JP2018111688A - Pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition containing a novel small molecule compound as an active ingredient, which suppresses the production of inducible MMPs, particularly MMP-9, rather than the production of constitutive MMP-2. A pharmaceutical composition containing a compound having a specific chemical structure as an active ingredient, which comprises a compound represented by the following formula. The pharmaceutical composition is useful as a prophylactic and / or therapeutic agent for autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease (ulcerative colitis, Crohn's disease), and osteoarthritis. [Selection diagram] None

Description

  The present invention relates to a pharmaceutical composition containing, as an active ingredient, a novel imide derivative exhibiting selective MMP-9 production inhibitory action.

  Matrix metalloproteases (MMPs) are a group of enzymes that play a major role in connective tissue degradation in vivo. The activity of MMPs is regulated by each step of 1) production of latent enzyme (proMMP) by gene expression, 2) activation of proMMP, and 3) activity inhibition by TIMP which is an inhibitor of active enzyme. There are two types of MMPs, a constitutive type and an inductive type. The former corresponds to MMP-2 and MMP-14, and the latter corresponds to many MMPs such as MMP-1, 3, 9, 13 and the like. In particular, MMP-9 has been observed to be produced or increased in rheumatoid arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematosus, and inflammatory bowel disease (ulcerative colitis, Crohn's disease). It has been suggested to be involved in pathological conditions [Ann. Rheum. Dis. 58, 691-697 (1999) (Non-Patent Document 1), J. MoI. Clin. Invest. 92, 179-185 (1993) (Non-Patent Document 2), Arthritis Rheum. 46, 2625-2631 (2002) (non-patent document 3), Lancet Neurol. 2, 747-756 (2003) (Non-patent Document 4), Arthritis Rheum. 50, 858-865 (2004) (Non-patent Document 5), Journal of Leukocyte Biology 79, 954-962 (2006) (Non-patent Document 9)].

Further, examination of MMP knockout mice also suggests that MMP-9 is involved in cancer formation and progression, and that MMP-9 has an important role in the progression of arthritis and joint destruction [J. Natl. Cancer Inst. 94, 1134-1142 (2002) (Non-Patent Document 6), J. Am. Immunol. 169, 2643-3647 (2002) (non-patent document 7)]. On the other hand, MMP-2 exhibits an anti-inflammatory action, and its degradation mechanism such as MCP-3 is considered [Science, 289, 1202-1206 (2000) (non-patent document 8)]. . Therefore, a drug that selectively inhibits MMP-9 production without affecting MMP-2 production can be expected as a novel therapeutic agent.
Japanese Laid-Open Patent Publication No. 2004-359657 (Patent Document 1) discloses leptomycin B or a derivative thereof, which is a drug that inhibits MMP-9 production.

  Furthermore, international publication pamphlets WO2010 / 050461 (Patent Document 2) and WO2011 / 136292 (Patent Document 3) disclose compounds that inhibit MMP-9 production. However, the ring having the imide structure of the general formula (I) of the present application is bonded to the substituent A via a carbon atom, whereas the compounds disclosed in Patent Documents 2 and 3 are substituted via a nitrogen atom. Bonded with groups A and W, the structure is different.

Japanese Laid-Open Patent Publication No. 2004-359657 International publication pamphlet WO2010 / 050461 International publication pamphlet WO2011-136292

Ann. Rheum. Dis. 58, 691-697 (1999) J. et al. Clin. Invest. 92, 179-185 (1993) Arthritis Rheum. 46, 2625-2631 (2002) Lancet Neurol. , Volume 2, pages 747-756 (2003) Arthritis Rheum. 50, 858-865 (2004). J. et al. Natl. Cancer Inst. 94, 1134-1142 (2002) J. et al. Immunol. 169, 2643-2647 (2002) Science, 289, 1202-1206 (2000) Journal of Leukocyte Biology Volume 79, 954-962 (2006)

  An object of the present invention is to provide a pharmaceutical composition containing, as an active ingredient, a novel low-molecular compound that suppresses the production of inducible MMPs, particularly MMP-9, rather than the production of constitutive MMP-2. .

In view of the above problems, the present inventors have conducted intensive studies for the purpose of finding a pharmaceutical composition containing a low molecular weight compound exhibiting an MMP-9 production inhibitory action as an active ingredient. As a result, the inventors have found that the imide derivatives in the present invention suppress the production of inducible MMPs, particularly MMP-9, rather than the production of constitutive MMP-2, and have completed the present invention. That is, the gist of the present invention is as follows.
[1] The following formula (I)

[Wherein, A represents a 5-membered heteroarylene containing 1 to 3 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or a phenylene or a 6-membered heteroarylene represented by the following formula:

[In the formula, Z ¹ , Z ² , Z ³ and Z ⁴ are the same or different and each represents a carbon atom or a nitrogen atom.)
These phenylenes and heteroarylenes are substituted with a halogen atom; a hydroxyl group; a nitro; a cyano; an amino optionally substituted mono- or di-substituted by alkyl having 1 to 6 carbon atoms, a halogen atom, a hydroxyl group, or alkoxy having 1 to 6 carbon atoms. An optionally substituted mono- or di-substituted amino, halogen atom, hydroxyl group, or alkoxy having 1 to 6 carbon atoms may be substituted. Cycloalkyl having 3 to 6 carbon atoms; amino optionally mono- or disubstituted with alkyl having 1 to 6 carbons; and amino or halogen atoms optionally mono- or di-substituted with alkyl having 1 to 6 carbons , One selected from a hydroxyl group or an alkoxy having 1 to 6 carbon atoms which may be substituted with an alkoxy having 1 to 6 carbon atoms, or the same or 2-3 substituents which became may be substituted with, the right bond is carbonyl, left bond is attached to the quaternary carbon to which R ² is attached. ]
R ^1a , R ^1b and R ^1c are the same or different and are each a hydrogen atom; a halogen atom; a hydroxyl group; a cyano; oxo; a carboxy; an amino or halogen atom which may be mono- or di-substituted by alkyl having 1 to 6 carbon atoms. , A hydroxyl group or an alkyl having 1 to 6 carbon atoms which may be substituted with a C 1-6 alkoxy; an amino, halogen atom, hydroxyl group or carbon which may be mono- or disubstituted with an alkyl having 1 to 6 carbon atoms An alkoxy group having 1 to 6 carbon atoms which may be substituted with alkoxy having 1 to 6 carbon atoms; an alkoxycarbonyl having 2 to 7 carbon atoms; an aminocarbonyl which may be mono- or di-substituted with alkyl having 1 to 6 carbon atoms; R ^1a, and two are together of ^{R 1b} and ^{R 1c,} cycloalkyl of 3 to 6 carbon atoms; or ^{R 1a,} two of ^{R 1b} and ^{R 1c} Turned cord, nitrogen atom, an atom selected from oxygen atom and sulfur atom containing 1-4, number of constituent atoms of the ring is 3 to 7 show a saturated non-aromatic heterocyclic group,
R ² may be mono- or di-substituted with alkyl having 1 to 6 carbons, substituted with cycloalkyl having 3 to 6 carbons, halogen atom, hydroxyl group or alkoxy having 1 to 6 carbons. An alkyl having 1 to 6 carbon atoms; a cycloalkyl having 3 to 6 carbon atoms which may be substituted with a halogen atom, a hydroxyl group, an alkoxy having 1 to 6 carbon atoms or amino; a nitrogen atom, an oxygen atom and a sulfur atom. A saturated non-aromatic heterocyclic group containing 1 to 4 atoms and having 3 to 7 ring atoms; aryl having 6 to 10 carbon atoms optionally substituted by the substituent B shown below; Or the heteroaryl which contains 1-6 atoms selected from the nitrogen atom, the oxygen atom, and the sulfur atom which may be substituted by the substituent B shown below, and has 5-10 constituent atoms in the ring ,
R ³ is a hydrogen atom; amino or halogen atom, hydroxyl group, alkoxy having 1 to 6 carbon atoms or acyloxy having 2 to 7 carbon atoms which may be mono- or di-substituted with alkyl having 1 to 6 carbon atoms; C1-6 alkyl; C3-6 cycloalkyl; C6-10 aryl moiety is halogen atom, hydroxyl group, C1-6 alkoxy, C1-6 alkyl or amino An arylalkyl having 1 to 6 carbon atoms in the alkyl part; or 1 to 6 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the number of atoms constituting the ring The heteroaryl part which is 5-10 is optionally substituted with a halogen atom, hydroxyl group, alkoxy having 1 to 6 carbons, alkyl having 1 to 6 carbons or amino, and the alkyl part having 1 to 6 carbons Represents a heteroarylalkyl,
W represents —N (R ^x ) — (wherein R ^x represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy having 1 to 6 carbon atoms or an acyloxy having 2 to 7 carbon atoms which may be substituted with 1 to 3 carbon atoms. 6) or a halogen atom, hydroxyl group, alkyl having 1 to 6 carbon atoms or methylene optionally substituted with alkoxy having 1 to 6 carbon atoms,
m + n represents 0, 1, 2 or 3,
X is a carbon atom (any one of R ^1a , R ^1b and R ^1c may be bonded to this carbon atom, but this carbon atom is not substituted with oxo) or a nitrogen atom (V is In the case of a bond, the nitrogen atom may be oxidized to be N-oxide)
V is a bond; carbonyl; a halogen atom, a hydroxyl group, or an alkylene having 1 to 6 carbon atoms which may be substituted with a C 1-6 alkoxy; an oxygen atom; or —N (R ^Y ) — (where R ^Y is A hydrogen atom, alkyl having 1 to 6 carbon atoms or acyl having 2 to 7 carbon atoms).
Y is a 5-membered cyclic group, a 6-membered cyclic group, a 5-membered cyclic group substituted with a 5-membered cyclic group, a 5-membered cyclic group substituted with a 6-membered cyclic group, or a 6-membered cyclic group substituted with a 5-membered cyclic group A 6-membered ring group substituted with a 6-membered ring group, a 5-membered and 5-membered condensed ring group, a 5-membered and 6-membered condensed ring group, or a 6-membered and 6-membered condensed ring group ( Here, the 5-membered ring and the 5-membered ring group contain 0 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the remainder is composed of carbon atoms. Containing 0 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, the remainder being composed of carbon atoms.), These ring groups are halogen atoms; hydroxyl groups; carbon numbers 1 to 6 C 1-6 alkyl optionally substituted with amino, halogen atom, hydroxyl group or C 1-6 alkoxy optionally mono- or di-substituted with alkyl A halogen atom, a hydroxyl group, amino, or a cycloalkyl having 3 to 6 carbon atoms that may be substituted with alkyl having 1 to 6 carbon atoms; or amino that may be mono- or di-substituted with alkyl having 1 to 6 carbon atoms; It may be substituted with a halogen atom, a hydroxyl group, an alkyl having 1 to 6 carbon atoms or an alkoxy having 1 to 6 carbon atoms which may be substituted with an alkoxy having 1 to 6 carbon atoms.
Substituent B
A halogen atom; a hydroxyl group; a cyano; an amino optionally substituted mono- or di-substituted with alkyl having 1 to 6 carbon atoms, a halogen atom, a hydroxyl group, or carbon atoms optionally substituted with alkoxy having 1 to 6 carbon atoms A cycloalkyl having 3 to 6 carbon atoms which may be substituted with a halogen atom, a hydroxyl group or amino; an amino, halogen atom, hydroxyl group or carbon which may be mono- or disubstituted with an alkyl having 1 to 6 carbon atoms C1-C6 alkoxy which may be substituted by C1-C6 alkoxy; Amino which may be mono- or di-substituted by C1-C6 alkyl or C3-C6 cycloalkyl. ]
Or a pharmacologically acceptable salt thereof (sometimes abbreviated as “compound (I)”) as an active ingredient.
[2] A is phenylene or 6-membered heteroarylene shown below

The pharmaceutical composition according to [1].
[3] Y is phenyl, pyridyl, pyrazinyl, pyridazinyl, naphthyl, quinolyl, or the ring group shown below

And these cyclic groups are substituted with a halogen atom; a hydroxyl group; an amino, halogen atom, hydroxyl group or alkoxy having 1 to 6 carbon atoms which may be mono- or disubstituted with alkyl having 1 to 6 carbon atoms. A C 1-6 alkyl; a halogen atom, a hydroxyl group, amino, or a C 3-6 cycloalkyl optionally substituted by a C 1-6 alkyl; or a mono C 1-6 alkyl Alternatively, it may be substituted with an optionally substituted amino, halogen atom, hydroxyl group, alkyl having 1 to 6 carbon atoms or alkoxy having 1 to 6 carbon atoms which may be substituted with alkoxy having 1 to 6 carbon atoms. The pharmaceutical composition according to [1] or [2].
[4] Phenyl or pyridyl wherein Y is represented by the following formula

(In the formula, Z ⁵ represents a carbon atom or a nitrogen atom,
R ⁴ and R ⁵ are the same or different and each represents an alkyl having 1 to 6 carbon atoms which may be substituted with a halogen atom; or a cycloalkyl having 3 to 6 carbon atoms which may be substituted with a halogen atom;
R ⁶ represents a hydrogen atom; an alkyl having 1 to 6 carbon atoms which may be substituted with a halogen atom; or a cycloalkyl having 3 to 6 carbon atoms which may be substituted with a halogen atom. )
Or a cyclic group represented by the following formula:

(These ring groups may be substituted with a halogen atom or alkyl having 1 to 6 carbon atoms.)
The pharmaceutical composition according to any one of [1] to [3].
[5] Phenyl or pyridyl wherein Y is represented by the following formula

(In the formula, Z ⁵ represents a carbon atom or a nitrogen atom,
R ⁴ and R ⁵ are the same or different and each represents alkyl having 1 to 6 carbon atoms; or cycloalkyl having 3 to 6 carbon atoms. )
The pharmaceutical composition according to any one of [1] to [4].
[6] Y is a pyridyl represented by the following formula

(In the formula, R ⁴ and R ⁵ are the same or different and each represents alkyl having 1 to 6 carbon atoms; or cycloalkyl having 3 to 6 carbon atoms.)
The pharmaceutical composition according to any one of [1] to [5].
[7] The pharmaceutical composition according to any one of [1] to [6], wherein V is a bond.
[8] The pharmaceutical composition according to any one of [1] to [7], wherein X is a nitrogen atom.
[9] The pharmaceutical composition according to any one of [1] to [8], wherein R ^1a , R ^1b and R ^1c are hydrogen atoms.
[10] The pharmaceutical composition according to any one of [1] to [9], wherein R ² is alkyl having 1 to 6 carbon atoms and R ³ is a hydrogen atom.
[11] The pharmaceutical composition according to any one of [1] to [10], wherein W is —NH— or methylene.
[12] The pharmaceutical composition according to any one of [1] to [11], wherein W is —NH—.
[13] (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione,
(R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} -5-methylimidazolidine-2,4-dione,
(R) -5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione,
(R) -5-methyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione,
(R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione,
5-isopropyl-5- {2-methoxy-4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione,
(R) -5- {4-[(S) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione,
(R) -5- {4-[(S) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1-carbonyl] phenyl} -5-ethylimidazolidine-2,4-dione,
(R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) -2,2-dimethylpiperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione ,
(R) -5- {4-[(S) -4- (3,5-dimethylpyridin-2-yl) -3-methylpiperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4 -Dione,
5-tert-butyl-5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione,
(R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-ethylimidazolidine-2,4-dione,
(R) -5-methyl-5- {4- [4- (4-methylbenzoyl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione,
(R) -5-methyl-5- [4- (4-p-tolyloxypiperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione,
(R) -5-isopropyl-5- {4- [4- (5-methylpyridine-2-carbonyl) piperidine-1-carbonyl] phenyl] imidazolidine-2,4-dione,
(R) -5-isopropyl-5- {4- [4- (6-methylbenzofuran-3-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione,
(R) -5- {4- [4- (4,6-dimethylbenzofuran-3-yl) piperidine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione,
(R) -5-isopropyl-5- {4- [4- (6-methylbenzoxazol-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione,
(R) -5- {4- [4- (5,7-dimethylindazol-1-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione,
(R) -5- {4- [4- (4,6-dimethyl-1H-indazol-3-yl) piperidine-1-carbonyl] phenyl} -5-methyl-imidazolidine-2,4-dione,
(R) -5-methyl-5- {4- [4- (1,4,6-trimethyl-1H-indazol-3-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione,
(R) -5- {4- [4- (4-Fluoro-6-methyl-1H-indazol-3-yl) piperidine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione,
5- {4- [4- (5-Cyclopropyl-3-methylpyridin-2-yl) piperazin-1-carbonyl] phenyl} -5- (tetrahydropyran-4-yl) imidazolidine-2,4-dione Or 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione as an active ingredient A pharmaceutical composition.
[14] The pharmaceutical composition according to any one of [1] to [13], which is an MMP-9 production inhibitor.
[15] The pharmaceutical composition according to any one of [1] to [13], which is a prophylactic and / or therapeutic agent for autoimmune disease or inflammatory bowel disease.
[16] The pharmaceutical composition according to [15], wherein the autoimmune disease is rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus.
[17] The pharmaceutical composition according to [15], wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
[18] The pharmaceutical composition according to any one of [1] to [13], which is a prophylactic and / or therapeutic agent for osteoarthritis.

  Since the compound in the present invention selectively suppresses the production of inducible MMPs, particularly MMP-9, rather than the production of constitutive MMP-2, the pharmaceutical composition of the present invention containing the compound as an active ingredient is It is useful as a preventive and / or therapeutic agent for autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease (ulcerative colitis, Crohn's disease), and osteoarthritis.

  The compound in the present invention is an imide derivative represented by the above general formula (I), a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof. The meanings of terms used in the present specification are described below, and the present invention is described in more detail. The following explanation of terms does not limit the present invention.

  The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

C1-C6 alkyl is linear or branched alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 3-methylbutyl, neopentyl, hexyl , 2-ethylbutyl and the like.
C1-C3 alkyl shows linear or branched alkyl, and methyl, ethyl, propyl, isopropyl, etc. are mentioned.

  Examples of the cycloalkyl having 3 to 6 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, ethylcyclopropyl, methylcyclobutyl, ethylcyclobutyl, methylcyclopentyl and the like.

  Examples of the aryl having 6 to 10 carbon atoms include phenyl and naphthyl.

  The arylalkyl refers to the above-mentioned alkyl having 1 to 6 carbon atoms substituted with the above-mentioned aryl having 6 to 10 carbon atoms, and examples thereof include benzyl, phenethyl, phenylpropyl, naphthylmethyl, naphthylethyl and the like.

1 to 6 atoms selected from nitrogen, oxygen and sulfur atoms, and heteroaryl having 5 to 10 ring atoms contain 1 to 3 nitrogen, oxygen and sulfur atoms A monocyclic aromatic heterocycle having 5 or 6 atoms in the ring, a condensed ring of the monocyclic aromatic heterocycle and benzene, and the two monocyclic aromatic heterocycles, which are the same or different, A monovalent group derived from a condensed ring is shown. Specific examples include pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furazanyl, pyridyl, pyranyl, thiopyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, , Isoindolyl, benzofuryl, benzothienyl, indazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, pyrrolopyridyl, pyrazolopyridyl, imidazolopyridyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, quinolyl, isoquinolyl, quinoxalyl, quinazolyl and the like.
A 5-membered heteroarylene containing 1 to 3 atoms selected from nitrogen, oxygen and sulfur atoms is derived from pyrrole, pyrazole, imidazole, triazole, thiophene, furan, oxazole, isoxazole, thiazole, isothiazole and furazane. Represents a divalent group.

  Heteroarylalkyl is an alkyl having 1 to 6 carbon atoms which is substituted with heteroaryl having 1 to 6 nitrogen atoms, oxygen atoms and sulfur atoms and having 5 to 10 ring atoms. Show.

  A saturated non-aromatic heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 3 to 7 ring atoms is a nitrogen atom, an oxygen atom and a sulfur atom 1 to 4 and a monovalent group derived from a saturated monocyclic heterocycle having 3 to 7 ring atoms. Specific examples include aziridinyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl , Thiomorpholinyl, and the like.

  C1-C6 alkoxy is linear or branched alkoxy and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, 3-methylbutoxy, neopentoxy Hexyloxy, 2-ethylbutoxy and the like.

  The acyl having 2 to 7 carbon atoms refers to a carbonyl substituted with the above alkyl having 1 to 6 carbon atoms, a carbonyl substituted with the above cycloalkyl having 3 to 6 carbon atoms, or a carbonyl substituted with phenyl, Examples include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, hexanoyl, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, benzoyl and the like.

  As acyloxy having 2 to 7 carbon atoms, acetoxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy, tert-butylcarbonyloxy, pentylcarbonyloxy, neopentylcarbonyl Examples include oxy, hexylcarbonyloxy, cyclopropylcarbonyloxy, cyclobutylcarbonyloxy, cyclopentylcarbonyloxy, cyclohexylcarbonyloxy, benzoyloxy and the like.

The alkoxy group having 2 to 7 carbon atoms refers to a group in which the above alkoxy having 1 to 6 carbon atoms is bonded to carbonyl, and includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, Examples include butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, 3-methylbutoxycarbonyl, neopentoxycarbonyl, hexyloxycarbonyl, 2-ethylbutoxycarbonyl and the like.
Examples of amino optionally substituted mono- or di-substituted with alkyl having 1 to 6 carbon atoms include amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino Pentylamino, 3-methylbutylamino, neopentylamino, hexylamino, 2-ethylbutylamino, dimethylamino, ethylmethylamino, diethylamino, methylpropylamino, ethylpropylamino, dipropylamino and the like.

  The aminocarbonyl which may be mono- or di-substituted with alkyl having 1 to 6 carbon atoms is an aminocarbonyl whose amino moiety is mono- or di-substituted with alkyl having 1 to 6 carbon atoms as described above. Show. Specific examples include aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylmethylaminocarbonyl and the like.

C1-C6 alkylene is linear or branched alkylene, and includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, ethylethylene and the like.
A 5-membered ring containing 0 to 4 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and the remainder composed of carbon atoms means a 5-membered carbocycle and a 5-membered heterocycle, and a nitrogen atom The 5-membered cyclic group containing 0 to 4 atoms selected from an oxygen atom and a sulfur atom, and the remainder composed of carbon atoms refers to a 5-membered carbocyclic group and a 5-membered heterocyclic group. Examples of the 5-membered carbocycle include cyclopentane, cyclopentene, and cyclopentadiene. Examples of the 5-membered carbocyclic group include monovalent groups derived from the 5-membered carbocycle. 5-membered heterocycles include 5-membered aromatic heterocycles and 5-membered non-aromatic heterocycles. The same applies to a 5-membered heterocyclic group. 5-membered heterocycles include pyrrole, pyrazole, imidazole, triazole, tetrazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, oxathiol, oxathiazole and some of these rings Alternatively, a ring in which all are reduced, and the like, and examples of the 5-membered heterocyclic group include monovalent groups derived from the 5-membered heterocyclic ring.
A 6-membered ring containing 0 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the remainder consisting of carbon atoms means a 6-membered carbocycle and a 6-membered heterocycle, The 6-membered cyclic group containing 0 to 4 atoms selected from an atom, an oxygen atom, and a sulfur atom, and the remainder composed of carbon atoms refers to a 6-membered carbocyclic group and a 6-membered heterocyclic group. Examples of the 6-membered carbocycle include benzene and cyclohexane, and examples of the 6-membered carbocyclic group include monovalent groups derived from the 6-membered carbocycle. The 6-membered heterocycle includes a 6-membered aromatic heterocycle and a 6-membered non-aromatic heterocycle. The same applies to a 6-membered heterocyclic group. Examples of the 6-membered heterocycle include pyran, thiopyran, pyridine, pyridazine, pyrimidine, pyrazine, triazine, tetrazine, oxazine, thioxazine and a ring in which part or all of them are reduced. Examples of the group include a monovalent group derived from the 6-membered heterocycle.

  In the present specification, the number of substituents in the case of “may be substituted” is 1 or 2 or more unless otherwise specified, and the types of substituents may be the same or different. Also good.

Next, preferred embodiments in the general formula (I) will be described.
A is thienylene or the following formula

(In the formula, Z ¹ , Z ² , Z ³ and Z ⁴ are the same or different and represent a carbon atom or a nitrogen atom.)
Is preferably phenylene or 6-membered heteroarylene, and more preferably phenylene or 6-membered heteroarylene. More specifically

It is preferable that

It is more preferable that As a particularly preferred example of A,

Can be mentioned.
When A has a substituent, the substituent is a halogen atom; a hydroxyl group; an amino optionally substituted mono- or di-substituted by alkyl having 1 to 6 carbon atoms, a halogen atom, a hydroxyl group, or having 1 to 6 carbon atoms. Substituted by alkoxy having 1 to 6 carbon atoms optionally substituted with alkoxy; and amino, halogen atom, hydroxyl group or alkoxy having 1 to 6 carbon atoms optionally mono- or disubstituted by alkyl having 1 to 6 carbon atoms It is preferably one selected from alkoxy having 1 to 6 carbon atoms which may be substituted, or the same or different 2 to 3 carbon atoms, halogen atom; hydroxyl group; alkyl having 1 to 6 carbon atoms; or 1 carbon atom It is more preferable that it is one selected from alkoxy having 6 to 6 or the same or different 2 to 3, more preferably a halogen atom or alkoxy having 1 to 6 carbon atoms. Masui.
The substituents in the case where A has a substituent are as described above, but those in which A is unsubstituted can also be mentioned as preferred embodiments.

R ^1a , R ^1b and R ^1c are the same or different and are each a hydrogen atom; a hydroxyl group; a cyano; an amino, a halogen atom, a hydroxyl group, or a carbon atom having 1 to Alkyl having 1 to 6 carbon atoms optionally substituted with 6 alkoxy; alkoxycarbonyl having 2 to 7 carbon atoms; aminocarbonyl optionally mono- or disubstituted with alkyl having 1 to 6 carbon atoms; or R ^1a , R ^1b and R ^{1c taken} together are preferably cycloalkyl having 3 to 6 ring atoms, hydrogen atom; hydroxyl group; cyano; hydroxyl group or alkoxy having 1 to 6 carbon atoms substituted alkyl of good 1 to 6 carbon atoms optionally; alkoxycarbonyl having 2 to 7 carbon atoms; or ^{R 1a,} two ^{R 1b} and ^{R 1c} together, the ring And more preferably the number of constituent atoms is a cycloalkyl is 3-6. Here, when two of R ^1a , R ^1b and R ^1c together form a ring, it is preferably a spiro ring. Particularly preferred examples of R ^1a include a hydrogen atom or alkyl having 1 to 3 carbon atoms, particularly preferred examples of R ^1b include a hydrogen atom or alkyl having 1 to 3 carbon atoms, and particularly preferred examples of R ^1c include a hydrogen atom. As the most preferred examples, R ^1a , R ^1b and R ^1c can be hydrogen atoms.

R ² may be mono- or di-substituted with alkyl having 1 to 6 carbons, substituted with cycloalkyl having 3 to 6 carbons, halogen atom, hydroxyl group or alkoxy having 1 to 6 carbons. An alkyl having 1 to 6 carbon atoms; a cycloalkyl having 3 to 6 carbon atoms which may be substituted with a halogen atom, a hydroxyl group, an alkoxy having 1 to 6 carbon atoms or amino; a nitrogen atom, an oxygen atom and a sulfur atom. Saturated non-aromatic heterocyclic group containing 1 to 4 atoms and having 3 to 7 ring atoms; aryl having 6 to 10 carbon atoms; or nitrogen atom, oxygen atom and sulfur atom It is preferably a heteroaryl containing 1 to 6 atoms and having 5 to 10 ring atoms, and may be mono- or di-substituted amino having 1 to 6 carbon atoms, 3 carbon atoms. ~ 6 A cycloalkyl, a halogen atom, a hydroxyl group, or an alkyl having 1 to 6 carbon atoms which may be substituted with an alkoxy having 1 to 6 carbon atoms; a halogen atom, a hydroxyl group, an alkoxy having 1 to 6 carbon atoms or amino substituted A good cycloalkyl having 3 to 6 carbon atoms; a saturated non-aromatic heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 3 to 7 ring atoms Or more preferably an aryl having 6 to 10 carbon atoms, optionally substituted with a halogen atom or an alkoxy having 1 to 6 carbon atoms; substituted with an alkoxy having 1 to 6 carbon atoms; It is even more preferable that they are C3-C6 cycloalkyl which may be made; Tetrahydropyranyl; or Phenyl. Particularly preferable examples of R ² include alkyl having 1 to 6 carbon atoms and tetrahydropyranyl, and most preferable examples include alkyl having 1 to 6 carbon atoms. The alkyl having 1 to 6 carbon atoms in the most preferred example of R ² is specifically methyl, ethyl or isopropyl.

R ³ is a hydrogen atom; amino or halogen atom, hydroxyl group, alkoxy having 1 to 6 carbon atoms or acyloxy having 2 to 7 carbon atoms which may be mono- or di-substituted with alkyl having 1 to 6 carbon atoms; Or an aryl moiety having 6 to 10 carbon atoms may be substituted with a halogen atom, a hydroxyl group, an alkoxy having 1 to 6 carbon atoms, an alkyl having 1 to 6 carbon atoms, or amino; The alkyl moiety is preferably an arylalkyl having 1 to 6 carbon atoms, and may be a hydrogen atom; or an alkyl having 1 to 6 carbon atoms which may be substituted with a hydroxyl group or acyloxy having 2 to 7 carbon atoms. More preferably, it is a hydrogen atom.

In another embodiment of the present invention, R ² is preferably alkyl having 1 to 6 carbons (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl) and R ³ is Preferably, it is a hydrogen atom.

W is preferably —N (R ^x ) — (wherein R ^x represents a C 1-6 alkyl optionally substituted with a hydrogen atom or a hydroxyl group) or methylene, —NH— or More preferred is methylene. As a particularly preferred example of W, —N (R ^x ) — (wherein R ^x represents a C 1-6 alkyl which may be substituted with a hydrogen atom or a hydroxyl group) can be exemplified, and —NH -Can be mentioned as the most preferred example.

  m + n is preferably 0, 1 or 2, more preferably 1 or 2, and even more preferably 2. More specifically, it is preferable that m is 0 or 1, and n is 0 or 1. More specifically, a preferable combination of m and n can be exemplified by (m, n) being (0,0), (0,1) or (1,1), and (0,1) or ( 1,1) is more preferable, and (1,1) is particularly preferable.

X is preferably a carbon atom or a nitrogen atom. More specifically, when m + n is 0 or 1, a carbon atom is preferable. When m + n is 2, both a carbon atom and a nitrogen atom are preferable, but a nitrogen atom is particularly preferable.
Specifically, preferred combinations of m, n and X are as follows:

Are mentioned,

As a more preferred specific example,

Can be mentioned as a particularly preferred specific example.
V is preferably a bond, carbonyl, alkylene having 1 to 6 carbon atoms, an oxygen atom or —NH—, more preferably a bond, carbonyl, methylene, oxygen atom or —NH—, and a bond, carbonyl, oxygen More preferably, it is an atom or -NH-. As a particularly preferred example of V, a bond or carbonyl can be mentioned, and a bond can be mentioned as the most preferred example.

The 5-membered ring group for Y is preferably pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl or furyl.
The 6-membered ring group for Y is preferably phenyl, pyridyl, pyrazinyl or pyridazinyl.
Y is phenyl, pyridyl, pyrazinyl, pyridazinyl, naphthyl, quinolyl or the ring group shown below

Preferably, phenyl, pyridyl or the ring group shown below

More preferably, phenyl, pyridyl or the ring group shown below

More preferably. As a particularly preferred example of Y, pyridyl can be mentioned, and more specifically,

Can be mentioned.
When Y has a substituent, the substituent is a halogen atom; an amino, halogen atom, hydroxyl group, or alkoxy having 1 to 6 carbon atoms which may be mono- or di-substituted with alkyl having 1 to 6 carbon atoms. Optionally substituted alkyl having 1 to 6 carbon atoms; halogen atom, hydroxyl group, amino or cycloalkyl having 1 to 6 carbon atoms optionally substituted with alkyl having 1 to 6 carbon atoms; or 1 to 6 carbon atoms Or an optionally substituted mono- or di-substituted amino, halogen atom, hydroxyl group, alkyl having 1 to 6 carbon atoms or alkoxy having 1 to 6 carbon atoms which may be substituted with alkoxy having 1 to 6 carbon atoms. It is preferably a halogen atom; an alkyl having 1 to 6 carbon atoms which may be substituted with a halogen atom; a cycloalkyl having 3 to 6 carbon atoms; or an alkoxy having 1 to 6 carbon atoms DOO are more preferable, and an alkyl of 1 to 6 carbon atoms; more preferably from or cycloalkyl having 3 to 6 carbon atoms. Particularly preferred examples of the substituent for Y include alkyl having 1 to 6 carbon atoms, and specific examples include methyl. The number of substituents is preferably 2 or 3.
Specifically, a particularly preferable example of Y is given as follows:

Can mention

Is most preferred.

  In another embodiment of the present invention, Y is preferably phenyl or pyridyl represented by the following formula

(In the formula, Z ⁵ represents a carbon atom or a nitrogen atom,
R ⁴ and R ⁵ are the same or different and each has 1 to 6 carbon atoms optionally substituted with a halogen atom (eg, methyl, ethyl); or 3 to 3 carbon atoms optionally substituted with a halogen atom. 6 cycloalkyl (eg cyclopropyl),
R ⁶ represents a hydrogen atom; an alkyl having 1 to 6 carbon atoms which may be substituted with a halogen atom (eg, methyl); or a cycloalkyl having 3 to 6 carbon atoms which may be substituted with a halogen atom. )
Or a cyclic group represented by the following formula:

(These ring groups may be substituted with a halogen atom (eg, fluorine atom, chlorine atom, bromine atom) or alkyl having 1 to 6 carbon atoms (eg, methyl).)
More preferably, phenyl or pyridyl represented by the following formula

(In the formula, Z ⁵ represents a carbon atom or a nitrogen atom,
R ⁴ and R ⁵ are the same or different and each represents alkyl having 1 to 6 carbon atoms (eg, methyl, ethyl); or cycloalkyl having 3 to 6 carbon atoms (eg, cyclopropyl). )
And even more preferably, pyridyl represented by the following formula:

(In the formula, R ⁴ and R ⁵ are the same or different and each represents alkyl having 1 to 6 carbon atoms (eg, methyl, ethyl); or cycloalkyl having 3 to 6 carbon atoms (eg, cyclopropyl).) It is.

Preferable examples of compound (I) include the following compounds.
[Compound IA]
A is a 5-membered heteroarylene (eg, thienylene) containing 1 to 3 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, or phenylene or 6-membered heteroarylene represented by the following formula:

[In the formula, Z ¹ = Z ² = Z ³ = Z ⁴ = carbon atom; Z ¹ = Z ² = Z ⁴ = carbon atom and Z ³ = nitrogen atom; or Z ¹ = Z ² = Z ³ = carbon atom And Z ⁴ = nitrogen atom.)
These phenylene and heteroarylene include a halogen atom (eg, fluorine atom, bromine atom); a hydroxyl group; an alkyl having 1 to 6 carbon atoms optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom) ( The right bond optionally substituted with 1 or the same or different 2 to 3 substituents selected from alkoxy having 1 to 6 carbons (eg, methoxy, ethoxy); The hand is bonded to the carbonyl, and the left bond is bonded to the quaternary carbon to which R ² is bonded. ],
R ^1a , R ^1b and R ^1c are the same or different from each other, and one or the same or different 2 selected from a hydrogen atom; a hydroxyl group; a cyano; a hydroxyl group and an alkoxy having 1 to 6 carbon atoms (eg, methoxy) C 1-6 alkyl optionally substituted with 3 substituents (eg methyl, ethyl, isopropyl); C 2-7 alkoxycarbonyl (eg methoxycarbonyl); aminocarbonyl; or R ^1a , R ^1b and R ^1c are taken together to form a cycloalkyl having 3 to 6 carbon atoms (eg, cyclobutyl),
R ² is substituted with one or the same or different 2 to 3 substituents selected from a halogen atom (eg, fluorine atom), a hydroxyl group and an alkoxy having 1 to 6 carbon atoms (eg, methoxy, ethoxy) May be substituted with an alkyl having 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl); may be substituted with alkoxy having 1 to 6 carbon atoms (eg, methoxy) Good C3-C6 cycloalkyl (e.g., cyclopropyl, cyclobutyl); contains 1-4 atoms selected from nitrogen, oxygen and sulfur atoms, and has 3-7 ring atoms A saturated non-aromatic heterocyclic group (eg, tetrahydropyranyl); or aryl having 6 to 10 carbon atoms (eg, phenyl),
One or the same or different 2-3 substituents selected from R ³ is a hydrogen atom; a hydroxyl group and an acyloxy having 2 to 7 carbon atoms (eg, acetoxy, propylcarbonyloxy, tert-butylcarbonyloxy) Or an alkyl moiety having 1 to 6 carbon atoms (eg, methyl, ethyl) which may be substituted with, or an aryl moiety having 6 to 10 carbon atoms may be substituted with an alkoxy having 1 to 6 carbon atoms (eg, methoxy) Well, it is an arylalkyl having 1 to 6 carbon atoms in the alkyl part (eg, benzyl),
W is —N (R ^x ) — (where R ^x is a hydrogen atom or a C 1-6 alkyl optionally substituted with a hydroxyl group (eg, methyl, ethyl)) or methylene. ,
m + n is 0, 1 or 2;
X is a carbon atom or a nitrogen atom,
V is a bond; carbonyl; alkylene having 1 to 6 carbon atoms (eg, methylene); oxygen atom; or —N (R ^Y ) — (where R ^Y is a hydrogen atom);
Y is a 6-membered ring group (eg, phenyl, pyridyl, pyrazinyl, pyridazinyl), a 5-membered ring group (eg, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, oxadiazolyl) substituted with a 6-membered ring group (eg, phenyl, pyridyl) , Triazolyl, thiadiazolyl, tetrazolyl) 5-membered and 6-membered condensed ring groups (eg, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzoisothiazolyl, benzofuryl, oxazolopyridinyl, Thiazolopyridyl, pyrrolopyridyl, dihydropyrrolopyridyl, indazolyl, indolyl) or a condensed ring group of 6-membered ring and 6-membered ring (eg, naphthyl, quinolyl) (wherein 5-membered ring and 5-membered ring group are nitrogen atom, oxygen Contains 0 to 4 atoms selected from atoms and sulfur atoms, with the remainder being carbon atoms Configured, 6-membered ring and 6-membered ring group nitrogen atom, an atom selected from oxygen atom and sulfur atom containing 0-4, the rest is composed of carbon atoms.)
These ring groups are halogen atoms (eg, fluorine atom, chlorine atom, bromine atom); those having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine atom) One or the same or different 2 selected from alkyl (eg, methyl, ethyl); cycloalkyl having 3 to 6 carbon atoms (eg, cyclopropyl); and alkoxy having 1 to 6 carbon atoms (eg, methoxy) May be substituted with ~ 3 substituents,
Compound (I).

[Compound IB]
A is a 5-membered heteroarylene (eg, thienylene) containing 1 to 3 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, or phenylene or 6-membered heteroarylene represented by the following formula:

[Wherein Z ¹ = Z ² = Z ³ = Z ⁴ = carbon atom; or Z ¹ = Z ² = Z ⁴ = carbon atom and Z ³ = nitrogen atom.)
These phenylene and heteroarylene are one or the same or different 2-3 substitutions selected from a halogen atom (eg, fluorine atom); a hydroxyl group; and an alkyl having 1 to 6 carbon atoms (eg, methyl). It may be substituted with a group, and the right bond is bonded to carbonyl and the left bond is bonded to the quaternary carbon to which R ² is bonded. ],
R ^1a , R ^1b and R ^1c are the same or different and each is selected from a hydrogen atom; a hydroxyl group; a cyano; an alkoxy having 1 to 6 carbon atoms (eg, methoxy), or the same or different 2-3 An alkyl having 1 to 6 carbon atoms (eg, methyl) optionally substituted with one substituent; an alkoxycarbonyl having 2 to 7 carbon atoms (eg, methoxycarbonyl); or two of R ^1a , R ^1b, and R ^1c Together are cycloalkyl having 3 to 6 carbon atoms (eg, cyclobutyl),
R ² may be substituted with one or the same or different 2 to 3 substituents selected from halogen atoms (eg, fluorine atoms) and C 1-6 alkoxy (eg, methoxy) Good alkyl having 1 to 6 carbon atoms (eg, methyl, ethyl, isopropyl, tert-butyl); cycloalkyl having 3 to 6 carbon atoms optionally substituted with alkoxy having 1 to 6 carbon atoms (eg, methoxy) ( Example, cyclopropyl, cyclobutyl); saturated non-aromatic heterocyclic group containing 1 to 4 atoms selected from nitrogen atom, oxygen atom and sulfur atom, and having 3 to 7 ring atoms (example Tetrahydropyranyl); or aryl having 6 to 10 carbon atoms (eg, phenyl),
R ³ is a hydrogen atom; or 1 to C 1 carbons optionally substituted with 1 to 3 identical or different substituents selected from acyloxy having 2 to 7 carbons (eg, acetoxy) 6 alkyls (eg, methyl),
W is —N (R ^x ) — (wherein R ^x is a hydrogen atom or an alkyl having 1 to 6 carbon atoms (eg, methyl)),
m + n is 0, 1 or 2;
X is a carbon atom or a nitrogen atom,
V is a bond; carbonyl; an oxygen atom; or —N (R ^Y ) — (where R ^Y is a hydrogen atom);
Y is a 6-membered ring group (eg, phenyl, pyridyl, pyrazinyl, pyridazinyl), a 5-membered ring group substituted with a 6-membered ring group (eg, phenyl) (eg, pyrazolyl, imidazolyl, thiazolyl, triazolyl, thiadiazolyl, tetrazolyl) ) Or a condensed ring group of 5-membered ring and 6-membered ring (eg, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuryl, oxazolopyridyl, thiazolopyridyl, dihydropyrrolopyridyl, indazolyl, indolyl) (here, 5-membered ring) And the 5-membered ring group contains 0 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the remainder is composed of carbon atoms, and the 6-membered and 6-membered ring groups are a nitrogen atom, an oxygen atom and Containing 0 to 4 atoms selected from sulfur atoms, the remainder being composed of carbon atoms). Atom (eg, fluorine atom); C 1-6 alkyl (eg, methyl) optionally substituted by 1 to 3 halogen atoms (eg, fluorine atom); and C 3-6 cycloalkyl Optionally substituted with one or the same or different 2-3 substituents selected from (eg, cyclopropyl),
Compound (I).

[Compound I-C]
A is phenylene represented by the following formula:

[In the formula, Z ¹ = Z ² = Z ³ = Z ⁴ = carbon atom.)
The phenylene may be substituted with one or the same or different 2 to 3 substituents selected from a halogen atom (eg, fluorine); and an alkoxy having 1 to 6 carbon atoms (eg, methoxy). Often, the right bond is bonded to the carbonyl and the left bond is bonded to the quaternary carbon to which R ² is bonded. ],
R ^1a , R ^1b and R ^1c are the same or different and each is a hydrogen atom; or alkyl having 1 to 6 carbons (eg, methyl),
R ² contains 1 to 4 atoms selected from a C 1-6 alkyl (eg, methyl, ethyl, isopropyl, tert-butyl); or a nitrogen atom, an oxygen atom and a sulfur atom; A saturated non-aromatic heterocyclic group having 3 to 7 atoms (eg, tetrahydropyranyl),
R ³ is a hydrogen atom,
W is -N (R ^x )-(where R ^x is a hydrogen atom);
m + n is 1 or 2,
X is a carbon atom or a nitrogen atom,
V is a bond; carbonyl; an oxygen atom; or —N (R ^Y ) — (where R ^Y is a hydrogen atom);
Y is a 6-membered ring group (eg, phenyl, pyridyl) or a 5-membered and 6-membered condensed ring group (eg, benzoxazolyl, benzofuryl, indazolyl) (where the 5-membered ring is a nitrogen atom, oxygen 0 to 4 atoms selected from an atom and a sulfur atom are contained, the remainder is composed of carbon atoms, and the 6-membered ring and 6-membered ring group are 0 to 0 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. 4 and the rest are composed of carbon atoms.), And these ring groups are halogen atoms (eg, fluorine atoms); alkyls having 1 to 6 carbon atoms (eg, methyl); and carbon numbers Optionally substituted with 1 or the same or different 2-3 substituents selected from 3-6 cycloalkyl (eg cyclopropyl),
Compound (I).

Preferable compounds of the present invention include, for example, compounds of Production Examples 1 to 355, and more preferably Production Examples 1, 3, 5, 6, 8, 22, 49, 50, 59, 80, 91. , 124, 150, 152, 186, 240, 245, 257, 272, 276
278, 280, 325 and 329 compounds.

In the present invention, the “pharmacologically acceptable salt” is not particularly limited as long as it is a pharmaceutically acceptable salt, a salt with an inorganic acid, a salt with an organic acid, a salt with an alkali metal, Examples include salts with alkaline earth metals, salts with inorganic bases, and salts with organic bases. In this specification, a salt includes a hydrate and a solvate.
The term “pharmacologically acceptable” as used herein is generally safe and harmless and may be biologically undesirable as long as it is preferable in other respects. It is useful in preparing pharmaceutical compositions containing those useful not only for use as a veterinary but also for veterinary use.
Next, although the compound in this invention can be manufactured with the following method, the manufacturing method is not limited to these.
Compound (I) in the present invention can be produced by the following method A, B, C, D, E or F.
(Method A)

(The symbols in the formula are as defined above.)
By reacting the compound represented by the general formula (II) with the compound represented by the general formula (III), a corresponding compound represented by the general formula (I) is obtained. The reaction proceeds at 0 ° C. to room temperature in a suitable solvent using a condensing agent. As the condensing agent, 4- (4,6-dimethoxy [1
. 3.5] triazin-2-yl) -4-methylmorpholinium chloride hydrate (DM
T-MM), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl) and the like. Examples of the solvent include methanol, N, N-dimethylformamide, chloroform, tetrahydrofuran and the like. Moreover, reaction may be accelerated | stimulated by adding 1-hydroxybenzotriazole (HOBt). When the compound represented by the general formula (III) forms a salt with an acid, the reaction proceeds by adding a base to neutralize.
(Method B)

(The symbols in the formula are as defined above.)
By reacting the compound represented by the general formula (IV) with the compound represented by the general formula (III), a corresponding compound represented by the general formula (I) is obtained. The reaction proceeds using a base in an appropriate solvent at 0 ° C. to room temperature. Examples of the base include aqueous sodium hydroxide, triethylamine, N-methylmorpholine, pyridine and the like. Examples of the solvent include tetrahydrofuran, dimethoxyethane, ethyl acetate, pyridine and the like.
(Method C)
First step

(In the formula, P represents an amino-protecting group, and other symbols are as defined above.)
The compound represented by the general formula (III) is obtained by deprotecting the protecting group P of the compound represented by the general formula (V). For example, when P in the formula is a Boc group, the reaction proceeds in an appropriate solvent at 0 ° C. to room temperature using an acid. Examples of the acid include hydrogen chloride / ethyl acetate, hydrogen chloride / 1,4-dioxane and the like. Examples of the solvent include chloroform, ethyl acetate, 1,4-dioxane, ethanol, methanol and the like.
Second step

(The symbols in the formula are as defined above.)
By reacting the compound represented by the general formula (II) with the compound represented by the general formula (III), a corresponding compound represented by the general formula (I) is obtained. The reaction proceeds at 0 ° C. to room temperature in a suitable solvent using a condensing agent. As the condensing agent, 4- (4,6-dimethoxy [1
. 3.5] triazin-2-yl) -4-methylmorpholinium chloride hydrate (DM
T-MM), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl) and the like. Examples of the solvent include methanol, N, N-dimethylformamide, chloroform, tetrahydrofuran and the like. Moreover, reaction may be accelerated | stimulated by adding 1-hydroxybenzotriazole (HOBt). When the compound represented by the general formula (III) forms a salt with an acid, the reaction proceeds by adding a base to neutralize.
(Method D: when R ³ in formula (I) is a group other than a hydrogen atom)

(In the formula, L represents a leaving group such as a halogen atom, and R ³ represents an amino, halogen atom, hydroxyl group, or alkoxy having 1 to 6 carbon atoms which may be mono- or disubstituted with alkyl having 1 to 6 carbon atoms. Or an alkyl group having 1 to 6 carbon atoms which may be substituted with acyloxy having 2 to 7 carbon atoms; a cycloalkyl having 3 to 6 carbon atoms; an aryl moiety having 6 to 10 carbon atoms is a halogen atom, a hydroxyl group, Aryl having 6 to 6 carbon atoms, alkyl having 1 to 6 carbon atoms or amino group and 1 to 6 carbon atoms in the alkyl portion; or an atom selected from a nitrogen atom, an oxygen atom and a sulfur atom Even if the heteroaryl part which contains 1-6 pieces and has 5-10 constituent atoms of the ring is substituted with a halogen atom, a hydroxyl group, an alkoxy having 1 to 6 carbons, an alkyl having 1 to 6 carbons or amino And a heteroarylalkyl having 1 to 6 carbon atoms in the alkyl part is preferred, and other symbols are as defined above.)
The compound represented by the general formula (I) is obtained by reacting the compound represented by the general formula (VI) with the compound represented by the general formula (VII). The reaction proceeds at 0 ° C. to 100 ° C. in a suitable solvent using a base. Examples of the base include potassium carbonate and sodium hydrogen carbonate. Examples of the solvent include N, N-dimethylformamide.
In the case where R ³ is alkyl having 1 to 6 carbons which may be mono-substituted with alkyl having 1 to 6 carbons, the general formula (1) protected with an appropriate amino-protecting group ( VII) is used to carry out the above reaction, followed by deprotection to obtain the corresponding compound represented by the general formula (I).
(Method E: W in General Formula (I) is —N (R ^x ) — (wherein R ^x is substituted with a substituent selected from a halogen atom, a hydroxyl group and an alkoxy having 1 to 6 carbon atoms) In the case of good alkyl having 1 to 6 carbon atoms))

(Wherein P ′ represents a protecting group, T represents a C 1-6 alkyl which may be substituted with a substituent selected from a halogen atom, a hydroxyl group and an alkoxy having 1 to 6 carbon atoms; Is as defined above.)
Step 1 A compound represented by the general formula (X) is obtained by reacting a compound represented by the general formula (VIII) with a compound represented by the general formula (IX). The reaction proceeds at 0 ° C. to 100 ° C. in a suitable solvent using a base. Examples of the base include potassium carbonate and sodium hydrogen carbonate. Examples of the solvent include N, N-dimethylformamide and tetrahydrofuran.
Second Step A compound represented by the general formula (XII) is obtained by reacting the compound represented by the general formula (X) with the compound represented by the general formula (XI). The reaction proceeds at 0 ° C. to 100 ° C. in a suitable solvent using a base. Examples of the base include potassium carbonate and sodium hydride. Examples of the solvent include N, N-dimethylformamide and tetrahydrofuran.
Third Step A compound represented by the general formula (XIII) is obtained by deprotecting the protecting group P ′ of the compound represented by the general formula (XII). For example, when P ′ in the formula is a 4-methoxybenzyl group, the reaction proceeds at 0 ° C. to 100 ° C. in an appropriate solvent using an acid. Examples of the acid include trifluoromethanesulfonic acid and trifluoromethanesulfonic anhydride. Examples of the solvent include 1,2-dichloroethane.
(Method F: when R ^1a in formula (I) is a C 1-6 alkyl substituted with a hydroxyl group)
1st process

(In the formula, P ″ represents a protecting group for a hydroxyl group, U represents an alkylene having 1 to 6 carbon atoms, and other symbols are as defined above.)
A compound represented by the general formula (XV) can be obtained by deprotecting the protecting groups P and P ″ of the compound represented by the general formula (XIV). For example, when P in the formula is a Boc group and P ″ is a TBS group, the reaction proceeds in an appropriate solvent at 0 ° C. to room temperature. Examples of the acid include hydrogen chloride / ethyl acetate, hydrogen chloride / 1,4-dioxane and the like. Examples of the solvent include chloroform, ethyl acetate, 1,4-dioxane, ethanol, methanol and the like.
Second step

(In the formula, R ³ represents a hydrogen atom; an amino, halogen atom, hydroxyl group, alkoxy having 1 to 6 carbon atoms, or acyloxy having 2 to 7 carbon atoms which may be mono- or di-substituted with alkyl having 1 to 6 carbon atoms. Optionally substituted alkyl having 1 to 6 carbon atoms; cycloalkyl having 3 to 6 carbon atoms; aryl moiety having 6 to 10 carbon atoms is a halogen atom, a hydroxyl group, alkoxy having 1 to 6 carbon atoms, or 1 to 6 carbon atoms. Arylalkyl having 1 to 6 carbon atoms in the alkyl part, which may be substituted with alkyl or amino, or 1 to 6 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, The heteroaryl moiety having 5 to 10 constituent atoms may be substituted with a halogen atom, a hydroxyl group, an alkoxy having 1 to 6 carbon atoms, an alkyl having 1 to 6 carbon atoms or an amino group, and the carbon number of the alkyl moiety may be 1 to 6 is a heteroarylalkyl, and other symbols are as defined above.)
By reacting the compound represented by the general formula (II) with the compound represented by the general formula (XV), a corresponding compound represented by the general formula (XVI) is obtained. The reaction proceeds at 0 ° C. to room temperature in a suitable solvent using a condensing agent. As the condensing agent, 4- (4,6-dimethoxy [
1.3.5] triazin-2-yl) -4-methylmorpholinium chloride hydrate (D
MT-MM), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl) and the like. Examples of the solvent include methanol, N, N-dimethylformamide, chloroform, tetrahydrofuran and the like. Moreover, reaction may be accelerated | stimulated by adding 1-hydroxybenzotriazole (HOBt). When the compound represented by the general formula (XV) forms a salt with an acid, the reaction proceeds by adding a base to neutralize.
The imide derivative represented by the general formula (I) produced by the above-described method can be purified to any purity by applying conventional purification means such as concentration, extraction, chromatography, reprecipitation, recrystallization and the like. Can be purified. Moreover, it can be set as a pharmacologically acceptable salt by processing with an acid or a base in a suitable solvent (water, alcohol, ether etc.) as needed. Furthermore, the hydrate or solvate can be obtained by treating the obtained compound of the present invention or a pharmacologically acceptable salt thereof with water, a hydrous solvent or other solvent (for example, alcohol). .

The imide derivative or pharmacologically acceptable salt thereof in the present invention includes a racemate, a stereoisomer, and a mixture of these compounds, and includes an isotope label and a radiolabel compound. Such isomers can be isolated by standard separation techniques including fractional crystallization and chiral column chromatography. The compound in the present invention has an asymmetric carbon atom. Thus, it includes enantiomers or diastereomers. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical / chemical differences in a manner well known in the art, for example by chromatography and / or fractional crystallization. Enantiomers can be obtained by chiral column chromatography or by reacting an enantiomer compound with an appropriate optically active compound to convert it to a diastereomeric mixture, separating each diastereomer, and then converting each diastereomer to the corresponding enantiomer. Can be separated by. All such isomers, including diastereomers, enantiomers and mixtures thereof are part of the compounds in the present invention.

  The compound in the present invention has a selective production inhibitory action on MMP-9, and the pharmaceutical composition of the present invention containing the compound as an active ingredient is effective for rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, etc. It can be used as a prophylactic or therapeutic agent for representative autoimmune diseases, inflammatory bowel diseases (ulcerative colitis, Crohn's disease) or osteoarthritis.

  In the present invention, “prevention” means an act of administering a pharmaceutical composition containing the compound of the present invention to an individual who has not developed a disease, disorder or symptom. “Treatment” means the act of administering a pharmaceutical composition containing the compound of the present invention to an individual who has already developed a disease, disorder or symptom. Therefore, the act of administering to an individual who has already developed illness, disease, or symptom in order to prevent worsening of the symptom, seizure, or recurrence is an aspect of “treatment”.

  The pharmaceutical composition of the present invention is prepared by mixing the compound of the present invention with pharmaceutically acceptable additives (excipients, binders, disintegrants, corrigents, flavoring agents, emulsifiers, diluents, solubilizers, etc.). And can be administered orally or parenterally. The pharmaceutical composition can be formulated according to a usual method.

  In this specification, parenteral means subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip method or local administration (intra-articular administration, transdermal administration, ophthalmic administration, transpulmonary administration, bronchial administration) , Nasal administration or rectal administration, etc.).

  The dose of the compound in the present invention depends on age, body weight, general health condition, sex, meal, administration time, administration method, excretion rate, the degree of the medical condition being treated at that time of the patient, or other It is decided in consideration of the factors. The daily dose of the compound in the present invention varies depending on the patient's condition and body weight, the type of compound, the administration route, etc., for example, parenterally, subcutaneously, intravenously, intramuscularly, intraarticularly, transdermally, About 0.001 to 100 mg / person / day is administered ocularly, pulmonary / bronchially, nasally or rectally, and orally about 0.01 to 1000 mg / person / day.

  EXAMPLES Hereinafter, although this invention is demonstrated in detail by a preparation example, a manufacture example, and an experiment example, this invention is not limited at all from these.

