KR100794515B1 - Novel Chromen-2-one based hydroxamic acid derivatives having anti-inflammatory activity, the preparation thereof and a composition containing the same for treating inflammatory disease - Google Patents

Novel Chromen-2-one based hydroxamic acid derivatives having anti-inflammatory activity, the preparation thereof and a composition containing the same for treating inflammatory disease Download PDF

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KR100794515B1
KR100794515B1 KR1020060065157A KR20060065157A KR100794515B1 KR 100794515 B1 KR100794515 B1 KR 100794515B1 KR 1020060065157 A KR1020060065157 A KR 1020060065157A KR 20060065157 A KR20060065157 A KR 20060065157A KR 100794515 B1 KR100794515 B1 KR 100794515B1
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methyl
oxo
chromen
hydroxy
phenyl
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KR20070008429A (en
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김명화
조보영
박준호
천광우
오병규
김광희
최종희
한균희
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제일약품주식회사
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
    • 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
    • C07D405/12—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 linked by a chain containing hetero atoms as chain links

Abstract

본 발명은 우수한 항염증 활성을 갖는 신규 화합물, 이의 제조방법 및 이를 포함하는 염증 질환의 치료를 위한 조성물을 제공한다. The present invention provides novel compounds having excellent anti-inflammatory activity, methods for their preparation and compositions for the treatment of inflammatory diseases comprising the same.

본 발명에 따른 화합물은 종양 괴사 인자-α 전환효소 (TNF-α converting enzyme)에 대해 강한 저해활성을 나타냄으로써, 이를 포함하는 조성물은 염증 질환, 특히 관절염의 치료를 위한 약제로써 이용가능하다.The compound according to the present invention exhibits a strong inhibitory activity against tumor necrosis factor-α converting enzyme (TNF-α converting enzyme), whereby the composition comprising the same can be used as a medicament for the treatment of inflammatory diseases, especially arthritis.

항염증물질, 염증질환, 관절염 Anti-inflammatory substances, inflammatory diseases, arthritis

Description

항염증 활성을 갖는 크로멘-2-온 모핵 히드록사민 산 유도체, 이의 제조방법 및 이를 포함하는 염증 질환의 치료를 위한 조성물 {Novel Chromen-2-one based hydroxamic acid derivatives having anti-inflammatory activity, the preparation thereof and a composition containing the same for treating inflammatory disease} Novel Chromen-2-one based hydroxamic acid derivatives having anti-inflammatory activity, the preparation according and a composition containing the same for treating inflammatory disease}

도 1은 여러 농도 (10, 30 및 100 mg/kg)의 본 발명의 화합물 (실시예 113)을 경구투여한 30분 후 리포폴리사카라이드를 복강투여하여 염증 유발된 마우스 혈액 내에 존재하는 TNF-α의 양을 측정한 실험 결과를 나타낸 도이고,1 shows TNF- present in inflammation-induced mouse blood by intraperitoneal administration of lipopolysaccharide 30 minutes after oral administration of the compounds of the invention (Example 113) at various concentrations (10, 30 and 100 mg / kg). Fig. shows the experimental results of measuring the amount of α,

도 2는 30 mg/kg의 농도로 본 발명의 화합물들 (실시예 110 내지 112)을 경구투여한 30분 후 리포폴리사카라이드를 복강투여하여 염증 유발된 마우스 혈액 내에 존재하는 TNF-α의 양을 측정한 실험 결과를 나타낸 도이며,Figure 2 shows the amount of TNF-α present in inflammation-induced mouse blood by intraperitoneal administration of lipopolysaccharide 30 minutes after oral administration of the compounds of the present invention (Examples 110-112) at a concentration of 30 mg / kg. Shows the experimental results of measuring

도 3은 정맥투여 독성시험에서 본 발명의 화합물(실시예 113)이 투여된 마우스 수컷의 시험일에 따른 체중변화를 나타낸 도이고, Figure 3 is a diagram showing the body weight change according to the test day of the male male administered the compound of the present invention (Example 113) in the intravenous toxicity test,

도 4는 정맥투여 독성시험에서 본 발명의 화합물(실시예 113)이 투여된 마우스 암컷의 시험일에 따른 체중변화를 나타낸 도이며, Figure 4 is a diagram showing the change in body weight according to the test day of the mouse female administered the compound of the present invention (Example 113) in the intravenous toxicity test,

도 5는 카라기난을 투여하여 유발된 부종의 시간변화 그래프를 나타낸 도이 고,5 is a diagram showing a time-varying graph of edema caused by administering carrageenan,

도 6은 카라기난을 투여하여 유발된 부종의 각 시간대에서 측정한 뒤꿈치 두께를 나타낸 도이다. 6 is a diagram showing the heel thickness measured at each time zone of edema caused by carrageenan administration.

본 발명은 항염증 활성을 갖는 크로멘-2-온 모핵 히드록사민 산 유도체, 이의 제조방법 및 이를 포함하는 염증 질환의 치료를 위한 조성물에 관한 것이다. The present invention relates to a chromium-2-one hair nucleophilic acid derivative having anti-inflammatory activity, a method for preparing the same, and a composition for the treatment of an inflammatory disease comprising the same.

염증은 상처나 질병에 반응하는 인체의 정상적인 현상이다. 상처가 있거나 질병이 있는 관절인 경우에는 부종, 통증, 관절이 뻣뻣한 증상 등을 동반한다. 대개 관절염의 경우 생기는 염증은 일시적인 것이나 때로는 장기적이면서 영구적인 불구의 상태를 초래하기도 한다. Inflammation is a normal condition in the body that responds to wounds or diseases. Injured or diseased joints are accompanied by swelling, pain, and stiff joints. Inflammation usually occurs in the case of arthritis, but sometimes results in a long and permanent disability.

일반적으로, 관절염, 즉 관절의 염증질환은 류마티스 관절염 (이하, RA라 함) 및 관절 염증 관련 질환과 같은 다양한 형태로 발생한다.In general, arthritis, or inflammatory disease of the joints, occurs in various forms, such as rheumatoid arthritis (hereinafter referred to as RA) and joint inflammation related diseases.

관절염은 특히, 관절낭 내층의 활액막에 염증성 변화로 특징지어지며 전신의 관절에서 부종과 통증이 유발되고, 심한 경우에는 신체 장애자가 될 수 있는 만성적으로 진행되는 질환이다. 또한 RA와 같은 관절염 질환은 진행성이고 변형 및 관절 불굴과 같은 관절 장애를 발생시켜, 종종 효과적인 치료의 결핍과 계속된 악화로 인한 심각한 육체적 장애를 일으킨다.Arthritis is a chronic progressive disease, characterized by inflammatory changes, especially in the synovial membrane of the lining of the articular capsule, causing swelling and pain in the joints of the whole body and, in severe cases, becoming a physically handicapped person. Arthritis diseases such as RA are also progressive and develop joint disorders such as deformation and joint instability, often causing severe physical disorders due to lack of effective treatment and continued exacerbation.

골관절염 (이하, OA라 함)은 그의 임상적 발현에 복합 다인자적 인과관계 및 상당한 다양성을 갖지만, OA를 일으키는 중요한 요소는 활액 염증으로 알려져 있다. 또한, 활액세포 및 연골세포사이의 상호작용의 결과로 활액 상해는 프로테오글리칸 (proteoglycan; PG)의 해리를 촉진할 수 있고, 활성화된 활액세포는 관절 연골의 손실을 유도할 수 있는 다수의 가용성 인자 (예를 들어, 인터루킨-1 (IL-1), 종양 괴사 인자-α (TNF-α) 및 프로스타글란딘)를 생산한다. 연골세포의 직접적인 상해는 또한 매트릭스 메탈로프로테아제 (matrix metalloproteinase; MMP) 활성 (예를 들어, 콜라게나제, 스트로멜리신 및 젤라티나제) 및 다양한 염증 매개자의 생산을 촉진한다. 어떠한 경우라도, 관절 연골의 감소된 기능성은 OA 질병 발생을 일으킨다. OA 관절 조직으로부터 PG의 소모는 PG가 연골에 부여하는 탄성이 감소됨에 따라 연골세포, 연골하골세포 및 활막세포에 비정상적인 기계적 응력을 부여한다. Osteoarthritis (hereinafter referred to as OA) has a complex multifactorial causality and considerable diversity in its clinical manifestations, but an important factor causing OA is known as synovial inflammation. In addition, synovial injury can promote the dissociation of proteoglycans (PGs) as a result of the interaction between synovial cells and chondrocytes, and activated synovial cells can induce a number of soluble factors that can lead to loss of articular cartilage ( For example interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α) and prostaglandins). Direct injury of chondrocytes also promotes the production of matrix metalloproteinase (MMP) activity (eg, collagenase, stromelysin and gelatinase) and various inflammatory mediators. In any case, the reduced functionality of articular cartilage results in OA disease development. Depletion of PG from OA joint tissue imparts abnormal mechanical stress to chondrocytes, subchondral osteoblasts and synovial cells as the elasticity imparted by the PG to cartilage is reduced.

골관절염 및 류마티스성 관절염은 연골 표면의 국소적 침식을 특징으로 하는 관절 연골의 파괴적 질환이다. 예를 들어, OA 환자의 대퇴두(大腿頭)로부터의 관절 연골은 대조군에 비해 방사성 동위원소로 표지된 황산염의 도입이 감소했다는 연구 결과가 밝혀졌는 데, 이는 OA에서의 연골 분해 속도가 증가하였다는 것을 시사하는 것이다 (Mankin et al. J. Bone Joint Surg. 52A, pp424-434, (1970)). 포유동물 세포에는 4 종류의 단백질 분해 효소, 즉 세린, 시스테인, 아스파르트산 및 메탈로프로테나제가 있다. OA 및 PA 환자에서의 관절 연골의 세포외 기질 분해에 대한 원인은 메탈로프로테나제라는 것이 유효한 증거에 의해 입증되었다. OA 환자 연골에서 콜라게나제 및 스트로멜리신의 활성 증가가 발견되었는데, 그 활성은 병변의 심 도와 서로 관련되어 있다 (Mankin et al. Arthritis Rhenum. 21, pp761-766, 1978 ; Woessner et al. Arthritis Rhenum. 26, pp63-68, 1983 및 Ibid. 27, pp305-312, 1984). 또한, 아그레카나제 (최근에 동정된 것으로 메탈로프로테나제 효소 활성을 지님)는 OA 및 RA 환자에서 발견되는 것으로서, 프로테오글리칸의 특이적 절단 생성물을 제공하는 것으로 입증되었다 (Lohmander L.S. et al. Arthritis Rheum. 36, pp1214-1222, 1993).Osteoarthritis and rheumatoid arthritis are destructive diseases of articular cartilage characterized by local erosion of the cartilage surface. For example, studies have shown that articular cartilage from the femoral head of an OA patient has decreased the introduction of radioisotope-labeled sulfate compared to the control group, which increased the rate of cartilage degradation in OA. (Mankin et al . J. Bone Joint Surg . 52A , pp424-434, (1970)). Mammalian cells have four types of proteolytic enzymes: serine, cysteine, aspartic acid and metalloproteinases. Evidence has shown that metalloproteinases are responsible for the extracellular matrix degradation of articular cartilage in OA and PA patients. Increased activity of collagenase and stromelysin was found in cartilage of OA patients, which activity correlated with the severity of the lesion (Mankin et al. Arthritis Rhenum . 21 , pp761-766, 1978; Woessner et al. Arthritis Rhenum 26 , pp63-68, 1983 and Ibid . 27 , pp305-312, 1984). In addition, agrecanase (which has recently been identified as having metalloproteinase enzyme activity) is found in OA and RA patients, and has been demonstrated to provide specific cleavage products of proteoglycans (Lohmander LS et al . Arthritis Rheum . 36 , pp 1214-1222, 1993).

종양 괴사 인자 (Tumor necrosis factor: TNF)는 세포와 결합된 시토킨으로서, 26kD 전구체형에서 17kD 활성형으로 프로세싱된다. TNF는 사람 및 동물에서 염증, 열, 및 급성 감염 및 쇽 동안 관찰되는 것과 유사한 급성기 반응 (acute phase response)의 1차 조절자인 것으로 밝혀졌다. 과량의 TNF는 죽음에까지 이르게 하는 것으로 밝혀졌다. 현재, 특이적 항체를 사용하여 TNF의 효과를 봉쇄하면 류마티스성 관절염, 인슐린 비의존성 당뇨병 (Lohmander L.S. et al. Arthritis Rheum. 36, pp1214-1222, 1993), 크론병 (Macdonald T. et al. Clin . Exp . Immunol . 81, p301, 1990) 등의 자가면역 질환을 비롯한 여러 상황에서 유익할 수 있는 것으로 밝혀졌다. Tumor necrosis factor (TNF) is a cytokine bound to cells and is processed from 26 kD precursor form to 17 kD active form. TNF has been shown to be the primary regulator of acute phase responses similar to those observed during inflammation, fever, and acute infections and shock in humans and animals. Excess TNF has been found to lead to death. Currently, using specific antibodies to block the effects of TNF can lead to rheumatoid arthritis, insulin-independent diabetes (Lohmander LS et al. Arthritis Rheum . 36 , pp1214-1222, 1993), Crohn's disease (Macdonald T. et al. Clin) . Exp., such as self Immunol. 81, p301, 1990) and other autoimmune diseases. It has been found that can be beneficial in many situations.

따라서, TNF의 생성을 억제하는 화합물은 염증성 질환의 치료에 있어 치료적 중요성이 있다. 최근, 기질 메탈로프로테나제 또는 메탈로프로테나제류 (후에, 종양 괴사 인자-α 전환효소 (Tumor necrosis factor-α convertase; TNF-C)로 공지됨)는 물론 다른 MP도 그 불활성형에서 활성형으로 전환될 수 있는 것으로 밝혀졌다 (Gearing et al., Nature, 370, p555, 1994). 따라서, 이 전환을 억제하고 그에 따라 세포로부터 활성 TNF-α가 분비되는 것을 억제하는 것이 염증성 질환의 치료에 있어 중요한 메카니즘이 될 것이다.Thus, compounds that inhibit the production of TNF are of therapeutic importance in the treatment of inflammatory diseases. Recently, matrix metalloproteinases or metalloproteinases (later known as Tumor necrosis factor-α convertase (TNF-C)) as well as other MPs are active in their inactive form. It has been found that it can be converted to the form (Gearing et al., Nature , 370 , p555, 1994). Therefore, inhibiting this conversion and thus inhibiting the release of active TNF-α from the cells will be an important mechanism in the treatment of inflammatory diseases.

TNF의 과잉 생성은 MMP로 매개되는 조직 분해를 특징으로 하는 다수 질환에서 두드러지기 때문에, MMP 및 TNF의 생성 모두를 억제하는 화합물은 두 메카니즘이 관련된 질환에서도 특별한 장점이 있다.Because overproduction of TNF is prominent in many diseases characterized by MMP-mediated tissue degradation, compounds that inhibit both MMP and TNF production have particular advantages even in diseases involving both mechanisms.

히드록사메이트 및 카르복실레이트 기재 MMP 억제제로 국제 공개 제92/213260호에서는 N-카르복시알킬펩티딜 화합물이 개시되어 있으며, 국제 공개 제90/05716호 및 국제 공개 제92/13831호에는 히드록삼산 기재 콜라게나제 억제제가 개시되어 있으며, 국제 공개 제94/02446호에는 하기 식의 천연 아미노산 유도체인 메탈로프로테나제 억제제가 개시되어 있다. 또한, 국제 공개 제95/09841호에는 히드록삼산 유도체이며 시토킨의 억제제인 화합물이 기재되어 있으며, 영국 특허 공개 제2 268 934호 및 국제 공개 제94124140호에는 TNF 생성의 억제제로서 MMP의 히드록사메이트 억제제가 개시되어 있다. Hydroxamate and carboxylate based MMP inhibitors disclose N-carboxyalkylpeptidyl compounds in WO 92/213260 and WO 90/05716 and WO 92/13831. A base collagenase inhibitor is disclosed, and International Publication No. 94/02446 discloses a metalloproteinase inhibitor which is a natural amino acid derivative of the formula: International Publication No. 95/09841 also describes compounds that are hydroxamic acid derivatives and inhibitors of cytokines, and British Patent Publication Nos. 2 268 934 and International Publication No. 94124140 disclose MMP's hydroxyl as an inhibitor of TNF production. Mate inhibitors are disclosed.

전통적으로 관절염은 코르티손 및 다른 부신피질 호르몬과 같은 스테로이드계, 아스피린, 피록시캄 및 인도메타신과 같은 비스테로이드계 항염증제, 오로타이오능금산과 같은 금작용제, 클로로퀴논제제 및 D-페니실아민과 같은 항류마티스제, 콜치신과 같은 통풍억제제, 및 시클로포스프 아미드, 아자티오프린, 메토트렉세이트 및 레바미솔과 같은 면역 억제제를 포함하여 다양한 작용제를 사용한 화학요법으로 치료되어 왔다. Traditionally, arthritis has been shown to include steroids such as cortisone and other corticosteroids, nonsteroidal anti-inflammatory agents such as aspirin, pyroxicam and indomethacin, gold agonists such as orothioactive acid, chloroquinones and D-phenicamine. Therapies such as antirheumatic agents, gout inhibitors such as colchicine, and immunosuppressants such as cyclophosphamide, azathioprine, methotrexate and levamisol have been treated with chemotherapy using various agents.

그러나, 상기의 치료제들은 근원적인 치료법이 아니며, 스테로이드 호르몬제 가 관절염 치료제로 알려지면서 많이 사용되기도 했으나, 그의 부작용이 명백해짐에 따라 그 사용은 어렵게 되었다.However, the above therapeutic agents are not the basic treatments, and steroid hormones have been widely used as known as arthritis drugs, but their use has become difficult as their side effects become apparent.

또, 관절염, 특히 만성 류마티스 관절염은 환자에게 심한 통증을 유발하므로 반드시 항염증제 등을 복용하여야만 하며, 지금까지 이러한 통증을 완화시키거나 관절의 종창을 제거하는 약제로서 아스피린제 및 브타졸린제 등이 오랫동안 널리 사용되어 왔다. 그러나 아스피린 등은 사람의 위에 치명적인 영향을 주므로 관절염을 치료하는데 필요한 양을 계속적으로 복용하는 것은 어렵다.In addition, arthritis, especially chronic rheumatoid arthritis, causes severe pain in patients, so be sure to take anti-inflammatory drugs, etc. Until now, aspirin and betazoline drugs have been widely used as drugs to alleviate these pains or remove joint swelling. Has been used. However, aspirin and the like have a fatal effect on the stomach, so it is difficult to continue taking the amount needed to treat arthritis.

기존의 이러한 화학요법적 약제는 약제의 장기간 사용을 방해하는 부작용, 항염증 효과의 결핍, 및 이미 발생한 관절염에 대한 효능의 부족과 같은 결점을 가지고 있으며, 현재는 관절염 치료에 진통작용이 우수한 인도메타신 및 푸르페낭산과 비스테로이드성의 각종 소염제 정도가 조제하여 사용되고 있는 실정이다.Existing chemotherapeutic agents have drawbacks such as side effects that hinder the long-term use of the drugs, lack of anti-inflammatory effects, and lack of efficacy against arthritis that has already occurred. Shin, furpenic acid and non-steroidal anti-inflammatory agent is used to prepare a degree.

따라서, 이러한 문제에 대한 해결책과 급성 염증성 증상과 고통에 대해 증상적인 효과를 보여주는 관절염 치료제의 개발이 요망되고 있으며, 현재 사용되고 있는 대부분의 관절염 치료제는 정도의 차이나 개인적인 차이가 있기는 하지만, 모두 어느 정도의 부작용을 가지고 있고, 특히 류마티스 관절염의 치료를 위해서는 약제를 장기간 복용할 필요가 있기 때문에, 부작용이 적은 약재를 개발하는 것이 매우 중요하다.Therefore, there is a need for a solution to these problems and the development of arthritis therapies that have symptomatic effects on acute inflammatory symptoms and pain, and most of the arthritis drugs currently in use have some differences or personal differences. It is very important to develop medicines with fewer side effects, because they have side effects, and especially for the treatment of rheumatoid arthritis, it is necessary to take the drug for a long time.

본 발명자들은 종양 괴사 인자-α 전환효소 (Tumor Necrosis Factor-α convertase)를 작용점으로 하여 TNF-α의 생성에 대해 강한 저해활성을 나타내는 물질을 개발하기 위한 연구를 계속 진행하던 중, 본 발명의 화합물이 우수한 TNF- α의 생성 저해활성을 나타냄을 발견하고, 본 발명을 완성하게 되었다.The inventors of the present invention, while continuing to study the development of a substance showing a strong inhibitory activity against the production of TNF-α by using the tumor necrosis Factor-α convertase as a point of action, the compound of the present invention It was found that this exhibited excellent inhibitory activity of TNF-α production, and completed the present invention.

본 발명의 목적은 우수한 항 염증효과를 나타내는 항염증 물질, 이의 제조방법 및 이를 포함하는 염증 질환의 치료를 위한 조성물을 제공하는 데 있다.It is an object of the present invention to provide an anti-inflammatory material, a method for preparing the same, and a composition for treating an inflammatory disease including the same, which exhibits an excellent anti-inflammatory effect.

상기 목적을 달성하기 위하여, 본 발명은 염증 관련 질환의 치료에 유용한, 하기 일반식 (Ⅰ)의 구조를 갖는 화합물 또는 이의 약학적으로 허용가능한 염 및 그 이성체를 제공한다:In order to achieve the above object, the present invention provides a compound having the structure of the general formula (I) or a pharmaceutically acceptable salt thereof and isomer thereof useful for the treatment of an inflammation related disease:

Figure 112006049660803-pat00001
Figure 112006049660803-pat00001

상기 식에서,Where

R1는 -OH, -NHOH, 또는 NHO-R',

Figure 112006049660803-pat00002
,
Figure 112006049660803-pat00003
이고, R'는 C1 내지 C3의 저급알킬기 또는 벤질기이고;R 1 is —OH, —NHOH, or NHO—R ′,
Figure 112006049660803-pat00002
,
Figure 112006049660803-pat00003
And, R 'is a lower alkyl group or a benzyl group of C 1 to C 3, and;

n은 0 내지 3의 정수이고;n is an integer from 0 to 3;

X는 질소원자 또는 탄소원자이고;X is a nitrogen atom or a carbon atom;

R2 내지 R6은 각각 독립적으로 수소원자, 히드록시기, 니트로, 할로겐, 아민, 아세트아미드, 카보아미드, 설폰 아미드기, C1 내지 C4의 저급 알킬기, C1 내지 C4의 저급 알켄일기 또는 C1 내지 C4의 저급 알콕시기로부터 선택된 하나이상의 치환기이며; R 2 to R 6 are each independently a hydrogen atom, a hydroxyl group, nitro, halogen, amine, acetamide, carboamide, sulfonamide group, C 1 to C 4 lower alkyl group, C 1 to C 4 lower alkenyl group or C At least one substituent selected from 1 to C 4 lower alkoxy groups;

R7 및 R8은 각각 독립적으로 수소원자 또는 수소원자, 니트로, 할로겐, 아민, 아세트아미드, 카보 아미드, 설폰 아미드기로 치환된 C1 내지 C20의 쇄상, 가지상 알킬기, 알켄일기, 알키닐기이고, 또는 A1 또는 A2로 치환되거나 비치환된 페닐기로 치환된 C1 내지 C20의 쇄상, 가지상 알킬기, 알켄일기, 알키닐기 또는 알콕시기로부터 선택된 하나이상의 치환기이며; R 7 and R 8 are each independently a hydrogen atom or a C 1 to C 20 chain, branched alkyl group, alkenyl group, alkynyl group substituted with hydrogen atom, nitro, halogen, amine, acetamide, carboamide, sulfonamide group Or one or more substituents selected from C 1 to C 20 chain, branched alkyl, alkenyl, alkynyl, or alkoxy groups substituted with a phenyl group unsubstituted or substituted with A 1 or A 2 ;

A1은 각각 독립적으로 니트로, 할로겐, 아민, 아세트아미드, 카보 아미드, 설폰 아미드기, 히드록시기, 아세틸기, 아세톡시기, 알킬카보닐기, 알킬에스테르기 또는 C1 내지 C5의 알콕시기, C1 내지 C5의 디알킬아민, C1 내지 C5의 모노알킬아민 또는 아민기로부터 선택된 하나이상의 치환기로 치환된 C1 내지 C20의 쇄상, 가지상 알킬기, 알켄일기, 알키닐기 또는 알콕시기이며, A 1 is each independently nitro, halogen, amine, acetamide, carbonamide, sulfonamide group, hydroxy group, acetyl group, acetoxy group, alkylcarbonyl group, alkylester group or C 1 to C 5 alkoxy group, C 1 to C 5-di-alkyl amine, C 1 to C 5 mono alkyl amine or a C chain of 1 to C 20 substituted with one or more substituents selected from an amine group, of the alkyl group, alkenyl group, alkynyl group or an alkoxy group,

A2는 Y-(CH2)o-P로서, P 치환기는 임의로 하나 이상의 R'치환기로 치환된 하나 이상의 5원 내지 7원의 시클릭환, 아릴 방향환, 헤테로 복소환 또는 이들이 상호 융합되거나 직접 연결된 환이며, 여기에서 R'는 수소원자, 니트로, 할로겐, 아민, 아세트아미드, 히드록시기, 카보아미드, 설폰 아미드기, 케톤기, C1 내지 C4의 저급 알킬기, 알켄일기 또는 저급 알콕시기이며, Y는 O, N, S로부터 선택된 이종원자 또는 탄소원자이며, o는 1 내지 20의 정수이며, 단 R7 및 R8가 동시에 수소원자는 아니며;A 2 is Y- (CH 2 ) oP, wherein the P substituent is one or more 5- to 7-membered cyclic rings, aryl aromatic rings, heteroheterocycles or optionally fused or directly connected to each other, optionally substituted with one or more R ′ substituents Wherein R 'is a hydrogen atom, nitro, halogen, amine, acetamide, hydroxy group, carboamide, sulfonamide group, ketone group, C 1 to C 4 lower alkyl group, alkenyl group or lower alkoxy group, Y Is a heteroatom or carbon atom selected from O, N, S, o is an integer from 1 to 20, provided that R 7 and R 8 are not hydrogen atoms at the same time;

(

Figure 112006049660803-pat00004
) 점선은 이중결합 또는 단일결합을 의미한다. (
Figure 112006049660803-pat00004
) Dashed line means double bond or single bond.

상기 화합물 (Ⅰ)의 보다 바람직한 군으로는 R1는 -OH, -NHOH이고; n은 0 내지 3의 정수이고; X는 N 원자, C 원자이고; R2 내지 R6은 각각 독립적으로 수소원자, 히드록시기, 니트로, 할로겐, C1 내지 C4의 저급 알킬기, C1 내지 C4의 알켄일기 또는 C1 내지 C4의 저급 알콕시기로부터 선택된 하나이상의 치환기이고; R7 및 R8중 하나가 수소원자이며, 남은 치환기는 각각 독립적으로 C1 내지 C10의 쇄상, 가지상 알킬기, 알켄일기, 알키닐기 또는, A1 또는 A2로 치환되거나 비치환된 페닐기로 치 환된 C1 내지 C10의 쇄상, 가지상 알킬기, 알켄일기 또는 알콕시기이며, 여기에서 A1은 각각 독립적으로 니트로, 할로겐, 아민, 아세트아미드, 카보 아미드, 설폰 아미드기, 히드록시기, 아세틸기, 아세톡시기, 알킬카보닐기, 알킬에스테르기 또는 C1 내지 C5의 알콕시기, C1 내지 C5의 디알킬아민, C1 내지 C5의 모노알킬아민 또는 아민기로 치환된 C1 내지 C10의 쇄상, 가지상 알킬기, 알켄일기, 알키닐기 또는 알콕시기이며, A2는 Y-(CH2)o-P로서, P 치환기는 하나 이상의 수소원자, 할로겐, 히드록시기, 아민, 카보닐기 또는 C1 내지 C5의 저급 알킬기, 알켄일기 또는 저급 알콕시기로 임의로 치환된 5 내지 7원의 페닐환과 같은 방향환, 피롤, 피페리딘, 피페라진, 피리미딘, 피리다진, 피롤리딘, 모폴린, 티아졸 등과 같은 복소환, 시클로펜탄, 시클로헥산 등과 같은 시클릭환 또는 이들이 상호 융합된 10 내지 20원의 퀴놀린, 퀴나졸린, 인돌 등과 같은 융합된 융합환이며, Y는 O 또는 N으로부터 선택된 이종원자 또는 탄소원자이며, o는 1 내지 5의 정수이며, 단 R7 및 R8이 동시에 수소원자는 아닌 화합물군을 들 수 있다. In a more preferred group of compound (I), R 1 is -OH, -NHOH; n is an integer from 0 to 3; X is N atom, C atom; R 2 to R 6 each independently represent a hydrogen atom, a hydroxy group, a nitro, halogen, C 1 to a lower alkyl group of C 4, C 1 to alkenyl or C 1 to one or more substituents selected from a lower alkoxy group of C 4 of the C 4 ego; One of R 7 and R 8 is a hydrogen atom, and the remaining substituents are each independently a C 1 to C 10 chain, branched alkyl group, alkenyl group, alkynyl group, or a phenyl group unsubstituted or substituted with A 1 or A 2 A substituted C 1 to C 10 chain, branched alkyl group, alkenyl group or alkoxy group, wherein A 1 is each independently nitro, halogen, amine, acetamide, carboamide, sulfonamide group, hydroxy group, acetyl group, acetoxy group group, alkyl carbonyl group, an alkyl ester or C 1 to C 5 alkoxy group, C 1 to C 5 of a dialkyl amine, C 1 to C 5 mono alkyl amine or a C 1 to C 10 substituted amine group of Is a chain, branched alkyl group, alkenyl group, alkynyl group, or alkoxy group of A 2 is Y- (CH 2 ) oP, and the P substituent is at least one hydrogen atom, halogen, hydroxy group, amine, carbonyl group or C 1 to C 5 , lower alkyl group, alkenyl group or lower al Aromatic rings, such as 5- to 7-membered phenyl rings, optionally substituted with a cock group, heterocycles such as pyrrole, piperidine, piperazine, pyrimidine, pyridazine, pyrrolidine, morpholine, thiazole, cyclopentane, cyclo A cyclic ring such as hexane or a fused ring such as 10 to 20 membered quinoline, quinazoline, indole, etc., to which they are fused together, Y is a heteroatom or carbon atom selected from O or N, and o is 1 to 5 And a group of compounds in which R 7 and R 8 are not hydrogen atoms at the same time.

또한 보다 구체적으로 본 발명은 염증 관련 질환의 치료에 유용한, 하기 일반식 (II)의 구조를 갖는 화합물 또는 이의 약리학적으로 허용가능한 염 및 그 이성체를 제공한다:More specifically, the present invention also provides a compound having the structure of the following general formula (II) or a pharmacologically acceptable salt thereof and isomer thereof useful for the treatment of an inflammation related disease:

Figure 112006049660803-pat00005
Figure 112006049660803-pat00005

상기 식에서 R1는 -OH, -NHOH 이고; n은 0 내지 3의 정수이고; X는 N 원자 또는 C 원자이고; R2 내지 R6은 각각 독립적으로 수소원자, 히드록시기, 할로겐, 아민, C1 내지 C4의 저급 알킬기, C1 내지 C4의 알켄일기 또는 C1 내지 C4의 저급 알콕시기로부터 선택된 하나이상의 치환기이고; R8 및 A3은 각각 독립적으로 수소원자 또는 수소원자, 니트로, 할로겐, 아민, 아세트아미드, 카보 아미드, 설폰 아미드기 또는 페닐기로 치환되거나 비치환된 C1 내지 C20의 쇄상, 가지상 알킬기, 알켄일기, 알키닐기, 알콕시기이며, 단 R8 및 A3가 동시에 수소원자는 아니며In which R 1 is -OH, -NHOH; n is an integer from 0 to 3; X is an N atom or a C atom; R 2 to R 6 are each independently at least one substituent selected from a hydrogen atom, a hydroxy group, a halogen, an amine, a C 1 to C 4 lower alkyl group, a C 1 to C 4 alkenyl group or a C 1 to C 4 lower alkoxy group ego; R 8 and A 3 are each independently a hydrogen atom or a C 1 unsubstituted or substituted with a hydrogen atom, nitro, halogen, amine, acetamide, carboamide, sulfonamide group or phenyl group. To C 20 chain, branched alkyl group, alkenyl group, alkynyl group, alkoxy group, provided that R 8 and A 3 are not hydrogen atoms at the same time

(

Figure 112006049660803-pat00006
) 점선은 이중결합 또는 단일결합을 의미한다. (
Figure 112006049660803-pat00006
) Dashed line means double bond or single bond.

상기 일반식(Ⅱ)의 보다 바람직한 화합물군으로는 n은 0 내지 2의 정수이고; ; R2 내지 R6은 각각 독립적으로 수소원자, 히드록시기, 할로겐, 아민, C1 내지 C4의 저급 알킬기, C1 내지 C4의 알켄일기 또는 C1 내지 C4의 저급 알콕시기로부터 선택된 하나이상의 치환기이고; R8 및 A3 중 하나가 수소원자이며, 남은 치환기는 각각 독립적으로 수소원자, 니트로, 할로겐, 아민, 아세트아미드, 카보 아미드, 설폰 아미드기 또는 페닐기로 치환되거나 비치환된 C1 내지 C10의 쇄상, 가지상 알킬기, 알켄일기 및 알키닐기로부터 선택된 하나이상의 치환기인 화합물군을 들 수 있다. As a more preferable compound group of the said general formula (II), n is an integer of 0-2; ; R 2 to R 6 are each independently at least one substituent selected from a hydrogen atom, a hydroxy group, a halogen, an amine, a C 1 to C 4 lower alkyl group, a C 1 to C 4 alkenyl group or a C 1 to C 4 lower alkoxy group ego; One of R 8 and A 3 is a hydrogen atom, and the remaining substituents each independently represent a hydrogen atom, a nitro, a halogen, an amine, an acetamide, a carboamide, a sulfonamide group, or a C 1 to C 10 unsubstituted or substituted with a phenyl group. And compound groups which are at least one substituent selected from chain, branched alkyl, alkenyl and alkynyl groups.

상기 일반식 (II) 화합물의 가장 바람직한 화합물들로서 하기와 같은 화합물들을 들 수 있으며, 본 발명은 발명의 범위를 이에 제한하고자 함이 아니다.The most preferable compounds of the general formula (II) compounds include the following compounds, and the present invention is not intended to limit the scope of the invention thereto.

2-(2-옥소-2H-크로멘-3-일메틸)-펜트-4-에노익 엑시드 히드록시아미드, N-히드록시-2-메틸-3-(6-메틸-2-옥소-2H-크로멘-3-일)-프로피온아미드, 2-(7-메톡시-2-옥소-2H-크로멘-3-일메틸)-펜트-4-에노익 엑시드 히드록시아미드, 2-(6-메톡시-2-옥소-2H-크로멘-3-일메틸)-펜트-4-에노익 엑시드 히드록시아미드, N-히드록시-3-(7-메톡시-2-옥소-2H-크로멘-3-일)-2-메틸-프로피온아미드, N-히드록시-2-메틸-3-(7-메틸-2-옥소-2H-크로멘-3-일)-프로피온아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-펜트-4-에노익 엑시드 히드록시아미드, 2-벤질-N-히드록시-3-(6-메톡시-2-옥소-2H-크로멘-3-일)-프로피온아미드, 2-벤질-N-히드록시-3-(2-옥소-2H-크로멘-3-일)-프로피온아미드, 2-벤질-N-히드록시-3-(7-메톡시-2-옥소-2H-크로멘-3-일)-프로피온아미드, 3-(7-플루오로-2-옥소-2H-크로멘-3-일)-N-히드록시-2-메틸-프로피온아미드, 3-(7-클로로-2-옥소-2H-크로멘-3-일)-N-히드록시-2-메틸-프로피온아미드, 2- 벤질-3-(7-클로로-2-옥소-2H-크로멘-3-일)-N-히드록시-프로피온아미드, 2-벤질-N-히드록시-3-(7-메틸-2-옥소-2H-크로멘-3-일)-프로피온아미드, 2-벤질-3-(7-플루오로-2-옥소-2H-크로멘-3-일)-N-히드록시-프로피온아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-6-페닐-헥사노익 엑시드 히드록시아미드, 4-메틸-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-펜타노익 엑시드 히드록시아미드, N-히드록시-3-메틸-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-도데카노익 엑시드 히드록시아미드, 3-(7-플루오로-6-메틸-2-옥소-2H-크로멘-3-일)-N-히드록시-2-메틸-프로피온아미드, N-히드록시-2-메틸-3-(2-옥소-2H-크로멘-3-일)프로피온아미드, 2-벤질-N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-프로피온아미드, N-히드록시-3-(6-메톡시-2-옥소-2H-크로멘-3-일)-아크릴아미드, 또는 N-히드록시-2,2-디메틸-3-(6-메틸-옥소-2H-크로멘-3-일)-프로피온아미드인 화합물.2- (2-oxo-2H-chromen-3-ylmethyl) -pent-4-enoic acid hydroxyamide, N -hydroxy-2-methyl-3- (6-methyl-2-oxo-2H -Cromen-3-yl) -propionamide, 2- (7-methoxy-2-oxo-2H-chromen-3-ylmethyl) -pent-4-enoic acid hydroxyamide, 2- (6 -Methoxy-2-oxo-2H-chromen-3-ylmethyl) -pent-4-enoic acid hydroxyamide, N -hydroxy-3- (7-methoxy-2-oxo-2H-chrome Men-3-yl) -2-methyl-propionamide, N -hydroxy-2-methyl-3- (7-methyl-2-oxo-2H-chromen-3-yl) -propionamide, 2- ( 6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -pent-4-enoic acid hydroxyamide, 2-benzyl- N -hydroxy-3- (6-methoxy-2-oxo -2H-chromen-3-yl) -propionamide, 2-benzyl- N -hydroxy-3- (2-oxo-2H-chromen-3-yl) -propionamide, 2-benzyl- N -hydroxy Roxy-3- (7-methoxy-2-oxo-2H-chromen-3-yl) -propionamide, 3- (7-fluoro-2-oxo-2H-chromen-3-yl) -N Hydroxy-2-meth Propionamide, 3- (7-chloro-2-oxo -2H- chromene-3-yl) - N-hydroxy-2-methyl-propionamide, 2-benzyl-3- (7-chloro-2 Oxo-2H-chromen-3-yl) -N -hydroxy-propionamide, 2-benzyl- N -hydroxy-3- (7-methyl-2-oxo-2H-chromen-3-yl)- Propionamide, 2-benzyl-3- (7-fluoro-2-oxo-2H-chromen-3-yl) -N -hydroxy-propionamide, 2- (6-methyl-2-oxo-2H- Chromen-3-ylmethyl) -6-phenyl-hexanoic acid hydroxyamide, 4-methyl-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -pentanoic acid acid hydroxide Hydroxyamide, N -hydroxy-3-methyl-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide, 2- (6-methyl-2-oxo-2H- Chromen-3-ylmethyl) -dodecanoic acid hydroxyamide, 3- (7-fluoro-6-methyl-2-oxo-2H-chromen-3-yl) -N -hydroxy-2- Methyl-propionamide, N -hydroxy-2-methyl-3- (2-oxo-2H-chromen-3-yl) propionamide, 2-benzyl- N -hydroxy-3- (6-Methyl-2-oxo-2H-chromen-3-yl) -propionamide, N -hydroxy-3- (6-methoxy-2-oxo- 2H -chromen-3-yl)- Acrylamide, or N -hydroxy-2,2-dimethyl-3- (6-methyl-oxo-2H-chromen-3-yl) -propionamide.

또한 보다 구체적으로 본 발명은 염증 관련 질환의 치료에 유용한, 하기 일반식 (III)의 구조를 갖는 화합물 또는 이의 약리학적으로 허용가능한 염 및 그 이성체를 제공한다:More specifically, the present invention also provides a compound having the structure of Formula (III) or a pharmacologically acceptable salt thereof and isomer thereof, useful for the treatment of inflammation-related diseases:

Figure 112006049660803-pat00007
Figure 112006049660803-pat00007

상기 식에서 R1는 -OH, -NHOH이고; n은 0 내지 3의 정수이고; m은 1 내지 10의 정수이고; X는 질소원자 또는 탄소원자이고; R2 내지 R6은 각각 독립적으로 수소원자, 히드록시기, 할로겐, 아민, C1 내지 C4의 저급 알킬기, C1 내지 C4의 저급 알켄일기 또는 C1 내지 C4의 저급 알콕시기로부터 선택된 하나이상의 치환기이며; A1은 각각 독립적으로 니트로, 할로겐 아민, 아세트아미드, 카보 아미드, 설폰 아미드기, 히드록시기, 아세틸기, 아세톡시기, 알킬카보닐기, 알킬에스테르기 또는, C1 내지 C5의 알콕시기, C1 내지 C5의 디알킬아민, C1 내지 C5의 모노알킬아민 또는 아민기로 치환된 C1 내지 C20의 쇄상, 가지상 알킬기, 알켄일기, 알키닐기 및 알콕시기로부터 선택된 하나이상의 치환기이다. In which R 1 is -OH, -NHOH; n is an integer from 0 to 3; m is an integer from 1 to 10; X is a nitrogen atom or a carbon atom; R 2 to R 6 each independently represent a hydrogen atom, a hydroxy group, halogen, amine, C 1 to a lower alkyl group, C 1 to a lower alkenyl group or a C 1 to a lower alkoxy group at least one group selected from a C 4 of the C 4 of the C 4 A substituent; A 1 is each independently nitro, halogen amine, acetamide, carbonamide, sulfonamide group, hydroxy group, acetyl group, acetoxy group, alkylcarbonyl group, alkylester group or C 1 to C 5 alkoxy group, C 1 to C 5 is a dialkyl amine, C 1 to C 5 chain of the group, monoalkyl amine or amine-substituted C 1 to C 20 a, of the alkyl group, alkenyl group, alkynyl group and one or more substituents selected from an alkoxy group.

상기 일반식(Ⅲ)의 보다 바람직한 화합물군으로는 R1는 -NHOH이고; n은 0 내지 2의 정수이고; m은 1 내지 5의 정수이고; R2 내지 R6은 각각 독립적으로 수소원 자, 할로겐, 아민, C1 내지 C4의 저급 알킬기, C1 내지 C4의 저급 알켄일기 또는 C1 내지 C4의 저급 알콕시기로부터 선택된 하나이상의 치환기이며; A1은 각각 독립적으로 니트로, 할로겐 아민, 아세트아미드, 카보 아미드, 설폰 아미드기, 히드록시기, 아세틸기, 아세톡시기, 알킬카보닐기, 알킬에스테르기, 또는 C1 내지 C5의 알콕시기, C1 내지 C5의 디알킬아민, C1 내지 C5의 모노알킬아민 또는 아민기로 치환된 C1 내지 C10의 쇄상, 가지상 알킬기, 알켄일기, 알키닐기, 알콕시기로부터 선택된 하나이상의 치환기인 화합물군을 들 수 있다. As a more preferable compound group of the general formula (III), R 1 is -NHOH; n is an integer from 0 to 2; m is an integer from 1 to 5; R 2 to R 6 are each party may independently wish, halogen, amine, C 1 to C lower alkyl group of 4, C 1 to C 4 lower alkene in the group or C 1 to one or more substituents selected from a lower alkoxy group of C 4 Is; A 1 is each independently nitro, halogen amine, acetamide, carbonamide, sulfonamide group, hydroxy group, acetyl group, acetoxy group, alkylcarbonyl group, alkylester group, or C 1 to C 5 alkoxy group, C 1 to C 5 of a dialkyl amine, C 1 to C 5 mono alkyl chain of C 1 to C 10 substituted with an amine or an amine, of the alkyl group, an alkenyl group, an alkynyl group, a compound group one or more substituents selected from an alkoxy group Can be mentioned.

상기 일반식 (III) 화합물의 가장 바람직한 화합물들로서 하기와 같은 화합물들을 들 수 있으며, 본 발명은 발명의 범위를 이에 제한하고자 함이 아니다.The most preferred compounds of the general formula (III) compounds include the following compounds, and the present invention is not intended to limit the scope of the invention thereto.

