,5-tetramethyl- [1,3] , 2] Dioxaborolan-2-yl) phenol 2.27 g (10.3 mmol) and potassium carbonate 2.59 g (18.7 mmol) were added, and the mixture was stirred at 80 ° C. for 2 hours. Water was added to the reaction mixture, the mixture was extracted twice with ethyl acetate, the organic layers were combined, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 10: 1 → 8: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 1.16 g (yield: 35%) of a yellow oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.33 (12H, s), 1.57-1.70 (2H, m), 1.87-1.98 (2H, m), 3.40-3.49 (2H, m), 3.55-3.65 (1H, m), 3.83-3.87 (2H, m), 3.91-4.00 (2H, m), 4.13-4.19 (2H, m), 6.87-6.94 (2H, m), 7.70-7.78 (2H, m) ..

(14c) 5-Bromobenzo [b] thiophene

After adding 7.1 mL (29 mmol) of sodium methoxide methanol solution (P = 28%) to 14 mL of methanol, 5.00 g (26.4 mmol) of 4-bromothiophenol was added under ice-cooling, and the mixture was stirred for 5 minutes. Bromoacetaldehyde diethyl acetal 4.5 mL (29 mmol) was added, and the mixture was heated under reflux for 3 hours. After distilling off the solvent under reduced pressure, 50 mL of water was added, and the mixture was extracted twice with 50 mL of ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate, 20: 1 → 10: 1, V / V), and the solvent of the target fraction was distilled off under reduced pressure to obtain 1-bromo-4- (2). , 2-Diethoxyethylsulfanyl) A yellow oil of benzene was obtained in an amount of 7.70 g (yield: 96%).
To 3.3 g of polyphosphate, 80 mL of chlorobenzene and 3.31 g (10.8 mmol) of 1-bromo-4- (2,2-diethoxyethylsulfanyl) benzene were added, and the mixture was heated under reflux for 1.5 hours. After allowing to cool, the supernatant was separated by decanting, n-hexane was added to the residue, and the supernatant was further separated. Saturated aqueous sodium hydrogen carbonate was added to the separated solution, the two layers were separated, and then the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate, 20: 1 → 10: 1, V / V), the solvent of the target fraction was distilled off under reduced pressure, and the white powder of the title compound was 191 mg (1 mg). Yield: 8%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 7.27 (1H, d, J = 5.4 Hz), 7.43 (1H, dd, J = 8.5, 1.9 Hz), 7.47 (1H, d, J = 5.4 Hz) , 7.73 (1H, d, J = 8.5 Hz), 7.96 (1H, d, J = 1.9 Hz).

(14d) 3-Bromo-5-cyanobenzo [b] thiophene

Compound 191 mg (0.896 mmol) prepared in Example 14 (14c) was dissolved in 4 mL of N, N-dimethylformamide, copper (I) cyanide (I) 241 mg (2.69 mmol) was added, and the mixture was added at 150 ° C. for 12 hours. Stirred. After allowing to cool, 20 mL of water and 20 mL of ethyl acetate were added, and the insoluble material was filtered off with Celite. After separating the two layers of the filtrate, the aqueous layer was extracted with 20 mL of ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate, 10: 1, V / V), the solvent for the target fraction was distilled off under reduced pressure, and 100 mg of a white powder of 5-cyanobenzo [b] thiophene was distilled off. (Yield: 70%) was obtained. Further, 100 mg (0.469 mmol) of the compound prepared in Example 14 (14c) was used and reacted in the same manner as above to obtain 23 mg (yield: 31%) of a white powder of 5-cyanobenzo [b] thiophene. ..
121 mg (0.760 mmol) of 5-cyanobenzo [b] thiophene was dissolved in 4 mL of acetic acid, 0.12 mL (2.3 mmol) of bromine was added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, 20 mL of saturated aqueous sodium hydrogen carbonate was added, the mixture was extracted with 20 mL of ethyl acetate, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried (Na ₂ SO ₄ ). The solvent was distilled off under reduced pressure to obtain 155 mg (yield: 86%) of a white powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 7.60 (1H, s), 7.63 (1H, dd, J = 8.3, 1.5 Hz), 7.96 (1H, d, J = 8.3 Hz), 8.16 (1H, 1H, d, J = 1.5 Hz).

(14e) 3- {4- [2- (Tetrahydropyran-4-yloxy) ethoxy] phenyl} benzo [b] thiophene-5-carbonitrile

Compound 152 mg (0.638 mmol) prepared in Example 14 (14d), compound 222 mg (0.637 mmol) prepared in Example 14 (14b), [1,1'-bis (diphenylphosphino) ferrocene] palladium ( II) Dichloride dichloromethane adduct 52 mg (0.064 mmol), tripotassium phosphate 407 mg (1.92 mmol) and tetrabutylammonium bromide 21 mg (0.065 mmol) were suspended in 4 mL of acetonitrile and heated to reflux for 12 hours under a nitrogen atmosphere. bottom. After allowing to cool, the solvent was evaporated under reduced pressure, 20 mL of water was added, and the mixture was extracted twice with 20 mL of ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate, 2: 1 → 1: 1, V / V), and the solvent of the target fraction was distilled off under reduced pressure to obtain a pale yellow viscous oil of the title compound. 0.19 g (yield: 78%) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.62-1.72 (2H, m), 1.93-2.02 (2H, m), 3.43-3.51 (2H, m), 3.60-3.68 (1H, m), 3.89 (2H, t, J = 4.9 Hz), 3.95-4.02 (2H, m), 4.21 (2H, t, J = 4.9 Hz), 7.04-7.10 (2H, m), 7.43-7.49 (2H, m), 7.48 (1H, s), 7.58 (1H, dd, J = 8.4, 1.3 Hz), 7.99 (1H, dd, J = 8.4, 0.6 Hz), 8.18 (1H, dd, J = 1.3, 0.6 Hz).

(14) 3- {4- [2- (Tetrahydropyran-4-yloxy) ethoxy] phenyl} benzo [b] thiophene-5-carboxamide

0.19 g (0.50 mmol) of the compound prepared in Example 14 (14e) was dissolved in 2.5 mL of dimethyl sulfoxide, and at room temperature 5.0 M sodium hydroxide water 0.15 mL (0.75 mmol) and 30% hydrogen peroxide solution 0.068 mL ( 0.75 mmol) was added, and the mixture was stirred at the same temperature for 40 minutes. 20 mL of water and 10 mL of diethyl ether were added, and the mixture was stirred for 30 minutes, and the precipitate was collected by filtration to give 135 mg (yield: 68%) of a white powder of the title compound.
IR ν (ATR) cm ^-1 : 1670
^{1 1} H-NMR (DMSO-d6, 400 MHz) δ: 1.38-1.48 (2H, m), 1.85-1.92 (2H, m), 3.29-3.41 (2H, m), 3.60-3.68 (1H, m), 3.78-3.85 (4H, m), 4.14-4.20 (2H, m), 7.10-7.15 (2H, m), 7.36-7.44 (1H, br), 7.53-7.58 (2H, m), 7.80 (1H, s) ), 7.89 (1H, dd, J = 8.4, 1.3 Hz), 8.10-8.15 (2H, m), 8.35 (1H, d, J = 1.3 Hz).
MS m / z: 420 [M + Na] ⁺ , 396 [MH] ^- .

Example 15

(15a) 3-ethynyl-4-hydroxybenzonitrile

5.20 g (25.2 mmol) of 3-bromo-4-hydroxybenzonitrile was dissolved in 40 mL of pyridine, 7.15 mL (75.7 mmol) of acetic anhydride was added under ice-cooling, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, diisopropyl ether was added, and the precipitate was collected by filtration to obtain 5.16 g (yield: 85%) of a white powder of 2-bromo-4-cyanophenyl acetate.
Dissolve 300 mg (1.25 mmol) of 2-bromo-4-cyanophenyl acetate in 5 mL of 1,4-dioxane, 246 mg (2.50 mmol) of trimethylsilylacetylene, 44 mg of bis (triphenylphosphine) palladium (II) dichloride (II). 0.063 mmol), copper iodide 12 mg (0.063 mmol), and triethylamine 0.35 mL (2.5 mmol) were added, nitrogen was bubbled for 2 minutes, and the mixture was stirred at 80 ° C. for 1 hour under a nitrogen atmosphere. After allowing to cool, water and ethyl acetate were added, and the insoluble material was filtered off. The two layers of the filtrate were separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. A similar reaction and treatment was carried out with 4.86 g (20.2 mmol) of 2-bromo-4-cyanophenyl acetate, which was combined with the previously obtained residue for column chromatography (n-hexane: ethyl acetate, 9: 1 → Purified by 7: 3, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 4.75 g (yield: 86%) of a light brown powder of 4-cyano-2-trimethylsilanylethynylphenyl phenyl acetate.
4-Cyano-2-trimethylsilanylethynylphenyl phenyl acetate 370 mg (1.44 mmol) is dissolved in 3 mL of methanol, potassium fluoride 184 mg (3.16 mmol) is added, and the mixture is stirred at room temperature for 2 hours, and then potassium fluoride 84. mg (1.4 mmol) was added, and the mixture was stirred at the same temperature for another 1 hour. 5% citric acid water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. Similar reactions and treatments were performed with 4.34 g (16.9 mmol) of 4-cyano-2-trimethylsilanylethynylphenyl acetate, combined with the previously obtained residue and column chromatography (chloroform: ethyl acetate, 9: 1). → Purified by 7: 3, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 2.49 g (yield: 95%) of a light brown powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 3.57 (1H, s), 6.31 (1H, s), 7.04 (1H, d, J = 8.5 Hz), 7.55 (1H, dd, J = 8.5, 2.0) Hz), 7.69 (1H, d, J = 2.0 Hz).