Preparation Example 1: Preparation of 4- (4-ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

To 5-ethyl-5- (4-methylphenyl) imidazolidine-2,4-dione (1.01 g), water (40 mL), 1N aqueous sodium hydroxide solution (7.7 mL) and potassium permanganate (2. 26 g) was added and the mixture was stirred at room temperature for 30 minutes and at 80 ° C. for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, poured into a mixture of ice and concentrated hydrochloric acid, and then ethyl acetate and saturated brine were added. After performing Celite filtration, the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After the activated carbon treatment, the filtrate was concentrated under reduced pressure. Hexane / ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to obtain the title compound (989 mg).
MS (ESI) m / z: 249 (M + H) ⁺

Preparation Example 2: Preparation of 2-fluoro-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

Ethanol (20.6 mL) and 28% aqueous ammonia (15.5 mL) were added to 1- (3-fluoro-4-methylphenyl) ethanone (5.20 g), then ammonium carbonate (13.12 g), potassium carbonate ( 5.66 g) and trimethylsilylcyanide (5.33 mL) were added, and the mixture was stirred at room temperature for 4 days. The reaction solution was ice-cooled and acidified by adding concentrated hydrochloric acid dropwise, and the precipitated solid was collected by filtration to give 5- (3-fluoro-4-methylphenyl) -5-methylimidazolidine-2, 4-dione (7.02 g) was obtained.
To the obtained 5- (3-fluoro-4-methylphenyl) -5-methylimidazolidine-2,4-dione (3.00 g), water (30 mL), 1N aqueous sodium hydroxide solution (27 mL) and permanganic acid Potassium (6.61 g) was added, and the mixture was stirred at room temperature for 30 minutes and at 80 ° C. for 90 minutes. The reaction mixture was ice-cooled, ethanol (30 mL) was slowly added, and the mixture was stirred at the same temperature for 10 min and at room temperature for 1 hr. After performing Celite filtration, the filtrate was concentrated under reduced pressure, and ethanol was distilled off. The remaining aqueous solution was ice-cooled and acidified with concentrated hydrochloric acid. After adding sodium chloride, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, acetic acid (50 mL) was added to the resulting residue, and the mixture was stirred for 2 hours under heating to reflux. The reaction solution was concentrated under reduced pressure. Hexane / ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to obtain the title compound (2.05 g).
MS (ESI) m / z: 251 (M−H) ⁻

Preparation Example 3: Preparation of 2-bromo-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

1- (3-Bromo-4-methylphenyl) ethanone (3.97 g), ethanol (7.5 mL), 28% aqueous ammonia (5.6 mL), ammonium carbonate (7.16 g), potassium carbonate (3.08 g) ), Trimethylsilylcyanide (2.79 mL) was added, and the mixture was stirred at room temperature for 16 hours, and further stirred at 60 ° C. for 6 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain 5- (3-bromo-4-methylphenyl) -5-methylimidazolidine-2,4-dione (4.4 g).
1-N sodium hydroxide aqueous solution (28 mL) of the obtained 5- (3-bromo-4-methylphenyl) -5-methylimidazolidine-2,4-dione (4.0 g) and potassium permanganate (6.7 g). ) And water (113 mL) were stirred at 95 ° C. for 2 hours, and then stirred at room temperature for 1.5 hours. Ethanol (20 mL) was added to the reaction solution and stirred for 1 hour. After performing Celite filtration, the filtrate was concentrated under reduced pressure, and ethanol was distilled off. The remaining aqueous solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The solvent was distilled off, acetic acid (20 mL) was added to the resulting residue, and the mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, hexane / ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to give the title compound (3.94 g).
MS (ESI) m / z: 313 (M + H) ⁺

Preparation Example 4: Preparation of 5- (4-methyl-2,5-dioxoimidazolidin-4-yl) pyridine-2-carboxylic acid

Ethanol (12 mL) and 28% aqueous ammonia (9 mL) were added to 1- (6-methylpyridin-3-yl) ethanone (3.00 g), then ammonium carbonate (8.53 g), potassium carbonate (3.68 g) And trimethylsilylcyanide (3.46 mL) were added and stirred at room temperature for 5 days. The reaction solution was concentrated under reduced pressure, and water was added to the resulting residue, followed by neutralization with concentrated hydrochloric acid. Sodium chloride was added, followed by extraction with ethyl acetate / tetrahydrofuran. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was recrystallized from hexane / ethyl acetate to obtain 5-methyl-5- (6-methylpyridin-3-yl) imidazolidine-2,4-dione (4.18 g).
Obtained 5-methyl-5- (6-methylpyridin-3-yl) imidazolidine-2,4
-Water (50 mL), 1N sodium hydroxide aqueous solution (21.5 mL), and potassium permanganate (8.76 g) were added to dione (3.67 g), and the mixture was stirred at 60 ° C for 2 hours and at 80 ° C for 3 hours. The reaction mixture was cooled to room temperature, ethanol (30 mL) was added, and the mixture was stirred at room temperature overnight. Activated carbon was added to the reaction solution, followed by filtration. The filtrate was concentrated under reduced pressure, ethanol was distilled off, water was added to the residue, and concentrated hydrochloric acid was added under ice cooling (pH 4-5). The precipitate was collected by filtration to obtain the title compound (3.27 g).
MS (ESI) m / z: 236 (M + H) ⁺

Preparation Example 5: Preparation of 4- (4-Isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

1-sodium hydroxide aqueous solution (4.0 mL) and potassium permanganate (920 mg) were added to 5-isopropyl-5- (p-tolyl) imidazolidine-2,4-dione (450 mg), and 3 hours at room temperature for 70 hours. Stir at 0 ° C. for 2 hours. Ethanol was added to the reaction solution under ice-cooling, and the mixture was stirred for 3 hours. Celite filtration was performed, and the filtrate was concentrated under reduced pressure. Water and 1N hydrochloric acid were added to the obtained residue, and the precipitate was collected by filtration to obtain the title compound (350 mg).
MS (ESI) m / z: 261 (M−H) ⁻

Preparation Example 6: Preparation of 4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

To (R) -5-methyl-5- (p-tolyl) imidazolidine-2,4-dione (2.21 g) synthesized according to the method described in Chirality, 4, 400-403 (1992) , Potassium permanganate (6.84 g), 1N aqueous sodium hydroxide solution (21.6 mL) and water (86 mL) were added, and the mixture was stirred at 95 ° C. for 4 hr. At room temperature, ethanol (20 mL) was added and stirred for 1 hour. After filtration through celite, 1N hydrochloric acid was added to the filtrate (about pH 4), and the mixture was extracted with ethyl acetate. After washing with saturated brine, the solvent was distilled off under reduced pressure. Acetic acid (50 mL) was added to the residue, and the mixture was stirred at 110 ° C. for 1 hr. Insoluble matter was removed by filtration while hot, and the filtrate was concentrated under reduced pressure. Hexane / ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (1.7 g).
MS (ESI) m / z: 235 (M + H) ⁺

Preparation Example 7: Preparation of 4- (4-butyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

To a mixture of 4-methylvalerophenone (1.00 g), ammonium carbonate (2.18 g), potassium carbonate (0.94 g), 28% aqueous ammonia (1.98 mL), ethanol (2.84 mL), trimethylsilylcyanide ( 0.851 mL) was sequentially added, and the mixture was stirred at 60 ° C. for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Hexane / ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to obtain 5-butyl-5- (p-tolyl) imidazolidine-2,4-dione (0.449 g).
To the obtained 5-butyl-5- (p-tolyl) imidazolidine-2,4-dione (0.444 g), 1N aqueous sodium hydroxide solution (3.6 mL), potassium permanganate (0.853 g), Water (14.4 mL) was added and stirred at 95 ° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, ethanol (3.4 mL) was added, and the mixture was stirred for 1 hr. After filtration through celite, 1N hydrochloric acid (7.5 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (0.472 g).
MS (ESI) m / z: 277 (M + H) ⁺

Preparation Example 8: Preparation of 2-methyl-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

To 4-acetyl-2-methylbenzoic acid methyl ester (1 g), ethanol (4 mL), 28% aqueous ammonia (3 mL), ammonium carbonate (2 g), trimethylsilylcyanide (0.774 mL), potassium carbonate (0.863 g) ) And stirred at 60 ° C. for 6 hours. An additional 28% aqueous ammonia solution (1.5 mL) was added, and the mixture was stirred at 60 ° C. for 1.5 hr. The reaction mixture was acidified with water and concentrated hydrochloric acid under ice cooling, and the precipitate was collected by filtration. The obtained precipitate was suspended in hexane / ethyl acetate and collected by filtration to give methyl 2-methyl-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoate. The ester (0.975 g) was obtained.
The obtained 2-methyl-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid methyl ester (0.872 g) was dissolved in acetic acid (13 mL) and concentrated hydrochloric acid (13 mL). And stirred at 80 ° C. for 15 hours. The reaction solution was concentrated under reduced pressure, and water was added to the resulting residue. The title compound (0.794 g) was obtained by filtering the precipitate.
MS (ESI) m / z: 247 (M−H) ⁻

Preparation Example 9: Preparation of 4- (4-methoxymethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

Under a nitrogen stream, 4- (chloroformyl) benzoic acid methyl ester (2.17 g) in acetonitrile (20 mL) was ice-cooled, and then 0.6 M trimethylsilyldiazomethane in hexane (36.4 mL) was added dropwise at room temperature. Stir for 2 hours. The reaction mixture was ice-cooled, methanol (10 mL) and boron trifluoride diethyl ether (2.05 mL) were added, and the mixture was stirred for 2 hr. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the obtained residue was purified by column chromatography (hexane: ethyl acetate) to give 4- (2-methoxyacetyl) benzoic acid methyl ester (1.68 g).
To the obtained 4- (2-methoxyacetyl) benzoic acid methyl ester (916 mg) was added 28% aqueous ammonium (2 mL) and ethanol (5 mL), followed by ammonium carbonate (1.69 g) and potassium carbonate (1.22 g). , Trimethylsilylcyanide (1.14 mL) was added, and the mixture was stirred at room temperature for 8 days. The reaction mixture was ice-cooled, water (10 mL) and concentrated sulfuric acid (30 mL) were added to acidify, and the mixture was stirred at 100 ° C. for 2 hr and 120 ° C. for 3 hr. Under ice-cooling, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, hexane / ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (759 mg).
MS (ESI) m / z: 263 (M−H) ⁻

Preparation Example 10: Preparation of 4- (2,5-dioxo-4-trifluoromethylimidazolidin-4-yl) benzoic acid

To 4- (trifluoroacetyl) benzoic acid (218 mg) was added 28% aqueous ammonia (1 mL) and water (1 mL), followed by ammonium carbonate (768 mg), potassium carbonate (828 mg) and trimethylsilylcyanide (0.52 mL). The mixture was further stirred at room temperature for 4 hours and at 80 ° C. for 8 hours. The reaction mixture was ice-cooled, acidified with concentrated hydrochloric acid, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, hexane / ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (136 mg).
MS (ESI) m / z: 287 (M−H) ⁻

Preparation Example 11: Preparation of 4- (4-cyclopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

4-Cyclopropanecarbonylbenzoic acid methyl ester (488 mg) was dissolved in tetrahydrofuran (5 mL) and methanol (3 mL), 1N aqueous sodium hydroxide solution (3.59 mL) was added under ice cooling, and the mixture was stirred for 30 min. Stir for 2 hours. The reaction mixture was ice-cooled, 1N hydrochloric acid (5 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. By distilling off the solvent, 4-cyclopropanecarbonylbenzoic acid (441 mg) was obtained.
To the obtained 4-cyclopropanecarbonylbenzoic acid (433 mg), 28% aqueous ammonia (6 mL), water (2 mL), ammonium carbonate (2.62 g), potassium carbonate (1.89 mg) and trimethylsilylcyanide (1.69 mL). ) And stirred at 80 ° C. for 34 hours. Under ice-cooling, the reaction mixture was acidified with water and concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. Hexane / ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to obtain the title compound (589 mg).
MS (ESI) m / z: 259 (M−H) ⁻

Preparation Example 12: Preparation of 4- (4-ethyl-2,5-dioxoimidazolidin-4-yl) -2-fluorobenzoic acid

1- (3-Fluoro-4-methylphenyl) propan-1-one (3.84 g) in ethanol (30 mL), 28% aqueous ammonia (15 mL), ammonium carbonate (6.82 g), potassium carbonate (4.91 g) ) And trimethylsilylcyanide (4.6 mL) were added, and the mixture was stirred at room temperature for 20 hours and at 80 ° C. for 20 hours. 28% aqueous ammonia (15 mL), ammonium carbonate (6.82 g), potassium carbonate (4.91 g) and trimethylsilylcyanide (4.6 mL) were added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was acidified with water and concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. Hexane / ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to give 5-ethyl-5- (3-fluoro-4-methylphenyl) imidazolidine-2,4-dione (3.56 g). Got.
To the obtained 5-ethyl-5- (3-fluoro-4-methylphenyl) imidazolidine-2,4-dione (1.59 g), water (16 mL), 12N aqueous sodium hydroxide solution (3.37 mL) and Potassium manganate (3.30 g) was added, and the mixture was stirred at 80 ° C. for 2.5 hours. The reaction mixture was ice-cooled, ethanol (15 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The remaining aqueous solution was acidified by adding concentrated hydrochloric acid under ice cooling. Saturated brine was added, and the mixture was extracted with ethyl acetate / tetrahydrofuran. The solvent was distilled off, acetic acid (20 mL) was added to the resulting residue, and the mixture was stirred for 1 hour under heating to reflux. The reaction solution was concentrated under reduced pressure to obtain the title compound (1.52 g).
MS (ESI) m / z: 265 (M−H) ⁻

Preparation Example 13: Preparation of 4- (4-tert-butyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

To a mixture of 2,2-dimethyl-1- (4-methylphenyl) propan-1-one (9.85 g), tert-butanol (100 mL) and water (50 mL), 4N aqueous sodium hydroxide solution (27.9 mL) And potassium permanganate (30.91 g) were added, and the mixture was stirred at 60 ° C. for 3 days. The reaction mixture was ice-cooled, ethanol (100 mL) was added, and the mixture was stirred at room temperature. Activated carbon was added to the reaction solution, followed by filtration. The filtrate was acidified with concentrated hydrochloric acid and concentrated under reduced pressure (ethanol was distilled off). The precipitate was collected by filtration to obtain 4- (2,2-dimethylpropionyl) benzoic acid (10.2 g).
Add 28% aqueous ammonia (20 mL), ammonium carbonate (7.44 g), potassium carbonate (5.36 g), and trimethylsilylcyanide (5.04 mL) to 4- (2,2-dimethylpropionyl) benzoic acid (4 g). The mixture was stirred at 120 ° C. for 1 hour under microwave irradiation. The reaction mixture was acidified with concentrated hydrochloric acid under ice-cooling. The precipitate was collected by filtration to give the title compound (5.32 g).
MS (ESI) m / z: 275 (M−H) ⁻

Preparation Example 14: Preparation of 4-((R) -4-ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

(2R) -2-amino-2- (4-methylphenyl) carboxylic acid / hydrochloride (965 mg) was dissolved in water (10 mL), sodium cyanate (812 mg) was added, and the mixture was stirred at room temperature for 16.5 hours. Then, it stirred at 100 degreeC for 2.5 hours. The reaction mixture was allowed to cool to room temperature, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in acetic acid and stirred at 70 ° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane / ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to obtain (R) -5-ethyl-5- (p-tolyl) imidazolidine-2,4-dione (720 mg). .
To the obtained (R) -5-ethyl-5- (p-tolyl) imidazolidine-2,4-dione (550 mg), 1N aqueous sodium hydroxide solution (7.5 mL), potassium permanganate (996 mg), Water (2.5 mL) was added and stirred at 70 ° C. for 2 hours. Ethanol was added to the reaction solution, and the mixture was stirred at room temperature for 20 minutes. After filtration through celite, the filtrate was concentrated under reduced pressure. 1N hydrochloric acid was added to the remaining aqueous solution (pH <2), and the precipitate was collected by filtration to obtain the title compound (560 mg).
MS (APCI) m / z: 247 (M−H) ⁻

Preparation Example 15: Preparation of 2-fluoro-4- (4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

To 1- (3-fluoro-4-methyl-phenyl) -2-methyl-propan-1-one (4360 mg), ethanol (5 mL), ammonium carbonate (768 mg), potassium carbonate (415 mg), 28% aqueous ammonia solution ( 5 mL) and trimethylsilylcyanide (0.40 mL) were added, and the mixture was stirred at 70 ° C. for 8 hours. 1N Hydrochloric acid was added to the reaction mixture (pH <2), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give 5- (3-fluoro-4-methylphenyl) -5-isopropylimidazolidine-2,4-dione ( 390 mg).
The obtained 5- (3-fluoro-4-methylphenyl) -5-isopropylimidazolidine-2,4-dione (390 mg) was dissolved in 1N aqueous sodium hydroxide solution (2.8 mL), and potassium permanganate ( 440 mg) and water (5 mL) were added and stirred at room temperature for 9 hours. Ethanol was added to the reaction solution and stirred at room temperature for 30 minutes. After filtration through celite, the filtrate was concentrated under reduced pressure. 1N hydrochloric acid was added to the remaining aqueous solution (pH <2), and the precipitate was collected by filtration to obtain the title compound (83 mg).

Preparation Example 16: Preparation of 4- (2,5-dioxo-4-propylimidazolidin-4-yl) benzoic acid

Ethanol (15 mL) into a mixture of 1- (p-tolyl) butan-1-one (4.87 g), ammonium carbonate (11.5 g), potassium carbonate (4.98 g), 28% aqueous ammonia (10.5 mL) , Trimethylsilylcyanide (4.46 mL) was sequentially added, and the mixture was stirred at 60 ° C. for 15 hours. The reaction solution was allowed to cool to room temperature, water was added, and the precipitate was collected by filtration to obtain 5-propyl-5- (p-tolyl) imidazolidine-2,4-dione (5.58 g).
To the obtained 5-propyl-5- (p-tolyl) imidazolidine-2,4-dione (2.0 g), 1N aqueous sodium hydroxide solution (17.2 mL), water (69 mL), potassium permanganate ( 4.08 g) was added and the mixture was stirred at 95 ° C. for 2 hours. Ethanol was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. After filtration through celite, the filtrate was concentrated under reduced pressure. Concentrated hydrochloric acid was added to the remaining aqueous solution (about pH 1), and the precipitate was collected by filtration to obtain the title compound (2.32 g).
MS (ESI) m / z: 261 (M−H) ⁻

Preparation Example 17: Preparation of 4- (2,5-dioxo-4-propylimidazolidin-4-yl) -2-fluorobenzoic acid

To a solution of 1- (3-fluoro-4-methylphenyl) butan-1-one (997 mg) in ethanol (2.8 mL), ammonium carbonate (2.13 g), potassium carbonate (918 mg), 28% aqueous ammonia solution (1 .94 mL) and trimethylsilylcyanide (0.823 mL) were added, and the mixture was stirred at 75 ° C. for 2 hours and at 60 ° C. for 1 hour. After standing overnight at room temperature, 28% aqueous ammonia (2 mL) was added, and the mixture was stirred at 60 ° C. for 6.5 hr. The reaction mixture is allowed to cool to room temperature, water is added, and the precipitate is collected by filtration to give 5- (3-fluoro-4-methylphenyl) -5-propylimidazolidine-2,4-dione (803 mg). Obtained.
To the obtained 5- (3-fluoro-4-methylphenyl) -5-propylimidazolidine-2,4-dione (790 mg), 1N aqueous sodium hydroxide solution (6.31 mL), water (25.3 mL), Potassium permanganate (1.50 g) was added, and the mixture was stirred at 95 ° C. for 1 hr. Ethanol was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. After filtration through celite, the filtrate was concentrated under reduced pressure. The remaining aqueous solution was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The solvent was distilled off, hexane / ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (664 mg).
MS (ESI) m / z: 279 (M−H) ⁻

Preparation Example 18: Preparation of 3-fluoro-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

1- (2-fluoro-4-methylphenyl) ethanone (5.53 g), ethanol (14.5 mL), 28% aqueous ammonia (10 mL), ammonium carbonate (13.9 g), potassium carbonate (6.0 g) To the suspension, trimethylsilylcyanide (5.4 mL) is added,
The mixture was stirred at 60 ° C. for 2 hours and at 80 ° C. for 1.5 hours. Water was added to the reaction solution, and the precipitate was collected by filtration to obtain 5- (2-fluoro-4-methylphenyl) -5-methylimidazolidine-2,4-dione (4.69 g).
To the obtained 5- (2-fluoro-4-methylphenyl) -5-methylimidazolidine-2,4-dione (4.69 g), potassium permanganate (10.0 g), 1N aqueous sodium hydroxide solution ( 42 mL) and water (168 mL) were added, and the mixture was stirred at 95 ° C. for 2.5 hours. Ethanol (40 mL) was added to the reaction mixture, and the mixture was stirred at room temperature. After filtration through Celite, 1N hydrochloric acid was added to the filtrate (about pH 4), and the precipitate was collected by filtration to obtain the title compound (3.38 g).
MS (ESI) m / z: 251 (M−H) ⁻

Preparation Example 19: Preparation of 4- (4-ethyl-2,5-dioxoimidazolidin-4-yl) -2-methylbenzoic acid

1- (4-Bromo-3-methylphenyl) propan-1-one (1.03 g), ethanol (4.5 mL), 28% aqueous ammonia (1.5 mL), ammonium carbonate (1.7 g), potassium carbonate (746 mg) was added with trimethylsilylcyanide (676 μL), and the mixture was stirred at room temperature for 2 hours and at 60 ° C. for 2 hours. Trimethylsilylcyanide (169 μL) and potassium carbonate (186 mg) were added to the reaction solution, and the mixture was stirred at 60 ° C. for 1 hour. Water was added to the reaction solution, and the precipitate was collected by filtration to obtain 5- (4-bromo-3-methylphenyl) -5-ethylimidazolidine-2,4-dione (990 mg).
5- (4-Bromo-3-methylphenyl) -5-ethylimidazolidine-2,4-dione (985 mg), zinc cyanide (233 mg), zinc (26 mg), 1,1′-bis ( A mixture of diphenylphosphino) ferrocene (183 mg), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct (171 mg) and N, N-dimethylacetamide (10 mL) was stirred at 130 ° C. for 6.5 hours. Water and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate, and the solvent was distilled off. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to give 4- (4-ethyl-2,5-dioxoimidazolidin-4-yl) -2-methylbenzonitrile (360 mg). It was.
Acetic acid (5 mL) and concentrated hydrochloric acid (5 mL) were added to the obtained 4- (4-ethyl-2,5-dioxoimidazolidin-4-yl) -2-methylbenzonitrile (360 mg) at 80 ° C. Stir for 2 days. Concentrated sulfuric acid (2.0 mL) was added to the reaction solution, followed by stirring at 100 ° C. for 1 day and at 120 ° C. for 1 day. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, water was added to the resulting residue, and the precipitate was collected by filtration to obtain the crude title compound (270 mg).
MS (ESI) m / z: 263 (M + H) ⁺

Preparation Example 20: Preparation of 4- (3-ethyl-2,5-dioxopyrrolidin-3-yl) benzoic acid

To 3-ethyl-3- (4-methylphenyl) pyrrolidine-2,5-dione (2.0 g), water (40 mL), 1N aqueous sodium hydroxide solution (18.41 mL), potassium permanganate (4.36 g) ) And stirred at room temperature overnight. Ethanol (20 mL) was added to the reaction mixture, and the mixture was stirred for 1 hr, and filtered through celite. The filtrate was concentrated under reduced pressure and acidified with concentrated hydrochloric acid. The title compound (1.63 g) was obtained by filtering the precipitate.
MS (ESI) m / z: 246 (M−H) ⁻

Preparation Example 21: Preparation of 3-iodo-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

1- (2-iodo-4-methylphenyl) ethanone (3.9 g), ethanol (7.5 mL), 28% aqueous ammonia (5 mL), ammonium carbonate (5.7 g), potassium carbonate (2.5 g) Trimethylsilyl cyanide (2.81 mL) was added to the suspension and stirred at 60 ° C. for 4.5 hours. Water was added to the reaction solution, and the precipitate was collected by filtration to obtain 5- (3-iodo-4-methylphenyl) -5-methylimidazolidine-2,4-dione (3.77 g).
To the obtained 5- (3-iodo-4-methylphenyl) -5-methylimidazolidine-2,4-dione (1.65 g), 1N aqueous sodium hydroxide solution (10 mL), water (40 mL), permanganese Potassium acid (2.37 g) was added and stirred at 95 ° C. for 5 hours. Ethanol (10 mL) was added to the reaction mixture, and the mixture was stirred at room temperature and filtered through celite. The filtrate was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The solvent was distilled off, acetic acid (20 mL) was added to the resulting residue, and the mixture was stirred at 80 ° C. for 3 hours. After concentration under reduced pressure, hexane / ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (1.39 g).
MS (ESI) m / z: 361 (M + H) ⁺

Preparation Example 22: 3-methoxy-4- (4-methyl-2,5-dioxoimidazolidine-4-
Il) Preparation of benzoic acid

4-acetyl-3-methoxybenzoic acid (0.5 g), water (2.3 mL), ammonium carbonate (0.99 g), potassium carbonate (1.07 g), 28% aqueous ammonia (2.3 mL), trimethylsilyl Cyanide (643 μL) was added and stirred at room temperature overnight. 1N hydrochloric acid was added to the reaction solution to make it acidic. The precipitate was collected by filtration to give the title compound (0.466 g).
MS (APCI) m / z: 265 (M + H) ⁺

Preparation Example 23: Preparation of 4- (4-hydroxymethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

1-M boron tribromide / dichloromethane solution (7.57 mL) was added to 4- (4-methoxymethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (200 mg) described in Preparation Example 9 at room temperature. For 4 days. The reaction mixture was ice-cooled, water was added, and insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and methanol was added to the resulting residue, followed by concentration under reduced pressure. Acetic acid (2 mL) and concentrated hydrochloric acid (2 mL) were added to the resulting residue, and the mixture was stirred at 80 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (126 mg).
MS (ESI) m / z: 249 (M−H) ⁻ , 251 (M + H) ⁺

Preparation Example 24: Preparation of 4- (4-ethoxymethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

A solution of methyl-4- (chloroformyl) benzoic acid (6.00 g) in acetonitrile (60 mL) is ice-cooled, 0.6M trimethylsilyldiazomethane / hexane solution (75.5 mL) is added dropwise, and the same temperature is maintained for 30 minutes at room temperature. For 2 hours. The reaction mixture was ice-cooled, ethanol (30 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hr. The reaction solution was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: chloroform) to obtain 4- (2-diazoacetyl) benzoic acid methyl ester (4.83 g).
4- (2-diazoacetyl) benzoic acid methyl ester (4.82 g) was dissolved in tetrahydrofuran (50 mL) and methanol (30 mL), and 1N aqueous sodium hydroxide solution (32.5 mL) was added under ice-cooling. For 30 minutes and at room temperature for 1.5 hours. 1N Hydrochloric acid (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was dissolved in acetonitrile (50 mL) and ethanol (50 mL). Boron trifluoride diethyl ether (7 mL) was added dropwise under ice cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was ice-cooled, brine was added, and the mixture was extracted with ethyl acetate. After performing activated carbon treatment, the solvent was distilled off to obtain 4- (2-ethoxyacetyl) benzoic acid (4.25 g).
4- (2-Ethoxyacetyl) benzoic acid (4.24 g) was added to water (20 mL), 28% aqueous ammonia (20 mL), ammonium carbonate (7.83 g), potassium carbonate (8.44 g) and trimethylsilylcyanide ( 5.29 mL) was added and stirred at room temperature for 20 hours. The reaction mixture was acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The solvent was distilled off, 2M hydrogen chloride / ethanol solution (80 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography and NH column chromatography (chloroform: methanol) to give 4- (4-ethoxymethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid. Acid ethyl ester (2.66 g) was obtained.
A 1N aqueous sodium hydroxide solution (26 mL) was added to 4- (4-ethoxymethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid ethyl ester (2.64 g) under ice cooling, and the mixture was stirred for 2 hours. . 1N Hydrochloric acid (30 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration to obtain the title compound (2.28 g).
MS (ESI) m / z: 277 (M−H) ⁻

Preparation Example 25: Preparation of 4- [4- (1-methoxy-1-methylethyl) -2,5-dioxoimidazolidin-4-yl] benzoic acid

Under a nitrogen stream, 4- (2-hydroxy-2-methylpropionyl) benzoic acid methyl ester (222 mg) in tetrahydrofuran (3 mL) was added with ice-cooled methyl iodide (0.186 mL) and 60% sodium hydride ( 160 mg) was added. After stirring at room temperature overnight, water (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. After the activated carbon treatment, the solvent was distilled off to obtain 4- (2-methoxy-2-methylpropionyl) benzoic acid methyl ester (234 mg).
To the obtained 4- (2-methoxy-2-methylpropionyl) benzoic acid methyl ester (225 mg), ammonium carbonate (481 mg), potassium carbonate (415 mg), trimethylsilylcyanide (0.389 mL) and 28% aqueous ammonia ( 2 mL) was added, and the mixture was stirred at 100 ° C. for 50 minutes under microwave irradiation. The reaction mixture was acidified with water and concentrated hydrochloric acid, and extracted with ethyl acetate / tetrahydrofuran. The solvent was distilled off, hexane / ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (101.5 mg).
MS (ESI) m / z: 291 (M−H) ⁻

Preparation Example 26: Preparation of 2,3-difluoro-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

To 1- (2,3-difluoro-4-methylphenyl) ethanone (2 g), ethanol (6 mL), ammonium carbonate (4.52 g), potassium carbonate (1.95 g), 28% aqueous ammonia (4.1 mL) , Trimethylsilylcyanide (1.8 mL) was added, and the mixture was stirred at 60 ° C. for 4 hours. 28% aqueous ammonia (3 mL) and ammonium carbonate (2.2 g) were added, and the mixture was stirred at 60 ° C. for 2 hr. Water was added to the reaction solution, followed by stirring for 1 hour under ice cooling. The precipitated solid was collected by filtration to obtain 5- (2,3-difluoro-4-methylphenyl) -5-methylimidazolidine-2,4-dione (2.2 g).
To the obtained 5- (2,3-difluoro-4-methylphenyl) -5-methylimidazolidine-2,4-dione (1 g), water (33 mL), 1N aqueous sodium hydroxide solution (8.3)
mL) and potassium permanganate (1.97 g) were added, and the mixture was stirred at 90 ° C. for 3 hours. Ethanol (6 mL) was added to the reaction mixture, and the mixture was stirred for 1 hr, and filtered through celite. The filtrate was concentrated under reduced pressure, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The solvent was distilled off, diisopropyl ether was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (0.91 g).
MS (APCI) m / z: 269 (M−H) ⁻

Preparation Example 27: Preparation of 4- (4-isobutyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

4- (3-methylbutyryl) benzoic acid (1.68 g), ammonium carbonate (3.13 g), potassium carbonate (1.35 g), 28% aqueous ammonia solution (5.0 mL), ethanol (6.7 mL), trimethylsilyl Cyanide (1.21 mL) was added and stirred at 60 ° C. for 17 hours. Ammonium carbonate (1.565 g), potassium carbonate (1.35 g), 28% aqueous ammonia solution (1.0 mL), ethanol (1.5 mL), trimethylsilylcyanide (1.21 mL) were added to the reaction solution, Stir at 24 ° C. for 24 hours. Under ice cooling, the reaction mixture was acidified with water and concentrated hydrochloric acid, and the precipitate was collected by filtration. The obtained precipitate was suspended in hexane / ethyl acetate / ethanol and collected by filtration to obtain the title compound (1.91 g).
MS (ESI) m / z: 275 (M−H) ⁻

Preparation Example 28: Preparation of 2-fluoro-4- (4-methoxymethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

1- (3-Fluoro-4-methylphenyl) -2-methoxyethanone (2.11 g), ammonium carbonate (4.18 g), potassium carbonate (3.20 g), ethanol (8.4 mL), 28% ammonia Trimethylsilyl cyanide (3.10 mL) was added to a mixture of water (6.3 mL), and the mixture was stirred at 60 ° C. for 1.5 hours. Ammonium carbonate (4.18 g), potassium carbonate (3.20 g), ethanol (8.4 mL), 28% aqueous ammonia (6.3 mL) and trimethylsilylcyanide (3.10 mL) were added, and the mixture was stirred at 60 ° C. overnight. did. Under ice-cooling, concentrated hydrochloric acid was added to the reaction solution to make it acidic. The precipitate was collected by filtration to obtain 5- (3-fluoro-4-methylphenyl) -5-methoxymethylimidazolidine-2,4-dinone (2.74 g).
To the obtained 5- (3-fluoro-4-methylphenyl) -5-methoxymethylimidazolidine-2,4-dinone (2.74 g), water (27.4 mL), 12N aqueous sodium hydroxide solution (1. 81 mL) and potassium permanganate (3.60 g) were added, and the mixture was stirred at room temperature for 6 hours. Potassium permanganate (3.42 g) was added, and the mixture was stirred at room temperature overnight. Ethanol was added to the reaction solution, followed by filtration through celite. The filtrate was concentrated under reduced pressure, water and concentrated hydrochloric acid were added to the resulting residue, and the precipitate was collected by filtration to give 2-fluoro-4- (4-methoxymethyl-2,5-dioxoimidazoline-4- Il) A crude product of benzoic acid (1.50 g) was obtained.
To a solution of the obtained 2-fluoro-4- (4-methoxymethyl-2,5-dioxoimidazolin-4-yl) benzoic acid crude product (1.03 g) in methanol (15 mL) was concentrated under ice-cooling. Sulfuric acid (5.15 mL) was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) and methyl 2-fluoro-4- (4-methoxymethyl-2,5-dioxoimidazolin-4-yl) benzoate. (293 mg) was obtained.
To the obtained methyl 2-fluoro-4- (4-methoxymethyl-2,5-dioxoimidazolin-4-yl) benzoate (293 mg) was added 1N aqueous sodium hydroxide solution (2.96 mL), and 4 Stir for hours. 1N Hydrochloric acid was added to the reaction mixture, and the precipitate was collected by filtration to give the title compound (230 mg).
MS (ESI) m / z: 281 (M−H) ⁻

Preparation Example 29 Preparation of 2-fluoro-4-((R) -4-methyl-2,5-dioxoimidazolidin-4yl) benzoic acid

5- (3-Fluoro-4-methylphenyl) -5-methylimidazolidine-2,4-dione (6.77 g), water (57.6 mL), 1N aqueous sodium hydroxide solution (21) described in Preparation Example 2 (S) -1-phenylethylamine (11.8 mL) was added to a mixed solution of 3 mL). Water (49.4 mL) and ethanol (12.1 mL) were added, and the precipitate was dissolved under heating. The mixture is allowed to cool to room temperature, and the precipitate is collected by filtration to give (R) -5- (3-fluoro-4-methylphenyl) -5-methylimidazolidine-2,4-dione. (S) -1- A crude phenylethylamine salt (2.67 g) was obtained. Water (40 mL) was added to the obtained crude product (2.67 g), and the mixture was refluxed for 3 hours. The mixture is allowed to cool to room temperature, and the precipitate is collected by filtration to give (R) -5- (3-fluoro-4-methylphenyl) -5-methylimidazolidine-2,4-dione. (S) -1- A phenylethylamine salt (2.23 g) was obtained.
(R) -5- (3-Fluoro-4-methylphenyl) -5-methylimidazolidine-2,4-dione (S) -1-phenylethylamine salt (2.58 g) was mixed with water (77.4 m).
L) and 1N hydrochloric acid (77.4 mL) were added, and the mixture was stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration to obtain (R) -5- (3-fluoro-4-methylphenyl) -5-methylimidazolidine-2,4-dione (1.71 g).
(R) -5- (3-Fluoro-4-methylphenyl) -5-methylimidazolidine-2,4-dione (1.7 g), water (17 mL), 12N aqueous sodium hydroxide solution (1.12 mL) , Potassium permanganate (2.24 g) was added, and the mixture was stirred at room temperature for 48 hours. Ethanol was added to the reaction solution, followed by filtration through celite. The filtrate was concentrated under reduced pressure, water and concentrated hydrochloric acid were added to the resulting residue, and the precipitate was collected by filtration. The obtained precipitate was suspended in hexane / ethyl acetate and collected by filtration to obtain the title compound (1.49 g).
MS (ESI) m / z: 251 (M−H) ⁻

Preparation 30: Preparation of 4- (2,5-dioxo-4-propylimidazolidin-4-yl) -3-fluorobenzoic acid

Under ice cooling, n-propylmagnesium bromide / tetrahydrofuran solution (1.02M) (8.0 mL) was added to a solution of 2-fluoro-N-methoxy-4, N-dimethylbenzamide (1.50 g) in tetrahydrofuran (20 mL). Added and stirred for 2 hours. 1N Hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to give 1- (2-fluoro-4-methylphenyl) butan-1-one (677 mg).
To a solution of 1- (2-fluoro-4-methylphenyl) butan-1-one (675 mg) in ethanol (1.89 mL), ammonium carbonate (1.44 g), potassium carbonate (621 mg), 28% aqueous ammonia solution (1 .31 mL) and trimethylsilylcyanide (0.557 mL) were added and stirred at room temperature overnight. A 28% aqueous ammonia solution (1.00 mL), ammonium carbonate (1.00 g), and trimethylsilylcyanide (0.20 mL) were added, and the mixture was stirred at 45 ° C. for 9 hours. The reaction mixture is allowed to cool to room temperature, water is added, and the precipitated solid is collected by filtration to give 5- (2-fluoro-4-methylphenyl) -5-propylimidazolidine-2,4-dione (572 mg). Got.
To 5- (2-fluoro-4-methylphenyl) -5-propylimidazolidine-2,4-dione (569 mg), 1N aqueous sodium hydroxide solution (4.54 mL), water (18.2 mL), permanganic acid Potassium (1.08 g) was added, and the mixture was stirred at room temperature for 15 hours and at 60 ° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, ethanol was added, and the mixture was stirred for 1 hr. After performing Celite filtration, the filtrate was concentrated under reduced pressure, and ethanol was distilled off. Under ice-cooling, concentrated hydrochloric acid was added to the remaining aqueous solution (about pH 1), and the precipitated solid was collected by filtration to obtain the title compound (352 mg).
MS (ESI) m / z: 279 (M−H) ⁻

Preparation Example 31: Preparation of 4- [2,5-dioxo-4- (3,3,3-trifluoropropyl) imidazolidin-4-yl] benzoic acid

Methanol (0.5 mL) and 1N aqueous sodium hydroxide (1.55 mL) were added to 4- (4,4,4-trifluorobutyryl) benzoic acid methyl ester (200 mg), and the mixture was stirred at room temperature for 4 hours. 1N Hydrochloric acid was added to the reaction mixture (pH <2), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4- (4,4,4-trifluorobutyryl) benzoic acid (183 mg).
To the obtained 4- (4,4,4-trifluorobutyryl) benzoic acid (180 mg), ammonium carbonate (280 mg), potassium carbonate (200 mg), 28% aqueous ammonia solution (2.5 mL), ethanol (2. 5 mL) and trimethylsilylcyanide (0.15 mL) were added, and the mixture was stirred at 100 ° C. for 2 hours under microwave irradiation. The reaction mixture was allowed to cool to room temperature, 1N hydrochloric acid was added (pH <2), and the precipitate was collected by filtration to give the title compound (169 mg).

Preparation 32: Preparation of 4- [2,5-dioxo-4- (tetrahydropyran-4-yl) imidazolidin-4-yl] benzoic acid

4- (4-Methylbenzoyl) oxane (0.2 g), ammonium carbonate (0.377 g), potassium carbonate (0.163 g), 28% aqueous ammonia solution (0.343 mL), ethanol (0.98 mL), water (0.98 mL) and trimethylsilylcyanide (0.147 mL) were added, and the mixture was stirred at 60 ° C. overnight. Ammonium carbonate (0.377 g), potassium carbonate (0.163 g), 28% aqueous ammonia solution (0.343 mL) and trimethylsilylcyanide (0.147 mL) were added, and the mixture was irradiated at 100 ° C. for 2.5 hours under microwave irradiation. Stir. Ammonium carbonate (0.377 g), potassium carbonate (0.163 g), 28% aqueous ammonia solution (0.343 mL) and trimethylsilylcyanide (0.147 mL) were added, and the mixture was irradiated at 100 ° C. for 1.5 hours under microwave irradiation. Stir. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Hexane was added to the resulting residue, and the precipitate was collected by filtration to give 5- (tetrahydropyran-4-yl) -5- (p-tolyl) imidazolidine-2,4-dione (0.186 g). Obtained.
To the obtained 5- (tetrahydropyran-4-yl) -5- (p-tolyl) imidazolidine-2,4-dione (0.180 g), 1N aqueous sodium hydroxide solution (0.132 mL), permanganic acid Potassium (0.332 g) and water (0.528 mL) were added, and the mixture was stirred at room temperature for 11 hours. Ethanol (1.32 mL) was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (0.183 g). MS (ESI) m / z: 303 (M−H) ⁻

Preparation Example 33 Preparation of 4- (4-cyclobutyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

To cyclobutyl (p-tolyl) methanone (4.75 g), ammonium carbonate (10.47 g), potassium carbonate (4.52 g), 28% aqueous ammonia solution (9.54 mL), ethanol (54.6 mL), water (27 3 mL) and trimethylsilylcyanide (4.09 mL) were added, and the mixture was stirred at 60 ° C. overnight. Under ice cooling, water was added to the reaction solution, and the precipitate was collected by filtration. The obtained precipitate was dissolved in ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, hexane was added to the obtained residue, and the precipitate was collected by filtration to obtain 5-cyclobutyl-5-p-tolyrimidazolidin-2,4-dione (3.64 g).
To the obtained 5-cyclobutyl-5-p-tolyrimidazolidin-2,4-dione (3.64 g), 1N aqueous sodium hydroxide solution (298 mL), potassium permanganate (4.94 g), water (119 mL) And stirred at room temperature for 16 hours and at 50 ° C. for 6 hours. Dimethyl sulfoxide (1.49 mL) was added to the reaction solution, followed by filtration through celite. The filtrate was acidified with 1N hydrochloric acid, and the precipitate was collected by filtration to give the title compound (3.78 g).
MS (ESI) m / z: 273 (M−H) ⁻

Preparation Example 34: Preparation of 4- (4-cyclopropyl-2,5-dioxoimidazolidin-4-yl) -2-fluorobenzoic acid

To a solution of cyclopropyl (3-fluoro-4-methylphenyl) methanone (2.11 g) in ethanol (6.1 mL), ammonium carbonate (4.66 g), potassium carbonate (2 g), 28% aqueous ammonia solution (4.24 mL). ) And trimethylsilylcyanide (1.8 mL) were sequentially added, and the mixture was stirred overnight at room temperature, and then stirred at 60 ° C. for 4 hours. 28% Aqueous ammonia solution (4.24 mL), ammonium carbonate (4.66 g), trimethylsilylcyanide (1.8 mL), potassium carbonate (2 g), ethanol (6.1 mL) were added, and the mixture was added at 45 ° C. for 6 hours, 60 hours. The mixture was stirred at ° C for 7 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate) to obtain 5-cyclopropyl-5- (3-fluoro-4-methylphenyl) imidazolidine-2,4-dione (1.1 g). It was.
To the obtained 5-cyclopropyl-5- (3-fluoro-4-methylphenyl) imidazolidine-2,4-dione (1.08 g), 1N aqueous sodium hydroxide solution (9 mL), water (36 mL), Potassium manganate (1.37 g) was added, and the mixture was stirred overnight at room temperature. Potassium permanganate (500 mg) was added, and the mixture was stirred overnight at room temperature. The reaction solution was filtered through Celite, and the obtained filtrate was acidified with concentrated hydrochloric acid and then separated with chloroform. The aqueous layer was concentrated under reduced pressure, and the precipitated solid was collected by filtration to obtain the title compound (500 mg).
MS (ESI) m / z: 279 (M + H) ⁺

Preparation Example 35 Preparation of 4- (4-Isopropyl-2,5-dioxoimidazolidin-4-yl) -3-methoxybenzoic acid

1) Preparation of 4-isobutyryl-3-methoxybenzoic acid 1- (4-Bromo-2-methoxyphenyl) -2-methylpropan-1-one (7.97 g) was added palladium acetate (0.674 g), 1 , 1′-bis (diphenylphosphino) ferrocene (0.832 g), methanol (24.3 mL), N, N-dimethylformamide (75 mL), triethylamine (8.36 mL) were added, and carbon monoxide atmosphere was used. Stir at 5 ° C. for 5 hours. The reaction mixture was poured into cold water and extracted with ethyl acetate. SH silica, activated carbon, and anhydrous sodium sulfate were added to the organic layer, followed by filtration. The filtrate was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with diethyl ether. SH silica, activated carbon, and anhydrous sodium sulfate were added to the organic layer, followed by filtration. The filtrate was concentrated under reduced pressure to obtain 4-isobutyryl-3-methoxybenzoic acid methyl ester (7.015 g).
To a solution of the obtained 4-isobutyryl-3-methoxybenzoic acid methyl ester (7.01 g) in tetrahydrofuran (148 mL) was added 2N aqueous sodium hydroxide solution (44.5 mL), and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and hexane was added to the remaining aqueous solution, followed by liquid separation. The aqueous layer was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Hexane / diisopropyl ether was added to the resulting residue, and the precipitate was collected by filtration to obtain 4-isobutyryl-3-methoxybenzoic acid (4.426 g).

2) Preparation of 4- (4-isopropyl-2,5-dioxoimidazolidin-4-yl) -3-methoxybenzoic acid 4-isobutyryl-3-methoxybenzoic acid (0.571 g) according to 1) above Water (2.3 mL), ammonium carbonate (1.98 g), potassium carbonate (1.07 g), 28% aqueous ammonia (4.6 mL), and trimethylsilylcyanide (1.29 mL) were added at 8O 0 C at 8 ° C. Stir for hours. The reaction mixture was acidified with 1N hydrochloric acid, and the precipitated solid was collected by filtration to give 4- (4-isopropyl-2,5-dioxoimidazolidin-4-yl) -3-methoxybenzoic acid ( 0.69 g) was obtained.
MS (APCI) m / z: 293 (M + H) ⁺

Preparation Example 36 Preparation of 4- [4- (2-methoxyethyl) -2,5-dioxoimidazolidin-4-yl] benzoic acid

3-methoxy-1- (4-methylphenyl) propan-1-one (651 mg), ammonium carbonate (1.24 g), potassium carbonate (0.949 g), ethanol (2.6 mL), 28% aqueous ammonia ( 2 mL) and trimethylsilylcyanide (893 μL) were added and stirred at 60 ° C. overnight. Under ice-cooling, concentrated hydrochloric acid was added to the reaction solution to make it acidic. The precipitate was collected by filtration to obtain 5- (2-methoxyethyl) -5- (p-tolyl) imidazolidine-2,4-dione (690 mg).
To the obtained 5- (2-methoxyethyl) -5- (p-tolyl) imidazolidine-2,4-dione (670 mg), water (6.7 mL), 12N aqueous sodium hydroxide solution (0.45 mL), Potassium permanganate (0.9 g) was added and stirred at room temperature for 30 hours. Potassium permanganate (0.86) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was ice-cooled, ethanol was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure.
Water and concentrated hydrochloric acid were added to the resulting residue, followed by filtration. The filtrate was extracted with a mixed solvent of chloroform and ethanol. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a crude product of the title compound (280 mg).
MS (ESI) m / z: 277 (M−H) ⁻

Preparation Example 37 Preparation of 4- (2,5-dioxo-4-phenylimidazolidin-4-yl) benzoic acid

To p-benzoylbenzoic acid (2 g), ammonium carbonate (3.4 g), potassium carbonate (3.67 g), trimethylsilylcyanide (2.3 mL), 28% aqueous ammonia (10 mL), water (10 mL), methanol ( 20 mL) was added and stirred at 60 ° C. overnight. Ammonium carbonate (3.4 g), potassium carbonate (3.67 g), trimethylsilylcyanide (2.3 mL), 28% aqueous ammonia (10 mL) and methanol (10 mL) were added, and the mixture was stirred at 60 ° C. overnight. Furthermore, potassium carbonate (2.44 g) and trimethylsilylcyanide (2.3 mL) were added, and the mixture was stirred at 60 ° C. overnight.
The reaction mixture was acidified with water and concentrated hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The solvent was distilled off, hexane / ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (2.6 g).
MS (ESI) m / z: 295 (M−H) ⁻

Preparation Example 38 Preparation of 4- [4- (2-methoxy-1,1-dimethylethyl) -2,5-dioxoimidazolidin-4-yl] benzoic acid

To a solution of 3-methoxy-2,2-dimethylpropanoic acid (2 g) in chloroform (20 mL) was added oxalyl chloride (1.95 mL) and N, N-dimethylformamide (one drop) under ice cooling, and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was concentrated under reduced pressure, and toluene (50 mL), 4- (methoxycarbonyl) phenylboric acid (2 g), tripotassium phosphate (4.72 g), bis (tricyclohexylphosphine) palladium (II) dichloride was added to the resulting residue. (39
0 mg) and water (0.6 mL) were added, and the mixture was heated to reflux for 30 minutes under a nitrogen stream. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to give 4- (3-methoxy-2,2-dimethylpropionyl) benzoic acid methyl ester (570 mg). To the obtained 4- (3-methoxy-2,2-dimethylpropionyl) benzoic acid methyl ester (560 mg) was added methanol (5 mL), tetrahydrofuran (5 mL), 1N aqueous sodium hydroxide solution (4.5 mL), and room temperature. For 3 hours. Ethyl acetate was added to the reaction solution, and back extraction was performed with water and an aqueous potassium carbonate solution. The separated aqueous layers were combined, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give 4- (3-methoxy-2,2-dimethylpropionyl) benzoic acid (518 mg).
4- (3-Methoxy-2,2-dimethylpropionyl) benzoic acid (503 mg), ammonium carbonate (1.02 g), potassium carbonate (1.47 g), trimethylsilylcyanide (831 μL), 28% aqueous ammonia (6 mL) ) And water (3 mL) were added, and the mixture was stirred at 150 ° C. for 1 hour under microwave irradiation. Trimethylsilylcyanide (831 μL) was added, and the mixture was stirred at 150 ° C. for 1 hour under microwave irradiation. Furthermore, potassium carbonate (1.47 g), trimethylsilylcyanide (1662 μL) and 28% aqueous ammonia (3 mL) were added, and the mixture was stirred at 150 ° C. for 2 hours under microwave irradiation. Water and ethyl acetate were added to the reaction mixture, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. Hexane / ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to obtain the title compound (552 mg).
MS (ESI) m / z: 307 (M + H) ⁺

Preparation Example 39 Preparation of 4- (4-Isopropyl-2,5-dioxoimidazolidin-4-yl) -3-methylbenzoic acid

To 1- (4-bromo-2-hydroxyphenyl) -2-methylpropan-1-one (12.89 g), 1,1′-bis (diphenylphosphino) ferrocene (2.94 g), dipalladium acetate ( II) (595 mg), N, N-dimethylformamide (133 mL), methanol (42.9 mL) and triethylamine (22.2 mL) were added, and the mixture was stirred at 80 ° C. for 14 hours in a carbon monoxide atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to give 3-hydroxy-4-isobutyrylbenzoic acid methyl ester (10.14 g).
To a solution of the obtained 3-hydroxy-4-isobutyrylbenzoic acid methyl ester (5 g) in dichloromethane (225 mL), N, N-diisopropylethylamine (19.6 mL), N-phenylbis (trifluoromethanesulfonimide) (16. 1 g) was added and stirred at room temperature for 20 hours. N-phenylbis (trifluoromethanesulfonimide) (9.0
g) was added and stirred at room temperature for 33 hours. Further, N-phenylbis (trifluoromethanesulfonimide) (9.0 g) and N, N-diisopropylethylamine (5 mL) were added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate) to obtain 4-isobutyryl-3-trifluoromethanesulfonyloxybenzoic acid methyl ester (7.99 g).
To the resulting 4-isobutyryl-3-trifluoromethanesulfonyloxybenzoic acid methyl ester (7 g), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride / dichloromethane adduct (806 mg), carbonic acid Potassium (6.82 g), 1,4-dioxane (132 mL) and 2,4,6-trimethylboroxine (5.5 mL) were added, and the mixture was stirred at 110 ° C. for 3 hours under an argon atmosphere. At room temperature, activated carbon and heavy metal-removed silica (SH Silica) were added to the reaction solution, followed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give 4-isobutyryl-3-methylbenzoic acid methyl ester (3.97 g).
Methanol (5 mL), 1N aqueous sodium hydroxide solution (15 mL) and tetrahydrofuran (8 mL) were added to the resulting 4-isobutyryl-3-methylbenzoic acid methyl ester (2.2 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and 1N hydrochloric acid was added. The precipitated solid was collected by filtration to obtain 4-isobutyryl-3-methylbenzoic acid. To the obtained 4-isobutyryl-3-methylbenzoic acid, ethanol (5 mL), 28% aqueous ammonia (3.5 mL), ammonium carbonate (3.8 g), potassium carbonate (1.66 g), trimethylsilylcyanide (1 0.5 mL) and stirred at 60 ° C. for 8 hours. Trimethylsilyl cyanide (3.75 mL) and potassium carbonate (6.9 g) were added, and the mixture was stirred at 80 to 100 ° C. for 1 day. Furthermore, trimethylsilylcyanide (3.75 mL) and potassium carbonate (6.9 g) were added, and the mixture was stirred at 60 ° C. for 1 day. The reaction mixture was neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The solvent was distilled off under reduced pressure, 1N hydrochloric acid, water and methanol were added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound as a crude product (943 mg).
MS (ESI) m / z: 275 (M−H) ⁻

Preparation 40: Preparation of 4- (4-ethyl-2,5-dioxoimidazolidin-4-yl) -3-fluorobenzoic acid

To 1- (4-bromo-2-fluorophenyl) propan-1-one (2.3 g), ethanol (5 mL), 28% aqueous ammonia (3.5 mL), ammonium carbonate (3.8 g), potassium carbonate ( 1.66 g) and trimethylsilylcyanide (1.5 mL) were added, and the mixture was stirred at 50 ° C. for about 5 hours. Trimethylsilylcyanide (0.25 mL), potassium carbonate (830 mg) and 28% aqueous ammonia (1.5 mL) were added, and the mixture was stirred at 60 ° C. for 8 hr. Water was added to the reaction solution, and the precipitate was collected by filtration. The obtained precipitate was suspended in diethyl ether / hexane and collected by filtration to give 5- (4-bromo-2-fluorophenyl) -5-ethylimidazolidine-2,4-dione (795 mg). Got.
The resulting 5- (4-bromo-2-fluorophenyl) -5-ethylimidazolidine-2,4-dione (789 mg) was added to zinc cyanide (450 mg), zinc (25 mg), 1,1′-bis. (Diphenylphosphino) ferrocene (177 mg), tris (dibenzylideneacetone) dipalladium (0) (146 mg), N, N-dimethylformamide (10 mL) were added, and the mixture was stirred at 130 ° C. for 7 hours. The reaction solution was purified by column chromatography (hexane: ethyl acetate). The solvent was distilled off, hexane / ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to give 4- (4-ethyl-2,5-dioxoimidazolidin-4-yl) -3- Fluorobenzonitrile (225 mg) was obtained.
The obtained 4- (4-ethyl-2,5-dioxoimidazolidin-4-yl) -3-fluorobenzonitrile (220 mg) was added to acetic acid (1 mL), concentrated hydrochloric acid (1 mL), concentrated sulfuric acid (1 mL). And stirred at 120 ° C. for 8.5 hours. Water was added and the precipitated solid was collected by filtration to obtain the title compound (211 mg).
MS (ESI) m / z: 265 (M−H) ⁻

Preparation Example 41: Preparation of 4- (3-methyl-2,5-dioxopyrrolidin-3-yl) benzoic acid

To 3-methyl-3- (4-methylphenyl) pyrrolidine-2,5-dione (698 mg), 1N aqueous sodium hydroxide solution (7.0 mL), water (28 mL), and potassium permanganate (1.09 g) were added. The mixture was further stirred at room temperature overnight. Ethanol was added, and the mixture was stirred at room temperature for 2 hours, and filtered through celite. The filtrate was concentrated under reduced pressure, acetic acid (50 mL) was added to the resulting residue, and the mixture was stirred with heating under reflux for 6 hr. Toluene (50 mL) was added to the reaction solution, and a Dean-Stark apparatus was attached, followed by heating under reflux for 1 hour. After distilling off the solvent, acetic acid (50 mL) was added, and the mixture was stirred for 6 hours under reflux with heating. The solvent was evaporated under reduced pressure, water and saturated brine were added to the obtained residue, and the mixture was extracted with tetrahydrofuran. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (512 mg).
MS (ESI) m / z: 232 (M−H) ⁻

Preparation Example 42 Preparation of 4- [4- (3-methoxypropyl) -2,5-dioxoimidazolidin-4-yl] benzoic acid

N, N-dimethylformamide (0.17 mL) and oxalyl chloride (2.41 mL) were added to a solution of 4-methoxybutyric acid (2.0 g) in chloroform (20 mL), and the mixture was stirred at room temperature. After completion of the reaction, the reaction solution was concentrated under reduced pressure. To the obtained residue, tetrahydrofuran (30 mL), 4- (ethoxycarbonyl) phenylzinc bromide (0.5 M, tetrahydrofuran solution) (23.4 mL), bis (triphenylphosphine) palladium (II) dichloride (0.41 g) And stirred at room temperature for 2 hours and at 60 ° C. for 2 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain ethyl 4- (4-methoxybutyryl) benzoate (830 mg).
Ethanol (8 mL), tetrahydrofuran (8 mL), 1N aqueous sodium hydroxide solution (6.6 mL) were added to the obtained ethyl 4- (4-methoxybutyryl) benzoate (830 mg), and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction solution, and back extraction was performed with water and an aqueous sodium hydrogen carbonate solution. The separated aqueous layers were combined and acidified with concentrated hydrochloric acid. The precipitate was collected by filtration to give 4- (4-methoxybutyryl) benzoic acid (490 mg).
To the obtained 4- (4-methoxybutyryl) benzoic acid (480 mg), ethanol (1.9 mL), ammonium carbonate (0.78 g), potassium carbonate (0.597 g), 28% aqueous ammonia (1.4 mL) ), Trimethylsilylcyanide (0.562 mL) was added, and the mixture was stirred at 60 ° C. overnight. The reaction mixture was acidified with concentrated hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, hexane / ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (650 mg).
MS (ESI) m / z: 293 (M + H) ⁺

Preparation Example 43: Preparation of 5- (4-tert-butyl-2,5-dioxoimidazolidin-4-yl) pyridine-2-carboxylic acid

2,2-Dimethyl-1- (6-methylpyridin-3-yl) propan-1-one (67
4 mg), ethanol (5.4 mL), 28% aqueous ammonia (4 mL), ammonium carbonate (1.33 g), potassium carbonate (1.02 g), trimethylsilylcyanide (0.959 mL) were added, and microwave irradiation was performed. , And stirred at 130 ° C. for 1 hour. The reaction solution was neutralized by adding water and concentrated hydrochloric acid, and the precipitate was collected by filtration to give 5-tert-butyl-5- (6-methylpyridin-3-yl) imidazolidine-2,4-dione ( 403 mg) was obtained.
To the obtained 5-tert-butyl-5- (6-methylpyridin-3-yl) imidazolidine-2,4-dione (403 mg), water (4 mL), 12N aqueous sodium hydroxide solution (0.272 mL), Potassium manganate (0.54 g) was added, and the mixture was stirred overnight at room temperature. Potassium permanganate (128 mg) was added, and the mixture was stirred at room temperature for 2 hr and at 50 ° C. overnight. Furthermore, potassium permanganate (128 mg) was added, and the mixture was stirred at 50 ° C. for 7 hours. Ethanol was added to the reaction solution, followed by Celite filtration. The filtrate was neutralized with concentrated hydrochloric acid and concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The solvent was distilled off, hexane / ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (247 mg).
MS (ESI) m / z: 278 (M + H) ⁺

Preparation 44: Preparation of 4- [4- (1-methoxycyclopropyl) -2,5-dioxoimidazolidin-4-yl] benzoic acid

Under a nitrogen stream, a solution of 1-hydroxycyclopropanecarboxylic acid (1.41 g) in chloroform (14 mL) was ice-cooled, oxalyl chloride (2.08 mL) and N, N-dimethylformamide (one drop) were added, and the mixture was stirred at room temperature for 3 hours. Stir for hours. The reaction solution was concentrated under reduced pressure, and toluene (40 mL), 4- (methoxycarbonyl) phenylboric acid (2.18 g), tripotassium phosphate (5.59 g), bis (tricyclohexylphosphine) palladium ( II) Dichloride (426 mg) was added, and the mixture was stirred at 60 ° C. for 1 hour and at 80 ° C. for 1 hour under a nitrogen stream. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain 4- (1-methoxycyclopropanecarbonyl) benzoic acid methyl ester (325 mg).
To the obtained 4- (1-methoxycyclopropanecarbonyl) benzoic acid methyl ester (315 mg), methanol (3 mL), tetrahydrofuran (3 mL), 1N aqueous sodium hydroxide solution (2.68 mL) were added, and the mixture was stirred at room temperature for 3 hours. did. The reaction mixture was acidified with 1N hydrochloric acid, saturated brine was added, and the mixture was extracted with ethyl acetate. After drying with sodium sulfate, the solvent was distilled off to obtain 4- (1-methoxycyclopropanecarbonyl) benzoic acid (232 mg).
To the obtained 4- (1-methoxycyclopropanecarbonyl) benzoic acid (225 mg), ammonium carbonate (490 mg), potassium carbonate (423 mg), trimethylsilylcyanide (0.398 mL) and 28% aqueous ammonia (2 mL) were added. The mixture was stirred at 80 ° C. for 30 minutes and at 100 ° C. for 1 hour under microwave irradiation. The reaction mixture was acidified with concentrated hydrochloric acid, water was added, and the mixture was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Hexane / ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to obtain the title compound (283 mg).
MS (ESI) m / z: 289 (M−H) ⁻

Preparation 45: Preparation of 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

1) Preparation of 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid / (R)-(+)-1-phenylethylamine salt described in Preparation Example 5 4- (4-Isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (200 mg), water (8 mL), 1N aqueous sodium hydroxide solution (0.458 mL), (R) -1-phenyl Ethylamine (59 μL) was added and stirred at 110 ° C. After confirming complete dissolution, the mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid. -A crude product (76.4 mg) of (R)-(+)-1-phenylethylamine salt was obtained. Crude product of the obtained 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid / (R)-(+)-1-phenylethylamine salt (76.3 mg) ) Was added water (3 mL), and the mixture was stirred at 80 ° C. for 20 minutes. The mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid / (R) -1-phenyl. Ethylamine salt (37.2 mg, 99.7% ee) was obtained.

2) Preparation of 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid 4-((R) -4- obtained by the same method as in 1) above Isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid. (R) -1-phenylethylamine salt (55.36 g, 97.1% ee) was suspended in water (250 mL), and 1N hydrochloric acid ( 155 mL) was added to adjust to acidity (pH 1-2). The mixture was stirred at room temperature for 1 hour, and the precipitate was collected by filtration to give 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (32.42 g, 98.7). % Ee) was obtained.
MS (ESI) m / z: 263 (M + H) ⁺

Preparation 46: Preparation of 6- (4-tert-butyl-2,5-dioxoimidazolidin-4-yl) nicotinic acid

To 2,2-dimethyl-1- (5-methylpyridin-2-yl) propan-1-one (0.3 g), water (1 mL), ethanol (1 mL), 28% aqueous ammonia solution (0.592 mL), Ammonium carbonate (0.65 g), potassium carbonate (0.327 g), and trimethylsilylcyanide (0.296 mL) were added, and the mixture was stirred at 130 ° C. for 1 hour under microwave irradiation. The reaction solution was neutralized with concentrated hydrochloric acid, and water was added. The precipitate was collected by filtration to give 5-tert-butyl-5- (5-methylpyridin-2-yl) imidazolidine-2,4-dione (0.287 g).
To the obtained 5-tert-butyl-5- (5-methylpyridin-2-yl) imidazolidine-2,4-dione (0.281 g), a 1N aqueous sodium hydroxide solution (2.28 mL), water (9 .12 mL) and potassium permanganate (0.396 g) were added and stirred at room temperature overnight. Potassium permanganate (54 mg) was added, and the mixture was stirred at 40 ° C. for 25 hours. Dimethyl sulfoxide (0.024 mL) was added to the reaction mixture, and the mixture was filtered through celite. 1N hydrochloric acid was added to the filtrate to make it acidic (pH 4 to 5), followed by filtration. The filtrate was extracted with ethyl acetate / tetrahydrofuran. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of the title compound (74 mg).
MS (ESI) m / z: 276 (M−H) ⁻

Preparation Example 47 Preparation of 4- (4-methyl-2,5-dioxoimidazolidin-4-yl) -2-trifluoromethylbenzoic acid

1- [4-Bromo-3- (trifluoromethyl) phenyl] ethane-1-one (3.2 g) was added to ethanol (12 mL), 28% aqueous ammonia (6 mL), ammonium carbonate (4.6 g), carbonic acid. Potassium (3.3 g) and trimethylsilylcyanide (3 mL) were added, and the mixture was stirred at room temperature for 1.5 hours and at 50 ° C. for 2 hours. Water (6 mL) was added, and the mixture was stirred at 50 ° C. for 1.5 hr. Furthermore, trimethylsilylcyanide (1.5 mL), potassium carbonate (1.65 g), ammonium carbonate (2.3 g) and 28% aqueous ammonia (3 mL) were added, and the mixture was stirred at 50 ° C. for 4 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration to obtain 5- (4-bromo-3-trifluoromethylphenyl) -5-methylimidazolidine-2,4-dione (3.2 g). It was.
To the obtained 5- (4-bromo-3-trifluoromethylphenyl) -5-methylimidazolidine-2,4-dione (3.2 g), zinc cyanide (2.8 g), zinc (134 mg), 1,1′-bis (diphenylphosphino) ferrocene (526 mg), tris (dibenzylideneacetone) dipalladium (0) (430 mg), N, N-dimethylformamide (32 mL) were added, and the mixture was stirred at 130 ° C. for 7 hours. . Chloroform was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give 4- (4-methyl-2,5-dioxoimidazolidin-4-yl) -2-tri Fluoromethylbenzonitrile (1.36 g) was obtained.
Acetic acid (5 mL), concentrated hydrochloric acid (5 mL), concentrated sulfuric acid was added to the obtained 4- (4-methyl-2,5-dioxoimidazolidin-4-yl) -2-trifluoromethylbenzonitrile (1.36 g). (3 mL) was added and stirred at 120 ° C. for 6 hours. Acetic acid (1 mL) and concentrated sulfuric acid (2 mL) were added, and the mixture was stirred at 120 ° C. for 8 hours. Furthermore, acetic acid (2 mL) and concentrated hydrochloric acid (2 mL) were added, and the mixture was stirred at 120 ° C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, acetic acid (3 mL), concentrated hydrochloric acid (1 mL), concentrated sulfuric acid (3 mL) were added to the resulting residue, and the mixture was stirred at 120 ° C. for 1.5 hours and at 150 ° C. for 3 hours under microwave irradiation. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure to obtain a crude product of the title compound (410 mg).
MS (ESI) m / z: 301 (M−H) ⁻

Preparation Example 48: Preparation of 2-hydroxy-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

1- (4-Bromo-3-methoxyphenyl) ethanone (1.36 g), ethanol (3 mL), 28% aqueous ammonia (3 mL), ammonium carbonate (2.26 g), potassium carbonate (1.63 g), trimethylsilyl Cyanide (1.48 mL) was added and stirred overnight at room temperature. Water (3 mL) was added, and the mixture was stirred at room temperature for 4 hr and at 50 ° C. for 3 hr. Furthermore, 28% aqueous ammonia (3 mL), ammonium carbonate (1.13 g), potassium carbonate (815 mg), and trimethylsilylcyanide (0.74 mL) were added, and the mixture was stirred at 50 ° C. for 3 hours. Water was added to the reaction solution, followed by concentration under reduced pressure until a solid precipitated. The precipitate was collected by filtration to obtain 5- (4-bromo-3-methoxyphenyl) -5-methylimidazolidine-2,4-dione (1.21 g).
To the obtained 5- (4-bromo-3-methoxyphenyl) -5-methylimidazolidine-2,4-dione (1.21 g), zinc cyanide (1.19 g), zinc (56 mg), 1, 1′-bis (diphenylphosphino) ferrocene (222 mg), tris (dibenzylideneacetone) dipalladium (0) (183 mg), N, N-dimethylformamide (13 mL) were added, and the mixture was stirred at 130 ° C. for 8 hours. Zinc (280 mg), 1,1′-bis (diphenylphosphino) ferrocene (222 mg) and tris (dibenzylideneacetone) dipalladium (0) (183 mg) were added, and the mixture was stirred at 130 ° C. for 8 hours. Furthermore, 1,1′-bis (diphenylphosphino) ferrocene (222 mg) and tris (dibenzylideneacetone) dipalladium (0) (183 mg) were added, and the mixture was stirred at 150 ° C. for 8 hours. Chloroform was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give 2-methoxy-4- (4-methyl-2,5-dioxoimidazolidin-4-yl). Benzonitrile (420 mg) was obtained.
To the obtained 2-methoxy-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzonitrile (420 mg), acetic acid (3 mL), concentrated hydrochloric acid (3 mL), concentrated sulfuric acid (3 mL) And stirred at 150 ° C. for 2 hours under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, water was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (133 mg).
MS (ESI) m / z: 249 (M−H) ⁻

Preparation 49: Preparation of 4- (3-isopropyl-2,5-dioxopyrrolidin-3-yl) benzoic acid

1) Preparation of 3-isopropyl-3- (p-tolyl) pyrrolidine-2,5-dione To a solution of 3-methyl-2- (p-tolyl) butyric acid methyl ester (5.2 g) in tetrahydrofuran (94 mL),- Under cooling to 78 ° C., lithium diisopropylamide (2M, heptane / tetrahydrofuran / ethylbenzene solution) (18.91 mL) was added dropwise and stirred for 1 hour. A solution of bromoacetonitrile (5.04 mL) in tetrahydrofuran (10 mL) was added, and the mixture was stirred at −78 ° C. for 2 hours. Aqueous ammonia chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane / ethyl acetate) to obtain 2-cyanomethyl-3-methyl-2- (p-tolyl) butyric acid methyl ester (5.81 g).
To the obtained 2-cyanomethyl-3-methyl-2- (p-tolyl) butyric acid methyl ester (500 mg), ethanol (5 mL), 30% aqueous hydrogen peroxide (5.68 mL), 1N aqueous sodium hydroxide solution (5 .56 mL) was added and stirred at room temperature overnight. 30% aqueous hydrogen peroxide (5.68 mL) was added, and the mixture was stirred at room temperature overnight. Furthermore, 30% aqueous hydrogen peroxide (5.68 mL) was added, and the mixture was stirred at room temperature overnight. Furthermore, ethanol (5 mL), 30% aqueous hydrogen peroxide (5.68 mL), 1N aqueous sodium hydroxide solution (5.56 mL) were added, and the mixture was stirred at room temperature overnight. After adding sodium bisulfite, it was acidified with concentrated hydrochloric acid. The precipitate was collected by filtration to give 3-isopropyl-3- (p-tolyl) pyrrolidine-2,5-dione (314 mg).

