WO2008066145A1

WO2008066145A1 - Thiazole derivative and use thereof as vap-1 inhibitor

Info

Publication number: WO2008066145A1
Application number: PCT/JP2007/073137
Authority: WO
Inventors: Tatsuya Matsukawa; Kazuhiro Masuzaki; Noriyuki Yamamoto; Makoto Takewaki; Hiroyuki Tanaka; Yosuke Kawai; Sumiyo Yamamoto
Original assignee: R-Tech Ueno, Ltd.
Priority date: 2006-11-30
Filing date: 2007-11-30
Publication date: 2008-06-05
Also published as: TW200835687A

Abstract

Disclosed are: a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, which is useful as a VAP-1 inhibitor; a pharmaceutical composition; a pharmaceutical agent for the prevention or treatment of a VAP-1-related disease such as macular edema and a disease associated with the increase in vascular permeability; and others. (I) wherein each symbol is as defined in the description.

Description

Specification

Thiazole derivatives and their use as VAP-1 inhibitors

Technical field

[0001] The present invention relates to a novel thiazole derivative (a compound represented by the following formula (I) (hereinafter also referred to as compound (I)) and a pharmaceutically acceptable salt thereof. Also referred to as a compound). In addition, the present invention relates to a blood vessel adhesion protein-1 inhibitor, a medicament for the prevention or treatment of vascular adhesion protein-1 related diseases, etc. comprising the compound of the present invention as an active ingredient.

Background art

[0002] Vascular adhesion protein-1 (hereinafter abbreviated as VAP-1) is an aminoxidase (semicarbazide-sensitive amine oxidase, SSAO) that is abundant in human plasma. Its expression is markedly increased in vascular endothelium and vascular smooth muscle at the site of inflammation. Although the physiological role of VAP-1 has not been elucidated until recently, the VAP-1 gene was cloned in 1998, and VAP-1 is an adhesion molecule under the control of inflammatory site force-in expression. As reported to be a membrane protein that regulates the rolling and migration of lymphocytes and NK cells! The substrate amine is thought to be an unknown force S, methylamine produced at any site in the body. It is also known that hydrogen peroxide and aldehydes resulting from the aminoxidase activity in the molecule are important factors for attachment activity.

Recent reports show that VAP-1 enzyme activity in plasma increases in both diabetic and diabetic patients, and this increase is associated with retinopathy complications! (Diabetologia, 42 (1999) 233-237 (Non-Patent Document 1), Diabetes Medicine, 16 (1999) 514- 521 (Non-Patent Document 2) )).

[0003] Furthermore, VAP-1 has been reported to be associated with the following diseases (1) to (6): (1) cirrhosis, essential stabilized hypertension, diabetes, arteries Hardening (see JP 61-239891 (Patent Document 1) and US Pat. No. 4,888,283 (Patent Document 2)); (2) Endothelial damage (in diabetes, arteriosclerosis and hypertension) , Cardiovascular disease associated with diabetes and uremia, pain associated with gout and arthritis, retinopathy (in diabetic patients) (see WO 1993/23023); (3) (connective tissue) Inflammatory diseases or symptoms (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and osteoarthritis or degenerative joint disease, Reiter syndrome, Siedalen syndrome, Behcet syndrome, relapsing polychondritis, systemic lupus erythematosus, discoid Lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, polymyalgia rheumatica, vasculitis, transient arthritis, polyarteritis nodosa, Wegener's granuloma Disease, mixed connective tissue disease and juvenile rheumatoid arthritis); gastrointestinal inflammatory disease or symptom [Crohn's disease, ulcerative colitis, irritable bowel syndrome (convulsive colon), liver fibrosis Oral mucosal inflammation (stomatitis) and recurrent phtal stomatitis]; inflammatory diseases or symptoms of the central nervous system (multiple sclerosis, Alzheimer's disease, and ischemia-reperfusion injury associated with ischemic stroke); lung inflammation Disease or symptom (asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease); (chronic) skin inflammatory disease or symptom (psoriasis, allergic lesions, lichen planus, rosacea eruption, contact dermatitis, Atopic dermatitis, erythema puerperum); microvascular and macrovascular disease (arteriosclerosis, vascular retinopathy, retinopathy, nephropathy, nephrotic syndromes and neuropathy (polyneuropathy, single nerve) Disorders and autonomic disorders), foot ulcers, joint problems and increased risk of infection) diseases related to carbohydrate metabolism (diabetes and diabetic complications); adipocyte differentiation or function or Diseases related to abnormalities of myocyte function (arteriosclerosis and obesity); Vascular diseases [Ischemic heart diseases including atherosclerosis, non-atherosclerosis, myocardial infarction and peripheral arterial occlusion, Reino and Reino Phenomenon, obstructive thrombotic vasculitis (Burger's disease)]; Chronic arthritis; Inflammatory bowel disease; Dermatosis (WO 2002/02090 pamphlet (Patent Document 4), WO 2002/02541 pamphlet (See Patent Document 5) and US Patent Application Publication No. 2002/0173521 (Patent Document 6)); (4) Diabetes (see International Publication No. 2002/38152 (Patent Document 7)); and (5 ) SSAO-mediated complications [diabetes (insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM)) and vascular complications (heart attack, angina pectoris, stroke, amputation, blindness and renal failure)] (international Open 2002/38153 Pan Fret (see Patent Document 8); (6) Diseases with increased vascular permeability [Age-related macular degeneration, age-related discoid macular degeneration, cystoid macular edema, eyelid edema, retinal edema, diabetic retinopathy, chorioretinopathy, neovascular macular disease, neovascular glaucoma, uveitis, iris Inflammation, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmitis, choroiditis, retinal pigment epitheliitis, conjunctivitis, ciliary inflammation, scleritis, superior scleritis, optic neuritis, retrobulbar neuritis , Keratitis, blepharitis, exudative retinal detachment, corneal ulcer, conjunctival ulcer, chronic monkey keratitis, tygeson keratitis, progressive Mohren ulcer, bacterial or viral infection, and ocular inflammatory disease caused by ophthalmic surgery , Eye inflammatory diseases caused by physical eye damage, itching, redness, symptoms caused by eye inflammatory diseases including edema and ulcers, erythema, polymorphic exudative erythema, erythema nodosum, annular erythema, edema Sclerosis, dermatitis, vascular neuropathic edema, throat Edema, glottis edema, subglottic laryngitis, bronchitis, rhinitis, pharyngitis, etc. sinusitis and laryngitis or otitis media] (see WO 2004/087138 pamphlet (Patent Document 9)).

[0004] International Publication No. 2004/067521 (Patent Document 10), International Publication No. 2004/0 87138 (Patent Document 9), International Publication No. 2006/011631 (Patent Document 11), and International Publication No. The 2006/028269 pamphlet (Patent Document 12) describes a thiazole derivative having a specific structure and is used for the prevention or treatment of VAP-1-related diseases such as macular edema and hypervascular disease. Is described.

[0005] It is described in International Publication No. 2004/067521 pamphlet (Patent Document 10), International Publication No. 2004/0 87138 pamphlet (Patent Document 9) and International Publication No. 2006/028269 pamphlet (Patent Document 12). The thiazole derivative having a specific structure conceptually includes a compound having a hydrazino group or a hydrazino carbonyl group at the end of the molecule. However, there are no specific disclosures (examples) or suggestions for compounds having a hydrazino group or a hydrazino carbonyl group at the end of the molecule, nor are there any specific disclosures or suggestions regarding pharmacological activities such as SSAO inhibitory activity or safety. .

Patent Document 1: JP-A 61-239891

Patent Document 2: U.S. Pat.No. 4,888,283

Patent Document 3: International Publication No. 1993/23023 Pamphlet

Patent Document 4: Pamphlet of International Publication No. 2002/02090 Patent Document 5: International Publication No. 2002/02541 Pamphlet

Patent Document 6: US Patent Application Publication No. 2002/0173521

Patent Document 7: International Publication No. 2002/38152 Pamphlet

Patent Document 8: International Publication No. 2002/38153 Pamphlet

Patent Document 9: International Publication No. 2004/087138 Pamphlet

Patent Document 10: International Publication No. 2004/067521 Pamphlet

Patent Document 11: International Publication No. 2006/011631 Pamphlet

Patent Document 12: International Publication No. 2006/028269 Pamphlet

Non-patent document 1: Diabetologia, 42 (1999) 233—237

Non-Patent Document 2: Diabetes Medicine, 16 (1999) 514— 521

Disclosure of the invention

Problems to be solved by the invention

[0006] An object of the present invention is to provide a novel thiazole derivative useful as a VAP-1 inhibitor, a medicament for the prevention and treatment of VAP-1 related diseases, and the like.

Means for solving the problem

[0007] As a result of intensive studies, the present inventors have a thiazole derivative having a specific functional group (hydrazino group or hydrazinocarbonyl group) at the molecular end, an excellent VAP-1 inhibitory activity, and The inventors have found that side effects which are excellent in enzyme selectivity and can be eliminated can be eliminated, and further research has been made to complete the present invention.

Therefore, the present invention is as follows.

(1) Formula (I):

[0009] [Chemical 1]

R ¹ — NH— X— Y— Z (I)

[0010] [where

R ¹ is asil;

X is substituted! /, May! /, A divalent residue derived from thiazole; Y is the formula (III):

[0011] [Chemical 2]

[Wherein J is a bond, lower alkylene, lower alkenylene, lower alkynylene, mono (CH 3)

2 n

— O— — (CH) — NH— (CH) — CO, or — (CH) —SO— (each formula

In 2 n 2 n 2 n 2, n is an integer from 0 to 6. );

L is a bond, O— — NH— — CO, or — SO —;

2

M is a bond, lower alkylene, lower alkenylene, or lower alkynylene. However, when J is (CH 2) 2 O, L is not O NH and SO—

2 n 2

Is — (CH) — NH, L is not — O and — NH but J is — (CH) −

2 n 2 n

In the case of CO, L is not —CO, but if J is — (CH 2) —SO—, L is —O

2 n 2

And not SO— (in each formula, n is as defined above). }

2

Z is the formula (II):

[0013] [Chemical 3

A― B― D― E (II)

[0014] {wherein A is a divalent residue induced by benzene force, or a divalent residue induced by thiophene force;

B is one NR ² — CO, one (CH) —, or one (CH) —CO— (wherein R ² is hydrogen,

2 n 2 n

Lower alkyl, or acyl; n represents an integer of 0 to 6; );

D is —NR ³ — (wherein R ³ represents hydrogen, lower alkyl, alkoxycarbonyl or acyl);

E represents an optionally substituted amino. }; Or a pharmaceutically acceptable salt thereof. (2) The compound represented by the formula (I) is N— {4 [2- (4hydrazinocarbophenyl) ethyl] -1,3 thiazole-2-yl} acetamide,

N— {4 [2— (4 hydrazinocarbonylmethylphenyl) ethyl] 1, 3 thiazole 2-yl} acetoamide,

N— (4 {2— [4 (Ν'methylhydrazinocarbonylmethinole) phenyl] ethyl} 1,3 thiazole-2-yl) acetamide,

Ν- (4- {2- [4- (Ν Methylhydrazinocarbonylmethinole) phenenole] ethyl} -1,3 thiazole-2-yl) acetamide,

Ν- (4- {2- [4- (Ν 'ethylhydrazinocarbonylmethinole) phenenole] ethyl} 1,3 thiazole-2-yl) acetamide,

Ν- (4- {2- [4- (Ν ', N'-dimethylhydrazinocarbonylmethyl) phenyl] ethyl} -1,3 thiazole-2-yl) acetamide,

Ν— {4 [2— (4 hydrazinocarbonylmethylphenethyl) ethyl] 5— (4-sulfamoylbenzyl) 1, 3 thiazole-2-inole} acetamide,

Ν— (4 1 {2— [4 1 (2 hydrazinocarbonylethyl) phenyl] ethyl} 1 1,3 thiazole-2-yl) acetamide,

4 (4- {2- [2- (Acetylamino) 1, 3 thiazole- 4-inore] echinore} phenol) semicarbazide,

Ν- (4- {2- [4- (Ν 'Acetylhydrazinocarbonylmethinole) phenenole] ethyl} 1, 3 thiazole-2-yl) acetamide,

Ν- (4- {2- [4- (Ν'-butanoylhydrazinocarbonylmethinole) phenenole] ethyl] -1,3 thiazol-2-yl) acetamide,

Ν- (4- {2- [4- (Ν 'Decanoylhydrazinocarbonylmethinole) phenenole] ethyl} -1,3 thiazole-2-yl) acetamide,

Ν— [4 1 (2— {4 [Ν '— (3 hydroxypropanoinole) hydrazinocarbonylmethyl] phenenole} ethyl) 1, 3 thiazole-2-inole] acetoamide,

Ν— [4 1 (2— {4 [Ν '— (6 Hydroxyhexanole) hydrazinocarbonylmethyl] phenenole} ethyl) 1,3 thiazole-2-inole] acetamide, Ethyl 2 — [(4 {2— [2 (Acetylamino) 1,3 Thiazole-4-yl] ethyl butyl 2— [(4 {2— [2 (Acetylamino) 1,3 Thiazole-4-yl] ethydecyl 2 — [(4 {2— [2— (acetylylamino) 1,3-thiazole-4 yl]

2 Hydroxyethinole 2 — [(4 {2— [2— (Acetylamino) -1,3 Thiazoles 4

4 (Hydrazino Carbonyl Methinole) Phenyl 2 Acetylamino 1, 3 Thiazonole 4 Powerful Noreboxylate,

N- (4-{[4- (hydrazinocarbonylmethyl) phenoxy] methyl} 1,3-thiazole-2-yl) acetamide,

2 (Acetylamino) N— [4 (Hydrazinocarbonylmethyl) phenyl] 1, 3 Thiazole-4 Carboxamide,

N— [4 mono ({[4 mono (hydrazinocarbonylmethyl) phenyl] amino} methyl) mono-1,3-thiazol-2-yl] acetamide,

N— {4 [2— (3 hydrazinocarbonylmethylphenenyl) ethyl] — 1, 3 thiazole 2-yl} acetoamide,

N— (4 {2— [5 (Hydrazinocarbonyl) thiophene 2-yl] ethyl)} 1, 3-Thiazole-2-yl) acetamide,

N— (4 {2— [5 (hydrazinocarbonylmethyl) thiophene 2-yl] ethyl) 1,3 thiazol-2-yl) acetamide,

N— (4 {2— [5 -— (2 hydrazinocarbonylethyl) thiophene 2-yl] ethyl} -1,3 thiazole-2-yl) acetamide,

N— (4 {2— [5 -— (2 hydrazinocarbonylethyl) thiophene 3-yl] ethyl} -1,3 thiazole-2-yl) acetamide,

N— {4 [2— (4 hydrazinophenole) ethyl] — 1, 3 thiazole-2-yl} ace amide, N- (4- {2- [4- (hydrazinomethinole) phenethyl] ethyl]} 1,3-thiazole-2-yl) acetamide,

N- (4- {2- [4- (2 hydrazinoethyl) phenyl] ethyl} -1,3 thiazole-2-yl) acetamide,

N- (4- {2- [4- (3 hydrazinopropinole) phenenole] ethyl} -1, 3 thiazonole —2-yl) acetamide,

N- (4- {2- [3- (2 hydrazinoethyl) phenyl] ethyl} -1,3 thiazole-2-yl) acetamide,

N- (4- {2- [5- (2 hydrazinoethyl) thiophene-2-yl] ethyl} 1,3-thiazol-2-yl) acetamide, or

N— (4— {2— [5— (3—t-Drazinopropyl) thiophene 2-yl] ethyl)} 1,3-thiazol-2-yl) acetamide,

The compound according to (1) above, or a pharmaceutically acceptable salt thereof.

(3) The compound according to (1) above, wherein the compound represented by the formula (I) is N— {4 [2- (4 hydrazinocarbonylmethylphenyl) ethyl] -1, thiazol-2-yl} acetamide A compound, or a pharmaceutically acceptable salt thereof.

(4) The compound according to any one of the above (1) to (3) or a pharmaceutically acceptable salt thereof for use as a medicament.

(5) A pharmaceutical composition comprising, as an active ingredient, the compound of any one of (1) to (3) above, or any of the compounds described above or a pharmaceutically acceptable salt thereof.

(6) A VAP-1 inhibitor comprising, as an active ingredient, the compound of any one of (1) to (3) above, or any one of the compounds described above or a pharmaceutically acceptable salt thereof.

(7) A pharmaceutical composition for preventing or treating a VAP-1-related disease, which comprises, as an active ingredient, the compound according to any one of (1) to (3) above, or any one of the compounds or a pharmaceutically acceptable salt thereof.

(8) The aforementioned VAP-1 related diseases are macular edema (diabetic and non-diabetic macular edema), age-related macular degeneration, age-related discoid macular degeneration, cystoid macular edema, eyelid edema, retinal edema, glycouria Pathological retinopathy, chorioretinopathy, neovascular macular disease, neovascular glaucoma, uveitis, iritis, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmitis, choroiditis, retinitis pigmentosa, Result Meningitis, ciliary inflammation, scleritis, episclerosis, optic neuritis, retrobulbar neuritis, keratitis, blepharitis, exudative retinal detachment, corneal ulcer, conjunctival ulcer, chronic monkey keratitis, tygeson Ocular inflammation including keratitis, progressive Mohren ulcers, ocular inflammatory diseases caused by bacterial or viral infections and by ophthalmic surgery, ocular inflammatory diseases caused by physical eye damage, itching, redness, edema and ulceration Symptoms caused by sexual disease, erythema, polymorphic exudative erythema, erythema nodosum, ring erythema, edematous sclerosis, dermatitis (psoriasis, allergic lesions, lichen planus, rosy sugar eczema, contact skin Inflammation, atopic dermatitis, erythematous folliculitis), vascular neuropathic edema, pharyngeal edema, glottal edema, hypoglottic pharyngitis, bronchitis, rhinitis, pharyngitis, sinusitis and pharyngitis or otitis media, Cirrhosis, essential fixed hypertension, diabetes Arteriosclerosis, endothelial damage (in diabetes, arteriosclerosis and hypertension), cardiovascular disease related to diabetes and uremia, pain associated with gout and arthritis, inflammatory diseases or symptoms of connective tissue (rheumatoid arthritis, ankylosing) Spondylitis, psoriatic arthritis and osteoarthritis or degenerative joint disease, Reiter syndrome, Siedalen syndrome, Behcet syndrome, relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic muscle Meningitis, polymyositis, dermatomyositis, polymyalgia rheumatica, vasculitis, transient arthritis, polyarteritis nodosa, Wegener's granulomatosis, mixed connective tissue disease and juvenile rheumatoid arthritis ), Inflammatory diseases or symptoms of the digestive tract [Crohn's disease, ulcerative colitis, irritable bowel syndrome (convulsive colon), liver fibrosis, inflammation of the oral mucosa ( Inflammatory diseases or symptoms of the central nervous system (multiple sclerosis, Alzheimer's disease, and ischemic reperfusion injury associated with ischemic stroke), pulmonary inflammatory diseases Or symptoms (asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease), microvascular and large blood vessel diseases (arteriosclerosis, retinopathy, nephropathy, nephrotic syndrome and neuropathy (polyneuropathy, mononeuropathy) Disorders and autonomic disorders), foot ulcers, joint problems and increased infection risk), diseases related to carbohydrate metabolism (diabetes and diabetic complications), adipocyte differentiation or function or smooth muscle cell function Diseases related to abnormalities (arteriosclerosis and obesity), vascular disease [ischemic heart disease including atherosclerosis, non-atherosclerosis, myocardial infarction and peripheral arterial occlusion, Reino disease Fine Leino one phenomenon, thromboangiitis obliterans (one disease Baja)], chronic arthritis, inflammatory bowel disease or, SSAO-mediated complications [diabetes (insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM)) and vascular complications (heart attack, angina, stroke, amputation, blindness and renal failure)], Physician for prevention or treatment of VAP-1 related diseases as described in (7) above

:

(9) Use of the compound according to any one of (1) to (3) above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament as a VAP-1 inhibitor.

(10) Use of the compound according to any one of (1) to (3) above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating a VAP-l related disease.

(11) VAP-1 related diseases are macular edema (diabetic and non-diabetic macular edema), age-related macular degeneration, age-related discoid macular degeneration, cystoid macular edema, eyelid edema, retinal edema, diabetic Retinopathy, choroidal retinopathy, neovascular macular disease, neovascular glaucoma, uveitis, iritis, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalitis, choroiditis, retinitis pigmentosa, conjunctivitis , Ciliitis, scleritis, episclerosis, optic neuritis, retrobulbar neuritis, keratitis, blepharitis, exudative retinal detachment, corneal ulcer, conjunctival ulcer, chronic monkey keratitis, Tigerson keratitis, Ocular inflammatory disease caused by progressive Morlen ulcer, bacterial or viral infection, and by ophthalmic surgery, ocular inflammatory disease caused by physical eye damage, itching, redness

Symptoms caused by ocular inflammatory diseases including edema and ulcers, erythema, polymorphic exudative erythema, erythema nodosum, erythema nodosum, edematous sclerosis, dermatitis (psoriasis, allergic lesions, lichen planus, Rose sucrose eczema, contact dermatitis, atopic dermatitis, erythema erythematosus, vascular neuropathic edema, pharyngeal edema, glottic edema, hypoglottic pharyngitis, bronchitis, rhinitis, pharyngitis, accessory Associated with rhinitis and pharyngitis or otitis media, cirrhosis, essential fixed hypertension, diabetes, arteriosclerosis, endothelial damage (in diabetes, arteriosclerosis and hypertension), cardiovascular disease associated with diabetes and uremia, gout and arthritis Pain, connective tissue inflammatory disease or condition (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and osteoarthritis or degenerative joint disease, Reiter syndrome, Siedalen syndrome, Behcet syndrome Relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, polymyalgia rheumatica, vasculitis, transient Arthritis, nodular polyarteritis, Wegener's granulomatosis, mixed connective tissue disease and Juvenile rheumatoid arthritis), inflammatory diseases or symptoms of the gastrointestinal tract [Crohn's disease, ulcerative colitis, irritable bowel syndrome (convulsive colon), fibrosis of the liver, inflammation of the oral mucosa (stomatitis and recurrent) Phthophagitis), inflammatory diseases or symptoms of the central nervous system (multiple sclerosis, Alzheimer's disease, and ischemia-reperfusion injury associated with ischemic stroke), pulmonary inflammatory diseases or symptoms (asthma, adults) Respiratory distress syndrome, chronic obstructive pulmonary disease), microvascular and large blood vessel diseases (arteriosclerosis, retinopathy, nephropathy, nephrotic syndrome and neuropathy (polyneuropathy, mononeuropathy and autonomic disorder), Diseases associated with carbohydrate metabolism (diabetes and diabetic complications), fat cell differentiation or function, or abnormal smooth muscle cell function, including foot ulcers, joint problems and increased risk of infection) (Arteriosclerosis and obesity), vascular disease [atherosclerosis, non-atherosclerosis, ischemic heart disease including myocardial infarction and peripheral artery occlusion, Reino and Reino phenomenon, obstructive thrombotic vasculitis ( Birja's disease)], chronic arthritis, inflammatory bowel disease, or SSAO-mediated complications [diabetes (insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM)) and vascular complications (heart attack, angina) Symptom, stroke, amputation, blindness and renal failure)].

(12) A method for inhibiting VAP-1 in a subject, which comprises administering to the subject an effective amount of the compound of any one of the above (1) to (3) or any one of the above or a pharmaceutically acceptable salt thereof .

(13) VAP-1-related disease in the subject, comprising administering to the subject an effective amount of the compound of any one of (1) to (3) above, or any of the above, or a pharmaceutically acceptable salt thereof. Prevention or treatment method.

(14) VAP-1 related diseases are macular edema (diabetic and non-diabetic macular edema), age-related macular degeneration, age-related discoid macular degeneration, cystoid macular edema, eyelid edema, retinal edema, diabetic Retinopathy, chorioretinopathy, neovascular macular disease, neovascular glaucoma, uveitis, iritis, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmitis, choroiditis, retinitis pigmentosa, conjunctivitis , Ciliary inflammation, scleritis, episclerosis, optic neuritis, retrobulbar neuritis, keratitis, blepharitis, exudative retinal detachment, corneal ulcer, conjunctival ulcer, chronic monkey keratitis, Tigerson keratitis, Ocular inflammatory disease caused by progressive Morlen ulcer, bacterial or viral infection, and by ophthalmic surgery, ocular inflammatory disease caused by physical eye damage, itching, redness Symptoms caused by ocular inflammatory diseases including edema and ulcers, erythema, polymorphic exudative erythema, erythema nodosum, erythema nodosum, edematous sclerosis, dermatitis (psoriasis, allergic lesions, lichen planus, Rose sucrose eczema, contact dermatitis, atopic dermatitis, erythema erythematosus, vascular neuropathic edema, pharyngeal edema, glottic edema, hypoglottic pharyngitis, bronchitis, rhinitis, pharyngitis, accessory Associated with rhinitis and pharyngitis or otitis media, cirrhosis, essential fixed hypertension, diabetes, arteriosclerosis, endothelial damage (in diabetes, arteriosclerosis and hypertension), cardiovascular disease associated with diabetes and uremia, gout and arthritis Pain, connective tissue inflammatory disease or condition (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and osteoarthritis or degenerative joint disease, Reiter syndrome, Siedalen syndrome, Behcet syndrome Relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, polymyalgia rheumatica, vasculitis, transient Arthritis, polyarteritis nodosa, Wegener's granulomatosis, mixed connective tissue disease and juvenile rheumatoid arthritis), inflammatory diseases or symptoms of the gastrointestinal tract [Crohn's disease, ulcerative colitis, irritable bowel syndrome ( Spastic colon), fibrosis of the liver, inflammation of the oral mucosa (stomatitis and recurrent phthah stomatitis)], inflammatory diseases or symptoms of the central nervous system (multiple sclerosis, Alzheimer's disease, and ischemic stroke) Related ischemia-reperfusion injury), pulmonary inflammatory diseases or symptoms (asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease), microvascular and large blood vessel diseases (arteriosclerosis, retinopathy, nephropathy, Nephrotic syndrome and neuropathy Diseases related to carbohydrate metabolism (diabetes and diabetic complications), adipocyte differentiation, including polyneuropathy, mononeuropathy and autonomic neuropathy), foot ulcers, joint problems and increased risk of infection) Or diseases associated with abnormal function or smooth muscle cell function (arteriosclerosis and obesity), vascular disease [ischemic heart disease including atherosclerosis, non-atherosclerosis, myocardial infarction and peripheral arterial occlusion, Reino Disease and Reino phenomenon, obstructive thrombotic vasculitis (Burger's disease)], chronic arthritis, inflammatory bowel disease, or S SAO-mediated complications [diabetes (insulin-dependent diabetes mellitus (IDDM) and non-insulin dependent) Diabetes mellitus (NIDDM)) and vascular complications (heart attack, angina pectoris, stroke, amputation, blindness and renal failure)] The invention's effect

[0017] Since the compound of the present invention is excellent in VAP-1 inhibitory activity and excellent in enzyme selectivity and can eliminate undesirable side effects and the like as a pharmaceutical product, it is useful for VAP-1 inhibitors and VAP-1 related diseases. It is useful as a preventive or therapeutic drug.

BEST MODE FOR CARRYING OUT THE INVENTION

[0018] In the above and following descriptions of the present specification, terms used for the present invention will be described in detail below.

The term “lower” is used to mean a group having !!-6, preferably;!-4 carbon atoms, unless otherwise specified.

“Lower alkyl” includes linear or branched alkyl having 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec butyl, tert-butyl, pentyl, tert pentyl) And hexyl), among them, more preferred is C 1 -C alkyl.

14

[0019] "Lower alkylene" includes linear or branched alkylene having 1 to 6 carbon atoms (eg, methylene, ethylene, trimethylene, propylene, ethylidene and propylidene), among others. More preferred is CC alkylene.