(15b) Benzofuran-5-Carbonitrile

Compound 215 mg (1.50 mmol) prepared in Example 15 (15a) was dissolved in 2 mL of pyridine, cyclopentadienylbis- (triphenylphosphine) ruthenium (II) chloride 55 mg (0.075 mmol) was added, and nitrogen was added. After stirring at 90 ° C. for 1.5 hours under an atmosphere, 28 mg (0.038 mmol) of cyclopentadienylbis- (triphenylphosphine) ruthenium (II) chloride was added, and the mixture was further stirred at the same temperature for 1 hour. After allowing to cool, water was added and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 9: 1 → 7: 3, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 60 mg (yield: 28%) of a white powder of the title compound.
The same reaction and treatment was carried out using 2.25 g (15.7 mmol) of the compound prepared in Example 15 (15a) to obtain 1.04 g (yield: 46%) of a white powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 6.85 (1H, d, J = 2.2 Hz), 7.55-7.61 (2H, m), 7.74 (1H, d, J = 2.2 Hz), 7.95 (1H, 1H, d, J = 1.0 Hz).

(15c) 3-Bromobenzofuran-5-Carbonitrile

500 mg (3.49 mmol) of the compound prepared in Example 15 (15b) was dissolved in 10 mL of methylene chloride, 0.36 mL (7.0 mmol) of bromine was added at room temperature, and the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was washed successively with 1 M aqueous sodium thiosulfate solution and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 10 mL of tetrahydrofuran, 1.75 mL (3.5 mmol) of 2.0 M potassium hydroxide methanol solution was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water and chloroform were added to the reaction solution, and the two layers were separated. The aqueous layer was extracted with chloroform, the organic layers were combined, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue and collected by filtration to obtain 596 mg (yield: 77%) of a white powder of the title compound. ^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 7.55-7.65 (2H, m), 7.78 (1H, s), 7.91 (1H, d, J = 1.4 Hz).

(15d) 3- {4- [2- (Tetrahydropyran-4-yloxy) ethoxy] Phenyl} Benzofuran-5-Carbonitrile

Compound 400 mg (1.80 mmol) prepared in Example 15 (15c) was dissolved in 6 mL of acetonitrile, and compound 570 mg (1.80 mmol) prepared in Example 14 (14b), [1,1'-bis (diphenyl). Phosphino) ferrocene] Palladium (II) dichloride dichloromethane adduct 134 mg (0.18 mmol), tripotassium phosphate 1.04 g (4.92 mmol), tetrabutylammonium bromide 53 mg (0.18 mmol) were added and nitrogen was bubbled for 2 minutes. .. After heating under reflux for 1 hour under a nitrogen atmosphere, 134 mg (0.18 mmol) of [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct was added, and the mixture was heated under reflux for another 2.5 hours. After allowing to cool, water and ethyl acetate were added, and the insoluble material was filtered off. After separating the two layers of the filtrate, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried (Na ₂ SO ₄ ). The solvent was evaporated under reduced pressure, and the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 9: 1 → 1: 1, V / V). The solvent of the target fraction was evaporated under reduced pressure to give 460 mg (yield: 77%) of a colorless oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.62-1.72 (2H, m), 1.92-2.02 (2H, m), 3.43-3.52 (2H, m), 3.59-3.67 (1H, m), 3.85 -3.91 (2H, m), 3.92-4.02 (2H, m), 4.15-4.24 (2H, m), 7.04-7.07 (2H, m), 7.49-7517 (2H, m), 7.60-7.64 (2H, m) m), 7.82 (1H, s), 8.12 (1H, s).

(15e) 2-Chloro-3- {4- [2- (tetrahydropyran-4-yloxy) ethoxy] phenyl} benzofuran-5-carbonitrile

105 mg (0.289 mmol) of the compound prepared in Example 15 (15d) was dissolved in 1 mL of benzene, 0.025 mL (0.30 mmol) of sulfuryl chloride was added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes and then brought to room temperature. Stirred for 1.5 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 9: 1 → 2: 3, V / V), the solvent of the target fraction was evaporated under reduced pressure, and the title compound was a colorless oil. A product of 80 mg (yield: 70%) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.62-1.72 (2H, m), 1.92-2.02 (2H, m), 3.43-3.52 (2H, m), 3.59-3.67 (1H, m), 3.85 -3.91 (2H, m), 3.92-4.02 (2H, m), 4.18-4.24 (2H, m), 7.07-7.09 (2H, m), 7.51-7.53 (2H, m), 7.55-7.61 (2H, m) m), 7.95 (1H, s).

(15) 2-Chloro-3- {4- [2- (tetrahydropyran-4-yloxy) ethoxy] phenyl} benzofuran-5-carboxamide

80 mg (0.20 mmol) of the compound prepared in Example 15 (15e) was dissolved in 1 mL of dimethyl sulfoxide, 83 mg (0.60 mmol) of potassium carbonate and 32 mg (1.0 mmol) of 30% hydrogen peroxide solution were added, and room temperature was added. Was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue and collected by filtration to give 55 mg (yield: 66%) of a white powder of the title compound.
IR ν (ATR) cm ^-1 : 3403, 3176, 1670
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.60-1.72 (2H, m), 1.90-2.00 (2H, m), 3.43-3.52 (2H, m), 3.58-3.67 (1H, m), 3.86 -3.91 (2H, m), 3.92-4.00 (2H, m), 4.17-4.24 (2H, m), 5.45-6.25 (2H, br), 7.06-7.08 (2H, m), 7.50-7.56 (3H, m) m), 7.78 (1H, dd, J = 8.6, 1.7 Hz), 8.09 (1H, d, J = 1.7 Hz).
MS (ESI) m / z: 416 [M + H ⁺ ].

Example 16

(16a) 1,4-Dioxaspiro [4.5] Deca-7-en-8-yl trifluoromethanesulfonate

Dissolve 2.40 g (15.4 mmol) of 1,4-cyclohexanedione monoethylene ketal and 7.15 g (20.0 mmol) of N-phenylbis (trifluoromethanesulfonimide) in 150 mL of tetrahydrofuran and 0.5 M potassium hexamethyl at -78 ° C. 40 mL (20 mmol) of disilazide toluene solution was added dropwise, and the mixture was stirred at the same temperature for 2.5 hours. The reaction mixture was poured into water, extracted with diethyl ether, the organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 10: 1, V / V), and the solvent for the target fraction was evaporated under reduced pressure. The obtained residue was purified again by column chromatography (Chromatorex NH, n-hexane: ethyl acetate, 9: 1 → 2: 3, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 4.68 g (yield: quantitative) of a slightly yellow oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.91 (2H, t, J = 6.6 Hz, 2.38-2.44 (2H, m), 2.51-2.58 (2H, m), 3.95-4.03 (4H, m) , 5.64-5.69 (1H, m).

(16b) 3- (1,4-dioxaspiro [4.5] deca-7-ene-8-yl) benzo [b] thiophene-5-carbonitrile

Compound 500 mg (2.10 mmol) prepared in Example 14 (14d) was dissolved in 10 mL of 1,4-oxane, potassium acetate 720 mg (7.34 mmol), bis (pinacolato) diboron 590 mg (2.32 mmol) and bis. (Triphenylphosphine) Palladium (II) dichloride 150 mg (0.214 mmol) was added, and the mixture was stirred at 100 ° C. for 4 hours under a nitrogen atmosphere. After allowing to cool, the reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 10: 1, V / V), and the solvent for the target fraction was distilled off under reduced pressure to 3- (4,4,5, A pale yellow powder containing 5-tetramethyl [1,3,2] dioxaborolan-2-yl) benzo [b] thiophene-5-carbonitrile was obtained in an amount of 486 mg.
Compound 330 mg (1.14 mmol) and 3- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) benzo [b] thiophene-5 prepared in Example 16 (16a). -Dissolve 486 mg of powder containing carbonitrile in 5 mL of 1,2-dimethoxyethane, a solution of 350 mg (3.02 mmol) of sodium carbonate in 5 mL of water, and a solution of lithium chloride 50 mg (1.2 mmol) in 0.5 mL of water. And tetrakis (triphenylphosphine) palladium (0) 66 mg (0.057 mmol) were sequentially added, and the mixture was stirred at 70 ° C. for 14 hours under a nitrogen atmosphere. After allowing to cool, the reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 10: 1 → 5: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 308 mg (yield: 90%) of a yellow oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.98 (2H, t, J = 6.6 Hz), 2.52-2.57 (2H, m), 2.64-2.71 (2H, m), 4.03-4.08 (4H, m) ), 5.91-5.96 (1H, m), 7.36 (1H, s), 7.54 (1H, dd, J = 8.3, 1.5 Hz), 7.92 (1H, d, J = 8.3 Hz), 8.21-8.25 (1H, s) m).

