WO2019235501A1 - Histone deacetylase inhibitor - Google Patents

Abstract

The present invention provides a novel compound which has HDAC2 inhibitory activity. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (In the formula, R¹ represents a hydrogen atom, a halogen atom, a substituted or unsubstituted furyl group, or the like; -L- represents -SO₂-, -SO-, -S- or -CH₂-; and R² represents a substituted or unsubstituted phenyl group, or a substituted or unsubstituted six-membered aromatic heterocyclic group.)

Description

Histone deacetylase inhibitor

The present invention relates to a compound having a HDAC2 inhibitory action and useful as a therapeutic or prophylactic agent for diseases involving HDAC2, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing them.

In recent years, many reports have suggested that the contribution of epigenetics control involving DNA methylation and histone chemical modification is important in the process of synaptic plasticity and memory formation.
Histone acetylation, which is known as a representative example of epigenetics control, is controlled by the function of histone acetylase (HAT) and histone deacetylase (HDAC).
There are 18 subtypes of human HDAC, which are roughly divided into 5 groups (class I, class IIa, class IIb, class III, class IV). HDACs are known to use a variety of proteins such as histones as substrates, and HDACs based on histones are generally thought to negatively regulate the expression of specific gene regions by histone deacetylation. Yes.
It has been suggested that HDACs control different gene groups for each subtype. It is known that HDAC2 belonging to class I is mainly involved in the control of gene groups related to nerve function. Non-clinical studies have shown that inhibition of HDAC2 enhances transcription of genes related to nerve function, resulting in enhancement of nerve function (Non-Patent Document 1).
HDAC2 is known to be upregulated in Alzheimer's dementia patients and model mice. Therefore, it is suggested that HDAC2 may be involved in the formation of the disease state by excessively suppressing gene transcription in the nervous system (Non-patent Document 2). Furthermore, since it has been reported that specific inhibition of HDAC2 in Alzheimer's disease model mice has an effect of improving impaired cognitive function, HDAC2 is a promising drug discovery target for Alzheimer-type dementia. It is attracting attention (Non-Patent Document 3). In recent years, reports suggesting that HDAC2 is also associated with other neurological diseases such as schizophrenia and depression, and HDAC2 inhibitors are expected to be widely applicable to neurodegenerative and psychiatric disorders (non-) Patent Document 4).
All HDAC inhibitors currently in clinical use are non-selective HDAC inhibitors that are indicated for cancer and inhibit multiple HDAC subtypes. These are known to cause side effects that are commonly observed with other anticancer agents, including thrombocytopenia. In order to clarify the mechanism of such side effects, a plurality of non-clinical studies have been conducted, and it has been revealed that inhibition of HDAC1 and 2 simultaneously causes suppression of cell proliferation (Non-patent Document 5). It is considered that the suppressive action of cell proliferation by simultaneous inhibition of HDAC1 and 2 is related to clinical side effects of known HDAC inhibitors. Therefore, creation of a compound that selectively inhibits HDAC2 is required, but HDAC1 and HDAC2 have very high amino acid homology, and it is assumed that creation of a compound that selectively inhibits HDAC2 is very difficult. Yes.
Patent Documents 1 to 4 and Non-Patent Documents 6 to 8 describe HDAC inhibitors, but the substantially disclosed compounds have structures different from the compounds of the present invention.

International Publication No. WO2012 / 149540 International Publication No. WO2010 / 065117 International Publication No. WO2017 / 004522 JP 2013-170164 A

An object of the present invention is a compound having a HDAC2 inhibitory action and preferably high HDAC2 / HDAC1 selectivity, and useful as a therapeutic or prophylactic agent for a disease related to HDAC2, or a pharmaceutically acceptable salt thereof, and the like It is to provide a pharmaceutical composition.

The present invention relates to the following.
(1) Formula (I):

(Where
R ¹ is a hydrogen atom, halogen, substituted or unsubstituted furyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyridyl, substituted or unsubstituted phenyl Or substituted or unsubstituted cyclohexenyl;
-L- is -SO _2- , -SO-, -S-, or -CH _2- ;
R ² is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 6-membered aromatic heterocyclic group;
However, when R ¹ is a hydrogen atom and -L- is -CH _2- , R ² is a substituted or unsubstituted 6-membered aromatic heterocyclic group)
(Wherein the following compounds:

Or a pharmaceutically acceptable salt thereof.
(2) The compound according to the above (1), or a pharmaceutically acceptable salt thereof, wherein R ¹ is substituted or unsubstituted furyl, substituted or unsubstituted pyridyl, or halogen.
(3) The compound according to (1) or a pharmaceutically acceptable salt thereof, wherein R ¹ is substituted or unsubstituted furyl.
(4) R ¹ is a group represented by the following:

Wherein n is an integer from 0 to 2; each R ³ is independently halogen or substituted or unsubstituted alkyl.
The compound according to (1) above, or a pharmaceutically acceptable salt thereof.
(5) R ¹ is a group represented by the following:

(In the formula, each symbol has the same meaning as (4) above)
The compound according to (1) above, or a pharmaceutically acceptable salt thereof.
(6) The compound according to (4) or (5) above, wherein n is 0, or a pharmaceutically acceptable salt thereof.
(7) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (6), wherein -L- is -SO _2- .
(8) The compound according to any one of (1) to (7) above, wherein R ² is phenyl, or a pharmaceutically acceptable salt thereof.
(9) Compounds shown below:

Or a pharmaceutically acceptable salt thereof.
(10) A pharmaceutical composition comprising the compound according to any one of (1) to (9) above, or a pharmaceutically acceptable salt thereof.
(11) The pharmaceutical composition according to the above (10), which is an HDAC2 inhibitor.
(12) An HDAC2 inhibitor comprising the compound according to any one of (1) to (9) above, or a pharmaceutically acceptable salt thereof.

(13) The pharmaceutical composition according to (10) above, for the treatment and / or prevention of a disease involving HDAC2.
(14) A method for treating and / or preventing a disease involving HDAC2, which comprises administering the compound according to any one of (1) to (9) above or a pharmaceutically acceptable salt thereof.
(15) Use of the compound according to any one of (1) to (9) above or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic and / or prophylactic agent for a disease involving HDAC2.
(16) The compound according to any one of the above (1) to (9) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease involving HDAC2.

The compound according to the present invention has an inhibitory action on HDAC2, and is useful as a therapeutic and / or prophylactic agent for diseases involving HDAC2.

The meaning of each term used in this specification will be described below. Unless otherwise specified, each term is used in the same meaning whether used alone or in combination with other terms.
The term “consisting of” means having only the configuration requirements.
The term “comprising” is not limited to the constituent elements and means that elements not described are not excluded.
Hereinafter, the present invention will be described with reference to embodiments. Throughout this specification, it should be understood that the singular forms also include the plural concept unless specifically stated otherwise. Thus, it should be understood that singular articles (eg, “a”, “an”, “the”, etc. in the case of English) also include the plural concept unless otherwise stated. In addition, it is to be understood that the terms used in the present specification are used in the meaning normally used in the above field unless otherwise specified. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control.

“Halogen” includes fluorine atom, chlorine atom, bromine atom, and iodine atom. In particular, a fluorine atom and a chlorine atom are preferable.

“Alkyl” includes straight or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , Isooctyl, n-nonyl, n-decyl and the like.
Preferred embodiments of “alkyl” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. Further preferred examples include methyl, ethyl, n-propyl, isopropyl and tert-butyl.

“Alkenyl” has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. These linear or branched hydrocarbon groups are included. For example, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, decenyl Etc.
Preferred embodiments of “alkenyl” include vinyl, allyl, propenyl, isopropenyl and butenyl.

“Alkynyl” has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Furthermore, you may have a double bond in arbitrary positions. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like.
Preferred embodiments of “alkynyl” include ethynyl, propynyl, butynyl and pentynyl.

“Alkylene” is a straight or branched divalent hydrocarbon having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. Includes groups. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.

The term “alkenylene” refers to a carbon number of 2 to 15, preferably 2 to 10, more preferably 2 to 6 and even more preferably 2 to 4 having one or more double bonds at an arbitrary position. And a linear or branched divalent hydrocarbon group. For example, vinylene, propenylene, butenylene, pentenylene, hexenylene and the like can be mentioned.

“Alkynylene” refers to carbon atoms of 2 to 15, preferably 2 to 10, more preferably 2 to 6, more preferably 2 to 4 carbon atoms having one or more triple bonds at any position. A linear or branched divalent hydrocarbon group is included. Furthermore, you may have a double bond in arbitrary positions. For example, ethynylene, propynylene, butynylene, pentynylene, hexynylene and the like can be mentioned.

The “aromatic carbocyclic group” means a cyclic aromatic hydrocarbon group having one or more rings. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned.
A preferred embodiment of the “aromatic carbocyclic group” includes phenyl.

The “aromatic carbocycle” means a ring derived from the above “aromatic carbocyclic group”.
A preferred embodiment of the “aromatic carbocycle” includes a benzene ring.

The “non-aromatic carbocyclic group” means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings. The “non-aromatic carbocyclic group” having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more non-aromatic carbocyclic groups.
Furthermore, the “non-aromatic carbocyclic group” includes a group which forms a bridge as described below or a group which forms a spiro ring.

The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like can be mentioned.
The non-aromatic carbocyclic group having 2 or more rings preferably has 8 to 20 carbon atoms, more preferably 8 to 16 carbon atoms. For example, indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like can be mentioned.

“Non-aromatic carbocyclic ring” means a ring derived from the above “non-aromatic carbocyclic group”.

“Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring To do.
The aromatic heterocyclic group having two or more rings includes those in which the ring in the above “aromatic carbocyclic group” is condensed to a monocyclic or two or more aromatic heterocyclic groups, You may have in any ring.
The monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members. Examples of the 5-membered aromatic heterocyclic group include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, and the like. Examples of the 6-membered aromatic heterocyclic group include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like. The bicyclic aromatic heterocyclic group is preferably 8 to 10 members, more preferably 9 or 10 members. For example, indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazoazolyl, benzoxadiazolyl, benzoisodiazolyl Ril, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl, etc. Is mentioned.
The aromatic heterocyclic group having 3 or more rings is preferably 13 to 15 members. Examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl and the like.

“Aromatic heterocycle” means a ring derived from the above “aromatic heterocyclic group”.
The monocyclic aromatic heterocyclic ring is preferably 5 to 8 members, more preferably 5 or 6 members. Examples of the 5-membered aromatic heterocycle include pyrroline ring, imidazoline ring, pyrazoline ring, triazole ring, tetrazole ring, furan ring, thiophene ring, isoxazole ring, oxazole ring, oxadiazole ring, isothiazole ring, thiazole ring. And thiadiazole ring. Examples of the 6-membered aromatic heterocycle include a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, and a triazine ring.
The bicyclic aromatic heterocyclic group is preferably 8 to 10 members, more preferably 9 or 10 members. For example, indole ring, isoindole ring, indazole ring, indolizine ring, quinoline ring, isoquinoline ring, cinnoline ring, phthalazine ring, quinazoline ring, naphthyridine ring, quinoxaline ring, purine ring, pteridine ring, benzimidazole ring, benzisoxazole Ring, benzoxazole ring, benzoxadiazole ring, benzisothiazole ring, benzothiazole ring, benzothiadiazole ring, benzofuran ring, isobenzofuran ring, benzothiophene ring, benzotriazole ring, imidazopyridine ring, triazolopyridine ring, imidazo Examples include a thiazole ring, a pyrazinopyridazine ring, an oxazolopyridine ring, a thiazolopyridine ring, and the like.
The aromatic heterocycle having 3 or more rings is preferably 13 to 15 members. Examples thereof include a carbazole ring, acridine ring, xanthene ring, phenothiazine ring, phenoxathiin ring, phenoxazine ring, dibenzofuran ring and the like.

"Non-aromatic heterocyclic group" means a monocyclic or bicyclic or more non-aromatic cyclic group having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring Means. The non-aromatic heterocyclic group having 2 or more rings is a monocyclic or 2 or more non-aromatic heterocyclic group, the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group”, and / Or each condensed ring in the “aromatic heterocyclic group” is condensed, and further, the ring in the above “aromatic heterocyclic group” is condensed to a monocyclic or two or more non-aromatic carbocyclic group The bond may be present in any ring.
Furthermore, the “non-aromatic heterocyclic group” includes a group that forms a bridge or a spiro ring as described below.

The monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members.
Examples of the 3-membered non-aromatic heterocyclic group include thiranyl, oxiranyl, and aziridinyl. Examples of the 4-membered non-aromatic heterocyclic group include oxetanyl and azetidinyl. Examples of the 5-membered non-aromatic heterocyclic group include oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, thiolanyl and the like. Can be mentioned. Examples of the 6-membered non-aromatic heterocyclic group include dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl , Hexahydropyrimidinyl, dioxazinyl, thiinyl, thiazinyl and the like. Examples of the 7-membered non-aromatic heterocyclic group include hexahydroazepinyl, tetrahydrodiazepinyl, and oxepanyl.
The non-aromatic heterocyclic group having 2 or more rings is preferably 8 to 20 members, more preferably 8 to 10 members. For example, indolinyl, isoindolinyl, chromanyl, isochromanyl and the like can be mentioned.

“Non-aromatic heterocyclic ring” means a ring derived from the above “non-aromatic heterocyclic group”.

“Trialkylsilyl” means a group in which the above three “alkyls” are bonded to a silicon atom. The three alkyl groups may be the same or different. For example, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.

“Alkyloxy”, “haloalkyloxy”, “alkylcarbonyloxy”, “alkylcarbonyl”, “alkyloxycarbonyl”, “alkylsulfanyl”, “alkylsulfinyl”, “alkylsulfonyl”, “alkyloxyalkyloxy”, and The alkyl part of “alkyloxyalkyl” has the same meaning as the above “alkyl”.
The alkenyl part of “alkenyloxy”, “alkenylcarbonyloxy”, “alkenylcarbonyl”, “alkenyloxycarbonyl”, “alkenylsulfanyl”, “alkenylsulfinyl” and “alkenylsulfonyl” has the same meaning as the above “alkenyl”.
The alkynyl part of “alkynyloxy”, “alkynylcarbonyloxy”, “alkynylcarbonyl”, “alkynyloxycarbonyl”, “alkynylsulfanyl”, “alkynylsulfinyl” and “alkynylsulfonyl” has the same meaning as the above “alkynyl”.

In the present specification, “may be substituted with substituent group α” means “may be substituted with one or more groups selected from substituent group α”.

Examples of the substituent of “substituted alkyl” include the following substituent group α. The carbon atom at any position may be bonded to one or more groups selected from the following substituent group α.

Substituent group α: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, cyano, and nitro.

“Substituted furyl”, “substituted oxazolyl”, “substituted pyrrolyl”, “substituted thienyl”, “substituted pyridyl”, “substituted phenyl”, and “substituted 6-membered aromatic heterocyclic group” “phenyl” and the respective “ Examples of the substituent on the ring of the “aromatic heterocyclic group” include the following substituent group B. Any ring-constituting atom may be bonded to one or more groups selected from the following substituent group B.
Substituent group B: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, penta Fluorothio, trialkylsilyl,
Alkyloxy optionally substituted with substituent group α, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, substituted with substituent group α Alkylcarbonyloxy which may be substituted, alkenylcarbonyloxy which may be substituted with substituent group α, alkynylcarbonyloxy which may be substituted with substituent group α, alkylcarbonyl which may be substituted with substituent group α , Alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkyloxycarbonyl optionally substituted with substituent group α, substituted with substituent group α Alkenyloxycarbonyl which may be substituted, alkynyloxycarbonyl which may be substituted with substituent group α, substituent group α Alkylsulfanyl which may be substituted, Alkenylsulfanyl which may be substituted with substituent group α, Alkynylsulfanyl which may be substituted with substituent group α, Alkylsulfinyl which may be substituted with substituent group α , Alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, substituted with substituent group α Alkenylsulfonyl which may be substituted, and alkynylsulfonyl which may be substituted with substituent group α.

Examples of the substituent of the ring constituent atom of “cyclohexenyl” of “substituted cyclohexenyl” include the following substituent group C. Any ring-constituting atom may be bonded to one or more groups selected from the following substituent group C.
Substituent group C: each substituent and oxo defined as substituent group B.

When “non-aromatic carbocycle”, “non-aromatic heterocycle”, “non-aromatic carbocyclic group” and “non-aromatic heterocyclic group” are substituted with “oxo”, as follows: It means a ring in which two hydrogen atoms on a carbon atom are substituted.

Preferred embodiments of R ¹ , R ² and -L- in the compound represented by the formula (I) are shown below. Examples of the compound represented by the formula (I) include all combinations of the specific examples shown below.

R ¹ is a hydrogen atom, halogen, substituted or unsubstituted furyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyridyl, substituted or unsubstituted phenyl Or substituted or unsubstituted cyclohexenyl (hereinafter referred to as A-1).
R ¹ is a hydrogen atom, halogen, substituted or unsubstituted furyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrrolyl, substituted thienyl, substituted or unsubstituted pyridyl, substituted or unsubstituted phenyl, or substituted or Unsubstituted cyclohexenyl (hereinafter referred to as A-2).
R ¹ is preferably substituted or unsubstituted furyl, substituted or unsubstituted pyridyl, or halogen. (Hereinafter referred to as A-3).
R ¹ is more preferably substituted or unsubstituted furyl (hereinafter referred to as A-4).
R ¹ is more preferably furyl optionally substituted with one or more groups selected from substituent group B (hereinafter referred to as A-5).
R ¹ is particularly preferably a group shown below:

(Wherein n is an integer of 0 to 2; each R ³ is independently halogen or substituted or unsubstituted alkyl) (hereinafter referred to as A-6).
R ¹ is particularly preferably a group shown below:

(Wherein n is an integer of 0 to 2; each R ³ is independently an alkyl optionally substituted with a substituent group α, or a halogen)
(Hereinafter referred to as A-7).
R ¹ is particularly preferably a group shown below:

(Wherein n and R ³ are the same as A-6) (hereinafter referred to as A-8).
R ¹ is particularly preferably a group shown below:

Wherein n is 0 or 1, and R ³ is alkyl optionally substituted with substituent group α,
Or halogen) (hereinafter referred to as A-9).
R ¹ is particularly preferably a group shown below:

(Hereinafter referred to as A-10).
R ¹ is particularly preferably a group shown below:

(Hereinafter referred to as A-11).

—L— is —SO ₂ —, —SO—, —S—, or —CH ₂ — (hereinafter referred to as B-1).
—L— is preferably —SO ₂ —, —SO—, or —S— (hereinafter referred to as B-2).
-L- is preferably -SO- (hereinafter referred to as B-3).
—L— is preferably —CH ₂ — (hereinafter referred to as B-4).
—L— is particularly preferably —SO ₂ — (hereinafter referred to as B-5).

R ² is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 6-membered aromatic heterocyclic group (hereinafter referred to as C-1).
R ² is preferably phenyl optionally substituted with one or more groups selected from substituent group B, or 6-membered optionally substituted with one or more groups selected from substituent group B An aromatic heterocyclic group (hereinafter referred to as C-2).
R ² is more preferably substituted or unsubstituted phenyl (hereinafter referred to as C-3).
R ² is particularly preferably phenyl optionally substituted with one or more groups selected from Substituent Group B (hereinafter referred to as C-4).
R ² is particularly preferably phenyl (hereinafter referred to as C-5).

The compounds of formula (I) are not limited to specific isomers, but all possible isomers (eg keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers) , Rotamers, etc.), racemates or mixtures thereof.