N-히드록시-4-(4-히드록시-페닐)-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 6-[4-(3-히드록시-프로폭시)-페닐]-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-헥사노익 엑시드 히드록시아미드, 6-[4-(3-메톡시-프로폭시)-페닐]-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-헥사노익 엑시드 히드록시아미드, 아세틱 엑시드 4-[3-히드록시카바모일-4-(6-메틸-2-옥소-2H-크로멘-3-일)-부틸]-페닐 에스터, 2-[3-(2-디메틸아미노-에톡시)-벤질]-N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-프로피온아미드, 4-[4-(3-디메틸아미노-프로폭시)-페닐]-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 5-[3-(3-디메틸아미노-프로폭시)-페닐]-2- (6-메틸-2-옥소-2H-크로멘-3-일메틸)-펜탄오익 엑시드 히드록시아미드, 5-[4-(3-디메틸아미노-프로폭시)-페닐]-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-펜탄오익 엑시드 히드록시아미드, 4-[4-(2-디메틸아미노-에톡시)-페닐]-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일-메틸)-부틸아미드, 4-[4-(2-디에틸아미노-에톡시)-페닐]-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 4-[4-(2-디이소프로필아미노-에톡시)-페닐]-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 6-[4-(3-디메틸아미노-프로폭시)-페닐]-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-헥사노익 엑시드 히드록시아미드, 4-[4-(3-디메틸아미노-프로폭시)-페닐]-N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 4-(4-부트-2-일옥시-페닐)-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 4-[4-(2-디에틸아미노-에톡시)-페닐]-N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 2-(7-클로로-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-디메틸아미노프로폭시)페닐]-N-히드록시-부틸아미드, 4-[4-(3-디메틸아미노-프로폭시)-페닐]-2-(7-플루오로-2-옥소-2H-크로멘-3-일메틸)-N-히드록시-부틸아미드, (4-[4-(3-디메틸아미노-프로필아미노)-페닐]-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 4-[4-(2-디에틸아미노-에톡시)-페닐]-N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드 하이드로클로라이드, 또는 {2-[4-(2-디에틸아미노-에톡시)-페닐]-에틸}-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-아민-N-카르보하이드록사믹 액시드 인 화합물. N -hydroxy-4- (4-hydroxy-phenyl) -2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide, 6- [4- (3-hydroxy Hydroxy-propoxy) -phenyl] -2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -hexanoic acid hydroxyamide, 6- [4- (3-methoxy-prop Foxy) -phenyl] -2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -hexanoic acid hydroxyamide, acetic acid 4- [3-hydroxycarbamoyl-4- (6-Methyl-2-oxo-2H-chromen-3-yl) -butyl] -phenyl ester, 2- [3- (2-dimethylamino-ethoxy) -benzyl] -N -hydroxy-3- (6-Methyl-2-oxo-2H-chromen-3-yl) -propionamide, 4- [4- (3-dimethylamino-propoxy) -phenyl] -N -hydroxy-2- (6- Methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide, 5- [3- (3-dimethylamino-propoxy) -phenyl] -2- (6-methyl-2-oxo-2H -Cromen-3-ylmethyl) -pentanoic acid hydroxyamide, 5- [4- (3-dimethylamino-propoxy) -phenyl] -2- (6-methyl-2-oxo-2H-chromen -3-ylmethyl) -pentaneoic Exe hydroxyamide, 4- [4- (2-dimethylamino-ethoxy) -phenyl] -N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-yl-methyl) -Butylamide, 4- [4- (2-diethylamino-ethoxy) -phenyl] -N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl)- Butylamide, 4- [4- (2-diisopropylamino-ethoxy) -phenyl] -N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl)- Butylamide, 6- [4- (3-dimethylamino-propoxy) -phenyl] -2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -hexanoic acid hydroxyamide, 4- [4- (3-Dimethylamino-propoxy) -phenyl] -N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide, 4- (4-But-2-yloxy-phenyl) -N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide, 4- [4- (2 -Diethylamino-ethoxy) -phenyl] -N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide, 2- (7-chloro-2 -Oxo-2H-chromen-3-ylmethyl) -4- [4- (3-di Butyl-amino-propoxy) phenyl] - N-hydroxy-butylamide, 4- [4- (3-dimethylamino-propoxy) -phenyl] -2- (7-fluoro-2-oxo -2H- chromene -3-ylmethyl) -N -hydroxy-butylamide, (4- [4- (3-dimethylamino-propylamino) -phenyl] -N -hydroxy-2- (6-methyl-2-oxo- 2H-chromen-3-ylmethyl) -butylamide, 4- [4- (2-diethylamino-ethoxy) -phenyl] -N -hydroxy-2- (7-methyl-2-oxo-2H -Chromen-3-ylmethyl) -butylamide hydrochloride, or {2- [4- (2-diethylamino-ethoxy) -phenyl] -ethyl}-(7-methyl-2-oxo-2H- Chromen-3-ylmethyl) -amine- N -carbohydroxyxamic acid phosphorus compound.

또한 보다 구체적으로 본 발명은 염증 관련 질환의 치료에 유용한, 하기 일반식 (IV)의 구조를 갖는 화합물 또는 이의 약리학적으로 허용가능한 염 및 그 이성체를 제공한다:More specifically, the present invention also provides a compound having the structure of Formula (IV) or a pharmacologically acceptable salt thereof and isomer thereof useful for the treatment of inflammation-related diseases:

Figure 112006049660803-pat00008
Figure 112006049660803-pat00008

상기 식에서 R1는 -OH, -NHOH 이고; n은 0 내지 3의 정수이고; m은 1 내지 10의 정수이고; X는 각각 독립적으로 질소원자 또는 탄소원자이고; R2 내지 R6은 각각 독립적으로 수소원자, 히드록시기, 할로겐, 아민, C1 내지 C4의 저급 알킬기, C1 내지 C4의 알켄일기 또는 C1 내지 C4의 저급 알콕시기로부터 선택된 하나이상의 치환기이며; P 치환기는 하나 이상의 R'치환기로 임의로 치환 가능한 5 내지 7원의 시클릭환, 아릴 방향환, 헤테로 복소환 또는 이들이 상호 융합되거나 직접 연결된 환이며, 여기에서 R'는 수소원자, 니트로, 할로겐, C1 내지 C5의 디알킬아민, C1 내지 C5의 모노알킬아민, 아민, 아세트아미드, 아세톡시기, 히드록시기, 카보아미드, 설폰 아미드기, 카보닐기, C1 내지 C10의 알킬기, 알켄일기 또는 알콕시기이며; Y는 O, N. 또는 C 원자이며; o는 1 내지 6의 정수이다. R in the above formulaOneIs -OH, -NHOH; n is an integer from 0 to 3; m is an integer from 1 to 10; Each X is independently a nitrogen atom or a carbon atom; R2 To R6Are each independently a hydrogen atom, a hydroxyl group, a halogen, an amine, or COne To C4Lower alkyl groups, COne To C4Alkenyl or COne To C4At least one substituent selected from lower alkoxy groups of; P substituent is a 5 to 7 membered cyclic ring, an aryl aromatic ring, a hetero heterocyclic ring or a ring in which they are mutually fused or directly connected to one or more R 'substituents, wherein R' is a hydrogen atom, nitro, halogen, COne To C5Of dialkylamines, COne To C5Monoalkylamine, amine, acetamide, acetoxy group, hydroxy group, carboamide, sulfonamide group, carbonyl group, COne To C10An alkyl group, an alkenyl group or an alkoxy group of; Y is O, N. or C atom; o is an integer from 1 to 6.

상기 일반식(Ⅳ)의 보다 바람직한 화합물군으로는 R1는 -OH, -NHOH 이고; n은 0 내지 2의 정수이고; m은 1 내지 5의 정수이고; X는 탄소원자이고; R2 내지 R6은 각각 독립적으로 수소원자, 히드록시기, 할로겐, 아민, C1 내지 C4의 저급 알킬기, C1 내지 C4의 저급 알켄일기 또는 C1 내지 C4의 저급 알콕시기로부터 선택된 하나이상의 치환기이며; P 치환기는 비치환되거나 또는 수소원자, 할로겐, 아미노, 히드록시기, 카보닐기, C1 내지 C4의 알킬, 알케닐 또는 알콕시기로부터 선택된 하나이상의 치환기로 치환 가능한 5 내지 7원의 페닐환과 같은 방향환, 피롤, 피레리딘, 피페라진, 피리미딘, 피리다진, 피롤리딘, 모폴린, 티아졸 등과 같은 복소환, 시클로펜탄, 시클로헥산 등과 같은 시클릭환 시클릭환 또는 이들이 상호 융합된 10 내지 20원의 퀴놀린, 퀴나졸린, 인돌 등과 같은 융합된 융합환이며, Y는 O, N 또는 C 원자이며, o는 1 내지 5의 정수인 화합물군을 들 수 있다. As a more preferable compound group of the general formula (IV), R 1 is -OH, -NHOH; n is an integer from 0 to 2; m is an integer from 1 to 5; X is a carbon atom; R 2 to R 6 each independently represent a hydrogen atom, a hydroxy group, halogen, amine, C 1 to a lower alkyl group, C 1 to a lower alkenyl group or a C 1 to a lower alkoxy group at least one group selected from a C 4 of the C 4 of the C 4 A substituent; P substituent is an aromatic ring such as a 5-7 membered phenyl ring which is unsubstituted or substituted with one or more substituents selected from hydrogen, halogen, amino, hydroxy, carbonyl, C 1 to C 4 alkyl, alkenyl or alkoxy groups , Heterocyclic ring such as pyrrole, pyriridine, piperazine, pyrimidine, pyridazine, pyrrolidine, morpholine, thiazole, cyclic ring cyclic rings such as cyclopentane, cyclohexane or the like or from 10 to 10 And a fused fused ring such as quinoline, quinazoline, indole and the like of 20 members, Y is O, N or C atom, and o is an integer of 1 to 5.

상기 일반식 (IV) 화합물의 가장 바람직한 화합물들로서 하기와 같은 화합물들을 들 수 있으며, 본 발명은 발명의 범위를 이에 제한하고자 함이 아니다.The most preferred compounds of the above general formula (IV) include the following compounds, and the present invention is not intended to limit the scope of the invention thereto.

2-(4-벤질옥시-벤질)-N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-프로피온아미드, 4-(4-벤질옥시-페닐)-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸 아미드, 2-(3-벤질옥시-벤질)-N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-프로피온아미드, 4-(3-벤질옥시-페닐)-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[3-(3-피리딘-4-일-프로폭시)-벤질]-프로피온아미드, 5-{4-[3-(4-디메틸아미노-페닐)-프로폭시]-페닐}-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-펜타노익 엑시드 히드록시아미드, 4-{4-[3-(4-아미노페닐)-프로폭시]-페닐}-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[4-(2-피페리딘-1-일-에톡시)-벤질]-프로피온아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-메틸-퀴놀린-4-일-메톡시)-페닐]-부틸아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[4-(2-모르폴린-4-일-에톡시)-벤질]-프로피온아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[4-(3-모르폴린-4-일-프로폭시)-벤질]-프로피온아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[4-(3-피리딘-4-일-프로폭시)-벤질]-프로피온아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[3-(3-모르폴린-4-일-프로폭시)-벤질]-프로피온아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-피페리딘-1-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-피리딘-4-일-프로폭시)-페닐]-부틸아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[4-(3-피페리딘-1-일-프로폭시)-벤질]-프로피온아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-모르폴린-4-일-프로폭시)-페닐]-부틸아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[3-(2-모르폴린-4-일-에톡시)-벤질] -프로피온아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(3-피페리딘-1-일-프로폭시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(2-피리딘-1-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(3-모르폴린-4-일-프로폭시)-페닐]-부틸아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[3-(2-피페리딘-1-일-에톡시)-벤질]-프로피온아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[3-(3-피페리딘-1-일-프로폭시)-벤질]-프로피온아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(3-피리딘-4-일-프로폭시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(2-메틸-퀴놀린-4-일-메톡시)-페닐]-부틸아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[3-(2-메틸-퀴놀린-4-일-메톡시)-벤질]-프로피온아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(4-피리딘-4-일-부톡시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-피리딘-4-일-에톡시)-페닐]-부틸아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[4-(4-피리딘-4-일-부톡시)-벤질]-프로피온아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[3-(4-피리딘-4-일-부톡시)-벤질]-프로피온아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-피페리딘-1-일-프로폭시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[4-(2-피페리딘-1-일-에톡시)- 페닐]-펜타노익 엑시드 히드록시아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[4-(3-피페리딘-1-일-프로폭시)-페닐]-펜타노익 엑시드 히드록시아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[4-(3-모르폴린-4-일-프로폭시)-페닐]-펜타노익 엑시드 히드록시아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[3-(2-모르폴린-4-일-에톡시)-페닐]-펜타노익 엑시드 히드록시아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[3-(3-모르폴린-4-일-프로폭시)-페닐]-펜타노익 엑시드 히드록시아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[3-(2-피페리딘-1-일-에톡시)-페닐]-펜탄오익 엑시드 히드록시아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[3-(3-피페리딘-1-일-프로폭시)-페닐]-펜타노익 엑시드 히드록시아미드, 4-{3-[3-(4-디메틸아미노-페닐)-프로폭시]-페닐}-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[4-(2-모르폴린-4-일-에톡시)-페닐]-펜타노익 엑시드 히드록시아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-피롤-1-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-{4-[2-(2-옥소-피롤리딘-1-일)-에톡시]-페닐}-부틸아미드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(2-피페리딘-1-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(3-피페리딘-1-일-프로폭시)-페닐]-부틸아미드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(3-모르폴린-4-일-프로폭시)-페닐]-부틸아미드, 4-[4-(3-[1,4']바이피페리디닐-1'-일-프로폭시)-페닐]-N-히드록시-2- (6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-모르폴린-4-일-프로폭시)-페닐]-부틸아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-6-[4-(3-피페리딘-1-일-프로폭시)-페닐]-헥사노익 엑시드 히드록시아미드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-피페리딘-1-일-프로폭시)-페닐]-부틸아미드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-피페리딘-1-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-{4-[3-(4-메틸-피페라진-1-일)-프로폭시]-페닐}-부틸아미드, N-히드록시-4-(4-3-[4-(2-히드록시-에틸)-피페라진-1-일]-프로폭시-페닐)-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 2-(7-플루오로-2-옥소-2H-크로멘-3-일메틸)-N-히드록시-4-[4-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드, 2-(7-클로로-2-옥소-2H-크로멘-3-일메틸)-N-히드록시-4-[4-(3-피페리딘-1-일-프로폭시)-페닐]-부틸아미드, 2-(7-클로로-2-옥소-2H-크로멘-3-일메틸)-N-히드록시-4-[4-(3-모르폴린-4-일-프로폭시)-페닐]-부틸아미드, 2-(7-플루오로-2-옥소-2H-크로멘-3-일메틸)-N-히드록시-4-[4-(3-피페리딘-1-일-프로폭시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-피롤리딘-1-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-{4-[2-(4-메틸-피페라진-1-일)-에톡시]-페닐}-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-피페라진-1-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-{4-[3-(4-옥 소-피페리딘-1-일)-프로폭시]-페닐}-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-피롤리딘-1-일-프로폭시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-{4-[3-(4-메틸-피페라진-1-일)-프로폭시]-페닐}-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-피페라진-1-일-프로폭시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-모르폴린-4-일-프로필아미노)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-피페리딘-1-일-프로필아미노)-페닐]-부틸아미드, 2-(7-플루오로-2-옥소-2H-크로멘-3-일메틸)-N-히드록시-4-[4-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드 하이드로클로라이드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드 하이드로클로라이드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-모르폴린-4-일-프로폭시)-페닐]-부틸아미드 하이드로클로라이드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-피페리딘-1-일-프로폭시)-페닐]-부틸아미드 하이드로클로라이드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(4-피페리딘-1-일-부틸)-페닐]-부틸아미드 하이드로크로라이드인 화합물2- (4-benzyloxy-benzyl) -N -hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -propionamide, 4- (4-benzyloxy-phenyl) N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butyl amide, 2- (3-benzyloxy-benzyl) -N -hydroxy-3- ( 6-Methyl-2-oxo-2H-chromen-3-yl) -propionamide, 4- (3-benzyloxy-phenyl) -N -hydroxy-2- (6-methyl-2-oxo-2H- Chromen-3-ylmethyl) -butylamide, N -hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [3- (3-pyridine-4- Yl-propoxy) -benzyl] -propionamide, 5- {4- [3- (4-dimethylamino-phenyl) -propoxy] -phenyl} -2- (6-methyl-2-oxo-2H-chrome Men-3-ylmethyl) -pentanoic acid hydroxyamide, 4- {4- [3- (4-aminophenyl) -propoxy] -phenyl} -N -hydroxy-2- (6-methyl-2 -Oxo-2H-chromen-3-ylmethyl) -butylamide, N -hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [4- (2 -piperidin-1-yl-ethoxy) -benzyl] -propionamide, N-hydroxy-2- (6-methyl-2-oxide -2H- chromene-3-ylmethyl) -4- [4- (2-methyl-quinolin-4-yl-methoxy) phenyl] butylamide, N-hydroxy-3- (6-methyl- 2-oxo-2H-chromen-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -propionamide, N -hydroxy-3- (6-methyl -2-oxo-2H-chromen-3-yl) -2- [4- (3-morpholin-4-yl-propoxy) -benzyl] -propionamide, N -hydroxy-3- (6- Methyl-2-oxo-2H-chromen-3-yl) -2- [4- (3-pyridin-4-yl-propoxy) -benzyl] -propionamide, N -hydroxy-3- (6- Methyl-2-oxo-2H-chromen-3-yl) -2- [3- (3-morpholin-4-yl-propoxy) -benzyl] -propionamide, N -hydroxy-2- (6 -Methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -butylamide, N -hydroxy-2 -(6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (3-pyridin-4-yl-propoxy) -phenyl] -butylamide, N -hydroxy- 3- (6-Methyl-2-oxo-2H-chromen-3-yl) -2- [4- (3-piperidin-1-yl-propoxy) -benzyl] -propionamide, N -hydride rock 2- (6-methyl-2-oxo -2H- chromene-3-yl) -4- [4- (3-morpholin-4-yl-propoxy) -phenyl] butylamide, N - Hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [3- (2-morpholin-4-yl-ethoxy) -benzyl] -propionamide, N -Hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (3-piperidin-1-yl-propoxy) -phenyl] -butyl Amide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (2-pyridin-1-yl-ethoxy) -phenyl]- Butylamide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (2-morpholin-4-yl-ethoxy) -phenyl ] -Butylamide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (3-morpholin-4-yl-propoxy) -Phenyl] -butylamide, N -hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [3- (2-piperidin-1-yl-e) Methoxy) -benzyl] -propionamide, N -hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [3- (3-piperidin-1-yl -Propoxy) -benzyl] -propionami , N-hydroxy-2- (6-methyl-2-oxo -2H- chromene-3-ylmethyl) -4- [3- (3-pyridin-4-yl-propoxy) -phenyl] -butyl Amide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (2-methyl-quinolin-4-yl-methoxy) -phenyl ] -Butylamide, N -hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [3- (2-methyl-quinolin-4-yl-methoxy) -Benzyl] -propionamide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (4-pyridin-4-yl-butoxy ) -Phenyl] -butylamide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (2-pyridin-4-yl-e) Methoxy) -phenyl] -butylamide, N -hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [4- (4-pyridin-4-yl-part Methoxy) -benzyl] -propionamide, N -hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [3- (4-pyridin-4-yl-part Methoxy) -benzyl] -propionamide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (3-piperidine-1- Mono-propoxy) -phenyl] -butyl Amide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -Butylamide, 2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -penta Norick acid hydroxyamide, 2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [4- (3-piperidin-1-yl-propoxy) -phenyl] -Pentanoic acid hydroxyamide, 2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [4- (3-morpholin-4-yl-propoxy) -phenyl ] -Pentanoic acid hydroxyamide, 2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [3- (2-morpholin-4-yl-ethoxy)- Phenyl] -pentanoic acid hydroxyamide, 2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [3- (3-morpholin-4-yl-propoxy) -Phenyl] -pentanoic acid hydroxyamide, 2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [3- (2-piperidin-1-yl- Methoxy) -phenyl] -pentanoic acid hydroxyamide, 2- (6-methyl-2-jade -2H-chromen-3-ylmethyl) -5- [3- (3-piperidin-1-yl-propoxy) -phenyl] -pentanoic acid hydroxyamide, 4- {3- [3- (4-Dimethylamino-phenyl) -propoxy] -phenyl} -N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide, 2- (6 -Methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -pentanoic acid hydroxyamide, N -hydroxy Oxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (2-pyrrole-1-yl-ethoxy) -phenyl] -butylamide, N − Hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- {4- [2- (2-oxo-pyrrolidin-1-yl) -ethoxy] -Phenyl} -butylamide, N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (2-piperidin-1-yl- Ethoxy) -phenyl] -butylamide, N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (3-piperidine-1 -Yl-propoxy) -phenyl] -butylamide, N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (2-morpholine -4 -Yl-ethoxy) -phenyl] -butylamide, N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (3-morpholine 4-yl-propoxy) -phenyl] -butylamide, 4- [4- (3- [1,4 '] bipiperidinyl-1'-yl-propoxy) -phenyl] -N -hydroxy 2- (6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide, N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-yl Methyl) -4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -butylamide, N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3 -Ylmethyl) -4- [4- (3-morpholin-4-yl-propoxy) -phenyl] -butylamide, 2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl ) -6- [4- (3-piperidin-1-yl-propoxy) -phenyl] -hexanoic acid hydroxyamide, N -hydroxy-2- (7-methyl-2-oxo-2H- Chromen-3-ylmethyl) -4- [4- (3-piperidin-1-yl-propoxy) -phenyl] -butylamide, N -hydroxy-2- (7-methyl-2-oxo -2H-chromen-3-ylmethyl) -4- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -butylamide, N -hydroxy-2- (7-methyl- 2- Bovine -2H- chromene-3-ylmethyl) -4- {4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} butylamide, N-hydroxy-4 -(4-3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy-phenyl) -2- (7-methyl-2-oxo-2H-chromen-3- Monomethyl) -butylamide, 2- (7-fluoro-2-oxo-2H-chromen-3-ylmethyl) -N -hydroxy-4- [4- (2-morpholin-4-yl- Ethoxy) -phenyl] -butylamide, 2- (7-chloro-2-oxo-2H-chromen-3-ylmethyl) -N -hydroxy-4- [4- (3-piperidine-1 -Yl-propoxy) -phenyl] -butylamide, 2- (7-chloro-2-oxo-2H-chromen-3-ylmethyl) -N -hydroxy-4- [4- (3-morpholine 4-yl-propoxy) -phenyl] -butylamide, 2- (7-fluoro-2-oxo-2H-chromen-3-ylmethyl) -N -hydroxy-4- [4- (3 -Piperidin-1-yl-propoxy) -phenyl] -butylamide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4 -(2-Pyrrolidin-1-yl-ethoxy) -phenyl] -butylamide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4 -{4- [2- (4- Butyl-piperazin-1-yl) -ethoxy] -phenyl} butylamide, N-hydroxy-2- (6-methyl-2-oxo -2H- chromene-3-ylmethyl) -4- [ 4- (2-piperazin-1-yl-ethoxy) -phenyl] -butylamide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4 -{4- [3- (4-oxo-piperidin-1-yl) -propoxy] -phenyl} -butylamide, N -hydroxy-2- (6-methyl-2-oxo-2H- Chromen-3-ylmethyl) -4- [4- (3-pyrrolidin-1-yl-propoxy) -phenyl] -butylamide, N -hydroxy-2- (6-methyl-2-oxo -2H-chromen-3-ylmethyl) -4- {4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -butylamide, N -hydroxy-2- (6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (3-piperazin-1-yl-propoxy) -phenyl] -butylamide, N -hydroxy- 2- (6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (3-morpholin-4-yl-propylamino) -phenyl] -butylamide, N -hydride Oxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (3-piperidin-1-yl-propylamino) -phenyl] -butylamide, 2-( 7-fluoro-2-oxo-2H-chromen-3-ylmethyl) -N -hydroxy-4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -butylamide hydro Chloride, N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -Butylamide hydrochloride, N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (3-morpholin-4-yl-propoxy ) -Phenyl] -butylamide hydrochloride, N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (3-piperidine-1 -Yl-propoxy) -phenyl] -butylamide hydrochloride, N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (4- Piperidin-1-yl-butyl) -phenyl] -butylamide hydrochloride

상기 일반식 (Ⅰ) 내지 일반식 (IV)로 표시되는 본 발명의 화합물들은 당해 기술분야에서 통상적인 방법에 따라 약학적으로 허용가능한 염 및 용매화물로 제조될 수 있다. The compounds of the present invention represented by general formulas (I) to (IV) may be prepared as pharmaceutically acceptable salts and solvates according to methods conventional in the art.

염으로는 약학적으로 허용가능한 유리산 (free acid)에 의해 형성된 산부가 염이 유용하다. 산 부가염은 통상의 방법, 예를 들면 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조한다. 동몰량의 화합물 및 물 중의 산 또는 알코올 (예, 글리콜 모노메틸에테르)을 가열하고 이어서 상기 혼합물을 증발시켜서 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.As salts are acid addition salts formed with pharmaceutically acceptable free acids. Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of the compound and acid or alcohol (eg, glycol monomethylether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.

이 때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고 유기산으로는 메탄술폰산, p-톨루엔술폰산, 아세트산, 트리플루오로아세트산, 시트르산, 말레인산 (maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만데르산, 프로피온산 (propionic acid), 구연산 (citric acid), 젖산 (lactic acid), 글리콜산 (glycollic acid), 글루콘산 (gluconic acid), 갈락투론산, 글루탐산, 글루타르산 (glutaric acid), 글루쿠론산 (glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 히드로 아이오딕산 등을 사용할 수 있다.In this case, organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as the inorganic acid, and methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, Citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid ( gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, and the like.

또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리토 금속염은, 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리토 금속 수산화물 용액 중에 용해하고, 비용해 화합물염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이 때, 금속염으로서는 특히 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하며, 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리토 금속염을 적당한 은염 (예, 질산은)과 반응시켜 얻는다.Bases can also be used to make pharmaceutically acceptable metal salts. An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. At this time, as the metal salt, it is particularly suitable to prepare sodium, potassium or calcium salts, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

상기의 일반식 (Ⅰ) 내지 일반식 (IV) 화합물의 약학적으로 허용가능한 염 은, 달리 지시되지 않는 한, 일반식 (Ⅰ) 내지 일반식 (IV) 화합물에 존재할 수 있는 산성 또는 염기성기의 염을 포함한다. 예를 들면, 약학적으로 허용가능한 염으로는 히드록시기의 나트륨, 칼슘 및 칼륨 염이 포함되며, 아미노기의 기타 약학적으로 허용가능한 염으로는 히드로브로마이드, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄설포네이트 (메실레이트) 및 p-톨루엔설포네이트 (토실레이트) 염이 있으며, 당업계에서 알려진 염의 제조방법이나 제조과정을 통하여 제조될 수 있다.Pharmaceutically acceptable salts of the above general formulas (I) to (IV) compounds, unless otherwise indicated, of acidic or basic groups which may be present in the general formulas (I) to (IV) compounds Salts. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen Phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts, which are known in the art. It can be prepared through.

또한, 상기의 일반식 (Ⅰ) 내지 일반식 (IV) 화합물은 비대칭 중심을 가지므로 상이한 거울상 이성질체 형태로 존재할 수 있으며, 일반식 (Ⅰ) 내지 일반식 (IV) 화합물의 모든 광학 이성질체 및 R 또는 S형 입체 이성질체 및 이들의 혼합물도 본 발명의 범주내에 포함되는 것으로 한다. 본 발명은 라세미체, 하나 이상의 거울상 이성질체 형태, 하나 이상의 부분 입체 이성질체 형태 또는 이들의 혼합물의 용도를 포함하며, 당업계에서 알려진 이성질체의 분리 방법이나 제조과정을 포함한다. In addition, the above general formulas (I) to (IV) have asymmetric centers and therefore may exist in different enantiomeric forms, and all optical isomers and Rs of the general formulas (I) to (IV) or S-type stereoisomers and mixtures thereof are also included within the scope of the present invention. The present invention encompasses the use of racemates, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof, and includes methods or processes for the separation of isomers known in the art.

본 발명의 다른 목적은 상기 일반식 (Ⅰ) 내지 일반식 (IV) 화합물의 제조방법을 제공하는 것으로, 하기의 반응식들에 도시된 방법에 의해 화학적으로 합성될 수 있지만, 이들 예로만 한정되는 것은 아니다. Another object of the present invention is to provide a method for preparing the compounds of Formulas (I) to (IV), which may be chemically synthesized by the methods shown in the following schemes, but is not limited thereto only. no.

하기의 반응식들은 본 발명의 대표적인 화합물들의 제조방법을 제조 단계별로 나타내는 것으로 본 발명의 여러 화합물들은 반응식 1 내지 반응식 6의 합성과 정에서 사용되는 시약, 용매 및 반응 순서를 바꾸는 등의 작은 변경으로 제조될 수 있다. 본 발명의 몇몇 화합물들은 반응식 1 내지 반응식 6의 범주에 포함되지 않는 과정에 따라 합성되었으며, 이러한 화합물들에 대한 상세한 합성 과정은 이들 각각의 실시예에 설명되어 있다.The following reaction schemes represent the preparation steps of the representative compounds of the present invention. The various compounds of the present invention are prepared with small changes such as changing the reagents, solvents, and reaction sequences used in the synthesis of Schemes 1 to 6. Can be. Some compounds of the present invention have been synthesized according to procedures not included in the scope of Schemes 1-6, and detailed synthesis procedures for these compounds are described in their respective examples.

Figure 112006049660803-pat00009
Figure 112006049660803-pat00009

반응식 (1)은 상업적으로 쉽게 확보할 수 있거나 합성한 알데히드(I)을 출발물질로 하여 화합물(V)을 제조하기 위한 4단계 제조과정을 나타낸다. Scheme (1) shows a four-step process for preparing compound (V) using commercially available or synthesized aldehyde (I) as a starting material.

제 1단계에서는 트리에틸아민, 디에틸이소프로필아민 등 염기의 존재하에 유기용매 중에서 화합물 (I)를 4-클로로카보닐-부티르 산 메틸-1-에스테르와 반응시켜 화합물 (II)를 제조한다. 이 때, 유기용매로는 디클로로메탄, 클로로포름 등을 사용할 수 있으며, 사용되는 염기는 출발물질인 화합물 (I)에 대해 2 내지 3 당량으로 사용될 수 있고, 이들의 반응은 상온 내지 0 ℃에서 수행할 수 있다. 제 2단계는, 상기 1단계에서 얻어진 화합물 (II)을 1,8-디아자비씨클로[5,4,0]운데크-7-엔 (1,8-Diazabicyclo[5,4,0]undec-7-ene, DBU) 존재하에 유기용매 중에서 반응시 켜 화합물 (III)를 제조한다. 이 때, 유기용매로는 톨루엔, 크실렌, 벤젠 등을 사용할 수 있다. 이 때, 상기 1,8-디아자비씨클로[5,4,0]운데크-7-엔 (DBU)의 사용량은 화합물 (II)에 대해 2 내지 3 당량으로 사용될 수 있으며, 이들의 반응은 상온 내지 110 ℃ 범위의 온도에서 수행할 수 있다. 제 3단계에서는 상기 2단계에서 얻어진 화합물(III)을 테트라히드로퓨란 용액에서 리티움 헥사메칠디실라진 (LIHMDS)과 반응시킨 후 요오드메탄, 아릴브로마이드 또는 벤질브로마이드를 첨가하여 화합물 (V)을 합성한다. 이때 사용되는 용매는 테트라히드로퓨란 외에 디에틸에테르 등의 에테르 용매를 사용할 수 있고, 반응은 -78 ℃내지 상온의 범위에서 수행할 수 있다. 제 4단계에서는, 상기 화합물 (IV)을 알콜 용매 중에서 히드록시아민이나 아민 염과 반응시켜 본 발명에 따른 화학식 (Ⅰ)의 화합물 중 치환체 X가 -NHOH인 화합물 (V)을 수득할 수 있다. 이때 사용되는 아민 염은 칼륨 히드록시아미드가 바람직하고, 그 사용량은 화합물 (IV)에 대해 2 내지 3 당량이 바람직하며, 이들의 반응은 상온 내지 0 ℃ 범위의 온도에서 수행할 수 있다.In the first step, compound (II) is prepared by reacting compound (I) with 4-chlorocarbonyl-butyric acid methyl-1-ester in an organic solvent in the presence of a base such as triethylamine and diethylisopropylamine. . In this case, dichloromethane, chloroform, and the like may be used as the organic solvent, and the base used may be used in 2 to 3 equivalents with respect to the starting compound (I), and the reaction thereof may be performed at room temperature to 0 ° C. Can be. In the second step, the compound (II) obtained in the first step is converted into 1,8-diazabicyclo [5,4,0] undec-7-ene (1,8-Diazabicyclo [5,4,0] undec- 7-ene, DBU) is reacted in an organic solvent to prepare compound (III). At this time, toluene, xylene, benzene or the like can be used as the organic solvent. In this case, the amount of the 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) may be used in an amount of 2 to 3 equivalents based on compound (II), and their reaction may be performed at room temperature. It may be carried out at a temperature in the range from to 110 ℃. In the third step, the compound (III) obtained in step 2 is reacted with Lithium hexamethyldisilazine (LIHMDS) in a tetrahydrofuran solution, and then iodine methane, arylbromide or benzylbromide is added to synthesize compound (V). do. The solvent used may be an ether solvent such as diethyl ether in addition to tetrahydrofuran, the reaction can be carried out in the range of -78 ℃ to room temperature. In the fourth step, Compound (IV) may be reacted with a hydroxyamine or an amine salt in an alcohol solvent to obtain Compound (V) in which the substituent X in the compound of Formula (I) according to the present invention is -NHOH. At this time, the amine salt used is preferably potassium hydroxyamide, the amount of the amine salt is preferably used in the amount of 2 to 3 equivalents relative to compound (IV), and their reaction can be carried out at a temperature ranging from room temperature to 0 ° C.

Figure 112006049660803-pat00010
Figure 112006049660803-pat00010

반응식 (2)는 상용 알데히드(Ia)로부터 화합물(XII)을 제조하기 위한 제 6단계 제조과정을 나타낸다.Scheme (2) shows the sixth step of preparation for preparing compound (XII) from commercial aldehyde (Ia).

제 1단계에서는 알데히드 (Ia)와 2,2-디메틸-1,3-디옥산-4,6-디온을 건조된 알콜 용액에서 보란디메칠아민 착화물과 반응시켜 화합물 (VII)을 합성한다. 이 반응에 사용되는 용매로는 메탄올이나 에탄올과 같은 알콜류가 바람직하며, 온도는 일반적으로 상온에서 반응시킨다. In the first step, compound (VII) is synthesized by reacting aldehyde (Ia) and 2,2-dimethyl-1,3-dioxane-4,6-dione with borandimethylamine complex in a dried alcohol solution. As a solvent used for this reaction, alcohols, such as methanol and ethanol, are preferable, and temperature is generally made to react at normal temperature.

제 2단계에서는 1단계에서 합성된 화합물 (VII)을 N,N-디메틸 메틸렌암모늄 요오드 염과 반응시켜 화합물(VIII)을 제조하는 과정이다. 이런 간단한 만니히 반 응에서 사용되어지는 용매로는 메탄올이나 에탄올과 같은 알콜류가 바람직하며 간단한 알콜 이외에 벤질 알콜을 사용하는 경우도 있다. 반응 온도는 사용되어지는 용매에 무관하게 약 65 ℃가 적당하다. 제 3단계에서는 상기반응에서 제조된 화합물(VIII)을 소디움 하이드라이드 염기의 존재하에 트리에틸포스포노아세테이트와 반응시켜 화합물 (IX)를 제조하는 과정으로 이 때 사용되어지는 유기용매로는 테트라히드로퓨란 등을 사용할 수 있다. 소디움 하이드라이드 염기는 트리에틸포스포노아세테이트에 대하여 1.2~1.5당량 사용할 수 있으며, 이들의 반응은 0 ℃에서 트리에틸포스포노아세테이트의 음이온을 형성시킨 후 상온 범위에서 아크릴레이트와 반응시키는 것이 적당하다. 제 4단계에서는 상기반응에서 제조된 화합물 (IX)를 유기용매 테트라히드로퓨란에 용해시키고 t-리튬부톡사이드를 넣어 30분 동안 반응시킨 후 반응 혼합물에 알데히드화합물을 넣고 반응시켜 화합물 (X)을 합성한다. 이때 반응온도는 상온이 바람직하고 사용되어지는 염의 량은 출발 물질 (IX)에 대해 1~2 당량정도 사용하는 것이 적당하다. 제 5단계에서는 상기반응에서 제조된 화합물 (IX)을 염산용액에서 탈보호화반응을 진행시킨 후 고리화 반응에 요구되어지는 고온반응에 적당한 유기용매인 자일렌을 사용하여 160 ℃에서 가열하여 화합물 (XI)을 수득할 수 있다. 제 6단계의 반응은 상기 반응에서 얻어진 화합물 (XI)을 사용하여 반응식 (1)의 제 4단계의 화합물 (V)의 제조하는 방법과 동일한 조건으로 화합물 (XII)를 얻을 수 있다. In the second step, a compound (VIII) is prepared by reacting the compound (VII) synthesized in step 1 with an N, N-dimethyl methylene ammonium iodine salt. As the solvent used in this simple Mannich reaction, alcohols such as methanol and ethanol are preferable, and benzyl alcohol may be used in addition to simple alcohol. The reaction temperature is suitably about 65 ° C. regardless of the solvent used. In the third step, the compound (VIII) prepared in the above reaction is reacted with triethylphosphonoacetate in the presence of sodium hydride base to prepare compound (IX). The organic solvent used at this time is tetrahydrofuran. Etc. can be used. The sodium hydride base may be used in an amount of 1.2 to 1.5 equivalents based on triethylphosphonoacetate, and the reaction thereof is appropriate to form an anion of triethylphosphonoacetate at 0 ° C. and then react with an acrylate at room temperature. In the fourth step, compound (IX) prepared in the above reaction was dissolved in tetrahydrofuran organic solvent, t -lithium butoxide was added and reacted for 30 minutes, and then an aldehyde compound was added to the reaction mixture to react compound (X). do. In this case, the reaction temperature is preferably room temperature, and the amount of salt used is suitably used in an amount of 1 to 2 equivalents based on the starting material (IX). In the fifth step, the compound (IX) prepared in the above reaction is subjected to a deprotection reaction in a hydrochloric acid solution, and then heated at 160 ° C. using xylene, which is an organic solvent suitable for the high temperature reaction required for the cyclization reaction, XI) can be obtained. In the reaction of the sixth step, the compound (XII) can be obtained under the same conditions as the preparation of the compound (V) in the fourth step of Scheme (1) using the compound (XI) obtained in the reaction.

Figure 112006049660803-pat00011
Figure 112006049660803-pat00011

반응식 (3)은 상용 화합물 또는 기존의 알려진 방법에 의하여 합성된 화합물 (XIII)로부터 히드록시아미드의 알파위치에 치환기가 붙은 화합물 (XXII)을 제조하기 위한 제조과정을 나타낸다. Scheme (3) shows a preparation process for preparing compound (XXII) having a substituent at the alpha position of hydroxyamide from a commercial compound or compound (XIII) synthesized by a known method.

제 1단계에서는 카복실산 화합물 (XIII)과 DMAP, 2,2-디메틸-1,3-디옥산- 4,6-디온을 건조된 디클로로메탄에 용해시키고 DCC를 건조된 디클로로메탄에 용해시켜 서서히 적가하여 반응시켜 화합물 (XIV)을 제조한다. 이때 사용되는 용매는 반응에 악영향을 미치지 않는 용매인 디클로로메탄, 클로로포름 등을 이용하여 반응을 수행한다. 반응 온도는 특별히 제한되지는 않으나, 일반적으로 냉온 내지 상온에서 수행한다. 제 2단계는, 상기 1단계에서 얻어진 화합물(XIV)을 디클로로메탄에 용해시켜 0℃로 낮추고 아세트산과 소듐 보로 하이드라이드을 천천히 넣어 반응하여 화합물 (XV)을 얻는다. 이때 사용되는 용매는 반응에 악영향을 미치지 않는 용매인 디클로로메탄, 클로로포름, 테트라하이드로푸란, 디에틸에테르 등을 이용하여 반응을 수행한다. 반응 온도는 특별히 제한되지는 않으나, 일반적으로 반응은 냉온 내지 상온에서 수행한다. 그다음 단계는 상기반응에서 얻어진 화합물 (XV)를 이용하여 반응식 (2)의 화합물 (XI)의 제조방법과 동일한 4단계의 조건으로 화합물 (XIX)을 합성한다. 제 7단계는 화합물 (XIX)을 에틸아세테이트에 용해시키고 Pd/C 10 %와 H2로 상온에서 반응하여 화합물 (XX)을 제조한다. 이 반응은 반응에 악영향을 미치지 않는 용매인 메탄올, 에탄올, 테트라하이드로푸란 등을 이용하여 반응을 수행한다. 제 8단계의 반응은 화합물 (XX)을 피페리딘 알킬클로라이드 염산염과 포타시움 카보메이트 등의 염기를 사용하여 반응시켜 화합물(XXI)을 합성한다. 이때 사용되는 염기는 일반적으로는 알코올(X=O)이나 아민((X=NH2)을 알킬화 시키는데 사용하는 일반적인 염기가 가능하다. In the first step, the carboxylic acid compound (XIII) and DMAP, 2,2-dimethyl-1,3-dioxane-4,6-dione are dissolved in dried dichloromethane, and DCC is dissolved in dried dichloromethane and slowly added dropwise. Reaction produces Compound (XIV). At this time, the solvent is used to perform the reaction using a solvent that does not adversely affect the reaction, dichloromethane, chloroform and the like. The reaction temperature is not particularly limited, but is generally performed at cold to room temperature. In the second step, the compound (XIV) obtained in step 1 is dissolved in dichloromethane, lowered to 0 ° C., and acetic acid and sodium borohydride are slowly reacted to obtain compound (XV). The solvent used at this time is carried out using a solvent that does not adversely affect the reaction using dichloromethane, chloroform, tetrahydrofuran, diethyl ether and the like. The reaction temperature is not particularly limited, but in general, the reaction is performed at cold to room temperature. The next step is to synthesize compound (XIX) under the same four steps as in the method for preparing compound (XI) of Scheme (2) using compound (XV) obtained in the above reaction. In the seventh step, compound (XIX) is dissolved in ethyl acetate and reacted with Pd / C 10% and H 2 at room temperature to prepare compound (XX). This reaction is carried out using methanol, ethanol, tetrahydrofuran and the like which do not adversely affect the reaction. In the eighth reaction, compound (XX) is reacted using piperidine alkylchloride hydrochloride with a base such as potassium potassium carbomate to synthesize compound (XXI). In this case, the base used may be a general base used to alkylate an alcohol (X = O) or an amine ((X = NH 2 )).

이러한 목적으로 바람직하게 사용할 수 있는 염기는 소디움 또는 포타시움 카보네이드, 탄산세시움 또는 수산화나트륨, 수산화칼륨, 소디움 메톡시드, 2,6-루티딘, 소디움 히드리드 등이 있고, 벤질 트리에틸 암모니움 클로라이드와 같은 상 전이촉매 (phase transfer catalyst)를 함께 사용할 수 있다. 또한 상기 반응은 소디움 또는 포타시움 요오디드를 촉매량으로 사용하여 반응시킬 수 있고, 바람직하게는 반응에 악영향을 미치지 않는 용매의 존재 하에서 수행하며, 이러한 목적으로 사용될 수 있는 용매의 예로는 디메틸 포름아미드, 메탄올, 에탄올 등의 알콜 용매 또는 물을 사용하여 반응을 수행한다. 반응 온도는 일반적으로 반응은 상온 내지 가온 하에 수행할 수 있고, 바람직하게는 가온에서 수행한다. 제 9단계의 반응은 상기 반응에서 얻어진 화합물(XXI)을 사용하여 반응식 (1)의 제 4단계의 화합물 (V)의 제조하는 방법과 동일한 조건으로 화합물 (XXII)를 얻을 수 있다. Bases which can preferably be used for this purpose include sodium or potassium potassium carbonate, cesium carbonate or sodium hydroxide, potassium hydroxide, sodium methoxide, 2,6-lutidine, sodium hydride and the like, benzyl triethyl ammonium chloride Phase transfer catalysts such as can be used together. In addition, the reaction may be reacted using a catalytic amount of sodium or potassium iodide, preferably performed in the presence of a solvent that does not adversely affect the reaction, and examples of the solvent that may be used for this purpose include dimethyl formamide, methanol The reaction is carried out using an alcohol solvent such as ethanol or water. The reaction temperature is generally the reaction can be carried out at room temperature to warm, preferably at warm. In the reaction of the ninth step, the compound (XXII) can be obtained under the same conditions as the preparation of the compound (V) in the fourth step of Scheme (1) using the compound (XXI) obtained in the reaction.

Figure 112006049660803-pat00012
Figure 112006049660803-pat00012

반응식 (4)은 상기 반응식 (3)에서와 같은 류의 화합물을 제조하는 반응으로 반응식 (3)에서 얻은 화합물 (XXa)를 사용하여 화합물 (XXIII)을 제조하는 3단계의 방법이다. Scheme (4) is a three-step process for preparing compound (XXIII) using compound (XXa) obtained in scheme (3) in a reaction for preparing a compound of the same kind as in scheme (3).