2) Preparation of 4- (3-Isopropyl-2,5-dioxopyrrolidin-3-yl) benzoic acid 3-Isopropyl-3- (p-tolyl) pyrrolidine-2,5-dione (720 mg, 1 above) Water (7.2 mL), 1N aqueous sodium hydroxide solution (6.23 mL) and potassium permanganate (1.42 g) were added to (see), and the mixture was stirred at room temperature overnight. Potassium permanganate (676 mg) was added, and the mixture was stirred at room temperature for 3.5 hours. Ethanol (6 mL) was added to the reaction mixture, and the mixture was stirred for 1 hr, and filtered through celite. The filtrate was concentrated under reduced pressure, and ethanol was distilled off. The remaining aqueous solution was acidified with concentrated hydrochloric acid and then extracted with a mixed solvent of chloroform and methanol. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (375 mg).
MS (ESI) m / z: 260 (M−H) ⁻

Preparation Example 50: Preparation of 6- (3-methyl-2,5-dioxopyrrolidin-3-yl) nicotinic acid

1) Preparation of 6- (tert-butoxycarbonylcyanomethyl) nicotinic acid ethyl ester To 6-chloronicotinic acid ethyl ester (11 g), cyanoacetic acid tert-butyl ester (8.88 mL), N, N-dimethylformamide (100 mL) ), Potassium carbonate (19.7 g) was added, and the mixture was stirred at 95 ° C. for 11 hours. Cyanoacetic acid tert-butyl ester (4 mL) and potassium carbonate (10 g) were added, and the mixture was stirred at 95 ° C. for 4 hr. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with water, 1N hydrochloric acid was added (about pH 4) under ice cooling, and the precipitate was collected by filtration. The obtained precipitate was suspended in diethyl ether and collected by filtration to obtain 6- (tert-butoxycarbonylcyanomethyl) nicotinic acid ethyl ester (16.228 g).

2) Preparation of 6- (tert-butoxycarbonylcyanomethylmethyl) nicotinic acid ethyl ester 6- (tert-butoxycarbonylcyanomethyl) nicotinic acid ethyl ester (1 g), potassium carbonate (1.43 g) according to 1) above To a mixed solution of N, N-dimethylformamide (70 mL), methyl iodide (0.24 mL) was added and stirred overnight at room temperature. Methyl iodide (0.11 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate) to give 6- (tert-butoxycarbonylcyanomethylmethyl) nicotinic acid ethyl ester (951 mg). .

3) Preparation of 6- (3-methyl-2,5-dioxopyrrolidin-3-yl) nicotinic acid 6- (tert-butoxycarbonylcyanomethylmethyl) nicotinic acid ethyl ester (300 mg) described in 2) above Montmorillonite K10 (100 mg) and toluene (6 mL) were added, and the mixture was stirred at 100 ° C. for 3 hours and then refluxed for 2 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain 6- (cyanomethylmethyl) nicotinic acid ethyl ester (193 mg).
A suspension of the obtained 6- (cyanomethylmethyl) nicotinic acid ethyl ester (189 mg) in tetrahydrofuran (3 mL) was stirred at room temperature under stirring with sodium hydride (40.8 mg, 60% oily) in tetrahydrofuran (2 mL). Added to. Next, after stirring the reaction solution at 90 ° C. for 30 minutes, bromoacetic acid methyl ester (0.094 mL) was added at room temperature. The reaction solution was stirred at 90 ° C. for 1 hour and then treated with a saturated aqueous ammonium chloride solution at room temperature. Extraction with ethyl acetate was performed, and the obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 6- (cyanomethoxycarbonylmethylmethylmethyl) nicotinic acid ethyl ester (220 mg).
Acetic acid (13 mL) and concentrated sulfuric acid (0.64 mL) were added to the obtained 6- (cyanomethoxycarbonylmethylmethylmethyl) nicotinic acid ethyl ester (216 mg), and the mixture was stirred at 140 ° C. for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 6- (3-methyl-2,5-dioxopyrrolidin-3-yl) nicotinic acid (85 mg).
MS (ESI) m / z: 235 (M + H) ⁺

Preparation Example 51: Preparation of 6- (3-ethyl-2,5-dioxopyrrolidin-3-yl) nicotinic acid

Using 6- (tert-butoxycarbonylcyanomethyl) nicotinic acid ethyl ester (1.00 g) and ethyl iodide (0.608 mL) described in 1) of Preparation Example 50, the same as in 2) of Preparation Example 50 By carrying out the reaction and the treatment, 6- (1-tert-butoxycarbonyl-1-cyanopropyl) nicotinic acid ethyl ester (1.05 g) was obtained.
Using the obtained 6- (1-tert-butoxycarbonyl-1-cyanopropyl) nicotinic acid ethyl ester (500 mg) and bromoacetic acid methyl ester (0.152 mL), the same reaction and treatment as in Preparation Example 50, 3) To give the title compound (155 mg).
MS (ESI) m / z: 249 (M + H) ⁺ , 247 (M−H) ⁻

Preparation Example 52 Preparation of 6- (3-Isopropyl-2,5-dioxopyrrolidin-3-yl) nicotinic acid

To a mixed solution of 6- (tert-butoxycarbonylcyanomethyl) nicotinic acid ethyl ester (1 g) and potassium carbonate (1.43 g) of N, N-dimethylformamide (70 mL) described in 1) of Preparation Example 50 -Iodopropane (0.376 mL) was added and stirred overnight at room temperature. 2-Iodopropane (1.03 mL) was added, and the mixture was stirred at 70 ° C. for 28 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate) to give 6- (1-tert-butoxycarbonyl-1-cyano-2-methylpropyl) nicotine. Acid ethyl ester (1.02 g) was obtained.
Similar to Preparation Example 50-3) using the obtained 6- (1-tert-butoxycarbonyl-1-cyano-2-methylpropyl) nicotinic acid ethyl ester (500 mg) and bromoacetic acid methyl ester (0.151 mL). The title compound (145 mg) was obtained by carrying out the reaction and treatment.
MS (ESI) m / z: 263 (M + H) ⁺ , 261 (M−H) ⁻

Preparation Example 53 Preparation of 4- (4-Ethyl-2,5-dioxoimidazolidin-4-yl) -3-methoxybenzoic acid

1- (4-Bromo-2-methoxyphenyl) propan-1-one (7.33 g), palladium acetate (0.339 g), 1,1′-bis (diphenylphosphino) ferrocene (1.672 g), Ethanol (35.2 mL), N, N-dimethylformamide (125 mL), and triethylamine (8.4 mL) were added, and the mixture was stirred at 80 ° C. for 6 hours in a carbon monoxide atmosphere. Water (150 mL) and ethyl acetate (150 mL) were added to the reaction mixture, and the mixture was stirred overnight at room temperature. Celite filtration was performed, and the filtrate was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, toluene was added to the resulting residue, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane / ethyl acetate) to obtain 3-methoxy-4-propionylbenzoic acid ethyl ester (6.166 g).
The obtained 3-methoxy-4-propionylbenzoic acid ethyl ester (1.0 g) was dissolved in ethanol (10 mL) and tetrahydrofuran (10 mL), 1N aqueous sodium hydroxide solution (8.89 mL) was added, and 4. Stir for 5 hours. 1N Hydrochloric acid (10 mL) was added to the reaction mixture, and the mixture was extracted with a mixed solvent of chloroform and methanol. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane / ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to obtain 3-methoxy-4-propionylbenzoic acid (639 mg).
To the obtained 3-methoxy-4-propionylbenzoic acid (620 mg), ammonium carbonate (1.075 g), potassium carbonate (0.823 g), ethanol (1.5 mL), 28% aqueous ammonia (2.5 mL), Trimethylsilylcyanide (0.774 mL) was added, and the mixture was stirred at 120 ° C. for 1.5 hours under microwave irradiation. Water and concentrated hydrochloric acid were added to the reaction solution under ice cooling to make it acidic (about pH 2), and the precipitated solid was collected by filtration to obtain the title compound (825 mg).
MS (ESI) m / z: 277 (M−H) ⁻

Preparation Example 54 Preparation of 4- (2,5-dioxo-4-propylimidazolidin-4-yl) -3-methoxybenzoic acid

1- (4-Bromo-2-methoxyphenyl) butan-1-one (5.7 g), palladium acetate (0.249 g), 1,1′-bis (diphenylphosphino) ferrocene (1.23 g), Ethanol (25.9 mL), N, N-dimethylformamide (55 mL), and triethylamine (6.2 mL) were added, and the mixture was stirred at 80 ° C. for 2 hours in a carbon monoxide atmosphere. The reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was filtered through celite. The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain 4-butyryl-3-methoxybenzoic acid ethyl ester (4.662 g).
The obtained 4-butyryl-3-methoxybenzoic acid ethyl ester (1.0 g) was dissolved in ethanol (10 mL) and tetrahydrofuran (10 mL), 1N aqueous sodium hydroxide solution (8.39 mL) was added, and the mixture was stirred at room temperature for 4 hours. Stir. 1N Hydrochloric acid (10 mL) was added to the reaction mixture, and the mixture was extracted with a mixed solvent of chloroform and methanol. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane / ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to obtain 4-butyryl-3-methoxybenzoic acid (636 mg).
To the obtained 4-butyryl-3-methoxybenzoic acid (620 mg), ammonium carbonate (1.007 g), potassium carbonate (0.771 g), ethanol (1.5 mL), 28% aqueous ammonia (2.5 mL), Trimethylsilylcyanide (0.726 mL) was added, and the mixture was stirred at 120 ° C. for 1.5 hours under microwave irradiation. The reaction mixture was acidified with water and concentrated hydrochloric acid under ice-cooling, and the precipitated solid was collected by filtration to obtain the title compound (755 mg).
MS (ESI) m / z: 291 (M−H) ⁻

Preparation Example 55: Preparation of 4- (4-difluoromethyl-2,5-dioxoimidazolidin-4-yl) -3-methoxybenzoic acid

1- (4-Bromo-2-methoxyphenyl) ethanone (26.15 g), palladium acetate (1.28 g), 1,1′-bis (diphenylphosphino) ferrocene (6.32 g), ethanol (133 mL) , N, N-dimethylformamide (290 mL) and triethylamine (31.8 mL) were added, and the mixture was stirred at 80 ° C. for 4 hours in a carbon monoxide atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate and SH silica gel were added to the resulting residue, followed by filtration through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain 4-acetyl-3-methoxybenzoic acid ethyl ester (23.0 g).
N-Butylamine (4.45 mL), molecular sieve 4A (5 g) and trifluoroacetic acid (catalytic amount) were added to a solution of the obtained 4-acetyl-3-methoxybenzoic acid ethyl ester (5 g) in cyclohexane (45 mL). And stirred for 18 hours under reflux. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with diisopropyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue (6.36 g) was dissolved in acetonitrile (110 mL), sodium sulfate (2.25 g) and selectfluor (21 g) were added, and the mixture was stirred under reflux for 4 hours. The reaction mixture was cooled to room temperature, 6N hydrochloric acid (20 mL) was added, and the mixture was stirred for 15 min, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain 4- (2,2-difluoroacetyl) -3-methoxybenzoic acid ethyl ester (3.39 g).
The obtained 4- (2,2-difluoroacetyl) -3-methoxybenzoic acid ethyl ester (1.0 g) was dissolved in ethanol (10 mL) and tetrahydrofuran (10 mL), and 1N aqueous sodium hydroxide solution (8.13 mL) was dissolved. And stirred at room temperature for 3 hours. 1N Hydrochloric acid (10 mL) was added to the reaction mixture, and the mixture was extracted with a mixed solvent of chloroform and methanol. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane / ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to obtain 4- (2,2-difluoroacetyl) -3-methoxybenzoic acid (667 mg).
To the obtained 4- (2,2-difluoroacetyl) -3-methoxybenzoic acid (620 mg), ammonium carbonate (0.973 g), potassium carbonate (0.745 g), 28% aqueous ammonia (2.5 mL), Trimethylsilylcyanide (0.701 mL) was added, and the mixture was stirred at 120 ° C. for 1.5 hours under microwave irradiation. The reaction mixture was acidified with water and concentrated hydrochloric acid under ice cooling, and extracted with a mixed solvent of chloroform and methanol. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane / ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to obtain the title compound (80 mg).
MS (ESI) m / z: 299 (M−H) ⁻

Preparation Example 56: Preparation of 3-ethoxy-4- (4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

1- (4-Bromo-2-hydroxyphenyl) -2-methylpropan-1-one (4.35 g) was dissolved in acetone (89.5 mL), and potassium carbonate (11.13 g), ethyl iodide (4 3 mL) and stirred at 60 ° C. overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1- (4-bromo-2-ethoxyphenyl) -2-methylpropan-1-one (5. 23 g) was obtained.
To the obtained 1- (4-bromo-2-ethoxyphenyl) -2-methylpropan-1-one (5.23 g), palladium acetate (0.25 g), 1,1′-bis (diphenylphosphino) Ferrocene (1.13 g), ethanol (23.7 mL), N, N-dimethylformamide (40.6 mL) and triethylamine (5.7 mL) were added, and the mixture was stirred at 80 ° C. for 4 hours in a carbon monoxide atmosphere. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was filtered through Celite, and the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain 3-ethoxy-4-isobutyrylbenzoic acid ethyl ester (3.94 g).
The obtained 3-ethoxy-4-isobutyrylbenzoic acid ethyl ester (680 mg) was dissolved in ethanol (6.8 mL) and tetrahydrofuran (6.8 mL), and 1N aqueous sodium hydroxide solution (5.4 mL) was added at room temperature. Stir for 4 hours. 1N Hydrochloric acid (10 mL) was added to the reaction mixture, and the mixture was extracted with a mixed solvent of chloroform and methanol. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane / ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to obtain 3-ethoxy-4-isobutyrylbenzoic acid (118 mg). The filtrate was concentrated under reduced pressure, hexane / diisopropyl ether was added to the resulting residue, and the precipitate was collected by filtration to give 3-ethoxy-4-isobutyrylbenzoic acid (403 mg).
To the obtained 3-ethoxy-4-isobutyrylbenzoic acid (495 mg), ammonium carbonate (0.756 g), potassium carbonate (0.579 g), 28% aqueous ammonia (2 mL), ethanol (1 mL), trimethylsilylcyanide ( 0.545 mL) was added, and the mixture was stirred at 120 ° C. for 3.5 hours under microwave irradiation. The reaction mixture was acidified with water and concentrated hydrochloric acid under ice cooling, and the precipitated solid was collected by filtration to obtain the title compound (615 mg).
MS (ESI) m / z: 305 (M−H) ⁻

Preparation Example 57 Preparation of 4- (4-Isopropyl-2,5-dioxoimidazolidin-4-yl) -5-methoxy-2-methylbenzoic acid

A solution of 3-bromo-4-methylanisole (5.36 g) in dichloromethane (10 mL) was added to a suspension of aluminum chloride (5.33 g) in dichloromethane (50 mL) under ice-cooling, and the mixture was stirred for 5 minutes. Isobutyryl chloride was added to the reaction solution, and the mixture was stirred for 45 minutes under ice cooling. Ice water was added to the reaction solution, 6N hydrochloric acid was added, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain 1- (4-bromo-2-methoxy-5-methylphenyl) -2-methylpropan-1-one (4.86 g). .
To the obtained 1- (4-bromo-2-methoxy-5-methylphenyl) -2-methylpropan-1-one (500 mg), ammonium carbonate (0.666 g), potassium carbonate (0.51 g), 28 % Aqueous ammonia (4 mL), ethanol (5 mL), and trimethylsilylcyanide (0.48 mL) were added, and the mixture was stirred at 130 ° C. for 1.5 hours under microwave irradiation. Ammonium carbonate (0.666 g), potassium carbonate (0.51 g), 28% aqueous ammonia (2 mL) and trimethylsilylcyanide (0.48 mL) were added, and the mixture was stirred at 130 ° C. for 2 hours under microwave irradiation. Further, ammonium carbonate (0.666 g), potassium carbonate (0.51 g), 28% aqueous ammonia (2 mL) and trimethylsilylcyanide (0.48 mL) were added, and the mixture was stirred at 130 ° C. for 1 hour under microwave irradiation. . The reaction mixture was acidified with water and concentrated hydrochloric acid under ice-cooling (about pH 3), and the precipitate was collected by filtration. The obtained precipitate was suspended in hexane / ethyl acetate and collected by filtration to give 5- (4-bromo-2-methoxy-5-methylphenyl) -5-isopropylimidazolidine-2,4- Dione (508 mg) was obtained.
To the obtained 5- (4-bromo-2-methoxy-5-methylphenyl) -5-isopropylimidazolidine-2,4-dione (300 mg), zinc cyanide (124 mg), zinc (5.8 mg), 1,1′-bis (diphenylphosphino) ferrocene (49 mg), tris (dibenzylideneacetone) dipalladium (0) (40 mg), N, N-dimethylformamide (3 mL) was added, and 150 ° C. under microwave irradiation. For 1 hour. Water and ethyl acetate were added to the reaction mixture, and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) and 4- (4-isopropyl-2,5-dioxoimidazolidin-4-yl) -5-methoxy-2-methylbenzonitrile (250 mg). Got.
The obtained 4- (4-isopropyl-2,5-dioxoimidazolidin-4-yl) -5-methoxy-2-methylbenzonitrile (245 mg) was added to 1,4-dioxane (1.47 mL), 6N. Hydrochloric acid (1.42 mL) was added, and the mixture was stirred overnight under reflux. The reaction solution was concentrated under reduced pressure, and 1,4-dioxane was distilled off. Acetic acid (1.47 mL) was added to the resulting residue, and the mixture was stirred at 150 ° C. for 2 hours under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (114 mg).
MS (ESI) m / z: 305 (M−H) ⁻

Preparation Example 58 Preparation of 5-hydroxy-4- (4-isopropyl-2,5-dioxoimidazolidin-4-yl) -2-methylbenzoic acid

The product by-produced in Preparation Example 57 was purified by column chromatography (chloroform: methanol) to obtain the title compound (16.3 mg).
MS (ESI) m / z: 291 (M−H) ⁻

Preparation 59: Preparation of 2-fluoro-4- (4-isopropyl-2,5-dioxoimidazolidin-4-yl) -5-methoxybenzoic acid

To 1- (4-bromo-5-fluoro-2-hydroxyphenyl) -2-methylpropan-1-one (6.63 g), acetone (130 mL), potassium carbonate (5.27 g), methyl iodide (4 8 mL) and stirred at 60 ° C. for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain 1- (4-bromo-5-fluoro-2-methoxyphenyl) -2-methylpropan-1-one (5 g).
To the obtained 1- (4-bromo-5-fluoro-2-methoxyphenyl) -2-methylpropan-1-one (5 g), palladium acetate (0.204 g), 1,1′-bis (diphenylphosphine) was added. Fino) ferrocene (1 g), methanol (14.7 mL), N, N-dimethylformamide (46 mL) and triethylamine (5.1 mL) were added, and the mixture was stirred at 80 ° C. for 17 hours in a carbon monoxide atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Anhydrous sodium sulfate and SH silica gel were added to the organic layer, followed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give 2-fluoro-4-isobutyryl-5-methoxybenzoic acid methyl ester (2.3 g).
Methanol (2 mL), tetrahydrofuran (3 mL), and 1N aqueous sodium hydroxide solution (6 mL) were added to the obtained 2-fluoro-4-isobutyryl-5-methoxybenzoic acid methyl ester (1 g), and the mixture was stirred at room temperature for 3.5 hours. did. 1N hydrochloric acid was added to the reaction solution, and the precipitate was collected by filtration to obtain 2-fluoro-4-isobutyryl-5-methoxybenzoic acid (790 mg).
To the obtained 2-fluoro-4-isobutyryl-5-methoxybenzoic acid (786 mg), ammonium carbonate (1.57 g), potassium carbonate (1.37 g), 28% aqueous ammonia (1.7 mL), water (1 7 mL) and trimethylsilylcyanide (1.23 mL) were added, and the mixture was stirred at 100 ° C. for 1 hour under microwave irradiation. 28% Aqueous ammonia (0.5 mL) and trimethylsilylcyanide (0.41 mL) were added, and the mixture was stirred at 120 ° C. for 1.5 hours under microwave irradiation. The reaction mixture was acidified with 3N hydrochloric acid, and the precipitate was collected by filtration. The obtained precipitate was washed with water and diethyl ether to obtain the title compound (608 mg).
MS (ESI) m / z: 309 (M−H) ⁻

Preparation 60: Preparation of 4- [4- (1,1-difluoroethyl) -2,5-dioxoimidazolidin-4-yl] -3-methoxybenzoic acid

To 3-methoxy-4-propionylbenzoic acid ethyl ester (3.55 g) described in Preparation Example 53, n-butylamine (2.2 g), molecular sieves 4A (3.55 g), cyclohexane (35 mL), Fluoroacetic acid (catalytic amount) was added, and the mixture was refluxed for 20.5 hours under stirring in an argon atmosphere. The reaction solution was filtered and washed with diisopropyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in acetonitrile (50 mL), sodium sulfate (1.5 g) and selectfluor (11.71 g) were added, and the mixture was stirred under reflux for 4 hours. The reaction mixture was cooled to room temperature, 6N hydrochloric acid (10 mL) was added, and the mixture was stirred at room temperature for 10 min, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain 4- (2,2-difluoropropionyl) -3-methoxybenzoic acid ethyl ester (3.284 g).
To the obtained 4- (2,2-difluoropropionyl) -3-methoxybenzoic acid ethyl ester (544 mg), ethanol (1 mL), tetrahydrofuran (2 mL), and 1N aqueous sodium hydroxide solution (3 mL) were added. Stir for hours. 1N hydrochloric acid was added to the reaction solution under ice cooling, and the precipitated solid was collected by filtration to obtain 4- (2,2-difluoropropionyl) -3-methoxybenzoic acid (381 mg).
To the obtained 4- (2,2-difluoropropionyl) -3-methoxybenzoic acid (378 mg), ammonium carbonate (744 mg), potassium carbonate (642 g), 28% aqueous ammonia (0.75 mL), water (0. 75 mL) and trimethylsilylcyanide (0.581 mL) were added, and the mixture was stirred at 100 ° C. for 1 hour under microwave irradiation. 3N hydrochloric acid was added to the reaction solution under ice cooling, and the precipitated solid was collected by filtration to obtain the title compound (423 mg).
MS (ESI) m / z: 313 (M−H) ⁻

Preparation Example 61 Preparation of 4- (4-tert-butyl-2,5-dioxoimidazolidin-4-yl) -3-methoxybenzoic acid

Sodium hydride (432 mg, 60% oily) was added to a solution of 4-isobutyryl-3-methoxybenzoic acid (600 mg) and tert-butanol (60 mg) described in Preparation Example 35 1) in tetrahydrofuran (12 mL) under ice-cooling. And stirred at room temperature for 3 hours under a nitrogen atmosphere. Methyl iodide (0.336 mL) was added to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Tert-butanol (60 mg) and methyl iodide (0.336 mL) were added, and the mixture was stirred at 50 ° C. for 3 hours under a nitrogen atmosphere. 1N Aqueous sodium hydroxide solution (3 mL) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. After acidifying with 1N hydrochloric acid, sodium bisulfite and saturated brine were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Ammonium carbonate (1.73 g), potassium carbonate (1.49 g), trimethylsilylcyanide (1.4 mL) and 28% aqueous ammonia (10 mL) were added to the resulting residue, and microwave irradiation was performed at 100 ° C. for 1 hour. , And stirred at 135 ° C. for 1 hour. Trimethylsilylcyanide (2.8 mL) was added, and the mixture was stirred at 135 ° C. for 2 hours under microwave irradiation. Further, trimethylsilylcyanide (2.8 mL) was added, and the mixture was stirred at 135 ° C. for 2 hours under microwave irradiation. Water, ethyl acetate and potassium carbonate were added to the reaction solution, followed by filtration through celite. The filtrate was acidified with concentrated hydrochloric acid under ice cooling and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and then treated with activated carbon. The solvent was distilled off, hexane / ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to give the title compound (673 mg).
MS (ESI) m / z: 305 (M−H) ⁻

Preparation Example 62 Preparation of 4- (4-difluoromethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

To 4- (2,2-difluoroacetyl) benzoic acid methyl ester (1.7 g), methanol (16 mL), tetrahydrofuran (5 mL), 1N aqueous sodium hydroxide solution (24 mL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, water and 1N hydrochloric acid were added to the resulting aqueous solution, and the precipitate was collected by filtration to obtain 4- (2,2-difluoroacetyl) benzoic acid (496 mg).
To the obtained 4- (2,2-difluoroacetyl) benzoic acid (496 mg), ammonium carbonate (960 mg), potassium carbonate (691 mg), 28% aqueous ammonia (5 mL), water (5 mL), trimethylsilylcyanide (0 625 mL) and stirred at 80 ° C. for 1 hour under microwave irradiation. Ammonium carbonate (480 mg), potassium carbonate (345 mg) and trimethylsilylcyanide (0.312 mL) were added, and the mixture was stirred at 80 ° C. for 1.5 hours under microwave irradiation. Water and concentrated hydrochloric acid were added to the reaction solution (about pH 1), and the mixture was extracted with ethyl acetate and chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane / ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to obtain the title compound (72 mg).
MS (ESI) m / z: 271 (M + H) ⁺ , 269 (M−H) ⁻

Preparation Example 63 Preparation of 4- (4-fluoromethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

Methanol (170 mL) and selectfluoro (25 g) were added to 4-acetylbenzoic acid methyl ester (6.3 g), and the mixture was refluxed for 2 days with stirring. Celite filtration was performed, and the filtrate was concentrated under reduced pressure. Chloroform was added to the resulting residue, followed by filtration (removal of insoluble materials). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to obtain 4- (2-fluoro-1,1-dimethoxyethyl) benzoic acid methyl ester (5.4 g).
The obtained 4- (2-fluoro-1,1-dimethoxyethyl) benzoic acid methyl ester (5.4 g) was dissolved in methanol (44 mL) and tetrahydrofuran (15 mL), and 1N aqueous sodium hydroxide solution ( 67 mL) was added and stirred at room temperature for 6 hours. Under ice-cooling, 2N hydrochloric acid was added to the reaction mixture, and the mixture was stirred for 1 hour, and the precipitate was collected by filtration. Dichloromethane (45 mL) and trifluoroacetic acid (10 mL) were added to the resulting precipitate (4.8 g), and the mixture was stirred at room temperature for 2 hours. The precipitate was collected by filtration to give 4- (2-fluoroacetyl) benzoic acid (3.68 g).
To the obtained 4- (2-fluoroacetyl) benzoic acid (910 mg), ammonium carbonate (1.2 g), potassium carbonate (2.07 g), 28% aqueous ammonia (9 mL), water (9 mL), trimethylsilylcyanide (1.8 mL) was added, and the mixture was stirred at 80 ° C. for 1.5 hours under microwave irradiation. Hydrochloric acid was added to the reaction solution, and the precipitate was collected by filtration. The obtained precipitate was recrystallized with a mixed solvent of ethanol and water to obtain the title compound (730 mg).
MS (ESI) m / z: 251 (M−H) ⁻

Preparation 64: Preparation of 6- (3-methoxymethyl-2,5-dioxopyrrolidin-3-yl) nicotinic acid

To 6- (tert-butoxycarbonylcyanomethyl) nicotinic acid ethyl ester (6.1 g) described in 1) of Preparation Example 50, N, N-dimethylformamide (400 mL), potassium carbonate (8.71 g), bromoacetic acid Ethyl (4.4 mL) was added, and the mixture was stirred at 70 ° C. for 1 hr and at room temperature overnight. The reaction mixture was filtered through celite, saturated 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 under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to give 2-cyano-2- (5-ethoxycarbonylpyridin-2-yl) succinic acid 1-tert-butyl ester 4-ethyl ester (6.222 g). )
To the obtained 2-cyano-2- (5-ethoxycarbonylpyridin-2-yl) succinic acid 1-tert-butyl ester 4-ethyl ester (6.2 g), toluene (50 mL) and montmorillonite K10 (2 g) were added. In addition, the mixture was stirred at 120 ° C. for 1.5 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain 6- [cyano (ethoxycarbonylmethyl) methyl] nicotinic acid ethyl ester (4.086 g).
To a solution of the obtained 6- [cyano (ethoxycarbonylmethyl) methyl] nicotinic acid ethyl ester (0.5 g) in N, N-dimethylformamide (9 mL) under ice-cooling, sodium hydride (60% oily) (0 .145 g) was added, and the mixture was stirred for 30 minutes under ice cooling and for 40 minutes at room temperature. Under ice cooling, chloromethyl methyl ether (0.272 mL) was added, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain 6- [cyano (ethoxycarbonylmethyl) (methoxymethyl) methyl] nicotinic acid ethyl ester (0.335 g).
To the obtained 6- [cyano (ethoxycarbonylmethyl) (methoxymethyl) methyl] nicotinic acid ethyl ester (0.171 g), ethanol (3 mL), hydrogen peroxide (0.982 mL), 1N aqueous sodium hydroxide solution ( 1.6 mL) was added and stirred at room temperature overnight. Under ice-cooling, 5% aqueous sodium bisulfite solution was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction solution was extracted with tetrahydrofuran. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (0.087 g).
MS (ESI) m / z: 265 (M + H) ⁺

Preparation 65: Preparation of 4-[(R) -1- (2,2-dimethylpropionyloxymethyl) -4-methyl-2,5-dioxoimidazolidin-4-yl] benzoic acid

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (1.5 g), 1-ethyl-3- (3′-dimethylaminopropyl) of Preparation Example 6 Carbodiimide hydrochloride (1.842 g) and 4-dimethylaminopyridine (0.156 g) were dissolved in dichloromethane (30 mL), benzyl alcohol (1.326 mL) was added, and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to give 4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid benzyl ester. (0.903 g) was obtained.
To a solution of the obtained 4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid benzyl ester (450 mg) in N, N-dimethylformamide (5 mL), potassium carbonate ( 230 mg) and chloromethyl 2,2-dimethylpropionate (0.211 mL) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate), and 4-[(R) -1- (2,2-dimethylpropionyloxymethyl) -4-methyl-2,5 -Dioxoimidazolidin-4-yl] benzoic acid benzyl ester (512 mg) was obtained.
The resulting 4-[(R) -1- (2,2-dimethylpropionyloxymethyl) -4-methyl-2,5-dioxoimidazolidin-4-yl] benzoic acid benzyl ester (512 mg) in methanol ( 10 mL) solution was added 10% palladium on carbon (100 mg) and stirred at room temperature for 2 hours under hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (400 mg).
MS (ESI) m / z: 349 (M + H) ⁺ , 347 (M−H) ⁻

Preparation Example 66 Preparation of 5- (4-Isopropyl-2,5-dioxoimidazolidin-4-yl) thiophene-2-carboxylic acid

To 5-isobutyrylthiophene-2-carboxylic acid (172 mg), ammonium carbonate (417 mg), potassium carbonate (240 mg), trimethylsilylcyanide (0.226 mL), 28% aqueous ammonia (2 mL) were added, and microwave irradiation was performed. Under stirring at 100 ° C. for 2 hours. The reaction mixture was poured into ice water, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Hexane / ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to obtain the title compound (207 mg).
MS (ESI) m / z: 267 (M−H) ⁻

Preparation Example 67: Preparation of 2- (piperidin-4-yl) -2H-indazole dihydrochloride

4-Aminopiperidine-1-carboxylic acid tert-butyl ester (500 mg), anhydrous magnesium sulfate (1 g), and ethanol (12 mL) were added to 2-nitrobenzaldehyde (377 mg), and the mixture was stirred at 90 ° C. for 3.5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. To the obtained residue, triethyl phosphite (4 mL) was added, and under microwave irradiation, 1
Stir at 50 ° C. for 40 minutes. The reaction solution was purified by column chromatography (hexane: ethyl acetate) to obtain 4- (indazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (490 mg).
The obtained 4- (indazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (490 mg) was dissolved in 1,4-dioxane (2.5 mL), and a 4N hydrogen chloride / 1,4-dioxane solution was obtained. (2.5 mL) was added and stirred at room temperature. After completion of the reaction, the solvent was distilled off to obtain the title compound (439 mg).
MS (ESI) m / z: 202 (M + H) ⁺

Preparation Example 68: Preparation of 5-chloro-2- (piperidin-4-yl) -2H-indazole dihydrochloride

4-Aminopiperidine-1-carboxylic acid tert-butyl ester (500 mg) and acetonitrile (10 mL) were added to 5-chloro-2-nitrobenzaldehyde (465 mg), and the mixture was stirred at 80 ° C. for 10 minutes under microwave irradiation. Triethyl phosphite (4.3 mL) was added, and the mixture was stirred at 130 ° C. for 1 hour under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate) to give 4- (5-chloroindazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (495 mg). )
The obtained 4- (5-chloroindazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (490 mg) was dissolved in 1,4-dioxane (2.4 mL), and 4N hydrogen chloride / 1,4. -Dioxane solution (2.4 mL) was added and stirred at room temperature. After completion of the reaction, the solvent was distilled off to obtain the title compound (432 mg).
MS (ESI) m / z: 236 (M + H) ⁺

Preparation 69: Preparation of 5-bromo-2- (piperidin-4-yl) -2H-indazole dihydrochloride

4-Aminopiperidine-1-carboxylic acid tert-butyl ester (1 g) and acetonitrile (10 mL) were added to 5-bromo-2-nitrobenzaldehyde (1.15 g), and the mixture was stirred at 80 ° C. for 10 minutes under microwave irradiation. did. Triethyl phosphite (8.5 mL) was added, and the mixture was stirred at 130 ° C. for 1 hour under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate) to give 4- (5-bromoindazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (1 .22 g) was obtained.
The obtained 4- (5-bromoindazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (150 mg) was dissolved in 1,4-dioxane (1.5 mL), and 4N hydrogen chloride / 1,4. -Dioxane solution (1.5 mL) was added and stirred at room temperature. After completion of the reaction, the solvent was distilled off to obtain the title compound (135 mg).
MS (ESI) m / z: 280 (M + H) ⁺

Preparation Example 70: Preparation of 5-methyl-2- (piperidin-4-yl) -2H-indazole dihydrochloride

By subjecting 5-methyl-2-nitrobenzaldehyde (206 mg) and 4-aminopiperidine-1-carboxylic acid tert-butyl ester (250 mg) to the same reaction and treatment as in Preparation 68, the crude product of the title compound (196 mg) was obtained.
MS (ESI) m / z: 216 (M + H) ⁺

Preparation 71: Preparation of 3,5-dichloro-2- (5-piperidin-4-yl [1,3,4] oxadiazol-2-yl) pyridine dihydrochloride

4-Hydrazinocarbonylpiperidine-1-carboxylic acid tert-butyl ester (500 mg), 3,5-dichloropyridine-2-carboxylic acid (475 mg), 1-hydroxybenzotriazole (420 mg), 1-ethyl-3- (3′-Dimethylaminopropyl) carbodiimide hydrochloride (590 mg), triethylamine (575 μL) and chloroform (10 mL) were added, and the mixture was stirred at room temperature overnight. The reaction solution was purified by column chromatography (chloroform: methanol) to give 4- [N ′-(3,5-dichloropyridine-2-carbonyl) hydrazinocarbonyl] piperidine-1-carboxylic acid tert-butyl ester (525 mg). )
To the obtained 4- [N ′-(3,5-dichloropyridine-2-carbonyl) hydrazinocarbonyl] piperidine-1-carboxylic acid tert-butyl ester (520 mg), p-toluenesulfonyl chloride (356 mg), tetrahydrofuran (10 mL) and triethylamine (350 μL) were added, and the mixture was stirred at 80 ° C. for 1 hour under microwave irradiation. The reaction solution was purified by column chromatography (hexane: ethyl acetate) to give 4- [5- (3,5-dichloropyridin-2-yl) [1,3,4] oxadiazol-2-yl] piperidine. A -1-carboxylic acid tert-butyl ester (327 mg) was obtained.
To the obtained 4- [5- (3,5-dichloropyridin-2-yl) [1,3,4] oxadiazol-2-yl] piperidine-1-carboxylic acid tert-butyl ester (300 mg), 1,4-Dioxane (3 mL), 4N hydrogen chloride / 1,4-dioxane solution (3 mL) was added, and the mixture was stirred at room temperature. After completion of the reaction, the solvent was distilled off to obtain the title compound (255 mg).
MS (ESI) m / z: 299 (M + H) ⁺

Preparation Example 72: Preparation of 5-methyl-2- (2-piperidin-4-ylthiazol-5-yl) pyridine hydrochloride

4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.5 g) Were added tetrakis (triphenylphosphine) palladium (0) (280 mg), tetrahydrofuran (20 mL), 2-bromothiazole (955 mg), and 2M aqueous sodium carbonate solution (1.65 mL), and 6.6 at 100 ° C. under a nitrogen atmosphere. Stir for 5 hours. The reaction solution was purified by column chromatography (hexane: ethyl acetate) to give 4- (thiazol-2-yl) -3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (557 mg). It was.
The resulting 4- (thiazol-2-yl) -3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (520 mg) was added to ethanol (10 mL), 10% palladium / carbon (53.5). % Water wet product) (260 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to give 4- (thiazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (480 mg).
Under a nitrogen atmosphere, bis (pinacolato) diboron (535 mg), (1,5-cyclooctadiene) (methoxy) iridium (I) dimer (58 mg), 4,4′-di-tert-butyl-2,2′- To a solution of bipyridine (94 mg) in tetrahydrofuran (7 mL) was added a solution of 4- (thiazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (470 mg) in tetrahydrofuran (3 mL), and the mixture was stirred at 70 ° C. for 5 hours. . The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give 4- [5- (4,4,5,5-tetramethyl [1,3,2] dioxaborolane. -2-yl) thiazol-2-yl] piperidine-1-carboxylic acid tert-butyl ester (407 mg) was obtained.
To 4- [5- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) thiazol-2-yl] piperidine-1-carboxylic acid tert-butyl ester (390 mg), 2-Bromo-5-methylpyridine (222 mg), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride / dichloromethane adduct (41 mg), toluene (7.8 mL), 2M aqueous sodium carbonate solution (1 mL) was added, and the mixture was stirred at 90 ° C. for 1.5 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate) to give 4- [5- (5-methylpyridin-2-yl) thiazol-2-yl] piperidine-1. -Carboxylic acid tert-butyl ester (232 mg) was obtained.
To the obtained 4- [5- (5-methylpyridin-2-yl) thiazol-2-yl] piperidine-1-carboxylic acid tert-butyl ester (225 mg), 1,4-dioxane (2.3 mL), A 4N hydrogen chloride / 1,4-dioxane solution (2.3 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off, diisopropyl ether was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (115 mg).
MS (ESI) m / z: 260 (M + H) ⁺

Preparation Example 73 Preparation of (2S, 4S) -2- (tert-butyldimethylsilanyloxymethyl) -4- (2,4-dimethylphenylamino) pyrrolidine-1-carboxylic acid tert-butyl ester

(2S, 4S) -4-amino-2- (tert-butyldimethylsilanyloxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg) was added to 2,4-dimethylbromobenzene (134 mg), tris ( Dibenzylideneacetone) dipalladium (0) (28 mg), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (38 mg), sodium tert-butoxide (87 mg), toluene (4 mL) were added, The mixture was stirred at 80 ° C. for 5 hours under a nitrogen atmosphere. The reaction solution was purified by silica gel column chromatography (hexane: ethyl acetate) to obtain the title compound (220 mg). MS (ESI) m / z: 435 (M + H) ⁺

Preparation Example 74 Preparation of 3,5-dimethyl-2 ', 3', 5 ', 6'-tetrahydro-1'H- [2,4'] bipyridinyl-4'-ol dihydrochloride

To a solution of 2-bromo-3,5-dimethylpyridine (2.0 g) in tetrahydrofuran (30 mL) was added 1.59 M n-butyllithium / hexane solution (7.04 mL) while cooling to -78 ° C., and the mixture was stirred for 1 hour. did. A solution of 1- (tert-butoxycarbonyl) -4-piperidone (2.23 g) in tetrahydrofuran (40 mL) was added, and the mixture was stirred at -78 ° C for 30 min. The reaction mixture was allowed to warm to room temperature, saturated aqueous sodium carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. By purifying the obtained residue by column chromatography (hexane: ethyl acetate) and NH column chromatography (hexane: ethyl acetate), 4′-hydroxy-3,5-dimethyl-3 ′, 4 ′, 5 ′, 6 '-Tetrahydro-2'H- [2,4'] bipyridinyl-1'-carboxylic acid tert-butyl ester (1.69 g) was obtained.
The obtained 4′-hydroxy-3,5-dimethyl-3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-carboxylic acid tert-butyl ester ( To a solution of 1.69 g) in ethyl acetate (10 mL) was added 4N hydrogen chloride / ethyl acetate solution (10 mL), and the mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration to give the title compound (1.384 g).
MS (ESI) m / z: 207 (M + H) ⁺

Preparation Example 75: Preparation of 4- [5- (2,4-dimethylphenyl) [1,3,4] oxadiazol-2-yl] piperidine hydrochloride

To 4- (hydrazinocarbonyl) piperidine-1-carboxylic acid tert-butyl ester (1 g), 2,4-dimethylbenzoic acid (802 mg), 1-hydroxybenzotriazole (833 mg), 1-ethyl-3- (3 '-Dimethylaminopropyl) carbodiimide hydrochloride (1.182 g) and N, N-dimethylformamide (10 mL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain 4- [N ′-(2,4-dimethylbenzoyl) hydrazinocarbonyl] piperidine-1-carboxylic acid tert-butyl ester (979 mg). It was.
To a solution of the obtained 4- [N ′-(2,4-dimethylbenzoyl) hydrazinocarbonyl] piperidine-1-carboxylic acid tert-butyl ester (979 mg) in tetrahydrofuran (15 mL), Burgess reagent (1.243 g) was added. The mixture was further stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) and 4- [5- (2,4-dimethylphenyl) [1,3,4] oxadiazol-2-yl] piperidine-1-carboxyl Acid tert-butyl ester (923 mg) was obtained.
4- [5- (2,4-Dimethylphenyl) [1,3,4] oxadiazol-2-yl] piperidine-1-carboxylic acid tert-butyl ester (923 mg) obtained in 1,4-dioxane (10 mL) To the solution was added 4N hydrogen chloride / 1,4-dioxane solution (6.46 mL), and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration to obtain the title compound (688 mg).
MS (ESI) m / z: 258 (M + H) ⁺

Preparation 76: Preparation of 5-methyl-2- (5-piperidin-4-yl-2H-pyrazol-3-yl) pyridine · dihydrochloride

4-Acetylpiperidine-1-carboxylic acid tert-butyl ester (1.353 g) was dissolved in tetrahydrofuran (10 mL) and N, N-dimethylformamide (5 mL), and sodium hydride (60% oily) (524 mg) was added. . After stirring at room temperature for 10 minutes, 5-methylpyridine-2-carboxylic acid methyl ester (900 mg) was added, and the mixture was stirred at 60 ° C. for 3 hours. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate), and 4- [3- (5-methylpyridin-2-yl) -3-oxopropionyl] piperidine-1-carboxylic acid tert-butyl ester (1 121 g).
The obtained 4- [3- (5-methylpyridin-2-yl) -3-oxopropionyl] piperidine-1-carboxylic acid tert-butyl ester (1.121 g) was added to ethanol (10 mL) and methanol (10 mL). After dissolution, hydrazine monohydrate (0.394 mL) was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate) to give 4- [5- (5-methylpyridin-2-yl) -1H-pyrazol-3-yl]. Piperidine-1-carboxylic acid tert-butyl ester (0.87 g) was obtained.
To the obtained 4- [5- (5-methylpyridin-2-yl) -1H-pyrazol-3-yl] piperidine-1-carboxylic acid tert-butyl ester (870 mg), 1,4-dioxane (15 mL), 4N hydrogen chloride / 1,4-dioxane solution (6.35 mL) was added, and the mixture was stirred overnight at room temperature. The precipitate was collected by filtration to obtain the title compound (826 mg). MS (ESI) m / z: 243 (M + H) ⁺

Preparation Example 77 Preparation of 4- [5- (p-tolyl) -1H-pyrazol-3-yl] piperidine

Oxalyl chloride (1.6 mL) and N, N-dimethylformamide (catalytic amount) were added to a solution of 1-[(benzyloxy) carbonyl] piperidine-4-carboxylic acid (4 g) in dichloromethane (20 mL) under ice cooling. And stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 4- (chlorocarbonyl) piperidine-1-carboxylic acid benzyl ester.
To a tetrahydrofuran (40 mL) solution of 4-methylacetophenone (3.1 g), lithium bis (trimethylsilyl) amide (about 0.5 mol / L, tetrahydrofuran solution) (45.6 mL) was added while cooling to −78 ° C., and 30 Stir for minutes. To this reaction solution, a solution of the above 4- (chlorocarbonyl) piperidine-1-carboxylic acid benzyl ester in tetrahydrofuran (40 mL) was added and stirred for 3.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain 4- [3-oxo-3- (p-tolyl) propionyl] piperidine-1-carboxylic acid benzyl ester (3.91 g).
To a solution of the obtained 4- [3-oxo-3- (p-tolyl) propionyl] piperidine-1-carboxylic acid benzyl ester (500 mg) in ethanol (5 mL), hydrazine monohydrate (0.32 mL) was added. The mixture was further stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure, water is added to the resulting residue, and the precipitate is collected by filtration to give 4- [5- (p-tolyl) -1H-pyrazol-3-yl] piperidine-1-carboxylic acid. The benzyl ester (168 mg) was obtained.
To the obtained 4- [5- (p-tolyl) -1H-pyrazol-3-yl] piperidine-1-carboxylic acid benzyl ester (160 mg), methanol (3 mL), tetrahydrofuran (3 mL), 10% palladium carbon ( 32 mg) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (100 mg).
MS (ESI) m / z: 242 (M + H) ⁺

Preparation 78: Preparation of 4- [2- (p-tolyl) -2H-tetrazol-5-yl] piperidine

1) Preparation of 4-methylbenzenediazonium chloride In a 50% ethanol (5 mL) solution of 4-methylaniline (500 mg) and concentrated hydrochloric acid (0.6 mL) at 5 ° C. or lower, sodium nitrite (321.9 mg) in water (1 mL) solution was added (preparation of 4-methylbenzenediazonium chloride solution).

2) Preparation of 4- [2- (p-tolyl) -2H-tetrazol-5-yl] piperidine 1- (tert-Butoxycarbonyl) -4-piperidinecarboxaldehyde (2 g) in ethanol (30 mL) was added to p. -Toluenesulfonyl hydrazide (1.7 g) was added and stirred at 30 ° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, diisopropyl ether (20 mL) and ethyl acetate (10 mL) were added to the resulting residue, and the precipitate was collected by filtration to give 4- (p-toluenesulfonylhydrazonomethyl) piperidine-1- Carboxylic acid tert-butyl ester (3 g) was obtained.
The obtained 4- (p-toluenesulfonylhydrazonomethyl) piperidine-1-carboxylic acid tert-butyl ester (1.7 g) in a pyridine (10 mL) solution was cooled to −10 ° C. to −15 ° C., and the above 1 The reaction solution (4-methylbenzenediazonium chloride solution) was added dropwise over 30 minutes. After stirring at 0 ° C. for 2 hours, the reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (diisopropyl ether: ethyl acetate) and 4- [2- (p-tolyl) -2H-tetrazol-5-yl] piperidine-1-carboxylic acid tert-butyl ester (300 mg). Got.
To the obtained 4- [2- (p-tolyl) -2H-tetrazol-5-yl] piperidine-1-carboxylic acid tert-butyl ester (100 mg) in 1,4-dioxane (5 mL) solution was added 4N hydrogen chloride. / 1,4-dioxane solution (5 mL) was added, and the mixture was stirred at 35 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was basified with 1N aqueous sodium hydroxide solution (pH 9). Extraction was performed with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 4- [2- (p-tolyl) -2H-tetrazol-5-yl] piperidine (60 mg).
MS (APCI) m / z: 244 (M + H) ⁺

Preparation Example 79 Preparation of 4- [1- (p-Tolyl) -1H- [1,2,3] triazol-4-yl] piperidine dihydrochloride

4-ethynylpiperidine-1-carboxylic acid tert-butyl ester (1.00 g), sodium ascorbate (0.757 g), copper sulfate pentahydrate (0.239 mg), tetrahydrofuran (30 mL), water (10 mL) ), 1-azido-4-methylbenzene (10 mL) was added, and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane: ethyl acetate) and 4- [1- (p-tolyl) -1H- [1,2,3] triazol-4-yl] piperidine-1-carboxylic acid tert -Butyl ester (0.861 mg) was obtained.
To the obtained 4- [1- (p-tolyl) -1H- [1,2,3] triazol-4-yl] piperidine-1-carboxylic acid tert-butyl ester (0.86 mg), 1,4- Dioxane (7 mL), methanol (10 mL), 4N hydrogen chloride / 1,4-dioxane solution (3.14 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to give the title compound (0.807 g).
MS (ESI) m / z: 243 (M + H) ⁺

Preparation Example 80 Preparation of 4- [1- (p-Tolyl) -1H-imidazol-4-yl] piperidine dihydrochloride

4- (1H-imidazol-4-yl) piperidine-1-carboxylic acid tert-butyl ester (370 mg), 4-iodotoluene (0.23 mL), potassium carbonate (407 mg), copper iodide (42 mg), 8 -Hydroxyquinoline (32 mg) and dimethyl sulfoxide (7 mL) were added, and the mixture was stirred at 100 ° C for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to give 4- [1- (p-tolyl) -1H-imidazol-4-yl] piperidine-1-carboxylic acid tert-butyl ester (277 mg). Obtained.
To the obtained 4- [1- (p-tolyl) -1H-imidazol-4-yl] piperidine-1-carboxylic acid tert-butyl ester (270 mg), 1,4-dioxane (3 mL), methanol (1 mL) A 4N hydrogen chloride / 1,4-dioxane solution (0.99 mL) was added, and the mixture was stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, and the precipitate was collected by filtration to obtain the title compound (253 mg).
MS (ESI) m / z: 242 (M + H) ⁺

Preparation Example 81: Preparation of 3,5-dimethyl-1 ', 2', 3 ', 4', 5 ', 6'-hexahydro [2,4'] bipyridinyl dihydrochloride

2-Bromo-3,5-dimethylpyridine (6.62 g), N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (10 g), sodium carbonate (7.54 g), 1,4-Dioxane (50 mL), water (50 mL), tetrakis (triphenylphosphine) palladium (0) (1.87 g) were added, and the mixture was stirred at 100 ° C. for 5 hours under a nitrogen stream. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and then treated with activated carbon. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate), and 3,5-dimethyl-3 ′, 6′-dihydro-2′H- [2,4 ′] bipyridinyl-1 '-Carboxylic acid tert-butyl ester (8.93 g) was obtained.
The obtained 3,5-dimethyl-3 ′, 6′-dihydro-2′H- [2,4 ′] bipyridinyl-1′-carboxylic acid tert-butyl ester (8.8 g) was dissolved in ethanol (100 mL). Then, 10% palladium carbon was added, and the mixture was stirred for 29 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 3,5-dimethyl-3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-. Carboxylic acid tert-butyl ester (8.58 g) was obtained.
3,5-Dimethyl-3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-carboxylic acid tert-butyl ester (8.55 g) with 2N hydrogen chloride / Methanol solution (70 mL) was added and stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and a mixed solvent of methanol and ethyl acetate was added to the resulting residue. The title compound (7.9 g) was obtained by filtering the precipitate.
MS (ESI) m / z: 191 (M + H) ⁺

Preparation Example 82: Preparation of 4- (2,4-dimethylphenyl) piperidine hydrochloride

Trifluoroacetic acid (10 mL) was added to 4- (2,4-dimethylphenyl) piperidin-4-ol (450 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in methanol (15 mL), 10% palladium carbon (250 mg) was added, and the mixture was stirred at room temperature for 5 hr under hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. A 2N hydrogen chloride / methanol solution was added to the resulting residue, followed by concentration under reduced pressure. Hexane / ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to obtain the title compound (211 mg). MS (ESI) m / z: 190 (M + H) ⁺

Preparative Example 83: Preparation of 3 ', 5'-dimethyl-3,4,5,6-tetrahydro-2H- [1,2'] bipyrazinyl

To 2-chloro-3,5-dimethylpyrazine (2.8 g), 1- (tert-butoxycarbonyl) piperazine (3.7 g), palladium (II) acetate (225 mg), 2- (dicyclohexylphosphino) -2 ', 4', 6'-Triisopropylbiphenyl (953 mg), sodium tert-butoxide (2.7 g) and toluene (40 mL) were added, and the mixture was stirred under reflux for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give 3 ′, 5′-dimethyl-2,3,5,6-tetrahydro- [1,2 ′] bipyrazinyl -4-carboxylic acid tert-butyl ester (5 g) was obtained.
The obtained 3 ′, 5′-dimethyl-2,3,5,6-tetrahydro- [1,2 ′] bipyrazinyl-4-carboxylic acid tert-butyl ester (5 g) was dissolved in chloroform (15 mL), and 4N A hydrogen chloride / ethyl acetate solution (15 mL) was added, and the mixture was stirred at room temperature overnight. 3 ', 5'-dimethyl-3,4,5,6-tetrahydro-2H- [1,2'] bipyrazinyl hydrochloride is added to the reaction solution by adding ethyl acetate (100 mL) and collecting the precipitate by filtration. (3.3 g) was obtained.
Saturated multistory water was added to the obtained 3 ′, 5′-dimethyl-3,4,5,6-tetrahydro-2H- [1,2 ′] bipyrazinyl hydrochloride (1.86 g), and the mixture was extracted with chloroform. The solvent was distilled off, and the obtained residue was purified by NH column chromatography (ethyl acetate: methanol) to obtain the title compound (960 mg).
MS (ESI) m / z: 193 (M + H) ⁺

Preparation Example 84: Preparation of 3,4,5-trimethyl-6-piperazin-1-ylpyridazine

3-Chloro-4,5,6-trimethylpyridazine (300 mg) was added to 1- (tert-butoxycarbonyl) piperazine (428 mg), palladium acetate (22 mg), 2- (dicyclohexylphosphino) -2 ′, 4 ′, 6′-Triisopropylbiphenyl (182.6 mg), sodium tert-butoxide (276 mg), and toluene (4 mL) were added, and the mixture was stirred at 110 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: ethyl acetate) to give tert-butyl 4- (4,5,6-trimethylpyridazin-3-yl) piperazine-1-carboxylate. The ester (297 mg) was obtained.
The obtained 4- (4,5,6-trimethylpyridazin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (297 mg) was dissolved in ethyl acetate (3 mL), and a 4N hydrogen chloride / ethyl acetate solution ( 2.6 mL) was added. After stirring at room temperature for 3 hours, the precipitate was collected by filtration. Saturated aqueous sodium hydrogen carbonate solution was added to the resulting precipitate, and the mixture was extracted with chloroform / methanol. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by NH column chromatography (ethyl acetate: methanol) to obtain the title compound (68.4 mg).
MS (ESI) m / z: 207 (M + H) ⁺

Preparation 85: Preparation of (3,5-dimethylpyridin-2-yl) piperidin-4-ylamine

2-bromo-3,5-dimethylpyridine (1 g), 4-amino-1- (tert-butoxycarbonyl) piperidine (1.29 g), tris (dibenzylideneacetone) dipalladium (0) (250 mg), 2 , 2′-bis (diphenylphosphino) -1,1′-binaphthyl (330 mg), sodium tert-butoxide (770 mg) and toluene (8 mL) were added, and the mixture was stirred at 120 ° C. overnight. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH column chromatography (hexane: ethyl acetate) to give 4- (3,5-dimethylpyridin-2-ylamino) piperidine-1-carboxylic acid tert-butyl ester (1.499 g). Obtained.
The obtained 4- (3,5-dimethylpyridin-2-ylamino) piperidine-1-carboxylic acid tert-butyl ester (610 mg) was dissolved in chloroform (3 mL), trifluoroacetic acid (2 mL) was added, and at room temperature. Stir for 3 hours. The reaction solution was charged into ion exchange chromatography, washed with methanol, and eluted with 1N ammonia / methanol solution to obtain the title compound (317.8 mg).
MS (APCI) m / z: 206 (M + H) ⁺

Preparation Example 86: Preparation of 3,5-dimethyl-2-((S) -pyrrolidin-3-yloxy) pyridine

To a solution of (S) -1- (tert-butoxycarbonyl) -3-hydroxypyrrolidine (2.26 g) and 2,3,5-trichloropyridine (2.2 g) in N, N-dimethylformamide (20 mL), ice Under cooling, sodium hydride (60% oily) (507 mg) was added, and the mixture was stirred at room temperature. After completion of the reaction, water was added and extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give (S) -3- (3,5-dichloropyridin-2-yloxy) pyrrolidine-1-carboxylic acid tert -Butyl ester (3.74 g) was obtained.
To the obtained (S) -3- (3,5-dichloropyridin-2-yloxy) pyrrolidine-1-carboxylic acid tert-butyl ester (3.74 g), 2,4,6-trimethylboroxine (4. 7 mL), palladium (II) acetate (252 mg), potassium fluoride (5.
21 g), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (922 mg) and 1,4-dioxane (38 mL) were added, and the mixture was refluxed for 4 hours with stirring. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to give (S) -3- (3,5-dimethylpyridin-2-yloxy) pyrrolidine-1-carboxylic acid tert-butyl ester (2. 96 g) was obtained.
The obtained (S) -3- (3,5-dimethylpyridin-2-yloxy) pyrrolidine-1-carboxylic acid tert-butyl ester (2.96 g) was dissolved in dichloromethane (15 mL). Fluoroacetic acid (7.6 mL) was added and stirred at room temperature. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The title compound (1.5 g) was obtained by distilling off the solvent.
MS (ESI) m / z: 193 (M + H) ⁺

Preparation 87: Preparation of 5-methyl-1-pyrrolidin-3-yl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine

To a solution of 2,3-dihydro-7-azaindole (2.8 g) and 1- (tert-butoxycarbonyl) -3-oxopyrrolidine (5.44 g) in methanol (28 mL) was added acetic acid (4. 67 mL) and sodium cyanoborohydride (1.76 g) were added, and the mixture was stirred at room temperature for 1.5 hours. 1- (tert-Butoxycarbonyl) -3-oxopyrrolidine (3 g) was added, and the mixture was stirred at room temperature for 1.5 hours. 2N Aqueous sodium hydroxide solution (80 mL) was added, and the mixture was concentrated under reduced pressure to distill off methanol. The remaining aqueous solution was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was back extracted with 1N hydrochloric acid. The aqueous layer was neutralized with an aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane: ethyl acetate) to give tert-butyl 3- (2,3-dihydropyrrolo [2,3-b] pyridin-1-yl) pyrrolidine-1-carboxylate The ester (2.96 g) was obtained.
The obtained 3- (2,3-dihydropyrrolo [2,3-b] pyridin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (2 g) was dissolved in N, N-dimethylformamide (20 mL). Under ice cooling, N-bromosuccinimide (1.26 g) was added and stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 3- (5-bromo-2,3-dihydropyrrolo [2,3-b] pyridin-1-yl) pyrrolidine. A -1-carboxylic acid tert-butyl ester (2.77 g) was obtained.
To the obtained 3- (5-bromo-2,3-dihydropyrrolo [2,3-b] pyridin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.2 g), 6-trimethylboroxine (4.24 mL), palladium (II) acetate (73.2 mg), potassium fluoride (757 mg), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (268 mg), 1,4 -Dioxane (12 mL) was added and refluxed for 1.5 hours with stirring. Water was added to the reaction solution and filtered through celite. The filtrate was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to give 3- (5-methyl-2,3-dihydropyrrolo [2,3-b] pyridin-1-yl) pyrrolidine-1-carboxyl Acid tert-butyl ester (792 mg) was obtained.
The obtained 3- (5-methyl-2,3-dihydropyrrolo [2,3-b] pyridin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg) was added to ethyl acetate (0.5 mL). ), Ethanol (0.5 mL), 4N hydrogen chloride / ethyl acetate solution (1.6 mL) were added, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with a mixed solvent of chloroform and methanol. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was fractionated by HPLC using XBridge Prep C18 OBD (10 mmol / L ammonium carbonate aqueous solution, acetonitrile). The resulting solution was extracted with a mixed solvent of chloroform and methanol. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (22.1 mg).
MS (ESI) m / z: 204 (M + H) ⁺