One or more hydrogen, carbon and / or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes are ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I and ^{Like 36} Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. The compound represented by the formula (I) also includes a compound substituted with such an isotope. The compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I). In addition, a “radiolabeling method” for producing the “radiolabeled substance” is also encompassed in the present invention, and the “radiolabeled substance” is useful as a metabolic pharmacokinetic study, a research in a binding assay, and / or a diagnostic tool. It is.

The radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art. For example, the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by catalytic dehalogenation reaction using tritium. In this method, a tritium gas is reacted with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that. Other suitable methods for preparing tritium labeled compounds can be referred to “Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)”. ^{The 14} C-labeled compound can be prepared by using a raw material having ¹⁴ C carbon.

Examples of the pharmaceutically acceptable salt of the compound represented by the formula (I) include, for example, a compound represented by the formula (I), an alkali metal (for example, lithium, sodium, potassium, etc.), Calcium, barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, Quinoline etc.) and amino acid salts, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid etc.) and organic acids (eg formic acid, acetic acid, propionic acid) , Trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, Maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p- toluenesulfonic acid, methanesulfonic acid, and salts with ethanesulfonic acid, etc.). Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.

The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.), a co-crystal and / or a crystal polymorph. Various solvates, co-crystals and polymorphs. The “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I). When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate. In addition, a crystal polymorph may be formed by recrystallizing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. “Co-crystal” means that the compound or salt represented by the formula (I) and the counter molecule are present in the same crystal lattice, and may contain any number of counter molecules.

The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo. A prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. A method for selecting and producing an appropriate prodrug derivative is described in, for example, “Design of Prodrugs, Elsevier, Amsterdam, 1985”. Prodrugs may themselves have activity.

When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, the compound having a hydroxyl group and a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable Examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or by reacting with a condensing agent. For example, CH ₃ COO—, C ₂ H ₅ COO—, tert-BuCOO—, C ₁₅ H ₃₁ COO—, PhCOO—, (m-NaOOCPh) COO—, NaOOCCH ₂ CH ₂ COO—, CH ₃ CH (NH ₂ ) COO—, CH ₂ N (CH ₃ ) ₂ COO—, CH ₃ SO ₃ —, CH ₃ CH ₂ SO ₃ —, CF ₃ SO ₃ —, CH ₂ FSO ₃ —, CF ₃ CH ₂ SO ₃ —, p -CH ₃ O-PhSO _3- , PhSO _3- , p-CH ₃ PhSO ₃ -can be mentioned.

(Method for producing the compound of the present invention)
The compound represented by the formula (I) can be produced, for example, by the general synthesis method shown below. Any of the starting materials and reaction reagents used in these syntheses are commercially available or can be prepared according to methods well known in the art using commercially available compounds. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.
The compounds of the present invention can be synthesized with reference to techniques known in the art.
In the following steps, when there are substituents that hinder the reaction (for example, hydroxy, mercapto, amino, formyl, carbonyl, carboxyl, etc.), Protective Groups in Organic Synthesis, Theodora W Greene (John Wiley & Sons), etc. Or may be removed at a desired stage.
Moreover, about all the following processes, the order of the process to implement can be changed suitably, and each intermediate body may be isolated and used for the following process. The reaction time, reaction temperature, solvent, reagent, protecting group, etc. are all merely examples, and are not particularly limited as long as the reaction is not hindered.

The compound represented by the formula (I) can be produced, for example, by the following synthesis route.

(Method A)

(In the formula, X is a halogen, P is a protecting group for an amino group such as a Boc group, and other symbols are as defined above.)
(First step)
Compound (iii) can be obtained by reacting compound (i) with compound (ii) in the presence of a condensing agent.
As the condensing agent, dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDCI, 4- (4,6-dimethoxy-1,3,5, -triazin-2-yl) -4- Examples thereof include methylmorpholinium chloride and HATU, and 1 to 5 molar equivalents can be used with respect to compound (ii).
The reaction temperature is −20 ° C. to 60 ° C., preferably 0 ° C. to 30 ° C.
The reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Examples of the reaction solvent include DMF, DMA, NMP, tetrahydrofuran, dioxane, dichloromethane, acetonitrile and the like, and these can be used alone or in combination.

(Second step)
Compound (v) can be obtained by reacting compound (iv) with compound (iii) in the presence of a metal catalyst and an additive.
Examples of the metal catalyst include copper (II) sulfate pentahydrate, copper (II) acetate, Ru (OAc) ₂ (PPh ₃ ) ₂ , RuCl ₂ (PPh ₃ ) _{3 and the} like, with respect to compound (iii) 0.001 to 1.0 molar equivalent can be used.
Examples of additives include sodium ascorbate, tris [(1-benzyl-1H-1,2,3-triazol-4-yl) methyl] amine, tetrabutylammonium bromide, tetrabutylammonium iodide, etc. 1 to 10 molar equivalents can be used with respect to (iii).
Compound (iv) can be used at 1 to 10 molar equivalents relative to compound (iii).
The reaction temperature is 0 ° C. to the reflux temperature of the solvent, and optionally under microwave irradiation.
The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
Examples of the reaction solvent include tetrahydrofuran, toluene, DMF, dioxane, dimethyl sulfoxide, acetonitrile, methanol, ethanol, water and the like, and these can be used alone or in combination.

(Third step)
Compound (vii) can be obtained by reacting compound (v) with boronic acid (vi) in the presence of a metal catalyst and a base.
Examples of the metal catalyst include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium and the like. 0.001 to 0.5 molar equivalent can be used with respect to compound (v).
Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, phosphorus Examples thereof include potassium oxyhydrogen, and 1 to 10 molar equivalents can be used with respect to compound (v).
Boronic acid (vi) can be used in an amount of 1 to 10 molar equivalents relative to compound (v).
The reaction temperature is 20 ° C. to the reflux temperature of the solvent, and optionally under microwave irradiation.
The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
Examples of the reaction solvent include tetrahydrofuran, toluene, DMF, dioxane, water and the like, and these can be used alone or in combination.

(4th process)
Compound (I) can be obtained by reacting compound (vii) with an acid or a Lewis acid.

Examples of the acid include hydrochloric acid-ethyl acetate, hydrochloric acid-methanol, hydrochloric acid-dioxane, sulfuric acid, formic acid, trifluoroacetic acid and the like. Examples of the Lewis acid include trimethylsilyl iodide, BBr ₃ , AlCl ₃ , BF _3. (Et ₂ O) and the like, and 1 to 10 molar equivalents can be used with respect to the compound (vii).
The reaction temperature is 0 ° C. to 60 ° C., preferably 0 ° C. to 20 ° C.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
Examples of the reaction solvent include methanol, ethanol, water, acetone, acetonitrile, DMF and the like, and these can be used alone or in combination.
For example, the method described in Journal of Medicinal Chemistry 2012, Vol. 55, pages 9562-9575 can be used as a reference.

(Method B)

(Wherein each symbol has the same meaning as above)
(First step)
Compound (ix) can be synthesized in the same manner as in the first step of Method A.
(Second step)
Compound (I) can be synthesized in the same manner as in the second step of Method A.

Since the compound according to the present invention has an HDAC2 inhibitory action, it is useful as a therapeutic and / or prophylactic agent for diseases involving HDAC2.
In the present invention, the term “therapeutic agent and / or prophylactic agent” includes a symptom improving agent.
Examples of the disease involving HDAC2 include cancer and neurological disease, and preferably neurological disease.
Examples of the neurological diseases include central nervous diseases (for example, neurodegenerative diseases). Examples of central nervous system diseases include Alzheimer's disease, Alzheimer's dementia, Alzheimer's senile dementia, mild cognitive impairment (MCI), memory loss, attention deficit symptoms related to Alzheimer's disease, neurodegeneration related to Alzheimer's disease, mixed Dementia of mixed vascular origin, dementia of degenerative origin, presenile dementia, senile dementia, dementia related to Parkinson's disease, vascular dementia, frontotemporal dementia, stroke , Progressive supranuclear palsy, cerebral cortex basal ganglia degeneration, schizophrenia, delirium, attention, deficit disorder (ADD), schizophrenic disorder, Rubinstein-Tevi syndrome, depression, mania, attention deficit disorder, drug epilepsy , Dementia, autism, fierceness, blunt emotion, anxiety, post-traumatic stress disorder (PTSD), psychosis, Examples include personality disorder, bipolar disorder, unipolar affective disorder, obsessive compulsive disorder, eating disorder, post-traumatic stress disorder, hypersensitivity, adolescent behavioral disorder and disinhibition, particularly preferably Alzheimer's disease It is done.
The compound of the present invention has not only an HDAC2 inhibitory action but also a usefulness as a medicine, and has any or all of the following excellent characteristics.
a) High HDAC2 selectivity.
b) High selectivity to HDAC2 over HDAC1.
c) High kinetic selectivity to HDAC2 over HDAC1. For example, in Test Example 1 described later, the rate constant k ₋₁ (HDAC2 k ₋₁ ) in HDAC2 inhibition is smaller than the rate constant k ₋₁ (HDAC1 k ₋₁ ) in HDAC1 inhibition. As another example, in Test Example 1 described later, the rate constant k ₋₂ (HDAC2 k ₋₂ ) in HDAC2 inhibition is smaller than the rate constant k ₋₂ (HDAC1 k ₋₂ ) in HDAC1 inhibition.
d) The inhibitory effect on CYP enzymes (for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
e) Good pharmacokinetics such as high bioavailability and moderate clearance.
f) High metabolic stability.
g) No irreversible inhibitory action on CYP enzymes (eg CYP3A4) within the concentration range of the measurement conditions described herein.
h) Not mutagenic.
i) Low cardiovascular risk.
j) High solubility.

The pharmaceutical composition of the present invention can be administered either orally or parenterally. Examples of parenteral administration include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop, and intravaginal administration.