제 1단계에서는 반응식 (3)에서 얻을 수 있는 화합물 (XXa)을 포타시움 카보네이트 등의 염기 하에 토실 알킬 클로라이드 화합물과 반응시켜 화합물 (XXI)을 얻는다. 이때 사용할 수 있는 염기는 소디움 또는 포타시움 카보네이드, 탄산세시움 등이고, 소디움 또는 포타시움 요오드를 촉매량으로 사용하여 반응시킬 수 있다. 이 반응은 바람직하게는 반응에 악영향을 미치지 않는 용매의 존재 하에서 수행하며, 이러한 목적으로 사용될 수 있는 용매의 예로는 디메틸 포름아미드, 메탄올, 에탄올 등의 알콜 용매 또는 아세톤을 사용하여 반응을 수행한다. 반응 온도는 일반적으로 반응은 상온 내지 가온 하에 수행할 수 있고, 바람직하게는 가온에서 수행한다. 제 2단계에서는 화합물(XXI)을 사용하여 1단계에서 사용한 염기를 이용하여 동일한 용매 즉 디메틸 포름아미드, 메탄올, 에탄올 등의 알콜 용매를 사용하여 피롤리딘과 반응시켜 화합물 (XXII)를 합성할 수 있다. 반응 온도는 일반적으로 반응은 상온 내지 가온 하에 수행할 수 있고, 바람직하게는 가온에서 수행한다. 제 3단계는 상기 반응에서 얻어진 화합물 (XXII)을 사용하여 반응식 (1)의 제 4단계의 화합물 (V)의 제조하는 방법과 동일한 조건으로 화합물 (XXIII)을 얻을 수 있다. In the first step, compound (XXa) obtained in Scheme (3) is reacted with a tosyl alkyl chloride compound under a base such as potassium carbonate to obtain compound (XXI). At this time, the base that can be used is sodium or potassium potassium carbonate, cesium carbonate, etc., can be reacted using a catalytic amount of sodium or potassium potassium iodine. The reaction is preferably carried out in the presence of a solvent which does not adversely affect the reaction, and examples of the solvent which can be used for this purpose are carried out using an alcohol solvent such as dimethyl formamide, methanol, ethanol or acetone. The reaction temperature is generally the reaction can be carried out at room temperature to warm, preferably at warm. In the second step, compound (XXII) can be synthesized by using compound (XXI) to react with pyrrolidine using the same solvent as the base used in step 1 using an alcohol solvent such as dimethyl formamide, methanol, ethanol or the like. have. The reaction temperature is generally the reaction can be carried out at room temperature to warm, preferably at warm. In the third step, the compound (XXIII) can be obtained under the same conditions as the method for preparing the compound (V) in the fourth step of Scheme (1) using the compound (XXII) obtained in the above reaction.

Figure 112006049660803-pat00013
Figure 112006049660803-pat00013

반응식 (5)은 상업적으로 쉽게 확보할 수 있거나 합성한 알데히드 (Ia)를 출발물질로 하여 화합물 (XXXI)을 제조하기 위한 8단계 제조과정을 나타낸다. Scheme (5) shows an eight-step preparation process for preparing compound (XXXI) using commercially available or synthesized aldehyde (Ia) as a starting material.

제 1단계 및 2단계에서는 알데히드 화합물 (Ia)을 이용하여 문헌 (Scetharamaiyer Padmanabhan, Ravikumar Peri and David J. Triggle, Syn. Comm., 26(4), pp 827-831, 1996)에 기재된 방법에 의하여 알데히드 화합물 (XXV)을 합성하였다. 제 3단계에서는 상기 합성된 알데히드 화합물 (XXV)과 알려진 방법에 의하여 합성된 2-(4-벤질옥시-페닐)-에틸아민 하이드로 클로라이드를 테트라하이드로퓨란에 녹인 후 트리에틸아민을 첨가하여 반응시킨 후 이민화합물을 합성한 다. 이 축합반응은 반응에 악영향을 미치지 않는 용매인 톨루엔, 벤젠, 알콜, 물 등을 사용하여 염기를 첨가하지 않고 반응시킬 수도 있고, 일반적으로 아민과 알데히드의 축합에 사용되는 디이소프로필아민, 피리딘, 피페리딘 등의 염기를 사용하여 반응시킬 수도 있다, 반응 온도는 특별히 제한되지는 않으나, 일반적으로 반응은 상온 내지 가온에서 수행한다. 합성된 이민 화합물을 메탄올, 테트라하이드로퓨란 혼합용액에 녹인 후 초산과 소디움 시아노 보로하이드라이드를 넣어 환원반응을 시켜 2급 아민 화합물 (XXVI)을 제조한다. 이때 사용되는 환원제는 일반적으로 이민을 아민으로 환원시킬 수 있는 포타시움 보로하이드라이드, 소디움 보로하이드라이드 등을 사용할 수 있고 용매는 반응에 악영향을 미치지 않는 용매인 알콜, 톨루엔, 벤젠, 테트라히드로퓨란 등을 이용하여 반응을 수행한다. 반응 온도는 특별히 제한되지는 않으나, 일반적으로 반응은 냉온 내지 상온에서 수행한다. In the first and second steps, an aldehyde compound (Ia) was used to describe the method described by Scetharamaiyer Padmanabhan, Ravikumar Peri and David J. Triggle, Syn. Comm. , 26 (4) , pp 827-831, 1996. Aldehyde Compound (XXV) was synthesized. In the third step, the synthesized aldehyde compound (XXV) and 2- (4-benzyloxy-phenyl) -ethylamine hydrochloride synthesized by a known method are dissolved in tetrahydrofuran and then reacted by adding triethylamine. Synthesize imine compounds. This condensation reaction may be carried out without addition of a base by using toluene, benzene, alcohol, water, and the like, which do not adversely affect the reaction, and is generally used for the condensation of amines and aldehydes, pyridine, The reaction may also be carried out using a base such as piperidine. The reaction temperature is not particularly limited, but in general, the reaction is performed at room temperature to warm. The synthesized imine compound is dissolved in a mixed solution of methanol and tetrahydrofuran, acetic acid and sodium cyano borohydride are added to a reduction reaction to prepare a secondary amine compound (XXVI). In this case, a reducing agent used may generally be potassium borohydride or sodium borohydride, which can reduce imine to amine, and the solvent may be alcohol, toluene, benzene, tetrahydrofuran, etc., which does not adversely affect the reaction. To carry out the reaction. The reaction temperature is not particularly limited, but in general, the reaction is performed at cold to room temperature.

제 4단계는, 상기 합성된 화합물 (XXVI)과 디-tert-부틸디카보네이트를 디클로로메탄에 녹인 후 디메틸 아미노피리딘을 첨가하여 반응시켜 화합물 (XXVII)을 얻었다. In the fourth step, the synthesized compound (XXVI) and di- tert -butyldicarbonate were dissolved in dichloromethane and reacted with the addition of dimethyl aminopyridine to obtain compound (XXVII).

제 5단계는, 상기 화합물 (XXVII)을 에틸아세테이트에 녹인 후 Pd/C을 넣고 수소가스 하에 반응시켜 화합물 (XXVIII)을 얻는다. 제 4, 5 단계의 반응은 일반적인 아민의 보호기 도입 방법과 알콜의 탈벤질 반응 조건에 의하여 진행할 수 있다. In the fifth step, the compound (XXVII) is dissolved in ethyl acetate, and then Pd / C is added and reacted under hydrogen gas to obtain a compound (XXVIII). The reaction of the fourth and fifth stages can be carried out by a general method of introducing a protecting group of an amine and debenzyl reaction conditions of an alcohol.

제 6단계는, 상기 화합물 (XXVIII)을 이용하여 세시움 카보네이트 등의 염기 존재 하에 촉매량의 소디움 요오드를 첨가하여 (2-클로로에틸)-디에틸 아민과 반응 시켜 화합물 (XXIX)를 얻는다. 이 반응은 일반적으로 알코올과 알킬 할라이드와의 에테르화 생성반응 (etherification reaction)으로 에테르 생성반응에 사용될 수 있는 염기의 존재 하에 수행한다. 이러한 목적으로 바람직하게 사용할 수 있는 염기의 예로는 소디움 히드리드 (NaH), 탄산세시움, 소디움 또는 포타시움 히드록시드를 사용할 수 있다. 또한 상기 반응은 바람직하게는 반응에 악영향을 미치지 않는 용매의 존재 하에서 수행하며, 이러한 목적으로 사용될 수 있는 용매의 예로는 디클로로메탄, 클로로포름, 테트라하이드로푸란, 디에틸에테르, 톨루엔, 디메틸포름아미드 또는 벤젠 등의 용매를 사용하여 반응을 수행한다. 반응 온도는 특별히 제한되지는 않으며 반응은 일반적으로 냉각 내지 가온 하에 수행할 수 있으며, 바람직하게는 냉각 내지 상온에서 수행한다. 제 7단계는, 상기화합물 (XXIX)을 4N-염산 수용액을 사용하여 아민의 탈보호화 반응을 수행하여 화합물 (XXX)을 얻는다. 이 반응은 일반적인 아민의 탈보호 반응조건에 의하여 진행할 수 있다. 제 8단계는, 상기 화합물 (XXX)을 피리딘에 녹인 후 히드록시 카바믹에시드 페닐에스터와 반응시켜 화합물 (XXXI)을 제조한다. 이때 반응 온도는 특별히 제한되지는 않으나, 일반적으로 반응은 상온 내지 가온에서 수행한다.In the sixth step, compound (XXVIII) is used to react with (2-chloroethyl) -diethyl amine in the presence of a base such as cesium carbonate to add a catalytic amount of sodium iodine to obtain compound (XXIX). This reaction is generally carried out in the presence of a base which can be used in the ether formation reaction in an etherification reaction of an alcohol with an alkyl halide. Examples of bases which can be preferably used for this purpose can include sodium hydride (NaH), cesium carbonate, sodium or potassium hydroxide. In addition, the reaction is preferably carried out in the presence of a solvent that does not adversely affect the reaction, examples of the solvent that can be used for this purpose include dichloromethane, chloroform, tetrahydrofuran, diethyl ether, toluene, dimethylformamide or benzene The reaction is carried out using a solvent such as the like. The reaction temperature is not particularly limited and the reaction can generally be carried out under cooling to warming, preferably at cooling to room temperature. In the seventh step, compound (XXIX) is subjected to deprotection reaction of amine using 4N aqueous hydrochloric acid solution to obtain compound (XXX). This reaction can be carried out by general deprotection conditions of the amine. In the eighth step, the compound (XXX) is dissolved in pyridine and then reacted with hydroxy carbamic acid phenyl ester to prepare compound (XXXI). At this time, the reaction temperature is not particularly limited, but in general, the reaction is performed at room temperature to warm.

Figure 112006049660803-pat00014
Figure 112006049660803-pat00014

반응식 (6)은 상용 화합물 (XXXII)로부터 화합물 (XXXXI)를 제조하기 위한 과정을 나타낸다.Scheme (6) shows the procedure for preparing compound (XXXXI) from commercial compound (XXXII).

제 1단계에서는 문헌 (Bajekudru Devadas et al., J. Med. Chem. 40 pp2607- 2625, 1997)에 기재된 방법에 의하여 합성된 메틸-2-[4-(4-하이드록시부틸)페닐]아세테이트에 tert-부틸디메틸실릴 클로라이드로 알코홀에 보호기를 도입하여 합성된 화합물 (XXXII)의 에스테르를 리튬알루미늄 하이드라이드로 환원반응을 시켜 알콜 화합물 (XXXIII)을 제조한다. 이 반응은 일반적인 에스테르를 알콜로 환원할 수 있는 조건에서 반응할 수 있다. 제 2단계는 상기 화합물 (XXXIII)을 메실 클로리드와 트리에틸아민 등의 염기 조건 하에 반응시켜 화합물 (XXXIV)을 제조한다. 이때 사용되는 용매는 반응에 악영향을 미치지 않는 용매인 톨루엔, 테트라하이드로푸란, 에테르, 클로로포름 등을 사용할 수 있으며 염기는 디이소프로필 아민, 피리딘, 피페리딘 등의 염기를 사용하여 반응시킬 수도 있다, 반응 온도는 특별히 제한되지는 않으나, 일반적으로 반응은 냉온 내지 상온에서 수행한다. 제 3단계는, 상기 화합물 (XXXIV)을 디메틸 포름아미드에 녹인 후 탄산칼륨 등의 염기 존재 하에 디에틸 말로네이트와 축합반응을 시켜 화합물 (XXXV)을 얻는다. 이때 사용되는 염기의 예로는 소디움히드리드 (NaH), 탄산세시움, 탄산 나트리움, 소디움 또는 포타시움 히드록시드 등을 사용할 수 있다. 또한 상기 반응은 바람직하게는 반응에 악영향을 미치지 않는 용매의 존재 하에서 수행하며, 이러한 목적으로 사용될 수 있는 용매의 예로는 알콜, 디클로로메탄 등의 용매를 사용하여 반응을 수행한다. 반응 온도는 특별히 제한되지는 않으며 반응은 일반적으로 냉각 내지 가온 하에 수행할 수 있으며, 바람직하게는 상온 내지 가온에서 수행한다. In the first step, methyl-2- [4- (4-hydroxybutyl) phenyl] acetate was synthesized by the method described in Bajekudru Devadas et al., J. Med. Chem. 40 pp2607-2625, 1997. An alcohol compound (XXXIII) was prepared by reducing the ester of the synthesized compound (XXXII) with lithium aluminum hydride by introducing a protecting group into the alcohol with tert-butyldimethylsilyl chloride. This reaction can be reacted under conditions capable of reducing common esters to alcohols. In the second step, the compound (XXXIII) is reacted under basic conditions such as mesyl chloride and triethylamine to prepare compound (XXXIV). In this case, toluene, tetrahydrofuran, ether, chloroform, and the like may be used as a solvent that does not adversely affect the reaction, and the base may be reacted using a base such as diisopropyl amine, pyridine, piperidine, or the like. The reaction temperature is not particularly limited, but in general, the reaction is performed at cold to room temperature. In the third step, the compound (XXXIV) is dissolved in dimethyl formamide and then condensed with diethyl malonate in the presence of a base such as potassium carbonate to obtain the compound (XXXV). At this time, examples of the base used may include sodium hydroxide (NaH), cesium carbonate, sodium carbonate, sodium or potassium potassium hydroxide, and the like. In addition, the reaction is preferably carried out in the presence of a solvent that does not adversely affect the reaction, examples of the solvent that can be used for this purpose is carried out using a solvent such as alcohol, dichloromethane. The reaction temperature is not particularly limited and the reaction can generally be carried out under cooling to warming, preferably at room temperature to warming.

제 4단계는, 상기 화합물 (XXXV)를 화합물 (XXXVI)로 변환시키는 에스테르의 가수분해 방법이다. 이 반응은 에탄올 용액에서 냉각 하에 화합물 (XXXV)과 같은 당량의 수산화칼륨을 에탄올에 녹여 적가 한 후 상온에서 반응시켜 제조할 수 있으며, 본 반응은 일반적인 에스테르의 가수분해 조건에서 반응할 수 있다.The fourth step is a hydrolysis method of the ester for converting the compound (XXXV) to compound (XXXVI). This reaction may be prepared by dissolving an equivalent amount of potassium hydroxide, such as compound (XXXV), in ethanol dropwise while cooling in an ethanol solution, followed by reaction at room temperature, and the reaction may be performed under hydrolysis conditions of general esters.

제 5단계는, 상기 화합물 (XXXVI)을 화합물 (XXXVII)로 변환시키는 반응으로 화합물 (XXXVI)을 디에틸 아민 등의 염기를 사용하여 포름알데히드 수용액을 첨가시키고 상온 내지 가온 하에서 반응시켜 제조한다. 이 반응은 디에틸아민 외에 디에틸아민 염산염, 피페리딘, 디메틸 아민, 피리딘 등의 염기을 사용할 수 있다. 또한 상기 반응은 바람직하게는 반응에 악영향을 미치지 않는 용매의 존재 하에서 수행하며, 이러한 목적으로 사용될 수 있는 용매의 예로는 물, 디메틸설폭시드, 에탄올 또는 디메틸포름아미드 등의 용매를 사용하여 반응을 수행한다. In the fifth step, the compound (XXXVI) is converted into the compound (XXXVII), and the compound (XXXVI) is prepared by adding an aqueous formaldehyde solution using a base such as diethyl amine and reacting at room temperature to warm. In addition to diethylamine, this reaction may use bases such as diethylamine hydrochloride, piperidine, dimethyl amine, pyridine and the like. In addition, the reaction is preferably carried out in the presence of a solvent that does not adversely affect the reaction, examples of the solvent that can be used for this purpose is carried out using a solvent such as water, dimethyl sulfoxide, ethanol or dimethylformamide do.

다음 단계의 화합물 (XXXVII)에서 화합물 (XXXVIII)을 얻는 방법은 반응식 (3)의 화합물 (XVI)에서 화합물 (XIX)을 얻는 동일한 방법을 사용하여 얻는 화합물을 산 조건 하에서 탈 보호화 반응을 수행하여 제조한다.The method for obtaining compound (XXXVIII) from compound (XXXVII) in the next step is carried out by deprotection of the compound obtained under acidic conditions using the same method for obtaining compound (XIX) from compound (XVI) in Scheme (3). Manufacture.

그 다음 단계인 화합물 (XXXIX)에서 화합물 (XXXX)을 얻는 방법은 반응식 (5)의 화합물 (XXV)에서 화합물 (XXVI)을 얻는 동일한 조건 하에서 제조한다.The next step, to obtain compound (XXXX) in compound (XXXIX), is prepared under the same conditions of obtaining compound (XXVI) in compound (XXV) in scheme (5).

마지막 단계의 화합물 (XXXX) 에서 화합물 (XXXXI)을 얻는 방법은 반응식 (1)의 화합물 (IV)에서 화합물 (V)을 얻는 동일한 조건 하에서 제조한다.The process for obtaining compound (XXXXI) in compound (XXXX) of the last step is prepared under the same conditions for obtaining compound (V) in compound (IV) of Scheme (1).

본 발명의 일반식 (Ⅰ) 내지 일반식 (IV) 화합물들은 염증 질환 특히 관절염으로 인한 통증 및 염증 치료에 유용하게 사용될 수 있다. The general formulas (I) to (IV) compounds of the present invention can be usefully used for the treatment of pain and inflammation caused by inflammatory diseases, in particular arthritis.

따라서 본 발명은 일반식 (Ⅰ) 내지 일반식 (IV) 화합물들을 유효성분으로 함유하는 통증 및 염증성 질환의 치료 및 예방용 약학 조성물을 제공한다.Accordingly, the present invention provides a pharmaceutical composition for the treatment and prevention of pain and inflammatory diseases containing the compounds of formula (I) to formula (IV) as an active ingredient.

바람직하게는, 상기 통증 질환은 관절염을 들 수 있으며, 예를 들어, 류마티스성 관절염 (rheumatoid arthritis), 척추성 관절염 (spondyloarthopathies), 통풍 (gout), 골관절염 (osteoarthritis), 전신성 홍반성 루푸스 (systemic lupus erythematosus) 및 유년기 관절염 (juvenile arthritis)을 포함한다. Preferably, the pain disease includes arthritis, for example, rheumatoid arthritis, spondyloarthopathies, gout, osteoarthritis, systemic lupus erythematosus) and juvenile arthritis.

또한, 본 발명의 화합물들은 염증성 질환을 치료하는데 사용될 수 있으며, 상기 염증성 증상으로는, 예를 들어, 근육염 (myositis), 치은염 (gingivitis), 활막염 (synovitis), 강직성 척추염 (ankylosing spondylitis), 활액낭염 (burstitis), 화상 (burns) 및 상처 등을 포함한다. 또한, 본 발명의 화합물들은 염증성 대장질환 (inflammatory bowel disease), 크론병 (Crohn's disease), 제 1형 당뇨병 (Type I diabetes), 건선 (Psoriasis) 등과 같은 질환에 수반되는 염증성 증상을 치료하는데 유용하다. In addition, the compounds of the present invention can be used to treat inflammatory diseases, and the inflammatory symptoms include, for example, myositis, gingivitis, synovitis, ankylosing spondylitis, bursitis ( burstitis, burns, wounds, and the like. In addition, the compounds of the present invention are useful for treating inflammatory symptoms associated with diseases such as inflammatory bowel disease, Crohn's disease, Type I diabetes, Psoriasis, and the like. .

본 발명의 화합물을 포함하는 조성물은 통상의 방법에 따른 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다. Compositions comprising a compound of the present invention may further comprise a suitable carrier, excipient or diluent according to conventional methods.

본 발명의 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

본 발명의 화합물을 포함하는 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. The compositions comprising the compounds of the present invention are each formulated in the form of oral dosage forms, external preparations, suppositories, or sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., in accordance with conventional methods. Can be used.

상세하게는, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트 (calcium carbonate), 수크로스 (sucrose), 락토오스 (lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는 데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.Specifically, when formulated, it may be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, and the like. Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and such solid preparations may include at least one excipient such as starch, calcium carbonate, sucrose in the extract. ), Lactose, gelatin and the like can be mixed. In addition to simple excipients, lubricants such as magnesium stearate, talc can also be used. Liquid preparations for oral use include suspensions, solvents, emulsions, and syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

본 발명의 화합물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 바람직한 효과를 위해서, 본 발명의 화합물은 0.0001 ~ 100 mg/kg으 로, 바람직하게는 0.001 ~ 100 mg/kg의 양을 일일 1회 내지 수회로 나누어 투여할 수 있다. 조성물에서 본 발명의 화합물은 전체 조성물 총 중량에 대하여 0.0001 ~ 50 중량%의 함량으로 배합될 수 있다.Preferred dosages of the compounds of the present invention depend on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, but may be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention may be administered in an amount of 0.0001 to 100 mg / kg, preferably 0.001 ~ 100 mg / kg divided once to several times daily. The compound of the present invention in the composition may be formulated in an amount of 0.0001 to 50% by weight based on the total weight of the total composition.

또한, 본 발명의 화합물의 약학적 투여 형태는 이들의 약학적 허용가능한 염의 형태로도 사용될 수 있고, 또한 단독으로 또는 타 약학적 활성 화합물과 결합뿐만 아니라 적당한 집합으로 사용될 수 있다. In addition, the pharmaceutical dosage forms of the compounds of the present invention may be used in the form of their pharmaceutically acceptable salts, and may be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.

본 발명의 약학 조성물은 쥐, 마우스, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 (intracerebroventricular) 주사에 의해 투여될 수 있다. The pharmaceutical composition of the present invention can be administered to mammals such as mice, mice, livestock, humans, etc. by various routes. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.

이하, 본 발명을 하기 실시예에 의거하여 좀더 상세하게 설명하고자 한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 이들 만으로 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail based on the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

실시예Example 1: 2-(2-옥소-2H- 1: 2- (2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-)- 펜트Pent -4--4- 에노익Enoick 엑시드EXID 히드록시아미드Hydroxyamide

단계 1. 펜탄디오익 엑시드 2-포밀-페닐 에스터 메틸 에스터의 합성Step 1.Synthesis of pentanedioic acid 2-formyl-phenyl ester methyl ester

Figure 112006049660803-pat00015
Figure 112006049660803-pat00015

2-히드록시-벤즈알데히드 (3.0 g, 24.57 mmol)을 디클로로메탄 (30 ml)에 녹인 후 ４-클로로카보닐-부티릭 엑시드 메틸 에스터 (4.4 g, 27.02 mmol)를　첨가한 다. ０℃에서 디이소프로필-에틸아민 (6.4 ml, 36.85 mmol)을 첨가하고 상온으로 서서히 온도를 올려 3시간동안 교반한 후 디클로로메탄으로 추출한다. 포화 염화나트륨 용액으로 씻어준 후 무수 황산 마그네슘으로 건조　후 여과, 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=4:1)하여 표제 화합물(5.3 g, 86 %, 무색 액체)을 얻었다.2-hydroxy-benzaldehyde (3.0 g, 24.57 mmol) is dissolved in dichloromethane (30 ml) and then 4-chlorocarbonyl-butyric acid methyl ester (4.4 g, 27.02 mmol) is added. Diisopropyl-ethylamine (6.4 ml, 36.85 mmol) was added at 0 ° C, the temperature was gradually raised to room temperature, stirred for 3 hours, and extracted with dichloromethane. After washing with saturated sodium chloride solution, drying with anhydrous magnesium sulfate, filtration and concentration under reduced pressure, the residue was purified by column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (5.3 g, 86%, colorless liquid).

1H-NMR (CDCl3, 400MHz) δ 10.09(s, 1H), 7.88(d, J=8.0, 1H), 7.63(t, J=8.8Hz, 1H), 7.41(t, J=7.6Hz, 1H), 7.18(t, J=8.0Hz, 1H), 3.70(s, 3H), 2.76(t, J=7.6Hz, 2H), 2.50(t, J=7.4Hz, 2H), 2.11(t, J=7.2Hz, 2H). 1 H-NMR (CDCl 3 , 400 MHz) δ 10.09 (s, 1H), 7.88 (d, J = 8.0, 1H), 7.63 (t, J = 8.8 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 3.70 (s, 3H), 2.76 (t, J = 7.6 Hz, 2H), 2.50 (t, J = 7.4 Hz, 2H), 2.11 (t, J = 7.2 Hz, 2H).

단계 2. 3-(2-옥소-2H-크로멘-3-일)-프로피오닉 엑시드 메틸 에스터의 합성Step 2. Synthesis of 3- (2-oxo-2H-chromen-3-yl) -propionic acid methyl ester

Figure 112006049660803-pat00016
Figure 112006049660803-pat00016

상기 제 1단계에서 얻은 화합물 (5.3 g, 21.18 mmol)을 톨루엔 (50 ml)에 녹인 후 DBU (3.4 ml, 23.30 mmol)를 첨가하고 3시간 동안 환류한다. 상온으로 온도를 서서히 내린 후 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=4:1)하여 표제 화합물(1.8 g, 37 %, 흰색 고체)을 얻었다.The compound obtained in the first step (5.3 g, 21.18 mmol) is dissolved in toluene (50 ml), then DBU (3.4 ml, 23.30 mmol) is added and refluxed for 3 hours. The mixture was slowly cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (1.8 g, 37%, white solid).

1H-NMR (CDCl3, 400MHz) δ 7.60(s, 1H), 7.44-7.50(m, 2H), 7.32(d, J=8.4Hz, 1H), 7.26(t, J=7.6Hz, 1H), 3.67(s, 3H), 2.90(t, J=7.2Hz, 2H), 2.72(t, J=7.2Hz, 2H). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.60 (s, 1 H), 7.44-7.50 (m, 2 H), 7.32 (d, J = 8.4 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H) , 3.67 (s, 3H), 2.90 (t, J = 7.2 Hz, 2H), 2.72 (t, J = 7.2 Hz, 2H).

단계 3. 2-(2-옥소-2H-크로멘-3-일메틸)-펜트-4-에노익 엑시드 메틸 에스터의 합성Step 3. Synthesis of 2- (2-oxo-2H-chromen-3-ylmethyl) -pent-4-enoic acid methyl ester

Figure 112006049660803-pat00017
Figure 112006049660803-pat00017

상기 제 2단계에서 얻은 화합물 (1.0 g, 4.31 mmol)을 테트라히드로퓨란 (20 ml)에 녹인 후 테트라히드로퓨란에 용해된 LiHMDS 1몰 용액 (650 ㎕, 6.46 mmol)을 -78℃ 상에서 첨가하여 1시간 동안 교반한다. 이 용액에 알릴 브로마이드 (560 ㎕, 6.46 mmol)를 첨가하고 -78 ℃에서 30분 동안 교반 후, 온도을 서서히 상온으로 올려 다시 5시간 동안 교반한다. 증류수로 반응을 종결하고 4M-염산 수용액으로 중화시킨 후 에틸 아세테이트로 유기물질을 추출한다. 포화 염화나트륨 수용액으로 씻어주고 무수 황산마그네슘으로 건조　후 여과한다. 이렇게 해서 얻어진 용액을 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=4:1)하여 표제 화합물(125 mg, 11 %, 노란색 오일)을 얻었다.The compound obtained in the second step (1.0 g, 4.31 mmol) was dissolved in tetrahydrofuran (20 ml), and then 1 mole solution of LiHMDS (650 µl, 6.46 mmol) dissolved in tetrahydrofuran was added at -78 ° C. Stir for hours. Allyl bromide (560 μl, 6.46 mmol) was added to the solution, stirred at −78 ° C. for 30 minutes, and the temperature was gradually raised to room temperature and stirred for another 5 hours. The reaction was terminated with distilled water, neutralized with 4M aqueous hydrochloric acid, and the organics were extracted with ethyl acetate. Wash with saturated aqueous sodium chloride solution, dry with anhydrous magnesium sulfate and filter. The solution thus obtained was concentrated under reduced pressure, and the residue was purified by column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (125 mg, 11%, yellow oil).

1H-NMR (CDCl3, 400MHz) δ 7.54(s, 1H), 7.44-7.50(m, 2H), 7.31(d, J=8.0Hz, 1H), 7.26(t, J=8.0Hz, 1H), 5.73-5.84(m, 1H), 5.06-5.13(m, 2H), 3.60(s, 3H), 2.99-3.06(m, 1H), 2.79-2.83(m, 2H), 2.33-2.49(m, 2H). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.54 (s, 1H), 7.44-7.50 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H) , 5.73-5.84 (m, 1H), 5.06-5.13 (m, 2H), 3.60 (s, 3H), 2.99-3.06 (m, 1H), 2.79-2.83 (m, 2H), 2.33-2.49 (m, 2H).

단계 4. 2-(2-옥소-2H-크로멘-3-일메틸)-펜트-4-에노익 엑시드 히드록시아미드의 합성Step 4. Synthesis of 2- (2-oxo-2H-chromen-3-ylmethyl) -pent-4-enoic acid hydroxyamide

Figure 112006049660803-pat00018
Figure 112006049660803-pat00018

상기 제 3단계에서 얻은 화합물 (0.12 g, 0.44 mmol)을 메탄올 (2 ml)을 용매로 하여 1.76 M 포타슘 히드록시 아민용액 (1.25 ml, 2.20 mmol)을 첨가 한 후 10시간 동안 상온에서 교반한다. 감압 농축하고 잔여물을 관 크로마토그래피 (클로로포름:메탄올=20:1)하여 표제 화합물 (26 mg, 22 %, 고체)을 얻었다.The compound (0.12 g, 0.44 mmol) obtained in the third step was added with 1.76 M potassium hydroxy amine solution (1.25 ml, 2.20 mmol) using methanol (2 ml) as a solvent, followed by stirring at room temperature for 10 hours. Concentration under reduced pressure and the residue was subjected to column chromatography (chloroform: methanol = 20: 1) to give the title compound (26 mg, 22%, solid).

1H-NMR (DMSO-d 6, 400MHz) δ 10.41(s, 1H), 8.69(s, 1H), 7.73(s, 1H), 7.64(d, J=7.6Hz, 1H), 7.56(t, J=7.6Hz, 1H), 7.38(t, J=8.0Hz, 1H), 7.33(t, J=7.6Hz, 1H), 5.67-5.77(m, 1H), 5.00-5.09(m, 2H), 2.45-2.60(m, 3H), 2.25-2.32(m, 1H), 2.13-2.19(m, 1H). 1 H-NMR (DMSO- d 6 , 400 MHz) δ 10.41 (s, 1H), 8.69 (s, 1H), 7.73 (s, 1H), 7.64 (d, J = 7.6Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 5.67-5.77 (m, 1H), 5.00-5.09 (m, 2H), 2.45-2.60 (m, 3H), 2.25-2.32 (m, 1H), 2.13-2.19 (m, 1H).

상기 실시예의 반응을 이용하여 하기와 같은 화합물들을 제조하였다.The following compounds were prepared using the reaction of the above example.

실시예 2: N-히드록시-2-메틸-3-(6-메틸-2-옥소-2H-크로멘-3-일)-프로피온아미드Example 2: N-hydroxy-2-methyl-3- (6-methyl-2-oxo-2H-chromen-3-yl) -propionamide

실시예Example 3: 2-(7- 3: 2- (7- 메톡시Methoxy -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-)- 펜트Pent -4--4- 에노익Enoick 엑시드EXID 히드록시아미드 Hydroxyamide

실시예 4: 2-(6-메톡시-2-옥소-2H-크로멘-3-일메틸)-펜트-4-에노익 엑시드 히드록시아미드 Example 4: 2- (6-methoxy-2-oxo-2H-chromen-3-ylmethyl) -pent-4-enoic acid hydroxyamide

실시예 5: N-히드록시-3-(7-메톡시-2-옥소-2H-크로멘-3-일)-2-메틸-프로피온아미드Example 5: N-hydroxy-3- (7-methoxy-2-oxo-2H-chromen-3-yl) -2-methyl-propionamide

실시예Example 6: N-히드록시-2- 6: N-hydroxy-2- 메틸methyl -3-(7--3- (7- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일)--3 days)- 프로피온아미드Propionamide

실시예 7: 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-펜트-4-에노익 엑시드 히드록시아미드Example 7: 2- (6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -pent-4-enoic acid hydroxyamide

실시예 8: 2-벤질-N-히드록시-3-(6-메톡시-2-옥소-2H-크로멘-3-일)-프로피온아미드Example 8: 2-benzyl-N-hydroxy-3- (6-methoxy-2-oxo-2H-chromen-3-yl) -propionamide

실시예 9: 2-벤질-N-히드록시-3-(2-옥소-2H-크로멘-3-일)-프로피온아미드Example 9: 2-benzyl-N-hydroxy-3- (2-oxo-2H-chromen-3-yl) -propionamide

실시예Example 10: 2-벤질-N-히드록시-3-(7- 10: 2-benzyl-N-hydroxy-3- (7- 메톡시Methoxy -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일)--3 days)- 프로피온아미드Propionamide

실시예 Example 화학구조Chemical structure NMR 스펙트럼 데이터 (1H 혹은 13C)NMR spectral data ( 1 H or 13 C) 2 2

Figure 112006049660803-pat00019
Figure 112006049660803-pat00019
7.65(s, 1H), 7.34~7.36(m, 2H), 7.21(d, J=9.1Hz, 1H), 2.64~2.75(m, 3H), 2.38(s, 3H), 1.20(d, J=7.3Hz, 3H)7.65 (s, 1H), 7.34-7.36 (m, 2H), 7.21 (d, J = 9.1 Hz, 1H), 2.64-2.75 (m, 3H), 2.38 (s, 3H), 1.20 (d, J = 7.3 Hz, 3H) 3 3
Figure 112006049660803-pat00020
Figure 112006049660803-pat00020
 10.41(br, 1H), 8.69(br, 1H), 7.66(s, 1H), 7.55(d, J=8.4Hz, 1H), 6.94(m, 1H), 5.67-5.77(m, 2H), 4.99-5.09(m, 1H), 3.84(s, 1H), 2.56-2.67(m, 2H), 2.20-2.30(m, 1H), 2.08-2.18(m, 2H)10.41 (br, 1H), 8.69 (br, 1H), 7.66 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 6.94 (m, 1H), 5.67-5.77 (m, 2H), 4.99 -5.09 (m, 1H), 3.84 (s, 1H), 2.56-2.67 (m, 2H), 2.20-2.30 (m, 1H), 2.08-2.18 (m, 2H) 4 4
Figure 112006049660803-pat00021
Figure 112006049660803-pat00021
 10.38(s, 1H), 8.69(s, 1H), 7.68(s, 1H), 7.32(d, J=9.2Hz, 1H ), 7.13-7.20(m, 3H), 5.67-5.77(m, 1H), 5.07(d, J= 15.2Hz, 1H), 5.01(d, J=10.4Hz, 1H), 3.79(s, 3H), 2.45- 2.61(m, 3H), 2.24-2.31(m, 1H), 2.12-2.19(m, 1H).10.38 (s, 1H), 8.69 (s, 1H), 7.68 (s, 1H), 7.32 (d, J = 9.2 Hz, 1H), 7.13-7.20 (m, 3H), 5.67-5.77 (m, 1H) , 5.07 (d, J = 15.2 Hz, 1H), 5.01 (d, J = 10.4 Hz, 1H), 3.79 (s, 3H), 2.45- 2.61 (m, 3H), 2.24-2.31 (m, 1H), 2.12-2.19 (m, 1 H). 5 5
Figure 112006049660803-pat00022
Figure 112006049660803-pat00022
 10.41(br, 1H), 8.68(br, 1H), 7.68(s, 1H), 7.50(d, J=8.8Hz, 1H), 6.98(s, 1H), 6.93(d, J=8.6Hz, 1H), 3.83(s, 3H), 2.44-2.58(m, 3H), 1.04(d, J=6.8Hz, 3H).10.41 (br, 1H), 8.68 (br, 1H), 7.68 (s, 1H), 7.50 (d, J = 8.8 Hz, 1H), 6.98 (s, 1H), 6.93 (d, J = 8.6 Hz, 1H ), 3.83 (s, 3H), 2.44-2.58 (m, 3H), 1.04 (d, J = 6.8 Hz, 3H). 6 6
Figure 112006049660803-pat00023
Figure 112006049660803-pat00023
 10.41(s, 1H), 8.68(s, 1H), 7.65(s, 1H), 7.52(d, J=7.6Hz, 1H), 7.21(s, 1H), 7.15(d, J=7.6Hz, 7H), 2.45-2.65(m, 3H), 2.39(s, 3H), 1.04(d, J=6.0Hz, 3H)10.41 (s, 1H), 8.68 (s, 1H), 7.65 (s, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.21 (s, 1H), 7.15 (d, J = 7.6 Hz, 7H ), 2.45-2.65 (m, 3H), 2.39 (s, 3H), 1.04 (d, J = 6.0 Hz, 3H) 7 7
Figure 112006049660803-pat00024
Figure 112006049660803-pat00024
 10.39(br, 1H), 8.66(br, 1H), 7.64(s, 1H), 7.41(s, 1H), 7.36(d, J=8.8Hz, 1H), 7.26(d, J=8.4Hz, 1H), 5.70-5.74(m, 2H), 4.98-5.10(m, 1H), 2.53-2.58(m, 2H), 2.30(s, 3H), 2.23-2.28(m, 1H), 2.12-2.17(m, 1H)10.39 (br, 1H), 8.66 (br, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H ), 5.70-5.74 (m, 2H), 4.98-5.10 (m, 1H), 2.53-2.58 (m, 2H), 2.30 (s, 3H), 2.23-2.28 (m, 1H), 2.12-2.17 (m) , 1H) 8 8
Figure 112006049660803-pat00025
Figure 112006049660803-pat00025
 10.36(br, 1H), 8.65(br, 1H), 7.68(s, 1H), 7.12-7.32(m, 8H), 3.79(s, 3H), 2.86-2.91(m, 1H), 2.55-2.74(m, 4H). 10.36 (br, 1H), 8.65 (br, 1H), 7.68 (s, 1H), 7.12-7.32 (m, 8H), 3.79 (s, 3H), 2.86-2.91 (m, 1H), 2.55-2.74 ( m, 4H). 9 9
Figure 112006049660803-pat00026
Figure 112006049660803-pat00026
 10.37(s, 1H), 8.66(s, 1H), 7.72(s, 1H), 7.63(d, J=7.6Hz, 1H), 7.55(t, J=7.8Hz, 1H), 7.15-7.37(m, 7H), 2.87-2.92 (m, 1H), 2.56-2.76(m, 4H). 10.37 (s, 1H), 8.66 (s, 1H), 7.72 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.15-7.37 (m , 7H), 2.87-2.92 (m, 1 H), 2.56-2.76 (m, 4H). 10 10
Figure 112006049660803-pat00027
Figure 112006049660803-pat00027
 10.35(br, 1H), 8.64(br, 1H), 7.66(s, 1H), 7.54(d, J=8.4Hz, 1H), 7.12-7.28(m, 5H), 6.91-6.97(m, 2H), 3.83(s, 3H), 2.72-2.73(m, 1H), 2.57-2.69(m, 4H).10.35 (br, 1H), 8.64 (br, 1H), 7.66 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.12-7.28 (m, 5H), 6.91-6.97 (m, 2H) , 3.83 (s, 3H), 2.72-2.73 (m, 1H), 2.57-2.69 (m, 4H).

실시예Example 11: 2-(4-벤질옥시-벤질)- 11: 2- (4-benzyloxy-benzyl)- NN -히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-프로피온아미드의 합성Synthesis of -hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -propionamide

중간체 (1) 화합물의 제조: 4-플루오로-2-히드록시-벤즈알데히드Preparation of Intermediate (1) Compound: 4-Fluoro-2-hydroxy-benzaldehyde

Figure 112006049660803-pat00028
Figure 112006049660803-pat00028

메탄올 (30 ml)용액에 4-플로로페놀 (5.0 ml, 56.02 mmol)과 마그네슘메톡사이드 (44.5 ml, 33.6 mmol, 8 % wt in MeOH)을 첨가하여 증류한다. 메탄올이 약 15 ml가 남으면, 톨루엔 42 ml를 넣어 증류하고, 증류 온도가 95℃에 이르면 파라포름알데히드 (5.18 g, 172.54 mmol)를 1시간 동안 천천히 가한다. 증류 온도를 95℃로 유지하면서 1시간 동안 증류한다. 추가로 1시간 동안 교반하고 상온으로 온도를 낮춘다. 10 ％ 황산용액 (63 ml)을 가하고, 2시간 동안 30~40 ℃로 교반한 후 톨루엔으로　추출한다. 무수 황산마그네슘으로 건조하여 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=8:1)하여 표제 화합물 (4.05 g, 51.6 %, 노란색 고체)을 얻었다.Distillation is performed by adding 4-fluorophenol (5.0 ml, 56.02 mmol) and magnesium methoxide (44.5 ml, 33.6 mmol, 8% wt in MeOH) to methanol (30 ml) solution. After about 15 ml of methanol is left, 42 ml of toluene is added and distilled. When the distillation temperature reaches 95 ° C, paraformaldehyde (5.18 g, 172.54 mmol) is slowly added for 1 hour. Distillation is carried out for 1 hour while maintaining the distillation temperature at 95 ℃. Stir for an additional 1 hour and lower the temperature to room temperature. 10% sulfuric acid solution (63 ml) is added, stirred at 30-40 ° C. for 2 hours, and then extracted with toluene. It was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (hexane: ethyl acetate = 8: 1) to give the title compound (4.05 g, 51.6%, yellow solid).

1H-NMR (CDCl3, 400MHz) δ 11.37(s, 1H), 9.84(s, 1H), 7.57(dd, J=8.6, 6.4Hz, 1H), 6.66~6.76(m, 2H) 1 H-NMR (CDCl 3 , 400 MHz) δ 11.37 (s, 1H), 9.84 (s, 1H), 7.57 (dd, J = 8.6, 6.4Hz, 1H), 6.66 ~ 6.76 (m, 2H)

중간체 (2)의 제조: 2-(4-메톡시벤질옥시)-4-플루오로-5-메틸-벤즈알데히드Preparation of Intermediate (2): 2- (4-methoxybenzyloxy) -4-fluoro-5-methyl-benzaldehyde

단계 1. 3-플푸오로-4-메틸페놀의 합성Step 1. Synthesis of 3-Fluoro-4-methylphenol

Figure 112006049660803-pat00029
Figure 112006049660803-pat00029

10 % 황산수용액 100 ml 에 3-플루오로-4-메틸아닐린 (5g, 39.951 mmol)을 용해시킨 후 온도를 0℃으로 낮춘다. 소듐나이트레이트 (5.5g, 79.902 mmol)를 천천히 적가 후 동온에서 30분 동안 교반한다. 다음 50℃에서 30분 동안 교반 후 다시 80℃ 에서 5시간 동안 반응하였다. 반응 혼합물을 찬 얼음물로 종결하고 에틸아세테이트로 추출하였다. 용매를 무수 황산마그네슘으로 건조하여 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=8:1)하여 표제 화합물 (2.26 g 반응수율 : 44.8 %, 무색 액체)을 얻었다.Dissolve 3-fluoro-4-methylaniline (5 g, 39.951 mmol) in 100 ml of 10% aqueous sulfuric acid solution, and lower the temperature to 0 ° C. Sodium nitrate (5.5 g, 79.902 mmol) is slowly added dropwise and stirred at room temperature for 30 minutes. Then, the mixture was stirred at 50 ° C. for 30 minutes and then reacted at 80 ° C. for 5 hours. The reaction mixture was terminated with cold ice water and extracted with ethyl acetate. The solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (hexane: ethyl acetate = 8: 1) to obtain the title compound (2.26 g reaction yield: 44.8%, colorless liquid).

1H NMR(400MHz, CDCl3): δ 6.98(t, J=8.6Hz, 1H), 6.52(m, 2H), 5.82(br, 1H), 2.12(s, 3H). 1 H NMR (400 MHz, CDCl 3 ): δ 6.98 (t, J = 8.6 Hz, 1H), 6.52 (m, 2H), 5.82 (br, 1H), 2.12 (s, 3H).