Preparation 88: Preparation of (3,5-dimethylpyridin-2-yl)-(S) -pyrrolidin-3-ylamine dihydrochloride

2-Bromo-3,5-dimethylpyridine (10.26 g) was added to (S) -1- (tert-butoxycarbonyl) -3-aminopyrrolidine (10.27 g), tris (dibenzylideneacetone) dipalladium (0 ) (505 mg), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (1 g), sodium tert-butoxide (7.24 g) and toluene (180 mL) were added, and the mixture was stirred at 80 ° C. for 3 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate). The solvent was distilled off, and ethyl acetate (50 mL), 4N hydrogen chloride / 1,4-dioxane solution (50 mL) and methanol (10 mL) were added to the resulting residue, and the mixture was stirred at room temperature for 2.5 hours. Diethyl ether was added to the reaction solution, and the supernatant was removed by decantation. Ethyl acetate / ethanol was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (11.9 g).
MS (ESI) m / z: 192 (M + H) ⁺

Preparation Example 89: Preparation of 5-methyl-1-piperidin-4-yl-1H-pyrrolo [2,3-b] pyridine

Tetrahydrofuran (30 mL) of 4- (hydroxy) piperidine-1-carboxylic acid benzyl ester (2 g), 5-bromo-1H-pyrrolo [2,3-b] pyridine (1.12 g), triphenylphosphine (2.97 g) ) Diisopropyl azodicarboxylate (2.2 mL) was added to the solution under ice cooling. After stirring overnight at room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane / ethyl acetate was added to the obtained residue, followed by filtration (removal of precipitated triphenylphosphine oxide). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) and NH column chromatography (hexane: ethyl acetate) to give 4- (5-bromopyrrolo [2,3-b] pyridine- 1-yl) piperidine-1-carboxylic acid benzyl ester (650 mg) was obtained.
The obtained 4- (5-bromopyrrolo [2,3-b] pyridin-1-yl) piperidine-1-carboxylic acid benzyl ester (640 mg) was added to 2,4,6-trimethylboroxine (504 mg), palladium acetate. (II) (35 mg), potassium fluoride (359 mg), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (127 mg), 1,4-dioxane (10 mL) were added, and the mixture was stirred for 2 hours under reflux. . 2,4,6-Trimethylboroxine (272 mg) was added, and the mixture was stirred for 2 hours under reflux. Water and ethyl acetate were added to the reaction mixture, and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give 4- (5-methylpyrrolo [2,3-b] pyridin-1-yl) piperidine-1-carboxylic acid The benzyl ester (476 mg) was obtained.
To a solution of the obtained 4- (5-methylpyrrolo [2,3-b] pyridin-1-yl) piperidine-1-carboxylic acid benzyl ester (380 mg) in ethanol (15 mL), 7.5% palladium carbon (114 mg). And stirred at room temperature for 7 hours under hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH column chromatography (ethyl acetate: methanol) to obtain the title compound (207 mg).
MS (ESI) m / z: 216 (M + H) ⁺

Preparation Example 90: Preparation of 5-methyl-1- (S) -pyrrolidin-3-yl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine

To a solution of (R) -3-hydroxypyrrolidine-1-carboxylic acid benzyl ester (2 g), 5-bromo-1H-pyrrolo [2,3-b] pyridine (1.78 g) in toluene (25 mL) at 80 ° C. Under heating, a toluene (7 mL) solution of cyanomethylenetributylphosphorane (4.364 g) was added. After stirring at 110 ° C. for 5 hours, the reaction solution was concentrated under reduced pressure. The resulting residue is purified by NH column chromatography (hexane: ethyl acetate) to give (S) -3- (5-bromopyrrolo [2,3-b] pyridin-1-yl) pyrrolidine-1-carboxylate benzyl The ester (2.78 g) was obtained.
To the obtained (S) -3- (5-bromopyrrolo [2,3-b] pyridin-1-yl) pyrrolidine-1-carboxylic acid benzyl ester (1.3 g), 2,4,6-trimethylboroxine was added. (2.26 g), palladium (II) acetate (156 mg), potassium fluoride (1.61 g), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (570 mg), 1,4-dioxane (40 mL) And stirred for 1 hour under reflux. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane: ethyl acetate) to give (S) -3- (5-methylpyrrolo [2,3-b] pyridin-1-yl) pyrrolidine-1-carboxylic acid benzyl ester (2.32 g) was obtained.
The obtained (S) -3- (5-methylpyrrolo [2,3-b] pyridin-1-yl) pyrrolidine-1-carboxylic acid benzyl ester (1.3 g) was dissolved in acetic acid (12 mL), and cyanohydrogen was obtained. Sodium borohydride (1.22 g) was added and stirred overnight at room temperature. Sodium cyanoborohydride (1.22 g) was added, and the mixture was stirred at room temperature for 3 days. To the reaction solution was added 2N aqueous sodium hydroxide solution (50 mL) under ice cooling. Basified with potassium carbonate and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. By purifying the obtained residue by column chromatography (hexane: ethyl acetate), (S) -3- (5-methyl-2,3-dihydropyrrolo [2,3-b] pyridin-1-yl) pyrrolidine -1-carboxylic acid benzyl ester (2.78 g) was obtained.
The obtained (S) -3- (5-methyl-2,3-dihydropyrrolo [2,3-b] pyridin-1-yl) pyrrolidine-1-carboxylic acid benzyl ester (1.12 g) was added to ethanol (15 mL). ), 7.5% palladium carbon (336 mg) was added, and the mixture was stirred at room temperature for 2 days under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethanol (20 mL), 7.5% palladium carbon (448 mg) was added, and the mixture was stirred at room temperature for 4 days under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH column chromatography (ethyl acetate: methanol) to obtain the title compound (479 mg).
MS (ESI) m / z: 204 (M + H) ⁺

Preparation 91: Preparation of 5-methyl-1- (S) -pyrrolidin-3-yl-1H-pyrrolo [2,3-b] pyridine

(S) -3- (5-Methylpyrrolo [2,3-b] pyridin-1-yl) pyrrolidine-1-carboxylic acid benzyl ester (1.02 g) obtained by the synthesis method described in Preparation Example 90 was treated with ethanol. (15 mL), 7.5% palladium carbon (306 mg) was added, and the mixture was stirred at room temperature for 8 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH column chromatography (ethyl acetate: methanol) to obtain the title compound (460 mg).
MS (ESI) m / z: 202 (M + H) ⁺

Preparation 92: Preparation of 3- (3,5-dimethylpyridin-2-ylamino) azetidine-1-carboxylic acid tert-butyl ester

2-Bromo-3,5-dimethylpyridine (1 g), 1- (tert-butoxycarbonyl) -3-aminoazetidine (1.11 g), tris (dibenzylideneacetone) dipalladium (0) (250 mg), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (330 mg), sodium tert-butoxide (770 mg) and toluene (8 mL) were added, and the mixture was stirred at 120 ° C. overnight. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH column chromatography (hexane: ethyl acetate) to give the title compound (965 mg).
MS (APCI) m / z: 278 (M + H) ⁺

Preparation Example 93: Preparation of (5-methylpyridin-2-yl) piperidin-4-ylmethanone dihydrochloride

To a solution of 2-bromo-5-methylpyridine (4.04 g) in toluene (70 mL) at −78 ° C. was added n-butyllithium / hexane solution (1.6 M) (16.9 mL). After stirring at −78 ° C. for 10 minutes, a solution of 4- (methoxymethylcarbamoyl) piperidine-1-carboxylic acid tert-butyl ester (6.4 g) in toluene (10 mL) was added. After stirring at −78 ° C. for 30 minutes, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain 4- (5-methylpyridine-2-carbonyl) piperidine-1-carboxylic acid tert-butyl ester (4.03 g).
To a solution of the obtained 4- (5-methylpyridine-2-carbonyl) piperidine-1-carboxylic acid tert-butyl ester (4.02 g) in chloroform (66 mL) was added 4N hydrogen chloride / ethyl acetate solution (33 mL). And stirred at room temperature overnight. Hexane was added to the reaction solution, and the precipitate was collected by filtration to obtain the title compound (3.61 g).
MS (ESI) m / z: 205 (M + H) ⁺

Preparation Example 94: Preparation of (3R, 4R) -4- (3,5-dimethylpyridin-2-ylamino) pyrrolidin-3-ol dihydrochloride

(3R, 4R) -3-Amino-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (1.35 g) was added to dichloromethane (67 mL), diisopropylethylamine (4.1 mL), 3,5-dimethylpyridine- N-oxide (986 mg) and bromotris (pyrrolidino) phosphonium hexafluorophosphate (3.73 g) were added, and the mixture was stirred at room temperature for 6.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give (3R, 4R) -3- (3,5-dimethylpyridin-2-ylamino) -4-hydroxy. Pyrrolidine-1-carboxylic acid tert-butyl ester (1 g) was obtained.
The obtained (3R, 4R) -3- (3,5-dimethylpyridin-2-ylamino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (1 g) was mixed with chloroform (10 mL), 4N hydrogen chloride. / Ethyl acetate solution (8.3 mL) was added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to obtain the title compound (1 g).
MS (ESI) m / z: 208 (M + H) ⁺

Preparation Example 95: Preparation of 5,7-dimethyl-1- (R) -pyrrolidin-3-yl-1H-indazole

(S) -1- (tert-butoxycarbonyl) -3-hydroxypyrrolidine (853 mg), 3-iodo-5,7-dimethyl-1H-indazole (620 mg), triphenylphosphine (1195 mg) in tetrahydrofuran (12 mL) Dissolved, diisopropyl azodicarboxylate (0.897 mL) was added under ice cooling, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and diisopropyl ether was added to the resulting residue, followed by filtration (removing the precipitate). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give (R) -3- (3-iodo-5,7-dimethylindazol-1-yl) pyrrolidine- 1-carboxylic acid tert-butyl ester (442 mg) was obtained.
To a solution of the obtained (R) -3- (3-iodo-5,7-dimethylindazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (435 mg) in ethanol (8.9 mL), 10% Palladium on carbon (44 mg) was added, and the mixture was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. To the reaction solution was added 1N aqueous sodium hydroxide solution (1.97 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. Water and ethyl acetate were added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (R) -3- (5,7-dimethylindazole-
1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (309 mg) was obtained.
To (R) -3- (5,7-dimethylindazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (361 mg) obtained by the above method and the same method as above, 1,4- Dioxane (5.4 mL), 4N hydrogen chloride / 1,4-dioxane solution (2.86 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue under ice cooling (about pH 8), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (239 mg).
MS (ESI) m / z: 216 (M + H) ⁺

Preparation Example 96: Preparation of 5,7-dimethyl-2-piperidin-4-yl-2H-indazole hydrochloride

1) 4- (3-Iodo-5,7-dimethylindazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester and 4- (3-iodo-5,7-dimethylindazol-1-yl) piperidine Preparation of -1-carboxylic acid tert-butyl ester 3-Iodo-5,7-dimethyl-1H-indazole (300 mg), 1- (tert-butoxycarbonyl) -4-hydroxypiperidine (488 mg), triphenylphosphine (578 mg) ) In tetrahydrofuran (6 mL) was added diethyl azodicarboxylate (40% toluene solution, approximately 2.2 mol / L) (1.002 mL) under ice cooling, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure, and diisopropyl ether was added to the resulting residue, followed by filtration (removing the precipitate). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give 4- (3-iodo-5,7-dimethylindazol-2-yl) piperidine-1-carboxylic acid. Tert-butyl ester (226.5 mg) and 4- (3-iodo-5,7-dimethylindazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (227.4 mg) were obtained.
Acqity UPLC BEH C18 (Waters) (2 mm × 50 mm, mobile phase A: 0.05% formic acid / water, mobile phase B: 0.05% formic acid / acetonitrile, gradient: B 5% → 98% 1 minute, flow rate: 0 In the analysis at 6 mL / min), the retention times were 1.38 minutes and 1.36 minutes, respectively.

2) Preparation of 5,7-dimethyl-2-piperidin-4-yl-2H-indazole · hydrochloride 4- (3-iodo-5,7-dimethylindazol-2-yl) piperidine- described in 1) above To 1-carboxylic acid tert-butyl ester (222 mg) was added methanol (4 mL), tetrahydrofuran (2 mL), 2N aqueous sodium hydroxide (0.488 mL), 10% palladium on carbon (22 mg), and at room temperature under a hydrogen atmosphere. Stir overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the obtained residue was purified by column chromatography (hexane: ethyl acetate) to give 4- (5,7-dimethylindazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester ( 154 mg) was obtained.
To the obtained 4- (5,7-dimethylindazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (150 mg), 1,4-dioxane (2.2 mL), 4N hydrogen chloride / 1,4 -Dioxane solution (1.14 mL) was added and stirred at room temperature for 1.5 hours. 4N hydrogen chloride / 1,4-dioxane solution (2 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, diethyl ether was added to the resulting residue, and the precipitate was collected by filtration to give 5,7-dimethyl-2-piperidin-4-yl-2H-indazole hydrochloride (150.7 mg). )
MS (ESI) m / z: 230 (M + H) ⁺

Preparation 97: Preparation of 5,7-dimethyl-1-piperidin-4-yl-1H-indazole hydrochloride

Using 4- (3-iodo-5,7-dimethylindazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (223 mg) described in Preparation Example 96-1) and Preparation Example 96-2) The title compound (116.5 mg) was obtained by carrying out the same reaction and treatment.
MS (ESI) m / z: 230 (M + H) ⁺

Preparation Example 98 Preparation of 4,6-dimethyl-3-piperidin-4-yl-1H-indazole

1) Preparation of 4-[(2,4-dibromo-6-fluorophenyl) hydroxymethyl] piperidine-1-carboxylic acid tert-butyl ester To a solution of diisopropylamine (1.21 mL) in tetrahydrofuran (8 mL) at −78 ° C. N-butyllithium / hexane solution (2.65 mol / L, 3.33 mL) was added. After stirring at 0 ° C. for 10 minutes, a solution of 1,3-dibromo-5-fluorobenzene (2 g) in tetrahydrofuran (25 mL) was added at −78 ° C. After stirring at −78 ° C. for 30 minutes, a solution of 1-Boc-4-piperidinecarboxaldehyde (1.85 g) in tetrahydrofuran (32 mL) was added. After stirring at 0 ° C. for 6.5 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH column chromatography (hexane: ethyl acetate) to give 4-[(2,4-dibromo-6-fluorophenyl) hydroxymethyl] piperidine-1-carboxylic acid tert-butyl ester (2 0.04 g) was obtained.

2) Preparation of 4- (2,4-dibromo-6-fluorobenzoyl) piperidine-1-carboxylic acid tert-butyl ester To a solution of oxalyl chloride (0.63 mL) in dichloromethane (8 mL), cooled to −78 ° C., A solution of dimethyl sulfoxide (0.785 mL) in dichloromethane (2 mL) was added. After stirring at −50 ° C. or lower for 5 minutes, 4-[(2,4-dibromo-6-fluorophenyl) hydroxymethyl] piperidine-1-carboxylic acid tert-butyl ester (1.72 g) as described in 1) above. Of dichloromethane (10 mL) was added. After stirring at −50 ° C. or lower for 20 minutes, triethylamine (3.08 mL) was added, and the mixture was stirred at room temperature for 5 minutes. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue is purified by column chromatography (hexane: ethyl acetate) to obtain 4- (2,4-dibromo-6-fluorobenzoyl) piperidine-1-carboxylic acid tert-butyl ester (1.714 g). It was.

3) Preparation of 4- (4,6-dibromo-1H-indazol-3-yl) piperidine-1-carboxylic acid tert-butyl ester 4- (2,4-dibromo) obtained by the same method as in 2) above Ethanol (74.8 mL) and hydrazine monohydrate (4.68 mL) were added to (-6-fluorobenzoyl) piperidine-1-carboxylic acid tert-butyl ester (3.74 g), and the mixture was stirred overnight under reflux. . The reaction solution was concentrated under reduced pressure, water was added to the resulting residue, and the precipitate was collected by filtration. The obtained precipitate was recrystallized from ethanol to obtain 4- (4,6-dibromo-1H-indazol-3-yl) piperidine-1-carboxylic acid tert-butyl ester (2.664 g).

4) Preparation of 4- [4,6-dibromo-1- (2-trimethylsilanylethoxymethyl) -1H-indazol-3-yl] piperidine-1-carboxylic acid tert-butyl ester Method similar to 3) above To a solution of 4- (4,6-dibromo-1H-indazol-3-yl) piperidine-1-carboxylic acid tert-butyl ester (900 mg) obtained in 1 above in N, N-dimethylformamide (18 mL) under ice-cooling. , Sodium hydride (60% oily) (102 mg) was added. After stirring for 3 minutes, 2- (chloromethoxy) ethyltrimethylsilane (0.482 mL) was added. After stirring for 1 hour under ice-cooling, water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate and hexane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to give 4- [4,6-dibromo-1- (2-trimethylsilanylethoxymethyl) -1H-indazol-3-yl] piperidine- 1-carboxylic acid tert-butyl ester (869 mg) was obtained.

5) Preparation of 4- [4,6-dimethyl-1- (2-trimethylsilanylethoxymethyl) -1H-indazol-3-yl] piperidine-1-carboxylic acid tert-butyl ester 4 described in 4) above -[4,6-dibromo-1- (2-trimethylsilanylethoxymethyl) -1H-indazol-3-yl] piperidine-1-carboxylic acid tert-butyl ester (130 mg), methylboronic acid (52.8 mg), Palladium (II) acetate (5 mg) was dissolved in anhydrous tetrahydrofuran (2.2 mL), and potassium fluoride (102.5 mg) and 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (18.1 mg) were added. The mixture was stirred at 70 ° C. for 10 hours under a nitrogen atmosphere. Again, 4- [4,6-dibromo-1- (2-trimethylsilanylethoxymethyl) -1H-indazol-3-yl] piperidine-1-carboxylic acid tert-butyl ester (740 mg) as described in 4) above And methylboronic acid (300.6 mg) was used to carry out a similar reaction. The combined solution of these two reaction solutions was filtered through NH silica gel. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give 4- [4,6-dimethyl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole. -3-yl] piperidine-1-carboxylic acid tert-butyl ester (617 mg) was obtained.

6) Preparation of 4,6-dimethyl-3-piperidin-4-yl-1H-indazole 4- [4,6-dimethyl-1- (2-trimethylsilanylethoxymethyl) -1H— according to 5) above Indazol-3-yl] piperidine-1-carboxylic acid tert-butyl ester (320 mg) was dissolved in 1,4-dioxane (6.4 mL), and 4N hydrogen chloride / 1,4-dioxane solution (1.7 mL) was dissolved. In addition, after stirring at 50 ° C. for 5.5 hours, a 4N hydrogen chloride / 1,4-dioxane solution (1.7 mL) was added, and the mixture was stirred at 80 ° C. for 26 hours. Further, 4N hydrogen chloride / 1,4-dioxane solution (1.7 mL) was added, and the mixture was stirred at 80 ° C. for 25 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration. To the obtained solid was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, diethyl ether was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (150 mg).
MS (ESI) m / z: 230 (M + H) ⁺

Preparation Example 99: Preparation of 1,4,6-trimethyl-3-piperidin-4-yl-1H-indazole hydrochloride

To a solution of 4- (4,6-dibromo-1H-indazol-3-yl) piperidine-1-carboxylic acid tert-butyl ester (800 mg, see Preparation 98) in N, N-dimethylformamide (16 mL). Sodium hydride (60% oily) (91 mg) was added under ice cooling. After stirring for 3 minutes under ice cooling, methyl iodide (0.152 mL) was added. After stirring for 1.5 hours under ice cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by column chromatography (hexane: ethyl acetate) to give 4- (4,6-dibromo-1-methyl-1H-indazol-3-yl) piperidine-1-carboxylic acid tert-butyl ester (748 mg) was obtained.
To the obtained 4- (4,6-dibromo-1-methyl-1H-indazol-3-yl) piperidine-1-carboxylic acid tert-butyl ester (748 mg), methylboronic acid (377 mg), palladium (II) acetate (35 mg), anhydrous tetrahydrofuran (16 mL), potassium fluoride (732 mg), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (129 mg) were added, and the mixture was stirred at 70 ° C. for 19 hours in a nitrogen atmosphere. By purifying the reaction solution by NH column chromatography (ethyl acetate) and column chromatography (hexane: ethyl acetate), 4- (1,4,6-trimethyl-1H-indazol-3-yl) piperidine-1-carboxylic acid The tert-butyl ester (485.6 mg) was obtained.
The obtained 4- (1,4,6-trimethyl-1H-indazol-3-yl) piperidine-1-carboxylic acid tert-butyl ester (481 mg) was dissolved in 1,4-dioxane (4.8 mL), 4N hydrogen chloride / 1,4-dioxane solution (3.5 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the resulting residue, and the precipitate was collected by filtration to give the title compound (449 mg).
MS (ESI) m / z: 244 (M + H) ⁺

Preparation Example 100: Preparation of 4-fluoro-6-methyl-3-piperidin-4-yl-1H-indazole

4- (2,4-Dibromo-6-fluorobenzoyl) piperidine-1-carboxylic acid tert-butyl ester (3.74 g, see Preparation 98), ethanol (75 mL), hydrazine monohydrate. (4.68 mL) was added, and the mixture was stirred overnight under reflux. The reaction solution was concentrated under reduced pressure, water was added to the resulting residue, and the precipitate was collected by filtration. The obtained precipitate was recrystallized with ethanol (35 mL), and the precipitate (4- (4,6-dibromo-1H-indazol-3-yl) piperidine-1-carboxylic acid tert-butyl ester) was collected by filtration. . The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give 4- (6-bromo-4-fluoro-1H-indazol-3-yl) piperidine-1-carboxylic acid. Acid tert-butyl ester (121 mg) was obtained.
N, N- of 4- (6-Bromo-4-fluoro-1H-indazol-3-yl) piperidine-1-carboxylic acid tert-butyl ester (170 mg) obtained by the above method and the same method as above. Sodium hydride (60% oily) (20 mg) was added to a dimethylformamide (3 mL) solution under ice cooling. After stirring at 0 ° C. for 1 minute, 2- (chloromethoxy) ethyltrimethylsilane (0.09 mL) was added. After stirring at 0 ° C. for 20 minutes, saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate / diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to give 4- [6-bromo-4-fluoro-1- (2-trimethylsilanylethoxymethyl) -1H-indazol-3-yl]. Piperidine-1-carboxylic acid tert-butyl ester (131 mg) was obtained.
4- [6-Bromo-4-fluoro-1- (2-trimethylsilanylethoxymethyl) -1H-indazol-3-yl] piperidine-1-carboxylic acid tert-butyl ester (130 mg) obtained, methyl boronic acid (37 mg) and palladium (II) acetate (6 mg) were dissolved in anhydrous tetrahydrofuran (2 mL), potassium fluoride (71 mg), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (20 mg) were added, and nitrogen was added. The mixture was stirred at 70 ° C. for 20 hours under an atmosphere. The reaction was filtered through NH silica gel. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate) to give 4- [4-fluoro-6-methyl-1- (2-trimethylsilanylethoxymethyl) -1H. -Indazol-3-yl] piperidine-1-carboxylic acid tert-butyl ester (52.6 mg) was obtained.
The obtained 4- [4-fluoro-6-methyl-1- (2-trimethylsilanylethoxymethyl) -1H-indazol-3-yl] piperidine-1-carboxylic acid tert-butyl ester (52 mg) was subjected to 4N chloride. Hydrogen / 1,4-dioxane solution (5 mL) was added, and the mixture was stirred at 70 ° C. for 4.5 hours. The reaction mixture was concentrated under reduced pressure, and 1,4-dioxane (3 mL) and 28% aqueous ammonia (1 mL) were added to the resulting residue, followed by stirring at 90 ° C. for 3 hours and at 70 ° C. overnight. To the reaction solution was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure to obtain the title compound (32 mg).
MS (ESI) m / z: 234 (M + H) ⁺

Preparation Example 101: Preparation of (2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-2-carboxylic acid methyl ester dihydrochloride

(2S, 4S) -4-Aminopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (150 mg) was dissolved in dichloromethane (2.5 mL), and diisopropylethylamine (0.32 mL), 3 , 5-Dimethylpyridine-N-oxide (60.5 mg) and bromotris (pyrrolidino) phosphonium hexafluorophosphate (298 mg) were added, and the mixture was stirred at room temperature overnight. The reaction solution was purified by NH column chromatography (hexane: ethyl acetate) to give (2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1,2-dicarboxylic acid 1-tert- Butyl ester 2-methyl ester (74 mg) was obtained.
To the obtained (2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (70 mg), 1,4- Dioxane (0.7 mL), 4N hydrogen chloride / 1,4-dioxane solution (1.4 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction solution was concentrated under reduced pressure to obtain the title compound (84 mg).
MS (ESI) m / z: 250 (M + H) ⁺

Preparation Example 102: Preparation of [(2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) pyrrolidin-2-yl] methanol dihydrochloride

(2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1,2-dicarboxylic acid 1-tertbutyl ester 2-methyl ester (310 mg, see Preparation Example 101) in tetrahydrofuran (6.2 mL) and methanol (3.1 mL) were dissolved, and lithium chloride (113 mg) and sodium borohydride (104 mg) were added under ice cooling. After stirring at room temperature overnight, 1N hydrochloric acid (5 mL) was added to the reaction solution. After concentration under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane: ethyl acetate) to give (2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2-hydroxymethylpyrrolidine-1-carboxylic acid Tert-butyl ester (261 mg) was obtained.
The obtained (2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2-hydroxymethylpyrrolidine-1-carboxylic acid tert-butyl ester (150 mg) was converted into 1,4-dioxane (1. 5N), 4N hydrogen chloride / 1,4-dioxane solution (3 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (133 mg).
MS (ESI) m / z: 222 (M + H) ⁺

Preparation Example 103: Preparation of (3,5-dimethylpyridin-2-yl) ((3S, 5R) -5-methylpyrrolidin-3-yl) amine dihydrochloride

(2R, 4S) -4-amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (368 mg) was added to dichloromethane (7 mL), diisopropylethylamine (1.2 mL), 3,5-dimethylpyridine-N—. Oxide (226 mg) and bromotris (pyrrolidino) phosphonium hexafluorophosphate (1114 mg) were added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by NH column chromatography (hexane: ethyl acetate) to give (2R, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2- Methylpyrrolidine-1-carboxylic acid tert-butyl ester (298 mg) was obtained.
The obtained (2R, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (295 mg) was added to 1,4-dioxane (3 mL). After dissolution, 4N hydrogen chloride / 1,4-dioxane solution (3 mL) was added and stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (264 mg).

Preparation Example 104: Preparation of (3,5-dimethylpyridin-2-yl) ((3S, 5S) -5-methylpyrrolidin-3-yl) amine dihydrochloride

(2S, 4S) -4-Amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (280 mg) was dissolved in dichloromethane (6 mL), and diisopropylethylamine (0.913 mL), 3,5-dimethylpyridine- N-oxide (172 mg) and bromotris (pyrrolidino) phosphonium hexafluorophosphate (847 mg) were added, and the mixture was stirred at room temperature overnight. 3,5-Dimethylpyridine-N-oxide (86 mg) and bromotris (pyrrolidino) phosphonium hexafluorophosphate (325 mg) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by NH column chromatography (hexane: ethyl acetate) to give (2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2- Methylpyrrolidine-1-carboxylic acid tert-butyl ester (192 mg) was obtained.
The resulting (2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (190 mg) was added to 1,4-dioxane (1.9 mL). ) 4N hydrogen chloride / 1,4-dioxane solution (1.9 mL) was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (182 mg).

Preparation Example 105: Preparation of (2S, 3S) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-2-carboxylic acid methyl ester dihydrochloride

To a solution of (2S, 3R) -3-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (3.31 g), triphenylphosphine (5.31 g) in tetrahydrofuran (48 mL), ice Under cooling, a solution of diisopropyl azodicarboxylate (4.09 g) in tetrahydrofuran (10 mL) was added. Next, a solution of diphenylphosphoric azide (4.35 mL) in tetrahydrofuran (10 mL) was added under ice cooling, and the mixture was stirred at room temperature for 6.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give (2S, 3S) -3-azidopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2 -The methyl ester (3.31 g) was obtained.
To a solution of the obtained (2S, 3S) -3-azidopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (3.31 g) in methanol (33 mL), 10% palladium carbon (0. 33 g) was added and stirred at room temperature for 5.5 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH column chromatography (hexane: ethyl acetate) to give (2S, 3S) -3-aminopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1. 44 g) was obtained.
The obtained (2S, 3S) -3-aminopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (450 mg) was added to dichloromethane (7 mL), diisopropylethylamine (1.2 mL), 3, 5 -Dimethylpyridine-N-oxide (250 mg) and bromotris (pyrrolidino) phosphonium hexafluorophosphate (1116 mg) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by NH column chromatography (hexane: ethyl acetate) to give (2S, 3S) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1 , 2-Dicarboxylic acid 1-tert-butyl ester 2-methyl ester (215 mg) was obtained.
The obtained (2S, 3S) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (215 mg) was converted to 1,4-dioxane. (2.15 mL), 4N hydrogen chloride / 1,4-dioxane solution (2.15 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction solution was concentrated under reduced pressure to obtain the title compound (213 mg).
MS (ESI) m / z: 250 (M + H) ⁺

Preparation Example 106: Preparation of (2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-2-carboxylic acid amide dihydrochloride

(2S, 4S) -4- (3,5-Dimethylpyridin-2-ylamino) pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (480 mg, see Preparation Example 101) , Ethanol (4.8 mL), 1N aqueous sodium hydroxide solution (2.75 mL) were added, and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (2.75 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure to give (2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1,2-dicarboxylic acid 1 -Tert-Butyl ester (640 mg) was obtained.
To the obtained (2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (230 mg), ammonium chloride (183 mg), 1- Hydroxybenzotriazole (140 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (200 mg), chloroform (5 mL) and triethylamine (0.67 mL) were added, and the mixture was stirred at room temperature for 6 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), and (2S, 4S) -2-carbamoyl-4- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1 -Carboxylic acid tert-butyl ester (172 mg) was obtained.
The resulting (2S, 4S) -2-carbamoyl-4- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1-carboxylic acid tert-butyl ester (70 mg) was added to 1,4-dioxane (0.7 mL). ) 4N hydrogen chloride / 1,4-dioxane solution (0.7 mL) was added, and the mixture was stirred at room temperature for 6.5 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (66 mg).
MS (ESI) m / z: 235 (M + H) ⁺

Preparation Example 107: Preparation of (3,5-dimethylpyridin-2-yl) ((3S, 5S) -5-methoxymethylpyrrolidin-3-yl) amine dihydrochloride

(2S, 4S) -4-amino-2-methoxymethylpyrrolidine-1-carboxylic acid tert-butyl ester (300 mg), 2-bromo-3,5-dimethylpyridine (291 mg), tris (dibenzylideneacetone) di Palladium (0) (30 mg), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (41 mg), sodium tert-butoxide (188 mg) and toluene (6 mL) were added, and 6 hours at 80 ° C. Stir. The reaction solution was purified by column chromatography (hexane: ethyl acetate) to give (2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2-methoxymethylpyrrolidine-1-carboxylic acid tert- Butyl ester (489 mg) was obtained.
The obtained (2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2-methoxymethylpyrrolidine-1-carboxylic acid tert-butyl ester (435 mg) was converted into 1,4-dioxane (4. 4N), 4N hydrogen chloride / 1,4-dioxane solution (4.4 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain the title compound (492 mg).
MS (ESI) m / z: 236 (M + H) ⁺

Preparation Example 108: Preparation of 2-[(2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) pyrrolidin-2-yl] propan-2-ol dihydrochloride

To a solution of (2S, 4R) -4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (3 g) in tetrahydrofuran (40 mL),
Under ice cooling, 3M methylmagnesium bromide / diethyl ether solution (14.3 mL) was added. After stirring for 15 minutes under ice-cooling, the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Hexane / diisopropyl ether was added to the resulting residue, and the precipitate was collected by filtration to give (2S, 4R) -4-hydroxy-2- (1-hydroxy-1-methylethyl) pyrrolidine-1-carboxylic acid tert. -Butyl ester (2.68 g) was obtained.
The obtained (2S, 4R) -4-hydroxy-2- (1-hydroxy-1-methylethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (2.68 g), 4- (dimethylamino) pyridine (0 .13 g) and triethylamine (3.05 mL) in dichloromethane (45 mL) were added a solution of methanesulfonyl chloride (1.01 mL) in dichloromethane (10 mL) under ice cooling. After stirring for 1.5 hours under ice cooling, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane: ethyl acetate) and (2S, 4R) -2- (1-hydroxy-1-methylethyl) -4-methanesulfonyloxypyrrolidine-1-carboxylate tert-butyl The ester (3.31 g) was obtained.
The obtained (2S, 4R) -2- (1-hydroxy-1-methylethyl) -4-methanesulfonyloxypyrrolidine-1-carboxylic acid tert-butyl ester (3.31 g) was dissolved in acetonitrile (37 mL). , Tetrabutylammonium azide (4.7 g) was added, and the mixture was stirred at 80 ° C. for 8.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give (2S, 4S) -4-azido-2- (1-hydroxy-1-methylethyl) pyrrolidine- 1-carboxylic acid tert-butyl ester (1.73 g) was obtained.
To a solution of the obtained (2S, 4S) -4-azido-2- (1-hydroxy-1-methylethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.73 g) in ethanol (32 mL), 10% Palladium on carbon (0.17 g) was added, and the mixture was stirred at room temperature for 3.5 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane: ethyl acetate) to give tert-butyl (2S, 4S) -4-amino-2- (1-hydroxy-1-methylethyl) pyrrolidine-1-carboxylate. The ester (1.324 g) was obtained.
The obtained (2S, 4S) -4-amino-2- (1-hydroxy-1-methylethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (250 mg) was dissolved in dichloromethane (4 mL), and diisopropylethylamine ( 0.67 mL), 3,5-dimethylpyridine-N-oxide (139 mg) and bromotris (pyrrolidino) phosphonium hexafluorophosphate (620 mg) were added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give (2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2- ( 1-Hydroxy-1-methylethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (265 mg) was obtained.
The obtained (2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2- (1-hydroxy-1-methylethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (260 mg) was added. This was dissolved in 1,4-dioxane (3 mL), and a 4N hydrogen chloride / 1,4-dioxane solution (3 mL) was added under ice cooling. The mixture was stirred for 1 hour under ice cooling, and then stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the title compound (265 mg).
MS (ESI) m / z: 250 (M + H) ⁺

Preparation Example 109: Preparation of 4- (4-p-tolylpyrazol-1-yl) piperidine hydrochloride

4- (4-Bromopyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (208 mg), 4-methylphenylboronic acid (95 mg), N, N-dimethylformamide (3.2 mL), 2M An aqueous sodium carbonate solution (946 μL) and [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride / dichloromethane complex (26 mg) were added, and the mixture was stirred at 80 ° C. After completion of the reaction, saturated brine was added, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give tert-butyl 4- [4- (p-tolyl) pyrazol-1-yl] piperidine-1-carboxylate. The ester (139 mg) was obtained.
The obtained 4- [4- (p-tolyl) pyrazol-1-yl] piperidine-1-carboxylic acid tert-butyl ester (138 mg) was dissolved in 1,4-dioxane (2 mL), and 4N hydrogen chloride / 1. , 4-Dioxane solution (1.01 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off, ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (112.6 mg).
MS (ESI) m / z: 242 (M + H) ⁺

Preparation Example 110: Preparation of 1- (3,5-dimethylpyridin-2-yl) -3-methylpiperazine

2-methylpiperazine-1-carboxylic acid tert-butyl ester (2 g), 2-bromo-3,5-dimethylpyridine (1.95 g), tris (dibenzylideneacetone) dipalladium (0) (183 mg), rac- Toluene (33 mL) was added to a mixture of 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (250 mg) and tert-butoxy sodium (1.3 g), and the mixture was stirred for 8 hours under heating to reflux. The reaction solution was cooled and filtered through celite. The filtrate was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give 4- (3,5-dimethylpyridin-2-yl) -2-methylpiperazine-1-carboxylic acid. Tert-butyl ester (1.61 g) was obtained. The obtained 4- (3,5-dimethylpyridin-2-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (1.61 g) was dissolved in ethyl acetate (10 mL), and 4N hydrogen chloride / An ethyl acetate solution (10 mL) and methanol (2 mL) were added, and the mixture was stirred at room temperature. After completion of the reaction, the solvent was distilled off, 1N aqueous sodium hydroxide solution was added to the resulting residue, and the mixture was extracted with ethyl acetate. The title compound (1.17 g) was obtained by distilling off the solvent.
MS (ESI) m / z: 206 (M + H) ⁺

Preparation Example 111: Preparation of (R) -1- (3,5-dimethylpyridin-2-yl) -2-methylpiperazine dihydrochloride

1) Preparation of (R) -4- (3,5-dimethylpyridin-2-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (R) -3-methylpiperazine-1-carboxylic acid tert -To a solution of butyl ester (500 mg), 3,5-dimethylpyridine-N-oxide (246 mg) and N, N-diisopropylethylamine (1.3 mL) in tetrahydrofuran (8 mL) was added bromotris (pyrrolidino) phosphonium hexafluorophosphate ( 1.21 g) was added and stirred at room temperature overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to give (R) -4- (3,5-dimethylpyridin-2-yl) -3-methylpiperazine-1-carboxyl. The acid tert-butyl ester (387 mg) was obtained.
MS (ESI) m / z: 306 (M + H) ⁺

2) Preparation of (R) -1- (3,5-dimethylpyridin-2-yl) -2-methylpiperazine dihydrochloride (R) -4- (3,5-dimethylpyridin-2-yl)- 3-Methylpiperazine-1-carboxylic acid tert-butyl ester (197 mg, see 1 above) is dissolved in ethyl acetate (1.3 mL), 4N hydrogen chloride / ethyl acetate solution (1.3 mL), methanol (1 3 mL) and stirred at room temperature. After completion of the reaction, the solvent was distilled off to obtain the title compound (199 mg).
MS (ESI) m / z: 206 (M + H) ⁺

Preparation 112: Preparation of (R) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1-carboxylic acid tert-butyl ester

2-Bromo-3,5-dimethylpyridine (204 μL) was added to (R) -3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (350 μL), tris (dibenzylideneacetone) dipalladium (0) (73. 8 mg), rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (100.4 mg), sodium tert-butoxy (232.4 mg), toluene (4 mL), and 7 at 120 ° C. Stir for hours. The reaction solution was cooled and filtered through celite. The filtrate was concentrated, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (459 mg). MS (APCI) m / z: 292 (M + H) ⁺

Preparation Example 113: Preparation of (3,5-dimethylpyridin-2-yl)-(R) -pyrrolidin-3-ylamine

To a solution of (R) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1-carboxylic acid tert-butyl ester (454 mg) described in Preparation Example 112 in chloroform (3 mL) was added trifluoroacetic acid (2 .09mL) and stirred at room temperature. After completion of the reaction, the reaction solution was diluted with methanol, charged to ion exchange chromatography, washed with methanol, and eluted with 1N ammonia / methanol solution to obtain the title compound (280 mg).
MS (APCI) m / z: 192 (M + H) ⁺

Preparation Example 114: Preparation of 4-((S) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

Using 4- (4-Isopropyl-2,5-dioxo-imidazolidin-4-yl) benzoic acid (10.45 g) and (S) -1-phenylethylamine (2.89 g) described in Preparation Example 5 By conducting the same method as in Preparation Example 45, 4-((S) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid · (S) -1-phenylethylamine salt (2 .15 g) was obtained.
To the obtained 4-((S) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid / (S) -1-phenylethylamine salt (1 g), water (10 mL) and 1N were added. Hydrochloric acid (10 mL) was added. The precipitate was collected by filtration to obtain the title compound (635 mg).
MS (ESI) m / z: 263 (M + H) ⁺

Preparation Example 115: Preparation of (S) -4- (3,5-dimethylpyridin-2-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester

To a solution of (S) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (2.5 g) and 3,5-dimethylpyridine-N-oxide (1.23 g) in tetrahydrofuran (40 mL), N, N— Diisopropylethylamine (6.4 mL) and bromotris (pyrrolidino) phosphonium hexafluorophosphate (6 g) were added, and the mixture was stirred at room temperature overnight. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane), and (S) -4- (3,5-dimethylpyridin-2-yl) -3-methylpiperazine-1-carboxyl The acid tert-butyl ester (1.27 g) was obtained.
MS (ESI) m / z: 306 (M + H) ⁺

Preparation Example 116: Preparation of 1- (3,5-dimethylpyridin-2-yl) -3,3-dimethylpiperazine dihydrochloride

By performing the same reaction and treatment as in Preparation Example 115 using 3,5-dimethylpyridine-N-oxide (574 mg) and 2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester (1 g), 4 -(3,5-Dimethylpyridin-2-yl) -2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.11 g) was obtained.
The obtained 4- (3,5-dimethylpyridin-2-yl) -2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.1 g) was dissolved in ethyl acetate (7 mL), and 4N chloride was obtained. A hydrogen / ethyl acetate solution (7 mL) and methanol (7 mL) were added, and the mixture was stirred at room temperature. After completion of the reaction, the solvent was distilled off to obtain the title compound (1.03 g). MS (ESI) m / z: 220 (M + H) ⁺

Preparation Example 117: Preparation of (R) -4- (3,5-dimethylpyridin-2-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester

(R) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (1 g), 2-bromo-3,5-dimethylpyridine (975 mg), tris (dibenzylideneacetone) dipalladium (0) (92 mg), Toluene (17 mL) was added to a mixture of rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (125 mg) and tert-butoxy sodium (650 mg), and the mixture was heated at 130 ° C. under microwave irradiation. Stir for hours. The reaction solution was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (220 mg).
MS (ESI) m / z: 306 (M + H) ⁺

Preparation Example 118: Preparation of (R) -1- (3,5-dimethylpyridin-2-yl) -3-methylpiperazine dihydrochloride

(R) -4- (3,5-dimethylpyridin-2-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (220 mg) described in Preparation Example 117 was added with ethyl acetate (1.5 mL). After dissolution, 4N hydrogen chloride / ethyl acetate solution (1.5 mL) and methanol (1.5 mL) were added, and the mixture was stirred at room temperature. After completion of the reaction, the solvent was distilled off to obtain the title compound (198 mg).
MS (ESI) m / z: 206 (M + H) ⁺

Preparation Example 119: Preparation of (R) -1- (3,5-dimethylpyridin-2-yl) -3-methylpiperazine

To (R) -4- (3,5-dimethylpyridin-2-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (2.4 g) described in Preparation Example 117, dichloromethane (50 mL), Trifluoroacetic acid (10 mL) was added and stirred at room temperature. After completion of the reaction, the solvent was distilled off, and an aqueous sodium hydroxide solution was added to the resulting residue, followed by extraction with chloroform. The solvent was distilled off and the precipitated solid was filtered off. The filtrate was concentrated, and the resulting residue was purified by NH-coated silica gel column chromatography (ethyl acetate: hexane) to obtain the title compound (1.08 g).
MS (ESI) m / z: 206 (M + H) ⁺

Preparation Example 120: Preparation of 4- (3,5-dimethylpyridin-2-yl) -3-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester

To 3-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester (1.5 g), tetrahydrofuran (28 mL), bromotris (pyrrolidino) phosphonium hexafluorophosphate (3.4 g), 3,5-dimethylpyridine-N- Oxide (690 mg) and N, N-diisopropylethylamine (3.58 mL) were added, and the mixture was stirred at room temperature for 4.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (773 mg).
MS (ESI) m / z: 322 (M + H) ⁺

Preparation Example 121: Preparation of 1- (3,5-dimethylpyridin-2-yl) -2-methoxymethylpiperazine dihydrochloride

4- (3,5-dimethylpyridin-2-yl) -3-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester (440 mg), methyl iodide (96 μL) of N, N- Sodium hydride (60% dispersion in liquid paraffin) (62 mg) was added to a dimethylformamide (7 mL) solution at 0 ° C., and the mixture was stirred at room temperature. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, and the obtained residue was purified by column chromatography (ethyl acetate: hexane), and 4- (3,5-dimethylpyridin-2-yl) -3-methoxymethylpiperazine-1-carboxylic acid tert- Butyl ester (245 mg) was obtained.
This compound (245 mg) was dissolved in methyl acetate (2 mL) and methanol (2 mL), 4N hydrogen chloride / ethyl acetate solution (2 mL) was added, and the mixture was stirred at room temperature. After completion of the reaction, the solvent was distilled off to obtain the title compound (230 mg).
MS (ESI) m / z: 236 (M + H) ⁺

Preparation Example 122: Preparation of (R) -1- (3,5-dimethylpyridin-2-yl) -3-ethylpiperazine

To a solution of (R) -2-ethylpiperazine-1-carboxylic acid tert-butyl ester (1 g) and 3,5-dimethylpyridine-N-oxide (546 mg) in tetrahydrofuran (18 mL) was added N, N-diisopropylethylamine (3 mL). ), And bromotris (pyrrolidino) phosphonium (2.8 g) hexafluorophosphate were added and stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to give (R) -4- (3,5-dimethylpyridin-2-yl) -2-ethylpiperazine-1-carboxyl. The acid tert-butyl ester (1.11 g) was obtained.
The obtained (R) -4- (3,5-dimethylpyridin-2-yl) -2-ethylpiperazine-1-carboxylic acid tert-butyl ester (1.11 g) was dissolved in ethyl acetate (5 mL), A 4N hydrogen chloride / ethyl acetate solution (5 mL) and methanol (5 mL) were added, and the mixture was stirred at room temperature. After completion of the reaction, an aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off to obtain the title compound (735 mg).
MS (ESI) m / z: 220 (M + H) ⁺

Preparation Example 123: Preparation of (S) -4- (3,5-dimethylpyridin-2-yl) -2-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester

(S) -2-Hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester (950 mg) was added to tetrahydrofuran (17 mL), 3,5-dimethylpyridine-N-oxide (515 mg), N, N-diisopropylethylamine (2 8 mL) and bromotris (pyrrolidino) phosphonium hexafluorophosphate (2.67 g) were added, and the mixture was stirred at room temperature for 5.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (640 mg).
MS (ESI) m / z: 322 (M + H) ⁺

Preparation Example 124: Preparation of (S) -4- (3,5-dimethylpyridin-2-yl) -2-methoxymethylpiperazine-1-carboxylic acid tert-butyl ester

1) (S) -4- (3,5-Dimethylpyridin-2-yl) -2-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester (83 mg) and methyl iodide (20 μL) described in Preparation Example 123 ) In N, N-dimethylformamide (1.3 mL) was added sodium hydride (60% oily) (11.3 mg) at 0 ° C. and stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off to obtain a crude product.

2) (S) -4- (3,5-Dimethylpyridin-2-yl) -2-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester (90 mg), methyl iodide (18 μL) described in Preparation Example 123 ) To give a crude product by carrying out the same reaction and treatment as in 1) above.
The obtained crude products 1) and 2) were combined and purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (97 mg).
MS (ESI) m / z: 336 (M + H) ⁺

Preparation Example 125: Preparation of 8- (3,5-dimethylpyridin-2-yl) -5,8-diazaspiro [3.5] nonane

To a solution of 5,8-diazaspiro [3,5] nonane dihydrochloride (350 mg) and 3,5-dimethylpyridine-N-oxide (205 mg) in tetrahydrofuran (7 mL) was added N, N-diisopropylethylamine (1.73 mL). ), Bromotris (pyrrolidino) phosphonium hexafluorophosphate (1.07 g) was added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, and the obtained residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (176 mg). MS (ESI) m / z: 232 (M + H) ⁺

Preparation Example 126: Preparation of (S) -1- (3,5-dimethylpyridin-2-yl) -3-methylpiperazine

To a solution of (S) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (2.0 g) and 3,5-dimethylpyridine-N-oxide (1.2 g) in tetrahydrofuran (40 mL), N, N— Diisopropylethylamine (6.4 mL) and bromotris (pyrrolidino) phosphonium hexafluorophosphate (6.06 g) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane), and (S) -4- (3,5-dimethylpyridin-2-yl) -2-methylpiperazine-1-carboxyl The acid tert-butyl ester (2.49 g) was obtained.
To the obtained (S) -4- (3,5-dimethylpyridin-2-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (2.49 g), ethyl acetate (15 mL), methanol ( 15 mL), 4N hydrogen chloride / ethyl acetate solution (13 mL) was added, and the mixture was stirred at room temperature. After completion of the reaction, 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (1.31 g).
MS (ESI) m / z: 206 (M + H) ⁺

Preparation Example 127: Preparation of [(R) -1- (3,5-dimethylpyridin-2-yl) piperazin-2-yl] methanol

(R) -3-Hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester (5 g) and 3,5-dimethylpyridine-N-oxide (2.7 g) were used for the same reaction and treatment as in Preparation Example 126. This gave the title compound (1.16 g).
MS (ESI) m / z: 222 (M + H) ⁺

Preparation Example 128: Preparation of [(S) -1- (3,5-dimethylpyridin-2-yl) piperazin-2-yl] methanol dihydrochloride

(S) -3-Hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester (730 mg) and 3,5-dimethylpyridine-N-oxide (395 mg) are used for the same reaction and treatment as in Preparation Example 115. Gave the title compound (230 mg). MS (ESI) m / z: 220 (M + H) ⁺

Preparation Example 129: Preparation of (S) -4- (3,5-dimethylpyridin-2-yl) piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester

(S) -piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2.6 g), methylene chloride (42 mL), N, N-diisopropylethylamine (6.8 mL), 3,5 -Dimethylpyridine-N-oxide (1.24 g) and bromotris (pyrrolidino) phosphonium hexafluorophosphate (6.42 g) were added, and the mixture was stirred at room temperature overnight. Bromotris (pyrrolidino) phosphonium hexafluorophosphate (676 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (1.52 g).
MS (ESI) m / z: 350 (M + H) ⁺

Preparation Example 130: Preparation of (S) -4- (3,5-dimethylpyridin-2-yl) piperazine-2-carboxylic acid methyl ester

(S) -piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2.4 g) and 3,5-dimethylpyridine-N-oxide (1.07 g) The title compound (620 mg) was obtained by carrying out the same reaction and treatment.
MS (ESI) m / z: 250 (M + H) ⁺

Preparation Example 131: Preparation of (S) -1- (3,5-dimethylpyridin-2-yl) -2-methylpiperazine dihydrochloride

(S) -4- (3,5-Dimethylpyridin-2-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.27 g) described in Preparation Example 115 was added with ethyl acetate (8 mL). After dissolution, 4N hydrogen chloride / ethyl acetate solution (8 mL) and methanol (8 mL) were added, and the mixture was stirred at room temperature. After completion of the reaction, the solvent was distilled off to obtain the title compound (1.39 g).
MS (ESI) m / z: 206 (M + H) ⁺

Preparation Example 132 Preparation of 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid chloride

  4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (1.44 g) described in Preparation Example 45 was added to 1,4-dioxane (11 mL) and thionyl chloride. (1.16 mL) was added and it stirred at 80 degreeC for 3 hours. The solvent was distilled off to obtain the title compound (1.48 g).

Preparation Example 133: Preparation of (S) -2-carbamoyl-4- (3,5-dimethylpyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester

To (S) -4- (3,5-dimethylpyridin-2-yl) piperazine-2-carboxylic acid methyl ester (700 mg) described in Preparation Example 130, ethanol (4 mL), 1N aqueous sodium hydroxide solution (4 mL) Was added. After stirring at room temperature for 4 hours, 1N hydrochloric acid (4 mL) was added at 0 ° C. The solvent was distilled off, and ammonium chloride (5 equivalents), chloroform (10 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide / hydrochloride (1.5 equivalents) were added to the resulting residue. , 1-hydroxybenzotriazole (1.5 equivalents) and triethylamine (7 equivalents) were added and stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (420 mg).
MS (ESI) m / z: 335 (M + H) ⁺

Preparation Example 134: Preparation of 4- [1- (p-tolyl) -1H-pyrazol-4-yl] piperidine

N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (927.6 mg), 1,2-dimethoxyethane (10 mL), water (5 mL), sodium carbonate (953.9 mg) 4-bromo-1- (p-tolyl) pyrazole (711.3 mg), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride · dichloromethane complex (122.5 mg), 90 Stir at 6 ° C. for 6 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was filtered through celite and extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to give 4- [1- (p-tolyl) -1H-pyrazol-4-yl] -3,6-dihydro- 2H-pyridine-1-carboxylic acid tert-butyl ester (651.6 mg) was obtained.
The obtained 4- [1- (p-tolyl) -1H-pyrazol-4-yl] -3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (300 mg) was dissolved in ethanol, Reduction was performed with H-cube (produced by ThalesNano) (catalyst: Pd-C, temperature: 60 ° C., flow rate: 1 mL / min). The solvent was distilled off to obtain 4- [1- (p-tolyl) -1H-pyrazol-4-yl] piperidine-1-carboxylic acid tert-butyl ester (297.8 mg).
To the obtained 4- [1- (p-tolyl) -1H-pyrazol-4-yl] piperidine-1-carboxylic acid tert-butyl ester (297.8 mg), methanol (2 mL), 4N hydrogen chloride / 1, 4-Dioxane solution (1.5 mL) was added and stirred at room temperature overnight. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The title compound (193.1 mg) was obtained by evaporating the solvent.
MS (ESI) m / z: 242 (M + H) ⁺

Preparation Example 135: Preparation of (1-benzoylpiperidin-4-yl) (2-hydroxy-4-methylphenyl) methanone

  Aluminum chloride (50 g) was added to a solution of 3-methylphenol (13 g) and 1-benzoylpiperidine-4-carbonyl chloride (31 g) in 1,2-dichloroethane (250 mL) with stirring, followed by heating for 1.5 hours. Refluxed. The reaction solution was poured into ice water and extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography to obtain the title compound (18 g).

Preparation Example 136: Preparation of 4- (6-methylbenzofuran-3-yl) piperidine hydrochloride

(1-Benzoylpiperidin-4-yl) (2-hydroxy-4-methylphenyl) methanone (18 g) described in Preparation Example 135 was added to N, N-dimethylformamide (100 mL), sodium hydride (60 in liquid paraffin). % Dispersion) (4.5 g) and ethyl bromoacetate (13 mL) were added, and the mixture was stirred at 100 ° C. for 30 minutes. After extraction with ethyl acetate, the solvent was distilled off, and the resulting residue was purified by column chromatography to obtain 3- (1-benzoylpiperidin-4-yl) -6-methylbenzofuran-2-carboxylic acid ethyl ester (5 g). Got.
Ethanol (20 mL), sodium hydroxide (5 g), and water (30 mL) were added to the obtained 3- (1-benzoylpiperidin-4-yl) -6-methylbenzofuran-2-carboxylic acid ethyl ester (5 g). The mixture was stirred under heating. The mixture was neutralized with hydrochloric acid and extracted with ethyl acetate. The solvent was distilled off, quinoline (50 mL) and copper (0.5 g) were added to the resulting residue (30 g), and the mixture was stirred at 180 ° C. for 3 hours. After adding hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography to obtain [4- (6-methylbenzofuran-3-yl) piperidin-1-yl) phenylmethanone (2 g).
Concentrated hydrochloric acid (25 mL) and acetic acid (25 mL) were added to the obtained [4- (6-methylbenzofuran-3-yl) piperidin-1-yl) phenylmethanone (2 g), and heated under reflux for 12 hours. Stir. The solvent was distilled off to obtain the title compound (1.1 g).

Preparation Example 137: Preparation of (1-benzoylpiperidin-4-yl) (2-hydroxy-3,5-dimethylphenyl) methanone

  2,4-Dimethylphenol (14 g) was dissolved in tetrahydrofuran (100 mL), triethylamine (30 mL) and 1-benzoylpiperidine-4-carbonyl chloride (30 g) were added, and the mixture was stirred at room temperature. After completion of the reaction, extraction was performed with ethyl acetate. The solvent was distilled off, and aluminum chloride (40 g) was added to the resulting residue (24 g), followed by stirring at 120 ° C. for 15 minutes. Under cooling, ice was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography to obtain the title compound (18 g).

Preparation Example 138: Preparation of 4- (5,7-dimethylbenzofuran-3-yl) piperidine hydrochloride

  The same reaction as in Preparation Example 136, using (1-benzoylpiperidin-4-yl) (2-hydroxy-3,5-dimethylphenyl) methanone (18 g) and ethyl bromoacetate (6 mL) described in Preparation Example 137, The title compound (4.5 g) was obtained by performing the treatment.

Preparation Example 139: Preparation of (1-benzoylpiperidin-4-yl) (2-hydroxy-4,5-dimethylphenyl) methanone

  The same reaction and treatment as in Preparation Example 135 were carried out using 3,4-dimethylanisole (24 g) and 1-benzoylpiperidine-4-carbonyl chloride (46 g) to obtain the title compound (40 g).

Preparation Example 140: Preparation of 4- (5,6-dimethylbenzofuran-3-yl) piperidine hydrochloride

  The same reaction as in Preparation Example 136, using (1-benzoylpiperidin-4-yl) (2-hydroxy-4,5-dimethylphenyl) methanone (15 g) and ethyl bromoacetate (5 mL) described in Preparation Example 139, The title compound (2.7 g) was obtained by performing the treatment.

Preparation Example 141: Preparation of (1-benzoylpiperidin-4-yl) (2-hydroxy-4,6-dimethylphenyl) methanone

  The title compound (35 g) was obtained by carrying out the same reaction and treatment as in Preparation Example 137 using 1-benzoylpiperidine-4-carbonyl chloride (50 g) and 3,5-dimethylphenol (25 g).

Preparation Example 142: Preparation of 4- (4,6-dimethylbenzofuran-3-yl) piperidine hydrochloride

  The same reaction as in Preparation Example 136, using (1-benzoylpiperidin-4-yl) (2-hydroxy-4,6-dimethylphenyl) methanone (35 g) and ethyl bromoacetate (13 mL) described in Preparation Example 141, The title compound (8 g) was obtained by performing the treatment.

Preparation Example 143: Preparation of 1-methyl-4-piperazin-1-yl-1H-indazole dihydrochloride

Piperazine-1-carboxylic acid tert-butyl ester (2.65 g), 4-((E) -1-bromopropenyl) -1-methyl-5-vinyl-1H-pyrazole (2 g), tris (dibenzylideneacetone) Toluene in a mixture of dipalladium (0) (86.8 mg), rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (88.5 mg) and sodium tert-butoxy (1.3 g) (35 mL) was added and stirred under heating to reflux. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added. After filtration through celite, the filtrate was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give 4- (1-methyl-1H-indazol-4-yl) piperazine-1-carboxylic acid tert-butyl ester (2.46 g) was obtained. 4- (1-Methyl-1H-indazol-4-yl) piperazine-1-carboxylic acid tert-butyl ester (2.46 g) to ethyl acetate (16 mL)
, Methanol (3.2 mL), 4N hydrogen chloride / ethyl acetate solution (16.5 mL) were added, and the mixture was stirred at room temperature. After completion of the reaction, the solvent was distilled off, and ethyl acetate was added to the resulting residue. The precipitated solid was collected by filtration to obtain the title compound (2.24 g).
MS (ESI) m / z: 217 (M + H) ⁺

Preparation Example 144: Preparation of 5-methyl-2- (piperidin-4-yl) oxazolo [5,4-b] pyridine

Methylene chloride (25 mL), pyridine (1.54 mL) and thionyl chloride (0.72 mL) were added to 1-[(benzyloxy) carbonyl] piperidine-4-carboxylic acid (2 g), and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added a solution of 3-amino-2-chloro-6-picoline (1.192 g), 4- (dimethylamino) pyridine (46 mg), triethylamine (2.11 mL) in methylene chloride (15 mL), and 2 at room temperature. Stir for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to give 4- (2-chloro-6-methylpyridin-3-ylcarbamoyl) piperidine-1-carboxylic acid benzyl ester. (2.996 g) was obtained.
To the obtained 4- (2-chloro-6-methylpyridin-3-ylcarbamoyl) piperidine-1-carboxylic acid benzyl ester (1.5 g), potassium carbonate (1.6 g), N, N-dimethylformamide ( 30 mL) was added, and the mixture was stirred at 200 ° C. for 20 minutes under microwave irradiation. After filtration of the reaction solution, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give 4- (5-methyloxazolo [5,4-b] pyridine-2. -Yl) Piperidine-1-carboxylic acid benzyl ester (1.068 g) was obtained.
The resulting 4- (5-methyloxazolo [5,4-b] pyridin-2-yl) piperidine-1-carboxylic acid benzyl ester (1.06 g) was added to ethanol (21 mL), 10% palladium / carbon ( 53.5% wet water product) (530 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (582 mg).
MS (ESI) m / z: 218 (M + H) ⁺

Preparation Example 145: Preparation of 6-methyl-2- (piperidin-4-yl) thiazolo [4,5-b] pyridine

To 1-[(benzyloxy) carbonyl] piperidine-4-carboxylic acid (3 g), methylene chloride (40 mL), pyridine (2.3 mL) and thionyl chloride (1.08 mL) were added, and the mixture was stirred at room temperature for 1.5 hours. did. To the reaction mixture was added a solution of 2-amino-3-bromo-5-methylpyridine (2.13 g), 4- (dimethylamino) pyridine (69 mg), triethylamine (3.2 mL) in methylene chloride (20 mL), and at room temperature. Stir for 5.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, diethyl ether was added to the resulting residue, and the precipitate was collected by filtration to give 4- (3-bromo-5-methylpyridin-2-ylcarbamoyl) piperidine-1-carboxylic acid benzyl ester. (2.285 g) was obtained.
To the obtained 4- (3-bromo-5-methylpyridin-2-ylcarbamoyl) piperidine-1-carboxylic acid benzyl ester (2.28 g), Lawesson's reagent (3.21 g) and toluene (45 mL) were added, Stir at 70 ° C. for 1 hour. The reaction solution is purified by column chromatography (hexane: ethyl acetate) to give 4- (3-bromo-5-methylpyridin-2-ylthiocarbamoyl) piperidine-1-carboxylic acid benzyl ester (1.774 g). It was.
To the obtained 4- (3-bromo-5-methylpyridin-2-ylthiocarbamoyl) piperidine-1-carboxylic acid benzyl ester (1.7 g), cesium carbonate (2.48 g), N, N-dimethylformamide (34 mL) was added, and the mixture was stirred at 160 ° C. for 20 minutes under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give 4- (6-methylthiazolo [4,5-b] pyridin-2-yl) piperidine-1-carboxyl. The acid benzyl ester (1.291 g) was obtained.
To the obtained 4- (6-methylthiazolo [4,5-b] pyridin-2-yl) piperidine-1-carboxylic acid benzyl ester (600 mg), trifluoroacetic acid (18 mL) and thioanisole (1.8 mL) were added. The mixture was further stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and water and diethyl ether were added to the resulting residue for liquid separation. The aqueous layer was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain a crude product of the title compound (821 mg).