14

“Lower alkenylene” includes linear or branched alkenylene having 2 to 6 carbon atoms (eg, vinylene, 1-propenylene, 1-methylenol, 1-propenylene, 2-methylinole). 1-propenylene, 2-propenylene, 2-butenylene, 1-butenylene, 3-butenylene, 2-pentenylene, 1-pentenylene, 3-pentenylene, 4-pentenylene, 1, 3--butagenylene, 1, 3 Pentagenylene, 2 Penten 4-ynylene, 2 Hexenylene, 1 Hexenylene, 5—Hexenylene, 3—Hexenylene, 4—Hexenylene, 3, 3—Dimethyl 1—propenylene, 2—Ethyl 1 —Propenylene, 1,3,5-hexahexyleneylene, 1,3-hexagenylene, 1,4 hexagenylene) and the like, and more preferred is C 1 -C alkenylene.

twenty four

The lower alkenylene may be E-form or Z-form, respectively. When the compound of the present invention has a lower alkenylene moiety, the compound of the present invention includes all stereoisomers in which the lower alkenylene moiety has an E structure and a Z structure. “Lower alkynylene” includes a straight or branched chain anolequinylene having 2 to 6 carbon atoms and having 3 to 3 bonds (eg, ethynylene, 1-propynylene, 1-methynylene, 1-propynylene, and 2 methylolene). 1-propynylene, 2 propynylene, 2 butynylene, 1-butynylene, 3'-tinylene, 2-pentynylene, 1-pentynylene, 3-pentynylene, 4-pentynylene, 2 pentyne-4-ynylene, 2 hexylene 1 hexylene, 5 hexylene, 3 hexylene, 4 hexylene, 3, 3 decyl 1-propynylene, 2 ethyl 1 propynylene, among which C 1 -C alkynyl is more preferred.

2 4 ren.

[0020] "Aryl" includes C C aryl (eg, phenyl and naphthyl) and the like,

6 10

The “aryl” may be substituted with 1 to 3 substituents, and the substitution position is not particularly limited.

“Aralkyl” has 6 to 6 aryl moieties; that is, the aryl moiety is a C 1 -C aryl of the above “aryl” and 1 to 6 alkyl moieties.

6 10

[That is, the C C alkyl having the above-mentioned “lower alkyl” as the alkyl moiety]

Aralkyl (eg, benzyl, phenethyl, 1-naphthylmethyl, 2-naphthylmethyl, 3-phenylpropyl, 4-phenylbutyl and 5-phenylpentinole).

“Cyclo lower alkyl” includes cycloalkyl having 3 to 6 carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) and the like.

“Cyclolower alkoxycarbonyl” includes cycloalkoxycarbonyl having a cycloalkyl portion of 3 to 6 carbon atoms (eg, cyclopropyloxycarbonyl, cyclobutynole, xicanoreponinore, cyclopentinore, xicanorepo). Ninore, cyclohexenole and xyloxycarbonyl).

“Heterocycle” includes “aromatic heterocycle” and “non-aromatic heterocycle”. “Aromatic heterocycle” is selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms;! To 5 to 10 containing 3 heteroatoms, including 10-membered aromatic heterocycles, etc. For example, thiophene, furan, pyronore, imidazolone, pyrazonole, thiazonole, isothiazonole, oxazole, isoxazole, pyridine, pyridazine, pyrimidine, pyrazine and the like. “Non-aromatic heterocycles” include 5- to 10-membered non-aromatic heterocycles containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Examples thereof include pyrrolidine, imidazoline, virazolidine, pyrazoline, piperidine, piperazine, morpholine, thioline monoreforin, dioxolane, diaxazolidine, thiazolidine, triazolidine and the like.

[0022] "Acyl" includes alkylcarbonyl, allylcarbonyl, and the like. “Alkylcarbonyl” includes an alkyl moiety having 1 to 6 carbon atoms [ie, the alkyl moiety is a C C alkyl of the above “lower alkyl”]

1 6

Acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, bivalolinole, hexanol, heptanol and decanol).

“Arylcarbonyl” has an aryl moiety of 6 to 10 carbon atoms [that is, the aryl moiety is a C C aryl of the above “aryl”]

6 10

“Alkoxycarbonyl” includes alkyloxycarbonyl, aralkyloxycarbonyl and the like.

"Alkyloxycarbonyl" includes an aralkyloxycarbonyl in which the alkyl moiety has 1 to 10 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, propoxy force noreboninole, isopropoxynoreponinole, butoxycanoleponinole, Isobutoxycanoleponinore, sec butoxycanoleponinore, tert butoxycanoleponinore, pentinorexanoreponinore, tert pentinorexanoreponinore, hexinorexanoreponinore and decinorexoxyl Etc.).

“Aralkyloxycarbonyl” has an aryl moiety of 6 to 10 carbon atoms [ie, the aryl moiety is a C C aryl of the above “aryl”] and an alkyl

6 10

The moiety has 1 to 6 carbon atoms [ie, the alkyl moiety is a C alkyl as defined above for “lower alkyl”] aralkyloxycarbonyl (eg, benzyloxycarboxyl)

1 6

Butyloxycarbonyl and 5-phenylpentyloxycarbonyl) Can be mentioned.

In the formula (I), “acyl” represented by R ¹ includes those defined above, and alkylcarbonyl (wherein the alkylcarbonyl is as defined above) is preferred. Acetyl and the like are particularly preferred.

[0025] In the formula (I), "/ substituted! /, May be! /, A divalent residue derived from thiazoleca," represented by X,

[0026] [Chemical 4]

[0027].

“Thiazole” may have a substituent, and the substitution position is not particularly limited. Examples of the “substituent” of the “optionally substituted thiazole” include the groups described in the following (1) to (; 12).

(1) Halogen (eg, fluorine, chlorine, bromine);

(2) alkoxycarbonyl as defined above (eg, ethoxycarbonyl);

(3) optionally substituted aryl (the aryl is as defined above, the aryl is SO (lower alkyl) (wherein the lower alkyl is as defined above)

2

The substitution position that may be substituted is not particularly limited) (eg, phenyl and 4 (methylsulfonyl) phenyl);

(4) Formula: —CONR ^a R ^b (wherein, R ^a is hydrogen, lower alkyl, aryl or aralkyl, and R ^b is hydrogen, lower alkyl, aryl or aralkyl, where the lower class Alkyl, aryl and aralkyl are as defined above (eg, N-methylaminocarbonyl, N-phenylaminocarbonyl, N, N dimethylamino force norbonyl and N benzylaminocarbonyl);

(5) Formula: — CONH— (CH 3) — Arele [wherein k is an integer from 0 to 6; Is as defined above, NO, 1 SO (lower alkyl) (wherein the lower

twenty two

Secondary alkyl is as defined above), -CF and O aryl (wherein

Three

The aryl may have 1 to 5 substituents selected from the group consisting of: and / or the substitution position is not particularly limited! ;

(6) Formula: CONH— (CH 3) —Heterocycle (wherein m is an integer of 0-6; the heterocycle

2 m

Is a group as defined above (eg, pyridine);

(7) Formula: CO heterocycle [wherein the heterocycle is as defined above (eg, pyrrolidine, piperidine, piperazine, thiomorpholine), and the heterocycle is —CO— (lower alkyl (Wherein the lower alkyl is as defined above), CO—O (lower alkyl) (wherein the lower alkyl is as defined above), SO (lower

2 alkyl) (wherein the lower alkyl is as defined above), oxo (ie, = 0) and the formula: —CONR ^d (where is hydrogen, lower alkyl, aryl or aralkyl. And R ^d is hydrogen, lower alkyl, aryl or aralkyl, wherein the lower alkyl, aryl and aralkyl are as defined above, 1-5 selected from the group consisting of The position at which the substituent may be substituted is not particularly limited];

(8) Formula: One (CH 3) -Areel [where t is an integer from! To 6;

2 t

S (lower alkyl) (wherein the lower alkyl is as defined above), so (lower alkyl) (wherein the lower alkyl is as defined above)

2

-SO —NRVRW (wherein R ^v is hydrogen, lower alkyl, aryl)

2

R ^w is hydrogen, lower alkyl, aryl or aralkyl, and the lower alkyl, aryl and aralkyl are as defined above), one CO (lower alkyl) (wherein Lower alkyl is as defined above.

2

), 1 NHCO—O (lower alkyl) (wherein the lower alkyl is as defined above) and —CONR ^e R ^f (where R ^e is hydrogen, lower alkyl, aryl or Is aralkyl, R ^f is hydrogen, lower alkyl, aryl or aralkyl, wherein the lower alkyl, aryl and aralkyl are as defined above) 1-5 selected from the group consisting of Substituent positions that may have substituents of Not defined] group;

(9) Formula: One (CH ² ). —Heterocycle [wherein o is an integer from 0 to 6; the heterocycle is as defined above (eg, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine) and oxo ( That is, = 0); —CO (lower alkyl) (wherein the lower alkyl is as defined above); —CO-0- (lower alkyl) (wherein the lower alkynole is -SO (lower alkyl) (wherein the lower alkyl

2

Kill is as defined above); -co- (heterocycle) wherein the heterocycle is as defined above (eg, pyrrolidine, piperazine and morpholine), and lower alkyl ( The lower alkyl is as defined above) and halogen (eg, fluorine, chlorine

, Bromine), and the substitution position that may have 1 to 5 substituents selected from the group consisting of bromine is not particularly limited); and the formula: —CONR ^g R ^h (where R ^g is hydrogen , Lower alkyl, aryl or aralkyl, R ^h is hydrogen, lower alkyl, aryl or aralkyl, and the lower alkyl, aryl and aralkyl are as defined above) A group having 1 to 5 substituents selected from: and may be substituted and the substitution position is not particularly limited];

(10) Formula: (CH 3) NRW [wherein p is an integer from 0 to 6; 1 ^ is hydrogen, isyl, low

2 p

Primary alkyl, aryl or aralkyl, R ^j is hydrogen, acyl, lower alkyl, aryl or aralkyl, wherein the acyl, lower alkyl, aryl or aranolyl is as defined above, wherein the lower alkyl is , Formula: CONRkR ¹ (wherein R ^k is hydrogen, lower alkyl, aryl or aralkyl, R ¹ is hydrogen, lower alkyl, aryl or aralkyl, and the lower alkyl, aryl and aralkyl are Having 1 to 5 substituents selected from the group consisting of groups as defined above! /, And the substitution positions are not particularly limited! /,] Groups;

(11) Formula: CON (H or lower alkyl) one (CHR ^m ) —T [wherein q is an integer of 0-6; the lower alkyl is as defined above; R ^m is , Hydrogen, aralkyl as defined above or alkyl as defined above (especially lower alkyl), which is substituted with 1 to 3 substituents selected from the group consisting of OH and CONH force.

2

The substitution position is not particularly limited; T is hydrogen; Formula: CONR ⁿ R ° (where R ⁿ is water) R, R, alkyl, aryl or aralkyl; Is a group of hydrogen, lower alkyl, aryl or aralkyl, wherein the lower alkyl, aryl and aralkyl are as defined above; NH—CO—R ^P (wherein R ^P is as defined above) A group of lower alkyl as defined above or aralkyl as defined above; —NH—SO (lower alkyl)

2

Group) (wherein the lower alkyl is as defined above); SO— (lower

2

Alkyl) (wherein the lower alkyl is as defined above); a heterocycle (wherein the heterocycle is as defined above (eg, pyridine, pyrrolidine and morpholine); ,;! To a group of 3 substituents (eg, oxo (ie, = 〇) may be substituted at any position); or CO (heterocycle) (wherein The ring is a group as defined above (eg, piperidine and morpholine)] group; and

(12) Formula: One (CH) CO— NRtR ¹¹ (wherein, r is an integer of 1-6; 1 ^ is hydrogen, low

2 r

A primary alkyl, aryl or aralkyl, is hydrogen, lower alkyl, aryl or aralkyl, where the lower alkyl, aryl and aralkyl are as defined above.

[0028] The substitution position on the aryl or heterocyclic ring is not particularly limited, and may be any position. Preferred examples of the above-mentioned “substituted, may! /, Thiazole” / and “substituent” include methylsulfonylbenzyl, sulfamoylbenzyl (eg, 4-sulfamoylbenzyl), and the like. The substitution position of the methylsulfonyl group, sulfamoyl group and the like is not particularly limited.

[0029] In the formula (I), "thiazoleca-derived divalent" of "substituted! /, Mayo! /, A divalent residue derived from thiazoleca," represented by X As the `` residue '' part,

[0030] [Chemical 5]

[0031] is preferred. “Substitution of Thiazoleca Derived Divalent Residues Which may be Substituted” As the “group”, methylsulfonylbenzyl, sulfamoylbenzyl (eg, 4-sulfamoylbenzyl) and the like are preferable!

[0032] Formula (III) represented by Y in formula (I): Examples of lower alkylene, lower alkenylene and lower alkynylene represented by J and M in JLM include those defined above.

[0033] Formula (III) represented by Y in formula (I): As a specific example of JLM, one (CH)

2 n

, One (CH) NH— (CH) One (CH) O— (CH) One (CH) CO— O

2 n 2 n 2 n 2 n 2 n

— (CH) I, (CH) — O— CO— (CH) I, (CH) — CO— NH— (CH)

2 n 2 n 2 n 2 n 2 n One (CH) One NH—CO— (CH) One (CH) One SO-NH- (CH) One

2 n 2 n 2 n 2 2 n is — (CH 2) — NH—SO— (CH 2) — (where n is an integer from 0 to 6), etc.

2 n 2 2 n

Can be mentioned. Of these, one (CH) (CH) -NH- (CH) (CH)

2 n 2 n 2 n 2 n

— CO— O— (CH) —, One (CH) — CO— NH— (CH) — Preferred (CH)

2 n 2 n 2 n 2 n

— Is particularly preferred. Specifically, one (CH) one CH-CO-, — CH—NH

2 2 2 2

— CO— O CO— NH.

[0034] Formula (II) represented by Z in Formula (I): a divalent residue derived from benzene represented by A in A—B—D—E, or a divalent residue derived from thiophene force Specifically, as a residue,

[0035] [Chemical 6]

Etc.

Examples of the lower alkyl and acyl represented by R ² in NR ² —CO— represented by B include those defined above. B is specifically a bond, NH—CO— (CH 2) 2 —CO— (wherein n is an integer from 0 to 2)) (CH 2) (where n is 0

2 n is an integer from 2 n to 3. ) And the like.

Examples of lower alkyl, alkoxycarbonyl and acyl represented by R ³ in NR ³ — represented by D include those defined above. Specific examples of D include NHN (CH 3) —. [0037] "Substituted! /, May! /, Amino" represented by E includes an unsubstituted amino group and an amino substituted with 1 or 2 substituents. “Optionally substituted amino” is represented by the formula —NR ⁴ R ⁵ .

R ⁴ and R ⁵ are each optionally substituted with hydrogen, unsubstituted or hydroxy, etc., lower alkyl, acyl (especially lower alkylcarbonyl, hydroxy lower alkyl force norbornyl), alkoxycarbonyl, hydroxyalkoxycarbonyl, aryleno, Examples include alcoholol, cyclo lower alkyl, cyclo lower alkoxycarbonyl, sulfuryl, sulfinyl, phosphoryl, and heterocyclic groups. The lower alkyl, asil (especially lower alkylcarbonyl), alkoxycarbonyl, aryl, aranolalkyl, cyclo lower alkyl, cyclo lower alkoxycarbonyl, and heterocycle are as defined above.

[0038] Specific examples of R ⁴ and R ⁵ include hydrogen, lower alkyl (eg, methyl, ethyl, etc.), acetyl, butanol, decanol, 3-hydroxypropanoyl, and 6-hydroxy. Examples include ethoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, decyloxycarbonyl, 2-hydroxyethoxycarbonyl, and the like.

In addition, the amino part of “Replaced! /, But also! /, Amino” represented by E is “Protective Groups in Organic Syntnesis 3rd Edition (from JonnWiley and Sons, 1999 Bako! It may be protected (that is, replaced) according to the method described in id, etc. R ⁴ R ⁵ may be the same or different.

[0039] Formula (II) represented by Z in Formula (I): B—D—E portion (molecular end) of A—B—D—E is a bond of B, NH—CO 2, or one (CH ) -CO- (where n is 0 to 2

2 n

It is an integer. D force S NH— or N (CH 3) —; and E is substituted

Three

A group which may be an amino group. Specifically, the B—D—E moiety includes CO—NH—NH—CH—CO—NH—NH CH—CO—NH—NH

2 2 2 2

-CH -CH CO— N (CH) —NH CH— CO— NH— NH— C H C

3 2 3 2 2 2 5

H CO— NH— N (CH) CH) CO— NH— NH NH— CO— NH—

2 3 2 2 2 2

NH NH— NH CH— NH— NH (CH) NH— NH (CH)

2 2 2 2 2 2 2 2 3

NH— NH CH— CO— NH— NH— CO— CH CH— CO— NH— NH— CO-O-CH CH CH— CO— NH— NH— CO— O— (CH) CH

2 3 2 2 3 3

CH CO— NH— NH— CO— O— (CH) OH CH— CO— NH— NH— C

2 2 2 2

O-O- (CH) CH CH— CO— NH— NH— CO— (CH) CH CH

2 9 3 2 2 2 3

CO— NH— NH— CO— (CH) OH CH— CO— NH— NH— CO— (C

2 2 5 2

H) CH or CH—CO—NH—NH—CO— (CH) —OH.

2 8 3 2 2 2

I can get lost. Preferably one (CH), one CO—NH—NH, one CH—CO—NH—NH.

2 2 2 2 2 Compound (I) includes N {4 [2- (4 hydrazinocarbophenyl) ethyl] 1,3 thiazole-2-yl} acetoamide,

N— {4 [2— (4 hydrazinocarbonylmethylphenyl) ethyl] 1,3 thiazole-2-yl} acetoamide,

N— (4 {2— [4 (Methylhydrazinocarbonylmethinole) phenyl] ethyl} 1,3 thiazole-2-yl) acetamide,

Ν- (4- {2- [4- (Ν'-butanoylhydrazinocarbonylmethinole) phenenole] ethyl -1, 3 thiazole-2yl) acetamide,

N- (4- {2- [4- (Ν 'Decanoylhydrazinocarbonylmethinole) phenenole] ethyl} -1,3 thiazole-2yl) acetamide,

Ν— [4 1 (2— {4 [Ν '— (6 Hydroxyhexanole) hydrazinocarbonylmethyl] phenenole} ethyl) 1,3 thiazole-2-inole] acetamide,

Ethyl 2— [(4 {2— [2 (Acetylamino) 1, 3 Thiazole-4-yl] ethyl butyl 2— [(4 {2- — [(4 {2— [2— (acetylylamino) 1,3-thiazole-4 yl]

2 Hydroxyethinole 2 — [(4 {2— [2— (Acetylamino) -1,3 Thiazoles 4

Ν- (4-{[4- (hydrazinocarbonylmethyl) phenoxy] methyl} 1, 3-thiazole —2-yl) acetamide,

2 (Acetylamino) Ν— [4 (Hydrazinocarbonylmethyl) phenyl] 1, 3 Thiazole-4 Carboxamide,

Ν— [4 (({[4 (hydrazinocarbonylmethyl) phenyl] amino} methyl) -1- 1,3-thiazol-2-yl] acetamide,

Ν— {4 [2— (3 hydrazinocarbonylmethylphenethyl) ethyl] — 1, 3 thiazole 2-yl} acetoamide,

Ν— (4 {2— [5 (hydrazinocarbonyl) thiophene 2-yl] ethyl)} 1, 3--thiazol-2-yl) acetamide,

Ν— (4 {2— [5 (Hydrazinocarbonylmethyl) thiophene 2 yl] ethyl} 1 , 3 thiazole-2-yl) acetamide,

Ν— (4 {2— [5— (2 hydrazinocarbonylethyl) thiophene 2 yl] ethyl] -1,3 thiazole-2 yl) acetamide,

Ν— (4 {2— [5— (2 hydrazinocarbonylethyl) thiophene 3-yl] ethyl} -1,3 thiazole-2-yl) acetamide,

Ν— {4 [2— (4 hydrazinophenyl) ethyl] — 1, 3 thiazole-2-yl} ace amide,

Ν- (4- {2- [4- (hydrazinomethinole) phenenole] ethyl]} 1,3-thiazole-2-yl) acetamide,

Ν- (4- {2- [4- (2 hydrazinoethyl) phenyl] ethyl} -1,3 thiazole-2-yl) acetamide,

Ν- (4- {2- [4- (3 hydrazinopropinole) phenenole] ethyl} -1,3 thiazonole —2-yl) acetamide,

Ν- (4- {2- [3- (2 hydrazinoethyl) phenyl] ethyl} -1,3 thiazole-2-yl) acetamide,

Ν- (4- {2- [5- (2 hydrazinoethyl) thiophene-2-yl] ethyl} 1, 3--thiazole-2-yl) acetamide,

N— (4— {2— [5 -— (3-trazazinopropyl) thiophene 2-yl] ethyl} 1,3-thiazol-2-yl) acetamide and the like. N- {4- [2- (4 hydrazinocarbonylmethylphenyl) ethyl] -1,3-thiazole-2yl} acetamide and the like are preferable.

[0041] When the compound (I) has an asymmetric carbon atom in the structure, the present invention includes all enantiomers and diastereomers.

[0042] Compound (I) may be a pharmaceutically acceptable salt. The pharmaceutically acceptable salt in the present invention is a normal pharmaceutically acceptable salt, and is not particularly limited as long as it is non-toxic, and examples thereof include salts with inorganic or organic bases, acid addition salts and the like. Salts with inorganic or organic bases include alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), ammonium salts, and amine salts (eg, bird And acid addition salts include mineral acids (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid). And organic acids (e.g., tartaric acid, acetic acid, citrate, malic acid, lactic acid, fumaric acid, maleic acid, benzoic acid, glycolic acid, darconic acid, succinic acid, and arenosulfonic acid (e.g., p- And salts derived from toluenesulfonic acid)).

[0043] The compound of the present invention can be used as a prodrug for the following medicaments. The term “prodrug” is intended to encompass all compounds that, after administration, convert to VAP-1 inhibitors in the body. The prodrug may be any pharmaceutically acceptable prodrug of the compound of the present invention.

[0044] The compound of the present invention can be used as an active ingredient of a medicament such as a VAP-1 inhibitor, a medicament for preventing or treating a VAP-1 related disease.

[0045] “Disease associated with vascular adhesion protein 1 (VAP-1)” is not particularly limited as long as VAP-1 is associated with the onset and / or progression of the disease. Macular edema (eg, diabetic and non-diabetic macular edema), age-related macular degeneration, age-related macular degeneration, cystoid macular edema, eyelid edema, retinal edema, diabetic retinopathy, chorioretinopathy, Angiogenic macular disease, neovascular glaucoma, uveitis, iritis, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmitis, choroiditis, retinitis pigmentosa, conjunctivitis, ciliitis, sclera Inflammation, superior scleritis, optic neuritis, retrobulbar neuritis, keratitis, blepharitis, exudative retinal detachment, corneal ulcer, conjunctival ulcer, chronic monkey keratitis, Tigerson keratitis, progressive Mohren ulcer, bacterial infection Or ocular inflammatory diseases caused by viral infections and by ophthalmic surgery, Ocular inflammatory diseases caused by physical damage, including itching, redness, edema and ulcers Symptoms caused by ocular inflammatory diseases, erythema, polymorphic exudative erythema, erythema nodosum, annular erythema, edema sclerosis, Dermatitis (eg, psoriasis, allergic lesions, lichen planus, rose-colored sugar eczema, contact dermatitis, atopic dermatitis, erythema erythematosus), vascular neuropathic edema, pharyngeal edema, glottic edema , Subglottic pharyngitis, bronchitis, rhinitis, pharyngitis, sinusitis and pharyngitis or otitis media], cirrhosis, essential fixed hypertension, diabetes, arteriosclerosis (eg, in diabetes, arteriosclerosis and hypertension) Cardiovascular disease associated with injury, diabetes and uremia, pain associated with gout and arthritis, inflammatory disease of connective tissue or Symptoms (e.g. rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and osteoarthritis or osteoarthritis, Reiter's syndrome, Siedalen syndrome, Behcet's syndrome, relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, Systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, rheumatic polymyalgia, vasculitis, transient arthritis, nodular polyarteritis, Wegener's granulomatosis, Mixed connective tissue disease and juvenile rheumatoid arthritis), inflammatory diseases or symptoms of the gastrointestinal tract [eg, Crohn's disease, ulcerative colitis, irritable bowel syndrome (eg, convulsive colon), fibrosis of the liver, oral mucosa Inflammation (eg, stomatitis and recurrent after stomatitis)], inflammatory diseases or symptoms of the central nervous system (eg, ischemia-reperfusion injury associated with multiple sclerosis, Alzheimer's disease, and ischemic stroke) , Pulmonary inflammatory diseases or symptoms (eg, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease), microvascular and macrovascular diseases (eg, arteriosclerosis, retinopathy, nephropathy, nephrotic syndrome and neuropathy) Diseases related to carbohydrate metabolism (eg, diabetes and diabetic complications), including (eg, polyneuropathy, mononeuropathy and autonomic neuropathy), foot ulcers, joint problems and increased risk of infection) Diseases associated with abnormalities in adipocyte differentiation or function or smooth muscle cell function (eg, arteriosclerosis and obesity), vascular diseases [eg, atherosclerosis, non-atherosclerosis, myocardial infarction and peripheral arteries Ischemic heart disease including obstruction, Reino disease and Reino phenomenon, obstructive thrombotic vasculitis (eg, Birja's disease)], chronic arthritis, inflammatory bowel disease, SSAO-mediated complications [eg, diabetes (eg, I Disease selected from the group consisting of insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) and vascular complications (eg, heart attack, angina pectoris, stroke, amputation, blindness and renal failure) including.

“Prevention or treatment of vascular adhesion protein 1 (VAP-1) -related diseases” refers to the treatment of VAP-1-related diseases with the compounds of the present invention having VAP-1 inhibitory activity (ie, VAP-1 inhibitors) ( It is intended to be administered to subjects for the purposes of prevention, symptom relief, symptom reduction, progression arrest and cure).

There are various administration targets for the medicament, pharmaceutical composition, VAP-1 inhibitor, medicament for preventing or treating VAP-1 related diseases in the present invention (hereinafter collectively referred to as the medicament of the present invention). Mammals (eg, mammals such as humans, mice, rats, pigs, dogs, cats, horses, tusks, etc.) Human).

[0047] The medicament of the present invention can be administered by any route. Administration routes in the present invention include systemic administration (eg, oral administration or injection administration), local administration, periocular administration (eg, subtenon administration), conjunctival administration, intraocular administration, subretinal administration, and choroidal administration. Administration (suprachoroidal) and post-ocular administration. The mode of administration of the medicament of the present invention may be appropriately determined depending on whether the application to a VAP-1 related disease is prophylactic or therapeutic.

[0048] The medicament of the present invention is preferably administered immediately after it has been determined that there is a risk of a target VAP-1 related disease such as mammals, particularly humans (prophylactic treatment), Or it is administered immediately after the subject begins to develop VAP-1 related disease (therapeutic treatment). The treatment plan may be appropriately determined according to the type of active ingredient to be used, the dose, the route of administration, the cause, and, if necessary, the degree of awareness of the VAP-1-related disease.

As a method for administering the medicament of the present invention, a method known per se in general medicaments can be used. As an administration route, an effective route may be appropriately selected, and one or more routes can be used. Therefore, the above administration routes are merely examples, and are not limited thereto.