단계 2. 4-플루오로-2-히드록시-5-메틸-벤즈알데히드과 2-플루오로-6-히드록시-3-메틸-벤즈알데히드의 합성Step 2. Synthesis of 4-fluoro-2-hydroxy-5-methyl-benzaldehyde and 2-fluoro-6-hydroxy-3-methyl-benzaldehyde

Figure 112006049660803-pat00030
Figure 112006049660803-pat00030

상기 제 1단계에서 제조한 화합물 (2.26 g, 17.920 mmol)을 8 % 마그네슘메톡사이드 메탄올용액 (14.2 ml, 10.762 mmol)에 용해시킨 후 단순증류방법으로 약 절반의 메탄올을 제거 후 다시 톨루엔을 첨가하여 단순증류 방법으로 모든 용매를 제거 후 95 ℃에서 파라포름알데히드 (1.66 g, 55.180 mmol)을 천천히 첨가 후 동온에서 1시간 동안 반응한다. 온도를 25℃으로 낮춘 후 10 % 황산수용액 20 ml을 첨가 후 다시 35 ℃에서 2시간 동안 반응하였다. 반응 혼합물을 찬 얼음물로 종결하고 톨루엔으로 추출하였다. 용매를 10 % 황산수용액으로 닦아준 후 무수 황산마그네슘으로 건조하여 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=13:1)하여 표제 화합물 (각 1.25 g 반응수율: 48.0 %, 300 mg, 반응수율: 11.5%, 무색 액체)을 얻었다.The compound prepared in step 1 (2.26 g, 17.920 mmol) was dissolved in 8% magnesium methoxide methanol solution (14.2 ml, 10.762 mmol), and about half of methanol was removed by simple distillation, and then toluene was added again. After removing all solvents by simple distillation, paraformaldehyde (1.66 g, 55.180 mmol) was slowly added at 95 ° C. and reacted at room temperature for 1 hour. After the temperature was lowered to 25 ° C., 20 ml of 10% aqueous sulfuric acid solution was added, followed by further reaction at 35 ° C. for 2 hours. The reaction mixture was terminated with cold ice water and extracted with toluene. The solvent was washed with 10% aqueous sulfuric acid solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (hexane: ethyl acetate = 13: 1) to give the title compound (each 1.25 g reaction yield: 48.0%, 300 mg). , Reaction yield: 11.5%, colorless liquid).

1H NMR(400MHz, CDCl3): δ 11.15(s, 1H), 9.98(s, 1H), 7.36(d, J=8.4Hz, 1H), 6.63(d, J=10.8Hz, 1H), 2.23(s, 3H). 1 H NMR (400 MHz, CDCl 3 ): δ 11.15 (s, 1H), 9.98 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 10.8 Hz, 1H), 2.23 (s, 3 H).

1H NMR(400MHz, CDCl3): δ 11.28(s, 1H), 10.26(s, 1H), 7.32(m, 1H), 6.67(d, J=8.4Hz, 1H), 2.10(s, 3H). 1 H NMR (400 MHz, CDCl 3 ): δ 11.28 (s, 1H), 10.26 (s, 1H), 7.32 (m, 1H), 6.67 (d, J = 8.4Hz, 1H), 2.10 (s, 3H) .

단계 3. 2-(4-메톡시벤질옥시)-4-플루오로-5-메틸-벤즈알데히드의 합성 Step 3. Synthesis of 2- (4-methoxybenzyloxy) -4-fluoro-5-methyl-benzaldehyde

Figure 112006049660803-pat00031
Figure 112006049660803-pat00031

상기 제 2단계에서 제조한 화합물 (1.25 g, 8.11 mmol)을 아세톤 (20 ml)에 용해시킨 후 탄산칼륨 (3.4 g, 24.330 mmol), 요오드화칼륨 (134 mg, 0.810 mmol), 4-메톡시벤질클로라이드를 첨가 후 온도를 55℃에서 4시간 동안 반응하였다. 반응 혼합물을 찬 얼음물로 종결하고 에틸아세테이트로 추출하였다. 용매를 무수 황산마그네슘으로 건조하여 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=7:1)하여 표제 화합물 (1.85 g 반응수율: 83.3 %, 노란 고체)을 얻었다. The compound prepared in step 2 (1.25 g, 8.11 mmol) was dissolved in acetone (20 ml), followed by potassium carbonate (3.4 g, 24.330 mmol), potassium iodide (134 mg, 0.810 mmol), 4-methoxybenzyl After adding chloride, the temperature was reacted at 55 ° C. for 4 hours. The reaction mixture was terminated with cold ice water and extracted with ethyl acetate. The solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (hexane: ethyl acetate = 7: 1) to obtain the title compound (1.85 g reaction yield: 83.3%, yellow solid).

1H NMR(400MHz, CDCl3): δ 10.38(s, 1H), 7.69(d, J=9.2Hz, 1H), 7.34(d, J=8.8Hz, 2H), 6.93(d, J=6H.8z, 2H), 6.72(d, J=11.2Hz, 1H), 5.06(s, 2H), 3.81(s, 3H), 2.21(s, 3H). 1 H NMR (400 MHz, CDCl 3 ): δ 10.38 (s, 1H), 7.69 (d, J = 9.2 Hz, 1H), 7.34 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 6H. 8z, 2H), 6.72 (d, J = 11.2 Hz, 1H), 5.06 (s, 2H), 3.81 (s, 3H), 2.21 (s, 3H).

최종 물질의 제조: 2-(4-벤질옥시-벤질)-Preparation of the final material: 2- (4-benzyloxy-benzyl)- NN -히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-프로피온아미드-Hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -propionamide

단계 1. 4-벤질옥시-벤즈알데히드의 합성Step 1. Synthesis of 4-benzyloxy-benzaldehyde

Figure 112006049660803-pat00032
Figure 112006049660803-pat00032

4-히드록시-벤즈알데히드 (2.70 g, 22.10 mmol)과 K2CO3 (4.58 g, 33.16 mmol)을 아세톤 (50 ml)에 용해시킨 후 벤질브로마이드 (3.15 ml, 26.53 mmol)을 넣어 7시간 동안 가열 환류 하였다. 반응 혼합물을 감압 농축하여 용매를 제거하고 물로 씻어준 후 에틸아세테이트로 추출하였다. 용매를 무수 황산마그네슘으로 건조하여 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=5:1)하여 표제 화합물 (4.44 g, 반응 수율: 95 %, 흰 고체)을 얻었다.4-hydroxy-benzaldehyde (2.70 g, 22.10 mmol) and K 2 CO 3 (4.58 g, 33.16 mmol) were dissolved in acetone (50 ml), and benzyl bromide (3.15 ml, 26.53 mmol) was added thereto and heated for 7 hours. Reflux. The reaction mixture was concentrated under reduced pressure to remove the solvent, washed with water and extracted with ethyl acetate. The solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (hexane: ethyl acetate = 5: 1) to obtain the title compound (4.44 g, reaction yield: 95%, white solid).

1H NMR(400MHz, CDCl3): δ 5.15(s, 2H, CH2), 7.09(d, J=8.8Hz, 2H, ArH), 7.35(m, 5H, ArH), 7.85(d, J=8.4Hz, 2H, ArH), 9.88(s, 1H, CHO) 1 H NMR (400 MHz, CDCl 3 ): δ 5.15 (s, 2H, CH 2), 7.09 (d, J = 8.8 Hz, 2H, ArH), 7.35 (m, 5H, ArH), 7.85 (d, J = 8.4 Hz, 2H, ArH), 9.88 (s, 1H, CHO)

단계 2. 5-(4-벤질옥시-벤질)-2,2-디메틸-[1,3]디옥산-4,6-디온의 합성 Step 2. Synthesis of 5- (4-benzyloxy-benzyl) -2,2-dimethyl- [1,3] dioxane-4,6-dione

Figure 112006049660803-pat00033
Figure 112006049660803-pat00033

보란디메틸아민 착화물 (1.01 g, 18.12 mmol)을 건조된 메탄올 (150 ml)에 용해시키고 2,2-디메틸-1,3-디옥산-4,6-디온 (2.61 g, 18.12 mmol)과 단계 1에서 제조한 화합물 (5.06 g, 23.55 mmol)을 천천히 넣어 상온에서 48시간 동안 반응하였다. 반응 혼합물을 찬 얼음물로 종결하고 용매를 감압 농축하여 제거한 다음 2N 염산 수용액으로 씻어준 후 에틸아세테이트로 추출하였다. 용매를 무수 황산마그네슘으로 건조하여 감압 농축하고 정제과정 없이 표제 화합물 (7.01 g, 반응 수율: 87 %, 흰 고체)을 얻었다.Boranedimethylamine complex (1.01 g, 18.12 mmol) is dissolved in dried methanol (150 ml) and subjected to 2,2-dimethyl-1,3-dioxane-4,6-dione (2.61 g, 18.12 mmol) Compound (5.06 g, 23.55 mmol) prepared in 1 was slowly added thereto and reacted at room temperature for 48 hours. Removed to terminate with cold ice water and the reaction mixture was concentrated under reduced pressure and the solvent then washed with 2 N aqueous hydrochloric acid and extracted with ethyl acetate. The solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and the title compound (7.01 g, reaction yield: 87%, white solid) was obtained without purification.

1H NMR(400MHz, CDCl3): δ 1.46(s, 3H, CH3), 1.72(s, 3H, CH3), 3.44(d, J=5.1Hz, 2H, CH2), 3.72(t, J=4.7Hz, 1H, CH), 5.03(s, 2H, CH2), 6.90(d, J=8.8Hz, 2H, ArH), 7.25(d, J=8.8Hz, 2H, ArH), 7.31~7.43(m, 5H, ArH) 1 H NMR (400 MHz, CDCl 3 ): δ 1.46 (s, 3H, CH 3 ), 1.72 (s, 3H, CH 3 ), 3.44 (d, J = 5.1 Hz, 2H, CH 2 ), 3.72 (t, J = 4.7Hz, 1H, CH), 5.03 (s, 2H, CH 2 ), 6.90 (d, J = 8.8Hz, 2H, ArH), 7.25 (d, J = 8.8Hz, 2H, ArH), 7.31 ~ 7.43 (m, 5H, ArH)

단계 3. 2-(4-벤질옥시-벤질)-아크릴릭 엑시드 에틸 에스터의 합성Step 3. Synthesis of 2- (4-benzyloxy-benzyl) -acrylic acid ethyl ester

Figure 112006049660803-pat00034
Figure 112006049660803-pat00034

단계 2에서 제조한 화합물 (160 mg, 0.47 mmol)과 N,N-디메틸메틸렌암모늄 아이오디드 (217 mg, 1.17 mmol)을 에탄올 (6 ml)에 용해시키고 85℃에서 5시간 동안 반응하였다. 반응 혼합물을 감압 농축하고 물로 씻어준 후 에틸아세테이트로 추출하였다. 용매를 무수 황산마그네슘으로 건조하여 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=3:1)하여 표제 화합물 (130 mg, 반응 수율: 93 %, 무색 액체)을 얻었다.Compound (160 mg, 0.47 mmol) and N , N -dimethylmethyleneammonium iodide (217 mg, 1.17 mmol) prepared in step 2 were dissolved in ethanol (6 ml) and reacted at 85 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, washed with water and extracted with ethyl acetate. The solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (130 mg, reaction yield: 93%, colorless liquid).

1H NMR(400MHz, CDCl3): δ 1.26(t, J=7.1Hz, 3H, CH3), 3.56(s, 2H, CH2), 4.19(q, J=6.9, 7.3Hz, 2H, CH2), 5.04(s, 2H, CH2), 5.44(s, 1H, CH), 6.20(s, 1H, CH), 6.92(d, J=8.8Hz, 2H, ArH), 7.10(d, J=8.4Hz, 2H, ArH), 7.32~7.44(m, 5H, ArH) 1 H NMR (400 MHz, CDCl 3 ): δ 1.26 (t, J = 7.1 Hz, 3H, CH 3 ), 3.56 (s, 2H, CH 2 ), 4.19 (q, J = 6.9, 7.3 Hz, 2H, CH 2 ), 5.04 (s, 2H, CH 2 ), 5.44 (s, 1H, CH), 6.20 (s, 1H, CH), 6.92 (d, J = 8Hz, 2H, ArH), 7.10 (d, J = 8.4 Hz, 2H, ArH), 7.32-7.44 (m, 5H, ArH)

단계 4. 2-(4-벤질옥시-벤질)-4-(디에톡시-포스포릴)-펜탄디오익 엑시드 디에틸 에스터의 합성Step 4. Synthesis of 2- (4-benzyloxy-benzyl) -4- (diethoxy-phosphoryl) -pentanedioic acid diethyl ester

Figure 112006049660803-pat00035
Figure 112006049660803-pat00035

트리에틸포스포노아세테이트 (6.45 ml, 32.25 mmol)을 건조된 THF (100 ml)에 용해시키고 0 ℃로 온도를 낮춘 후 소듐하이드라이드 (774 mg, 32.25 mmol)을 천천히 넣어 1시간 동안 교반하였다. 반응 혼합물에 단계 3에서 제조한 화합물 (3.18 g, 10.74 mmol)을 건조된 THF (5 ml)에 용해시켜 넣고 상온에서 18시간 동안 반응 하였다. 찬 얼음물로 반응을 종결하고 암모늄클로라이드 수용액으로 씻은 다음 에틸아세테이트로 추출하였다. 용매를 무수 황산마그네슘으로 건조하여 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=1:2)하여 표제 화합물 (3.96 g, 반응 수율: 70 %, 무색 액체)을 얻었다.Triethylphosphonoacetate (6.45 ml, 32.25 mmol) was dissolved in dried THF (100 ml), the temperature was lowered to 0 ° C. and sodium hydride (774 mg, 32.25 mmol) was slowly added and stirred for 1 hour. In the reaction mixture, the compound (3.18 g, 10.74 mmol) prepared in Step 3 was dissolved in dried THF (5 ml) and reacted at room temperature for 18 hours. The reaction was terminated with cold ice water, washed with an aqueous ammonium chloride solution and extracted with ethyl acetate. The solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (hexane: ethyl acetate = 1: 2) to obtain the title compound (3.96 g, reaction yield: 70%, colorless liquid).

1H NMR(400MHz, CDCl3): δ 1.24~1.35(m, 12H, CH3x4), 2.01~2.49(m, 3H, CHx3), 2.61~2.78(m, 1H, CH), 2.81~3.25(m, 2H, CHx2), 4.01~4.21(m, 8H, CH2x4), 5.02(s, 1H, CH2), 6.88(d, J=8.0Hz, 2H, ArH), 7.05(d, J=8.0Hz, 2H, ArH), 7.31~7.43(m, 5H, ArH) 1 H NMR (400 MHz, CDCl 3 ): δ 1.24 to 1.35 (m, 12H, CH 3 x4), 2.01 to 2.49 (m, 3H, CHx3), 2.61 to 2.78 (m, 1H, CH), 2.81 to 3.25 ( m, 2H, CHx2), 4.01 ~ 4.21 (m, 8H, CH 2 x4), 5.02 (s, 1H, CH 2), 6.88 (d, J = 8.0Hz, 2H, ArH), 7.05 (d, J = 8.0 Hz, 2H, ArH), 7.31-7.43 (m, 5H, ArH)

단계 5. 2-(4-벤질옥시-벤질)-4-[2-(4-메톡시-벤질옥시)-5-메틸-벤질리딘]-펜탄디오익 엑시드 디에틸 에스터의 합성Step 5. Synthesis of 2- (4-benzyloxy-benzyl) -4- [2- (4-methoxy-benzyloxy) -5-methyl-benzylidene] -pentanedioic acid diethyl ester

Figure 112006049660803-pat00036
Figure 112006049660803-pat00036

단계 4에서 제조한 화합물 (5.10 g, 9.79 mmol)을 건조된 THF (100 ml)에 용해시키고 tert-리튬부톡사이드 (1M THF 용액: 16.32 ml, 16.32 mmol)을 넣어 30분 동안 반응하였다. 반응 혼합물에 2-(4-메톡시-벤질록시)-5-메틸-벤즈알데히드 (1.67 g, 6.53 mmol)을 넣고 상온에서 18시간 동안 반응 한 다음 찬 얼음물로 반응을 종결하고 에틸아세테이트로 추출하였다. 용매를 무수 황산마그네슘으로 건조하여 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=7:1)하여 표제 화합물 (2.70 g, 반응 수율: 66 %, 무색 액체)을 얻었다.The compound (5.10 g, 9.79 mmol) prepared in step 4 was dissolved in dried THF (100 ml), and tert -lithium butoxide (1 M THF solution: 16.32 ml, 16.32 mmol) was added and reacted for 30 minutes. 2- (4-methoxy-benzyloxy) -5-methyl-benzaldehyde (1.67 g, 6.53 mmol) was added to the reaction mixture, which was reacted at room temperature for 18 hours. The reaction was quenched with cold ice water and extracted with ethyl acetate. The solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (hexane: ethyl acetate = 7: 1) to give the title compound (2.70 g, reaction yield: 66%, colorless liquid).

1H NMR(400MHz, CDCl3): δ 0.98~1.03(m, 3H, CH3), 1.25~1.34(m, sH, CH3), 2.29(s, 3H, CH3), 2.63~2.97(m, 6H, CHx6), 3.78(s, 3H, CH3), 3.84~3.94(m, 2H, CH2), 4.21~4.26(m, 2H, CH2), 4.98(s, 2H, CH2), 5.00(s, 2H, CH2), 6.79~6.87(m, 4H, ArH), 6.97(d, J=8.8Hz, 2H, ArH), 7.07(d, J=8.1Hz, 2H, ArH), 7.29~7.42(m, 8H, ArH) 1 H NMR (400 MHz, CDCl 3 ): δ 0.98 to 1.03 (m, 3H, CH 3 ), 1.25 to 1.34 (m, sH, CH 3 ), 2.29 (s, 3H, CH 3 ), 2.63 to 2.97 (m , 6H, CHx6), 3.78 (s, 3H, CH 3 ), 3.84-3.94 (m, 2H, CH 2 ), 4.21-4.26 (m, 2H, CH 2 ), 4.98 (s, 2H, CH 2 ), 5.00 (s, 2H, CH 2 ), 6.79 ~ 6.87 (m, 4H, ArH), 6.97 (d, J = 8.8Hz, 2H, ArH), 7.07 (d, J = 8.1Hz, 2H, ArH), 7.29 ~ 7.42 (m, 8H, ArH)

단계 6. 2-(4-벤질옥시-벤질)-4-(2-히드록시-5-메틸-벤질리딘)-펜탄디오익 엑시드 디에틸 에스터의 합성Step 6. Synthesis of 2- (4-benzyloxy-benzyl) -4- (2-hydroxy-5-methyl-benzylidene) -pentanedioic acid diethyl ester

Figure 112006049660803-pat00037
Figure 112006049660803-pat00037

단계 5에서 제조한 화합물 (2.70 g, 4.33 mmol)을 1,4-디옥산 (30 ml)에 용해시킨 후 0 ℃로 온도를 낮추고 4N 염산 수용액 (32 ml, 130.03 mmol)을 넣어 상온에서 24시간 동안 반응하였다. 반응 혼합물을 찬 얼음물로 종결하고 에틸아세테이트로 추출하여 용매를 무수 황산 마그네슘으로 건조한 다음 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=2:1)하여 표제 화합물 (1.89 g, 반응 수율: 87 %, 노란 액체)을 얻었다.The compound prepared in step 5 (2.70 g, 4.33 mmol) was dissolved in 1,4-dioxane (30 ml), and the temperature was lowered to 0 ° C., and 4N hydrochloric acid aqueous solution (32 ml, 130.03 mmol) was added thereto at room temperature for 24 hours. Reaction. The reaction mixture was terminated with cold ice water, extracted with ethyl acetate, the solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and the residue was purified by column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (1.89 g, reaction yield: 87%, yellow liquid).

1H NMR(400MHz, CDCl3): δ 1.26(t, J=7.1Hz, 3H, CH3), 1.32(t, J=6.9Hz, 3H, CH3), 2.27(s, 3H, CH3), 2.59~2.67(m, 2H, CHx2), 2.75~2.85(m, 2H, CHx2), 2.95~2.99(m, 1H, CH), 3.84~4.00(m, 1H, CH), 4.22~4.27(m, 2H, CH2), 5.01(s, 2H, CH2), 6.79(d, J=8.4Hz, 2H, ArH), 6.84(d, J=8.8Hz, 2H, ArH), 6.98(s, 1H, ArH), 7.00~7.10(m, 2H, ArH), 7.29~7.42(m, 5H, ArH) 1 H NMR (400 MHz, CDCl 3 ): δ 1.26 (t, J = 7.1 Hz, 3H, CH 3 ), 1.32 (t, J = 6.9 Hz, 3H, CH 3 ), 2.27 (s, 3H, CH 3 ) , 2.59 to 2.67 (m, 2H, CHx2), 2.75 to 2.85 (m, 2H, CHx2), 2.95 to 2.99 (m, 1H, CH), 3.84 to 4.00 (m, 1H, CH), 4.22 to 4.27 (m , 2H, CH 2 ), 5.01 (s, 2H, CH 2 ), 6.79 (d, J = 8.4 Hz, 2H, ArH), 6.84 (d, J = 8.8 Hz, 2H, ArH), 6.98 (s, 1H , ArH), 7.00-7.10 (m, 2H, ArH), 7.29-7.42 (m, 5H, ArH)

단계 7. 2-(4-벤질옥시-벤질)-3-(6-메틸-2-옥소-2H-크로멘-3-일)-프로피오닉 엑시드 에틸 에스터의 합성Step 7. Synthesis of 2- (4-benzyloxy-benzyl) -3- (6-methyl-2-oxo-2H-chromen-3-yl) -propionic acid ethyl ester

Figure 112006049660803-pat00038
Figure 112006049660803-pat00038

단계 6에서 제조한 화합물 (600 mg, 1.19 mmol)을 자일렌 (10 ml)에 용해시켜 sealed tube를 사용하여 200 ℃에서 96시간 동안 반응하였다. 반응 혼합물을 상온으로 낮춘 후 용매를 감압 농축하여 제거하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=4:1)하여 표제 화합물 (520 mg, 반응 수율: 96 %, 무색 액체)을 얻었다.Compound (600 mg, 1.19 mmol) prepared in step 6 was dissolved in xylene (10 ml) and reacted for 96 hours at 200 ° C. using a sealed tube. After the reaction mixture was cooled to room temperature, the solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (520 mg, reaction yield: 96%, colorless liquid).

1H NMR(400MHz, CDCl3): δ 0.99(t, J=7.1Hz, 3H, CH3), 2.38(s, 3H, CH3), 2.74~2.81(m, 3H, CHx3), 2.83~2.98(m, 1H, CH), 3.16~3.22(m, 1H, CH), 3.91~3.97(m, 2H, CH2), 5.02(s, 2H, CH2), 6.89(d, J=8.4Hz, 2H, ArH), 7.10(d, J=8.4Hz, 2H, ArH), 7.18(d, J=8.4Hz, 2H, ArH), 7.29~7.44(m, 7H, ArH) 1 H NMR (400 MHz, CDCl 3 ): δ 0.99 (t, J = 7.1 Hz, 3H, CH 3 ), 2.38 (s, 3H, CH 3 ), 2.74 to 2.81 (m, 3H, CHx3), 2.83 to 2.98 (m, 1H, CH), 3.16 to 3.22 (m, 1H, CH), 3.91 to 3.97 (m, 2H, CH 2 ), 5.02 (s, 2H, CH 2 ), 6.89 (d, J = 8.4 Hz, 2H, ArH), 7.10 (d, J = 8.4 Hz, 2H, ArH), 7.18 (d, J = 8.4 Hz, 2H, ArH), 7.29-7.44 (m, 7H, ArH)

단계 8. 2-(4-벤질옥시-벤질)-Step 8. 2- (4-Benzyloxy-benzyl)- NN -히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-프로피온아미드의 합성Synthesis of -hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -propionamide

Figure 112006049660803-pat00039
Figure 112006049660803-pat00039

단계 7에서 제조한 화합물 (190 mg, 0.41 mmol)을 메탄올에 용해된 1.76 M NH2OH KCl (1.18 ml, 2.08 mmol)을 넣어 상온에서 하루 동안 반응하였다. 반응 혼합물을 감압 농축하여 용매를 제거 하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=1:1)하여 표제 화합물 (27 mg, 반응 수율: 15 %, 흰 고체)을 얻었다.The compound (190 mg, 0.41 mmol) prepared in step 7 was added to 1.76 M NH 2 OH KCl (1.18 ml, 2.08 mmol) dissolved in methanol, and reacted at room temperature for one day. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was subjected to column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (27 mg, reaction yield: 15%, white solid).

1H NMR(400MHz, DMSO-d 6 ): δ 2.34(s, 3H, CH3), 2.54~2.69(m, 4H, CHx4), 2.79(m, 1H, CH), 5.04(s, 2H, CH2), 6.91(d, J=8.0Hz, 2H, ArH), 7.32~7.45(m, 7H, ArH), 7.64(s, 1H, ArH), 8.65(s, 1H, OH), 10.35(s, 1H, NH) 1 H NMR (400 MHz, DMSO- d 6 ): δ 2.34 (s, 3H, CH 3 ), 2.54-2.69 (m, 4H, CHx4), 2.79 (m, 1H, CH), 5.04 (s, 2H, CH 2 ), 6.91 (d, J = 8.0 Hz, 2H, ArH), 7.32-7.45 (m, 7H, ArH), 7.64 (s, 1H, ArH), 8.65 (s, 1H, OH), 10.35 (s, 1H, NH)

상기 실시예의 반응을 이용하여 하기와 같은 화합물들을 제조하였다.The following compounds were prepared using the reaction of the above example.

실시예Example 12: 4-(4- 12: 4- (4- 벤질옥시Benzyloxy -- 페닐Phenyl )-)- NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-)- 부틸아미드Butylamide

실시예Example 13: 3-(7- 13: 3- (7- 플루오로Fluoro -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일)--3 days)- NN -히드록시-2-Hydroxy-2- 메틸methyl -- 프로피온아미드Propionamide

실시예Example 14: 2-(3- 14: 2- (3- 벤질옥시Benzyloxy -벤질)--benzyl)- NN -히드록시-3-(6--Hydroxy-3- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일)--3 days)- 프로피온아미드Propionamide

실시예Example 15: 4-(3- 15: 4- (3- 벤질옥시Benzyloxy -- 페닐Phenyl )-)- NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-)- 부틸아미드Butylamide

실시예Example 16: 3-(7-클로로-2-옥소-2H-크로멘-3-일)- 16: 3- (7-chloro-2-oxo-2H-chromen-3-yl)- NN -히드록시-2-메틸-프로피온아미드.Hydroxy-2-methyl-propionamide.

실시예Example 17: 2-벤질-3-(7- 17: 2-benzyl-3- (7- 클로로Chloro -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일)--3 days)- NN -히드록시--Hydroxy- 프로피온아미드Propionamide

실시예Example 18: 2-벤질- 18: 2-benzyl- NN -히드록시-3-(7-Hydroxy-3- (7- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일)--3 days)- 프로피온아미드Propionamide

실시예Example 19: 2-벤질-3-(7- 19: 2-benzyl-3- (7- 플루오로Fluoro -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일)--3 days)- NN -히드록시--Hydroxy- 프로피온아미드Propionamide

실시예Example 20: 2-(6- 20: 2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-6-) -6- 페닐Phenyl -- 헥사노익Hexanoic 엑시드EXID 히드록시아미드 Hydroxyamide

실시예 21: 4-메틸-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-펜타노익 엑시드 히드록시아미드Example 21 4-Methyl-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -pentanoic acid hydroxyamide

실시예Example 22:  22: NN -히드록시-3--Hydroxy-3- 메틸methyl -2-(6--2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-)- 부틸아미드Butylamide

실시예 23: 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-도데카노익 엑시드 히드록시아미드Example 23: 2- (6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -dodecanoic acid hydroxyamide

실시예Example 24: 3-(7- 24: 3- (7- 플루오로Fluoro -6--6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일)--3 days)- NN -히드록시-2-Hydroxy-2- 메틸methyl -- 프로피온아미드Propionamide

실시예 Example 화학구조Chemical structure NMR 스펙트럼 데이터 (1H 혹은 13C)NMR spectral data ( 1 H or 13 C) 12  12

Figure 112006049660803-pat00040
Figure 112006049660803-pat00040
10.46(s, 1H), 8.74(s, 1H), 7.64(s, 1H), 7.26-7.44(m, 8H), 7.08(d, J=7.2Hz, 2H), 6.90(d, J=7.2Hz, 2H), 5.05(s, 2H), 2.61(d, J=6.8Hz, 2H), 2.43-2.46(m, 3H), 2.35(s, 3H), 1.74-1.77(m, 1H), 1.61-1.62(m, 1H)10.46 (s, 1H), 8.74 (s, 1H), 7.64 (s, 1H), 7.26-7.44 (m, 8H), 7.08 (d, J = 7.2 Hz, 2H), 6.90 (d, J = 7.2 Hz , 2H), 5.05 (s, 2H), 2.61 (d, J = 6.8Hz, 2H), 2.43-2.46 (m, 3H), 2.35 (s, 3H), 1.74-1.77 (m, 1H), 1.61- 1.62 (m, 1 H) 13 13
Figure 112006049660803-pat00041
Figure 112006049660803-pat00041
 10.41(br, 1H), 8.68(br, 1H), 7.77(s, 1H), 7.21-7.77(m, 3H), 2.46-2.63(m, 3H), 1.05(d, J=6.4Hz, 2H)10.41 (br, 1H), 8.68 (br, 1H), 7.77 (s, 1H), 7.21-7.77 (m, 3H), 2.46-2.63 (m, 3H), 1.05 (d, J = 6.4 Hz, 2H) 14 14
Figure 112006049660803-pat00042
Figure 112006049660803-pat00042
 10.38(s, 1H), 8.66(s, 1H), 7.64(s, 1H), 7.14-7.44(m, 7H), 6.76-6.85(m, 3H), 5.03(s, 2H), 2.75-2.87(m, 2H), 2.57-2.67(m, 3H), 2.33(s, 3H) 10.38 (s, 1H), 8.66 (s, 1H), 7.64 (s, 1H), 7.14-7.44 (m, 7H), 6.76-6.85 (m, 3H), 5.03 (s, 2H), 2.75-2.87 ( m, 2H), 2.57-2.67 (m, 3H), 2.33 (s, 3H) 15  15
Figure 112006049660803-pat00043
Figure 112006049660803-pat00043
 10.47(s, 1H), 8.75(s, 1H), 7.66(s, 1H), 6.74-7.45(m, 12H), 5.06(s, 2H), 2.44-2.63(m, 5H), 2.34(s, 3H), 1.62-1.86(m, 2H) 10.47 (s, 1H), 8.75 (s, 1H), 7.66 (s, 1H), 6.74-7.45 (m, 12H), 5.06 (s, 2H), 2.44-2.63 (m, 5H), 2.34 (s, 3H), 1.62-1.86 (m, 2H) 16 16
Figure 112006049660803-pat00044
Figure 112006049660803-pat00044
 10.42(s, 1H), 8.70(s, 1H), 7.81(s, 1H), 7.68-7.70(m, 1H),7.58(s, 1H), 7.40-7.42(m 1H), 2.61-2.64(m, 2H), 1.05-1.06(m, 3H)10.42 (s, 1H), 8.70 (s, 1H), 7.81 (s, 1H), 7.68-7.70 (m, 1H), 7.58 (s, 1H), 7.40-7.42 (m 1H), 2.61-2.64 (m , 2H), 1.05-1.06 (m, 3H)

실시예 Example 화학구조Chemical structure NMR 스펙트럼 데이터 (1H 혹은 13C)NMR spectral data ( 1 H or 13 C) 17 17

Figure 112006049660803-pat00045
Figure 112006049660803-pat00045
10.34(s, 1H), 8.62(br, 1H), 7.65-7.72(m, 2H), 7.55(s, 1H), 7.38(s, 1H), 7.16-7.26(m, 5H), 2.85-2.90(m, 1H), 2.55-2.72(m, 4H)10.34 (s, 1H), 8.62 (br, 1H), 7.65-7.72 (m, 2H), 7.55 (s, 1H), 7.38 (s, 1H), 7.16-7.26 (m, 5H), 2.85-2.90 ( m, 1H), 2.55-2.72 (m, 4H) 18 18
Figure 112006049660803-pat00046
Figure 112006049660803-pat00046
 10.35(s, 1H), 8.63(s, 1H), 7.68(s, 1H), 7.51(d, J=8.0Hz, 1H), 7.14-7.28(m, 7H), 2.86-2.91(m, 1H), 2.54-2.74(m, 4H), 2.39(s, 3H)10.35 (s, 1H), 8.63 (s, 1H), 7.68 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.14-7.28 (m, 7H), 2.86-2.91 (m, 1H) , 2.54-2.74 (m, 4H), 2.39 (s, 3H) 19 19
Figure 112006049660803-pat00047
Figure 112006049660803-pat00047
 10.36(s, 1H), 8.65(s, 1H), 7.74(s, 1H), 7.18-7.74(m, 7H), 2.54-2.88(m, 5H)10.36 (s, 1H), 8.65 (s, 1H), 7.74 (s, 1H), 7.18-7.74 (m, 7H), 2.54-2.88 (m, 5H) 20   20
Figure 112006049660803-pat00048
Figure 112006049660803-pat00048
 10.35(br, 1H), 8.64(br, 1H), 7.66(s, 1H), 7.54(d, J=8.4Hz, 1H), 7.16-7.28(m, 5H), 6.91-6.97(m, 2H), 2.44-2.66(m, 8H), 2.30(s, 3H), 2.44-2.66(m, 8H), 1.65-1.77(m, 3H)10.35 (br, 1H), 8.64 (br, 1H), 7.66 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.16-7.28 (m, 5H), 6.91-6.97 (m, 2H) , 2.44-2.66 (m, 8H), 2.30 (s, 3H), 2.44-2.66 (m, 8H), 1.65-1.77 (m, 3H) 21 21
Figure 112006049660803-pat00049
Figure 112006049660803-pat00049
 10.37(br, 1H), 8.56(br, 1H), 7.62(s, 1H), 7.42(s, 1H), 7.37(m, 1H), 7.27(d, J=8.4Hz, 1H), 2.68(m, 1H), 2.57(m, 2H), 2.35(s, 3H), 2.13(m, 1H), 1.75(m, 1H), 0.97(d, J=6.4Hz, 3H), 0.89(d, J=6.8Hz, 3H)10.37 (br, 1H), 8.56 (br, 1H), 7.62 (s, 1H), 7.42 (s, 1H), 7.37 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 2.68 (m , 1H), 2.57 (m, 2H), 2.35 (s, 3H), 2.13 (m, 1H), 1.75 (m, 1H), 0.97 (d, J = 6.4 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H) 22 22
Figure 112006049660803-pat00050
Figure 112006049660803-pat00050
 10.29(s, 1H), 8.62(s, 1H), 7.62(s, 1H), 7.42(s, 1H), 7.37(d, J=8.4Hz, 1H), 7.27(d, J=8.4Hz, 1H), 2.35(s, 3H), 1.74-2.69(m, 4H), 1.97(d, J=6.6Hz, 1H), 1.89(d, J=6.6Hz, 1H)10.29 (s, 1H), 8.62 (s, 1H), 7.62 (s, 1H), 7.42 (s, 1H), 7.37 (d, J = 8.4Hz, 1H), 7.27 (d, J = 8.4Hz, 1H ), 2.35 (s, 3H), 1.74-2.69 (m, 4H), 1.97 (d, J = 6.6 Hz, 1H), 1.89 (d, J = 6.6 Hz, 1H) 23  23
Figure 112006049660803-pat00051
Figure 112006049660803-pat00051
 10.37(s, 1H), 8.66(s, 1H), 7.63(s, 1H), 7.36(d, J=8.8Hz, 1H), 7.26(d, J=8.1Hz, 1H), 2.34(s, 5H), 1.21(s, 16H), 0.82-0.85(m, 3H)10.37 (s, 1H), 8.66 (s, 1H), 7.63 (s, 1H), 7.36 (d, J = 8.8Hz, 1H), 7.26 (d, J = 8.1Hz, 1H), 2.34 (s, 5H ), 1.21 (s, 16H), 0.82-0.85 (m, 3H) 24 24
Figure 112006049660803-pat00052
Figure 112006049660803-pat00052
 10.40(br, 1H), 8.67(br, 1H), 7.68(s, 1H), 7.56(d, J=8.0Hz, 1H), 7.31(d, J=10.4Hz, 1H), 2.31(s, 3H), 1.02(d, J=6.4Hz, 2H)10.40 (br, 1H), 8.67 (br, 1H), 7.68 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 10.4 Hz, 1H), 2.31 (s, 3H ), 1.02 (d, J = 6.4 Hz, 2H)

실시예Example 25:  25: NN -히드록시-4-(4-히드록시-페닐)-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드-Hydroxy-4- (4-hydroxy-phenyl) -2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide

4-(4-히드록시페닐)-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부티릭 엑시드 에틸 에스터 (70 mg, 0.18 mmol)를 실시예 11의 단계 8과 동일한 방법으로 실험하여 표제 화합물 (18 mg, 반응 수율: 27 %, 흰 고체)을 얻었다.4- (4-hydroxyphenyl) -2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butyric acid ethyl ester (70 mg, 0.18 mmol) was prepared in Example 11 Experiment in the same manner as 8 to obtain the title compound (18 mg, reaction yield: 27%, white solid).

1H NMR(400MHz, DMSO-d 6 ): δ 1.57~1.61(m, 1H, CH), 1.74~1.78(m, 1H, CH), 2.35(s, 3H, CH3), 2.37~2.41(m, 3H, CH2, CH), 2.59~2.61(m, 2H, CH2), 6.56(d, J=8.0Hz, 2H, ArH), 6.94(d, J=7.7Hz, 2H, ArH), 7.28(d, J=8.0Hz, 1H, ArH), 7.36(d, J=8.4Hz, 1H, ArH), 7.41(s, 1H, ArH), 7.64(s, 1H, ArH), 8.74(s, 1H, OH), 10.45(s, 1H, NH) 1 H NMR (400 MHz, DMSO- d 6 ): δ 1.57-1.61 (m, 1H, CH), 1.74-1.78 (m, 1H, CH), 2.35 (s, 3H, CH 3 ), 2.37-2.41 (m , 3H, CH 2 , CH), 2.59 to 2.61 (m, 2H, CH 2 ), 6.56 (d, J = 8.0 Hz, 2H, ArH), 6.94 (d, J = 7.7 Hz, 2H, ArH), 7.28 (d, J = 8.0 Hz, 1H, ArH), 7.36 (d, J = 8.4 Hz, 1H, ArH), 7.41 (s, 1H, ArH), 7.64 (s, 1H, ArH), 8.74 (s, 1H , OH), 10.45 (s, 1H, NH)

실시예 26: Example 26: NN -히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[4-(2-피페리딘-1-일-에톡시)-벤질]-프로피온아미드-Hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -propionamide

단계 1: 2-(4-히드록시-벤질)-3-(6-메틸-2-옥소-2H-크로멘-3-일)-프로피오닉 엑시드 에틸 에스터의 합성Step 1: Synthesis of 2- (4-hydroxy-benzyl) -3- (6-methyl-2-oxo-2H-chromen-3-yl) -propionic acid ethyl ester

Figure 112006049660803-pat00053
Figure 112006049660803-pat00053

실시예 11의 단계7에서 제조한 화합물 (400 mg, 0.87 mmol)을 에탄올 (10 ml)에 용해시키고 Pd/C 10 %와 H2로 5시간 동안 상온에서 반응하였다. 반응 혼합물을 셀라이트 충전물로 걸러내고 용매를 감압 농축하여 정제 과정 없이 표제 화합물 (300 mg, 반응 수율: 94 %, 무색 액체)을 얻었다.Compound (400 mg, 0.87 mmol) prepared in step 7 of Example 11 was dissolved in ethanol (10 ml) and reacted with Pd / C 10% and H 2 at room temperature for 5 hours. The reaction mixture was filtered through a celite charge and the solvent was concentrated under reduced pressure to afford the title compound (300 mg, reaction yield: 94%, colorless liquid) without purification.

1H NMR(400MHz, CDCl3): δ 1.01(t, J=7.1Hz, 3H, CH3), 2.38(s, 3H, CH3), 2.73~2.85(m, 3H, CHx3), 2.92~2.97(m, 1H, CH), 3.16~3.20(m, 1H, CH), 3.93~3.99(m, 2H, CH2), 6.76(d, J=8.4Hz, 2H, ArH), 7.05(d, J=8.4Hz, 2H, ArH), 7.19(d, J=8.4Hz, 2H, ArH), 7.28(s, 1H, ArH), 7.46(s, 1H, ArH) 1 H NMR (400 MHz, CDCl 3 ): δ 1.01 (t, J = 7.1 Hz, 3H, CH 3 ), 2.38 (s, 3H, CH 3 ), 2.73-2.85 (m, 3H, CHx3), 2.92-2.97 (m, 1H, CH), 3.16 to 3.20 (m, 1H, CH), 3.93 to 3.99 (m, 2H, CH 2 ), 6.76 (d, J = 8.4 Hz, 2H, ArH), 7.05 (d, J = 8.4 Hz, 2H, ArH), 7.19 (d, J = 8.4 Hz, 2H, ArH), 7.28 (s, 1H, ArH), 7.46 (s, 1H, ArH)

단계 2: 3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[4-(2-피페리딘-1-일-에톡시)-벤질]-프로피오닉 Step 2: 3- (6-Methyl-2-oxo-2H-chromen-3-yl) -2- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -propionic 엑시드EXID 에틸 에스터의 합성 Synthesis of Ethyl Ester

Figure 112006049660803-pat00054
Figure 112006049660803-pat00054

단계 1에서 제조한 화합물 (120 mg, 0.35 mmol)과 1-(2-클로로에틸)-피페리딘. HCl (90 mg, 0.49 mmol), 아이오도 나트륨 (74 mg, 0.49 mmol), 세슘카보네이트 (320 mg, 0.98 mmol)을 DMF (5 ml)에 용해시킨 후 85℃에서 18시간 동안 반응 한다. 반응혼합물을 암모니움 클로라이드수용액으로 반응을 종결하고 클로로포름으로 추출하여 용매를 무수 황산마그네슘으로 건조한 다음 감압 농축하였다. 잔여물을 관 크로마토그래피 (헥산:에칠아세테이트=2:1)하여 표제 화합물 (120 mg, 반응 수율: 78 %, 노란 액체)을 얻었다.Compound (120 mg, 0.35 mmol) prepared in step 1 and 1- (2-chloroethyl) -piperidine. HCl (90 mg, 0.49 mmol), sodium iodo (74 mg, 0.49 mmol) and cesium carbonate (320 mg, 0.98 mmol) were dissolved in DMF (5 ml) and reacted at 85 ° C. for 18 hours. The reaction mixture was terminated with an aqueous solution of ammonium chloride, extracted with chloroform, the solvent was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (120 mg, reaction yield: 78%, yellow liquid).

1H NMR(400MHz, CDCl3): δ 1.02(t, J=7.1Hz, 3H, CH3), 1.79~1.82(m, 4H, CH2x2), 1.98~2.13(m, 2H, CH2), 2.38(s, 3H, CH3), 2.73~2.84(m, 4H, CH2x2), 2.93~2.98(m, 4H, CHx4), 3.15~3.19(m, 3H, CHx3), 3.97(q, J=7.1, 7.3Hz, 2H, CH2), 4.20~4.28(m, 2H, CH2), 6.79(d, J=8.4Hz, 2H, ArH), 7.10(d, J=8.4Hz, 2H, ArH), 7.18~7.20(m, 2H, ArH), 7.26~7.28(m, 1H, ArH), 7.45(s, 1H, ArH) 1 H NMR (400 MHz, CDCl 3 ): δ 1.02 (t, J = 7.1 Hz, 3H, CH 3 ), 1.79-1.82 (m, 4H, CH2x2), 1.98-2.13 (m, 2H, CH 2 ), 2.38 (s, 3H, CH 3 ), 2.73 to 2.84 (m, 4H, CH2x2), 2.93 to 2.98 (m, 4H, CHx4), 3.15 to 3.19 (m, 3H, CHx3), 3.97 (q, J = 7.1, 7.3 Hz, 2H, CH 2 ), 4.20 to 4.28 (m, 2H, CH 2 ), 6.79 (d, J = 8.4 Hz, 2H, ArH), 7.10 (d, J = 8.4 Hz, 2H, ArH), 7.18 ~ 7.20 (m, 2H, ArH), 7.26-7.28 (m, 1H, ArH), 7.45 (s, 1H, ArH)

상기 실시예의 반응을 이용하여 하기와 같은 화합물들을 제조하였다.The following compounds were prepared using the reaction of the above example.

