WO2022255399A1

WO2022255399A1 - G9a inhibitor

Info

Publication number: WO2022255399A1
Application number: PCT/JP2022/022270
Authority: WO
Inventors: 稔吉田; 文幸白井; 昭博伊藤; 翔平高瀬
Original assignee: 国立研究開発法人理化学研究所; 学校法人東京薬科大学
Priority date: 2021-06-01
Filing date: 2022-06-01
Publication date: 2022-12-08

Abstract

The present invention pertains to a compound represented by general formula (I) or a pharmacologically acceptable salt thereof and a pharmaceutical use thereof, for example, a pharmaceutical composition that is to be used for preventing or treating at least one disease selected from the group of diseases consisting of proliferative diseases such as cancer, β-globin disorders, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy and autism.

Description

G9a inhibitor

The present invention relates to a derivative having histone methyltransferase G9a inhibitory activity useful as a drug, or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing it, and its medical use.

Lysine methylation of histones is a biochemical reaction in which a methyl group is added to the ε-amino group of histone lysine residues using S-adenosylmethionine (SAM) as a methyl group donor. Histone lysine methylation plays an important role in transcriptional regulation and is important in a variety of biological processes, including cell proliferation and cell differentiation. Histone methyltransferase (also referred to as lysine methyltransferase) is known as an enzyme that catalyzes the lysine methylation reaction of histones (Non-Patent Document 1).

G9a and GLP (G9a-like protein) are the main enzymes that catalyze the mono- and dimethylation (H3K9me1 and H3K9me2) of the 9th lysine residue of histone H3. Also known as EHMT2 and EHMT1 (euchromatin histone-lysine N-methyltransferases 2 and 1).

H3K9me2 is an epigenetic mark involved in transcriptional repression. G9a and GLP are involved in epigenetic transcriptional repression through H3K9me2.

Therefore, G9a inhibition is thought to be useful in regulating biological processes such as cell proliferation and cell differentiation mediated by transcriptional repression by H3K9me2. Diseases for which G9a inhibitors may be effective include β-globin disorders such as sickle cell disease, gastric cancer, hepatocellular carcinoma, leukemia such as acute myelogenous leukemia and chronic myelogenous leukemia, and cervical cancer. cancer, neuroblastoma, glioma, pancreatic cancer, colorectal cancer, head and neck squamous cell carcinoma, breast cancer, lung cancer, ovarian cancer, melanoma, fibrosis such as pulmonary fibrosis and renal fibrosis, pain, Alzheimer's disease neurodegenerative diseases such as disease and Friedreich's ataxia, viral infections such as Prader-Willi syndrome, malaria, foot-and-mouth disease, and bullous stomatitis, cardiomyopathy, acute myocardial infarction, myopathy, and autism. Furthermore, it has been suggested that inhibition of G9a may also be effective in suppressing cancer metastasis. In addition, inhibition of G9a has been shown to be effective in sex reversal (Non-Patent Documents 1-26).

Compounds having G9a inhibitory activity include BIX-01294 (Patent Document 1), quinazolines (Patent Document 2), 2-aminoindoles (Patent Document 3), heteroaryls (Patent Document 4), tricyclic compounds (Patent Document 5) and the like are known, but the structure is different from that of the compound of the present invention.

WO2012/023285 WO2013/140148 US2015/0274660 Japanese Patent Application Publication No. 2019-513778 Japanese Patent Publication No. 2019-511472

The present invention has been made in view of the above-mentioned problems of the prior art, and has excellent G9a inhibitory activity, for example, is useful for treating β-globin abnormalities such as sickle cell disease. Compounds and pharmacologically acceptable salts thereof also useful for the treatment of proliferative diseases such as cancer, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy, autism, etc. and G9a inhibitors and pharmaceutical compositions containing them. A further object of the present invention is to provide a method for producing the compound and a pharmacologically acceptable salt thereof, and an intermediate compound useful for the production.

At present, no compound has been found that has an excellent G9a inhibitory effect and can be a fully satisfactory pharmaceutical agent as a prophylactic and therapeutic agent for the various pathologies described above.

An object of the present invention is to provide a compound that has a G9a inhibitory action and excellent pharmacokinetic properties as a pharmaceutical.

The present inventors have not only optimized the enzymatic activity, but also performed X-ray complex structural analysis with the G9a protein to identify the structure required for G9a inhibitory activity, and various parameters that affect pharmacokinetics as a drug. As a result of intensive studies on the optimization of the compound represented by the following general formula (I) (hereinafter sometimes referred to as compound (I)), or a pharmacologically acceptable salt thereof has a G9a inhibitory action , found that it avoids P-gp affinity and maintains high water solubility, which are necessary for having sufficiently satisfactory pharmacokinetics as a drug, and completed the present invention.
That is, the present invention is as follows.

[1] General formula (I):

[In the formula (I), R ¹ and R ² are bonded to each other to form a ring, and together with the pyrrole ring to which R ¹ and R ² are bonded, the structure of A1) below is taken, and * is the formula (I ) indicates the bonding position with -CO- in;

R ³ is C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl group, halo C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylamino group, C ₁ -C ₆ acyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₃ -C ₁₀ cycloalkyl group or hydroxy C ₁ -C ₆ alkyl group (the C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl group, halo C ₁ _-C6 alkyl groups, C1 _- _C6 alkoxy groups, C1 _- _C6 alkylamino groups, C1 _- _C6 acyl groups, _C1 - _C6 alkoxycarbonyl groups, _C3 - _C10 cycloalkyl groups and hydroxy C ₁ -C ₆ alkyl group is a substituent selected from the group consisting of C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylamino group and hydroxy C ₁ -C ₆ alkyl group may be substituted one or more times, and the substituents may be bonded to each other to form a ring);
X represents a carbon atom or a nitrogen atom at any of the 4-, 5-, 6-, and 7-positions, and is an indole or azaindole ring, respectively;
R ⁶ and R ⁷ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, a halo C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylamino group, C ₁ -C ₆ acyl group, C ₁ -C ₆ alkoxycarbonyl group, C ₃ -C ₁₀ cycloalkyl group or hydroxy C ₁ -C ₆ alkyl group (the C ₁ -C ₆ Alkyl Group, C ₂ -C ₆ Alkenyl Group, Halo C ₁ -C ₆ Alkyl Group, C ₁ -C ₆ Alkoxy Group, C ₁ -C ₆ Alkylamino Group, C ₁ -C ₆ Acyl Group, C ₁ -C ₆ Alkoxycarbonyl groups, C ₃ -C ₁₀ cycloalkyl groups and hydroxy C ₁ -C ₆ alkyl groups are C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, C ₁ -C ₆ alkylamino groups and hydroxy C ₁ may be substituted with one or more substituents selected from the group consisting of ~ _C6 alkyl groups, and the substituents may be bonded to each other to form a ring);
R ⁴ is B1) below, * indicates the bonding position with -N- in formula (I);

R ⁸ and R ⁹ are each independently a hydrogen atom, a C ₁ -C ₆ alkyl group or a hydroxy C ₁ -C ₆ alkyl group;
R ⁸ and R ⁹ may be joined together to form a ring;
R ⁸ and R ⁹ may combine with RingA to form a ring;
m is 0 or 1;
RingA is an aromatic hydrocarbon ring group, a _C3 - _C10 cycloalkyl group, a 5- to 10-membered heteroaryl group or a 3- to 10-membered heterocycloalkyl group, each of which may be substituted with R ¹⁰ , R ¹¹ and R ¹² is a group;
R ¹⁰ and R ¹¹ each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a cyano group, a carbamoyl group (—CONH ₂ ), a C ₁ -C ₆ alkyl group, a halo C ₁ -C ₆ alkyl group, a hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylsulfanyl, halo C ₁ -C ₆ alkylsulfanyl, C ₁ -C ₆ acyl a C ₁ -C ₆ alkoxycarbonyl group, a C ₁ -C ₆ alkylaminocarbonyl group or a C ₁ -C ₆ acylamino group;
R ¹² is -(CR ¹³ R ¹⁴ ) _r -V-(CR ¹⁵ R ¹⁶ ) _q -(W) _n -Q;
V is a bond, -O- or -NR ¹⁷ -;
W is -NR ¹⁸ -;
R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group;
q and r are each independently an integer from 0 to 6;
n is 0 or 1;
Q is a hydrogen atom, a hydroxyl group, a C ₁ to C ₆ alkyl group, a C ₃ to C ₁₀ cycloalkyl group, a 5 to 10 membered heteroaryl group or a 3 to 10 membered heterocycloalkyl group (the C ₁ to C ₆ alkylamino group , C ₃ to C ₁₀ cycloalkyl groups, 5 to 10 membered heteroaryl groups and 3 to 10 membered heterocycloalkyl groups are halogen atoms, C ₁ to C ₆ alkyl groups, C ₁ to C ₆ alkoxy groups, C ₁ to substituted with one or more substituents selected from the group consisting of C ₆ alkylamino group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ alkylaminocarbonyl group and hydroxy C ₁ -C ₆ alkyl group may be);
R ¹⁰ , R ¹¹ and R ¹² may combine with each other to form a ring]
A compound represented by or a pharmacologically acceptable salt thereof.