(16c) 3- (4-Hydroxycyclohexa-1-enyl) benzo [b] thiophene-5-carbonitrile

2.08 g (6.99 mmol) of the compound prepared in Example 16 (16b) was dissolved in 40 mL of tetrahydrofuran, 21 mL (21 mmol) of 1.0 M hydrochloric acid was added, and the mixture was stirred at 40 ° C. for 3 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water and saturated brine, and dried (Na ₂ SO ₄ ). The solvent was distilled off under reduced pressure to obtain 1.72 g (yield: 97%) of a yellow powder of 3- (4-oxohexa-1-eneyl) benzo [b] thiophene-5-carbonitrile.
Dissolve 1.72 g (6.79 mmol) of 3- (4-oxohexa-1-eneyl) benzo [b] thiophene-5-carbonitrile in a mixed solvent of 50 mL ethanol and 17 mL tetrahydrofuran, and sodium borohydride under ice-cooling. After adding 514 mg (13.6 mmol) and stirring at room temperature for 1 hr, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 3: 1 → 2: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 1.49 g (yield: 86%) of a pale yellow powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.50-1.60 (1H, br), 1.85-1.95 (1H, m), 2.03-2.11 (1H, m), 2.26-2.36 (1H, m), 2.47 -2.72 (3H, m), 4.12-4.21 (1H, m), 5.92-5.98 (1H, m), 7.35 (1H, s), 7.54 (1H, dd, J = 8.3, 1.5 Hz), 7.93 (1H) , d, J = 8.3 Hz), 8.20-8.24 (1H, m).

(16d) 3- {4- [2- (Tetrahydropyran-4-yloxy) ethoxy] cyclohex-1-enyl} benzo [b] thiophene-5-carbonitrile

The compound 0.88 g (3.5 mmol) prepared in Example 16 (16c) was dissolved in 10 mL of N, N-dimethylformamide, and sodium hydride (P = 60%) 207 mg (5.2 mmol) was added under ice-cooling. , Stirred at room temperature for 15 minutes. 1.44 g (6.89 mmol) of 4- (2-bromoethoxy) tetrahydropyran was added to the reaction mixture, and the mixture was stirred for 13.5 hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 10: 1, V / V), and the solvent for the target fraction was evaporated under reduced pressure. The obtained residue was purified by column chromatography (Chromatorex NH, n-hexane: ethyl acetate, 4: 1, V / V) again, and the solvent of the target fraction was distilled off under reduced pressure to obtain a colorless oil of the title compound. A product of 0.30 g (yield: 25%) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.57-1.67 (2H, m), 1.87-1.97 (3H, m), 1.96-2.04 (1H, m), 2.29-2.68 (4H, m), 3.39 -3.80 (8H, m), 3.92-3.98 (2H, m), 5.91-5.97 (1H, m), 7.33 (1H, s), 7.54 (1H, dd, J = 8.3, 1.5 Hz), 7.92 (1H) , d, J = 8.3 Hz), 8.21 (1H, d, J = 1.5 Hz).

(16) 3- {4- [2- (Tetrahydropyran-4-yloxy) ethoxy] cyclohex-1-enyl} benzo [b] thiophene-5-carboxamide

0.30 g (0.78 mmol) of the compound prepared in Example 16 (16d) was dissolved in 1.5 mL of dimethyl sulfoxide, and at room temperature, 5.0 M sodium hydroxide water 0.23 mL (1.2 mmol) and 30% hydrogen hydrogen peroxide solution 0.12 mL ( 1.2 mmol) was added, and after stirring for 1 hour, 0.12 mL (0.60 mmol) of 5.0 M sodium hydroxide water and 0.06 mL (0.67 mmol) of 30% hydrogen hydrogen solution were added, and the mixture was stirred for 30 minutes. 10 mL of water was added, and the mixture was extracted twice with 20 mL of ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue and collected by filtration to give 161 mg (yield: 51%) of a white powder of the title compound.
IR ν (ATR) cm ^-1 : 1655
^{1 1} H-NMR (DMSO-d6, 400 MHz) δ: 1.33-1.43 (2H, m), 1.68-1.78 (1H, m), 1.79-1.88 (2H, m), 1.98-2.08 (1H, m), 2.15-2.24 (1H, m), 2.47-2.64 (3H, m), 3.26-3.36 (2H, m), 3.46-3.54 (1H, m), 3.54-3.65 (4H, m), 3.67-3.74 (1H) , m), 3.74-3.80 (2H, m), 5.98-6.03 (1H, m), 7.38-7.48 (1H, br), 7.64 (1H, s), 7.85 (1H, dd, J = 8.3, 1.5 Hz) ), 8.03 (1H, d, J = 8.3 Hz), 8.10-8.18 (1H, br), 8.38 (1H, d, J = 1.3 Hz).
MS (ESI) m / z: 402 [M + H] ⁺ .

Example 17

(17a) 1-Phenylazetidine-3-ol

Suspend 200 mg of 20% Pd (OH) _2- C (wet) in 10 mL of methanol, add 2.00 g (8.36 mmol) of 1-benzhydryl azetidine-3-ol, 0.3 MPa, at room temperature 18 Time contact hydrogenation was added. After filtering Pd (OH) _2- C with Celite, methanol was distilled off under reduced pressure, 10 mL of n-hexane was added to the residue, and the supernatant was removed by decanting. The obtained residue was dried under reduced pressure to obtain 706 mg of powder.
The resulting powder 700 mg, iodobenzene 2.77 g (13.6 mmol), copper iodide 159 mg (0.835 mmol), 2-acetylcyclohexanone 0.22 mL (1.7 mmol) and cesium carbonate 5.44 g (16.7 mmol) N, N- It was suspended in 4 mL of dimethylformamide and stirred at 50 ° C. for 15 hours. After allowing to cool, 20 mL of water was added, and the mixture was extracted twice with 20 mL of ethyl acetate. The ethyl acetate layers were combined, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and ethyl acetate was distilled off under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate, 10: 1 → 3: 1 → 2: 1, V / V), the solvent of the target fraction was distilled off under reduced pressure, and the title compound was yellow. An oily substance of 875 mg (yield: 70%) was obtained.
Reaction and treatment with 1-benzhydryl azetidine-3-ol 6.93 g (29.0 mmol) in the same manner as above gave 3.34 g (yield: 77%) of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.15-2.30 (1H, m), 3.65 (2H, dd, J = 8.6, 4.5 Hz), 4.13-4.22 (2H, m), 4.69-4.80 (1H) , m), 6.45-6.53 (2H, m), 6.73-6.82 (1H, m), 7.18-7.28 (2H, m).

(17b) 3- [2- (tert-butyldimethylsilanyloxy) ethoxy] -1- (4-iodophenyl) azetidine

The compound 1.81 g (12.1 mmol) and (2-bromoethoxy) -tert-butyldimethylsilane 3.19 g (13.3 mmol) prepared in Example 17 (17a) were dissolved in 18 mL of N, N-dimethylformamide and brought to room temperature. Sodium hydride (P = 60%) 629 mg (16 mmol) was added, and the mixture was stirred under a nitrogen atmosphere at the same temperature for 4 hours. It was poured into 90 mL of ice water and extracted with 100 mL and 50 mL of diethyl ether. The diethyl ether layers were combined, washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and diethyl ether was distilled off under reduced pressure. The residue was purified by column chromatography (diethyl ether: n-hexane, 1:30 → 1:10 → 1: 5, V / V), the solvent for the target fraction was distilled off under reduced pressure, and 3- [2 A pale yellow oil of-(tert-butyldimethylsilanyloxy) ethoxy] -1-phenylazetidine was obtained in an amount of 827 mg (yield: 22%).
Dissolve 915 mg (2.96 mmol) of 3- [2- (tert-butyldimethylsilanyloxy) ethoxy] -1-phenylazetidine in 9 mL of methylene chloride, add 373 mg (4.44 mmol) of baking soda and 9 mL of water. After adding 827 mg (3.26 mmol) of iodine in portions over 15 minutes at room temperature, the mixture was stirred at the same temperature for 1.5 hours. 10 mL of 5% sodium thiosulfate was added, methylene chloride was distilled off under reduced pressure, and the mixture was extracted with 20 mL of ethyl acetate. The ethyl acetate layer was washed successively with 5% aqueous sodium thiosulfate solution and saturated brine, dried (Na ₂ SO ₄ ), and ethyl acetate was distilled off under reduced pressure. The residue was purified by column chromatography (Chromatorex NH, diethyl ether: n-hexane, 0: 1 → 1: 6, V / V), the solvent of the target fraction was distilled off under reduced pressure, and the title compound was slightly yellow. An oily substance of 1.25 g (yield: 97%) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 0.07 (6H, s), 0.89 (9H, s), 3.51 (2H, t, J = 5.1 Hz), 3.68 (2H, dd, J = 8.2, 4.5) Hz), 3.76 (2H, t, J = 5.1 Hz), 4.04-4.11 (2H, m), 4.43-4.53 (1H, m), 6.20-6.28 (2H, m), 7.42-7.49 (2H, m) ..