In the case of oral administration, solid preparations for internal use (eg, tablets, powders, granules, capsules, pills, films, etc.) and liquids for internal use (eg, suspensions, emulsions, elixirs, syrups) Preparations, limonade agents, spirits, fragrances, extracts, decoctions, tinctures, etc.), etc. The tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets, and powders and granules are dry syrups Alternatively, the capsule may be a soft capsule, a microcapsule or a sustained release capsule.

In the case of parenteral administration, injections, drops, external preparations (eg eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coating agents, mouthwashes, enemas, Any commonly used dosage form such as an ointment, a plaster, a jelly, a cream, a patch, a patch, a powder for external use, a suppository and the like can be suitably administered. The injection may be an emulsion such as O / W, W / O, O / W / O, W / O / W type.

Various pharmaceutical additives such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition. Furthermore, the pharmaceutical composition can be obtained by changing the effective amount, dosage form and / or various pharmaceutical additives of the compound of the present invention as appropriate, so that it can be used for pediatric, elderly, critically ill patients or surgery. You can also The pediatric pharmaceutical composition is preferably administered to a patient under the age of 12 or 15 years. Also, the pediatric pharmaceutical composition can be administered to patients less than 27 days after birth, 28 to 23 months after birth, 2 to 11 years old, or 12 to 17 years old or 18 years old. The elderly pharmaceutical composition is preferably administered to a patient over 65 years of age.

The dose of the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, weight, type and degree of disease, route of administration, etc., but when administered orally, usually 0.05 to 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.

The compound of the present invention can be used in combination with a concomitant drug for the purpose of enhancing the action of the compound or reducing the dose of the compound. In this case, the administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference.

Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, and Test Examples, but the present invention is not limited thereto.

Moreover, the abbreviation used in this specification represents the following meaning.
Boc: tert-butoxycarbonyl Ph: phenyl

Proton nuclear magnetic resonance spectra ( ¹ H NMR) and carbon nuclear magnetic resonance spectra ( ¹³ C NMR) were recorded using a BURKER AVANCE 300 spectrometer in the solvents described. The chemical shift (δ) is expressed in parts per million compared to the internal standard tetramethylsilane. Electrospray ionization (ESI) mass spectra were recorded on a BRUKER HCTplus mass spectrometer. Reagents and solvents were purchased from Aldrich, Merck, Nacalai Tesque, Tokyo Chemical Industry, Wako Pure Chemical Industries, Kishida Chemical, Kanto Chemical, and used without purification. Flash column chromatography was performed using silica gel purchased from Merck silica gel. Further, when NMR data is shown, there are cases where not all measured peaks are described.

Example 1 Synthesis of Compound I-001

Step 1 Synthesis of Compound 27

To a solution of compound 24 (157.7 mg, 1.08 mmol) in N, N-dimethylformamide (10 ml), compound 26 (353.8 mg, 3.27 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide Hydrochloride (271.3 mg, 1.42 mmol) and 1-hydroxybenzotriazole monohydrate (176.2 mg, 1.30 mmol) were added, and the mixture was stirred at room temperature for 13 hours. The reaction solution was diluted with a saturated aqueous sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain Compound 27 (173.2 g, 68%).
¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.71 (s, 1 H), 7.99 (d, J = 8.4 Hz, 2 H), 7.61 (d, J = 8.4 Hz, 2 H), 7.16 (d, J = 7.0 Hz, 1 H), 6.98 (dt, J = 1.6, 8.0 Hz, 1 H), 6.78 (dd, J = 1.3, 8.0 Hz, 1 H), 6.59 (dt, J = 1.3 , 7.0 Hz, 1 H), 4.39 (s, 1 H); ¹³ C NMR (DMSO-d ₆ , 75 MHz, δ; ppm) 167.4, 165.0, 143.7, 135.2, 132.0, 129.1, 128.5, 127.2, 127.1, 125.0, 123.5, 116.7, 116.5, 83.4, 83.3.
Step 2 Synthesis of Compound I-001

In a mixed solvent of dimethyl sulfoxide (8 mL) and water (2 mL), compound 27 (173.2 mg, 0.733 mmol), copper (II) sulfate pentahydrate (95.1 mg, 0.381 mmol), sodium ascorbate ( 151.6 mg, 0.765 mmol) and compound 25 (221.3 mg, 1.12 mmol) were added and stirred at 50 ° C. for 13 hours. The reaction mixture was filtered through a Celite (registered trademark) pad, brine was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate alone) to obtain Compound I-001 (101.5 mg, 32%).
¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.72 (s, 1 H), 8.73 (s, 1 H), 8.08 (d, J = 8.4 Hz, 2 H), 8.00 (d, J = 8.4 Hz, 2 H), 7.60-7.85 (m, 5 H), 7.18 (d, J = 6.7 Hz, 1 H), 6.96 (dt, J = 1.2, 6.3 Hz, 1 H), 6.79 (dd, J = 1.2, 8.0 Hz, 1 H), 6.61 (dt, J = 1.2, 8.0 Hz, 1 H), 6.39 (s, 2 H), 4.92 (s, 2 H); ¹³ C NMR (DMSO-d ₆ , 75 MHz, δ; ppm) 164.8, 145.9, 143.2, 136.0, 134.9, 134.1, 132.6, 129.6, 128.5, 126.7, 126.5, 125.0, 123.7, 123.2, 116.2, 116.1; ESI-MS (m / z): 434.3 [M + H] ⁺ .

Example 2 Synthesis of Compound I-012

Step 1 Synthesis of Compound 19

To a tetrahydrofuran solution (15 ml) of compound 18 (3.013 g, 13.8 mmol) was added di-tert-butyl dicarbonate (6.053 g, 27.7 mmol) and dimethylaminopyridine (348.1 mg, 2.850 mmol). The mixture was further stirred at room temperature for 18 hours. The reaction mixture was concentrated, tetrahydrofuran (15 mL) and 2 mol / L aqueous sodium hydroxide solution (15 mL) were added to the obtained residue, and the mixture was heated with stirring under reflux for 3 hr. Sodium hydroxide (1 g) was added to the reaction mixture, and the mixture was stirred under heating for 20.5 hours under reflux, and then diluted with water. The resulting mixture was extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to obtain Compound 19 (3.991 g, 91%).
¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.64 (s, 1 H), 8.12 (d, J = 2.4 Hz, 1 H), 7.84 (dd, J = 2.4, 8.7 Hz, 1 H ), 7.64 (d, J = 8.7 Hz, 1 H), 1.45 (s, 9 H); ¹³ C NMR (DMSO-d ₆ , 75 MHz, δ; ppm) 152.6, 141.8, 137.2, 132.6, 127.9, 126.0 , 115.2, 81.3, 28.3.
Step 2 Synthesis of Compound 20

To a solution of compound 19 (2.45 g, 7.71 mmol) in N, N-dimethylformamide (20 ml) was added saturated aqueous ammonium chloride solution (7 mL) and zinc (3.75 g, 57.4 mmol), and the mixture was heated at 80 ° C. for 2 hours. Stir. The reaction mixture was filtered through a Celite (registered trademark) pad and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain Compound 20 (1.75 g, 79%).
¹ H NMR (DMSO-d ₆ ,, 300 MHz, δ; ppm) 8.32 (s, 1 H), 7.17 (d, J = 8.4 Hz, 1 H), 6.86 (d, J = 2.1 Hz, 1 H) , 6.65 (dd, J = 2.1, 8.4 Hz. 1 H), 5.16 (s, 2 H), 1.46 (s, 9 H); ¹³ C NMR (DMSO-d ₆ , 75 MHz, δ; ppm) 153.9, 143.4, 126.3, 123.5, 118.8, 117.8, 117.3, 79.4, 28.6.
Step 3 Synthesis of Compound 21

Compound 20 (256.1 mg, 0.892 mmol) in N, N-dimethylformamide solution (10 ml) was added compound 24 (151.8 mg, 1.04 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Salt (232.5 mg, 1.21 mmol) and 1-hydroxybenzotriazole monohydrate (151.3 mg, 1.12 mmol) were sequentially added, and the mixture was stirred at room temperature for 13.5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain Compound 21 (326.4 g, 88%).
¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.90 (s, 1 H), 8.82 (s, 1 H), 7.96 (d, J = 8.4 Hz, 2 H), 7.74 (d, J = 2.4 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 2 H), 7.55 (d, J = 8.7 Hz, 1 H), 7.39 (dd, J = 2.4, 8.7 Hz. 1 H), 4.43 (s, 1 H), 1.44 (s, 9 H); ¹³ C NMR (DMSO-d ₆ , 75 MHz, δ; ppm) 165.2, 153.7, 134.6, 132.4, 132.2, 131.9, 131.3, 129.9, 129.0, 128.8 , 128.5, 125.7, 125.6, 115.6, 83.7, 83.2, 80.4, 28.5.
Step 4 Synthesis of Compound 22

To a mixed solvent of dimethyl sulfoxide (8 mL) and water (2 mL), compound 21 (326.4 mg, 0.786 mmol), copper (II) sulfate pentahydrate (93.6 mg, 0.375 mmol), sodium ascorbate ( 144.3 mg, 0.728 mmol) and compound 25 (227.5 mg, 1.15 mmol) were added and stirred at 50 ° C. for 18.5 hours. The reaction mixture was filtered through a Celite (registered trademark) pad, brine was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate alone) to obtain Compound 22 (250.4 mg, 52%).
¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.92 (s, 1 H), 8.86 (s, 1 H), 8.74 (s, 1 H), 8.05 (s, 4 H), 7.75- 7.88 (m, 3 H), 7.64-7.69 (m, 2 H), 7.55 (d, J = 8.7 Hz, 1 H), 7.39 (dd, J = 2.4, 8.7 Hz, 1 H), 6.41 (s, 2 H), 1.46 (s. 9 H); ¹³ C NMR (DMSO-d ₆ , 75 MHz, δ; ppm) 165.5, 153.7, 146.2, 136.4, 135.4, 134.0, 133.6, 131.8, 131.5, 130.1, 129.02 and 128.98, 128.9 128.7, 125.9, 125.7, 124.4, 115.8, 80.4, 67.8, 28.5; ESI-MS (m / z): 612.1 [M + H] ⁺ .
Step 5 Synthesis of Compound I-012