[2] In formula (I), R ¹ and R ² are bonded to each other to form a ring, and together with the pyrrole ring to which R ¹ and R ² are bonded, take the following structure A1);

R ³ is a C ₁ -C ₆ alkyl group or a C ₃ -C ₁₀ cycloalkyl group;
X represents a carbon atom or a nitrogen atom at any of the 4-, 5-, 6-, and 7-positions, and is an indole or azaindole ring, respectively;
R ⁶ and R ⁷ are each independently a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or a halogen atom;
The compound according to [1], or a pharmacologically acceptable salt thereof.

[3] In formula (I), R ¹ and R ² are bonded to each other to form a ring, and together with the pyrrole ring to which R ¹ and R ² are bonded, take the following structure A1a);

R ³ is a C ₁ -C ₆ alkyl group;
R ⁶ and R ⁷ are each independently a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or a halogen atom;
The compound according to [2], or a pharmacologically acceptable salt thereof.

[4] In formula (I), R ¹ and R ² are bonded to each other to form a ring, and together with the pyrrole ring to which R ¹ and R ² are bonded, the following A1b), A1c), A1d) and A1e );

[5] Below,

or a pharmaceutically acceptable salt thereof.

[6] A G9a enzyme inhibitory composition containing the compound of any one of [1] to [5] or a pharmacologically acceptable salt thereof as an active ingredient.
[7] A pharmaceutical composition containing the compound of any one of [1] to [5] or a pharmacologically acceptable salt thereof as an active ingredient.
[8] At least selected from a group of diseases consisting of proliferative diseases such as cancer, β-globin disorders, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy, and autism Use of the compound or a pharmacologically acceptable salt thereof according to any one of [1] to [5] for manufacturing a medicament for the prevention or treatment of a kind of disease.
[9] At least selected from a group of diseases consisting of proliferative diseases such as cancer, β-globin disorders, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy, and autism A pharmaceutical composition containing the compound or a pharmacologically acceptable salt thereof according to any one of [1] to [5] and a pharmaceutically acceptable carrier, which is used for the prevention or treatment of a kind of disease.

Compound (I) or a pharmacologically acceptable salt thereof, for example, exhibited potent G9a enzyme inhibitory activity.

Therefore, the compound (I) according to the present invention or a pharmacologically acceptable salt thereof is useful for proliferative diseases such as cancer, β-globin abnormalities, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, It is useful as a therapeutic or preventive agent for malaria, viral infections, myopathy, autism, and the like.

Furthermore, compound (I) or a pharmacologically acceptable salt thereof according to the present invention can be used in various pathological conditions (e.g., β-globin disorders such as sickle cell disease, gastric cancer, hepatocellular carcinoma, acute bone marrow disease, etc.). Leukemia such as leukemia and chronic myelogenous leukemia, cervical cancer, neuroblastoma, glioma, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer, breast cancer, lung cancer, ovarian cancer, melanoma, lung Fibrosis such as fibrosis and renal fibrosis, pain, neurodegenerative diseases such as Alzheimer's disease, Prader-Willi syndrome, malaria, foot-and-mouth disease, viral infections such as vesicular stomatitis, cardiomyopathy, myopathy, autism, etc.) It has high utility for treatment, prevention or suppression. In addition, compound (I) or a pharmacologically acceptable salt thereof according to the present invention is highly useful for suppressing cancer metastasis and sex reassignment.

Terms used in this specification will be explained.
A "halogen atom" as referred to herein means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

The “C ₁ -C ₆ alkyl group” as used herein means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Examples of C ₁ -C ₆ alkyl groups include methyl group, ethyl group, 1-propyl group, isopropyl group, 1-butyl group, isobutyl group, sec-butyl group, tert-butyl group, 1-pentyl group and isopentyl group. , neopentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, 1-hexyl group, isohexyl group and the like. In addition, the “C ₁ -C ₃ alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 3 carbon atoms.

As used herein, a "C ₂ -C ₆ alkenyl group" means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and having at least one double bond. C ₂ -C ₆ alkenyl groups such as vinyl group, 2-propenyl group, 1-propenyl group, 1-buten-1-yl group, 1-buten-2-yl group and 1-buten-3-yl group , 2-buten-1-yl group, 2-buten-2-yl group, 1-penten-1-yl group, 1-penten-2-yl group, 1-penten-3-yl group, 2-pentene- 1-yl group, 2-penten-2-yl group, 2-penten-3-yl group, 1-hexen-1-yl group, 1-hexen-2-yl group, 1-hexen-3-yl group, 2-methyl-1-propen-1-yl group and the like.

As used herein, a "C ₁ -C ₆ acyl group" means an acyl group derived from a straight or branched chain aliphatic carboxylic acid having 1 to 6 carbon atoms. Examples include formyl group, acetyl group, propanoyl group, 1-butanoyl group, 1-pentanoyl group, 1-hexanoyl group and the like.

The “halo C ₁ -C ₆ alkyl group” as used herein means a C ₁ -C ₆ alkyl group in which at least one hydrogen atom is substituted with the same or different halogen atom. Examples of halo C ₁ -C ₆ alkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2-difluoroethyl and 1,1-difluoroethyl. group, 1,2-difluoroethyl group, 1-chloro-2-fluoroethyl group, 2,2,2-trifluoroethyl group, 1,1,2,2,2-pentafluoroethyl group, 2,2, 2-trichloroethyl group, 3-fluoropropyl group, 2-fluoropropyl group, 1-fluoropropyl group, 3,3-difluoropropyl group, 2,2-difluoropropyl group, 1,1-difluoropropyl group, 4- fluorobutyl group, 5-fluoropentyl group, 6-fluorohexyl group and the like.

The “hydroxy C ₁ -C ₆ alkyl group” as used herein means the above C ₁ -C ₆ alkyl group in which at least one hydrogen atom is substituted with a hydroxyl group. Hydroxy C ₁ -C ₆ alkyl groups such as hydroxymethyl group, 1-hydroxyethyl group, 1-hydroxy-1,1-dimethylmethyl group, 2-hydroxyethyl group, 2-hydroxy-2-methylpropyl group, 3-hydroxypropyl group and the like. Further, "hydroxy C ₁ -C ₃ alkyl group" means a hydroxyalkyl group having 1 to 3 carbon atoms.

The “C ₁ -C ₆ alkoxy group” as used herein means a straight or branched chain alkoxy group having 1 to 6 carbon atoms. Examples of C ₁ -C ₆ alkoxy groups include methoxy, ethoxy, 1-propoxy, isopropoxy, isobutoxy, 1-butoxy, sec-butoxy, tert-butoxy, 1-pentyloxy, 1-hexyloxy group and the like.

The “halo C ₁ -C ₆ alkoxy group” as used herein means a C ₁ -C ₆ alkoxy group in which at least one hydrogen atom is substituted with the same or different halogen atom. Examples of halo C ₁ -C ₆ alkoxy groups include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-chloroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,1- difluoroethoxy group, 1,2-difluoroethoxy group, 1-chloro-2-fluoroethoxy group, 2,2,2-trifluoroethoxy group, 1,1,2,2,2-pentafluoroethoxy group, 2, 2,2-trichloroethoxy group, 3-fluoropropoxy group, 2-fluoropropoxy group, 1-fluoropropoxy group, 3,3-difluoropropoxy group, 2,2-difluoropropoxy group, 1,1-difluoropropoxy group, 4-fluorobutoxy group, 5-fluoropentyloxy group, 6-fluorohexyloxy group and the like.

The “C ₁ -C ₆ alkoxycarbonyl group” as used herein means a carbonyl group to which a straight or branched chain alkoxy group having 1 to 6 carbon atoms is attached. Examples of C ₁ to C ₆ alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, 1-propoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, 1-butoxycarbonyl, sec-butoxycarbonyl, tert- butoxycarbonyl group, 1-pentyloxycarbonyl group, 1-hexyloxycarbonyl group and the like.

The "C ₁ -C ₆ alkylamino group" as used herein means a linear or branched alkyl group in which 1 or 2 hydrogen atoms in the amino group have a total of 1 to 6 carbon atoms. It means a substituted amino group. Examples of C ₁ -C ₆ alkylamino groups include methylamino group, ethylamino group, 1-propylamino group, isopropylamino group, 1-butylamino group, isobutylamino group, sec-butylamino group and tert-butylamino group. group, 1-pentylamino group, isopentylamino group, neopentylamino group, 1-methylbutylamino group, 2-methylbutylamino group, 1,2-dimethylpropylamino group, 1-hexylamino group, isohexylamino group, dimethylamino group, diethylamino group, N-ethyl-N-methylamino group, N-ethyl-N-propylamino group and the like.

