KR101128372B1 - 1H-pyridin-2-one derivatives - Google Patents

1H-pyridin-2-one derivatives Download PDF

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KR101128372B1
KR101128372B1 KR1020040038416A KR20040038416A KR101128372B1 KR 101128372 B1 KR101128372 B1 KR 101128372B1 KR 1020040038416 A KR1020040038416 A KR 1020040038416A KR 20040038416 A KR20040038416 A KR 20040038416A KR 101128372 B1 KR101128372 B1 KR 101128372B1
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compound
imidazol
amino
pyridin
phenyl
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KR20050112948A (en
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구본암
남웅현
홍우상
이원일
고광석
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주식회사 씨앤드씨신약연구소
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

본 발명은 만성 폐색성 폐질환(COPD), 천식, 만성 기관지염, 건선, 궤양성 대장염, 크론씨병(국한성 회장염), 죽상동맥경화증, 류마티스성 관절염, 골다공증, 골관절염, 우울증, 기억손상증, 염증 매개성 만성 조직괴사증, 및 PDE4에 의해 매개되는 다른 질환의 치료에 유용하며 신규한 1H-피리딘-2-온 유도체, 약제학적으로 허용되는 그의 염, 및 입체화학적 이성체에 관한 것이다.






The present invention relates to chronic obstructive pulmonary disease (COPD), asthma, chronic bronchitis, psoriasis, ulcerative colitis, Crohn's disease (local ileitis), atherosclerosis, rheumatoid arthritis, osteoporosis, osteoarthritis, depression, memory impairment, inflammation mediated inflammation Novel 1 H -pyridin-2-one derivatives, pharmaceutically acceptable salts thereof, and stereochemical isomers, useful for the treatment of sexual chronic histopathy and other diseases mediated by PDE4.






Description

1Ｈ-피리딘-2-온 유도체 {1H-pyridin-2-one derivatives}1H-pyridin-2-one derivatives

본 발명은 포스포디에스테라제4(PDE4)에 의해 매개되는 질환의 치료용 의약으로 유용하며 신규한 1H-피리딘-2-온 유도체, 약제학적으로 허용되는 그의 염, 및 입체화학적 이성체에 관한 것이다. 본 발명에 따른 화합물은 특히 만성 폐색성 폐질환(COPD), 천식, 만성 기관지염, 건선, 궤양성 대장염, 크론씨병(국한성 회장염), 죽상동맥경화증, 류마티스성 관절염, 골다공증, 골관절염, 우울증, 기억손상증, 염증 매개성 만성 조직괴사증의 치료에 유용하다.The present invention is useful as a medicament for the treatment of diseases mediated by phosphodiesterase 4 (PDE4) and relates to novel 1 H -pyridin-2-one derivatives, pharmaceutically acceptable salts thereof, and stereochemical isomers. will be. The compounds according to the invention are particularly characterized by chronic obstructive pulmonary disease (COPD), asthma, chronic bronchitis, psoriasis, ulcerative colitis, Crohn's disease (local ileitis), atherosclerosis, rheumatoid arthritis, osteoporosis, osteoarthritis, depression, memory damage It is useful for the treatment of inflammatory and mediated chronic tissue necrosis.

사이클릭 아데노신 3',5'-모노포스페이트(cAMP)는 제 1차 전달자(호르몬, 신경 전달 물질 또는 오타코이드)와 세포 기능 반응자 사이를 매개하는 중간체로서 세포내에 일반적인 제 2차 전달자이다. 제 1차 전달자는 cAMP 합성에 관여하는 효소를 자극하고, 이에 따라 합성된 cAMP는 연관된 세포에 따라 매우 많은 기능(물질 대사, 수축 또는 분비)을 조절한다.Cyclic adenosine 3 ', 5'-monophosphate (cAMP) is a secondary secondary messenger that is common in cells as an intermediate that mediates between primary messengers (hormones, neurotransmitters or otacoids) and cellular functional responders. The primary messenger stimulates the enzymes involved in cAMP synthesis, whereby the synthesized cAMP regulates a great many functions (metabolism, contraction or secretion) depending on the cells involved.

cAMP는 사이클릭 뉴클레오티드 포스포디에스테라제(cAMP의 가수 분해를 촉진 하여 불활성 아데노신 5'-모노포스페이트를 만드는 세포내 효소)에 의해 분해되면서 이것의 영향은 사라진다.cAMP is degraded by cyclic nucleotide phosphodiesterase (an intracellular enzyme that promotes hydrolysis of cAMP to make inactive adenosine 5'-monophosphate) and its effects disappear.

11종 이상의 주요 사이클릭 뉴클레오티드 포스포디에스테라제(PDE)과(科)가 포유 동물에서 판별되었고, 그 구조, 동력학적 거동, 기질 특이성, 또는 효과기에 대한 감작성에 따라 1부터 11까지의 번호를 부여하였다[Beavo J.A. et a1 (1990) Trends Pharmacol. Sci., 150-155; 및 Beavo J.A. et a1 (1994) Molecular Pharmacol., 399-405 참조]. 이중 포스포디에스테라제4(PDE4) 효소는 cAMP에 특이적이고 롤리프람(rolipram)에 의해 억제되는 효소이다.At least 11 major cyclic nucleotide phosphodiesterases (PDEs) have been identified in mammals and numbered from 1 to 11 depending on their structure, kinetic behavior, substrate specificity, or sensitivity to effectors. Was given [Beavo JA et a 1 (1990) Trends Pharmacol. Sci., 150-155; And Beavo J.A. et al (1994) Molecular Pharmacol., 399-405]. Dual phosphodiesterase 4 (PDE4) enzymes are enzymes specific for cAMP and inhibited by rolipram.

비특이적 포스포디에스테라제 억제제 화합물은 공지되어 있고, 이것은 몇몇 효소과(科)를 억제한다. 이것은 테오필린과 같은 특정 메틸 크산틴의 경우에 그러하다. 이 화합물은 특히 목표 세포외의 세포에 존재하는 PDE류에 작용하기 때문에 치료 지수가 낮다. 반대로, 특정 PDE과는 다양한 약제에 의해 선택적으로 억제될 수 있다. 사이클릭 뉴클레오티드의 가수 분해는 억제제에 민감한 PDE류가 발견되는 세포 내에서만 완화되고, 따라서 그 농도가 증가한다.Nonspecific phosphodiesterase inhibitor compounds are known, which inhibit some family of enzymes. This is true of certain methyl xanthines, such as theophylline. This compound has a low therapeutic index, especially because it acts on PDEs present in cells other than target cells. In contrast, certain PDEs may be selectively inhibited by a variety of agents. Hydrolysis of cyclic nucleotides is alleviated only in cells where inhibitor-sensitive PDEs are found, thus increasing their concentration.

중추 신경계, 심장, 맥관(脈管) 내피, 혈관 평활근 및 공기 경로, 골수선 및 임파선의 평활근을 포함하는 많은 조직에서 확인된 포스포디에스테라제4(PDE4)의 특별한 이점이 알려졌다.Particular benefits of phosphodiesterase 4 (PDE4) have been identified in many tissues, including the central nervous system, heart, vasculature endothelial, vascular smooth muscle and air pathways, bone marrow and lymphatic smooth muscle.

염증에 연관된 세포 내에서 cAMP가 증가하면 세포의 활동을 억제한다: 비만 세포, 단핵 세포, 다형핵(多形核) 호산구 및 호염기구 내에 있는 매개체의 합성 및 분비의 억제, 다형핵 호중구 및 호산구의 화학 주성 및 탈과립의 억제, 임파구의 증식 및 분화의 억제.Increasing cAMP in cells involved in inflammation inhibits cell activity: inhibition of the synthesis and secretion of mediators in mast cells, mononuclear cells, polymorphic eosinophils and basophils, polymorphonuclear neutrophils and eosinophils Inhibition of chemotaxis and degranulation, inhibition of lymphocyte proliferation and differentiation.

T 임파구 및 다형핵 호산구와 같은 다양한 종류의 백혈구에 의해 만들어지는 사이토킨, 특히 TNF 및 인터루킨은 염증 증상의 유발, 특히 호흡기 경로의 알레르기 항원에 의한 자극에 대한 반응에 중요한 역할을 한다.Cytokines, in particular TNF and interleukin, produced by various types of white blood cells, such as T lymphocytes and polymorphonuclear eosinophils, play an important role in the induction of inflammatory symptoms, in particular in response to stimulation by allergens in the respiratory pathway.

또한, cAMP는 흡입 경로를 통해 유입되면 평활근을 수축시키는데, PDE4 억제제는 이러한 기관지 이완을 유발한다.In addition, cAMP contracts smooth muscle when introduced through the inhalation pathway, and PDE4 inhibitors cause this bronchial relaxation.

만성 폐색성 폐질환(COPD)는 서서히 발병하는 만성 질환인데, 호흡기 경로의 폐색(호흡기 경로의 염증 및 호중구 개수의 증가와 관련됨)이 특징이다. 폐 기능의 손상은 (기관지 확장제로 사용하여 증상을 개선시킬 수는 있지만) 대부분의 경우에 회복되지 않는다.Chronic obstructive pulmonary disease (COPD) is a slowly developing chronic disease characterized by obstruction of the respiratory pathway (associated with inflammation in the respiratory pathway and an increase in the number of neutrophils). Impairment of pulmonary function does not recover in most cases (although it can be used as a bronchodilator to improve symptoms).

만성 폐색성 폐질환의 임상학적 증상은 발병의 심도에 따라, 회복될 수 있는 단순한 기관지염에서부터 만성 호흡 부전과 같은 회복될 수 없는 증상까지 다양하다. 만성 폐색성 폐질환을 앓고 있는 환자의 주요한 임상 특징은 만성 기관지염 및/또는 기종(호흡기 경로의 염증 및/또는 호중구 개수의 증가와 관련됨)이다. 이는 현재 미국에서 45세 이상 연령 인구 중에서 사망률이 4번째에 이르는 중대한 질환이고, 전세계적으로도 발병은 증가 추세이며, 특히 중국 및 동남아시아와 같이 남성 흡연 인구가 많은 나라에서는 10년내 환자가 3배 정도 증가할 것으로 추정되고 있다. 우리나라도 예외는 아니어서 청소년 흡연률이 세계 최고 수준인 점을 감안한다면, 상당기간 동안은 지속적으로 유병률이 증가할 것으로 판단된다. 그러나, 이 질병에 대한 기초적 지식이 아직 부족하여서, 중대한 질환임에도 불구하고, 연 구나 뚜렷한 치료제가 없이 대증치료에 의존하고 있는 실정이다. 현재, COPD 환자를 치료 또는 조절하는데 있어서, 금연을 권장하거나 질환의 진행정도에 따라 기관지 이완제, 항염증제, 또는 이 둘의 병용 투여가 실시되고 있기는 하나, 근본적으로 질병의 진행에는 별효과를 나타내지 못하고 있다.The clinical symptoms of chronic obstructive pulmonary disease range from simple bronchitis that can be recovered to irreversible symptoms such as chronic respiratory failure, depending on the severity of the onset. The main clinical features of patients with chronic obstructive pulmonary disease are chronic bronchitis and / or emphysema (associated with inflammation of the respiratory pathway and / or an increase in the number of neutrophils). This is the fourth most serious disease in the United States, with the fourth highest mortality rate among people age 45 and older, and the incidence is increasing worldwide, especially in countries with a large number of male smokers such as China and Southeast Asia. It is estimated to increase. Korea is no exception, given that the youth smoking rate is the highest in the world, the prevalence will continue to increase for a considerable period of time. However, the basic knowledge of the disease is still lacking, and despite the serious disease, there is no situation or remedy and relies on symptomatic treatment. Currently, in treating or controlling COPD patients, broncholeptics, anti-inflammatory drugs, or a combination of both are recommended, depending on the progression of the smoking cessation or the progression of the disease, but have no fundamental effect on disease progression. have.

한편, 약물개발 측면에서 보았을 때, 현재 다양한 측면에서 약물개발이 이루어져 오고 있다. 지난 10여년간 제약업계에서 개발하여 왔으나, 아직까지 임상시험에서는 별 효과를 거두지 못한 호중구 엘라스타제 억제제도 있으며, 실제 COPD 환자들이 겪는 기침이나, 빈호흡, 과다한 점액(가래) 형성을 차단해주는 새로운 대증치료 개념으로 약물 개발이 이루어지고 있기도 하고, COPD 질환의 급성 악화에 대한 위험을 줄이는 접근법으로 약물 개발을 진행하고 있기도 하다. 새로운 항염증기전으로서 CCR5 수용체 조절제, LTB4 길항제, IL-8 조절제 등이 개발되고 있으나,아직 뚜렷한 임상 보고자료나 임상 진입 약물은 없는 실정이다.Meanwhile, in terms of drug development, drug development has been made in various aspects. Some neutrophil elastase inhibitors, which have been developed in the pharmaceutical industry for over a decade, but have not yet worked well in clinical trials, are new symptomatic treatments that block coughing, poor breathing, and excessive mucus formation in actual COPD patients. Drug development is under way as a concept, and drug development is underway as an approach to reduce the risk of acute exacerbations of COPD disease. CCR5 receptor modulators, LTB4 antagonists, and IL-8 modulators have been developed as new anti-inflammatory mechanisms, but there are no clear clinical reports or clinical entry drugs.

최근에, 제 2세대 선택적 포스포디에스테라제-4 억제제가 만성 폐색성 폐질환의 치료에 잠재적으로 유효한 물질로 제안되었다[Doherty, Chemical Biology 1999, 3:466-473; Mohammed et al., Anti-inflammatory ＆ Immunodilatory Investigational Drugs 1999 1(1):1-28; 및 Schmidt et al., Clinical and Experimental Allergy, 29, supplement 2, 99-109 참조]. 최근에 개발된 여러 종류의 포스포디에스테라제-4 억제제중, GSK에서 개발중인 아리플로(ariflo)(경구 투여가 가능한 PDE4 억제제)가 만성 폐색성 폐질환의 치료에 가능성이 있음이 제기되었다[Nieman et al., Am J Respir Crit Care Med 1998, 157:A413; Underwood et al., Eur Respir J 1998, 12:86s; Compton et al., Am J Respir Crit Care Med 1999, 159:A522; 1999년 10월 12일에 마드리드에서 개최된 '유럽 호흡기 학회('European Respiratory Society')에서 콤프톤(Compton)이 진술한 구두 보고; 및 1999년 6월 27-30일에 파리에서 개최된 염증에 관한 제 4차 세계 회의에서 토르피(Torphy)와 언더우드(Underwood)가 진술한 구두 보고 참조]. 아리플로는 현재 만성 폐색성 폐질환 치료를 위해 제 3상 임상 실험 연구 중에 있다.Recently, second generation selective phosphodiesterase-4 inhibitors have been proposed as potentially effective substances for the treatment of chronic obstructive pulmonary disease [Doherty, Chemical Biology 1999, 3: 466-473; Mohammed et al., Anti-inflammatory & Immunodilatory Investigational Drugs 1999 1 (1): 1-28; And Schmidt et al., Clinical and Experimental Allergy, 29, supplement 2, 99-109]. Among the various types of phosphodiesterase-4 inhibitors that have been developed recently, ariflo (oral PDE4 inhibitor) developed by GSK has been suggested to be a potential treatment for chronic obstructive pulmonary disease. Nieman et al., Am J Respir Crit Care Med 1998, 157: A413; Underwood et al., Eur Respir J 1998, 12:86 s; Compton et al., Am J Respir Crit Care Med 1999, 159: A522; An oral report made by Compton at the European Respiratory Society held in Madrid on October 12, 1999; And oral reports made by Torphy and Underwood at the Fourth World Conference on Inflammation held in Paris, June 27-30, 1999]. Ariflo is currently in Phase III clinical trials for the treatment of chronic obstructive pulmonary disease.

그러나, 아리플로는 많은 결점을 갖고 있다는 것을 지적하지 않을 수 없다. 특히, 일회 복용량으로 20mg의 투여를 한 후에 구역질 및 구토와 같은 심각한 부작용이 나타났다고 보고되었다[Murdoch et al., Am J Respir Crit Care Med 1998, 157:A409 참조]. 그 정도의 낮은 투여량에서도 부작용이 나타난다는 것은 아리플로의 사용에 제한을 가하는 것이 되고, 매일 일회 투여하는 제약 제제로서의 사용을 방해해, 환자에게 불편을 끼칠 것이다. However, it must be pointed out that Ariflo has many shortcomings. In particular, serious side effects such as nausea and vomiting have been reported after administration of 20 mg in a single dose (see Murdoch et al., Am J Respir Crit Care Med 1998, 157: A409). Side effects even at such low doses would place restrictions on the use of ariflo and interfere with the use of pharmaceutical formulations administered once daily, causing inconvenience to the patient.

이에 강력하고 안전한 PDE4 억제제를 얻고 발전시키기 위한 광범위한 연구가 최근 수년간 이루어져 왔다. 이것은 많은 잠재적인 PDE4 억제제가 다른 과의 포스포디에스테라제에 활성을 나타낸다는 사실 때문에 어려움이 있는 것으로 밝혀졌고, 또한 원인은 정확히 밝혀져 있지 않으나, 중추신경계에서의 PDE4 억제작용으로 인해 구토, 구역질이 유발된다는 보고가 있기도 하다. 현재, cAMP에 의해 조절되는 기능의 정도를 고려하면, PDE4 억제제의 선택성의 부족과 치료농도에서 나타날 수 있는 부작용이 주요한 문제점 중의 하나이다.
Extensive research has been undertaken in recent years to obtain and develop potent and safe PDE4 inhibitors. This has been found to be difficult due to the fact that many potential PDE4 inhibitors are active in phosphodiesterases of other families, and the cause is not known, but due to PDE4 inhibitory activity in the central nervous system, nausea and nausea Some have been reported to be triggered. Currently, considering the degree of function regulated by cAMP, the lack of selectivity of PDE4 inhibitors and side effects that may occur at therapeutic concentrations are one of the major problems.

따라서 강력하고 선택적인 PDE4 억제제, 즉, 다른 과에 속하는 PDE들에는 작용하지 않으면서 PDE4에는 효과적으로 작용하는 억제제가 필요하다. 또한 그 약제는 치료 농도에서 구토나 구역질이 나타나지 않으며, 직접적인 기관지 이완작용과 항염증작용을 통해 COPD 질환의 급성 악화를 막고, 환자의 삶의 질을 개선시키며, 무엇보다도 질병의 점진적인 악화를 치료할 수 있어야 한다. 따라서 본 발명자들은 이러한 약제의 개발 요구에 부응하여 신규한 1H-피리딘-2-온 유도체를 개발하였으며, 이를 PCT/KR2003/002615호로 기출원한 바 있다. 그러나 본 발명자들은 이에 만족하지 않고 좀더 효과적인 화합물을 개발하고자 지속적인 연구를 수행하였으며, 그 결과 하기 화학식 1로 나타내는 신규한 1H-피리딘-2-온 유도체가 좀더 바람직한 생체내(in vivo) 억제활성을 나타냄을 발견하고 본 발명을 완성하게 되었다. Thus, there is a need for potent and selective PDE4 inhibitors, ie inhibitors that work effectively on PDE4 while not on PDEs belonging to other families. In addition, the drug does not show vomiting or nausea at therapeutic concentrations, and direct bronchial relaxation and anti-inflammatory action can prevent acute exacerbation of COPD disease, improve the quality of life of patients, and most of all, treat the progressive exacerbation of disease. Should be Accordingly, the present inventors have developed a novel 1 H -pyridin-2-one derivative in response to the development of such a drug, which has been filed as PCT / KR2003 / 002615. However, the present inventors have not been satisfied with this, and have conducted continuous studies to develop more effective compounds. As a result, the novel 1H -pyridin-2-one derivative represented by the following Chemical Formula 1 has more preferable in vivo inhibitory activity. It has been found that the present invention has been completed.

따라서 본 발명은 하기 화학식 1의 신규한 1H-피리딘-2-온 유도체, 약제학적으로 허용되는 그의 염, 또는 입체화학적 이성체를 제공함을 목적으로 한다. It is therefore an object of the present invention to provide novel 1 H -pyridin-2-one derivatives of the general formula (1), pharmaceutically acceptable salts thereof, or stereochemical isomers thereof.

본 발명은 또한, 하기 화학식 1의 1H-피리딘-2-온 유도체, 약제학적으로 허용되는 그의 염, 또는 입체화학적 이성체의 제조방법을 제공함을 목적으로 한다.Another object of the present invention is to provide a method for preparing a 1 H -pyridin-2-one derivative of Formula 1, a pharmaceutically acceptable salt thereof, or a stereochemical isomer.

본 발명은 또한, 활성 성분으로서 하기 화학식 1의 신규한 1H-피리딘-2-온 유도체, 약제학적으로 허용되는 그의 염, 또는 입체화학적 이성체를 약제학적으로 허용되는 담체와 함께 함유함을 특징으로 하는 PDE4 억제제 조성물을 제공함을 목적으로 한다.
The present invention is also characterized as containing, as an active ingredient, a novel 1 H -pyridin-2-one derivative of the formula (1), a pharmaceutically acceptable salt thereof, or a stereochemical isomer together with a pharmaceutically acceptable carrier. It is an object to provide a PDE4 inhibitor composition.

본 발명은 하기 화학식 1의 신규한 1H-피리딘-2-온 유도체, 약제학적으로 허용되는 그의 염, 또는 입체화학적 이성체에 관한 것이다:The present invention relates to novel 1 H -pyridin-2-one derivatives of formula (1), pharmaceutically acceptable salts thereof, or stereochemical isomers thereof:

Figure 112004022905826-pat00001
Figure 112004022905826-pat00001

상기 식에서In the above formula

R1은 C6-C12-아릴을 나타내거나, 질소, 산소, 및 황으로 구성된 그룹으로부터 선택된 1 내지 3개의 헤테로 원자를 포함하는 5 내지 12-원 헤테로아릴을 나타내며, 이들은 각각 할로겐 및 하이드록시-C1-C6-알킬로 구성된 그룹으로부터 선택된 1 또는 2개의 치환체에 의해 치환되거나 비치환되고, R 1 represents C 6 -C 12 -aryl, or 5 to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, which are halogen and hydroxy, respectively Unsubstituted or substituted by one or two substituents selected from the group consisting of -C 1 -C 6 -alkyl,

R2는 C3-C8-사이클로알킬을 나타내거나, C6-C12 -아릴을 나타내거나, 질소, 산소, 및 황으로 구성된 그룹으로부터 선택된 1 내지 3개의 헤테로 원자를 포함하는 5 내지 12-원 헤테로아릴을 나타내며, 이들은 각각 할로겐, 하이드록시, C1-C6-알킬, C1-C6-알콕시, 할로게노-C1-C6-알킬, 할로게노-C 1-C6-알콕시, 및 C3-C8-사이클로알킬-C1-C6-알콕시로 구성된 그룹으로부터 선택된 1 또는 2개의 치환체에 의해 치환 되거나 비치환되고, R 2 represents C 3 -C 8 -cycloalkyl, C 6 -C 12 -aryl, or 5 to 12-containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur Membered heteroaryl, which is halogen, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogeno-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkoxy , And unsubstituted or substituted by one or two substituents selected from the group consisting of C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkoxy,

R3 및 R4는 각각 독립적으로 수소 또는 C1-C6-알킬을 나타낸다. R 3 and R 4 each independently represent hydrogen or C 1 -C 6 -alkyl.

다른 언급이 없는 한, 본 발명에서 언급된 알킬은 선형 또는 분지쇄일 수 있다. Unless stated otherwise, the alkyl mentioned in the present invention may be linear or branched.

포스포디에스테라제 효소, 특히 효소 PDE4의 억제제, 특히 선택적 억제제로서 유용한 상기 화학식 1의 화합물 중에서도 바람직한 화합물은 R1이 할로겐 및 하이드록시-C1-C6-알킬로 구성된 그룹으로부터 선택된 1 또는 2개의 치환체에 의해 치환되거나 비치환된 이미다졸을 나타내는 화합물, 약제학적으로 허용되는 그의 염, 또는 입체화학적 이성체이다.Among the compounds of formula (I) useful as phosphodiesterase enzymes, in particular inhibitors of the enzyme PDE4, in particular selective inhibitors, preferred are those wherein R 1 is selected from the group consisting of halogen and hydroxy-C 1 -C 6 -alkyl A compound representing an imidazole unsubstituted or substituted by two substituents, a pharmaceutically acceptable salt thereof, or a stereochemical isomer.

또한 바람직한 화합물은 R2가 할로겐, 하이드록시, C1-C6-알킬, C 1-C6-알콕시, 할로게노-C1-C6-알킬, 할로게노-C1-C6-알콕시, 및 C3 -C8-사이클로알킬-C1-C6-알콕시로 구성된 그룹으로부터 선택된 1 또는 2개의 치환체에 의해 치환되거나 비치환된 페닐을 나타내는 화합물, 약제학적으로 허용되는 그의 염, 또는 입체화학적 이성체이다.Further preferred compounds are those in which R 2 is halogen, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogeno-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkoxy, And a phenyl substituted or unsubstituted by one or two substituents selected from the group consisting of C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkoxy, pharmaceutically acceptable salts thereof, or stereochemically Isomers.