실시예Example 27:  27: NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[4-(2-) -4- [4- (2- 메틸methyl -퀴놀린-4-일--Quinolin-4-yl- 메톡시Methoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예 28: Example 28: NN -히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[4-(2-모르폴린-4-일-에톡시)-벤질]-프로피온아미드-Hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -propionamide

실시예Example 29:  29: NN -히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[4-(3-모르폴린-4-일-프로폭시)-벤질]-프로피온아미드-Hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [4- (3-morpholin-4-yl-propoxy) -benzyl] -propionamide

실시예 30: Example 30: NN -히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[4-(3-피리딘-4-일-프로폭시)-벤질]-프로피온아미드-Hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [4- (3-pyridin-4-yl-propoxy) -benzyl] -propionamide

실시예Example 31:  31: NN -히드록시-3-(6--Hydroxy-3- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일)-2-[3-(3-피리딘-4-일--3-yl) -2- [3- (3-pyridin-4-yl- 프로폭시Propoxy )-벤질]-)-benzyl]- 프로피온아미드Propionamide

실시예Example 32:  32: NN -히드록시-3-(6--Hydroxy-3- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일)-2-[3-(3-모르폴린-4-일--3-yl) -2- [3- (3-morpholin-4-yl- 프로폭시Propoxy )-벤질]-)-benzyl]- 프로피온아미드Propionamide

실시예Example 33:  33: NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[4-(2-피페리딘-1-일-) -4- [4- (2-piperidin-1-yl- 에톡시Ethoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예Example 34:  34: NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[4-(3-피리딘-4-일-) -4- [4- (3-pyridin-4-yl- 프로폭시Propoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예 35: Example 35: NN -히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[4-(3-피페리딘-1-일-프로폭시)-벤질]-프로피온아미드-Hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [4- (3-piperidin-1-yl-propoxy) -benzyl] -propionamide

실시예Example 36:  36: NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[4-(3-모르폴린-4-일-) -4- [4- (3-morpholin-4-yl- 프로폭시Propoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예Example 37:  37: NN -히드록시-3-(6--Hydroxy-3- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일)-2-[3-(2-모르폴린-4-일--3-yl) -2- [3- (2-morpholin-4-yl- 에톡시Ethoxy )-벤질]-)-benzyl]- 프로피온아미드Propionamide

실시예 38: Example 38: NN -히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(3-피페리딘-1-일-프로폭시)-페닐]-부틸아미드-Hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (3-piperidin-1-yl-propoxy) -phenyl] -butyl amides

실시예Example 39:  39: NN -히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(2-피리딘-1-일-에톡시)-페닐]-부틸아미드-Hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (2-pyridin-1-yl-ethoxy) -phenyl] -butylamide

실시예 40: Example 40: NN -히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드-Hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (2-morpholin-4-yl-ethoxy) -phenyl] -butylamide

실시예Example 41:  41: NN -히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(3-모르폴린-4-일-프로폭시)-페닐]-부틸아미드-Hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (3-morpholin-4-yl-propoxy) -phenyl] -butylamide

실시예Example 42:  42: NN -히드록시-3-(6--Hydroxy-3- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일)-2-[3-(2-피페리딘-1-일--3-yl) -2- [3- (2-piperidin-1-yl- 에톡시Ethoxy )-벤질]-)-benzyl]- 프로피온아미드Propionamide

실시예Example 43:  43: NN -히드록시-3-(6--Hydroxy-3- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일)-2-[3-(3-피페리딘-1-일--3-yl) -2- [3- (3-piperidin-1-yl- 프로폭시Propoxy )-벤질]-)-benzyl]- 프로피온아미드Propionamide

실시예Example 44:  44: NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[3-(3-피리딘-4-일-) -4- [3- (3-pyridin-4-yl- 프로폭시Propoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예Example 45:  45: NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[3-(2-) -4- [3- (2- 메틸methyl -퀴놀린-4-일--Quinolin-4-yl- 메톡시Methoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예Example 46:  46: NN -히드록시-3-(6--Hydroxy-3- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일)-2-[3-(2--3-yl) -2- [3- (2- 메틸methyl -퀴놀린-4-일--Quinolin-4-yl- 메톡시Methoxy )-벤질]-)-benzyl]- 프로피온아미드Propionamide

실시예Example 47:  47: NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[3-(4-피리딘-4-일-) -4- [3- (4-pyridin-4-yl-) 부톡시Butoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예Example 48:  48: NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[4-(2-피리딘-4-일-) -4- [4- (2-pyridin-4-yl- 에톡시Ethoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예Example 49:  49: NN -히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[4-(4-피리딘-4-일-부톡시)-벤질]-프로피온아미드-Hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [4- (4-pyridin-4-yl-butoxy) -benzyl] -propionamide

실시예Example 50:  50: NN -히드록시-3-(6--Hydroxy-3- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일)-2-[3-(4-피리딘-4-일--3-yl) -2- [3- (4-pyridin-4-yl- 부톡시Butoxy )-벤질]-)-benzyl]- 프로피온아미드Propionamide

실시예Example 51:  51: NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[4-(3-피페리딘-1-일-) -4- [4- (3-piperidin-1-yl- 프로폭시Propoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예Example 52: 2-[3-(2-디메틸아미노- 52: 2- [3- (2-dimethylamino-) 에톡시Ethoxy )-벤질]-)-benzyl]- NN -히드록시-3-(6--Hydroxy-3- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일)--3 days)- 프로피온아미드Propionamide

실시예Example 53:  53: NN -히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드-Hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -butylamide

실시예 54: 4-[4-(3-디메틸아미노-프로폭시)-페닐]-Example 54: 4- [4- (3-dimethylamino-propoxy) -phenyl]- NN -히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드-Hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide

실시예Example 55: 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[4-(2-피페리딘-1-일-에톡시)-페닐]-펜타노익 엑시드 히드록시아미드 55: 2- (6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -pentanoic acid Hydroxyamide

실시예 56: 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[4-(3-피페리딘-1-일-프로폭시)-페닐]-펜타노익 엑시드 히드록시아미드Example 56: 2- (6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [4- (3-piperidin-1-yl-propoxy) -phenyl] -penta Norick Exe Hydroxyamide

실시예Example 57: 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[4-(3-모르폴린-4-일-프로폭시)-페닐]-펜타노익 엑시드 히드록시아미드 57: 2- (6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [4- (3-morpholin-4-yl-propoxy) -phenyl] -pentanoic acid hydroxide Oxyamide

실시예 58: 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[3-(2-모르폴린-4-일-에톡시)-페닐]-펜타노익 엑시드 히드록시아미드Example 58: 2- (6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [3- (2-morpholin-4-yl-ethoxy) -phenyl] -pentanoic EXID hydroxyamide

실시예Example 59: 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[3-(3-모르폴린-4-일-프로폭시)-페닐]-펜타노익 엑시드 히드록시아미드 59: 2- (6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [3- (3-morpholin-4-yl-propoxy) -phenyl] -pentanoic acid hydroxide Oxyamide

실시예 60: 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[3-(2-피페리딘-1-일-에톡시)-페닐]-펜탄오익 엑시드 히드록시아미드Example 60: 2- (6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [3- (2-piperidin-1-yl-ethoxy) -phenyl] -pentane Ouck Exe Hydroxyamide

실시예Example 61: 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[3-(3-피페리딘-1-일-프로폭시)-페닐]-펜타노익 엑시드 히드록시아미드 61: 2- (6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [3- (3-piperidin-1-yl-propoxy) -phenyl] -pentanoic acid Hydroxyamide

실시예Example 62: 4-3-[3-(4-디메틸아미노- 62: 4-3- [3- (4-dimethylamino-) 페닐Phenyl )-)- 프로폭시Propoxy ]-]- 페닐Phenyl -- NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-)- 부틸아미드Butylamide

실시예Example 63: 5-[3-(3-디메틸아미노-프로폭시)-페닐]-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-펜탄오익  63: 5- [3- (3-dimethylamino-propoxy) -phenyl] -2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -pentanouic 엑시드EXID 히드록시아미드Hydroxyamide

실시예 64: 5-[4-(3-디메틸아미노-프로폭시)-페닐]-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-펜탄오익 엑시드 히드록시아미드Example 64: 5- [4- (3-Dimethylamino-propoxy) -phenyl] -2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -pentanoic acid hydroxyamide

실시예Example 65: 4-[4-(2-디메틸아미노- 65: 4- [4- (2-dimethylamino- 에톡시Ethoxy )-)- 페닐Phenyl ]-]- NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일--3 days- 메틸methyl )-)- 부틸아미드Butylamide

실시예Example 66: 2-(6- 66: 2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-5-[4-(2-모르폴린-4-일-) -5- [4- (2-morpholin-4-yl- 에톡시Ethoxy )-페닐]-펜타노익 ) -Phenyl] -pentanoic 엑시드EXID 히드록시아미드Hydroxyamide

실시예Example 67: 5-4-[3-(4-디메틸아미노-페닐)-프로폭시]-페닐-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-펜타노익 엑시드 히드록시아미드 67: 5-4- [3- (4-dimethylamino-phenyl) -propoxy] -phenyl-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -pentanoic acid hydroxide Oxyamide

실시예Example 68:  68: NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[4-(2-피롤-1-일-) -4- [4- (2-pyrrole-1-yl- 에톡시Ethoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예Example 69:  69: NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-4-[2-(2-옥소-) -4-4- [2- (2-oxo- 피롤리딘Pyrrolidine -1-일)--1 day)- 에톡시Ethoxy ]-]- 페닐Phenyl -- 부틸아미드Butylamide

실시예 70: 4-4-[3-(4-아미노페닐)-프로폭시]-페닐-Example 70: 4-4- [3- (4-aminophenyl) -propoxy] -phenyl- NN -히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드-Hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide

실시예Example 71: 4-[4-(2- 71: 4- [4- (2- 디에틸아미노Diethylamino -- 에톡시Ethoxy )-)- 페닐Phenyl ]-]- NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-)- 부틸아미드Butylamide

실시예Example 72: 4-[4-(2- 72: 4- [4- (2- 디이소프로필아미노Diisopropylamino -- 에톡시Ethoxy )-)- 페닐Phenyl ]-]- NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-)- 부틸아미드Butylamide

실시예Example 73:  73: NN -히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(2-피페리딘-1-일-에톡시)-페닐]-부틸아미드-Hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (2-piperidin-1-yl-ethoxy) -phenyl] -butyl amides

실시예 74: Example 74: NN -히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(3-피페리딘-1-일-프로폭시)-페닐]-부틸아미드-Hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (3-piperidin-1-yl-propoxy) -phenyl] -butyl amides

실시예Example 75:  75: NN -히드록시-2-(7-Hydroxy-2- (7- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[3-(2-모르폴린-4-일-) -4- [3- (2-morpholin-4-yl- 에톡시Ethoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예Example 76:  76: NN -히드록시-2-(7-Hydroxy-2- (7- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[3-(3-모르폴린-4-일-) -4- [3- (3-morpholin-4-yl- 프로폭시Propoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예Example 77: 4-[4-(3-[1,4'] 77: 4- [4- (3- [1,4 '] 바이피페리디닐Bipiperidinyl -1'-일--1 day- 프로폭시Propoxy )-)- 페닐Phenyl ]-]- NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-)- 부틸아미드Butylamide

실시예Example 78:  78: NN -히드록시-2-(7-Hydroxy-2- (7- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[4-(2-모르폴린-4-일-) -4- [4- (2-morpholin-4-yl- 에톡시Ethoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예Example 79:  79: NN -히드록시-2-(7-Hydroxy-2- (7- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[4-(3-모르폴린-4-일-) -4- [4- (3-morpholin-4-yl- 프로폭시Propoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예 80: 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-6-[4-(3-피페리딘-1-일-프로폭시)-페닐]-헥사노익 엑시드 히드록시아미드Example 80: 2- (6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -6- [4- (3-piperidin-1-yl-propoxy) -phenyl] -hexa Norick Exe Hydroxyamide

실시예Example 81: 6-[4-(3-디메틸아미노-프로폭시)-페닐]-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-헥사노익 엑시드 히드록시아미드 81: 6- [4- (3-Dimethylamino-propoxy) -phenyl] -2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -hexanoic acid hydroxyamide

실시예 82: Example 82: NN -히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-피페리딘-1-일-프로폭시)-페닐]-부틸아미드-Hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (3-piperidin-1-yl-propoxy) -phenyl] -butyl amides

실시예Example 83:  83: NN -히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-피페리딘-1-일-에톡시)-페닐]-부틸아미드-Hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -butyl amides

실시예 84: Example 84: NN -히드록시-4-(4-히드록시-페닐)-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드-Hydroxy-4- (4-hydroxy-phenyl) -2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide

실시예Example 85: 6-[4-(3-히드록시-프로폭시)-페닐]-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-헥사노익 엑시드 히드록시아미드 85: 6- [4- (3-hydroxy-propoxy) -phenyl] -2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -hexanoic acid hydroxyamide

실시예 86: 6-[4-(3-메톡시-프로폭시)-페닐]-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-헥사노익 엑시드 히드록시아미드Example 86 6- [4- (3-methoxy-propoxy) -phenyl] -2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -hexanoic acid hydroxyamide

실시예Example 87: 4-[4-(3-디메틸아미노- 87: 4- [4- (3-dimethylamino- 프로폭시Propoxy )-)- 페닐Phenyl ]-]- NN -히드록시-2-(7-Hydroxy-2- (7- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-)- 부틸아미드Butylamide

실시예Example 88: 4-(4- 88: 4- (4- 부트Boot -2--2- 일옥시Iloxy -- 페닐Phenyl )-)- NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-)- 부틸아미드Butylamide

실시예Example 89:  89: 아세틱Acetic 엑시드EXID 4-[3-히드록시카바모일-4-(6-메틸-2-옥소-2H-크로멘-3-일)-부틸]-페닐 에스터 4- [3-hydroxycarbamoyl-4- (6-methyl-2-oxo-2H-chromen-3-yl) -butyl] -phenyl ester

실시예 90: Example 90: NN -히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-4-[3-(4-메틸-피페라진-1-일)-프로폭시]-페닐-부틸아미드-Hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4-4- [3- (4-methyl-piperazin-1-yl) -propoxy]- Phenyl-butylamide

실시예Example 91: 4-[4-(2-디에틸아미노-에톡시)-페닐]- 91: 4- [4- (2-diethylamino-ethoxy) -phenyl]- NN -히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드-Hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide

실시예Example 92:  92: NN -히드록시-4-(4-3-[4-(2-히드록시-에틸)-피페라진-1-일]--Hydroxy-4- (4-3- [4- (2-hydroxy-ethyl) -piperazin-1-yl]- 프로폭시Propoxy -- 페닐Phenyl )-2-(7-) -2- (7- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-)- 부틸아미드Butylamide

실시예Example 93: 2-(7- 93: 2- (7- 클로로Chloro -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[4-(3-디메틸아미노-) -4- [4- (3-dimethylamino- 프로폭시Propoxy )) 페닐Phenyl ]-]- NN -히드록시--Hydroxy- 부틸아미드Butylamide

실시예Example 94: 2-(7- 94: 2- (7- 플루오로Fluoro -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-)- NN -히드록시-4-[4-(2-모르폴린-4-일--Hydroxy-4- [4- (2-morpholin-4-yl- 에톡시Ethoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예Example 95: 2-(7- 95: 2- (7- 클로로Chloro -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-)- NN -히드록시-4-[4-(3-피페리딘-1-일--Hydroxy-4- [4- (3-piperidin-1-yl- 프로폭시Propoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예Example 96: 2-(7- 96: 2- (7- 클로로Chloro -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-)- NN -히드록시-4-[4-(3-모르폴린-4-일--Hydroxy-4- [4- (3-morpholin-4-yl- 프로폭시Propoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예Example 97: 2-(7- 97: 2- (7- 플루오로Fluoro -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-)- NN -히드록시-4-[4-(3-피페리딘-1-일--Hydroxy-4- [4- (3-piperidin-1-yl- 프로폭시Propoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예Example 98: 4-[4-(3-디메틸아미노- 98: 4- [4- (3-dimethylamino- 프로폭시Propoxy )-)- 페닐Phenyl ]-2-(7-] -2- (7- 플루오로Fluoro -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-)- NN -히드록시--Hydroxy- 부틸아미드Butylamide

실시예 Example 화학구조Chemical structure NMR 스펙트럼 데이터 (1H 혹은 13C)NMR spectral data ( 1 H or 13 C) 27   27

Figure 112006049660803-pat00055
Figure 112006049660803-pat00055
10.47(s, 1H), 8.75(s, 1H), 8.10(d, J=8.0Hz, 1H), 7.96(d, J=8.4Hz, 1H) 7.74(t, J=7.4Hz, 1H) 7.65(s, 1H), 7.58(t, J=7.6Hz, 1H) 7.54(s, 1H), 7.41(s, 1H) 7.37(d, J=8.4Hz, 1H) 7.27(d, J=7.6Hz, 1H) 7.13(d, J=8.0Hz, 2H) 7.04(d, J=8.4Hz, 2H) 5.56(s, 2H) 2.65(s, 3H) 2.61(d, J=6.8Hz, 2H) 2.45-2.50(m, 3H) 2.34(s, 3H), 1.74-1.84(m, 1H), 1.62-1.65(m, 1H)10.47 (s, 1H), 8.75 (s, 1H), 8.10 (d, J = 8.0Hz, 1H), 7.96 (d, J = 8.4Hz, 1H) 7.74 (t, J = 7.4Hz, 1H) 7.65 ( s, 1H), 7.58 (t, J = 7.6 Hz, 1H) 7.54 (s, 1H), 7.41 (s, 1H) 7.37 (d, J = 8.4 Hz, 1H) 7.27 (d, J = 7.6 Hz, 1H ) 7.13 (d, J = 8.0 Hz, 2H) 7.04 (d, J = 8.4 Hz, 2H) 5.56 (s, 2H) 2.65 (s, 3H) 2.61 (d, J = 6.8 Hz, 2H) 2.45-2.50 ( m, 3H) 2.34 (s, 3H), 1.74-1.84 (m, 1H), 1.62-1.65 (m, 1H) 28  28
Figure 112006049660803-pat00056
Figure 112006049660803-pat00056
 10.34(s, 1H), 8.67(br s, 1H), 7.64(s, 1H), 7.41(s, 1H), 7.35(d, J=8.0Hz, 1H), 7.24(d, J=8.4Hz, 1H), 7.07(d, J=7.7Hz, 2H), 6.83(d, J=7.7Hz, 2H), 4.01(t, J=4.9Hz, 2H), 3.33~3.56(m, 4H), 2.80-2.84(m, 1H), 2.60-2.79(m, 8H), 2.45-2.57(m, 4H,) 2.34(s, 3H) 10.34 (s, 1H), 8.67 (br s, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 7.7 Hz, 2H), 6.83 (d, J = 7.7 Hz, 2H), 4.01 (t, J = 4.9 Hz, 2H), 3.33-3.56 (m, 4H), 2.80- 2.84 (m, 1H), 2.60-2.79 (m, 8H), 2.45-2.57 (m, 4H,) 2.34 (s, 3H) 2929
Figure 112006049660803-pat00057
Figure 112006049660803-pat00057
 10.39(s, 1H), 8.39(br s, 1H), 7.75(s, 1H), 7.42(s, 1H), 7.35(d, J=8.6Hz, 1H), 7.27(d, J=8.4Hz, 1H), 7.08(d, J=8.4Hz, 2H), 6.81(d, J=8.4Hz, 2H), 3.38-3.44(m, 4H), 2.94-2.95(m, 1H), 2.86-2.98(m, 2H), 2.83-2.87(m, 1H), 2.68-2.73(m, 1H), 2.63-2.65(m, 2H), 2.34-2.49(m, 2H), 2.34(s, 3H), 1.89-1.99(m, 4H), 1.18-1.86(m, 2H) 10.39 (s, 1H), 8.39 (br s, 1H), 7.75 (s, 1H), 7.42 (s, 1H), 7.35 (d, J = 8.6Hz, 1H), 7.27 (d, J = 8.4Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 3.38-3.44 (m, 4H), 2.94-2.95 (m, 1H), 2.86-2.98 (m , 2H), 2.83-2.87 (m, 1H), 2.68-2.73 (m, 1H), 2.63-2.65 (m, 2H), 2.34-2.49 (m, 2H), 2.34 (s, 3H), 1.89-1.99 (m, 4H), 1.18-1.86 (m, 2H) 3030
Figure 112006049660803-pat00058
Figure 112006049660803-pat00058
 10.34(br s, 1H), 8.44(d, J=5.8Hz, 2H), 7.64(s, 1H), 7.31-7.41(m, 2H), 7.25-7.26(m, 3H), 7.07(d, J=8.8Hz, 2H), 6.81(d, J=8.4Hz, 2H), 3.91(t, J=7.1Hz, 2H), 2.64-2.86(m, 5H), 2.50-2.62(m, 2H), 2.34(s, 3H), 1.98-2.06(m, 2H) 10.34 (br s, 1H), 8.44 (d, J = 5.8 Hz, 2H), 7.64 (s, 1H), 7.31-7.41 (m, 2H), 7.25-7.26 (m, 3H), 7.07 (d, J) = 8.8 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 3.91 (t, J = 7.1 Hz, 2H), 2.64-2.86 (m, 5H), 2.50-2.62 (m, 2H), 2.34 (s, 3H), 1.98-2.06 (m, 2H) 3131
Figure 112006049660803-pat00059
Figure 112006049660803-pat00059
 10.37(br, 1H), 8.66(br, 1H), 7.66(s, 1H), 7.41(s, 1H), 7.36(d, J=8.8Hz, 1H), 7.26(m, 3H), 7.16(m, 1H), 6.75(m, 2H), 6.49(d, J=7.6Hz, 1H), 6.39(s, 1H), 6.17(d, J=8.0Hz, 1H), 3.92(m, 2H), 2.58-2.89(m, 5H), 2.35(s, 3H), 2.03-2.19(m, 4H). 10.37 (br, 1H), 8.66 (br, 1H), 7.66 (s, 1H), 7.41 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.26 (m, 3H), 7.16 (m , 1H), 6.75 (m, 2H), 6.49 (d, J = 7.6 Hz, 1H), 6.39 (s, 1H), 6.17 (d, J = 8.0 Hz, 1H), 3.92 (m, 2H), 2.58 -2.89 (m, 5H), 2.35 (s, 3H), 2.03-2.19 (m, 4H). 3232
Figure 112006049660803-pat00060
Figure 112006049660803-pat00060
 10.34(s, 1H), 8.56(s, 1H), 7.76(s, 1H), 7.63(s, 1H), 7.34-7.42(m, 2H), 7.23-7.26(m, 1H), 7.11-7.15(m, 1H), 6.70-6.72(m, 2H), 3.94-3.96(m, 3H), 3.21-3.38(m, 2H), 2.56-2.89(m, 6H), 2.41-2.44(m, 6H), 2.33(s, 3H), 1.85-1.89(m, 2H)10.34 (s, 1H), 8.56 (s, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.34-7.42 (m, 2H), 7.23-7.26 (m, 1H), 7.11-7.15 ( m, 1H), 6.70-6.72 (m, 2H), 3.94-3.96 (m, 3H), 3.21-3.38 (m, 2H), 2.56-2.89 (m, 6H), 2.41-2.44 (m, 6H), 2.33 (s, 3H), 1.85-1.89 (m, 2H) 3333
Figure 112006049660803-pat00061
Figure 112006049660803-pat00061
 10.46(s, 1H), 8.74(s, 1H), 7.64(s, 1H), 7.41(s, 1H), 7.37(d, J=8.8Hz, 1H), 7.27(d, J=8.4Hz, 1H), 7.05(d, J= 8.8Hz, 2H), 6.81(d, J=8.8Hz, 2H), 4.00(t, J=6.0Hz, 2H), 2.60-2.63(m, 4H), 2.41-2.46(m, 7H), 2.34(s, 3H), 1.74- 1.76(m, 1H), 1.60-1.64(m, 1H), 1.45-1.51(m, 4H), 1.36 -1.39(m, 2H).10.46 (s, 1H), 8.74 (s, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 7.37 (d, J = 8.8Hz, 1H), 7.27 (d, J = 8.4Hz, 1H ), 7.05 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 4.00 (t, J = 6.0 Hz, 2H), 2.60-2.63 (m, 4H), 2.41-2.46 (m, 7H), 2.34 (s, 3H), 1.74- 1.76 (m, 1H), 1.60-1.64 (m, 1H), 1.45-1.51 (m, 4H), 1.36 -1.39 (m, 2H). 3434
Figure 112006049660803-pat00062
Figure 112006049660803-pat00062
 10.45(s, 1H), 8.74(s, 1H), 8.45(dd, J=16Hz, 4.4Hz, 2H) 7.64(s, 1H), 7.41(s, 1H), 7.37(d, J=8.4Hz, 1H), 7.25- 7.28(m, 3H), 7.06(d, J=8.0Hz, 2H), 6.81(d, J=7.6Hz, 2H ), 3.92(t, J=6.2Hz, 2H), 2.74(t, J=6.8Hz, 2H), 2.60(d, J= 6.8Hz, 2H), 2.42-2.46(m, 3H), 2.34(s, 3H), 2.00-2.05 (m, 2H), 1.74-1.79(m, 1H), 1.60-1.62(m, 1H)10.45 (s, 1H), 8.74 (s, 1H), 8.45 (dd, J = 16 Hz, 4.4 Hz, 2H) 7.64 (s, 1H), 7.41 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.25- 7.28 (m, 3H), 7.06 (d, J = 8.0 Hz, 2H), 6.81 (d, J = 7.6 Hz, 2H), 3.92 (t, J = 6.2 Hz, 2H), 2.74 ( t, J = 6.8 Hz, 2H), 2.60 (d, J = 6.8 Hz, 2H), 2.42-2.46 (m, 3H), 2.34 (s, 3H), 2.00-2.05 (m, 2H), 1.74-1.79 (m, 1 H), 1.60-1.62 (m, 1 H)

실시예 Example 화학구조Chemical structure NMR 스펙트럼 데이터 (1H 혹은 13C)NMR spectral data ( 1 H or 13 C) 3535

Figure 112006049660803-pat00063
Figure 112006049660803-pat00063
10.38(br, 1H), 8.65(br, 1H), 7.65(s, 1H), 7.42(m, 2H), 7.38(d, J=8.4Hz, 1H), 7.18(m, 1H), 6.70(m, 3H), 4.00(m, 2H), 2.61(m, 3H), 2.49(m, 8H), 2.44(s, 3H), 1.47-2.35(m, 8H)10.38 (br, 1H), 8.65 (br, 1H), 7.65 (s, 1H), 7.42 (m, 2H), 7.38 (d, J = 8.4 Hz, 1H), 7.18 (m, 1H), 6.70 (m) , 3H), 4.00 (m, 2H), 2.61 (m, 3H), 2.49 (m, 8H), 2.44 (s, 3H), 1.47-2.35 (m, 8H) 3636
Figure 112006049660803-pat00064
Figure 112006049660803-pat00064
 10.46(s, 1H), 8.73(br, 1H), 7.64(s, 1H), 7.41(s, 1H), 7.38(d, J=8.0Hz, 1H), 7.28(d, J=8.0Hz, 1H), 7.06(d, J= 8.0Hz, 2H), 6.81(d, J=8.4Hz, 2H), 3.96(t, J=6.0Hz, 2H), 3.50-3.57(m, 4H) 2.61(d, J=6.8Hz, 2H), 2.37-2.46(m, 9H), 2.34(s, 3H), 1.76-1.83(m, 3H), 1.61-1.63(m, 1H)10.46 (s, 1H), 8.73 (br, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H ), 7.06 (d, J = 8.0 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 3.96 (t, J = 6.0 Hz, 2H), 3.50-3.57 (m, 4H) 2.61 (d, J = 6.8 Hz, 2H), 2.37-2.46 (m, 9H), 2.34 (s, 3H), 1.76-1.83 (m, 3H), 1.61-1.63 (m, 1H) 3737
Figure 112006049660803-pat00065
Figure 112006049660803-pat00065
 10.37(s, 1H), 8.67(s, 1H), 7.95(s, 1H), 7.65(s, 1H), 7.35-7.41(m, 2H), 7.25-7.27(m, 1H), 7.13-7.17(m, 1H), 6.73-6.76(m, 2H), 4.02-4.05(m, 2H), 3.56-3.57(m, 4H), 2.55-2.89(m, 1H), 2.35(s, 3H)10.37 (s, 1H), 8.67 (s, 1H), 7.95 (s, 1H), 7.65 (s, 1H), 7.35-7.41 (m, 2H), 7.25-7.27 (m, 1H), 7.13-7.17 ( m, 1H), 6.73-6.76 (m, 2H), 4.02-4.05 (m, 2H), 3.56-3.57 (m, 4H), 2.55-2.89 (m, 1H), 2.35 (s, 3H) 3838
Figure 112006049660803-pat00066
Figure 112006049660803-pat00066
 10.36(br s, 1H), 7.66(s, 1H), 7.41(s, 1H), 7.36(d, J=8.4Hz, 1H), 7.28(d, J=8.4Hz, 1H), 7.15(t, J=8.2Hz, 1H), 6.70-6.73(m, 3H), 3.94(t, J=6.4Hz, 2H), 2.60-2.62(m, 1H), 2.46-2.55(m, 4H), 2.38-2.42(m, 4H), 2.35(s, 3H), 1.79-1.92(m, 6H), 1.64-1.66(m, 2H), 1.47-1.52(m, 4H), 1.22-1.38(m, 2H), 10.36 (br s, 1H), 7.66 (s, 1H), 7.41 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.15 (t, J = 8.2 Hz, 1H), 6.70-6.73 (m, 3H), 3.94 (t, J = 6.4 Hz, 2H), 2.60-2.62 (m, 1H), 2.46-2.55 (m, 4H), 2.38-2.42 (m, 4H), 2.35 (s, 3H), 1.79-1.92 (m, 6H), 1.64-1.66 (m, 2H), 1.47-1.52 (m, 4H), 1.22-1.38 (m, 2H), 3939
Figure 112006049660803-pat00067
Figure 112006049660803-pat00067
 10.37(s, 1H), 7.65(s, 1H), 7.41(s, 1H), 7.36(d, J=8.4Hz, 1H), 7.28(d, J=8.4Hz, 1H), 7.15(t, J=8.2Hz, 1H), 6.68-6.79(m, 3H), 4.02(t, J=5.8Hz, 2H), 2.55-2.69(m, 5H), 2.40-2.49(m, 4H), 2.35(s, 3H), 1.36-1.38(m, 2H), 1.74-1.79(m, 2H), 1.64-1.70(m, 2H), 1.46-1.52(m, 4H)10.37 (s, 1H), 7.65 (s, 1H), 7.41 (s, 1H), 7.36 (d, J = 8.4Hz, 1H), 7.28 (d, J = 8.4Hz, 1H), 7.15 (t, J = 8.2 Hz, 1H), 6.68-6.79 (m, 3H), 4.02 (t, J = 5.8 Hz, 2H), 2.55-2.69 (m, 5H), 2.40-2.49 (m, 4H), 2.35 (s, 3H), 1.36-1.38 (m, 2H), 1.74-1.79 (m, 2H), 1.64-1.70 (m, 2H), 1.46-1.52 (m, 4H) 4040
Figure 112006049660803-pat00068
Figure 112006049660803-pat00068
 10.47(s, 1H), 8.74(br s, 1H), 7.65(s, 1H), 7.42(s, 1H), 7.38(d, J=8.4Hz, 1H), 7.28(d, J=8.4Hz, 1H), 7.16(t, J=7.9Hz, 1H), 6.72-6.74(m, 1H), 4.04(t, J=5.5Hz, 2H), 3.56-3.70(m, 4H), 2.61-2.67(m, 5H), 2.46-2.57(m, 4H), 2.35(s, 3H), 1.78-1.79(m, 2H), 1.65-1.68(m, 2H) 10.47 (s, 1H), 8.74 (br s, 1H), 7.65 (s, 1H), 7.42 (s, 1H), 7.38 (d, J = 8.4Hz, 1H), 7.28 (d, J = 8.4Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 6.72-6.74 (m, 1H), 4.04 (t, J = 5.5 Hz, 2H), 3.56-3.70 (m, 4H), 2.61-2.67 (m , 5H), 2.46-2.57 (m, 4H), 2.35 (s, 3H), 1.78-1.79 (m, 2H), 1.65-1.68 (m, 2H) 4141
Figure 112006049660803-pat00069
Figure 112006049660803-pat00069
 10.47(br s, 1H), 7.65(s, 1H), 7.41(s, 1H), 7.36(d, J=8.4Hz, 1H), 7.28(d, J=8.0Hz, 1H), 7.15(t, J=7.5Hz, 1H), 6.65-6.73(m, 3H), 3.95(t, J=6.0Hz, 2H), 3.56-3.69(m, 4H), 2.60-2.62(m, 2H), 2.49~2.55(m, 3H), 2.37-2.46(m, 4H), 2.35(s, 3H), 1.80-1.87(m, 4H), 1.64-1.77(m, 2H)10.47 (br s, 1H), 7.65 (s, 1H), 7.41 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 6.65-6.73 (m, 3H), 3.95 (t, J = 6.0 Hz, 2H), 3.56-3.69 (m, 4H), 2.60-2.62 (m, 2H), 2.49-2.55 (m, 3H), 2.37-2.46 (m, 4H), 2.35 (s, 3H), 1.80-1.87 (m, 4H), 1.64-1.77 (m, 2H) 4242
Figure 112006049660803-pat00070
Figure 112006049660803-pat00070
 10.37(br, 1H), 8.65(br, 1H), 7.66(s, 1H), 7.38(m, 2H), 7.26(d, J=8.4Hz, 1H), 7.15(m, 1H), 6.75(m, 3H), 4.04(m, 2H), 3.34(s, 8H), 2.50-2.89(m, 6H), 2.35(s, 3H), 1.87(s, 1H), 1.23(s, 2H).10.37 (br, 1H), 8.65 (br, 1H), 7.66 (s, 1H), 7.38 (m, 2H), 7.26 (d, J = 8.4 Hz, 1H), 7.15 (m, 1H), 6.75 (m , 3H), 4.04 (m, 2H), 3.34 (s, 8H), 2.50-2.89 (m, 6H), 2.35 (s, 3H), 1.87 (s, 1H), 1.23 (s, 2H).

실시예 Example 화학구조Chemical structure NMR 스펙트럼 데이터 (1H 혹은 13C)NMR spectral data ( 1 H or 13 C) 4343

Figure 112006049660803-pat00071
Figure 112006049660803-pat00071
10.38(br, 1H), 8.65(br, 1H), 7.65(s, 1H), 7.42(m, 2H), 7.38(d, J=8.4Hz, 1H), 7.18(m, 1H), 6.70(m, 3H), 4.00(m, 2H), 2.61(m, 3H), 2.49(m, 8H), 2.44(s, 3H), 1.47-2.35(m, 8H)10.38 (br, 1H), 8.65 (br, 1H), 7.65 (s, 1H), 7.42 (m, 2H), 7.38 (d, J = 8.4 Hz, 1H), 7.18 (m, 1H), 6.70 (m) , 3H), 4.00 (m, 2H), 2.61 (m, 3H), 2.49 (m, 8H), 2.44 (s, 3H), 1.47-2.35 (m, 8H) 4444
Figure 112006049660803-pat00072
Figure 112006049660803-pat00072
 10.47(br, 1H), 8.89(br, 1H), 8.45(d, J=4.4Hz, 1H), 7.62(s, 1H), 7.37(m, 2H), 7.25(m, 3H), 7.09(d, J=8.4Hz, 2H), 6.82(d, J=8.4Hz, 2H), 3.98(m, 2H), 2.50-2.88(m, 6H), 2.39(s, 3H), 1.99-2.08(m, 4H)10.47 (br, 1H), 8.89 (br, 1H), 8.45 (d, J = 4.4 Hz, 1H), 7.62 (s, 1H), 7.37 (m, 2H), 7.25 (m, 3H), 7.09 (d , J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 3.98 (m, 2H), 2.50-2.88 (m, 6H), 2.39 (s, 3H), 1.99-2.08 (m, 4H) 4545
Figure 112006049660803-pat00073
Figure 112006049660803-pat00073
 10.57(br, 1H), 10.31(br, 1H), 8.46(m, 2H), 8.09(m, 2H), 7.89(m, 3H), 6.49-7.24(m, 6H), 5.84(m, 2H), 3.67(d, J=3.2Hz, 1H), 3.14(s, 3H), 2.63-2.71(m, 2H), 2.07-2.31(m, 4H), 1.73(d, J=14.4Hz, 6H)10.57 (br, 1H), 10.31 (br, 1H), 8.46 (m, 2H), 8.09 (m, 2H), 7.89 (m, 3H), 6.49-7.24 (m, 6H), 5.84 (m, 2H) , 3.67 (d, J = 3.2 Hz, 1H), 3.14 (s, 3H), 2.63-2.71 (m, 2H), 2.07-2.31 (m, 4H), 1.73 (d, J = 14.4 Hz, 6H) 4646
Figure 112006049660803-pat00074
Figure 112006049660803-pat00074
 10.42(br, 1H), 8.73(br, 1H), 7.95(d, J=8.4Hz, 1H), 7.73(t, J=7.0Hz, 1H), 7.65(s, 1H), 7.55-7.59(m, 3H), 7.33-7.39(m, 1H), 7.19-7.25(m, 2H), 6.94-7.00(m, 2H), 6.82(d, J=7.7Hz, 1H), 2.76-2.91(m, 3H), 2.58-2.70(m, 6H), 2.31(s, 2H)10.42 (br, 1H), 8.73 (br, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.73 (t, J = 7.0 Hz, 1H), 7.65 (s, 1H), 7.55-7.59 (m , 3H), 7.33-7.39 (m, 1H), 7.19-7.25 (m, 2H), 6.94-7.00 (m, 2H), 6.82 (d, J = 7.7 Hz, 1H), 2.76-2.91 (m, 3H ), 2.58-2.70 (m, 6H), 2.31 (s, 2H) 4747
Figure 112006049660803-pat00075
Figure 112006049660803-pat00075
 10.47(s, 1H), 8.76(s, 1H), 8.45(d, J=5.4Hz, 2H), 7.65(s, 1H), 7.41(s, 1H), 6.71-7.38(m, 8H), 3.62-3.42(m, 3H), 2.44-2.66(m, 6H), 2.34(s, 3H), 1.65-1.77(m, 6H).10.47 (s, 1H), 8.76 (s, 1H), 8.45 (d, J = 5.4 Hz, 2H), 7.65 (s, 1H), 7.41 (s, 1H), 6.71-7.38 (m, 8H), 3.62 -3.42 (m, 3H), 2.44-2.66 (m, 6H), 2.34 (s, 3H), 1.65-1.77 (m, 6H). 4848
Figure 112006049660803-pat00076
Figure 112006049660803-pat00076
 10.44(s, 1H), 8.72(s, 1H), 8.43(dd, J=16Hz, 4.4Hz, 2H) 7.62(s, 1H), 7.39(s, 1H), 7.31-7.36(m, 2H), 7.22-7.26 (m, 2H), 7.04(d, J=8.0Hz, 2H), 6.80(d, J=7.6Hz, 2H), 4.17(t, J=6.2Hz, 2H), 3.01(t, J=6.2Hz, 2H), 2.58(d, J= 6.8Hz, 2H), 2.40-2.43(m, 3H), 2.32(s, 3H), 1.72-1.73 (m, 1H), 1.57-1.60(m, 1H)10.44 (s, 1H), 8.72 (s, 1H), 8.43 (dd, J = 16 Hz, 4.4 Hz, 2H) 7.62 (s, 1H), 7.39 (s, 1H), 7.31-7.36 (m, 2H), 7.22-7.26 (m, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 7.6 Hz, 2H), 4.17 (t, J = 6.2 Hz, 2H), 3.01 (t, J = 6.2 Hz, 2H), 2.58 (d, J = 6.8 Hz, 2H), 2.40-2.43 (m, 3H), 2.32 (s, 3H), 1.72-1.73 (m, 1H), 1.57-1.60 (m, 1H) 4949
Figure 112006049660803-pat00077
Figure 112006049660803-pat00077
 10.34(br s, 1H), 8.44(s, 2H), 7.64(s, 1H), 7.35-7.41(m, 2H), 7.20-7.24(m, 3H), 7.07(d, J=7.3Hz, 2H), 6.81(d, J=7.3Hz, 2H), 3.38-3.92(m, 2H), 2.58-2.65(m, 7H), 2.34(s, 3H), 1.60-1.71(m, 4H)10.34 (br s, 1H), 8.44 (s, 2H), 7.64 (s, 1H), 7.35-7.41 (m, 2H), 7.20-7.24 (m, 3H), 7.07 (d, J = 7.3 Hz, 2H ), 6.81 (d, J = 7.3 Hz, 2H), 3.38-3.92 (m, 2H), 2.58-2.65 (m, 7H), 2.34 (s, 3H), 1.60-1.71 (m, 4H) 5050
Figure 112006049660803-pat00078
Figure 112006049660803-pat00078
 10.37(s, 1H), 8.66(s, 1H), 8.46(d, J=5.6Hz, 2H), 7.65(s, 1H), 7.41(s, 1H), 6.71-7.38(m, 8H), 3.95(d, J=5.6Hz, 2H), 2.56-2.67(m, 7H), 2.35(s, 3H), 1.65-1.77(m, 4H)10.37 (s, 1H), 8.66 (s, 1H), 8.46 (d, J = 5.6 Hz, 2H), 7.65 (s, 1H), 7.41 (s, 1H), 6.71-7.38 (m, 8H), 3.95 (d, J = 5.6 Hz, 2H), 2.56-2.67 (m, 7H), 2.35 (s, 3H), 1.65-1.77 (m, 4H)

실시예 Example 화학구조Chemical structure NMR 스펙트럼 데이터 (1H 혹은 13C)NMR spectral data ( 1 H or 13 C) 5151