The dose (dosage) of the medicament of the present invention in an animal including humans, particularly in a subject to be administered such as a human, may be an amount sufficient to exert a desired reaction on the subject to be administered over a reasonable period of time. The dose is appropriately determined according to the strength of the active ingredient used, the age, species, symptom or disease state and weight of the subject to be administered, various factors including the degree of the disease, route of administration, timing and frequency. That's fine. The dose may be appropriately adjusted according to the route of administration, timing and frequency. Depending on the symptom or disease state, long-term treatment requiring multiple doses may be required.

[0049] The dose and dosing schedule can be determined by techniques found in the usual range known to those skilled in the art. In general, treatment or prophylaxis begins with a dose that is less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. The medicament of the present invention (such as a VAP-1 inhibitor) is usually about 0.03 ng / kg body weight. 1 dose per day to about 300 mg / kg body weight / day, preferably about 0.003 μg / kg body weight / day to about 10 mg / kg body weight / day, or 2 to 4 doses per day Administration can be continuous or continuous.

The pharmaceutical composition of the present invention preferably comprises a “pharmaceutically acceptable carrier” and, as an active ingredient, an amount of a compound of the present invention sufficient to prevent or therapeutically treat a VAP-1-related disease. (VAP-1 inhibitor). The carrier may be any of those commonly used as pharmaceuticals, except where limited by physicochemical considerations (eg, solubility and lack of reactivity to the compound) and route of administration. There is no particular limitation.

[0050] The amount of the compound of the present invention in the medicament of the present invention may vary depending on the formulation of the composition.

. 1S usually 0. 00001-10 0 weight ^_0/0, preferably <(or 0. 00;! ~ 5 weight ^_0/0, which is still more preferably <ί or 0. 001 ;!% by weight.

[0051] The dosage form of the medicament of the present invention is not particularly limited, and can be administered in various forms in order to achieve the desired VAP-1 inhibitory action. The medicament of the present invention can be formulated orally or parenterally by formulating the compound of the present invention alone or in combination with an additive such as a pharmaceutically acceptable carrier or diluent. The characteristics and properties of the formulation are determined by the solubility and chemical properties of the active ingredient used, the chosen route of administration and standard pharmaceutical practice. Preparations for oral administration include solid dosage forms (eg, capsules, tablets, powders) or liquid forms (eg, solutions or suspensions). Examples of the preparation used for parenteral administration include injection and infusion in the form of a sterile solution or suspension. The solid oral preparation may contain usual excipients and the like. Liquid oral preparations may contain various fragrances, colorants, preservatives, stabilizers, solubilizers or suspending agents and the like. Parenteral preparations are, for example, sterile aqueous or non-aqueous solutions or suspensions and may contain various various preservatives, stabilizers, buffers, solubilizers or suspending agents and the like. Various isotonic agents may be added as necessary.

The medicament of the present invention may contain other pharmaceutically active compounds as long as the effects of the present invention are not inhibited.

[0052] The medicament of the present invention may also have other pharmaceutically active compounds as long as the effects of the present invention are not inhibited. Can be co-administered. “Simultaneous administration” means that other pharmaceutically active compounds are administered prior to, at the same time (eg, in the same formulation or in another formulation) or after administration of the medicament of the present invention. . For example, a corticosteroid, prednisone, methylprednisone, dexamethasone, or triamcinolone acetinide or a non-corticosteroid anti-inflammatory compound (eg, ibuprofen or flubiprofen) can be co-administered. Similarly, vitamins and minerals (eg, zinc, antioxidants (eg, carotenoids (eg, xanthophyll carotenoid-like zeaxanthin or rutin))) and micronutrients can be co-administered.

The compounds of the present invention are useful for the manufacture of a medicament such as a VAP-1 inhibitor, a pharmaceutical agent for preventing or treating VAP-1 related diseases.

[0053] Compound (I) can be produced by the following procedure, but is not limited to this procedure. One skilled in the art can modify the procedure according to a conventional method known per se. Compound (I) has the formula:

[0054] [Chemical 7]

R ¹ — NH— X— Y— A— B— D— E

[Wherein each symbol is the same as defined above.]

I will show you in

Scheme 1 below shows the procedure for the production method of compound (I).

Compound (I) can be produced by chemically bonding three compounds (1), (2) and (3) as partial structures represented in Scheme 1 below. Compounds (1), (2) and (3) may use salts thereof.

There are two methods for combining (1) and (2), then combining (3), (2) and (3) first, and finally (1). Compound (I) can be produced in either order. In addition, if necessary, the deprotection reaction of D—E may be converted to a pharmaceutically acceptable salt. The method for producing compound (I) is not limited to the procedure described above, and those skilled in the art can appropriately modify the procedure according to a conventional method known per se.

[0056] [Chemical 8]

——► R ¹ — H— X— Y— A— B— D— E

[0057] (In each formula,

XYABD and E are the same as defined above. L ² is a reactive functional group that forms a chemical bond with L ³ of compound (2) to form Y. L ³ is a reactive functional group that forms a chemical bond with L 2 of compound (1) to form Y. L ⁴ is a functional group that reacts with compound (3) to construct B in order to construct a hydrazine structure or an acyl hydrazine structure at the molecular end of compound (I). L ⁵ is hydrogen, lower alkyl, alkoxycarbonyl, acyl or protecting group. )

L ² of compound (1) forms a chemical bond with L ³ of compound (2) and is a reactive functional group necessary to form Y. For example, (CH 2) CHO (CH 2) OH (CH )

2 u 2 u 2

—Halogen, One (CH) — C〇〇H, One (CH) — C〇 One Halogen, One (CH) — NH u 2 u 2 u 2 u 2-(CH)-SO H-(CH)-SO —Halogen, or one (CH) — invited from 〇H

2 u 3 2 u 2 2 u

Derived one (CH) — O-facyl (eg, one (CH) — O-acetyl), one (CH) −

2 u 2 u 2 u sulfonic acid esters (eg, one (CH) —〇S〇 CH etc.) or one (CH) —halogen

Wittig reagent derived from 2 u 2 3 2 u and the like (wherein u is an integer of 06. Examples of halogen include chlorine, bromine and iodine). It is not limited to.

Compound (1) or a salt thereof may be commercially available, or can also be produced according to a method known per se described in International Publication No. 2004/047521.

[0058] L ³ of compound (2) forms a chemical bond with L ² of compound (1) and is a reactive functional group necessary for forming Y. For example, (CH 3) CHO (CH 2) OH (CH)

2 2 2

—Halogen, One (CH) — C〇H, One (CH) — C〇One Halogen, One (CH) — NH

2 v 2 v 2 v 2

-Derived from (CH)-SO H-(CH)-SO—halogen or one (CH) —OH One (CH) —O asinole (eg,-(CH) —O acechinole),-(CH) source

2 2 2 Norephonic acid ester (eg, one (CH) -OSO CH, etc.) or one (CH) —halogen

2 2 3 2

(Wherein V is an integer of 0 to 6. Examples of halogen include chlorine, bromine and iodine), but are not particularly limited. L ⁴ is a functional group necessary for reacting with the compound (3) to construct a hydrazine structure or a acyl hydrazine structure at the molecular end of the compound (I) and constructing B. For example, (CH 2) -CH

2 w

○, One (CH) — 〇H, One (CH) — Halogen, One (CH) — C 〇H, One (CH) — C

2 w 2 w 2 w 2 w

O One halogen, one (CH ² ) — NHR ^2, etc. (in each formula, w is an integer from 0 to 6)

2 w

Examples of the gene include chlorine, bromine and iodine. R ² is the same as defined above. ) Is not particularly limited.

Compound (2) or a salt thereof may be commercially available, or produced according to a method known per se described in International Publication No. 2004/047521, International Publication No. 2006/011631, and the like. You can also

[0059] Compound (3) is a hydrazine equivalent for constructing a hydrazine structure or an acyl hydrazine structure at the molecular end of compound (I), and may be a commercially available product or a method known per se Can also be manufactured. In addition, the protecting group in L ⁵ is a functional group that is introduced for the purpose of avoiding unnecessary reactions and removed by the final step. For example, protection such as (CH 3) 2 C OCO shown in the production example Groups. Low at L ⁵

3 3

Examples of the primary alkyl, alkoxycarbonyl, and acyl are the same as the lower alkyl, alkoxycarbonyl, and acyl represented by the aforementioned R ³ .

[0060] In the case of producing compound (I) in which Y is a carbon chain, compound (1) is obtained using Wittig reaction, Horner-Emmons reaction, aldol condensation reaction, Claisen condensation, or similar carbon-carbon bond-forming reaction. ) Or a salt thereof with a compound (2) or a salt thereof (some! /, Is a compound obtained by condensing compounds (2) and (3) in advance), and lower alkenylene is included! /, Contains lower alkynylene Build Y. Suitable salts of compounds (1) and (2) may be the same as those exemplified for compound (I). Various carbon-carbon bond forming reactions can be used. As a preferable example, when using the Wittig reaction and similar reactions, L ² is — (CH ² ) —CHO, and L ^{3 is —} (CH 2). Derived from halogen, etc. From phosphonium salts (Wittig reagent), or L ² is one (CH) — from halogen, etc.

2 u

Induced phosphonium salts (Wittig reagent) and L ³ is-(CH) -CHO

2

(In each formula, u V is the same as defined above. Examples of the halogen include chlorine, bromine, and iodine.) The reaction is usually carried out in potassium tert butoxide, hydrogen in conventional solvents such as N, N dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, and other organic solvents that do not adversely affect the reaction, or mixtures thereof. It is carried out in the presence of a common base such as sodium hydroxide or sodium hydroxide. The reaction is not particularly important, and the reaction is carried out under cooling or heating. The product can be isolated or purified by known separation or purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transition, chromatography, etc., and the compound (I ) Can be converted to the same salts as those exemplified above.

[0061] If necessary, lower alkenylene or lower alkynylene can be hydrogenated to be converted to lower alkylene. When Y is converted to an alkylene bond, a hydrogenation reaction is carried out according to a conventional method in the presence of various homogeneous or heterogeneous catalysts. In particular, catalytic hydrogenation using a heterogeneous catalyst is preferably performed in the presence of a catalyst such as palladium carbon.

[0062] When producing compound (I) wherein Y is a group containing an ester, amide or sulfonamide, compound (1) or a salt thereof is converted to compound (2) or a salt thereof (or compound (2) and ( 3) is condensed with a pre-condensed compound) to form an ester or amide bond. In this case, L ² is-(CH) —OH (CH) -NH (CH) halogen, etc.

2 u 2 u 2 2 u

L ^{3 is} (CH) COOH (CH) CO halogen, CH) SO H

2 2 2 3-(CH)-SO—A force that is a halogen or the like, or L ² is one (CH) — COOH-(

2 2 2 u

CH) —C〇 One halogen, one (CH)-SO H-(CH)-SO halogen, etc.

2 u 2 u 3 2 u 2

L ³ is — (CH 2) —〇H— (CH 2) —NH— (CH 2) —halogen, etc.

2 2 2 2

Y can be constructed based on a typical organic synthesis method (in each formula, uV is the same as defined above. Examples of halogen include chlorine, bromine, and iodine). The reaction is usually normal solvents such as dichloromethane, acetone, tetrahydrofuran, jetyl ether, N, N dimethylformamide, and does not adversely affect the reaction! /, Any other organic solvents It is carried out in a medium or a mixture thereof. If necessary, a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carpositimide hydrochloride, N, N'-dicyclohexyl carpositimide, N, N'-carbonyldiimidazole is used. It can also be used in the presence of additives such as N, N-dimethylenoyl 4-aminoviridine, 1-hydroxybenzotriazole, 1-hydroxysuccinimide, 3,4 dihydro-3 hydroxy-4oxo1,2,3 benzotriazine. Done. The reaction temperature is not particularly important. The reaction is carried out under cooling or heating.

[0063] When producing compound (I) wherein Y is a group containing an amine, L ² is-(CH) — NH;

2 2 is its salt, etc., and L ³ is-(CH) 1 CH 0, 1 (CH 2) 1 halogen, etc.

twenty two

Or L ² is one (CH) — CH ○, one (CH) — halogen, etc., and L ³ is one (CH) — N

2 u 2 u 2

H or its salt, etc., and Y can be constructed based on general organic synthesis methods.

2

(In each formula, U and V are as defined above. Examples of the halogen include chlorine, bromine and iodine.) The reaction is usually performed using a conventional solvent such as tetrahydrofuran, jetyl ether, alcohols, and any other organic solvent that does not adversely affect the reaction, or a mixture thereof as a reaction solvent by condensing an amine with an aldehyde to form a Schiff base. This is reduced with sodium borohydride or sodium borohydride to construct a secondary amine structure. Alternatively, the same structure is constructed by a condensation reaction between an amine and a halogen compound. When using halogen compounds, N, N diisopropylamine, triethylamine, potassium carbonate and other bases are used as reactants, which adversely affect normal solvents such as tetrahydrofuran, acetonitrile, N, N dimethylformamide, and reactions. Or other organic solvents or mixtures thereof are used as reaction solvents. The reaction is not particularly important, and the reaction is carried out under cooling to heating. The product can also be converted to a salt similar to the salt exemplified for compound (I).

[0064] When producing compound (I) wherein Y is a group containing an ether bond, L ² is one (CH) —

2

〇H etc., L ³ is one (CH) ―〇H,-(CH) -halogen, one (CH) -sulfone

2 2 2

Force that is an acid ester or the like, or L ² is one (CH 3) ―〇H,-(CH) halogen,

2 u 2 u

CH 3) -sulfonic acid ester, etc., L ³ is-(CH 2) —〇H, etc.

2 u 2

Y can be constructed based on organic synthesis techniques (where u and V are as defined above) It is. Examples of halogen include chlorine, bromine and iodine. ). The ether bond can be formed by the Williamson method, an ether synthesis method from an aromatic halide using a copper catalyst or the like, a Mitsunobu reaction, or other known production methods. These reactions are usually carried out in conventional solvents such as acetonitrile, dichloromethane, acetone, tetrahydrofuran, N, N dimethylformamide, and any other organic solvent that does not adversely affect the reaction, or mixtures thereof. Done. The reaction temperature is not particularly important. The reaction is carried out under cooling or heating. In addition, the product can be converted to a salt similar to the salt exemplified for compound (I).

[0065] The molecular end of the compound (I) is a hydrazinocarbonyl group or a hydrazino group.

An example of a method for introducing a hydrazinocarbonyl group or a hydrazino group at the molecular end of compound (I) is shown in Scheme 2 below.

[0066] [Chemical 9

Scheme 2

(1 + 2) or (2) (3)

R ¹ — H— X— Y— A— B— D— E

[0067] (In each formula,

X, Y, A, B, D, and Ε are the same as defined for compound (I).

L ⁴ and L ⁵ are the same as defined above. )

In the case of producing compound (I) where Β is (CH 2) 2 CO 2, compound (2) (or

2 n

(CH 2) —COOH as L ⁴ of compound (1) and (2))

2 w

Esters, such as-(CH) -COOCH, or one (CH) — C 0 halogen (

2 w 3 2 w

In each formula, w is the same as defined above. Examples of the halogen include chlorine, bromine and iodine. ) Structure is required. The compound (2) may be incorporated in advance as a carboxyl group from the raw material stage, or may be constructed as a part of the synthesis process by hydrolysis of the corresponding carboxylic acid ester, oxidation of alcohol or the like. By condensing carboxylic acid, carboxylic acid ester, or acid halide and hydrazine or protected hydrazine), hydrazinocarbonyl group (in formula (I), B is one (CH ) — CO—, D is one NR ³ —, E is an optionally substituted amino group)

2 w

To construct. (W is the same as defined above.) The reaction is usually a conventional solvent such as dichloromethane, acetonitrile, tetrahydrofuran, N, N dimethylformamide, and any reaction that does not adversely affect the reaction. It is carried out in other organic solvents or mixtures thereof. When synthesizing from a carboxylic acid, a condensing agent such as 1, 1'-carbonyldiimidazole or N, ''-dicyclohexyl carpositimide is used. Further, the condensation reaction may be carried out after induction into an acid halide with thionyl chloride, oxalyl chloride or the like. In addition, the condensation reaction with hydrazine can be carried out according to various known methods.

[0068] When producing compound (I) where Β is NR ² — CO ² , the structure of NHR ² is required as L ⁴ . The compound (2) may be preliminarily incorporated as an amino group or protected amino group from the raw material stage, and may be constructed as a part of the synthesis process by reduction of the nitro group. By treating the amino group with, for example, tert butyl 2 (1H-imidazole-1-ylcarbonyl) hydrazinecarboxylate prepared from 1,1′-carbonyldiimidazole and tert-butoxy-powered rubazate, B is NR ² — CO—, D is NR ³ —, E is substituted! /, May! /, And can be constructed as a terminal structure of an amino group. The reaction is usually carried out in a conventional solvent such as dichloromethane, acetonitrile, tetrahydrofuran, N, N dimethylformamide, and any other organic solvent or mixture thereof that does not adversely affect the reaction! . The reaction temperature is not particularly important. The reaction is carried out under cooling or heating.

[0069] In the case of producing the compound (I) wherein B is-(CH)-, the compound (2) (or the compound (

1) and (2))) as L ⁴ — (CH 2) —CHO, — (CH 2) —Halogen

2 w 2 w

Or — (CH 2) OH (wherein, w is as defined above.

2 w

Examples are elemental, bromine and iodine. ) And other structures are required. These functional groups (formyl group, halogen is! / Or hydroxyl group) may be incorporated in advance in the compound (2) from the raw material stage, and the formyl group may be reduced by reduction of the corresponding carboxylic acid, carboxylate ester, or alcohol. As a result of oxidation of the halogen, the corresponding halogenated alcohol and water Acid groups may be constructed as part of the synthesis process by reduction of the corresponding carboxylic acid, carboxylic acid ester, hydrolysis of the carboxylic acid ester, or the acid, a ride, etc.

[0070] Condensation of a formyl group (aldehyde) and hydrazines (or protected hydrazines) to form a Schiff base, which is reduced with sodium borohydride, sodium borohydride, etc. to form a hydrazino group To do. Alternatively, the same structure is constructed by a condensation reaction between hydrazines (or protected hydrazines) and a halogen compound. The reaction is usually carried out in a conventional solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, and any other organic solvent that does not adversely influence the reaction, or a mixture thereof. The reaction temperature is not particularly important. The reaction is carried out under cooling or heating.

In addition to the above method, Mitsunobu reaction can be used as a method for constructing a hydrazino group from a hydroxyl group (alcohol). Using tert-butyl (1,3-dioxone 1,3-dihydro-2H-isoindole-2-yl) rubamate as the hydrazine equivalent, condensing triphenylphosphine and jetylazodicarboxylate as reactants Let The phthalimide moiety is removed by hydrazine decomposition, and then the tert-butoxycarbonyl group is removed with an acid to form a hydrazino group at the molecular end of compound (I) (in formula (I), B is CH , D is NR ³ —

2

, E can be substituted amino groups). In addition, hydrazino groups can be constructed according to various known organic chemical methods.

[0072] The compound (I) thus produced can be isolated or purified by a known separation or purification means such as crystallization, recrystallization, phase transition, chromatography and the like. It can also be converted to a pharmaceutically acceptable salt.

[0073] Hereinafter, the present invention will be described in more detail with reference to Examples (Production Examples and Test Examples). However, this does not limit the present invention.

Example

[0074] The raw material compounds used in the following production examples can be produced by a known method (International Publication No. 2004/067521, International Publication No. 2006/011631, International Publication No. 2006/028269), etc. .

[0075] Production Example 1 Synthesis of N- {4- [2- (4-hydrazinocarboylphenyl) ethyl] -l, 3-thiazol-2-yl} acetamide

[0076] [Chemical 10]

[0077] 4- {2- [2- (Acetylamino) -1,3-thiazol-4-yl] ethyl} Methyl benzoate (913.1 mg, 3.000 mmol) was added ethanol (25 ml) and water (2.5 ml). In addition, a suspended state was obtained. 6N Aqueous sodium hydroxide solution (2.5 ml, 15 mmol) was added at 0 ° C, and the mixture was stirred at room temperature for 24 hr. After cooling to 0 ° C., 1N hydrochloric acid (15 ml) was added and stirred. Ethanol was distilled off under reduced pressure, and water (10 ml) was added to the residue and stirred. The formed solid was collected by filtration and washed twice with water. The residue was dried under reduced pressure to give 4- {2- [2- (acetylamino) -1,3-thiazol-4-yl] ethyl} benzoic acid (517.3 mg, 1.782 mmol, yield 59.4%) as a white solid.

[0078] [Chemical 11]

Step ~ 2

[0079] 4- {2- [2- (Acetylamino) -1,3-thiazol-4-yl] ethyl} In a solution of benzoic acid (583.0 mg, 2.00 8 mmol) in anhydrous N, N-dimethylformamide (5 ml) 1,1′-Carbonyldiimidazole (486.5 mg, 3.000 mmol) was added and stirred at 50 ° C. for 2 hours. After cooling to room temperature, hydrazine 'monohydrate (0.49 ml, lOmmol) was added and stirred at room temperature for 6 hours. Water (10 ml) was added and stirred, and the resulting solid was collected by filtration. Washed 3 times with water and 3 times with ethyl acetate. The title compound (548.3 mg, 1.801 mmol, yield 89.6%) was obtained as a white solid by drying under reduced pressure.

Melting point: 219-221 ° C H-NMR (200MHz, DMSO-d6): δ (ppm): 12.00 (1H, brs), 9.68 (1H, brs), 7.72 (2H, d, J = 8.1Hz), 7.26 (2H, d, J = 8.1Hz), 6.73 (1H, s), 4.46 (2H, brs), 3.55_281 (4mm, m), 2.11 (3H, s)

¹³ C-NMR (50 MHz, DMSO-d6): δ (ppm): 168.7, 166.3, 157.9, 150.6, 145.2, 131.5, 128.7, 127.5, 108.0, 34.8, 32.9, 23.0

[0080] Production Example 2

Synthesis of N- {4- [2- (4-hydrazinocarbonylmethylphenyl) ethyl] -l, 3-thiazol-2-yl} acetoamide

[0081] [Chemical 12]

[0082] 2- (4- {2- [2- (Acetylamino) -1,3-thiazol-4-yl] ethyl} phenyl) acetic acid (913.1 mg, 3.000 mmol) in anhydrous N, N-dimethyl 1,1′-carbonyldiimidazole (729.7 mg, 4.500 mmol) was added to a formamide (7.5 ml) solution, and the mixture was stirred at 50 ° C. for 1 hour. After cooling to room temperature, hydrazine monohydrate (0.73 ml, 15 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (25 ml) was added and stirred, and the resulting solid was collected by filtration. The solid was washed 3 times with water, 3 times with ethyl acetate and 2 times with tetrahydrofuran. Drying under reduced pressure gave the title compound (538.1 mg, 1.690 mmol, yield 56.3%) as a white solid.

Melting point 200 ~ 202 ° C

¹ H-NMR (200 MHz, DMSO_d6): δ (ppm): 12 · 08 (1Η, brs), 9 · 18 (1Η, brs), 7.20—7.04 (4 H, m), 6 · 74 (1Η, s ), 4 · 21 (2Η, brs), 3.40-3 · 25 (2Η, m), 3 · 00— 2 · 80 (4Η, m), 2 · 11 (3Η, s) 1 ³ C-NMR (50 MHz , DMSO— d6): δ (ppm): 169.8, 168.4, 157.6, 150.5, 139.6, 133.9, 1 29.0, 128.2, 107.5, 40.3, 34.3, 33.0, 22.7

[0083] Production Example 3

Synthesis of N- (4- {2- [4- (N'_Methylhydrazinocarbonylmethyl) phenyl] ethyl} -l, 3-thiazol-2-yl) acetamide

Production Example 4 Synthesis of N- (4- {2- [4- (N-methylhydrazinocarbonylmethyl) phenyl] ethyl} -l, 3-thiazol-2-yl) acetamide

[Chemical 13]

Condensation of 4- {2- [2- (acetylamino) -1,3-thiazol-4-yl] ethyl} phenylacetic acid (l.OOg, 3.29 mmol) with methyl hydrazine by a method similar to Preparation Example 2. I let you. The crude product was purified by silica force gel column chromatography (Fuji Silysia NH-DM2035, 70 g, dichloromethane: methanol = 30: 1) to obtain two fractions. The highly polar fraction was concentrated under reduced pressure, and the precipitated crystals were washed with diisopropyl ether. The crystals were dried and N- (4- {2- [4- (N'_methylhydrazinocarbonylmethinole) phenenole] ethyl} -1,3-thiazole-2-inole) acetamide ( Preparation Example 3, the title compound) (0.30 g, 0.905 mmol, yield 27.5%) was obtained.

Melting point 179-181 ° C

^: H-NMR (200MHz, DMSO-d6): δ (ppm): 12 · 08 (1Η, brs), 9 · 48 (1Η, brs), 7.20— 7 · 05 (4H, m), 6 · 74 ( 1Η, s), 4 · 80 (1Η, brs), 3 · 28 (2Η, s), 3.00—2 · 75 (4Η, m), 2.45- 2 · 35 (3Η, m), 2 · 12 (3Η , S)

¹³ C-NMR (50MHz, DMSO-d6): δ (ppm): 169.4, 168.7, 157.9, 150.9, 139.9, 134.1, 129.3, 128.6, 107.8, 40.8, 34.7, 33.3, (23.0, 22.9)

(A part of the peak was observed by splitting with the s-cis / s-trans isomer of the amide bond.) Further, the low-polar fraction was concentrated under reduced pressure, and the precipitated crystals were washed with diisopropyl ether. The obtained crystals were recrystallized from tetrahydrofuran / diisopropyl ether and dried to give N- (4- {2- [4- (N-methylhydrazinocarbonylmethyl) phenyl] ethyl} -1,3-thiazole-as a white solid. 2-yl) acetoamide (Production Example 4, title compound) (0.14 g, 0.42 mmol, yield 12.8%) was obtained. Melting point 173 ~ 176 ° C

¹ H-NMR (200 MHz, DMSO-d6): δ (ppm): 12.08 (1H, brs), 7.20—7000 (4 mm, m), 6.75 (1H, s), 4.78 (2H, s), 3.78 (2H, s), 3.01 (3H, s), 2.95—2.80 (4 (, m), 2.11 (3H, m)

1 ³ C-NMR (50 MHz, DMSO-d6): δ (ppm): 172.4, 168.4, 157.6, 150.6, 139.2, 134.7, 1 29.4, 128.1, 107.5, 38.3, 34.4, 33.1, (22.7, 22.6)

(Partial peaks are observed due to s-cis / s-trans isomers of amide bonds)

[0086] Production Example 5

Synthesis of Ν- (4- {2- [4- (Ν'-Ethylhydrazinocarbonylmethyl) phenyl] ethyl} -1,3-thiazol-2-yl) acetamide

[0087] [Chemical 14]

[0088] By a method similar to Production Example 2, 4- {2- [2- (acetylamino) -1,3-thiazol-4-yl] ethyl} phenylacetic acid (l.OOg, 3.29 mmol) was added. Condensed with tilhydrazine. Ethylhydrazine was prepared by treating ethylhydrazine oxalate with about 2.4 equivalents of sodium hydroxide. The crude product was purified by silica gel column chromatography (Fuji Silysia NH-DM2035, 40 g, dichloromethane: methanol = 40: 1). The fraction containing the desired product was concentrated, and the precipitated crystals were collected by filtration and washed with diisopropyl ether. Drying afforded the title compound (129.6 mg, 0.374 mmol, yield 22.8%) as a white solid.