본 발명에 따른 화학식 1의 화합물 중에서도 대표적인 화합물은 하기 그룹에서 선택된다:Among the compounds of the formula 1 according to the present invention, representative compounds are selected from the following groups:

1-아미노-4-이미다졸-1-일-6-페닐-1H-피리딘-2-온(화합물 1);1-amino-4-imidazol-1-yl-6-phenyl-1 H -pyridin-2-one (Compound 1);

1-아미노-4-이미다졸-1-일-6-(2-메톡시-페닐)-1H-피리딘-2-온(화합물 2); 1-amino-4-imidazol-1-yl-6- (2-methoxy-phenyl) -1 H -pyridin-2-one (Compound 2);

1-아미노-4-이미다졸-1-일-6-(3-메톡시페닐)-1H-피리딘-2-온(화합물 3);1-amino-4-imidazol-1-yl-6- (3-methoxyphenyl) -1 H -pyridin-2-one (Compound 3);

1-아미노-6-(3-하이드록시페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 4);1-amino-6- (3-hydroxyphenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 4);

1-아미노-4-이미다졸-1-일-6-(3-트리플루오로메톡시-페닐)-1H-피리딘-2-온 (화합물 5);1-amino-4-imidazol-1-yl-6- (3-trifluoromethoxy-phenyl) -1 H -pyridin-2-one (compound 5);

1-아미노-6-(3-디플루오로메톡시페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 6);1-amino-6- (3-difluoromethoxyphenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 6);

1-아미노-6-(3-에톡시-페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 7);1-amino-6- (3-ethoxy-phenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 7);

1-아미노-4-이미다졸-1-일-6-(3-이소프로폭시-페닐)-1H-피리딘-2-온(화합물 8);1-amino-4-imidazol-1-yl-6- (3-isopropoxy-phenyl) -1 H -pyridin-2-one (Compound 8);

1-아미노-4-이미다졸-1-일-6-페닐-1H-피리딘-2-온 2염산염(화합물 9);1-amino-4-imidazol-1-yl-6-phenyl-1 H -pyridin-2-one dihydrochloride (Compound 9);

1-아미노-6-사이클로프로필-4-이미다졸-1-일-1H-피리딘-2-온(화합물 10);1-amino-6-cyclopropyl-4-imidazol-1-yl-1 H -pyridin-2-one (Compound 10);

1-아미노-4-(2-클로로-이미다졸-1-일)-6-사이클로헥실-1H-피리딘-2-온(화합물 11);1-amino-4- (2-chloro-imidazol-1-yl) -6-cyclohexyl-1 H -pyridin-2-one (Compound 11);

1-아미노-6-(4,4-디플루오로-사이클로헥실)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 12);1-amino-6- (4,4-difluoro-cyclohexyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 12);

1-아미노-6-(4-플루오로-페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 13);1-amino-6- (4-fluoro-phenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 13);

1-아미노-6-(3-플루오로-페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 14);1-amino-6- (3-fluoro-phenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 14);

1-아미노-6-사이클로헥실-4-이미다졸-1-일-3-메틸-1H-피리딘-2-온(화합물 15);1-amino-6-cyclohexyl-4-imidazol-1-yl-3-methyl-1 H -pyridin-2-one (Compound 15);

1-아미노-4-이미다졸-1-일-6-(3-프로폭시-페닐)-1H-피리딘-2-온(화합물 16); 1-amino-4-imidazol-1-yl-6- (3-propoxy-phenyl) -1 H -pyridin-2-one (Compound 16);

1-아미노-6-(3-사이클로프로필메톡시-페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 17);1-amino-6- (3-cyclopropylmethoxy-phenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 17);

1-아미노-4-이미다졸-1-일-1H-[2,2']바이피리디닐-6-온(화합물 18);1-amino-4-imidazol-1-yl-1H- [2,2 '] bipyridinyl-6-one (Compound 18);

1-아미노-4-이미다졸-1-일-1H-[2,3']바이피리디닐-6-온(화합물 19);1-amino-4-imidazol-1-yl-1H- [2,3 '] bipyridinyl-6-one (Compound 19);

1-아미노-4-이미다졸-1-일-1H-[2,4']바이피리디닐-6-온(화합물 20);1-amino-4-imidazol-1-yl-1H- [2,4 '] bipyridinyl-6-one (Compound 20);

1-아미노-4-이미다졸-1-일-6-(4-메톡시-페닐)-1H-피리딘-2-온(화합물 21);1-amino-4-imidazol-1-yl-6- (4-methoxy-phenyl) -1 H -pyridin-2-one (Compound 21);

1-아미노-6-사이클로헥실-4-(4-하이드록시메틸-페닐)-1H-피리딘-2-온(화합물22);1-amino-6-cyclohexyl-4- (4-hydroxymethyl-phenyl) -1 H -pyridin-2-one (compound 22);

1-아미노-6-사이클로헥실-4-(3-하이드록시메틸-페닐)-1H-피리딘-2-온(화합물23);1-amino-6-cyclohexyl-4- (3-hydroxymethyl-phenyl) -1 H -pyridin-2-one (compound 23);

1'-아미노-6'-페닐-1'H-[3,4']바이피리디닐-2'-온(화합물 24);1'-amino-6'-phenyl-1'H- [3,4 '] bipyridinyl-2'-one (compound 24);

1'-아미노-6'-페닐-1'H-[4,4']바이피리디닐-2'-온(화합물 25);1'-amino-6'-phenyl-1'H- [4,4 '] bipyridinyl-2'-one (compound 25);

1-아미노-4-이미다졸-1-일-6-m-톨릴-1H-피리딘-2-온(화합물 26); 및 1-amino-4-imidazol-1-yl-6-m-tolyl-1 H -pyridin-2-one (Compound 26); And

1-아미노-4-이미다졸-1-일-6-(3-트리플루오로메틸-페닐)-1H-피리딘-2-온(화합물 27). 1-amino-4-imidazol-1-yl-6- (3-trifluoromethyl-phenyl) -1 H -pyridin-2-one (compound 27).

상기 대표적인 화합물 중에서도 특히 바람직한 화합물은 Among the representative compounds, particularly preferred compounds are

1-아미노-4-이미다졸-1-일-6-페닐-1H-피리딘-2-온(화합물 1);1-amino-4-imidazol-1-yl-6-phenyl-1 H -pyridin-2-one (Compound 1);

1-아미노-4-이미다졸-1-일-6-(3-메톡시페닐)-1H-피리딘-2-온(화합물 3);1-amino-4-imidazol-1-yl-6- (3-methoxyphenyl) -1 H -pyridin-2-one (Compound 3);

1-아미노-4-이미다졸-1-일-6-(3-트리플루오로메톡시-페닐)-1H-피리딘-2-온 (화합물 5); 1-amino-4-imidazol-1-yl-6- (3-trifluoromethoxy-phenyl) -1 H -pyridin-2-one (compound 5);

1-아미노-6-(3-디플루오로메톡시페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 6);1-amino-6- (3-difluoromethoxyphenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 6);

1-아미노-6-(3-에톡시-페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 7);1-amino-6- (3-ethoxy-phenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 7);

1-아미노-6-(4-플루오로-페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 13);1-amino-6- (4-fluoro-phenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 13);

1-아미노-6-(3-플루오로-페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 14); 및 1-amino-6- (3-fluoro-phenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 14); And

1-아미노-4-이미다졸-1-일-6-(3-트리플루오로메틸-페닐)-1H-피리딘-2-온(화합물 27) 중에서 선택된 화합물이다.1-amino-4-imidazol-1-yl-6- (3-trifluoromethyl-phenyl) -1 H -pyridin-2-one (compound 27).

본 발명에 따른 상기 화합물은 또한 약제학적으로 허용되는 염을 형성할 수 있다. 이러한 약제학적으로 허용되는 염에는, 약제학적으로 허용되는 음이온을 함유하는 무독성 산부가염을 형성하는 산, 예를 들면, 염산, 황산, 질산, 인산, 브롬화수소산, 요오드화수소산 등과 같은 무기산, 타르타르산, 포름산, 시트르산, 아세트산, 트리클로로아세트산 또는 트리플루오로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산 등과 같은 유기 카본산, 메탄설폰산, 벤젠설폰산, p-톨루엔설폰산 또는 나프탈설폰산 등과 같은 설폰산 등에 의해 형성된 산부가염이 포함되며, 아울러 나트륨, 칼륨 등의 알칼리금속과의 염이 포함된다. 그밖에도, 피리디논 유도체가 속하는 기술분야에서 공지되어 사용되고 있는 다른 산 또는 염기와의 염을 언급할 수 있다. 이들은 통상의 전환공정에 의하여 제조된다.The compounds according to the invention may also form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids, tartaric acid, formic acid, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and the like. , Organic carbonic acids such as citric acid, acetic acid, trichloroacetic acid or trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc., sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalsulfonic acid Acid addition salts formed by phonic acid and the like are included, and salts with alkali metals such as sodium and potassium are also included. In addition, mention may be made of salts with other acids or bases known and used in the art to which the pyridinone derivative belongs. These are manufactured by the usual conversion process.

본 발명에 따른 화합물은 또한 치환체의 종류에 따라 비대칭탄소를 포함할 수 있으며, 이러한 비대칭탄소를 중심으로 R 또는 S 이성체, 라세미체를 포함한 이 들 이성체의 혼합물 형태로 존재할 수 있다. 순수한 입체이성체는 당업계에 공지된 통상의 분할 방법에 따라 얻을 수 있다. 따라서 본 발명에 따른 화합물의 이러한 입체화학적 이성체도 본 발명의 범위에 포함된다. The compounds according to the invention may also comprise asymmetric carbons, depending on the type of substituents, and may exist in the form of mixtures of these isomers, including the R or S isomers and racemates around these asymmetric carbons. Pure stereoisomers can be obtained according to conventional cleavage methods known in the art. Thus such stereochemical isomers of the compounds according to the invention are also included within the scope of the invention.

상기 본 발명에 따른 화합물은 하기 기술하는 방법에 의거하여 제조할 수 있으며, 따라서 본 발명은 또한 이러한 화학식 1 화합물의 제조방법에 관한 것이다.The compound according to the present invention can be prepared based on the method described below, and thus the present invention also relates to a method for preparing such a compound of formula (I).

좀더 구체적으로, 화학식 1의 화합물은, 하기 화학식 9의 화합물을 하기 화학식 8의 화합물과 축합반응시켜 하기 화학식 7의 화합물을 수득하고, 화학식 7의 화합물을 고리화 반응시켜 하기 화학식 6의 화합물을 수득하고, 화학식 6의 화합물을 할로겐화 반응시켜 하기 화학식 5의 화합물을 수득하고, 화학식 5의 화합물을 하기 화학식 4의 화합물과 커플링 반응시켜 치환된 하기 화학식 3의 화합물을 수득하고, 화학식 3의 화합물을 하기 화학식 2의 하이드라진과 치환반응시킴을 특징으로 하여 제조할 수 있다:More specifically, the compound of Formula 1 may be condensed with a compound of Formula 9 with a compound of Formula 8 to obtain a compound of Formula 7, and a compound of Formula 7 may be cyclized to obtain a compound of Formula 6 And halogenating the compound of formula 6 to obtain a compound of formula 5, coupling the compound of formula 5 with a compound of formula 4 to obtain a substituted compound of formula 3, It can be prepared by the substitution reaction with hydrazine of the formula (2):

[화학식 1][Formula 1]

Figure 112004022905826-pat00002
Figure 112004022905826-pat00002

Figure 112004022905826-pat00003
Figure 112004022905826-pat00003

Figure 112004022905826-pat00004
Figure 112004022905826-pat00004

Figure 112004022905826-pat00005
Figure 112004022905826-pat00005

Figure 112004022905826-pat00006
Figure 112004022905826-pat00006

Figure 112004022905826-pat00007
Figure 112004022905826-pat00007

Figure 112004022905826-pat00008
Figure 112004022905826-pat00008

Figure 112004022905826-pat00009
Figure 112004022905826-pat00009

Figure 112004022905826-pat00010
Figure 112004022905826-pat00010

상기 식에서,Where

R1, R2, R3, 및 R4는 앞에서 정의한 바와 같고,R 1 , R 2 , R 3 , and R 4 are as defined above,

X는 반응성 이탈기, 바람직하게는 하이드록시 또는 할로겐을 나타내며, X represents a reactive leaving group, preferably hydroxy or halogen,

P 및 P'는 각각 독립적으로 C1-C6-알킬을 나타낸다.P and P 'each independently represent C 1 -C 6 -alkyl.

상기 제조방법을 아래에서 보다 구체적으로 설명한다.The manufacturing method will be described in more detail below.

화학식 9의 화합물과 화학식 8의 화합물의 축합반응은 적절한 용매 및 염기의 존재하에 통상적인 방법에 따라 수행된다. 이때, 용매로는 일반적으로 반응에 악영향을 미치지 않는 통상적인 것을 사용할 수 있으며, 바람직한 용매의 예로는 테트라하이드로퓨란, 아세토니트릴, 디메톡시에탄과 같은 극성 비양성자성 용매를 들 수 있고, 이중에서도 디메톡시에탄이 특히 바람직하다. 반응에 첨가되는 염기로는 포타슘 t-부톡사이드, 소듐에톡사이드, 소듐하이드라이드와 같은 일반적인 염기를 사용할 수 있고, 소듐하이드라이드가 바람직하다. 반응은 약 5시간 내지 24시간, 바람직하게는 8시간동안, 실온 내지 100℃, 바람직하게는 100℃에서 수행된다.The condensation reaction of the compound of formula 9 with the compound of formula 8 is carried out according to conventional methods in the presence of a suitable solvent and base. In this case, as the solvent, a conventional one which generally does not adversely affect the reaction can be used, and examples of the preferred solvent include polar aprotic solvents such as tetrahydrofuran, acetonitrile, dimethoxyethane, and dimethicone. Especially preferred is oxyethane. As the base to be added to the reaction, a general base such as potassium t-butoxide, sodium ethoxide, sodium hydride can be used, and sodium hydride is preferable. The reaction is carried out at room temperature to 100 ° C., preferably at 100 ° C. for about 5 to 24 hours, preferably 8 hours.

출발물질로 사용된 화학식 9와 8의 화합물은 문헌(JACS. 89. 25. 1967. 6623-6628; Tetrahedron, 52. 16. 1967. 5799-5804; Yakugaku Zashi, 87. 1967. 1209; 및 Chem. Ber, 27. 1894. 1141)의 방법을 참고하여 제조하거나, 상업적으로 시그마(Sigma), 알드리치(Aldrich), 머크(Merck) 등의 시약회사에서 구입할 수 있다.Compounds of formulas (9) and (8) used as starting materials are described in JACS . 89. 25. 1967. 6623-6628; Tetrahedron , 52. 16. 1967. 5799-5804; Yakugaku Zashi , 87. 1967. 1209; and Chem. Ber , 27. 1894. 1141) or commercially available from reagent companies such as Sigma, Aldrich and Merck.

다음 단계로, 상기 방법에 따라 수득된 화학식 7의 화합물을 적절한 용매 및 촉매의 존재하에 통상적인 방법에 따라 고리화 반응시켜 화학식 6의 알콜 화합물을 수득한다. 이때, 용매로는, 일반적으로 반응에 악영향을 미치지 않는 상적인 것을 사용할 수 있으며, 바람직한 용매의 예로는 테트라하이드로퓨란, 에틸에테르, 디메톡시에탄과 같은 극성 비양성자성 용매를 들 수 있고, 그중에서도 에틸에테르가 특히 바람직하다. 촉매로는, 일반적인 안하이드라이드가 사용되며, 트리플루오로아세틸안하이드라이드가 바람직하게 사용된다. 반응은 약 30분 내지 10시간, 바람직하게는 2 시간동안, 100℃ 내지 실온, 바람직하게는 실온에서 수행된다.In the next step, the compound of formula 7 obtained according to the above process is cyclized according to a conventional method in the presence of a suitable solvent and a catalyst to obtain an alcohol compound of formula 6. At this time, as a solvent, the normal thing which generally does not adversely affect a reaction can be used, As an example of a preferable solvent, Polar aprotic solvents, such as tetrahydrofuran, ethyl ether, and dimethoxyethane, are mentioned, Among them, ethyl Ether is particularly preferred. As the catalyst, a common anhydride is used, and trifluoroacetylanhydride is preferably used. The reaction is carried out at about 100 ° C. to room temperature, preferably at room temperature for about 30 minutes to 10 hours, preferably 2 hours.

화학식 6의 화합물을 디메틸포름아미드와 에틸에테르의 혼합용매에서 일반적인 할로겐화제, 바람직하게는 트리브로모포스핀을 첨가하여 반응시키면 4번 위치의 알콜이 할로겐으로 치환된 화학식 5의 할로겐 화합물을 얻는다. 반응은 1시간 내지 24시간, 바람직하게는 8시간동안, 0℃에서 반응을 시작하여 실온 내지 60℃, 바람직하게는 60℃에서 수행된다.When the compound of Formula 6 is reacted with a general halogenating agent, preferably tribromophosphine, in a mixed solvent of dimethylformamide and ethyl ether, a halogen compound of Formula 5 is obtained in which the alcohol at position 4 is substituted with halogen. The reaction is carried out at room temperature to 60 ° C, preferably 60 ° C, starting the reaction at 0 ° C for 1 hour to 24 hours, preferably 8 hours.

화학식 5의 화합물과 화학식 4의 화합물을 테트라하이드로퓨란, 아세토니트릴, 디메틸포름아미드와 같은 비양성자성 용매, 바람직하게는 아세토니트릴 용매 중에서 포타슘카보네이트, 소듐하이드로카보네이트와 같은 염기, 바람직하게는 포타슘카보네이트를 첨가하고, 소듐요오다이드, 포타슘요오다이드와 같은 촉매, 바람직하게는 포타슘요오다이드를 사용하여 반응시키면 화학식 3의 화합물을 얻는다. 반응은 2 내지 20시간, 바람직하게는 5시간동안, 실온 내지 환류 조건, 바람직하게는 환류가열하에서 수행된다.Compounds of the formula (5) and the formula (4) are converted to a base such as potassium carbonate, sodium hydrocarbonate, preferably potassium carbonate, in an aprotic solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, preferably acetonitrile solvent. When added and reacted with a catalyst such as sodium iodide, potassium iodide, preferably potassium iodide, a compound of formula 3 is obtained. The reaction is carried out for 2 to 20 hours, preferably 5 hours, at room temperature to reflux conditions, preferably under reflux heating.

화학식 3의 화합물을 에탄올, 메탄올, 물, 디메틸포름아미드와 같은 극성 비양성자성 용매, 바람직하게는 에탄올 용매 중에서 화학식 2의 하이드라진과 반응시키면 화학식 1의 화합물을 얻는다. 반응은 5 내지 48시간, 바람직하게는 8시간 동안, 실온 내지 환류가열, 바람직하게는 실온에서 수행된다.The compound of formula 3 is reacted with hydrazine of formula 2 in a polar aprotic solvent, preferably ethanol solvent, such as ethanol, methanol, water, dimethylformamide to obtain the compound of formula 1. The reaction is carried out at room temperature to reflux heating, preferably at room temperature for 5 to 48 hours, preferably 8 hours.

상기 설명된 제조방법들은 후술하는 실시예를 통하여 보다 구체적으로 설명될 것이다. 그러나 본 발명에 따른 화합물의 제조방법이 본 명세서에 설명한 것으로만 한정되는 것은 아니며, 본 명세서에 기재되거나 선행문헌에 개시된 여러가지 합성방법을 임의로 조합함으로써 용이하게 제조할 수 있고, 이러한 조합은 본 발명이 속하는 기술 분야의 당업자에게 범용화된 통상의 기술이다.The manufacturing methods described above will be described in more detail through the following examples. However, the method for preparing the compound according to the present invention is not limited to the one described herein, and can be easily prepared by arbitrarily combining various synthetic methods described in the present specification or disclosed in the prior literature, and such a combination can be prepared by the present invention. It is a common technique generalized to those skilled in the art.

한편, 본 발명에 따른 화합물은 상술한 바와 같이 우수한 선택적 PDE4 억제활성을 가지고 있으며, 따라서 본 발명은 활성 성분으로서 유효량의 화합물, 그의 약제학적으로 허용되는 염, 또는 입체화학적 이성체를 약제학적으로 허용되는 담체와 함께 함유함을 특징으로 하는 PDE4 억제제 조성물에 관한 것이다.On the other hand, the compound according to the present invention has excellent selective PDE4 inhibitory activity as described above, and thus the present invention provides a pharmaceutically acceptable amount of a compound, a pharmaceutically acceptable salt thereof, or a stereochemical isomer thereof as an active ingredient. A PDE4 inhibitor composition is characterized by containing together with a carrier.

본 발명에 따른 조성물은 강력한 PDE4 억제활성을 나타내기 때문에, COPD, 천식, 만성 기관지염, 건선, 궤양성 대장염, 크론씨병(국한성 회장염), 죽상동맥경화증, 류마티스성 관절염, 골다공증, 골관절염, 우울증, 기억손상증, 염증 매개성 만성 조직괴사증, 및 PDE4에 의해 매개되는 기타 질환의 치료에 유용하다.Since the composition according to the present invention exhibits a strong PDE4 inhibitory activity, COPD, asthma, chronic bronchitis, psoriasis, ulcerative colitis, Crohn's disease (local ileitis), atherosclerosis, rheumatoid arthritis, osteoporosis, osteoarthritis, depression, memory It is useful for the treatment of injuries, inflammatory mediated chronic tissue necrosis, and other diseases mediated by PDE4.

본 발명의 화합물은 경구 또는 비경구 투여에 적합한 약제학적 제제의 형태 로 제형화될 수 있다. 상기 약제학적 제제는 산제, 입제, 정제, 캡슐, 시럽 또는 현탁액의 형태로 경구 투여될 수 있으며; 또는 그의 용액, 유제 또는 현탁액을 이용하여 주사액 형태로 비경구 투여될 수 있다. 약제학적 제제는 또한 흡입제 형태로 호흡기에 분사 투여되거나, 좌제의 형태로 직장 투여될 수 있다.The compounds of the present invention may be formulated in the form of pharmaceutical preparations suitable for oral or parenteral administration. The pharmaceutical preparations can be administered orally in the form of powders, granules, tablets, capsules, syrups or suspensions; Or parenterally in the form of injections using their solutions, emulsions or suspensions. Pharmaceutical formulations may also be administered by spray to the respiratory system in the form of inhalants or rectally in the form of suppositories.

약제학적 제제를 제조함에 있어서, 활성 성분인 본 발명의 화합물은 약제학적으로 허용되는 담체, 예를 들어, 수용해제, 결합제, 안정화제, 및/또는 희석제와 혼합될 수 있다. 본 발명의 화합물을 주사액 형태로 사용할 경우, 약제학적으로 허용되는 완충액, 용해 보조제 또는 등장제를 본 발명의 조성물에 혼합할 수 있다.In preparing pharmaceutical formulations, the compounds of the present invention, which are active ingredients, may be mixed with pharmaceutically acceptable carriers such as water soluble, binder, stabilizer, and / or diluent. When the compounds of the invention are used in the form of injectable solutions, pharmaceutically acceptable buffers, dissolution aids or isotonic agents may be mixed in the compositions of the invention.

투여량 및 투여 시간은 질병의 종류, 상태, 연령, 체중, 및 투여 형태에 따라 달라질 수 있으며, 상기 조성물은 성인에 있어서, 활성 화합물을 기준으로 하여 1일 0.1~2,000mg, 바람직하게는 1~200mg 을 1회 또는 수회로 나누어서 투여한다.Dosage and time may vary depending on the type, condition, age, weight, and dosage form of the disease, wherein the composition is 0.1-2,000 mg / day, preferably 1- 1, based on the active compound in adults. 200 mg is administered once or in divided doses.

본 발명의 조성물을 10마리의 쥐에 100mg/kg의 양으로 투여하고, 1일후 그 상태를 확인한 결과, 사망하거나 심각한 질환을 초래한 쥐는 없었으며, 따라서 독성은 없는 것으로 확인되었다.The composition of the present invention was administered to 10 rats in an amount of 100 mg / kg, and after 1 day, the condition was confirmed, and there was no rat that caused death or serious disease, and thus no toxicity.

이하, 본 발명을 하기 실시예 및 실험예에 의하여 더욱 구체적으로 설명한다.
Hereinafter, the present invention will be described in more detail with reference to the following Examples and Experimental Examples.

실시예 1Example 1

1-아미노-4-이미다졸-1-일-6-페닐-11-amino-4-imidazol-1-yl-6-phenyl-1 HH -피리딘-2-온 (화합물 1)의 합성Synthesis of Pyridin-2-one (Compound 1)

a) 3,5-디옥소-5-페닐-펜타노산의 합성a) Synthesis of 3,5-dioxo-5-phenyl-pentanoic acid

500㎖ 플라스크에 환류장치를 하고 NaH(10g, 0.264mol)를 넣고 디메톡시에탄 (DME)(200㎖)으로 묽힌 다음 100℃까지 가열하여 환류시켰다. 1시간 후 벤조산 메틸에스테르(10g, 0.0735mol)와 3-옥소-부티르산 에틸에스테르(11.47g, 0.0882mol)를 DME(200㎖)으로 묽힌 용액을 30분에 걸쳐 서서히 가한 다음 8시간동안 환류시켰다. 반응액을 실온으로 냉각시킨 다음 감압하에 용매를 제거하고 물(200㎖)를 넣고 2시간동안 실온에서 교반하였다. 2N-HCl 수용액으로 반응액을 산성화하고 에틸아세테이트(200㎖)로 2번 추출하였다. 추출액은 MgSO4로 건조, 여과한 다음 감압하에 증류하였다. 잔사는 n-헥산/에틸 아세테이트를 이용하여 고체화하여 흰색 고체상의 표제화합물(11.1g, 73.3%)을 얻었다.A 500 mL flask was refluxed, NaH (10 g, 0.264 mol) was added, diluted with dimethoxyethane (DME) (200 mL), and heated to reflux for 100 ° C. After 1 hour, a solution of benzoic acid methyl ester (10 g, 0.0735 mol) and 3-oxo-butyric acid ethyl ester (11.47 g, 0.0882 mol) diluted with DME (200 mL) was slowly added over 30 minutes, followed by reflux for 8 hours. After the reaction solution was cooled to room temperature, the solvent was removed under reduced pressure, water (200 mL) was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction solution was acidified with 2N-HCl aqueous solution and extracted twice with ethyl acetate (200 mL). The extract was dried over MgSO 4 , filtered and distilled under reduced pressure. The residue was solidified using n-hexane / ethyl acetate to obtain the title compound (11.1 g, 73.3%) as a white solid.

1H-NMR(CDCl3); δ = 15.49(s, 1H), 7.91(m, 2H), 7.50(m, 3H), 6.28(s, 1H), 3.56(s, 2H) 1 H-NMR (CDCl 3 ); δ = 15.49 (s, 1H), 7.91 (m, 2H), 7.50 (m, 3H), 6.28 (s, 1H), 3.56 (s, 2H)

b) 4-하이드록시-6-페닐-피란-2-온의 합성b) Synthesis of 4-hydroxy-6-phenyl-pyran-2-one

500㎖ 플라스크에서 3,5-디옥소-5-페닐-펜타노산(11g, 0.053 mol)을 에테르(70㎖)에 녹이고 0℃로 냉각시킨 다음 트리플루오로아세틱안하이드라이드 [(TFA)2O; 22g, 0.106mol]를 30분에 걸쳐 서서히 적가하였다. 3시간 후 반응액을 여과하여 감압하에 건조시킨 후 우유빛 고체상의 표제화합물(9.1g, 92%)을 얻었다.In a 500 mL flask, 3,5-dioxo-5-phenyl-pentanoic acid (11 g, 0.053 mol) was dissolved in ether (70 mL), cooled to 0 ° C., and then trifluoroacetic anhydride [(TFA) 2 O ; 22 g, 0.106 mol] was slowly added dropwise over 30 minutes. After 3 hours, the reaction solution was filtered and dried under reduced pressure to obtain the title compound (9.1 g, 92%) as a milky solid.