The “C ₁ -C ₆ alkylaminocarbonyl group” as used herein means a carbonyl group to which a linear or branched alkylamino group having a total of 1 to 6 carbon atoms is bonded. Examples of C ₁ -C ₆ alkylaminocarbonyl groups include methylaminocarbonyl, ethylaminocarbonyl, 1-propylaminocarbonyl, isopropylaminocarbonyl, 1-butylaminocarbonyl, isobutylaminocarbonyl and sec-butyl. aminocarbonyl group, tert-butylaminocarbonyl group, 1-pentylaminocarbonyl group, isopentylaminocarbonyl group, neopentylaminocarbonyl group, 1-methylbutylaminocarbonyl group, 2-methylbutylaminocarbonyl group, 1,2- dimethylpropylaminocarbonyl group, 1-hexylaminocarbonyl group, isohexylaminocarbonyl group, dimethylaminocarbonyl group, diethylaminocarbonyl group, N-ethyl-N-methylaminocarbonyl group, N-ethyl-N-propylaminocarbonyl group, etc. is mentioned.

A "C ₁ -C ₆ acylamino group" as used herein means that 1 or 2 hydrogen atoms of an amino group are substituted with a linear or branched acyl group having 1 to 6 carbon atoms. means an amino group. The C ₁ -C ₆ acylamino group includes, for example, formylamino group, acetylamino group, 1-propanoylamino group, 1-butanoylamino group, 1-pentanoylamino group, hexanoylamino group and the like.

The “C ₁ -C ₆ alkylsulfanyl group” as used herein means a group in which a straight or branched chain alkyl group having 1 to 6 carbon atoms is bonded to a sulfur atom. Examples of C ₁ -C ₆ alkylsulfanyl groups include methylsulfanyl group, ethylsulfanyl group, 1-propylsulfanyl group, isopropylsulfanyl group, 1-butylsulfanyl group, isobutylsulfanyl group, sec-butylsulfanyl group and tert-butylsulfanyl group. and the like.

The “halo C ₁ -C ₆ alkylsulfanyl group” as used herein means a C ₁ -C ₆ alkylsulfanyl group in which at least one hydrogen atom is substituted with the same or different halogen atom. halo C ₁ -C ₆ alkylsulfanyl group, for example, fluoromethylsulfanyl group, difluoromethylsulfanyl group, trifluoromethylsulfanyl group, 2-fluoroethylsulfanyl group, 2-chloroethylsulfanyl group, 2,2-difluoroethylsulfanyl group; group, 1,1-difluoroethylsulfanyl group, 1,2-difluoroethylsulfanyl group, 1-chloro-2-fluoroethylsulfanyl group, 2,2,2-trifluoroethylsulfanyl group, 1,1,2,2 , 2-pentafluoroethylsulfanyl group, 2,2,2-trichloroethylsulfanyl group, 3-fluoropropylsulfanyl group, 2-fluoropropylsulfanyl group, 1-fluoropropylsulfanyl group, 3,3-difluoropropylsulfanyl group, 2,2-difluoropropylsulfanyl group, 1,1-difluoropropylsulfanyl group, 4-fluorobutylsulfanyl group, 5-fluoropentylsulfanyl group, 6-fluorohexylsulfanyl group and the like.

The "aromatic hydrocarbon ring group" shown in this specification includes, for example, phenyl group, indenyl group, 1-naphthyl group, 2-naphthyl group, azulenyl group, heptalenyl group, biphenyl group, indacenyl group, acenaphthyl group, fluorenyl group, phenalenyl group, phenanthrenyl group, anthracenyl group, benzocyclooctenyl group and the like.

A "5- to 10-membered heteroaryl group" as used herein includes 1 to 4 endocyclic heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur atoms. means a to 10-membered monocyclic aromatic heterocyclic group or fused ring aromatic heterocyclic group, wherein the nitrogen and sulfur atoms are optionally oxidized (ie, N→O, SO or SO ₂ ). Examples of 5- to 10-membered heteroaryl groups include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzo triazolyl group, benzisoxazolyl group, benzisothiazolyl group, benzimidazolinyl group, furanyl group, imidazolidinyl group, imidazolyl group, 1H-indazolyl group, imidazolopyridinyl group, indolenyl group, indolizinyl group, 3H-indolyl group, isobenzofuranyl group, isoindazolyl group, isoindolyl group, isoquinolinyl group, isothiazolyl group, isothiazolopyridinyl group, isoxazolyl group, isoxazolopyridinyl group, naphthyridinyl group, 1,2,3- oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl group, oxazolidinyl group, oxazolyl group, oxazolopyridinyl group, oxazolidinylperimidinyl group, oxindolyl group, pyrimidinyl group, pyrazinyl group, pyrazolidinyl group, pyrazolinyl group, pyrazolopyridinyl group, pyrazolyl group, pyridazinyl group, pyridooxazolyl group, pyridoimidazolyl group, pyridothiazolyl group, pyridinyl group, pyrrolopyridinyl group, quinazolinyl group, quinolinyl group, 4H-quinolidinyl group, quinoxalinyl group, quinuclidinyl group, tetrazolyl group, 6H-1,2,5-thiadiazinyl group, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, 1,3,4-thiadiazolyl group, thianthrenyl group, thiazolyl group, thienyl group, thiazolopyridinyl group, thienothiazolyl group, thienooxazolyl group, thienoimidazolyl group, thiophenyl triazinyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, 1,2,5-triazolyl group and 1,3,4-triazolyl group. Also included are fused ring and spirocyclic compounds containing the above heterocycles.

The “C ₃ -C ₁₀ cycloalkyl group” as used herein means a monocyclic or bicyclic saturated alicyclic hydrocarbon group having 3 to 10 carbon atoms, and is a bridged type, spiro type can be Examples of C ₃ -C ₁₀ cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, spiroheptyl, spirooctyl and octahydropentalenyl groups. mentioned. The C ₃ -C ₁₀ cycloalkyl group may also be fused with a further aromatic hydrocarbon ring group or 5-10 membered heteroaryl group, wherein the aromatic hydrocarbon ring group or 5-10 membered heteroaryl group is The condensed C ₃ -C ₁₀ cycloalkyl group includes a dihydroindenyl group, a tetrahydronaphthyl group, and the like.

Further, "C ₃ -C ₄ cycloalkyl group" means a cycloalkyl group having 3 to 4 carbon atoms.

The "3- to 10-membered heterocycloalkyl group" shown herein contains 1 to 4 endocyclic heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur atoms. , monocyclic, bicyclic or tricyclic heterocycloalkyl groups having 3-10 membered rings, wherein the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., N→O, SO or SO ₂ ), the nitrogen atom may be substituted or unsubstituted, may have 1 to 3 carbonyl groups, have 1 double bond in the ring, good too. A 3- to 10-membered heterocycloalkyl group may also be bridged or spiro. A 3-10 membered heterocycloalkyl group may be optionally fused with a further aromatic hydrocarbon ring group or a 5-10 membered heteroaryl group. 3- to 10-membered heterocycloalkyl groups such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, azocanyl, dihydropyrrolyl, tetrahydropyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxidethiomorpholinyl group, 1,1-dioxidethiomorpholinyl group, oxazepinyl group, thiazepanyl group, 1-oxide-1,4-thiazepanyl group, 1,1-dioxide-1,4-thiazepanyl group , 1,4-diazepanyl group, 1,4-oxazocanyl group, 1,5-oxazocanyl group, oxetanyl group, tetrahydrofuranyl group, tetrahydropyranyl group, octahydrocyclopenta[c]pyrrolyl group, 3-azabicyclo[3. 2.0]heptanyl group, 3-azabicyclo[3.1.0]hexanyl group, 5-azabicyclo[2.1.1]hexanyl group, 2-azabicyclo[2.1.1]hexanyl group, 2-azabicyclo[ 4.1.0]heptanyl group, 3-azabicyclo[4.1.0]heptanyl group, 2-azabicyclo[4.2.0]octanyl group, 3-azabicyclo[4.2.0]octanyl group, 3- azabicyclo[3.1.1]heptanyl group, 2-azabicyclo[2,2,1]heptanyl group, 6-azabicyclo[3.1.1]heptanyl group, 8-azabicyclo[3.2.1]octanyl group, 3-azabicyclo[3.2.1]octanyl group, 6-azabicyclo[3.2.1]octanyl group, 4-azaspiro[2.4]heptanyl group, 5-azaspiro[2.4]heptanyl group, 1- oxo-5-azaspiro[2.4]heptanyl group, 5-azaspiro[3.4]octanyl group, 6-azaspiro[3.4]octanyl group, 2-oxo-6-azaspiro[3.4]octanyl group, 1-oxo-6-azaspiro[3.4]octanyl group, 4-azaspiro[2.5]octanyl group, 5-azaspiro[2.5]octanyl group, 6-azaspiro[2.5]octanyl group, 1- Oxa-5-azaspiro[2.5]octanyl group, 4-oxa-7-azaspiro[2.5]octanyl group, 1-oxa-6-azaspiro[2.5]octanyl group, 2,6-diazaspiro[3 .4] octanyl group and the like.

As used herein, the term “bonded to each other to form a ring” refers to removing any one hydrogen atom from each of the two substituents forming the ring, and bonding the hydrogen-free sites to each other. means For example, when the methylene group has two substituents, if the two substituents forming the ring are a methyl group and a 1-hydroxyethyl group,

is mentioned.