Melting point 182 ~ 186 ° C

¹ H-NMR (200MHz, DMSO_d6): δ (ppm): 12 · 08 (1Η, brs), 9.55—9 · 41 (1Η, br), 7.20—7.05 (4Η, m), 6 · 73 ( 1Η, s), 4.90_4 · 70 (1Η, m), 3.30 (2Η, s), 2.98-2.79 (4Η, m), 2.79-2.5 9 (2Η, m), 2.11 (3Η, s) , 0 · 94 (3Η, t, J = 7.1Hz)

¹³ C-NMR (50 MHz, DMSO-d6): δ (ppm): 169.5, 168.7, 157.9, 150.8, 139.9, 134.2, 129.3, 128.6, 107.8, 45.8, 40.6, 34.7, 33.3, (23.0, 22.9), 13.5

(Partial peaks are observed due to s-cis / s-trans isomers of amide bonds)

[0089] Production Example 6 Synthesis of Ν- (4- {2- [4- (Ν ', Ν'-dimethylhydrazinocarbonylmethyl) phenyl] ethyl} -l, 3-thiazol-2-yl) acetamide

[0090] [Chemical 15]

[0091] 4- {2- [2- (acetylylamino) -1,3-thiazol-4-yl] ethyl} phenylacetic acid (l.OOg, 3.29 mmol) was added to N by a method similar to Production Example 2. , And condensed with N-dimethylhydrazine. The crude product was purified by silica gel column chromatography (Fuji Silysia NH-DM2035, 40 g, dichloromethane: methanol = 30: 1). The fraction containing the desired product was concentrated, and the precipitated crystals were collected by filtration and washed with diisopropyl ether. Drying gave the title compound (0.88 g, 0.254 mmol, yield 77.3%) as a pale yellow solid.

Melting point 186 ~ 189 ° C

¹ H-NMR (200MHz, DMSO— d6): δ (ppm): 12 · 08 (1Η, brs), 8 · 99 (1Η Χ 2/3, brs), 8.33 (1 HX l / 3, brs), 7.23-7.10 (4H, m), 6.73 (lH X 2/3, s), 6.72 (lH X l / 3, s), 3.61 (2H X 1/3), 3.22 (2H X 2/3, s) , 3.00-2.75 (4H, m), 2.45 (6H X 2/3, s), 2.41 (6H X l / 3, s), 2.11 (3H, s)

¹³ C-NMR (50 MHz, DMSO_d6): δ (ppm): 173.0, 168.7, 167.9, 157.9, 150.9, 139.9, 1 39.6, 134.2, 129.7, 129.3, 128.6, 128.5, 107.8, 48.3, 46.9, 46.8, 41.0, 38.5, 34.7, 3 3.4, 23.0, 22.9

(Observed as a mixture of s-cis / s-trans isomers of amide bonds)

[0092] Production Example 7

Synthesis of N- {4- [2- (4-hydrazinocarbonylmethylphenyl) ethyl] -5_ (4-sulfamoylbenzyl) -1,3-thiazol-2-yl} acetamide

[0093] [Chemical 16] Step-1

CHCI ₃

[0094] Ethyl 2-acetylamino-5-benzyl-1,3-thiazole-4-carboxylate (10.08 g,

(33.12 mmol) in Kuroguchi Form (200 ml) was added dropwise Kuroguchi Sulfuric Acid (22.1 ml, 331 mmol) at 0 ° C. and stirred at room temperature for 17 hours. The reaction solution was poured into ice water (400 ml) and extracted with tetrahydrofuran. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure, and purify the residue by silica gel column chromatography (Fuji Silysia BW-300SP, 300 g, dichloromethane: methanol = 40: 1) to obtain ethyl 2-acetylamino-5_ (4-chlorosulfonylbenzyl) -1 as a pale yellow solid. , 3-thiazole-4-carboxylate (8.07 g, 20.0 mmol, yield 60.5%) was obtained.

[0095] [Chemical 17]

Step-2

[0096] Ethyl 2-acetylamino-5_ (4-chlorosulfonylbenzyl) -1,3-thiazole-4-carboxylate (8.00 g, 19.9 mmol) in tetrahydrofuran (160 ml) at 0 ° C with 28% aqueous ammonia ( 90.7 ml, 1.34 mol) was added dropwise and stirred at room temperature for 2 hours. Saturated ammonium chloride water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and diisopropyl ether (300 ml) was added to the residue. The produced solid was collected by filtration and washed with diisopropyl ether. The residue was dried under reduced pressure to obtain ethyl 2-acetylamino-5_ (4-sulfamoylbenzyl) -1,3-thiazole-4-streptoxylate (6.69 g, 17.5 mmol, yield 87.9%) as a white solid.

[0097] [Chemical 18] Step-3

[0098] Lithium borohydride was suspended in a suspension of ethyl 2-acetylamino-5_ (4-sulfamoylbenzyl) -1,3-thiazole-4-carboxylate (6.50 g, 17.0 mmol) in tetrahydrofuran (195 ml). (4.36 g, 170 mmol) was added, and the mixture was heated to reflux for 17 hours. The reaction mixture was cooled to 0 ° C., and 6N hydrochloric acid (28.3 ml, 170 mmol) was added dropwise. The mixture was concentrated to about 1/5 volume under reduced pressure, water (210 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and diisopropyl ether (300 ml) was added to the residue. The produced solid was collected by filtration and washed with diisopropyl ether. N- [4-Hydroxymethyl-5_ (4-sulfamoylbenzyl) -1,3-thiazol-2-yl] acetamide (3.90 g, 11.4 mmol, yield 67.4%) Got.

[0099] [Chemical 19]

Step-4

[0100] N- [4-Hydroxymethyl-5_ (4-sulfamoylbenzyl) -1,3-thiazol-2-yl] acetamide (3.38 g, 9.90 mmol) in dichloromethane (240 ml), methanol (12 ml ) Was dissolved in a mixed solvent, activated manganese dioxide (33.8 g, 389 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered through celite (trade name, diatomaceous earth), and the filtrate was concentrated under reduced pressure. Diisopropyl ether (100 ml) was added to the concentrated residue, and the precipitated solid was collected by filtration and washed with diisopropyl ether. Dried under reduced pressure, N- [4-formyl-5_ (4-sulfamoylpentyl) -1,3-thiazol-2-yl] acetamide (2.39 g, 7.04 mmol, yield 71.1%) as a pale yellow solid Got.

[0101] [Chemical 20] Step-5

[0102] To a solution of (4-carboxymethylbenzyl) triphenylphosphonium bromide (8.859 g, 18.03 mmol) in anhydrous N, N-dimethylformamide (80 ml) at 0 ° C, potassium tert-butoxide (5.058 g, 4 5.08 mmol) was added and stirred at room temperature for 30 minutes. Next, a solution of N_ [4_formyl-5_ (4_sulfamoylbenzyl) -1,3-thiazol-2-yl] acetamide (2.04 g, 6.01 mmol) in anhydrous N, N-dimethylformamide (30 ml) was added. And stirred for 5 hours. Under cooling, water was added and washed with ethyl acetate (200 ml). The aqueous layer was acidified with 1N hydrochloric acid (pH 5) and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and crude (4- {2- [2-acetylamino-5_ (4-sulfamoylpentyl) -1,3-thiazol-4-yl] bur} phenyl) acetic acid (Yellow white solid) 3.04 g) was obtained.

[0103] [Chemical 21]

Step-o

[0104] Crude (4- {2- [2-acetylamino-5- (4-sulfamoylbenzyl) -1,3-thiazol-4-yl] bur} phenyl) acetic acid (3.04 g) in methanol (100 ml ), Tetrahydrofuran (100 ml) and acetic acid (10 ml), 10% palladium on carbon was added, and hydrogenated at room temperature and normal pressure. The reaction solution was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Merck 9385, 90 g, dichloromethane: methanol = 5: 1 → 1: 1). Purify again with silica gel column chromatography (Merck 9385, 90 g, dichloromethane: tetrahydrofuran = 5: 1), and use (4- {2- [2-acetylamino-5_ (4-sulfamoylbenzyl)- 1,3-thiazol-4-yl] ethyl} phenyl) acetic acid (1.70 g, 3.59 mmol, yield 59.7% [from St mark-5]). [0105] [Chemical 22]

Step-7

[0106] (4- {2- [2-acetylamino-5_ (4-sulfamoylbenzyl) -1,3-thiazol-4-yl] ethyl) phenyl) acetic acid (50.0 mg, 0.105 mmol) in anhydrous N 1,1′_carbonyldiimidazole (45.1 mg, 0.278 mmol) was added to a solution of, N-dimethylformamide (lml), and the mixture was stirred at 50 ° C. for 2 hours. After cooling to room temperature, hydrazine monohydrate (0.05 ml, l. Lmmol) was added and stirred for 17 hours. Ice water (5 ml) and saturated aqueous sodium hydrogen carbonate (5 ml) were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentration to dryness gave the title compound (12.0 mg, 0.025 mmol, yield 23.4%) as a white solid.

Melting point 183 ~ 186 ° C

¹ H-NMR (200MHz, DMSO— d6): δ (ppm): 12 · 01 (1Η, brs), 9 · 20 (1Η, brs), 7 · 70 (2Η, d, J = 7.7Hz), 7 · 35_6 · 92 (6Η, m), 4 · 40 (2Η, br), 3.95 (2Η, s), 3 · 30 (2Η, s), 2.90_2 · 70 (4Η, m), 2 · 07 (3Η, s)

¹³ C-NMR (50 MHz, DMSO): δ (ppm): 169.9, 168.3, 155.4, 145.7 144.8, 142.3, 139.6, 134.0, 129.1, 128.9, 128.4, 126.1, 123.1, 115.8, 34.8, 30.7, 22.5

[0107] Production Example 8

Synthesis of N- (4- {2- [4- (2-hydrazinocarbonylethyl) phenyl] ethyl} -l, 3-thiazol-2-ynole) acetamide

[0108] [Chemical 23]

[0109] Carbon tetrachloride (150 ml) was added to 3_ (4-methylphenyl) -2-propenoic acid (8.110 g, 50.00 mmol), suspended, and N-bromosuccinimide (8.899 g, 50.00 mmol), peroxidized. Benzyl (25% water content, 161.6 mg, 0.500 mmol) was added. The mixture was heated to reflux for 17 hours, cooled to room temperature, and concentrated under reduced pressure. The resulting solid was collected by filtration and washed twice with ethyl acetate. Drying under reduced pressure gave 3-[(4-bromomethyl) phenyl] -2-propenoic acid (7.777 g, 32.26 mmol, yield 64.5%) as a light brown solid.

[0110] [Chemical 24]

Step— 2

[0111] Triphenylphosphine (9.059 g, 34.54 mmol) was added to a solution of 3- [4- (bromomethyl) phenyl] -2-propenoic acid (8.327 g, 34.54 mmol) in anhydrous toluene (135 ml) and heated for 4 hours. Refluxed. After cooling to room temperature, the precipitated solid was collected by filtration and washed three times with diisopropyl ether. The mixture was dried under reduced pressure to give {4- [2- (carboxyl) ethylene] benzyl} (triphenyl) phosphonium bromide (15.64 g, 31.07 mmol, yield 89.8%) as a light brown solid.

[0112] [Chemical 25]

Step-3

[0113] {4- [2- (Carboxy) ethylene] benzyl} (triphenyleno) phosphonium bromide (5.537 g, l l.OOmmol) in anhydrous N, N-dimethylformamide (50 ml) in potassium tert- Butoxide (3.3 66 g, 30.00 mmol) was added at 0 ° C, and the mixture was stirred at room temperature for 30 min. A solution of N_ (4_formyl-1,3_thiazol-2-yl) acetamide (1.702 g, lO.OOmmol) in anhydrous N, N-dimethylformamide (8 ml) was added and stirred at room temperature for 1 hour. Water (100 ml) was added and washed twice with ethyl acetate. Water layer IN hydrochloric acid (25 ml) was added thereto and stirred, and the precipitated solid was collected by filtration and washed with water. After drying under reduced pressure, 3_ (4- {2- [2- (acetylylamino) -1,3-thiazol-4-yl] bur} phenol) -2-propenoic acid (2.913 g, 9.266 mmol, The yield was 92.7%).

[Chemical 26]

Step-4

[0115] 3_ (4- {2- [2- (Acetyllamino) -1,3-thiazol-4-yl] bur} phenyl) -2-propenoic acid (2.913 g, 9.266 mmol) in tetrahydrofuran (300 ml), Suspended in a mixed solvent of methanol (300 ml) and acetic acid (60 ml), 10% palladium carbon (2.337 g, containing 50% water) was added, and hydrogen was added at room temperature and normal pressure (about 100 hours). The reaction was filtered through celite. The filtrate was concentrated under reduced pressure, and the resulting solid was collected by filtration and washed with diisopropyl ether. Drying under reduced pressure gave a white solid. The mother liquor concentrate was purified by silica gel column chromatography (Fuji Silysia BW-300SP, 75 g, methanol: dichloromethane = 1: 20). Fractions containing the desired product were collected and dried under reduced pressure, and the resulting solid was washed with diisopropyl ether and dried under reduced pressure to obtain a white solid. The product was integrated and 3_ (4- {2- [2- (acetylylamino) -1,3-thiazol-4-yl] ethyl} phenyl) propionic acid (2.383 g, 7.485 mmol, yield 80.8%) Obtained.

[0116] [Chemical 27]

Step— 5

[0117] 3_ (4- {2- [2- (Acetyllamino) -1,3-thiazol-4-yl] ethyl) phenyl) propionic acid (573.1 mg, 1.800 mmol) in anhydrous N, N-dimethyl 1,1′-Carbonyldiimidazole (437.8 mg, 2.700 mmol) was added to a formamide (4.5 ml) solution, and the mixture was stirred at 50 ° C. for 1 hour. After cooling to room temperature, hydrazine 'monohydrate (0.43 ml, 9.0 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. water ( 10 ml) was added and stirred, and the resulting solid was collected by filtration. Washed 3 times with water and 3 times with ethyl acetate. Drying under reduced pressure gave the title compound (525.7 mg, 1.581 mmol, yield 87.9%) as a white solid.

Melting point 196 ~ 198 ° C

¹ H-NMR (200MHz, DMSO-d6): δ (ppm): 12 · 06 (1Η, brs), 8 · 93 (1Η, brs), 7.17-7.02 (4H, m), 6.72 (1H, s) , 4 · 14 (2Η, brs), 2.90_2 · 78 (4Η, m), 2.75 (2H, t, J = 7.7Hz), 2.27 (2H, t, J = 7.7Hz), 2.10 (3H, s)

¹³ C-NMR (50 MHz, DMSO): δ (ppm): 171.0, 168.4, 157.6, 150.6, 139.1, 138.9, 128.4, 128.3, 107.5, 35.3, 34.4, 33.1, 30.8, 22.4

[0118] Production Example 9

Synthesis of 4- (4- {2- [2- (acetylylamino) -1,3-thiazol-4-inole] ethyl) phenenole) semicarbazide

[0119] [Chemical 28]

Step-1

[0120] To a solution of 1,1'_carbonyldiimidazole (810.8 mg, 5.000 mmol) in anhydrous tetrahydrofuran (5 ml) was added tert-butoxycarbazate (660.8 mg, 5.000 mmol), and the mixture was stirred at room temperature for 1 hour. Add N- {4- [2- (4-aminophenenyl) ethyl] -1,3-thiazol-2-yl} acetamide (518.7 mg, 2.000 mmol), triethylamine (0.42 ml, 3.0 mmol) at room temperature. For 17 hours. Ethyl acetate (40 ml) and water (30 ml) were added and stirred, and the mixture was allowed to stand and separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP, 45 g, ethyl acetate: hexane = 7: 3 → 9: 1). Fractions containing the desired product are concentrated, and the resulting solid is washed with diisopropyl ether and dried under reduced pressure to give N′-tert-butoxycarbonyl-4- (4- {2- [2- (acetylylamino) − 1,3-thiazole-4-ynole] ethyl} phenenole) semicarbazi (663.4 mg, 1.581 mmol, yield 79.1%) was obtained.

[0121] [Chemical 29]

Step2

[0122] N'-tert-butoxycarbonyl _4- (4- {2- [2- (acetylylamino) -1,3-thiazol-4-yl] ethyl} phenyl) semicarbazide (629.3mg, 1.500mmol) A 4M hydrogen chloride dioxane solution (7.5 ml, 30 mmol) was added to a dichloromethane (7.5 ml) solution, and the mixture was stirred at room temperature for 2.5 hours. Concentrated under reduced pressure, aqueous sodium bicarbonate (80 ml), ethyl acetate (250 ml) and tetrahydrofuran (50 ml) were added to the residue, and the mixture was allowed to stand and separated. The aqueous layer was extracted twice with an ethyl acetate-tetrahydrofuran mixed solution (5: 1) and five times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to dryness to give the title compound (308.4 mg, 0.966 mmol, yield 64.3%) as a slightly pink solid. Melting point 233-236 ° C

¹ H-NMR (200MHz, DMSO-d6): δ (ppm): 12 · 08 (1Η, brs), 8 · 53 (1Η, brs), 7 · 39 (2Η, d, J = 8.3Hz), 7 34 (1Η, brs), 7/04 (2Η, d, J = 8.3Hz), 6.71 (1H, s), 4.31 (2H, brs), 2.90-2.7 8 (4H, m), 2.11 (3H, s)

¹³ C-NMR (50 MHz, DMSO): δ (ppm): 168.1, 157.3, 150.4, 137.7, 134.2, 128.2, 118.1, 107.2, 33.9, 33.0, 22.3

[0123] Production Example 10

Synthesis of Ν- (4- {2- [4- (Ν'-Acetylhydrazinocarbonylmethyl) phenyl] ethyl} -l, 3-thiazol-2-yl) acetamide

[0124] [Chemical 30]

[0125] 2- (4- {2- [2- (Acetyllamino) -1,3-thiazol-4-yl] ethyl) phenyl) acetic acid (913.1 1,1'-carbonyldiimidazole (729.7 mg, 4.500 mmol) was added to a solution of mg, 3.000 mmol) in anhydrous N, N-dimethylformamide (7.5 ml), and the mixture was stirred at 50 ° C for 1 hour. After cooling to room temperature, acetohydrazide (1.11 lg, 15.00 mmol) was added and stirred at room temperature for 1 hour. Water (100 ml) and ethyl acetate (50 ml) were added and stirred, and the precipitated solid was collected by filtration and washed twice with water and three times with ethyl acetate. Drying under reduced pressure gave the title compound (635.9 mg, 1.764 mmol, yield 58.8%) as a white solid.

Melting point 223-225 ° C

¹ H-NMR (200 MHz, DMSO_d6): δ (ppm): 12 · 07 (1Η, brs), 9 · 95 (1Η, brs), 9 · 78 (1Η, br s), 7.23-7.06 (4H, m ), 6.72 (1H, s), 3.39 (2H, s), 2.98-2.75 (4H, m), 2.10 (2H, s), 1.82 (3H, s)

¹³ C-NMR (50 MHz, DMSO-d6): δ (ppm): 169.5, 168.7, 168.4, 157.9, 150.8, 140.0, 1 33.7, 129.4, 128.6, 107.8, 34.7, 33.3, 22.9, 21.0

[0126] Production Example 11

Synthesis of N- (4- {2- [4- (N'_butanoylhydrazinocarbonylmethyl) phenyl] ethyl} -l, 3-thiazol-2-yl) acetamide

[0127] [Chemical 31]

Step 1

To a solution of methyl butanoate (4.0 ml, 35.3 mmol) in anhydrous methanol (8 ml), hydrazine monohydrate (2.1 ml, 42.3 mmol) was added dropwise at room temperature, and the mixture was stirred for 18 hours. After concentration under reduced pressure, methyl butanoate was removed by azeotropic distillation with methanol five times. The concentrated residue was purified by a silica gel column (S mark-pak Sil, 10 g 25 cc, ethyl acetate), and the obtained crystals were washed with diisopropyl ether. Drying under reduced pressure gave butane hydrazide (1.387 g, 13.56 mmol, yield 38.5%) as white crystals.

[0129] [Chemical 32]

[0130] 2- (4- {2- [2- (Acetylamino) -1,3-thiazol-4-yl] ethyl) phenyl) acetic acid (304.5 mg, l.OOOmmol) in anhydrous N, N- 1,1′-carbonyldiimidazole (244.0 mg, 1.505 mmol) was added to a dimethylformamide (lml) solution, and the mixture was stirred at 50 ° C. for 1 hour. After cooling to room temperature, butane hydrazide (307.1 mg, 3.007 mmol) and anhydrous N, N-dimethylformamide (lml) were added, and the mixture was stirred at room temperature for 2 hours. Water (15 ml) was added and stirred, and the precipitated solid was collected by filtration. The solid was washed 3 times with water and 3 times with ethyl acetate. Drying under reduced pressure gave the title compound (24 8.9 mg, 0.641 mmol, yield 64.1%) as a pale yellow solid.

Melting point 215 ~ 217 ° C

¹ H-NMR (200 MHz, DMSO-d6): δ (ppm): 12 · 06 (1Η, brs), 9 · 95 (1Η, brs), 9 · 71 (1Η, br s), 7.26-7.03 (4H , M), 6.72 (1H, s), 3.39 (2H, s), 2.99-2.79 (4 mm, m), 2.10 (3H, s), 2.06 (2H, t, J = 7.1 Hz), 1.62- 1.40 (2H, m), 0.86 (3H, t, J = 7.3Hz)

¹³ C-NMR (50 MHz, DMSO-d6): δ (ppm): 171.1, 169.2, 168.4, 157.6, 150.5, 139.7, 1 33.4, 129.1, 128.3, 107.5, 35.2, 34.4, 33.0, 22.7, 18.6, 13.7

[0131] Production Example 12

Synthesis of N- (4- {2- [4- (N'_decanolhydrazinocarbonylmethyl) phenyl] ethyl} -l, 3-thiazol-2-yl) acetamide

[0132] [Chemical 33]

Step-丄

NH ₂ NH ₂ H ₂ 0 _u

(CH ₂ ) ₈ CH ₃ ^ H ₂ N'N 丫 (CH ₂ ) _B CH ₃

Hydrazine monohydrate (1.9 ml, 39.2 mmol) was added dropwise to a solution of MeOH O methyl decanoate (7.0 ml, 32.4 mmol) in anhydrous methanol (15 ml). Stir at room temperature for 29 hours, concentrate under reduced pressure, and add 1 with methanol. It azeotroped twice. The obtained solid was washed with hexane and then dried under reduced pressure to obtain decanhydrazide (2.197 g, 11.79 mmol, yield 36.1%) as white crystals.

[0134] [Chemical 34]

Step-2

[0135] 2- (4- {2- [2- (Acetylamino) -1,3-thiazol-4-yl] ethyl) phenyl) acetic acid (304.4 mg, l.OOOmmol) in anhydrous N, N- To the dimethylformamide (2 ml) solution was added 1,1′-carbonyldiimidazole (243.2 mg, 1.500 mmol), and the mixture was stirred at 50 ° C. for 1 hour. After cooling to room temperature, decanhydrazide (838.3 mg, 4.500 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Water (20 ml) was added and stirred, and the resulting solid was collected by filtration and washed 3 times with water and 5 times with ethyl acetate. Drying under reduced pressure gave the title compound (301.3 mg, 0.638 mmol, yield 63.8%) as a white solid.

Melting point 203-205 ° C

¹ H-NMR (200 MHz, DMSO-d6): δ (ppm): 12 · 06 (1Η, brs), 9 · 94 (1Η, brs), 9 · 70 (1Η, br s), 7.25-7.04 (4H , M), 6.72 (1H, s), 3.38 (2H, s), 2.97-2.76 (4 mm, m), 2.10 (3H, s), 2.07 (2H, t, J = 7.6 Hz), 1.57- 1.36 (2H, m), 1.36-1.14 (12H, m), 0.84 (3H, t, J = 6.2Hz) 1 3 C-NMR (50MHz, DMSO- d6): δ (ppm): 171.2, 169.2, 168.4 , 157.6, 150.5, 139.7, 1 33.4, 129.1, 128.3, 107.5, 34.4, 33.3, 33.0, 29.1, 29.0, 28.9, 28.7, 25.2, 22.7, 22.3, 14.1

[0136] Production Example 13

N- [4- (2- {4- [N '-(3-hydroxypropanoyl) hydrazinocarbonylmethyl] phenyl} ethyl) -1,3-thiazol-2-yl] acetamide Composition

[0137] [Chemical 35]

Step-1

EtaSiCI

NH ₂ NH ₂ H ₂ 0 H

MeOH DMF [0138] Hydrazine monohydrate (1.4 ml, 28.7 mmol) was added dropwise at 0 ° C to a solution of β-propiolatatatone (1.5 ml, 23.9 mmol) in anhydrous methanol (8 ml). The mixture was warmed to room temperature and stirred for 7 hours. After concentration under reduced pressure, anhydrous N, N-dimethylformamide (20 ml) and imidazole (1.954 g, 28.70 mmol) were added to the residue and stirred. Triethylsilyl chloride (4.8 ml, 28.7 mmol) was added dropwise at 0 ° C, and the mixture was warmed to room temperature and stirred for 2.5 hours. Water (100 ml) and ethyl acetate (100 ml) were added and stirred, and the mixture was allowed to stand and separated. The organic layer was washed with saturated aqueous ammonium chloride and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silica BW-300SP, 127 g, ethyl acetate), and 3 _ [(triethylsilyl) oxy] propanehydrazide (1.289 g, 5.903 mmol, yield 24.7 as a colorless liquid) %).

[0139] [Chemical 36]

Ste-2

[0140] 2- (4- {2- [2- (Acetylamino) -1,3-thiazol-4-yl] ethyl) phenyl) acetic acid (456.5 mg, 1.500 mmol) in anhydrous N, N-dimethyl To the formamide (2 ml) solution was added 1,1′-carbonyldiimidazole (364.8 mg, 2.250 mmol), and the mixture was stirred at 50 ° C. for 1 hour. After cooling to room temperature, a solution of 3 _ [(triethylsilyl) oxy] propanehydrazide (982.7 mg, 4.50 mmol) in anhydrous N, N-dimethylformamide (lml) was added and stirred at room temperature for 16 hours. Water (30 ml) was added and stirred, and the resulting solid was collected by filtration. The solid was washed twice with water and three times with ethyl acetate, and then dried under reduced pressure. As a white solid, N- [4- {2- [4_ (N '-{3-[(triethylsilyl) oxy] propanoyl} hydrazinocanole (Bonylmethinole) phenenoyl] ethyl} -1,3-thiazol-2-yl) acetamide (515.8 mg, 1.0 22 mmol, yield 68.1%) was obtained.

[0141] [Chemical 37]

Step— 3

[0142] N- (4- {2- [4- (N '-{3-[(Triethylsilyl) oxy] propanoyl} hydrazinocarbonylmethenole) phenenole] etyl 1,3-thiazole-2-inole) To tetrahydrofuran (501.7 mg, 0.099 mmol) was added tetrahydrofuran (3 ml), water (lml) and acetic acid (lml), and the mixture was stirred at room temperature for 1 hour. Concentrated under reduced pressure and azeotroped with ethyl acetate three times to remove acetic acid. The obtained solid was washed with ethyl acetate and dried under reduced pressure to give the title compound (355.5 mg, 0.911 mmol, 91.7% yield) as a pale yellow solid. Melting point 198-200 ° C

¹ H-NMR (200MHz, DMSO_d6): δ (ppm): 12 · 07 (1Η, brs), 10:00 (1Η, brs), 9 · 76 (1Η, b rs), 7.26-7.04 (4H, m ), 6.72 (1H, s), 4.58 (1H, t, J = 5.2Hz), 3.66-3.53 (2mm, m), 3.39 (2H, s), 2.98-2.78 (4H, m), 2.26 (2H, t, J = 6.7Hz), 2.10 (3H, s)

¹³ C-NMR (50 MHz, DMSO-d6): δ (ppm): 169.6, 169.1, 168.4, 157.6, 150.6, 139.7, 1 33.4, 129.1, 128.3, 107.5, 57.5, 37.3, 34.4, 33.4, 33.1, 32.4, 22.7

[0143] Production Example 14

N- [4- (2- {4- [N '-(6-Hydroxyhexanoyl) hydrazinocarbonylmethinole] phenole} ethyl) -1,3-thiazole-2-yl] acetamide synthesis

[0144] [Chemical 38]

Step-1

[0145] To a solution of ε-caprolatatam (4.0 ml, 37.9 mmol) in anhydrous methanol (8 ml) was added dropwise hydrazine 'monohydrate (2.2 ml, 45.0 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. After azeotroping with methanol three times, the residue was dissolved in methanol. The mixture was cooled to 0 ° C, and the precipitated crystals were collected by filtration. Drying under reduced pressure gave 6-hydroxyhexanehydrazide (3.446 g, 2 3.57 mmol, yield 62.3%) as white crystals.