1H-NMR(CDCl3); δ = 7.78(m, 2H), 7.43(m, 3H), 6.49(s, 1H), 5.47(d, 1H, J=1.8Hz) 1 H-NMR (CDCl 3 ); δ = 7.78 (m, 2H), 7.43 (m, 3H), 6.49 (s, 1H), 5.47 (d, 1H, J = 1.8 Hz)

c) 4-브로모-6-페닐-피란-2-온의 합성c) Synthesis of 4-bromo-6-phenyl-pyran-2-one

2000㎖ 플라스크에서 4-하이드록시-6-페닐-피란-2-온(48g, 0.255mol)을 톨루엔(toluene)(700㎖)에 녹이고 P2O5(169g, 0.561mol)와 테트라부틸암모늄브로마이드 (90g, 0.281mol)를 가한 다음 반응온도를 110℃로 올리고 8시간 동안 가열하였다. 생성물을 포함하는 반응액을 따라내고 잔사는 톨루엔(200㎖)으로 2회 세척한 후 용매를 합하여 감압하에 증류하였다. 잔사는 n-헥산/에틸 아세테이트=10/1(v/v) 용매로 용출하는 실리카 겔 칼럼 크로마토그래피로 정제하였다. 생성물을 함유하는 분획을 합하고 증발시켜 흰색 고체상의 표제화합물(26g, 41%)을 얻었다.4-hydroxy-6-phenyl-pyran-2-one (48 g, 0.255 mol) was dissolved in toluene (700 ml) in a 2000 ml flask, and P 2 O 5 (169 g, 0.561 mol) and tetrabutylammonium bromide (90 g, 0.281 mol) was added and the reaction temperature was raised to 110 ° C. and heated for 8 hours. The reaction solution containing the product was decanted and the residue was washed twice with toluene (200 mL), and the solvents were combined and distilled under reduced pressure. The residue was purified by silica gel column chromatography eluting with a solvent of n-hexane / ethyl acetate = 10/1 (v / v). Fractions containing product were combined and evaporated to afford the title compound (26 g, 41%) as a white solid.

1H-NMR(CDCl3); δ = 7.83(m, 2H), 7.49(m, 3H), 6.82(d, 1H, J=2.1Hz), 6.58(d, 1H, J=1.5Hz) 1 H-NMR (CDCl 3 ); δ = 7.83 (m, 2H), 7.49 (m, 3H), 6.82 (d, 1H, J = 2.1 Hz), 6.58 (d, 1H, J = 1.5 Hz)

d) 4-이미다졸-1-일-6-페닐-피란-2-온의 합성d) Synthesis of 4-imidazol-1-yl-6-phenyl-pyran-2-one

250㎖ 플라스크에 4-브로모-6-페닐-피란-2-온(13g, 0.05mol)과 이미다졸 (10.5g, 0.16mol)을 넣고 아세토니트릴(15㎖)을 가하여 녹인 다음 K2CO3(22g, 0.16mol)와 KI(830mg, 10%mol/mol)를 가하였다. 반응물을 8시간 동안 환류 가열하였다. 실온으로 냉각시킨 후 물(100㎖)을 가하고 에틸아세테이트(250㎖)로 2회 추출하였다. 추출액을 MgSO4로 건조, 여과하고 감압하에 증류하였다. 잔사는 MC/MeOH=20/1(v/v) 용매로 용출하는 실리카 겔 칼럼 크로마토그래피로 정제하였다. 생성물을 함유하는 분획을 합하고 증발시켜 흰색 고체상의 표제화합물(10.2g, 86%) 을 얻었다In a 250 ml flask, 4-bromo-6-phenyl-pyran-2-one (13 g, 0.05 mol) and imidazole (10.5 g, 0.16 mol) were added and dissolved in acetonitrile (15 ml), followed by K 2 CO 3 (22 g, 0.16 mol) and KI (830 mg, 10% mol / mol) were added. The reaction was heated to reflux for 8 hours. After cooling to room temperature, water (100 mL) was added and extracted twice with ethyl acetate (250 mL). The extract was dried over MgSO 4 , filtered and distilled under reduced pressure. The residue was purified by silica gel column chromatography eluting with a MC / MeOH = 20/1 (v / v) solvent. Fractions containing product were combined and evaporated to give the title compound (10.2 g, 86%) as a white solid.

1H-NMR(CDCl3); δ = 8.06(s, 1H), 7.90(m, 2H), 7.51(m, 3H), 7.38(s, 1H), 7.29(s, 1H), 6.84(d, 1H, J=2.1Hz), 6.24(d, 1H, J=2.1Hz) 1 H-NMR (CDCl 3 ); δ = 8.06 (s, 1H), 7.90 (m, 2H), 7.51 (m, 3H), 7.38 (s, 1H), 7.29 (s, 1H), 6.84 (d, 1H, J = 2.1 Hz), 6.24 (d, 1H, J = 2.1 Hz)

e) 1-아미노-4-이미다졸-1-일-6-페닐-1e) 1-amino-4-imidazol-1-yl-6-phenyl-1 HH -피리딘-2-온의 합성Synthesis of -pyridin-2-one

4-이미다졸-1-일-6-페닐-피란-2-온(3.01g, 0.0126mol)을 에탄올(100㎖)에 녹이고 하이드라진 수화물(12.0㎖, 0.126mol)을 적가한 후 10시간 동안 실온에서 교반하였다. 반응 용액을 감압하에 증류하고 잔사는 MC/MeOH=30/1(v/v) 용매로 용출하는 실리카 겔 칼럼 크로마토그래피로 정제하였다. 생성물을 함유하는 분획을 합하고 증발시켜 흰색 고체상의 표제화합물(1.2g, 37%)을 얻었다.4-imidazol-1-yl-6-phenyl-pyran-2-one (3.01 g, 0.0126 mol) was dissolved in ethanol (100 mL) and hydrazine hydrate (12.0 mL, 0.126 mol) was added dropwise, followed by room temperature for 10 hours. Stirred at. The reaction solution was distilled off under reduced pressure and the residue was purified by silica gel column chromatography eluting with a MC / MeOH = 30/1 (v / v) solvent. Fractions containing product were combined and evaporated to afford the title compound (1.2 g, 37%) as a white solid.

1H-NMR(CDCl3); δ = 8.05(s, 1H), 7.56(m, 5H), 7.36(m, 1H), 7.19(s, 1H), 6.71(d, 1H, J=2.7Hz), 6.44(d, 1H, J=2.4Hz) 1 H-NMR (CDCl 3 ); δ = 8.05 (s, 1H), 7.56 (m, 5H), 7.36 (m, 1H), 7.19 (s, 1H), 6.71 (d, 1H, J = 2.7 Hz), 6.44 (d, 1H, J = 2.4 Hz)

MS(ESI); 253(M++1)
MS (ESI); 253 (M + +1)

실시예 2Example 2

1-아미노-4-이미다졸-1-일-6-(2-메톡시-페닐)-11-amino-4-imidazol-1-yl-6- (2-methoxy-phenyl) -1 HH -피리딘-2-온(화합물 2)의 합성Synthesis of Pyridin-2-one (Compound 2)

a) 5-(2-메톡시-페닐)-3,5-디옥소-펜타노산의 합성a) Synthesis of 5- (2-methoxy-phenyl) -3,5-dioxo-pentanoic acid

실시예 1)의 a)와 동일한 방법으로 2-메톡시-벤조산 메틸에스테르(5.0g, 30.089mmol)와 3-옥소-부티르산 에틸에스테르(3.92g, 30.089mmol)를 반응시켜 표제화합물(4.3g, 60.5%)을 얻었다.In the same manner as in a) of Example 1), 2-methoxy-benzoic acid methyl ester (5.0 g, 30.089 mmol) and 3-oxo-butyric acid ethyl ester (3.92 g, 30.089 mmol) were reacted to obtain the title compound (4.3 g, 60.5%).

1H-NMR(CDCl3); δ = 7.92(m, 1H), 7.48(m, 1H), 7.02(m, 2H), 6.63(s, 1H), 3.89(s, 3H), 3.50(s, 2H) 1 H-NMR (CDCl 3 ); δ = 7.92 (m, 1H), 7.48 (m, 1H), 7.02 (m, 2H), 6.63 (s, 1H), 3.89 (s, 3H), 3.50 (s, 2H)

b) 4-하이드록시-6-(2-메톡시-페닐)-피란-2-온의 합성b) Synthesis of 4-hydroxy-6- (2-methoxy-phenyl) -pyran-2-one

실시예 1)의 b)와 동일한 방법으로 5-(2-메톡시-페닐)-3,5-디옥소-펜타노산 (3.1g, 13.12mmol)을 반응시켜 표제화합물(2.78g, 97%)을 얻었다.In the same manner as in b) of Example 1), 5- (2-methoxy-phenyl) -3,5-dioxo-pentanoic acid (3.1 g, 13.12 mmol) was reacted to give the title compound (2.78 g, 97%). Got.

1H-NMR(CDCl3); δ = 7.93(m, 1H), 7.41(m, 1H), 6.99(m, 3H), 5.49(d, 1H, J=2.4Hz), 3.92(s, 3H) 1 H-NMR (CDCl 3 ); δ = 7.93 (m, 1H), 7.41 (m, 1H), 6.99 (m, 3H), 5.49 (d, 1H, J = 2.4 Hz), 3.92 (s, 3H)

c) 4-브로모-6-(2-메톡시-페닐)-피란-2-온의 합성c) Synthesis of 4-bromo-6- (2-methoxy-phenyl) -pyran-2-one

실시예 1)의 c)와 동일한 방법으로 4-하이드록시-6-(2-메톡시-페닐)-피란-2-온(2.93g, 13.427mmol)을 반응시켜 표제화합물(2.6g, 70%)을 얻었다.4-hydroxy-6- (2-methoxy-phenyl) -pyran-2-one (2.93 g, 13.427 mmol) was reacted in the same manner as c) of Example 1) to give the title compound (2.6 g, 70%). )

1H-NMR(CDCl3); δ = 7.95(m, 1H), 7.46(m, 1H), 7.31(d, 1H, J=1.5Hz), 7.06(m, 2H), 6.54(d, 1H, J=1.5Hz), 3.95(s, 3H) 1 H-NMR (CDCl 3 ); δ = 7.95 (m, 1H), 7.46 (m, 1H), 7.31 (d, 1H, J = 1.5 Hz), 7.06 (m, 2H), 6.54 (d, 1H, J = 1.5 Hz), 3.95 (s , 3H)

d) 4-이미다졸-1-일-6-(2-메톡시-페닐)-피란-2-온의 합성d) Synthesis of 4-imidazol-1-yl-6- (2-methoxy-phenyl) -pyran-2-one

실시예 1)의 d)와 동일한 방법으로 4-브로모-6-(2-메톡시-페닐)-피란-2-온 (2.6g, 9.249mmol)을 반응시켜 표제화합물(2.38g, 96%)을 얻었다. 4-Bromo-6- (2-methoxy-phenyl) -pyran-2-one (2.6 g, 9.249 mmol) was reacted in the same manner as d) of Example 1) to give the title compound (2.38 g, 96%). )                     

1H-NMR(CDCl3); δ = 8.03-7.03(m, 8H), 6.19(d, 1H, J=2.1Hz) 1 H-NMR (CDCl 3 ); δ = 8.03-7.03 (m, 8H), 6.19 (d, 1H, J = 2.1 Hz)

e) 1-아미노-4-이미다졸-1-일-6-(2-메톡시-페닐)-1e) 1-amino-4-imidazol-1-yl-6- (2-methoxy-phenyl) -1 HH -피리딘-2-온의 합성Synthesis of -pyridin-2-one

실시예 1)의 e)와 동일한 방법으로 4-이미다졸-1-일-6-(2-메톡시-페닐)- 피란-2-온(1.5g, 5.591mmol)을 반응시켜 표제화합물(534mg, 34%)을 얻었다.In the same manner as in e) of Example 1), 4-imidazol-1-yl-6- (2-methoxy-phenyl) -pyran-2-one (1.5 g, 5.591 mmol) was reacted to give the title compound (534 mg). , 34%).

1H-NMR(CDCl3); δ = 7.94(s, 1H), 7.55(m, 1H), 7.39-7.03(m, 5H), 6.67(d, 1H, J=2.7Hz), 6.28(d, 1H, J=2.7Hz), 5.60(s, 2H), 3.90(s, 3H) 1 H-NMR (CDCl 3 ); δ = 7.94 (s, 1H), 7.55 (m, 1H), 7.39-7.03 (m, 5H), 6.67 (d, 1H, J = 2.7 Hz), 6.28 (d, 1H, J = 2.7 Hz), 5.60 (s, 2H), 3.90 (s, 3H)

MS(ESI); 283(M++1)
MS (ESI); 283 (M + +1)

실시예 3Example 3

1-아미노-4-이미다졸-1-일-6-(3-메톡시페닐)-11-amino-4-imidazol-1-yl-6- (3-methoxyphenyl) -1 HH -피리딘-2-온(화합물 3)의 합성Synthesis of Pyridin-2-one (Compound 3)

a) 5-(3-메톡시페닐)-3,5-디옥소-펜타노산의 합성a) Synthesis of 5- (3-methoxyphenyl) -3,5-dioxo-pentanoic acid

실시예 1)의 a)와 동일한 방법으로 3-메톡시벤조산 메틸에스테르(20g, 0.120mol)와 3-옥소-부티르산 에틸에스테르(18.8g, 0.144mol)를 반응시켜 갈색 고체상의 표제화합물(22.2g, 78.0%)을 얻었다.In the same manner as in a) of Example 1), 3-methoxybenzoic acid methyl ester (20 g, 0.120 mol) and 3-oxo-butyric acid ethyl ester (18.8 g, 0.144 mol) were reacted to give the title compound (22.2 g as a brown solid). , 78.0%).

1H-NMR(CDCl3); δ = 15.43(s, 1H), 7.34-7.47(m, 3H), 7.10(dd, 1H, J=7.3Hz, J=2.0Hz), 6.26(s, 1H), 3.87(s, 3H), 3.56(d, 2H, J=8.0Hz) 1 H-NMR (CDCl 3 ); δ = 15.43 (s, 1H), 7.34-7.47 (m, 3H), 7.10 (dd, 1H, J = 7.3 Hz, J = 2.0 Hz), 6.26 (s, 1H), 3.87 (s, 3H), 3.56 (d, 2H, J = 8.0Hz)

b) 4-하이드록시-6-(3-메톡시페닐)-피란-2-온의 합성b) Synthesis of 4-hydroxy-6- (3-methoxyphenyl) -pyran-2-one

실시예 1)의 b)와 동일한 방법으로 5-(3-메톡시페닐)-3,5-디옥소-펜타노산 (22g, 93.1mmol)을 반응시켜 황색 고체상의 표제화합물(19.5g, 96.0%)을 얻었다.In the same manner as in b) of Example 1), 5- (3-methoxyphenyl) -3,5-dioxo-pentanoic acid (22 g, 93.1 mmol) was reacted to give the title compound (19.5 g, 96.0%) as a yellow solid. )

1H-NMR(CDCl3); δ = 7.35-7.40(m, 3H), 7.05-7.08(m, 1H), 6.62(d, 1H, J=1.9Hz), 6.35(d, 1H, J=1.9Hz), 3.88(s, 3H) 1 H-NMR (CDCl 3 ); δ = 7.35-7.40 (m, 3H), 7.05-7.08 (m, 1H), 6.62 (d, 1H, J = 1.9 Hz), 6.35 (d, 1H, J = 1.9 Hz), 3.88 (s, 3H)

c) 4-브로모-6-(3-메톡시페닐)-피란-2-온의 합성c) Synthesis of 4-bromo-6- (3-methoxyphenyl) -pyran-2-one

실시예 1)의 c)와 동일한 방법으로 4-하이드록시-6-(3-메톡시페닐)-피란-2-온(19.5g, 89.4mmol)을 반응시켜 미황색 고체상의 표제화합물(12.6g, 50.2%)을 얻었다.In the same manner as in c) of Example 1), 4-hydroxy-6- (3-methoxyphenyl) -pyran-2-one (19.5 g, 89.4 mmol) was reacted to give the title compound (12.6 g, 50.2%).

1H-NMR(CDCl3); δ = 7.33-7.39(m, 3H), 7.02-7.06(m, 1H), 6.82(d, 1H, J=1.5Hz), 6.58(d, 1H, J=1.5Hz), 3.87(s, 3H) 1 H-NMR (CDCl 3 ); δ = 7.33-7.39 (m, 3H), 7.02-7.06 (m, 1H), 6.82 (d, 1H, J = 1.5 Hz), 6.58 (d, 1H, J = 1.5 Hz), 3.87 (s, 3H)

d) 4-이미다졸-1-일-6-(3-메톡시페닐)-피란-2-온의 합성d) Synthesis of 4-imidazol-1-yl-6- (3-methoxyphenyl) -pyran-2-one

실시예 1)의 d)와 동일한 방법으로 4-브로모-6-(3-메톡시페닐)-피란-2-온 (12.6g, 44.8mmol)을 반응시켜 갈색 고체상의 표제화합물(8.3g, 69.0%)을 얻었다.In the same manner as in d) of Example 1), 4-bromo-6- (3-methoxyphenyl) -pyran-2-one (12.6 g, 44.8 mmol) was reacted to give the title compound (8.3 g, 69.0%).

1H-NMR(CDCl3); δ = 8.06(s, 1H), 7.29-7.47(m, 5H), 7.08(dt, 1H, J=7.2Hz), 6.81(d, 1H, J=1.9Hz), 6.24(d, 1H, J=1.9Hz), 3.89(s, 3H) 1 H-NMR (CDCl 3 ); δ = 8.06 (s, 1H), 7.29-7.47 (m, 5H), 7.08 (dt, 1H, J = 7.2 Hz), 6.81 (d, 1H, J = 1.9 Hz), 6.24 (d, 1H, J = 1.9 Hz), 3.89 (s, 3H)

e) 1-아미노-4-이미다졸-1-일-6-(3-메톡시페닐)-1e) 1-amino-4-imidazol-1-yl-6- (3-methoxyphenyl) -1 HH -피리딘-2-온의 합성Synthesis of -pyridin-2-one

실시예 1)의 e)와 동일한 방법으로 4-이미다졸-1-일-6-(3-메톡시페닐)-피란-2-온(660mg, 2.46mmol)을 반응시켜 우유빛 고체상의 표제화합물(364mg, 52.4%)을 얻었다.In the same manner as in e) of Example 1), 4-imidazol-1-yl-6- (3-methoxyphenyl) -pyran-2-one (660 mg, 2.46 mmol) was reacted to give the title compound as a milky solid. (364 mg, 52.4%) was obtained.

1H-NMR(CDCl3); δ = 7.95(s, 1H), 7.44(t, 1H, J=8.2Hz), 7.23-7.31(m, 2H), 7.04-7.12(m, 3H), 6.65(d, 1H, J=2.7Hz), 6.32(d, 1H, J=2.7Hz), 5.28(s, 2H), 3.87(s, 3H) 1 H-NMR (CDCl 3 ); δ = 7.95 (s, 1H), 7.44 (t, 1H, J = 8.2 Hz), 7.23-7.31 (m, 2H), 7.04-7.12 (m, 3H), 6.65 (d, 1H, J = 2.7 Hz) , 6.32 (d, 1H, J = 2.7 Hz), 5.28 (s, 2H), 3.87 (s, 3H)

MS(ESI); 282(M+)
MS (ESI); 282 (M + )

실시예 4Example 4

1-아미노-6-(3-하이드록시페닐)-4-이미다졸-1-일-11-amino-6- (3-hydroxyphenyl) -4-imidazol-1-yl-1 HH -피리딘-2-온(화합물 4)의 합성Synthesis of Pyridin-2-one (Compound 4)

실시예 3)에서 얻은 1-아미노-4-이미다졸-1-일-6-(3-메톡시페닐)-1H-피리딘-2-온(32mg, 0.113mmol)을 디클로로메탄(1.5㎖)에 녹인 후 30℃로 냉각시켰다. BBr3 디클로로메탄 1M 용액(0.23㎖, 0.226mmol)을 천천히 적가한 후 실온에서 5시간 동안 반응시켰다. 물로 희석한 후 디클로로메탄(100㎖)으로 3회 추출하였다. 추출액을 MgSO4로 건조, 여과한 다음 감압하에 증류하였다. 잔사는 디클로로메탄/메탄올= 10/1(v/v) 용매로 용출하는 실리카 겔 칼럼 크로마토그래피로 정제하였다. 생성물을 함유하는 분획을 합하고 증발시켜 미황색 고체상의 표제화합물(14mg, 46.0%)을 얻었다.1-amino-4-imidazol-1-yl-6- (3-methoxyphenyl) -1 H -pyridin-2-one (32 mg, 0.113 mmol) obtained in Example 3) was diluted with dichloromethane (1.5 mL). It was dissolved in and cooled to 30 ℃. BBr 3 dichloromethane 1M solution (0.23 ml, 0.226 mmol) was slowly added dropwise and reacted at room temperature for 5 hours. Dilution with water followed by extraction three times with dichloromethane (100 mL). The extract was dried over MgSO 4 , filtered and distilled under reduced pressure. The residue was purified by silica gel column chromatography eluting with a solvent of dichloromethane / methanol = 10/1 (v / v). Fractions containing product were combined and evaporated to afford the title compound (14 mg, 46.0%) as a pale yellow solid.

1H-NMR(DMSO-d6); δ = 9.62(brs, 1H), 8.41(s, 1H), 7.85(s, 1H), 7.18(t, 1H, J=7.8Hz), 6.92-7.01(m, 3H), 6.78-6.80(m, 2H), 6.62(d, 1H, J=2.7Hz), 5.72(s, 2H) 1 H-NMR (DMSO-d 6 ); δ = 9.62 (brs, 1H), 8.41 (s, 1H), 7.85 (s, 1H), 7.18 (t, 1H, J = 7.8 Hz), 6.92-7.01 (m, 3H), 6.78-6.80 (m, 2H), 6.62 (d, 1H, J = 2.7 Hz), 5.72 (s, 2H)

MS(ESI); 269(M++1)
MS (ESI); 269 (M + +1)

실시예 5 Example 5

1-아미노-4-이미다졸-1-일-6-(3-트리플루오로메톡시-페닐)-11-amino-4-imidazol-1-yl-6- (3-trifluoromethoxy-phenyl) -1 HH -피리딘-2-온 (화합물 5)의 합성Synthesis of Pyridin-2-one (Compound 5)

a) 3,5-디옥소-5-(3-트리플루오로메톡시-페닐)-펜타노산의 합성a) Synthesis of 3,5-dioxo-5- (3-trifluoromethoxy-phenyl) -pentanoic acid

실시예 1)의 a)와 동일한 방법으로 3-트리플루오로메톡시-벤조산 메틸에스테르(5.0g, 22.7mmol)와 3-옥소-부티르산 에틸에스테르(3.25g, 24.9mmol)를 반응시켜 표제화합물(4.2g, 64%)을 얻었다.In the same manner as in a) of Example 1), 3-trifluoromethoxy-benzoic acid methyl ester (5.0 g, 22.7 mmol) and 3-oxo-butyric acid ethyl ester (3.25 g, 24.9 mmol) were reacted to obtain the title compound (4.2). g, 64%).

1H-NMR(CDCl3); δ = 7.81(d, 1H), 7.72(s, 1H), 7.51-7.37(m, 2H), 6.29(s, 1H), 3.52(s, 3H) 1 H-NMR (CDCl 3 ); δ = 7.81 (d, 1H), 7.72 (s, 1H), 7.51-7.37 (m, 2H), 6.29 (s, 1H), 3.52 (s, 3H)

b) 4-하이드록시-6-(3-트리플루오로메톡시-페닐)-피란-2-온의 합성b) Synthesis of 4-hydroxy-6- (3-trifluoromethoxy-phenyl) -pyran-2-one

실시예 1)의 b)와 동일한 방법으로 3,5-디옥소-5-(3-트리플루오로메톡시-페닐)-펜타노산(2.85g, 9.82mmol)을 반응시켜 표제화합물(2.25g, 84%)을 얻었다.3,5-dioxo-5- (3-trifluoromethoxy-phenyl) -pentanoic acid (2.85 g, 9.82 mmol) was reacted in the same manner as b) of Example 1) to give the title compound (2.25 g, 84 %) Was obtained.

1H-NMR(CD3OD); δ = 7.82(d, 1H), 7.71(s, 1H), 7.59(s, 1H), 7.56(d, 1H), 7.38(d, 1H), 6.64(s, 1H) 1 H-NMR (CD 3 OD); δ = 7.82 (d, 1H), 7.71 (s, 1H), 7.59 (s, 1H), 7.56 (d, 1H), 7.38 (d, 1H), 6.64 (s, 1H)

c) 4-브로모-6-(3-트리플루오로메톡시-페닐)-피란-2-온의 합성c) Synthesis of 4-bromo-6- (3-trifluoromethoxy-phenyl) -pyran-2-one

실시예 1)의 c)와 동일한 방법으로 4-하이드록시-6-(3-트리플루오로메톡시-페닐)-피란-2-온(4.0g, 14.7mmol)을 반응시켜 표제화합물(3.8g, 78%)을 얻었다.In the same manner as in c) of Example 1), 4-hydroxy-6- (3-trifluoromethoxy-phenyl) -pyran-2-one (4.0 g, 14.7 mmol) was reacted to give the title compound (3.8 g, 78%).

1H-NMR(CDCl3); δ = 7.76(d, 1H), 7.65(s, 1H), 7.52(t, 1H), 7.37(d, 1H), 6.83(d, 1H), 6.63(d, 1H) 1 H-NMR (CDCl 3 ); δ = 7.76 (d, 1H), 7.65 (s, 1H), 7.52 (t, 1H), 7.37 (d, 1H), 6.83 (d, 1H), 6.63 (d, 1H)

d) 4-이미다졸-1-일-6-(3-트리플루오로메톡시-페닐)-피란-2-온의 합성d) Synthesis of 4-imidazol-1-yl-6- (3-trifluoromethoxy-phenyl) -pyran-2-one

실시예 1)의 d)와 동일한 방법으로 4-브로모-6-(3-트리플루오로메톡시-페닐) -피란-2-온(3.0g, 8.93mmol)을 반응시켜 표제화합물(2.4g, 84%)을 얻었다.In the same manner as in d) of Example 1), 4-bromo-6- (3-trifluoromethoxy-phenyl) -pyran-2-one (3.0 g, 8.93 mmol) was reacted to give the title compound (2.4 g, 84%).

1H-NMR(CDCl3); δ = 8.06(s, 1H), 7.84(d, 1H), 7.73(s, 1H), 7.57(t, 1H), 7.42-7.30(m, 3H), 6.84(d, 1H), 6.28(d, 1H) 1 H-NMR (CDCl 3 ); δ = 8.06 (s, 1H), 7.84 (d, 1H), 7.73 (s, 1H), 7.57 (t, 1H), 7.42-7.30 (m, 3H), 6.84 (d, 1H), 6.28 (d, 1H)

e) 1-아미노-4-이미다졸-1-일-6-(3-트리플루오로메톡시-페닐)-1e) 1-amino-4-imidazol-1-yl-6- (3-trifluoromethoxy-phenyl) -1 HH -피리딘-2-온의 합성Synthesis of -pyridin-2-one

실시예 1)의 e)와 동일한 방법으로 4-이미다졸-1-일-6-(3-트리플루오로메톡시-페닐)-피란-2-온(2.0g, 6.2mmol)을 반응시켜 표제화합물(1.01g, 50%)을 얻었다.In the same manner as in e) of Example 1), 4-imidazol-1-yl-6- (3-trifluoromethoxy-phenyl) -pyran-2-one (2.0 g, 6.2 mmol) was reacted to give the title compound. (1.01 g, 50%) was obtained.