(17c) 1- (4- {3- [2- (tert-butyldimethylsilanyloxy) ethoxy] azetidine-1-yl} phenyl) -5,6-dimethoxy-2-methylindole

Compound 658 mg (3.44 mmol) prepared in Example 1 (1b), compound 1.25 g (2.88 mmol) prepared in Example 17 (17b), copper iodide 27 mg (0.14 mmol), trans-N, N'. -Dimethylcyclohexane-1,2-diamine 61 mg (0.43 mmol) and tripotassium phosphate 1.28 g (6.03 mmol) are suspended in 3 mL of toluene, nitrogen is bubbled, and then stirred at 100 ° C. for 15 hours under a nitrogen atmosphere. bottom. After allowing to cool, 20 mL of water and 40 mL of ethyl acetate were added, the insoluble material was filtered off, and the two layers of the filtrate were separated. The ethyl acetate layer was washed successively with water and saturated brine, dried (Na ₂ SO ₄ ), and ethyl acetate was distilled off under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate, 10: 1 → 5: 1, V / V), the solvent of the target fraction was distilled off under reduced pressure, and the yellow powder of the title compound was 755 mg (5). Yield: 53%) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 0.09 (6H, s), 0.91 (9H, s), 2.21 (3H, s), 3.55 (2H, t, J = 5.1 Hz), 3.78 (3H, s) s), 3.78-3.85 (4H, m), 3.91 (3H, s), 4.16-4.24 (2H, m), 4.50-4.60 (1H, m), 6.22 (1H, s), 6.53-6.60 (3H, s) m), 7.01 (1H, s), 7.12-7.19 (2H, m).

(17d) 2- {1- [4- (5,6-dimethoxy-2-methylindole-1-yl) phenyl] azetidine-3-yloxy} ethyl acetate

To 743 mg (1.38 mmol) of the compound prepared in Example 17 (17c) was added 4.1 mL (4.1 mmol) of a 1.0 M tetra-n-butylammonium tetrahydrofuran tetrahydrofuran solution at room temperature, and the mixture was stirred at the same temperature for 50 minutes. After distilling off tetrahydrofuran under reduced pressure, add 20 mL of water to the residue, extract with 50 mL of ethyl acetate, wash the ethyl acetate layer sequentially with water and saturated brine, dry (Na ₂ SO ₄ ), and reduce the pressure. The lower ethyl acetate was distilled off.
The obtained residue was dissolved in 7 mL of methylene chloride, 0.38 mL (2.7 mmol) of triethylamine and 0.15 mL (2.1 mmol) of acetyl chloride were added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. After adding 20 mL of water and 20 mL of methylene chloride and separating the two layers, the methylene chloride layer was washed successively with water and saturated brine, and dried (Na ₂ SO ₄ ). Methylene chloride is distilled off under reduced pressure, the residue is purified by column chromatography (Chromatorex NH, n-hexane: ethyl acetate, 6: 1 → 4: 1, V / V), and then the solvent of the target fraction is reduced under reduced pressure. Distillation gave 461 mg (yield: 79%) of a white powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.11 (3H, s), 2.21 (3H, s), 3.69 (2H, t, J = 4.8 Hz), 3.78 (3H, s), 3.84 (2H, 2H, dd, J = 8.3, 4.9 Hz), 3.91 (3H, s), 4.19-4.30 (4H, m), 4.49-4.59 (1H, m), 6.22 (1H, s), 6.54 (1H, s), 6.54 -6.60 (3H, m), 7.01 (1H, s), 7.13-7.20 (2H, m).

(17e) 2- {1- [4- (3-Acetyl-5,6-dimethoxy-2-methylindole-1-yl) phenyl] azetidine-3-yloxy} ethyl acetate

Compound 454 mg (1.07 mmol) prepared in Example 17 (17d) was dissolved in 5.5 mL of methylene chloride, followed by ice-cooled acetyl chloride 0.11 mL (1.5 mmol) and titanium (IV) chloride 0.18 mL (1.6 mmol). In addition, the mixture was stirred at the same temperature for 30 minutes. 20 mL of ice water was added, and the mixture was stirred at room temperature until the precipitate dissolved, and then the two layers were separated. The methylene chloride layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (Na ₂ SO ₄ ), and methylene chloride was distilled off under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate, 3: 1 → 2: 1 → 1: 1 → 2: 3, V / V), and then the solvent for the target fraction was distilled off under reduced pressure. A white powder of the title compound (120 mg) (yield: 24%) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.11 (3H, s), 2.50 (3H, s), 2.65 (3H, s), 3.70 (2H, t, J = 4.8 Hz), 3.77 (3H, s) s), 3.86 (2H, dd, J = 8.3, 4.6 Hz), 3.98 (3H, s), 4.20-4.30 (4H, m), 4.51-4.60 (1H, m), 6.45 (1H, s), 6.54 -6.60 (2H, m), 7.01 (1H, s), 7.13-7.20 (2H, m).

(17) 2- {1- [4- (3-Acetyl-5,6-dimethoxy-2-methylindole-1-yl) phenyl] azetidine-3-yloxy} ethanol

115 mg (0.247 mmol) of the compound prepared in Example 17 (17e) was dissolved in 1 mL of methylene chloride, and 1 mL of methanol and 0.24 mL (1.2 mmol) of 5.0 M sodium hydroxide water were added at room temperature to the same temperature. Stirred for 2 hours. After distilling off the solvent under reduced pressure, 10 mL of water was added, and methanol was added until the precipitate was dissolved. After distilling off methanol under reduced pressure, the precipitate was collected by filtration to give 98 mg (yield: 85%) of a white powder of the title compound.
IR ν (ATR) cm ^-1 : 1608
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.85-2.00 (1H, br), 2.50 (3H, s), 2.64 (3H, s), 3.60 (2H, t, J = 4.5 Hz), 3.76- 3.84 (2H, m), 3.77 (3H, s), 3.87 (2H, dd, J = 7.9, 4.3 Hz), 3.98 (3H, s), 4.20-4.28 (2H, m), 4.51-4.60 (1H, m) m), 6.45 (1H, s), 6.56-6.62 (2H, m), 7.09-7.16 (2H, m), 7.68 (1H, s).
MS m / z: 427 [M + H] ⁺ .

Example 18

(18a) 3-Carbamoyl-5,6-dimethoxy-2-methyl-1-{4- [3- (2-acetoxyethoxy) azetidine-1-yl] phenyl} indole

200 mg (0.470 mmol) of the compound prepared in Example 17 (17d) was dissolved in 2 mL of methylene chloride, 0.062 mL (0.71 mmol) of chlorosulfonyl isocyanate was added dropwise at -78 ° C, and the mixture was stirred at the same temperature for 5 minutes. bottom. Diisopropyl ether was added to the reaction solution, and the precipitated powder was collected by filtration to obtain 300 mg of white powder.
The obtained white powder (300 mg) was dissolved in 2 mL of acetic acid, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted twice with chloroform. The chloroform layers were combined, washed with saturated brine, and dried (Na ₂ SO ₄ ). Chloroform was distilled off under reduced pressure to obtain 200 mg (yield: 91%) of a white powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.11 (3H, s), 2.48 (3H, s), 3.65-3.72 (2H, m), 3.78 (3H, s), 3.83-3.87 (2H, m) ), 3.96 (3H, s), 4.17-4.30 (4H, m), 4.49-4.57 (1H, m), 5.55-5.67 (2H, br), 6.49 (1H, s), 6.56-6.58 (2H, m) ), 7.10-7.13 (2H, m), 7.37 (1H, s).