[0146] [Chemical 39] Step— 2

[0147] Imidazole (817.4 mg, 12.00 mmol) was added to a solution of 6-hydroxyhexanehydrazide (1.462 g, lO.OOmmol) in anhydrous N, N_dimethylformamide (10 ml). Triethylsilyl chloride (2.0 ml, 12.0 mmol) was added dropwise at 0 ° C. The mixture was warmed to room temperature and stirred for 1.5 hours. Water (40 ml) and ethyl acetate (40 ml) were added and stirred, and the mixture was allowed to stand and separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated aqueous ammonium chloride and saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (Fuji Silica BW-300SP, 68 g, hexane: ethyl acetate = 3: 7 → 2: 8 → 1: 9 → 0/10) to give 6- [ (Triethylsilyl) oxy] hexanehydrazide (1.913 g, 7.345 mmol, yield 73.4%) was obtained.

[0148] [Chemical 40]

Step— 3

[0149] 2- (4- {2- [2- (Acetylamino) -1,3-thiazol-4-yl] ethyl) phenyl) acetic acid (305.0 mg, 1.002 mmol) in anhydrous N, N-dimethyl 1,1′-carbonyldiimidazole (244.1 mg, 1.505 mmol) was added to a formamide (lml) solution, and the mixture was stirred at 50 ° C. for 1 hour. After cooling to room temperature, a solution of 6_triethylcylinoleoxy-1-hexanehydrazide (781.4 mg, 3.000 mmol) in anhydrous N, N-dimethylformamide (0.5 ml) was added, and the mixture was stirred at room temperature for 17 hours. Water (15 ml) was added and stirred, and the precipitated solid was collected by filtration and washed 3 times with water and 3 times with ethyl acetate. Dry under reduced pressure and white solid as N- (4- {2- [4- (N '-{6-[(triethylsilyl) oxy] hexanoyl} hydrazinocarbonylmethinole) pheninole] ethyl} -1,3-thiazole- 2-yl) acetoamide (315.0 mg, 0.576 mmol, yield 57.5%) was obtained.

[0150] [Chemical 41] Step-4

[0151] N- (4- {2- [4- (N '-{6-[(Triethylsilyl) oxy] hexanoyl} hydrazinocarbonylmethole) phenenole] etyll, 1,3-thiazole-2-inole) To tetrahydrofuran (371.2 mg, 0.679 mmol) was added tetrahydrofuran (3 ml), water (lml) and acetic acid (lml), and the mixture was stirred at room temperature for 30 minutes. After concentration under reduced pressure, the residue was azeotroped with ethyl acetate five times to remove acetic acid. The resulting solid was collected by filtration and washed 3 times with ethyl acetate. Drying under reduced pressure gave the title compound (286.1 mg, 0.661 mmol, yield 9 7.4%) as a white solid.

Melting point 174-178 ° C

¹ H-NMR (200 MHz, DMSO-d6): δ (ppm): 12 · 07 (1Η, brs), 9 · 96 (1Η, brs), 9 · 71 (1Η, br s), 7.28-7.0K4H, m), 6.72 (1H, s), 4.33 (1H, t, J = 5.1Hz), 3.48-3.32 (4 mm, m), 2.97-2.78 (4H, m), 2.10 (3H, s) , 2 · 08 (2Η, t, J = 7.5Hz), 1.60— 1 · 12 (6Η, m)

1 ³ C-NMR (50 MHz, DMSO-d6): δ (ppm): 171.2, 169.2, 168.4, 157.6, 150.5, 139.7, 133.5, 129.1, 128.3, 107.5, 60.8, 34.4, 33.4, 33.0, 32.4, 25.3, 25.2, 22.7

[0152] Production Example 15

Ethyl 2-[(4- {2- [2- (Acetylamino) -1,3-thiazole-4-inole] ethyl} phenenole) ase [0153] [Chemical 42]

[0154] 2- (4- {2- [2- (Acetylamino) -1,3-thiazol-4-yl] ethyl) phenyl) acetic acid (304.4 mg, l.OOOmmol) in anhydrous N, N- 1,1′-carbonyldiimidazole (243.2 mg, 1.500 mmol) was added to a dimethylformamide (3 ml) solution, and the mixture was stirred at 50 ° C. for 1 hour. After cooling to room temperature, ethyl hydrazine carboxylate (312.3 mg, 3.000 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. Water (10 ml) was added and stirred, and the precipitated solid was collected by filtration. After washing with ethyl acetate three times and drying under reduced pressure, the title compound (261.5 mg, 0.670 mmol, yield 67.0%) was obtained as a pale yellow solid. Melting point: 176-178 ° C

¹ H-NMR (200 MHz, DMSO-d6): δ (ppm): 12.08 (1H, brs), 9.85 (1H, brs), 8.99 (1H, br s), 7.25-7.06 (4H, m), 6.73 ( 1H, s), 4.01 (2H, q, J = 6.9Hz), 3.36 (2H, s), 2.99—2.76 (4 H, m), 2.10 (3H, s), 1.16 (3H, t, J = 6.9 Hz)

¹³ C-NMR (50 MHz, DMSO-d6): δ (ppm): 170.0, 168.4, 157.6, 156.4, 150.5, 139.8, 133.3, 129.1, 128.3, 107.5, 60.6, 34.3, 33.3, 22.6, 14.7

[0155] Production Example 16

Butyl 2-[(4- {2- [2- (acetylylamino) -1,3-thiazole-4-inole] ethyl)

[0156] [Chemical 43]

Step-1

0 NH ₂ NH ₂ H ₂ 0 0 n-BuO 8 CI _TUC n-Bu. z N "^

[0157] Hydrazine monohydrate (1.5 ml, 30.9 mmol) was suspended in anhydrous tetrahydrofuran (20 ml), and butyl chloroformate (1.0 ml, 7.7 mmol) was added dropwise at 0 ° C. The temperature was raised to room temperature and stirred for 16 hours. After concentration under reduced pressure, water was added to the residue, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP, 36 g, hexane: ethinole acetate = 1: 1 → 1: 3), and butylhydrazinecarboxylate (869.5 mg, 6.579 mmol, yield 85.5%) was obtained.

[0158] [Chemical 44] Step— 2

[0159] 2- (4- {2- [2- (Acetylamino) -1,3-thiazol-4-yl] ethyl) phenyl) acetic acid (304.8 mg, l.OOlmmol) in anhydrous N, N- 1,1′-carbonyldiimidazole (243.6 mg, 1.502 mmol) was added to a dimethylformamide (lml) solution, and the mixture was stirred at 50 ° C. for 1 hour. After cooling to room temperature, butylhydrazinecarboxylate (264.8 mg, 2.004 mmol) was added, and the mixture was stirred at room temperature for 24 hours. Water (20 ml) and ethyl acetate (20 ml) were added and stirred. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed twice with water and once with saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was suspended in ethyl acetate and filtered. The obtained solid was washed with ethyl acetate three times and dried under reduced pressure to give the title compound (295.4 mg, 0.706 mmol, yield 70.5%) as a pale yellow solid.

Melting point 120 ~ 122 ° C

¹ H-NMR (200MHz, CDC1): δ (ppm): 10 · 27 (1Η, brs), 8 · 66 (1Η, brs), 7 · 86 (1Η, brs), 7

· 18-6 · 95 (4Η, m), 6 · 50 (1Η, s), 4 · 13 (1Η, t, J = 6.6Hz), 3 · 57 (2Η, s), 2 · 91_2 · 83 ( 4Η, m), 2 · 25 (3Η, s), 1 · 68_1 · 50 (2Η, m), 1.44- 1 · 23 (2Η, m), 0 · 90 (3Η, t, J = 7.2Hz)

1 ³ C-NMR (50 MHz, CDC1): δ (ppm): 171.7, 168.6, 158.8, 157.7, 150.0, 140.3, 131.

5, 129.0, 128.8, 107.7, 66.1, 40.9, 34.8, 33.0, 22.8, 18.9, 13.6

[0160] Production Example 17

Decyl 2-[(4- {2- [2- (acetylylamino) -1,3-thiazol-4-inole] ethyl)

[0161] [Chemical 45]

Step-1

[0162] Hydrazine 'monohydrate (1.27 ml, 26. lmmol) was suspended in anhydrous tetrahydrofuran (20ml), and decylchloroformate (1.50ml, 6.52mmol) was added dropwise at 0 ° C. The mixture was warmed to room temperature and stirred for 6.5 hours. After concentration under reduced pressure, water (20 ml) was added, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP, 30 g, hexane: ethyl acetate = 2: 1 → 1: 2), and decylhydrazinecarboxylate (1.22 2 mg, 5.649 as a white solid). mmol, yield 86.7%).

[0163] [Chem 46]

Step-2

[0164] 2- (4- {2- [2- (Acetylamino) -1,3-thiazol-4-yl] ethyl) phenyl) acetic acid (304.4 mg, l.OOOmmol) in anhydrous N, N- 1,1′-carbonyldiimidazole (243.6 mg, 1.500 mmol) was added to a dimethylformamide (lml) solution, and the mixture was stirred at 50 ° C. for 1 hour. After cooling to room temperature, decylhydrazinecarboxylate (649. Omg, 3.000 mmol) was added, and the mixture was stirred at room temperature for 22 hours. Water (50 ml), saturated brine (50 ml) and ethyl acetate (100 ml) were added and stirred, and the mixture was allowed to stand and separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography twice (Fuji Silysia BW-300SP, 30 g and 20 g, hexane: ethyl acetate = 3: 7) to give the title compound as a white solid (391. lmg, 0.778 mmol, Yield 77.8%).

Melting point 128 ~ 130 ° C

¹ H-NMR (200MHz, CDCl): δ (ppm): 10 · 72 (1Η, brs), 9 · 23 (1Η, brs), 8 · 36 (1Η, brs), 7

.17-6.89 (4Η, m), 6 · 47 (1Η, s), 4 · 10 (2Η, t, J = 6.7Hz), 3 · 54 (2Η, s), 2 · 93— 2 · 77 ( 4Η, m), 2.22 (3Η, s), 1 · 78— 1 · 50 (4Η, m), 1 · 39— 1 · 17 (12Η, m), 0 · 87 (3Η, t, J = (6.4Hz)

1 ³ C-NMR (50 MHz, CDCl): δ (ppm): 171.7, 168.5, 158.8, 157.7, 150.0, 140.3, 131.5

, 129.0, 128.8, 107.7, 66.5, 40.9, 34.9, 33.0, 31.9, 29.5, 29.3, 29.2, 28.7, 25.7, 22.9, 22.6, 14.1 [0165] Production Example 18

2-Hydroxyethylenole 2-[(4- {2- [2- (acetylylamino) -1,3-thiazol-4-inole] ethyl)}

[0166] [Chemical 47]

Ste -1

Hydrazine monohydrate (1.7 ml, 35.0 mmol) was added dropwise to a solution of ethylene carbonate (2.600 g, 29.53 mmol) in anhydrous methanol (5 ml). The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The mixture was heated and dissolved in 2-propanol V (30 ml), cooled, and the precipitated crystals were collected by filtration. The crystals were washed 3 times with 2-propanol and twice with ethyl acetate. By drying under reduced pressure, 2-hydroxyethylhydrazinecarboxylate (1.745 g, 14.53 mmol, yield 49.2%) was obtained as white crystals.

[0168] [Chemical 48]

Step 2

[0169] Imidazole (245. lmg, 3.601mmol) was added to a solution of 2-hydroxyethylhydrazinecarboxylate (360.9mg, 3.005mmol) in anhydrous N, N_dimethylformamide (lml). Triethylsilyl chloride (0.60 ml, 3.60 mmol) was added dropwise at 0 ° C and stirred for 30 minutes. The mixture was warmed to room temperature and stirred for 2.5 hours. Water and ethyl acetate were added and stirred, and the mixture was allowed to stand and separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed twice with saturated aqueous ammonium chloride and once with saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was subjected to silica gel column chromatography twice (first time: Fuji Silica BW-300SP, 20 g, dichloromethane: methanol = 20: 1, second time: Fuji Silica NH-DM1020, 18 g, dichloromethane: methanol = 40: 1) spirit 2-[(Triethylsilyl) oxy] e as a pale yellow liquid

(531.9 mg, 2.269 mmol, yield 75.6%).

[0170] [Chemical 49]

Step— 3

[0171] 2- (4- {2- [2- (Acetylamino) -1,3-thiazol-4-yl] ethyl) phenyl) acetic acid (608.7 mg, 2.000 mmol) in anhydrous N, N-dimethyl To the formamide (2 ml) solution was added 1,1′-carbonyldiimidazole (486.5 mg, 3.000 mmol), and the mixture was stirred at 50 ° C. for 1 hour. After cooling to room temperature, 2 _ [(triethylsilyl) oxy] ethylhydrazinecarboxylate (1.466 g, 6.000 mmol) was added, and the mixture was stirred at room temperature for 28 hours. Water (20 ml), ethyl acetate (40 ml) and saturated brine (20 ml) were added and stirred, and the mixture was allowed to stand and separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP, 100 g, hexane: ethyl acetate = 3: 7 → 2: 8) to give 2-[(triethylsilyl) oxy] ethyl 2-[(4- {2 -[2- (Acetylamino) -1,3-thiazol-4-inole] ethyl} feninole) acetyl] hydrazinecarboxylate (809. 5 mg, 1.555 mmol, yield 77.7%) was obtained.

[0172] [Chemical 50]

[0173] 2-[(Triethylsilyl) oxy] ethyl 2-[(4- {2- [2- (acetylylamino) -1,3-thiazole-4-inole] ethyl} pheninole) acetylino] hydrazine power noroxylate ( To tetrahydrofuran (45.5 ml, 1.470 mmol) were added tetrahydrofuran (4 ml), water (4 ml) and acetic acid (12 ml), and the mixture was stirred at room temperature for 15 minutes. Concentrated under reduced pressure and azeotroped with ethyl acetate five times to remove acetic acid. The concentrated residue was washed 3 times with water and 3 times with ethyl acetate. Drying under reduced pressure gave the title compound (453. lmg, 1.115 mmol, yield 75.8%) as a white solid.

Melting point: 176-179 ° C

¹ H-NMR (200 MHz, DMSO—d6): δ (ppm): 12 · 07 (1Η, brs), 9.85 (1H, brs), 9.05 (1H, br s), 7.24-7.03 (4H, m), 6.73 (1H, s), 4.76 (1H, br), 3.98 (2H, t, J = 4.6Hz), 3.60—3.47 (4 H, m), 3.37 (2H, s), 2.98— 2 · 79 (4Η , M), 2.10 (3H, s)

¹³ C-NMR (50 MHz, DMSO_d6): δ (ppm): 170.0, 168.4, 157.6, 156.5, 150.5, 139.7, 1 33.2, 129.1, 128.3, 107.5, 66.5, 59.4, 34.4, 33.0, 22.6

[0174] Production Example 19

Synthesis of 4- (hydrazinocarbonylmethyl) phenyl 2-acetylamino-1,3-thiazole-4-carboxylate

[0175] [Chemical 51] itep-l

Η

[0176] 1M hydrazine / tetrahydrofuran solution (80.0ml, 80.0mmol) in (4-hydroxy) phenol at -78 ° C A solution of methyl nyl acetate (3.323 g, 20.00 mmol) in tetrahydrofuran (20 ml) was added. The temperature was gradually raised to room temperature, and the mixture was stirred at room temperature for 17 hours. The precipitated crystals were collected by filtration and washed 3 times with diisopropyl ether. Drying under reduced pressure gave 2- (4-hydroxyphenyl) acetohydrazide (2.187 g, 13.16 mmol, yield 65.8%) as a white solid.

[Chemical 52]

Step-2

[0178] A mixture of 2- (4-hydroxyphenyl) acetohydrazide (2.150 g, 12.94 mmol), di-tert-butyl dicarbonate (3.106 g, 14.23 mmol) and tetrahydrofuran (5 ml) at 0 ° C. Iodine (164.0 mg, 1.2 98 mmol) was added. The mixture was warmed to room temperature and stirred for 3 hours. Tetrahydrofuran (30 ml) was added to the reaction mixture, and the mixture was further stirred for 8.5 hours. The reaction solution was filtered through a silica gel pad (Fuji Silysia BW-300SP, 100 g) and washed with a mixed solvent of ethyl acetate / hexane (2: 1). The filtrate was concentrated to dryness and ethyl acetate (50 ml) was added. The resulting solid was collected by filtration, and washed once with ethyl acetate and five times with disopropyl ether. The residue was dried under reduced pressure to obtain tert-butyl 2-[(4-hydroxypheneno) acetyl] hydrazinecarboxylate (2.301 g, 8.639 mmol, yield 66.8%) as a white solid. Secondary crystals (529.7 mg, 1.989 mmol, yield 15.4%) were recovered from the mother liquor concentrate. (Total yield of primary and secondary crystals 82.2%)

[0179] [Chemical 53]

Step-3

[0180] Anhydrous N of 2- (acetylamino) -1,3-thiazole-4-carboxylic acid (750.0 mg, 4.028 mmol) To the N-dimethylformamide (9 ml) solution was added 1,1′-carbonyldiimidazole (751.4 mg, 4.634 mmol), and the mixture was stirred at 50 ° C. for 1 hour. After cooling to room temperature, tert-butyl 2 _ [(4_hydroxyphenyl) acetyl] hydrazinecarboxylate (1.394 g, 5.234 mmol) and N, N_dimethyl-4-aminoviridine (24.6 mg, 0.20 mmol) were added. . After stirring at 50 ° C. for 8 hours, the mixture was cooled to room temperature and poured into ice-cooled saturated aqueous sodium hydrogen carbonate (250 ml). Extraction was performed 3 times with ethyl acetate, and the combined organic layer was washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous ammonium chloride and saturated brine. The solution was filtered through a silica gel pad (Fuji Silysia BW-300SP, 50 g) and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (25 ml). Disopropyl ether (100 ml) was added dropwise at room temperature and stirred for 1 hour. The precipitate was collected by filtration and washed 3 times with diisopropyl ether. After drying under reduced pressure, 4- {2- [2- (tert-butoxycarbonyl) hydrazino] carbonylmethyl} phenyl 2- (acetylamino) -1,3-thiazole-4-carboxylate (1.539 g, 3.542 as a white solid) mmol, yield 87.9%).

[0181] [Chemical 54]

Step-4

[0182] 4- {2- [2- (tert-Butoxycarbonyl) hydrazino] carbonylmethyl} phenyl 2- (acetylamino) -1,3-thiazole-4-carboxylate (565.0 mg, 1.300 mmol) was converted to dioxane (5 · 7 ml) and 4M hydrogen chloride dioxane solution (22.6 ml, 90.4 ml) was added. After stirring at room temperature for 2 hours, dichloromethane (45 ml) was added and stirred for 30 minutes. The precipitate was collected by filtration and washed 3 times with dichloromethane. Drying under reduced pressure gave the title compound (477.6 mg, 1.288 mmol, yield 99.1%) as a white solid.

Melting point 205-209 ° C

¹ H-NMR (200MHz, DMSO_d6): δ (ppm): 12 · 58 (1Η, brs), 11 · 44 (1Η, brs), 11.00-9.90 (2Η, br), 8 · 29 (1Η, s) , 7 · 38 (2 d, d, J = 8.4Hz), 7 · 21 (2Η, d, J = 8.4Hz), 3 · 63 (2Η, s), 2.16 (3H, s)

13

C-NMR (50MHz, DMSO-d6): δ (ppm): 169.7, 169.4, 159.7, 158.6, 149.5, 139.9, 1 32.7, 130.5, 124.8, 121.9, 22.7

[0183] Production Example 20

Synthesis of N- (4-{[4- (hydrazinocarbonylmethyl) phenoxy] methyl} -1,3-thiazol-2-yl) acetamide

[0184] [Chemical 55]

[0185] Anhydrous acetonitrile (80 ml) of N- (4-chloromethyl-1,3-thiazol-2-inole) acetamide (4.000 g, 20.98 mmol), methyl (4-hydroxyphenyl) acetate (6.972 g, 41.96 mmol) ) To the solution were added N, N-diisopropylethylamine (8.135 g, 62.94 mmol) and potassium potassium yowi (696.5 mg, 4.196 mmol). After stirring at 70 ° C for 36 hours, the mixture was cooled to room temperature. After concentration under reduced pressure, 1N hydrochloric acid (100 ml) was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid, saturated aqueous sodium carbonate, and saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP, 200 g, ethyl acetate: hexane = 2: 3 → 3: 2) to obtain a white solid (1.631 g). Jetyl ether (100 ml) was added and suspended therein, and hexane (50 ml) was added. The resulting solid was collected by filtration and washed with a 20% jetyl ether / hexane mixed solvent. Drying under reduced pressure gave {4-[(2-acetylamino-1,3-thiazol-4-yl) methoxy] phenyl} methyl acetate (1.385 g, 4.32 7 mmol, yield 20.6%) as a white solid .

[0186] [Chemical 56]

Step 2

[0187] {4-[(2-Acetylamino-1,3-thiazol-4-yl) methoxy] phenyl} methyl acetate (800.0 IN sodium hydroxide aqueous solution (6.25 ml, 6.25 mmol) was added dropwise at 0 ° C to a solution of mg, 2.500 mmol) in dioxane (8 ml). The mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, and water (20 ml) was added. 1N hydrochloric acid (9.0 ml, 9.0 mmol) was added dropwise at 0 ° C. [Additional water (30 ml) was added while hydrochloric acid was added]. After stirring at 0 ° C for 30 minutes, the precipitate was collected by filtration and washed with ice water. After sufficiently draining the mother liquor, it was washed with hexane. Drying under reduced pressure gave {4-[(2-acetylamino-1,3-thiazol-4-yl) methoxy] phenyl} acetic acid (728.3 mg, 2.377 mmol, yield 95.1%) as a white solid.

Yes

[0188] [Chemical 57] Step- 3 'ΝΗ ₂

[0189] A solution of {4-[(2-acetylamino-1,3-thiazol-4-yl) methoxy] phenyl} acetic acid (720.0 mg, 2.3 50 mmol) in anhydrous N, N-dimethylformamide (5.5 ml) 1,1′-Carbonyldiimidazole (571.6 mg, 3.525 mmol) was added to the mixture, and the mixture was stirred at 50 ° C. for 1 hour. After cooling to _25 ° C, hydrazine monohydrate (0.57 ml, 11.8 mmol) was added, and the temperature was gradually raised to room temperature and stirred for 30 minutes. Cool to 0 ° C. and add water (90 ml). After stirring at 0 ° C. for 20 minutes, the precipitate was collected by filtration and washed 4 times with water and 2 times with ethyl acetate. Drying under reduced pressure gave the title compound (662.5 mg, 2.068 mmol, yield 88.0%) as a fine yellowish solid.

[Recrystallization] N, N-dimethylformamide (40 ml) was added to fine yellowish solid (640.0 mg, 1.998 mmol) and dissolved by heating at about 60 ° C. After cooling to room temperature, ethyl acetate (160 ml) was added dropwise. After stirring for 1 hour at room temperature, the precipitated crystals were collected by filtration and washed with ethyl acetate three times. Drying under reduced pressure gave the title compound (549.7 mg, 1.716 mmol, recovery rate 85.9%) as a white solid.

Melting point 216 ~ 219 ° C

¹ H-NMR (200MHz, DMSO_d6): δ (ppm): 12 · 15 (1Η, brs), 9 · 15 (1Η, brs), 7 · 16 (1Η, s), 7 · 14 (2Η, d, J = 8.6Hz), 6 · 91 (2Η, d, J = 8.6Hz), 5.00 (2Η, s), 4 · 25 (2Η, brs), 3 · 25 (2Η, s), 2.11 (3H , S) C-NMR (50MHz, DMSO-d6): δ (ppm): 170.0, 168.6, 158.3, 157.0, 146.6, 130.1, 1 28.6, 114.6, 111.5, 65.6, 22.6

[0190] Production Example 21

Synthesis of 2- (acetylamino) -N- [4- (hydrazinocarbonylmethyl) phenyl] -1,3-thiazole-4-carboxamide hydrochloride

[0191] [Chemical 58]

[0192] To a solution of 2- (acetylamino) -1,3-thiazole-4-carboxylic acid (183.2 mg, l.OOOmmol) in anhydrous N, N-dimethylformamide (3.0 ml), 1,1'-carbonyldiimidazole ( 243.2 mg, 1.500 mmol) was added, and the mixture was stirred at 45 ° C for 1.5 hours. After cooling to room temperature, tert-butyl 2 _ [(4_aminophenyl) acetyl] hydrazinecarboxylate (530.6 mg, 2.000 mmol) was added and stirred for 1 hour. After stirring at 45 ° C for 2.5 hours, the mixture was cooled to room temperature. Water (20 ml) was added and the resulting solid was collected by filtration and washed twice with ethyl acetate. Dried under reduced pressure and tert-butyl 2 _ {[4-({[2- (acetylylamino) -1,3-thiazol-4-yl] carbol} amino) phenyl] acetyl} hydrazinecarboxylate as a light brown solid (291.5 mg, 0.672 mmol, yield 67.2%) was obtained.

[0193] [Chemical 59]

Step— 2

tert-Butyl 2-{[4-({[2- (Acetylamino) -1,3-thiazol-4-yl] carboninole} amino) phenenole] acetyl] hydrazinecarboxylate (260. lmg, 0.600 mmol) in anhydrous dichloromethane (3 ml) was added 4M hydrogen chloride dioxane solution (3.0 ml, 3.0 mmol) and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and azeotroped with ethyl acetate three times. Residue in ethyl acetate The suspension was collected by filtration and washed twice with ethyl acetate. Drying under reduced pressure gave the title compound (185.0 mg, 0.500 mmol, 83.4%) as a white solid.

Melting point 248 ~ 255 ° C

¹ H-NMR (200 MHz, DMSO—d6): δ (ppm): 12.27 (1H, brs), 11.29 (1H, brs), 10.18 (2H, brs), 9.68 (1H, brs), 7.85 (1H, s ), 7.59 (2H, d, J = 8.4Hz), 7.17 (2H, d, J = 8.4Hz), 3.46 (2H, s), 2.08 (3Η, s)

¹ C-NMR (50 MHz, DMSO-d6): δ (ppm): 168.1, 167.6, 157.7, 156.3, 142.7, 135.6, 1 28.4, 127.9, 118.3, 116.7, 20.9

[0195] Production Example 22

Synthesis of N- [4-({[4- (hydrazinocarbonylmethyl) phenyl] amino} methyl) -l, 3-thiazole-2-ino] acetoamide dihydrochloride

[0196] [Chemical 60]

Steo-1

[0197] To a solution of 4-nitrophenylacetic acid (3.623 g, 20.00 mmol) in anhydrous tetrahydrofuran (70 ml) was added 1,1-carbonyldiimidazole (4.865 g, 30.00 mmol), and the mixture was stirred at room temperature for 30 minutes. tert-Butylcarbazate (6.608 g, 50.00 mmol) was added and stirred for 1 hour. The solvent was distilled off under reduced pressure, and ethyl acetate (250 ml) and 0.5N hydrochloric acid (180 ml) were added and stirred. After standing, liquid separation was performed, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP, 300 g, hexane: ethyl acetate = 1: 1) and tert-butyl 2-[(4-nitrophenyl) acetyl] as a white solid. Hydrazine carboxylate (4.566 g, 15.46 mmol, yield 77.3%) was obtained.