1H-NMR(CDCl3); δ = 8.55(s, 1H), 7.89(s, 1H), 7.80-7.72(m, 3H), 7.59(d, 1H), 7.31(s, 1H), 7.00(d, 1H), 6.93(d, 1H) 1 H-NMR (CDCl 3 ); δ = 8.55 (s, 1H), 7.89 (s, 1H), 7.80-7.72 (m, 3H), 7.59 (d, 1H), 7.31 (s, 1H), 7.00 (d, 1H), 6.93 (d, 1H)

MS(ESI); 337(M++1)
MS (ESI); 337 (M + +1)

실시예 6 Example 6

1-아미노-6-(3-디플루오로메톡시페닐)-4-이미다졸-1-일-11-amino-6- (3-difluoromethoxyphenyl) -4-imidazol-1-yl-1 HH -피리딘-2-온(화합물 6)의 합성Synthesis of Pyridin-2-one (Compound 6)

a) 6-(3-하이드록시페닐)-4-이미다졸-1-일-피란-2-온의 합성a) Synthesis of 6- (3-hydroxyphenyl) -4-imidazol-1-yl-pyran-2-one

실시예 3)의 d)에서 얻은 4-이미다졸-1-일-6-(3-메톡시페닐)-피란-2-온 (1.33g, 4.96mmol)을 실시예 4)와 동일한 방법으로 반응시켜 표제화합물(864mg, 68.5%)을 얻었다.4-imidazol-1-yl-6- (3-methoxyphenyl) -pyran-2-one (1.33 g, 4.96 mmol) obtained in d) of Example 3) was reacted in the same manner as in Example 4). The title compound (864 mg, 68.5%) was obtained.

1H-NMR(DMSO-d6); δ = 9.32(s, 1H), 8.34(s, 1H), 6.99-7.61(m, 7H), 6.32(d, 1H, J=1.9Hz) 1 H-NMR (DMSO-d 6 ); δ = 9.32 (s, 1H), 8.34 (s, 1H), 6.99-7.61 (m, 7H), 6.32 (d, 1H, J = 1.9 Hz)

b) 6-(3-디플루오로메톡시페닐)-4-이미다졸-1-일-피란-2-온의 합성b) Synthesis of 6- (3-difluoromethoxyphenyl) -4-imidazol-1-yl-pyran-2-one

6-(3-하이드록시페닐)-4-이미다졸-1-일-피란-2-온(530mg, 2.08mmol)을 DMF (16㎖)에 녹인 후 Cs2CO3(747mg, 2.29mmol)과 메틸 2-클로로-2,2-디플루오로아세테이트(0.33㎖, 3.13mmol)를 가한 다음 90℃에서 일야 교반시켰다. 상온으로 냉각시킨 반응액을 물로 희석한 후 디클로로메탄(100㎖)으로 2회 추출하였다. 추출액은 MgSO4로 건조, 여과한 다음 감압하에 증류하였다. 잔사는 디클로로메탄/메탄올=50/1 (v/v) 용매로 용출하는 실리카 겔 칼럼 크로마토그래피로 정제하였다. 생성물을 함유하는 분획을 합하고 증발시켜 갈색 고체상의 표제화합물(298mg, 47.0%)을 얻었다. 6- (3-hydroxyphenyl) -4-imidazol-1-yl-pyran-2-one (530 mg, 2.08 mmol) was dissolved in DMF (16 mL), followed by Cs 2 CO 3 (747 mg, 2.29 mmol). Methyl 2-chloro-2,2-difluoroacetate (0.33 mL, 3.13 mmol) was added and then stirred overnight at 90 ° C. The reaction solution cooled to room temperature was diluted with water and then extracted twice with dichloromethane (100 mL). The extract was dried over MgSO 4 , filtered and distilled under reduced pressure. The residue was purified by silica gel column chromatography eluting with a solvent of dichloromethane / methanol = 50/1 (v / v). Fractions containing product were combined and evaporated to afford the title compound (298 mg, 47.0%) as a brown solid.

1H-NMR(CDCl3); δ = 8.12(s, 1H), 7.27-7.78(m, 6H), 6.83(d, 1H), 6.61(t, 1H, J=41.6Hz), 6.31(d, 1H) 1 H-NMR (CDCl 3 ); δ = 8.12 (s, 1H), 7.27-7.78 (m, 6H), 6.83 (d, 1H), 6.61 (t, 1H, J = 41.6 Hz), 6.31 (d, 1H)

c) 1-아미노-6-(3-디플루오로메톡시페닐)-4-이미다졸-1-일-1c) 1-amino-6- (3-difluoromethoxyphenyl) -4-imidazol-1-yl-1 HH -피리딘-2-온의 합성Synthesis of -pyridin-2-one

실시예 1의 e)와 동일한 방법으로 6-(3-디플루오로메톡시페닐)-4-이미다졸-1-일-피란-2-온(295mg, 0.97mmol)과 하이드라진 수화물(0.47㎖, 9.70mmol)을 반응시켜 표제화합물(160mg, 51.8%)을 얻었다.6- (3-Difluoromethoxyphenyl) -4-imidazol-1-yl-pyran-2-one (295 mg, 0.97 mmol) and hydrazine hydrate (0.47 mL, 9.70) in the same manner as in Example 1 e) mmol) was reacted to obtain the title compound (160 mg, 51.8%).

1H-NMR(CDCl3); δ = 7.95(s, 1H), 7.52(t, 1H, J=7.9Hz), 7.24-7.42(m, 5H), 6.68(d, 1H, J=2.7Hz), 6.59(t, 1H, J=73.0Hz), 6.32(d, 1H, J=3.1Hz), 5.15(s, 2H) 1 H-NMR (CDCl 3 ); δ = 7.95 (s, 1H), 7.52 (t, 1H, J = 7.9 Hz), 7.24-7.42 (m, 5H), 6.68 (d, 1H, J = 2.7 Hz), 6.59 (t, 1H, J = 73.0 Hz), 6.32 (d, 1H, J = 3.1 Hz), 5.15 (s, 2H)

MS(ESI); 318(M+)
MS (ESI); 318 (M + )

실시예 7Example 7

1-아미노-6-(3-에톡시-페닐)-4-이미다졸-1-일-11-amino-6- (3-ethoxy-phenyl) -4-imidazol-1-yl-1 HH -피리딘-2-온(화합물 7)의 합성Synthesis of Pyridin-2-one (Compound 7)

a) 6-(3-에톡시-페닐)-4-이미다졸-1-일-피란-2-온의 합성a) Synthesis of 6- (3-ethoxy-phenyl) -4-imidazol-1-yl-pyran-2-one

실시예 6)의 a)에서 얻은 6-(3-하이드록시-페닐)-4-이미다졸-1-일- 피란-2-온(200mg, 0.786mmol)을 DMF(10㎖)에 녹이고 Cs2CO3(282mg, 0.864mmol)을 넣은 후, 에틸요오다이드(192㎕, 2.35mmol)를 가하였다. 8시간 후 에틸아세테이트(25㎖)를 가하고 물(20㎖x3회)로 세척하였다. 유기층은 MgSO4로 건조, 여과하고 감압 하에 증류하였다. 잔사는 MC/MeOH=30/1(v/v) 용매로 용출하는 실리카 겔 칼럼 크로마토그래피로 정제하였다. 생성물을 함유하는 분획을 합하고 증발시켜 표제화합물 (111mg, 51%)을 얻었다.6- (3-hydroxy-phenyl) -4-imidazol-1-yl-pyran-2-one (200 mg, 0.786 mmol) obtained in a) of Example 6) was dissolved in DMF (10 mL) and Cs 2 CO 3 (282 mg, 0.864 mmol) was added thereto, and ethyl iodide (192 μl, 2.35 mmol) was added thereto. After 8 hours, ethyl acetate (25 ml) was added and washed with water (20 ml × 3 times). The organic layer was dried over MgSO 4 , filtered and distilled under reduced pressure. The residue was purified by silica gel column chromatography eluting with a MC / MeOH = 30/1 (v / v) solvent. Fractions containing product were combined and evaporated to give the title compound (111 mg, 51%).

1H-NMR(CDCl3); δ = 7.45-7.25(m, 5H), 7.07(m, 1H), 6.80(d, 1H, J=1.2Hz), 6.23(d, 1H, J=1.8Hz), 4.12(q, 2H, J=13.9Hz)), 1.47(t, 3H) 1 H-NMR (CDCl 3 ); δ = 7.45-7.25 (m, 5H), 7.07 (m, 1H), 6.80 (d, 1H, J = 1.2 Hz), 6.23 (d, 1H, J = 1.8 Hz), 4.12 (q, 2H, J = 13.9 Hz)), 1.47 (t, 3H)

b) 1-아미노-6-(3-에톡시-페닐)-4-이미다졸-1-일-1b) 1-amino-6- (3-ethoxy-phenyl) -4-imidazol-1-yl-1 HH -피리딘-2-온의 합성Synthesis of -pyridin-2-one

실시예 1)의 e)와 동일한 방법으로 6-(3-에톡시-페닐)-4-이미다졸-1-일- 피란-2-온(36mg, 0.1275mmol)을 반응시켜 표제화합물(16.8mg, 44%)을 얻었다.6- (3-ethoxy-phenyl) -4-imidazol-1-yl-pyran-2-one (36 mg, 0.1275 mmol) was reacted in the same manner as in e) of Example 1) to give the title compound (16.8 mg). , 44%).

1H-NMR(CDCl3); δ = 7.93(s, 1H), 7.44-7.03(m, 6H), 6.65(d, 1H, J=3.3Hz), 6.31(d, 1H, J=2.7Hz), 5.28(s, 2H), 4.10(q, 2H), 1.47(t, 3H) 1 H-NMR (CDCl 3 ); δ = 7.93 (s, 1H), 7.44-7.03 (m, 6H), 6.65 (d, 1H, J = 3.3 Hz), 6.31 (d, 1H, J = 2.7 Hz), 5.28 (s, 2H), 4.10 (q, 2H), 1.47 (t, 3H)

MS(ESI); 297(M++1)
MS (ESI); 297 (M + +1)

실시예 8Example 8

1-아미노-4-이미다졸-1-일-6-(3-이소프로폭시-페닐)-11-amino-4-imidazol-1-yl-6- (3-isopropoxy-phenyl) -1 HH -피리딘-2-온(화합물 8)의 합성Synthesis of Pyridin-2-one (Compound 8)

a) 4-이미다졸-1-일-6-(3-이소프로폭시-페닐)-피란-2-온의 합성a) Synthesis of 4-imidazol-1-yl-6- (3-isopropoxy-phenyl) -pyran-2-one

실시예 6)의 a)에서 얻은 6-(3-하이드록시-페닐)-4-이미다졸-1-일- 피란-2-온(200mg, 0.786mmol)과 이소프로필브로마이드(222㎕, 2.359mmol)를 실시예 7)의 a)와 동일한 방법으로 반응시켜 표제화합물(176mg, 76%)을 얻었다.6- (3-hydroxy-phenyl) -4-imidazol-1-yl-pyran-2-one (200 mg, 0.786 mmol) and isopropyl bromide (222 μL, 2.359 mmol) obtained in a) of Example 6) ) Was reacted in the same manner as in a) of Example 7) to obtain the title compound (176 mg, 76%).

1H-NMR(CDCl3); δ = 8.05(s, 1H), 7.44-7.23(m, 5H), 7.05(m, 1H), 6.80(d, 1H, J=1.8Hz), 6.23(d, 1H, J=2.1Hz), 4.64(m 1H), 1.38(s, 3H), 1.36(s, 3H) 1 H-NMR (CDCl 3 ); δ = 8.05 (s, 1H), 7.44-7.23 (m, 5H), 7.05 (m, 1H), 6.80 (d, 1H, J = 1.8 Hz), 6.23 (d, 1H, J = 2.1 Hz), 4.64 (m 1H), 1.38 (s, 3H), 1.36 (s, 3H)

b) 1-아미노-4-이미다졸-1-일-6-(3-이소프로폭시-페닐)-1b) 1-amino-4-imidazol-1-yl-6- (3-isopropoxy-phenyl) -1 HH -피리딘-2-온의 합성Synthesis of -pyridin-2-one

실시예 1)의 e)와 동일한 방법으로 4-이미다졸-1-일-6-(3-이소프로폭시-페닐)-피란-2-온(170mg, 0.573mmol)을 반응시켜 표제화합물(70mg, 39%)을 얻었다.In the same manner as in e) of Example 1), 4-imidazol-1-yl-6- (3-isopropoxy-phenyl) -pyran-2-one (170 mg, 0.573 mmol) was reacted to give the title compound (70 mg). , 39%).

1H-NMR(CDCl3); δ = 7.94(s, 1H), 7.43-7.02(m, 6H), 6.65(d, 1H, J=1.8Hz), 6.32(d, 1H, J=2.7Hz), 5.29(s, 2H), 4.61(m, 1H), 1.39(s, 3H), 1.37(s, 3H)
 1 H-NMR (CDCl 3 ); δ = 7.94 (s, 1H), 7.43-7.02 (m, 6H), 6.65 (d, 1H, J = 1.8 Hz), 6.32 (d, 1H, J = 2.7 Hz), 5.29 (s, 2H), 4.61 (m, 1 H), 1.39 (s, 3 H), 1.37 (s, 3 H)

실시예 9 Example 9

1-아미노-4-이미다졸-1-일-6-페닐-11-amino-4-imidazol-1-yl-6-phenyl-1 HH -피리딘-2-온 2염산염(화합물 9)의 합성 Synthesis of Pyridin-2-one Dihydrochloride (Compound 9)

실시예 1)에서 얻은 1-아미노-4-이미다졸-1-일-6-페닐-1H-피리딘-2-온(52mg, 0.206mmol)을 메탄올(20㎖)에 녹인 후 0℃ 냉각하에 HCl 가스를 포화시켰다. 일야교반한 후 감압증발시키고 감압건조시켜 미황색 고체상의 표제화합물(65mg, 97.0%)을 얻었다. 1-amino-4-imidazol-1-yl-6-phenyl-1 H -pyridin-2-one (52 mg, 0.206 mmol) obtained in Example 1) was dissolved in methanol (20 mL) and then cooled to 0 ° C. HCl gas was saturated. After stirring overnight, the product was evaporated under reduced pressure and dried under reduced pressure to obtain the title compound (65 mg, 97.0%) as a pale yellow solid.

1H-NMR(DMSO-d6); δ = 9.63(s, 1H), 8.36(s, 1H), 7.79(s, 1H), 7.67-7.71 (m, 2H), 7.51-7.54(m, 3H), 7.10(d, 1H, J=2.8Hz), 6.84(d, 1H, J=3.1Hz) 1 H-NMR (DMSO-d 6 ); δ = 9.63 (s, 1H), 8.36 (s, 1H), 7.79 (s, 1H), 7.67-7.71 (m, 2H), 7.51-7.54 (m, 3H), 7.10 (d, 1H, J = 2.8 Hz), 6.84 (d, 1H, J = 3.1 Hz)

MS(ESI); 253[M-2HCl]
MS (ESI); 253 [M-2HCl]

실시예 10 Example 10

1-아미노-6-사이클로프로필-4-이미다졸-1-일-11-amino-6-cyclopropyl-4-imidazol-1-yl-1 HH -피리딘-2-온(화합물 10)의 합성Synthesis of Pyridin-2-one (Compound 10)

a) 5-사이클로프로필-3,5-디옥소-펜타노산의 합성a) Synthesis of 5-cyclopropyl-3,5-dioxo-pentanoic acid

실시예 1의 a)와 동일한 방법으로 사이클로프로판 카르복실산 메틸에스테르 (5g, 49.9mmol)를 반응시켜 표제화합물(4.5g, 53.0%)을 얻었다.Cyclopropane carboxylic acid methyl ester (5 g, 49.9 mmol) was reacted in the same manner as in a) of Example 1 to obtain the title compound (4.5 g, 53.0%).

1H-NMR(CDCl3); δ = 5.74(s, 1H), 3.38(s, 2H), 1.62-1.67(m, 1H), 0.97- 1.19(m, 4H) 1 H-NMR (CDCl 3 ); δ = 5.74 (s, 1H), 3.38 (s, 2H), 1.62-1.67 (m, 1H), 0.97-1.19 (m, 4H)

b) 4-브로모-6-사이클로프로필-피란-2-온의 합성b) Synthesis of 4-bromo-6-cyclopropyl-pyran-2-one

실시예 1의 b)와 동일한 방법으로 5-사이클로프로필-3,5-디옥소-펜타노산 (4.5g, 26.4mmol)을 반응시켜 중간체 6-사이클로프로필-4-하이드록시-피란-2-온 (3.04g, 76.0%)을 얻고, 이것을 다시 실시예 1)의 c)와 동일한 방법으로 반응시켜 표제화합물(2.47g, 58.0%)을 얻었다.Intermediate 6-cyclopropyl-4-hydroxy-pyran-2-one by reacting 5-cyclopropyl-3,5-dioxo-pentanoic acid (4.5 g, 26.4 mmol) in the same manner as in b) of Example 1 (3.04 g, 76.0%) was obtained and reacted in the same manner as in c) of Example 1) to obtain the title compound (2.47 g, 58.0%).

1H-NMR(CDCl3); δ = 6.37(d, 1H, J=1.5Hz), 6.25(s, 1H), 1.70-1.79(m, 1H), 0.99-1.16(m, 4H) 1 H-NMR (CDCl 3 ); δ = 6.37 (d, 1H, J = 1.5 Hz), 6.25 (s, 1H), 1.70-1.79 (m, 1H), 0.99-1.16 (m, 4H)

c) 6-사이클로프로필-4-이미다졸-1-일-피란-2-온의 합성c) Synthesis of 6-cyclopropyl-4-imidazol-1-yl-pyran-2-one

실시예 1의 d)와 동일한 방법으로 4-브로모-6-사이클로프로필-피란-2-온 (1.6g, 7.44mmol)을 반응시켜 표제화합물(1.42g, 94.4%)을 얻었다.4-Bromo-6-cyclopropyl-pyran-2-one (1.6 g, 7.44 mmol) was reacted in the same manner as in d) of Example 1, to obtain the title compound (1.42 g, 94.4%).

1H-NMR(CDCl3); δ = 7.97(s, 1H), 7.30(s, 1H), 7.24(s, 1H), 6.29(d, 1H, J=2.0Hz), 6.04(d, 1H, J=2.0Hz), 1.85-1.90(m, 1H), 1.05-1.26(m, 4H) 1 H-NMR (CDCl 3 ); δ = 7.97 (s, 1H), 7.30 (s, 1H), 7.24 (s, 1H), 6.29 (d, 1H, J = 2.0 Hz), 6.04 (d, 1H, J = 2.0 Hz), 1.85-1.90 (m, 1 H), 1.05-1.26 (m, 4 H)

d) 1-아미노-6-사이클로프로필-4-이미다졸-1-일-1d) 1-amino-6-cyclopropyl-4-imidazol-1-yl-1 HH -피리딘-2-온의 합성Synthesis of -pyridin-2-one

실시예 1의 e)와 동일한 방법으로 6-사이클로프로필-4-이미다졸-1-일-피란-2-온(1.42g, 7.02mmol)을 반응시켜 표제화합물(847mg, 56.0%)을 얻었다.6-cyclopropyl-4-imidazol-1-yl-pyran-2-one (1.42 g, 7.02 mmol) was reacted in the same manner as in e) of Example 1, to obtain the title compound (847 mg, 56.0%).

1H-NMR(CDCl3); δ = 7.88(s, 1H), 7.25(s, 1H), 7.20(s, 1H), 6.50(d, 1H, J=2.7Hz), 5.95(d, 1H, J=2.2Hz), 2.38-2.44(m, 1H), 1.15-1.21(m, 2H), 0.80-0.86 (m, 2H) 1 H-NMR (CDCl 3 ); δ = 7.88 (s, 1H), 7.25 (s, 1H), 7.20 (s, 1H), 6.50 (d, 1H, J = 2.7 Hz), 5.95 (d, 1H, J = 2.2 Hz), 2.38-2.44 (m, 1H), 1.15-1.21 (m, 2H), 0.80-0.86 (m, 2H)

MS(ESI); 217(M++1)
MS (ESI); 217 (M + +1)

실시예 11 Example 11

1-아미노-4-(2-클로로-이미다졸-1-일)-6-사이클로헥실-11-amino-4- (2-chloro-imidazol-1-yl) -6-cyclohexyl-1 HH -피리딘-2-온(화합물 11)의 합성Synthesis of Pyridin-2-one (Compound 11)

a) 5-사이클로헥실-3,5-디옥소-펜타노산의 합성a) Synthesis of 5-cyclohexyl-3,5-dioxo-pentanoic acid

사이클로헥산 카르복실산 에틸에스테르(50g, 0.351mol)와 3-옥소-부티르산 에틸에스테르(50g, 0.386mol)를 실시예 1)의 a)와 동일한 방법으로 반응시켜 무색 액체상의 표제화합물(52g, 70%)을 얻었다.Cyclohexane carboxylic acid ethyl ester (50 g, 0.351 mol) and 3-oxo-butyric acid ethyl ester (50 g, 0.386 mol) were reacted in the same manner as in a) of Example 1) to give the title compound as a colorless liquid (52 g, 70 %) Was obtained.

1H-NMR(CDCl3); δ = 5.63(s, 1H), 3.35(s, 2H), 2.15(m, 1H), 1.9-1.15(m, 10H) 1 H-NMR (CDCl 3 ); δ = 5.63 (s, 1H), 3.35 (s, 2H), 2.15 (m, 1H), 1.9-1.15 (m, 10H)

MS(ESI); 213(M++1)MS (ESI); 213 (M + +1)

b) 6-사이클로헥실-4-하이드록시-피란-2-온의 합성b) Synthesis of 6-cyclohexyl-4-hydroxy-pyran-2-one

5-사이클로헥실-3,5-디옥소-펜타노산(30g, 0.142 mol)을 실시예 1)의 b)와 동일한 방법으로 반응시켜 우유빛 고체상의 표제화합물(27g, 99%)을 얻었다.5-cyclohexyl-3,5-dioxo-pentanoic acid (30 g, 0.142 mol) was reacted in the same manner as b) of Example 1), to obtain the title compound (27 g, 99%) in the form of a milky solid.

1H-NMR(CDCl3); δ = 5.98(d, 1H), 5.08(d, 1H), 2.44(m, 1H), 2.05-1.10(m, 10H) 1 H-NMR (CDCl 3 ); δ = 5.98 (d, 1H), 5.08 (d, 1H), 2.44 (m, 1H), 2.05-1.10 (m, 10H)

MS(ESI); 195(M++1)MS (ESI); 195 (M + +1)

c) 4-브로모-6-사이클로헥실-피란-2-온의 합성c) Synthesis of 4-bromo-6-cyclohexyl-pyran-2-one

6-사이클로헥실-4-하이드록시-피란-2-온(373mg, 1.922mmol)을 실시예 1)의 c)와 동일한 방법으로 반응시켜 엷은 노란색 고체상의 표제화합물(241mg, 49%)을 얻었다.6-cyclohexyl-4-hydroxy-pyran-2-one (373 mg, 1.922 mmol) was reacted in the same manner as in c) of Example 1), to obtain the title compound (241 mg, 49%) as a pale yellow solid.

1H-NMR(CDCl3); δ = 6.34(d, 1H), 5.88(d, 1H), 2.44(m, 1H), 2.05-1.10(m, 10H) 1 H-NMR (CDCl 3 ); δ = 6.34 (d, 1H), 5.88 (d, 1H), 2.44 (m, 1H), 2.05-1.10 (m, 10H)

MS(ESI); 258(M++1)MS (ESI); 258 (M + +1)

d) 4-(2-클로로-이미다졸-1-일)-6-사이클로헥실-피란-2-온의 합성d) Synthesis of 4- (2-chloro-imidazol-1-yl) -6-cyclohexyl-pyran-2-one

4-브로모-6-사이클로헥실-피란-2-온(1.80g, 7.00mmol)과 2-클로로-1H-이미다졸(861mg, 8.40mmol)을 실시예 1)의 d)와 동일한 방법으로 반응시켜 우유빛 고체상의 표제화합물(1.78g, 91%)을 얻었다.Reaction of 4-bromo-6-cyclohexyl-pyran-2-one (1.80 g, 7.00 mmol) with 2-chloro-1H-imidazole (861 mg, 8.40 mmol) in the same manner as in d) of Example 1) The title compound (1.78 g, 91%) was obtained as a milky solid.

1H-NMR(CD3OD); δ = 7.53(d, J=1.5, 1H), 7.11(d, J=1.5, 1H), 6.48(d, J=1.9, 1H), 6.39(d, J=1.9, 1H), 2.13-1.66(m, 5H), 1.60-1.21(m, 5H) 1 H-NMR (CD 3 OD); δ = 7.53 (d, J = 1.5 , 1H), 7.11 (d, J = 1.5 , 1H), 6.48 (d, J = 1.9 , 1H), 6.39 (d, J = 1.9 , 1H), 2.13-1.66 ( m, 5H), 1.60-1.21 (m, 5H)

MS(ESI); 279(M++1)MS (ESI); 279 (M + +1)

e) 1-아미노-4-(2-클로로-이미다졸-1-일)-6-사이클로헥실-1e) 1-amino-4- (2-chloro-imidazol-1-yl) -6-cyclohexyl-1 HH -피리딘-2-온의 합성 Synthesis of -pyridin-2-one

4-(2-클로로-이미다졸-1-일)-6-사이클로헥실-피란-2-온(428mg, 1.54mmol)을 실시예 1)의 e)와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(166mg, 37%)을 얻었다.4- (2-Chloro-imidazol-1-yl) -6-cyclohexyl-pyran-2-one (428 mg, 1.54 mmol) was reacted in the same manner as in e) of Example 1) to give the title compound as a white solid. (166 mg, 37%) was obtained.