(18) 3-Carbamoyl-5,6-dimethoxy-2-methyl-1-{4- [3- (2-hydroxyethoxy) azetidine-1-yl] phenyl} indole

200 mg (0.430 mmol) of the compound prepared in Example 18 (18a) was dissolved in 4 mL of a mixture of methylene chloride-methanol (1: 1), and at room temperature 5.0 M sodium hydroxide water 0.43 mL (2.2 mmol) was added. In addition, the mixture was stirred at the same temperature for 30 minutes. 4 mL of water was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The precipitated powder was collected by filtration and washed with diisopropyl ether to give 130 mg (yield: 71%) of a white powder of the title compound.
IR ν (ATR) cm ^-1 : 3220-3050, 1648.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.96 (1H, t, J = 6.0 Hz), 2.47 (3H, s), 3.57-3.62 (2H, m), 3.78 (3H, s), 3.78- 3.89 (4H, m), 3.96 (3H, s), 4.20-4.23 (2H, m), 4.50-4.60 (1H, m), 5.58-5.70 (2H, br), 6.49 (1H, s), 6.57- 6.59 (2H, m), 7.10-7.13 (2H, m), 7.37 (1H, s).
MS (EMS) m / z: 426 [M + H ⁺ ].

Example 19

(19a) 1- (4-Nitrophenyl) -3- [2- (Tetrahydropyran-2-yloxy) ethoxy] Azetidine

1-Benz hydryl-3- [2- (tetrahydropyran-2-yloxy) ethoxy] azetidine prepared in Example 9 (9c) by suspending 3.0 g of 20% palladium hydroxide in 250 mL of methanol 23.8 g (64.8 mmol). ) Was added, and catalytic hydrogenation was performed at 25 ° C. and 0.40 MPa for 3 hours. After the insoluble material was filtered off, the solvent was distilled off under reduced pressure to obtain 23.3 g (yield: 98%) of a brown oil of 3- [2- (tetrahydropyran-2-yloxy) ethoxy] azetidine.
3- [2- (Tetrahydropyran-2-yloxy) ethoxy] azetidine 3.00 g (8.16 mmol) was dissolved in 30 mL of N, N-dimethylformamide, 4-nitrofluorobenzene 1.04 mL (9.79 mmol), diisopropylethylamine 2.13. mL (12.2 mmol) was added, and the mixture was stirred at 60 ° C. for 15 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried (Na ₂ SO ₄ ). The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate, 4: 1 → 1: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 2.08 g (yield: 79%) of a yellow oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.50-1.88 (6H, m), 3.48-3.64 (2H, m), 3.65-3.69 (2H, m), 3.84-3.98 (4H, m), 4.20 -4.26 (2H, m), 4.53-4.57 (1H, m), 4.61-4.63 (1H, m), 6.30-6.32 (2H, m), 8.08-8.11 (2H, m).

(19b) 4- {3- [2- (Tetrahydropyran-2-yloxy) ethoxy] Azetidine-1-yl} Phenylamine

500 mg of 5% palladium carbon was suspended in 30 mL of methanol, 2.07 g (6.42 mmol) of the compound prepared in Example 19 (19a) was added, and catalytic hydrogenation was carried out at 25 ° C. and 0.40 MPa for 1 hour. After the insoluble material was filtered off, the solvent was distilled off under reduced pressure to obtain 1.9 g (yield: quantitative) of a brown oily substance of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.46-1.88 (6H, m), 3.25-3.40 (2H, br), 3.45-3.55 (1H, m), 3.56-3.65 (5H, m), 3.83 -3.90 (2H, m), 4.02-4.06 (2H, m), 4.44-4.47 (1H, m), 4.61-4.63 (1H, m), 6.35-6.37 (2H, m), 6.61-6.63 (2H, m) m).

(19c) N- (4-iodo-6-methoxypyridin-3-yl) -2,2-dimethylpropionamide

13.2 g (10.6 mmol) of 6-methoxypyridin-3-ylamine is dissolved in 130 mL of methylene chloride, 17.7 mL (12.7 mmol) of triethylamine and 13.6 mL (11.1 mmol) of pivaloyl chloride are added under ice-cooling, and 30 at the same temperature. Stir for minutes. The reaction mixture was washed successively with water and saturated brine, and dried (Na ₂ SO ₄ ). Methylene chloride was distilled off under reduced pressure to obtain 22.0 g (yield: quantitative) of a slightly red powder of N- (6-methoxypyridin-3-yl) -2,2-dimethylpropionamide.
Dissolve 25.2 g (0.120 mol) of N- (6-methoxypyridin-3-yl) -2,2-dimethylpropionamide in 200 mL of tetrahydrofuran and at -78 ° C, add 200 mL of 1.7 M tert-butyllithium pentane solution (200 mL). 0.34 mol) was added dropwise over 1 hour. After stirring at the same temperature for 30 minutes, a solution of 55.2 g (0.220 mol) of iodine in 200 mL of tetrahydrofuran was added dropwise over 1 hour, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, and dried (Na ₂ SO ₄ ). Ethyl acetate was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 40: 1 → 8: 1 → 6: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 15.0 g (yield: 37%) of a light brown powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.36 (9H, s), 3.90 (3H, s), 7.23 (1H, s), 7.33-7.40 (1H, br), 8.69 (1H, s).

(19d) 4-Iodine-6-methoxypyridin-3-ylacetamide

To 15.0 g (44.9 mmol) of the compound prepared in Example 19 (19c), 165 mL of 10% sulfuric acid water was added, and the mixture was heated under reflux for 8 hours. The reaction mixture was neutralized with sodium bicarbonate, extracted twice with ethyl acetate, and dried (Na ₂ SO ₄ ). Ethyl acetate was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 3: 1, V / V). The solvent of the target fraction was distilled off under reduced pressure to obtain 6.0 g (yield: 54%) of a light brown powder of 4-iodo-6-methoxypyridin-3-ylamine.
Dissolve 5.10 g (20.4 mmol) of 4-iodo-6-methoxypyridin-3-ylamine in 50 mL of methylene chloride, add 4.27 mL (30.6 mmol) of triethylamine and 1.74 mL (24.5 mmol) of acetyl chloride under ice-cooling, and add to room temperature. Was stirred for 1 hour. The reaction mixture was washed successively with water and saturated brine, and dried (Na ₂ SO ₄ ). Dichloromethane chloride was distilled off under reduced pressure, diisopropyl ether was added to the residue, and the mixture was collected by filtration to obtain 4.60 g (yield: 77%) of a white powder of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.24 (3H, s), 3.91 (3H, s), 6.96-7.10 (1H, br), 7.24 (1H, s), 8.59 (1H, s).

(19e) N- [6-methoxy-4- (4- {3- [2- (tetrahydropyran-2-yloxy) ethoxy] azetidine-1-yl} phenylamino) pyridin-3-yl] acetamide

Compound 3.46 g (11.8 mmol) prepared in Example 19 (19b) was dissolved in 35 mL of tert-butanol, and compound 3.46 g (11.8 mmol) prepared in Example 19 (19d), tris (dibenzylideneacetone) di Add 540 mg (0.590 mmol) of palladium (0), 562 mg (1.18 mmol) of 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl, 5.00 g (23.6 mmol) of tripotassium phosphate, and nitrogen. The mixture was heated and refluxed for 2 hours in an atmosphere. Water was added to the reaction solution, the mixture was extracted twice with ethyl acetate, the organic layers were combined, washed successively with water and saturated brine, and dried (Na ₂ SO ₄ ). Ethyl acetate was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 3: 1, chloroform: methanol, 50: 1 → 20: 1, V / V). The solvent of the target fraction was evaporated under reduced pressure to give 4.50 g (yield: 83%) of a light brown oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.50-1.80 (6H, m), 1.96 (1H, s), 2.24 (2H, s), 3.46-3.92 (11H, m), 4.05-4.20 (2H) , m), 4.45-4.55 (1H, m), 4.60-4.70 (1H, m), 6.07-6.30 (2H, m), 6.40-6.54 (2H, m), 6.95-7.10 (2H, m), 7.76 -7.84 (1H, s).

(19f) 2- {1- [4- (6-Methoxy-2-methyl-imidazole [4,5-c] pyridin-1-yl) phenyl] azetidine-3-yloxy} ethyl acetate

4.50 g (9.85 mmol) of the compound prepared in Example 19 (19e) was dissolved in 20 mL of acetic acid and 20 mL of acetic anhydride, and after stirring at 80 ° C. for 5 hours in a nitrogen atmosphere, 10 mL of acetic acid and 10 mL of acetic anhydride were added. The mixture was added and stirred at the same temperature for another 3 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, extracted twice with ethyl acetate, washed successively with water and saturated brine, and dried (Na ₂ SO ₄ ). Ethyl acetate was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (Chromatorex NH, n-hexane: ethyl acetate, 1: 1, V / V). The solvent of the target fraction was evaporated under reduced pressure to give 2.07 g (yield: 53%) of a light brown oil of the title compound.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.11 (3H, s), 2.43 (3H, s), 3.65-3.75 (2H, m), 3.80-3.88 (2H, m), 3.94 (3H, s) ), 4.18-4.30 (4H, m), 4.50-4.60 (1H, m), 6.39 (1H, s), 6.55-6.57 (2H, m), 7.11-7.14 (2H, m), 8.56 (1H, s) ).