The present embodiment will be described in more detail below.
In the following description, the definitions of the functional groups in the general formulas may be omitted by citing the definitions already described. The definitions quoted refer to the definitions set forth in the description of the embodiments set forth below.
In addition, regarding definitions of functional groups in general formulas, definitions represented by the same reference numerals are common among general formulas including the reference unless otherwise specified.

This embodiment relates to a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
General formula (I):

Preferred compounds of the present embodiment include, for example, the following compounds.

Furthermore, compound (I) of the present embodiment or a pharmacologically acceptable salt thereof may exist as a hydrate or solvate. Any hydrate and solvate formed by the derivative represented by the general formula (I) or a salt thereof, including the preferred compounds specifically described above, are included in the scope of the present invention. be. Solvents that can form solvates include methanol, ethanol, isopropyl alcohol, acetone, ethyl acetate, dichloromethane, diisopropyl ether, and the like.

Compound (I) of the present embodiment can be a pharmacologically acceptable salt thereof, if necessary. Pharmaceutically acceptable salts refer to salts with pharmaceutically acceptable non-toxic bases or acids (eg, inorganic or organic bases and inorganic or organic acids). A pharmaceutically acceptable salt of compound (I) of the present embodiment is described in J. Chem. Pharm. Sci. 1977, 66, 1-19, and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) or a method according thereto can be done.

Salts derived from pharmaceutically acceptable non-toxic bases include salts with inorganic bases such as sodium salts, potassium salts, calcium salts and magnesium salts, and salts with organic bases such as piperidine, morpholine, pyrrolidine, arginine and lysine. Salt can be mentioned.

Salts derived from pharmaceutically acceptable non-toxic acids include, for example, acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, formic acid, acetic acid, maleic acid, fumaric acid, succinic acid. , lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid and palmitic acid.

The compound (I) of the present embodiment or a pharmacologically acceptable salt thereof also includes stereoisomers such as racemates and optically active forms.

When compound (I) of the present embodiment is an optical isomer having one or more asymmetric carbon atoms or sulfur atoms, compound (I) of the present embodiment has a steric configuration at each asymmetric carbon atom or sulfur atom. may be in either the R configuration or the S configuration. The invention also includes any single enantiomer, single diastereomer, mixture of enantiomers or mixture of diastereomers. Furthermore, in the mixture of optically active substances, a racemate consisting of equal amounts of each optical isomer is also included in the scope of the present invention. When compound (I) of this embodiment is a racemic solid or crystal, racemic compounds, racemic mixtures and racemic solid solutions are also included in the scope of the present invention.

In compound (I) of the present embodiment, diastereomeric mixtures can be separated into their respective diastereomers by commonly used methods such as chromatography and crystallization. The respective diastereomers can also be made by using stereochemically uniform starting materials or by synthetic methods employing stereoselective reactions.

When compound (I) of the present embodiment has geometric isomers such as cis isomers and trans isomers, the present invention includes all such geometric isomers.

When compound (I) of the present embodiment has tautomers, the present invention includes all of the tautomers.

Compound (I) of the present embodiment or a pharmacologically acceptable salt thereof may be a compound labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, etc.) or the like. Such compounds are also included in the present invention.

Furthermore, compound (I) of the present embodiment or a pharmacologically acceptable salt thereof may be a deuterium conversion product in which ¹ H is converted to ² H (D). Such compounds are also included in the present invention.

Method for producing compound (I) of the present embodiment, compound (I) of the present embodiment can be prepared, for example, by the method described in detail in the following synthetic pathways 1 to 2 or a method analogous thereto, or by other methods described in literature or by those methods. It can be manufactured according to the method according to.

Compounds (2) to (10) in the formula may form salts, and examples of such salts include those similar to the salts of compound (I). In addition, the compound obtained in each step can be used in the next reaction as a reaction solution or after being obtained as a crude product. It can be easily isolated and purified.

[Synthetic route 1]
Compound (I) (the compound represented by the following formula (2)) can be produced, for example, by the method shown in Synthetic Route 1, a method analogous thereto, or a method described in other literatures or a method analogous thereto. can.

(In the formula, PG represents a protective group such as a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, an allyloxycarbonyl group, an acetyl group, a benzoyl group or a tert-butyldimethylsilyl group. , R ¹ , R ² , R ³ and R ⁴ are as defined above.)

Step 1-1
Compound (5) can be produced by amidating compound (3) with compound (4).

As reaction conditions, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, ethyl acetate, dichloromethane, acetonitrile, toluene, benzene, 1,4-dioxane, tetrahydrofuran, etc., or a mixture thereof Compound (4) and the like are added in a solvent, and the reaction can be carried out at 0° C. to room temperature, optionally with heating under reflux. If necessary, a base such as triethylamine or N,N-diisopropylethylamine can be added. Also, if necessary, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU), 1-ethyl -3-(3-dimethylaminopropyl)carbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), or 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4 -Condensing agents such as methylmorpholinium chloride (DMT-MM), N,N-dimethyl-4-aminopyridine, pyridine, 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azabenzotriazole (HOAt ) can be added.

Step 1-2
Compound (6) can be produced by removing the protecting group of compound (5). As reaction conditions, when PG is a tert-butoxycarbonyl group, trifluoro Add an acid such as acetic acid, p-toluenesulfonic acid, hydrogen chloride, hydrobromic acid, sulfuric acid, boron trifluoride diethyl ether complex, boron tribromide, or aluminum chloride, and heat from -78°C to room temperature in some cases. It can be carried out at reflux.

When PG is a benzyloxycarbonyl group, methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, water, tetrahydrofuran, tert-butyl methyl ether, N,N-dimethylformamide, toluene etc., or in a mixed solvent thereof, under a hydrogen atmosphere, by adding a catalyst such as palladium carbon, rhodium carbon, platinum carbon, or platinum oxide, and heating from 0° C. to reflux. If desired, an acid such as acetic acid, trifluoroacetic acid, or 2,2,2-trifluoroethanol can be added as a reaction accelerator. Alternatively, methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, water, tetrahydrofuran, tert-butyl methyl ether, N,N-dimethylformamide, toluene, or a mixed solvent thereof The reaction can be carried out by adding an acid such as trifluoroacetic acid and heating at 0° C. to reflux.

Step 1-3
Compound (2) can be produced by amidating compound (6) with compound (7).
As reaction conditions, compound (7) or a salt thereof such as aniline, benzylamine or the like is added, and the reaction can be carried out in the same manner as in step 1-1.

[Synthetic route 2]
The above compound (2) can be produced, for example, according to the method detailed in Synthetic Route 2 or a method analogous thereto, or the method described in other literatures or a method analogous thereto.

(In the formula, R ²⁰ represents a C ₁ -C ₆ alkyl group, and R ¹ , R ² , R ³ and R ⁴ are as defined above.)

Step 2-1
Compound (9) can be produced by amidating compound (8) with compound (7).
As the reaction conditions, the same method as in step 1-1 can be used.

Step 2-2
Compound (10) can be produced by hydrolyzing compound (9).
As the reaction conditions, water, methanol, ethanol, 1-propanol, isopropyl alcohol, tetrahydrofuran, 1,4-dioxane, etc., or a water-containing mixed solvent thereof, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, carbonate By adding an alkali metal salt such as sodium or cesium carbonate, the reaction can be carried out at 0° C. to reflux under basic conditions. Further, by adding hydrogen chloride or the like in water, tetrahydrofuran, 1,4-dioxane, or a mixed solvent containing water thereof, the reaction can be carried out under acidic conditions at 0° C. to heating under reflux.

Step 2-3
Compound (2) can be produced by amidating compound (10) with compound (4).
As for the reaction conditions, compound (4) and the like can be added, and the reaction can be carried out in the same manner as in step 1-1.

The synthetic route shown above is an example of a method for producing compound (I) of the present embodiment, and compound (I) of the present embodiment can be produced by the method shown above, a method analogous thereto, or other It can be produced according to the method described in the literature or a method based thereon. These production methods allow various modifications to the schemes that can be easily understood by those skilled in the art.

In addition, when a protective group is required depending on the type of functional group, it can be carried out by appropriately combining introduction and elimination operations according to a conventional method. Regarding the type, introduction and elimination of protective groups, see, for example, Theodra W. et al. Green & Peter G. M. Wuts, "Greene's Protective Groups in Organic Synthesis", fourth edition, Wiley-Interscience, 2006.

Intermediates used to produce compound (I) of the present embodiment may optionally be isolated and purified by solvent extraction, crystallization, recrystallization, chromatography, and isolation/purification means well known to those skilled in the art. It can be isolated and purified by graphics, preparative high-performance liquid chromatography, or the like.

In addition, intermediates may be used as crude products in the next reaction without isolation and purification, if necessary.

The "G9a inhibitory action" in the present embodiment is the action of inhibiting G9a, which is a major enzyme involved in mono- and dimethylation (H3K9me1 and H3K9me2) at the 9th lysine residue of histone H3.

Compound (I) of the present embodiment, or a pharmacologically acceptable salt thereof, exhibits potent inhibitory activity, for example, in a G9a inhibitory activity test.