1H-NMR(DMSO-d6); δ = 7.63(d, J=1.5, 1H), 7.08(d, J=1.5, 1H), 6.50 (d, J=2.5, 1H), 6.28(d, J=2.5, 1H), 6.00(d, 1H), 5.98(s, 1H), 3.21(m, 1H), 2.10-1.60(m, 5H), 1.46-1.10(m, 5H) 1 H-NMR (DMSO- d6 ); δ = 7.63 (d, J = 1.5 , 1H), 7.08 (d, J = 1.5 , 1H), 6.50 (d, J = 2.5 , 1H), 6.28 (d, J = 2.5 , 1H), 6.00 (d, 1H), 5.98 (s, 1H), 3.21 (m, 1H), 2.10-1.60 (m, 5H), 1.46-1.10 (m, 5H)

MS(ESI); 293(M++1)
MS (ESI); 293 (M + +1)

실시예 12 Example 12

1-아미노-6-(4,4-디플루오로-사이클로헥실)-4-이미다졸-1-일-11-amino-6- (4,4-difluoro-cyclohexyl) -4-imidazol-1-yl-1 HH -피리딘-2-온(화합물 12)의 합성Synthesis of Pyridin-2-one (Compound 12)

a) 6-(4,4-디플루오로-사이클로헥실)-4-하이드록시-피란-2-온의 합성a) Synthesis of 6- (4,4-difluoro-cyclohexyl) -4-hydroxy-pyran-2-one

4,4-디플루오로-사이클로헥산카르복실산 메틸에스테르(9.00g, 46.8mmol)와 3-옥소-부티르산 에틸에스테르(7.16㎖, 56.2mmol)를 실시예 1)의 a)와 동일한 방법으로 반응시켜 갈색 액체(9.07g, 78%)를 얻었다. 이 갈색의 액체를 실시예 1)의 b)와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(5.87g, 54%)을 얻었다.Reaction of 4,4-difluoro-cyclohexanecarboxylic acid methyl ester (9.00 g, 46.8 mmol) with 3-oxo-butyric acid ethyl ester (7.16 mL, 56.2 mmol) in the same manner as a) of Example 1) To give a brown liquid (9.07 g, 78%). This brown liquid was reacted in the same manner as in b) of Example 1) to obtain the title compound (5.87 g, 54%) as a white solid.

1H-NMR(CD3OD); δ = 6.01(d, 1H), 5.35(d, 1H), 2.62(m, 1H), 2.22-1.60(m, 8H) 1 H-NMR (CD 3 OD); δ = 6.01 (d, 1H), 5.35 (d, 1H), 2.62 (m, 1H), 2.22-1.60 (m, 8H)

MS(ESI); 229(M-H)MS (ESI); 229 (M-H)

b) 4-브로모-6-(4,4-디플루오로-사이클로헥실)-피란-2-온의 합성b) Synthesis of 4-bromo-6- (4,4-difluoro-cyclohexyl) -pyran-2-one

6-(4,4-디플루오로-사이클로헥실)-4-하이드록시-피란-2-온(3.47g, 15.1mmol)을 실시예 1)의 c)와 동일한 방법으로 반응시켜 갈색 고체상의 표제화합물(3.69g, 84%)을 얻었다.6- (4,4-difluoro-cyclohexyl) -4-hydroxy-pyran-2-one (3.47 g, 15.1 mmol) was reacted in the same manner as in c) of Example 1) to give a title as a brown solid. Compound (3.69 g, 84%) was obtained.

1H-NMR(CDCl3); δ = 6.49(d, 1H), 6.18(d, 1H), 2.50(m, 1H), 2.32-1.66(m, 8H) 1 H-NMR (CDCl 3 ); δ = 6.49 (d, 1H), 6.18 (d, 1H), 2.50 (m, 1H), 2.32-1.66 (m, 8H)

MS(ESI); 293(M) MS (ESI); 293 (M)                     

c) 6-(4,4-디플루오로-사이클로헥실)-4-이미다졸-1-일-피란-2-온의 합성c) Synthesis of 6- (4,4-difluoro-cyclohexyl) -4-imidazol-1-yl-pyran-2-one

4-브로모-6-(4,4-디플루오로-사이클로헥실)-피란-2-온(1.51g, 5.15mmol)과 이미다졸(1.05g, 15.5mmol)을 실시예 1)의 d)와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(1.08g, 75%)을 얻었다.4-bromo-6- (4,4-difluoro-cyclohexyl) -pyran-2-one (1.51 g, 5.15 mmol) and imidazole (1.05 g, 15.5 mmol) in Example 1) d) The reaction was carried out in the same manner as to obtain the title compound (1.08 g, 75%) as a white solid.

1H-NMR(DMSO-d6); δ = 8.60(s, 1H), 8.00(m, 1H), 7.18(m, 1H), 6.89(d,1H) 6.61(d, 1H), 2.73(m, 1H), 2.22-1.58(m, 8H) 1 H-NMR (DMSO- d6 ); δ = 8.60 (s, 1H), 8.00 (m, 1H), 7.18 (m, 1H), 6.89 (d, 1H) 6.61 (d, 1H), 2.73 (m, 1H), 2.22-1.58 (m, 8H) )

MS(ESI); 281(M++1)MS (ESI); 281 (M + +1)

d) 1-아미노-6-(4,4-디플루오로-사이클로헥실)-4-이미다졸-1-일-1d) 1-amino-6- (4,4-difluoro-cyclohexyl) -4-imidazol-1-yl-1 HH -피리딘-2-온의 합성Synthesis of -pyridin-2-one

6-(4,4-디플루오로-사이클로헥실)-4-이미다졸-1-일-피란-2-온(940mg, 3.35mmol)을 실시예 1)의 e)와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(464mg, 47%)을 얻었다.6- (4,4-difluoro-cyclohexyl) -4-imidazol-1-yl-pyran-2-one (940 mg, 3.35 mmol) was reacted in the same manner as in e) of Example 1) to give white color. The title compound (464 mg, 47%) was obtained as a solid.

1H-NMR(DMSO-d6); δ = 8.49(m, 1H), 7.93(m, 1H), 7.10(m, 1H), 6.76(d, 1H), 6.56(d, 1H), 5.89(s, 1H), 5.87(s, 1H), 3.38(m, 1H), 2.24-1.60(m, 8H) 1 H-NMR (DMSO- d6 ); δ = 8.49 (m, 1H), 7.93 (m, 1H), 7.10 (m, 1H), 6.76 (d, 1H), 6.56 (d, 1H), 5.89 (s, 1H), 5.87 (s, 1H) , 3.38 (m, 1 H), 2.24-1.60 (m, 8 H)

MS(ESI); 295(M++1)
MS (ESI); 295 (M + +1)

실시예 13 Example 13

1-아미노-6-(4-플루오로-페닐)-4-이미다졸-1-일-11-amino-6- (4-fluoro-phenyl) -4-imidazol-1-yl-1 HH -피리딘-2-온(화합물 13) 의 합성Synthesis of Pyridin-2-one (Compound 13)

a) 6-(4-플루오로-페닐)-4-하이드록시-피란-2-온의 합성a) Synthesis of 6- (4-fluoro-phenyl) -4-hydroxy-pyran-2-one

4-플루오로-벤조산 t-부틸에스테르(15g, 76.4mmol)와 3-옥소-부티르산 에틸에스테르(11.7㎖, 91.8mmol)를 실시예 1)의 a)와 동일한 방법으로 반응시켜 갈색 액체를 얻었다. 이 갈색 액체를 실시예 1)의 b)와 동일한 방법으로 반응시켜 연노랑색 고체상의 표제화합물(8.98g, 57%)을 얻었다.4-fluoro-benzoic acid t-butyl ester (15 g, 76.4 mmol) and 3-oxo-butyric acid ethyl ester (11.7 mL, 91.8 mmol) were reacted in the same manner as in a) of Example 1) to obtain a brown liquid. This brown liquid was reacted in the same manner as in b) of Example 1) to obtain the title compound (8.98 g, 57%) as a pale yellow solid.

1H-NMR(CD3OD); δ = 7.92(m, 2H), 7.24(m, 2H), 6.67(m, 1H), 5.48(m, 1H) 1 H-NMR (CD 3 OD); δ = 7.92 (m, 2H), 7.24 (m, 2H), 6.67 (m, 1H), 5.48 (m, 1H)

MS(ESI); 205(M-H)MS (ESI); 205 (M-H)

b) 6-(4-플루오로-페닐)-4-이미다졸-1-일-피란-2-온의 합성b) Synthesis of 6- (4-fluoro-phenyl) -4-imidazol-1-yl-pyran-2-one

6-(4-플루오로-페닐)-4-하이드록시-피란-2-온(6.00g, 29.1mmol)을 실시예 1)의 c)와 동일한 방법으로 반응시켜 갈색 고체상의 화합물(6.26g, 80%)을 얻었다. 이 화합물을 이미다졸(431mg, 6.33mmol)과 실시예 1)의 d)와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(1.03g, 76%)을 얻었다.6- (4-fluoro-phenyl) -4-hydroxy-pyran-2-one (6.00 g, 29.1 mmol) was reacted in the same manner as in c) of Example 1) to give a brown solid compound (6.26 g, 80%). This compound was reacted with imidazole (431 mg, 6.33 mmol) in the same manner as d) of Example 1) to obtain the title compound (1.03 g, 76%) as a white solid.

1H-NMR(DMSO-d6); δ = 8.72(s, 1H), 8.11(m, 3H), 7.65(m, 1H), 7.44(m, 2H), 7.22(d, 1H), 6.74(d, 1H) 1 H-NMR (DMSO- d6 ); δ = 8.72 (s, 1H), 8.11 (m, 3H), 7.65 (m, 1H), 7.44 (m, 2H), 7.22 (d, 1H), 6.74 (d, 1H)

MS(ESI); 257(M++1)MS (ESI); 257 (M + +1)

c) 1-아미노-6-(4-플루오로-페닐)-4-이미다졸-1-일-1c) 1-amino-6- (4-fluoro-phenyl) -4-imidazol-1-yl-1 HH -피리딘-2-온의 합성Synthesis of -pyridin-2-one

6-(4-플루오로-페닐)-4-이미다졸-1-일-피란-2-온(251mg, 0.980mmol)을 실시 예 1)의 e)와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(148mg, 56%)을 얻었다.6- (4-fluoro-phenyl) -4-imidazol-1-yl-pyran-2-one (251 mg, 0.980 mmol) was reacted in the same manner as in e) of Example 1) to give the title compound as a white solid. (148 mg, 56%) was obtained.

1H-NMR(DMSO-d6); δ = 8.81(s, 1H), 7.96(m, 1H), 7.73(m, 2H), 7.34(m, 2H), 7.12(m, 1H), 6.92(d, 1H), 6.76(d, 1H), 5.78(s, 1H), 5.77(s, 1H) 1 H-NMR (DMSO- d6 ); δ = 8.81 (s, 1H), 7.96 (m, 1H), 7.73 (m, 2H), 7.34 (m, 2H), 7.12 (m, 1H), 6.92 (d, 1H), 6.76 (d, 1H) , 5.78 (s, 1H), 5.77 (s, 1H)

MS(ESI); 271(M++1)
MS (ESI); 271 (M + +1)

실시예 14 Example 14

1-아미노-6-(3-플루오로-페닐)-4-이미다졸-1-일-11-amino-6- (3-fluoro-phenyl) -4-imidazol-1-yl-1 HH -피리딘-2-온(화합물 14)의 합성Synthesis of Pyridin-2-one (Compound 14)

a) 6-(3-플루오로-페닐)-4-하이드록시-피란-2-온의 합성a) Synthesis of 6- (3-fluoro-phenyl) -4-hydroxy-pyran-2-one

3-옥소-부티르산 에틸에스테르(7.58㎖, 59.5mmole)를 THF(120㎖)에 용해시킨 후 -78℃로 냉각시켰다. 여기에 리튬디이소프로필아미드(LDA)(헥산중 2.0M, 74.3㎖, 149mmole)와 N,N,N`,N`-테트라메틸에틸렌디아민(8.97㎖, 59.5mmole)을 천천히 적가하고 3시간에 걸쳐 0℃까지 승온하면서 교반하였다. 테트라하이드로-피란-4-카르복실산 메틸에스테르(10.0g, 59.5mmole)를 THF(50㎖)에 희석시킨 용액을 서서히 적가하고 실온에서 18시간동안 교반하였다. 감압하에 용매를 제거시킨 후 5N-NaOH 수용액(30㎖)를 넣고 2시간동안 실온에서 교반하였다. 2N-HCl 수용액으로 반응액을 산성화하고 에틸아세테이트(200㎖)로 2회 추출하였다. 추출액은 MgSO4로 건조, 여과한 다음 감압하에 증류하였다. 잔사는 n-헥산/에틸 아세테이트=2/1(v/v) 용매로 용 출하는 실리카 겔 칼럼 크로마토그래피로 정제하였다. 생성물을 함유하는 분획을 합하고 증발시켜 옅은 갈색의 액체를 얻었다. 이 갈색 액체를 250㎖ 플라스크에서 에테르(80㎖)에 녹인 후 0℃로 냉각한 다음 (TFA)2O(10.9㎖, 77.4mmol)를 30분에 걸쳐 서서히 적가하였다. 8시간 후 거름종이로 여과하여 연노랑색 고체상의 표제화합물(5.76g, 47%)을 얻었다.3-oxo-butyric acid ethyl ester (7.58 mL, 59.5 mmol) was dissolved in THF (120 mL) and then cooled to -78 ° C. Lithium diisopropylamide (LDA) (2.0M in hexane, 74.3ml, 149mmole) and N, N, N`, N`-tetramethylethylenediamine (8.97ml, 59.5mmole) were slowly added dropwise and added for 3 hours. It stirred, heating up to 0 degreeC over. A solution of tetrahydro-pyran-4-carboxylic acid methyl ester (10.0 g, 59.5 mmol) diluted in THF (50 mL) was slowly added dropwise and stirred at room temperature for 18 hours. After the solvent was removed under reduced pressure, 5N-NaOH aqueous solution (30 mL) was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction solution was acidified with 2N-HCl aqueous solution and extracted twice with ethyl acetate (200 mL). The extract was dried over MgSO 4 , filtered and distilled under reduced pressure. The residue was purified by silica gel column chromatography eluting with a solvent of n-hexane / ethyl acetate = 2/1 (v / v). Fractions containing product were combined and evaporated to give a pale brown liquid. This brown liquid was dissolved in ether (80 mL) in a 250 mL flask, cooled to 0 ° C. and (TFA) 2 O (10.9 mL, 77.4 mmol) was added slowly dropwise over 30 minutes. After 8 hours, the resultant was filtered through a filter paper to obtain the title compound (5.76 g, 47%) as a pale yellow solid.

1H-NMR(CDCl3); δ = 7.65-7.15(m, 4H), 6.64(d, 1H), 6.40(d, 1H) 1 H-NMR (CDCl 3 ); δ = 7.65-7.15 (m, 4H), 6.64 (d, 1H), 6.40 (d, 1H)

MS(ESI); 205(M-H)MS (ESI); 205 (M-H)

b) 4-브로모-6-(3-플루오로-페닐)-피란-2-온의 합성b) Synthesis of 4-bromo-6- (3-fluoro-phenyl) -pyran-2-one

250㎖ 플라스크에서 6-(3-플루오로-페닐)-4-하이드록시-피란-2-온(1.01g, 4.90mmol)을 실시예 1)의 c)와 동일한 방법으로 반응시켜 갈색 고체상의 표제화합물(962mg, 73%)을 얻었다.6- (3-Fluoro-phenyl) -4-hydroxy-pyran-2-one (1.01 g, 4.90 mmol) in a 250 ml flask was reacted in the same manner as in c) of Example 1) to give the title as a brown solid. Compound (962 mg, 73%) was obtained.

1H-NMR(CDCl3); δ = 7.65-7.40(m, 3H), 7.25-7.14(m, 1H), 6.82(m, 1H), 6.61(m, 1H) 1 H-NMR (CDCl 3 ); δ = 7.65-7.40 (m, 3H), 7.25-7.14 (m, 1H), 6.82 (m, 1H), 6.61 (m, 1H)

c) 6-(3-플루오로-페닐)-4-이미다졸-1-일-피란-2-온의 합성c) Synthesis of 6- (3-fluoro-phenyl) -4-imidazol-1-yl-pyran-2-one

4-브로모-6-(3-플루오로-페닐)-피란-2-온(400mg, 1.49mmol)과 이미다졸 (304mg, 4.46mmol)을 실시예 1)의 d)와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(309mg, 81%)을 얻었다.4-Bromo-6- (3-fluoro-phenyl) -pyran-2-one (400 mg, 1.49 mmol) and imidazole (304 mg, 4.46 mmol) were reacted in the same manner as in d) of Example 1). The title compound (309 mg, 81%) was obtained as a white solid.

1H-NMR(CD3OD); δ = 8.61(m, 1H), 7.94-7.48(m, 5H), 7.32(m, 1H), 7.24(m, 1H), 6.63(m, 1H) 1 H-NMR (CD 3 OD); δ = 8.61 (m, 1H), 7.94-7.48 (m, 5H), 7.32 (m, 1H), 7.24 (m, 1H), 6.63 (m, 1H)

d) 1-아미노-6-(3-플루오로-페닐)-4-이미다졸-1-일-1d) 1-amino-6- (3-fluoro-phenyl) -4-imidazol-1-yl-1 HH -피리딘-2-온의 합성Synthesis of -pyridin-2-one

6-(3-플루오로-페닐)-4-이미다졸-1-일-피란-2-온(254mg, 0.991mmol)을 실시예 1)의 e)와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(153mg, 57%)을 얻었다.6- (3-fluoro-phenyl) -4-imidazol-1-yl-pyran-2-one (254 mg, 0.991 mmol) was reacted in the same manner as in e) of Example 1) to give the title compound as a white solid. (153 mg, 57%) was obtained.

1H-NMR(DMSO); δ = 8.50(s, 1H), 7.95(m, 2H), 7.54(m, 3H), 7.34(m, 1H), 7.12(m, 1H), 6.94(d, J=2.670, 1H), 6.79(d, J=2.670, 1H), 5.78(s. 1H), 5.77(s, 1H) 1 H-NMR (DMSO); δ = 8.50 (s, 1H), 7.95 (m, 2H), 7.54 (m, 3H), 7.34 (m, 1H), 7.12 (m, 1H), 6.94 (d, J = 2.670, 1H), 6.79 ( d, J = 2.670, 1H), 5.78 (s. 1H), 5.77 (s, 1H)

MS(ESI); 271(M++1)
MS (ESI); 271 (M + +1)

실시예 15 Example 15

1-아미노-6-사이클로헥실-4-이미다졸-1-일-3-메틸-11-amino-6-cyclohexyl-4-imidazol-1-yl-3-methyl-1 HH -피리딘-2-온(화합물 15)의 합성Synthesis of Pyridin-2-one (Compound 15)

a) 6-사이클로헥실-4-하이드록시-3-메틸-피란-2-온의 합성a) Synthesis of 6-cyclohexyl-4-hydroxy-3-methyl-pyran-2-one

60%-NaH(4.65g, 0.116mole)를 DME(70㎖)에 현탁시킨 후 70℃까지 가열, 환류시켰다. 여기에 사이클로헥산 카르복실산 메틸에스테르(5.00g, 0.0352mole)와 2-메틸-3-옥소-부티르산 에틸에스테르(90%, 6.20g, 0.0387mole)를 DME(30㎖)에 희석시킨 용액을 45분에 걸쳐 가한 후 18시간 동안 가열, 환류시켰다. 실온까지 식힌 다음 감압하에 용매를 제거하고 물(50㎖)을 가하여 2시간 동안 교반시켰다. 2N-HCl로 산성화하고 에틸아세테이트(50㎖x2)로 추출한 후 유기층을 포화 식염수(50㎖)로 세척하였다. 유기층을 MgSO4로 건조 후 여과하고 감압농축하여 얻은 잔사를 에틸아세테이트/n-헥산으로 재결정화하여 흰색 고체상의 표제화합물(4.80g, 66%)을 얻었다.60% -NaH (4.65 g, 0.116 mole) was suspended in DME (70 mL), and then heated to reflux to 70 ° C. Here, a solution obtained by diluting cyclohexane carboxylic acid methyl ester (5.00 g, 0.0352 mole) and 2-methyl-3-oxo-butyric acid ethyl ester (90%, 6.20 g, 0.0387 mole) in DME (30 mL) was prepared. After addition over minutes, it was heated to reflux for 18 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and water (50 mL) was added thereto, followed by stirring for 2 hours. Acidified with 2N-HCl and extracted with ethyl acetate (50 mL × 2), the organic layer was washed with saturated brine (50 mL). The organic layer was dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate / n-hexane to obtain the title compound (4.80 g, 66%) as a white solid.

1H-NMR(CDCl3); δ = 8.46(brs, 1H), 6.02(s, 1H), 2.35(m, 1H), 1.96(s, 3H), 1.90-1.15(m, 10H) 1 H-NMR (CDCl 3 ); δ = 8.46 (brs, 1H), 6.02 (s, 1H), 2.35 (m, 1H), 1.96 (s, 3H), 1.90-1.15 (m, 10H)

MS ; 209[M++1], 231MS; 209 [M + +1], 231

b) 4-브로모-6-사이클로헥실-3-메틸-피란-2-온의 합성b) Synthesis of 4-bromo-6-cyclohexyl-3-methyl-pyran-2-one

플라스크에 디메틸포름아미드(30㎖)를 넣고 -10℃로 냉각한 다음 PBr3(3.38㎖, 0.0371mole)를 에테르(30㎖)로 묽힌 용액을 10분에 걸쳐 적가하였다. 10분 후에 6-사이클로헥실-4-하이드록시-3-메틸-피란-2-온(1.93g, 0.00927mole)을 DMF(20㎖)에 녹인 용액을 30분에 걸쳐 서서히 적가하였다. 반응액을 60℃로 가열하고 10시간동안 교반하였다. 반응액을 실온으로 냉각시킨 후 물(50㎖)을 넣고 에틸 아세테이트(200㎖)로 추출한 다음 추출액은 MgSO4로 건조, 여과하고 감압하에 증류하였다. 잔사는 n-헥산/에틸 아세테이트=10/1(v/v) 용매로 용출하는 실리카 겔 칼럼 크로마토그래피로 정제하였다. 생성물을 함유하는 분획을 합하고 증발시켜 흰색 고체상의 표제화합물(1.89g, 75%)을 얻었다.Dimethylformamide (30 mL) was added to the flask, cooled to −10 ° C., and a solution of PBr 3 (3.38 mL, 0.0371 mole) diluted with ether (30 mL) was added dropwise over 10 minutes. After 10 minutes, a solution of 6-cyclohexyl-4-hydroxy-3-methyl-pyran-2-one (1.93 g, 0.00927 mole) in DMF (20 mL) was slowly added dropwise over 30 minutes. The reaction solution was heated to 60 ° C. and stirred for 10 hours. After the reaction mixture was cooled to room temperature, water (50 mL) was added thereto, followed by extraction with ethyl acetate (200 mL). The extract was dried over MgSO 4 , filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography eluting with a solvent of n-hexane / ethyl acetate = 10/1 (v / v). Fractions containing product were combined and evaporated to afford the title compound (1.89 g, 75%) as a white solid.

1H-NMR(CDCl3); δ = 6.14(s, 1H), 2.40(m, 1H), 2.04(s, 3H), 1.95-1.20(m, 10H) 1 H-NMR (CDCl 3 ); δ = 6.14 (s, 1H), 2.40 (m, 1H), 2.04 (s, 3H), 1.95-1.20 (m, 10H)

c) 6-사이클로헥실-4-이미다졸-1-일-3-메틸-피란-2-온의 합성c) Synthesis of 6-cyclohexyl-4-imidazol-1-yl-3-methyl-pyran-2-one

4-브로모-6-사이클로헥실-3-메틸-피란-2-온(672mg, 2.48mmol)을 실시예 1)의 d)와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(425mg, 66%)을 얻었다.4-Bromo-6-cyclohexyl-3-methyl-pyran-2-one (672 mg, 2.48 mmol) was reacted in the same manner as d) of Example 1) to give the title compound as a white solid (425 mg, 66%). Got.

1H-NMR(CDCl3); δ = 7.68(s, 1H), 7.24(d, 1H), 7.12(d, 1H), 5.95(s, 1H), 2.48-2.40(m, 1H), 2.08(s, 3H), 2.02-1.75(m, 4H), 1.48-1.18(m, 6H) 1 H-NMR (CDCl 3 ); δ = 7.68 (s, 1H), 7.24 (d, 1H), 7.12 (d, 1H), 5.95 (s, 1H), 2.48-2.40 (m, 1H), 2.08 (s, 3H), 2.02-1.75 ( m, 4H), 1.48-1.18 (m, 6H)

d) 1-아미노-6-사이클로헥실-4-이미다졸-1-일-3-메틸-1d) 1-amino-6-cyclohexyl-4-imidazol-1-yl-3-methyl-1 HH -피리딘-2-온의 합성 Synthesis of -pyridin-2-one

6-사이클로헥실-4-이미다졸-1-일-3-메틸-피란-2-온(410mg, 1.59mmol)을 실시예 1)의 e)과 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(240mg, 56%)을 얻었다.6-cyclohexyl-4-imidazol-1-yl-3-methyl-pyran-2-one (410 mg, 1.59 mmol) was reacted in the same manner as in e) of Example 1) to give the title compound as a white solid (240 mg). , 56%).

1H-NMR(CDCl3); δ = 7.64(s, 1H), 7.20(d, 1H), 7.06(d, 1H), 5.95(s, 1H), 5.10(s, 2H), 3.25-3.15(m, 1H), 2.10(s, 3H), 2.00-1.76(m, 4H), 1.48-1.22(m, 6H) 1 H-NMR (CDCl 3 ); δ = 7.64 (s, 1H), 7.20 (d, 1H), 7.06 (d, 1H), 5.95 (s, 1H), 5.10 (s, 2H), 3.25-3.15 (m, 1H), 2.10 (s, 3H), 2.00-1.76 (m, 4H), 1.48-1.22 (m, 6H)

MS(ESI); 273(M++1)
MS (ESI); 273 (M + +1)

실시예 16 Example 16

1-아미노-4-이미다졸-1-일-6-(3-프로폭시-페닐)-11-amino-4-imidazol-1-yl-6- (3-propoxy-phenyl) -1 HH -피리딘-2-온(화합물 16)의 합성Synthesis of Pyridin-2-one (Compound 16)

a) 4-이미다졸-1-일-6-(3-프로폭시-페닐)-피란-2-온의 합성a) Synthesis of 4-imidazol-1-yl-6- (3-propoxy-phenyl) -pyran-2-one

실시예 6)의 a)에서 얻은 6-(3-하이드록시-페닐)-4-이미다졸-1-일- 피란-2-온(270mg, 1.06mmmol)과 1-요오도-프로판(0.21㎖, 2.12mmol)을 실시예 7)의 a)와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(210mg, 67%)을 얻었다.6- (3-hydroxy-phenyl) -4-imidazol-1-yl-pyran-2-one (270 mg, 1.06 mmol) and 1-iodo-propane (0.21 mL) obtained in a) of Example 6) , 2.12 mmol) was reacted in the same manner as in a) of Example 7) to obtain the title compound (210 mg, 67%) as a white solid.