Preparation Example 146: Preparation of 5-methyl-2- (piperidin-4-yl) thiazolo [5,4-b] pyridine trifluoroacetate

4- (2-Chloro-6-methylpyridin-3-ylcarbamoyl) piperidine-1-carboxylic acid benzyl ester (1.42 g) was added with Lawesson's reagent (2.22 g) and toluene (30 mL) at 70 ° C. Stir for 3 hours. The reaction solution was purified by column chromatography (hexane: ethyl acetate) to give 4- (5-methylthiazolo [5,4-b] pyridin-2-yl) piperidine-1-carboxylic acid benzyl ester (603 mg). .
To the obtained 4- (5-methylthiazolo [5,4-b] pyridin-2-yl) piperidine-1-carboxylic acid benzyl ester (600 mg), trifluoroacetic acid (18 mL) and thioanisole (1.8 mL) were added. The mixture was further stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give a crude product of the title compound (2236 mg).

Preparation Example 147: Preparation of 1- (3,5-dicyclopropylpyridin-2-yl) piperazine dihydrochloride

N, N-dimethylformamide (40 mL) and potassium carbonate (22 g) were added to a toluene (80 mL) solution of 2,3,5-trichloropyridine (12.1 g) and 1-Boc-piperazine (14.9 g). The mixture was stirred at 120 ° C. for 7 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then the solvent was distilled off. The obtained residue is purified by column chromatography (hexane: ethyl acetate) to give 4- (3,5-dichloropyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (13.08 g). It was.
To the obtained 4- (3,5-dichloropyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (5.3 g), toluene (160 mL), water (16 mL), bis (tricyclohexylphosphine) Palladium (II) dichloride (0.59 g), tripotassium phosphate (16.9 g) and cyclopropylboronic acid (4.13 g) were added, and the mixture was stirred at 100 ° C. After completion of the reaction, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then the solvent was distilled off. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to give 4- (3,5-dicyclopropylpyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (3.12 g). Got.
The obtained 4- (3,5-dicyclopropylpyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (3.11 g) was dissolved in ethyl acetate (10 mL), and 4N hydrogen chloride / ethyl acetate was dissolved. Solution (10 mL) was added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then the solvent was distilled off. The obtained residue was purified by column chromatography (hexane: ethyl acetate). The solvent was distilled off, and the resulting residue was dissolved in ethyl acetate (20 mL), and 4N hydrogen chloride / ethyl acetate solution (4.5 mL) was added. The title compound (1.91 g) was obtained by filtering the precipitate.

Preparation Example 148: Preparation of 4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid

  4- (4-Methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (24.4 g) was dissolved in tetrahydrofuran (488 mL), cinchonine (16.87 g) was added, and the mixture was stirred at room temperature for 8 hours. . The precipitated solid was collected by filtration and dried under reduced pressure. 1N Hydrochloric acid (150 mL) was added to the obtained crude product (26.42 g), and the mixture was stirred at room temperature for 6 hr. The precipitate was collected by filtration to give 4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (9.39 g, 99.6% ee).

Production Example 1: Synthesis of (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (230 mg), 1- (3,5-dimethylpyridin-2-yl) described in Preparation Example 6 Piperazine (188 mg) and 1-hydroxybenzotriazole (139 mg) were dissolved in N, N-dimethylformamide (3.3 mL), and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (200 mg) was dissolved. And stirred at room temperature overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: methanol). The title compound (224.2 mg) was obtained by distilling off the solvent and recrystallizing the resulting residue with a mixed solvent of ethanol and water.
MS (APCI) m / z: 408 (M + H) ⁺

Production Example 2: (R) -5- {4- [4- (3,5-dicyclopropylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione Synthesis of

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (80 mg), 1- (3,5-dicyclopropylpyridine-2-yl described in Preparation Example 6 Yl) Piperazine (83 mg) and 1-hydroxybenzotriazole (48.5 mg) were dissolved in N, N-dimethylformamide (1.2 mL), and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide / hydrochloric acid was dissolved. Salt (68.8 mg) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (80.3 mg).
MS (APCI) m / z: 460 (M + H) ⁺

Production Example 3: (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} -5-methylimidazolidine-2,4 -Synthesis of dione

2-Fluoro-4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (790 mg) described in Preparation Example 29, 1- (3,5-dimethylpyridine- 2-yl) piperazine (784.7 mg), 1-hydroxybenzotriazole (507.9 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (780.7 mg) was added to chloroform (23. 7 mL) and N, N-dimethylformamide (
7.9 mL) was dissolved in a mixed solvent, triethylamine (960.5 μL) was added, and the mixture was stirred at room temperature. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (1210 mg).
MS (APCI) m / z: 426 (M + H) ⁺

Production Example 4: (R) -5- {4- [4- (5-Ethyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione Synthesis of

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (100 mg), 1- (5-ethyl-3-methylpyridine-2-yl) described in Preparation Example 6 Yl) piperazine (87.7 mg) and 1-hydroxybenzotriazole (60.6 mg) were dissolved in N, N-dimethylformamide (1.5 mL) to give 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide. -Hydrochloride (85.9 mg) was added and stirred at room temperature overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (138 mg).
MS (APCI) m / z: 422 (M + H) ⁺

Production Example 5: (R) -5- {4- [4- (5-Cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4- Synthesis of dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (100 mg), 1- (5-cyclopropyl-3-methylpyridine-2, as described in Preparation Example 6. -Yl) piperazine (92.8 mg) and 1-hydroxybenzotriazole (60.6 mg) were dissolved in N, N-dimethylformamide (1.5 mL) to give 1-ethyl-3- (3′-dimethylaminopropyl). Carbodiimide hydrochloride (85.9 mg) was added, and the mixture was stirred overnight at room temperature. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (152.3 mg).
MS (APCI) m / z: 434 (M + H) ⁺

Production Example 6: (R) -5-methyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione Synthesis of

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (100 mg), 1- (3,5,6-trimethylpyridine-2-yl described in Preparation Example 6 Yl) piperazine (87.7 mg) and 1-hydroxybenzotriazole (60.6 mg) were dissolved in N, N-dimethylformamide (2.5 mL) to give 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide. -Hydrochloride (85.9 mg) was added and stirred at room temperature overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (99.5 mg).
MS (APCI) m / z: 422 (M + H) ⁺

Production Example 7: Synthesis of (R) -5- {4- [4- (2,4-dimethylphenyl) piperazine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione

4-((R) -4-Methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (100 mg), 1- (2,4-dimethylphenyl) piperazine (81. 2 mg), 1-hydroxybenzotriazole (60.6 mg) was dissolved in N, N-dimethylformamide (1.5 mL), and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (85. 9 mg) was added and stirred at room temperature overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (130.5 mg).
MS (APCI) m / z: 407 (M + H) ⁺

Production Example 8: Synthesis of (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (2.88 g) described in Preparation Example 45 was added to N, N-dimethylformamide (43.9 mL). Dissolve 1- (3,5-dimethylpyridin-2-yl) piperazine hydrochloride (2.75 g), 1-hydroxybenzotriazole (1.63 g), 1-ethyl-3- (3′-dimethylamino) Propyl) carbodiimide hydrochloride (2.32 g) and N, N-diisopropylethylamine (4.21 mL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the precipitate was collected by filtration. The obtained precipitate was recrystallized with a mixed solvent of ethanol and water to obtain the title compound (3.84 g).
MS (ESI) m / z: 436 (M + H) ⁺

Production Example 9: (R) -5- {4- [4- (3,5-dicyclopropylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-ethylimidazolidine-2,4-dione And (S) -5- {4- [4- (3,5-dicyclopropylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-ethylimidazolidine-2,4-dione

4- (4-Ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (70 mg), 1- (3,5-dicyclopropylpyridin-2-yl) piperazine described in Preparation Example 1 75 mg), 1-hydroxybenzotriazole (37.8 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (80 mg), diisopropylethylamine (1 mL) in N, N-dimethylformamide (5 mL) ) And stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH column chromatography (chloroform: methanol), and 5- {4- [4- (3,5-dicyclopropylpyridin-2-yl) piperazine-1-carbonyl] phenyl}- 5-Ethylimidazolidine-2,4-dione (78.6 mg) was obtained.
The obtained 5- {4- [4- (3,5-dicyclopropylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-ethylimidazolidine-2,4-dione (70 mg) was converted into CHIRALPAK. (Daicel) By separation by HPLC using IC (tetrahydrofuran / ethanol / diethylamine), both enantiomers of the title compound (28.9 mg (MS (APCI) m / z: 474 (M + H) ⁺ compound having a short retention time) ⁺ ) And 28.7 mg (MS (APCI) m / z: 474 (M + H) ⁺ )) of the compound having a long retention time.
In the analysis with CHIRALPAK (Daicel) IC-3 (4.6 mm × 150 mm, tetrahydrofuran / ethanol / diethylamine = 10/90 / 0.1, flow rate 0.5 mL / min), each holding time was 5.5 minutes. 11.1 minutes.

Production Example 10: (R) -5-ethyl-5- {4- [4- (5-ethyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione And (S) -5-ethyl-5- {4- [4- (5-ethyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (75 mg), 1- (5-ethyl-3-methylpyridin-2-yl) piperazine described in Preparation Example 1 75 mg), 1-hydroxybenzotriazole (40 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (86 mg), diisopropylethylamine (1 mL) in N, N-dimethylformamide (4 mL). Dissolved and stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH column chromatography (chloroform: methanol) to give 5-ethyl-5- {4- [4- (5-ethyl-3-methylpyridin-2-yl) piperazine-1-carbonyl. ] Phenyl} imidazolidine-2,4-dione (125 mg) was obtained.
The obtained 5-ethyl-5- {4- [4- (5-ethyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione (98 mg) was converted into CHIRALPAK. (Daicel) By separation by HPLC using IC (tetrahydrofuran / ethanol / diethylamine), both enantiomers (compound 35.7 mg (MS (APCI) m / z: 436 (M + H) ^{+ with} a short retention time) ⁺ ) And 35.2 mg (MS (APCI) m / z: 436 (M + H) ⁺ )) having a long retention time.
In the analysis with CHIRALPAK (Daicel) IC-3 (4.6 mm × 150 mm, tetrahydrofuran / ethanol / diethylamine = 10/90 / 0.1, flow rate 0.5 mL / min), each holding time was 5.4 minutes. It was 9.7 minutes.

Production Example 11: (R) -5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-ethylimidazolidine-2,4- Of dione and (S) -5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-ethylimidazolidine-2,4-dione Composition

4- (4-Ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (75 mg), 1- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine described in Preparation Example 1 (80 mg), 1-hydroxybenzotriazole (40 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (86 mg), diisopropylethylamine (1 mL) in N, N-dimethylformamide (4 mL) And stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH column chromatography (chloroform: methanol), and 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl}. -5-Ethylimidazolidine-2,4-dione (103.6 mg) was obtained.
5- {4- [4- (5-Cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-ethylimidazolidine-2,4-dione (98 mg) was obtained. By separation by HPLC using CHIRALPAK (Daicel) IC (tetrahydrofuran / ethanol / diethylamine), both of the enantiomers (compound 34.4 mg (MS (APCI) m / z: 448 (M + H) with a short retention time) ⁺ ) And 19.9 mg (MS (APCI) m / z: 448 (M + H) ⁺ ) of the compound having a long retention time were obtained.
In the analysis with CHIRALPAK (Daicel) IC-3 (4.6 mm × 150 mm, tetrahydrofuran / ethanol / diethylamine = 10/90 / 0.1, flow rate 0.5 mL / min), each holding time was 5.6 minutes. 10.8 minutes.

Production Example 12: (R) -5- {4- [4- (2,4-dimethylphenyl) piperazine-1-carbonyl] phenyl} -5-ethylimidazolidine-2,4-dione and (S) -5 Synthesis of-{4- [4- (2,4-dimethylphenyl) piperazine-1-carbonyl] phenyl} -5-ethylimidazolidine-2,4-dione

4- (4-Ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (75 mg), 1- (2,4-dimethylphenyl) piperazine (70 mg, CAS: 1013−) described in Preparation Example 1 76-9), 1-hydroxybenzotriazole (40 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (86 mg), diisopropylethylamine (1 mL) were added to N, N-dimethylformamide (4 mL). ) And stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH column chromatography (chloroform: methanol), and 5- {4- [4- (2,4-dimethylphenyl) piperazine-1-carbonyl] phenyl} -5-ethylimidazolidine- 2,4-dione (116.1 mg) was obtained.
The obtained 5- {4- [4- (2,4-dimethylphenyl) piperazine-1-carbonyl] phenyl} -5-ethylimidazolidine-2,4-dione (106 mg) was converted into CHIRALPAK (Daicel) IC (tetrahydrofuran). / Ethanol / diethylamine) fractionated by HPLC, the title both enantiomers (compound 36.8 mg (MS (APCI) m / z: 421 (M + H) ⁺ ) with short retention time) and long retention time 37.8 mg (MS (APCI) m / z: 421 (M + H) ⁺ )) of the compound was obtained.
In the analysis with CHIRALPAK (Daicel) IC-3 (4.6 mm × 150 mm, tetrahydrofuran / ethanol / diethylamine = 10/90 / 0.1, flow rate 0.5 mL / min), each holding time was 5.3 minutes. 10.8 minutes.

Production Example 13: (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-fluorophenyl} -5-methylimidazolidine-2,4 -Dione and (S) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-fluorophenyl} -5-methylimidazolidine-2,4- Synthesis of dione

3-Fluoro-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (252 mg) described in Preparation Example 18 was dissolved in tetrahydrofuran (10 mL), and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (230 mg), 1-hydroxybenzotriazole (162 mg), 1- (3,5-dimethylpyridin-2-yl) piperazine (230 mg) were added, and the mixture was stirred at room temperature overnight. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to give 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl]- 2-Fluorophenyl} -5-methylimidazolidine-2,4-dione (343 mg) was obtained.
5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-fluorophenyl} -5-methylimidazolidine-2,4-dione (racemate) ) (98 mg) was separated by HPLC using CHIRALPAK (Daicel) IA (tetrahydrofuran / ethanol / diethylamine) to give 47.2 mg (MS (APCI) m / z : 426 (M + H) ⁺ ) and 37.4 mg (MS (APCI) m / z: 426 (M + H) ⁺ )) having a long retention time.
In the analysis with CHIRALPAK (Daicel) IA-3 (4.6 mm × 150 mm, tetrahydrofuran / ethanol / diethylamine = 10/90 / 0.1, flow rate 0.5 mL / min), each holding time was 5.8 minutes. It was 7.6 minutes.

Production Example 14: (R) -5-ethyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione And (S) -5-ethyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (55 mg), 1- (3,5,6-trimethylpyridin-2-yl) piperazine described in Preparation Example 1 58 mg), 1-hydroxybenzotriazole (32 mg) was dissolved in N, N-dimethylformamide (2 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (45 mg) was added, and room temperature was added. And stirred overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to give 5-ethyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine. -1-Carbonyl] phenyl} imidazolidine-2,4-dione (85.4 mg) was obtained.
Obtained 5-ethyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione (85.4 mg) Was separated by a medium pressure column using CHIRALFLASH (Daicel) IC (tetrahydrofuran / ethanol / diethylamine) to give the title enantiomer (compound 42.5 mg (MS (APCI) m / z: 436) having a short retention time). (M + H) ⁺ ) and 37 mg of a compound having a long retention time (MS (APCI) m / z: 436 (M + H) ⁺ )) were obtained.
In the analysis with CHIRALPAK (Daicel) IC (4.6 mm × 100 mm, tetrahydrofuran / ethanol / diethylamine = 10/90 / 0.1, flow rate 0.3 mL / min), the retention times were 6.8 minutes and 13. It was 4 minutes.

Production Example 15: Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-methoxyphenyl} -5-methylimidazolidine-2,4-dione

3-methoxy-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (132 mg), 1- (3,5-dimethylpyridin-2-yl) described in Preparation Example 22 Piperazine (105 mg) and 1-hydroxybenzotriazole (74 mg) were dissolved in N, N-dimethylformamide (1.7 mL) to give 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (105 mg). And stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (122.2 mg).
MS (APCI) m / z: 438 (M + H) ⁺

Production Example 16: 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2,3-difluorophenyl} -5-methylimidazolidine-2,4-dione Synthesis of

2,3-difluoro-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (135 mg), 1- (3,5-dimethylpyridine-2-yl described in Preparation Example 26 Yl) piperazine (105 mg) and 1-hydroxybenzotriazole (74 mg) were dissolved in N, N-dimethylformamide (1.7 mL), and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride ( 105 mg) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the obtained residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (149 mg). MS (APCI) m / z: 444 (M + H) ⁺

Production Example 17: Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-methoxyphenyl} -5-isopropylimidazolidine-2,4-dione

4- (4-Isopropyl-2,5-dioxoimidazolidin-4-yl) -3-methoxybenzoic acid (146 mg), 1- (3,5-dimethylpyridin-2-yl) described in Preparation Example 35 Piperazine (105 mg) and 1-hydroxybenzotriazole (74 mg) were dissolved in N, N-dimethylformamide (1.7 mL) to give 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (105 mg). And stirred at room temperature overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (152.9 mg).
MS (APCI) m / z: 466 (M + H) ⁺

Production Example 18: Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-hydroxyphenyl} -5-methylimidazolidine-2,4-dione

5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-methoxyphenyl} -5-methylimidazolidine-2,4-dione described in Preparation Example 15 Dichloromethane (6 mL) was added to (100 mg), 1 mol / L boron tribromide dichloromethane solution (1.2 mL) was added to −78 ° C. with cooling and stirring, and the mixture was stirred while warming to room temperature. The reaction solution was poured into ice water, neutralized with sodium bicarbonate, and extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain a crude product (54 mg) of the title compound. The resulting crude product (54 mg) was fractionated by HPLC using XBridge Prep C18 OBD (Waters) (10 mmol / L aqueous ammonium carbonate solution, acetonitrile). After extraction with ethyl acetate, the solvent was distilled off to obtain the title compound (20.8 mg).
MS (APCI) m / z: 424 (M + H) ⁺

Production Example 19: (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -3- (2-hydroxyethyl) -5-methylimidazo Synthesis of lysine-2,4-dione

(R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione described in Preparation Example 1 (204 mg) was dissolved in N, N-dimethylformamide (1 mL), 2-bromoethanol (43 μL) and potassium carbonate (90 mg) were added, and the mixture was stirred at room temperature overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (74.6 mg).
MS (ESI) m / z: 452 (M + H) ⁺

Production Example 20: Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-hydroxyphenyl} -5-isopropylimidazolidine-2,4-dione

5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-methoxyphenyl} -5-isopropylimidazolidine-2,4-dione described in Preparation Example 17 Dichloromethane (6 mL) was added to (100 mg), 1 mol / L boron tribromide dichloromethane solution (2.2 mL) was added with cooling and stirring to −78 ° C., and the mixture was stirred while warming to room temperature. The reaction solution was poured into ice water, neutralized with sodium bicarbonate, and extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (60.4 mg).
MS (APCI) m / z: 452 (M + H) ⁺

Production Example 21: 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -2-methoxyphenyl} -5-isopropylimidazolidine-2,4- Synthesis of dione

4- (4-Isopropyl-2,5-dioxoimidazolidin-4-yl) -3-methoxybenzoic acid (146 mg), 1- (5-cyclopropyl-3-methylpyridine-2) according to Preparation Example 35 -Il) piperazine hydrochloride (140 mg), 1-hydroxybenzotriazole (74 mg), triethylamine (0.17 mL) were dissolved in N, N-dimethylformamide (1.7 mL) to give 1-ethyl-3- (3 '-Dimethylaminopropyl) carbodiimide hydrochloride (105 mg) was added, and the mixture was stirred overnight at room temperature. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (205.1 mg).
MS (APCI) m / z: 492 (M + H) ⁺

Production Example 22: 5-Isopropyl-5- {2-methoxy-4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione Synthesis of

4- (4-Isopropyl-2,5-dioxoimidazolidin-4-yl) -3-methoxybenzoic acid (146 mg) described in Preparation Example 35, 1- (3,5,6-trimethylpyridine-2- Yl) piperazine (113 mg) and 1-hydroxybenzotriazole (74 mg) were dissolved in N, N-dimethylformamide (1.7 mL), and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride ( 105 mg) was added and stirred at room temperature overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the obtained residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (190.7 mg).
MS (APCI) m / z: 480 (M + H) ⁺

Production Example 23: (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-methoxyphenyl} -5-isopropylimidazolidine-2,4 -Dione and (S) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-methoxyphenyl} -5-isopropylimidazolidine-2,4- Synthesis of dione

5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-methoxyphenyl} -5-isopropylimidazolidine-2,4-dione (186 mg, Production Example 17) Were separated by HPLC using CHIRALPAK (Daicel) IC (hexane / chloroform / 2-propanol) to give the title enantiomer (compound 83.6 mg (MS (APCI)) m / z: 466 (M + H) ⁺ ) and a compound having a long retention time of 82.2 mg (MS (APCI) m / z: 466 (M + H) ⁺ )).
Each retention time in the analysis with CHIRALPAK (Daicel) IC-3 (4.6 mm × 150 mm, hexane / 2-propanol / tetrahydrofuran / diethylamine = 60/20/20 / 0.1, flow rate 0.5 mL / min) Was 7.7 minutes and 9.7 minutes.

Production Example 24: (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -1- (2-hydroxyethyl) -5-methylimidazo Synthesis of lysine-2,4-dione

(R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione described in Preparation Example 1 (300 mg) was dissolved in N, N-dimethylformamide (1.5 mL), 4-methoxybenzyl chloride (0.12 mL), potassium carbonate (132 mg), potassium iodide (1
2 mg) was added and stirred at room temperature overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to give (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1 -Carbonyl] phenyl} -3- (4-methoxybenzyl) -5-methylimidazolidine-2,4-dione (242.1 mg) was obtained.
The obtained (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -3- (4-methoxybenzyl) -5-methylimidazolidine -2,4-dione (242.1 mg), 2- (2-bromoethoxy) tetrahydropyran (152 μL) were dissolved in N, N-dimethylformamide (2 mL), and sodium hydride (in liquid paraffin was added under ice cooling). 60% dispersion) (44 mg) was added, and the mixture was stirred overnight at room temperature. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to give (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1 -Carbonyl] phenyl} -3- (4-methoxybenzyl) -5-methyl-1- [2- (tetrahydropyran-2-yloxy) ethyl] imidazolidine-2,4-dione (262 mg) was obtained.
The obtained (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -3- (4-methoxybenzyl) -5-methyl-1 -[2- (Tetrahydropyran-2-yloxy) ethyl] imidazolidine-2,4-dione (262 mg) was dissolved in 1,2-dichloroethane (7 mL), trifluoromethanesulfonic acid (0.5 mL) was added, Stir at 70 ° C. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (52.9 mg). MS (APCI) m / z: 452 (M + H) ⁺

Production Example 25: (R) -5- {4- [4- (6-Fluorobenzo [d] isoxazol-3-yl) piperidine-1-carbonyl] phenyl} -5-fluoromethylimidazolidine-2,4- Dione and (S) -5- {4- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidine-1-carbonyl] phenyl} -5-fluoromethylimidazolidine-2,4-dione Composition

4- (4-Fluoromethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (168 mg), 6-fluoro-3- (piperidin-4-yl) benzo [d] described in Preparation Example 63 Isoxazole (147 mg) and 1-hydroxybenzotriazole (99 mg) were dissolved in N, N-dimethylformamide (1 mL), and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (140 mg) was added. And stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to give 5- {4- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidine-1- Carbonyl] phenyl} -5-fluoromethylimidazolidine-2,4-dione (205.3 mg) was obtained.
The resulting 5- {4- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidine-1-carbonyl] phenyl} -5-fluoromethylimidazolidine-2,4-dione (167 mg) was CHIRALPAK (Daicel) IC (Hexane / Methanol /
The title enantiomer (compound 62.8 mg (MS (APCI) m / z: 455 (M + H) ⁺ ) with a short retention time) and compound 64. with a long retention time were separated by HPLC using tetrahydrofuran. 1 mg (MS (APCI) m / z: 455 (M + H) ⁺ )) was obtained.
In the analysis with CHIRALPAK (Daicel) IC-3 (4.6 mm × 150 mm, hexane / methanol / tetrahydrofuran = 60/20/20, flow rate 0.5 mL / min), the retention times were 6.6 minutes and 12. It was 4 minutes.

Production Example 26: (R) -5- {4- [4- (6-Fluorobenzo [d] isoxazol-3-yl) piperidine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione Synthesis of

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (117 mg), 6-fluoro-3- (piperidin-4-yl) benzone as described in Preparation Example 6 [D] Isoxazole (111 mg) and 1-hydroxybenzotriazole (74.3 mg) were dissolved in N, N-dimethylformamide (1 mL) to give 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride. (105 mg) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (196.3 mg).
MS (APCI) m / z: 437 (M + H) ⁺

Production Example 27: (R) -5-ethyl-5- {4- [4- (1-p-tolyl-1H-pyrazol-4-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4- Synthesis of dione

4-((R) -4-ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (61.7 mg) described in Preparation Example 14 and 4- [1-(- p-tolyl)-
1H-pyrazol-4-yl] piperidine (60 mg) and 1-hydroxybenzotriazole (35.3 mg) were dissolved in N, N-dimethylformamide (1.5 mL) to give 1-ethyl-3- (3′-dimethyl). Aminopropyl) carbodiimide hydrochloride (50 mg) was added and stirred at room temperature overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (98 mg).
MS (APCI) m / z: 472 (M + H) ⁺

Production Example 28: (R) -5-methyl-5- {4- [4- (1-p-tolyl-1H-pyrazol-4-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4- Synthesis of dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (58.2 mg) described in Preparation Example 6 and 4- [1- ( p-tolyl) -1H-pyrazol-4-yl] piperidine (60 mg) and 1-hydroxybenzotriazole (35.3 mg) were dissolved in N, N-dimethylformamide (1.5 mL) to give 1-ethyl-3- (3′-Dimethylaminopropyl) carbodiimide hydrochloride (50 mg) was added and stirred overnight at room temperature. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (92.8 mg).
MS (APCI) m / z: 458 (M + H) ⁺

Production Example 29: (R) -5-isopropyl-5- {4- [4- (1-p-tolyl-1H-pyrazol-4-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4- Synthesis of dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (79.4 mg) described in Preparation Example 45, 4- [1- ( p-Tolyl) -1H-pyrazol-4-yl] piperidine (73 mg) and 1-hydroxybenzotriazole (42.9 mg) were dissolved in N, N-dimethylformamide (1.5 mL) to give 1-ethyl-3- (3′-Dimethylaminopropyl) carbodiimide hydrochloride (60.9 mg) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (109.4 mg).
MS (APCI) m / z: 486 (M + H) ⁺

Production Example 30: Synthesis of 5- {3-bromo-4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione

2-Bromo-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (118 mg) described in Preparation Example 3 was dissolved in tetrahydrofuran (2 mL), and 1-ethyl-3- Add (3′-dimethylaminopropyl) carbodiimide hydrochloride (76 mg), 1-hydroxybenzotriazole (108 mg), 1- (3,5-dimethylpyridin-2-yl) piperazine (72 mg) and stir at room temperature overnight. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (130 mg).
MS (ESI) m / z: 486 (M + H) ⁺

Production Example 31 Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-methylphenyl} -5-methylimidazolidine-2,4-dione

To 2-methyl-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (150 mg) described in Preparation Example 8, 1- (3,5-dimethylpyridin-2-yl ) Piperazine (127.1 mg), 1-hydroxybenzotriazole (98 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (150.6 mg), chloroform (2 mL), N, N— Dimethylformamide (1 mL) was added and stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (191.3 mg).
MS (ESI) m / z: 422 (M + H) ⁺

Production Example 32: (R) -5- {2-fluoro-4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methylimidazolidine-2 , 4-dione and (S) -5- {2-fluoro-4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methylimidazolidine- Synthesis of 2,4-dione

3-Fluoro-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (126 mg) described in Preparation Example 18 was dissolved in tetrahydrofuran (5 mL), and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (115 mg), 1-hydroxybenzotriazole (162 mg), 1- (3,5,6-trimethylpyridin-2-yl) piperazine (113 mg), triethylamine (168 μL) And stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to give 5- {2-fluoro-4- [4- (3,5,6-trimethylpyridin-2-yl). Piperazine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione (172 mg) was obtained.
5- {2-Fluoro-4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione ( 150 mg) was fractionated on a medium pressure column using CHIRALFLASH (Daicel) IA (ethanol / diethylamine) to give both the enantiomers (compound 51.5 mg (MS (ESI) m / z: 440) having a short retention time). (M + H) ⁺ ) and a compound having a long retention time of 34.6 mg (MS (ESI) m / z: 440 (M + H) ⁺ )) were obtained.
In the analysis with CHIRALPAK (Daicel) IA (4.6 mm × 100 mm, ethanol / diethylamine = 100 / 0.1, flow rate 0.5 mL / min), the retention times were 4.6 minutes and 6.6 minutes, respectively. It was.

Production Example 33: (R) -5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -2-fluorophenyl} -5-methylimidazolidine- 2,4-dione and (S) -5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -2-fluorophenyl} -5-methylimidazo Synthesis of lysine-2,4-dione

3-Fluoro-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (126 mg) described in Preparation Example 18 was dissolved in tetrahydrofuran (5 mL), and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (115 mg), 1- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine (130 mg), 1-hydroxybenzotriazole (162 mg) were added, and room temperature was added. And stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to give 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1 -Carbonyl] -2-fluorophenyl} -5-methylimidazolidine-2,4-dione (219 mg) was obtained.
5- {4- [4- (5-Cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -2-fluorophenyl} -5-methylimidazolidine-2,4-dione obtained (150 mg) was fractionated on a medium pressure column using CHIRALFLASH (Daicel) IA (ethanol / diethylamine / tetrahydrofuran) to give both the enantiomers (48.5 mg (MS (APCI) m / MS (APCI) m / z: 452 (M + H) ⁺ ) and 61 mg (MS (APCI) m / z: 452 (M + H) ⁺ )) having a long retention time were obtained.
In the analysis with CHIRALPAK (Daicel) IA (4.6 mm × 100 mm, tetrahydrofuran / ethanol / diethylamine = 10/90 / 0.1, flow rate 0.5 mL / min), the retention times were 4.8 minutes and 7. It was 8 minutes.

Production Example 34: (R) -5- {4- [4- (5-ethyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -2-fluorophenyl} -5-methylimidazolidine-2 , 4-dione and (S) -5- {4- [4- (5-ethyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -2-fluorophenyl} -5-methylimidazolidine- Synthesis of 2,4-dione

3-Fluoro-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (126 mg) described in Preparation Example 18 was dissolved in tetrahydrofuran (5 mL), and 1-ethyl-3- Add (3′-dimethylaminopropyl) carbodiimide hydrochloride (115 mg), 1- (5-ethyl-3-methylpyridin-2-yl) piperazine (130 mg), 1-hydroxybenzotriazole (162 mg) at room temperature. Stir overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to give 5- {4- [4- (5-ethyl-3-methylpyridin-2-yl) piperazine-1- Carbonyl] -2-fluorophenyl} -5-methylimidazolidine-2,4-dione (196 mg) was obtained.
5- {4- [4- (5-Ethyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -2-fluorophenyl} -5-methylimidazolidine-2,4-dione ( 150 mg) was fractionated on a medium pressure column using CHIRALFLASH (Daicel) IA (ethanol / diethylamine / tetrahydrofuran) to give 37.5 mg (MS (APCI) m / z : 440 (M + H) ⁺ ) and a compound having a long retention time 34.5 mg (MS (APCI) m / z: 440 (M + H) ⁺ )).
In analysis with CHIRALPAK (Daicel) IA (4.6 mm × 100 mm, tetrahydrofuran / ethanol / diethylamine = 10/90 / 0.1, flow rate 0.5 mL / min), the retention times were 4.1 minutes and 5. 9 minutes.

Production Example 35: (R) -5- {4- [4- (3,5-dicyclopropylpyridin-2-yl) piperazine-1-carbonyl] -2-fluorophenyl} -5-methylimidazolidine-2 , 4-dione and (S) -5- {4- [4- (3,5-dicyclopropylpyridin-2-yl) piperazine-1-carbonyl] -2-fluorophenyl} -5-methylimidazolidine- Synthesis of 2,4-dione

3-Fluoro-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (126 mg) described in Preparation Example 18 was dissolved in tetrahydrofuran (5 mL), and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (115 mg), 1-hydroxybenzotriazole (162 mg), 1- (3,5-dicyclopropylpyridin-2-yl) piperazine dihydrochloride (190 mg), Triethylamine (168 μL) was added and stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to give 5- {4- [4- (3,5-dicyclopropylpyridin-2-yl) piperazine-1- Carbonyl] -2-fluorophenyl} -5-methylimidazolidine-2,4-dione (60 mg) was obtained.
The resulting 5- {4- [4- (3,5-dicyclopropylpyridin-2-yl) piperazine-1-carbonyl] -2-fluorophenyl} -5-methylimidazolidine-2,4-dione ( 60 mg) was fractionated on a medium pressure column using CHIRALFLASH (Daicel) IA (hexane / ethanol / diethylamine) to give the title both enantiomers (compound 18 mg (MS (ESI) m / z: 478) with a short retention time. (M + H) ⁺ ) and a compound having a long retention time of 16 mg (MS (ESI) m / z: 478 (M + H) ⁺ )) were obtained.
In the analysis with CHIRALPAK (Daicel) IA-3 (4.6 mm × 150 mm, ethanol / diethylamine = 100 / 0.1, flow rate 0.5 mL / min), the retention times were 11.0 minutes and 25.9 minutes, respectively. Met.

Production Example 36: (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-methylphenyl} -5-ethylimidazolidine-2,4 -Dione and (S) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-methylphenyl} -5-ethylimidazolidine-2,4- Synthesis of dione

To a crude product (209 mg) of 4- (4-ethyl-2,5-dioxoimidazolidin-4-yl) -2-methylbenzoic acid described in Preparation Example 19, tetrahydrofuran (8 mL), N, N-dimethyl Formamide (1 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (183 mg), 1-hydroxybenzotriazole (129 mg), 1- (3,5-dimethylpyridin-2-yl) Piperazine (190 mg) and triethylamine (278 μL) were added, and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration. The resulting crude product was purified by column chromatography (chloroform: methanol) to give 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-methylphenyl. } -5-ethylimidazolidine-2,4-dione (130 mg) was obtained.
Obtained 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-methylphenyl} -5-ethylimidazolidine-2,4-dione (110 mg) Was separated by a medium pressure column using CHIRALFLASH (Daicel) IA (tetrahydrofuran / ethanol / diethylamine) to give the title enantiomer (compound 34 mg (MS (ESI) m / z: 436 (M + H) with a short retention time). ) ⁺ ) And 45 mg of a compound having a long retention time (MS (ESI) m / z: 436 (M + H) ⁺ )).
In the analysis with CHIRALPAK (Daicel) IC-3 (4.6 mm × 150 mm, hexane / ethanol / diethylamine = 10/90 / 0.1, flow rate 0.5 mL / min), each holding time was 7.4 minutes. It was 15.9 minutes.

Production Example 37: (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-methylphenyl} -5-isopropylimidazolidine-2,4 -Dione and (S) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-methylphenyl} -5-isopropylimidazolidine-2,4- Synthesis of dione

4- (4-Isopropyl-2,5-dioxoimidazolidine-4- described in Preparation Example 39
Yl) -3-methylbenzoic acid crude product (138 mg), tetrahydrofuran (5 mL), 1-hydroxybenzotriazole (81 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (115 mg) ), Triethylamine (168 μL) and 1- (3,5-dimethylpyridin-2-yl) piperazine (115 mg) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate: methanol) to give 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1 -Carbonyl] -2-methylphenyl} -5-isopropylimidazolidine-2,4-dione (137 mg) was obtained.
Obtained 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-methylphenyl} -5-isopropylimidazolidine-2,4-dione (119 mg) Was separated by HPLC using CHIRALPAK (Daicel) IF (tetrahydrofuran / ethanol / diethylamine) to give the title enantiomer (compound 59.4 mg (MS (APCI) m / z: 450 (M + H) with a short retention time). ) ⁺ ) And 59 mg (MS (APCI) m / z: 450 (M + H) ⁺ )) having a long retention time were obtained.
In the analysis with CHIRALPAK (Daicel) IC-3 (4.6 mm × 150 mm, tetrahydrofuran / ethanol / diethylamine = 5/95 / 0.1, flow rate 0.5 mL / min), each holding time was 8.0 minutes. It was 6.3 minutes.

Production Example 38: (R) -5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -3-methylphenyl} -5-ethylimidazolidine- 2,4-dione and (S) -5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -3-methylphenyl} -5-ethylimidazo Synthesis of lysine-2,4-dione

To a crude product (131 mg) of 4- (4-ethyl-2,5-dioxoimidazolidin-4-yl) -2-methylbenzoic acid described in Preparation Example 19, tetrahydrofuran (5 mL), triethylamine (168 μL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (115 mg), 1-hydroxybenzotriazole (81 mg), 1- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine ( 130 mg) was added and stirred at room temperature overnight. The reaction solution was purified by column chromatography (chloroform: methanol) to give 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -3-methylphenyl. } -5-Ethylimidazolidine-2,4-dione was obtained. 5- {4- [4- (5-Cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -3-methylphenyl} -5-ethylimidazolidine-2,4-dione obtained Was separated by a medium pressure column using CHIRALFLASH (Daicel) IC (ethanol / dimethylamine) to give both enantiomers of the title compound (18.5 mg of short retention time compound (MS (ESI) m / z: 462 ( M + H) ⁺ ) and a compound having a long retention time of 17.8 mg (MS (ESI) m / z: 462 (M + H) ⁺ )) were obtained.
In the analysis with CHIRALPAK (Daicel) IC-3 (4.6 mm × 150 mm, ethanol / diethylamine = 100 / 0.1, flow rate 0.5 mL / min), the retention times were 7.2 minutes and 14.5 minutes, respectively. Met.

Production Example 39: (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-fluorophenyl} -5-ethylimidazolidine-2,4 -Dione and (S) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-fluorophenyl} -5-ethylimidazolidine-2,4- Synthesis of dione

4- (4-Ethyl-2,5-dioxoimidazolidin-4-yl) -3-fluorobenzoic acid (133 mg) described in Preparation Example 40 was added to tetrahydrofuran (5 mL), triethylamine (168 μL), 1-ethyl. Add 3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (115 mg), 1-hydroxybenzotriazole (81 mg), 1- (3,5-dimethylpyridin-2-yl) piperazine (115 mg), and add room temperature. And stirred overnight. The reaction solution was purified by column chromatography (chloroform: methanol), and 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-fluorophenyl} -5. -Ethylimidazolidine-2,4-dione (75 mg) was obtained.
Obtained 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-fluorophenyl} -5-ethylimidazolidine-2,4-dione (55 mg) Was separated by HPLC using CHIRALPAK (Daicel) IF (hexane / ethanol / tetrahydrofuran / diethylamine) to give both enantiomers of the title compound (16.1 mg (MS (APCI) m / z: 440) having a short retention time). (M + H) ⁺ ) and a compound having a long retention time (16.1 mg, MS (APCI) m / z: 440 (M + H) ⁺ )) were obtained.
In the analysis with CHIRALPAK (Daicel) IF-3 (4.6 mm × 150 mm, hexane / ethanol / tetrahydrofuran / diethylamine = 40/30/30 / 0.1, flow rate 0.5 mL / min), each holding time was 7 0.0 minutes and 8.3 minutes.

Production Example 40: 5- {4- [4- (5-Cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -2-methylphenyl} -5-isopropylimidazolidine-2,4- Synthesis of dione

To a crude product (138 mg) of 4- (4-isopropyl-2,5-dioxoimidazolidin-4-yl) -3-methylbenzoic acid described in Preparation Example 39, tetrahydrofuran (5 mL), 1-ethyl-3 -(3'-dimethylaminopropyl) carbodiimide hydrochloride (115 mg), 1-hydroxybenzotriazole (81 mg), triethylamine (168 μL), 1- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine ( 123 mg) was added and stirred at room temperature for 6.5 hours. The reaction solution was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (118 mg).
MS (ESI) m / z: 476 (M + H) ⁺

Production Example 41: 5-Isopropyl-5- {2-methyl-4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione Synthesis of

4- (4-Isopropyl-2,5-dioxoimidazolidin-4-yl) -3-methylbenzoic acid crude product (138 mg) described in Preparation Example 39, 1- (3,5,6-trimethylpyridine The title compound (85 mg) was obtained by carrying out the same reaction and treatment as in Production Example 40 using 2-yl) piperazine (130 mg).
MS (ESI) m / z: 464 (M + H) ⁺

Production Example 42: 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -2-fluorophenyl} -5-ethylimidazolidine-2,4- Synthesis of dione

4- (4-Ethyl-2,5-dioxoimidazolidin-4-yl) -3-fluorobenzoic acid (67 mg) described in Preparation Example 40 was added to tetrahydrofuran (2.5 mL), triethylamine (87 μL), 1 -Ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (58 mg), 1-hydroxybenzotriazole (40 mg), 1- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine hydrochloride Salt (76 mg) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (85 mg).
MS (ESI) m / z: 466 (M + H) ⁺

Production Example 43: 5-ethyl-5- {2-fluoro-4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione Synthesis of

4- (4-Ethyl-2,5-dioxoimidazolidin-4-yl) -3-fluorobenzoic acid (62 mg) described in Preparation Example 40 was added to tetrahydrofuran (2.3 mL), N, N-dimethylformamide. (3 mL), triethylamine (405 μL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (53 mg), 1-hydroxybenzotriazole (74 mg), 1- (3,5,6-trimethyl Pyridin-2-yl) piperazine (60 mg) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (35 mg).
MS (ESI) m / z: 454 (M + H) ⁺

Production Example 44: 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -5-fluoro-2-methoxyphenyl} -5-isopropylimidazolidine-2,4 -Synthesis of dione

To 2-fluoro-4- (4-isopropyl-2,5-dioxoimidazolidin-4-yl) -5-methoxybenzoic acid (310 mg) described in Preparation Example 59, tetrahydrofuran (10 mL), 1-ethyl- 3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (230 mg), 1-hydroxybenzotriazole (162 mg), triethylamine (350 μL), 1- (3,5-dimethylpyridin-2-yl) piperazine (230 mg) And stirred at room temperature overnight. Water was added to the reaction mixture, and the precipitate was collected by filtration to obtain the title compound (380 mg).
MS (ESI) m / z: 484 (M + H) ⁺

Production Example 45: 5- (1,1-difluoroethyl) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-methoxyphenyl} imidazolidine- Synthesis of 2,4-dione

To 4- [4- (1,1-difluoroethyl) -2,5-dioxo-imidazolidin-4-yl] -3-methoxybenzoic acid (157 mg) described in Preparation Example 60, tetrahydrofuran (5 mL), 1 -Ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (115 mg), N, N-dimethylformamide (2 mL), 1-hydroxybenzotriazole (81 mg), triethylamine (175 μL), 1- (3 5-Dimethylpyridin-2-yl) piperazine (115 mg) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (77 mg).
MS (ESI) m / z: 488 (M + H) ⁺

Production Example 46: 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -5-fluoro-2-hydroxyphenyl} -5-isopropylimidazolidine-2,4 -Synthesis of dione

5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -5-fluoro-2-methoxyphenyl} -5-isopropylimidazolidine-2 described in Preparation Example 44 1,2-Dichloroethane (10 mL) was added to 1,4-dione (242 mg), and 1 mol / L boron tribromide dichloromethane solution (2.5 mL) was added with cooling and stirring to 0 ° C., followed by stirring while raising the temperature to room temperature. did. After stirring for 1.5 hours at 40 ° C. and 1.5 hours at 80 ° C. under microwave irradiation, toluene (2 mL) and a 1 mol / L boron tribromide dichloromethane solution (2.5 mL) were added. Stir for 5 hours. After stirring at room temperature overnight, the reaction mixture was poured into an aqueous sodium bicarbonate solution and extracted with chloroform. The solvent was distilled off, and the resulting residue was fractionated by HPLC using XBridge Phenyl (0.05% trifluoroacetic acid / water, 0.05% trifluoroacetic acid / acetonitrile). To the obtained solution was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was distilled off to obtain the title compound (21 mg).
MS (ESI) m / z: 470 (M + H) ⁺

Production Example 47: 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isopropyl-3- (4-methoxybenzyl) imidazolidine-2, Synthesis of 4-dione

1) Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione described in Preparation Example 5 4- (4-Isopropyl-2,5-dioxo-imidazolidin-4-yl) benzoic acid (180 mg), 1- (3,5-dimethylpyridin-2-yl) piperazine (160 mg), 1-hydroxybenzotriazole (92 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (150 mg), diisopropylethylamine (2.3 mL) were dissolved in N, N-dimethylformamide (7 mL) and overnight at room temperature. Stir. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH column chromatography (chloroform: methanol), and 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5- Isopropylimidazolidine-2,4-dione (240 mg) was obtained.
MS (ESI) m / z: 436 (M + H) ⁺

2) 5- {4- [4- (3,5-Dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isopropyl-3- (4-methoxybenzyl) imidazolidine-2,4- Synthesis of dione 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione (217 mg, 1 above) Potassium carbonate (90 mg), N, N-dimethylformamide (5 mL), potassium iodide (8.3 mg) and 4-methoxybenzyl bromide (109 μL) were added to the mixture, and the mixture was stirred at room temperature. After completion of the reaction, water was added and the precipitated solid was collected by filtration, and 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isopropyl-3. -(4-Methoxybenzyl) imidazolidine-2,4-dione (278 mg) was obtained.
MS (ESI) m / z: 556 (M + H) ⁺

Production Example 48: (R) -5-difluoromethyl-5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione and Synthesis of (S) -5-difluoromethyl-5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Difluoromethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (270 mg) described in Preparation Example 62 was added to tetrahydrofuran (10 mL), 1-hydroxybenzotriazole (162 mg), 1- Ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (230 mg), triethylamine (350 μL), 1- (3,5-dimethylpyridin-2-yl) piperazine (230 mg), N, N-dimethylformamide (3 mL) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give 5-difluoromethyl-5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine- 1-Carbonyl] phenyl} imidazolidine-2,4-dione (221 mg) was obtained.
The obtained 5-difluoromethyl-5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione (220 mg) was converted into CHIRALPAK ( Daicel) By separation by HPLC using IF (2-propanol / tetrahydrofuran / diethylamine), both of the enantiomers (compound 57 mg (MS (ESI) m / z: 444 (M + H) ⁺ ) having a short retention time) And 94 mg (MS (ESI) m / z: 444 (M + H) ^<+> ) of compound with a long retention time was obtained.
In the analysis with CHIRALPAK (Daicel) IF-3 (4.6 mm × 50 mm, 2-propanol / tetrahydrofuran / diethylamine = 85/15 / 0.1, flow rate 0.5 mL / min), each holding time was 5.6. Minutes and 10.9 minutes.

Production Example 49: (R) -5- {4-[(S) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4 -Synthesis of dione

To 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (136 mg) described in Preparation Example 45, tetrahydrofuran (5 mL), 1-ethyl-3- (3 '-Dimethylaminopropyl) carbodiimide hydrochloride (115 mg), 1-hydroxybenzotriazole (81 mg), triethylamine (280 μL), (3,5-dimethyl-pyridin-2-yl)-(S ) -Pyrrolidin-3-ylamine dihydrochloride (158 mg) and N, N-dimethylformamide (2 mL) were added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (131 mg).
MS (ESI) m / z: 436 (M + H) ⁺

Production Example 50: (R) -5- {4-[(S) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1-carbonyl] phenyl} -5-ethylimidazolidine-2,4 -Synthesis of dione

4-((R) -4-ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (124 mg) as described in Preparation Example 14 and (3,5-dimethyl-pyridine as described in Preparation Example 88 -2-yl)-(S) -pyrrolidin-3-ylamine dihydrochloride (158 mg) was used for the same reaction and treatment as in Production Example 49 to obtain the title compound (102 mg).
MS (ESI) m / z: 422 (M + H) ⁺

Production Example 51: (R) -5- {4-[(S) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4 -Synthesis of dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (117 mg) described in Preparation Example 6 was added to (3,5-dimethyl- The title compound (45 mg) was obtained by carrying out the same reaction and treatment as in Production Example 49 using pyridin-2-yl)-(S) -pyrrolidin-3-ylamine dihydrochloride (158 mg).
MS (ESI) m / z: 408 (M + H) ⁺

Production Example 52: (R) -5- {4-[(S) -4- (3,5-dimethylpyridin-2-yl) -2-methylpiperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine -2,4-dione and (R) -5- {4-[(R) -4- (3,5-dimethylpyridin-2-yl) -2-methylpiperazine-1-carbonyl] phenyl} -5 Synthesis of isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (262 mg) described in Preparation Example 45 was added to tetrahydrofuran (10 mL), 1-ethyl-3- (3 '-Dimethylaminopropyl) carbodiimide hydrochloride (230 mg), 1-hydroxybenzotriazole (162 mg), triethylamine (350 μL), 1- (3,5-dimethylpyridin-2-yl) -3 described in Preparation Example 110 -Methylpiperazine (226 mg) and N, N-dimethylformamide (3 mL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), and (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) -2- Methylpiperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione (339 mg) was obtained.
The obtained (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) -2-methylpiperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4- Dione (150 mg) was fractionated by HPLC using CHIRALPAK (Daicel) IF (ethanol / tetrahydrofuran / diethylamine) to give the title diastereomers (compound 71.8 mg (MS (ESI) m / z: 450 (M + H) ⁺ ) and a compound having a long retention time 63.8 mg (MS (ESI) m / z: 450 (
M + H) ⁺ ) was obtained.
In the analysis with CHIRALPAK (Daicel) IF-3 (4.6 mm × 150 mm, ethanol / tetrahydrofuran / diethylamine = 90/10 / 0.1, flow rate 0.5 mL / min), each holding time was 11.8 minutes. 13.5 minutes.

Production Example 53: (R) -5- {4-[(S) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1-carbonyl] phenyl} -5-fluoromethylimidazolidine-2, 4-dione and (S) -5- {4-[(S) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1-carbonyl] phenyl} -5-fluoromethylimidazolidine-2, Synthesis of 4-dione

4- (4-Fluoromethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (126 mg) described in Preparation Example 63 was added to (3,5-dimethyl-pyridine-2 described in Preparation Example 88. -Yl)-(S) -pyrrolidin-3-ylamine dihydrochloride (158.5 mg), tetrahydrofuran (5 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (115 mg), 1-Hydroxybenzotriazole (81 mg), triethylamine (315 μL) and N, N-dimethylformamide (1.5 mL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to give 5- {4-[(S) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1- Carbonyl] phenyl} -5-fluoromethylimidazolidine-2,4-dione (95 mg) was obtained.
The resulting 5- {4-[(S) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1-carbonyl] phenyl} -5-fluoromethylimidazolidine-2,4-dione (55 mg) ) Was separated by HPLC using CHIRALPAK (Daicel) IC (hexane / ethanol / diethylamine) to give the title diastereomers (13.5 mg of short retention time compound (MS (ESI) m / z: 426). (M + H) ⁺ ) and a compound having a long retention time of 14.1 mg (MS (ESI) m / z: 426 (M + H) ⁺ )) were obtained.
In the analysis with CHIRALPAK (Daicel) IC-3 (4.6 mm × 150 mm, hexane / ethanol / diethylamine = 10/90 / 0.1, flow rate 0.5 mL / min), each holding time was 5.7 minutes. 10.1 minutes.

Production Example 54: (R) -5- {4-[(R) -4- (3,5-dimethylpyridin-2-yl) -3-methylpiperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine Synthesis of -2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (186 mg) described in Preparation Example 45 was added to (R) -1- ( 3,5-dimethylpyridin-2-yl) -2-methylpiperazine dihydrochloride (198 mg), tetrahydrofuran (7 mL), 1-hydroxybenzotriazole (144 mg), 1-ethyl-3- (3′-dimethylamino) Propyl) carbodiimide hydrochloride (204 mg), triethylamine (446 μL) and N, N-dimethylformamide (1 mL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (220 mg).
MS (ESI) m / z: 450 (M + H) ⁺

Production Example 55: (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-fluoromethylimidazolidine-2,4-dione and Synthesis of (S) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-fluoromethylimidazolidine-2,4-dione

To 4- (4-fluoromethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (252 mg) described in Preparation Example 63, 1- (3,5-dimethylpyridin-2-yl) piperazine ( 230 mg), tetrahydrofuran (10 mL), 1-hydroxybenzotriazole (162 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (230 mg), triethylamine (350 μL), N, N-dimethylformamide (1.5 mL) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to give 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl. } -5-Fluoromethylimidazolidine-2,4-dione (288 mg) was obtained.
The obtained 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-fluoromethylimidazolidine-2,4-dione (200 mg) was converted into CHIRALPAK ( Daicel) By separation by HPLC using IF (2-propanol / tetrahydrofuran / diethylamine), both the enantiomers (85 mg of a compound having a short retention time (MS (ESI) m / z: 426 (M + H) ⁺ )) And 80 mg (MS (ESI) m / z: 426 (M + H) ⁺ ) having a long retention time was obtained.
In the analysis with CHIRALPAK (Daicel) IF-3 (4.6 mm × 50 mm, 2-propanol / tetrahydrofuran / diethylamine = 80/20 / 0.1, flow rate 0.5 mL / min), each retention time was 5.5. Minutes and 8.9 minutes.

Production Example 56: (R) -5- {4-[(R) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4 -Synthesis of dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (131 mg) described in Preparation Example 45 was added to (3,5-dimethylpyridine described in Preparation Example 113. -2-yl)-(R) -pyrrolidin-3-ylamine (131 mg), tetrahydrofuran (5 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (143 mg), 1-hydroxybenzo Triazole (101 mg), triethylamine (174 μL) and N, N-dimethylformamide (0.5 mL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain a crude product of the title compound. The resulting crude product was fractionated by HPLC using Cosmosil Cholester (0.05% trifluoroacetic acid / water, 0.05% trifluoroacetic acid / acetonitrile). Saturated aqueous sodium hydrogen carbonate solution was added to the resulting solution, and the mixture was extracted with chloroform. The solvent was distilled off to obtain the title compound (103 mg).
MS (ESI) m / z: 436 (M + H) ⁺

Production Example 57: (S) -5- {4-[(S) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4 -Synthesis of dione

4-((S) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid) (131 mg) described in Preparation Example 114 was added to (3,5-dimethyl) described in Preparation Example 88. -Pyridin-2-yl)-(S) -pyrrolidin-3-ylamine dihydrochloride (158 mg), tetrahydrofuran (5 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (115 mg) ), 1-hydroxybenzotriazole (81 mg), triethylamine (315 μL) and N, N-dimethylformamide (1 mL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (159 mg).
MS (ESI) m / z: 436 (M + H) ⁺

Production Example 58: 5- {4-[(S) -4- (3,5-dimethylpyridin-2-yl) -3-methylpiperazine-1-carbonyl] phenyl} -5-fluoromethylimidazolidine-2, Synthesis of 4-dione

4- (4-Fluoromethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (76 mg) described in Preparation Example 63 was added to (S) -1- (3,5 described in Preparation Example 131. -Dimethylpyridin-2-yl) -2-methylpiperazine dihydrochloride (116 mg), tetrahydrofuran (3 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (75 mg), 1- Hydroxybenzotriazole (53 mg) and triethylamine (189 μL) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (65 mg).
MS (ESI) m / z: 440 (M + H) ⁺

Production Example 59: (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) -2,2-dimethylpiperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2 Of 1,4-dione

To 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (169 mg) described in Preparation Example 45, 1- (3,5- Dimethylpyridin-2-yl) -3,3-dimethylpiperazine dihydrochloride (198 mg), tetrahydrofuran (6.4 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (160 mg) , 1-hydroxybenzotriazole (105 mg), triethylamine (405 μL) and N, N-dimethylformamide (2 mL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the precipitate was collected by filtration to obtain the title compound (219 mg).
MS (ESI) m / z: 464 (M + H) ⁺

Production Example 60: (R) -5- {4-[(S) -4- (3,5-dimethylpyridin-2-yl) -3-methylpiperazine-1-carbonyl] phenyl} -5-methylimidazolidine Synthesis of -2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (70 mg) described in Preparation Example 6 was added to (S) -1- ( 3,5-Dimethylpyridin-2-yl) -2-methylpiperazine dihydrochloride (83 mg), tetrahydrofuran (3 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (75 mg) , 1-hydroxybenzotriazole (50 mg), triethylamine (189 μL), N, N-dimethylformamide (2 mL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (30 mg).
MS (ESI) m / z: 422 (M + H) ⁺

Production Example 61: (R) -5- {4-[(R) -4- (3,5-dimethylpyridin-2-yl) -2-methylpiperazine-1-carbonyl] phenyl} -5-methylimidazolidine Synthesis of -2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (70 mg) described in Preparation Example 6 was added to (R) -1- ( 3,5-dimethylpyridin-2-yl) -3-methylpiperazine dihydrochloride (87 mg), N, N-dimethylformamide (4 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide Hydrochloride (75 mg), 1-hydroxybenzotriazole (53 mg) and triethylamine (189 μL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, and the obtained residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (46 mg).
MS (ESI) m / z: 422 (M + H) ⁺

Production Example 62: (R) -5-fluoromethyl-5- {4- [4- (5-methylpyridin-2-ylamino) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione and (S ) -5-Fluoromethyl-5- {4- [4- (5-methylpyridin-2-ylamino) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Fluoromethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (76 mg) described in Preparation Example 63 was added to tetrahydrofuran (3 mL) and (5-methylpyridin-2-yl) piperidine. -4-ylamine (57 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (75 mg), 1-hydroxybenzotriazole (53 mg), triethylamine (105 μL), N, N-dimethylformamide (1 mL) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to give 5-fluoromethyl-5- {4- [4- (5-methylpyridin-2-ylamino) piperidine-1-carbonyl. ] Phenyl} imidazolidine-2,4-dione (62.2 mg) was obtained.
The obtained 5-fluoromethyl-5- {4- [4- (5-methylpyridin-2-ylamino) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione (40 mg) was converted into CHIRALPAK (Daicel). By fractionating by HPLC using IC (hexane / 2-propanol / tetrahydrofuran / diethylamine), the title enantiomer (compound 13.5 mg (MS (ESI) m / z: 426 (M + H) with a short retention time) was obtained. ⁺ ) And 12.7 mg (MS (ESI) m / z: 426 (M + H) ⁺ ) of the compound having a long retention time were obtained.
Each retention time in the analysis with CHIRALPAK (Daicel) IC-3 (4.6 mm × 150 mm, hexane / 2-propanol / tetrahydrofuran / diethylamine = 60/20/20 / 0.1, flow rate 0.5 mL / min) Were 6.7 minutes and 11.6 minutes.