(19) 2- {1- [4- (6-Methoxy-2-methylimidazole [4,5-c] pyridin-1-yl) phenyl] azetidine-3-yloxy} ethanol

2.07 g (5.22 mmol) of the compound prepared in Example 19 (19f) was dissolved in 20 mL of methanol, 3.1 mL (15 mmol) of 5.0 M sodium hydroxide water was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. .. Methanol was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue, the insoluble material was collected by filtration, and the obtained powder was purified by column chromatography (Chromatorex NH, n-hexane: ethyl acetate, 1: 1 → 0: 1, V / V). The solvent of the target fraction was evaporated under reduced pressure, diisopropyl ether was added to the residue, and the insoluble material was collected by filtration to obtain 1.35 g (yield: 73%) of a slightly red powder of the title compound.
IR ν (ATR) cm ^-1 : 3100-3200, 1623
^{1 1} H-NMR (DMSO-d6, 400 MHz) δ: 2.35 (3H, s), 3.40-3.60 (4H, m), 3.68-3.78 (2H, m), 3.83 (3H, s), 4.10-4.20 ( 2H, m), 4.44-4.54 (1H, m), 4.65-4.73 (1H, m), 6.31 (1H, s), 6.58-6.60 (2H, m), 7.27-7.30 (2H, m), 8.45 ( 1H, s).
MS m / z: 355 [M + H] ⁺ , 353 [MH] ^- .

Example 20

(20a) 7-Methoxyquinoline-4-ol

To 12.3 g (0.100 mol) of 3-methoxyaniline, 21.6 g (0.100 mol) of diethyl ethoxymethylene malonate was added, and the mixture was stirred at 110 ° C. for 75 minutes, 150 mL of diphenyl ether was added, and the mixture was stirred at 230 ° C. for 8.5 hours. The reaction was cooled to room temperature and poured into 200 mL of ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate to obtain 8.56 g (yield: 35%) of a light brown powder of ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate.
To 8.56 g (34.6 mmol) of ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate, 85 mL (170 mmol) of 2.0 M sodium hydroxide water was added, and the mixture was heated under reflux for 1.0 hour. The reaction mixture was cooled to room temperature, 80 mL of 2.0 M hydrochloric acid was added, the precipitate was collected by filtration, washed with water, and dried. 40 mL of diphenyl ether was added to the obtained powder, and the mixture was heated under reflux for 40 minutes. The reaction solution was cooled to room temperature, and the supernatant was removed by decanting. 5.0 M sodium hydroxide water was added to the residue, washed twice with ethyl acetate, and 5% citric acid water was added to the aqueous layer to adjust the pH to 2. The precipitate was collected by filtration and washed with diisopropyl ether to give 1.30 g (yield: 21%) of a white powder of the title compound.
^{1 1} H-NMR (DMSO-d6, 400 MHz) δ: 3.85 (3H, s), 5.93 (1H, d, J = 6.8 Hz), 6.82-6.97 (2H, m), 7.72-7.84 (1H, m) , 7.94-8.05 (1H, m), 11.45-11.60 (1H, br).

(20) 7-Methoxy-1- [4- (3- (morpholine-4-yl) azetidine-1-yl) phenyl] -1H-quinoline-4-one hydrochloride

Compound 594 mg (3.39 mmol), 4- [1- (4-iodophenyl) azetidine-3-yl] morpholine 1.17 g (3.39 mmol) prepared in Example 20 (20a) was suspended in 8 mL of dimethyl sulfoxide. Add 141 μL (0.678 mmol) of 2,2,6,6-tetramethyl-3,5-heptandione, 65 mg (0.34 mmol) of copper iodide, 1.44 g (6.78 mmol) of tripotassium phosphate, and add 1 nitrogen. Bubbling was carried out for 1 minute, and the mixture was stirred at 120 ° C. for 9 hours under a nitrogen atmosphere, and then further stirred at room temperature for 5 hours. 100 mL of water and 100 mL of chloroform were added to the reaction mixture, the insoluble material was filtered off, the two layers were separated, and the aqueous layer was extracted 3 times with chloroform. The organic layers were combined, washed with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: methanol, 98: 2 → 95: 5, V / V), the solvent of the target fraction was distilled off under reduced pressure, and 7-methoxy-1- [4]. -(3- (Morpholine-4-yl) azetidine-1-yl) phenyl] -1H-quinoline-4-one light brown powder 975 mg (yield: 73%) was obtained.
7-Methone-1- [4- (3- (morpholine-4-yl) azetidine-1-yl) phenyl] -1H-quinoline-4-one 800 mg (2.04 mmol) was suspended in 10 mL of methanol. 8.6 M hydrogen chloride isopropanol solution under ice cooling 712 μL (6.1 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. 80 mL of diisopropyl ether was added to the reaction mixture, and the precipitate was collected by filtration to give 933 mg (yield: 99%) of orange powder of the title compound.
IR ν (ATR) cm ^-1 : 1608
^{1 1} H-NMR (DMSO-d6, 400 MHz) δ: 3.00-3.14 (2H, m), 3.33-3.48 (2H, m), 3.72 (3H, s), 3.80-3.96 (2H, m), 3.97- 4.08 (2H, m), 4.18-4.24 (2H, m), 4.25-4.38 (3H, m), 6.44 (1H, d, J = 2.2 Hz), 6.66-6.74 (3H, m), 7.24 (1H, m) dd, J = 8.6, 2.2 Hz), 7.41-7.46 (2H, m), 8.25 (1H, d, J = 8.6 Hz), 8.31 (1H, d, J = 7.2 Hz).
MS m / z: 392 [M + H] ⁺ .

Example 21

(21a) Methyl 8- {4- [2- (tetrahydropyran-4-yloxy) ethoxy] phenyl} naphthalene-2-carboxylate

Methyl 8-bromonaphthalene-2-carboxylate 495 mg (1.87 mmol) and compound 650 mg (1.87 mmol) prepared in Example 14 (14b) were dissolved in 10 mL of N, N-dimethylformamide and tripotassium phosphate. 793 mg (3.74 mmol) and tetrakis (triphenylphosphine) palladium (0) 216 mg (0.187 mmol) were added, and the mixture was stirred at 90 ° C. for 7 hours under a nitrogen atmosphere. After allowing to cool, water and ethyl acetate were added to the reaction solution, the insoluble material was removed by filtration through Celite, the two layers of the filtrate were separated, the organic layer was washed with saturated brine, and dried (Na ₂ SO ₄ ). .. The solvent was distilled off under reduced pressure, the residue was purified by column chromatography (n-hexane: ethyl acetate, 3: 1, V / V), and the solvent of the target fraction was distilled off under reduced pressure. An oily substance of 565 mg (yield: 74%) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.63-1.73 (2H, m), 1.94-2.02 (2H, m), 3.44-3.52 (2H, m), 3.61-3.68 (1H, m), 3.88 -3.93 (5H, m), 3.99 (2H, dt, J = 12.0, 4.2 Hz), 4.21-4.25 (2H, m), 7.05-7.09 (2H, m), 7.39-7.43 (2H, m), 7.46 (1H, dd, J = 7.1, 1.0 Hz), 7.58-7.63 (1H, m), 7.30 (1H, d, J = 8.0 Hz), 7.93 (1H, d, J = 8.6 Hz), 8.06 (1H, 1H, dd, J = 8.6, 1.5 Hz), 8.66-8.68 (1H, m).

(21) 8- {4- [2- (Tetrahydropyran-4-yloxy) ethoxy] phenyl} naphthalene-2-carboxamide

350 mg (0.861 mmol) of the compound prepared in Example 21 (21a) was dissolved in 6 mL of tetrahydrofuran, 3 mL of methanol and 2.2 mL (2.2 mmol) of 1.0 M lithium hydroxide water were added, and the mixture was stirred at room temperature for 9 hours. .. Methanol and tetrahydrofuran were distilled off under reduced pressure, 10 mL of water and 0.40 mL (2.4 mmol) of 6.0 M hydrochloric acid were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure to give 330 mg of white powder.
After dissolving 330 mg of the obtained white powder in 5 mL of N, N-dimethylformamide, 500 mg of ammonium carbonate, 125 mg (0.925 mmol) of 1-hydroxybenzotriazole and 1- [3- (dimethylamino) propyl] -3 -Ethylcarbodiimide hydrochloride 177 mg (0.923 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried (Na ₂ SO ₄ ). The solvent was evaporated under reduced pressure, the residue was purified by column chromatography (chloroform: methanol, 1: 0 → 9: 1, V / V), and the solvent of the target fraction was evaporated under reduced pressure. The obtained powder (260 mg) was dissolved in 16 mL of ethyl acetate by heating, and the mixture was stirred for 3 hours while returning to room temperature. The precipitate was collected by filtration to give 221 mg (yield: 67%) of a white powder of the title compound.
IR ν (ATR) cm ^-1 : 3406, 3195, 1668
^{1 1} H-NMR (DMSO-d6, 400 MHz) δ: 1.38-1.48 (2H, m), 1.85-1.92 (2H, m), 3.31-3.38 (2H, m), 3.55-3.63 (1H, m), 3.78-3.85 (4H, m), 4.16-4.20 (2H, m), 7.09-7.13 (2H, m), 7.38-7.46 (4H, m), 7.63 (1H, dd, J = 8.3, 7.1 Hz), 7.93-7.98 (2H, m), 8.01-8.08 (2H, m), 8.38-8.40 (1H, m).
MS m / z: 414 [M + H] ⁺ , 390 [MH] ^- .