1H-NMR(CDCl3); δ = 8.05(s, 1H), 7.45-7.35(m, 4H), 7.28(d, 1H), 7.08- 7.04(m, 1H), 6.82(d, 1H), 6.23(d, 1H), 3.99(t, 2H), 1.90-1.80(m, 2H), 1.06(t, 3H) 1 H-NMR (CDCl 3 ); δ = 8.05 (s, 1H), 7.45-7.35 (m, 4H), 7.28 (d, 1H), 7.08-7.04 (m, 1H), 6.82 (d, 1H), 6.23 (d, 1H), 3.99 ( t, 2H), 1.90-1.80 (m, 2H), 1.06 (t, 3H)

b) 1-아미노-4-이미다졸-1-일-6-(3-프로폭시-페닐)-1b) 1-amino-4-imidazol-1-yl-6- (3-propoxy-phenyl) -1 HH -피리딘-2-온의 합성Synthesis of -pyridin-2-one

4-이미다졸-1-일-6-(3-프로폭시-페닐)-피란-2-온(200mg, 0.675mmol)을 실시예 1)의 e)과 동일한 방법으로 반응시켜 미황색 고체상의 표제화합물(110mg, 53%)을 얻었다.4-Imidazol-1-yl-6- (3-propoxy-phenyl) -pyran-2-one (200 mg, 0.675 mmol) was reacted in the same manner as in e) of Example 1) to give the title compound as a pale yellow solid. (110 mg, 53%) was obtained.

1H-NMR(CDCl3); δ = 7.94(s, 1H), 7.45-7.38(m, 1H), 7.30(d, 1H), 7.23(d, 1H), 7.10-7.02(m, 3H), 6.65(d, 1H), 6.32(d, 1H), 5.28(s, 2H), 3.96(t, 2H), 1.90-1.80(m, 2H), 1.04(t, 3H) 1 H-NMR (CDCl 3 ); δ = 7.94 (s, 1H), 7.45-7.38 (m, 1H), 7.30 (d, 1H), 7.23 (d, 1H), 7.10-7.02 (m, 3H), 6.65 (d, 1H), 6.32 ( d, 1H), 5.28 (s, 2H), 3.96 (t, 2H), 1.90-1.80 (m, 2H), 1.04 (t, 3H)

MS(ESI); 311(M++1)
MS (ESI); 311 (M + +1)

실시예 17 Example 17

1-아미노-6-(3-사이클로프로필메톡시-페닐)-4-이미다졸-1-일-11-amino-6- (3-cyclopropylmethoxy-phenyl) -4-imidazol-1-yl-1 HH -피리딘-2-온 (화합물 17)의 합성Synthesis of Pyridin-2-one (Compound 17)

a) 6-(3-사이클로프로필메톡시-페닐)-4-이미다졸-1-일-피란-2-온의 합성a) Synthesis of 6- (3-cyclopropylmethoxy-phenyl) -4-imidazol-1-yl-pyran-2-one

실시예 6)의 a)에서 얻은 6-(3-하이드록시-페닐)-4-이미다졸-1-일- 피란-2-온(203mg, 0.799mmmol)과 브로모메틸-사이클로프로판(0.16㎖, 1.60mmol)을 실시예 7의 a)와 동일한 방법으로 반응시켜 미황색 고체상의 표제화합물(160mg, 65%)을 얻었다.6- (3-hydroxy-phenyl) -4-imidazol-1-yl-pyran-2-one (203 mg, 0.799 mmol) and bromomethyl-cyclopropane (0.16 mL) obtained in a) of Example 6) , 1.60 mmol) was reacted in the same manner as in a) of Example 7 to obtain the title compound (160 mg, 65%) as a pale yellow solid.

1H-NMR(CDCl3); δ = 8.05(s, 1H), 7.45-7.36(m, 4H), 7.28(d, 1H), 7.10- 7.06(m, 1H), 6.82(d, 1H), 6.23(d, 1H), 3.88(d, 2H), 1.35-1.28(m, 1H), 0.72-0.67(m, 2H), 0.43-0.38(m, 2H) 1 H-NMR (CDCl 3 ); δ = 8.05 (s, 1H), 7.45-7.36 (m, 4H), 7.28 (d, 1H), 7.10- 7.06 (m, 1H), 6.82 (d, 1H), 6.23 (d, 1H), 3.88 ( d, 2H), 1.35-1.28 (m, 1H), 0.72-0.67 (m, 2H), 0.43-0.38 (m, 2H)

b) 1-아미노-6-(3-사이클로프로필메톡시-페닐)-4-이미다졸-1-일-1b) 1-amino-6- (3-cyclopropylmethoxy-phenyl) -4-imidazol-1-yl-1 HH -피리딘-2-온의 합성Synthesis of -pyridin-2-one

6-(3-사이클로프로필메톡시-페닐)-4-이미다졸-1-일-피란-2-온(200mg, 0.649mmol)을 실시예 1)의 e)와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(115mg, 55%)을 얻었다.6- (3-cyclopropylmethoxy-phenyl) -4-imidazol-1-yl-pyran-2-one (200 mg, 0.649 mmol) was reacted in the same manner as in e) of Example 1) to give a white solid phase. The title compound (115 mg, 55%) was obtained.

1H-NMR(CDCl3); δ = 7.94(s, 1H), 7.44-7.38(m, 1H), 7.28(d, 1H), 7.22(d, 1H), 7.10-7.02(m, 3H), 6.65(d, 1H), 6.32(d, 1H), 5.26(s, 2H), 3.85(d, 2H), 1.34-1.25(m, 1H), 0.70-0.63(m, 2H), 0.40-0.35(m, 2H) 1 H-NMR (CDCl 3 ); δ = 7.94 (s, 1H), 7.44-7.38 (m, 1H), 7.28 (d, 1H), 7.22 (d, 1H), 7.10-7.02 (m, 3H), 6.65 (d, 1H), 6.32 ( d, 1H), 5.26 (s, 2H), 3.85 (d, 2H), 1.34-1.25 (m, 1H), 0.70-0.63 (m, 2H), 0.40-0.35 (m, 2H)

MS(ESI); 323(M++1)
MS (ESI); 323 (M + +1)

실시예 18 Example 18

1-아미노-4-이미다졸-1-일-11-amino-4-imidazol-1-yl-1 HH -[2,2']바이피리디닐-6-온(화합물 18)의 합성Synthesis of-[2,2 '] bipyridinyl-6-one (Compound 18)

a) 에틸 5-(2-피리딜)-3,5-디옥소펜타노에이트의 합성a) Synthesis of ethyl 5- (2-pyridyl) -3,5-dioxopentanoate

건조된 250㎖ 플라스크에서 에틸 아세토아세테이트(10g, 76.864mmol)를 무수 디에틸에테르(100㎖)에 용해시킨 후 반응액을 질소 분위기하에서 -78℃로 냉각시켰다. 여기에 리튬 디이소프로필아미드(LDA) (헥산중 2.0N, 96.1㎖, 192.160mmol)를 적가한 다음 N,N,N',N'-테트라메틸에틸렌디아민(TMEDA)(9.95㎖, 76.864mmol)을 적가하고 반응액을 3시간에 걸쳐 0℃로 승온하면서 교반하였다. 반응용액에 메틸 피콜리네이트(11.62g, 76.864mmol)를 무수 디에틸에테르(100㎖)에 희석시킨 용액을 적가하고 실온에서 18 시간 동안 교반한 후 아세트산(11㎖)을 적가하여 10분간 교반하여 반응을 종결시켰다. 석출된 황색 고체를 거른 후 디에틸에테르로 세척하였다. 걸러진 황색 고체를 물에 녹인 후 1N HCl을 이용하여 pH=4~5 에서 메틸렌클로라이드(CH2Cl2)를 이용하여 추출한 다음 추출액은 MgSO4로 건조, 여과한 후 감압하에 증류하였다. 잔사는 에틸 아세테이트/n-헥산=2/1(v/v)용매로 용출하는 실리카 겔 칼럼 크로마토그래피로 정제하였다. 생성물을 함유하는 분획을 합하고 증발시켜 갈색 액상의 표제화합물(14.5g, 80.1%)을 얻었다.Ethyl acetoacetate (10 g, 76.864 mmol) was dissolved in anhydrous diethyl ether (100 mL) in a dried 250 mL flask, and the reaction solution was cooled to -78 ° C under nitrogen atmosphere. To this was added lithium diisopropylamide (LDA) (2.0N in hexane, 96.1 mL, 192.160 mmol) dropwise followed by N, N, N ', N'-tetramethylethylenediamine (TMEDA) (9.95 mL, 76.864 mmol) Was added dropwise and the reaction solution was stirred while heating to 0 ° C. over 3 hours. A solution of methyl picolinate (11.62 g, 76.864 mmol) diluted in anhydrous diethyl ether (100 mL) was added dropwise to the reaction solution, and stirred at room temperature for 18 hours, followed by dropwise addition of acetic acid (11 mL) for 10 minutes. The reaction was terminated. The precipitated yellow solid was filtered off and washed with diethyl ether. The filtered yellow solid was dissolved in water, extracted using methylene chloride (CH 2 Cl 2 ) at pH = 4-5 using 1N HCl, and the extract was dried over MgSO 4 , filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography eluting with a solvent of ethyl acetate / n-hexane = 2/1 (v / v). Fractions containing the product were combined and evaporated to give the title compound (14.5 g, 80.1%) as a brown liquid.

1H-NMR(CDCl3); δ = 9.07(s, 1H), 8.74(d, 1H), 8.16(d, 1H), 7.41(dd, 1H), 6.32(s, 1H), 4.22(q, 2H), 3.50(s, 2H), 1.31(t, 3H) 1 H-NMR (CDCl 3 ); δ = 9.07 (s, 1H), 8.74 (d, 1H), 8.16 (d, 1H), 7.41 (dd, 1H), 6.32 (s, 1H), 4.22 (q, 2H), 3.50 (s, 2H) , 1.31 (t, 3H)

b) 4-하이드록시-6-(2-피리딜)-피란-2-온의 합성b) Synthesis of 4-hydroxy-6- (2-pyridyl) -pyran-2-one

에틸 5-(2-피리딜)-3,5-디옥소펜타노에이트(5.63g, 23.933mmol)를 감압하에서 150~160℃로 가열하여 30분간 교반하였다. 반응액을 실온으로 식힌 후 디에틸에테르(15㎖)를 가하고 10분간 교반하고 석출된 고체를 여과하고 디에틸에테르로 세척하고 건조하여 황색 고체상의 표제화합물(3.4g, 75.1%)을 얻었다.Ethyl 5- (2-pyridyl) -3,5-dioxopentanoate (5.63 g, 23.933 mmol) was heated to 150-160 ° C. under reduced pressure and stirred for 30 minutes. After the reaction mixture was cooled to room temperature, diethyl ether (15 mL) was added thereto, stirred for 10 minutes, and the precipitated solid was filtered, washed with diethyl ether, and dried to obtain the title compound (3.4 g, 75.1%) as a yellow solid.

1H-NMR(CDCl3+DMSO-d6); δ = 8.64(d, 1H), 8.00(d, 1H), 7.81(m, 1H), 7.33 (m, 1H), 7.17(d, 1H), 5.64(d, 4H) 1 H-NMR (CDCl 3 + DMSO-d 6 ); δ = 8.64 (d, 1H), 8.00 (d, 1H), 7.81 (m, 1H), 7.33 (m, 1H), 7.17 (d, 1H), 5.64 (d, 4H)

c) 4-이미다졸-1-일-6-피리딘-2-일-피란-2-온의 합성c) Synthesis of 4-imidazol-1-yl-6-pyridin-2-yl-pyran-2-one

4-하이드록시-6-(2-피리딜)-2-피론(1.40g, 7.401mmol)과 카르보닐디이미다졸 (CDI)(3.12g, 19.243mmol)을 실시예 1)의 d)와 동일한 방법으로 반응시켜 갈색 액상의 표제화합물(1.2g, 67.8%)을 얻었다.4-hydroxy-6- (2-pyridyl) -2-pyrone (1.40 g, 7.401 mmol) and carbonyldiimidazole (CDI) (3.12 g, 19.243 mmol) were the same as in d) of Example 1). The reaction was carried out to give the title compound (1.2g, 67.8%) in brown liquid.

1H-NMR(CDCl3); δ = 8.60(d, 1H), 8.04(s, 1H), 7.97(d, 1H), 7.78(t, 1H), 7.55(d, 1H), 7.34(m, 2H), 7.17(m, 1H), 6.22(s, 1H) 1 H-NMR (CDCl 3 ); δ = 8.60 (d, 1H), 8.04 (s, 1H), 7.97 (d, 1H), 7.78 (t, 1H), 7.55 (d, 1H), 7.34 (m, 2H), 7.17 (m, 1H) , 6.22 (s, 1H)

d) 1-아미노-4-이미다졸-1-일-1d) 1-amino-4-imidazol-1-yl-1 HH -[2,2']바이피리디닐-6-온의 합성Synthesis of-[2,2 '] bipyridinyl-6-one

4-이미다졸-1-일-6-피리딘-2-일-피란-2-온(260mg, 1.087mmol)을 실시예 1)의 e)와 동일한 방법으로 반응시켜 연한 노란색 고체상의 표제화합물(179mg, 65.1%)을 얻었다.4-Imidazol-1-yl-6-pyridin-2-yl-pyran-2-one (260 mg, 1.087 mmol) was reacted in the same manner as in e) of Example 1) to give the title compound (179 mg) as a pale yellow solid. , 65.1%).

1H-NMR(CDCl3); δ = 8.75(d, 1H), 7.95(s, 1H), 7.92(dd, 1H), 7.71(d, 1H), 7.47(m, 1H), 7.32(s 1H), 7.23(s, 1H), 6.71(d, 1H), 6.51(s, 2H), 6.47(d, 1H) 1 H-NMR (CDCl 3 ); δ = 8.75 (d, 1H), 7.95 (s, 1H), 7.92 (dd, 1H), 7.71 (d, 1H), 7.47 (m, 1H), 7.32 (s 1H), 7.23 (s, 1H), 6.71 (d, 1H), 6.51 (s, 2H), 6.47 (d, 1H)

MS(ESI); 254(M++1)
MS (ESI); 254 (M + +1)

실시예 19 Example 19

1-아미노-4-이미다졸-1-일-11-amino-4-imidazol-1-yl-1 HH -[2,3']바이피리디닐-6-온(화합물 19)의 합성Synthesis of-[2,3 '] bipyridinyl-6-one (Compound 19)

a) 에틸 5-(3-피리딜)-3,5-디옥소펜타노에이트의 합성a) Synthesis of ethyl 5- (3-pyridyl) -3,5-dioxopentanoate

메틸 니코티네이트(4.5g, 34.589mmol)를 실시예 18)의 a)와 동일한 방법으로 반응시켜 갈색 액상의 표제화합물(6.4g, 78.6%)을 얻었다.Methyl nicotinate (4.5 g, 34.589 mmol) was reacted in the same manner as in a) of Example 18), to obtain a brown liquid title compound (6.4 g, 78.6%).

1H-NMR(CDCl3); δ = 9.07(d, 1H), 8.76(dd, 1H), 8.18(m, 1H), 7.41(dd, 1H), 6.32(s, 1H), 4.22(q, 2H), 3.50(s, 2H), 1.31(t, 3H) 1 H-NMR (CDCl 3 ); δ = 9.07 (d, 1H), 8.76 (dd, 1H), 8.18 (m, 1H), 7.41 (dd, 1H), 6.32 (s, 1H), 4.22 (q, 2H), 3.50 (s, 2H) , 1.31 (t, 3H)

b) 4-하이드록시-6-(3-피리딜)-피란-2-온의 합성b) Synthesis of 4-hydroxy-6- (3-pyridyl) -pyran-2-one

에틸 5-(3-피리딜)-3,5-디옥소펜타노에이트(1.75g, 7.439mmol)를 실시예 18)의 b)와 동일한 방법으로 반응시켜 연한 노란색 고체상의 표제화합물(1.1mg, 78.0%)을 얻었다.Reaction of ethyl 5- (3-pyridyl) -3,5-dioxopentanoate (1.75 g, 7.439 mmol) in the same manner as b) of Example 18) gave the title compound (1.1 mg, 78.0%).

1H-NMR(CDCl3+DMSO-d6); δ = 9.02(d, 1H), 8.66(dd, 1H), 8.11(m, 1H), 7.42(dd, 1H), 6.57(d, 1H), 5.58(d, 1H) 1 H-NMR (CDCl 3 + DMSO-d 6 ); δ = 9.02 (d, 1H), 8.66 (dd, 1H), 8.11 (m, 1H), 7.42 (dd, 1H), 6.57 (d, 1H), 5.58 (d, 1H)

c) 4-이미다졸-1-일-6-피리딘-3-일-피란-2-온의 합성c) Synthesis of 4-imidazol-1-yl-6-pyridin-3-yl-pyran-2-one

4-하이드록시-6-(3-피리딜)-피란-2-온(520mg, 2.749mmol)을 실시예 1)의 d)와 동일한 방법으로 반응시켜 연한 노란색 고체상의 표제화합물(455mg, 68.4%)을 얻었다.4-hydroxy-6- (3-pyridyl) -pyran-2-one (520 mg, 2.749 mmol) was reacted in the same manner as d) of Example 1) to give the title compound (455 mg, 68.4%) as a pale yellow solid. )

1H-NMR(CDCl3+MeOH-d4); δ = 9.02(d, 1H), 8.66(dd, 1H), 8.11(m, 1H), 7.42 (dd, 1H), 6.57(d, 1H), 5.58(d, 1H) 1 H-NMR (CDCl 3 + MeOH-d 4 ); δ = 9.02 (d, 1H), 8.66 (dd, 1H), 8.11 (m, 1H), 7.42 (dd, 1H), 6.57 (d, 1H), 5.58 (d, 1H)

d) 1-아미노-4-이미다졸-1-일-1d) 1-amino-4-imidazol-1-yl-1 HH -[2,3']바이피리디닐-6-온의 합성Synthesis of-[2,3 '] bipyridinyl-6-one

4-이미다졸-1-일-6-피리딘-3-일-피란-2-온(43mg, 0.167mmol)을 실시예 1)의 e)와 동일한 방법으로 반응시켜 연한 노란색 고체상의 표제화합물(25mg, 59.5%)을 얻었다.4-Imidazol-1-yl-6-pyridin-3-yl-pyran-2-one (43 mg, 0.167 mmol) was reacted in the same manner as in e) of Example 1) to give the title compound as a pale yellow solid (25 mg). , 59.5%).

1H-NMR(DMSO-d4); δ = 8.85(d, 1H), 8.66(dd, 1H), 8.51(s, 1H), 8.11(m, 1H), 7.96(s, 1H), 7.54(m, 1H), 7.13(s, 1H), 6.96(d, 1H), 6.86(d, 1H), 5.78(s, 2H) 1 H-NMR (DMSO-d 4 ); δ = 8.85 (d, 1H), 8.66 (dd, 1H), 8.51 (s, 1H), 8.11 (m, 1H), 7.96 (s, 1H), 7.54 (m, 1H), 7.13 (s, 1H) , 6.96 (d, 1H), 6.86 (d, 1H), 5.78 (s, 2H)

MS(ESI); 254(M++1)
MS (ESI); 254 (M + +1)

실시예 20 Example 20

1-아미노-4-이미다졸-1-일-11-amino-4-imidazol-1-yl-1 HH -[2,4']바이피리디닐-6-온(화합물 20)의 합성Synthesis of-[2,4 '] bipyridinyl-6-one (Compound 20)

a) 에틸 5-(4-피리딜)-3,5-디옥소펜타노에이트의 합성a) Synthesis of ethyl 5- (4-pyridyl) -3,5-dioxopentanoate

메틸 이소니코티네이트(18.3g, 0.133mol)를 실시예 18)의 a)와 동일한 방법 으로 반응시켜 갈색 액상의 표제화합물(23.54g, 75.0%)을 얻었다.Methyl isonicotinate (18.3 g, 0.133 mol) was reacted in the same manner as in a) of Example 18) to obtain a brown liquid title compound (23.54 g, 75.0%).

1H-NMR(CDCl3); δ = 15.28(bs, 1H), 8.76(d, 1H), 7.67(dd, 1H), 6.35(s, 1H), 4.23(q, 2H), 3.52(s, 2H), 1.31(t, 3H) 1 H-NMR (CDCl 3 ); δ = 15.28 (bs, 1H), 8.76 (d, 1H), 7.67 (dd, 1H), 6.35 (s, 1H), 4.23 (q, 2H), 3.52 (s, 2H), 1.31 (t, 3H)

b) 4-하이드록시-6-(4-피리딜)-피란-2-온의 합성b) Synthesis of 4-hydroxy-6- (4-pyridyl) -pyran-2-one

에틸 5-(4-피리딜)-3,5-디옥소펜타노에이트(4.1g, 17.429mmol)를 실시예 18)의 b)와 동일한 방법으로 반응시켜 연한 노란색 고체상의 표제화합물(2.15g, 65.2%)을 얻었다.Reaction of ethyl 5- (4-pyridyl) -3,5-dioxopentanoate (4.1 g, 17.429 mmol) in the same manner as b) of Example 18) gave the title compound (2.15 g, 65.2%).

1H-NMR(DMSO-d4); δ = 12.05(bs, 1H), 8.72(d, 2H), 7.80(d, 2H), 7.02(s, 2H), 5.50(s, 1H) 1 H-NMR (DMSO-d 4 ); δ = 12.05 (bs, 1H), 8.72 (d, 2H), 7.80 (d, 2H), 7.02 (s, 2H), 5.50 (s, 1H)

c) 4-이미다졸-1-일-6-피리딘-4-일-피란-2-온의 합성c) Synthesis of 4-imidazol-1-yl-6-pyridin-4-yl-pyran-2-one

4-하이드록시-6-(4-피리딜)-피란-2-온(1.75mg, 9.251mmol)을 실시예 1)의 d)와 동일한 방법으로 반응시켜 연한 노란색 고체상의 표제화합물(1.32mg, 59.7%)을 얻었다.4-hydroxy-6- (4-pyridyl) -pyran-2-one (1.75 mg, 9.251 mmol) was reacted in the same manner as d) of Example 1) to give the title compound (1.32 mg, 59.7%).

1H-NMR(CDCl3); δ = 8.83(dd, 2H), 8.01(s, 1H), 7.73(dd, 2H), 7.38(s, 1H), 7.31(s, 1H), 6.97(d, 1H), 6.35(d, 1H) 1 H-NMR (CDCl 3 ); δ = 8.83 (dd, 2H), 8.01 (s, 1H), 7.73 (dd, 2H), 7.38 (s, 1H), 7.31 (s, 1H), 6.97 (d, 1H), 6.35 (d, 1H)

d) 1-아미노-4-이미다졸-1-일-1d) 1-amino-4-imidazol-1-yl-1 HH -[2,4']바이피리디닐-6-온의 합성Synthesis of-[2,4 '] bipyridinyl-6-one

4-이미다졸-1-일-6-피리딘-4-일-피란-2-온(90mg, 0.0376mmol)을 실시예 1)의 e)와 동일한 방법으로 반응시켜 연한 노란색 고체상의 표제화합물(66mg, 69.5%)을 얻었다.4-Imidazol-1-yl-6-pyridin-4-yl-pyran-2-one (90 mg, 0.0376 mmol) was reacted in the same manner as in e) of Example 1) to give the title compound as a pale yellow solid (66 mg). , 69.5%).

1H-NMR(DMSO-d4); δ = 8.73(d, 2H), 8.51(s, 1H), 7.96(s, 1H), 7.69(d, 2H), 7.13(s, 1H), 6.98(d, 1H), 6.84(d, 1H), 5.78(s, 2H) 1 H-NMR (DMSO-d 4 ); δ = 8.73 (d, 2H), 8.51 (s, 1H), 7.96 (s, 1H), 7.69 (d, 2H), 7.13 (s, 1H), 6.98 (d, 1H), 6.84 (d, 1H) , 5.78 (s, 2H)

MS(ESI); 254(M++1)
MS (ESI); 254 (M + +1)

실시예 21 Example 21

1-아미노-4-이미다졸-1-일-6-(4-메톡시-페닐)-11-amino-4-imidazol-1-yl-6- (4-methoxy-phenyl) -1 HH -피리딘-2-온(화합물 21)의 합성Synthesis of Pyridin-2-one (Compound 21)

a) 5-(4-메톡시-페닐)-3,5-디옥소-펜타노산의 합성a) Synthesis of 5- (4-methoxy-phenyl) -3,5-dioxo-pentanoic acid

메틸 4-메톡시벤조에이트(20g, 0.120mol)를 실시예 1)의 a)와 동일한 방법으로 반응시켜 노란색 고체상의 표제화합물(21.0g, 73.9%)을 얻었다.Methyl 4-methoxybenzoate (20 g, 0.120 mol) was reacted in the same manner as in a) of Example 1), to obtain the title compound (21.0 g, 73.9%) as a yellow solid.

1H-NMR(CDCl3); δ = 12.62(bs, 1H), 7.92(d, 2H), 7.06(d, 2H), 6.55(s, 1H), 3.80(s, 3H), 3.47(s, 2H) 1 H-NMR (CDCl 3 ); δ = 12.62 (bs, 1H), 7.92 (d, 2H), 7.06 (d, 2H), 6.55 (s, 1H), 3.80 (s, 3H), 3.47 (s, 2H)

b) 4-하이드록시-6-(4-메톡시-페닐)-피란-2-온의 합성b) Synthesis of 4-hydroxy-6- (4-methoxy-phenyl) -pyran-2-one

5-(4-메톡시-페닐)-3,5-디옥소-펜타노산(19g, 31.750mmol)을 실시예 18)의 b)와 동일한 방법으로 반응시켜 연한 노란색 고체상의 표제화합물(5.8g, 83.7%)을 얻었다.5- (4-methoxy-phenyl) -3,5-dioxo-pentanoic acid (19 g, 31.750 mmol) was reacted in the same manner as b) of Example 18) to give the title compound (5.8 g, 83.7%).

1H-NMR(DMSO-d6); δ = 11.75(bs, 1H), 7.82(d, 2H), 7.07(d, 2H), 6.62(s, 1H), 5.33(s, 1H), 3.82(s, 3H) 1 H-NMR (DMSO-d 6 ); δ = 11.75 (bs, 1H), 7.82 (d, 2H), 7.07 (d, 2H), 6.62 (s, 1H), 5.33 (s, 1H), 3.82 (s, 3H)

c) 4-브로모-6-(4-메톡시-페닐)-피란-2-온의 합성c) Synthesis of 4-bromo-6- (4-methoxy-phenyl) -pyran-2-one

4-하이드록시-6-(4-메톡시-페닐)-피란-2-온(3.5g, 16.040mmol)을 실시예 1)의 c)와 동일한 방법으로 반응시켜 연한 노란색 고체상의 표제화합물(3.4g, 75.4%)을 얻었다.4-hydroxy-6- (4-methoxy-phenyl) -pyran-2-one (3.5 g, 16.040 mmol) was reacted in the same manner as in c) of Example 1) to give the title compound (3.4) as a pale yellow solid. g, 75.4%).