To a mixed solution of compound 22 (261.4 mg, 0.427 mmol) in tetrahydrofuran (4 mL) and water (2 mL) was added sodium carbonate (68.4 mg, 0.645 mmol), tri (o-tolyl) phosphine (26.0 mg, 0.0854 mmol), and 2-furanylboronic acid (62.1 mg, 0.555 mmol) were added. Nitrogen gas was blown into the reaction solution for 5 minutes, tetrakis (triphenylphosphine) palladium (30.6 mg, 0.0265 mmol) was added, and the mixture was heated to reflux for 17 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was dried using anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain Compound 23 (76.2 mg, 30%).
To a dichloromethane solution (5 mL) of compound 23 (76.2 mg, 0.127 mmol) was added trifluoroacetic acid (500 μL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with a saturated aqueous sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The organic layer was dried using anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate alone) to obtain Compound I-012 (33.8 mg, 53%).
¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.77 (s, 1 H), 8.71 (s, 1 H), 8.11 (d, J = 8.7 Hz, 2 H), 8.02 (d, J = 8.7 Hz, 2 H), 7.75-7.79 (m, 3 H), 7.55-7.69 (m, 3 H), 7.34 (dd, J = 2.1, 8.4 Hz, 1 H), 6.83 (d, J = 8.4 Hz, 1 H), 6.62 (dd, J = 0.6, 3.3 Hz, 1 H), 6.51 (dd, J = 1.0, 3.3 Hz, 1 H), 6.40 (s, 2 H), 5.18 (s, 2 H ); ¹³ C NMR (DMSO-d ₆ , 75 MHz, δ; ppm) 165.5, 154.3, 146.4, 143.5, 141.7, 136.5, 135.4, 134.5, 133.2, 130.1, 129.1, 129.0, 125.5, 124.2, 123.7, 122.9, 119.7, 116.7, 112.2, 102.9, 67.8; ESI-MS (m / z): 500.3 [M + H] ⁺ .

The following compounds were synthesized in the same manner as described above.

Examples Compound I-006

¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.73 (s, 1 H), 8.71 (s, 1 H), 7.95-8.15 (m, 4 H), 8.09 (d, J = 8.7 Hz , 2 H), 8.00 (d, J = 8.7 Hz, 2 H), 7.75-7.84 (m, 3 H), 7.64-7.69 (m, 2 H), 7.25 (d, J = 2.2 Hz, 1 H) , 7.07 (dd, J = 2.2, 8.4 Hz, 1 H), 6.75 (d, J = 8.9 Hz, 1 H), 6.40 (s, 2 H), 5.96-5.98 (m, 1 H), 4.93 (s , 2 H), 2.30-2.31 (m, 2 H), 2.14-2.16 (m, 2 H), 1.67-1.72 (m, 2 H), 1.56-1.62 8 m, 2 H); ¹³ C NMR (DMSO- d ₆ , 75 MHz, δ; ppm) 165.3, 146.4, 142.4, 136.5, 135.8, 135.4, 134.6, 133.1, 130.8, 130.1, 129.0, 125.5, 124.1, 123.4, 123.3, 121.1, 116.4, 67.8, 27.2, 25.7, 23.2, 22.4; ESI-MS (m / z): 514.3 [M + H] ⁺

Examples Compound I-007

¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.80 (s, 1 H), 8.71 (s, 1 H), 8.12 (d, J = 8.1 Hz, 2 H), 8.02 (d, J = 8.1 Hz, 2 H), 7.75-7.85 (m, 3 H), 7.76-7.82 (m, 3 H), 7.64-7.69 (m, 2 H), 7.56-7.59 (m, 3H), 7.33-7.43 (m, 3 H), 7.25-7.28 (m, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 6.40 (s, 2 H), 5.12 (s, 2 H); ¹³ C NMR ( DMSO-d ₆ , 75 MHz, δ; ppm) 165.4, 146.4, 143.3, 140.7, 136.5, 135.4, 134.6, 133.1, 130.1, 129.3, 129.1, 129.0, 128.6, 126.5, 126.0, 125.5, 125.3, 125.2, 124.2, 124.0, 117.0, 67.8; ESI-MS (m / z): 510.3 [M + H] ⁺ .

Examples Compound I-008

¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.81 (s, 1 H), 8.72 (s, 1 H), 8.10 (d, J = 8.5 Hz, 2 H), 8.02 (d, J = 8.5 Hz, 2 H), 7.73-7.82 (m, 3 H), 7.50-7.70 (m, 4 H), 7.30 (dd, J = 2.2, 8.4 Hz, 1 H), 7.25 (t, J = 9.0 Hz, 2 H), 6.87 (d, J = 8.4 Hz, 1 H), 6.40 (s, 2 H), 5.13 (s, 2 H); ¹³ C NMR (DMSO-d ₆ , 75 MHz, δ; ppm ) 165.5, 163.2, 160.0, 146.4, 143.3, 137.3, 137.2, 136.5, 135.5, 134.6, 133.2, 130.1, 129.2, 129.1, 127.9, 127.8, 127.7, 125.6, 125.4, 125.3, 124.3, 124.0, 117.1, 116.2, 115.9 , 67.8; ESI-MS (m / z): 528.3 [M + H] ⁺ .

Examples Compound I-009

¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.79 (s, 1 H), 8.71 (s, 1 H), 8.11 (d, J = 8.4 Hz, 2 H), 8.02 (d, J = 8.4 Hz, 2 H), 7.78-7.82 (m, 3 H), 7.56-7.77 (m, 5 H), 7.44 (d, J = 8.4 Hz, 2 H), 7.35 (dd, J = 2.1, 8.4 Hz, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 6.40 (s, 2 H), 5.19 (s, 2 H); ¹³ C NMR (DMSO-d ₆ , 75 MHz, δ; ppm ) 165.5, 146.4, 143.7, 139.5, 136.5, 135.4, 134.6, 133.2, 131.1, 130.1, 129.2, 129.1, 129.0, 127.6, 127.1, 125.5, 125.3, 125.2, 124.2, 124.0, 116.9, 67.8; ESI-MS (m / z): 544.0 [M + H] ⁺ .

Examples Compound I-010

¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 10.97 (s, 1 H), 9.79 (s, 1 H), 8.72 (s, 1 H), 8.11 (d, J = 8.4 Hz, 2 H), 8.02 (d, J = 8.4 Hz, 2 H), 7.76-7.84 (m, 3 H), 7.64-7.69 (m, 2 H), 7.44 (s, 1 H), 7.28 (d, J = 6.9 Hz, 1 H), 6.78 (d, J = 8.1 Hz, 1 H), 6.71 (s, 1 H), 6.40 (s, 2 H), 6.25 (s, 1 H), 6.04 (d, 1 H ), 4.90 (s, 2 H); ¹³ C NMR (DMSO-d ₆ , 75 MHz, δ; ppm) 165.3, 146.4, 141.9, 136.5, 135.4, 134.6, 133.1, 132.7, 132.5, 132.2, 130.1, 129.9, 129.0, 126.4, 126.2, 125.6, 124.2, 123.9, 122.9, 118.1, 116.8, 109.1, 103.6, 67.8; ESI-MS (m / z): 499.1 [M + H] ⁺ .

Examples Compound I-011

¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.78 (s, 1 H), 8.71 (s, 1 H), 8.29 (s, 1 H), 8.11 (d, J = 8.7 Hz, 2 H), 8.02 (d, J = 8.7 Hz, 2 H), 7.75-7.85 (m, 3 H), 7.61-7.72 (m, 2 H), 7.54-7.60 (m, 1 H), 7.34-7.39 ( m, 2 H), 6.86 (d, J = 8.4 Hz, 1 H), 6.39 (s, 2 H), 5.34 (s, 2 H); ¹³ C NMR (DMSO-d ₆ , 75 MHz, δ; ppm ) 165.6, 151.7, 150.8, 146.4, 144.5, 136.5, 135.4, 134.5, 133.2, 132.4, 131.9, 131.7, 130.1, 129.4, 129.2, 129.1, 129.0, 125.5, 124.2, 123.7, 123.6, 123.5, 119.2, 116.6, 116.1 , 67.8; ESI-MS (m / z): 501.3 [M + H] ⁺ .

Examples Compound I-013

¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.79 (s, 1 H), 8.71 (s, 1 H), 8.73 (s, 1 H), 8.11 (d, J = 8.7 Hz, 2 H), 7.82-7.97 (m, 3 H), 7.75-7.80 (m, 3 H), 7.64-7.69 (m, 3 H), 7.41 (d, J = 2.1 Hz, 1 H), 7.25 (dd, J = 2.4, 8.4 Hz, 1 H), 6.82-6.83 (m, 2 H), 6.40 (s, 2 H), 5.00 (s, 2 H); ¹³ C NMR (DMSO-d ₆ , 75 MHz, δ Ppm) 165.3, 146.4, 144.3, 143.0, 137.8, 136.5, 135.4, 134.5, 133.1, 130.1, 129.0, 126.4, 125.5, 124.7, 124.6, 124.2, 123.9, 120.7, 116.8, 109.0, 67.8; ESI-MS (m / z): 500.3 [M + H] ⁺ .