As a result, compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is useful for proliferative diseases such as cancer, β-globin abnormalities, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, , malaria, viral infections, myopathy, autism, etc., or as a preventive agent therefor.

A medicament containing compound (I) of the present embodiment as an active ingredient can be made into various dosage forms depending on the usage. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, liquids, ointments, suppositories, patches, sublingual agents, and the like.

These medicaments can be configured as pharmaceutical compositions containing the compound (I) of the present embodiment as an active ingredient and pharmaceutically acceptable additives by a known method depending on the dosage form. . Additives contained in the pharmaceutical composition include excipients, disintegrants, binders, lubricants, diluents, buffers, tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, agents, solubilizers, and the like. The pharmaceutical composition can be prepared by appropriately mixing compound (I) of the present embodiment with an additive, or by diluting/dissolving compound (I) with an additive.

The pharmaceutical according to this embodiment can be administered systemically or locally, orally or parenterally (nasally, pulmonary, intravenously, intrarectally, subcutaneously, intramuscularly, transdermally, etc.).

The present specification includes the contents described in the specification of Japanese Patent Application No. 2021-092001, which is the basis of the priority of this application.

The present invention will be described in more detail below based on Test Examples, Examples, and Reference Examples. In addition, since the raw material compounds used in the production of compound (I) also include novel compounds, production examples of the raw material compounds are also described as reference examples. The present invention is not limited to the compounds described in the Examples below and may be varied without departing from the scope of the invention.

Of the symbols used in each reference example, each example, and each table, ¹ H-NMR means a spectrum measured by proton nuclear magnetic resonance spectroscopy. CDCl ₃ means chloroform-d, DMSO-D6 means dimethylsulfoxide-d ₆ , CD ₃ OD means methanol-d ₄ . MS (ESI ⁺ ) and MS (ESI ⁻ ) are electrospray ionization methods, MS (FI ⁺ ) is field ionization methods, MS (FD ⁺ ) is field desorption ionization methods, MS (EI ⁺ ) is electron ionization methods, MS (CI ⁺ ) means mass spectral data measured by a chemical ionization method. Room temperature means 1 to 30°C.

To 2-((tert-butoxycarbonyl)amino)-4-cyclopropylbutanoic acid ethyl ester (2.71 g) was added water/ethanol=1/1 (20 mL) and 8M aqueous sodium hydroxide solution (4.38 mL). Stir at 40° C. for 1 hour. After allowing to cool, concentrated hydrochloric acid (3.5 mL) and saturated NaHCO ₃ aqueous solution (1.0 mL) were added to adjust the pH to 3, and the precipitated solid was collected by filtration. After washing with water, vacuum drying gave 2.19 g (90.1%) of 2-((tert-butoxycarbonyl)amino)-4-cyclopropylbutanoic acid.

Under a nitrogen atmosphere, 2-((tert-butoxycarbonyl)amino)-4-cyclopropylbutanoic acid (1.70 g) was dissolved in dimethylformamide (28 mL), and 4-(dimethylamino)methylbenzylamine (1.83 g ), 1-hydroxybenzotriazole monohydrate (1.61 g) and N,N-diisopropylethylamine (4.51 mL) were added and cooled with ice. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.01 g) was added thereto, and the mixture was stirred overnight at room temperature. Saturated saline was added to the reaction solution, and the mixture was stirred and separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer was washed once with water (10 mL) and once with saturated brine, and dried over sodium sulfate. The concentrated residue was purified by silica gel column (Yamazen 2L+L; 0-20% methanol in dichloromethane solution), suspended and washed with IPE to give tert-butyl (4-cyclopropyl-1-((4-((dimethylamino )methyl)benzyl)amino)-1-oxobutan-2-yl)carbamate (2.11 g, 77.3%) was obtained.

tert-butyl (4-cyclopropyl-1-((4-((dimethylamino)methyl)benzyl)amino)-1-oxobutan-2-yl)carbamate (1.98g, 5.08mmol) was added with 2M hydrochloric acid/ethanol (25.4 mL, 50.8 mmol HCl) was added and stirred at 40°C for 2 hours. After allowing to cool, the reaction solution was concentrated under reduced pressure and azeotroped three times with ethyl acetate. The solidified solid was suspended and washed with ethyl acetate to give 2-amino-4-cyclopropyl-N-(4-((dimethylamino)methyl)benzyl)butanamide dihydrochloride (2.00 g, quant.). obtained.

¹ H-NMR (DMSO-D6, 400MHz) δ: -0.06 - 0.01 (2H, m), 0.33 - 0.42 (2H, m), 0.61 - 0.70 (1H, m), 1.13 - 1.21 (2H, m), 1.81 - 1.89 (2H, m), 2.63 (3H, s), 2.64 (3H, s), 3.80 - 3.89 (1H, m), 4.24 (2H, d, J = 6.5 Hz), 4.36 (2H, d, J = 7.5 Hz), 7.36 (2H, d, J = 10.0 Hz), 7.56 (2H, d, J = 10.0 Hz), 8.36 (3H, d, J = 4.5 Hz), 9.26 (1H, t, J = 7.5 Hz), 11.19 (1H, br s).
MS (ESI ⁺ ): 290 [M+H] ⁺

Under a nitrogen atmosphere, 5-fluoro-3-methyl-1H-indole-2-carboxylic acid (53.8 mg) was dissolved in dimethylformamide (4.0 mL), and 2-amino-4-cyclopropyl-N-(4 -((dimethylamino)methyl)benzyl)butanamide dihydrochloride (101 mg), 1-hydroxybenzotriazole monohydrate (64.0 mg), and N,N-diisopropylethylamine (170 μL, 0.976 mmol) were added. Ice cold. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80.2 mg) was added thereto, and the mixture was stirred overnight at room temperature. Saturated saline (6 mL) was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate (6 mL+3 mL). The organic layer was washed with water (3 mL) and saturated brine (3 mL) and dried over sodium sulfate. The residue obtained by filtration and concentration under reduced pressure was purified by silica gel column (Yamazen 2L+L; 0-20% methanol in dichloromethane solution) to give N-(4-cyclopropyl-1-((4-((dimethylamino)methyl)benzyl) Amino)-1-oxobutan-2-yl)-5-fluoro-3-methyl-1H-indole-2-carboxamide (94.6 mg, 72.8%) was obtained.

¹ H-NMR (DMSO-D6, 400MHz) δ: -0.05 - 0.01 (2H, m), 0.34 - 0.42 (2H, m), 0.64 - 0.74 (1H, m), 1.25 (2H, q, J = 7.5 Hz), 1.74 - 1.96 (2H, m), 2.12 (6H, s), 2.48 (3H, s), 3.36 (2H, s), 4.27 (1H, dd, J = 15.2, 5.9 Hz), 4.33 (1H , dd, J = 15.2, 6.0 Hz), 4.54 (1H, td, J = 8.3, 5.3 Hz), 7.07 (1H, td, J = 9.2, 2.6 Hz), 7.22 (4H, s), 7.33 - 7.44 ( 2H, m), 7.93 (1H, d, J = 7.9 Hz), 8.59 (1H, t, J = 6.0 Hz), 11.42 (1H, br s).
MS (ESI ⁺ ): 465 [M+H] ⁺

Using the corresponding starting materials and reactants, the following Examples 1-2 to 1-17 were obtained by the same method as in Example 1-1, the method described in Step 1-3, or a method analogous thereto. rice field.

Under a nitrogen atmosphere, 3-methyl-1H-indole-2-carboxylic acid (1.1 g) was dissolved in dimethylformamide (20 mL), ethyl 2-amino-4-cyclopropylbutanoate monohydrochloride (1.11 g). , N,N-diisopropylethylamine (1.18 mL) was added and cooled with ice. 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (2.62 g) was added thereto and stirred at room temperature for 15 hours. did. Water and ethyl acetate were added to the reaction mixture and the mixture was stirred, and then the aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column (hexane-ethyl acetate) to give ethyl 4-cyclopropyl-2-(3-methyl-1H-indole-2-carboxamide)butanoate (1.27 g, 73%).

¹ H-NMR (CHLOROFORM-D, 500 MHz) δ: -0.04 - 0.10 (2H, m), 0.44 (2H, d, J = 8.2 Hz), 0.65- 0.77 (1H, m), 1.20 - 1.43 (2H , m), 1.33 (3H, t, J = 7.2 Hz), 1.90 - 1.99 (1H, m), 2.08 - 2.19 (1H, m), 2.64 (3H, s), 4.20 - 4.33 (2H, m), 4.89 (1H, dt, J = 7.2, 7.0 Hz), 6.67 (1H, d, J = 7.7 Hz), 7.15 (1H, t, J = 7.7 Hz), 7.29 (1H, t, J = 7.6 Hz), 7.38 (1H, d, J = 8.3 Hz), 7.64 (1H, d, J = 8.3 Hz), 8.99 (1H, br s).
MS (ESI ⁺ ): 329 [M+H] ⁺

The obtained ester (1.22 g) was dissolved in ethanol (20 mL), and 3 mL of 8N aqueous sodium hydroxide solution was added at room temperature. After stirring at room temperature for 15 hours, the mixture was neutralized with 2N hydrochloric acid and extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated to give 4-cyclopropyl-2-(3-methyl-1H-indole-2-carboxamide)butanoic acid ( 1.0 g, 90%) was obtained.