1H-NMR(DMSO-d6); δ = 7.87(d, 2H), 7.30(s, 1H), 7.07(d, 2H), 6.67(s, 1H), 3.84(s, 1H) 1 H-NMR (DMSO-d 6 ); δ = 7.87 (d, 2H), 7.30 (s, 1H), 7.07 (d, 2H), 6.67 (s, 1H), 3.84 (s, 1H)

d) 4-이미다졸-1-일-6-(4-메톡시-페닐)-피란-2-온의 합성d) Synthesis of 4-imidazol-1-yl-6- (4-methoxy-phenyl) -pyran-2-one

4-브로모-6-(4-메톡시-페닐)-피란-2-온(3.4mg, 12.095mmol)을 실시예 1)의 d)와 동일한 방법으로 반응시켜 연한 노란색 고체상의 표제화합물(2.7mg, 83.3%)을 얻었다.4-Bromo-6- (4-methoxy-phenyl) -pyran-2-one (3.4 mg, 12.095 mmol) was reacted in the same manner as in d) of Example 1) to give the title compound (2.7) as a pale yellow solid. mg, 83.3%).

1H-NMR(DMSO-d6); δ = 8.78(s, 1H), 8.18(s, 1H), 8.05(d, 2H), 7.59(s, 2H), 7.21(s, 1H), 7.08(d, 2H), 6.68(s, 1H), 3.83(s, 3H) 1 H-NMR (DMSO-d 6 ); δ = 8.78 (s, 1H), 8.18 (s, 1H), 8.05 (d, 2H), 7.59 (s, 2H), 7.21 (s, 1H), 7.08 (d, 2H), 6.68 (s, 1H) , 3.83 (s, 3H)

e) 1-아미노-4-이미다졸-1-일-6-(4-메톡시-페닐)-1e) 1-amino-4-imidazol-1-yl-6- (4-methoxy-phenyl) -1 HH -피리딘-2-온의 합성Synthesis of -pyridin-2-one

4-이미다졸-1-일-6-(4-메톡시-페닐)-피란-2-온(390mg, 1.454mmol)을 실시예 1)의 e)와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(312mg, 76.1%)을 얻었다.4-Imidazol-1-yl-6- (4-methoxy-phenyl) -pyran-2-one (390 mg, 1.454 mmol) was reacted in the same manner as in e) of Example 1) to give the title compound as a white solid. (312 mg, 76.1%) was obtained.

1H-NMR(DMSO-d6); δ = 8.50(s, 1H), 7.95(s, 1H), 7.63(d, 2H), 7.11(s, 1H), 7.03(d, 2H), 6.97(d, 1H), 6.72(d, 1H), 5.83(s, 2H), 3.82(s, 3H) 1 H-NMR (DMSO-d 6 ); δ = 8.50 (s, 1H), 7.95 (s, 1H), 7.63 (d, 2H), 7.11 (s, 1H), 7.03 (d, 2H), 6.97 (d, 1H), 6.72 (d, 1H) , 5.83 (s, 2H), 3.82 (s, 3H)

MS(ESI); 283(M++1)
MS (ESI); 283 (M + +1)

실시예 22 Example 22

1-아미노-6-사이클로헥실-4-(4-하이드록시메틸-페닐)-11-amino-6-cyclohexyl-4- (4-hydroxymethyl-phenyl) -1 HH -피리딘-2-온(화합물22)의 합성Synthesis of Pyridin-2-one (Compound 22)

a) 6-사이클로헥실-4-(4-하이드록시메틸-페닐)-피란-2-온의 합성a) Synthesis of 6-cyclohexyl-4- (4-hydroxymethyl-phenyl) -pyran-2-one

환류장치를 한 플라스크(50㎖)에서 실시예 11)의 c)에서 얻은 4-브로모-6-사이클로헥실-피란-2-온(500mg, 1.945mmol)을 톨루엔(15㎖)과 에탄올(3㎖)에 희석시킨 후, 여기에 4-(하이드록시메틸)벤젠보론산(325mg, 2.140mmol), 테트라키스(트리페닐포스핀)팔라듐(Pd(PPh3)4)(112mg, 0.0973mmol), 및 나트륨 카보네이트(2M in water, 2.14㎖, 4.279mmol)를 적가하고 가열하여 5시간 동안 환류시켰다. 반응용액을 실온으로 냉각시킨 후 물을 적가하여 반응을 종결시킨 후 반응용액을 감압하에 증류하고 에틸 아세테이트를 이용하여 추출한 다음 추출액은 MgSO4로 건조, 여과한 후 감압하에 증류하였다. 잔사는 에틸 아세테이트/n-헥산=1/1(v/v) 용매로 용출하는 실리카 겔 칼럼 크로마토그래피로 정제한 후 생성물을 함유하는 분획을 합하고 증발시켜 흰색 고체상의 표제화합물(455mg, 82.3%)을 얻었다.In a flask (50 ml) with reflux, 4-bromo-6-cyclohexyl-pyran-2-one (500 mg, 1.945 mmol) obtained in c) of Example 11) was dissolved in toluene (15 ml) and ethanol (3). After dilution in 4-ml, 4- (hydroxymethyl) benzeneboronic acid (325 mg, 2.140 mmol), tetrakis (triphenylphosphine) palladium (Pd (PPh 3 ) 4 ) (112 mg, 0.0973 mmol), And sodium carbonate (2M in water, 2.14 mL, 4.279 mmol) was added dropwise and heated to reflux for 5 hours. After the reaction solution was cooled to room temperature, water was added dropwise to terminate the reaction. The reaction solution was distilled under reduced pressure, extracted with ethyl acetate, and the extract was dried over MgSO 4 , filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate / n-hexane = 1/1 (v / v) solvent, and then the fractions containing the product were combined and evaporated to give the titled compound as a white solid (455 mg, 82.3%). Got.

1H-NMR(CDCl3); δ = 7.56(d, 2H), 7.46(d, 2H), 6.30(d, 1H), 6.26(d, 1H), 4.77(s, 2H), 2.48(m, 1H), 2.20~1.850(m, 5H), 1.50~1.20(m, 5H) 1 H-NMR (CDCl 3 ); δ = 7.56 (d, 2H), 7.46 (d, 2H), 6.30 (d, 1H), 6.26 (d, 1H), 4.77 (s, 2H), 2.48 (m, 1H), 2.20-1.850 (m, 5H), 1.50-1.20 (m, 5H)

b) 1-아미노-6-사이클로헥실-4-(4-하이드록시메틸-페닐)-1b) 1-amino-6-cyclohexyl-4- (4-hydroxymethyl-phenyl) -1 HH -피리딘-2-온의 합성Synthesis of -pyridin-2-one

6-사이클로헥실-4-(4-하이드록시메틸-페닐)-피란-2-온(350mg, 1.231mmol)을 실시예 1)의 e)와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(278mg, 75.7%)을 얻었다.6-cyclohexyl-4- (4-hydroxymethyl-phenyl) -pyran-2-one (350 mg, 1.231 mmol) was reacted in the same manner as in e) of Example 1) to give the title compound (278 mg, 75.7%).

1H-NMR(DMSO-d6); δ = 7.65(d, 2H), 7.39(d, 2H), 6.59(d, 1H), 6.38(d, 1H), 5.93(d, 1H), 5.23(t, 1H), 4.55(d, 2H), 3.18(m, 1H), 1.99~1.80(m, 5H), 1.40~1.20(m, 5H) 1 H-NMR (DMSO-d 6 ); δ = 7.65 (d, 2H), 7.39 (d, 2H), 6.59 (d, 1H), 6.38 (d, 1H), 5.93 (d, 1H), 5.23 (t, 1H), 4.55 (d, 2H) , 3.18 (m, 1H), 1.99-1.80 (m, 5H), 1.40-1.20 (m, 5H)

MS(ESI); 299(M++1)
MS (ESI); 299 (M + +1)

실시예 23 Example 23

1-아미노-6-사이클로헥실-4-(3-하이드록시메틸-페닐)-11-amino-6-cyclohexyl-4- (3-hydroxymethyl-phenyl) -1 HH -피리딘-2-온(화합물23)의 합성Synthesis of Pyridin-2-one (Compound 23)

a) 6-사이클로헥실-4-(3-하이드록시메틸-페닐)-피란-2-온의 합성a) Synthesis of 6-cyclohexyl-4- (3-hydroxymethyl-phenyl) -pyran-2-one

3-(하이드록시메틸)벤젠보론산(325mg, 2.140mmol)과 실시예 11)의 c)에서 얻은 4-브로모-6-사이클로헥실-피란-2-온(500mg, 1.945mmol)을 실시예 22의 a)와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(400mg, 72.3%)을 얻었다. 4- (Bromo-6-cyclohexyl-pyran-2-one (500 mg, 1.945 mmol) obtained in c) of Example 11) with 3- (hydroxymethyl) benzeneboronic acid (325 mg, 2.140 mmol) The reaction was carried out in the same manner as in a) of 22, to obtain the title compound (400 mg, 72.3%) as a white solid.                     

1H-NMR(CDCl3); δ = 7.59(s, 1H), 7.47(d, 2H), 6.30(d, 1H), 6.27(d, 1H), 4.77(s, 2H), 2.45(m, 1H), 2.20~1.850(m, 5H), 1.50~1.20(m, 5H) 1 H-NMR (CDCl 3 ); δ = 7.59 (s, 1H), 7.47 (d, 2H), 6.30 (d, 1H), 6.27 (d, 1H), 4.77 (s, 2H), 2.45 (m, 1H), 2.20-1.850 (m, 5H), 1.50-1.20 (m, 5H)

b) 1-아미노-6-사이클로헥실-4-(3-하이드록시메틸-페닐)-1b) 1-amino-6-cyclohexyl-4- (3-hydroxymethyl-phenyl) -1 HH -피리딘-2-온의 합성Synthesis of -pyridin-2-one

6-사이클로헥실-4-(3-하이드록시메틸-페닐)-피란-2-온(395mg, 1.389mmol)을 를 실시예 1)의 e)와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(312mg, 75.4%)을 얻었다.6-cyclohexyl-4- (3-hydroxymethyl-phenyl) -pyran-2-one (395 mg, 1.389 mmol) was reacted in the same manner as in e) of Example 1) to give the title compound (312 mg) as a white solid. , 75.4%).

1H-NMR(DMSO-d6); δ = 7.57(s, 1H), 7.43(m, 3H), 6.67(d, 1H), 6.31(d, 1H), 5.09(bs, 1H), 4.77(s, 2H), 3.22(m, 1H), 2.00~1.85(m, 5H), 1.50~1.35(m, 5H) 1 H-NMR (DMSO-d 6 ); δ = 7.57 (s, 1H), 7.43 (m, 3H), 6.67 (d, 1H), 6.31 (d, 1H), 5.09 (bs, 1H), 4.77 (s, 2H), 3.22 (m, 1H) , 2.00 to 1.85 (m, 5H), 1.50 to 1.35 (m, 5H)

MS(ESI); 299(M++1)
MS (ESI); 299 (M + +1)

실시예 24 Example 24

1'-아미노-6'-페닐-1'H-[3,4']바이피리디닐-2'-온(화합물 24)의 합성Synthesis of 1'-amino-6'-phenyl-1'H- [3,4 '] bipyridinyl-2'-one (Compound 24)

a) 6-페닐-4-피리딘-3-일-피란-2-온의 합성a) Synthesis of 6-phenyl-4-pyridin-3-yl-pyran-2-one

실시예 1)의 c)에서 얻은 4-브로모-6-페닐-피란-2-온(50mg, 0.199mmol)과 피리딘-3-보론산(55mg, 0.448mmol)을 실시예 22)의 a)와 동일한 방법으로 반응시켜 연갈색 고체상의 표제화합물(40mg, 81%)을 얻었다. 4-bromo-6-phenyl-pyran-2-one (50 mg, 0.199 mmol) and pyridine-3-boronic acid (55 mg, 0.448 mmol) obtained in c) of Example 1) were prepared in Example 22). The reaction was carried out in the same manner as to obtain the title compound (40 mg, 81%) as a light brown solid.                     

1H-NMR(CDCl3); δ = 8.95(d, 1H), 8.78-8.74(m, 1H), 7.96-7.92(m, 1H), 7.72-7.68(m, 1H), 7.54-7.45(m, 5H), 6.95(d, 1H), 6.48(d, 1H) 1 H-NMR (CDCl 3 ); δ = 8.95 (d, 1H), 8.78-8.74 (m, 1H), 7.96-7.92 (m, 1H), 7.72-7.68 (m, 1H), 7.54-7.45 (m, 5H), 6.95 (d, 1H) ), 6.48 (d, 1 H)

b) 1'-아미노-6'-페닐-1'H-[3,4']바이피리디닐-2'-온의 합성b) Synthesis of 1'-amino-6'-phenyl-1'H- [3,4 '] bipyridinyl-2'-one

6-페닐-4-피리딘-3-일-피란-2-온(48mg, 0.193mmol)을 실시예 1)의 e)와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(24mg, 47%)을 얻었다.6-phenyl-4-pyridin-3-yl-pyran-2-one (48 mg, 0.193 mmol) was reacted in the same manner as in e) of Example 1) to obtain the title compound (24 mg, 47%) as a white solid. .

1H-NMR(CDCl3); δ = 8.90(d, 1H), 8.70-8.66(m, 1H), 7.92-7.86(m, 1H), 7.60-7.48(m, 5H), 7.42-7.38(m, 1H), 6.88(d, 1H), 6.42(d, 1H), 5.32(s, 2H) 1 H-NMR (CDCl 3 ); δ = 8.90 (d, 1H), 8.70-8.66 (m, 1H), 7.92-7.86 (m, 1H), 7.60-7.48 (m, 5H), 7.42-7.38 (m, 1H), 6.88 (d, 1H) ), 6.42 (d, 1 H), 5.32 (s, 2 H)

MS(ESI); 263(M+), 264(M++1)
MS (ESI); 263 (M + ), 264 (M + +1)

실시예 25Example 25

1'-아미노-6'-페닐-1'H-[4,4']바이피리디닐-2'-온(화합물 25)의 합성Synthesis of 1'-amino-6'-phenyl-1'H- [4,4 '] bipyridinyl-2'-one (Compound 25)

a) 6-페닐-4-피리딘-4-일-피란-2-온의 합성a) Synthesis of 6-phenyl-4-pyridin-4-yl-pyran-2-one

실시예 1)의 c)에서 얻은 4-브로모-6-페닐-피란-2-온(50mg, 0.199mmol)과 피리딘-4-보론산(55mg, 0.448mmol)을 실시예 22의 a)와 동일한 방법으로 반응시켜 연갈색 고체상의 표제화합물(30mg, 61%)을 얻었다.4-Bromo-6-phenyl-pyran-2-one (50 mg, 0.199 mmol) and pyridin-4-boronic acid (55 mg, 0.448 mmol) obtained in Example c) of Example 1) were prepared. The reaction was carried out in the same manner to obtain the title compound (30 mg, 61%) as a light brown solid.

1H-NMR(CDCl3); δ = 8.82-8.78(m, 2H), 7.94-7.90(m, 2H), 7.56-7.50(m, 5H), 6.92(d, 1H), 6.52(d, 1H) 1 H-NMR (CDCl 3 ); δ = 8.82-8.78 (m, 2H), 7.94-7.90 (m, 2H), 7.56-7.50 (m, 5H), 6.92 (d, 1H), 6.52 (d, 1H)

b) 1'-아미노-6'-페닐-1'H-[4,4']바이피리디닐-2'-온의 합성b) Synthesis of 1'-amino-6'-phenyl-1'H- [4,4 '] bipyridinyl-2'-one

6-페닐-4-피리딘-4-일-피란-2-온(17mg, 0.0682mmol)을 실시예 1)의 e)와 동일한 방법으로 반응시켜 미황색 고체상의 표제화합물(9mg, 50%)을 얻었다.6-phenyl-4-pyridin-4-yl-pyran-2-one (17 mg, 0.0682 mmol) was reacted in the same manner as in e) of Example 1) to obtain the title compound (9 mg, 50%) as a pale yellow solid. .

1H-NMR(CDCl3); δ = 8.74-8.70(m, 2H), 7.58-7.42(m, 7H), 6.92(d, 1H), 6.42(d, 1H), 5.35(s, 2H) 1 H-NMR (CDCl 3 ); δ = 8.74-8.70 (m, 2H), 7.58-7.42 (m, 7H), 6.92 (d, 1H), 6.42 (d, 1H), 5.35 (s, 2H)

MS(ESI); 263(M+)
MS (ESI); 263 (M + )

실시예 26 Example 26

1-아미노-4-이미다졸-1-일-6-m-톨릴-11-amino-4-imidazol-1-yl-6-m-tolyl-1 HH -피리딘-2-온(화합물 26)의 합성Synthesis of Pyridin-2-one (Compound 26)

a) 4-하이드록시-6-m-톨릴-피란-2-온의 합성a) Synthesis of 4-hydroxy-6-m-tolyl-pyran-2-one

실시예 1)의 a), b)와 동일한 방법으로 3-메틸-벤조산 에틸에스테르(12g, 80 mmol)를 반응시켜 연갈색 고체상의 표제화합물(7.4g, 45.8%)을 얻었다.3-methyl-benzoic acid ethyl ester (12 g, 80 mmol) was reacted in the same manner as in a) and b) of Example 1) to obtain the title compound (7.4 g, 45.8%) as a light brown solid.

1H-NMR (CD3OD); δ = 7.63-7.68(2H, m), 7.33-7.37(2H, m), 6.66(1H, s), 5.47 (1H, d, J = 1.8 Hz), 2.41(3H, s) 1 H-NMR (CD 3 OD); δ = 7.63-7.68 (2H, m), 7.33-7.37 (2H, m), 6.66 (1H, s), 5.47 (1H, d, J = 1.8 Hz), 2.41 (3H, s)

b) 4-브로모-6-m-톨릴-피란-2-온의 합성b) Synthesis of 4-bromo-6-m-tolyl-pyran-2-one

실시예 1)의 c)와 동일한 방법으로 4-하이드록시-6-m-톨릴-피란-2-온(5.0g, 24.7mmol)을 반응시켜 연갈색 고체상의 표제화합물(5.0g, 76.2%)을 얻었다.In the same manner as in c) of Example 1), 4-hydroxy-6-m-tolyl-pyran-2-one (5.0 g, 24.7 mmol) was reacted to obtain the title compound (5.0 g, 76.2%) as a light brown solid. Got it.

1H-NMR (CDCl3); δ = 7.60-7.64(2H, m), 7.26-7.35(2H, m), 6.81(1H, d, J = 1.8 Hz), 6.56(1H, d, J = 1.8 Hz), 2.41(3H, s) 1 H-NMR (CDCl 3 ); δ = 7.60-7.64 (2H, m), 7.26-7.35 (2H, m), 6.81 (1H, d, J = 1.8 Hz), 6.56 (1H, d, J = 1.8 Hz), 2.41 (3H, s)

c) 4-이미다졸-1-일-6-m-톨릴-피란-2-온의 합성c) Synthesis of 4-imidazol-1-yl-6-m-tolyl-pyran-2-one

실시예 1)의 d)와 동일한 방법으로 4-브로모-6-m-톨릴-피란-2-온(1.5g, 5.66 mmol)을 반응시켜 흰색 고체상의 표제화합물(600mg, 42%)을 얻었다.In the same manner as in d) of Example 1), 4-bromo-6-m-tolyl-pyran-2-one (1.5 g, 5.66 mmol) was reacted to obtain the title compound (600 mg, 42%) as a white solid. .

1H-NMR (CDCl3); δ = 8.06(1H, s), 7.68-7.72(2H, m), 7.26-7.40(4H, m), 6.81(1H, d, J = 1.8 Hz), 6.22(1H, d, J = 1.8 Hz), 2.45(3H, s) 1 H-NMR (CDCl 3 ); δ = 8.06 (1H, s), 7.68-7.72 (2H, m), 7.26-7.40 (4H, m), 6.81 (1H, d, J = 1.8 Hz), 6.22 (1H, d, J = 1.8 Hz) , 2.45 (3H, s)

d) 1-아미노-4-이미다졸-1-일-6-m-톨릴-1d) 1-amino-4-imidazol-1-yl-6-m-tolyl-1 HH -피리딘-2-온의 합성Synthesis of -pyridin-2-one

실시예 1)의 e)와 동일한 방법으로 4-이미다졸-1-일-6-m-톨릴-피란-2-온 (200mg, 0.79 mmol)을 반응시켜 흰색 고체상의 표제화합물(43mg, 20%)을 얻었다.In the same manner as in e) of Example 1), 4-imidazol-1-yl-6-m-tolyl-pyran-2-one (200 mg, 0.79 mmol) was reacted to give the title compound as a white solid (43 mg, 20%). )

1H-NMR (CDCl3); δ = 7.94(1H, s), 7.22-7.41(6H, m), 6.64(1H, d, J = 3.0 Hz), 6.30(1H, d, J = 3.3 Hz), 5.27(2H, s), 2.45(3H, s) 1 H-NMR (CDCl 3 ); δ = 7.94 (1H, s), 7.22-7.41 (6H, m), 6.64 (1H, d, J = 3.0 Hz), 6.30 (1H, d, J = 3.3 Hz), 5.27 (2H, s), 2.45 (3H, s)

MS (ESI): 267 (M++1)
MS (ESI): 267 (M + +1)

실시예 27 Example 27

1-아미노-4-이미다졸-1-일-6-(3-트리플루오로메틸-페닐)-11-amino-4-imidazol-1-yl-6- (3-trifluoromethyl-phenyl) -1 HH -피리딘-2-온(화합물 27)의 합성Synthesis of Pyridin-2-one (Compound 27)

a) 4-하이드록시-6-(3-트리플루오로메틸-페닐)-피란-2-온의 합성a) Synthesis of 4-hydroxy-6- (3-trifluoromethyl-phenyl) -pyran-2-one

3-트리플루오로메틸-벤조산 메틸에스테르(12.97g, 0.0635mole)와 3-옥소-부티르산 에틸에스테르(8.85㎖, 0.0699mole)를 실시예 1)의 a)과 동일한 방법으로 반 응시켜 황색 고체상의 3,5-디옥소-5-(3-트리플루오로메틸-페닐)-펜타노산(10g, 57%)을 얻고, 이것을 다시 실시예 1)의 b)과 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(7.8g, 83%)을 얻었다.3-trifluoromethyl-benzoic acid methyl ester (12.97 g, 0.0635 mole) and 3-oxo-butyric acid ethyl ester (8.85 mL, 0.0699 mole) were reacted in the same manner as in a) of Example 1) to give a yellow solid. 3,5-dioxo-5- (3-trifluoromethyl-phenyl) -pentanoic acid (10 g, 57%) was obtained, which was reacted in the same manner as in b) of Example 1) to give the title of a white solid. Compound (7.8 g, 83%) was obtained.

1H-NMR(CDCl3); δ = 8.08(s, 1H), 8.04-8.00(m, 1H), 7.75-7.58(m, 2H), 6.58(d, 1H), 5.54(d, 1H) 1 H-NMR (CDCl 3 ); δ = 8.08 (s, 1H), 8.04-8.00 (m, 1H), 7.75-7.58 (m, 2H), 6.58 (d, 1H), 5.54 (d, 1H)

b) 4-이미다졸-1-일-6-(3-트리플루오로메틸-페닐)-피란-2-온의 합성b) Synthesis of 4-imidazol-1-yl-6- (3-trifluoromethyl-phenyl) -pyran-2-one

4-하이드록시-6-(3-트리플루오로메틸-페닐)-피란-2-온(4.3g, 0.0168mole)을 실시예 18)의 c)과 동일한 방법으로 반응시켜 황색 고체상의 표제화합물(2.6g, 51%)을 얻었다.4-hydroxy-6- (3-trifluoromethyl-phenyl) -pyran-2-one (4.3 g, 0.0168 mole) was reacted in the same manner as in c) of Example 18), to give the title compound as a yellow solid ( 2.6 g, 51%).

1H-NMR(CDCl3); δ = 8.15-8.06(m, 3H), 7.83-7.79(m, 1H), 7.70-7.64(m, 1H), 7.40(d, 1H), 7.32(d, 1H), 6.88(d, 1H), 6.30(d, 1H) 1 H-NMR (CDCl 3 ); δ = 8.15-8.06 (m, 3H), 7.83-7.79 (m, 1H), 7.70-7.64 (m, 1H), 7.40 (d, 1H), 7.32 (d, 1H), 6.88 (d, 1H), 6.30 (d, 1 H)

c) 1-아미노-4-이미다졸-1-일-6-(3-트리플루오로메틸-페닐)-1c) 1-amino-4-imidazol-1-yl-6- (3-trifluoromethyl-phenyl) -1 HH -피리딘-2-온 의 합성Of pyridine-2-one

4-이미다졸-1-일-6-(3-트리플루오로메틸-페닐)-피란-2-온(380mg, 1.241mmol)을 실시예 1)의 e)과 동일한 방법으로 반응시켜 미황색 고체상의 표제화합물 (215mg, 54%)을 얻었다.4-Imidazol-1-yl-6- (3-trifluoromethyl-phenyl) -pyran-2-one (380 mg, 1.241 mmol) was reacted in the same manner as in e) of Example 1) to give a slightly yellow solid phase. The title compound (215 mg, 54%) was obtained.

1H-NMR(CDCl3); δ = 7.96(s, 1H), 7.84-7.74(m, 3H), 7.70-7.64(m, 1H), 7.32(d, 1H), 7.24(d, 1H), 6.68(d, 1H), 6.32(d, 1H), 5.08(s, 2H) 1 H-NMR (CDCl 3 ); δ = 7.96 (s, 1H), 7.84-7.74 (m, 3H), 7.70-7.64 (m, 1H), 7.32 (d, 1H), 7.24 (d, 1H), 6.68 (d, 1H), 6.32 ( d, 1H), 5.08 (s, 2H)

MS(ESI); 321(M++1)
MS (ESI); 321 (M + +1)

실험예 1Experimental Example 1

LPDE4(Low Affinity for Rolipram, 롤리프람 저친화성) 억제활성LPDE4 (Low Affinity for Rolipram)

SD 렛트(수컷, 200-300g)의 폐를 적출한 뒤, 곧바로 적출 완충액(50mM 트리스HCl(pH 6.5), 2mM EDTA, 5mM 2-메르캅토에탄올, 2mM 벤즈아미딘, 10μM 류펩틴)으로 옮기고 난 다음, 먼저 가위로 일차 세절하고 폴리트론(polytron)을 이용하여 균질화하였다. 위에서 얻어진 균질화물을 35000g에서 1시간 동안 원심분리하고, 그 상층액을 디에틸아미노에틸(DEAE)-세파로즈(sepharose) 컬럼에 주입하여 연속적으로 50-1000mM의 나트륨 아세테이트 농도 경사 하에 PDE4 효소를 용출시켰다(유속: 3㎖/분, 분별증류 부피: 5㎖). 각각의 분획에 0.1%가 되도록 소 혈청 알부민을 넣어주고, PDE4 활성이 있는 분획을 모아 사용시까지 보관하였다.The lungs of SD rats (male, 200-300 g) were removed and immediately transferred to extraction buffer (50 mM TrisHCl (pH 6.5), 2 mM EDTA, 5 mM 2-mercaptoethanol, 2 mM benzamidine, 10 μM leupetin) Next, it was first sliced with scissors and homogenized using polytron. The homogenate obtained above was centrifuged at 35000 g for 1 hour, and the supernatant was injected into a diethylaminoethyl (DEAE) -sepharose column to continuously elute the PDE4 enzyme under a gradient of sodium acetate concentration of 50-1000 mM. (Flow rate: 3 ml / min, fractional distillation volume: 5 ml). Bovine serum albumin was added to each fraction to 0.1%, and fractions with PDE4 activity were collected and stored until use.