Figure 112006049660803-pat00079
Figure 112006049660803-pat00079
10.45(s, 1H), 8.73(s, 1H), 7.64(s, 1H), 7.41(s, 1H), 7.37(d, J=8.0Hz, 1H), 7.27(d, J=8.0Hz, 1H), 7.05(d, J= 8.4Hz, 2H), 6.80(d, J=8.0Hz, 2H), 3.93(t, J=6.4Hz, 2H), 2.61(d, J=6.8Hz, 2H), 2.40-2.44(m, 3H), 2.31-2.36(m, 6H), 2.35(s, 3H), 1.75-1.83(m, 3H), 1.60-1.62(m, 1H), 1.46-1.47(m, 4H), 1.36-1.37(m, 2H)10.45 (s, 1H), 8.73 (s, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H ), 7.05 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.0 Hz, 2H), 3.93 (t, J = 6.4 Hz, 2H), 2.61 (d, J = 6.8 Hz, 2H), 2.40-2.44 (m, 3H), 2.31-2.36 (m, 6H), 2.35 (s, 3H), 1.75-1.83 (m, 3H), 1.60-1.62 (m, 1H), 1.46-1.47 (m, 4H ), 1.36-1.37 (m, 2H) 5252
Figure 112006049660803-pat00080
Figure 112006049660803-pat00080
 10.44(s, 1H), 8.64(s, 1H), 7.69(s, 1H), 7.34-7.41(m, 1H), 7.17-7.27(m, 2H), 6.79-6.88(m, 4H), 4.29-4.31(m, 2H), 3.40-3.45(m, 2H), 3.28-3.36(m, 1H), 2.80(s, 6H), 2.52-2.68(m, 2H), 2.33(s, 3H)10.44 (s, 1H), 8.64 (s, 1H), 7.69 (s, 1H), 7.34-7.41 (m, 1H), 7.17-7.27 (m, 2H), 6.79-6.88 (m, 4H), 4.29- 4.31 (m, 2H), 3.40-3.45 (m, 2H), 3.28-3.36 (m, 1H), 2.80 (s, 6H), 2.52-2.68 (m, 2H), 2.33 (s, 3H) 5353
Figure 112006049660803-pat00081
Figure 112006049660803-pat00081
 10.47(s, 1H), 8.75(br s, 1H), 7.65(s, 1H), 7.41(s, 1H), 7.36(d, J=8.4Hz, 1H), 7.28(d, J=8.4Hz, 1H), 7.05(d, J=8.0Hz, 2H), 6.84(d, J=8.4Hz, 2H), 4.02(t, J=5.7Hz, 2H), 3.55-3.57(m, 4H), 2.55-2.67(m, 5H), 2.42-2.45(m, 4H), 2.35(s, 3H), 1.76-1.79(m, 2H), 1.60-1.74(m, 2H)10.47 (s, 1H), 8.75 (br s, 1H), 7.65 (s, 1H), 7.41 (s, 1H), 7.36 (d, J = 8.4Hz, 1H), 7.28 (d, J = 8.4Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 4.02 (t, J = 5.7 Hz, 2H), 3.55-3.57 (m, 4H), 2.55- 2.67 (m, 5H), 2.42-2.45 (m, 4H), 2.35 (s, 3H), 1.76-1.79 (m, 2H), 1.60-1.74 (m, 2H) 5454
Figure 112006049660803-pat00082
Figure 112006049660803-pat00082
 10.52(s, 1H), 8.77(br s, 1H), 7.67(s, 1H), 7.42(s, 1H), 7.36(d, J=8.4Hz, 1H), 7.28(d, J=8.4Hz, 2), 7.05(d, J=8.4Hz, 2H), 6.82(d, J=8.4Hz, 2H), 3.94(t, J=6.4Hz, 2H), 2.51~2.61(m, 2H), 2.40~2.49(m, 7H), 2.35(s, 3H), 2.19(s, 6H), 1.81~1.89(m, 2H), 1.69~1.79(m, 1H), 1.59~1.63(m, 1H)10.52 (s, 1H), 8.77 (br s, 1H), 7.67 (s, 1H), 7.42 (s, 1H), 7.36 (d, J = 8.4Hz, 1H), 7.28 (d, J = 8.4Hz, 2), 7.05 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 3.94 (t, J = 6.4 Hz, 2H), 2.51-2.61 (m, 2H), 2.40- 2.49 (m, 7H), 2.35 (s, 3H), 2.19 (s, 6H), 1.81-1.89 (m, 2H), 1.69-1.79 (m, 1H), 1.59-1.63 (m, 1H) 5555
Figure 112006049660803-pat00083
Figure 112006049660803-pat00083
 10.43(s, 1H), 8.69(s, 1H), 7.65(s, 1H), 7.43(s, 1H), 7.38(d, J=8.4Hz, 1H), 7.28(d, J=8.4Hz, 1H), 7.10(d, J=7.9Hz, 2H), 6.86(d, J=7.9Hz, 2H), 2.35(s, 3H), 1.37-4.05(m, 23H)10.43 (s, 1H), 8.69 (s, 1H), 7.65 (s, 1H), 7.43 (s, 1H), 7.38 (d, J = 8.4Hz, 1H), 7.28 (d, J = 8.4Hz, 1H ), 7.10 (d, J = 7.9 Hz, 2H), 6.86 (d, J = 7.9 Hz, 2H), 2.35 (s, 3H), 1.37-4.05 (m, 23H) 5656
Figure 112006049660803-pat00084
Figure 112006049660803-pat00084
 10.44(s, 1H), 8.70(br, 1H), 7.65(s, 1H), 7.43(s, 1H), 7.38(d, J=8.2Hz, 1H), 7.28(d, J=8.2Hz, 1H), 7.07(d, J=8.4Hz, 2H), 6.81(d, J=8.4Hz, 2H), 2.35(s, 3H), 1.34-4.03(m, 25H)10.44 (s, 1H), 8.70 (br, 1H), 7.65 (s, 1H), 7.43 (s, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H ), 7.07 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 2.35 (s, 3H), 1.34-4.03 (m, 25H) 5757
Figure 112006049660803-pat00085
Figure 112006049660803-pat00085
 10.42(s, 1H), 8.69(s, 1H), 7.64(s, 1H), 7.42(s, 1H), 7.37(d, J=8.4Hz, 1H), 7.28(d, J=8.4Hz, 1H), 7.04(d, J= 8.4Hz, 2H), 6.78(d, J=8.4Hz, 2H), 3.93(t, J=6.2Hz, 2H), 3.59(t, J=4.2Hz, 4H), 2.46-2.57(m, 11H), 2.35(s, 3H), 1.85-1.90(m, 2H), 1.44-1.52(m, 3H), 1.33-1.37(m, 1H)10.42 (s, 1H), 8.69 (s, 1H), 7.64 (s, 1H), 7.42 (s, 1H), 7.37 (d, J = 8.4Hz, 1H), 7.28 (d, J = 8.4Hz, 1H ), 7.04 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 3.93 (t, J = 6.2 Hz, 2H), 3.59 (t, J = 4.2 Hz, 4H), 2.46-2.57 (m, 11H), 2.35 (s, 3H), 1.85-1.90 (m, 2H), 1.44-1.52 (m, 3H), 1.33-1.37 (m, 1H) 5858
Figure 112006049660803-pat00086
Figure 112006049660803-pat00086
 10.43(br s, 1H), 8.71(br s, 1H), 7.64(s, 1H), 7.36~7.42(m, 2H), 7.28(d, J=8.0Hz, 1H), 7.13(t, J=6.9Hz, 1H), 6.67~6.75(m, 3H), 4.01~4.04(m, 2H), 3.35~3.61(m, 4H), 2.61~2.77(m, 1H), 2.46~2.55(m, 8H), 2.35(s, 3H), 1.43~1.61(m, 2H), 1.33~1.41(m, 2H)10.43 (br s, 1H), 8.71 (br s, 1H), 7.64 (s, 1H), 7.36-7.42 (m, 2H), 7.28 (d, J = 8.0 Hz, 1H), 7.13 (t, J = 6.9 Hz, 1H), 6.67 to 6.75 (m, 3H), 4.01 to 4.04 (m, 2H), 3.35 to 3.61 (m, 4H), 2.61 to 2.77 (m, 1H), 2.46 to 2.55 (m, 8H) , 2.35 (s, 3H), 1.43 ~ 1.61 (m, 2H), 1.33 ~ 1.41 (m, 2H)

실시예 Example 화학구조Chemical structure NMR 스펙트럼 데이터 (1H 혹은 13C)NMR spectral data ( 1 H or 13 C) 5959

Figure 112006049660803-pat00087
Figure 112006049660803-pat00087
10.43(s, 1H), 8.70(br s, 1H), 7.64(s, 1H), 7.42(s, 1H), 7.38(d, J=8.8Hz, 1H), 7.28(d, J=8.0Hz, 1H), 7.13(t, J=7.9Hz, 1H), 6.69~6.72(m, 3H), 3.95(t, J=6.4Hz, 2H), 3.49~3.57(m, 4H), 2.53~2.63(m, 3H), 2.37~2.46(m, 6H), 2.35(s, 3H), 1.76~1.88(m, 2H), 1.46~1.57(m, 4H) 10.43 (s, 1H), 8.70 (br s, 1H), 7.64 (s, 1H), 7.42 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.13 (t, J = 7.9 Hz, 1H), 6.69-6.72 (m, 3H), 3.95 (t, J = 6.4 Hz, 2H), 3.49-3.57 (m, 4H), 2.53-2.63 (m , 3H), 2.37-2.46 (m, 6H), 2.35 (s, 3H), 1.76-1.88 (m, 2H), 1.46-1.57 (m, 4H) 6060
Figure 112006049660803-pat00088
Figure 112006049660803-pat00088
 10.43(s, 1H), 8.71(br s, 1H), 7.58(s, 1H), 7.36~7.41(m, 2H), 7.28(d, J=7.9Hz, 1H), 7.13(t, J=7.1Hz, 1H), 6.70~6.84(m, 3H), 4.10~4.11(m, 4H), 4.01~4.04(m, 2H), 2.61~2.77(m, 1H), 2.46~2.55(m, 8H), 2.35(s, 3H), 1.74~1.76(m, 2H), 1.71~1.73(m, 2H), 1.46~1.52(m, 2H), 1.37~1.38(m, 2H) 10.43 (s, 1H), 8.71 (br s, 1H), 7.58 (s, 1H), 7.36-7.41 (m, 2H), 7.28 (d, J = 7.9 Hz, 1H), 7.13 (t, J = 7.1 Hz, 1H), 6.70-6.84 (m, 3H), 4.10-4.41 (m, 4H), 4.01-4.04 (m, 2H), 2.61-2.77 (m, 1H), 2.46-2.55 (m, 8H), 2.35 (s, 3H), 1.74-1.76 (m, 2H), 1.71-1.73 (m, 2H), 1.46-1.52 (m, 2H), 1.37-1.38 (m, 2H) 6161
Figure 112006049660803-pat00089
Figure 112006049660803-pat00089
 10.43(s, 1H), 8.70(br, 1H), 7.64(s, 1H), 7.42(s, 1H), 7.38(d, J=8.8Hz, 1H), 7.28(d, J=8.0Hz, 1H), 7.13(t, J=7.9Hz, 1H), 6.69-6.72(m, 3H), 3.95(t, J=6.4Hz, 2H), 3.49-3.57(m, 3H), 2.53-2.63(m, 3H), 2.37-2.46(m, 6H), 2.35(s, 3H), 1.76-1.88(m, 2H), 1.46-1.57(m, 6H)10.43 (s, 1H), 8.70 (br, 1H), 7.64 (s, 1H), 7.42 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H ), 7.13 (t, J = 7.9 Hz, 1H), 6.69-6.72 (m, 3H), 3.95 (t, J = 6.4 Hz, 2H), 3.49-3.57 (m, 3H), 2.53-2.63 (m, 3H), 2.37-2.46 (m, 6H), 2.35 (s, 3H), 1.76-1.88 (m, 2H), 1.46-1.57 (m, 6H) 6262
Figure 112006049660803-pat00090
Figure 112006049660803-pat00090
 10.48(s, 1H), 8.75(s, 1H), 7.65(s, 1H), 7.42(s, 1H), 6.64-7.39(m, 10H), 3.90(t, J=6.4Hz, 2H), 2.83(s, 6H), 2.46-2.66(m, 6H), 2.35(s, 3H), 1.65-2.18(m, 5H)10.48 (s, 1H), 8.75 (s, 1H), 7.65 (s, 1H), 7.42 (s, 1H), 6.64-7.39 (m, 10H), 3.90 (t, J = 6.4 Hz, 2H), 2.83 (s, 6H), 2.46-2.66 (m, 6H), 2.35 (s, 3H), 1.65-2.18 (m, 5H) 6363
Figure 112006049660803-pat00091
Figure 112006049660803-pat00091
 10.42(s, 1H), 7.64(s, 1H), 7.42(s, 1H), 7.37(d, J=8.4Hz, 1H), 7.28(d, J=8.0Hz, 1H), 7.13(t, J=7.7Hz, 1H), 6.69~6.72(m, 3H), 3.94(t, J=6.2Hz, 2H), 2.53~2.58(m, 2H), 2.37~2.45(m, 7H), 2.35(s, 3H), 2.15(s, 6H), 1.79~1.86(m, 2H), 1.48~1.55(m, 3H), 1.36~1.38(m, 1H)10.42 (s, 1H), 7.64 (s, 1H), 7.42 (s, 1H), 7.37 (d, J = 8.4Hz, 1H), 7.28 (d, J = 8.0Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 6.69-6.72 (m, 3H), 3.94 (t, J = 6.2 Hz, 2H), 2.53-2.58 (m, 2H), 2.37-2.45 (m, 7H), 2.35 (s, 3H), 2.15 (s, 6H), 1.79-1.86 (m, 2H), 1.48-1.55 (m, 3H), 1.36-1.38 (m, 1H) 6464
Figure 112006049660803-pat00092
Figure 112006049660803-pat00092
 10.42(s, 1H), 8.69(br s, 1H), 7.64(s, 1H), 7.42(s, 1H), 7.37(d, J=8.4Hz, 1H), 7.29(d, J=8.4Hz, 1H), 7.04(d, J=7.7Hz, 2H), 6.79(d, J=8.0Hz, 2H), 3.88~3.93(m, 2H), 2.42~2.55(m, 9H), 2.35(s, 3H), 2.20(s, 6H), 1.78~1.84(m, 2H), 1.72~1.76(m, 3H), 1.33~1.48(m, 1H) 10.42 (s, 1H), 8.69 (br s, 1H), 7.64 (s, 1H), 7.42 (s, 1H), 7.37 (d, J = 8.4Hz, 1H), 7.29 (d, J = 8.4Hz, 1H), 7.04 (d, J = 7.7 Hz, 2H), 6.79 (d, J = 8.0 Hz, 2H), 3.88-3.93 (m, 2H), 2.42-2.55 (m, 9H), 2.35 (s, 3H ), 2.20 (s, 6H), 1.78-1.84 (m, 2H), 1.72-1.76 (m, 3H), 1.33-1.48 (m, 1H) 6565
Figure 112006049660803-pat00093
Figure 112006049660803-pat00093
 10.43(s, 1H), 8.71(s, 1H), 7.61(s, 1H), 7.32-7.38(m, 2H), 7.23-7.25(m, 1H), 7.02-7.04(m, 2H), 6.78-6.80(m, 2H), 3.94-3.98(m, 2H), 2.39-2.46(m, 4H), 2.31(s, 2H), 2.17(s, 6H), 1.73(br, 1H), 1.57(br, 1H)10.43 (s, 1H), 8.71 (s, 1H), 7.61 (s, 1H), 7.32-7.38 (m, 2H), 7.23-7.25 (m, 1H), 7.02-7.04 (m, 2H), 6.78- 6.80 (m, 2H), 3.94-3.98 (m, 2H), 2.39-2.46 (m, 4H), 2.31 (s, 2H), 2.17 (s, 6H), 1.73 (br, 1H), 1.57 (br, 1H) 6666
Figure 112006049660803-pat00094
Figure 112006049660803-pat00094
 10.51(br, 1H), 8.89(br, 1H), 7.65(s, 1H), 7.43(m, 3H), 7.09(d, J=8.4Hz, 1H), 6.87(d, J=8.4Hz, 1H), 6.41(m, 1H), 4.01(s, 1H), 3.51(s, 6H), 2.65(m, 2H), 2.33(s, 12H), 1.53-1.81(m, 5H).10.51 (br, 1H), 8.89 (br, 1H), 7.65 (s, 1H), 7.43 (m, 3H), 7.09 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H ), 6.41 (m, 1H), 4.01 (s, 1H), 3.51 (s, 6H), 2.65 (m, 2H), 2.33 (s, 12H), 1.53-1.81 (m, 5H).

실시예 Example 화학구조Chemical structure NMR 스펙트럼 데이터 (1H 혹은 13C)NMR spectral data ( 1 H or 13 C) 6767

Figure 112006049660803-pat00095
Figure 112006049660803-pat00095
10.44(br, 1H), 8.70(br, 1H), 7.65(s, 1H), 7.42(s, 1H), 7.37(d, J=8.4Hz, 1H), 7.27(d, J=8.0Hz, 1H), 7.13(m, 1H), 7.02(d, J=8.8Hz, 2H), 6.75(d, J=7.6Hz, 2H), 6.67(m, 3H), 3.90(m, 2H), 2.83(s, 6H), 2.66(s, 3H), 2.46(s, 2H), 2.29(m, 3H), 2.16(m, 2H), 1.78(m, 2H), 1.66(m, 2H), 1.55(m, 2H)10.44 (br, 1H), 8.70 (br, 1H), 7.65 (s, 1H), 7.42 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H ), 7.13 (m, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 7.6 Hz, 2H), 6.67 (m, 3H), 3.90 (m, 2H), 2.83 (s , 6H), 2.66 (s, 3H), 2.46 (s, 2H), 2.29 (m, 3H), 2.16 (m, 2H), 1.78 (m, 2H), 1.66 (m, 2H), 1.55 (m, 2H) 6868
Figure 112006049660803-pat00096
Figure 112006049660803-pat00096
 10.44(br, 1H), 8.76(br, 1H), 7.62(s, 1H), 7.23-7.38(m, 3H), 7.03(d, J=8.0Hz, 2H), 6.65-6.91(m, 4H), 5.96(s, 2H), 4.21(t, J=5.6Hz, 2H), 4.14(t, J=5.6Hz, 2H), 2.42- 2.57(m, 5H), 2.32(s, 3H), 1.74-1.79(m, 1H), 1.58-1.62 (m, 1H)10.44 (br, 1H), 8.76 (br, 1H), 7.62 (s, 1H), 7.23-7.38 (m, 3H), 7.03 (d, J = 8.0 Hz, 2H), 6.65-6.91 (m, 4H) , 5.96 (s, 2H), 4.21 (t, J = 5.6Hz, 2H), 4.14 (t, J = 5.6Hz, 2H), 2.42- 2.57 (m, 5H), 2.32 (s, 3H), 1.74- 1.79 (m, 1 H), 1.58-1.62 (m, 1 H) 6969
Figure 112006049660803-pat00097
Figure 112006049660803-pat00097
 10.46(s, 1H), 8.74(s, 1H), 7.65(s, 1H), 7.41(s, 1H), 7.37(d, J=8.8Hz, 1H), 7.27(d, J=8.4Hz, 1H), 7.07(d, J= 8.4Hz, 2H), 6.83(d, J=8.8Hz, 2H), 4.02(t, J=5.2Hz, 2H), 3.51(t, J=5.2Hz, 2H), 3.43(t, J=7.2Hz, 2H), 2.42-2.61 (m, 5H), 2.35(s, 3H), 2.20(t, J=8.0Hz, 2H), 1.86-1.93 (m, 2H), 1.72-1.81(m, 1H), 1.58-1.64(m, 1H)10.46 (s, 1H), 8.74 (s, 1H), 7.65 (s, 1H), 7.41 (s, 1H), 7.37 (d, J = 8.8Hz, 1H), 7.27 (d, J = 8.4Hz, 1H ), 7.07 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 4.02 (t, J = 5.2 Hz, 2H), 3.51 (t, J = 5.2 Hz, 2H), 3.43 (t, J = 7.2 Hz, 2H), 2.42-2.61 (m, 5H), 2.35 (s, 3H), 2.20 (t, J = 8.0 Hz, 2H), 1.86-1.93 (m, 2H), 1.72 -1.81 (m, 1H), 1.58-1.64 (m, 1H) 7070
Figure 112006049660803-pat00098
Figure 112006049660803-pat00098
 10.46(br s, 1H), 8.75(br s, 1H), 7.64(s, 1H), 7.41(s, 1H), 7.36(d, J=8.8Hz, 1H), 7.28(d, J=8.0Hz, 1H), 7.04(d, J=8.0Hz, 2H), 6.84(d, J=7.8Hz, 2H), 6.81(d, J=7.7Hz, 2H), 6.48(d, J=7.3Hz, 2H), 4.83(br s, 2H), 3.87(t, J=6.2Hz, 2H), 2.55~2.61(m, 2H), 2.45~2.53(m, 5H), 2.35(s, 3H), 1.87~1.91(m, 2H), 1.70~1.79(m, 1H), 1.56~1.64(m, 1H)10.46 (br s, 1H), 8.75 (br s, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 8.0 Hz , 1H), 7.04 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 7.8 Hz, 2H), 6.81 (d, J = 7.7 Hz, 2H), 6.48 (d, J = 7.3 Hz, 2H ), 4.83 (br s, 2H), 3.87 (t, J = 6.2 Hz, 2H), 2.55-2.61 (m, 2H), 2.45-2.53 (m, 5H), 2.35 (s, 3H), 1.87-1.91 (m, 2H), 1.70 to 1.79 (m, 1H), 1.56 to 1.64 (m, 1H) 7171
Figure 112006049660803-pat00099
Figure 112006049660803-pat00099
 10.46(s, 1H), 8.74(s, 1H), 7.64(s, 1H), 7.41(s, 1H), 7.37(d, J=8.4Hz, 1H), 7.27(d, J=8.4Hz, 1H), 7.06(d, J= 8.4Hz, 2H), 6.81(d, J=8.4Hz, 2H), 3.96(t, J=6.2Hz, 2H), 2.76(br, 2H), 2.60(d, J=7.2Hz, 2H), 2.42-2.55(m, 7H), 2.35(s, 3H), 1.74-1.79(m, 1H), 1.60-1.62(m, 1H), 0.97 (t, J=7.0Hz, 6H)10.46 (s, 1H), 8.74 (s, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 7.37 (d, J = 8.4Hz, 1H), 7.27 (d, J = 8.4Hz, 1H ), 7.06 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 3.96 (t, J = 6.2 Hz, 2H), 2.76 (br, 2H), 2.60 (d, J = 7.2 Hz, 2H), 2.42-2.55 (m, 7H), 2.35 (s, 3H), 1.74-1.79 (m, 1H), 1.60-1.62 (m, 1H), 0.97 (t, J = 7.0 Hz, 6H) 7272
Figure 112006049660803-pat00100
Figure 112006049660803-pat00100
 10.46(s, 1H), 8.74(s, 1H), 7.64(s, 1H), 7.41(s, 1H), 7.37(d, J=7.6Hz, 1H), 7.27(d, J=8.4Hz, 1H), 7.06(d, J= 8.4Hz, 2H), 6.80(d, J=7.6Hz, 2H), 3.81(t, J=6.0Hz, 2H), 2.97-3.02(m, 2H) 2.72(t, J=6.8Hz, 2H), 2.60(d, J=6.8Hz, 2H), 2.42-2.46(m, 3H), 2.34(s, 3H), 1.70-1.82(m, 1H), 1.54-1.66(m, 1H)10.46 (s, 1H), 8.74 (s, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H ), 7.06 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 7.6 Hz, 2H), 3.81 (t, J = 6.0 Hz, 2H), 2.97-3.02 (m, 2H) 2.72 (t, J = 6.8 Hz, 2H), 2.60 (d, J = 6.8 Hz, 2H), 2.42-2.46 (m, 3H), 2.34 (s, 3H), 1.70-1.82 (m, 1H), 1.54-1.66 (m , 1H) 7373
Figure 112006049660803-pat00101
Figure 112006049660803-pat00101
 10.48(br s, 1H), 8.77(br s, 1H), 7.67(s, 1H), 7.50~ 7.52(m, 1H), 7.15~7.21(m, 3H), 6.67~6.77(m, 3H), 4.97~4.05(m, 2H), 2.57~2.63(m, 5H), 2.40~2.49(m, 4H), 2.39(s, 3H), 1.76~1.79(m, 2H), 1.60~1.74(m, 2H), 1.43~1.55(m, 4H), 1.34~1.39(m, 2H)10.48 (br s, 1H), 8.77 (br s, 1H), 7.67 (s, 1H), 7.50-7.52 (m, 1H), 7.15-7.71 (m, 3H), 6.67-6.67 (m, 3H), 4.97-4.05 (m, 2H), 2.57-2.63 (m, 5H), 2.40-2.49 (m, 4H), 2.39 (s, 3H), 1.76-1.79 (m, 2H), 1.60-1.74 (m, 2H) ), 1.43-1.55 (m, 4H), 1.34-1.39 (m, 2H) 7474
Figure 112006049660803-pat00102
Figure 112006049660803-pat00102
 10.48(br s, 1H), 8.75(br s, 1H), 7.68(s, 1H), 7.50(d, J=8.0Hz, 1H), 7.14~7.21(m, 3H), 6.71~6.74(m, 3H), 3.95(t, J=6.2Hz, 2H), 2.59~2.61(m, 3H), 2.45~2.53(m, 6H), 2.39(s, 3H), 1.89~1.90(m, 2H), 1.72~1.78(m, 2H), 1.64~1.66(m, 2H), 1.52~1.54(m, 4H), 1.37~1.44(m, 2H)10.48 (br s, 1H), 8.75 (br s, 1H), 7.68 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.14-7.21 (m, 3H), 6.71-6.74 (m, 3H), 3.95 (t, J = 6.2 Hz, 2H), 2.59-2.61 (m, 3H), 2.45-2.53 (m, 6H), 2.39 (s, 3H), 1.89-1.90 (m, 2H), 1.72 ~ 1.78 (m, 2H), 1.64-1.66 (m, 2H), 1.52-1.54 (m, 4H), 1.37-1.44 (m, 2H)

실시예 Example 화학구조Chemical structure NMR 스펙트럼 데이터 (1H 혹은 13C)NMR spectral data ( 1 H or 13 C) 7575

Figure 112006049660803-pat00103
Figure 112006049660803-pat00103
10.47(s, 1H), 8.75(s, 1H), 7.67(s, 1H), 7.51(d, J=7.67 Hz, 1H), 7.20(s, 1H), 7.15(d, J=8.0Hz, 2H), 6.72-6.73 (m, 3H), 4.03(t, J=5.6Hz, 2H), 3.51-3.60(m, 4H), 2.65 (t, J=5.2Hz, 2H), 2.60(d, J=7.2Hz, 2H), 2.37-2.49(m, 7H), 2.39(s, 3H), 1.77-1.82(m, 1H), 1.62-1.67(m, 1H)10.47 (s, 1H), 8.75 (s, 1H), 7.67 (s, 1H), 7.51 (d, J = 7.67 Hz, 1H), 7.20 (s, 1H), 7.15 (d, J = 8.0Hz, 2H ), 6.72-6.73 (m, 3H), 4.03 (t, J = 5.6 Hz, 2H), 3.51-3.60 (m, 4H), 2.65 (t, J = 5.2 Hz, 2H), 2.60 (d, J = 7.2 Hz, 2H), 2.37-2.49 (m, 7H), 2.39 (s, 3H), 1.77-1.82 (m, 1H), 1.62-1.67 (m, 1H) 7676
Figure 112006049660803-pat00104
Figure 112006049660803-pat00104
 10.47(s, 1H), 8.75(s, 1H), 7.67(s, 1H), 7.50(d, J=8.0Hz, 1H), 7.20(s, 1H), 7.15(d, J=8.4Hz, 2H), 6.67-6.75(m, 3H), 3.95(t, J=5.6Hz, 2H), 3.487-3.62(m, 4H), 2.59(d, J=6.8Hz, 2H), 2.24-2.47(m, 9H), 2.34(s, 3H), 1.74-1.84 (m, 3H), 1.62-1.68(m, 1H)10.47 (s, 1H), 8.75 (s, 1H), 7.67 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 7.15 (d, J = 8.4 Hz, 2H ), 6.67-6.75 (m, 3H), 3.95 (t, J = 5.6 Hz, 2H), 3.487-3.62 (m, 4H), 2.59 (d, J = 6.8 Hz, 2H), 2.24-2.47 (m, 9H), 2.34 (s, 3H), 1.74-1.84 (m, 3H), 1.62-1.68 (m, 1H) 7777
Figure 112006049660803-pat00105
Figure 112006049660803-pat00105
 10.5(s, 1H), 8.79(s, 1H), 7.65(s, 1H), 7.34-7.40(m, 2H), 7.25(d, J=8.4Hz, 1H), 7.05(d, J=8.4Hz, 2H), 6.80(d, J=8.4Hz, 2H), 4.09-4.11(m, 1H), 3.97(s, 2H), 2.58-2.73(m, 2H), 2.33-2.43(m, 5H), 1.92-1.99(m, 4H), 1.75(s, 3H), 1.61-1.64(m, 2H), 1.42(s, 3H), 1.33(s, 1H), 1.21(s, 6H), 0.82-0.84(m, 3H)10.5 (s, 1H), 8.79 (s, 1H), 7.65 (s, 1H), 7.34-7.40 (m, 2H), 7.25 (d, J = 8.4Hz, 1H), 7.05 (d, J = 8.4Hz , 2H), 6.80 (d, J = 8.4 Hz, 2H), 4.09-4.11 (m, 1H), 3.97 (s, 2H), 2.58-2.73 (m, 2H), 2.33-2.43 (m, 5H), 1.92-1.99 (m, 4H), 1.75 (s, 3H), 1.61-1.64 (m, 2H), 1.42 (s, 3H), 1.33 (s, 1H), 1.21 (s, 6H), 0.82-0.84 ( m, 3H) 7878
Figure 112006049660803-pat00106
Figure 112006049660803-pat00106
 10.46(s, 1H), 8.74(s, 1H), 7.66(s, 1H), 7.51(d, J=8.0Hz, 1H), 7.21(s, 1H), 7.15(d, J=7.6Hz, 1H), 7.06(d, J=8.4Hz, 2H), 6.82(d, J=8.4Hz, 2H), 4.02(t, J=5.6Hz, 2H), 3.56(t, J=4.4Hz, 4H), 2.65(t, J=5.6Hz, 2H), 2.59(d, J=7.2Hz, 2H), 2.41-2.47(m, 7H), 2.39(s, 3H), 1.72-1.82(m, 1H), 1.56-1.66(m, 1H)10.46 (s, 1H), 8.74 (s, 1H), 7.66 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 7.15 (d, J = 7.6 Hz, 1H ), 7.06 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 4.02 (t, J = 5.6 Hz, 2H), 3.56 (t, J = 4.4 Hz, 4H), 2.65 (t, J = 5.6 Hz, 2H), 2.59 (d, J = 7.2 Hz, 2H), 2.41-2.47 (m, 7H), 2.39 (s, 3H), 1.72-1.82 (m, 1H), 1.56 -1.66 (m, 1H) 7979
Figure 112006049660803-pat00107
Figure 112006049660803-pat00107
 10.46(s, 1H), 8.74(s, 1H), 7.67(s, 1H), 7.51(d, J=7.6Hz, 1H), 7.21(s, 1H), 7.15(d, J=8.0Hz, 1H), 7.06(d, J=8.4Hz, 2H), 6.80(d, J=8.0Hz, 2H), 3.94(t, J=6.2Hz, 2H), 3.56(t, J=4.4Hz, 4H), 2.59(d, J=6.4Hz, 2H), 2.35-2.47(m, 7H), 2.39(s, 3H), 1.74-1.85(m, 3H), 1.56-1.66(m, 1H)10.46 (s, 1H), 8.74 (s, 1H), 7.67 (s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.21 (s, 1H), 7.15 (d, J = 8.0 Hz, 1H ), 7.06 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.0 Hz, 2H), 3.94 (t, J = 6.2 Hz, 2H), 3.56 (t, J = 4.4 Hz, 4H), 2.59 (d, J = 6.4 Hz, 2H), 2.35-2.47 (m, 7H), 2.39 (s, 3H), 1.74-1.85 (m, 3H), 1.56-1.66 (m, 1H) 8080
Figure 112006049660803-pat00108
Figure 112006049660803-pat00108
 10.40(s, 1H), 8.68(br, 1H), 7.65(s, 1H), 7.43(s, 1H), 7.38(d, J=8.4Hz, 1H), 7.28(d, J=8.4Hz, 1H), 7.08(d, J=8.8Hz, 2H), 6.82(d, J=8.8Hz, 2H), 3.97(t, J=6.0Hz, 2H), 3.25-3.42(m, 3H), 2.71-2.90(m, 3H), 2.36-2.55(m, 3H), 2.35(s, 3H), 1.97-2.01(m, 2H), 1.37-1.70(m, 10H), 1.14-1.25(m, 4H)10.40 (s, 1H), 8.68 (br, 1H), 7.65 (s, 1H), 7.43 (s, 1H), 7.38 (d, J = 8.4Hz, 1H), 7.28 (d, J = 8.4Hz, 1H ), 7.08 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 3.97 (t, J = 6.0 Hz, 2H), 3.25-3.42 (m, 3H), 2.71-2.90 (m, 3H), 2.36-2.55 (m, 3H), 2.35 (s, 3H), 1.97-2.01 (m, 2H), 1.37-1.70 (m, 10H), 1.14-1.25 (m, 4H) 8181
Figure 112006049660803-pat00109
Figure 112006049660803-pat00109
 10.40(s, 1H), 8.68(br,1H), 7.65(s, 1H), 7.43(s, 1H), 7.38(d, J=8.4Hz, 1H), 7.28(d, J=8.4Hz, 1H), 7.08(d, J=8.8Hz, 2H), 6.82(d, J=8.8Hz, 2H), 3.96(t, J=6.4Hz, 2H), 2.69-2.82(m, 1H), 2.49-2.57(m, 2H), 2.32-2.49(m, 2H), 2.35(s, 3H), 1.92-2.01(m, 2H), 1.32-1.60(m, 4H), 1.15-1.27(m, 3H)10.40 (s, 1H), 8.68 (br, 1H), 7.65 (s, 1H), 7.43 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H ), 7.08 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 3.96 (t, J = 6.4 Hz, 2H), 2.69-2.82 (m, 1H), 2.49-2.57 (m, 2H), 2.32-2.49 (m, 2H), 2.35 (s, 3H), 1.92-2.01 (m, 2H), 1.32-1.60 (m, 4H), 1.15-1.27 (m, 3H) 8282
Figure 112006049660803-pat00110
Figure 112006049660803-pat00110
 10.47(br s, 1H), 8.75(br s, 1H), 7.67(s, 1H), 7.50(d, J=8.0Hz, 1H), 7.21(s, 1H), 3.94(t, J=6.4Hz, 1H), 2.58~2.60(m, 3H), 2.42~2.46(m, 6H), 2.39(s, 3H), 1.72~1.76(m, 2H), 1.59~1.62(m, 2H), 1.52~1.58(m, 4H), 1.37~1.42(m, 2H)10.47 (br s, 1H), 8.75 (br s, 1H), 7.67 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 3.94 (t, J = 6.4 Hz , 1H), 2.58-2.60 (m, 3H), 2.42-2.46 (m, 6H), 2.39 (s, 3H), 1.72-1.76 (m, 2H), 1.59-1.62 (m, 2H), 1.52-1.58 (m, 4H), 1.37-1.42 (m, 2H)

실시예 Example 화학구조Chemical structure NMR 스펙트럼 데이터 (1H 혹은 13C)NMR spectral data ( 1 H or 13 C) 8383

Figure 112006049660803-pat00111
Figure 112006049660803-pat00111
10.46(br s, 1H), 8.74(br s, 1H), 7.67(s, 1H), 7.50(d, J=7.7Hz, 1H), 7.21(s, 1H), 7.16(d, J=7.7Hz, 1H), 7.05(d, J=8.4Hz, 2H), 6.83(d, J=8.8Hz, 2H), 4.00(t, J=5.8Hz, 2H), 2.55~2.65(m, 5H), 2.42~2.44(m, 4H), 2.39(s, 3H), 1.74~1.79(m, 2H), 1.50~1.62(m, 2H), 1.46~1.49(m, 4H), 1.36~1.38(m, 2H)10.46 (br s, 1H), 8.74 (br s, 1H), 7.67 (s, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.21 (s, 1H), 7.16 (d, J = 7.7 Hz , 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 4.00 (t, J = 5.8 Hz, 2H), 2.55-2.65 (m, 5H), 2.42 ~ 2.44 (m, 4H), 2.39 (s, 3H), 1.74-1.79 (m, 2H), 1.50-1.62 (m, 2H), 1.46-1.49 (m, 4H), 1.36-1.38 (m, 2H) 8484
Figure 112006049660803-pat00112
Figure 112006049660803-pat00112
 10.45(s, 1H, NH), 8.74(s, 1H, OH), 7.64(s, 1H, ArH), 7.41(s, 1H, ArH), 7.36(d, J=8.4Hz, 1H, ArH), 7.28(d, J=8.0Hz, 1H, ArH), 6.94(d, J=7.7Hz, 2H, ArH), 6.56(d, J=8.0Hz, 2H, ArH), 2.59~2.61(m, 2H, CH2), 2.37~2.41(m, 3H, CH2, CH), 2.35(s, 3H, CH3), 1.74~1.78(m, 1H, CH), 1.57~1.61(m, 1H, CH) 10.45 (s, 1H, NH), 8.74 (s, 1H, OH), 7.64 (s, 1H, ArH), 7.41 (s, 1H, ArH), 7.36 (d, J = 8.4 Hz, 1H, ArH), 7.28 (d, J = 8.0Hz, 1H, ArH), 6.94 (d, J = 7.7Hz, 2H, ArH), 6.56 (d, J = 8.0Hz, 2H, ArH), 2.59 ~ 2.61 (m, 2H, CH2), 2.37-2.41 (m, 3H, CH2, CH), 2.35 (s, 3H, CH3), 1.74-1.78 (m, 1H, CH), 1.57-1.61 (m, 1H, CH) 8585
Figure 112006049660803-pat00113
Figure 112006049660803-pat00113
 10.48(s, 1H), 8.74(s, 1H), 1.55-1.65(m, 1H) 7.65(s, 1H), 7.41(s, 1H), 7.37(d, J=8.4Hz, 1H), 7.27(d, J=8.4Hz, 1H), 7.06(d, J=8.4Hz, 2H), 6.81(d, J=8.4Hz, 2H), 4.54(t, J=6.2Hz, 4H), 3.97(t, J=6.4Hz, 2H), 3.52-3.54(m, 2H), 2.60(d, J=6.8Hz, 2H), 2.35-2.53(m, 3H), 2.35(s, 3H), 1.84(t, J=6.0Hz, 2H), 1.65-1.90(m, 1H), 1.55-1.65(m, 1H)10.48 (s, 1H), 8.74 (s, 1H), 1.55-1.65 (m, 1H) 7.65 (s, 1H), 7.41 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.27 ( d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 4.54 (t, J = 6.2 Hz, 4H), 3.97 (t, J = 6.4 Hz, 2H), 3.52-3.54 (m, 2H), 2.60 (d, J = 6.8 Hz, 2H), 2.35-2.53 (m, 3H), 2.35 (s, 3H), 1.84 (t, J = 6.0 Hz, 2H), 1.65-1.90 (m, 1H), 1.55-1.65 (m, 1H) 8686
Figure 112006049660803-pat00114
Figure 112006049660803-pat00114
 10.46(s, 1H), 8.74(s, 1H), 7.64(s, 1H), 7.41(s, 1H), 7.37(d, J=8.4Hz, 1H), 7.27(d, J=8.4Hz, 1H), 7.06(d, J=8.4Hz, 2H), 6.81(d, J=8.4Hz, 2H), 4.53(t, J=6.2Hz, 1H), 3.97(t, J=6.4Hz, 2H), 3.54(q, J=5.6Hz, 2H), 3.17(d, J=4.8Hz, 1H), 3.33(s, 3H), 2.60(d, J=6.8Hz, 1H), 2.35-2.53(m, 2H), 2.35(s, 3H), 1.84(t, J=6.0Hz, 2H), 1.65-1.90(m, 1H), 10.46 (s, 1H), 8.74 (s, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 7.37 (d, J = 8.4Hz, 1H), 7.27 (d, J = 8.4Hz, 1H ), 7.06 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 4.53 (t, J = 6.2 Hz, 1H), 3.97 (t, J = 6.4 Hz, 2H), 3.54 (q, J = 5.6 Hz, 2H), 3.17 (d, J = 4.8 Hz, 1H), 3.33 (s, 3H), 2.60 (d, J = 6.8 Hz, 1H), 2.35-2.53 (m, 2H ), 2.35 (s, 3H), 1.84 (t, J = 6.0 Hz, 2H), 1.65-1.90 (m, 1H), 8787
Figure 112006049660803-pat00115
Figure 112006049660803-pat00115
 10.47(s, 1H), 8.74(s, 1H), 7.67(s, 1H), 7.51(d, J=8.0Hz, 1H), 7.21(s, 1H), 7.15(d, J=8.4Hz, 1H), 7.06(d, J=8.4Hz, 2H), 6.80(d, J=8.4Hz, 2H), 3.93(t, J=6.4Hz, 2H), 2.59(d, J=6.8Hz, 2H), 2.35-2.45(m, 3H), 2.39(s, 3H), 1.74-1.85(m, 3H), 1.58-1.66(m, 1H).10.47 (s, 1H), 8.74 (s, 1H), 7.67 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H ), 7.06 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 3.93 (t, J = 6.4 Hz, 2H), 2.59 (d, J = 6.8 Hz, 2H), 2.35-2.45 (m, 3H), 2.39 (s, 3H), 1.74-1.85 (m, 3H), 1.58-1.66 (m, 1H). 8888
Figure 112006049660803-pat00116
Figure 112006049660803-pat00116
 10.47(s, 1H), 8.74(s, 1H), 7.64(s, 1H), 7.41(s, 1H), 7.36(d, J=7.7Hz, 1H), 7.28(d, J=7.7Hz, 1H), 7.07(d, J=7.7Hz, 2H), 6.86(d, J=8.0Hz, 2H), 4.67(s, 2H), 2.60~2.62(m, 3H), 2.40~2.46(m, 2H), 2.35(s, 3H), 1.82(s, 3H), 1.64~1.80(m, 1H), 1.58~1.63(m, 1H) 10.47 (s, 1H), 8.74 (s, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 7.36 (d, J = 7.7Hz, 1H), 7.28 (d, J = 7.7Hz, 1H ), 7.07 (d, J = 7.7 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H), 4.67 (s, 2H), 2.60-2.62 (m, 3H), 2.40-2.46 (m, 2H) , 2.35 (s, 3H), 1.82 (s, 3H), 1.64 ~ 1.80 (m, 1H), 1.58 ~ 1.63 (m, 1H) 8989
Figure 112006049660803-pat00117
Figure 112006049660803-pat00117
 11.73(s, 1H), 9.13(s, 1H), 7.68(s, 1H), 7.41(s, 1H), 7.37(d, J=8.8Hz, 1H), 7.27(d, J=8.4Hz, 1H), 6.96(d, J= 8.4Hz, 2H), 6.64(d, J=8.0Hz, 2H), 2.45-2.63(m, 5H), 2.35(s, 3H), 2.10(s, 3H), 1.72-1.82(m, 1H), 1.61-1.67 (m, 1H).11.73 (s, 1H), 9.13 (s, 1H), 7.68 (s, 1H), 7.41 (s, 1H), 7.37 (d, J = 8.8Hz, 1H), 7.27 (d, J = 8.4Hz, 1H ), 6.96 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 8.0 Hz, 2H), 2.45-2.63 (m, 5H), 2.35 (s, 3H), 2.10 (s, 3H), 1.72 -1.82 (m, 1 H), 1.61-1.67 (m, 1H).