¹ H-NMR (CHLOROFORM-D, 500 MHz) δ: -0.09 - 0.08 (2H, m), 0.45 (2H, dd, J = 8.0, 1.6 Hz), 0.67 - 0.75 (1H, m), 1.28 - 1.46 (2H, m), 1.94 - 2.03 (1H, m), 2.16 - 2.24 (1H, m), 2.62 (3H, s), 4.89 (1H, q, J = 6.9 Hz), 6.56 (1H, d, J = 7.5 Hz), 7.14 (1H, t, J = 7.5 Hz), 7.29 (1H, t, J = 7.5 Hz), 7.37 (1H, d, J = 8.0 Hz), 7.63 (1H, d, J = 8.2 Hz), 9.04 (1H, br s).
MS (ESI ⁺ ): 301 [M+H] ⁺

Under a nitrogen atmosphere, 4-cyclopropyl-2-(3-methyl-1H-indole-2-carboxamido)butanoic acid (50 mg), 4-dimethylaminomethylbenzylamine (47.4 mg) and N,N-diisopropylethylamine ( 0.074 mL) of dimethylformamide solution was ice-cooled. 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (82.3 mg) was added thereto and stirred overnight at room temperature. . Water (5 mL) was added to the reaction mixture, and the aqueous layer was extracted twice with ethyl acetate. The organic layer was washed once with water (10 mL) and once with saturated brine (10 mL), and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column (Yamazen S; 0-20% methanol in dichloromethane solution), N-(4-cyclopropyl-1-((4-((dimethylamino)methyl)benzyl) Amino)-1-oxobutan-2-yl)-3-methyl-1H-indole-2-carboxamide (43 mg, 58%) was obtained.

¹ H-NMR (CHLOROFORM-D, 500MHz) δ: -0.07 - 0.03 (2H, m), 0.38 - 0.42 (2H, m), 0.62 - 0.70 (1H, m), 1.21 - 1.40 (2H, m), 1.84 - 1.92 (1H, m), 2.07 - 2.15 (H, m), 2.22 (6H, s), 2.62 (3H, s), 3.38 (2H, s), 4.40 (1H, dd, J = 14.8, 5.6 Hz), 4.52 (1H, dd, J = 14.8, 6.0 Hz), 4.74 (1H, td, J = 7.5, 5.9 Hz), 6.60 (1H, t, J = 5.7 Hz), 6.92 (1H, d, J = 7.7 Hz), 7.14 (1H, ddd, J = 8.0, 6.8, 1.1 Hz), 7.19 - 7.31 (6H, m), 7.64 (1H, d, J = 7.9 Hz), 9.07 (1H, br s).
MS (ESI ⁺ ): 447 [M+H] ⁺

Using the corresponding starting materials and reactants, the following Examples 2-2 to 2-25 are obtained by the same method as in Example 2-1, the method described in Step 2-3, or a method analogous thereto. rice field.

Under a nitrogen atmosphere, sodium triacetoxyborohydride (2.42 g) was added to a dichloromethane solution of 3-formylbenzonitrile (1.0 g), Boc-piperazine (1.49 g) and acetic acid (0.53 mL) at room temperature. added with After stirring for 18 hours at room temperature, the mixture was diluted with 20 mL of water, adjusted to pH 9, and extracted three times with dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=10:0-7:3) to give tert-butyl 4-(3-cyanobenzyl)piperazine-1-carboxylate.

¹ H-NMR (CHLOROFORM-D, 500MHz) δ: 1.46 (9H, s), 2.35 - 2.41 (4H, m), 3.41 - 3.46 (4H, m), 3.53 (2H, s), 7.43 (1H, t , J = 7.7 Hz), 7.53 - 7.58 (2H, m), 7.66 (1H, s).
MS (FI ⁺ ): 302 [M+H] ⁺

Under a nitrogen atmosphere, hydrogen Sodium borohydride (126 mg) was added over 30 minutes. After the reaction mixture was stirred overnight, 1N sodium hydroxide aqueous solution and chloroform were added and stirred. The aqueous layer was separated and extracted twice with chloroform. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (chloroform:methanol=10:0-6:4) to give tert-butyl 4-(3-(aminomethyl)benzyl)piperazine-1-carboxylate.

¹ H-NMR (CHLOROFORM-D, 500MHz) δ: 1.45 (9H, s), 2.32 - 2.44 (4H, m), 3.38 - 3.46 (4H, m), 3.50 (2H, s), 3.86 (2H, s ), 7.17 - 7.24 (2H, m), 7.22 - 7.33 (2H, m).MS (ESI ⁺ ): 306 [M+H] ⁺

Using the corresponding starting materials and reactants, the following Reference Example 3-2 was obtained by the same method as Reference Example 3-1 or a method according thereto.

Using the starting material obtained in Reference Example 3-1, tert-butyl 4-(3- ((4-Cyclopropyl-2-(3-methyl-1H-indole-2-carboxamido)butanamido)methyl)benzyl)piperazine-1-carboxylate was obtained.

4N hydrochloric acid/dioxane (1.5 mL) was added to the methanol solution of this Boc-protected form (44 mg), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. Chloroform and a saturated sodium bicarbonate solution were added to the solidified residue, and the aqueous layer was separated and extracted with chloroform three times. The combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 34 mg (quant.) of N-(4-cyclopropyl-1-oxo-((3 -((Piperazin-1-ylmethyl)benzyl)amino)butan-2-yl)-3-methyl-1H-indole-2-carboxamide was obtained.

¹ H-NMR (CHLOROFORM-D, 500MHz) δ: -0.11 - -0.03 (2H, m), 0.31 - 0.38 (2H, m), 0.57 - 0.65 (1H, m), 1.19 - 1.35 (2H, m) , 1.83 - 1.92 (1H, m), 2.00 - 2.09 (1H, m), 2.23 - 2.33 (4H, m), 2.58 (3H, s), 2.75 - 2.81 (4H, m), 3.34 (2H, d, J = 2.6 Hz), 4.38 (1H, dd, J = 15.0, 5.6 Hz), 4.47 (1H, dd, J = 15.0, 5.9 Hz), 4.79 - 4.86 (1H, m), 5.29 (1H, br s) , 7.08 - 7.25 (7H, m), 7.35 - 7.43 (2H, m), 7.61 (1H, dd, J = 8.0, 1.1 Hz), 9.74 (1H, br s).
MS (ESI ⁺ ): 488 [M+H] ⁺

Using the corresponding starting materials and reactants, the following Examples 3-2 and 3-3 are obtained by the same method as in Example 3-1, the method described in Step 2-3, or a method analogous thereto. rice field.

Under a nitrogen atmosphere, tert-butyl (4-hydroxybenzyl) carbamate (515 mg), benzyl 4-hydroxypiperidine-1-carboxylate (595 mg), triphenylphosphine (726 mg) in tetrahydrofuran solution (10 mL), bis azodicarboxylate (2-Methoxyethyl) (648 mg) was added at room temperature and stirred for 20 hours. Water and ethyl acetate were added to separate the layers, and the aqueous layer was extracted once with ethyl acetate. The combined organic layer was washed twice with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=9:1-2:1), and benzyl 4-(4-(((tert-butoxycarbonyl)amino)methyl)phenoxy)piperidine-1- Carboxylate (659 mg, 65%) was obtained.

4M hydrochloric acid/dioxane (2 mL) was added to an ethanol solution (1 mL) of the obtained Boc-protected compound (138 mg), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain solidified benzyl 4-(4-(aminomethyl)phenoxy)piperidine-1-carboxylate.hydrochloride (120 mg, quant.).
MS (ESI ⁺ ): 341 [M+H] ⁺

Using the corresponding starting materials and reactants, the following Reference Examples 4-2 to 4-3 were obtained by the same method as Reference Example 4-1 or a method according thereto.

Benzyl 4-(4-(( 76 mg (46%) of 4-cyclopropyl-2-(3-methyl-1H-indole-2-carboxamido)butanamido)methyl)benzyl)piperazine-1-carboxylate were obtained.

A methanol (5 mL) solution of the obtained Cbz derivative (76 mg) and 50% hydrous 5% palladium carbon (20 mg) was placed in a medium-pressure reduction vessel and subjected to catalytic reduction under a hydrogen atmosphere for 5 hours. The reaction solution was filtered through celite and then concentrated under reduced pressure. The residue was purified by aminosilica column chromatography (chloroform:methanol=10:0 to 9:1) and 34 mg (57%) of N-(4-cyclopropyl-1-((4-(piperidine-4 -yloxy)benzyl)amino)-1-oxobutan-2-yl)-3-methyl-1H-indole-2-carboxamide is obtained.