The compounds shown in Tables 1-1 to 1-71 below were produced according to the methods shown in Examples 1 to 21.

(Test Example 1)
The CDK8 inhibitory activity of the Example compound was evaluated by the following method.

The test compound dissolved in DMSO was diluted with assay buffer (QSS Assist STK ELISA Kit (CDK8 / CycC), Carna Bioscience) to obtain a primary dilution solution having a DMSO concentration of 4%. After dispensing 10 μL of the above primary dilution solution into a streptavidin-coated 96-well plate, _{10 μL of an assay buffer mixture containing 1 μM substrate (Carna Biosciences), 20 mM MgCl 2} (Carna Biosciences) and 400 μM ATP (Carna Biosciences) was added. After the above addition, 20 μL of a kinase solution (0.15 ng / μL CDK8 / CycC (Carna Bioscience) diluted with an assay buffer was used for measuring the CDK8 inhibitory activity) was further added. After the above addition, the mixture was allowed to stand at 20 to 30 ° C. for 30 minutes. After completion of the reaction, the solution in the wells was discarded and immediately washed 4 times with 250 μL of wash buffer (50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 0.02% Tween-20) per well. 200 μL of blocking buffer (assay buffer containing 0.1% BSA) was added to each well, and the mixture was allowed to stand at room temperature for 30 minutes. The solution in the wells was discarded, 100 μL of the primary antibody solution (Carna Bioscience) was added to each well, and the mixture was allowed to stand at room temperature for 30 minutes. The solution in the wells was discarded and immediately washed 4 times with 250 μL wash buffer per well. 100 μL of HRP-labeled secondary antibody solution (Carna Biosciences) was added to each well, and the mixture was allowed to stand at room temperature for 30 minutes. The solution in the wells was discarded and immediately washed 4 times with 250 μL wash buffer per well. 100 μL of a coloring reagent (ELISA POD substrate TMB kit (HYPER), Nacalai Tesque) was added to each well, and the mixture was reacted at room temperature for 5 minutes. After stopping the reaction by adding 100 μL of a color reaction terminator (Nacalai Tesque) to each well, the absorbance (450 nm) was measured with a plate reader.

The absorbance of the well without the test compound was controlled, and the absorbance of the well without the enzyme was used as a blank to determine the CDK8 inhibition rate at 1 μM of the test compound.

Compounds 1, 6, 8, 10, 14, 19, 20, 21, 28, 31, 38, 48, 57, 63, 78, 112, 117, 120, 149, 163, 172 and 176 are 90% at 1 μM. The above CDK8 inhibition rate was shown.

(Test Example 2)
The human acute myeloid leukemia MV4; 11 cell proliferation inhibitory activity of the Example compound was evaluated by the following method.

Human acute myeloid leukemia MV4; 11 (purchased from American Type Culture Collection) cell suspension 100 μL (10,000 cells / well) was seeded in 96-well plates and cultured in a 5% carbon dioxide incubator at 37 ° C. for 1 day. .. After the above culture, the test compound was added so as to have a concentration of 1 μM, and the cells were further cultured for 3 days. After the above culture, 40 μL of MTS / PMS solution (CellTiter 96 (registered trademark) AQueuus One Solution Cell Proliferation Assay (Promega)) was added to a 96-well plate, reacted for 1 hour, and then absorbed by a plate reader (490 nm). Was measured.

The absorbance of the wells to which the test compound was not added was controlled, and the absorbance of the wells in which cells were not seeded was used as a blank, and the cell proliferation inhibition rate at 1 μM of the test compound was determined.

Compounds 1, 6, 8, 10, 14, 19, 20, 21, 28, 31, 38, 48, 57, 63, 78, 112, 117, 120, 149, 163, 172 and 176 are 50% at 1 μM. The above cell proliferation inhibition rate was shown.

(Test Example 3)
The osteoblast differentiation effect of the Example compound was evaluated by the following method.

Mouse bone marrow-derived mesenchymal cell line ST2 cells (obtained by: Institute of Physical and Chemical Research) in 96-well plate in α-MEM medium containing 10% fetal bovine serum (obtained from GIBCO BRL Cat.No.12000-022) , 4 × 10 ³ cells / 0.1 mL / well, seeded and cultured for 24 hours under _{37 ° C. and 5% CO 2 conditions.} The test compound was then added to a final concentration of 0.001-10 μM, and DMSO with a final concentration of 0.1% (v / v) was added to the control. After culturing for another 4 days, the alkaline phosphatase (ALP) activity was measured by the following method.
After removal of the medium of 96 well plate cultured, PBS buffer (KCl 0.2 g / L, KH 2 PO 4 0.2 g / L, Na 2 HPO 4 · 12H 2 O 2.9 g / L, NaCl 8 g / L) 100 The cells were washed with μL / well, _{50 μL / well of cell lysate (10 mM MgCl 2} , 2% (v / v) TritonX-100) was added, and the mixture was stirred at room temperature for 3 minutes. Substrate solution (50 mM diethanolamine (Wako Pure Chemicals Cat.No.099-03112), 20 mM p-nitrophenylphosphite (Nacalai Tesque Cat.No.25019-81)) 50 μL / well was added, and 9 at room temperature. After allowing to stand for 1 minute, 50 μL / well of 1 N NaOH was added to stop the reaction, and the absorbance at 405 nm was measured using a microplate reader (Dainippon Pharmaceutical Co., Ltd.).

The rate of increase (%) in the absorbance of the test compound when the absorbance of the control was set to 100% was calculated, and the degree of differentiation of osteoblasts was evaluated.

In this test, all Example compounds showed more than 200% alkaline phosphatase activity at 0.1 μg / mL.

(Test Example 4)
The effect of the Example compound on bone mineral density was evaluated by the following method.

12-week-old female F344 rats (SLC) underwent ovariectomy or sham surgery under anesthesia. From the day after the operation, the test compound was suspended in a 0.5% methylcellulose solution (Wako Pure Chemical Industries, Ltd. Cat.No.133-14255) and orally administered once a day for 6 or 7 days a week. A 0.5% methylcellulose solution was orally administered to the control group. Eight weeks after administration, all blood was collected from the abdominal aorta under anesthesia and euthanized, and the left and right femurs were removed.
After removing the soft tissue from the removed femur, the bone density was measured using a DXA device DCS-600R (Aroca Co., Ltd.). Bone density was evaluated by dividing the entire femur and the entire femur into three equal parts, the proximal end, the diaphysis, and the distal end.

In this study, compounds 2, 3, 36, 38, 40, 54, 92, 102, 120 and 167 significantly increased bone mineral density below 10 mg / kg.

From the above results, the compound (I) of the present invention has an excellent inhibitory activity on cyclin-dependent kinase (CDK) 8 and a high cell proliferation inhibitory activity on human acute myeloid leukemia MV4; 11 cells. It was found that it has an excellent osteoblast differentiation effect and a bone density increasing effect.

Pharmaceutical example 1 (manufacturing of capsule)
1) Example compound (Compound (I)) 10 mg
2) Fine powdered cellulose 10 mg
3) Lactose 19 mg
4) Magnesium stearate 1 mg
40 mg in total
1), 2), 3) and 4) are mixed and filled in gelatin capsules.

Pharmaceutical example 2 (Manufacturing of tablets)
1) Example compound (Compound (I)) 10 g
2) Lactose 50 g
3) Corn starch 15 g
4) Carboxymethyl cellulose calcium 44 g
5) Magnesium stearate 1 g
1000 tablets total 120 g
The whole amount of 1), 2) and 3) and 30 g of 4) are kneaded with water, vacuum dried, and then granulated. 14 g of 4) and 1 g of 5) are mixed with this sized powder and locked with a lock press. In this way, 1000 tablets containing 10 mg of the Example compound per tablet are obtained.

Compound (I) of the present invention has excellent inhibitory activity against cyclin-dependent kinase (CDK) 8. Therefore, according to the present invention, it is possible to provide an excellent CDK8 inhibitor. Further, according to the present invention, it is possible to provide a medicine useful as a preventive and / or therapeutic agent for a disease related to CDK8, a disease related to bone metabolism such as osteoporosis, and a cell proliferation disease such as cancer.
This application is based on Japanese Patent Application No. 2018-189561 and Japanese Patent Application No. 2018-206050, the contents of which are incorporated herein by reference.