실시예 Example 화학구조Chemical structure NMR 스펙트럼 데이터 (1H 혹은 13C)NMR spectral data ( 1 H or 13 C) 9090

Figure 112006049660803-pat00118
Figure 112006049660803-pat00118
10.46(s, 1H), 8.75(br s, 1H), 7.67(s, 1H), 7.50(d, J=8.0Hz, 1H), 7.21(s, 1H), 7.16(d, J=8.0Hz, 1H), 7.04(d, J=8.8Hz, 2H), 6.81(d, J=8.4Hz, 2H), 3.93(t, J=6.4Hz, 2H), 2.50-2.60(m, 2H), 2.41-2.44(m, 7H), 2.39(s, 3H), 2.19-2.38(m, 4H), 2.14(s, 3H), 1.79-1.85(m, 4H), 1.60-1.63(m, 2H)10.46 (s, 1H), 8.75 (br s, 1H), 7.67 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 3.93 (t, J = 6.4 Hz, 2H), 2.50-2.60 (m, 2H), 2.41- 2.44 (m, 7H), 2.39 (s, 3H), 2.19-2.38 (m, 4H), 2.14 (s, 3H), 1.79-1.85 (m, 4H), 1.60-1.63 (m, 2H) 9191
Figure 112006049660803-pat00119
Figure 112006049660803-pat00119
 10.47(s, 1H), 8.75(br s, 1H), 7.67(s, 1H), 7.50(d, J=7.7Hz, 1H), 7.21(s, 1H), 7.07(d, J=7.7Hz, 1H), 7.05(d, J=8.0Hz, 2H), 6.82(d, J=8.4Hz, 2H), 3.96(t, J=6.0Hz, 2H), 2.75-2.78(m, 2H), 2.53-2.60(m, 5H), 2.42-2.46(m, 4H), 2.39(s, 3H), 1.74-1.79(m, 1H), 1.60-1.65(m, 1H), 0.97(t, J=7.1Hz, 6H) 10.47 (s, 1H), 8.75 (br s, 1H), 7.67 (s, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.21 (s, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 3.96 (t, J = 6.0 Hz, 2H), 2.75-2.78 (m, 2H), 2.53- 2.60 (m, 5H), 2.42-2.46 (m, 4H), 2.39 (s, 3H), 1.74-1.79 (m, 1H), 1.60-1.65 (m, 1H), 0.97 (t, J = 7.1 Hz, 6H) 9292
Figure 112006049660803-pat00120
Figure 112006049660803-pat00120
 11.30(s, 1H), 10.50(s, 1H), 7.67(s, 1H), 7.51(d, J=7.6Hz, 1H), 7.21(s, 1H), 7.15(d, J=7.6Hz, 1H), 7.05(d, J=8.4Hz, 2H), 6.80(d, J=8.4Hz, 2H), 3.93(t, J=6.4Hz, 2H), 3.47(t, J=6.0Hz, 2H), 3.27-3.40(m, 3H), 2.49(s, 3H), 2.33-2.70(m, 10H), 1.65-1.90(m, 3H), 1.55-1.65(m, 1H), 1.23-1.25(m, 2H) 11.30 (s, 1H), 10.50 (s, 1H), 7.67 (s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.21 (s, 1H), 7.15 (d, J = 7.6 Hz, 1H ), 7.05 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 3.93 (t, J = 6.4 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 3.27-3.40 (m, 3H), 2.49 (s, 3H), 2.33-2.70 (m, 10H), 1.65-1.90 (m, 3H), 1.55-1.65 (m, 1H), 1.23-1.25 (m, 2H ) 9393
Figure 112006049660803-pat00121
Figure 112006049660803-pat00121
 10.45(s, 1H), 8.75(br s, 1H), 7.63~7.72(m, 2H), 7.54~7.58(m, 1H), 7.37~7.41(m, 1H), 6.94(d, J=7.7Hz, 2H), 6.66(d, J=7.7Hz, 2H), 2.59~2.62(m, 2H), 2.39~2.42(m, 3H), 1.73~1.76(m, 1H), 1.60~1.63(m, 1H), 10.45 (s, 1H), 8.75 (br s, 1H), 7.63-7.72 (m, 2H), 7.54-7.58 (m, 1H), 7.37-7.41 (m, 1H), 6.94 (d, J = 7.7 Hz , 2H), 6.66 (d, J = 7.7 Hz, 2H), 2.59-2.62 (m, 2H), 2.39-2.42 (m, 3H), 1.73-1.76 (m, 1H), 1.60-1.63 (m, 1H ), 9494
Figure 112006049660803-pat00122
Figure 112006049660803-pat00122
 11.30(s, 1H). 10.50(s, 1H), 7.75(s, 1H), 7.70-7.75(m, 1H), 7.38(d, J=9.6Hz, 2H), 7.23(t, J=8.4Hz, 1H), 7.12(d, J=8.0Hz, 2H), 6.90(d, J=8.0Hz, 2H), 4.38(br, 2H), 3.95(d, J=9.6Hz, 2H), 3.82(t, J=11.2Hz, 2H), 3.45-3.51(m, 4H), 3.17-3.19(m, 2H), 2.60(d, J=6.8Hz, 2H), 2.44-2.50(m, 3H), 1.73-1.80(m, 1H) ,1.61-1.63(m, 1H)11.30 (s, 1 H). 10.50 (s, 1H), 7.75 (s, 1H), 7.70-7.75 (m, 1H), 7.38 (d, J = 9.6 Hz, 2H), 7.23 (t, J = 8.4 Hz, 1H), 7.12 (d , J = 8.0 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 4.38 (br, 2H), 3.95 (d, J = 9.6 Hz, 2H), 3.82 (t, J = 11.2 Hz, 2H ), 3.45-3.51 (m, 4H), 3.17-3.19 (m, 2H), 2.60 (d, J = 6.8 Hz, 2H), 2.44-2.50 (m, 3H), 1.73-1.80 (m, 1H), 1.61-1.63 (m, 1 H) 9595
Figure 112006049660803-pat00123
Figure 112006049660803-pat00123
 10.47(br, 1H), 8.75(s, 1H), 7.37(s, 1H), 7.67(d, J=8.4Hz, 1H), 7.57(s, 1H), 7.39(d, J=8.4Hz, 1H), 7.06(d, J=8.4Hz, 2H), 6.80(d, J=8.4Hz, 2H), 3.93(t, J=6.0Hz, 2H), 2.52-2.61(m, 2H), 2.40-2.50(m, 6H), 1.62-1.85(m, 4H), 1.40-1.55(m, 7H), 1.38-1.40(m, 2H)10.47 (br, 1H), 8.75 (s, 1H), 7.37 (s, 1H), 7.67 (d, J = 8.4Hz, 1H), 7.57 (s, 1H), 7.39 (d, J = 8.4Hz, 1H ), 7.06 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 3.93 (t, J = 6.0 Hz, 2H), 2.52-2.61 (m, 2H), 2.40-2.50 (m, 6H), 1.62-1.85 (m, 4H), 1.40-1.55 (m, 7H), 1.38-1.40 (m, 2H) 9696
Figure 112006049660803-pat00124
Figure 112006049660803-pat00124
 10.46(s, 1H, NH), 8.74(s, 1H, OH), 7.72(s, 1H), 7.66(d, J=8.4Hz, 1H), 7.58(s, 1H), 7.39(t, J=8.4Hz, 1H), 7.06(d, J=8.4Hz, 2H), 6.80(d, J=8.4Hz, 2H), 3.92(t, J=6.0Hz, 2H), 3.50-3.60(m, 4H), 2.52-2.62(m, 2H), 2.20-2.50(m, 9H), 1.70-1.89(m, 3H), 1.50-1.62(m, 1H)10.46 (s, 1H, NH), 8.74 (s, 1H, OH), 7.72 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.58 (s, 1H), 7.39 (t, J = 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 3.92 (t, J = 6.0 Hz, 2H), 3.50-3.60 (m, 4H) , 2.52-2.62 (m, 2H), 2.20-2.50 (m, 9H), 1.70-1.89 (m, 3H), 1.50-1.62 (m, 1H)

실시예 Example 화학구조Chemical structure NMR 스펙트럼 데이터 (1H 혹은 13C)NMR spectral data ( 1 H or 13 C) 9797

Figure 112006049660803-pat00125
Figure 112006049660803-pat00125
10.48(br, 1H), 8.75(s, 1H), 7.74(s, 1H), 7.72(d, J=8.4Hz, 1H), 7.39(d, J=9.2Hz, 1H), 7.23(t, J=8.4Hz, 1H), 7.08(d, J=8.4Hz, 2H), 6.82(d, J=8.4Hz, 2H), 3.93-4.05(m, 2H), 2.71-3.01(m, 4H), 2.55-2.61(m, 2H), 2.40-2.50(m, 4H), 2.00-2.17(m, 2H), 1.50-1.80(m, 7H), 1.38-1.50(m, 2H) 10.48 (br, 1H), 8.75 (s, 1H), 7.74 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 9.2 Hz, 1H), 7.23 (t, J = 8.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 3.93-4.05 (m, 2H), 2.71-3.01 (m, 4H), 2.55 -2.61 (m, 2H), 2.40-2.50 (m, 4H), 2.00-2.17 (m, 2H), 1.50-1.80 (m, 7H), 1.38-1.50 (m, 2H) 9898
Figure 112006049660803-pat00126
Figure 112006049660803-pat00126
 10.48(br, 1H), 8.75(s, 1H), 7.73(s, 1H), 7.72(d, J=8.4Hz, 1H), 7.39(d, J=9.2Hz, 1H), 7.23(t, J=8.4Hz, 1H), 7.07(d, J=8.4Hz, 2H), 6.81(d, J=8.4Hz, 2H), 3.95(t, J=6.4Hz, 2H), 2.40-2.50(m, 3H), 2.35(s, 6H), 2.52-2.70(m, 4H), 1.84-1.91(m, 2H), 1.72-1.80(m, 1H), 1.55-1.65(m, 1H)10.48 (br, 1H), 8.75 (s, 1H), 7.73 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 9.2 Hz, 1H), 7.23 (t, J = 8.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 3.95 (t, J = 6.4 Hz, 2H), 2.40-2.50 (m, 3H ), 2.35 (s, 6H), 2.52-2.70 (m, 4H), 1.84-1.91 (m, 2H), 1.72-1.80 (m, 1H), 1.55-1.65 (m, 1H)

실시예Example 99:  99: NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[4-(2-) -4- [4- (2- 피롤리딘Pyrrolidine -1-일--1 day- 에톡시Ethoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

단계 1. 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-피롤리딘-1-일-에톡시)-페닐]-부티릭 엑시드 에틸 에스터의 합성Step 1. 2- (6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -butyric Synthesis of Ext Ethyl Ester

Figure 112006049660803-pat00127
Figure 112006049660803-pat00127

제조한 화합물 (107.0 mg, 0.24 mmol)과 피롤리딘 (30.2 ㎕, 0.36 mmol), 요오드화 나트륨 (54.3 mg, 0.36 mmol), 세슘카보네이트 (220.4 mg, 0.36 mmol)을 디메틸포름아미드 (2 ml)에 용해시킨 후 80 ℃에서 12시간 동안 반응하였다. 반응 혼합물을 암모늄 클로라이드 수용액으로 종결하고 디클로로메탄으로 추출하여 용매를 무수 황산 마그네슘으로 건조한 다음 감압 농축하였다. 잔여물을 관 크로마토그래피 (디클로로메탄:메탄올=9:1)하여 표제 화합물 (94.7 mg, 87.6 %)을 얻었다.Prepared compound (107.0 mg, 0.24 mmol), pyrrolidine (30.2 μl, 0.36 mmol), sodium iodide (54.3 mg, 0.36 mmol), cesium carbonate (220.4 mg, 0.36 mmol) in dimethylformamide (2 ml) After dissolution, the reaction was carried out at 80 ° C. for 12 hours. The reaction mixture was terminated with an aqueous ammonium chloride solution and extracted with dichloromethane, the solvent was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (dichloromethane: methanol = 9: 1) to give the title compound (94.7 mg, 87.6%).

1H-NMR (CDCl3, 400MHz) δ 7.43(s, 1H), 7.18-7.29(m, 2H), 7.09(d, J=8.8, 2H), 6.84(d, J=8.8, 2H), 4.17(t, J=5.9, 2H), 4.03-4.11(m, 2H), 3.01(t, J=5.9, 2H), 2.58-3.00(m, 8H), 2.39(s, 3H), 1.81-2.05(m, 7H), 1.16(t, J=7.02, 3H). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.43 (s, 1H), 7.18-7.29 (m, 2H), 7.09 (d, J = 8.8, 2H), 6.84 (d, J = 8.8, 2H), 4.17 (t, J = 5.9, 2H), 4.03-4.11 (m, 2H), 3.01 (t, J = 5.9, 2H), 2.58-3.00 (m, 8H), 2.39 (s, 3H), 1.81-2.05 ( m, 7H), 1.16 (t, J = 7.02, 3H).

단계 2. N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-피롤리딘-1-일-에톡시)-페닐]-부틸아미드의 합성Step 2. N-hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (2-pyrrolidin-1-yl-ethoxy)- Synthesis of Phenyl] -Butylamide

Figure 112006049660803-pat00128
Figure 112006049660803-pat00128

상기 제 1단계에서 얻은 화합물 (110.0 mg, 0.23 mmol)을 메탄올 (1 ml)로 하여 1.76 M 포타슘 히드록시 아민용액 (3.0 ml, 5.28 mmol)을 첨가 한 후 3시간 동안 상온에서 교반한다. 1 M 염산용액으로 반응을 종결 시킨 후 (pH=7) 결과　된　용액를 에틸아세테이트로 추출한다. 무수 황산 마그네슘으로 건조하여 감압 농축하고, 에틸아세테이트와 에틸에테르로 재결정하여 표제 화합물 (28.9 mg, 27.0 %, 노란색 고체)을 얻었다.1.76 M potassium hydroxyamine solution (3.0 ml, 5.28 mmol) was added to the obtained compound (110.0 mg, 0.23 mmol) in methanol (1 ml), followed by stirring at room temperature for 3 hours. After completion of the reaction with 1 M hydrochloric acid solution (pH = 7), the resulting solution was extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and recrystallized with ethyl acetate and ethyl ether to obtain the title compound (28.9 mg, 27.0%, yellow solid).

1H-NMR (DMSO-d 6, 400MHz) δ 10.47(s, 1H), 8.75(s, 1H), 7.65(s, 1H), 7.42(s, 1H), 7.38(d, J=8.4Hz, 1H), 7.28(d, J=8.4Hz, 1H), 7.08(d, J=8.1Hz, 2H), 6.85(d, J=8.1Hz, 2H), 4.07(m, 2H), 2.35(s, 3H), 1.60-4.07(m, 17H) 1 H-NMR (DMSO- d 6 , 400 MHz) δ 10.47 (s, 1H), 8.75 (s, 1H), 7.65 (s, 1H), 7.42 (s, 1H), 7.38 (d, J = 8.4Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.1 Hz, 2H), 6.85 (d, J = 8.1 Hz, 2H), 4.07 (m, 2H), 2.35 (s, 3H), 1.60-4.07 (m, 17H)

상기 실시예의 반응을 이용하여 하기와 같은 화합물들을 제조하였다.The following compounds were prepared using the reaction of the above example.

실시예Example 100:  100: NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-{4-[2-(4-) -4- {4- [2- (4- 메틸methyl -피페라진-1-일)-Piperazin-1-yl) 에톡시Ethoxy ]-]- 페닐Phenyl }-}- 부틸아미드Butylamide

실시예Example 101:  101: NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[4-(2-피페라진-1-일-) -4- [4- (2-piperazin-1-yl- 에톡시Ethoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예Example 102:  102: NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-{4-[3-(4-옥소-피페리딘-1-일)-) -4- {4- [3- (4-oxo-piperidin-1-yl)- 프로폭시Propoxy ]-]- 페닐Phenyl }-}- 부틸아미드Butylamide

실시예Example 103:  103: NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[4-(3-) -4- [4- (3- 피롤리딘Pyrrolidine -1-일--1 day- 프로폭시Propoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예Example 104:  104: NN -히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-{4-[3-(4-메틸-피페라진-1-일)-프로폭시]-페닐}-부틸아미드-Hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- {4- [3- (4-methyl-piperazin-1-yl) -propoxy] -Phenyl} -butylamide

실시예Example 105:  105: NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[4-(3-피페라진-1-일-) -4- [4- (3-piperazin-1-yl- 프로폭시Propoxy )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예 Example 화학구조Chemical structure NMR 스펙트럼 데이터 (1H 혹은 13C)NMR spectral data ( 1 H or 13 C) 100100

Figure 112006049660803-pat00129
Figure 112006049660803-pat00129
10.32(br, 1H), 8.89(br, 1H), 7.67(s, 1H), 7.42(s, 1H), 7.37(d, J=8.4Hz, 1H), 7.27(d, J=8.4Hz, 1H), 7.06(d, J=8.4Hz, 2H), 6.82(d, J=8.4Hz, 2H), 3.16(s, 3H), 2.35(s, 3H), 2.13-4.02(m, 19H)10.32 (br, 1H), 8.89 (br, 1H), 7.67 (s, 1H), 7.42 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H ), 7.06 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 3.16 (s, 3H), 2.35 (s, 3H), 2.13-4.02 (m, 19H) 101101
Figure 112006049660803-pat00130
Figure 112006049660803-pat00130
 10.47(br, 1H), 10.37(br, 1H), 8.71(br, 1H), 7.67(s, 1H), 7.42(s, 1H), 7.37(d, J=8.4Hz, 1H), 7.27(d, J=8.4Hz, 1H), 7.06(d, J=8.4Hz, 2H), 6.82(d, J=8.4Hz, 2H), 2.35(s, 3H), 1.60-4.03(m, 19H)10.47 (br, 1H), 10.37 (br, 1H), 8.71 (br, 1H), 7.67 (s, 1H), 7.42 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.27 (d , J = 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 2.35 (s, 3H), 1.60-4.03 (m, 19H) 102102
Figure 112006049660803-pat00131
Figure 112006049660803-pat00131
 10.46(s, 1H), 8.75(s, 1H), 7.64(s, 1H), 7.41(s, 1H), 7.37(d, J=8.4Hz, 1H), 7.27(d, J=8.4Hz, 1H), 7.06(d, J=8.4Hz, 2H), 6.81(d, J=8.4Hz, 2H), 4.11-4.15(m, 1H), 3.95(t, J=6.4Hz, 2H), 3.66(d, J=4.8Hz, 2H), 2.60(d, J=7.2Hz, 2H), 2.35-2.53(m, 8H), 2.34(s, 3H), 2.19(t, J=5.6Hz, 2H), 1.85(t, J=6.8Hz, 2H), 1.74-1.79(m, 1H), 1.60-1.62(m, 1H)10.46 (s, 1H), 8.75 (s, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 7.37 (d, J = 8.4Hz, 1H), 7.27 (d, J = 8.4Hz, 1H ), 7.06 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 4.11-4.15 (m, 1H), 3.95 (t, J = 6.4 Hz, 2H), 3.66 (d , J = 4.8 Hz, 2H), 2.60 (d, J = 7.2 Hz, 2H), 2.35-2.53 (m, 8H), 2.34 (s, 3H), 2.19 (t, J = 5.6 Hz, 2H), 1.85 (t, J = 6.8 Hz, 2H), 1.74-1.79 (m, 1H), 1.60-1.62 (m, 1H) 103103
Figure 112006049660803-pat00132
Figure 112006049660803-pat00132
 10.47(br s, 1H), 8.74(s, 1H), 7.65(s, 1H), 7.42(s, 1H), 7.36(d, J=8.4Hz, 1H), 7.28(d, J=8.4Hz, 1H), 7.05(d, J=8.4Hz, 2H), 6.82(d, J=8.8Hz, 2H), 3.96(t, J=6.2Hz, 2H), 2.52-2.61(m, 6H), 2.42-2.49(m, 5H), 2.35(s, 3H), 1.88-1.91(m, 2H), 1.76-1.79(m, 6H), 1.60-1.72(m, 2H)10.47 (br s, 1H), 8.74 (s, 1H), 7.65 (s, 1H), 7.42 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 3.96 (t, J = 6.2 Hz, 2H), 2.52-2.61 (m, 6H), 2.42- 2.49 (m, 5H), 2.35 (s, 3H), 1.88-1.91 (m, 2H), 1.76-1.79 (m, 6H), 1.60-1.72 (m, 2H) 104104
Figure 112006049660803-pat00133
Figure 112006049660803-pat00133
 10.47(s, 1H), 8.75(br s, 1H), 7.64(s, 1H), 7.41(s, 1H), 7.36(d, J=8.4Hz, 1H), 7.28(d, J=8.4Hz, 1H), 7.05(d, J=7.7Hz, 2H), 6.81(d, J=7.3Hz, 2H), 3.93(t, J=6.0Hz, 2H), 2.59~2.61(m, 2H), 2.38~2.49(m, 11H), 2.35(s, 3H), 2.17(s, 3H), 1.74~1.90(m, 4H), 1.59~1.62(m, 2H), 10.47 (s, 1H), 8.75 (br s, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 7.36 (d, J = 8.4Hz, 1H), 7.28 (d, J = 8.4Hz, 1H), 7.05 (d, J = 7.7 Hz, 2H), 6.81 (d, J = 7.3 Hz, 2H), 3.93 (t, J = 6.0 Hz, 2H), 2.59-2.61 (m, 2H), 2.38- 2.49 (m, 11H), 2.35 (s, 3H), 2.17 (s, 3H), 1.74-1.90 (m, 4H), 1.59-1.62 (m, 2H), 105105
Figure 112006049660803-pat00134
Figure 112006049660803-pat00134
 10.47(s, 1H), 8.74(br s, 1H), 7.65(s, 1H), 7.41(s, 1H), 7.36(d, J=8.0Hz, 1H), 7.28(d, J=8.4Hz, 1H), 7.06(d, J=8.0Hz, 1H), 6.83(d, J=7.7Hz, 2H), 4.12(t, J=6.0Hz, 2H), 3.99(t, J=6.0Hz, 2H), 1.60-1.63(m, 1H), 3.16-3.34(m, 4H), 2.60-2.63(m, 5H), 2.38-2.47(m, 2H), 2.35(s, 3H), 1.98-2.01(m, 2H), 1.75-1.76(m, 1H) 10.47 (s, 1H), 8.74 (br s, 1H), 7.65 (s, 1H), 7.41 (s, 1H), 7.36 (d, J = 8.0Hz, 1H), 7.28 (d, J = 8.4Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 7.7 Hz, 2H), 4.12 (t, J = 6.0 Hz, 2H), 3.99 (t, J = 6.0 Hz, 2H) , 1.60-1.63 (m, 1H), 3.16-3.34 (m, 4H), 2.60-2.63 (m, 5H), 2.38-2.47 (m, 2H), 2.35 (s, 3H), 1.98-2.01 (m, 2H), 1.75-1.76 (m, 1H)

실시예 106: Example 106: NN -히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-모르폴린-4-일-프로필아미노)-페닐]-부틸아미드-Hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (3-morpholin-4-yl-propylamino) -phenyl] -butylamide

단계 1. 2,2-디메틸-5-[2-(4-니트로-페닐)-아세틸]-[1,3]디옥산-4,6-디온의 합성Step 1. Synthesis of 2,2-dimethyl-5- [2- (4-nitro-phenyl) -acetyl]-[1,3] dioxane-4,6-dione

Figure 112006049660803-pat00135
Figure 112006049660803-pat00135

4-니트로-페닐-아세틱 엑시드 (8.0 g, 44.16 mmol)을 디클로로메탄 (150 ml)에 녹인 후 2,2-디메틸-1,3-디옥산-4,6-디온 (7.0 g, 48.57 mmol), 4-디메틸아미노-피리딘 (8.67 g, 70.65 mmol), 그리고 1,3-디시클로헥실카르보디이미드 (10.5 g, 50.78 mmol)를 ０℃에서 차례로 첨가한다. 상온으로 서서히 온도를 올리면서 밤새 교반 후 여과하고, 10 % 포타슘히드로젠술페이트 수용액과 포화 염화나트륨 수용액으로 씻어준다. 무수 황산마그네슘으로 건조　후 여과하고 감압 농축하여 표제 화합물 (12.9 g, 95 %, 흰색 고체)을 얻었다.4-nitro-phenyl-acetic acid (8.0 g, 44.16 mmol) was dissolved in dichloromethane (150 ml) and then 2,2-dimethyl-1,3-dioxane-4,6-dione (7.0 g, 48.57 mmol ), 4-dimethylamino-pyridine (8.67 g, 70.65 mmol), and 1,3-dicyclohexylcarbodiimide (10.5 g, 50.78 mmol) are added sequentially at 0 ° C. After slowly raising the temperature to room temperature, the mixture was stirred overnight, filtered, and washed with 10% aqueous potassium hydrogensulfate solution and saturated aqueous sodium chloride solution. Dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (12.9 g, 95%, white solid).

1H-NMR (CDCl3, 400MHz) δ 8.19(d, J=8.8, 2H), 7.58(d, J=8.8, 2H), 4.52(s, 2H), 1.74(s, 6H). 1 H-NMR (CDCl 3 , 400 MHz) δ 8.19 (d, J = 8.8, 2H), 7.58 (d, J = 8.8, 2H), 4.52 (s, 2H), 1.74 (s, 6H).

단계 2. 2,2-디메틸-5-[2-(4-니트로-페닐)-에틸]-[1,3]디옥산-4,6-디온의 합성Step 2. Synthesis of 2,2-dimethyl-5- [2- (4-nitro-phenyl) -ethyl]-[1,3] dioxane-4,6-dione

Figure 112006049660803-pat00136
Figure 112006049660803-pat00136

상기 제 1단계에서 얻은 화합물 (12.9 g, 41.98 mmol)을 디클로로메탄 (150 ml)에 녹인 후 아세틱 엑시드 (28.8 ml, 503.80 mmol)를 0 ℃에서 첨가한다. 나트륨보로하이드라이드 (4.0 g. 10.50 mmol)를 1시간에 걸쳐 같은 온도에서 첨가한 후 5시간 동안 교반한다. 포화 염화나트륨 수용액과 물로 차례로 씻어주고 무수 황산마그네슘으로 건조　후 여과한다. 이렇게 해서 얻어진 용액을 감압 농축하고 잔여물을 재결정 (헥산/에틸아세테이트)하여 표제 화합물 (10.7 g, 37 %, 흰색 고체)을 얻었다.The compound obtained in the first step (12.9 g, 41.98 mmol) is dissolved in dichloromethane (150 ml), and acetic acid (28.8 ml, 503.80 mmol) is added at 0 ° C. Sodium borohydride (4.0 g. 10.50 mmol) is added at the same temperature over 1 hour and then stirred for 5 hours. Wash with saturated aqueous sodium chloride solution and water, dry with anhydrous magnesium sulfate and filter. The solution thus obtained was concentrated under reduced pressure, and the residue was recrystallized (hexane / ethyl acetate) to give the title compound (10.7 g, 37%, white solid).

1H-NMR (CDCl3, 400MHz) δ 8.17(d, J=8.8Hz, 2H), 7.42(d, J=8.8Hz, 2H), 3.56(t, J=5.0Hz, 1H), 2.90-2.94(m, 2H), 2.40-2.46(m, 2H), 1.79(s, 6H). 1 H-NMR (CDCl 3 , 400 MHz) δ 8.17 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 3.56 (t, J = 5.0 Hz, 1H), 2.90-2.94 (m, 2H), 2.40-2.46 (m, 2H), 1.79 (s, 6H).

단계 3. 2-메틸렌-4-(4-니트로-페닐)-부티릭 엑시드 에틸 에스터의 합성Step 3. Synthesis of 2-methylene-4- (4-nitro-phenyl) -butyric acid ethyl ester

Figure 112006049660803-pat00137
Figure 112006049660803-pat00137

·상기 제 2단계에서 얻은 화합물 (10.7 g, 36.49 mmol)과 N,N-디메틸메틸렌암모늄 아이오디드 (16.9 g, 91.21 mmol)을 에탄올 (6 ml)에 용해시키고 65 ℃에서 밤새 교반한다. 반응 혼합물을 감압 농축하고 디에틸 에테르와 포화 탄산수소나트륨 수용액으로 추출한다. 10 % 포타슘히드로젠술페이트 수용액과 포화 염화나트륨 수용액으로 차례로 씻어준다. 무수 황산마그네슘으로 건조　후 여과하고 감압 농축하여 표제 화합물 (8.7 g, 96 %, 노란색 오일)을 얻었다.Dissolve the compound (10.7 g, 36.49 mmol) and N , N -dimethylmethyleneammonium iodide (16.9 g, 91.21 mmol) obtained in the second step in ethanol (6 ml) and stir overnight at 65 ° C. The reaction mixture is concentrated under reduced pressure and extracted with diethyl ether and saturated aqueous sodium hydrogen carbonate solution. Wash sequentially with 10% aqueous potassium hydrogensulfate solution and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure to obtain the title compound (8.7 g, 96%, yellow oil).

1H-NMR (CDCl3, 400MHz) δ 8.15(dd, J=2.0, 6.8Hz, 2H), 7.34(dd, J=2.0, 6.8Hz, 2H), 6.17(s, 1H), 5.49(s, 1H), 4.23(qt, J=6.8Hz, 2H), 2.91(t, J=7.6, 2H), 2.64(t, J=7.6Hz, 2H) 1.32(t, J=7.0Hz, 3H). 1 H-NMR (CDCl 3 , 400 MHz) δ 8.15 (dd, J = 2.0, 6.8 Hz, 2H), 7.34 (dd, J = 2.0, 6.8 Hz, 2H), 6.17 (s, 1H), 5.49 (s, 1H), 4.23 (qt, J = 6.8 Hz, 2H), 2.91 (t, J = 7.6, 2H), 2.64 (t, J = 7.6 Hz, 2H) 1.32 (t, J = 7.0 Hz, 3H).

단계 4. 2-(디에톡시-포스포릴)-4-[2-(4-니트로-페닐)-에틸]-펜탄디오익 엑시드 디에틸 에스터의 합성Step 4. Synthesis of 2- (diethoxy-phosphoryl) -4- [2- (4-nitro-phenyl) -ethyl] -pentanedioic acid diethyl ester

Figure 112006049660803-pat00138
Figure 112006049660803-pat00138

트리에틸포스포노아세테이트 (21 ml, 104.71 mmol)을 건조된 THF (300 ml)에 용해시키고 0 ℃로 온도를 낮춘 후 나트륨하이드라이드 (4.2 g, 104.71 mmol)을 천천히 넣어 1시간 동안 교반한다. 반응 혼합물에 상기 제 3단계에서 얻은 화합물 (8.7 g, 34.90 mmol)을 건조된 THF (50 ml)에 용해시켜 넣고 상온에서 밤새 교반하였다. 찬 얼음물로 반응을 종결하고 암모늄클로라이드 수용액으로 씻은 다음 에틸아세테이트로 추출하였다. 용매를 무수 황산마그네슘으로 건조하여 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=1:2)하여 표제 화합물 (11.1 g, 72 %, 노란색 액체)을 얻었다.Triethylphosphonoacetate (21 ml, 104.71 mmol) is dissolved in dried THF (300 ml), the temperature is lowered to 0 ° C. and sodium hydride (4.2 g, 104.71 mmol) is slowly added and stirred for 1 hour. In the reaction mixture, the compound (8.7 g, 34.90 mmol) obtained in the third step was dissolved in dried THF (50 ml) and stirred at room temperature overnight. The reaction was terminated with cold ice water, washed with an aqueous ammonium chloride solution and extracted with ethyl acetate. The solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (hexane: ethyl acetate = 1: 2) to obtain the title compound (11.1 g, 72%, yellow liquid).

1H NMR(400MHz, CDCl3): δ 8.08(d, J=8.4Hz, 2H), 7.27(d, J=8.4Hz, 2H), 4.05-4.16(m, 8H), 2.87-2.99(m, 1H), 2.61-2.68(m, 2H), 2.30-2.46(m, 1H), 1.89-2.17(m, 3H), 1.72-1.79(m, 1H), 1.24~1.35(m, 12H). 1 H NMR (400 MHz, CDCl 3 ): δ 8.08 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 4.05-4.16 (m, 8H), 2.87-2.99 (m, 1H), 2.61-2.68 (m, 2H), 2.30-2.46 (m, 1H), 1.89-2.17 (m, 3H), 1.72-1.79 (m, 1H), 1.24-1.35 (m, 12H).

단계 5. 2-[2-(4-메톡시-벤질옥시)-벤질리딘]-4-[2-(4-니트로-페닐)-에틸]-펜탄디오익 엑시드 디에틸 에스터의 합성Step 5. Synthesis of 2- [2- (4-methoxy-benzyloxy) -benzylidene] -4- [2- (4-nitro-phenyl) -ethyl] -pentanedioic acid diethyl ester

Figure 112006049660803-pat00139
Figure 112006049660803-pat00139

단계 4에서 제조한 화합물 (8.4 g, 17.74 mmol)을 실시예 11 단계 5와 동일한 방법으로 실험하여 표제 화합물 (5.4 g, 반응수율: 81 %, 노란색 액체)을 얻었다.      The compound prepared in Step 4 (8.4 g, 17.74 mmol) was tested in the same manner as in Example 11 Step 5 to obtain the title compound (5.4 g, reaction yield: 81%, yellow liquid).

1H NMR(400MHz, CDCl3): δ 8.03(d, J=8.4Hz, 2H), 7.90(s, 1H) 7.30(d, J=8.4Hz, 2H), 7.17(d, J=8.4Hz, 2H), 7.05-7.07(m, 2H), 6.87(d, J=8.4Hz, 2H), 6.83(d, J=8.0Hz, 1H), 4.96(s, 2H), 4.21-4.23(m, 2H), 3.94-3.14(m, 2H), 3.80(s, 3H), 2.63-2.97(m, 5H), 2.28(s, 3H), 1.62-1.84(m, 2H), 1.25-1.32(m, 3H), 1.15-1.19(m, 3H). 1 H NMR (400 MHz, CDCl 3 ): δ 8.03 (d, J = 8.4 Hz, 2H), 7.90 (s, 1H) 7.30 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.05-7.07 (m, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.0 Hz, 1H), 4.96 (s, 2H), 4.21-4.23 (m, 2H ), 3.94-3.14 (m, 2H), 3.80 (s, 3H), 2.63-2.97 (m, 5H), 2.28 (s, 3H), 1.62-1.84 (m, 2H), 1.25-1.32 (m, 3H) ), 1.15-1.19 (m, 3 H).

단계 6. 2-(2-히드록시-벤질리딘)-4-[2-(4-니트로-페닐)-에틸]-펜타디오익 엑시드 디에틸 에스터의 합성Step 6. Synthesis of 2- (2-hydroxy-benzylidene) -4- [2- (4-nitro-phenyl) -ethyl] -pentadiic acid diethyl ester

Figure 112006049660803-pat00140
Figure 112006049660803-pat00140

단계 5에서 제조한 화합물 (5.4 g, 9.38 mmol)을 실시예 11 단계 6과 동일한 방법으로 실험하여 표제 화합물 (4.1 g, 반응수율: 97 %, 노란색 액체)을 얻었다.      The compound prepared in Step 5 (5.4 g, 9.38 mmol) was tested in the same manner as in Example 11 Step 6, to obtain the title compound (4.1 g, reaction yield: 97%, yellow liquid).

1H NMR(400MHz, CDCl3): δ 8.10(d, J=8.4Hz, 2H), 7.72(s, 1H) 7.23(d, J=8.4Hz, 2H), 7.01(d, J=8.4Hz, 1H), 6.91(m, 1H), 6.76(d, J=8.4Hz, 1H), 5.62(s, 1H), 4.22-4.27(m, 2H), 3.96-4.15(m, 2H), 2.56-2.84(m, 5H), 2.26(s, 3H), 1.72-1.94(m, 2H), 1.29-1.33(m, 3H), 1.17-1.20(m, 3H). 1 H NMR (400 MHz, CDCl 3 ): δ 8.10 (d, J = 8.4 Hz, 2H), 7.72 (s, 1H) 7.23 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 1H), 6.91 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H), 5.62 (s, 1H), 4.22-4.27 (m, 2H), 3.96-4.15 (m, 2H), 2.56-2.84 (m, 5H), 2.26 (s, 3H), 1.72-1.94 (m, 2H), 1.29-1.33 (m, 3H), 1.17-1.20 (m, 3H).

단계 7. 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-(4-니트로-페닐)-부티릭 엑시드 에틸 에스터의 합성Step 7. Synthesis of 2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- (4-nitro-phenyl) -butyric acid ethyl ester

Figure 112006049660803-pat00141
Figure 112006049660803-pat00141

단계 6에서 제조한 화합물 (2.0 g, 4.53 mmol)을 실시예 11 단계 7과 동일한 방법으로 실험하여 표제 화합물 (1.0 g, 반응수율: 54 %, 흰색 고체)을 얻었다.     The compound prepared in Step 6 (2.0 g, 4.53 mmol) was tested in the same manner as in Example 11 Step 7, to obtain the title compound (1.0 g, reaction yield: 54%, white solid).

1H NMR(400MHz, CDCl3): δ 8.14(d, J=8.8Hz, 2H), 7.45(s, 1H), 7.35(d, J=8.8Hz, 2H), 7.29(d, J=8.4Hz, 1H), 7.20-7.22(m, 2H), 4.06-4.08(m, 2H), 2.74-2.97(m, 5H), 2.39(s, 3H), 2.01-2.10(m, 1H), 1.83-1.92(m, 1H), 1.15(t, J=7.2Hz, 3H). 1 H NMR (400 MHz, CDCl 3 ): δ 8.14 (d, J = 8.8 Hz, 2H), 7.45 (s, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.4 Hz , 1H), 7.20-7.22 (m, 2H), 4.06-4.08 (m, 2H), 2.74-2.97 (m, 5H), 2.39 (s, 3H), 2.01-2.10 (m, 1H), 1.83-1.92 (m, 1 H), 1.15 (t, J = 7.2 Hz, 3H).

단계 8. 4-(4-아미노-페닐)-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부티릭 엑시드에틸 에스터의 합성Step 8. Synthesis of 4- (4-amino-phenyl) -2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butyric acid ethyl ester

Figure 112006049660803-pat00142
Figure 112006049660803-pat00142

단계 7에서 제조한 화합물 (1.45 g, 3.54 mmol)을 에틸아세테이트 (10 ml)에 용해시키고 Pd/C 10 %와 H2로 밤새 상온에서 반응하였다. 반응 혼합물을 셀라이트 충전물로 걸러내고 용매를 감압 농축한 후 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=1:2)하여 표제 화합물 (1.3 g, 97 %, 노란색 고체)을 얻었다.The compound (1.45 g, 3.54 mmol) prepared in step 7 was dissolved in ethyl acetate (10 ml) and reacted with Pd / C 10% and H 2 at room temperature overnight. The reaction mixture was filtered through a celite charge, the solvent was concentrated under reduced pressure, and the residue was subjected to column chromatography (hexane: ethyl acetate = 1: 2) to give the title compound (1.3 g, 97%, yellow solid).

1H NMR(400MHz, CDCl3): δ 7.42(s, 1H), 7.27(m, 1H), 7.20(d, J=8.8Hz, 2H), 6.97(d, J=8.4Hz, 2H), 6.62(d, J=8.4Hz, 2H), 4.06-4.09(m, 2H), 3.57(s, 2H), 2.55-2.97(m, 5H), 2.39(s, 3H), 1.93-2.01(m, 1H), 1.76-1.87(m, 1H), 1.16(t, J=7.2Hz, 3H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.42 (s, 1 H), 7.27 (m, 1 H), 7.20 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 8.4 Hz, 2H), 4.06-4.09 (m, 2H), 3.57 (s, 2H), 2.55-2.97 (m, 5H), 2.39 (s, 3H), 1.93-2.01 (m, 1H ), 1.76-1.87 (m, 1H), 1.16 (t, J = 7.2 Hz, 3H).

단계 9. 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-모르폴린-4-일-프로필아미노)-페닐]-부티릭 엑시드 에틸 에스터의 합성Step 9. 2- (6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (3-morpholin-4-yl-propylamino) -phenyl] -butyric acid Synthesis of Ethyl Ester

Figure 112006049660803-pat00143
Figure 112006049660803-pat00143

4-(4-아미노페닐)-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부티릭 엑시드 에틸 에스터 (150 mg, 0.39 mmol)과 탄산칼륨 (136 mg, 0.98 mmol), 요오드화칼륨 촉매량을 DMF (5 ml)에 용해시켜 0 ℃로 낮추고 4-(3-클로로프로필)-모르폴린 (71 mg, 0.43 mmol)을 넣어 100 ℃에서 36시간 동안 반응하였다. 반응 혼합물을 찬 얼음물로 종결하고 클로로포름으로 추출한 다음 무수 황산 마그네슘으로 건조하여 용매를 감압 농축하였다. 잔여물을 관 크로마토그래피 (에틸아세테이트)하여 표제화합물 (52 mg, 반응 수율: 27 %, 노란 액체)을 얻었다.   4- (4-aminophenyl) -2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butyric acid ethyl ester (150 mg, 0.39 mmol) and potassium carbonate (136 mg, 0.98 mmol), the potassium iodide catalyst amount was dissolved in DMF (5 ml), lowered to 0 ° C., and 4- (3-chloropropyl) -morpholine (71 mg, 0.43 mmol) was added thereto and reacted at 100 ° C. for 36 hours. The reaction mixture was terminated with cold ice water, extracted with chloroform and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate) to give the title compound (52 mg, reaction yield: 27%, yellow liquid).

1H NMR(400MHz, CDCl3): δ 1.15(t, J=7.1Hz, 3H, CH3), 1.76~1.90(m, 4H, CH2x2), 1.92~2.05(m, 2H, CH2), 2.38(s, 3H, CH3), 2.41~2.50(m, 4H, CH2x2), 2.52~2.66(m, 1H, CH), 2.75~2.81(m, 2H, CH2), 2.89~2.94(m, 1H, CH), 3.17(t, J=6.6Hz, 1H, CH), 3.70~3.75(m, 4H, CH2x2), 4.04~4.18(m, 2H, CH2), 4.20~4.25(m, 2H, CH2), 6.53(d, J=8.0Hz, 1H, ArH), 6.64(s, 1H, ArH), 6.98(d, J=8.0Hz, 1H, ArH), 7.13(d, J=8.4Hz, 1H, ArH), 7.18(d, J=8.0Hz, 1H, ArH), 7.28~7.29(m, 2H, ArH), 7.42(s, 1H, ArH) 1 H NMR (400 MHz, CDCl 3 ): δ 1.15 (t, J = 7.1 Hz, 3H, CH 3 ), 1.76-1.90 (m, 4H, CH2x2), 1.92-2.05 (m, 2H, CH 2 ), 2.38 (s, 3H, CH 3 ), 2.41 to 2.50 (m, 4H, CH2x2), 2.52 to 2.66 (m, 1H, CH), 2.75 to 2.81 (m, 2H, CH 2 ), 2.89 to 2.94 (m, 1H , CH), 3.17 (t, J = 6.6 Hz, 1H, CH), 3.70-3.75 (m, 4H, CH2x2), 4.04-4.18 (m, 2H, CH 2 ), 4.20-4.25 (m, 2H, CH 2 ), 6.53 (d, J = 8.0 Hz, 1H, ArH), 6.64 (s, 1H, ArH), 6.98 (d, J = 8.0 Hz, 1H, ArH), 7.13 (d, J = 8.4 Hz, 1H , ArH), 7.18 (d, J = 8.0 Hz, 1H, ArH), 7.28-7.29 (m, 2H, ArH), 7.42 (s, 1H, ArH)

단계10.Step 10. N N -히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-모르폴린-4-일-프로필아미노)-페닐]-부틸아미드의 합성-Hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (3-morpholin-4-yl-propylamino) -phenyl] -butylamide Synthesis of

Figure 112006049660803-pat00144
Figure 112006049660803-pat00144

상기 9단계에서 제조한 화합물 (50 mg, 0.09 mmol)을 실시예 11의 단계 8과 동일한 방법으로 실험하여 표제 화합물 (37 mg, 반응 수율: 84 %, 노란 고체)을 얻었다.       The compound prepared in Step 9 (50 mg, 0.09 mmol) was tested in the same manner as in Step 8 of Example 11, to obtain the title compound (37 mg, reaction yield: 84%, yellow solid).

1H NMR(400MHz, DMSO-d 6 ): δ 1.55~1.77(m, 6H, CH2x3), 2.34~2.44(m, 4H, CH2x2), 2.44~2.50(m, 3H, CH2, CH), 2.57~2.59(m, 2H, CH2), 3.42~3.56(m, 4H, CH2x2), 4.02~4.09(m, 2H, CH2), 6.45(d, J=7.7Hz, 1H, ArH), 6.85(d, J=7.7Hz, 1H, ArH), 7.07(d, J=7.7Hz, 1H, ArH), 7.28(d, J=7.7Hz, 1H, ArH), 7.35~7.41(m, 3H, ArH), 7.63(s, 1H, ArH), 8.75(br s, 1H, OH), 10.47(s, 1H, NH) 1 H NMR (400 MHz, DMSO- d 6 ): δ 1.55-1.77 (m, 6H, CH 2x3), 2.34-2.44 (m, 4H, CH2x2), 2.44-2.50 (m, 3H, CH 2 , CH), 2.57 ~ 2.59 (m, 2H, CH 2 ), 3.42-3.56 (m, 4H, CH2x2), 4.02-4.09 (m, 2H, CH 2 ), 6.45 (d, J = 7.7 Hz, 1H, ArH), 6.85 ( d, J = 7.7 Hz, 1H, ArH), 7.07 (d, J = 7.7 Hz, 1H, ArH), 7.28 (d, J = 7.7 Hz, 1H, ArH), 7.35-7.41 (m, 3H, ArH) , 7.63 (s, 1H, ArH), 8.75 (br s, 1H, OH), 10.47 (s, 1H, NH)

상기 실시예의 반응을 이용하여 하기와 같은 화합물들을 제조하였다.The following compounds were prepared using the reaction of the above example.

실시예Example 107:  107: NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[4-(3-피페리딘-1-일-) -4- [4- (3-piperidin-1-yl- 프로필아미노Propylamino )-)- 페닐Phenyl ]-]- 부틸아미드Butylamide

실시예Example 108: (4-[4-(3-디메틸아미노- 108: (4- [4- (3-dimethylamino- 프로필아미노Propylamino )-)- 페닐Phenyl ]-]- NN -히드록시-2-(6--Hydroxy-2- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-)- 부틸아미드Butylamide

실시예 Example 화학구조Chemical structure NMR 스펙트럼 데이터 (1H 혹은 13C)NMR spectral data ( 1 H or 13 C) 107107

Figure 112006049660803-pat00145
Figure 112006049660803-pat00145
10.48(s, 1H), 9.53(s, 1H), 8.75(s, 1H), 7.63(s, 1H), 7.41(s, 1H), 7.28-7.38(m, 4H) 7.06(d, J=7.6Hz, 2H), 4.08(t, J=6.4Hz, 2H), 2.60(d, J=6.4Hz, 2H), 2.32-2.44 (m, 9H), 2.34(s, 3H), 1.73-1.85(m, 3H), 1.48-1.66(m, 5H), 1.34-1.44(m, 2H).10.48 (s, 1H), 9.53 (s, 1H), 8.75 (s, 1H), 7.63 (s, 1H), 7.41 (s, 1H), 7.28-7.38 (m, 4H) 7.06 (d, J = 7.6 Hz, 2H), 4.08 (t, J = 6.4 Hz, 2H), 2.60 (d, J = 6.4 Hz, 2H), 2.32-2.44 (m, 9H), 2.34 (s, 3H), 1.73-1.85 (m , 3H), 1.48-1.66 (m, 5H), 1.34-1.44 (m, 2H). 108108
Figure 112006049660803-pat00146
Figure 112006049660803-pat00146
 10.58(br, 1H), 9.58(s, 1H), 8.82(s, 1H), 7.68(s, 1H), 7.41(s, 1H), 7.27-7.35(m, 4H) 7.05(d, J=8.4Hz, 2H), 4.06(t, J=6.4Hz, 2H), 2.59(d, J=6.4Hz, 2H), 2.42-2.50 (m, 3H), 2.34(s, 3H), 2.28(t, J=6.6Hz, 2H), 2.09(s, 6H), 1.69-1.74(m, 3H), 1.58-1.62(m, 1H)10.58 (br, 1H), 9.58 (s, 1H), 8.82 (s, 1H), 7.68 (s, 1H), 7.41 (s, 1H), 7.27-7.35 (m, 4H) 7.05 (d, J = 8.4 Hz, 2H), 4.06 (t, J = 6.4 Hz, 2H), 2.59 (d, J = 6.4 Hz, 2H), 2.42-2.50 (m, 3H), 2.34 (s, 3H), 2.28 (t, J = 6.6 Hz, 2H), 2.09 (s, 6H), 1.69-1.74 (m, 3H), 1.58-1.62 (m, 1H)

실시예Example 109: 2-(7- 109: 2- (7- 플루오로Fluoro -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-)- NN -히드록시-4-[4-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드 -Hydroxy-4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -butylamide 하이드로클로라이드Hydrochloride

단계 1. 2-(7-플루오로-2-옥소-2H-크로멘-3-일메틸)-N-히드록시-4-[4-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드 하이드로클로라이드의 합성Step 1. 2- (7-Fluoro-2-oxo-2H-chromen-3-ylmethyl) -N-hydroxy-4- [4- (2-morpholin-4-yl-ethoxy)- Synthesis of Phenyl] -butylamide Hydrochloride

Figure 112006049660803-pat00147
Figure 112006049660803-pat00147

메탄올 용매 2 ml 에 2-(7-플루오로-2-옥소-2H-크로멘-3-일메틸)-N-히드록시-4-[4-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드 (46 mg, 0.09 mmol)을 용해시킨 후 온도를 0 ℃ 으로 낮춘 후 2 N 염산 에테르용액 (1 ml)를 천천히 적가 후 실온에서 5시간 동안 교반한다. 반응용액속의 고체화합물을 감압필터하여 표제화합물 (40 mg 반응수율: 81.6 %, 노란색고체)을 얻었다.2- (7-fluoro-2-oxo-2H-chromen-3-ylmethyl) -N -hydroxy-4- [4- (2-morpholin-4-yl-ethoxy in 2 ml of methanol solvent After dissolving) -phenyl] -butylamide (46 mg, 0.09 mmol), the temperature was lowered to 0 ° C., and 2 N hydrochloric acid ether solution (1 ml) was slowly added dropwise, followed by stirring at room temperature for 5 hours. The solid compound in the reaction solution was filtered under reduced pressure to obtain the title compound (40 mg yield: 81.6%, yellow solid).