[0198] [Chemical 61] Step-2

[0199] tert-Butyl 2-[(4-nitrophenyl) acetyl] hydrazine carboxylate (4.496 g, 15.

22 mmol) was dissolved in ethyl acetate (90 ml), 10% palladium on carbon (0.899 g) was added, and hydrogenated at room temperature for 12 hours. The mixture was filtered through a celite pad, and the filtrate was concentrated under reduced pressure. The resulting solid was suspended in tert-butyl methyl ether and filtered. It was dried under reduced pressure. As a white solid, tert-butynole 2-[(4-aminophenenyl) acetyl] hydrazinecarboxylate (3.666 g, 13. 59 mmol, yield 89.3%) was obtained.

[0200] [Chemical 62]

Step— 3—

[0201] N- (4-Formyl-1,3-thiazol-2-inole) acetamide (510.6 mg, 3.000 mmol) and tert-butyl 2-[(4-aminophenino) acetyl] hydrazine carboxylate (795.9 mg, 3.000 mmol) was dissolved in anhydrous tetrahydrofuran (50 ml) and heated to reflux for 2 hours. The solvent was distilled off, ethyl acetate (5 ml) and tert-butyl methyl ether (50 ml) were added to the residue, and the precipitated solid was collected by filtration. After drying under reduced pressure, tert-butyl 2-{[4-({[2- (acetylylamino) -1,3-thiazol-4-yl] methylidene} amino) phenyl] acetyl} hydrazine carboxylate (1.233 g, 2.953 mmol, yield 98.5%).

[0202] [Chemical 63]

Step-4

[0203] tert-Butyl 2-{[4-({[2- (acetylylamino) -1,3-thiazol-4-yl] methylidene} amino) phenenole] acetyl} hydrazine carboxylate (918.5 mg, 2.200 mmol) was dissolved in anhydrous methanol (25 ml) and cooled to 0 ° C. Sodium borohydride (83.2 mg, 2.20 mmol) was added and stirred at 0 ° C. for 40 minutes. Acetic acid (0.5 ml) was added and stirred for 30 minutes. The solvent was distilled off under reduced pressure, ethyl acetate (100 ml) and methanol (50 ml) were added, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP, 60 g, dichloromethane: methanol = 20: 1 → 10: 1). The fraction containing the desired product was concentrated, and the resulting solid was suspended in ethyl acetate (20 ml) and collected by filtration. Dry under reduced pressure and tert-butyl 2-{[4 _ ({[2- (acetylylamino) -1,3-thiazol-4-yl] methyl} amino) phe as a white solid:

Hydrazinecarboxylate (640 · lmg, 1.526 mmol, yield 69.4%) was obtained.

[0204] [Chemical 64]

Step-5

[0205] tert-Butyl 2-{[4-({[2- (acetylylamino) -1,3-thiazol-4-yl] methinole} aminol] acetyl} hydrazinecarboxylate (320.0 mg, 0.763 mmol) Was suspended in anhydrous dichloromethane (5.7 ml), 4M hydrogen chloride dioxane solution (5.7 ml) was added, and the mixture was stirred at room temperature for 3 hours The reaction mixture was concentrated under reduced pressure and azeotroped three times with ethyl acetate. Was suspended in ethyl acetate, collected by filtration, washed twice with ethyl acetate, and dried under reduced pressure to give the title compound (297.3 mg, 0.758 mmol, yield 99.3%) as a white solid.

Melting point 162 ~ 165 ° C

¹ H-NMR (200MHz, DMSO_d6): δ (ppm): 12 · 06 (1Η, brs), 11 · 17 (1Η, brs), 10 · 40 (3Η, brs), 7 · 04 (2Η, d, J = 8.2Hz), 6.90 (1Η, s), 6.69 (2H, d, J = 8.2Hz), 4.25 (2H, s), 3.41 (2 H, s), 2.11 (3H, s)

¹³ C-NMR (50 MHz, DMSO-d6): δ (ppm): 169.6, 169.0, 158.3, 143.3, 137.7, 132.7, 1 30.4, 121.2, 113.2, 48.2, 39.0, 22.7 [0206] Production Example 23

Synthesis of N- {4- [2- (3-hydrazinocarbonylmethylphenyl) ethyl] -1,3-thiazol-2-yl} acetoamide

[0207] [Chemical 65]

Step-

[0208] N-bromosuccinimide (30.00 g, 168.6 mmol) was added to a solution of m-tolylacetic acid (25.00 g, 166.5 mmol) in anhydrous carbon tetrachloride (200 ml), and the temperature was gradually raised to the boiling point. The mixture was heated to reflux for 5.5 hours and then cooled to room temperature. The reaction solution was filtered to remove insoluble matters, and the insoluble matters were washed twice with carbon tetrachloride (100 ml). The filtrate was concentrated, carbon tetrachloride (60 ml) was added to the residue, and it was dissolved by heating at about 70 ° C. The mixture was cooled to about 40 ° C., and hexane (300 ml) was added dropwise. After stirring at room temperature for 30 minutes, the precipitated crystals were filtered and washed with hexane. The residue was dried under reduced pressure to give (3-promomethylphenyl) acetic acid (22.80 g, 99.53 mmol, yield 59.8%) as a white solid.

[0209] [Chemical 66]

Step— 2—

[0210] (3-Bromomethylphenol) acetic acid (22.00 g, 96.04 mmol), triphenylphosphine (30.23 g,

A solution of 115.2 mmol) anhydrous acetonitrile (300 ml) was heated to reflux for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to about 100 g. Jetyl ether (200 ml) was added, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration and washed 3 times with jetyl ether. Drying under reduced pressure gave [(3-Carbonylmethinole) benzyl] (Triphenylenole) phosphonium bromide (43.60 g 88.73 mmol, yield 92.4%) as a white solid.

[0211] [Chemical 67]

[0212] [(3-Carbonylmethinole) benzyl] (Triphenylenole) phosphonium bromide (9.529 g, 19.39 mmol) in anhydrous N, N-dimethylformamide (85 ml) suspension at 0 ° C tert-Butoxide (5. 935 g, 52.89 mmol) was added in small portions. After stirring at room temperature for 30 minutes, (4-formyl-1,3-thiazol-2-yl) acetamide (3.000 g, 17.63 mmol) was added and stirred for 3 hours. After cooling to 0 ° C., water (200 ml) was added, and the mixture was washed twice with ethyl acetate (100 ml). At 0 ° C, 6N hydrochloric acid was added dropwise to the aqueous layer to adjust the pH to 3, followed by stirring for 30 minutes. The precipitate was collected by filtration and washed three times with water and twice with diisopropyl ether. Drying under reduced pressure gave 3_ {2- [2- (acetylamino) -1,3-thiazol-4-yl] bur} phenylacetic acid (4.625 g, 15.30 mmol, yield 86.8%) as a white solid. .

[0213] [Chemical 68]

Step-4

[0214] 3_ {2- [2- (Acetyllamino) -1,3-thiazol-4-yl] bur} phenylacetic acid (4.500 g, 14.

88 mmol) was dissolved in a mixed solvent of tetrahydrofuran (225 ml) and methanol (90 ml), and 20% palladium carbon (50% water content, 1.800 g) was added. Hydrogenated at room temperature to 30 ° C at 4 atmospheres. After completion of the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated. Jetyl ether (100 ml) was added to the residue, and the precipitate was collected by filtration. After washing with jetyl ether three times, drying under reduced pressure, 3_ {2- [2- (acetylamino) -1,3-thiazol-4-yl] ethyl} phenylacetic acid (4.152g, 13.64) as a white solid mmol, yield 91.7%).

[0215] [Chem 69] Step 5

[0216] 3- {2- [2- (Acetylamino) -1,3-thiazol-4-yl] ethyl} phenylacetic acid (l.OOOg, 3.

To a solution of 286 mmol) in anhydrous N, N-dimethylformamide (9 ml) was added 1,1′-carbonyldiimidazole (799.1 mg, 4.928 mmol), and the mixture was stirred at 50 ° C. for 1 hour. After cooling to _15 ° C, hydrazine monohydrate (0.80ml, 16.4mmol) was added, and the temperature was gradually raised to 5 ° C. Water (150 ml) was added at 0 ° C, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave a crude product (968 mg) as a pale yellow solid. The crude product was dissolved in a mixed solvent of dichloromethane / methanol (85:15), filtered through chemically modified silica gel (Fuji Silysia NH-DM2035, 40 g), and washed with a mixed solvent of dichloromethane / methanol (10: 1). The filtrate was concentrated under reduced pressure, and the residue was suspended in ethyl acetate and collected by filtration. After washing with ethyl acetate three times and drying under reduced pressure, the title compound (848.5 mg, 2.665 mmol, yield 81.1%) was obtained as a white solid.

Melting point 179-181 ° C

¹ H-NMR (200 MHz, DMSO-d6): δ (ppm): 12 · 07 (1Η, brs), 9 · 17 (1Η, brs), 7.22-7.01 (4 H, m), 6.74 (1H, s ), 4.20 (2H, brs), 3.30 (2H, s), 2 · 95— 2 · 80 (4Η, m), 2.10 (3H, s) 1 ³ C-NMR (50 MHz, DMSO-d6): δ ( ppm): 169.7, 168.4, 157.6, 150.5, 141.5, 136.4, 1 29.1, 128.3, 126.7, 126.5, 107.5, 40.6, 34.8, 33.0, 22.6

[0217] Production Example 24

Synthesis of N- (4- {2- [5- (hydrazinocarbonyl) thiophen-2-yl] ethyl} -l, 3-thiazol-2-ynole) acetamide

[0218] [Chemical 70] Stetr

[0219] Triphenylphosphine (7.703 g, 29.37 mmol) was added to a solution of N- (4-chloromethyl-1,3-thiazol-2-yl) acetamide (4.000 g, 20.98 mmol) in anhydrous acetonitrile (100 ml). The mixture was heated to reflux for 15 hours. After cooling to room temperature, the solvent was distilled off to about half amount. The precipitated crystals were collected by filtration and washed with isopropyl ether. After drying under reduced pressure, {[2- (acetylamino) -1,3-thiazol-4-yl] methyl} (triphenyleno) phosphonium chloride (9.251 g, 20.4 2 mmol, yield 97.3%) as a white solid Got.

[0220] [Chemical 71]

Steo-2

AcHN

[0221] Anhydrous N, N-dimethylformamide (3.771 g, 8.325 mmol) of {[2- (acetylamino) -1,3-thiazol-4-yl] methyl} (triphenylenole) phosphonium chloride (3.771 g, 8.325 mmol) 35 ml) was added potassium te rt-butoxide (2.515 g, 22.41 mmol) at 0 ° C. and stirred for 15 minutes. 5_formylthiophene-2-carboxylic acid (l.OOOg, 6.404 mmol) was added in small portions and stirred at 0 ° C for 30 minutes. After warming to room temperature and stirring for 2 hours, the reaction mixture was poured into ice water (300 ml). After stirring for 30 minutes, it was washed twice with ethyl acetate. The aqueous layer was cooled to 0 ° C, and 6N hydrochloric acid was added dropwise to adjust the pH to 3. After stirring at 0-5 ° C for 2 hours, the precipitated crystals were collected by filtration, washed with water three times and diisopropyl ether twice. 5_ {2- [2- (Acetyllamino) -1,3-thiazol-4-yl] bur} thiophene-2-carboxylic acid (1.104 g, 3.751 mmol, yield 58.6%) Got.

[0222] [Chemical 72] Step-3

[0223] 5_ {2- [2- (Acetylamino) -1,3-thiazol-4-yl] bur} thiophene-2-carboxylic acid OOO.Omg, 3.058mmol) in tetrahydrofuran (250ml), methanol (100ml) It was dissolved in a mixed solvent. 20% palladium on carbon was added and hydrogenated at room temperature and 4 atm. After completion of the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. Jetyl ether (100 ml) was added to the concentrated residue, and the precipitate was collected by filtration and washed with jetyl ether. 5_ {2- [2- (Acetyllamino) -1,3-thiazol-4-yl] ethyl} thiophene-2-force rubonic acid (738.1mg, 2.490mml, yield 81.4%) )

[0224] [Chemical 73]

Step-4

[0225] 5_ {2- [2- (Acetylamino) -1,3-thiazol-4-yl] ethyl} thiophene-2-carboxylic acid (350.0 mg, 1.18 lmmol) in anhydrous N, N-dimethylformamide (3 ml ) 1,1′-Carbonyldiimidazole (287.2 mg, 1.77 lmmol) was added to the solution and stirred at 50 ° C. for 1 hour. After cooling to room temperature, diisopropyl ether (15 ml) was added dropwise. After stirring for 5 minutes, the precipitate was collected by filtration and washed twice with diisopropyl ether and three times with ethyl acetate. After drying under reduced pressure, N- (4- {2- [5- (imidazol-1-carbonyl) -thiophen-2-yl] ethyl} -1,3-thiazol-2-yl) as a yellow solid Acetamide (346.2 mg, 0.999 mmol, 84.6% yield) was obtained.

[0226] [Chemical 74]

Step— 5—

[0227] N- (4- {2- [5_ (Imidazol-1-carbonyl) thiophen-2-yl] ethyl} -1, 1M hydrazine / tetrahydrofuran solution (4.76ml, 4.76mmol) at 0 ° C, A suspension of 3-thiazol-2-yl) acetamide (330.0 mg, 0.953 mmol) in anhydrous tetrahydrofuran (15 ml) was added dropwise. After stirring at 0 ° C for 1 hour, the mixture was stirred at room temperature for 30 minutes. Water (2 ml) was added at 0 ° C, and the mixture was concentrated under reduced pressure. Water (33 ml) was added to the residue, and the mixture was stirred at 0 ° C for 20 minutes. The resulting solid was collected by filtration and washed 5 times with water and twice with ethyl acetate. Drying under reduced pressure gave the title compound (278.6 mg, 0.898 mmol, yield 94.2%) as an off-white solid.

Melting point 193-196 ° C

¹ H-NMR (200MHz, DMSO—d6): δ (ppm): 12 · 06 (1Η, brs), 9 · 61 (1Η, brs), 7 · 48 (1Η, d, J = 3.6Hz), 6 · 82 (1Η, d, J = 3.6Hz), 6.76 (1H, s), 4.39 (2H, brs), 3.14 (2Η, d, J = 7.1Hz), 2 • 91 (2H, d, J = 7.1Hz), 2.49 (3H, s)

¹³ C-NMR (50 MHz, DMSO-d6): δ (ppm): 168.7, 161.7, 158.0, 149.8, 149.0, 136.3, 1 27.8, 126.1, 108.5, 33.2, 29.4, 23.0

[0228] Production Example 25

Synthesis of N- (4- {2- [5- (hydrazinocarbonylmethyl) thiophen-2-yl] ethyl] -l, 3-thiazol-2-yl) acetamide

[0229] [Chemical 75]

[0230] 3- (5_ {2- [2- (Acetyllamino) -1,3-thiazol-4-yl] ethyl) thiophen-2-yl) acetic acid (300.0 mg, 0.967 mmol) in anhydrous N, 1,1′-Carbonyldiimidazole (235.0 mg, 1.449 mmol) was added to an N-dimethylformamide (3 ml) solution, and the mixture was stirred at 50 ° C. for 1 hour. After cooling to 0 ° C, hydrazine 'monohydrate (0.23 ml, 4.8 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0 ° C, water (50 ml) was added, and the mixture was stirred. The precipitated solid was collected by filtration and washed 5 times with water. Drying under reduced pressure gave a pale yellow solid (206.7 mg). This was purified by silica gel column chromatography (Fuji Silysia FL-60D, 100 g, dichloromethane: methanol = 85: 15). Further purification was performed by silica gel column chromatography (Fuji Silysia NH-DM2035, 80 g, dichloromethane: methanol = 1 0: 1). Concentrate the fraction containing the desired product under reduced pressure to obtain a solid with ethyl acetate. Washed twice and dried under reduced pressure to give the title compound (144.7 mg, 0.446 mmol, yield 46.1%) as a fine yellowish white solid.

Melting point 202 ~ 205 ° C

¹ H-NMR (200 MHz, DMSO-d6): δ (ppm): 12 · 08 (1Η, brs), 9 · 18 (1Η, brs), 6 · 78 (1Η, s), 6 · 66 (1Η, d, J = 3.4Hz), 6.63 (1Η, d, J = 3.4Hz), 4.22 (2H, brs), 3.46 (2H, s), 3.08 (2Η, t, J = 7.1Hz), 2.88 (2H, t, J = 7.1Hz), 2.11 (3H, s)

¹³ C-NMR (50 MHz, DMSO-d6): δ (ppm): 168.4, 168.1, 157.4, 149.6, 142.5, 135.1, 1 25.4, 123.8, 107.6, 34.8, 32.9, 28.7, 22.4

[0231] Production Example 26

Synthesis of N- (4- {2- [5- (2-hydrazinocarbonylethyl) thiophen-2-yl] ethyl} -l, 3-thiazol-2-yl) acetamide

[0232] [Chemical 76]

[0233] Anhydrous 3- (5- {2- [2- (acetylylamino) -1,3-thiazol-4-yl] ethyl) thiophen-2-yl) propionic acid (840.0 mg, 2.589 mmol) 1,1′-Carbonyldiimidazole (629.8 mg, 3.884 mmol) was added to a N, N-dimethylformamide (6.5 ml) solution, and the mixture was stirred at 50 ° C. for 1 hour. After cooling to 1O 0 C, hydrazine 'monohydrate (0.63 ml, 13.0 mmol) was added and stirred at room temperature for 2.5 hours. The mixture was cooled to 0 ° C., and water (20 ml) was added and stirred. The precipitated solid was collected by filtration and washed 5 times with water and 4 times with ethyl acetate. Drying under reduced pressure gave the title compound (731.7 mg, 2.16 2 mmol, yield 83.5%) as a white solid.

Melting point 188 ~ 191 ° C

¹ H-NMR (200 MHz, DMSO-d6): δ (ppm): 12 · 00 (1Η, brs), 9 · 00 (1Η, brs), 6 · 78 (1Η, s), 6 · 61 (2Η, s), 4 · 19 (2Η, br), 3.12- 3 · 00 (2Η, m), 2.98_2 · 82 (4Η, m), 2 · 32 (2Η, t, J = 7.6H z), 2.11 (3H, s)

¹³ C-NMR (50 MHz, DMSO-d6): δ (ppm): 170.5, 168.4, 157.7, 149.9, 141.8, 141.5, 1 24.3, 124.2, 107.9, 35.3, 33.2, 29.1, 25.5, 22.6 [0234] Production Example 27

Synthesis of N- (4- {2- [5- (2- -3-yl) e-1,3-l-2-yl) acetamide

[0235] [Chemical 77]

Step 1

Ethylene glycol (69.18 g 1115 mmol) and p-toluenesulfonic acid (424.0 mg 2.229 mmol) were added to a solution of thiophene-3-carbaldehyde (25.00 g 222.9 mmol) in toluene (250 ml). While separating the water produced by the water sample tube (Dean-Stark trap), the mixture was cooled to 0 ° C., heated under reflux for 4 hours, added with saturated aqueous sodium hydrogen carbonate (50 ml), stirred, allowed to stand and separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was filtered through a silica gel pad (Fuji Silysia BW-300SP, 100 g) and washed with an ethyl acetate / hexane mixed solvent (1: 2 1000 ml). The filtrate was concentrated under reduced pressure to give 2- (thiophen-3-yl) -1,3-dioxolane (33.40 g 213.8 mmol, yield 95.9%) as a yellow oil.

[0237] [Chemical 78]

Step— 2

[0238] A solution of 2- (thiophen-3-yl) -1,3-dioxolane (10.00 g 64.02 mmol) in anhydrous tetrahydrofuran (50 ml) was cooled in a dry ice-methanol bath, and the reaction solution temperature was -55. An n-butyllithium hexane solution (1.59M, 44.3 ml, 70.4 mmol) was added dropwise so as not to exceed ° C. After stirring for 1 hour, chlorotrimethylsilane (8.94ml 70.4m so that the reaction liquid temperature does not exceed -60 ° C mol) was added dropwise. After stirring at -78 to -60 ° C for 30 minutes, the temperature was raised to 0 ° C over 30 minutes, followed by stirring at 0 ° C for 1 hour. The reaction solution was cooled again in a dry ice-methanol bath, and n-butyllithium hexane solution (1.59M, 46.3 ml, 73.6 mmol) was added dropwise so that the reaction solution temperature did not exceed -60 ° C. After stirring at −78 to −60 ° C. for 1 hour, N, N-dimethylformamide (12.4 ml, 160 mmol) was added dropwise, and the mixture was further stirred for 1 hour. The temperature was raised to 0 ° C. over 1 hour, and a saturated aqueous ammonium chloride solution (100 ml) was added. The extract was washed 3 times with ethyl acetate, and the combined organic layer was washed twice with 0.2N hydrochloric acid and once with saturated brine. Anhydrous magnesium sulfate and activated carbon were added to the organic layer, and the mixture was stirred for 5 minutes and filtered. The filtrate was concentrated under reduced pressure, and 4- (1,3-dioxolan-2-inole) -5- (trimethylsilyl) thiophene-2-carbaldehyde (16.09 g, 62.76 mmol, yield 98.0%) as an orange oil. Got.

[0239] [Chemical 79]

Step— 3

[0240] 4- (1,3-Dioxolan-2-yl) -5- (trimethylsilyl) thiophene-2-carbaldehyde (1 2.82g, 50.00mmol) in chloroform solution (128ml) at 0 ° C (Triphenylphosphanylidene) Methyl acetate (17.55 g, 52.50 mmol) was added in small portions. After stirring at 0 ° C for 1 hour, the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and jetyl ether (200 ml) was added to the residue and stirred. Insoluble matter (mainly triphenylphosphine oxide) was filtered off and washed 4 times with jetyl ether (50 ml). The filtrate was concentrated under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (Fuji Silica BW-300SP, 450 g, ethyl acetate: hexane = 1: 6) as a pale yellow oil (2Ε) -3- [4- (1,3-Dioxolan-2-yl) -5- (trimethylsilyl) thiophen-2-yl] methyl acrylate (13.76 g, 44.04 mmol, yield 88.1%) was obtained.

[0241] [Chemical 80] Step-4

[0242] (2E) -3- [4- (l, 3-Dioxolan-2-yl) -5- (trimethylsilyl) thiophene-2-methyl lurate (4.000 g, 12.80 mmol) in tetrahydrofuran (20 ml) Water (0.2 ml) was added to the solution and cooled to 0 ° C. Tetraptyl ammonium fluoride tetrahydrofuran solution (1M, 13.4 ml, 13.4 mmol) was added, and the mixture was stirred at 0 ° C. for 5 minutes and at room temperature for 10 minutes. The mixture was cooled to 0 ° C, saturated aqueous ammonium chloride solution (40 ml) was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated Japanese salt water and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP, 200 g, ethyl acetate: hexane = 1: 3) to give (2Ε) -3- [4- (1, 3-Dioxolan-2-yl) thiophen-2-yl] methyl acrylate (3.065 g, 12.76 mmol, 99.7%) was obtained.

[0243] [Chemical 81]

¾tep-5

[0244] (2Ε) -3- [4- (1,3-Dioxolan-2-yl) thiophen-2-yl] methyl acrylate (3.050 g, 12.69 mmol) in tetrahydrofuran (10 ml) in acetic acid ( 30 ml) and water (10 ml) were added, and the mixture was stirred at 50 ° C for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and water (30 ml) was added to the residue. Extraction was performed 3 times with ethyl acetate, and the combined organic layers were washed with saturated brine. After drying over anhydrous magnesium sulfate, the mixture was concentrated to about 50 ml under reduced pressure, and hexane (200 ml) was added. Again, the solution was concentrated under reduced pressure to about 50 ml, and the precipitate was collected by filtration. After washing with hexane three times and drying under reduced pressure, methyl (2E) -3_ (4-formylthiophen-2-yl) acrylate (2.213 g, 11.28 mmol, 88.9%) was obtained as a white solid. [0245] [Chemical 82]

Step— 6

[0246] {[2- (Acetylamino) -1,3-thiazol-4-yl] methyl} (triphenylenole) phosphonium chloride (6.602 g, 14.58 mmol) was added to anhydrous N, N-dimethylformamide ( 30 ml) was added and cooled to 0 ° C. Potassium tert-butoxide (3.146 g, 28.03 mmol) was added, and the mixture was stirred at 0 ° C. for 15 min. (2E) -3_ (4-forminorethiophen-2-yl) methyl acrylate (2.200 g, ll · 21 mmol) in anhydrous N, N-dimethylformamide (30 ml) was added dropwise at 1 ° C. Stir for hours. The reaction solution was poured into ice-cooled dilute hydrochloric acid (600 ml, containing 15 mmol as HC1). Sodium chloride (10 g) was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-30 0SP, 500 g, ethyl acetate: hexane = 1: 1) to give (2E) -3- (4- {2- [2- ( Acetylamino) -1,3-thiazol-4-yl] bur} thiophen-2-yl) methinole acrylate (3.090 g, 9.241 mmol, 82.4%) was obtained.

[0247] [Chemical 83]

Step— 7

[0248] (2E) -3- (4- {2- [2- (Acetyllamino) -1,3-thiazol-4-yl] bur} thiophen-2-ynole) methyl acrylate (3.000 g, 8.971 mmol) was dissolved in ethyl acetate (400 ml) and acetic acid (100 ml). 20% palladium carbon was added and hydrogenated at normal pressure and room temperature. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji silica BW-300SP, 100 g, ethyl acetate: hexane = 2: 3) to give 3_ (4- {2- [2- (acetylylamino) -1, 3-thiazol-4-yl] ethyl} thiophen-2-yl) propionate (2.521 g, 7.449 mmol, yield 83.0%) was obtained. [0249] [Chemical 84]

Step— 8

oxane

[0250] Methyl 3- (4- {2- [2- (acetylylamino) -1,3-thiazol-4-yl] ethyl) thiophene-2-yl) propionate (l.OOOg, 2.955 mmol) IN sodium hydroxide aqueous solution (7.39 ml, 7.39 mmol) was added dropwise at 0 ° C to a dioxane (10 ml) solution. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. Water (20 ml) was added to the residue, cooled to 0 ° C., and 1N hydrochloric acid (10.5 ml, 10.5 mmol) was added dropwise. After stirring at 0 ° C for 30 minutes, the precipitate was collected by filtration, washed with water 10 times, with jetyl ether 3 times, and with dichloromethane 3 times. 3_ (4- {2- [2- (acetylylamino) -1,3-thiazol-4-yl] ethyl} thiophene-2-yl) propionic acid (934.5mg, 2.881m) mol, yield 97.5%).

[0251] [Chemical 85]

Step-9

[0252] 3- (4- {2- [2- (Acetylamino) -1,3-thiazol-4-yl] ethyl} thiophene-2-yl) propionic acid (800.0 mg, 2.466 mmol) in anhydrous To the N, N-dimethylformamide (6 ml) solution was added 1,1′-carbonyldiimidazole (599.8 mg, 3.699 mmol), and the mixture was stirred at 50 ° C. for 1 hour. After cooling to -20 ° C, hydrazine monohydrate (0.60 ml, 12.3 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was cooled to 0 ° C., water (90 ml) was added and stirred for 30 minutes, and the precipitated solid was collected by filtration. The extract was washed 5 times with water and 3 times with ethyl acetate and then dried under reduced pressure to give the title compound (763.3 mg, 2.255 mmol, yield 91.5%) as a white solid.