Claims (27)

General formula (I):

[In the formula, each substituent is defined as follows.
Ring A:

(R ⁴ :
C _1-6 alkylcarbonyl group, C _1-6 alkylthiocarbonyl group, carbamoyl group, C _1-6 alkoxycarbonyl group or carboxy group,
R ⁵ :
Hydrogen atom, C _1-6 alkyl group or halogen atom,
R ⁶ :
C _1-6 alkyl group, halogen atom, amino group, hydroxy C _1-6 alkyl group, carboxy C _1-6 alkyl group or hydrogen atom (provided that T is = CH- and U is = N-),
R ⁷ :
Hydrogen atom or C _1-6 alkyl group,
R ⁸ :
Hydrogen atom, C _1-6 alkyl group or C _1-6 alkyl carbonyl group,
R ⁹ :
Hydrogen atom or C _1-6 alkyl group),
R ¹ :
Hydrogen atom, halogen atom, cyano group, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 alkyl sulfanyl group, C _1-6 alkyl carbonyl group, carbamoyl group or heterocyclic group,
T and U:
If either T or U is = N-, the other is = CR ^2- ,
Both T and U = CR ^2- ,
R ² :
Hydrogen atom, halogen atom, C _1-6 alkyl group or C _1-6 alkoxy group,
R ³ :
−BDEG
(B:
C _6-14 arylene group, C _3-8 cycloalkenylene group, -heterocycle-or-saturated heterocycle-,
D:
Single bond, -O (CH ₂ ) _n -,-(CH ₂ ) _n O- or -saturated heterocycle-,
n:
An integer of any one selected from 1 to 4,
E:
Single bond, -O-, -N (R ¹⁰ )-, -CO- or -CONH-,
R ¹⁰ :
_{A hydrogen atom, a C 1-6} alkyl group which may be substituted with any group selected from the substituent group α,
G:
Hydrogen atom, C _{1-6 alkyl group may be substituted with any group selected from the substituent group α, C 3} which may be substituted with any group selected from the substituent group α _-8 Cycloalkyl group, C _6-14 aryl group which may be substituted with any group selected from the substituent group α, or any group selected from the substituent group α Saturated heterocyclic groups, which may be substituted with a good heterocyclic group or any group selected from the substituent group α,
Substituent group α:
Heterocyclic group, saturated heterocyclic group, halogen atom, cyano group, C _1-6 alkylcarbonyl group, C _1-6 alkylcarbonyloxy group, C _1-6 alkylcarbonylamino group, C _1-6 alkoxycarbonyl group, C _1-6 alkoxy C _1-6 alkyl group, hydroxy C _1-6 alkyl group, hydroxy C _1-6 alkoxy group, C _1-6 alkylsulfonyl group, C _1-6 alkylsulfonylamino group, aminosulfonylamino group, carboxy Group, carboxy C _1-6 alkylcarbonyloxy group, carbamoyl group, hydroxy group, C _1-6 alkoxy group, C _1-6 alkyl group, C _3-8 cycloalkyl group, amino group, amino C _1-6 alkylcarbonyl Oxy group, mono or di-C _1-6 alkylamino group, 4-hydroxy tetrahydrofuran-3-yloxy group, mono or di-C _1-6 alkylphosphono group,

(N is an integer of any one selected from 1 to 4))] or a pharmaceutically acceptable salt thereof. Ring A is

The compound according to claim 1, wherein R ⁴ is an acetyl group, a carbamoyl group or a carboxy group, and R ⁵ is a methyl group, or a pharmaceutically acceptable salt thereof. Ring A is

The compound according to claim 1, wherein R ⁷ is a methyl group and R ⁹ is a hydrogen atom, or a pharmaceutically acceptable salt thereof. Ring A is

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ^{7 is a methyl group.} Ring A is

The compound according to claim 1 or a pharmaceutically acceptable salt thereof. Ring A is

The compound according to claim 1 or a pharmaceutically acceptable salt thereof. Ring A is

In and, R ⁶ is chlorine, a methyl group or a carboxymethyl group, a compound or a pharmaceutically acceptable salt thereof according to claim 1. The compound according to any one of claims 1 to 7, wherein R ¹ is a cyano group, a methoxy group, a methyl sulfanyl group, an acetyl group, a carbamoyl group or an imidazolyl group, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 8, wherein T is = CH- and U is = N-, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 8, wherein T is = CH-, U is = CR ^2- , and R ^{2 is a hydrogen atom, a fluorine atom or a methoxy group.} A pharmaceutically acceptable salt. B is

The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof. B is

The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 12, wherein D is a single bond, −O (CH ₂ ) _n − or − saturated heterocycle −, and n is 2, or a pharmaceutically acceptable compound thereof. salt. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein E is a single bond or -O-. G is a hydroxy group, an amino group, a carboxy group, an aminosulfonylamino group, a diethylphosphono group or

The compound according to any one of claims 1 to 14, which is a C _1-6 alkyl group, a phenyl group, a tetrahydropyranyl group, a tethydrofuranyl group, a piperazinyl group or a morpholinyl group substituted with. A pharmaceutically acceptable salt. Any compound selected from the group of compounds described below or a pharmaceutically acceptable salt thereof.
(1) 3-Acetyl-5,6-dimethoxy-2-methyl-1- [4- (morpholine-4-yl) phenyl] indole

(2) 3-Acetyl-5,6-dimethoxy-2-methyl-1-{4- [3- (2-oxo-2λ ^5- [1,3,2] dioxaphosphinan-2-yl) propoxy ] Phenyl} indole

(3) 3-Acetyl-1-{4- [3- (2-Hydroxyethoxy) azetidine-1-yl] phenyl} -6-methoxy-2-methylindole

(4) 3-Acetyl-1-{4- [4- (3-aminopropyl) piperidine-1-yl] phenyl} -5,6-dimethoxy-2-methylindole

(5) 3-Acetyl-6-methoxy-2-methyl-1- [4- (4- (morpholine-4-yl) butoxy) phenyl] indole hydrochloride

(6) 3-Acetyl-5-Fluoro-6-Methoxy-2-methyl-1- (1-phenylpiperidine-4-yl) indole

(7) 3- {1- [4- (3-Acetyl-5,6-dimethoxy-2-methylindole-1-yl) phenyl] piperidin-4-yl} propionic acid

(8) 1- [4- (4-Acetylpiperazin-1-yl) phenyl] -5,6-dimethoxy-2-methylindole-3-carboxamide

(9) 1- {4- [4- (2-Hydroxyethoxy) piperidine-1-yl] phenyl} -6-methoxy-2-methyl-1H-pyrrolo [3,2-c] pyridine-3-carboxamide

Any compound selected from the group of compounds described below or a pharmaceutically acceptable salt thereof.
(1) 2- {1- [4- (6-Methoxy-2-methylimidazole [4,5-c] pyridin-1-yl) phenyl] azetidine-3-yloxy} ethanol

(2) Diethyl (1- (4- (5-fluoro-6-methoxy-2-methyl-1H-benzo [d] imidazol-1-yl) phenyl) azetidine-3-yloxy) methylphosphonate

The compounds listed below or pharmaceutically acceptable salts thereof.
(1) 4- {4- [3- (2-Hydroxyethoxy) azetidine-1-yl] phenyl} -6-methoxy-1-methyl-1H- [1,7] naphthididine-2-one

The compounds listed below or pharmaceutically acceptable salts thereof.
(1) 7-Methoxy-1- [4- (3- (morpholine-4-yl) azetidine-1-yl) phenyl] -1H-quinoline-4-one dihydrochloride

The compounds listed below or pharmaceutically acceptable salts thereof.
(1) 2-oxo-4- {4- [2- (tetrahydropyran-4-yloxy) ethoxy] phenyl} -2H-chromen-6-carboxamide

Any compound selected from the group of compounds described below or a pharmaceutically acceptable salt thereof.
(1) 1- {4- [3- (2-Hydroxyethoxy) azetidine-1-yl] phenyl} -7-methoxy-4-methyl-1,4-dihydro-2H-pyrido [3,4-b] Pyrazine-3-on

(2) 1-{4- [3- (2-Sulfamoylaminoethoxy) azetidine-1-yl] phenyl} -7-methoxy-4-methyl-1,4-dihydro-2H-pyrido [3,4 -b] Pyrazine-3-on

Any compound selected from the group of compounds described below or a pharmaceutically acceptable salt thereof.
(1) 8- {4- [2- (Tetrahydropyran-4-yloxy) ethoxy] phenyl} naphthalene-2-carboxamide

(2) 3- {4- [2- (Tetrahydropyran-4-yloxy) ethoxy] phenyl} benzo [b] thiophene-5-carboxamide

A pharmaceutical composition containing the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof as an active ingredient. A CDK8 inhibitor containing the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition containing, as an active ingredient, the compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, which is used for preventing or treating a disease related to CDK8. A pharmaceutical composition containing, as an active ingredient, the compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, which is used for preventing or treating a disease related to bone metabolism. A pharmaceutical composition containing, as an active ingredient, the compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, which is used for preventing or treating cancer.