Production Example 63: 5- {4-[(R) -4- (3,5-dimethylpyridin-2-yl) -2-methylpiperazine-1-carbonyl] phenyl} -5-fluoromethylimidazolidine-2, Synthesis of 4-dione

4- (4-Fluoromethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (76 mg) described in Preparation Example 63 was added to (R) -1- (3,5 described in Preparation Example 119. -Dimethylpyridin-2-yl) -3-methylpiperazine (80 mg), tetrahydrofuran (3 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (75 mg), 1-hydroxybenzotriazole ( 53 mg) and triethylamine (210 μL) were added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (75 mg).
MS (ESI) m / z: 440 (M + H) ⁺

Production Example 64: (S) -4- (3,5-dimethylpyridin-2-yl) -1- [4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) Synthesis of benzoyl] piperazine-2-carboxylic acid methyl ester

To (S) -4- (3,5-dimethylpyridin-2-yl) piperazine-2-carboxylic acid methyl ester (620 mg) described in Preparation Example 130, 4-((R)- 4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (465 mg), tetrahydrofuran (18 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (440 mg), 1-hydroxybenzotriazole (310 mg) and triethylamine (620 μL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (581 mg).
MS (ESI) m / z: 494 (M + H) ⁺

Production Example 65: (R) -5- {4- [8- (3,5-dimethylpyridin-2-yl) -5,8-diazaspiro [3.5] nonane-5-carbonyl] phenyl} -5 Synthesis of isopropylimidazolidine-2,4-dione

To a solution of 5,8-diazaspiro [3,5] nonane dihydrochloride (199 mg), 3,5-dimethylpyridine-N-oxide (117 mg) in tetrahydrofuran (4 mL), N, N-diisopropylethylamine (980 μL), Bromotris (pyrrolidino) phosphonium hexafluorophosphate (606 mg) was added and stirred overnight at room temperature. To the reaction solution, N, N-diisopropylethylamine (341 μL), 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (262 mg) described in Preparation Example 45, Bromotris (pyrrolidino) phosphonium hexafluorophosphate (466 mg) was added, and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (89.2 mg).
MS (ESI) m / z: 476 (M + H) ⁺

Production Example 66: (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) -3-methoxymethylpiperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2, Synthesis of 4-dione

To 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52 mg) described in Preparation Example 45, 1- (3,5- Dimethylpyridin-2-yl) -2-methoxymethylpiperazine dihydrochloride (62 mg), tetrahydrofuran (2 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (50 mg), 1- Hydroxybenzotriazole (35 mg) and triethylamine (126 μL) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (53 mg).
MS (ESI) m / z: 480 (M + H) ⁺

Production Example 67: (R) -5- {4-[(R) -4- (3,5-dimethylpyridin-2-yl) -2-ethylpiperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine Synthesis of -2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (131 mg) described in Preparation Example 45 was added to (R) -1- ( 3,5-dimethylpyridin-2-yl) -3-ethylpiperazine (109 mg), tetrahydrofuran (5 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (125 mg), 1-hydroxy Benzotriazole (88 mg) and triethylamine (178 μL) were added, and the mixture was stirred at room temperature for 5.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (132 mg).
MS (ESI) m / z: 464 (M + H) ⁺

Production Example 68: (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) -2,2-dimethylpiperazine-1-carbonyl] phenyl} -5-methylimidazolidine-2 Of 1,4-dione

To 1- (3,5-dimethylpyridin-2-yl) -3,3-dimethylpiperazine dihydrochloride (88 mg) described in Preparation Example 116, tetrahydrofuran (3 mL) and 4- ( (R) -4-Methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (70 mg), triethylamine (189 μL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (75 mg) and 1-hydroxybenzotriazole (53 mg) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (87 mg).
MS (ESI) m / z: 436 (M + H) ⁺

Production Example 69: 5- {4- [4- (3,5-dimethylpyridin-2-yl) -2,2-dimethylpiperazine-1-carbonyl] phenyl} -5-fluoromethylimidazolidine-2,4- Synthesis of dione

To 1- (3,5-dimethylpyridin-2-yl) -3,3-dimethylpiperazine dihydrochloride (146 mg) described in Preparation Example 116, tetrahydrofuran (5 mL), and 4- ( 4-fluoromethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (126 mg), triethylamine (314 μL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (125 mg) , 1-hydroxybenzotriazole (88 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (112 mg).
MS (ESI) m / z: 454 (M + H) ⁺

Production Example 70: (R) -5- {4-[(S) -4- (3,5-dimethylpyridin-2-yl) -2-methoxymethylpiperazine-1-carbonyl] phenyl} -5-isopropylimidazo Synthesis of lysine-2,4-dione

(S) -4- (3,5-dimethylpyridin-2-yl) -2-methoxymethylpiperazine-1-carboxylic acid tert-butyl ester (97 mg) described in Preparation Example 124 was added to methyl acetate (1.5 mL) , Dissolved in methanol (1.5 mL), 4N hydrogen chloride / ethyl acetate solution (1.5 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off, and the resulting residue was added tetrahydrofuran (3 mL), triethylamine (182 μL), 4-((R) -4-isopropyl-2,5-dioxoimidazolidine-4- Yl) Benzoic acid (76 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (72 mg) and 1-hydroxybenzotriazole (51 mg) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the obtained residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (46 mg).
MS (ESI) m / z: 480 (M + H) ⁺

Production Example 71: (R) -5- {4- [8- (3,5-dimethylpyridin-2-yl) -5,
Synthesis of 8-diazaspiro [3.5] nonane-5-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (70 mg) described in Preparation Example 6 was added to tetrahydrofuran (3 mL), and 8- (3,5-dimethylpyridin-2-yl) -5,8-diazaspiro [3.5] nonane (70 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (75 mg), 1-hydroxybenzotriazole (53 mg) and triethylamine (105 μL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (76 mg).
MS (ESI) m / z: 448 (M + H) ⁺

Production Example 72: 5- {4-[(S) -4- (3,5-dimethylpyridin-2-yl) -2-methylpiperazine-1-carbonyl] phenyl} -5-fluoromethylimidazolidine-2, Synthesis of 4-dione

4- (4-Fluoromethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (76 mg) described in Preparation Example 63 was added to tetrahydrofuran (3 mL), and (S) -1 described in Preparation Example 126. -(3,5-dimethylpyridin-2-yl) -3-methylpiperazine (62 mg), triethylamine (105 μL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (75 mg), 1 -Hydroxybenzotriazole (53 mg) was added and stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (71 mg).
MS (ESI) m / z: 440 (M + H) ⁺

Production Example 73: (R) -5- {4-[(R) -4- (3,5-dimethylpyridin-2-yl) -3-hydroxymethylpiperazine-1-carbonyl] phenyl} -5-isopropylimidazo Synthesis of lysine-2,4-dione

To ((R) -1- (3,5-dimethylpyridin-2-yl) piperazin-2-yl] methanol (110 mg) described in Preparation Example 127, 4-((R)- 4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (130 mg), tetrahydrofuran (5 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (125 mg), 1-Hydroxybenzotriazole (90 mg) and triethylamine (175 μL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (115 mg).
MS (ESI) m / z: 466 (M + H) ⁺

Production Example 74: (R) -5- {4-[(S) -4- (3,5-dimethylpyridin-2-yl) -3-hydroxymethylpiperazine-1-carbonyl] phenyl} -5-isopropylimidazo Synthesis of lysine-2,4-dione

To [(S) -1- (3,5-dimethylpyridin-2-yl) piperazin-2-yl] methanol dihydrochloride (88 mg) described in Preparation Example 128, 4- ( (R) -4-Isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (80 mg), tetrahydrofuran (3 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (75 mg), 1-hydroxybenzotriazole (53 mg), and triethylamine (188 μL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (60 mg).
MS (ESI) m / z: 466 (M + H) ⁺

Production Example 75: Synthesis of (R) -5-isopropyl-5- {4- [4- (7-methylbenzoxazol-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

To 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (79 mg) described in Preparation Example 45, 7-methyl-2- (piperidin-4-yl) -1,3-benzoxazole (65 mg), tetrahydrofuran (3 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (86 mg), 1-hydroxybenzotriazole (60 mg) were added, and room temperature was added. And stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (82 mg).
MS (ESI) m / z: 461 (M + H) ⁺

Production Example 76: (R) -5-methyl-5- {4- [4- (5-p-tolyl [1,3,4]] oxadiazol-2-yl) piperidin-1-carbonyl] phenyl} imidazo Synthesis of lysine-2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (117 mg) described in Preparation Example 6 was added to 4- [5- (4-methylphenyl) -1 , 3,4-oxadiazol-2-yl] piperidine (73 mg), tetrahydrofuran (3 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (75 mg), 1-hydroxybenzotriazole (53 mg) and triethylamine (105 μL) were added, and the mixture was stirred at room temperature. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (85.3 mg).
MS (ESI) m / z: 460 (M + H) ⁺

Production Example 77: (R) -5-ethyl-5- {4- [4- (5-o-tolyl [1,3,4]] oxadiazol-2-yl) piperidin-1-carbonyl] phenyl} imidazo Synthesis of lysine-2,4-dione

4-((R) -4-ethyl-2,5-dioxo-imidazolidin-4-yl) benzoic acid (50 mg) described in Preparation Example 14 was added to 4- [5- (2-methylphenyl) -1 , 3,4-oxadiazol-2-yl] piperidine (48 mg), tetrahydrofuran (2 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (58 mg), 1-hydroxybenzotriazole (40 mg) and triethylamine (70 μL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (90 mg).
MS (ESI) m / z: 474 (M + H) ⁺

Production Example 78: 5-Fluoromethyl-5- {4- [4- (5-o-tolyl [1,3,4]] oxadiazol-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2 Of 1,4-dione

4- [5- (2-Methylphenyl) -1,3,4-oxadiazol-2-yl] piperidine (48 mg) and 4- (4-fluoromethyl-2,5-dioxo described in Preparation 63 -Imidazolidin-4-yl) benzoic acid (46 mg) was used for the same reaction and treatment as in Production Example 77 to obtain the title compound (67 mg).
MS (ESI) m / z: 478 (M + H) ⁺

Production Example 79: (R) -5-isopropyl-5- {4- [4- (5-phenyl [1,3,4]] oxadiazol-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine- Synthesis of 2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (79 mg) described in Preparation Example 45 was added to 4- (5-phenyl-1,3,4-). Oxadiazol-2-yl) piperidine (70 mg), tetrahydrofuran (3 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (75 mg), 1-hydroxybenzotriazole (53 mg), triethylamine (105 μL) and N, N-dimethylformamide (0.3 mL) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (85 mg).
MS (ESI) m / z: 474 (M + H) ⁺

Production Example 80: (R) -5- {4-[(S) -4- (3,5-dimethylpyridin-2-yl) -3-methylpiperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine Synthesis of -2,4-dione

Dissolve (S) -4- (3,5-dimethylpyridin-2-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (140 mg) described in Preparation Example 115 in ethanol (2.5 mL) 4N hydrogen chloride / ethyl acetate solution (2.5 mL) was added, and the mixture was stirred at room temperature. After completion of the reaction, water and 1N aqueous sodium hydroxide solution were added, followed by extraction with ethyl acetate. The solvent was distilled off to obtain (S) -1- (3,5-dimethylpyridin-2-yl) -2-methylpiperazine (103 mg).
To the obtained (S) -1- (3,5-dimethylpyridin-2-yl) -2-methylpiperazine (103 mg), 4-((R) -4-isopropyl-2, described in Preparation Example 45 was added. 5-dioxoimidazolidin-4-yl) benzoic acid (128 mg), tetrahydrofuran (5 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (115 mg), 1-hydroxybenzotriazole ( 81 mg), triethylamine (174 μL), N, N-dimethylformamide (2 mL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (97 mg).
MS (ESI) m / z: 450 (M + H) ⁺

Production Example 81: (R) -5-isopropyl-5- {4- [4- (5-p-tolyl [1,3,4] oxadiazol-2-yl) piperidin-1-carbonyl] phenyl} imidazo Synthesis of lysine-2,4-dione

4-((R) -4-Isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid chloride (126 mg) described in Preparation Example 132 was added to pyridine (1.5 mL), 4- [5- (4-Methylphenyl) -1,3,4-oxadiazol-2-yl] piperidine trifluoroacetate (102 mg) was added, and the mixture was stirred at 80 ° C. for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (70 mg).
MS (ESI) m / z: 488 (M + H) ⁺

Production Example 82: (R) -5-isopropyl-5- {4- [4- (5-o-tolyl [1,3,4]] oxadiazol-2-yl) piperidine-1-carbonyl] phenyl} imidazo Synthesis of lysine-2,4-dione

4- [5- (2-Methylphenyl) -1,3,4-oxadiazol-2-yl] piperidine trifluoroacetate (102 mg) and 4-((R) -4 described in Preparation Example 132 The title compound (65 mg) was obtained by carrying out the same reaction and treatment as in Production Example 81 using -isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid chloride (210 mg).
MS (ESI) m / z: 488 (M + H) ⁺

Production Example 83: (S) -4- (3,5-dimethylpyridin-2-yl) -1- [4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) Of Benzoyl] piperazine-2-carbonitrile

(S) -2-carbamoyl-4- (3,5-dimethylpyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (420 mg) described in Preparation Example 133 and 4- By performing the same reaction and treatment as in Production Example 70 using ((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (328 mg), (S) -4- (3,5-dimethylpyridin-2-yl) -1- [4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoyl] piperazine-2-carboxylic acid amide ( 390 mg) was obtained (MS (ESI) m / z: 479 (M + H) ⁺ ).
The obtained (S) -4- (3,5-dimethylpyridin-2-yl) -1- [4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoyl To a solution of piperazine-2-carboxylic acid amide (300 mg) and triethylamine (524 μL) in tetrahydrofuran (3.1 mL) was added trifluoroacetic anhydride (260 μL) at 0 ° C. After stirring overnight at room temperature, triethylamine (262 μL) and trifluoroacetic anhydride (130 μL) were added, and the mixture was stirred at 0 ° C. for 2 hours. To the reaction solution were added potassium carbonate (650 mg) and water (1 mL), and the mixture was stirred at 40 ° C. for 0.5 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the obtained residue was purified by column chromatography (ethyl acetate: hexane) to obtain the title compound (162 mg).
MS (ESI) m / z: 461 (M + H) ⁺

Production Example 84: Synthesis of 5- {4- [4- (2,4-dimethylphenyl) piperidine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione

4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (70 mg), 4- (2,4-dimethylphenyl) piperidine hydrochloride (68 mg) described in Preparation Example 82, To a mixture of 1-hydroxybenzotriazole (49 mg) and chloroform (2 ml) was added triethylamine (0.050 ml) and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (75 mg) at room temperature. Stir for 2 days. Ethyl acetate was added to the reaction solution, the organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. Hexane / ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to obtain the title compound (83 mg).
MS (ESI) m / z: 406 (M + H) ⁺

Production Example 85: Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} -5-methylimidazolidine-2,4-dione

2-Fluoro-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (93 mg), 1- (3,5-dimethylpyridin-2-yl) described in Preparation Example 2 To a mixture of piperazine (70 mg), 1-hydroxybenzotriazole (59 mg) and chloroform (2 ml) was added 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (91 mg), and the mixture was stirred at room temperature for 2 days. Stir. The reaction solution was purified by NH column chromatography (chloroform: methanol) and column chromatography (chloroform: methanol) to obtain the title compound (105.9 mg).
MS (ESI) m / z: 426 (M + H) ⁺

Production Example 86: (S) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methoxymethylimidazolidine-2,4-dione and Synthesis of (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methoxymethylimidazolidine-2,4-dione

4- (4-methoxymethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (113 mg), 1- (3,5-dimethylpyridin-2-yl) piperazine (90 mg) according to Preparation Example 9 ), 1-hydroxybenzotriazole (69 mg) and chloroform (3 ml) were added 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (123 mg) and stirred at room temperature for 2 days. The reaction solution was purified by NH column chromatography (chloroform: methanol) and column chromatography (chloroform: methanol) to give 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl. ] Phenyl} -5-methoxymethylimidazolidine-2
, 4-dione (129 mg) was obtained.
The obtained 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methoxymethylimidazolidine-2,4-dione (100 mg) was converted into CHIRALPAK ( Daicel) By separation with HPLC (ethanol / diethylamine) using IC, both of the enantiomers (compound 44 mg (MS (ESI) m / z: 438 (M + H) ⁺ ) with a short retention time) and retention time 44 mg of long compound (MS (ESI) m / z: 438 (M + H) ⁺ )) was obtained.
In the analysis with CHIRALPAK (Daicel) IC-3 (4.6 mm × 150 mm, ethanol / diethylamine = 100 / 0.1, flow rate 0.5 mL / min), the retention times were 9.3 minutes and 14.8 minutes, respectively. Met.

Production Example 87: Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-trifluoromethylimidazolidine-2,4-dione

4- (2,5-Dioxo-4-trifluoromethylimidazolidin-4-yl) benzoic acid (123 mg), 1- (3,5-dimethylpyridin-2-yl) piperazine (90 mg) described in Preparation Example 10 ), 1-hydroxybenzotriazole (69 mg) and chloroform (3 ml) were added 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (123 mg) and stirred at room temperature for 2 days. The reaction solution was purified by NH column chromatography (chloroform: methanol) and column chromatography (chloroform: methanol) to obtain the title compound (83 mg).
MS (ESI) m / z: 462 (M + H) ⁺

Production Example 88 Synthesis of 5-cyclopropyl-5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Cyclopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (111 mg), 1- (3,5-dimethylpyridin-2-yl) piperazine (90 mg) described in Preparation Example 11 ), 1-hydroxybenzotriazole (69 mg) and chloroform (3 ml) were added 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (123 mg) and stirred at room temperature for 2 days. The reaction solution was purified by NH column chromatography (chloroform: methanol) and column chromatography (chloroform: methanol) to obtain the title compound (102 mg).
MS (ESI) m / z: 434 (M + H) ⁺

Production Example 89: 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} -5-ethylimidazolidine-2,4- Synthesis of dione

4- (4-Ethyl-2,5-dioxoimidazolidin-4-yl) -2-fluorobenzoic acid (150 mg), 1- (5-cyclopropyl-3-methylpyridine-2, as described in Preparation Example 12. -Il) piperazine (246 mg), 1-hydroxybenzotriazole (114 mg), triethylamine (0.235 ml) and chloroform (3 ml) in a mixture of 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (216 mg) was added and stirred at room temperature for 2 days. The reaction solution was purified by NH column chromatography (chloroform: methanol) and column chromatography (chloroform: methanol) to obtain the title compound (115 mg).
MS (ESI) m / z: 466 (M + H) ⁺

Production Example 90: Synthesis of 5-tert-butyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-tert-butyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (120 mg), 1- (3,5,6-trimethylpyridin-2-yl) as described in Preparation Example 13 To a mixture of piperazine (134 mg), 1-hydroxybenzotriazole (76 mg), triethylamine (0.121 ml) and chloroform (3 ml), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (125 mg) And stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. After drying with sodium sulfate, the solvent was distilled off. The resulting residue was purified by column chromatography (chloroform: methanol) and NH column chromatography (chloroform: methanol) to obtain the title compound (192 mg).
MS (ESI) m / z: 464 (M + H) ⁺

Preparation Example 91: 5-tert-butyl-5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione Composition

4- (4-tert-butyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (120 mg), 1- (5-cyclopropyl-3-methylpyridin-2-yl) described in Preparation Example 13 ) The title compound (160 mg) was obtained by carrying out the same reaction and treatment as in Production Example 90 using piperazine (142 mg).
MS (ESI) m / z: 476 (M + H) ⁺

Production Example 92 Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-hydroxymethylimidazolidine-2,4-dione

4- (4-Hydroxymethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (125 mg), 1- (3,5-dimethylpyridin-2-yl) piperazine hydrochloride as described in Preparation Example 23 To a mixture of salt (228 mg), 1-hydroxybenzotriazole (101 mg), triethylamine (0.279 ml), chloroform (3 ml) and N, N-dimethylformamide (1 ml) was added 1-ethyl-3- (3′-dimethyl). Aminopropyl) carbodiimide hydrochloride (153 mg) was added and stirred at room temperature for 16 hours. The reaction solution was purified by NH column chromatography (chloroform: methanol) to obtain the title compound (89 mg).
MS (ESI) m / z: 424 (M + H) ⁺

Production Example 93: 5-ethyl-5- {3-fluoro-4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione Synthesis of

4- (4-Ethyl-2,5-dioxoimidazolidin-4-yl) -2-fluorobenzoic acid (150 mg) described in Preparation Example 12, 1- (3,5,6-trimethylpyridine-2- Yl) Piperazine (232 mg) was used for the same reaction and treatment as in Production Example 89 to obtain the title compound (183 mg).
MS (ESI) m / z: 454 (M + H) ⁺

Production Example 94 Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} -5-ethylimidazolidine-2,4-dione

4- (4-Ethyl-2,5-dioxoimidazolidin-4-yl) -2-fluorobenzoic acid (150 mg), 1- (3,5-dimethylpyridin-2-yl) described in Preparation Example 12 The title compound (103 mg) was obtained by carrying out the same reaction and treatment as in Production Example 89 using piperazine (215 mg).
MS (ESI) m / z: 440 (M + H) ⁺

Production Example 95 Synthesis of 5-tert-butyl-5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-tert-butyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (120 mg), 1- (3,5-dimethylpyridin-2-yl) piperazine described in Preparation Example 13 125 mg), 1-hydroxybenzotriazole (76 mg), triethylamine (0.121 ml) and chloroform (3 ml) were added with 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (125 mg). And stirred at room temperature for 2 days. The reaction solution was purified by column chromatography (chloroform: methanol) and NH column chromatography (chloroform: methanol) to obtain the title compound (123 mg).
MS (ESI) m / z: 450 (M + H) ⁺

Production Example 96: 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5- (1-methoxy-1-methylethyl) imidazolidine-2, Synthesis of 4-dione

4- [4- (1-Methoxy-1-methylethyl) -2,5-dioxoimidazolidin-4-yl] benzoic acid (99 mg), 1- (3,5-dimethylpyridine, described in Preparation Example 25 2-yl) piperazine hydrochloride (116 mg), 1-hydroxybenzotriazole (60 mg), triethylamine (0.142 ml) and chloroform (3 ml) were mixed with 1-ethyl-3- (3′-dimethylaminopropyl). ) Carbodiimide hydrochloride (97 mg) was added and stirred at room temperature for 3 hours. The reaction solution was purified by column chromatography (chloroform: methanol) and NH column chromatography (chloroform: methanol) to obtain the title compound (133 mg).
MS (ESI) m / z: 466 (M + H) ⁺

Production Example 97 Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-ethoxymethylimidazolidine-2,4-dione

4- (4-Ethoxymethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (150 mg) described in Preparation Example 24 was added to 1- (3,5-dimethylpyridin-2-yl) piperazine. Add hydrochloride (160 mg), 1-hydroxybenzotriazole (87 mg), triethylamine (0.225 ml), chloroform (3 ml), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (155 mg) And stirred at room temperature for 5 hours. The reaction solution was purified by column chromatography (chloroform: methanol) and NH column chromatography (chloroform: methanol) to obtain the title compound (218 mg).
MS (ESI) m / z: 452 (M + H) ⁺

Production Example 98 Synthesis of 5-ethoxymethyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Ethoxymethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (150 mg), 1- (3,5,6-trimethylpyridin-2-yl) piperazine described in Preparation Example 24 (144 mg), 1-hydroxybenzotriazole (87 mg), triethylamine (0.151 ml) and chloroform (3 ml) were mixed with 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (155 mg). The mixture was further stirred at room temperature for 5 hours. The reaction solution was purified by NH column chromatography (chloroform: methanol) and column chromatography (chloroform: methanol) to obtain the title compound (197 mg).
MS (ESI) m / z: 466 (M + H) ⁺

Preparation Example 99: Synthesis of 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-ethoxymethylimidazolidine-2,4-dione

4- (4-Ethoxymethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (150 mg), 1- (5-cyclopropyl-3-methylpyridin-2-yl) as described in Preparation 24 The title compound (207 mg) was obtained by conducting the same reaction and treatment as in Production Example 98 using piperazine (152 mg).
MS (ESI) m / z: 478 (M + H) ⁺

Production Example 100: Synthesis of 5-trifluoromethyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (2,5-dioxo-4-trifluoromethylimidazolidin-4-yl) benzoic acid (150 mg), 1- (3,5,6-trimethylpyridin-2-yl) piperazine described in Preparation Example 10 (128 mg), 1-hydroxybenzotriazole (84 mg), triethylamine (0.145 ml) and chloroform (3 ml) were mixed with 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (150 mg). The mixture was further stirred at room temperature for 18 hours. The reaction solution was purified by column chromatography (chloroform: methanol) and NH column chromatography (chloroform: methanol) to obtain the title compound (72 mg).
MS (ESI) m / z: 476 (M + H) ⁺

Preparation Example 101: 5- {4- [4- (5-Cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-trifluoromethylimidazolidine-2,4-dione Composition

4- (2,5-dioxo-4-trifluoromethylimidazolidin-4-yl) benzoic acid (150 mg), 1- (5-cyclopropyl-3-methylpyridin-2-yl) as described in Preparation Example 10 The title compound (89 mg) was obtained by carrying out the same reaction and treatment as in Production Example 100 using piperazine (136 mg).
MS (ESI) m / z: 488 (M + H) ⁺

Production Example 102: Synthesis of 5-methoxymethyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Methoxymethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (145 mg), 1- (3,5,6-trimethylpyridin-2-yl) piperazine described in Preparation Example 9 (140 mg), 1-hydroxybenzotriazole (92 mg), triethylamine (0.158 ml) and chloroform (3 ml) were mixed with 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (163 mg). In addition, the mixture was stirred at room temperature for 20 hours. The reaction solution was purified by column chromatography (chloroform: methanol) and NH column chromatography (chloroform: methanol) to obtain the title compound (149 mg).
MS (ESI) m / z: 452 (M + H) ⁺

Production Example 103: Synthesis of 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methoxymethylimidazolidine-2,4-dione

4- (4-Methoxymethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (145 mg), 1- (5-cyclopropyl-3-methylpyridin-2-yl) as described in Preparation Example 9 The title compound (148 mg) was obtained by carrying out the same reaction and treatment as in Production Example 102 using piperazine (148 mg).
MS (ESI) m / z: 464 (M + H) ⁺

Production Example 104: Synthesis of 5-cyclopropyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Cyclopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (130 mg), 1- (3,5,6-trimethylpyridin-2-yl) piperazine described in Preparation Example 11 (123 mg), 1-hydroxybenzotriazole (81 mg), triethylamine (0.139 ml) and chloroform (3 ml) were mixed with 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (144 mg). The mixture was further stirred at room temperature for 5 hours. The reaction solution was purified by column chromatography (chloroform: methanol) and NH column chromatography (chloroform: methanol) to obtain the title compound (167 mg).
MS (ESI) m / z: 448 (M + H) ⁺

Production Example 105: Synthesis of 5-cyclopropyl-5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Cyclopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (130 mg), 1- (5-cyclopropyl-3-methylpyridin-2-yl) as described in Preparation Example 11 The title compound (168 mg) was obtained by conducting the same reaction and treatment as in Production Example 104 using piperazine (130 mg).
MS (ESI) m / z: 460 (M + H) ⁺

Production Example 106: Synthesis of 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-phenylimidazolidine-2,4-dione

4- (2,5-Dioxo-4-phenylimidazolidin-4-yl) benzoic acid (150 mg), 1- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine (150 mg) described in Preparation Example 37 121 mg), 1-hydroxybenzotriazole (82 mg), triethylamine (0.155 ml) and chloroform (3 ml) were added with 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (146 mg). And stirred at room temperature for 2 days. The reaction solution was purified by column chromatography (chloroform: methanol) and NH column chromatography (chloroform: methanol) to obtain the title compound (71 mg).
MS (ESI) m / z: 496 (M + H) ⁺

Production Example 107: Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-phenylimidazolidine-2,4-dione

4- (2,5-dioxo-4-phenylimidazolidin-4-yl) benzoic acid (150 mg), 1- (3,5-dimethylpyridin-2-yl) piperazine hydrochloride according to Preparation Example 37 ( 127 mg), 1-hydroxybenzotriazole (82 mg), triethylamine (0.232 ml) and chloroform (3 ml) were added with 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (146 mg). And stirred at room temperature for 2 days. The reaction solution was purified by NH-coated silica gel column chromatography (chloroform: methanol) and silica gel column chromatography (chloroform: methanol) to obtain the title compound (63 mg).
MS (ESI) m / z: 470 (M + H) ⁺

Production Example 108: Synthesis of 5-phenyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (2,5-Dioxo-4-phenylimidazolidin-4-yl) benzoic acid (150 mg), 1- (3,5,6-trimethylpyridin-2-yl) piperazine (114 mg) described in Preparation Example 37 ) Was used for the same reaction and treatment as in Production Example 106 to obtain the title compound (58 mg).
MS (ESI) m / z: 484 (M + H) ⁺

Production Example 109: 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5- (2-methoxy-1,1-dimethylethyl) imidazolidine- Synthesis of 2,4-dione

4- [4- (2-methoxy-1,1-dimethylethyl) -2,5-dioxoimidazolidin-4-yl] benzoic acid (120 mg) described in Preparation Example 38, 1- (3,5- To a mixture of dimethylpyridin-2-yl) piperazine hydrochloride (107 mg), 1-hydroxybenzotriazole (64 mg), triethylamine (0.164 ml) and chloroform (3 ml) was added 1-ethyl-3- (3′-dimethyl). Aminopropyl) carbodiimide hydrochloride (90 mg) was added and stirred at room temperature for 4 days. The reaction solution was purified by NH column chromatography (chloroform: methanol) and column chromatography (chloroform: methanol) to obtain the title compound (153 mg).
MS (ESI) m / z: 480 (M + H) ⁺

Production Example 110: 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5- (2-methoxy-1,1-dimethylethyl) Synthesis of imidazolidine-2,4-dione

4- [4- (2-methoxy-1,1-dimethylethyl) -2,5-dioxoimidazolidin-4-yl] benzoic acid (120 mg), 1- (5-cyclopropyl) described in Preparation Example 38 To a mixture of -3-methylpyridin-2-yl) piperazine (102 mg), 1-hydroxybenzotriazole (64 mg), triethylamine (0.109 ml) and chloroform (3 ml), 1-ethyl-3- (3′-dimethyl) was added. Aminopropyl) carbodiimide hydrochloride (90 mg) was added and stirred at room temperature for 4 days. The reaction solution was purified by NH column chromatography (chloroform: methanol) and column chromatography (chloroform: methanol) to obtain the title compound (162 mg).
MS (ESI) m / z: 506 (M + H) ⁺

Production Example 111: 5- (2-methoxy-1,1-dimethylethyl) -5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazo Synthesis of lysine-2,4-dione

4- [4- (2-methoxy-1,1-dimethylethyl) -2,5-dioxoimidazolidin-4-yl] benzoic acid (120 mg) described in Preparation Example 38, 1- (3,5, The title compound (167 mg) was obtained by carrying out the same reaction and treatment as in Production Example 110 using 6-trimethylpyridin-2-yl) piperazine (97 mg).
MS (ESI) m / z: 494 (M + H) ⁺

Production Example 112: 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5- (1-methoxycyclopropyl) imidazolidine-2,4-dione Synthesis of

4- [4- (1-methoxycyclopropyl) -2,5-dioxoimidazolidin-4-yl] benzoic acid (80 mg) described in Preparation Example 44, 1- (3,5-dimethylpyridine-2- Yl) Piperazine hydrochloride (75 mg), 1-hydroxybenzotriazole (45 mg), triethylamine (58 mg) and chloroform (3 ml) in a mixture of 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (64 mg) was added and stirred at room temperature for 18 hours. The reaction solution was purified by column chromatography and NH column chromatography (chloroform: methanol) to obtain the title compound (92 mg).
MS (ESI) m / z: 464 (M + H) ⁺

Production Example 113: 5-tert-butyl-5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-methoxyphenyl} imidazolidine-2,4-dione Synthesis of

4- (4-tert-butyl-2,5-dioxoimidazolidin-4-yl) -3-methoxybenzoic acid (100 mg), 1- (3,5-dimethylpyridine-2-yl described in Preparation Example 61 Yl) Piperazine hydrochloride (149 mg), 1-hydroxybenzotriazole (90.3 mg), diisopropylethylamine (0.142 ml) and chloroform (3 ml) in a mixture of 1-ethyl-3- (3′-dimethylaminopropyl) ) Carbodiimide hydrochloride (125 mg) was added and stirred at room temperature for 20 hours. The reaction solution was purified by NH column chromatography (chloroform: methanol) and column chromatography (chloroform: methanol) to obtain the title compound (94.6 mg).
MS (ESI) m / z: 480 (M + H) ⁺

Production Example 114: Synthesis of 5- {5- [4- (3,5-dimethylpyridin-2-yl) piperazin-1-carbonyl] thiophen-2-yl} -5-isopropylimidazolidine-2,4-dione

5- (4-Isopropyl-2,5-dioxoimidazolidin-4-yl) thiophene-2-carboxylic acid (50 mg), 1- (3,5-dimethylpyridin-2-yl) according to Preparation Example 66 To a mixture of piperazine hydrochloride (50.9 mg), 1-hydroxybenzotriazole (30 mg), triethylamine (0.052 ml) and chloroform (1.5 ml), 1-ethyl-3- (3′-dimethylaminopropyl) Carbodiimide hydrochloride (50 mg) was added, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Hexane / ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to obtain the title compound (63.5 mg).
MS (ESI) m / z: 442 (M + H) ⁺ , 440 (M−H) ⁻

Production Example 115: Synthesis of 5- {4- [4- (2,4-dimethylphenyl) piperazine-1-carbonyl] -3-fluorophenyl} -5-methylimidazolidine-2,4-dione

To a solution of 1- (2,4-dimethylphenyl) piperazine (114 mg) in N, N-dimethylformamide (4 mL) was added 2-fluoro-4- (4-methyl-2,5-dioxo described in Preparation Example 2. Imidazolidin-4-yl) benzoic acid (126 mg), 1-hydroxybenzotriazole (67 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (170 mg), diisopropylethylamine (0.2 mL) ) And stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH column chromatography (chloroform: methanol) to obtain the title compound (198 mg).
MS (ESI) m / z: 425 (M + H) ⁺

Production Example 116: 5- {4- [4- (3,5-dicyclopropylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} -5-methylimidazolidine-2,4-dione Synthesis of

2-Fluoro-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (126 mg) described in Preparation Example 2 and 1- (3,5-di-acid described in Preparation Example 147. The title compound (183 mg) was obtained by carrying out the same reaction and treatment as in Production Example 115 using cyclopropylpyridin-2-yl) piperazine dihydrochloride (189 mg).
MS (ESI) m / z: 478 (M + H) ⁺

Production Example 117: (R) -5- {3-fluoro-4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methylimidazolidine-2 , 4-dione and (S) -5- {3-fluoro-4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methylimidazolidine- Synthesis of 2,4-dione

2-Fluoro-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (126 mg), 1- (3,5,6-trimethylpyridine-2-yl described in Preparation Example 2 Yl) Piperazine (123 mg) was used for the same reaction and treatment as in Production Example 115 to give 5- {3-fluoro-4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine. -1-Carbonyl] phenyl} -5-methylimidazolidine-2,4-dione (183 mg) was obtained.
5- {3-Fluoro-4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione ( 120 mg) was fractionated on a medium pressure column using CHIRALFLASH (Daicel) IA (hexane / ethanol / diethylamine) to give 52 mg (MS (ESI) m / z: 440 of the compound having a short retention time). (M + H) ⁺ ) and 51 mg of a compound having a long retention time (MS (ESI) m / z: 440 (M + H) ⁺ )) were obtained.
In the analysis with CHIRALPAK (Daicel) IA-3 (4.6 mm × 150 mm, hexane / ethanol / diethylamine = 10/90 / 0.1, flow rate 0.5 mL / min), each holding time was 5.5 minutes. It was 7.7 minutes.

Production Example 118: (R) -5- {4- [4- (5-Ethyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} -5-methylimidazolidine-2 , 4-dione and (S) -5- {4- [4- (5-ethyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} -5-methylimidazolidine- Synthesis of 2,4-dione

2-Fluoro-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (126 mg), 1- (5-ethyl-3-methylpyridine-2-yl) described in Preparation Example 2 Yl) Piperazine (123 mg) was used for the same reaction and treatment as in Production Example 115 to give 5- {4- [4- (5-ethyl-3-methylpyridin-2-yl) piperazine-1-carbonyl. ] -3-Fluorophenyl} -5-methylimidazolidine-2,4-dione (207 mg) was obtained.
5- {4- [4- (5-Ethyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} -5-methylimidazolidine-2,4-dione ( 132 mg) was fractionated on a medium pressure column using CHIRALFLASH (Daicel) IA (hexane / ethanol / diethylamine) to give 38.7 mg (MS (ESI) m / z of the compound having a short retention time). : 440 (M + H) ⁺ ) and a compound having a long retention time 12.7 mg (MS (ESI) m / z: 440 (M + H) ⁺ )).
In the analysis with CHIRALPAK (Daicel) IA-3 (4.6 mm × 150 mm, ethanol / diethylamine = 100 / 0.1, flow rate 0.5 mL / min), the retention times were 6.3 minutes and 12.4 minutes, respectively. Met.

Production Example 119: (R) -5- {4- [4- (5-Cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} -5-methylimidazolidine- 2,4-dione and (S) -5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} -5-methylimidazo Synthesis of lysine-2,4-dione

2-Fluoro-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (126 mg) described in Preparation Example 2, 1- (5-cyclopropyl-3-methylpyridine-2) -Il) Piperazine (130 mg) was used for the same reaction and treatment as in Production Example 115 to give 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1 -Carbonyl] -3-fluorophenyl} -5-methylimidazolidine-2,4-dione (158 mg) was obtained.
5- {4- [4- (5-Cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} -5-methylimidazolidine-2,4-dione obtained (106 mg) was fractionated on a medium pressure column using CHIRALFLASH (Daicel) IA (hexane / ethanol / diethylamine = 10/90 / 0.1) to give both the enantiomers (compound 30. with short retention time). 8mg (MS (ESI) m / z: 452 (M + H) +) and long compound retention time 31.5mg (MS (ESI) m / z: 452 (M + H) +)) was obtained.
In the analysis with CHIRALPAK (Daicel) IA-3 (4.6 mm × 150 mm, ethanol / diethylamine = 100 / 0.1, flow rate 0.5 mL / min), the retention times were 10.4 minutes and 18.3 minutes, respectively. Met.

Production Example 120: Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} -5-isopropylimidazolidine-2,4-dione

To 2-fluoro-4- (4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (83 mg) described in Preparation Example 15 was added 1- (3,5-dimethylpyridin-2-yl. ) Piperazine (68 mg), N, N-dimethylformamide (5 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (80 mg), 1-hydroxybenzotriazole (40 mg), diisopropylethylamine ( 0.08 mL) was added and stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH column chromatography (chloroform: methanol) to obtain the title compound (128 mg).
MS (ESI) m / z: 454 (M + H) ⁺

Production Example 121: 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5- (3,3,3-trifluoropropyl) imidazolidine-2 Of 1,4-dione

4- [2,5-Dioxo-4- (3,3,3-trifluoropropyl) imidazolidin-4-yl] benzoic acid (100 mg) described in Preparation Example 31 was added to 1- (3,5-dimethyl). Pyridin-2-yl) piperazine hydrochloride (86 mg), N, N-dimethylformamide (3 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (90 mg), 1-hydroxybenzo Triazole (43 mg) and diisopropylethylamine (0.13 mL) were added, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH column chromatography (chloroform: methanol) to obtain the title compound (49.3 mg).
MS (ESI) m / z: 490 (M + H) ⁺

Production Example 122: 5- {3-Fluoro-4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione Synthesis of

2-Fluoro-4- (4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (47 mg) described in Preparation Example 15 was added to 1- (3,5,6-trimethylpyridine-2. -Yl) piperazine (42 mg), N, N-dimethylformamide (3 mL), 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (48 mg), 1-hydroxybenzotriazole (22 mg), diisopropyl Ethylamine (0.06 mL) was added and stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH column chromatography (chloroform: methanol) to obtain the title compound (46.6 mg).
MS (ESI) m / z: 468 (M + H) ⁺

Production Example 123: 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} -5-isopropylimidazolidine-2,4- Synthesis of dione

2-Fluoro-4- (4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (51 mg), 1- (5-cyclopropyl-3-methylpyridine-2) described in Preparation Example 15 -Ill) The title compound (51.3 mg) was obtained by carrying out the same reaction and treatment as in Production Example 122 using piperazine (47 mg).
MS (ESI) m / z: 480 (M + H) ⁺

Production Example 124: Synthesis of (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-ethylimidazolidine-2,4-dione

4-((R) -4-ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (250 mg), 1- (3,5-dimethylpyridin-2-yl) described in Preparation Example 14 Piperazine hydrochloride (270 mg), 1-hydroxybenzotriazole (135 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (280 mg), diisopropylethylamine (0.4 mL) were added to N, N -Dissolved in dimethylformamide (10 mL) and stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH column chromatography (chloroform: methanol) to obtain the title compound (367 mg).
MS (ESI) m / z: 422 (M + H) ⁺

Production Example 125: (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-methylphenyl} -5-methylimidazolidine-2,4 -Dione and (S) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-methylphenyl} -5-methylimidazolidine-2,4- Synthesis of dione

To 2-methyl-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (150 mg) described in Preparation Example 8, 1- (3,5-dimethylpyridin-2-yl ) Piperazine (127 mg), 1-hydroxybenzotriazole (98 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (150 mg), chloroform (2 mL), N, N-dimethylformamide (1 mL) ) And stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, and the solvent was distilled off. The obtained residue was purified by column chromatography (chloroform: methanol) to give 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-methylphenyl}. -5-methylimidazolidine-2,4-dione (191 mg) was obtained.
Obtained 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-methylphenyl} -5-methylimidazolidine-2,4-dione (100 mg) Were separated by HPLC using CHIRALPAK (Daicel) IC (ethanol / diethylamine = 100 / 0.1) to give 49 mg (MS (ESI) m / z: 422 of the compound having a short retention time). (M + H) ⁺ )) and 50 mg of a compound having a long retention time (MS (ESI) m / z: 422 (M + H) ⁺ )) were obtained.
In the analysis with CHIRALPAK (Daicel) IC-3 (4.6 mm × 150 mm, ethanol / diethylamine = 100 / 0.1, flow rate 0.5 mL / min), the respective retention times were 7.3 minutes and 11.0. Minutes.

Production Example 126: 5-methyl-5- {3-methyl-4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione Synthesis of

2-methyl-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg) described in Preparation Example 8 was added to 1- (3,5,6-trimethylpyridine-2. -Yl) piperazine (45.5 mg), 1-hydroxybenzotriazole (33 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (50 mg), chloroform (1.5 mL), N, N-dimethylformamide (0.5 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, and the solvent was distilled off. The obtained residue was purified by column chromatography (hexane: ethyl acetate: methanol). The solvent was distilled off, hexane / ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (48.6 mg).
MS (ESI) m / z: 436 (M + H) ⁺

Production example 127: 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -3-methylphenyl} -5-methylimidazolidine-2,4- Synthesis of dione

2-methyl-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg), 1- (5-cyclopropyl-3-methylpyridine-2) described in Preparation Example 8 -Il) The title compound (56.4 mg) was obtained by carrying out the same reaction and treatment as in Production Example 126 using piperazine (48.1 mg).
MS (ESI) m / z: 448 (M + H) ⁺

Production Example 128: 5- {4- [4- (5-Ethyl-3-methyl-pyridin-2-yl) -piperazine-1-carbonyl] -3-methyl-phenyl} -5-methyl-imidazolidine-2 Of 1,4-dione

2-methyl-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg), 1- (5-ethyl-3-methylpyridine-2-yl) described in Preparation Example 8 Yl) Piperazine (45.5 mg) was used for the same reaction and treatment as in Production Example 126 to obtain the title compound (61.7 mg).
MS (ESI) m / z: 436 (M + H) ⁺

Production Example 129: 5- {4- [4- (3,5-dicyclopropylpyridin-2-yl) piperazine-1-carbonyl] -3-methylphenyl} -5-methylimidazolidine-2,4-dione Synthesis of

To 2-methyl-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg) described in Preparation Example 8, 1- (3,5- Dicyclopropylpyridin-2-yl) piperazine dihydrochloride (70 mg), 1-hydroxybenzotriazole (33 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (50 mg), N , N-dimethylformamide (0.5 mL) and triethylamine (59 μL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, and the solvent was distilled off. The obtained residue was purified by column chromatography (hexane: ethyl acetate: methanol). The solvent was distilled off, hexane / ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (45.4 mg).
MS (ESI) m / z: 474 (M + H) ⁺

Production Example 130: Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isobutylimidazolidine-2,4-dione

4- (4-Isobutyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (80 mg) described in Preparation Example 27 was added to 1- (3,5-dimethylpyridin-2-yl) piperazine (61 mg). ), 1-hydroxybenzotriazole (47 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (72 mg), chloroform (2.5 mL), N, N-dimethylformamide (1 mL). The mixture was further stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, and the solvent was distilled off. The obtained residue was purified by column chromatography (hexane: ethyl acetate: methanol). The solvent was distilled off, hexane / ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (94 mg).
MS (ESI) m / z: 450 (M + H) ⁺

Production Example 131: Synthesis of 5-isobutyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Isobutyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (80 mg), 1- (3,5,6-trimethylpyridin-2-yl) piperazine described in Preparation Example 27 ( 89 mg) was used for the same reaction and treatment as in Production Example 130 to obtain the title compound (73 mg).
MS (ESI) m / z: 464 (M + H) ⁺

Production Example 132: Synthesis of 5- {4- [4- (2,4-dimethylphenyl) piperazine-1-carbonyl] phenyl} -5-isobutylimidazolidine-2,4-dione

4- (4-Isobutyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (80 mg) described in Preparation Example 27 was added to 1- (2,4-dimethylphenyl) piperazine (61 mg), 1- Hydroxybenzotriazole (47 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (72 mg) and chloroform (2.5 mL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, and the solvent was distilled off. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (80 mg).
MS (ESI) m / z: 449 (M + H) ⁺

Production Example 133: Synthesis of 5- {4- [4- (5-ethyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isobutylimidazolidine-2,4-dione

4- (4-Isobutyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (80 mg) described in Preparation Example 27 was added to 1- (5-ethyl-3-methylpyridin-2-yl) piperazine. (65 mg), 1-hydroxybenzotriazole (47 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (72 mg), chloroform (2.5 mL), N, N-dimethylformamide (0 0.5 mL) and stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, and the solvent was distilled off. The obtained residue was purified by column chromatography (hexane: ethyl acetate: methanol). The solvent was distilled off, hexane / ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (95.8 mg).
MS (ESI) m / z: 464 (M + H) ⁺

Production Example 134: Synthesis of 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isobutylimidazolidine-2,4-dione

4- (4-Isobutyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (80 mg), 1- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine described in Preparation Example 27 (69 mg) was used for the same reaction and treatment as in Production Example 133, whereby the title compound (101 mg) was obtained.
MS (ESI) m / z: 476 (M + H) ⁺

Production Example 135: Synthesis of 5- {4- [4- (3,5-dicyclopropylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isobutylimidazolidine-2,4-dione

4- (4-Isobutyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (80 mg) described in Preparation Example 27, 1- (3,5-dicyclopropylpyridine- described in Preparation Example 147 The title compound (94.6 mg) was obtained by carrying out the same reaction and treatment as in Production Example 132 using 2-yl) piperazine dihydrochloride (101 mg).
MS (ESI) m / z: 502 (M + H) ⁺

Production Example 136: 5- [4- (3 ′, 5′-dimethyl-2,3,5,6-tetrahydro [1,2 ′] bipyrazinyl-4-carbonyl) phenyl] -5-isopropylimidazolidine-2, Synthesis of 4-dione

4- (4-Isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg) described in Preparation Example 5 was added to 3,5-dimethyl-3,4,5 described in Preparation Example 83. , 6-Tetrahydro-2H- [1,2 '] bipyrazinyl (40 mg), 1-hydroxybenzotriazole (31 mg), 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (48 mg), chloroform (3 mL) and N, N-dimethylformamide (0.5 mL) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, extracted with chloroform, and the solvent was distilled off. The obtained residue was purified by column chromatography (chloroform: methanol). The solvent was distilled off, hexane / ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (46 mg).
MS (ESI) m / z: 437 (M + H) ⁺

Production Example 137: 5-tert-butyl-5- [4- (3 ′, 5′-dimethyl-2,3,5,6-tetrahydro [1,2 ′] bipyrazinyl-4-carbonyl) phenyl] imidazolidine- Synthesis of 2,4-dione

4- (4-tert-butyl-2,5-dioxo-imidazolidin-4-yl) benzoic acid (50 mg) described in Preparation Example 13, 3,5-dimethyl-3,4, described in Preparation Example 83 The title compound (55 mg) was obtained by carrying out the same reaction and treatment as in Production Example 136 using 5,6-tetrahydro-2H- [1,2 '] bipyrazinyl (38 mg).
MS (ESI) m / z: 451 (M + H) ⁺

Production Example 138: 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-methoxy-5-methylphenyl} -5-isopropylimidazolidine-2,4 -Synthesis of dione

4- (4-Isopropyl-2,5-dioxoimidazolidin-4-yl) -5-methoxy-2-methylbenzoic acid (103 mg) described in Preparation Example 57 was added to 1- (3,5-dimethylpyridine. -2-yl) piperazine hydrochloride (84.2 mg), 1-hydroxybenzotriazole (54.5 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (83.8 mg), Tetrahydrofuran (3 mL) and triethylamine (0.056 mL) were added, and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction solution, and the precipitate was collected by filtration. The obtained precipitate was suspended in hexane / ethyl acetate and collected by filtration to obtain the title compound (110.9 mg).
MS (ESI) m / z: 480 (M + H) ⁺

Production Example 139: 5- {4- [4- (3,5-Dimethyl-pyridin-2-yl) -piperazine-1-carbonyl] -2-hydroxy-5-methyl-phenyl} -5-isopropyl-imidazolidine Synthesis of -2,4-dione

To 5-hydroxy-4- (4-isopropyl-2,5-dioxoimidazolidin-4-yl) -2-methylbenzoic acid (11 mg) described in Preparation Example 58, 1- (3,5-dimethylpyridine 2-yl) piperazine hydrochloride (9.4 mg), 1-hydroxybenzotriazole (6.1 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (9.4 mg), Tetrahydrofuran (2 mL) and triethylamine (6.3 μL) were added, and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic solvent was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (13.4 mg). MS (ESI) m / z: 466 (M + H) ⁺

Production Example 140: (R) -5-ethyl-5- {4- [4- (4,5,6-trimethylpyridazin-3-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione Synthesis of

4-((R) -4-ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (24 mg) described in Preparation Example 14 was added to 3,4,5-trimethyl described in Preparation Example 84. -6- (piperazin-1-yl) pyridazine (20 mg), tetrahydrofuran (2 mL), 1-
Hydroxybenzotriazole (16 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (24 mg) and N, N-dimethylformamide (0.5 mL) were added, and the mixture was stirred at room temperature overnight. To the reaction solution was added saturated brine, and the mixture was extracted with ethyl acetate / methanol. The organic solvent was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (25.5 mg).
MS (ESI) m / z: 437 (M + H) ⁺

Production Example 141: (R) -5-isopropyl-5- {4- [4- (4,5,6-trimethylpyridazin-3-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione Synthesis of

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (25.4 mg) described in Preparation Example 45, 3,4,5- described in Preparation Example 84 The same reaction and treatment as in Production Example 140 were carried out using trimethyl-6- (piperazin-1-yl) pyridazine (20 mg) to obtain the title compound (25.1 mg).
MS (ESI) m / z: 451 (M + H) ⁺

Production Example 142: Synthesis of (R) -5-isopropyl-5- {4- [4- (5-methylpyridin-2-yloxy) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg) described in Preparation Example 45 was added to 5-methyl-2- (piperidin-4-yloxy). Add pyridine (36.7 mg), tetrahydrofuran (1.5 mL), 1-hydroxybenzotriazole (31 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (48 mg) and overnight at room temperature. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate / methanol. The organic solvent was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (80.2 mg).
MS (ESI) m / z: 437 (M + H) ⁺

Production Example 143: Synthesis of (R) -5-isopropyl-5- {4- [4- (5-methylpyridin-2-ylamino) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg), (5-methyl-pyridin-2-yl) -piperidine- as described in Preparation Example 45 The title compound (60.4 mg) was obtained by carrying out the same reaction and treatment as in Production Example 142 using 4-yl-amine (36.5 mg).
MS (ESI) m / z: 436 (M + H) ⁺

Production Example 144: Synthesis of (R) -5- {4- [4- (3,5-dimethylpyridin-2-ylamino) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg) described in Preparation Example 45, (3,5-dimethylpyridine- The title compound (84.5 mg) was obtained by carrying out the same reaction and treatment as in Production Example 142 using 2-yl) piperidin-4-ylamine (39 mg).
MS (ESI) m / z: 450 (M + H) ⁺

Production Example 145: Synthesis of (R) -5-isopropyl-5- {4- [4- (4-methylbenzoyl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

Using 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg) and 4- (4-methylbenzoyl) piperidine (39 mg) described in Preparation Example 45 The title compound (46.3 mg) was obtained by carrying out the same reaction and treatment as in Production Example 142.
MS (ESI) m / z: 448 (M + H) ⁺

Production Example 146: (R) -5- {4-[(S) -3- (3,5-dimethylpyridin-2-yloxy) pyrrolidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4 -Synthesis of dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg) described in Preparation Example 45 was added to 3,5-dimethyl-2 described in Preparation Example 86. -((S) -pyrrolidin-3-yloxy) pyridine (37 mg), tetrahydrofuran (1.5 mL), 1-hydroxybenzotriazole (31 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide / hydrochloric acid Salt (48 mg) was added and stirred at room temperature overnight. Water was added to the reaction solution, and the precipitate was collected by filtration. The obtained precipitate was suspended in hexane / ethyl acetate and collected by filtration to obtain the title compound (79.8 mg).
MS (ESI) m / z: 437 (M + H) ⁺

Production Example 147: (R) -5-isopropyl-5- {4- [3- (5-methyl-2,3-dihydropyrrolo [2,3-b] pyridin-1-yl) pyrrolidine-1-carbonyl] Synthesis of phenyl} imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (32.3 mg) described in Preparation Example 45, 5-methyl-1- described in Preparation Example 87 Pyrrolidin-3-yl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine (25 mg), tetrahydrofuran (1.5 mL), 1-hydroxybenzotriazole (20 mg), 1-ethyl-3- ( 3′-Dimethylaminopropyl) carbodiimide hydrochloride (31 mg) was added, and the mixture was stirred at room temperature overnight. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: methanol). The title compound (20.4 mg) was obtained by fractionating the obtained residue by HPLC using XBridge Prep C18 OBD (Waters) (10 mmol / L aqueous ammonium carbonate solution, acetonitrile).
MS (ESI) m / z: 448 (M + H) ⁺

Production Example 148: Synthesis of (R) -5-isopropyl-5- [4- (4-p-tolyloxypiperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg), 4- (4-methylphenoxy) piperidine (36.5 mg) described in Preparation Example 45 Was used for the same reaction and treatment as in Production Example 146 to obtain the title compound (70.7 mg).
MS (ESI) m / z: 436 (M + H) ⁺

Production Example 149: Synthesis of (R) -5-methyl-5- {4- [4- (5-methylpyridin-2-ylamino) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (30 mg), (5-methylpyridin-2-yl) (piperidine-4) described in Preparation Example 6 -Yl) amine (24.5 mg), 1-hydroxybenzotriazole (20.8 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (31.9 mg), tetrahydrofuran (2 mL). The mixture was further stirred at room temperature overnight. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (47.2 mg).
MS (ESI) m / z: 408 (M + H) ⁺

Production Example 150: Synthesis of (R) -5-methyl-5- {4- [4- (4-methylbenzoyl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

Using 4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (30 mg) and 4- (4-methylbenzoyl) piperidine (26 mg) described in Preparation Example 6 The title compound (33.5 mg) was obtained by carrying out the same reaction and treatment as in Production Example 149.
MS (ESI) m / z: 420 (M + H) ⁺

Production Example 151 Synthesis of 5-fluoromethyl-5- {4- [4- (4-methylbenzoyl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Fluoromethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg) described in Preparation Example 63 was added to 4- (4-methylbenzoyl) piperidine (40.3 mg), 1 -Hydroxybenzotriazole (32.1 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (49.4 mg) and tetrahydrofuran (2 mL) were added, and the mixture was stirred at room temperature overnight. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (22.6 mg).
MS (ESI) m / z: 438 (M + H) ⁺

Production Example 152: Synthesis of (R) -5-methyl-5- [4- (4-p-tolyloxypiperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (30 mg), 4- (4-methylphenoxy) piperidine (24.5 mg) described in Preparation Example 6 Was used for the same reaction and treatment as in Production Example 149 to give the title compound (46.9 mg).
MS (ESI) m / z: 408 (M + H) ⁺

Production Example 153: Synthesis of 5-fluoromethyl-5- [4- (4-p-tolyloxypiperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

Using 4- (4-fluoromethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg), 4- (4-methylphenoxy) piperidine (37.9 mg) described in Preparation Example 63 The title compound (79.4 mg) was obtained by carrying out the same reaction and treatment as in Production Example 151.
MS (ESI) m / z: 426 (M + H) ⁺

Production Example 154: Synthesis of 3- {4-[(S) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1-carbonyl] phenyl} -3-ethylpyrrolidine-2,5-dione

4- (3-Ethyl-2,5-dioxopyrrolidin-3-yl) benzoic acid (100 mg) described in Preparation Example 20 was added to (3,5-dimethylpyridin-2-yl) described in Preparation Example 88. -(S) -pyrrolidin-3-ylamine dihydrochloride (106.9 mg), 1-hydroxybenzotriazole (65.6 mg), 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride ( 100.8 mg), tetrahydrofuran (4.5 mL), and triethylamine (0.118 mL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: methanol). The solvent was distilled off, and the obtained residue was fractionated by HPLC using Capcellpak C18 UG80 (0.05% trifluoroacetic acid / water, 0.05% trifluoroacetic acid / acetonitrile) to give the title compound (110 0.5 mg) was obtained.
MS (ESI) m / z: 421 (M + H) ⁺

Production Example 155: (R) -5-isopropyl-5- {4-[(S) -3- (5-methylpyridin-2-ylamino) pyrrolidine-1-carbonyl] phenyl} imidazolidine-2,4-dione Synthesis of

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (30 mg) described in Preparation Example 45 was added to (5-methylpyridin-2-yl)-(S ) -Pyrrolidin-3-ylamine (20.3 mg), 1-hydroxybenzotriazole (18.5 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (28.5 mg), tetrahydrofuran ( 2.5 mL) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (46.2 mg).
MS (ESI) m / z: 422 (M + H) ⁺

Production Example 156: (R) -5-fluoromethyl-5- {4- [4- (5-methylpyridin-2-yloxy) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione and (S ) -5-Fluoromethyl-5- {4- [4- (5-methylpyridin-2-yloxy) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Fluoromethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (100 mg), 5-methyl-2- (piperidin-4-yloxy) pyridine (76. 2 mg) was used for the same reaction and treatment as in Production Example 151 to give 5-fluoromethyl-5- {4- [4- (5-methylpyridin-2-yloxy) piperidine-1-carbonyl] phenyl} Imidazolidine-2,4-dione (170 mg) was obtained.
The resulting 5-fluoromethyl-5- {4- [4- (5-methyl-pyridin-2-yloxy) -piperidine-1-carbonyl] -phenyl} -imidazolidine-2,4-dione (170 mg) was By fractionating by HPLC using CHIRALPAK (Daicel) IF (hexane / ethanol / tetrahydrofuran / diethylamine), 77.4 mg of the title enantiomer (compound with a short retention time, 77.4 mg (MS (ESI) m / z: 427 ( M + H) ⁺ ) and 74.7 mg (MS (ESI) m / z: 427 (M + H) ⁺ )) of a compound having a long retention time were obtained.
CHIRALPAK (Daicel) IF-3 (4.6 mm × 150 mm, hexane / ethanol / tetrahydrofuran / diethylamine = 50/30/20 / 0.1, flow rate 0.5
In the analysis at mL / min), the retention times were 8.8 minutes and 10.9 minutes, respectively.