Examples Compound I-014

¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.78 (s, 1 H), 8.71 (s, 1 H), 8.10 (d, J = 8.4 Hz, 2 H), 8.01 (d, J = 8.4 Hz, 2 H), 7.75-7.85 (m, 3 H), 7.60-7.70 (m, 2 H), 7.42 (d, J = 2.1 Hz, 1 H), 7.23 (dd, J = 2.1, 8.4 Hz, 1 H), 7.03 (d, J = 3.6 Hz, 1 H), 6.81 (d, J = 8.4 Hz, 1 H), 6.73 (d, J = 2.4 Hz, 1 H), 6.40 (s, 2 H), 5.12 (s, 2 H), 2.43 (s, 3 H); ¹³ C NMR (DMSO-d ₆ , 75 MHz, δ; ppm) 165.4, 146.4, 143.2, 142.3, 137.0, 136.5, 135.4, 134.5 , 133.2, 130.1, 129.1, 129.0, 126.9, 125.5, 124.2, 124.1, 124.0, 123.8, 123.1, 121.2, 116.9, 67.8, 15.5; ESI-MS (m / z): 530.3 [M + H] ⁺ .

Examples Compound I-015

¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.78 (s, 1 H), 8.72 (s, 1 H), 8.11 (d, J = 8.9 Hz, 2 H), 8.02 (d, J = 8.8 Hz, 2 H), 7.76-7.84 (m, 3 H), 7.64-7.69 (m, 2 H), 7.44 (s, 1 H), 7.27 (dd, J = 2.1, 8.4 Hz, 1 H) , 7.08 (s, 1 H), 6.93 (s, 1 H), 6.81 (d, J = 8.2 Hz, 1 H), 6.40 (s, 2 H), 5.17 (s, 2 H), 2.20 (s, 3 H); ¹³ C NMR (DMSO-d ₆ , 75 MHz, δ; ppm) 165.4, 146.4, 144.3, 143.4, 138.5, 136.5, 135.4, 133.2, 130.1, 129.1, 129.0, 125.5, 124.2, 123.8, 122.9, 118.7, 116.8, 67.8, 16.0; ESI-MS (m / z): 530.2 [M + H] ⁺ .

Examples Compound I-016

¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.77 (s, 1 H), 8.71 (s, 1 H), 8.11 (d, J = 8.4 Hz, 2 H), 8.02 (d, J = 8.4 Hz, 2 H), 7.75-7.84 (m, 3 H), 7.64-7.69 (m, 2 H), 7.49 (d, J = 2.1 Hz, 1 H), 7.28 (dd, J = 2.1, 8.4 Hz, 1 H), 6.81 (d, J = 8.4 Hz, 1 H), 6.48 (d, J = 3.0 Hz, 1 H), 6.40 (s, 2 H), 6.10 (d, J = 1.2 Hz, 1 H), 5.12 (s, 2 H), 2.31 (s, 3 H); ¹³ C NMR (DMSO-d ₆ , 75 MHz, δ; ppm) 165.4, 152.6, 150.3, 146.4, 143.0, 136.5, 135.4, 134.5 , 133.1, 130.1, 129.1, 129.0, 125.5, 124.2, 123.7, 122.3, 120.1, 116.7, 108.2, 103.7, 67.8, 13.9; ESI-MS (m / z): 514.1 [M + H] ⁺ .

Examples Compound I-017

¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.77 (s, 1 H), 8.71 (s, 1 H), 8.10 (d, J = 8.1 Hz, 2 H), 8.02 (d, J = 8.1 Hz, 2 H), 7.78-7.84 (m, 3 H), 7.64-7.69 (m, 2 H), 7.50 (s, 1 H), 7.26 (d, J = 8.4 Hz, 1 H), 6.82 (d, J = 8.4 Hz, 1 H), 6.60 (t, J = 3.3 Hz, 1 H), 6.40 (s, 2 H), 5.80 (dd, J = 3.3, 6.6 Hz, 1 H), 5.22 ( s, 2 H); ¹³ C NMR (DMSO-d ₆ , 75 MHz, δ; ppm) 165.5, 154.6, 146.4, 145.1, 143.6, 136.5, 135.4, 134.5, 133.2, 130.1, 129.1, 129.0, 125.5, 124.2, 123.7, 122.3, 118.5, 116.7, 103.8, 67.8; ESI-MS (m / z): 518.1 [M + H] ⁺ .

Examples Compound I-018

¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.80 (s, 1 H), 8.71 (s, 1 H), 8.10 (d, J = 8.5 Hz, 2 H), 8.01 (d, J = 8.5 Hz, 2 H), 7.65-7.82 (m, 3 H), 7.65-7.70 (m, 2 H), 7.40-7.55 (m, 2 H), 7.25-7.50 (m, 4 H), 6.88 ( d, J = 8.4 Hz, 1 H), 6.40 (s, 2 H), 5.20 (s, 2 H); ESI-MS (m / z): 528.3 [M + H] ⁺ .

Examples Compound I-019

¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.81 (s, 1 H), 8.81 (d, J = 2.1 Hz, 1 H), 8.71 (s, 1 H), 8.45 (dd, J = 1.5, 4.8 Hz, 1 H), 8.12 (d, J = 8.7 Hz, 2 H), 8.02 (d, J = 8.7 Hz, 2 H), 7.93-7.99 (m, 1 H), 7.74-7.85 ( m, 3 H), 7.63-7.70 (m, 2 H), 7.60 (d, J = 2.1 Hz, 1 H), 7.38-7.45 (m, 2 H), 6.92 (d, J = 8.4 Hz, 1 H ), 6.40 (s, 2 H), 5.24 (s, 2 H); ESI-MS (m / z): 511.3 [M + H] ⁺ .

Examples Compound I-020

¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.72 (s, 1 H), 8.71 (s, 1 H), 8.07 (d, J = 8.7 Hz, 2 H), 8.01 (d, J = 8.7 Hz, 2 H), 7.74-7.85 (m, 3 H), 7.62-7.70 (m, 2 H), 7.18 (dd, J = 2.7, 10.2 Hz, 1 H), 6.75-6.89 (m, 2 H), 6.40 (s, 2 H), 4.87 (s, 2 H); ESI-MS (m / z): 452.3 [M + H] ⁺ .

Reference Example Compound B

¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.76 (s, 1 H), 8.69 (s, 1 H), 8.55-8.53 (m, 1 H), 8.09 (d, J = 8.4 Hz , 2 H), 7.96 (d, J = 8.4 Hz, 2H), 7.72 (td, J = 1.8, 7.8 Hz, 1 H), 7.50 (d, J = 2.1 Hz, 1H), 7.38-7.24 (m, 5 H), 7.06 (dd, J = 3.6, 5.1 Hz, 1 H), 6.83 (d, J = 8.4 Hz, 1 H), 5.17 (s, 2 H), 4.85 (t, J = 7.2 Hz, 2H ), 3.42 (t, J = 7.2 Hz, 2H); ¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 157.2, 149.2, 145.4, 144.2, 143.0, 136.2, 133.6, 133.5, 128.5, 128.2, 124.7, 124.0, 123.4, 123.2, 122.3, 122.3, 121.9, 121.0, 116.4, 48.9, 37.43; ESI-MS (m / z): 467.1 [M + H] ⁺ .

Reference Example Compound C

¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.78 (d, J = 2.1 Hz, 1 H), 8.55 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H), 7.99 ( d, J = 8.4 Hz, 2 H), 7.64-7.56 (m, 5 H), 7.50 (d, J = 2.1 Hz, 1H), 7.36 (dd, J = 1.2, 5.1 Hz, 1 H), 7.31 ( dd, J = 2.1, 8.4 Hz, 1H), 7.26 (dd, 1.2, 3.6 Hz, 1H), 7.06 (dd, 3.6, 5.1 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1 H), 6.00 (d, J = 13.2 Hz, 1H), 5.76 (d, J = 13.2 Hz, 1H), 5.17 (s, 2 H): ¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 167.1, 149.8, 145.4 , 144.2, 143.0, 140.2, 133.8, 133.0, 131.7, 129.3, 128.6, 128.2, 124.9, 124.3, 124.0, 123.5, 123.3, 123.2, 122.3, 121.0, 116.4, 68.7; ESI-MS (m / z): 500.1 [ M + H] ⁺ .

Reference Example Compound A

¹ H NMR (DMSO-d ₆ , 300 MHz, δ; ppm) 9.79 (s, 1 H), 8.71 (s, 1 H), 8.11 (d, J = 8.4 Hz, 2 H), 8.12 (d, J = 8.4 Hz, 2 H), 7.84-7.75 (m, 3 H), 7.69-7.64 (m, 2 H), 7.50 (d, J = 2.1 Hz, 1 H), 7.36 (dd, J = 1.2, 5.1 Hz, 1 H), 7.31 (dd, J = 2.1, 8.4 Hz, 1 H), 7.26 (dd, J = 1.2, 3.6 Hz, 1 H), 7.06 (dd, J = 3.6, 5.1 Hz, 1 H) , 6.83 (d, J = 8.4 Hz, 1 H), 6.40 (s, 2 H), 5.17 (s, 2 H); ¹³ C NMR (CDCl ₃ , 75 MHz, δ; ppm) 147.4, 146.5, 145.9, 143.1, 136.0, 134.9, 134.0, 137.8, 129.6, 128.6, 128.5, 128.2, 125.0, 124.0, 123.2, 122.3, 121.0, 116.4, 67.6; ESI-MS (m / z): 516.1 [M + H] ⁺ .

Hereinafter, biological test examples of the compounds of the present invention will be described.

(Test Example 1: HDAC1 and HDAC2 binding inhibition test)
Each enzymological parameter in the model shown in the following formula was calculated. E indicates an enzyme, I indicates an inhibitor, and E: I indicates a complex of the enzyme and the inhibitor (slow-binding A and slow-binding B). In the model in which a structural change occurs in a more stable complex after the enzyme-inhibitor complex is formed, E: I ^* indicates the stable complex (slow-binding B). The rate constant k ₁ is the rate constant in the complex formation of the enzyme and the inhibitor, the rate constant k ₋₁ is the dissociation rate constant of the enzyme and the inhibitor, and the rate constant k ₂ is the structure change to a stable complex. The rate constant and the rate constant k- ₂ indicate the rate constant when returning from the stable complex to the original complex. Furthermore, K _i represents an inhibition constant, and K _i ^* represents an apparent inhibition constant when a structural change occurs in a more stable complex after formation of the enzyme-inhibitor complex.