¹ H-NMR (CHLOROFORM-D, 500MHz) δ: -0.05 - 0.05 (2H, m), 0.42 (2H, d, J = 7.7 Hz), 0.63 - 0.71 (1H, m), 1.22 - 1.40 (2H, m), 1.52 - 1.68 (3H, m), 1.84 - 1.92 (1H, m), 1.95 - 2.02 (2H, m), 2.08 - 2.16 (1H, m), 2.63 (3H, s), 2.67 - 2.74 ( 2H, m), 3.09 - 3.16 (2H, m), 4.30 - 4.40 (2H, m), 4.45 (1H, dd, J = 14.6, 6.0 Hz), 4.69 (1H, td, J = 6.8, 7.3 Hz) , 6.33 (1H, t, J = 5.3 Hz), 6.79 (1H, d, J = 7.4 Hz), 6.86 (2H, d, J = 8.6 Hz), 7.15 (1H, t, J = 7.6 Hz), 7.18 (2H, d, J = 8.6 Hz), 7.29 (1H, t, J = 7.6 Hz), 7.36 (1H, d, J = 8.3 Hz), 7.64 (1H, d, J = 8.3 Hz), 8.94 (1H , br s).
MS (ESI ⁺ ): 489 [M+H] ⁺

Using the corresponding starting materials and reactants, the following Examples 4-2 to 4-3 are obtained by the same method as in Example 4-1, the method described in Step 2-3, or a method analogous thereto. rice field.

Under a nitrogen atmosphere, S-2-((tert-butoxycarbonyl)amino)-4-cyclopropylbutanoic acid (480 mg) was dissolved in dimethylformamide (5 mL), 4-(dimethylamino)methylbenzylamine (515 mg), N,N-diisopropylethylamine (0.44 mL) was added and ice-cooled. 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (975 mg) was added thereto, and the mixture was stirred overnight at room temperature. Saturated saline (10 mL) was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate (10 mL×2). The organic layer was washed once with water (10 mL) and once with saturated brine (10 mL), and dried over sodium sulfate. The concentrated residue was purified by silica gel column (Yamazen M; 0-20% methanol in dichloromethane) and concentrated to give 255 mg (33.2%) of S-tert-butyl (4-cyclopropyl-1-(( 4-((dimethylamino)methyl)benzyl)amino)-1-oxobut-2-yl)carbamate was obtained.

4M hydrochloric acid/dioxane (8 mL) was added to tert-butyl (4-cyclopropyl-1-((4-((dimethylamino)methyl)benzyl)amino)-1-oxobut-2-yl)carbamate (255 mg). Stir at room temperature for 1 hour. After allowing to cool, the reaction solution was concentrated under reduced pressure and azeotroped three times with ethyl acetate. By suspending and washing the solidified solid with ethyl acetate, 2.00 g (quant.) of S-2-amino-4-cyclopropyl-N-(4-((dimethylamino)methyl)benzyl)butanamide・2 Hydrochloride salt was obtained.

¹ H-NMR (DMSO-D6, 500MHz) δ: -0.06 - 0.01 (2H, m), 0.33 - 0.42 (2H, m), 0.61 - 0.70 (1H, m), 1.13 - 1.21 (2H, m), 1.81 - 1.89 (2H, m), 2.63 (3H, s), 2.64 (3H, s), 3.80 - 3.89 (1H, m), 4.24 (2H, d, J = 6.5 Hz), 4.36 (2H, d, J = 7.5 Hz), 7.36 (2H, d, J = 10.0 Hz), 7.56 (2H, d, J = 10.0 Hz), 8.36 (3H, d, J = 4.5 Hz), 9.26 (1H, t, J = 7.5 Hz), 11.19 (1H, br s).
MS (ESI ⁺ ): 290 [M+H] ⁺

Using the corresponding starting materials and reactants, the following Reference Examples 5-2 to 5-18 were prepared by the same method as in Reference Example 5-1, the method described in Steps 1-1 and 1-2, or a method analogous thereto. got

Under a nitrogen atmosphere, 3-methyl-1H-indole-2-carboxylic acid (58 mg) was dissolved in dimethylformamide (5.0 mL), and S-2-amino-4-cyclopropyl-N-(4-((dimethyl Amino)methyl)benzyl)butanamide dihydrochloride (100 mg) and N,N-diisopropylethylamine (0.156 mL) were added and ice-cooled. 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (136 mg) was added thereto, and the mixture was stirred overnight at room temperature. Saturated saline (5 mL) was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate (10 mL×2). The organic layer was washed once with water (10 mL) and once with saturated brine (10 mL), and dried over sodium sulfate. The concentrated residue was purified by silica gel column (Yamazen S; 0-20% methanol in dichloromethane) and concentrated to give 41 mg (33.2%) of SN-(4-cyclopropyl-1-((4 -((dimethylamino)methyl)benzyl)amino)-1-oxobutan-2-yl)-3-methyl-1H-indole-2-carboxamide was obtained.

¹ H-NMR (CHLOROFORM-D, 500MHz) δ: -0.07 - 0.03 (2H, m), 0.38 - 0.42 (2H, m), 0.62 - 0.70 (1H, m), 1.21 - 1.40 (2H, m), 1.84 - 1.92 (1H, m), 2.07 - 2.15 (1H, m), 2.22 (6H, s), 2.62 (3H, s), 3.38 (2H, s), 4.40 (1H, dd, J = 14.8, 5.6 Hz), 4.52 (1H, dd, J = 14.8, 6.0 Hz), 4.74 (1H, td, J = 7.5, 5.9 Hz), 6.60 (1H, t, J = 5.7 Hz), 6.92 (1H, d, J = 7.7 Hz), 7.14 (1H, ddd, J = 8.0, 6.8, 1.1 Hz), 7.19 - 7.31 (6H, m), 7.64 (1H, d, J = 7.9 Hz), 9.07 (1H, br s).
MS (ESI ⁺ ): 447 [M+H] ⁺

Using the corresponding starting materials and reactants, the following Examples 5-2 to 5-31 are obtained by the same method as in Example 5-1, the method described in Step 1-3, or a method analogous thereto. rice field.

<Test Example 1>
G9a Inhibitory Activity Test The G9a inhibitory activity of the compounds was evaluated by measuring the G9a enzymatic activity by Amplified Luminescence Proximity Homogeneous Assay (ALPHA). First, recombinant human G9a protein (Active Motif, #31410) diluted with Tris buffer (50 mM Tris-HCl [pH 9.0], 50 mM NaCl, 0.01% Tween-20, 1 mM DTT) (final concentration 0 025 nM) and 0.5 μL of the test compound were added to a 384-well microplate (AlphaPlate-384 Shallow Well, PerkinElmer, #6008359), mixed by vortexing, and allowed to stand at room temperature for 10 minutes. 500 nM of biotinylated histone H3 peptide (1-21) (AnaSpec, #61702) and 150 μM of SAM (SIGMA, #A7007) were premixed 1:1, 2 μL was added to each well, mixed by vortexing, and left at room temperature. It was allowed to stand for 1 hour. ＡｌｐｈａＬＩＳＡａｎｔｉ－Ｈ３Ｋ９ｍｅ２ａｃｃｅｐｔｏｒｂｅａｄｓ（ＰｅｒｋｉｎＥｌｍｅｒ，＃ＡＬ１１７Ｍ）とＡｌｐｈａＳｃｒｅｅｎｓｔｒｅｐｔａｖｉｄｉｎｄｏｎｏｒｂｅａｄｓ（ＰｅｒｋｉｎＥｌｍｅｒ，＃６７６０００２）をｅｐｉｇｅｎｅｔｉｃｂｕｆｆｅｒ（ＰｅｒｋｉｎＥｌｍｅｒ，ＡｌｐｈａＬＩＳＡＥｐｉｇｅｎｅｔｉｃｓＢｕｆｆｅｒＫｉｔ＃ＡＬ００８Ｃ）で添加後の最終濃度が１０μｇ／ｍｌになるようにEach solution was diluted, added in the dark, and then allowed to stand at room temperature for 1 hour. Measurements were then taken using an EnSpire Alpha plate reader (PerkinElmer, Waltham, Mass., USA). For the G9a inhibitory activity of the test compound, the inhibitory rate of the compound is calculated based on the value of the control without the addition of the compound as 0% and the value of the control without the addition of the enzyme as 100%, and the G9a enzyme activity is inhibited to 50%. The concentration of compound (IC ₅₀ value) required to achieve this was calculated. The results are shown below.
In the table, the enzyme inhibitory activity is IC ₅₀ (μM) = <5, >1 = +; <1, >0.1 = ++; <0.1, >0.02 = +++; <0.02 =++++.