Melting point: 174-177 ° C

¹ H-NMR (200MHz, DMSO_d6): δ (ppm): 12 · 05 (1Η, brs), 9 · 00 (1Η, brs), 6 · 90 (1Η, s), 6 · 74 (1Η, s) , 6.70 (1Η, s), 4.17 (2Η, br), 2.95 (2Η, t, J = 7.5Hz), 2.90_2 · 70 (4Η, m), 2.3 3 (2H, t, J = 7.5Hz), 2.10 (3H, s)

¹³ C-NMR (50 MHz, DMSO-d6): δ (ppm): 170.4, 168.4, 157.6, 150.6, 143.7, 141.5, 1 26.0, 118.5, 107.4, 35.3, 32.0, 29.6, 25.6, 22.7

[0253] Production Example 28

Synthesis of N- {4- [2- (4-hydrazinophenyl) ethyl] -l, 3-thiazol-2-yl} acetoamide hydrochloride

[0254] [Chemical 86]

[0255] N- {4- [2- (4-Aminopheninole) ethyl] -1,3-thiazole-2-inole} acetamide (525.3 mg, 2 • OlOmmol) in a suspension of water (15 ml) with 6N A solution of hydrochloric acid (1.0 ml, 6.0 mmol), ice (lg) and sodium nitrite (14 Omg, 2.00 mmol) in water (lml) was added, and the mixture was stirred at 0 ° C for 45 minutes. A solution of sodium sulfite (1.26 7 g, 10.05 mmol) in water (7 ml) was added at 0 ° C, and the temperature was raised to 65 ° C. Concentrated hydrochloric acid (0.4 ml) was added, and the mixture was stirred for 4 hours and then cooled to 0 ° C. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (492.3 mg, 1.574 mmol, yield 78.3%) as a yellow solid.

Melting point 143 ~ 146 ° C

¹ H-NMR (200 MHz, DMSO— d6): δ (ppm): 12 · 11 (1Η, brs), 7 · 65 (2Η, d, J = 8.1 Hz), 7.39 (2H, d, J = 8.1 Hz) ), 6.76 (1H, s), 4 · 07 (4Η, brs), 3 · 10−2 · 78 (4Η, m), 2 · 12 (3Η, s) 1 ³ C-NMR (50MHz, DMSO): δ (ppm): 168.5, 157.8, 150.0, 148.9, 146.0, 129.6, 122.8, 107.8, 34.6, 32.5, 22.7

[0256] Production Example 29

Synthesis of N- (4- {2- [4- (hydrazinomethyl) phenyl] ethyl} -l, 3-thiazol-2-yl) acetamide dihydrochloride

[0257] [Chemical 87]

[0258] N- (4- {2- [4- (Hydroxymethinole) phenenole] ethyl} -l, 3-thiazol-2-inole) acetamide (2.581 g, 9.340 mmol) in dichloromethane (200 ml) , Dissolved in a mixed solvent of methanol (10 ml). Activated manganese dioxide (16.24 g, 186.7 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the resulting solid was collected by filtration. Drying under reduced pressure gave N- {4- [2- (4-formylphenyl) ethyl] -1,3-thiazol-2-yl} acetamide (2.373 mg, 8.650 mmol, yield 92.6%) as a white solid. .

[0259] [Chemical 88]

Step- 2

[0260] To a solution of N- {4- [2- (4-forminolevenole) ethyl] -1,3-thiazole-2-inole} acetamide (863.5 mg, 3.148 mmol) in anhydrous tetrahydrofuran (10 ml) was added tert- Butylcarbaze Kl. 249 g, 9.451 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Further, tert-butyl carbazate (1.250 g, 9.458 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After concentration under reduced pressure, diisopropyl ether was added to the residue, and the resulting solid was collected by filtration. After drying under reduced pressure, tert-butyl 4- {2- [2- (acetylamino) -1,3-thiazol-4-yl] ethyl} -2-benzylidenehydrazine strength lpoxylate (977.5 mg, 2.516 mmol, yield) Rate 79.9%).

[0261] [Chemical 89] Step-3

[0262] tert-Butyl 4- {2- [2- (acetylamino) -1,3-thiazol-4-yl] ethyl} -2-benzylidene hydrazine carboxylate (3.051 g, 7.854 mmol) in anhydrous tetrahydrofuran ( 80 ml) To the solution was added a solution of sodium cyanoborohydride (986.6 mg, 15.70 mmol) and p-toluenesulfonic acid monohydrate (1.493 g, 7.849 mmol) in tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for 3 hours. It was. A solution of sodium cyanoborohydride (246.6 mg, 3.924 mmol) and p-toluenesulfonic acid monohydrate (373.3 mg, 1.962 mmol) in tetrahydrofuran (5 ml) was added, and the mixture was stirred at room temperature for 2 hr. Ethyl acetate (80 ml), water (80 ml) and saturated brine (80 ml) were added and stirred, and the mixture was allowed to stand and separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, diisopropyl ether / ethyl acetate mixed solvent (3: 1) was added to the concentrated residue, and the resulting solid was collected by filtration. The solid was washed with dichloromethane, dried under reduced pressure, and tert-butinole 2- (4- {2- [2- (acetylamino) -1,3-thiazol-4-yl] ethyl} phenylmethyl) hydrazine as a white solid Carboxylate (1.330 g, 3.406 mmol, yield 43.4%) was obtained.

[0263] [Chemical 90]

Step-4

tert-butyl 2- (4- {2- [2- (acetylamino) -1,3-thiazole-4-inole] ethyl} phenylmethyl) hydrazinecarboxylate (1.624 g, 4.159 mmol) in anhydrous dichloromethane (20.8 ml) A 4M hydrogen chloride dioxane solution (41.6 ml, 1.66 mmol) was added to the suspension, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the resulting solid was collected by filtration. The solid was dissolved in methanol (40 ml), ethyl acetate (120 ml) was added, and the precipitated crystals were collected by filtration. similar The recrystallization operation was repeated three times to obtain the title compound (918.4 mg, 2.528 mmol, yield 6 0.8%) as a white solid.

Melting point 194 ~ 196 ° C

¹ H-NMR (200 MHz, DMSO-d6): δ (ppm): 12 · 07 (1Η, brs), 7 · 30 (2Η, d, J = 8.1 Hz), 7.21 (2H, d, J = 8.1 Hz) ), 6.72 (1H, s), 4.00 (2H, s), 3 · 01_2 · 80 (4Η, m), 2.10 (3H, s)

1 ³ C-NMR (50 MHz, DMSO): δ (ppm): 168.4, 157.7, 150.2, 141.7, 131.3, 129.7, 128. 6, 107.6, 53.7, 34.4, 32.8, 22.7

[0265] Production Example 30

Synthesis of N- (4- {2- [4- (2-hydrazinoethinole) phenenole] ethyl]}-l, 3-thiazol-2-inole) acetamidohydrochloride

[0266] [Chemical 91]

Ste-1

[0267] N- (4- {2- [4- (2-Hydroxyethinole) phenenole] ethenole} thiazole-2-inole) acetamide (1 • 800 g, 6.199 mmol), tert-butyl (1, In a solution of 3-dioxo-1,3-dihydro-2H-isoindole-2-inole) strength rubamate (2.032 g, 7.749 mmol) and triphenylphosphine (2.520 g, 9.608 mmol) in water-free tetrahydrofuran (150 ml) 0 An anhydrous tetrahydrofuran (15 ml) solution of jetylazodicarboxylate (4.23 ml of a 2.2 M toluene solution obtained by distilling off the solvent, 9.31 mmol) was added dropwise at ° C. The mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP, 170 g, ethyl acetate: hexane = 1: 1), and tert-butyl (2- {4- [2- (2- Acetylamino-1,3-thiazol-4-yl) ethyl] phenyl} ethyl)-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) force rubamate (2.449 g 4.581 mmol, yield 73.9%).

[0268] [Chemical 92] Step- 2

[0269] tert-Butyl (2- {4- [2- (2-acetylamino-1,3-thiazol-4-yl) ethyl] phenyl} -ethyl)-(1,3-dioxo-1,3 To a solution of -dihydroisoindole-2-yl) rubamate (2.134 g, 3.99 2 mmol) in anhydrous tetrahydrofuran (32 ml), methyl hydrazine (0.32 ml, 6.00 mmol) was added dropwise at -20 ° C. After stirring at room temperature for 15 hours, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP, 50 g, dichloromethane: methanol = 30: 1) and tert-butyl N- (2- {4- [2- (2- (2- Acetylamino-1,3-thiazol-4-yl) ethyl] phenyl} hydrylcarboxylate (1 · 481 g, 3.661 mmol, yield 91.7%) was obtained.

[0270] [Chemical 93]

Step—>}

tert-butyl N- (2- {4- [2- (2-acetylamino-1,3-thiazol-4-yl) ethyl] phenyl} hydryl) hydrazinecarboxylate (1.363 g, 3.369 mmol) (10 ml) and methanol (20 ml) in a mixed solvent. 1M hydrogen chloride jetyl ether solution (50.5 ml, 5 0.5 mol) was added dropwise, and the mixture was stirred at room temperature for 15 hours and concentrated under reduced pressure. Jetyl ether (30 ml) was added to the concentrated residue, and the mixture was concentrated again under reduced pressure. This operation was repeated three times to remove excess hydrogen chloride. Jetyl ether (50 ml) was added to the residue and filtered. The resulting solid is jetil Washed 3 times with ether and 2 times with ethyl acetate. It was dried under reduced pressure to give the title compound (1.260 g, 3.340 mmol, yield 99.1%) as an off-white solid.

Melting point 142-144 ° C

^: H-NMR (200MHz, DMSO-d6): δ (ppm): 12 · 10 (1H, brs), 7 · 28—7 · 08 (4Η, m), 6.74 (1 H, s), 3.69 (2H , t, J = 7.0Hz), 2 · 95_2 · 72 (6Η, m), 2.10 (3H, s)

¹³ C-NMR (50 MHz, DMSO): δ (ppm): 168.5, 157.7, 153.1, 150.3, 135.6, 129.1, 128.5, 107.6, 49.9, 34.3, 33.0, 32.8, 22.7

[0272] Production Example 31

Synthesis of N- (4- {2- [4- (3-hydrazinopropinole) phenenole] ethyl} -l, 3-thiazol-2-inole) acetoamido dihydrochloride

[0273] [Chemical 94]

Step-1

[0274] 3_ (4- {2- [2- (Acetyllamino) -1,3-thiazol-4-yl] ethyl) phenyl) propionic acid (1.019 g, 3.200 mmol) in anhydrous N, N-dimethyl 1,1′-carbonyldiimidazole (778.3 mg, 4.800 mmol) was added to a formamide (8 ml) solution, and the mixture was stirred at 50 ° C. for 1 hour. Methanol (2.6 ml, 64 mmol) was added, and the mixture was stirred at 50 ° C for 3 hours. After cooling to room temperature, water (24 ml) was added and stirred, and the resulting solid was collected by filtration and washed with water three times. Dried under reduced pressure to give methyl 3_ (4- {2- [2- (acetylylamino) -1,3-thiazol-4-inole] ethyl} pheninole) propionate (943.6 mg, 2.839 mmol, yield 88.7%) as a white solid Obtained.

[0275] [Chemical 95]

Step— 2

[0276] Methyl 3- (4- {2- [2- (acetylylamino) -1,3-thiazol-4-yl] ethyl) phenyl) propionate (997.3 mg, 3.000 mmol) in anhydrous tetrahydrofuran (20 ml ) 1.5M diisobutylaluminum hydride (6.0ml, 9.0mmol) was added dropwise to the solution at -78 ° C. After stirring at _78 ° C for 30 minutes, the mixture was warmed to room temperature over 1 hour and stirred at room temperature for 1 hour. The mixture was cooled to 0 ° C, mixed with water (1.5 ml) / tetrahydrofuran (15 ml), and stirred at room temperature for 1 hour. Anhydrous magnesium sulfate was added, and the mixture was further stirred for 30 minutes. Insolubles were filtered off, and the filtrate was dried under reduced pressure. The residue was purified by silica gel chromatography (Fuji Silysia BW-300SP, 40 g, ethyl acetate: hexane = 1: 1) to give N- (4- {2- [4- (3-hydroxy Propyl) phenyl] ethyl 1,3-thiazol-2-yl) acetamide (645.9 mg, 2.122 mmol, yield 70.7%) was obtained.

[0277] [Chemical 96]

Step— 3—

[0278] N- (4- {2- [4- (3-Hydroxypropinole) phenenyl] ethyl} -1,3-thiazole-2-inole) acetamide (643.7 mg, 2.115 mmol) in anhydrous tetrahydrofuran (50ml) solution with tert-butyl (1,3-dioxo-1,3-dihydro-2H-isoindole-2-inole) strength rubamate (693.2mg, 2.643mmol), triphenylphosphine (857.8mg, 3.270mmol) ) Was added. The mixture was cooled to 0 ° C., and a 2.2 M toluene solution of diethylazodicarboxylate (1.44 ml, 3.17 mmol) was added dropwise. The mixture was stirred at room temperature for 14 hours and concentrated under reduced pressure. Silica gel column chromatography of the concentrated residue (first time: Fuji Silysia B W-300SP, 100 g, ethyl acetate: hexane = 4: 6, second time: Fuji Silysia BW-300SP, 50 g, ethyl acetate: hexane = 4: 6) and tert-butyl [3_ (4- {2- [2- (acetylamino) -1,3-thiazol-4-yl] ethyl} phenyl) propyl] (1 , 3-Dioxo-1,3-dihydro-2H-isoindole-2-yl) strength rubamate (776.9 mg, 1.416 mmol, yield 67.0%) was obtained.

[0279] [Chemical 97] Step— 4

[0280] tert-butyl [3- (4- {2- [2- (acetylylamino) -1,3-thiazol-4-yl] ethyl} phenyl) propyl] (1,3-dioxo-1, Methylhydrazine (921, 1.7 mmol) was added at −15 ° C. to a solution of 3-dihydro-2H-isoindole-2-yl) strength rubamate (760.5 mg, 1.386 mmol) in anhydrous tetrahydrofuran (10 ml). The mixture was warmed to room temperature over 1 hour and stirred at room temperature for 6 hours. Ethyl acetate (10 ml) was added, the resulting solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP, 20 g, ethyl acetate: hexane = 4: 6 → 5: 5 → 6: 4), and tert-butyl N- [3- (4 -{2- [2- (Acetylamino) -1,3-thiazol-4-inole] ethenole} feninole) propyl] hydrazinecarboxylate (544.6 mg, 1.3 Olmmol, yield 93.9%) was obtained.

[0281] [Chemical 98]

St — 5

tert-Butyl N- [3- (4- {2- [2- (acetylylamino) -1,3-thiazol-4-inole] ethyl} phenol) propyl] hydrazinecarboxylate (449. lmg, 1.073 mmol) 4M hydrogen chloride dioxane solution (10.7ml, 42.8mmol) was added to a solution of methanol (10ml) and stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, washed, and the solid was collected by filtration. The solid was dissolved in methanol (10 ml), ethyl acetate (80 ml) was added, and the crystals were collected by filtration. Recrystallization was repeated twice to obtain the title compound (369. lmg, 0.943 mmol, yield 87.9%) as a white solid.

Melting point 133-136 ° C

¹ H-NMR (200MHz, DMSO-d6): δ (ppm): 12 · 10 (1Η, brs), 7 · 69 (5Η, brs), 7.18-7.04 ( 4H, m), 6.72 (1H, s), 2.96- 2.78 (6mm, m), 2.58 (2H, t, J = 7.3Hz), 2.11 (3H, s), 1.92-1.7

4 (2H, m)

¹³ C-NMR (50 MHz, DMSO): δ (ppm): 168.4, 157.7, 150.4, 139.2, 138.6, 128.5, 107.6, 50.1, 34.4, 33.0, 31.8, 26.6, 22.7

[0283] Production Example 32

Synthesis of N- (4- {2- [3- (2-hydrazinoethinole) phenolino] ethyl]}-l, 3-thiazol-2-inole) acetamide hydrochloride

[0284] [Chemical 99]

SteD-1

[0285] 3_ {2- [2- (Acetylamino) -1,3-thiazol-4-yl] ethyl} phenylacetic acid (l.OOOg, 3.

To a solution of 286 mmol) in anhydrous N, N-dimethylformamide (4.5 ml) was added 1,1′-carbonyldiimidazole (799.1 mg, 4.928 mmol), and the mixture was stirred at 50 ° C. for 1 hour. After cooling to 0 ° C, methanol (4.0 ml, 99 mmol) was added. After stirring at room temperature for 5 hours, water (200 ml) was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (Fuji Silysia BW-300 SP, 100 g, ethyl acetate: hexane = 2: 3) to give 3_ {2- [2- (acetyleneamino) -1,3- Thiazol-4-yl] ethyl} phenyl acetate (949.5 mg, 2.982 mmol, yield 90.8%) was obtained.

[0286] [Chemical 100]

Step— 2

[0287] 3_ {2- [2- (Acetyllamino) -1,3-thiazol-4-yl] ethyl} phenyl acetate (900. To a solution of Omg, 2.827 mmol) in anhydrous tetrahydrofuran (20 ml) was added dropwise 1.5 M diisobutylaluminum tonoleene hydride solution (5.65 ml, 8.48 mmol) at -78 ° C. The temperature was gradually raised from _78 ° C to 0 ° C over 3 hours with stirring. A mixed solution of water (1.5 ml) and tetrahydrofuran (15 ml) was added dropwise at 0 ° C. The mixture was warmed to room temperature and stirred for 30 minutes. Anhydrous magnesium sulfate (5 g) was added, and the mixture was further stirred for 30 minutes. The residue was washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP, 100 g, ethyl acetate: hexane = 2: 1) to give N- (4- {2- [3- (2-hydroxy Ethynole) phenol] ethyl} -1,3-thiazole-2-inole) acetamide (577.3 mg, 1.988 mmol, 70.3%) was obtained.

[0288] [Chemical 101]

Step— 3

[0289] N- (4- {2- [3- (2-Hydroxyethyl) phenyl] ethyl} -1,3-thiazol-2-yl) acetamide (570.0 mg, 1.963 mmol), tert-butanol (1,3-dioxo-1,3_dihydro-2H-isoindole-2-inole) strength rubamate (643.5 mg, 2.454 mmol), triphenylphosphine (798.0 mg, 3.0 43 mmol) in anhydrous tetrahydrofuran (50 ml) At 0 ° C, a solution of jetylazodicarboxylate (2.2M toluene solution 1.34 ml in which the solvent was distilled off, 2.95 mmol) in anhydrous tetrahydrofuran (3 ml) was added dropwise. The mixture was stirred at room temperature for 13.5 hours and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP, 120 g, ethyl acetate: hexane = 1: 1), and tert-butyl (2- {4- [3_ (2-acetylamino) was obtained as a colorless oil. -1,3-thiazol 4-ethyl) etinore] fenenore} ethyl) (1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) force rubamate (748.4mg, 1.400 mmol, yield 71.3%).

[0290] [Chemical 102] Step-4

[0291] tert-Butyl (2- {4- [3- (2-acetylamino-1,3-thiazol-4-yl) ethyl] phenyl)} (1,3-dioxo-1,3- Methylhydrazine (0.09 ml, 1.7 mmo 1) was added dropwise at −20 ° C. to a solution of dihydroisoindole-2-yl) rubamate (730.8 mg, 1.36 7 mmo) in anhydrous tetrahydrofuran (10 ml). The mixture was warmed to room temperature and stirred for 14 hours. The reaction mixture was concentrated under reduced pressure, jetyl ether (100 ml) was added, and the insoluble material was collected by filtration. The insoluble material was washed with jetyl ether, and the filtrate was concentrated. The concentrated residue was purified by silica gel column chromatography (Fuji Silysia BW-300 SP 100 g, dichloromethane: methanol = 10: 1), and tert-butyl N- (2- {4- [3_ (2-acetylylamino-1) was obtained as a white solid. , 3-thiazol-4-yl) ethyl] phenyl} ethyl) hydrazine carboxylate H-NMR purity analysis: approx. 93%, 2-methyl-2,3-dihydrophthalazine -1,4 -Dione contained, 570.2 mg, pure content 530 mg, 1.31 mmol, yield 95.8%).

[0292] [Chemical 103]

tert-butyl N- (2- {4- [3- (2-acetylamino-1,3-thiazol-4-yl) ethyl] phenyl} hydryl) hydrazine carboxylate (purity 93%, 500.0 mg, pure Min. 1.148 mmol) was dissolved in a mixed solvent of dichloromethane (3.5 ml) and methanol (7 ml). 1M hydrogen chloride jetyl ether solution (17.3 ml, 17.3 mmol) was added, and the mixture was stirred at room temperature for 17 hours and concentrated under reduced pressure. Jetyl ether (20 ml) was added to the concentrated residue, and the mixture was concentrated again under reduced pressure to remove hydrogen chloride. Jetyl ether (20 ml) was added to the residue and filtered, and the resulting solid was washed three times with jetyl ether and five times with dichloromethane. Dry under reduced pressure to give the title compound (369.4 mg, 1.0 84 mmol, yield 94.4%).

Melting point 105-118 ° C (melting point is not very clear)

¹ H-NMR (200MHz, D 0, DSS = 0ppm): δ (ppm): 7.40-7.25 (1Η, m), 7.25-7.10 (3H, m), 6.91 (1H, s), 3.40 (2H , t, J = 7.5Hz), 3.15- 2.90 (6mm, m), 2.38 (3H, s)

1 ³ C-NMR (50 MHz, D 0, DSS = 0 ppm): δ (ppm): 174.3, 163.4, 144.1, 143.5, 139.6, 13 2.0, 131.6, 130.1, 129.5, 112.6, 54.7, 36.1, 33.3, 31.7, 25.0

[0294] Production Example 33

Synthesis of N- (4- {2- [5- (2-hydrazinoethyl) thiophen-2-yl] ethyl} -l, 3-thiazole-2-ynole) acetamido maleate

[0295] [Chemical 104]

Step-丄

POCI ₃ OHC, NO S, .OAc

PhNMeCHO

Under an inert gas stream, phosphorus oxychloride (32.53 g, 212.1 mmol) was added to N-methylformanilide (28.67 g, 212. 10101 ₀ 1), and the mixture was allowed to stand at room temperature for 30 minutes. While stirring, 2-thiophen-2-ylethyl acetate (36.1 lg, 212.1 mmol) was added dropwise, and the mixture was stirred at room temperature for 14 hours. N-methylformanilide (1.434 g, 10.61 mmol) and phosphorus oxychloride (1.627 g, 10.61 mmol) were mixed and allowed to stand for 30 minutes, and then added to the reaction solution. After stirring at room temperature for 6 hours, the reaction solution was poured into ice water and extracted with jetyl ether. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP, 600 g, ethyl acetate: hexane = 1: 3) to give 2- (5_formylthiophene-2-yl as a pale yellow oil. ) Ethyl acetate (4 1.63 g, 210.0 mmol, yield 99.0%) was obtained.

[0297] [Chemical 105] Step— 2

OHC \, .OAc

[0298] 2- (5_formylthiophen-2-yl) ethyl acetate (40.00 g, 201.8 mmol) was dissolved in a 20% methanol / tetrahydrofuran mixed solvent (400 ml). The mixture was cooled to -25 ° C, sodium borohydride (3.053 g, 80.71 mml) was added, and the mixture was stirred at _25 to 0 ° C for 1.5 hours. The reaction mixture was poured into ice-cooled 2N hydrochloric acid (200 ml), sodium chloride (5 g) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride and saturated brine. Anhydrous magnesium sulfate and activated carbon were added and stirred, followed by filtration. The filtrate was concentrated under reduced pressure to give 2- (5_hydroxymethylthiophen-2-yl) ethyl acetate (39.91 g, 199.3 mmol, 98.8%) as a colorless oil.

[0299] [Chem 106]

Step-3

[0300] Triethylamine (21.01 g, 207.6 mmol) was added to a solution of 2- (5_hydroxymethylthiophen-2-yl) ethyl acetate (39.60 g, 197.8 mmol) in anhydrous dichloromethane (200 ml) at 0 ° C. Thionyl chloride (24.70 g, 207.6 mmol) was added dropwise. After stirring at 0 ° C for 5 hours, the reaction mixture was poured into ice water (200 g) and extracted with jetyl ether. The organic layer was washed with saturated brine, saturated aqueous sodium hydrogen carbonate, saturated aqueous ammonium chloride and saturated brine. Anhydrous magnesium sulfate and activated carbon were added and stirred, followed by filtration. The filtrate was concentrated under reduced pressure to give 2- (5_chloromethylthiophen-2-yl) ethyl acetate (42 · 12 g, 192.6 mmol, 97.4%) as an orange oil.

[0301] [Chemical 107] Step-4

[0302] Triphenylphosphine (50.37 g, 192.0 mmol) was added to a solution of 2- (5_chloromethylthiophen-2-inole) ethyl acetate (42.00 g, 192.0 mmol) in anhydrous acetonitrile (210 ml). After stirring at 80 ° C for 6 hours, the mixture was cooled to room temperature. Diisopropyl ether (420 ml) was added dropwise and stirred for 1 hour. The precipitated crystals were collected by filtration and washed with diisopropyl ether. After drying under reduced pressure, [5_ (2-acetoxyl) thiophen-2-ylmethyl] triphenylphosphine chloride (72.09 g, 149.9 mmol, yield 78.1%) was obtained as a white solid.

[0303] [Chemical 108]

[0304] Suspension of [5_ (2-acetoxichechinole) thiophen-2-ylmethyl] triphenylphosphonium chloride (19.68 g, 40.91 mmol) in anhydrous tetrahydrofuran (20 ml) at −25 ° C. tert-Butoxide tetrahydrofuran solution (1M, 40.0 ml, 40.0 mmol) was added dropwise. After stirring for 30 minutes, N- (4-formyl-1,3-thiazol-2-yl) acetamide (6.330 g, 37.19 mmol) in anhydrous N, N_dimethylformamide (35 ml) was added and stirred for 20 minutes. . The temperature was raised to 0 ° C over 2 hours, and the reaction solution was poured into ice water (200 ml). The mixture was extracted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous ammonium chloride and saturated brine. Magnesium sulfate and activated carbon were added and stirred. Filter and concentrate the filtrate in vacuo. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP, 600 g, ethyl acetate: hexane = 2: 3) to give 2- {5_ [2- (2-acetylamino) -1 as a pale yellow oil. , 3-thiazol-4-inole) vininole] thiophen-2-yl} ethyl acetate (8.539 g, 25.38 mmol, yield 68.2%) was obtained. [0305] [Chem 109]

Step-6

[0306] 2- (5- {2- [2- (Acetylamino) -1,3-thiazol-4-yl] bul} thiophen-2-yl) ethyl acetate (9.795 g, 29.11 mmol) acetic acid Acetic acid (50 ml) and 10% palladium carbon (3.918 g) were added to an ethyl (200 ml) solution, and hydrogenated at room temperature and normal pressure. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 ml) and washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous ammonium chloride and saturated brine. After drying over anhydrous magnesium sulfate, concentrating to dryness, 2- (5_ {2- [2- (acetylylamino) -1,3-thiazole-4-inole] ethinole} thiophene-2-inole as a pale yellowish white solid ) Ethyl acetate (9.320 g, 27.54 mmol, 94.6% yield) was obtained.

[0307] [Chem 110]

[0308] 2- (5_ {2- [2- (Acetyllamino) -1,3-thiazol-4-yl] ethyl) thiophen-2-yl) ethyl acetate (9.300 g, 27.48 mmol) in anhydrous methanol To the (250 ml) solution was added dried potassium carbonate (3.798 g, 27.48 mmol) and stirred for 2 hours. Acetic acid (1.65 g, 27.5 mmol) was added, and the mixture was concentrated under reduced pressure. Water (150 ml) was added to the residue and extracted with ethyl acetate. The organic layer was washed successively with saturated brine, saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride and saturated brine. Anhydrous magnesium sulfate and activated carbon were added, stirred and filtered. The filtrate was concentrated to about 75 m, and diisopropyl ether (200 ml) was added dropwise. The mixture was stirred for 30 minutes, and the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether and dried under reduced pressure. As white crystals, N- (4- {2- [5_ (2-hydroxyethyl) thiophen-2-yl] ethyl} thiazole-2-yl) acetamide ( 7.684 g, 25.92 mmol, 94.3% yield).