(Each experimental condition)
HDAC1 (SignalChem, H83-30G), HDAC2 (SignalChem, H84-30G), fluorescent substrate (AcLGK (Ac) -AMC), kinetic HDAC assay developer (BPS, # 53029), HDAC assayBPS # 5 Using.
Using an HDAC assay buffer, a 2 ng / μL enzyme solution and a developer solution (diluted 20 times) were prepared. In addition, a fluorescent substrate was dissolved using an assay buffer containing 5% DMSO to prepare a 200 μM substrate solution. Further, an inhibitor solution was prepared using an assay buffer containing 10% DMSO.
In a 96-well plate, 20 μL of the enzyme solution was added to a mixture of 10 μL of the inhibitor solution, 20 μL of the substrate solution, and 50 μL of the developer solution. Under the condition of 30 ° C., the release of the fluorophore in each well was detected by measuring the fluorescence and continuously recorded every 2 minutes.
Using Grapfit 7.0 software, the concentration of the enzyme reaction product was calculated using fluorescence data obtained by subtracting the background value, and it was confirmed whether the calculated value could be approximated to equation (2). When approximated to the equation (2), further check the approximation to the equation (3) (slow-binding A) or the approximation to the equations (4) and (5) (slow-binding B), The target enzymological parameters were calculated accordingly. Here, the concentration and the enzyme reaction rate of the enzyme reaction product in [P] and V _s respectively time t. V ₀ represents the initial rate of the enzyme reaction, k _obs represents the apparent rate constant, K _m represents the Michaelis constant, [S] represents the substrate concentration, and [I] represents the inhibitor concentration.

[P] = V _s t + (V ₀ −V _s ) (1−exp (−k _obs t)) / k _obs (2)
k _obs = k ₁ (1+ [S] / K _m ) [I] + k ₋₁ (3)
k _obs = k ₂ [I] / ([I] + K _i ^* (1+ [S] / K _m ) + k ₋₂ (4)
K _i = K _i ^* {k ₋₂ / (k ₂ + k ₋₂ )} (5)

The test results of the compounds of the present invention and comparative examples are shown in the following table. In Tables 1 to 3 and Table 5, the rate constant was calculated with n = 3. In Table 4, the rate constant was calculated with n = 1.

(Test Example 2: CYP inhibition test)
Using commercially available pooled human liver microsomes, O-deethylation of 7-ethoxyresorufin (CYP1A2), a typical substrate metabolic reaction of the major human CYP5 species (CYP1A2, 2C9, 2C19, 2D6, 3A4), Methyl-hydroxylation (CYP2C9), mephenytoin 4′-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenadine hydroxylation (CYP3A4) are used as indicators. The degree of inhibition by the compound of the present invention is evaluated.

The reaction conditions were as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 μmol / L (4 points) .

In a 96-well plate, 5 kinds of each substrate, human liver microsome, and the compound of the present invention are added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH as a coenzyme is added to start a metabolic reaction as an index. After reacting at 37 ° C. for 15 minutes, the reaction is stopped by adding a methanol / acetonitrile = 1/1 (V / V) solution. After centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the centrifugation supernatant was quantified with a fluorescent multilabel counter or LC / MS / MS, and tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxylated. The body (CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite), and terfenadine alcohol (CYP3A4 metabolite) are quantified by LC / MS / MS. The dilution concentration and the dilution solvent are changed as necessary.

A control solution (100%) was obtained by adding only DMSO, which is a solvent in which the compound was dissolved, instead of the compound of the present invention to the reaction solution, and the residual activity (%) was calculated. IC ₅₀ is calculated by inverse estimation.

(Test Example 3: CYP3A4 (MDZ) MBI test)
The CYP3A4 inhibition of the compound of the present invention is a test for evaluating the mechanism based inhibition (MBI) ability from the enhancement of the inhibitory action resulting from the metabolic reaction of the compound of the present invention. Pooled human liver microsomes are used to evaluate CYP3A4 inhibition using midazolam (MDZ) 1-hydroxylation as an indicator.

The reaction conditions are as follows: substrate, 10 μmol / L MDZ; pre-reaction time, 0 or 30 minutes; substrate metabolic reaction time, 2 minutes; reaction temperature, 37 ° C .; pooled human liver microsomes, 0.5 mg / mL during pre-reaction, 0.05 mg / mL at the time of reaction (at 10-fold dilution); concentration at the time of pre-reaction of the compound of the present invention 1, 5, 10, 20 μmol / L (4 points).

A pooled human liver microsome and the compound solution of the present invention were added to a 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the composition of the above-mentioned pre-reaction, and K-Pi containing the substrate was added to another 96-well plate. A part of the solution was transferred so that it was diluted to 1/10 with the buffer solution, and NADPH as a coenzyme was added to start a reaction as an index (Preincubation 0 min). After a predetermined time reaction, methanol / acetonitrile = 1 The reaction is stopped by adding a 1/1 (V / V) solution. In addition, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (Preincubation 30 min), and after pre-reaction for a predetermined time, the plate is diluted to 1/10 with K-Pi buffer containing the substrate on another plate. Start the reaction with the part as the indicator. After the reaction for a predetermined time, the reaction is stopped by adding a methanol / acetonitrile = 1/1 (V / V) solution. The plate on which each index reaction has been performed is centrifuged at 3000 rpm for 15 minutes, and 1-hydroxymidazolam in the centrifuged supernatant is quantified by LC / MS / MS. The dilution concentration and the dilution solvent are changed as necessary.

A control (100%) was obtained by adding only DMSO, which is a solvent in which the compound was dissolved, instead of the compound of the present invention to the reaction solution, and calculating the residual activity (%) when each concentration of the compound of the present invention was added, Using the concentration and the inhibition rate, IC is calculated by inverse estimation using a logistic model. Preincubation 0 min IC / Preincubation 30 min IC is the Shifted IC value, and if the Shifted IC is 1.5 or more, it is “Positive”, and if the Shifted IC is 1.0 or less, it is “Negative”.

(Test Example 4: BA test)
Study Material and Method for Oral Absorption (1) Animal used: Mouse or rat is used.
(2) Breeding conditions: Mice or rats are allowed to freely take solid feed and sterilized tap water.
(3) Setting of dosage and grouping: oral administration and intravenous administration at a predetermined dosage. Set the group as follows. (Dose may vary for each compound)
Oral administration 2-60 μmol / kg or 1-30 mg / kg (n = 2-3)
Intravenous administration 1-30 μmol / kg or 0.5-10 mg / kg (n = 2-3)
(4) Preparation of administration solution: Oral administration is administered as a solution or suspension. Intravenous administration is administered after solubilization.
(5) Administration method: Oral administration is forcibly administered into the stomach with an oral sonde. Intravenous administration is performed from the tail vein using a syringe with an injection needle.
(6) Evaluation item: Blood is collected over time, and the concentration of the compound of the present invention in plasma is measured using LC / MS / MS.
(7) Statistical analysis: The plasma concentration-time curve area (AUC) was calculated by the non-linear least square method for plasma compound concentration transition, and the dose ratio and AUC ratio of the oral administration group and intravenous administration group were calculated. From the above, the bioavailability (BA) of the compound of the present invention is calculated.
The dilution concentration and the dilution solvent are changed as necessary.

(Test Example 5: Clearance evaluation test)
Experimental Materials and Methods (1) Animals used: SD rats are used.
(2) Breeding conditions: SD rats are allowed to freely take solid feed and sterilized tap water.
(3) Setting of dosage and grouping: Intravenous administration is administered at a predetermined dosage. Set the group as follows.
Intravenous administration 1 μmol / kg (n = 2)
(4) Preparation of dosing solution: dimethyl sulfoxide / propylene glycol = 1/1 solubilized and used.
(5) Administration method: Administer from the tail vein using a syringe with an injection needle.
(6) Evaluation item: Blood is collected over time, and the concentration of the compound of the present invention in plasma is measured using LC / MS / MS.
(7) Statistical analysis: Whole body clearance (CLtot) is calculated by moment analysis method for plasma concentration of the compound of the present invention. The dilution concentration and the dilution solvent are changed as necessary.

(Test Example 6: Metabolic stability test)
A commercially available pooled human liver microsome is reacted with the compound of the present invention for a certain period of time, and the residual ratio is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver.

A commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual rate is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver.

In 0.2 mL buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL human liver microsomes in the presence of 1 mmol / L NADPH React at 37 ° C. for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction solution is added to 100 μL of a methanol / acetonitrile = 1/1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the supernatant was quantified by LC / MS / MS or solid phase extraction (SPE) / MS, and the remaining amount of the compound of the present invention after the reaction was defined as 100% at 0 minutes. calculate. The hydrolysis reaction is carried out in the absence of NADPH, the glucuronic acid conjugation reaction is carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation is carried out thereafter. The dilution concentration and dilution solvent are changed as necessary.