<Test Example 2>
Globin Gene Expression Test The effect of the obtained compounds on the expression level of fetal globin gene in human erythroid cell line HUDEP-2 was evaluated by quantitative PCR. HUDEP-2 cells were grown in Stemline II hematopoietic stem cell growth medium (Sigma) containing 1 μM dexamethasone (Sigma), 1 μg/ml doxycycline (Sigma), 50 ng/ml recombinant human SCF (R&D SYSTEMS), and 3 IU/mL epoetin alfa (Toho Yakuhin). cultured. A cell solution was prepared from the cultured cells in a cell culture medium so that the concentration of the cultured cells was 1×10 ⁵ cells/mL. Then, the cell solution was seeded in a 6-well plate (VIOLAMO) at 2 mL/well, and the test compound (DMSO solution) was added at 2 μL/well (DMSO final concentration 0.1%), 37° C., 5% CO ₂ conditions. was cultured for 4 days. A DMSO solution was added at 2 μL/well as a control. The cultured cells were collected by centrifugation at 7500 rpm, 4° C. for 5 minutes, and RNA was extracted using Tissue Total RNA Mini Kit (Chiyoda Science). Thereafter, using ReverTra Ace qPCR RT Master Mix (TOYOBO), cDNA was synthesized by reverse transcription at 37°C for 15 minutes and then at 50°C for 5 minutes. Using the diluted cDNA as a template, it was mixed with THUNDERBIRD SYBR qPCR (TOYOBO), and the CFX Connect Real-Time PCR Detection System (BIORAD) was used to detect the fetal β-globin gene, the adult β-globin gene, and the GAPDH gene as a reference. was measured. The following gene primers were used. Fetal β-globin Forward: 5′-TGGATGATCTCAAGGGCAC-3′; Reverse: 5′-TCAGTGGTATCTGGAGGACA-3′, Adult β-globin Forward: 5′-CAGTGCAGGCTGCCTATC-3′; Reverse: 5′-ATACTTGTGGGCCAGGGCAT-3′, GAPDH Forward: 5'-GCACCGTCAAGGCTGAGAAC-3'; Reverse: 5'-TGGTGAAGACGCCAGTGGA-3'. Gene expression analysis was performed using the ΔΔCt method, with the control to which 0.1% DMSO solution was added as 1.
In the table, the expression level ratio is expressed as <1.25=+;>1.25, <1.5=++;>1.5=+++ relative to DMSO only (1.0). did.

<Test Example 3>
P-gp affinity test The compounds synthesized in the examples were evaluated for P-gp substrate property by the following method, and were found to be good, for example, better than the compounds described in PCT/JP2020/043966. Met.

We evaluated whether the resulting compound could be a substrate for P-glycoprotein (P-gp). Using MDR1-MDCKII cells and MDCKII cells expressing P-glycoprotein (MDR1), adding the obtained compound to the apical side or the basolateral side, measuring the compound concentration on each side after incubation for 2 hours, Apparent membrane permeability coefficient (Papp) and flux ratio (PappBtA/PappAtB) of each cell were calculated to evaluate drug transport ability by P-glycoprotein.

The compounds according to the present invention are useful for proliferative diseases such as cancer, β-globin abnormalities, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy, and autism due to G9a enzyme inhibitory activity. It is useful as a therapeutic or preventive agent for diseases and the like.

All publications, patents and patent applications cited in this specification shall be incorporated herein by reference.

Claims

General formula (I):

[In the formula (I), R 1 and R 2 are bonded to each other to form a ring, and together with the pyrrole ring to which R 1 and R 2 are bonded, the structure of A1) below is taken, and * is the formula (I ) indicates the bonding position with -CO- in;

R 3 is C 1 -C 6 alkyl group, C 2 -C 6 alkenyl group, halo C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, C 1 -C 6 alkylamino group, C 1 -C 6 acyl group, C 1 -C 6 alkoxycarbonyl group, C 3 -C 10 cycloalkyl group or hydroxy C 1 -C 6 alkyl group (the C 1 -C 6 alkyl group, C 2 -C 6 alkenyl group, halo C 1 -C6 alkyl groups, C1 - C6 alkoxy groups, C1 - C6 alkylamino groups, C1 - C6 acyl groups, C1 - C6 alkoxycarbonyl groups, C3 - C10 cycloalkyl groups and hydroxy C 1 -C 6 alkyl group is a substituent selected from the group consisting of C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, C 1 -C 6 alkylamino group and hydroxy C 1 -C 6 alkyl group may be substituted one or more times, and the substituents may be bonded to each other to form a ring);
X represents a carbon atom or a nitrogen atom at any of the 4-, 5-, 6-, and 7-positions, and is an indole or azaindole ring, respectively;
R 6 and R 7 are each independently a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a halo C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, C 1 -C 6 alkylamino group, C 1 -C 6 acyl group, C 1 -C 6 alkoxycarbonyl group, C 3 -C 10 cycloalkyl group or hydroxy C 1 -C 6 alkyl group (the C 1 -C 6 Alkyl Group, C 2 -C 6 Alkenyl Group, Halo C 1 -C 6 Alkyl Group, C 1 -C 6 Alkoxy Group, C 1 -C 6 Alkylamino Group, C 1 -C 6 Acyl Group, C 1 -C 6 Alkoxycarbonyl groups, C 3 -C 10 cycloalkyl groups and hydroxy C 1 -C 6 alkyl groups are C 1 -C 6 alkyl groups, C 1 -C 6 alkoxy groups, C 1 -C 6 alkylamino groups and hydroxy C 1 may be substituted with one or more substituents selected from the group consisting of ~ C6 alkyl groups, and the substituents may be bonded to each other to form a ring);
R 4 is B1) below, * indicates the bonding position with -N- in formula (I);

R 8 and R 9 are each independently a hydrogen atom, a C 1 -C 6 alkyl group or a hydroxy C 1 -C 6 alkyl group;
R 8 and R 9 may be joined together to form a ring;
R 8 and R 9 may combine with RingA to form a ring;
m is 0 or 1;
RingA is an aromatic hydrocarbon ring group, a C3 - C10 cycloalkyl group, a 5- to 10-membered heteroaryl group or a 3- to 10-membered heterocycloalkyl group, each of which may be substituted with R 10 , R 11 and R 12 is a group;
R 10 and R 11 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a cyano group, a carbamoyl group (—CONH 2 ), a C 1 -C 6 alkyl group, a halo C 1 -C 6 alkyl group, a hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 alkylsulfanyl, halo C 1 -C 6 alkylsulfanyl, C 1 -C 6 acyl a C 1 -C 6 alkoxycarbonyl group, a C 1 -C 6 alkylaminocarbonyl group or a C 1 -C 6 acylamino group;
R 12 is -(CR 13 R 14 ) r -V-(CR 15 R 16 ) q -(W) n -Q;
V is a bond, -O- or -NR 17 -;
W is -NR 18 -;
R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are each independently a hydrogen atom or a C 1 -C 6 alkyl group;
q and r are each independently an integer from 0 to 6;
n is 0 or 1;
Q is a hydrogen atom, a hydroxyl group, a C 1 to C 6 alkyl group, a C 3 to C 10 cycloalkyl group, a 5 to 10 membered heteroaryl group or a 3 to 10 membered heterocycloalkyl group (the C 1 to C 6 alkylamino group , C 3 to C 10 cycloalkyl groups, 5 to 10 membered heteroaryl groups and 3 to 10 membered heterocycloalkyl groups are halogen atoms, C 1 to C 6 alkyl groups, C 1 to C 6 alkoxy groups, C 1 to substituted with one or more substituents selected from the group consisting of C 6 alkylamino group, C 1 -C 6 alkoxycarbonyl group, C 1 -C 6 alkylaminocarbonyl group and hydroxy C 1 -C 6 alkyl group may be);
R 10 , R 11 and R 12 may combine with each other to form a ring]
A compound represented by or a pharmacologically acceptable salt thereof.
In formula (I), R 1 and R 2 are bonded to each other to form a ring, and together with the pyrrole ring to which R 1 and R 2 are bonded, take the following structure A1);

R 3 is a C 1 -C 6 alkyl group or a C 3 -C 10 cycloalkyl group;
X represents a carbon atom or a nitrogen atom at any of the 4-, 5-, 6-, and 7-positions, and is an indole or azaindole ring, respectively;
R 6 and R 7 are each independently a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group or a halogen atom;
A compound according to claim 1, or a pharmacologically acceptable salt thereof.
In formula (I), R 1 and R 2 are bonded to each other to form a ring, and together with the pyrrole ring to which R 1 and R 2 are bonded, have the following structure A1a);

R 3 is a C 1 -C 6 alkyl group;
R 6 and R 7 are each independently a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group or a halogen atom;
3. A compound according to claim 2, or a pharmacologically acceptable salt thereof.
In formula (I), R 1 and R 2 are bonded to each other to form a ring, and together with the pyrrole ring to which R 1 and R 2 are bonded, any of the following A1b), A1c), A1d) and A1e) take the structure of;

R 3 is a C 1 -C 6 alkyl group;
R 6 and R 7 are each independently a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group or a halogen atom;
3. A compound according to claim 2, or a pharmacologically acceptable salt thereof.
Less than,

or a pharmaceutically acceptable salt thereof.
A G9a enzyme inhibitory composition containing the compound according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof as an active ingredient.
A pharmaceutical composition containing the compound according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof as an active ingredient.
At least one disease selected from the group consisting of proliferative diseases such as cancer, β-globin disorders, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy and autism Use of the compound according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof for manufacturing a medicament for the prevention or treatment of
At least one disease selected from the group consisting of proliferative diseases such as cancer, β-globin disorders, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy and autism 6. A pharmaceutical composition containing the compound according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof and a pharmaceutically acceptable carrier, which is used for the prevention or treatment of .