분석 완충액(50mM 트리스 HCl(pH 6.5), 5mM MgCl2, 4mM 2-메르캅토에탄올, 0.15mg/㎖ 소 혈청 알부민(BSA))을 제조하고, 분획에 남아 있는 PDE3 활성을 억제하기 위하여 모든 분석을 cGMP 존재하에 실시하였다. 총 반응량은 100㎕이고, 기질로 [3H]cAMP 0.25μM을 첨가하였고, 30℃에서 30분간 반응을 수행한 다음, 비등수에 1분간 담가두어 반응을 정지시키고, 바로 얼음위로 옮겼다. 여기에 뱀 독액 (5mg/㎖) 10㎕를 모든 웰(well)에 추가하여 30℃에서 20분간 추가 반응시켰다. 그 후, AG1-X8수지를 넣어 생성물인 [3H]아데노신을 분리하고, 방사활성을 섬광 계수기(scintillation counting)를 통하여 측정하였다. 각 농도에서 본 발명에 따른 화합물에 의해 억제된 양을 %로 나타내, 50% 억제시의 화합물 농도를 IC50값으로 산정하였다. 본 발명에 따른 화합물의 LPDE4 억제활성은 표 1에 나타내었다.
Assay buffer (50 mM Tris HCl (pH 6.5), 5 mM MgCl 2 , 4 mM 2-mercaptoethanol, 0.15 mg / ml bovine serum albumin (BSA)) was prepared and all assays were carried out to inhibit PDE3 activity remaining in the fractions. It was carried out in the presence of cGMP. The total reaction amount was 100 µl, and 0.25 µM of [ 3 H] cAMP was added as a substrate. The reaction was carried out at 30 ° C. for 30 minutes, and then immersed in boiling water for 1 minute to stop the reaction and immediately transferred onto ice. 10 μl of snake venom solution (5 mg / ml) was added to all wells, and further reacted at 30 ° C. for 20 minutes. Thereafter, AG1-X8 resin was added to separate [ 3 H] adenosine as a product, and radioactivity was measured by scintillation counting. The amount inhibited by the compound according to the invention at each concentration is expressed in% and the compound concentration at 50% inhibition was calculated as an IC 50 value. LPDE4 inhibitory activity of the compounds according to the invention is shown in Table 1.

실험예 2Experimental Example 2

HPDE4(High Affinity for Rolipram, 롤리프람 고친화성) 억제활성HPDE4 (High Affinity for Rolipram) inhibitory activity

SD 렛트(수컷, 200-300g)의 뇌를 적출한 뒤, 곧바로 적출 완충액(50mM 트리스 HCl(pH 8.0), 2mM MgCl2, 0.1mM DTT, 10μM 류펩틴)으로 옮긴 다음, 먼저 가위로 일차 세절하고 폴리트론을 이용하여 균질화하였다. 위에서 얻어진 균질화물을 45000g에서 1시간 동안 원심분리하고, 얻어진 펠릿을 완충액(50mM 트리스 HCl(pH 8.0), 2mM MgCl2)에 재현탁시킨 후, 분주하여 사용시까지 -20℃에 보관하였다.The brains of SD rats (males, 200-300 g) were removed and immediately transferred to extraction buffer (50 mM Tris HCl (pH 8.0), 2 mM MgCl 2 , 0.1 mM DTT, 10 μM Lupeptin), followed by first slicing with scissors. Homogenized using polytron. The homogenate obtained above was centrifuged at 45000 g for 1 hour, and the resulting pellet was resuspended in buffer (50 mM Tris HCl (pH 8.0), 2 mM MgCl 2 ), then aliquoted and stored at -20 ° C until use.

분석 완충액(50mM 트리스 HCl(pH 8.0), 5mM MgCl2, 0.05mM 5'-AMP)을 제조하고, 총 반응량은 200㎕로 하였으며, 뇌 균질화물은 웰 당 200㎍씩 첨가하였다. 최종적으로 [3H]-(±)롤리프람을 3nM이 되도록 추가하여 30℃에서 1시간동안 배양한 다음, 결합된 롤리프람은 원심분리(3000rpm, 3 분)에 의한 여과방법으로 분리하였다. 비특이적 결합은 RP73401 10μM 존재 하에 측정하였다. 방사활성은 섬광 계수기를 통하여 측정하였고, 각 농도의 본 발명 화합물에 의해 감소된 방사활성의 양을 %로나타냄으로써, 50% 억제시의 화합물 농도를 IC50값으로 산정하였다. 본 발명에 따른 화합물의 HPDE4 억제활성은 표 1에 나타내었다. Assay buffer (50 mM Tris HCl (pH 8.0), 5 mM MgCl 2 , 0.05 mM 5′-AMP) was prepared, total reaction volume was 200 μl and brain homogenate was added at 200 μg per well. Finally, [ 3 H]-(±) rolipram was added to 3 nM and incubated at 30 ° C. for 1 hour, and the combined roliprams were separated by filtration by centrifugation (3000 rpm, 3 minutes). . Nonspecific binding was measured in the presence of 10 μM of RP73401. Radioactivity was measured through a scintillation counter and the compound concentration at 50% inhibition was calculated as an IC 50 value by expressing the amount of radioactivity reduced by the compound of the present invention at each concentration. The HPDE4 inhibitory activity of the compounds according to the invention is shown in Table 1.

화합물 번호Compound number LPDE4(nM) 또는
10-5M에서의 억제율(%)LPDE4 (nM) or
% Inhibition at 10 -5 M HPDE4(nM) 또는
10-5M에서의 억제율(%)HPDE4 (nM) or
% Inhibition at 10 -5 M 1One 17.5%17.5% 363363 33 16%16% 174174 44 6.1%6.1% 25202520 55 4440044400 292292 66 3390033900 3838 77 6040060400 386386 88 6670066700 36103610 99 4100041000 493493 1111 1560015600 12201220 1212 9100091000 34903490 1313 3420034200 501501 1414 6200062000 365365 1616 5550055500 33603360 1717 6080060800 36803680 1919 -0.90%-0.90% 82308230 2020 14%14% 13411341 2121 4.4%4.4% 56805680 2222 1420014200 704704 2323 1240012400 962962 2424 2100021000 16561656 2525 2360023600 848848 2626 4180041800 13101310 2727 6090060900 936936

실험예 3Experimental Example 3

마우스에서 LPS-유도된 호중구성 염증(neutrophilic inflammation)LPS-induced neutrophilic inflammation in mice

balb/c 마우스(암컷, 20g)에 케타민(ketamin)과 자일라진(Zylazine)이 혼합된 마취제를 복강내 투여하여 마취시킨 후, 리포폴리사카라이드 (Lipopolysaccharide; LPS)를 500ng/50㎕의 농도로 10분 간격으로 2회 기관내에 직접 투여하였다. 약물은 LPS 투여하기 1시간 전에 경구로 투여하였다. LPS를 투여한지 18시간 후에 식염수(saline)를 사용하여 Bronchoalveolar lavage(BAL)를 취하고 12,000 rpm에서 2분간 원심분리하였다. 상층액은 버리고, 펠렛에 들어 있는 세포들 을 식염수로 재현탁시킨 후, 메틸렌 블루(methylene blue)로 염색하여 전체 세포수를 세었다. 약물이 투여되지 않은 대조군에서 계수된 총 염증세포수를 100%로 하고, 약물 투여군에서의 감소된 염증세포를 %로 나타냄으로써 50% 억제시의 약물 농도를 ED50값으로 산정하였다.Balb / c mice (female, 20g) were anesthetized by intraperitoneal administration of an anesthetic mixed with ketamine and xylazine, followed by lipopolysaccharide (LPS) at a concentration of 500ng / 50μl. Administration was directly intratracheally twice at 10 minute intervals. The drug was administered orally 1 hour prior to LPS administration. Eighteen hours after LPS administration, Bronchoalveolar lavage (BAL) was taken using saline and centrifuged at 12,000 rpm for 2 minutes. The supernatant was discarded, the cells in the pellet were resuspended in saline, and then stained with methylene blue to count the total number of cells. The total inflammatory cell count counted in the control group not administered with the drug was 100%, and the reduced inflammatory cell count in the drug administration group was expressed as%, and the drug concentration at 50% inhibition was calculated as the ED 50 value.

본 발명에 따른 화합물의 ED50값을 하기 표 2에 나타내었다. 표 2에서 비교 물질로 사용된 하기 구조의 화합물은 본 출원인에 의한 선행 출원 PCT/KR2003/002615호의 실시예 19에 개시된 화합물이다.The ED 50 values of the compounds according to the invention are shown in Table 2 below. The compound of the following structure used as comparative material in Table 2 is the compound disclosed in Example 19 of the prior application PCT / KR2003 / 002615 by the applicant.

Figure 112004022905826-pat00011
Figure 112004022905826-pat00011

화합물compound In vivo COPD model (ED50) In vivo COPD model (ED50) PCT/KR2003/002615호
실시예 19 화합물PCT / KR2003 / 002615
Example 19 Compound 37mg/kg p.o.37 mg / kg p.o. 화합물 1Compound 1 7.7mg/kg p.o.7.7 mg / kg p.o. 화합물 6Compound 6 7.5mg/kg p.o.7.5 mg / kg p.o. 화합물 13Compound 13 9.53mg/kg p.o.9.53 mg / kg p.o.

상기 표 1의 결과로부터 알 수 있듯이, 본 발명에 따른 화합물은 강력한 PDE4 억제활성을 나타내고 있다. 또한, 상기 표 2의 결과에 의해 본원 발명의 가장 근접한 선행기술이라 할 수 있는 선행특허출원 제PCT/KR2003/002615호에 개시된 화합물에 비해서도 본 발명의 화합물이 생체내 염증억제에 있어 매우 우수한 활성을 나타냄을 확인할 수 있다. 또한, 본 발명의 화합물은 치료 농도에서 구토나 구역질이 나타나지 않으며, 따라서 직접적인 기관지 이완작용과 항염증작용을 통해 COPD 질환의 급성 악화를 막고, 환자의 삶의 질을 개선시키며, 무엇보다도 질병의 점진적인 악화를 치료할 수 있다.As can be seen from the results of Table 1, the compound according to the present invention exhibits a potent PDE4 inhibitory activity. In addition, as a result of Table 2, the compound of the present invention has a very excellent activity in inhibiting inflammation in vivo, compared to the compound disclosed in the prior patent application PCT / KR2003 / 002615, which is the closest prior art of the present invention. It can be seen that. In addition, the compounds of the present invention do not show vomiting or nausea at therapeutic concentrations, thus preventing acute exacerbation of COPD disease, improving the quality of life of patients, and, above all, progressive disease through direct bronchial relaxation and anti-inflammatory action. It can cure exacerbations.

Claims (10)

하기 화학식 1의 1H-피리딘-2-온 화합물(단, 1-아미노-4,6-디페닐-2-피리돈은 제외한다) 또는 약제학적으로 허용되는 그의 염:1 H -pyridin-2-one compound of formula (1), except 1-amino-4,6-diphenyl-2-pyridone, or a pharmaceutically acceptable salt thereof: [화학식 1][Formula 1]
Figure 112011043092835-pat00012
Figure 112011043092835-pat00012
 상기 식에서In the above formula R1은 페닐, 이미다졸을 나타내며, 이들은 각각 할로겐 및 하이드록시-C1-C6-알킬로 구성된 그룹으로부터 선택된 1 또는 2개의 치환체에 의해 치환되거나 비치환되고, R 1 represents phenyl, imidazole, which are unsubstituted or substituted by one or two substituents selected from the group consisting of halogen and hydroxy-C 1 -C 6 -alkyl, respectively, R2는 C3-C8-사이클로알킬을 나타내거나, 페닐을 나타내거나, 피리딘을 나타내며, 이들은 각각 할로겐, 하이드록시, C1-C6-알킬, C1-C6-알콕시, 할로게노-C1-C6-알킬, 할로게노-C1-C6-알콕시, 및 C3-C8-사이클로알킬-C1-C6-알콕시로 구성된 그룹으로부터 선택된 1 또는 2개의 치환체에 의해 치환되거나 비치환되고, R 2 represents C 3 -C 8 -cycloalkyl, phenyl or pyridine, each of which is halogen, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogeno- Substituted by one or two substituents selected from the group consisting of C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkoxy, and C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkoxy Unsubstituted, R3 는 수소이고, R4는 각각 독립적으로 수소 또는 C1-C6-알킬을 나타낸다. R 3 is hydrogen and R 4 each independently represents hydrogen or C 1 -C 6 -alkyl. 제1항에 있어서, R1이 할로겐 및 하이드록시-C1-C6-알킬로 구성된 그룹으로부터 선택된 1 또는 2개의 치환체에 의해 치환되거나 비치환된 이미다졸을 나타내는 화합물 또는 약제학적으로 허용되는 그의 염.The compound or pharmaceutically acceptable thereof according to claim 1, wherein R 1 represents imidazole unsubstituted or substituted by one or two substituents selected from the group consisting of halogen and hydroxy-C 1 -C 6 -alkyl. salt. 제1항에 있어서, R2가 할로겐, 하이드록시, C1-C6-알킬, C1-C6-알콕시, 할로게노-C1-C6-알킬, 할로게노-C1-C6-알콕시, 및 C3-C8-사이클로알킬-C1-C6-알콕시로 구성된 그룹으로부터 선택된 1 또는 2개의 치환체에 의해 치환된 페닐을 나타내는 화합물 또는 약제학적으로 허용되는 그의 염.The compound of claim 1, wherein R 2 is halogen, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogeno-C 1 -C 6 -alkyl, halogeno-C 1 -C 6- A compound or a pharmaceutically acceptable salt thereof that represents alkoxy and phenyl substituted by one or two substituents selected from the group consisting of C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkoxy. 제1항에 있어서, 하기 그룹에서 선택되는 화합물 또는 약제학적으로 허용되는 그의 염:A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the following groups: 1-아미노-4-이미다졸-1-일-6-페닐-1H-피리딘-2-온(화합물 1);1-amino-4-imidazol-1-yl-6-phenyl-1 H -pyridin-2-one (Compound 1); 1-아미노-4-이미다졸-1-일-6-(2-메톡시-페닐)-1H-피리딘-2-온(화합물 2);1-amino-4-imidazol-1-yl-6- (2-methoxy-phenyl) -1 H -pyridin-2-one (Compound 2); 1-아미노-4-이미다졸-1-일-6-(3-메톡시페닐)-1H-피리딘-2-온(화합물 3);1-amino-4-imidazol-1-yl-6- (3-methoxyphenyl) -1 H -pyridin-2-one (Compound 3); 1-아미노-6-(3-하이드록시페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 4);1-amino-6- (3-hydroxyphenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 4); 1-아미노-4-이미다졸-1-일-6-(3-트리플루오로메톡시-페닐)-1H-피리딘-2-온 (화합물 5);1-amino-4-imidazol-1-yl-6- (3-trifluoromethoxy-phenyl) -1 H -pyridin-2-one (compound 5); 1-아미노-6-(3-디플루오로메톡시페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 6);1-amino-6- (3-difluoromethoxyphenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 6); 1-아미노-6-(3-에톡시-페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 7);1-amino-6- (3-ethoxy-phenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 7); 1-아미노-4-이미다졸-1-일-6-(3-이소프로폭시-페닐)-1H-피리딘-2-온(화합물 8);1-amino-4-imidazol-1-yl-6- (3-isopropoxy-phenyl) -1 H -pyridin-2-one (Compound 8); 1-아미노-4-이미다졸-1-일-6-페닐-1H-피리딘-2-온 2염산염(화합물 9);1-amino-4-imidazol-1-yl-6-phenyl-1 H -pyridin-2-one dihydrochloride (Compound 9); 1-아미노-6-사이클로프로필-4-이미다졸-1-일-1H-피리딘-2-온(화합물 10);1-amino-6-cyclopropyl-4-imidazol-1-yl-1 H -pyridin-2-one (Compound 10); 1-아미노-4-(2-클로로-이미다졸-1-일)-6-사이클로헥실-1H-피리딘-2-온(화합물 11);1-amino-4- (2-chloro-imidazol-1-yl) -6-cyclohexyl-1 H -pyridin-2-one (Compound 11); 1-아미노-6-(4,4-디플루오로-사이클로헥실)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 12);1-amino-6- (4,4-difluoro-cyclohexyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 12); 1-아미노-6-(4-플루오로-페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 13);1-amino-6- (4-fluoro-phenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 13); 1-아미노-6-(3-플루오로-페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 14);1-amino-6- (3-fluoro-phenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 14); 1-아미노-6-사이클로헥실-4-이미다졸-1-일-3-메틸-1H-피리딘-2-온(화합물 15);1-amino-6-cyclohexyl-4-imidazol-1-yl-3-methyl-1 H -pyridin-2-one (Compound 15); 1-아미노-4-이미다졸-1-일-6-(3-프로폭시-페닐)-1H-피리딘-2-온(화합물 16);1-amino-4-imidazol-1-yl-6- (3-propoxy-phenyl) -1 H -pyridin-2-one (Compound 16); 1-아미노-6-(3-사이클로프로필메톡시-페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 17);1-amino-6- (3-cyclopropylmethoxy-phenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 17); 1-아미노-4-이미다졸-1-일-1H-[2,2']바이피리디닐-6-온(화합물 18);1-amino-4-imidazol-1-yl-1H- [2,2 '] bipyridinyl-6-one (Compound 18); 1-아미노-4-이미다졸-1-일-1H-[2,3']바이피리디닐-6-온(화합물 19);1-amino-4-imidazol-1-yl-1H- [2,3 '] bipyridinyl-6-one (Compound 19); 1-아미노-4-이미다졸-1-일-1H-[2,4']바이피리디닐-6-온(화합물 20);1-amino-4-imidazol-1-yl-1H- [2,4 '] bipyridinyl-6-one (Compound 20); 1-아미노-4-이미다졸-1-일-6-(4-메톡시-페닐)-1H-피리딘-2-온(화합물 21);1-amino-4-imidazol-1-yl-6- (4-methoxy-phenyl) -1 H -pyridin-2-one (Compound 21); 1-아미노-6-사이클로헥실-4-(4-하이드록시메틸-페닐)-1H-피리딘-2-온(화합물22);1-amino-6-cyclohexyl-4- (4-hydroxymethyl-phenyl) -1 H -pyridin-2-one (compound 22); 1-아미노-6-사이클로헥실-4-(3-하이드록시메틸-페닐)-1H-피리딘-2-온(화합물23);1-amino-6-cyclohexyl-4- (3-hydroxymethyl-phenyl) -1 H -pyridin-2-one (compound 23); 1'-아미노-6'-페닐-1'H-[3,4']바이피리디닐-2'-온(화합물 24);1'-amino-6'-phenyl-1'H- [3,4 '] bipyridinyl-2'-one (compound 24); 1'-아미노-6'-페닐-1'H-[4,4']바이피리디닐-2'-온(화합물 25);1'-amino-6'-phenyl-1'H- [4,4 '] bipyridinyl-2'-one (compound 25); 1-아미노-4-이미다졸-1-일-6-m-톨릴-1H-피리딘-2-온(화합물 26); 및 1-amino-4-imidazol-1-yl-6-m-tolyl-1 H -pyridin-2-one (Compound 26); And 1-아미노-4-이미다졸-1-일-6-(3-트리플루오로메틸-페닐)-1H-피리딘-2-온(화합물 27). 1-amino-4-imidazol-1-yl-6- (3-trifluoromethyl-phenyl) -1 H -pyridin-2-one (compound 27). 제4항에 있어서, 하기 그룹에서 선택되는 화합물 또는 약제학적으로 허용되는 그의 염:The compound according to claim 4 or a pharmaceutically acceptable salt thereof, selected from the following groups: 1-아미노-4-이미다졸-1-일-6-페닐-1H-피리딘-2-온(화합물 1);1-amino-4-imidazol-1-yl-6-phenyl-1 H -pyridin-2-one (Compound 1); 1-아미노-4-이미다졸-1-일-6-(3-메톡시페닐)-1H-피리딘-2-온(화합물 3);1-amino-4-imidazol-1-yl-6- (3-methoxyphenyl) -1 H -pyridin-2-one (Compound 3); 1-아미노-4-이미다졸-1-일-6-(3-트리플루오로메톡시-페닐)-1H-피리딘-2-온 (화합물 5);1-amino-4-imidazol-1-yl-6- (3-trifluoromethoxy-phenyl) -1 H -pyridin-2-one (compound 5); 1-아미노-6-(3-디플루오로메톡시페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 6);1-amino-6- (3-difluoromethoxyphenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 6); 1-아미노-6-(3-에톡시-페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 7);1-amino-6- (3-ethoxy-phenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 7); 1-아미노-6-(4-플루오로-페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 13); 1-amino-6- (4-fluoro-phenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 13); 1-아미노-6-(3-플루오로-페닐)-4-이미다졸-1-일-1H-피리딘-2-온(화합물 14); 및1-amino-6- (3-fluoro-phenyl) -4-imidazol-1-yl-1 H -pyridin-2-one (Compound 14); And 1-아미노-4-이미다졸-1-일-6-(3-트리플루오로메틸-페닐)-1H-피리딘-2-온(화합물 27).1-amino-4-imidazol-1-yl-6- (3-trifluoromethyl-phenyl) -1 H -pyridin-2-one (compound 27). 하기 화학식 9의 화합물을 하기 화학식 8의 화합물과 축합반응시켜 하기 화학식 7의 화합물을 수득하고, 화학식 7의 화합물을 고리화 반응시켜 하기 화학식 6의 화합물을 수득하고, 화학식 6의 화합물을 할로겐화 반응시켜 하기 화학식 5의 화합물을 수득하고, 화학식 5의 화합물을 하기 화학식 4의 화합물과 커플링 반응시켜 치환된 하기 화학식 3의 화합물을 수득하고, 화학식 3의 화합물을 하기 화학식 2의 하이드라진과 치환반응시킴을 특징으로 하여 하기 화학식 1의 화합물 또는 약제학적으로 허용되는 그의 염을 제조하는 방법:Condensation of a compound of formula 9 with a compound of formula 8 to yield a compound of formula 7, a compound of formula 7 to cyclize to yield a compound of formula 6, and halogenation of a compound of formula 6 To obtain a compound of formula (5), and to react the compound of formula (5) with a compound of formula (4) to obtain a substituted compound of formula (3), and to substitute the compound of formula 3 with hydrazine of the formula (2) Characterized in that for preparing a compound of formula (1) or a pharmaceutically acceptable salt thereof: [화학식 1][Formula 1]
Figure 112011043092835-pat00013
Figure 112011043092835-pat00013
 [화학식 2][Formula 2]
Figure 112011043092835-pat00014
Figure 112011043092835-pat00014
 [화학식 3](3)
Figure 112011043092835-pat00015
Figure 112011043092835-pat00015
 [화학식 4][Formula 4]
Figure 112011043092835-pat00016
Figure 112011043092835-pat00016
 [화학식 5][Chemical Formula 5]
Figure 112011043092835-pat00017
Figure 112011043092835-pat00017
 [화학식 6][Formula 6]
Figure 112011043092835-pat00018
Figure 112011043092835-pat00018
 [화학식 7][Formula 7]
Figure 112011043092835-pat00019
Figure 112011043092835-pat00019
 [화학식 8][Formula 8]
Figure 112011043092835-pat00020
Figure 112011043092835-pat00020
 [화학식 9][Formula 9]
Figure 112011043092835-pat00021
Figure 112011043092835-pat00021
 상기 식에서,Where R1, R2, R3, 및 R4는 제1항에서 정의한 바와 같고,R 1 , R 2 , R 3 , and R 4 are as defined in claim 1, X는 할로겐을 나타내며, X represents halogen, P 및 P'는 각각 독립적으로 C1-C6-알킬을 나타낸다.P and P 'each independently represent C 1 -C 6 -alkyl. 활성 성분으로서 유효량의 제1항에 정의된 화학식 1의 화합물 또는 약제학적으로 허용되는 그의 염을 약제학적으로 허용되는 담체와 함께 함유함을 특징으로 하는 만성 폐색성 폐질환(COPD), 천식, 만성 기관지염, 건선, 궤양성 대장염, 크론씨병(국한성 회장염), 죽상동맥경화증, 류마티스성 관절염, 골다공증, 골관절염, 우울증, 기억손상증 및 염증 매개성 만성 조직괴사증으로 구성된 군에서 선택되는 포스포디에스테라제 4(PDE4) 매개 질환 치료용 조성물.Chronic obstructive pulmonary disease (COPD), asthma, chronic, characterized in that it contains as an active ingredient an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof as defined in claim 1 together with a pharmaceutically acceptable carrier. Phosphodiesterase selected from the group consisting of bronchitis, psoriasis, ulcerative colitis, Crohn's disease (local ileitis), atherosclerosis, rheumatoid arthritis, osteoporosis, osteoarthritis, depression, memory impairment and inflammatory mediated chronic tissue necrosis 4 (PDE4) mediated disease treatment composition. 삭제delete 제7항에 있어서, 만성 폐색성 폐질환의 치료제로서 사용되는 조성물.8. A composition according to claim 7, which is used as a therapeutic agent for chronic obstructive pulmonary disease. 제7항 또는 9항에 있어서, 경구투여용 제제로 제형화된 조성물.The composition of claim 7 or 9 formulated as a preparation for oral administration.
KR1020040038416A 2004-05-28 2004-05-28 1H-pyridin-2-one derivatives KR101128372B1 (en)

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KR102284525B1 (en) 2021-03-03 2021-08-02 박준용 Electric wire processing automation system

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Tetrahedron Letters, Vol. 21, No. 41, pp 4025-4026 (1980)*

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KR102284525B1 (en) 2021-03-03 2021-08-02 박준용 Electric wire processing automation system

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