Production Example 157: (R) -5-isopropyl-5- {4- [4- (5-methylpyrrolo [2,3-b] pyridin-1-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2, Synthesis of 4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg) described in Preparation Example 45 was added to 5-methyl-1-piperidine described in Preparation Example 89. -4-yl-1H-indole (41 mg), 1-hydroxybenzotriazole (31 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (48 mg), tetrahydrofuran (2 mL) were added, Stir at room temperature overnight. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol). The title compound (65.1 mg) was obtained by fractionating the residue obtained by HPLC using XBridge Prep C18 OBD (Waters) (10 mmol / L ammonium carbonate aqueous solution, acetonitrile).
MS (ESI) m / z: 460 (M + H) ⁺

Production Example 158: (R) -5-isopropyl-5- {4-[(S) -3- (5-methyl-2,3-dihydropyrrolo [2,3-b] pyridin-1-yl) pyrrolidine- Synthesis of 1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg) described in Preparation Example 45, 5-methyl-1- (S ) -Pyrrolidin-3-yl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine (39m
Using g), the title compound (63.4 mg) was obtained by carrying out the same reaction and treatment as in Production Example 157.
MS (ESI) m / z: 448 (M + H) ⁺

Production Example 159: (R) -5-isopropyl-5- {4-[(S) -3- (5-methylpyrrolo [2,3-b] pyridin-1-yl) pyrrolidine-1-carbonyl] phenyl} imidazo Synthesis of lysine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg) described in Preparation Example 45, 5-methyl-1- (S ) -Pyrrolidin-3-yl-1H-pyrrolo [2,3-b] pyridine (38 mg) was used for the same reaction and treatment as in Production Example 157 to obtain the title compound (72.3 mg).
MS (ESI) m / z: 446 (M + H) ⁺

Production Example 160: (R) -5-methyl-5- {4-[(S) -3- (5-methyl-2,3-dihydropyrrolo [2,3-b] pyridin-1-yl) pyrrolidine- Synthesis of 1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg) described in Preparation Example 6 was added to 5-methyl-1- ( S) -Pyrrolidin-3-yl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine (43 mg), tetrahydrofuran (2 mL), 1-hydroxybenzotriazole (35 mg), 1-ethyl-3- (3′-Dimethylaminopropyl) carbodiimide hydrochloride (53 mg) and triethylamine (0.06 mL) were added, and the mixture was stirred at room temperature for 1.5 hours. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol). The title compound (39.6 mg) was obtained by fractionating the obtained residue by HPLC using XBridge Prep C18 OBD (Waters) (10 mmol / L aqueous ammonium carbonate solution, acetonitrile).
MS (ESI) m / z: 420 (M + H) ⁺

Production Example 161: (R) -5- (4- {4- [5- (4-fluorophenyl)-[1,3,4] oxadiazol-2-yl] piperidine-1-carbonyl} phenyl)- Synthesis of 5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (70 mg), 2- (4-fluorophenyl) -5- (piperidine-) described in Preparation Example 45 4-yl) -1,3,4-oxadiazole (79 mg), 1-hydroxybenzotriazole (54 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (79 mg) , N-dimethylformamide (2 mL) and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (95 mg).
MS (APCI) m / z: 492 (M + H) ⁺

Production Example 162: (R) -5- (4- {4- [5- (2,4-dimethylphenyl)-[1,3,4] oxadiazol-2-yl] piperidine-1-carbonyl} phenyl ) -5 Synthesis of methylimidazolidine-2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (80 mg) described in Preparation Example 6 and 4- [5- (2, 4-Dimethylphenyl)-[1,3,4] oxadiazol-2-yl] piperidine hydrochloride (131 mg), 1-hydroxybenzotriazole (69 mg), 1-ethyl-3- (3′-dimethylamino) Propyl) carbodiimide hydrochloride (98 mg) was dissolved in chloroform (3 mL), triethylamine (0.142 mL) was added, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (70 mg).
MS (ESI) m / z: 474 (M + H) ⁺

Production Example 163: (R) -5- (4- {4- [5- (2,4-dimethylphenyl)-[1,3,4] oxadiazol-2-yl] piperidin-1-carbonyl} phenyl ) -5-Ethylimidazolidine-2,4-dione synthesis

4-((R) -4-ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (80 mg) described in Preparation Example 14 and 4- [5- (2, 4-Dimethylphenyl)-[1,3,4] oxadiazol-2-yl] piperidine hydrochloride (123 mg) was used for the same reaction and treatment as in Production Example 162 to give the title compound (104 mg). Got.
MS (ESI) m / z: 488 (M + H) ⁺

Production Example 164: (R) -5-isopropyl-5- (4- {4- [5- (5-methylpyridyl-2-yl) -1H-pyrazol-3-yl] piperidin-1-carbonyl} phenyl) Synthesis of imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (73 mg) described in Preparation Example 45, 5-methyl-2- (5 -Piperidin-4-yl-2H-pyrazol-3-yl) pyridine dihydrochloride (80 mg), 1-hydroxybenzotriazole (51 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide / hydrochloric acid The salt (73 mg) was dissolved in chloroform (3 mL), triethylamine (0.106 mL) was added, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (77 mg).
MS (ESI) m / z: 487 (M + H) ⁺

Production Example 165: 3-ethyl-3- {5- [4- (5-p-tolyl-1H-pyrazol-3-yl) piperidin-1-carbonyl] pyridin-2-yl] pyrrolidine-2,5-dione Synthesis of

6- (3-Ethyl-2,5-dioxopyrrolidin-3-yl) nicotinic acid (64 mg) described in Preparation Example 51, 4- [5- (p-tolyl) -1H- The title compound (61 mg) was obtained by carrying out the same reaction and treatment as in Production Example 164 using pyrazol-3-yl] piperidine (60 mg).
MS (ESI) m / z: 472 (M + H) ⁺

Production Example 166: (R) -5- [4- (3,5-dimethyl-3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-carbonyl ) Synthesis of phenyl] -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (80 mg) described in Preparation Example 45, 3,5-dimethyl-1 ′ described in Preparation Example 81 , 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl dihydrochloride (96 mg), 1-hydroxy-7-azabenzotriazole (62 mg), 1-ethyl- 3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (88 mg) was dissolved in dichloromethane (3 mL), triethylamine (0.127 mL) was added, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (101 mg).
MS (ESI) m / z: 435 (M + H) ⁺

Production Example 167: (R) -5- [4- (3,5-dimethyl-3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-carbonyl ) Synthesis of phenyl] -5-ethylimidazolidine-2,4-dione

4-((R) -4-ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (80 mg) as described in Preparation Example 14, 3,5-dimethyl-1 ′ as described in Preparation Example 81 , 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl dihydrochloride (102 mg) was used to carry out the same reaction and treatment as in Production Example 166 to give the title. Compound (125 mg) was obtained.
MS (ESI) m / z: 421 (M + H) ⁺

Production Example 168: 2,2-dimethylpropionic acid (R) -4- {4- [4- (5,7-dimethylindazol-2-yl) piperidine-1-carbonyl] phenyl} -4-methyl-2, Synthesis of 5-dioxoimidazolidin-1-ylmethyl ester

4-[(R) -1- (2,2-dimethylpropionyloxymethyl) -4-methyl-2,5-dioxoimidazolidin-4-yl] benzoic acid (80 mg), preparation as described in Preparation Example 65 5,7-Dimethyl-2-piperidin-4-yl-2H-indazole hydrochloride (67 mg), 1-hydroxy-7-azabenzotriazole (47 mg), 1-ethyl-3- (3 '-Dimethylaminopropyl) carbodiimide hydrochloride (66 mg) was dissolved in dichloromethane (3 mL), triethylamine (0.096 mL) was added, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (128 mg).
MS (ESI) m / z: 560 (M + H) ⁺

Production Example 169: (R) -5-methyl-5- {4- [4- (2-p-tolyl-2H-tetrazol-5-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4- Synthesis of dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (80 mg) described in Preparation Example 6 and 4- [2- (p- Tolyl) -2H-tetrazol-5-yl] piperidine (100 mg), 1-hydroxy-7-azabenzotriazole (70 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (98 mg) Was dissolved in dichloromethane (3 mL) and stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (147 mg).
MS (ESI) m / z: 460 (M + H) ⁺

Production Example 170: (R) -5-ethyl-5- {4- [4- (2-p-tolyl-2H-tetrazol-5-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4- Synthesis of dione

4-((R) -4-ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (80 mg) described in Preparation Example 14 and 4- [2- (p- (Tryl) -2H-tetrazol-5-yl] piperidine (94 mg) was used for the same reaction and treatment as in Production Example 169 to obtain the title compound (137 mg).
MS (ESI) m / z: 474 (M + H) ⁺

Production Example 171: 3-methoxymethyl-3- {5- [4- (5-p-tolyl-1H-pyrazol-3-yl) piperidin-1-carbonyl] pyridin-2-yl} pyrrolidine-2,5- Synthesis of dione

6- (3-methoxymethyl-2,5-dioxopyrrolidin-3-yl) nicotinic acid (51 mg), 4- [5- (p-tolyl) -1H-pyrazol-3-yl, according to Preparation Example 64 ] Piperidine (42 mg, see Preparation 77), 1-hydroxy-7-azabenzotriazole (36 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (50 mg) in dichloromethane (3 mL) and stirred at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (12 mg).
MS (ESI) m / z: 488 (M + H) ⁺

Production Example 172: (R) -5-methyl-5- {4- [4- (1-p-tolyl-1H- [1,2,3] triazol-4-yl) piperidin-1-carbonyl] phenyl} Synthesis of imidazolidine-2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (80 mg) described in Preparation Example 6 and 4- [1- (p- Tolyl) -1H- [1,2,3] triazol-4-yl] piperidine dihydrochloride (118 mg), 1-hydroxy-7-azabenzotriazole (70 mg), 1-ethyl-3- (3′- Dimethylaminopropyl) carbodiimide hydrochloride (98 mg) was dissolved in dichloromethane (3 mL) and stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (154 mg). MS (ESI) m / z: 459 (M + H) ⁺

Production Example 173: (R) -5-ethyl-5- {4- [4- (1-p-tolyl-1H- [1,2,3] triazol-4-yl) piperidin-1-carbonyl] phenyl} Synthesis of imidazolidine-2,4-dione

4-((R) -4-ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (80 mg) described in Preparation Example 14 and 4- [1- (p- (Tolyl) -1H- [1,2,3] triazol-4-yl] piperidine dihydrochloride (112 mg) was used for the same reaction and treatment as in Production Example 172 to obtain the title compound (149 mg). It was. MS (ESI) m / z: 473 (M + H) ⁺

Production Example 174: (R) -5-methyl-5- {4- [4- (1-p-tolyl-1H-imidazol-4-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4- Synthesis of dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (72 mg) described in Preparation Example 6 and 4- [1- (p- Tolyl) -1H-imidazol-4-yl] piperidine dihydrochloride (80 mg), 1-hydroxy-7-azabenzotriazole (52 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide / hydrochloric acid The salt (73 mg) was dissolved in dichloromethane (3 mL), triethylamine (0.106 mL) was added, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (109 mg).
MS (ESI) m / z: 458 (M + H) ⁺

Production Example 175: (R) -5-ethyl-5- {4- [4- (1-p-tolyl-1H-imidazol-4-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4- Synthesis of dione

4-((R) -4-ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (76 mg) described in Preparation Example 14 and 4- [1- (p- (Tryl) -1H-imidazol-4-yl] piperidine dihydrochloride (80 mg) was used for the same reaction and treatment as in Production Example 174 to obtain the title compound (115 mg).
MS (ESI) m / z: 472 (M + H) ⁺

Production Example 176: (R) -5- [4- (3,5-dimethyl-3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-carbonyl ) Synthesis of phenyl] -5-methylimidazolidine-2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (80 mg) described in Preparation Example 6, 3,5-dimethyl-1 ′ described in Preparation Example 81 , 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl dihydrochloride (108 mg) was used to carry out the same reaction and treatment as in Production Example 166 to give Compound (139 mg) was obtained.
MS (ESI) m / z: 407 (M + H) ⁺

Production Example 177: 5- [4- (3,5-dimethyl-3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-carbonyl) -2- Synthesis of fluorophenyl] -5-ethylimidazolidine-2,4-dione

4- (4-Ethyl-2,5-dioxoimidazolidin-4-yl) -3-fluorobenzoic acid (150 mg) described in Preparation Example 40, 3,5-dimethyl-1 ′ described in Preparation Example 81 , 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl dihydrochloride (178 mg), 1-hydroxy-7-azabenzotriazole (115 mg), 1-ethyl- 3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (162 mg) was dissolved in dichloromethane (3 mL), triethylamine (0.235 mL) was added, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (247 mg).
MS (ESI) m / z: 439 (M + H) ⁺

Production Example 178: 5-ethyl-5- {2-fluoro-4- [4- (1-p-tolyl-1H- [1,2,3] triazol-4-yl) piperidin-1-carbonyl] phenyl} Synthesis of imidazolidine-2,4-dione

4- (4-Ethyl-2,5-dioxoimidazolidin-4-yl) -3-fluorobenzoic acid (150 mg) described in Preparation Example 40, 4- [1- (p- (Tolyl) -1H- [1,2,3] triazol-4-yl] piperidine dihydrochloride (195 mg) was used for the same reaction and treatment as in Production Example 177 to give the title compound (265 mg). It was.
MS (ESI) m / z: 491 (M + H) ⁺

Production Example 179: 3- [5- (3,5-dimethyl-3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-carbonyl) pyridine-2 -Yl] -3-ethylpyrrolidine-2,5-dione synthesis

6- (3-Ethyl-2,5-dioxopyrrolidin-3-yl) nicotinic acid (170 mg) described in Preparation Example 51, 3,5-dimethyl-1 ′, 2 ′, 3 described in Preparation Example 81 The title compound (266 mg) was prepared by carrying out the same reaction and treatment as in Production Example 166 using ', 4', 5 ', 6'-hexahydro- [2,4'] bipyridinyl dihydrochloride (216 mg). Obtained.
MS (ESI) m / z: 421 (M + H) ⁺

Production Example 180: Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-hydroxyphenyl} -5-methylimidazolidine-2,4-dione

2-hydroxy-4- (4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (123 mg) and 1- (3,5-dimethylpyridin-2-yl) described in Preparation Example 48 The title compound (92 mg) was obtained by carrying out the same reaction and treatment as in Production Example 42 using piperazine (113 mg).
MS (ESI) m / z: 424 (M + H) ⁺

Preparation Example 181: 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5- (2-methoxyethyl) imidazolidine-2,4-dione Composition

To a crude product (280 mg) of 4- [4- (2-methoxyethyl) -2,5-dioxoimidazolidin-4-yl] benzoic acid described in Preparation Example 36, 1- (3,5-dimethylpyridine -2-yl) piperazine hydrochloride (145.7 mg), chloroform (8.4 mL), N, N-dimethylformamide (2.8 mL), 1-hydroxybenzotriazole (93.7 mg), 1-ethyl-3 -(3'-dimethylaminopropyl) carbodiimide hydrochloride (143.1 mg) and triethylamine (178.4 μL) were added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (135 mg).
MS (ESI) m / z: 452 (M + H) ⁺

Production Example 182: Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isopropyl-1-methylimidazolidine-2,4-dione

5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isopropyl-3- (4-methoxybenzyl) imidazolidine-2,4-dione ( 260 mg, see Preparation Example 47) in N, N-dimethylformamide (4.7 mL), and under a nitrogen atmosphere, sodium hydride (60% dispersion in liquid paraffin) (23 mg), methyl iodide (35 μL) ) Was added and stirred at room temperature. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The solvent was distilled off and 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isopropyl-3- (4-methoxybenzyl) -1- Methylimidazolidine-2,4-dione (256 mg) was obtained.
5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-
Carbonyl] phenyl} -5-isopropyl-3- (4-methoxybenzyl) -1-methylimidazolidine-2,4-dione (256 mg) was dissolved in 1,2-dichloroethane (4.7 mL), and trifluoromethanesulfone was dissolved. Acid anhydride (366 μL) was added and stirred at 70 ° C. After completion of the reaction, an aqueous sodium hydrogen carbonate solution was added under ice cooling, followed by extraction with chloroform. The solvent was distilled off, hexane was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (67 mg).
MS (ESI) m / z: 450 (M + H) ⁺

Production Example 183: 5- [4- (3,5-Dimethyl-3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-carbonyl) phenyl]- Synthesis of 5-fluoromethylimidazolidine-2,4-dione

4- (4-Fluoromethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (150 mg) described in Preparation Example 63, 3,5-dimethyl-1 ′, 2 ′ described in Preparation Example 81 , 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl dihydrochloride (188 mg) was used for the same reaction and treatment as in Production Example 166 to give the title compound (202 mg )
MS (ESI) m / z: 425 (M + H) ⁺

Production Example 184: 3- [5- (3,5-dimethyl-3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-carbonyl) pyridine-2 -Yl] -3-Isopropylpyrrolidine-2,5-dione synthesis

6- (3-Isopropyl-2,5-dioxopyrrolidin-3-yl) nicotinic acid (90 mg) described in Preparation Example 52, 3,5-dimethyl-1 ′, 2 ′, 3 described in Preparation Example 81 ', 4', 5 ', 6'-Hexahydro- [2,4'] bipyridinyl dihydrochloride (108 mg)
Was used for the same reaction and treatment as in Production Example 166 to give the title compound (149 mg).
MS (ESI) m / z: 435 (M + H) ⁺

Production Example 185: (R) -5- {4- [3- (3,5-dimethylpyridin-2-ylamino) azetidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione / hydrochloric acid Salt synthesis

3- (3,5-Dimethylpyridin-2-ylamino) azetidine-1-carboxylic acid tert-butyl ester (122 mg) described in Preparation Example 92 was dissolved in chloroform (3 mL), and a 4N hydrogen chloride / ethyl acetate solution ( 1.1 mL) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (105 mg) according to Preparation Example 45 was added to the resulting residue. -Hydroxybenzotriazole (65 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (92 mg), N, N-dimethylformamide (4 mL), triethylamine (0.223 mL) were added at room temperature. And stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to give an oil. The obtained oil was dissolved in ethyl acetate, and 4N hydrogen chloride / ethyl acetate solution (0.2 mL) was added. The title compound (90 mg) was obtained by distilling off the solvent.
MS (APCI) m / z: 422 (M + H) ⁺

Production Example 186: Synthesis of (R) -5-isopropyl-5- {4- [4- (5-methylpyridine-2-carbonyl) piperidine-1-carbonyl] phenyl] imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (105 mg) described in Preparation Example 45, (5-methylpyridine-2-yl) described in Preparation Example 93 Yl) piperidin-4-ylmethanone dihydrochloride (122 mg), 1-hydroxybenzotriazole (81 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (115 mg) in tetrahydrofuran (4 mL) And triethylamine (0.233 mL) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (101 mg).
MS (ESI) m / z: 449 (M + H) ⁺

Production Example 187: (R) -5- {4-[(3R, 4R) -3- (3,5-dimethylpyridin-2-ylamino) -4-hydroxypyrrolidine-1-carbonyl] phenyl} -5-isopropyl Synthesis of imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (105 mg) described in Preparation Example 45, (3R, 4R) -4- described in Preparation Example 94 The title compound (85 mg) was obtained by carrying out the same reaction and treatment as in Production Example 186 using (3,5-dimethylpyridin-2-ylamino) pyrrolidin-3-ol · dihydrochloride (134 mg).
MS (ESI) m / z: 452 (M + H) ⁺

Production Example 188: (R) -5-ethyl-5- {4- [4- (5-p-toluyl-1H-pyrazol-3-yl) piperidin-1-carbonyl] phenyl} imidazolidine-2,4- Synthesis of dione

4-((R) -4-ethyl-2,5-dioxoimidazolidine-4 described in Preparation Example 14
-Il) Benzoic acid (75 mg), 4- [5- (p-tolyl) -1H-pyrazol-3-yl] piperidine (101 mg) described in Preparation Example 77, and the same reaction and treatment as in Production Example 186 To give the title compound (34 mg).
MS (ESI) m / z: 472 (M + H) ⁺

Production Example 189: (2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -1- [4-((R) -4-isopropyl-2,5-dioxoimidazolidine-4- Yl) benzoyl] pyrrolidine-2-carboxylic acid methyl ester

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (48.8 mg) described in Preparation Example 45, (2S, 4S)-described in Preparation Example 101 4- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-2-carboxylic acid methyl ester dihydrochloride (60 mg), 1-hydroxybenzotriazole (37.7 mg), 1-ethyl-3- (3 ′ A mixture of -dimethylaminopropyl) carbodiimide hydrochloride (53.5 mg), triethylamine (0.104 mL) and N, N-dimethylformamide (1.2 mL) was stirred at room temperature for 7.5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (73 mg).
MS (APCI) m / z: 494.6 (M + H) ⁺

Production Example 190: (R) -5- {4-[(2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2-hydroxymethylpyrrolidine-1-carbonyl] phenyl} -5 Synthesis of isopropylimidazolidine-2,4-dione

[(2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) pyrrolidin-2-yl] methanol dihydrochloride described in Preparation Example 102 was converted to N, N-dimethylformamide (1.8 mL). N, O-bis (trimethylsilyl) acetamide (76.3 mg) and triethylamine (0.175 mL) were added, and the mixture was stirred at room temperature for 3 hours. In the reaction solution, 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (82 mg), 1-hydroxybenzotriazole (65 mg), 1- Ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (90 mg) was added, and the mixture was stirred at room temperature for 2.5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (63 mg).
MS (APCI) m / z: 466 (M + H) ⁺

Production Example 191: (R) -5- {4-[(2R, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2-methylpyrrolidine-1-carbonyl] phenyl} -5-isopropyl Synthesis of imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (75.4 mg) as described in Preparation Example 45, (3,5-dimethyl as described in Preparation Example 103 The title compound (Pyridin-2-yl) ((3S, 5R) -5-methylpyrrolidin-3-yl) amine dihydrochloride (80 mg) was subjected to the same reaction and treatment as in Production Example 189. 68 mg) was obtained.
MS (APCI) m / z: 450 (M + H) ⁺

Production Example 192: Synthesis of 3- {5- [4- (3,5-dimethylpyridin-2-yl) piperazin-1-carbonyl] pyridin-2-yl} -3-methoxymethylpyrrolidine-2,5-dione

6- (3-methoxymethyl-2,5-dioxopyrrolidin-3-yl) nicotinic acid (83 mg) described in Preparation Example 64 was added to 1- (3,5-dimethylpyridin-2-yl) piperazine (78 .8 mg), N, N-dimethylformamide (5 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (66.3 mg), 1-hydroxybenzotriazole monohydrate (46 0.8 mg) and triethylamine (0.087 mL) were added, and the mixture was stirred at room temperature overnight. The residue obtained by concentrating the reaction solution under reduced pressure was purified by column chromatography (chloroform: methanol) to obtain the title compound (75 mg).
MS (ESI) m / z: 438 (M + H) ⁺

Production Example 193: (R) -5- {4-[(2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2-methylpyrrolidine-1-carbonyl] phenyl} -5-isopropyl Synthesis of imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (75.4 mg) as described in Preparation Example 45, (3,5-dimethyl as described in Preparation Example 104 Pyridin-2-yl) ((3S, 5S) -5-methylpyrrolidin-3-yl) amine dihydrochloride (80 mg) was used for the same reaction and treatment as in Production Example 189 to give the title compound ( 61 mg) was obtained.
MS (APCI) m / z: 450 (M + H) ⁺

Production Example 194: 3- {5-[(S) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidin-1-carbonyl] pyridin-2-yl} -3-methoxymethylpyrrolidine-2,5 -Synthesis of dione

6- (3-methoxymethyl-2,5-dioxopyrrolidin-3-yl) nicotinic acid (200 mg) described in Preparation Example 64, (3,5-dimethylpyridin-2-yl) described in Preparation Example 88 The title compound (268 mg) was obtained by carrying out the same reaction and treatment as in Production Example 189 using ((S) -pyrrolidin-3-yl) amine dihydrochloride (220 mg).
MS (ESI) m / z: 438 (M + H) ⁺

Production Example 195: (2S, 3S) -3- (3,5-dimethylpyridin-2-ylamino) -1- [4-((R) -4-isopropyl-2,5-dioxoimidazolidine-4- Yl) benzoyl] pyrrolidine-2-carboxylic acid methyl ester

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (75.4 mg) described in Preparation Example 45, (2S, 3S)-described in Preparation Example 105 The title compound (36 mg) was prepared by carrying out the same reaction and treatment as in Production Example 189 using 3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-2-carboxylic acid methyl ester · dihydrochloride (80 mg). )
MS (ESI) m / z: 494 (M + H) ⁺

Production Example 196: (R) -5- {4-[(2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2-hydroxymethylpyrrolidine-1-carbonyl] phenyl} -5 Synthesis of methylimidazolidine-2,4-dione

[(2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) pyrrolidin-2-yl] methanol dihydrochloride (100 mg) described in Preparation Example 102 was added to N, N-dimethylformamide (2 mL). ), N, O-bis (trimethylsilyl) acetamide (90 mg) and triethylamine (0.190 mL) were added, and the mixture was stirred at room temperature for 2 hours. In the reaction solution, 4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (96 mg), 1-hydroxybenzotriazole (69 mg), 1- Ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (98 mg) was added, and the mixture was stirred at room temperature overnight. To the reaction solution were added 1N aqueous sodium hydroxide solution and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (58 mg).
MS (APCI) m / z: 438 (M + H) ⁺

Production Example 197: (2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -1- [4-((R) -4-isopropyl-2,5-dioxoimidazolidine-4- Yl) benzoyl] pyrrolidine-2-carboxylic acid amide

To (2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-2-carboxylic acid amide dihydrochloride (64 mg) described in Preparation Example 106, 4- ((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (60 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (60 mg), 1-Hydroxybenzotriazole (42 mg), N, N-dimethylformamide (1.3 mL) and triethylamine (0.12 mL) were added, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (79 mg).
MS (ESI) m / z: 479 (M + H) ⁺

Production Example 198: (2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -1- [4-((R) -4-isopropyl-2,5-dioxoimidazolidine-4- Yl) benzoyl] pyrrolidine-2-carbonitrile

(2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -1- [4-((R) -4-isopropyl-2,5-dioxoimidazolidine-] described in Preparation Example 197 4-yl) benzoyl] pyrrolidine-2-carboxylic acid amide (60 mg) was dissolved in tetrahydrofuran (2.4 mL), and triethylamine (0.055 mL) and trifluoroacetic anhydride (0.035 mL) were added under ice-cooling. The mixture was stirred for 5.5 hours while raising the temperature to room temperature. Trifluoroacetic anhydride (0.035 mL) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (32 mg).
MS (ESI) m / z: 461 (M + H) ⁺

Production Example 199: (R) -5- {4-[(2R, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2-methylpyrrolidin-1-carbonyl] phenyl} -5-methyl Synthesis of imidazolidine-2,4-dione

The (3,5-dimethylpyridin-2-yl) ((3S, 5R) -5-methylpyrrolidin-3-yl) amine dihydrochloride (60 mg) described in Preparation Example 103 was used as described in Preparation Example 6. 4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (61 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (62 mg ), 1-hydroxybenzotriazole (44 mg), chloroform (0.6 mL), tetrahydrofuran (0.6 mL) and triethylamine (0.12 mL) were added, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (42 mg).
MS (ESI) m / z: 422 (M + H) ⁺

Production Example 200: (R) -5- {4-[(2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2-methoxymethylpyrrolidine-1-carbonyl] phenyl} -5 Synthesis of isopropylimidazolidine-2,4-dione

Described in Preparation Example 45 in (3,5-dimethylpyridin-2-yl) ((3S, 5S) -5-methoxymethylpyrrolidin-3-yl) amine dihydrochloride (80 mg) described in Preparation Example 107 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (75 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride ( 75 mg), 1-hydroxybenzotriazole (53 mg), chloroform (1.2 mL), tetrahydrofuran (1.2 mL) and triethylamine (0.145 mL) were added, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (91 mg).
MS (ESI) m / z: 480 (M + H) ⁺

Production Example 201: (R) -5- {4-[(2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2-methoxymethylpyrrolidine-1-carbonyl] phenyl} -5 Synthesis of methylimidazolidine-2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (67 mg) described in Preparation Example 6 and (3,5-dimethylpyridine- 2-yl) ((3S, 5S) -5-methoxymethylpyrrolidin-3-yl) amine dihydrochloride (80 mg) was used for the same reaction and treatment as in Production Example 200 to give the title compound (90 mg )
MS (ESI) m / z: 452 (M + H) ⁺

Production Example 202: (R) -5- {4-[(2S, 4S) -4- (2,4-dimethylphenylamino) -2-hydroxymethylpyrrolidine-1-carbonyl] phenyl} -5-isopropylimidazolidine Synthesis of -2,4-dione

To (2S, 4S) -2- (tert-butyldimethylsilanyloxymethyl) -4- (2,4-dimethylphenylamino) pyrrolidine-1-carboxylic acid tert-butyl ester (220 mg) described in Preparation Example 73 1,4-dioxane (2.2 mL), 4N hydrogen chloride / 1,4-dioxane solution (2.2 mL) was added. The mixture was stirred at room temperature for 2.5 hours and concentrated under reduced pressure. To the obtained residue (60 mg), 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (61 mg), 1-ethyl-3 described in Preparation Example 45 was added. -(3'-dimethylaminopropyl) carbodiimide hydrochloride (67 mg), 1-hydroxybenzotriazole (47 mg), chloroform (0.6 mL), tetrahydrofuran (0.6 mL), triethylamine (0.098 mL) were added, and room temperature was added. And stirred overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (23 mg).
MS (ESI) m / z: 465 (M + H) ⁺

Production Example 203: (R) -5- {4-[(2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2- (1-hydroxy-1-methylethyl) pyrrolidine-1 -Carbonyl) phenyl] -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (49 mg) described in Preparation Example 45, 2-[(2S, 4S) described in Preparation Example 108 By performing the same reaction and treatment as in Production Example 200 using -4- (3,5-dimethylpyridin-2-ylamino) pyrrolidin-2-yl] propan-2-ol dihydrochloride (60 mg), The title compound (60 mg) was obtained.
MS (ESI) m / z: 494 (M + H) ⁺

Production Example 204: 3- {5-[(2R, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2-methylpyrrolidin-1-carbonyl] pyridin-2-yl} -3-methoxy Synthesis of methylpyrrolidine-2,5-dione dihydrochloride

To (3,5-dimethylpyridin-2-yl) ((3S, 5R) -5-methylpyrrolidin-3-yl) amine dihydrochloride (80 mg) described in Preparation Example 103, described in Preparation Example 64 6- (3-Methoxymethyl-2,5-dioxopyrrolidin-3-yl) nicotinic acid (84 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (83 mg), 1- Hydroxybenzotriazole (58 mg), chloroform (1.2 mL), tetrahydrofuran (1.2 mL) and triethylamine (0.16 mL) were added, and the mixture was stirred at room temperature for 8 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol). The solvent was distilled off, the resulting residue was dissolved in ethyl acetate, and a 4N hydrogen chloride / ethyl acetate solution was added. The precipitate was collected by filtration to give the title compound (100 mg).
MS (ESI) m / z: 452 (M + H) ⁺

Production Example 205: Synthesis of (R) -5- {4- [3- (2,4-dimethylbenzyl) pyrrolidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione

3- (2,4-Dimethylbenzyl) pyrrolidine (100 mg) was mixed with chloroform (2 mL), triethylamine (0.295 mL), 4-((R) -4-isopropyl-2,5-di-acid described in Preparation Example 45. Oxoimidazolidin-4-yl) benzoic acid (140 mg), 1
-Ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (150 mg) and 1-hydroxybenzotriazole (107 mg) were added, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (104 mg).
MS (ESI) m / z: 434 (M + H) ⁺

Production Example 206: (R) -5- {4-[(2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) -2- (1-hydroxy-1-methylethyl) pyrrolidine-1 -Carbonyl) phenyl] -5-methylimidazolidine-2,4-dione

Prepared to 2-[(2S, 4S) -4- (3,5-dimethylpyridin-2-ylamino) pyrrolidin-2-yl] propan-2-ol dihydrochloride (80 mg) described in Preparation Example 108. 4-((R) -4-Methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (64 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide described in Example 6 -Hydrochloride (72 mg), 1-hydroxybenzotriazole (50 mg), chloroform (1.6 mL) and triethylamine (0.14 mL) were added, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the obtained residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (78 mg).
MS (ESI) m / z: 466 (M + H) ⁺

Production Example 207: Synthesis of (R) -5- [4- (4-indazol-2-ylpiperidine-1-carbonyl) phenyl] -5-isopropylimidazolidine-2,4-dione

2- (Piperidin-4-yl) -2H-indazole dihydrochloride as described in Preparation Example 67
80 mg), 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (98 mg), 1-ethyl-3- (3′- Dimethylaminopropyl) carbodiimide · hydrochloride (97 mg), 1-hydroxybenzotriazole (70 mg), chloroform (1.6 mL) and triethylamine (190 μL) were added, and the mixture was stirred at room temperature. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution and chloroform were added, and the precipitate was collected by filtration. The obtained precipitate was suspended in ethanol / water and collected by filtration to obtain the title compound (110 mg).
MS (ESI) m / z: 446 (M + H) ⁺

Production Example 208: Synthesis of (R) -5- {4- [4- (5-chloroindazol-2-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (85 mg) described in Preparation Example 45 and 5-chloro-2- (piperidine described in Preparation Example 68 The title compound (105 mg) was obtained by carrying out the same reaction and treatment as in Production Example 207 using -4-yl) -2H-indazole dihydrochloride (80 mg).
MS (ESI) m / z: 480 (M + H) ⁺

Production Example 209: Synthesis of (R) -5- {4- [4- (5-bromoindazol-2-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (73 mg) described in Preparation Example 45 and 5-bromo-2- (piperidine described in Preparation Example 69 The title compound (78 mg) was obtained by carrying out the same reaction and treatment as in Production Example 207 using -4-yl) -2H-indazole dihydrochloride (80 mg).
MS (ESI) m / z: 524 (M + H) ⁺

Production Example 210: Synthesis of (R) -5- {4- [4- (5-bromoindazol-2-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (70 mg) described in Preparation Example 45, 5-methyl-2- (piperidine described in Preparation Example 70 Using the crude product of (-4-yl) -2H-indazole dihydrochloride (60 mg), the same reaction and treatment as in Production Example 207 were carried out to obtain the title compound (65 mg).
MS (ESI) m / z: 460 (M + H) ⁺

Production Example 211: Synthesis of (R) -5-methyl-5- {4- [4- (5-methylindazol-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (61 mg) as described in Preparation Example 6, and 5-methyl-2- (piperidine as described in Preparation Example 70 Using the crude product (60 mg) of -4-yl) -2H-indazole dihydrochloride, the title compound (67 mg) was obtained by carrying out the same reaction and treatment as in Production Example 206.
MS (ESI) m / z: 432 (M + H) ⁺

Production Example 212: (R) -5-isopropyl-5- {4- [4- (2-methylbenzoyl)]
Synthesis of piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (97 mg), (piperidin-4-yl) (o-tolyl) methanone described in Preparation Example 45 ( The title compound (84 mg) was obtained by carrying out the same reaction and treatment as in Production Example 205 using 81 mg).
MS (ESI) m / z: 448 (M + H) ⁺

Production Example 213: (R) -5- (4- {4- [5- (3,5-dichloropyridin-2-yl) [1,3,4] oxadiazol-2-yl] piperidine-1- Carbonyl} phenyl) -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (62 mg) as described in Preparation Example 45, 3,5-dichloro-2-2 as described in Preparation Example 71 The title compound was obtained by carrying out the same reaction and treatment as in Production Example 206 using (5-piperidin-4-yl [1,3,4] oxadiazol-2-yl) pyridine · dihydrochloride (80 mg). (59 mg) was obtained.
MS (ESI) m / z: 543 (M + H) ⁺

Production Example 214: Synthesis of (R) -5-ethyl-5- {4- [4- (5-methylbenzothiazol-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (72 mg) described in Preparation Example 14 was added to 5-methyl-2- (piperidin-4-yl) -1,3-benzothiazole (80 mg), 1-hydroxybenzotriazole (70 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (100 mg), triethylamine (145 μL), chloroform (1 .6 mL) was added and stirred at room temperature. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (91 mg).
MS (ESI) m / z: 463 (M + H) ⁺

Production Example 215: (R) -5-methyl-5- (4- {4- [5- (5-methylpyridin-2-yl) thiazol-2-yl] piperidine-1-carbonyl} phenyl) imidazolidine- Synthesis of 2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (42 mg) described in Preparation Example 6 was added to 5-methyl-2- ( 2-piperidin-4-ylthiazol-5-yl) pyridine hydrochloride (55 mg), 1-hydroxybenzotriazole (34 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (48 mg) ), Triethylamine (70 μL) and chloroform (1.1 mL) were added, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (49 mg).
MS (ESI) m / z: 476 (M + H) ⁺

Production Example 216: (R) -5-ethyl-5- (4- {4- [5- (5-methylpyridin-2-yl) thiazol-2-yl] piperidine-1-carbonyl} phenyl) imidazolidine- Synthesis of 2,4-dione

4-((R) -4-ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (42 mg) as described in Preparation Example 14 and 5-methyl-2- (2 as described in Preparation Example 72 The title compound (46 mg) was obtained by carrying out the same reaction and treatment as in Production Example 215 using -piperidin-4-ylthiazol-5-yl) pyridine hydrochloride (55 mg).
MS (APCI) m / z: 490 (M + H) ⁺

Production Example 217: (R) -5- {3-fluoro-4- [4- (6-methylbenzoxazol-2-yl) piperidine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4- Synthesis of dione

2-Fluoro-4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (93 mg), 6-methyl-2- (piperidine-4) described in Preparation Example 29 The title compound (46 mg) was obtained by carrying out the same reaction and treatment as in Production Example 214 using -yl) -1,3-benzoxazole (80 mg).
MS (ESI) m / z: 451 (M + H) ⁺

Production Example 218: (R) -5-ethyl-5- {4- [4- (5-methyloxazolo [5,4-b] pyridin-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine- Synthesis of 2,4-dione

4-((R) -4-ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (95 mg) as described in Preparation Example 14, 5-methyl-2- (piperidine as described in Preparation Example 144 The title compound (110 mg) was obtained by carrying out the same reaction and treatment as in Production Example 214 using -4-yl) oxazolo [5,4-b] pyridine (81 mg).
MS (ESI) m / z: 448 (M + H) ⁺

Production Example 219: (R) -5-ethyl-5- {4- [4- (6-methylthiazolo [4,5-b] pyridin-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2, Synthesis of 4-dione

4-((R) -4-ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (89 mg) described in Preparation Example 14, 6-methyl-2- (piperidine described in Preparation Example 145 The title compound (59 mg) was obtained by carrying out the same reaction and treatment as in Production Example 214 using a crude product of (-4-yl) thiazolo [4,5-b] pyridine (152 mg).
MS (ESI) m / z: 464 (M + H) ⁺

Production Example 220: (R) -5-isopropyl-5- {4- [4- (6-methylthiazolo [4,5-b] pyridin-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2, Synthesis of 4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (135 mg) described in Preparation Example 45, 6-methyl-2- (piperidine described in Preparation Example 145 Using the crude product of (-4-yl) thiazolo [4,5-b] pyridine (200 mg), the same reaction and treatment as in Production Example 214 were carried out to obtain the title compound (112 mg).
MS (ESI) m / z: 478 (M + H) ⁺

Production Example 221: (R) -5-isopropyl-5- {4- [4- (5-methyloxazolo [5,4-b] pyridin-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine- Synthesis of 2,4-dione

To 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (105 mg) described in Preparation Example 45, 5-methyl-2- ( Piperidin-4-yl) oxazolo [5,4-b] pyridine (80 mg), 1-hydroxybenzotriazole (75 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (105 mg), Triethylamine (155 μL) and chloroform (1.6 mL) were added, and the mixture was stirred at room temperature. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the precipitate was collected by filtration. The obtained precipitate was suspended in ethanol / water and collected by filtration to obtain the title compound (117 mg).
MS (ESI) m / z: 462 (M + H) ⁺

Production Example 222: (R) -5-isopropyl-5- {4- [4- (5-methylthiazolo [5,4-b] pyridin-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2, Synthesis of 4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (115 mg) as described in Preparation Example 45, 5-methyl-2- (piperidine as described in Preparation Example 146 -4-yl) thiazolo [5,4-b] pyridine / trifluoroacetate crude product (500 mg) was used for the same reaction and treatment as in Production Example 221 to obtain the title compound (114 mg). .
MS (ESI) m / z: 478 (M + H) ⁺

Production Example 223: Synthesis of (R) -5-methyl-5- {4- [4- (6-methylbenzothiazol-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (78 mg), 6-methyl-2- (piperidin-4-yl)-described in Preparation Example 6 The title compound (100 mg) was obtained by carrying out the same reaction and treatment as in Production Example 214 using 1,3-benzothiazole hydrochloride (80 mg).
MS (ESI) m / z: 449 (M + H) ⁺

Production Example 224: Synthesis of (R) -5-ethyl-5- {4- [4- (6-methylbenzothiazol-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (81 mg), 6-methyl-2- (piperidin-4-yl)-described in Preparation Example 14 The title compound (107 mg) was obtained by carrying out the same reaction and treatment as in Production Example 214 using 1,3-benzothiazole hydrochloride (80 mg).
MS (ESI) m / z: 463 (M + H) ⁺

Production Example 225: Synthesis of (R) -5-isopropyl-5- {4- [4- (6-methylbenzothiazol-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (105 mg), 6-methyl-2- (piperidin-4-yl)-described in Preparation Example 45 The title compound (103 mg) was obtained by carrying out the same reaction and treatment as in Production Example 221 using 1,3-benzothiazole hydrochloride (80 mg).
MS (ESI) m / z: 477 (M + H) ⁺

Production Example 226: Synthesis of 3-methoxymethyl-3- {5- [4- (6-methylbenzothiazol-2-yl) piperidin-1-carbonyl] pyridin-2-yl} pyrrolidin-2,5-dione

6- (3-methoxymethyl-2,5-dioxopyrrolidin-3-yl) nicotinic acid (87 mg), 6-methyl-2- (piperidin-4-yl) -1,3- described in Preparation Example 64 The title compound (101 mg) was obtained by carrying out the same reaction and treatment as in Production Example 214 using benzothiazole hydrochloride (80 mg).
MS (ESI) m / z: 479 (M + H) ⁺

Production Example 227: (R) -5-isopropyl-5- {4- [4- (5-phenyl [1,3,4] thiadiazol-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2, Synthesis of 4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg) described in Preparation Example 45 was added to 4- (5-phenyl [1,3,3). 4] thiadiazol-2-yl) piperidine hydrochloride (56.4 mg), 1-hydroxybenzotriazole (28.4 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (40. 3 mg) and N, N-dimethylformamide (1 mL) were added, and the mixture was stirred at room temperature overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and water, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (92 mg).
MS (APCI) m / z: 490 (M + H) ⁺

Production Example 228: Synthesis of (R) -5- [4- (4-Benzoxazol-2-ylpiperidine-1-carbonyl) phenyl] -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 2-piperidin-4-ylbenzoxazole (40. The title compound (78 mg) was obtained by carrying out the same reaction and treatment as in Production Example 227 using 5 mg).
MS (APCI) m / z: 447 (M + H) ⁺

Production Example 229: Synthesis of (R) -5-isopropyl-5- {4- [4- (4-methylbenzyl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (100 mg) described in Preparation Example 45 was added 4- (4-methylbenzyl) piperidine (95 mg), 1-hydroxybenzotriazole (51 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (110 mg), triethylamine (0.064 mL), N, N-dimethylformamide (2 mL) were added, Stir at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate / hexane. The organic layer was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (117 mg).
MS (ESI) m / z: 434 (M + H) ⁺

Production Example 230: (R) -5-isopropyl-5- {4- [4- (5-methoxybenzo [d] isoxazol-3-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione Synthesis of

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 5-methoxy-3- (4-piperidyl)-described in Preparation Example 45 The title compound (64 mg) was obtained by carrying out the same reaction and treatment as in Production Example 227 using 1,2-benzisoxazole hydrochloride (28.4 mg).
MS (APCI) m / z: 477 (M + H) ⁺

Production Example 231: Synthesis of (R) -5- {4- [4- (4,6-dimethylbenzofuran-3-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione

To 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg) described in Preparation Example 45, 4- (4,6-dimethylbenzofuran-3 -Yl) piperidine hydrochloride (53.2 mg, see Preparation 142), 1-hydroxybenzotriazole (28.4 mg), 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (40.3 mg) and N, N-dimethylformamide (1 mL) were added, and the mixture was stirred overnight at room temperature. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: ethyl acetate) to obtain the title compound (90 mg).
MS (APCI) m / z: 474 (M + H) ⁺

Production Example 232: Synthesis of (R) -5- {4- [4- (5,6-dimethylbenzofuran-3-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg) described in Preparation Example 45, 4- (5,6-dimethylbenzofuran-3- Yl) Piperidine hydrochloride (53.2 mg, see Preparation Example 140) was used for the same reaction and treatment as Production Example 231 to obtain the title compound (92 mg).
MS (APCI) m / z: 474 (M + H) ⁺

Production Example 233: (R) -5- {4- [4- (5,7-dimethyl-benzofuran-3-yl) -piperidine-1-carbonyl] -phenyl} -5-isopropyl-imidazolidine-2,4 -Synthesis of dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 4- (5,7-dimethyl-benzofuran-3, as described in Preparation Example 45 -The title compound (73 mg) was obtained by carrying out the same reaction and treatment as in Production Example 227 using piperidine hydrochloride (53.2 mg, see Preparation Example 138).
MS (APCI) m / z: 474 (M + H) ⁺

Production Example 234: Synthesis of (R) -5- {4- [4- (6-fluorobenzofuran-3-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 4- (6-fluoro-1-benzofuran-3) described in Preparation Example 45 -The title compound (47 mg) was obtained by carrying out the same reaction and treatment as in Production Example 227 using piperidine (43.9 mg).
MS (APCI) m / z: 464 (M + H) ⁺

Production Example 235: (R) -5- {4- [4- (5-fluorobenzo [d] isoxazol-3-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione Synthesis of

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 5-fluoro-3- (4-piperidinyl)-described in Preparation Example 45 The title compound (60 mg) was obtained by carrying out the same reaction and treatment as in Production Example 227 using 1,2-benzisoxazole (44 mg).
MS (APCI) m / z: 465 (M + H) ⁺

Preparation Example 236: (R) -5- {4- [4- (5-Chlorobenzo [d] isoxazol-3-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione Composition

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 5-chloro-3- (piperidin-4-yl) according to Preparation Example 45 ) The title compound (67 mg) was obtained by carrying out the same reaction and treatment as in Production Example 227 using benzo [d] isoxazole (47.3 mg).
MS (APCI) m / z: 481 (M + H) ⁺

Production Example 237: Synthesis of (R) -5- {4- [4- (5-chlorobenzofuran-3-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione

To 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg) described in Preparation Example 45, 4- (5-chlorobenzofuran-3-yl) was added. ) Piperidine (47.1 mg), 1-hydroxybenzotriazole (28.4 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (40.3 mg), N, N-dimethylformamide ( 1 mL) was added and stirred at room temperature overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (59 mg).
MS (APCI) m / z: 480 (M + H) ⁺

Production Example 238: (R) -5- {4- [4- (6-Fluorobenzo [d] isoxazol-3-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione Synthesis of

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 6-fluoro-3- (4-piperidinyl) described in Preparation Example 45 ) -1,2-Benzisoxazole (44 mg) was used for the same reaction and treatment as in Production Example 227 to obtain the title compound (60 mg).
MS (APCI) m / z: 465 (M + H) ⁺

Production Example 239: Synthesis of (R) -5-isopropyl-5- {4- [4- (5-methylbenzofuran-3-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 4- (5-methyl-1-benzofuran-3) according to Preparation Example 45 -Il) Piperidine (43.1 mg) was used for the same reaction and treatment as in Production Example 237 to obtain the title compound (56 mg).
MS (APCI) m / z: 460 (M + H) ⁺

Production Example 240: Synthesis of (R) -5-isopropyl-5- {4- [4- (6-methylbenzofuran-3-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 4- (6-methylbenzofuran-3-yl) described in Preparation Example 45 The title compound (60 mg) was obtained by carrying out the same reaction and treatment as in Production Example 227 using piperidine hydrochloride (43.1 mg, see Preparation Example 136).
MS (APCI) m / z: 460 (M + H) ⁺

Production Example 241: (R) -5- (4- {4- [5- (4-chlorophenyl) [1,3,4] oxadiazol-2-yl] piperidine-1-carbonyl} phenyl) -5 Synthesis of isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 4- [5- (4-chlorophenyl) -1 as described in Preparation Example 45 , 3,4-oxadiazol-2-yl] piperidine hydrobromide (68.9 mg) was used for the same reaction and treatment as in Production Example 227 to obtain the title compound (9 mg). .
MS (APCI) m / z: 508 (M + H) ⁺

Production Example 242: Synthesis of (R) -5-isopropyl-5- [4- (4-naphthalen-2-ylpiperidine-1-carbonyl) phenyl] imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 4- (2-naphthyl) piperidine hydrochloride as described in Preparation Example 45 ( 49.6 mg) was used for the same reaction and treatment as in Production Example 227 to obtain the title compound (86 mg).
MS (APCI) m / z: 456 (M + H) ⁺

Production Example 243: (R) -5-isopropyl-5- {4- [4- (1-methyl-1H-benzoimidazol-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione Synthesis of

To 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg) described in Preparation Example 45, 1-methyl-2- (piperazine-1- Yl) -1H-benzimidazole dihydrochloride (57.8 mg), 1-hydroxybenzotriazole (28.4 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (40.3 mg) ), N, N-dimethylformamide (1 mL) was added, and the mixture was stirred at room temperature overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (70 mg).
MS (APCI) m / z: 461 (M + H) ⁺

Production Example 244: Synthesis of (R) -5- [4- (4-benzothiazol-2-ylpiperidin-1-carbonyl) phenyl] -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 2- (4-piperidinyl) -1,3- described in Preparation Example 45 The title compound (70 mg) was obtained by carrying out the same reaction and treatment as in Production Example 227 using benzothiazole (43.7 mg).
MS (APCI) m / z: 463 (M + H) ⁺

Production Example 245: Synthesis of (R) -5- {4- [4- (4,6-dimethylbenzofuran-3-yl) piperidine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg) described in Preparation Example 6 was added to 4- (4,6-dimethylbenzofuran-3-yl. ) Piperidine hydrochloride (57 mg, see Preparation 142), 1-hydroxybenzotriazole (29 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (53 mg), triethylamine ( 59 μL) and dichloromethane (2 mL) were added and stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (54 mg).
MS (ESI) m / z: 446 (M + H) ⁺

Production Example 246: Synthesis of (R) -5-methyl-5- {4- [4- (6-methylbenzofuran-3-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg) described in Preparation Example 6 was added to 4- (6-methylbenzofuran-3-yl) piperidine. Hydrochloride salt (46 mg, see Preparation Example 136), 1-hydroxybenzotriazole (29 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (53 mg), triethylamine (0. 03 mL) and dichloromethane (2 mL) were added, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (33 mg).
MS (ESI) m / z: 432 (M + H) ⁺

Preparation Example 247: (R) -5-isopropyl-5- {4- [4- (1-methyl-1H-indazol-4-yl) piperazine-1-carbonyl] phenyl) imidazolidine-2,4-dione Composition

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg) described in Preparation Example 45 was added to 1-methyl-4 described in Preparation Example 143. -Piperazin-1-yl-1H-indazole dihydrochloride (57.8 mg), 1-hydroxybenzotriazole (28 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (40 mg) , Triethylamine (0.056 mL) and N, N-dimethylformamide (1 mL) were added, and the mixture was stirred at room temperature overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium hydrogen carbonate solution, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (85 mg).
MS (APCI) m / z: 461 (M + H) ⁺

Production Example 248: (R) -5- {4- [4- (5-Fluoro-1-methyl-1H-indol-3-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2, Synthesis of 4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 5-fluoro-1-methyl-3-piperidine- described in Preparation Example 45 The title compound (79 mg) was obtained by carrying out the same reaction and treatment as in Production Example 231 using 4-yl-1H-indole (46.5 mg).
MS (APCI) m / z: 477 (M + H) ⁺

Production Example 249: (R) -5- {4- [4- (6-Fluorobenzo [d] isothiazol-3-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4- Synthesis of dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 6-fluoro-3- (piperidin-4-yl) according to Preparation Example 45 ) The title compound (43 mg) was obtained by carrying out the same reaction and treatment as in Production Example 231 using benzo [d] isothiazole (47.3 mg).
MS (APCI) m / z: 481 (M + H) ⁺

Production Example 250: (R) -5- {4- [4- (6-Fluoro-1-methyl-1H-indazol-3-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2, Synthesis of 4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 6-fluoro-1-methyl-3- (piperidine) according to Preparation Example 45 The title compound (72 mg) was obtained by carrying out the same reaction and treatment as in Production Example 243 using -4-yl) -1H-indazole (47.7 mg).
MS (APCI) m / z: 478 (M + H) ⁺

Preparation Example 251: (R) -5- {4- [4- (6-Fluoro-1H-indazol-3-yl) piperidin-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione Composition

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 6-fluoro-3- (piperidin-4-yl) according to Preparation Example 45 ) -1H-indazole (43.9 mg) was used for the same reaction and treatment as in Production Example 243 to obtain the title compound (72 mg).
MS (APCI) m / z: 464 (M + H) ⁺

Preparation Example 252: Synthesis of (R) -5- [4- (4-Benzo [d] isoxazol-3-ylpiperazine-1-carbonyl) phenyl] -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 3-piperazin-1-yl-1,2- according to Preparation Example 45 The title compound (75 mg) was obtained by carrying out the same reaction and treatment as in Production Example 231 using benzisoxazole (40.6 mg).
MS (APCI) m / z: 448 (M + H) ⁺

Production Example 253: (R) -5- {4- [4- (6-Chlorobenzo [d] isothiazol-3-yl) piperazine-1-carbonyl) phenyl] -5-isopropylimidazolidine-2,4-dione Synthesis of

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 6-chloro-3- (piperazin-1-yl) according to Preparation Example 45 ) The title compound (99 mg) was obtained by carrying out the same reaction and treatment as in Production Example 231 using benzo [d] isothiazole (50.8 mg).
MS (APCI) m / z: 498 (M + H) ⁺

Production Example 254: Synthesis of (R) -5-isopropyl-5- {4- [4- (4-phenylthiazol-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

To 4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg) described in Preparation Example 45, 4- (4-phenyl-1,3- Thiazol-2-yl) piperidine (48.9 mg), 1-hydroxybenzotriazole (28.4 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (40.3 mg), N, N-dimethylformamide (1 mL) was added, and the mixture was stirred at room temperature overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH column chromatography (chloroform: methanol) to obtain the title compound (15 mg).
MS (APCI) m / z: 489 (M + H) ⁺

Production Example 255: Synthesis of (R) -5-isopropyl-5- [4- (4-quinolin-2-ylpiperazine-1-carbonyl) phenyl] imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 2- (piperazin-1-yl) quinoline (42 The title compound (74 mg) was obtained by carrying out the same reaction and treatment as in Production Example 227 using .7 mg).
MS (APCI) m / z: 458 (M + H) ⁺

Production Example 256: (R) -5- {4- [4- (6-Chloro-5-methylbenzoxazol-2-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4- Synthesis of dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 6-chloro-5-methyl-2-piperidine- described in Preparation Example 45 The title compound (79 mg) was obtained by carrying out the same reaction and treatment as in Production Example 227 using 4-yl-1,3-benzoxazole (50.1 mg).
MS (APCI) m / z: 495 (M + H) ⁺

Production Example 257: Synthesis of (R) -5-isopropyl-5- {4- [4- (6-methylbenzoxazol-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 6-methyl-2- (piperidin-4-yl) according to Preparation Example 45 ) -1,3-Benzoxazole (43.3 mg) was used for the same reaction and treatment as in Production Example 227 to obtain the title compound (76 mg).
MS (APCI) m / z: 461 (M + H) ⁺

Production Example 258: Synthesis of (R) -5-isopropyl-5- {4- [4- (4-methylbenzoxazol-2-yl) piperidine-1-carbonyl] phenyl} -imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 4-methyl-2-piperidin-4-yl- according to Preparation Example 45 The title compound (79 mg) was obtained by carrying out the same reaction and treatment as in Production Example 231 using 1,3-benzoxazole (43.3 mg).
MS (APCI) m / z: 461 (M + H) ⁺

Production Example 259: Synthesis of (R) -5-isopropyl-5- {4- [4- (5-phenylthiazol-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 4- (5-phenylthiazol-2-yl) described in Preparation Example 45 The title compound (94 mg) was obtained by conducting the same reaction and treatment as in Production Example 227 using piperidine (48.9 mg).
MS (APCI) m / z: 489 (M + H) ⁺

Production Example 260: Synthesis of (R) -5-isopropyl-5- {4- [4- (3-phenylisoxazol-5-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg) described in Preparation Example 45, 4- (3-phenylisoxazole-5- Yl) Piperidine (45.7 mg) was used for the same reaction and treatment as in Production Example 237 to obtain the title compound (39 mg).
MS (APCI) m / z: 473 (M + H) ⁺

Production Example 261: Synthesis of (R) -5- {4- [4- (1H-indol-2-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 2- (piperidin-4-yl) -1H- described in Preparation Example 45 The title compound (74 mg) was obtained by carrying out the same reaction and treatment as in Production Example 237 using indole (40.1 mg).
MS (APCI) m / z: 445 (M + H) ⁺

Preparation Example 262: (R) -5-isopropyl-5- {4- [4- (5-trifluoromethylbenzothiazol-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione Composition

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 2- (piperidin-4-yl) -5- 5 described in Preparation Example 45 The title compound (97 mg) was obtained by carrying out the same reaction and treatment as in Production Example 237 using (trifluoromethyl) -1,3-benzothiazole (57.1 mg).
MS (APCI) m / z: 531 (M + H) ⁺

Production Example 263: Synthesis of (R) -5- {4- [4- (5-chlorobenzooxazol-2-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 5-chloro-2- (piperidin-4-yl) according to Preparation Example 45 ) -1,3-benzoxazole (47.3 mg) was used for the same reaction and treatment as in Production Example 237 to obtain the title compound (77 mg).
MS (APCI) m / z: 481 (M + H) ⁺

Production Example 264: Synthesis of (R) -5-isopropyl-5- {4- [4- (5-methylbenzothiazol-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 5-methyl-2- (piperidin-4-yl) according to Preparation Example 45 ) -1,3-benzothiazole (46.5 mg) was used for the same reaction and treatment as in Production Example 237 to obtain the title compound (84 mg).
MS (APCI) m / z: 477 (M + H) ⁺

Production Example 265: (R) -5- (4- {4- [5- (4-chlorophenyl) -1H-pyrazol-3-yl] piperidine-1-carbonyl} phenyl} -5-isopropylimidazolidine-2, Synthesis of 4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg), 4- [5- (4-chlorophenyl) -1H described in Preparation Example 45 -Pyrazol-3-yl] piperidine (52.4 mg) was used for the same reaction and treatment as in Production Example 243 to obtain the title compound (97 mg).
MS (APCI) m / z: 506 (M + H) ⁺

Production Example 266: Synthesis of (R) -5-isopropyl-5- [4- (4-naphthalen-2-ylpiperazine-1-carbonyl) phenyl] imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.5 mg) described in Preparation Example 45 was added to 1- (naphthalen-2-yl) piperazine. Hydrochloride (52.4 mg), 1-hydroxybenzotriazole (28.4 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (40.3 mg), triethylamine (0.028 mL), N, N-dimethylformamide (1 mL) was added, and the mixture was stirred at room temperature overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (97 mg).
MS (APCI) m / z: 457 (M + H) ⁺

Production Example 267: Synthesis of (R) -5-methyl-5- {4- [4- (6-methylbenzoxazol-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (46.8 mg), 6-methyl-2-piperidin-4-yl- described in Preparation Example 6 The title compound (58 mg) was obtained by carrying out the same reaction and treatment as in Production Example 254 using 1,3-benzoxazole (43.3 mg).
MS (APCI) m / z: 433 (M + H) ⁺

Production Example 268: (R) -5-methyl-5- {4- [4- (5-trifluoromethylbenzothiazol-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione Composition

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (46.8 mg), 2- (piperidin-4-yl) -5- 5 described in Preparation Example 6 The title compound (67 mg) was obtained by carrying out the same reaction and treatment as in Production Example 227 using (trifluoromethyl) -1,3-benzothiazole (57.3 mg).
MS (APCI) m / z: 503 (M + H) ⁺

Production Example 269: (R) -5- (4- {4- [5- (4-chlorophenyl) -1H-pyrazol-3-yl] piperidine-1-carbonyl} phenyl) -5-methylimidazolidine-2, Synthesis of 4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (46.8 mg), 4- [5- (4-chlorophenyl) -1H described in Preparation Example 6 -Pyrazol-3-yl] piperidine (52.4 mg) was used for the same reaction and treatment as in Production Example 227 to obtain the title compound (91 mg).
MS (APCI) m / z: 478 (M + H) ⁺

Production Example 270: (R) -5-isopropyl-5- {4- [4- (1-methyl-1H-benzoimidazol-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione Synthesis of

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (67 mg), 1-methyl-2-piperidin-4-yl-1H- described in Preparation Example 45 To a mixture of benzimidazole dihydrochloride (70 mg), 1-hydroxybenzotriazole (39 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (56 mg) and chloroform (3 mL), triethylamine was added. (0.102 mL) was added, and the mixture was stirred at room temperature for 3.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (71.3 mg).
MS (ESI) m / z: 460 (M + H) ⁺

Production Example 271: Synthesis of (R) -5- {4- [4- (5,7-dimethylindazol-2-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52 mg) as described in Preparation Example 45, 5,7-dimethyl-2-yl as described in Preparation Example 96 Piperidin-4-yl-2H-indazole hydrochloride (50 mg), 1-hydroxybenzotriazole (31 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (43 mg), chloroform (1 mL) ) Was added to the mixture, and the mixture was stirred at room temperature for 3.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (51.2 mg).
MS (ESI) m / z: 474 (M + H) ⁺

Production Example 272: Synthesis of (R) -5- {4- [4- (5,7-dimethylindazol-1-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52 mg) described in Preparation Example 45, 5,7-dimethyl-1-described in Preparation Example 97 The title compound (73.4 mg) was obtained by carrying out the same reaction and treatment as in Production Example 271 using piperidin-4-yl-1H-indazole hydrochloride (50 mg).
MS (ESI) m / z: 474 (M + H) ⁺

Production Example 273: Synthesis of (R) -5- {4- [4- (5,7-dimethylindazol-2-yl) piperidine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (46 mg) as described in Preparation Example 6 and 5,7-dimethyl-2-yl as described in Preparation Example 96 The title compound (43.3 mg) was obtained by carrying out the same reaction and treatment as in Production Example 271 using piperidin-4-yl-2H-indazole hydrochloride (50 mg).
MS (ESI) m / z: 446 (M + H) ⁺

Production Example 274: Synthesis of (R) -5- {4- [4- (5,7-dimethylindazol-1-yl) piperidine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (46 mg) as described in Preparation Example 6, 5,7-dimethyl-1- The title compound (59.3 mg) was obtained by conducting the same reaction and treatment as in Production Example 271 using piperidin-4-yl-1H-indazole hydrochloride (50 mg).
MS (ESI) m / z: 446 (M + H) ⁺

Production Example 275: (R) -5- {4- [4- (4,6-dimethyl-1H-indazol-3-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4- Synthesis of dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (14.4 mg) as described in Preparation 45, 4,6-dimethyl- 3-piperidin-4-yl-1H-indazole (12 mg), 1-hydroxybenzotriazole (8.5 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (12 mg), triethylamine ( A mixture of 0.01 mL) and chloroform (0.2 mL) was stirred at room temperature for 6 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (18.0 mg).
MS (ESI) m / z: 474 (M + H) ⁺

Production Example 276: (R) -5- {4- [4- (4,6-dimethyl-1H-indazol-3-yl) piperidin-1-carbonyl] phenyl} -5-methyl-imidazolidine-2,4 -Synthesis of dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (46 mg) described in Preparation Example 6 and 4,6-dimethyl-3- Mixture of piperidin-4-yl-1H-indazole (50 mg), 1-hydroxybenzotriazole (31 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (43 mg), chloroform (1 mL) Was added with triethylamine (0.029 mL) and stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (72.3 mg).
MS (ESI) m / z: 446 (M + H) ⁺

Production Example 277: (R) -5-isopropyl-5- {4- [4- (1,4,6-trimethyl-1H-indazol-3-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2, Synthesis of 4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.2 mg) as described in Preparation Example 45, 1,4,6- Trimethyl-3-piperidin-4-yl-1H-indazole hydrochloride (60 mg), 1-hydroxybenzotriazole (30.8 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride ( 43.6 mg), triethylamine (0.085 mL), and chloroform (1.2 mL) were stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (50.9 mg).
MS (ESI) m / z: 488 (M + H) ⁺

Production Example 278: (R) -5-methyl-5- {4- [4- (1,4,6-trimethyl-1H-indazol-3-yl) piperidin-1-carbonyl] phenyl} imidazolidine-
Synthesis of 2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (46.7 mg) as described in Preparation Example 6, 1,4,6- The title compound (49 mg) was obtained by carrying out the same reaction and treatment as in Production Example 277 using trimethyl-3-piperidin-4-yl-1H-indazole hydrochloride (60 mg).
MS (ESI) m / z: 460 (M + H) ⁺

Production Example 279: Synthesis of (R) -5- {4- [4- (5-chlorobenzothiazol-2-yl) piperidine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (50 mg), 5-chloro-2-piperidin-4-yl-1, as described in Preparation Example 6. 3-benzothiazole (51 mg), 1-hydroxybenzotriazole (33 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (47 mg), triethylamine (0.037 mL), chloroform (1 mL) The mixture was stirred at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (49.7 mg).
MS (ESI) m / z: 469 (M + H) ⁺

Production Example 280: (R) -5- {4- [4- (4-fluoro-6-methyl-1H-indazol-3-yl) piperidine-1-carbonyl] phenyl} -5-methylimidazolidine-2, Synthesis of 4-dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (28 mg) as described in Preparation Example 6, 4-fluoro-6-methyl- as described in Preparation Example 100 3-piperidin-4-yl-1H-indazole (32 mg), 1-hydroxybenzotriazole (18 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (26 mg), chloroform (1 mL) To the mixture was added triethylamine (0.034 mL), and the mixture was stirred at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (18 mg).
MS (ESI) m / z: 450 (M + H) ⁺

Production Example 281: (R) -5-methyl-5- {4- [4- (5-p-toluyl-1H-pyrazol-3-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4- Synthesis of dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (102 mg) described in Preparation Example 6 and 4- (5-p-tolyl) described in Preparation Example 77. -1H-pyrazol-3-yl) piperidine (96 mg), 1-hydroxybenzotriazole (67 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (96 mg), triethylamine (69 μL), A mixture of chloroform (1 mL) was stirred at room temperature overnight. Saturated sodium hydrogen carbonate aqueous solution and chloroform were added to the reaction solution, followed by decantation. The precipitate was washed with water, ethanol was added, and the resulting ethanol solution was concentrated under reduced pressure. The organic layer of the supernatant liquid was also concentrated under reduced pressure. The obtained residues were combined and purified by column chromatography (chloroform: methanol) to obtain the title compound (125 mg).
MS (ESI) m / z: 458 (M + H) ⁺

Production Example 282: Synthesis of (R) -5- {4- [4- (2,3-dimethylphenyl) piperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxo-imidazolidin-4-yl) benzoic acid (76 mg) described in Preparation Example 45 was added to 1- (2,3-dimethylphenyl) piperazine / hydrochloric acid. Salt (63.5 mg), 1-hydroxybenzotriazole (37.3 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (52.9 mg), triethylamine (39 μL), N, N -Dimethylformamide (1 mL) was added, and it stirred at room temperature for 3 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (94 mg).
MS (APCI) m / z: 435 (M + H) ⁺

Production Example 283: Synthesis of (R) -5- {4- [4- (3,4-dimethylphenyl) piperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxo-imidazolidin-4-yl) benzoic acid (76 mg) described in Preparation Example 45 was added to 1- (3,4-dimethylphenyl) piperazine (53 mg). 3 mg), 1-hydroxybenzotriazole (37.3 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (52.9 mg), N, N-dimethylformamide (1 mL) was added. And stirred at room temperature for 3 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (91 mg).
MS (APCI) m / z: 435 (M + H) ⁺

Production Example 284: Synthesis of (R) -5-isopropyl-5- {4- [4- (3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxo-imidazolidin-4-yl) benzoic acid (76 mg) and 1- (3-methylpyridin-2-yl) piperazine described in Preparation Example 45 ( 49.6 mg) was used for the same reaction and treatment as in Production Example 283 to obtain the title compound (83 mg).
MS (APCI) m / z: 422 (M + H) ⁺

Production Example 285: Synthesis of (R) -5- {4- [4- (2,6-dimethylphenyl) piperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione

4-((R) -4-Isopropyl-2,5-dioxo-imidazolidin-4-yl) benzoic acid (79 mg) and 1- (2,6-dimethylphenyl) piperazine (68. 9 mg) was used for the same reaction and treatment as in Production Example 283 to obtain the title compound (68 mg).
MS (ESI) m / z: 435 (M + H) ⁺

Production Example 286: Synthesis of 5- {4- [4- (2,4-dimethylphenyl) piperazine-1-carbonyl] phenyl} -5-propylimidazolidine-2,4-dione

4- (2,5-Dioxo-4-propylimidazolidin-4-yl) benzoic acid (200 mg) described in Preparation Example 16 was added to 1- (2,4-dimethylphenyl) piperazine (145 mg), 1-ethyl -3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (176 mg), 1-hydroxybenzotriazole monohydrate (103 mg), N, N-dimethylformamide (5 mL), triethylamine (0.213 mL). In addition, the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with chloroform. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (241 mg).
MS (ESI) m / z: 435 (M + H) ⁺

Production Example 287: Synthesis of 5-propyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (2,5-dioxo-4-propylimidazolidin-4-yl) benzoic acid (200 mg), 1- (3,5,6-trimethylpyridin-2-yl) piperazine described in Preparation Example 16 (157 mg) ) Was used for the same reaction and treatment as in Production Example 286 to give the title compound (163 mg).
MS (ESI) m / z: 450 (M + H) ⁺

Production Example 288: Synthesis of 5- {4- [4- (3,5-dicyclopropylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-propylimidazolidine-2,4-dione

4- (2,5-dioxo-4-propylimidazolidin-4-yl) benzoic acid (200 mg) described in Preparation Example 16 was added to 1- (3,5-dicyclopropylpyridine- described in Preparation Example 147. 2-yl) piperazine dihydrochloride (213 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (176 mg), 1-hydroxybenzotriazole monohydrate (103 mg), N , N-dimethylformamide (5 mL) and triethylamine (0.426 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (157 mg).
MS (ESI) m / z: 488 (M + H) ⁺

Production Example 289: Synthesis of 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-propylimidazolidine-2,4-dione

4- (2,5-Dioxo-4-propylimidazolidin-4-yl) benzoic acid (100 mg), 1- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine described in Preparation Example 16 The title compound (132 mg) was obtained by carrying out the same reaction and treatment as in Production Example 286 using 83 mg).
MS (ESI) m / z: 462 (M + H) ⁺

Production Example 290: Synthesis of 5- {4- [4- (5-ethyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-propylimidazolidine-2,4-dione

4- (2,5-Dioxo-4-propylimidazolidin-4-yl) benzoic acid (100 mg), 1- (5-ethyl-3-methylpyridin-2-yl) piperazine (79 mg) described in Preparation Example 16 The title compound (131 mg) was obtained by carrying out the same reaction and treatment as in Production Example 286.
MS (ESI) m / z: 450 (M + H) ⁺

Production Example 291: Synthesis of 3- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -3-methylpyrrolidine-2,5-dione

4- (3-Methyl-2,5-dioxopyrrolidin-3-yl) benzoic acid (209 mg) described in Preparation Example 41 was added to 1- (3,5-dimethylpyridin-2-yl) piperazine (256 mg). , 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (257 mg), 1-hydroxybenzotriazole monohydrate (181 mg), N, N-dimethylformamide (10 mL), triethylamine (0 375 mL) and stirred at room temperature overnight. Water was added to the reaction solution, followed by extraction with chloroform. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (183 mg).
MS (ESI) m / z: 407 (M + H) ⁺

Production Example 292: Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} -5-propylimidazolidine-2,4-dione

4- (2,5-Dioxo-4-propylimidazolidin-4-yl) -2-fluorobenzoic acid (100 mg) described in Preparation Example 17 was added to 1- (3,5-dimethylpyridin-2-yl). Piperazine (68.3 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (82.1 mg), 1-hydroxybenzotriazole monohydrate (48.2 mg), N, N -Dimethylformamide (5 mL) and triethylamine (0.1 mL) were added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (136 mg).
MS (ESI) m / z: 454 (M + H) ⁺

Production Example 293: 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} -5-propylimidazolidine-2,4- Synthesis of dione

4- (2,5-dioxo-4-propylimidazolidin-4-yl) -2-fluorobenzoic acid (100 mg), 1- (5-cyclopropyl-3-methylpyridine-2-yl) described in Preparation Example 17 Yl) Piperazine (77.6 mg) was used for the same reaction and treatment as in Production Example 292 to obtain the title compound (143 mg).
MS (ESI) m / z: 480 (M + H) ⁺

Production Example 294: 5- {3-Fluoro-4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-propylimidazolidine-2,4-dione Synthesis of

4- (2,5-Dioxo-4-propylimidazolidin-4-yl) -2-fluorobenzoic acid (100 mg), 1- (3,5,6-trimethylpyridin-2-yl described in Preparation Example 17 ) The title compound (79 mg) was obtained by carrying out the same reaction and treatment as in Production Example 292 using piperazine (73.3 mg).
MS (ESI) m / z: 468 (M + H) ⁺

Production Example 295: (R) -5-propyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione And (S) -5-propyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

5-propyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione (122 mg, see Preparation Example 287) Are separated by a medium pressure column using CHIRALFLASH (Daicel) IC (hexane / ethanol / diethylamine) to give 28 mg (MS (ESI) m / z: 450 (M + H) ⁺ ) and 32 mg of a compound having a long retention time (MS (ESI) m / z: 450 (M + H) ⁺ )) were obtained.
In the analysis with CHIRALPAK (Daicel) IC-3 (4.6 mm × 150 mm, hexane / ethanol / diethylamine = 10/90 / 0.1, flow rate 0.5 mL / min), each holding time was 7.9 minutes. 13.9 minutes.