[0309] [Chem 111]

Step— 8

[0310] N- (4- {2- [5- (2-Hydroxyethinore) thiophene-2-inole] ethinole} thiazole-2-inole) acetamide (1.200 g, 4.048 mmol), tert-butinole ( To a solution of 1,3-dioxo-1,3_dihydro-2H-isoindole-2-inole) rubamate (1.327 g, 5.060 mmol), triphenylphosphine (1.646 g, 6.07 2 mmol) in anhydrous tetrahydrofuran (100 ml) An anhydrous tetrahydrofuran (5 ml) solution of jetillazodicarboxylate (2.76 ml of a 2.2 M toluene solution obtained by distilling off the solvent, 6.07 mmol) was added dropwise at ° C. The mixture was stirred for 15 hours while gradually warming from 0 ° C to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Fuji Silysia BW-300 SP, 350 g, ethyl acetate: hexane = 1: 1) to give tert-butyl [2_ (5_ {2 -[2- (Acetylamino) -1,3-thiazol-4-inore] ethinole} thiophen-2-yl) ethyl]-(1,3-dioxo-1,3-dihydro-2H-isoindole-2- Inole) strength rubamate (1.571 g, 2.905 mmol, yield 71.8%) was obtained.

[0311] [Chem 112]

Ste-9

[0312] tert-Butyl [2- (5_ {2- [2- (acetylylamino) -1,3-thiazol-4-yl] ethyl) thiophen-2-yl) ethyl]-(1,3- Dioxo-1,3-dihydro-2H-isoindole-2-yl) carbamate (1.570 g, 2.904 mmol) in anhydrous tetrahydrofuran (20 ml) at -20 ° C methyl hydrazine (0.19 ml, 3.6 mmol) Was dripped. Stir for 7 hours while gradually warming from _20 ° C to room temperature did. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in dichloromethane (30 ml), and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Fuji silica BW-30 0SP, 200 g, ethyl acetate: hexane = 3: 2 → 2: 1). The fraction containing the desired product was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 ml). The insoluble material was filtered off, and the filtrate was concentrated to give tert-butyl N- [2- (5- {2- [2- (acetylylamino) -1,3-thiazol-4-yl] ethinole} as a white solid} Thiophen-2-inole) ethyl] hydrazinecarboxylate (1.068 g, 2.601 mmol, yield 89.6%) was obtained.

[0313] [Chem 113]

Step-10

[0314] tert-Butyl N- [2- (5- {2- [2- (acetylylamino) -1,3-thiazol-4-yl] ethyl] thiophen-2-inole) ethyl] hydrazinecarboxylate ( 996 · lmg, 2.426 mmol) was dissolved in a mixed solvent of anhydrous methanol (15 ml) and anhydrous dichloromethane (7.5 ml). 1M hydrogen chloride jetyl ether solution (36.4 ml, 36.4 mmol) was added, and the mixture was stirred at room temperature for 22 hours. After concentration under reduced pressure, the residue was suspended in anhydrous jetyl ether (50 ml). The precipitate was collected by filtration and washed with anhydrous jetyl ether and ethyl acetate. Drying under reduced pressure gave crude hydrochloride (923.9 mg) as an off-white solid. The crude hydrochloride was dissolved in water (25 ml) and saturated aqueous sodium bicarbonate (25 ml) was added. Sodium chloride (7 g) was added, followed by extraction with ethyl acetate. The organic layer was filtered through activated carbon, anhydrous magnesium sulfate, and celite. The filtrate was poured into a solution of maleic acid (619.6 mg, 5.338 mmol) in ethyl acetate (5 ml) and concentrated under reduced pressure. The concentrated residue was dissolved in anhydrous methanol (15 ml), and diethyl ether (200 ml) was added. The precipitated crystals were collected by filtration, washed with anhydrous jetyl ether and ethyl acetate, and dried under reduced pressure. The crystals were dissolved again in anhydrous methanol (10 ml), and ethyl acetate (200 ml) was added. The precipitated crystals were collected by filtration and washed with anhydrous jetyl ether and ethyl acetate. After drying under reduced pressure, the title compound (460.8 mg, 1.080 mmol, yield) was obtained as a pale yellow solid. 44.5%).

Melting point 135.5-138 ° C

¹ H-NMR (200MHz, D Ο): δ (ppm): 6.77 (2H, d, J = 3.5Hz), 6.70 (1H, s), 6.67 (2H, d, J = 3.5Hz), 6.30 (2H , s), 3.36 (2H, t—like), 3 · 13 (4Η, t, J = 6.9Hz), 2.96 (2H, t, J = 6.9Hz), 2.

25 (3H, s)

¹³ C-NMR (50 MHz, DO / DMSO-d6): δ (ppm): 173.1, 172.2, 160.0, 151.5, 145.3, 13 8.3, 136.7, 127.9, 126.7, 111.0, 53.5, 33.9, 30.3, 27.0, 23.9

[0315] Production Example 34

Synthesis of N- (4- {2- [5- (3-hydrazinopropyl) thiophen-2-yl] ethyl} -l, 3-thiazol-2-ynole) acetamide hydrochloride

[0316] [Chemical 114]

Step-丄

[0317] N- (4- {2- [5- (3-hydroxypropyl) thiophen-2-yl] ethyl] -1,3-thiazol-2-yl) acetamide (710.0 mg, 2.287 mmol), tert-Butyl (1,3-dioxo-1,3_dihydro-2H-isoindole-2-inole) strength rubamate (750.0 mg, 2.859 mmol), triphenylphosphine (929 • 8 mg, 3.545 mmol) in anhydrous tetrahydrofuran ( 50 ml) was added dropwise with a solution of tetrahydrofuran (3.0 ml) in anhydrous ethyltetrahydrofuranate (3.43 mmol) obtained by distilling off the solvent from 1.56 ml of 2.2M toluene solution at 0 ° C. The mixture was stirred at room temperature for 14 hours and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP, 130 g, ethyl acetate: hexane = 1: 1) and tert-butyl (3- {5_ [2- (2-acetylamino)-was obtained as a white solid. 1,3-thiazol-4-yl) ethyl] thiophen-2-yl} propyl) (1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) force rubamate (871.3mg 1.571 mmol, yield 68.7%).

[0318] [Chemical 115] Step-2

[0319] tert-Butyl (3- {5- [2- (2-acetylamino-1,3-thiazol-4-yl) ethyl] thiophene-2-yl} propyl) (1,3-dioxo- Methylhydrazine (0.10 ml, 1.9 mmol) was added dropwise to a solution of 1,3-dihydro-2H-isoindole-2-yl) carbamate (860.0 mg, 1.550 mmol) in anhydrous tetrahydrofuran (10 ml) at -20 ° C. did. The mixture was warmed to room temperature and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, jetyl ether (100 ml) was added, and insoluble material was collected by filtration. The insoluble material was washed with Jetier® Tel and the filtrate was concentrated. Ethyl acetate (30 ml) was added to the concentrated residue, and the insoluble material was collected by filtration. The insoluble material was washed with ethyl acetate and the filtrate was concentrated. The concentrated residue was purified by silica gel chromatography (Fuji Silysia FL-60D, 100 g, ethyl acetate: hexane = 1: 1) and tert-butyl N- (3- {5- [2- ( 2-acetylamino-1,3-thiazole-4-inole) ethinole] thiophene-2-inole} propyl) hydrazinecarboxylate Purity analysis by H-NMR: approx. 95.3%, 2-methyl-2,3-dihydrophthalazine -613.8 mg containing 1,4-dione, 585 mg pure, 1.38 mmol, yield 88.9%).

[0320] [Chem 116]

Step 3

tert-butyl N- (3- {5- [2- (2-acetylamino-1,3-thiazol-4-yl) ethyl] thiophene-2-inole} propyl) hydrazinecarboxylate (purity 95.3%, 580.0 mg, pure content 1.30 mmo 1) was dissolved in a mixed solvent of dichloromethane (4 ml) and methanol (8 ml). A 1M hydrogen chloride ethyl ether solution (19.2 ml, 19.2 mmol) was added, and the mixture was stirred at room temperature for 10.5 hours and concentrated under reduced pressure. Jetyl ether (20 ml) was added to the concentrated residue, and the mixture was concentrated again under reduced pressure to remove hydrogen chloride. The residue was filtered by adding jetyl ether (20 ml), and the resulting solid was washed five times with jetyl ether. Drying under reduced pressure gave the title compound (430.5 mg, 1.193 mmol, yield 91.6%) as a white solid.

Melting point 80 ~ 105 ° C (melting point is not so clear)

'H-NMR (200MHZ, D 0, DSS = 0ppm): δ (ppm): 6 · 98 (1Η, s), 6 · 74 (1Η, d, J = 3.4Hz), 6 • 71 (1H, d , J = 3.4Hz), 3 · 25_3 · 05 (6Η, m), 2.89 (2H, t, J = 7.4Hz), 2.38 (3H, s), 2.01 (2H, quintet, J = 7.6Hz)

¹³ C-NMR (50 MHz, D 0, DSS = 0 ppm): δ (ppm): 174.3, 163.4, 144.7, 143.7, 127.9, 1 27.6, 112.9, 53.0, 32.1, 30.6, 28.8, 25.0, 21.8, 17.7

[0322] Test Example 1

Enzyme activity inhibitory effect on human and rat VAP-1 enzyme (SSAO)

About the compound of this invention obtained by the manufacture example, the enzyme activity inhibitory effect with respect to a human and rat VAP-1 enzyme (SSAO) was investigated with the following method.

VAP-1 enzyme (SSAO) activity in both humans and rats was measured by radiochemical enzyme assay using ¹⁴ C-benzylamine as an artificial substrate. cDNA libraries Karahi preparative and rat VAP-1 was cloned, was expressed cell extract, together with the test compound solution (final concentration ^{^{1 X 10- 7 ~1 X 10- 11}} mol / L), 20 at room temperature Pre-incubated for minutes. Then is added the ¹⁴ C_ Penjinoreamin (final concentration ^{1 X 10- 5 mol / L)} , in a final volume of 200 mu L, they were incubated for 2 hours at 37 ° C. The enzymatic reaction was terminated by adding 2 mol / L (200 L) citrate. The oxidized product was extracted into 1 mL toluene / ethyl acetate (1: 1), and its radioactivity was measured with a liquid scintillation counter. The results are shown in Tables 1 and 2.

As shown in Tables 1 and 2, the compounds of the present invention significantly inhibited the enzyme activity of human and rat SSAO.

[0323] [Table 1] [] D¾¾0324

y (^! SA〇A¾ In vitroSV t:- Human and rat S SAO (VAP-1) inhibitory activity in in vitro tests

Test example 2

Inhibitory effect of enzyme activity on VAP-1 enzyme (SSAO) in rat retina With respect to the compounds of the present invention obtained in Production Examples and Comparative Examples, the enzyme activity inhibitory effect on VAP-1 enzyme (SSAO) in rat retina was examined by the following method.

Diabetes in rats was induced by intravenous injection of 50 mg / mL / kg streptozotocin (STZ) in 2 mmol / L citrate buffer (pH 4.5) after fasting for about 20 hours. Plasma glucose levels were checked by the hexokinase method. Three days after STZ treatment, the rats were diagnosed with diabetes showing plasma glucose levels of 350 mg / dl or higher.

On day 7 after STZ treatment, a test compound solution (lmg / ml) was injected subconjunctivally (0.05 mg / eye) into the rear eye of rats. The retinas were harvested 3 hours after administration, the SSAO activity in the retina, using a ¹⁴ C_ Benjiruamin (final concentration 1 X 10- ⁵ mol / L) as substrates, it has been conducted under the measured radiochemical enzyme Atsusi. The results are shown in Table 3.

As shown in Table 3, administration of the compound of the present invention significantly suppressed the SSAO enzyme activity in the retina compared to the vehicle control group.

[Table 3]

S S A O activity in the retina (pmol / min / mg protein)

**: D mnett test indicates a significant difference (ρ <0 · 01 vs. vehicle control group). *: Significant difference by Dumiett's test (p 0.05 corresponding to vehicle control group). [0327] Test Example 3

Enzyme activity inhibitory effect on human monoamine oxidase enzymes (MAO-A and MAO-B) For the compounds of the present invention obtained in the production examples, human monoamine oxidase enzymes (MAO-A and MAO-B) The enzyme activity inhibitory effect on) was investigated.

Recombinant human MAO-A and MAO-B enzymes were obtained from Sigma. Human MAO-A and MAO-B activities were measured using MAO Detection Kit (Fluoro MAO, Cell Technorogy Inc.). Atsey was performed in a 96-well plate. f Reaction buffer was added to each well 40〃L, and 50 L of MAO-A or MAO-B was added. Then test compound solution (final concentration ^{^{1 X 10- 5 ~1 X 10- 1Q}} m 0 l / L) was added 10 mu L, and 20 minutes Incubate Pies at 37 ° C. The reaction cocktail was charged with 100 μL and incubated at 37 ° C for 2 hours with a final volume of 200 μL. Then, using a Manoletis petatro microplate reader (Varioskan, Thermo Fisher Scientific), the excitation light was 570 nm and fluorescence at 590 nm was detected. The results are shown in Table 4.

As shown in Table 4, the compounds of the present invention had no significant inhibitory effect on human MAO-A and MAO-B. Since it does not substantially inhibit other monoamine oxidases, it can be seen that the compound of the present invention selectively inhibits SSAO.

[0328] [Table 4]

Enzyme activity inhibitory effect on human monoamine oxidase enzymes (MA0-A and MA0-B)

Industrial applicability

[0329] The present invention provides a compound of formula (I) useful as a VAP-1 inhibitor.

[0330] [Chemical 117]

R “NH— X— Y— Z (')

[0331] (In the formula, each symbol is as defined above)

Or a pharmaceutically acceptable salt thereof, a pharmaceutical composition, a medicament for the prevention or treatment of VAP-1 related diseases such as macular edema and hypervascular disease To do.

This application is based on Japanese Patent Application No. 2006-325061 filed in Japan, the contents of which are incorporated in full herein.

Claims

Claim Formula (I)

[Chemical 1]

R ¹ —— NH——X—— Y—— Z (I)

[Where

R ¹ is asil;

X is substituted! /, May! /, A divalent residue derived from thiazole;

Y is the formula (III):

[Chemical 2]

{Wherein J is a bond, lower alkylene, lower alkenylene, lower alkynylene, mono (CH)

2 n

— O— — (CH) — NH— (CH) — CO, or — (CH) —SO— (each formula

In 2 n 2 n 2 n 2, n is an integer from 0 to 6. );

L is a bond, O— — NH— — CO, or — SO —;

2

M is a bond, lower alkylene, lower alkenylene, or lower alkynylene. However, when J is one (CH) — O, L is not one O NH and one SO—

2 n 2

Is — (CH) — NH, L is not — O and — NH but J is — (CH) −

2 n 2 n

In the case of CO, L is not —CO, but if J is — (CH 2) —SO—, L is —O

2 n 2

And not SO— (in each formula, n is as defined above). }

2

Z is the formula (II):

[Chemical 3]

A― B 1 D― E (II) {Wherein A is a divalent residue derived from benzene force or a divalent residue derived from thiophene force;

B is — NR ² — CO—, — (CH) —, or — (CH) —CO— (wherein R ² is hydrogen,

2 n 2 n

Lower alkyl, or acyl; n represents an integer of 0 to 6; );

D is NR ³ — (wherein R ³ represents hydrogen, lower alkyl, alkoxycarbonyl or acyl);

E represents an optionally substituted amino. }; Or a pharmaceutically acceptable salt thereof.

The compound represented by the formula (I) is N {4 [2- (4 hydrazinocarbophenyl) ethyl] -1,3 thiazole-2-yl} acetamide,

Ν- (4- {2- [4- (Ν 'Acetylhydrazinocarbonylmethinole) phenolino] ethyl N- (4- {2- [4- (N'-butanoylhydrazinocarbonylmethinole) phenenole] ethyl]}-1,3 thiazole-2-yl) acetamide,

2 Hydroxyethinole 2 — [(4 {2— [2— (Acetylamino) -1,3 Thiazoles 4

Ν— (4 {2— [5 (hydrazinocarbonyl) thiophene 2-yl] ethyl)} 1, 3--thiazol-2-yl) acetamide, N— (4 {2— [5 (hydrazinocarbonylmethyl) thiophene 2-yl] ethyl) 1,3 thiazol-2-yl) acetamide,

N— {4 [2— (4 hydrazinophenole) ethyl] — 1, 3 thiazole-2-yl} ace amide,

N- (4- {2- [4- (hydrazinomethinole) phenethyl] ethyl]} 1,3-thiazole-2-yl) acetamide,

N- (4- {2- [4- (2 hydrazinoethyl) phenyl] ethyl} -1,3 thiazole-2-yl) acetamide,

N- (4- {2- [3- (2 hydrazinoethyl) phenyl] ethyl} -1,3 thiazole-2-yl) acetamide,

The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

[3] The compound according to claim 1, wherein the compound represented by the formula (I) is N— {4 [2- (4 hydrazinocarbonylmethylphenyl) ethyl] 1, thiazol-2-yl} acetamide. Product, or a pharmaceutically acceptable salt thereof.

[4] The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[5] A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.

[6] A VAP-1 inhibitor comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.

[7] A medicament for preventing or treating a VAP-1 related disease, comprising as an active ingredient the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

[8] Said VAP-1 related diseases are macular edema (diabetic and non-diabetic macular edema), age-related macular degeneration, age-related discoid macular degeneration, cystoid macular edema, eyelid edema, retinal edema, diabetes Retinopathy, chorioretinopathy, neovascular maculopathy, neovascular glaucoma, uveitis, iritis, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmitis, choroiditis, retinitis pigmentosa, conjunctiva Inflammation, ciliitis, scleritis, scleritis, optic neuritis, retrobulbar neuritis, keratitis, blepharitis, exudative retinal detachment, corneal ulcer, conjunctival ulcer, chronic monkey keratitis, Tyegson keratitis Ocular inflammatory diseases, including progressive Morlen ulcers, bacterial or viral infections, and ocular inflammatory diseases caused by ophthalmic surgery, ocular inflammatory diseases caused by physical eye damage, itching, redness, edema and ulceration Symptoms caused by the disease, erythema, polymorphic exudative erythema Erythema nodosum, ring erythema, edematous sclerosis, dermatitis (psoriasis, allergic lesions, lichen planus, rose sucrose eczema, contact dermatitis, atopic dermatitis, erythematous erythema), pulse Tuberculosis edema, pharyngeal edema, glottal edema, hypoglottic pharyngitis, bronchitis, rhinitis, pharyngitis, sinusitis and pharyngitis or otitis media, cirrhosis, essential fixed hypertension, diabetes, arteriosclerosis, (diabetes, Endothelial damage (in arteriosclerosis and hypertension), cardiovascular disease associated with diabetes and uremia, pain associated with gout and arthritis, inflammatory diseases or symptoms of connective tissue (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and bone) Arthritis or deformed joint disease, Reiter syndrome, Siedalen syndrome, Behcet syndrome, relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, systemic Sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, polymyalgia rheumatica, vasculitis, transient arthritis, nodular polyarteritis, Wegener's granulomatosis, mixed connective tissue disease And juvenile rheumatoid arthritis), inflammatory diseases or symptoms of the gastrointestinal tract [Crohn's disease, ulcerative colitis, irritable bowel syndrome (convulsive colon), fibrosis of the liver, inflammation of the oral mucosa (stomatitis and recurrent) Pharyngitis), central nervous system inflammatory diseases or symptoms (multiple sclerosis, Alzheimer's disease, and ischemia-reperfusion injury associated with ischemic stroke), pulmonary inflammatory diseases or Symptoms (asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease), microvascular and macrovascular diseases (arteriosclerosis, retinopathy, nephropathy, nephrotic syndrome and neuropathy (polyneuropathy, mononeuropathy and autonomy) Diseases related to carbohydrate metabolism (diabetes and diabetic complications), adipocyte differentiation or function, or abnormal smooth muscle cell function, including neuropathy), foot ulcers, joint problems and increased risk of infection Related diseases (arteriosclerosis and obesity), vascular disease [atherosclerosis, non-atherosclerosis, ischemic heart disease including myocardial infarction and peripheral artery occlusion, Reino's disease and Reino's phenomenon, obstructive thrombus Vasculitis (Burja's disease)], chronic arthritis, inflammatory bowel disease, or SSAO-mediated complications [diabetes (insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent sugars) The medicament for the prevention or treatment of a VAP-1 related disease according to claim 7, which is urinary disease (NIDDM)) and vascular complications (heart attack, angina pectoris, stroke, amputation, blindness and renal failure).

[9] Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament as a VAP-1 inhibitor.

[10] Use of the compound according to any one of claims;! To 3 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating a VAP-1 related disease.

[11] Said VAP-1 related diseases are macular edema (diabetic and non-diabetic macular edema), age-related macular degeneration, age-related discoid macular degeneration, cystoid macular edema, eyelid edema, retinal edema, diabetes Retinopathy, chorioretinopathy, neovascular maculopathy, neovascular glaucoma, uveitis, iritis, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmitis, choroiditis, retinitis pigmentosa, conjunctiva Inflammation, ciliitis, scleritis, scleritis, optic neuritis, retrobulbar neuritis, keratitis, blepharitis, exudative retinal detachment, corneal ulcer, conjunctival ulcer, chronic monkey keratitis, Tyegson keratitis Ocular inflammatory diseases, including progressive Morlen ulcers, bacterial or viral infections, and ocular inflammatory diseases caused by ophthalmic surgery, ocular inflammatory diseases caused by physical eye damage, itching, redness, edema and ulceration Symptoms caused by the disease, erythema, polymorphic exudative erythema Erythema nodosum, ring erythema, edematous sclerosis, dermatitis (psoriasis, allergic lesions, lichen planus, rose sucrose eczema, contact dermatitis, atopic dermatitis, erythematous erythema), pulse Tubular neuropathic edema, pharyngeal edema, glottic edema, hypoglottic pharyngitis, bronchitis, rhinitis, pharyngitis, sinusitis and pharyngitis or otitis media, cirrhosis, essential fixed hypertension, diabetes, arteries Sclerosis, endothelium damage (in diabetes, arteriosclerosis and hypertension), cardiovascular disease associated with diabetes and uremia, pain associated with gout and arthritis, inflammatory diseases or symptoms of connective tissue (rheumatoid arthritis, ankylosing spondylitis) Psoriasis arthritis and osteoarthritis or deformed joint disease, Reiter syndrome, Siedalen syndrome, Behcet syndrome, relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, Polymyositis, dermatomyositis, polymyalgia rheumatica, vasculitis, transient arthritis, nodular polyarteritis, Wegener's granulomatosis, mixed connective tissue disease and juvenile rheumatoid arthritis), gastrointestinal tract Inflammatory diseases or symptoms [Crohn's disease, ulcerative colitis, irritable bowel syndrome (convulsive colon), liver fibrosis, inflammation of the oral mucosa (stomatitis Recurrent after mouth stomatitis)], inflammatory diseases or symptoms of the central nervous system (multiple sclerosis, Alzheimer's disease, and ischemic reperfusion injury associated with ischemic stroke), pulmonary inflammatory diseases or symptoms (asthma) , Adult respiratory distress syndrome, chronic obstructive pulmonary disease), microvascular and macrovascular disease (arteriosclerosis, retinopathy, nephropathy, nephrotic syndrome and neuropathy (polyneuropathy, mononeuropathy and autonomic disorder) Related to carbohydrate metabolism (diabetes and diabetic complications), adipocyte differentiation or function, or abnormal smooth muscle cell function, including ulcers, foot ulcers, joint problems and increased risk of infection Diseases (arteriosclerosis and obesity), vascular diseases [ischemic heart disease including atherosclerosis, non-atherosclerosis, myocardial infarction and peripheral arterial occlusion, Reino's disease and Innocism, obstructive thrombotic vasculitis (Burger's disease)], chronic arthritis, inflammatory bowel disease, or SSAO-mediated complications [diabetes (insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) ))) And vascular complications (heart attack, angina pectoris, stroke, amputation, blindness and renal failure)].

[12] A method for inhibiting VAP-1 in a subject, comprising administering an effective amount of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof to the subject.

[13] A method for preventing or treating a VAP-1-related disease in a subject, comprising administering an effective amount of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof to the subject.

[14] Said VAP-1 related disease is macular edema (diabetic and non-diabetic macular edema), aging Macular degeneration, age-related discoid macular degeneration, cystoid macular edema, eyelid edema, retinal edema, diabetic retinopathy, choroidal retinopathy, neovascular macular disease, neovascular glaucoma, uveitis, iritis, retina Vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmitis, choroiditis, retinitis pigmentosa, conjunctivitis, ciliary inflammation, scleritis, episclerosis, optic neuritis, retrobulbar neuritis, cornea Inflammation, blepharitis, exudative retinal detachment, corneal ulcer, conjunctival ulcer, chronic monkey keratitis, Tigerson keratitis, progressive Mohren ulcer, ocular inflammatory disease caused by bacterial or viral infection, and by ophthalmic surgery, eye Ocular inflammatory disease caused by physical damage of the eyes, symptoms caused by ocular inflammatory diseases including itching, redness, edema and ulcers, erythema, polymorphic exudative erythema, erythema nodosum, annular erythema, edematous sclerosis , Dermatitis (psoriasis, allergic lesions, Lichen planus, rose sucrose eczema, contact dermatitis, atopic dermatitis, erythema erythematosus), vascular neuropathic edema, pharyngeal edema, glottic edema, glottic pharyngitis, bronchitis, rhinitis, Pharyngitis, sinusitis and pharyngitis or otitis media, cirrhosis, essential fixed hypertension, diabetes, arteriosclerosis, endothelial damage (in diabetes, arteriosclerosis and hypertension), cardiovascular disease related to diabetes and uremia, gout and Pain associated with arthritis, inflammatory diseases or symptoms of connective tissue (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and osteoarthritis or deformed joint disease, Reiter syndrome, Siedalen syndrome, Behcet syndrome, relapsing polychondral cartilage Inflammation, systemic lupus erythematosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, polymyalgia rheumatica, vasculitis , Transient arthritis, polyarteritis nodosa, Wegener's granulomatosis, mixed connective tissue disease and juvenile rheumatoid arthritis), inflammatory diseases or symptoms of the gastrointestinal tract (Crohn's disease, ulcerative colitis, irritability) Bowel syndrome (convulsive colon), liver fibrosis, inflammation of the oral mucosa (stomatitis and recurrent phlegmous stomatitis)], inflammatory diseases or symptoms of the central nervous system (multiple sclerosis, Alzheimer's disease, and ischemic) Stroke-related ischemia-reperfusion injury), pulmonary inflammatory diseases or symptoms (asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease), microvascular and macrovascular diseases (arteriosclerosis, retinopathy, nephropathy, nephrosis) Diseases related to carbohydrate metabolism (including diabetes and diabetic causes), including syndromes and neurological disorders (polyneuropathy, mononeuropathy and autonomic neuropathy), foot ulcers, joint problems and increased risk of infection) Complications), abnormal diseases associated with the function of differentiation or function or smooth muscle cells of the adipose cells (arteries Sclerosis and obesity), vascular disease [atherosclerosis, non-atherosclerosis, ischemic heart disease including myocardial infarction and peripheral arterial occlusion, Reino disease and Reino phenomenon, obstructive thrombotic vasculitis (Burger Disease)], chronic arthritis, inflammatory bowel disease, or S SAO-mediated complications [diabetes (insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM)) and vascular complications (heart attack, angina) , Stroke, amputation, blindness and renal failure)]. The method for preventing or treating a VAP-1 related disease according to claim 13.