(Test Example 7: Fluctuation Ames Test)
The mutagenicity of the compound of the present invention is evaluated.
20 μL of Salmonella typhimurium TA98 strain, TA100 strain, which has been cryopreserved, is inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For strain TA98, 7.70 to 8.00 mL of the bacterial solution is centrifuged (2000 × g, 10 minutes) to remove the culture solution. Micro F buffer (K ₂ HPO ₄ : 3.5 g / L, KH ₂ PO ₄ : 1 g / L, (NH ₄ ) ₂ SO ₄ : 1 g / L, citrate Bacteria were suspended in sodium dihydrate: 0.25 g / L, MgSO ₄ · 7H ₂ 0: 0.1 g / L, and 120 mL Exposure medium (biotin: 8 μg / mL, histidine: 0.2 μg / mL, Glucose: MicroF buffer containing 8 mg / mL). For the TA100 strain, add 3.10 to 3.42 mL of bacterial solution to 120 to 130 mL of Exposure medium to prepare a test bacterial solution. Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at a 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 μg / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 μg / mL 2-aminoanthracene DMSO solution for the strain and 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 μL of the test bacterial solution (under the metabolic activation conditions, 498 μL of the test bacterial solution and S9 mix 90 μL of the mixture) and incubate with shaking at 37 ° C. for 90 minutes. 460 μL of the bacterial solution exposed to the compound of the present invention was added to 2300 μL of indicator medium (BioF: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL). 50 μL each, and dispense into microwells at 48 wells / dose, followed by static culture at 37 ° C. for 3 days. Since wells containing bacteria that have acquired growth ability due to mutation of the amino acid (histidine) synthase gene change from purple to yellow due to pH change, the number of bacterial growth wells that changed to yellow in 48 wells per dose was counted. Evaluation is made in comparison with the negative control group. Those with negative mutagenicity are shown as (−), and those with positive mutagenicity are shown as (+).
The dilution concentration and the dilution solvent are changed as necessary.

(Test Example 8: hERG test)
Delayed rectification plays an important role in ventricular repolarization process using CHO cells expressing human ether-a-go-go related gene (hERG) channel for the purpose of assessing the risk of prolonging the electrocardiogram QT interval of the compound of the present invention The effect of the compounds of the present invention on the K ⁺ current (I _Kr ) will be examined.
Using a fully automatic patch clamp system (QPatch; Sophion Bioscience A / S), the cell was held at a membrane potential of −80 mV by the whole cell patch clamp method, and after giving a leak potential of −50 mV, depolarization stimulation of +20 mV for 2 seconds, further records the _{I Kr} induced repolarization stimulated when given 2 seconds -50 mV. Extracellular fluid adjusted to 0.1% dimethyl sulfoxide (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl ₂ : 2 mmol / L, MgCl ₂ : 1 mmol / L, glucose: 10 mmol / L , HEPES (4- (2-hydroxyethyl) -1-piperazine etheresufonic acid, 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7.4) The extracellular solution in which the compound of the invention is dissolved at the target concentration is applied to the cells for 7 minutes or longer at room temperature. From the obtained I _Kr , the absolute value of the maximum tail current is measured based on the current value at the holding membrane potential by using analysis software (QPatch Assay software; Sophion Bioscience A / S). Further, the maximum tail current after application of the compound of the present invention relative to the maximum tail current after application of the medium is calculated as an inhibition rate, and the influence of the compound of the present invention on I _Kr is evaluated. The dilution concentration and the dilution solvent are changed as necessary.

(Test Example 8: Solubility test)
The solubility of the compound of the present invention is determined under the condition of adding 1% DMSO. A 10 mmol / L compound solution is prepared in DMSO. 2 μL of the compound solution of the present invention is added to 198 μL of JP-1 solution and JP-2 solution, respectively. After shaking for 1 hour at room temperature, the mixture is filtered with suction. The filtrate was diluted 10 or 100 times with methanol / water = 1/1 (V / V) or acetonitrile / methanol / water = 1/11/2 (V / V / V), and LC / MS was determined by the absolute calibration curve method. Alternatively, the concentration in the filtrate is measured using solid phase extraction (SPE) / MS. The dilution concentration and the dilution solvent are changed as necessary.

The composition of JP-1 solution is as follows.
Add water to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to make 1000 mL.
The composition of JP-2 solution is as follows.
1 volume of water is added to 1 volume of 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in water to 1000 mL.

(Test Example 8: Powder solubility test)
An appropriate amount of the compound of the present invention is put in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to make 1000 mL), JP-2 solution (potassium dihydrogen phosphate 3 .40 g and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in water to make 1000 mL, add 1 volume of water to 1 volume), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (1.08 g of TCA to JP -2 solution is added to make 100 mL) 200 μL at a time. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C. for 1 hour, the mixture is filtered, and 100 μL of methanol is added to 100 μL of each filtrate to perform 2-fold dilution. Change the dilution factor as necessary. Check for bubbles and deposits, seal and shake. The compound of the present invention is quantified using HPLC by the absolute calibration curve method. The dilution concentration and the dilution solvent are changed as necessary.

(Test Example 9: Ames test)
The mutagenicity of the compound of the present invention is evaluated by the Ames test using Salmonella typhimurium TA98, TA100, TA1535, TA1537, and Escherichia coli WP2uvrA as test strains. In a DMSO solution of the compound of the present invention, 0.5 mL of S9mix is mixed under metabolic activation conditions, and 0.5 mL of a phosphate buffer and 0.1 mL of a test bacterial solution are mixed under non-metabolic activation conditions, and histidine and biotin are mixed. Overlay on a minimal glucose agar plate with 2 mL of layered soft agar containing tryptophan. At the same time for negative control substance (DMSO) and positive control substance (2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide, sodium azide, 9-aminoacridine, or 2-aminoanthracene) The same applies. After culturing at 37 ° C. for 48 hours, the appeared revertant colonies are counted and evaluated by comparison with the negative control group. A case where the number of revertant colonies increases in a concentration-dependent manner and is more than twice the number of colonies in the negative control group is judged as positive (+). The dilution concentration and the dilution solvent are changed as necessary.

(Test Example 10: Photohemolysis test)
The compound of the present invention is dissolved at a desired concentration, and mixed with 0.1 to 0.0008% concentration of erythrocyte suspension (2.5 v / v%) prepared from sheep defibrinated blood on a microplate, and ultraviolet fluorescent. Light irradiation (10 J / cm ² , 290 to 400 nm) was performed in the UVA and UVB regions using a lamp (GL20SE lamp, Sankyo Electric and FL20S-BLB lamp, Panasonic). Collect the mixture after the light irradiation and centrifuge. The supernatant after centrifugation is collected and transferred to a microplate, and then the absorbance (540 or 630 nm) of the supernatant is measured and a determination based on the absorbance is performed. Absorbance at 540 and 630 nm is an indicator of biological membrane damage (photohemolysis rate%) and lipid membrane peroxidation (methemoglobin production), respectively. The case where the photohemolysis rate is less than 10% and the amount of change in absorbance at 630 nm is less than 0.05 is (−), the photohemolysis rate is 10% or more, and the amount of change in absorbance at 630 nm is 0. The case of 05 or more is defined as (+).

(Test Example 11: P-gp substrate test)
The compound of the present invention is added to one side of a transwell (registered trademark, CORNING) obtained by monolayer culture of human MDR1-expressing cells or parent cells, and allowed to react for a certain period of time. For MDR1-expressing cells and parent cells, the membrane permeability coefficient was calculated from the axial side to the basolateral side (A → B) and from the basolateral side to the apical side (B → A), and the Efflux Ratio (ER; Calculate the ratio of B → A and A → B membrane permeability coefficient). The Efflux Ratio (ER value) between the MDR1-expressing cell and the parent cell is compared to determine whether the compound of the present invention is a P-gp substrate.

The following formulation examples are merely illustrative and are not intended to limit the scope of the invention in any way.
The compounds of the invention may be administered topically by any conventional route, in particular enterally, for example orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injections or suspensions. Thus, for example, it can be administered as a pharmaceutical composition in the form of a lotion, gel, ointment or cream, or in the form of a nasal or suppository. A pharmaceutical composition comprising a compound of the invention in free form or in the form of a pharmaceutically acceptable salt, together with at least one pharmaceutically acceptable carrier or diluent, is mixed in a conventional manner, It can be produced by granulation or coating methods. For example, an oral composition can be a tablet, granule, or capsule containing an excipient, a disintegrant, a binder, a lubricant and the like and an active ingredient. The injectable composition may be a solution or suspension, may be sterilized, and may contain preservatives, stabilizers, buffering agents, and the like.

The compound according to the present invention has an HDAC2 inhibitory action and is considered to be useful as a therapeutic and / or prophylactic agent for diseases or conditions involving HDAC2.

Claims (12)

1. Formula (I):
   

   

   
   (Where
   R ¹ is a hydrogen atom, halogen, substituted or unsubstituted furyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyridyl, substituted or unsubstituted phenyl Or substituted or unsubstituted cyclohexenyl;
   -L- is -SO _2- , -SO-, -S-, or -CH _2- ;
   R ² is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 6-membered aromatic heterocyclic group;
   However, when R ¹ is a hydrogen atom and -L- is -CH _2- , R ² is a substituted or unsubstituted 6-membered aromatic heterocyclic group)
   (Wherein the following compounds:
   

   

   
   Or a pharmaceutically acceptable salt thereof.
2. Salts R ¹ is the substituted or unsubstituted furyl, substituted or unsubstituted pyridyl, or halogen The compound of claim 1, or is a pharmaceutically acceptable.
3. The compound according to claim 1, wherein R ¹ is substituted or unsubstituted furyl, or a pharmaceutically acceptable salt thereof.
4. R ¹ is a group represented by the following:
   

   

   
   Wherein n is an integer from 0 to 2; each R ³ is independently halogen or substituted or unsubstituted alkyl.
   The compound according to claim 1, or a pharmaceutically acceptable salt thereof.
5. R ¹ is a group represented by the following:
   

   

   
   (Wherein each symbol has the same meaning as in claim 4)
   The compound according to claim 1, or a pharmaceutically acceptable salt thereof.
6. 6. The compound according to claim 4 or 5, wherein n is 0, or a pharmaceutically acceptable salt thereof.
7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein -L- is -SO _2- .
8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R ² is phenyl.
9. The following compounds:
   

   

   
   Or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.
11. The pharmaceutical composition according to claim 10, which is an HDAC2 inhibitor.
12. An HDAC2 inhibitor comprising the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.