Production Example 296: (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-propylimidazolidine-2,4-dione and ( Synthesis of S) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-propylimidazolidine-2,4-dione

4- (2,5-Dioxo-4-propylimidazolidin-4-yl) benzoic acid (400 mg) described in Preparation Example 16 was added to 1- (3,5-dimethylpyridin-2-yl) piperazine (293 mg). , 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (353 mg), 1-hydroxybenzotriazole monohydrate (207 mg), N, N-dimethylformamide (10 mL), triethylamine (0 .43 mL) was added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to give 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1 -Carbonyl] phenyl} -5-propylimidazolidine-2,4-dione (484 mg) was obtained.
The obtained 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-propylimidazolidine-2,4-dione (300 mg) was converted into CHIRALFLASH (Daicel). ) Separation through a medium pressure column using IC (hexane / ethanol / diethylamine) gave the title both enantiomers (149 mg of compound with short retention time (MS (ESI) m / z: 436 (M + H) ⁺ )) and 143 mg (MS (ESI) m / z: 436 (M + H) ⁺ ) of a compound having a long retention time was obtained.
In the analysis with CHIRALPAK (Daicel) IC-3 (4.6 mm × 150 mm, hexane / ethanol / diethylamine = 10/90 / 0.1, flow rate 0.5 mL / min), each holding time was 8.8 minutes. It was 16.6 minutes.

Production Example 297: Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-fluorophenyl} -5-propylimidazolidine-2,4-dione

4- (2,5-Dioxo-4-propylimidazolidin-4-yl) -3-fluorobenzoic acid (120 mg) described in Preparation Example 30 was added to 1- (3,5-dimethylpyridin-2-yl). Piperazine (90 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (90.3 mg), 1-hydroxybenzotriazole monohydrate (63.6 mg), N, N-dimethyl Formamide (5 mL), triethylamine (0.1
2 mL) was added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (166 mg).
MS (ESI) m / z: 454 (M + H) ⁺

Production Example 298: 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -2-fluorophenyl} -5-propylimidazolidine-2,4- Synthesis of dione

4- (2,5-Dioxo-4-propylimidazolidin-4-yl) -3-fluorobenzoic acid (120 mg) described in Preparation Example 30 and 1- (5-cyclopropyl-3-methylpyridine-2- Yl) Piperazine (102 mg) was used for the same reaction and treatment as in Production Example 297 to obtain the title compound (174 mg).
MS (ESI) m / z: 480 (M + H) ⁺

Production Example 299: 5- {2-Fluoro-4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-propylimidazolidine-2,4-dione Synthesis of

4- (2,5-Dioxo-4-propylimidazolidin-4-yl) -3-fluorobenzoic acid (101 mg) described in Preparation Example 30 was added to 1- (3,5,6-trimethylpyridine-2- Yl) piperazine (96.7 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (90 mg), 1-hydroxybenzotriazole monohydrate (63.6 mg), N, N -Dimethylformamide (5 mL) and triethylamine (0.12 mL) were added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (130 mg).
MS (ESI) m / z: 468 (M + H) ⁺

Production Example 300: 5-cyclopropyl-5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} imidazolidine-2,4 -Synthesis of dione

4- (4-Cyclopropyl-2,5-dioxoimidazolidin-4-yl) -2-fluorobenzoic acid (150 mg) described in Preparation Example 34, 1- (5-cyclopropyl-3-methylpyridine- The title compound (207 mg) was obtained by carrying out the same reaction and treatment as in Production Example 297 using 2-yl) piperazine (129 mg).
MS (ESI) m / z: 478 (M + H) ⁺

Production Example 301: 5-cyclopropyl-5- {3-fluoro-4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4- Synthesis of dione

4- (4-Cyclopropyl-2,5-dioxoimidazolidin-4-yl) -2-fluorobenzoic acid (150 mg), 1- (3,5,6-trimethylpyridine-2, as described in Preparation Example 34 -Ill) The title compound (205 mg) was obtained by carrying out the same reaction and treatment as in Production Example 297 using piperazine (122 mg).
MS (ESI) m / z: 466 (M + H) ⁺

Production Example 302: Synthesis of 3- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -3-methylpyrrolidine-2,5-dione

4- (3-methyl-2,5-dioxopyrrolidin-3-yl) benzoic acid (150 mg), 1- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine, as described in Preparation Example 41 The title compound (151 mg) was obtained by carrying out the same reaction and treatment as in Production Example 291 using hydrochloride (245 mg).
MS (ESI) m / z: 433 (M + H) ⁺

Production Example 303: Synthesis of 3-methyl-3- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} pyrrolidine-2,5-dione

4- (3-Methyl-2,5-dioxopyrrolidin-3-yl) benzoic acid (150 mg), 1- (3,5,6-trimethylpyridin-2-yl) piperazine (198 mg) according to Preparation Example 41 ) Was used for the same reaction and treatment as in Production Example 291 to obtain the title compound (134 mg).
MS (ESI) m / z: 421 (M + H) ⁺

Preparation Example 304: 5-cyclopropyl-5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} imidazolidine-2,4-dione Composition

4- (4-Cyclopropyl-2,5-dioxoimidazolidin-4-yl) -2-fluorobenzoic acid (150 mg), 1- (3,5-dimethylpyridin-2-yl, as described in Preparation Example 34 ) The title compound (133 mg) was obtained by carrying out the same reaction and treatment as in Production Example 297 using piperazine (113 mg).
MS (ESI) m / z: 452 (M + H) ⁺

Production Example 305: (R) -5- {4- [4- (5-Cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-propylimidazolidine-2,4- Of dione and (S) -5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-propylimidazolidine-2,4-dione Composition

5- {4- [4- (5-Cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-propylimidazolidine-2,4-dione (90 mg, Preparation Example 289) Fraction) on a medium pressure column using CHIRALFLASH (Daicel) IC (ethanol / hexane / diethylamine) to give 30 mg (MS (ESI) m / z of the compound having a short retention time). : 462 (M + H) ⁺ ) and a compound having a long retention time of 32 mg (MS (ESI) m / z: 462 (M + H) ⁺ )).
In the analysis with CHIRALPAK (Daicel) IC-3 (4.6 mm × 150 mm, ethanol / diethylamine = 100 / 0.1, flow rate 0.5 mL / min), the respective retention times were 8.5 minutes and 15.0 minutes. Met.

Production Example 306: (R) -3- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -3-methylpyrrolidine-2,5-dione and (S ) -3- {4- [4- (3,5-Dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -3-methylpyrrolidine-2,5-dione

3- {4- [4- (3,5-Dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -3-methylpyrrolidine-2,5-dione (168 mg, see Preparation Example 291) Were separated by HPLC (tetrahydrofuran / ethanol / diethylamine) using CHIRALPAK (Daicel) ID to give 79.3 mg (MS (ESI) m / z: 407 (M + H ) ⁺ ) And a compound having a long retention time of 78.6 mg (MS (ESI) m / z: 407 (M + H) ⁺ )).
In the analysis with CHIRALPAK (Daicel) ID-3 (4.6 mm × 150 mm, tetrahydrofuran / ethanol / diethylamine = 20/80 / 0.1, flow rate 0.5 mL / min), each holding time was 7.6 minutes. It was 10.0 minutes.

Production Example 307: Synthesis of 3- {5- [4- (3,5-dimethylpyridin-2-yl) piperazin-1-carbonyl] pyridin-2-yl} -3-methylpyrrolidine-2,5-dione

6- (3-Methyl-2,5-dioxopyrrolidin-3-yl) nicotinic acid (40 mg) described in Preparation Example 50 was added to 1- (3,5-dimethylpyridin-2-yl) piperazine (42. 8 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (36 mg), 1-hydroxybenzotriazole monohydrate (25.4 mg), N, N-dimethylformamide (3 mL) , Triethylamine (0.048 mL) was added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (58 mg).
MS (ESI) m / z: 408 (M + H) ⁺

Production Example 308: Synthesis of 3- {5- [4- (3,5-dimethylpyridin-2-yl) piperazin-1-carbonyl] pyridin-2-yl} -3-isopropylpyrrolidine-2,5-dione

To 6- (3-isopropyl-2,5-dioxopyrrolidin-3-yl) nicotinic acid (52.7 mg) described in Preparation Example 52, 1- (3,5-dimethylpyridin-2-yl) piperazine ( 50.3 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (42.4 mg), 1-hydroxybenzotriazole monohydrate (30 mg), N, N-dimethylformamide ( 3 mL) and triethylamine (0.056 mL) were added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (75 mg).
MS (ESI) m / z: 436 (M + H) ⁺

Production Example 309: 5- [4- (4′-hydroxy-3,5-dimethyl-3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′- Carbonyl) phenyl] -5-isopropylimidazolidine-2,4-dione

4-((R) -4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (52.7 mg) described in Preparation Example 45, 3,5-dimethyl- described in Preparation Example 74 2 ′, 3 ′, 5 ′, 6′-tetrahydro-1′H- [2,4 ′] bipyridinyl-4′-ol dihydrochloride (58.9 mg), 1-hydroxybenzotriazole monohydrate (28.5 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (40.5 mg), triethylamine (0.084 mL) were dissolved in N, N-dimethylformamide (3 mL), Stir at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (74 mg).
MS (ESI) m / z: 451 (M + H) ⁺

Production Example 310: (R) -3- {5- [4- (3,5-dimethylpyridin-2-yl) piperazin-1-carbonyl] pyridin-2-yl} -3-methoxymethylpyrrolidine-2,5 -Dione and (S) -3- {5- [4- (3,5-dimethylpyridin-2-yl) piperazin-1-carbonyl] pyridin-2-yl} -3-methoxymethylpyrrolidine-2,5- Synthesis of dione

3- {5- [4- (3,5-Dimethylpyridin-2-yl) piperazin-1-carbonyl] pyridin-2-yl} -3-methoxymethylpyrrolidine-2,5-dione (397 mg, Production Example 192) Were separated by HPLC using CHIRALPAK (Daicel) IA (2-propanol / tetrahydrofuran / acetic acid) to give 186 mg (MS (ESI) m / MS) of the title enantiomer (compound with a short retention time). z: 438 (M + H) ⁺ ) and 188 mg (MS (ESI) m / z: 438 (M + H) ⁺ )) having a long retention time were obtained.
In the analysis with CHIRALPAK (Daicel) IA-3 (4.6 mm × 150 mm, 2-propanol / tetrahydrofuran / acetic acid = 90/10 / 0.5, flow rate 0.5 mL / min), each retention time was 6.6. And 8.5 minutes.

Production Example 311: (R) -3- {5- [4- (3,5-dimethylpyridin-2-yl) piperazin-1-carbonyl] pyridin-2-yl} -3-ethylpyrrolidine-2,5- Of dione and (S) -3- {5- [4- (3,5-dimethylpyridin-2-yl) piperazin-1-carbonyl] pyridin-2-yl} -3-ethylpyrrolidine-2,5-dione Composition

6- (3-Ethyl-2,5-dioxopyrrolidin-3-yl) nicotinic acid (500 mg, see Preparation 51), 1- (3,5-dimethylpyridin-2-yl) piperazine (425 mg) ), 1-hydroxybenzotriazole monohydrate (300 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (425 mg) was dissolved in N, N-dimethylformamide (30 mL). , Triethylamine (0.56 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to give 3- {5- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl. ] Pyridin-2-yl} -3-ethylpyrrolidine-2,5-dione (868 mg) was obtained.
The resulting 3- {5- [4- (3,5-dimethylpyridin-2-yl) piperazin-1-carbonyl] pyridin-2-yl} -3-ethylpyrrolidine-2,5-dione (862 mg) was recovered. By fractionating by HPLC (2-propanol / tetrahydrofuran / diethylamine) using CHIRALPAK (Daicel) IA, both the enantiomers (449 mg (MS (ESI) m / z: 422 (M + H)) ⁺ ) And 446 mg (MS (ESI) m / z: 422 (M + H) ⁺ ) of the compound having a long retention time were obtained.
In the analysis with CHIRALPAK (Daicel) IA-3 (4.6 mm × 50 mm, 2-propanol / tetrahydrofuran / diethylamine = 70/30 / 0.1, flow rate 0.5 mL / min), each holding time was 5.1. And 11.1 minutes.

Production Example 312: Synthesis of 5-butyl-5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

To a solution of 1- (3,5-dimethylpyridin-2-yl) piperazine (48 mg) in N, N-dimethylformamide (0.5 mL), 4- (4-butyl-2,5- Dioxoimidazolidin-4-yl) benzoic acid (69 mg), 1-hydroxybenzotriazole (37 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (53 mg), diisopropylethylamine (0 049 mL) and stirred at room temperature overnight. The reaction solution was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (55 mg).
MS (APCI) m / z: 450 (M + H) ⁺

Production Example 313: Synthesis of 5-butyl-5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

To a solution of 1- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine (54 mg) in N, N-dimethylformamide (0.5 mL) was added 4- (4-butyl-2 described in Preparation Example 7). , 5-Dioxoimidazolidin-4-yl) benzoic acid (69 mg), 1-hydroxybenzotriazole (37 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (53 mg), diisopropyl Ethylamine (0.049 mL) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting residue was purified by column chromatography (hexane: ethyl acetate and chloroform: methanol) to obtain the title compound (73 mg).
MS (ESI) m / z: 476 (M + H) ⁺

Production Example 314: Synthesis of 5-butyl-5- {4- [4- (5-ethyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Butyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (69 mg), 1- (5-ethyl-3-methylpyridin-2-yl) piperazine (69 mg) described in Preparation Example 7 51 mg) was used for the same reaction and treatment as in Production Example 313 to obtain the title compound (77 mg).
MS (ESI) m / z: 464 (M + H) ⁺

Production Example 315: Synthesis of 5-butyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Butyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (69 mg), 1- (3,5,6-trimethylpyridin-2-yl) piperazine described in Preparation Example 7 51 mg) was used for the same reaction and treatment as in Production Example 313 to give the title compound (4
3 mg) was obtained.
MS (ESI) m / z: 464 (M + H) ⁺

Production Example 316: Synthesis of 5-butyl-5- {4- [4- (3,5-dicyclopropylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Butyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (69 mg) described in Preparation Example 7 and 1- (3,5-dicyclopropylpyridine- described in Preparation Example 147 The title compound (67 mg) was obtained by carrying out the same reaction and treatment as in Production Example 313 using 2-yl) piperazine dihydrochloride (79 mg).
MS (ESI) m / z: 502 (M + H) ⁺

Production Example 317: Synthesis of 5-butyl-5- {4- [4- (2,4-dimethylphenyl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Butyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (111 mg) described in Preparation Example 7 was added to 1- (2,4-dimethylphenyl) piperazine (76 mg), N, Add N-dimethylformamide (0.8 mL), 1-hydroxybenzotriazole (59 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (84 mg), diisopropylethylamine (0.077 mL) And stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. Ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to obtain the title compound (93 mg).
MS (ESI) m / z: 449 (M + H) ⁺

Production Example 318: 3- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-
Synthesis of 1-carbonyl] phenyl} -3-ethylpyrrolidine-2,5-dione

4- (3-Ethyl-2,5-dioxopyrrolidin-3-yl) benzoic acid (240 mg) described in Preparation Example 20 was added to N, N-dimethylformamide (2 mL), 1- (3,5-dimethyl). Pyridin-2-yl) piperazine hydrochloride (251 mg), 1-hydroxybenzotriazole (149 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (211 mg), diisopropylethylamine (0. 383 mL) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. Ethanol / water was added to the obtained residue, and the precipitate was collected by filtration to obtain the title compound (229 mg).
MS (ESI) m / z: 419 (M−H) ⁻

Production Example 319: Synthesis of 3- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -3-ethyl-1-methylpyrrolidine-2,5-dione

To 3- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -3-ethylpyrrolidine-2,5-dione (25 mg) described in Preparation Example 318, N, N-dimethylformamide (0.25 mL), potassium carbonate (24 mg), and methyl iodide (8.4 mg) were added, and the mixture was stirred at room temperature for 1.5 hours. Ethyl acetate was added to the reaction solution and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (23 mg).
MS (ESI) m / z: 435 (M + H) ⁺

Production Example 320: 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazin-1-carbonyl] phenyl} -5- (tetrahydropyran-4-yl) imidazolidine-
Synthesis of 2,4-dione

4- [2,5-Dioxo-4- (tetrahydropyran-4-yl) imidazolidin-4-yl] benzoic acid (183 mg) described in Preparation Example 32 was added to N, N-dimethylformamide (1.32 mL). 1- (3,5-dimethylpyridin-2-yl) piperazine hydrochloride (165 mg), 1-hydroxybenzotriazole (99 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (140 mg) and diisopropylethylamine (0.253 mL) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (107 mg).
MS (ESI) m / z: 476 (M−H) ⁻

Production Example 321: Synthesis of 5-cyclobutyl-5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Cyclobutyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (247 mg), 1- (3,5-dimethylpyridin-2-yl) piperazine (251 mg) described in Preparation Example 33 , 1-hydroxybenzotriazole (149 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (211 mg) was dissolved in N, N-dimethylformamide (4.0 mL), and diisopropylethylamine ( 0.383 mL) was added and stirred at room temperature overnight. Water was added to the reaction solution, and the precipitate was collected by filtration. The obtained precipitate was dissolved in ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off. Ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to obtain the title compound (312 mg).
MS (ESI) m / z: 446 (M−H) ⁻

Production Example 322: Synthesis of 5-cyclobutyl-5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Cyclobutyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (247 mg) and 1- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine according to Preparation Example 33 (239 mg) was used for the same reaction and treatment as in Production Example 321 to obtain the title compound (255 mg).
MS (ESI) m / z: 472 (M−H) ⁻

Production Example 323: Synthesis of 5-cyclobutyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Cyclobutyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (247 mg), 1- (3,5,6-trimethylpyridin-2-yl) piperazine described in Preparation Example 33 ( 226 mg) was used for the same reaction and treatment as in Production Example 321 to obtain the title compound (315 mg).
MS (ESI) m / z: 460 (M−H) ⁻

Production Example 324: (R) -3- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -3-ethylpyrrolidine-2,5-dione and (S
) -3- {4- [4- (3,5-Dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -3-ethylpyrrolidine-2,5-dione

3- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -3-ethylpyrrolidine-2,5-dione (169 mg) described in Preparation Example 318 was converted into CHIRALPAK. (Daicel) By fractionation by HPLC using IC (tetrahydrofuran / ethanol / diethylamine), both of the enantiomers (compound having a short retention time: 76 mg (MS (ESI) m / z: 419 (MH) ⁻ ) And 74 mg (MS (ESI) m / z: 419 (M−H) ⁻ ) of a compound having a long retention time.
In the analysis with CHIRALPAK (Daicel) IC-3 (4.6 mm × 150 mm, tetrahydrofuran / ethanol / diethylamine = 15/85 / 0.1, flow rate 0.5 mL / min), each holding time was 7.3 minutes. It was 8.6 minutes.

Production Example 325: 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazin-1-carbonyl] phenyl} -5- (tetrahydropyran-4-yl) imidazolidine-2 Of 1,4-dione

1- (5-Cyclopropyl-3-methylpyridin-2-yl) piperazine (172 mg) was added to N, N-dimethylformamide (3.2 mL), 4- [2,5-dioxo- 4- (Tetrahydropyran-4-yl) imidazolidin-4-yl] benzoic acid (239 mg), 1-hydroxybenzotriazole (107 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (151 mg) and diisopropylethylamine (0.138 mL) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, hexane / ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (186 mg).
MS (ESI) m / z: 502 (M−H) ⁻

Production Example 326: 5- (Tetrahydropyran-4-yl) -5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2, Synthesis of 4-dione

4- [2,5-dioxo-4- (tetrahydropyran-4-yl) imidazolidin-4-yl] benzoic acid (239 mg) described in Preparation Example 32, 1- (3,5,6-trimethylpyridine- The title compound (180 mg) was obtained by carrying out the same reaction and treatment as in Production Example 325 using 2-yl) piperazine (162 mg).
MS (ESI) m / z: 490 (M−H) ⁻

Production Example 327: 5-tert-butyl-5- {5- [4- (3,5-dimethylpyridin-2-yl) piperazin-1-carbonyl] pyridin-2-yl} imidazolidine-2,4-dione Synthesis of

Crude product of 6- (4-tert-butyl-2,5-dioxoimidazolidin-4-yl) nicotinic acid (119 mg, see Preparation 46) and 1- (3,5-dimethylpyridine-2 -Il) The title compound (88 mg) was obtained by carrying out the same reaction and treatment as in Production Example 321 using piperazine (108 mg).
MS (ESI) m / z: 451 (M + H) ⁺

Production Example 328: Synthesis of 5-isopropyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4- (4-Isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (100 mg), 1- (3,5,6-trimethylpyridin-2-yl) piperazine described in Preparation Example 5 86.1 mg), 1-hydroxybenzotriazole (61.8 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (95 mg), chloroform (3 mL), N, N-dimethylformamide ( 1 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (131.5 mg).
MS (ESI) m / z: 450 (M + H) ⁺

Production Example 329: Synthesis of 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione

4- (4-Isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (100 mg), 1- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine described in Preparation Example 5 (91.1 mg) was used for the same reaction and treatment as in Production Example 328 to give the title compound (102.9 mg).
MS (ESI) m / z: 462 (M + H) ⁺

Production Example 330: Synthesis of 3-ethyl-3- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} pyrrolidine-2,4-dione

4- (3-Ethyl-2,5-dioxopyrrolidin-3-yl) benzoic acid (150 mg), 1- (3,5,6-trimethylpyridin-2-yl) piperazine described in Preparation Example 20 (137 mg) ) Was used for the same reaction and treatment as in Production Example 328 to obtain the title compound (106 mg).
MS (ESI) m / z: 435 (M + H) ⁺

Production Example 331: Synthesis of 3- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -3-ethylpyrrolidine-2,4-dione

4- (3-Ethyl-2,5-dioxopyrrolidin-3-yl) benzoic acid (150 mg), 1- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine described in Preparation Example 20 The title compound (101.6 mg) was obtained by carrying out the same reaction and treatment as in Production Example 328 using 145 mg).
MS (ESI) m / z: 447 (M + H) ⁺

Preparation Example 332: 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} -5-methoxymethylimidazolidine-2,4-dione Composition

To 2-fluoro-4- (4-methoxymethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (95 mg) described in Preparation Example 28, 1- (3,5-dimethylpyridin-2- Yl) piperazine hydrochloride (84.3 mg), chloroform (2.8 mL), N, N-dimethylformamide (1 mL), 1-hydroxybenzotriazole (54.6 mg), 1-ethyl-3- (3′- Dimethylaminopropyl) carbodiimide hydrochloride (83.9 mg) and triethylamine (0.103 mL) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (60.3 mg).
MS (ESI) m / z: 456 (M + H) ⁺

Production Example 333: 5- {3-Fluoro-4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methoxymethylimidazolidine-2,4- Synthesis of dione

2-Fluoro-4- (4-methoxymethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (85 mg), 1- (3,5,6-trimethylpyridine-2 described in Preparation Example 28 -Yl) piperazine (68 mg), 1-hydroxybenzotriazole (48.8 mg), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (75.1 mg), chloroform (2.6 mL), A mixture of N, N-dimethylformamide (0.8 mL) was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (75.6 mg).
MS (ESI) m / z: 470 (M + H) ⁺

Production Example 334: 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} -5-methoxymethylimidazolidine-2,4 -Synthesis of dione

2-Fluoro-4- (4-methoxymethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (85 mg), 1- (5-cyclopropyl-3-methylpyridine-, described in Preparation Example 28 The title compound (74.9 mg) was obtained by carrying out the same reaction and treatment as in Production Example 333 using 2-yl) piperazine (72 mg).
MS (ESI) m / z: 482 (M + H) ⁺

Production Example 335: 5-tert-butyl-5- {6- [4- (3,5-dimethylpyridin-2-yl) piperazin-1-carbonyl] pyridin-3-yl} imidazolidine-2,4-dione Synthesis of

5- (4-tert-butyl-2,5-dioxoimidazolidin-4-yl) pyridine-2-carboxylic acid (240 mg) described in Preparation Example 43, 1- (3,5-dimethylpyridine-2- Yl) The title compound (256.7 mg) was obtained by carrying out the same reaction and treatment as in Production Example 332 using piperazine hydrochloride (216.8 mg).
MS (ESI) m / z: 451 (M + H) ⁺

Production Example 336: Synthesis of 3- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -3-isopropylpyrrolidine-2,5-dione

4- (3-Isopropyl-2,5-dioxopyrrolidin-3-yl) benzoic acid (120 mg), 1- (3,5-dimethylpyridin-2-yl) piperazine hydrochloride according to Preparation Example 49 ( The title compound (156 mg) was obtained by carrying out the same reaction and treatment as in Production Example 332 using 112.8 mg).
MS (ESI) m / z: 435 (M + H) ⁺

Production Example 337: Synthesis of 3-isopropyl-3- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} pyrrolidine-2,5-dione

4- (3-Isopropyl-2,5-dioxopyrrolidin-3-yl) benzoic acid (120 mg), 1- (3,5,6-trimethylpyridin-2-yl) piperazine (101) described in Preparation Example 49 The same reaction and treatment as in Production Example 333 were performed to obtain the title compound (140 mg).
MS (ESI) m / z: 449 (M + H) ⁺

Production Example 338: Synthesis of 3- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -3-isopropylpyrrolidine-2,5-dione

4- (3-isopropyl-2,5-dioxopyrrolidin-3-yl) benzoic acid (120 mg), 1- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine, as described in Preparation Example 49 The title compound (146 mg) was obtained by carrying out the same reaction and treatment as in Production Example 332 using hydrochloride (125.6 mg).
MS (ESI) m / z: 461 (M + H) ⁺

Production Example 339: Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-methoxyphenyl} -5-ethylimidazolidine-2,4-dione

4- (4-Ethyl-2,5-dioxoimidazolidin-4-yl) -3-methoxybenzoic acid (220 mg), 1- (3,5-dimethylpyridin-2-yl) according to Preparation Example 53 The title compound (157 mg) was obtained by carrying out the same reaction and treatment as in Production Example 332 using piperazine hydrochloride (198.1 mg).
MS (ESI) m / z: 452 (M + H) ⁺

Production Example 340: Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-methoxyphenyl} -5-propylimidazolidine-2,4-dione

4- (2,5-Dioxo-4-propylimidazolidin-4-yl) -3-methoxybenzoic acid (220 mg), 1- (3,5-dimethylpyridin-2-yl) piperazine described in Preparation Example 54 The title compound (289 mg) was obtained by carrying out the same reaction and treatment as in Production Example 332 using hydrochloride (188.5 mg).
MS (ESI) m / z: 466 (M + H) ⁺

Production Example 341: Preparation of 5-difluoromethyl-5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-methoxyphenyl} imidazolidine-2,4-dione Composition

4- (4-Difluoromethyl-2,5-dioxoimidazolidin-4-yl) -3-methoxybenzoic acid (150 mg), 1- (3,5-dimethylpyridin-2-yl) according to Preparation Example 55 ) The title compound (199 mg) was obtained by carrying out the same reaction and treatment as in Production Example 332 using piperazine hydrochloride (125.2 mg).
MS (ESI) m / z: 474 (M + H) ⁺

Production Example 342: Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -2-ethoxyphenyl} -5-isopropylimidazolidine-2,4-dione

3-Ethoxy-4- (4-isopropyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (180 mg), 1- (3,5-dimethylpyridin-2-yl) described in Preparation Example 56 The title compound (127.3 mg) was obtained by conducting the same reaction and treatment as in Production Example 332 using piperazine hydrochloride (147.2 mg).
MS (ESI) m / z: 480 (M + H) ⁺

Production Example 343: 3- {5- [4- (4,6-Dimethyl-benzofuran-3-yl) piperidin-1-carbonyl] pyridin-2-yl} -3-methoxymethyl-pyrrolidine-2,5-dione Synthesis of

To 6- (3-methoxymethyl-2,5-dioxopyrrolidin-3-yl) nicotinic acid (55 mg) described in Preparation Example 64, 4- (4,6-dimethylbenzofuran-3-yl) piperidine / hydrochloric acid Salt (55 mg, see Preparation 142), 1-hydroxybenzotriazole (28 mg), dichloromethane (2 mL), triethylamine (0.058 mL), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide. Hydrochloric acid salt (52 mg) was added and stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate) to obtain the title compound (77.3 mg).
MS (ESI) m / z: 476 (M + H) ⁺

Production Example 344: (R) -5- {4-[(R) -3- (5,7-dimethylindazol-1-yl) pyrrolidine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4 -Synthesis of dione

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (73 mg) described in Preparation Example 6 was added to 5,7-dimethyl-1 described in Preparation Example 95. -(R) -Pyrrolidin-3-yl-1H-indazole (67 mg), 1-hydroxybenzotriazole (42 mg), dichloromethane (1.4 mL), triethylamine (0.044 mL), 1-ethyl-3- (3 ' -Dimethylaminopropyl) carbodiimide hydrochloride (78 mg) was added and stirred at room temperature. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution and filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (95.5 mg).
MS (ESI) m / z: 432 (M + H) ⁺

Production Example 345: (R) -5-methyl-5- {4- [4- (6-methyl-1H-indol-3-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione Composition

4-((R) -4-methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (56 mg), 6-methyl-3-piperidin-4-yl-1H- described in Preparation Example 6 The same reaction and treatment as in Production Example 344 were performed using indole (52 mg) to obtain the title compound (34 mg).
MS (ESI) m / z: 431 (M + H) ⁺

Production Example 346: Synthesis of (R) -5-methyl-5- {4- [4- (4-p-toluylpyrazol-1-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione

4-((R) -4-Methyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (59.6 mg) described in Preparation Example 6 was added to 4- (4- p-Toluylpyrazol-1-yl) piperidine hydrochloride (71 mg), 1-hydroxybenzotriazole (34 mg), dichloromethane (1.2 mL), triethylamine (89 μL), 1-ethyl-3- (3′-dimethylamino) Propyl) carbodiimide hydrochloride (63 mg) was added and stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform: methanol) to obtain the title compound (71.9 mg).
MS (ESI) m / z: 458 (M + H) ⁺

Production Example 347: Synthesis of (R) -5- {4- [4- (5,7-dimethylindazol-2-yl) piperidine-1-carbonyl] phenyl} -5-ethylimidazolidine-2,4-dione

4-((R) -4-ethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (57.4 mg) as described in Preparation Example 14, 5,7-dimethyl- as described in Preparation Example 96 The title compound (82.6 mg) was obtained by carrying out the same reaction and treatment as in Production Example 346 using 2-piperidin-4-yl-2H-indazole hydrochloride (61 mg) and dichloromethane (2 mL).
MS (ESI) m / z: 460 (M + H) ⁺

Preparation Example 348: (R) -5- {4- [4- (5,7-dimethylindazol-2-yl) piperidine-1-carbonyl] phenyl} -5-fluoromethylimidazolidine-2,4-dione Composition

4- (4-Fluoromethyl-2,5-dioxoimidazolidin-4-yl) benzoic acid (55 mg) described in Preparation Example 63, 5,7-dimethyl-2-piperidine-4 described in Preparation Example 96 The title compound (57.5 mg) was obtained by carrying out the same reaction and treatment as in Production Example 346 using -yl-2H-indazole hydrochloride (58 mg) and dichloromethane (2 mL).
MS (ESI) m / z: 464 (M + H) ⁺

Production Example 349: 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-trifluoromethylphenyl} -5-methylimidazolidine-2,4-dione Synthesis of

4- (4-Methyl-2,5-dioxoimidazolidin-4-yl) -2-trifluoromethylbenzoic acid crude product (150 mg) and 1- (3,5-dimethylpyridine described in Preparation Example 47 The title compound (52 mg) was obtained by carrying out the same reaction and treatment as in Production Example 42 using 2-yl) piperazine (115 mg).
MS (ESI) m / z: 476 (M + H) ⁺

Production Example 350: Acetic acid (R) -4- {4- [4- (5,7-dimethylindazol-2-yl) piperidine-1-carbonyl] phenyl] -4-methyl-2,5-dioxoimidazolidine Synthesis of -1-ylmethyl ester

(R) -5- {4- [4- (5,7-dimethylindazol-2-yl) piperidin-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione (120 mg, Production Example 273) And potassium carbonate (45 mg) was dissolved in N, N-dimethylformamide (2 mL), chloromethyl acetate (31 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then the solvent was distilled off. The obtained residue was purified by column chromatography (ethyl acetate: methanol) to obtain the title compound (39 mg).
MS (ESI) m / z: 518 (M + H) ⁺

Production Example 351: Butyric acid (R) -4- {4- [4- (5,7-dimethylindazol-2-yl) piperidine-1-carbonyl] phenyl} -4-methyl-2,5-dioxoimidazolidine Synthesis of -1-ylmethyl ester

(R) -5- {4- [4- (5,7-dimethylindazol-2-yl) piperidin-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione (120 mg, Production Example 273) The title compound (54 mg) was obtained by carrying out the same reaction and treatment as in Production Example 350 using chloromethyl butyrate (39 mg).
MS (ESI) m / z: 546 (M + H) ⁺

Preparation Example 352: (R) -5-isopropyl-5- {4- [4- (6-methyl-1H-indol-3-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione Composition

4-((R) -4-isopropyl-2,5-dioxo-imidazolidin-4-yl) benzoic acid (53 mg), 6-methyl-3-piperidin-4-yl-1H- described in Preparation Example 45 The title compound (54.5 mg) was obtained by carrying out the same reaction and treatment as in Production Example 344 using indole (43 mg).
MS (ESI) m / z: 459 (M + H) ⁺

Production Example 353: Synthesis of 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isopropyl-3-methylimidazolidine-2,4-dione

5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione (435 mg, Preparation Example 47-1) Potassium carbonate (180 mg), N, N-dimethylformamide (10 mL), and methyl iodide (75 μL) were added to the mixture, and the mixture was stirred at room temperature for 7 hours. After completion of the reaction, water was added and the precipitate was collected by filtration to obtain the title compound (382 mg).
MS (ESI) m / z: 450 (M + H) ⁺

Production Example 354: 5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isopropyl-1,3-dimethylimidazolidine-2,4-dione Synthesis of

5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isopropyl-3-methylimidazolidine-2,4-dione described in Preparation Example 353 (225 mg) was added with N, N-dimethylformamide (5 mL), sodium hydride (60% dispersion in liquid paraffin) (24 mg), and methyl iodide (37 μL) in a nitrogen atmosphere and stirred at room temperature. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The solvent was evaporated under reduced pressure, ethyl acetate / hexane was added to the resulting residue, and the precipitate was collected by filtration to give the title compound (206 mg).
MS (ESI) m / z: 464 (M + H) ⁺

Production Example 355: 2,2-dimethylpropionic acid (R) -4-methyl-2,5-dioxo-4- {4- [4- (5-p-tolyl- [1,3,4]] oxadiazole -2-yl) piperidin-1-carbonyl] phenyl} imidazolidin-1-ylmethyl ester

(R) -5-methyl-5- {4- [4- (5-p-toluyl [1,3,4]] oxadiazol-2-yl) piperidine-1-carbonyl] phenyl described in Preparation Example 76 } Imidazolidine-2,4-dione (80 mg) and chloromethyl 2,2-dimethylpropionate (28 mg) were used for the same reaction and treatment as in Production Example 350 to obtain the title compound (66 mg). .
MS (ESI) m / z: 574 (M + H) ⁺

Test Example 1 Effect of human TNFα-stimulated THP-1 cells on proMMP-9 production 1 × 10 ⁷ THP-1 cells (human monocytic leukemia cell line) in culture medium (10% fetal bovine serum / RPMI1640 medium) / ML and dispensed into 96-well multiplates. This was equilibrated under conditions of 37 ° C./5% CO ₂ , and human TNFα (final concentration 10 ng / mL) and a culture solution in which the test compound was dissolved were added. After incubation for 24 hours under the condition of 37 ° C./5% CO ₂ , the culture solution was centrifuged to collect the culture supernatant, and the following measurements were performed.
Quantification of proMMP-9 in the culture supernatant The proMMP-9 concentration in the collected culture supernatant was quantified using a commercially available measurement reagent (GE Healthcare MMP-9, Human, Biotrak ELISA System).
Calculation of proMMP-9 Inhibition Rate The proMMP-9 inhibition rate of the test compound was determined based on the concentration of proMMP-9 in the culture supernatant induced by stimulation with human TNFα when no test compound was added (only the solvent was added). The proMMP-9 concentration in the culture supernatant when added (solvent only) and unstimulated with human TNFα is Min, and the proMMP-9 concentration in the culture supernatant induced by stimulation with human TNFα when the test compound is added is Test It was calculated by the following formula.
% Inhibition = 100 − ((Test−Min) / (Max−Min) × 100).
Furthermore, the concentration of the test compound that suppresses proMMP-9 production in human TNFα-stimulated THP-1 cells by 50% (IC ₅₀ value) is 5, ₅₀ and 500 nmol / L or 1, 10 and 100 nmol / L of the test compound. The proMMP-9 inhibition rate was calculated from 3 points.

Test Example 2 Effect of THP-1 cells on constitutive proMMP-2 production THP-1 cells (human monocytic leukemia cell line) were cultured in a culture medium (10% fetal bovine serum / RPMI1640 medium) at 1 × 10 ⁷ cells / Prepared in mL and dispensed into 96-well multiplates. This was equilibrated under conditions of 37 ° C./5% CO ₂ , and then a culture solution in which the test compound was dissolved was added. After incubation for 24 hours under the condition of 37 ° C./5% CO ₂ , the culture solution was centrifuged to collect the culture supernatant, and the following measurements were performed.
Quantification of proMMP-2 in culture supernatant The proMMP-2 concentration in the collected culture supernatant was quantified using a commercially available measuring reagent (MMP-2, Human, Biotrak ELISA System manufactured by GE Healthcare).
Calculation of proMMP-2 Inhibition Rate The proMMP-2 inhibition rate of the test compound is determined based on the concentration of proMMP-2 in the culture supernatant when the test compound is not added (only the solvent is added), and in the culture supernatant when the test compound is added. The proMMP-2 concentration was calculated according to the following formula as Test.
% Inhibition = 100 − ((Test / Cont) × 100).
Furthermore, the concentration (IC ₅₀ value) of the test compound that suppresses proMMP-2 production by 50% was calculated from 3 points using the proMMP-2 inhibition rate at the test compound concentrations of 0.1, 1 and 10 μmol / L. .
Table 1 shows the results of Test Example 1 and Table 2 shows the results of Test Example 2.

  MMP-9 is produced as proMMP-9 as a precursor from stimulated cells, and is activated extracellularly to express physiological activity as MMP-9. That is, evaluating inhibition of proMMP-9 produced from cells indicates that inhibition of MMP-9 production is being evaluated. The same applies to MMP-2. Evaluating suppression of proMMP-2 produced from cells indicates that MMP-2 production suppression is being evaluated.

Test Example 3 Rat Monoiodoacetic acid-induced osteoarthritis model suppressive effect on articular cartilage injury marker release Monoiodoacetic acid solution (0.3 mg / 25μL) in the right hind knee joint cavity of anesthetized rats (LEW, male, 7 weeks old) ) Was injected. The test compound was orally administered at a dose of 1 mg / kg once a day from immediately after monoiodoacetic acid injection to the fourth day. On the fifth day, 20 μL of a cold phosphate buffer solution was injected into the right hind knee joint space of a rat euthanized, and a joint space washing solution was collected. The concentration of the cartilage injury marker COMP (Cartilage Oligomeric Matrix Protein) in the joint cavity washing solution was quantified using a commercially available measuring reagent (Animal COMP ELISA Kit manufactured by Anamer Medical).
Calculation of COMP Inhibition Rate of Cartilage Injury Marker COMP Inhibition rate of the test compound was determined by comparing the COMP concentration in the joint cavity washing solution of the pathological group (monoclonal administration of the solvent alone) with the monoiodoacetic acid solution administration, Max, The COMP concentration in the joint cavity washing solution was Min, and the COMP concentration in the joint cavity washing solution of the test compound administration group was Test, and the calculation was performed according to the following formula.
% Inhibition = 100 − ((Test−Min) / (Max−Min) × 100).
The results of Test Example 3 of the Production Example Compound in the present invention are shown in Table 3 below.

  The results of Test Example 3 of the compound described in Patent Document 3 (International Publication Pamphlet WO2011 / 136292) are shown in Table 4 below.

  The structure of the compound in the present invention is shown in the upper part, and the structure of the compound described in Patent Document 3 is shown in the lower part. Comparing the structures of the compound of the present invention and the compound described in Patent Document 3, the compound of the present invention has the leftmost heterocycle and the remaining part bonded via a carbon atom, whereas Patent Document 3 The compounds described in 1 are different in that they are bonded via a nitrogen atom. When the structure of Production Example 1 which is a compound in the present invention and Example 450 described in Patent Document 3 are compared, only the position where the remaining part is bonded to the leftmost heterocycle is different. The same. The same applies to the structures of Production Example 8 which is a compound in the present invention and Example 571 described in Patent Document 3. When the inhibition rate of the cartilage injury marker COMP of Production Example 1 which is a compound in the present invention and Example 450 described in Patent Document 3 is compared, the compound in the present invention is more than 5 times superior. Further, when the inhibition rate of the cartilage injury marker COMP of Example 571 described in Production Example 8 which is a compound in the present invention and Patent Document 3 was compared, the compound in the present invention was 30 times or more superior. In addition, it is 55.3% suppression at 0.3 mg / kg when it is 10 times better than Example 571 described in Patent Document 3, and 55.3% at 0.1 mg / kg when it is 30 times better. Although it was suppressed by 3%, Production Example 8 which is a compound in the present invention suppressed by 84.3% at 0.1 mg / kg.

Test Example 4 Enteritis score of mouse dextran sulfate-induced colitis model (Disease Activity
Inhibitory action on Index, DAI) Mice (C57BL / 6J strain, male, 6 weeks old) were allowed to freely take 2.0% (w / v) dextran sulfate solution for 5 days and then replaced with water. It was evaluated with. The test compound was orally administered at a dose of 30 mg / kg twice a day for 5 days after ingestion of the dextran sulfate solution and thereafter until the 10th day. On the 3rd, 5th, 7th, and 10th days from the start of the test, scores of weight loss, stool consistency, occult blood or gross bleeding were scored by 0 to 4 points, respectively. The average value of the total score was defined as Disease Activity Index (DAI), which is an index of enteropathological condition. The criteria for determining the Stool consistency score and the Occult blood or gross bleeding score were as follows.

The evaluation results are shown by calculating the area under the curve (AUC) using DAI on the third, fifth, seventh and tenth days.
The results of Test Example 4 of the Production Example Compound in the present invention are shown in the following table.

  As is clear from the results of Test Examples 1 and 2, the compound of the present invention has a selective MMP-9 production inhibitory action, and safety in which the occurrence of side effects caused by the inhibition of MMP-2 production is suppressed. It is a high compound. Furthermore, since the compound in the present invention has an inhibitory action on the release of articular cartilage injury marker in a monoiodoacetic acid-induced osteoarthritis model (Test Example 3), the pharmaceutical of the present invention containing the compound as an active ingredient The composition is useful as a prophylactic and / or therapeutic agent for osteoarthritis. In addition, since the compound in the present invention has an inhibitory action on the enteritis score of the dextran sulfate-induced colitis model (Test Example 4), the pharmaceutical composition of the present invention containing the compound as an active ingredient is inflammatory. It is useful as a preventive and / or therapeutic agent for bowel disease (ulcerative colitis, Crohn's disease).

  Since the compound in the present invention selectively suppresses the production of inducible MMPs, particularly MMP-9, rather than the production of constitutive MMP-2, the pharmaceutical composition of the present invention containing the compound as an active ingredient Is useful as a prophylactic and / or therapeutic agent for autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases (ulcerative colitis, Crohn's disease), and osteoarthritis.

Claims (18)

Formula (I)
[Wherein, A represents a 5-membered heteroarylene containing 1 to 3 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or a phenylene or a 6-membered heteroarylene represented by the following formula:
[In the formula, Z ¹ , Z ² , Z ³ and Z ⁴ are the same or different and each represents a carbon atom or a nitrogen atom.)
These phenylenes and heteroarylenes are substituted with a halogen atom; a hydroxyl group; a nitro; a cyano; an amino optionally substituted mono- or di-substituted by alkyl having 1 to 6 carbon atoms, a halogen atom, a hydroxyl group, or alkoxy having 1 to 6 carbon atoms. An optionally substituted mono- or di-substituted amino, halogen atom, hydroxyl group, or alkoxy having 1 to 6 carbon atoms may be substituted. Cycloalkyl having 3 to 6 carbon atoms; amino optionally mono- or disubstituted with alkyl having 1 to 6 carbons; and amino or halogen atoms optionally mono- or di-substituted with alkyl having 1 to 6 carbons , One selected from a hydroxyl group or an alkoxy having 1 to 6 carbon atoms which may be substituted with an alkoxy having 1 to 6 carbon atoms, or the same or 2-3 substituents which became may be substituted with, the right bond is carbonyl, left bond is attached to the quaternary carbon to which R ² is attached. ]
R ^1a , R ^1b and R ^1c are the same or different and are each a hydrogen atom; a halogen atom; a hydroxyl group; a cyano; oxo; a carboxy; an amino or halogen atom which may be mono- or di-substituted by alkyl having 1 to 6 carbon atoms. , A hydroxyl group or an alkyl having 1 to 6 carbon atoms which may be substituted with a C 1-6 alkoxy; an amino, halogen atom, hydroxyl group or carbon which may be mono- or disubstituted with an alkyl having 1 to 6 carbon atoms An alkoxy group having 1 to 6 carbon atoms which may be substituted with alkoxy having 1 to 6 carbon atoms; an alkoxycarbonyl having 2 to 7 carbon atoms; an aminocarbonyl which may be mono- or di-substituted with alkyl having 1 to 6 carbon atoms; R ^1a, and two are together of ^{R 1b} and ^{R 1c,} cycloalkyl of 3 to 6 carbon atoms; or ^{R 1a,} two of ^{R 1b} and ^{R 1c} Turned cord, nitrogen atom, an atom selected from oxygen atom and sulfur atom containing 1-4, number of constituent atoms of the ring is 3 to 7 show a saturated non-aromatic heterocyclic group,
R ² may be mono- or di-substituted with alkyl having 1 to 6 carbons, substituted with cycloalkyl having 3 to 6 carbons, halogen atom, hydroxyl group or alkoxy having 1 to 6 carbons. An alkyl having 1 to 6 carbon atoms; a cycloalkyl having 3 to 6 carbon atoms which may be substituted with a halogen atom, a hydroxyl group, an alkoxy having 1 to 6 carbon atoms or amino; a nitrogen atom, an oxygen atom and a sulfur atom. A saturated non-aromatic heterocyclic group containing 1 to 4 atoms and having 3 to 7 ring atoms; aryl having 6 to 10 carbon atoms optionally substituted by the substituent B shown below; Or the heteroaryl which contains 1-6 atoms selected from the nitrogen atom, the oxygen atom, and the sulfur atom which may be substituted by the substituent B shown below, and has 5-10 constituent atoms in the ring ,
R ³ is a hydrogen atom; amino or halogen atom, hydroxyl group, alkoxy having 1 to 6 carbon atoms or acyloxy having 2 to 7 carbon atoms which may be mono- or di-substituted with alkyl having 1 to 6 carbon atoms; C1-6 alkyl; C3-6 cycloalkyl; C6-10 aryl moiety is halogen atom, hydroxyl group, C1-6 alkoxy, C1-6 alkyl or amino An arylalkyl having 1 to 6 carbon atoms in the alkyl part; or 1 to 6 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the number of atoms constituting the ring The heteroaryl part which is 5-10 is optionally substituted with a halogen atom, hydroxyl group, alkoxy having 1 to 6 carbons, alkyl having 1 to 6 carbons or amino, and the alkyl part having 1 to 6 carbons Represents a heteroarylalkyl,
W represents —N (R ^x ) — (wherein R ^x represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy having 1 to 6 carbon atoms or an acyloxy having 2 to 7 carbon atoms which may be substituted with 1 to 3 carbon atoms. 6) or a halogen atom, hydroxyl group, alkyl having 1 to 6 carbon atoms or methylene optionally substituted with alkoxy having 1 to 6 carbon atoms,
m + n represents 0, 1, 2 or 3,
X is a carbon atom (any one of R ^1a , R ^1b and R ^1c may be bonded to this carbon atom, but this carbon atom is not substituted with oxo) or a nitrogen atom (V is In the case of a bond, the nitrogen atom may be oxidized to be N-oxide)
V is a bond; carbonyl; a halogen atom, a hydroxyl group, or an alkylene having 1 to 6 carbon atoms which may be substituted with a C 1-6 alkoxy; an oxygen atom; or —N (R ^Y ) — (where R ^Y is A hydrogen atom, alkyl having 1 to 6 carbon atoms or acyl having 2 to 7 carbon atoms).
Y is a 5-membered cyclic group, a 6-membered cyclic group, a 5-membered cyclic group substituted with a 5-membered cyclic group, a 5-membered cyclic group substituted with a 6-membered cyclic group, or a 6-membered cyclic group substituted with a 5-membered cyclic group A 6-membered ring group substituted with a 6-membered ring group, a 5-membered and 5-membered condensed ring group, a 5-membered and 6-membered condensed ring group, or a 6-membered and 6-membered condensed ring group ( Here, the 5-membered ring and the 5-membered ring group contain 0 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the remainder is composed of carbon atoms. Containing 0 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, the remainder being composed of carbon atoms.), These ring groups are halogen atoms; hydroxyl groups; carbon numbers 1 to 6 C 1-6 alkyl optionally substituted with amino, halogen atom, hydroxyl group or C 1-6 alkoxy optionally mono- or di-substituted with alkyl A halogen atom, a hydroxyl group, amino, or a cycloalkyl having 3 to 6 carbon atoms that may be substituted with alkyl having 1 to 6 carbon atoms; or amino that may be mono- or di-substituted with alkyl having 1 to 6 carbon atoms; It may be substituted with a halogen atom, a hydroxyl group, an alkyl having 1 to 6 carbon atoms or an alkoxy having 1 to 6 carbon atoms which may be substituted with an alkoxy having 1 to 6 carbon atoms.
Substituent B
A halogen atom; a hydroxyl group; a cyano; an amino optionally substituted mono- or di-substituted with alkyl having 1 to 6 carbon atoms, a halogen atom, a hydroxyl group, or carbon atoms optionally substituted with alkoxy having 1 to 6 carbon atoms A cycloalkyl having 3 to 6 carbon atoms which may be substituted with a halogen atom, a hydroxyl group or amino; an amino, halogen atom, hydroxyl group or carbon which may be mono- or disubstituted with an alkyl having 1 to 6 carbon atoms C1-C6 alkoxy which may be substituted by C1-C6 alkoxy; Amino which may be mono- or di-substituted by C1-C6 alkyl or C3-C6 cycloalkyl. ]
Or a pharmacologically acceptable salt thereof as an active ingredient. A is the following phenylene or 6-membered heteroarylene
The pharmaceutical composition according to claim 1. Y is phenyl, pyridyl, pyrazinyl, pyridazinyl, naphthyl, quinolyl or the ring group shown below
And these cyclic groups are substituted with a halogen atom; a hydroxyl group; an amino, halogen atom, hydroxyl group or alkoxy having 1 to 6 carbon atoms which may be mono- or disubstituted with alkyl having 1 to 6 carbon atoms. A C 1-6 alkyl; a halogen atom, a hydroxyl group, amino, or a C 3-6 cycloalkyl optionally substituted by a C 1-6 alkyl; or a mono C 1-6 alkyl Alternatively, it may be substituted with an optionally substituted amino, halogen atom, hydroxyl group, alkyl having 1 to 6 carbon atoms or alkoxy having 1 to 6 carbon atoms which may be substituted with alkoxy having 1 to 6 carbon atoms. The pharmaceutical composition according to claim 1 or 2, which is good. Y or phenyl or pyridyl represented by the following formula
(In the formula, Z ⁵ represents a carbon atom or a nitrogen atom,
R ⁴ and R ⁵ are the same or different and each represents an alkyl having 1 to 6 carbon atoms which may be substituted with a halogen atom; or a cycloalkyl having 3 to 6 carbon atoms which may be substituted with a halogen atom;
R ⁶ represents a hydrogen atom; an alkyl having 1 to 6 carbon atoms which may be substituted with a halogen atom; or a cycloalkyl having 3 to 6 carbon atoms which may be substituted with a halogen atom. )
Or a cyclic group represented by the following formula:
(These ring groups may be substituted with a halogen atom or alkyl having 1 to 6 carbon atoms.)
The pharmaceutical composition according to any one of claims 1 to 3. Y is phenyl or pyridyl represented by the following formula
(In the formula, Z ⁵ represents a carbon atom or a nitrogen atom,
R ⁴ and R ⁵ are the same or different and each represents alkyl having 1 to 6 carbon atoms; or cycloalkyl having 3 to 6 carbon atoms. )
The pharmaceutical composition according to any one of claims 1 to 4. Y is a pyridyl represented by the following formula
(In the formula, R ⁴ and R ⁵ are the same or different and each represents alkyl having 1 to 6 carbon atoms; or cycloalkyl having 3 to 6 carbon atoms.)
The pharmaceutical composition according to any one of claims 1 to 5.   The pharmaceutical composition according to any one of claims 1 to 6, wherein V is a bond.   X is a nitrogen atom, The pharmaceutical composition of any one of Claims 1-7. R ^<1a> , R ^<1b> and R ^<1c> are hydrogen atoms, The pharmaceutical composition of any one of Claims 1-8. The pharmaceutical composition according to any one of claims 1 to 9, wherein R ² is alkyl having 1 to 6 carbon atoms, and R ³ is a hydrogen atom.   The pharmaceutical composition according to any one of claims 1 to 10, wherein W is -NH- or methylene.   The pharmaceutical composition according to any one of claims 1 to 11, wherein W is -NH-. (R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione,
(R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] -3-fluorophenyl} -5-methylimidazolidine-2,4-dione,
(R) -5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione,
(R) -5-methyl-5- {4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione,
(R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione,
5-isopropyl-5- {2-methoxy-4- [4- (3,5,6-trimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione,
(R) -5- {4-[(S) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione,
(R) -5- {4-[(S) -3- (3,5-dimethylpyridin-2-ylamino) pyrrolidine-1-carbonyl] phenyl} -5-ethylimidazolidine-2,4-dione,
(R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) -2,2-dimethylpiperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione ,
(R) -5- {4-[(S) -4- (3,5-dimethylpyridin-2-yl) -3-methylpiperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4 -Dione,
5-tert-butyl-5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} imidazolidine-2,4-dione,
(R) -5- {4- [4- (3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-ethylimidazolidine-2,4-dione,
(R) -5-methyl-5- {4- [4- (4-methylbenzoyl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione,
(R) -5-methyl-5- [4- (4-p-tolyloxypiperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione,
(R) -5-isopropyl-5- {4- [4- (5-methylpyridine-2-carbonyl) piperidine-1-carbonyl] phenyl] imidazolidine-2,4-dione,
(R) -5-isopropyl-5- {4- [4- (6-methylbenzofuran-3-yl)
Piperidin-1-carbonyl] phenyl} imidazolidine-2,4-dione,
(R) -5- {4- [4- (4,6-dimethylbenzofuran-3-yl) piperidine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione,
(R) -5-isopropyl-5- {4- [4- (6-methylbenzoxazol-2-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione,
(R) -5- {4- [4- (5,7-dimethylindazol-1-yl) piperidine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione,
(R) -5- {4- [4- (4,6-dimethyl-1H-indazol-3-yl) piperidine-1-carbonyl] phenyl} -5-methyl-imidazolidine-2,4-dione,
(R) -5-methyl-5- {4- [4- (1,4,6-trimethyl-1H-indazol-3-yl) piperidine-1-carbonyl] phenyl} imidazolidine-2,4-dione,
(R) -5- {4- [4- (4-Fluoro-6-methyl-1H-indazol-3-yl) piperidine-1-carbonyl] phenyl} -5-methylimidazolidine-2,4-dione,
5- {4- [4- (5-Cyclopropyl-3-methylpyridin-2-yl) piperazin-1-carbonyl] phenyl} -5- (tetrahydropyran-4-yl) imidazolidine-2,4-dione Or 5- {4- [4- (5-cyclopropyl-3-methylpyridin-2-yl) piperazine-1-carbonyl] phenyl} -5-isopropylimidazolidine-2,4-dione as an active ingredient A pharmaceutical composition.   The pharmaceutical composition according to any one of claims 1 to 13, which is an MMP-9 production inhibitor.   The pharmaceutical composition according to any one of claims 1 to 13, which is a prophylactic and / or therapeutic agent for autoimmune disease or inflammatory bowel disease.   The pharmaceutical composition according to claim 15, wherein the autoimmune disease is rheumatoid arthritis, multiple sclerosis or systemic lupus erythematosus.   The pharmaceutical composition according to claim 15, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.   The pharmaceutical composition according to any one of claims 1 to 13, which is a prophylactic and / or therapeutic agent for osteoarthritis.