1H NMR(400MHz, DMSO-d3): 1.55-1.68(m, H), 1.71-1.83(m, 1H), 2.36-2.49(m, 7H), 2.60(d, J=6.8Hz, 2H), 2.65(t, J=5.4Hz, 2H), 3.56(t, J=4.8Hz, 4H), 4.03(t, J=6.0Hz, 2H), 6.82(d, J=8.4Hz, 2H), 7.06(d, J=8.4Hz, 2H), 7.20-7.22(m, 1H), 7.72(s, 1H), 8.75(s, 1H), 10.47(s, 1H) 1 H NMR (400 MHz, DMSO-d 3 ): 1.55-1.68 (m, H), 1.71-1.83 (m, 1H), 2.36-2.49 (m, 7H), 2.60 (d, J = 6.8 Hz, 2H) , 2.65 (t, J = 5.4 Hz, 2H), 3.56 (t, J = 4.8 Hz, 4H), 4.03 (t, J = 6.0 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 7.20-7.22 (m, 1H), 7.72 (s, 1H), 8.75 (s, 1H), 10.47 (s, 1H)

상기 실시예의 반응을 이용하여 하기와 같은 화합물들을 제조하였다.The following compounds were prepared using the reaction of the above example.

실시예 110: N -히드록시-2-(7- 메틸 -2-옥소-2H- 크로멘 -3- 일메틸 )-4-[4-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드 하이드로클로라이드 Example 110 N -hydroxy-2- (7- methyl -2-oxo-2H -chromen- 3- ylmethyl ) -4- [4- (2-morpholin-4-yl-ethoxy)- Phenyl] -butylamide hydrochloride

실시예Example 111:  111: NN -히드록시-2-(7-Hydroxy-2- (7- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[4-(3-모르폴린-4-일-프로폭시)-페닐]-부틸아미드 ) -4- [4- (3-morpholin-4-yl-propoxy) -phenyl] -butylamide 하이드로클로라이드Hydrochloride

실시예Example 112:  112: NN -히드록시-2-(7-Hydroxy-2- (7- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[4-(3-피페리딘-1-일-프로폭시)-페닐]-부틸아미드 ) -4- [4- (3-piperidin-1-yl-propoxy) -phenyl] -butylamide 하이드로클로라이드Hydrochloride

실시예Example 113: 4-[4-(2- 113: 4- [4- (2- 디에틸아미노Diethylamino -- 에톡시Ethoxy )-)- 페닐Phenyl ]-]- NN -히드록시-2-(7-Hydroxy-2- (7- 메틸methyl -2-옥소-2H-크로멘-3-일메틸)-부틸아미드 2-oxo-2H-chromen-3-ylmethyl) -butylamide 하이드로클로라이드Hydrochloride

실시예 Example 화학구조Chemical structure NMR 스펙트럼 데이터 (1H 혹은 13C)NMR spectral data ( 1 H or 13 C) 110110

Figure 112006049660803-pat00148
Figure 112006049660803-pat00148
11.44(s, 1H), 10.52(s, 1H), 7.69(s, 1H), 7.51(d, J= 8.0Hz, 1H), 7.20(s, 1H), 7.10-7.14(m, 3H), 6.89(d, J=8.4Hz, 2H), 4.38(t, J=5.6Hz, 2H), 3.82-3.93(m, 4H), 3.48-3.51(m, 4H), 2.45-2.58(m, 5H), 2.39(s, 3H), 1.72-1.82(m, 1H), 1.56-1.66(m, 1H)11.44 (s, 1H), 10.52 (s, 1H), 7.69 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 7.10-7.14 (m, 3H), 6.89 (d, J = 8.4 Hz, 2H), 4.38 (t, J = 5.6 Hz, 2H), 3.82-3.93 (m, 4H), 3.48-3.51 (m, 4H), 2.45-2.58 (m, 5H), 2.39 (s, 3H), 1.72-1.82 (m, 1H), 1.56-1.66 (m, 1H) 111111
Figure 112006049660803-pat00149
Figure 112006049660803-pat00149
 10.84(s, 1H), 10.49(s, 1H), 7.68(s, 1H), 7.51(d, J=7.6Hz, 1H), 7.21(s, 1H), 7.15(d, J=8.0Hz, 1H), 7.08(d, J=8.0Hz, 2H), 6.83(d, J=7.6Hz, 2H), 3.94-4.00(m, 4H), 3.74-3.80(m, 2H), 3.43-3.46(m, 2H), 3.21-3.25(m, 2H), 3.05-3.07(m, 2H), 2.59(d, J=6.8Hz, 2H), 2.42-2.46(m, 3H), 2.39(s, 3H), 2.13-2.17(m, 2H), 1.71-1.77(m, 1H), 1.59-1.63(m, 1H)10.84 (s, 1H), 10.49 (s, 1H), 7.68 (s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.21 (s, 1H), 7.15 (d, J = 8.0 Hz, 1H ), 7.08 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 7.6 Hz, 2H), 3.94-4.00 (m, 4H), 3.74-3.80 (m, 2H), 3.43-3.46 (m, 2H), 3.21-3.25 (m, 2H), 3.05-3.07 (m, 2H), 2.59 (d, J = 6.8 Hz, 2H), 2.42-2.46 (m, 3H), 2.39 (s, 3H), 2.13 -2.17 (m, 2H), 1.71-1.77 (m, 1H), 1.59-1.63 (m, 1H) 112112
Figure 112006049660803-pat00150
Figure 112006049660803-pat00150
 11.30(s, 1H), 10.50(s, 1H), 7.67(s, 1H), 7.19(s, 1H), 7.14(d, J=8.4Hz, 1H), 7.06(d, J=8.0Hz, 2H), 6.81(d, J=8.0Hz, 2H), 3.99-4.03(m, 2H), 2.85-2.98(m, 5H), 2.58(d, J=6.8Hz, 2H), 2.42(t, J=7.2Hz, 3H), 2.33(s, 3H), 2.05(br, 2H), 1.58-1.77(m, 7H) 11.30 (s, 1H), 10.50 (s, 1H), 7.67 (s, 1H), 7.19 (s, 1H), 7.14 (d, J = 8.4Hz, 1H), 7.06 (d, J = 8.0Hz, 2H ), 6.81 (d, J = 8.0 Hz, 2H), 3.99-4.03 (m, 2H), 2.85-2.98 (m, 5H), 2.58 (d, J = 6.8 Hz, 2H), 2.42 (t, J = 7.2 Hz, 3H), 2.33 (s, 3H), 2.05 (br, 2H), 1.58-1.77 (m, 7H) 113113
Figure 112006049660803-pat00151
Figure 112006049660803-pat00151
 10.56(s, 1H), 10.49(s, 1H), 7.66(s, 1H), 7.48(d, J=8.0Hz, 1H), 7.18(s, 1H), 7.08-7.12(m, 3H), 6.86(d, J=8.0Hz, 2H), 4.30(t, J=6.2Hz, 2H), 3.43(t, J=6.0Hz, 2H), 2.59(d, J=7.2Hz, 2H), 2.43-2.47(m, 5H), 2.36(s, 3H), 1.74-1.79(m, 1H), 1.56-1.61(m, 1H) 1.21(t, J= 7.2Hz, 6H)10.56 (s, 1H), 10.49 (s, 1H), 7.66 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.08-7.12 (m, 3H), 6.86 (d, J = 8.0 Hz, 2H), 4.30 (t, J = 6.2 Hz, 2H), 3.43 (t, J = 6.0 Hz, 2H), 2.59 (d, J = 7.2 Hz, 2H), 2.43-2.47 (m, 5H), 2.36 (s, 3H), 1.74-1.79 (m, 1H), 1.56-1.61 (m, 1H) 1.21 (t, J = 7.2 Hz, 6H)

실시예Example 114: {2-[4-(2- 114: {2- [4- (2- 디에틸아미노Diethylamino -- 에톡시Ethoxy )-)- 페닐Phenyl ]-에틸}-(7-] -Ethyl}-(7- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일메틸)-아민--3-ylmethyl) -amine- NN -카르보하이드록사믹 Carbohydroxamic 엑시드EXID

단계 1. [2-(4-히드록시-페닐)-에틸]-카바믹 엑시드 tert-부틸 에스터의 합성Step 1. Synthesis of [2- (4-hydroxy-phenyl) -ethyl] -carbamic acid tert-butyl ester

Figure 112006049660803-pat00152
Figure 112006049660803-pat00152

에틸아세테이트 (25 ml)용액에 티라민 (2.03 ml, 14.80 mmol)을 첨가한다. 디-tert-부틸 디카보네이트 (3.39 g, 15.5 mmol)을 상온에서 천천히 가하고, 에틸아세테이트 (30 ml)를 첨가한다. 물로 씻어주고, 묽은 시트르산 용액, 포화 소듐바이카보네이트 용액 및 포화 염화나트륨 용액으로 씻어 준 후 무수 황산 마그네슘으로 건조 후 여과한다. 감압 농축하고 잔여물을 재결정 (에틸아세테이트/페트롤늄에테르)하여 표제 화합물 (3.41 g, 97.2 %, 흰색 고체)을 얻었다.To the ethyl acetate (25 ml) solution is added tyramine (2.03 ml, 14.80 mmol). Di- tert -butyl dicarbonate (3.39 g, 15.5 mmol) is slowly added at room temperature and ethyl acetate (30 ml) is added. Wash with water, wash with dilute citric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, dry with anhydrous magnesium sulfate and filter. Concentration under reduced pressure and the residue was recrystallized (ethyl acetate / petroleum ether) to give the title compound (3.41 g, 97.2%, white solid).

1H-NMR (CDCl3, 400MHz) δ 7.01(d, J=8.4Hz, 2H), 6.78(d, J=8.4Hz, 2H), 6.31(br, 1H). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.01 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 6.31 (br, 1H).

단계 2. [2-(4-벤질옥시-페닐)-에틸]-카바믹 엑시드 tert-부틸 에스터의 합성Step 2. Synthesis of [2- (4-benzyloxy-phenyl) -ethyl] -carbamic acid tert-butyl ester

Figure 112006049660803-pat00153
Figure 112006049660803-pat00153

상기 제 1단계에서 얻은 화합물 (0.10 g, 0.43 mmol)을 디메틸포름아미드 (3 ml)에 녹인 후 벤질브로마이드 (0.06 ml, 0.51 mmol)를 첨가한다. 포타슘카보네이트 (0.18 g, 1.28 mmol)을 첨가하고 4시간 동안 교반한 후 에틸 아세테이트로 추출한다. 포화 암모늄크로라이드 용액으로 씻어 준 후 무수 황산 나트륨으로 건조 후 여과한다. 감압 농축하고 고체를 헥산으로 씻어주어 표제 화합물 (0.13 g, 93.6 %, 흰색 고체)을 얻었다.The compound obtained in the first step (0.10 g, 0.43 mmol) is dissolved in dimethylformamide (3 ml), and then benzyl bromide (0.06 ml, 0.51 mmol) is added. Potassium carbonate (0.18 g, 1.28 mmol) is added and stirred for 4 hours and then extracted with ethyl acetate. After washing with saturated ammonium chloride solution, dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure and the solid was washed with hexane to give the title compound (0.13 g, 93.6%, white solid).

1H-NMR (CDCl3, 400MHz) δ 6.91-7.45(m, 9H), 5.05(s, 2H), 4.52(br, 1H), 2.72-3.35(m, 4H), 1.43(s, 9H). 1 H-NMR (CDCl 3 , 400 MHz) δ 6.91-7.45 (m, 9H), 5.05 (s, 2H), 4.52 (br, 1H), 2.72-3.35 (m, 4H), 1.43 (s, 9H).

단계 3. 2-(4-벤질옥시-페닐)-에틸아민 하이드로클로라이드의 합성Step 3. Synthesis of 2- (4-benzyloxy-phenyl) -ethylamine hydrochloride

Figure 112006049660803-pat00154
Figure 112006049660803-pat00154

상기 제 2단계에서 얻은 화합물 (0.13 g, 0.40 mmol)을 1,4-다이옥산 (1 ml)에 녹인 후 0.7 M 염산용액 (1.1 ml, 0.80 mmol in 1,4-dioxane)을 첨가하고 12시간 동안 교반 하였다. 에틸 아세테이트를 첨가하고 여과하여 표제 화합물 (0.065 g, 61.2 %, 흰색 고체)을 얻었다.The compound obtained in step 2 (0.13 g, 0.40 mmol) was dissolved in 1,4-dioxane (1 ml), and 0.7 M hydrochloric acid solution (1.1 ml, 0.80 mmol in 1,4-dioxane) was added for 12 hours. Stirred. Ethyl acetate was added and filtered to afford the title compound (0.065 g, 61.2%, white solid).

1H-NMR (CDCl3, 400MHz) δ 7.84(br, 1H), 6.96-7.45(m, 9H), 5.08(s, 2H), 2.77-3.00(m, 4H). 1 H-NMR (CDCl 3 , 400 MHz) δ 7.84 (br, 1H), 6.96-7.45 (m, 9H), 5.08 (s, 2H), 2.77-3.00 (m, 4H).

단계 4. 3-[2-(4-벤질옥시-페닐)-에틸아미노]-메틸-7-메틸-크로멘-2-온의 합성Step 4. Synthesis of 3- [2- (4-benzyloxy-phenyl) -ethylamino] -methyl-7-methyl-chromen-2-one

Figure 112006049660803-pat00155
Figure 112006049660803-pat00155

문헌 (Scetharamaiyer Padmanabhan, Ravikumar Peri and David J. Triggle, Syn. Comm., 26(4), pp 827-831, 1996)의 방법과 같이하여 얻은 7-메틸-2-옥소-2H-크로멘-3-카발데히드 (0.38 g, 2.02 mmol)와　상기 제 3단계에서 얻은 화합물 (0.73 g, 2.83 mmol)을 메탄올 (12 ml) 와　테트라하이드로퓨란 (6 ml)녹인 후 트리에틸아민 (0.96 ml, 6.87 mmol)을 첨가 한 후 3시간 동안 상온에서 교반한다. 0℃로 온도를 낮춘 후 아세트 산 (0.41 ml, 7.07 mmol)와 소듐시아노보로하이드라이드 (0.178 g, 2.83 mmol)를 천천히 가하였다. 2시간 후 물 (0.1 ml)로　반응을 종결하고, 감압 농축하다. 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=１:1)하여 표제 화합물 (0.24 g, 29.1 %, 흰색 고체)을 얻었다.7-methyl-2-oxo-2H-chromen-3 obtained by the method of Statharamaiyer Padmanabhan, Ravikumar Peri and David J. Triggle, Syn. Comm. , 26 (4) , pp 827-831, 1996 -Carbaldehyde (0.38 g, 2.02 mmol) and the compound obtained in the third step (0.73 g, 2.83 mmol) were dissolved in methanol (12 ml) and tetrahydrofuran (6 ml), followed by triethylamine (0.96 ml, 6.87 mmol). ) Is added and stirred at room temperature for 3 hours. After lowering the temperature to 0 ° C., acetic acid (0.41 ml, 7.07 mmol) and sodium cyanoborohydride (0.178 g, 2.83 mmol) were slowly added. After 2 hours the reaction is terminated with water (0.1 ml) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (0.24 g, 29.1%, white solid).

1H-NMR (CDCl3, 400MHz) δ 6.79-7.79(m, 13H), 5.05(s, 2H), 4.57(m, 1H), 2.78-3.54(m, 6H), 2.28(s, 3H) 1 H-NMR (CDCl 3 , 400 MHz) δ 6.79-7.79 (m, 13H), 5.05 (s, 2H), 4.57 (m, 1H), 2.78-3.54 (m, 6H), 2.28 (s, 3H)

단계 5. [2-(4-벤질옥시-페닐)-에틸]-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-카바믹 엑시드 tert-부틸 에스터의 합성Step 5. Synthesis of [2- (4-benzyloxy-phenyl) -ethyl]-(7-methyl-2-oxo-2H-chromen-3-ylmethyl) -carbamic acid tert-butyl ester

Figure 112006049660803-pat00156
Figure 112006049660803-pat00156

상기 제 4단계에서 얻은 화합물 (0.18 g, 0.45 mmol)과 디-t-부틸디카보네이트 (0.15 g, 0.67 mmol)을 메틸렌클로라이드 (5 ml)에 녹인 후 디메틸아미노피리딘 (0.14 ml, 1.12 mmol)을 첨가한 후 12시간 동안 상온에서 교반한다. 메틸렌클로라이드로 추출하고 황산 나트륨으로 건조 후 여과한다. 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=3:1)하여 표제 화합물 (0.20 g, 90.6 %)을 얻었다.The compound obtained in step 4 (0.18 g, 0.45 mmol) and di-t-butyldicarbonate (0.15 g, 0.67 mmol) were dissolved in methylene chloride (5 ml), followed by dimethylaminopyridine (0.14 ml, 1.12 mmol). After addition, the mixture is stirred at room temperature for 12 hours. Extract with methylene chloride, dry over sodium sulfate and filter. Concentration under reduced pressure and the residue was subjected to column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (0.20 g, 90.6%).

1H-NMR (CDCl3, 400MHz) δ 6.79-7.79(m, 13H), 5.06(s, 2H), 4.55(m, 1H), 3.52(q, J=6.4Hz, 2H), 3.33(s, 2H), 2.82(t, J=6.4Hz, 2H), 2.31(s, 3H), 1.49(s, 9H). 1 H-NMR (CDCl 3 , 400 MHz) δ 6.79-7.79 (m, 13H), 5.06 (s, 2H), 4.55 (m, 1H), 3.52 (q, J = 6.4 Hz, 2H), 3.33 (s, 2H), 2.82 (t, J = 6.4 Hz, 2H), 2.31 (s, 3H), 1.49 (s, 9H).

단계 6. [2-(4-히드록시-페닐)-에틸]-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-카바믹 엑시드 tert-부틸 에스터의 합성Step 6. Synthesis of [2- (4-hydroxy-phenyl) -ethyl]-(7-methyl-2-oxo-2H-chromen-3-ylmethyl) -carbamic acid tert-butyl ester

Figure 112006049660803-pat00157
Figure 112006049660803-pat00157

상기 제 5단계에서 얻은 화합물 (0.20 g, 0.40 mmol)과 팔라듐 챠콜 (0.03 g, 15 % w/w)을 에틸아세테이트 (20 ml)에 녹인 후 수소 하에서 48시간 동안 교반한다. 여과 후 감압 농축하여 표제 화합물 (0.17 g, 100 %)을 얻었다.The compound (0.20 g, 0.40 mmol) and palladium charcoal (0.03 g, 15% w / w) obtained in the fifth step are dissolved in ethyl acetate (20 ml), and then stirred for 48 hours under hydrogen. Filtration and concentration under reduced pressure gave the title compound (0.17 g, 100%).

1H-NMR (CDCl3, 400MHz) δ 6.77-7.79(m, 8H), 6.40(br, 1H), 3.81(q, J=6.4Hz, 2H), 3.63(s, 2H), 2.80(t, J=6.4Hz, 2H), 2.32(s, 3H), 1.50(s, 9H). 1 H-NMR (CDCl 3 , 400 MHz) δ 6.77-7.79 (m, 8H), 6.40 (br, 1H), 3.81 (q, J = 6.4 Hz, 2H), 3.63 (s, 2H), 2.80 (t, J = 6.4 Hz, 2H), 2.32 (s, 3H), 1.50 (s, 9H).

단계 7. 2-[4-(2-디에틸아미노-에톡시)-페닐]-에틸-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-카바믹 엑시드 tert-부틸 에스터의 합성Step 7. 2- [4- (2-Diethylamino-ethoxy) -phenyl] -ethyl- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -carbamic acid tert-butyl Synthesis of esters

Figure 112006049660803-pat00158
Figure 112006049660803-pat00158

상기 제 6단계에서 얻은 화합물 (100.4 mg, 0.25 mmol), (2-클로로-에틸)-디에틸-아민 하이드로클로라이드 (63.3 mg, 0.37 mmol), 세슘카보네이트 (239.7 mg, 0.74 mmol) 및 요오드화나트륨 (55.1 mg, 0.37 mmol)을 디메틸포름아미드 (3 ml)에 녹인 후 80 ℃에서 4시간 동안 교반한다. 에틸 아세테이트로 추출하고 여과 후 황산나트륨으로 건조 후 여과한다. 감압 농축하고 잔여물을 다음 반응과정에 직접 사용한다.Compound (100.4 mg, 0.25 mmol), (2-chloro-ethyl) -diethyl-amine hydrochloride (63.3 mg, 0.37 mmol) obtained in the sixth step, cesium carbonate (239.7 mg, 0.74 mmol) and sodium iodide ( 55.1 mg, 0.37 mmol) is dissolved in dimethylformamide (3 ml) and stirred at 80 ° C. for 4 hours. Extract with ethyl acetate, filter, dry over sodium sulfate and filter. Concentrate under reduced pressure and use the residue directly in the next reaction.

단계 8. 3-({2-[4-(2-디에틸아미노-에톡시)-페닐]-에틸아미노}-메틸)-7-메틸-크로멘-2-온의 합성Step 8. Synthesis of 3-({2- [4- (2-Diethylamino-ethoxy) -phenyl] -ethylamino} -methyl) -7-methyl-chromen-2-one

Figure 112006049660803-pat00159
Figure 112006049660803-pat00159

상기 제 7단계에서 얻은 화합물 (47.4 mg, 0.09 mmol)을 1,4-다이옥산 (1 ml)에 녹인 후 4.0 M 염산용액 (0.23 ml, 0.93 mmol in 1,4-dioxane)을 첨가하고 12시간 동안 교반 하였다. 2N 수산화나트륨 수용액으로 염기성(pH=8)이 되게 한 후 에틸아세테이트로 추출한다. 황산나트륨으로 건조 후 여과하고 감압 농축하여 표제 화합물 (23.2 mg, 60.9 %)을 얻었다.The compound obtained in step 7 (47.4 mg, 0.09 mmol) was dissolved in 1,4-dioxane (1 ml), and 4.0 M hydrochloric acid solution (0.23 ml, 0.93 mmol in 1,4-dioxane) was added for 12 hours. Stirred. The mixture was made basic (pH = 8) with 2N aqueous sodium hydroxide solution, and extracted with ethyl acetate. After drying over sodium sulfate, filtration and concentration under reduced pressure gave the title compound (23.2 mg, 60.9%).

1H-NMR (CDCl3, 400MHz) δ 7.51(s, 1H), 7.31(d, J=7.7Hz, 1H), 7.07-7.27(m, 4H), 6.84(d, J=8.4Hz, 2H), 4.04(t, J=6.4Hz, 2H), 3.70(s, 2H), 2.62-2.90(m, 10H), 2.44(s, 3H), 1.08(t, J=6.4Hz, 6H) 1 H-NMR (CDCl 3 , 400 MHz) δ 7.51 (s, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.07-7.27 (m, 4H), 6.84 (d, J = 8.4 Hz, 2H) , 4.04 (t, J = 6.4 Hz, 2H), 3.70 (s, 2H), 2.62-2.90 (m, 10H), 2.44 (s, 3H), 1.08 (t, J = 6.4 Hz, 6H)

단계 9. {2-[4-(2-디에틸아미노-에톡시)-페닐]-에틸}-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-아민-N-카보하이드록사믹 엑시드의 합성Step 9. {2- [4- (2-Diethylamino-ethoxy) -phenyl] -ethyl}-(7-methyl-2-oxo-2H-chromen-3-ylmethyl) -amine-N- Synthesis of Carbohydroxamic Acid

Figure 112006049660803-pat00160
Figure 112006049660803-pat00160

상기 제 8단계에서 얻은 화합물 (23.2 mg, 0.06 mmol)을 피리딘 (1 ml)에 녹인 후 하이드록시-카바믹 엑시드 페닐 에스터 (10.4 mg, 0.07 mmol)을 첨가하고 40℃에서 2일 동안 교반 하였다. 감압 농축하여 얻은 잔여물에 에틸아세테이트를 가하고 여과하여 표제 화합물 (9.2 mg, 34.6 %)을 얻었다.The compound obtained in step 8 (23.2 mg, 0.06 mmol) was dissolved in pyridine (1 ml), and then hydroxy-carbamic acid phenyl ester (10.4 mg, 0.07 mmol) was added and stirred at 40 ° C. for 2 days. Ethyl acetate was added to the residue obtained by concentration under reduced pressure, followed by filtration to obtain the title compound (9.2 mg, 34.6%).

1H-NMR (CDCl3, 400MHz) δ 9.09(br, 1H), 8.17(br, 1H), 6.87-7.561(m, 8H), 2.20-4.13(m, 20H). 1 H-NMR (CDCl 3 , 400 MHz) δ 9.09 (br, 1H), 8.17 (br, 1H), 6.87-7.561 (m, 8H), 2.20-4.13 (m, 20H).

실시예Example 115:  115: NN -히드록시-2,2-디메틸-3-(6--Hydroxy-2,2-dimethyl-3- (6- 메틸methyl -옥소-2H--Oxo-2H- 크로멘Chromen -3-일)--3 days)- 프로피온아미드Propionamide

단계 1. 2,2-디메틸-펜탄디오익 엑시드 디메틸 에스터의 합성Step 1. Synthesis of 2,2-dimethyl-pentanedioic acid dimethyl ester

Figure 112006049660803-pat00161
Figure 112006049660803-pat00161

2,2-디메틸-펜탄디오익 엑시드 (500 mg, 1.12 mmol)를 메탄올 (15 ml)에 용해시키고 촉매량의 황산을 적가 하여 12시간 환류하였다. 종결된 반응 혼합물의 용매를 감압 농축하여 제거한 다음 에틸아세테이트에 용해시키고 유기 용매층을 포화 탄산나트륨으로 씻어준 후 무수 황산나트륨으로 건조하여 용매를 감압 농축하여 표제화합물 (510 mg, 반응수율: 86.8 %, 무색액체)을 얻었다. 2,2-dimethyl-pentanedioic acid (500 mg, 1.12 mmol) was dissolved in methanol (15 ml) and refluxed for 12 hours with the addition of a catalytic amount of sulfuric acid dropwise. The solvent of the reaction mixture was concentrated under reduced pressure, and then removed. The solvent was dissolved in ethyl acetate. The organic solvent layer was washed with saturated sodium carbonate, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The title compound (510 mg, reaction yield: 86.8%, colorless) Liquid).

1H NMR(400Mhz, CDCl3); δ 3.67(s, 6H), 2.26-2.30(m, 2H), 1.86-1.90(m, 2H), 1.19(s, 6H) 1 H NMR (400 Mhz, CDCl 3 ); δ 3.67 (s, 6H), 2.26-2.30 (m, 2H), 1.86-1.90 (m, 2H), 1.19 (s, 6H)

단계 2. 2,2-디메틸-펜타노익 엑시드 5-(2-포르밀-4-메틸-페닐) 에스터-1-메틸 에스터의 합성Step 2. Synthesis of 2,2-dimethyl-pentanoic acid 5- (2-formyl-4-methyl-phenyl) ester-1-methyl ester

Figure 112006049660803-pat00162
Figure 112006049660803-pat00162

2,2-디메틸-펜탄디오익 엑시드 디메틸 에스터 (500 mg, 3.72 mmol)를 메탄올(10 ml)에 용해시키고 포타슘히드록시드 (200 mg, 3.7 mmol)를 첨가하여 상온에서 16시간 동안 교반하였다. 종결된 반응 혼합물을 2N HCl으로 산성화 (pH=3)하고 에틸아세테이트로 추출을 한 후 무수 황산나트륨으로 건조하여 용매를 감압 농축한후 디클로로메탄 (20 ml)에 녹인후 옥살릴클로라이드 (0.75 ml, 8.6 mmol)을 천천히 적가한 후 상온에서 14시간 동안 교반하였다. 반응이 종결된후 반응물을 감압농축한 다음 다시 디클로로메탄 (20 ml)에 녹인후 2-히드록시-5-메틸 벤즈알데히드 (250 mg, 1.83 mmol)과 트리에틸아민 (051 ml, 3.7 mmol)을 첨가한 후 상온에서 14시간동안 교반하였다. 반응이 종결된 후 반응물을 1 N 염산용액 (15 ml)과 물 (15 ml)로 씻어주었고, 무수황산나트륨으로 건조하여 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=8:1)하여 표제 화합물 (350 mg, 반응수율: 45.1 %, 무색 액체)을 얻었다2,2-Dimethyl-pentanedioic acid dimethyl ester (500 mg, 3.72 mmol) was dissolved in methanol (10 ml) and potassium hydroxide (200 mg, 3.7 mmol) was added and stirred at room temperature for 16 hours. The resulting reaction mixture was acidified with 2 N HCl (pH = 3), extracted with ethyl acetate, dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, dissolved in dichloromethane (20 ml) and oxalyl chloride (0.75 ml, 8.6 mmol) was slowly added dropwise and stirred at room temperature for 14 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and then dissolved in dichloromethane (20 ml), followed by addition of 2-hydroxy-5-methyl benzaldehyde (250 mg, 1.83 mmol) and triethylamine (051 ml, 3.7 mmol). After stirring at room temperature for 14 hours. After the reaction was completed, the reaction was washed with 1 N hydrochloric acid solution (15 ml) and water (15 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography (hexane: ethyl acetate = 8: 1). The title compound (350 mg, reaction yield: 45.1%, colorless liquid) was obtained.

1H NMR(400Mhz, CDCl3); δ 10.06(s, 1H), 7.67(s, 1H), 7.42(d, J=8.4Hz, 1H), 7.06(d, J=8.4Hz, H), 3.70(s, 3H), 2.62-2.66(m, 2H), 2.41(s, 3H), 2.01-2.05(m, 2H), 1.26(s, 6H) 1 H NMR (400 Mhz, CDCl 3 ); δ 10.06 (s, 1H), 7.67 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, H), 3.70 (s, 3H), 2.62-2.66 ( m, 2H), 2.41 (s, 3H), 2.01-2.05 (m, 2H), 1.26 (s, 6H)

단계 3. 2,2-디메틸-3-(6-메틸-2-옥소-2H-크로멘-3-일)-프로피오닉 엑시드 메틸 에스터의 합성Step 3. Synthesis of 2,2-dimethyl-3- (6-methyl-2-oxo-2H-chromen-3-yl) -propionic acid methyl ester

Figure 112006049660803-pat00163
Figure 112006049660803-pat00163

6-(2-포르밀-4-메틸-페닐)-2,2-디메틸-5-옥소-헥사노익 엑시드 메틸 에스터 (350 mg, 1.19 mmol)를 톨루엔 (10 ml)에 용해시키고 DBU (0.27 ml, 1.78 mmol)를 넣었다. 6시간동안 환류시킨 후 용매를 감압 농축하여 용매를 제거하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=4:1)하여 표제화합물 (115 mg, 반응수율; 35.3 %, 무색액체)을 얻었다.6- (2-formyl-4-methyl-phenyl) -2,2-dimethyl-5-oxo-hexanoic acid methyl ester (350 mg, 1.19 mmol) is dissolved in toluene (10 ml) and DBU (0.27 ml , 1.78 mmol) was added. After refluxing for 6 hours, the solvent was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (115 mg, reaction yield; 35.3%, colorless liquid).

1H NMR(400Mhz, CDCl3); δ 7.44(s, 1H), 7.28(d, J=8.4Hz, 1H), 7.21(s, 1H), 7.19(d, J=8.4Hz, H), 3.68(s, 3H), 2.86(s, 2H), 2.39(s, 3H), 1.26(s, 6H) 1 H NMR (400 Mhz, CDCl 3 ); δ 7.44 (s, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.21 (s, 1H), 7.19 (d, J = 8.4 Hz, H), 3.68 (s, 3H), 2.86 (s, 2H), 2.39 (s, 3H), 1.26 (s, 6H)

단계 4. N-히드록시-2,2-디메틸-3-(6-메틸-옥소-2H-크로멘-3-일)-프로피온아미드의 합성Step 4. Synthesis of N-hydroxy-2,2-dimethyl-3- (6-methyl-oxo-2H-chromen-3-yl) -propionamide

Figure 112006049660803-pat00164
Figure 112006049660803-pat00164

2,2-디메틸-3-(7-메틸-3-옥소-3,4-디하이드로-나프탈렌-2-일)-프로피오닉 엑시드 메틸 에스터 (115 mg, 0.42 mmol)를 메탄올 (5 ml)에 녹인후 1 M 수산화나트륨 수용액 10 ml를 넣고 실온에서 2시간 동안 교반하였다. 반응이 종결된 후 2 M HCl으로 pH=3으로 산성화한 후 에틸아세테이트로 추출한 후 무수 황산나트륨으로 건조시키고 용매를 감압 농축한 후 얻은 잔류물을 질소 하 실온에서 디클로로메탄 (5 ml)에 녹인 후 에틸클로로포르메이트 (45 mg, 0.42 mmol)를 천천히 넣어준 다음 실온에서 2시간 동안 교반하였다. 반응이 완결되면 정제 과정 없이 반응용액에 트리에틸아민 (0.1 ml, 0.76 mmol) NH2OHㆍHCl(52.8 mg, 0.76 mmol)을 넣어주고 실온에서 3시간 교반하였다. 반응이 종결된 후 포화 암모늄클로라이드 용액으로 씻어준 다음 유기 용매 층을 무수 황산나트륨으로 건조한 다음 용매를 감압 농축하였다. 에테르로 재결정하여 표제화합물 (65 mg, 반응수율: 56.5 %, 흰색고체)을 얻었다.2,2-dimethyl-3- (7-methyl-3-oxo-3,4-dihydro-naphthalen-2-yl) -propionic acid methyl ester (115 mg, 0.42 mmol) in methanol (5 ml) After melting, 10 ml of 1 M aqueous sodium hydroxide solution was added thereto, and the resultant was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was acidified to pH = 3 with 2 M HCl, extracted with ethyl acetate, dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (5 ml) at room temperature under nitrogen. Chloroformate (45 mg, 0.42 mmol) was added slowly and stirred at room temperature for 2 hours. Upon completion of the reaction, triethylamine (0.1 ml, 0.76 mmol) NH 2 OH.HCl (52.8 mg, 0.76 mmol) was added to the reaction solution without purification. The mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was washed with saturated ammonium chloride solution, the organic solvent layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Recrystallization with ether gave the title compound (65 mg, reaction yield: 56.5%, white solid).

1H NMR(400MHz, DMSO-d3); δ 10.39(s, 1H), 8.64(s, 1H), 7.63(s, 1H), 7.42(s, 1H), 7.38(d, J=8.4Hz, 1H), 7.26(d, J=8.4Hz, 1H), 2.69(s, 2H), 2.35(s, 3H), 1.08(s, 6H) 1 H NMR (400 MHz, DMSO-d 3 ); δ 10.39 (s, 1H), 8.64 (s, 1H), 7.63 (s, 1H), 7.42 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 2.69 (s, 2H), 2.35 (s, 3H), 1.08 (s, 6H)

실시예Example 116:  116: NN -히드록시-2-(7-Hydroxy-2- (7- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3--3- 일메틸Methyl )-4-[4-(4-피페리딘-1-일-부틸)-페닐]-부틸아미드 ) -4- [4- (4-piperidin-1-yl-butyl) -phenyl] -butylamide 하이드로크로라이드Hydrochloride

단계 1: Step 1: 메틸methyl 2-{4-[4-( 2- {4- [4- ( terttert -- 부틸디메틸실라닐옥시Butyldimethylsilanyloxy )부틸]) Butyl] 페닐Phenyl } 아세테이트의 합성} Synthesis of Acetate

Figure 112006049660803-pat00165
Figure 112006049660803-pat00165

메틸2-[4-(4-히드록시부틸)페닐]아세테이트 (J. Med. Chem., 40, pp2609-2625, 1997 ; 100mg, 0.320mmol)과 tert-부틸디메틸실릴크로아이드 (72.3 mg, 0.480 mmol), 이미다졸 (21.8 mg, 0.320 mmol)을 건조된 THF (4 ml)에 용해시킨 후 상온에서 24시간 동안 반응하였다 반응 혼합물을 찬 얼음물로 종결하고 에틸아세테이트로 추출하였다. 용매를 무수 황산마그네슘으로 건조하여 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=7:1)하여 표제 화합물 (107.7 mg 반응수율: 99.9 %, 무색 액체)을 얻었다.Methyl 2- [4- (4-hydroxybutyl) phenyl] acetate ( J. Med. Chem., 40 , pp 2609-2625, 1997; 100 mg, 0.320 mmol) and tert -butyldimethylsilyl croid (72.3 mg, 0.480 mmol) and imidazole (21.8 mg, 0.320 mmol) were dissolved in dried THF (4 ml) and reacted at room temperature for 24 hours. The reaction mixture was terminated with cold ice water and extracted with ethyl acetate. The solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (hexane: ethyl acetate = 7: 1) to obtain the title compound (107.7 mg reaction yield: 99.9%, colorless liquid).

1H NMR(400MHz, CDCl3): δ 7.19(d, J=8.0Hz, 2H), 7.14(d, J=8.0Hz, 2H), 3.69(s, 3H), 3.61(m, 3H), 2.61(t, 2H), 1.64(m, 2H), 1.55(m, 2H), 0.92(s, 9H), 0.05(s, 6H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.19 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 3.69 (s, 3H), 3.61 (m, 3H), 2.61 (t, 2H), 1.64 (m, 2H), 1.55 (m, 2H), 0.92 (s, 9H), 0.05 (s, 6H).

단계 2: 2-{4-[4-(Step 2: 2- {4- [4- ( tert-tert- 부틸-디메틸실라닐옥시)-부틸]-페닐}-에틴올의 합성Synthesis of Butyl-dimethylsilanyloxy) -butyl] -phenyl} -ethynol

Figure 112006049660803-pat00166
Figure 112006049660803-pat00166

상기 제 1단계에서 제조한 화합물 (107.7 mg, 0.320 mmol)을 건조된 THF (4 ml)에 용해시킨 후 온도를 0 ℃으로 낮춘 후 리튬알루미늄하이드라이드 (12.1 mg, 0.320 mmol)을 천천히 첨가 후 상온에서 30분간 반응하였다. 반응혼합물에 0.012 ml 의 물과 0.012 ml 의 5 % 메탄올과 0.036 ml의 물을 순서대로 첨가하여 반응을 종결한 후 반응 혼합물을 셀라이트 필터를 통과시킨 후 용매를 감압 농축하고 정제과정 없이 표제 화합물 (373.7 mg, 반응 수율: 99.9 %, 무색 액체)을 얻었다.After dissolving the compound prepared in step 1 (107.7 mg, 0.320 mmol) in dried THF (4 ml) and lowering the temperature to 0 ℃, slowly adding lithium aluminum hydride (12.1 mg, 0.320 mmol) to room temperature Reaction was carried out for 30 minutes. After completion of the reaction by adding 0.012 ml of water, 0.012 ml of 5% methanol and 0.036 ml of water to the reaction mixture in order, the reaction mixture was passed through a celite filter, the solvent was concentrated under reduced pressure and the title compound ( 373.7 mg, reaction yield: 99.9%, colorless liquid).

1H NMR(400MHz, CDCl3): δ 7.14(s, 4H), 3.83(t, 2H), 3.63(t, 2H), 2.60(t, 2H), 1.67(m, 3H), 1.57(m, 2H), 0.92(s, 9H), 0.06(s, 6H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.14 (s, 4H), 3.83 (t, 2H), 3.63 (t, 2H), 2.60 (t, 2H), 1.67 (m, 3H), 1.57 (m, 2H), 0.92 (s, 9H), 0.06 (s, 6H).

단계 3: 메탄술포닉 엑시드 2-{4-(Step 3: methanesulphonic acid 2- {4- ( terttert -부틸-디메틸-실라닐옥시)-부틸}-페닐-에틸 에스터의 합성Synthesis of -butyl-dimethyl-silanyloxy) -butyl} -phenyl-ethyl ester

Figure 112006049660803-pat00167
Figure 112006049660803-pat00167

상기 제 2단계에서 제조한 화합물 (88 mg, 0.327 mmol)을 건조된 디클로로메탄 (2 ml)에 용해시킨 후 온도를 0 ℃으로 낮춘 후 메탄술포닐크로라이드 (0.025 ml, 0.327 mmol), 트리에틸아민 (0.046 ml, 0.327 mmol)을 첨가 후 동온에서 1시간 동안 반응하였다. 반응 혼합물을 찬 얼음물로 종결하고 에틸아세테이트로 추출하였다. 용매를 무수 황산마그네슘으로 건조하여 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=3:1)하여 표제 화합물 (110 mg 반응수율: 98.5 %, 무색 액체)을 얻었다. The compound (88 mg, 0.327 mmol) prepared in the second step was dissolved in dried dichloromethane (2 ml), and then the temperature was lowered to 0 ° C. and then methanesulfonyl chloride (0.025 ml, 0.327 mmol) and triethyl After adding amine (0.046 ml, 0.327 mmol), the reaction was carried out at room temperature for 1 hour. The reaction mixture was terminated with cold ice water and extracted with ethyl acetate. The solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (110 mg reaction yield: 98.5%, colorless liquid).

1H NMR(400MHz, CDCl3): δ 7.13(s, 4H), 4.37(t, 2H), 3.63(t, 2H), 3.00(t, 2H), 2.81(s, 3H), 2.59(t, 2H), 1.61(m, 3H), 1.52(m, 2H), 0.88(s, 9H), 0.06(s, 6H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.13 (s, 4H), 4.37 (t, 2H), 3.63 (t, 2H), 3.00 (t, 2H), 2.81 (s, 3H), 2.59 (t, 2H), 1.61 (m, 3H), 1.52 (m, 2H), 0.88 (s, 9H), 0.06 (s, 6H).

단계 4: 2-{2-[4-(3-히드록시프로필)-페닐]-에틸}-말로닉 엑시드 디에틸 에스터의 합성Step 4: Synthesis of 2- {2- [4- (3-hydroxypropyl) -phenyl] -ethyl} -malonic acid diethyl ester

Figure 112006049660803-pat00168
Figure 112006049660803-pat00168

상기 제 3단계에서 제조한 화합물 (110 mg, 0.2845 mmol)을 건조된 THF (2 ml)에 용해시킨 후 디에틸말로네이트 (0.052 ml, 0.341 mmol), 탄산칼륨 (47.2 mg, 0.341 mmol)을 첨가 후 70 ℃에서 24시간 동안 반응하였다. 반응 혼합물을 찬 얼음물로 종결하고 에틸아세테이트로 추출하였다. 용매를 무수 황산마그네슘으로 건조하여 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=15:1)하여 표제 화합물 (63.1 mg 반응수율: 51.0 %, 무색 액체)을 얻었다. The compound prepared in step 3 (110 mg, 0.2845 mmol) was dissolved in dried THF (2 ml), and then diethylmalonate (0.052 ml, 0.341 mmol) and potassium carbonate (47.2 mg, 0.341 mmol) were added. After reacting at 70 ℃ for 24 hours. The reaction mixture was terminated with cold ice water and extracted with ethyl acetate. The solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (hexane: ethyl acetate = 15: 1) to obtain the title compound (63.1 mg reaction yield: 51.0%, colorless liquid).

1H NMR(400MHz, CDCl3): δ 7.12(d, J=2.8Hz, 2H), 7.09(d, J=2.8Hz, 2H), 4.19(m, 4H), 3.71(m, 2H), 3.67(m, 2H), 3.03(m, 2H), 2.59(m, 2H), 1.56-1.75(m, 5H), 1.25(m, 6H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.12 (d, J = 2.8 Hz, 2H), 7.09 (d, J = 2.8 Hz, 2H), 4.19 (m, 4H), 3.71 (m, 2H), 3.67 (m, 2H), 3.03 (m, 2H), 2.59 (m, 2H), 1.56-1.75 (m, 5H), 1.25 (m, 6H).

단계 5: 2-(2-{4-[3-(Step 5: 2- (2- {4- [3- ( terttert -부틸-디메틸-실라닐옥시)-프로필]-페닐}-에틸)-말로닉 엑시드 디에틸 에스터의 합성Synthesis of -butyl-dimethyl-silanyloxy) -propyl] -phenyl} -ethyl) -malonic acid diethyl ester

Figure 112006049660803-pat00169
Figure 112006049660803-pat00169

상기 4단계에서 제조한 화합물 (63.1 mg, 0.187 mmol)과 tert-부틸디메틸실릴 크로라이드 (32.1 mg, 0.210 mmol), 이미다졸 (14.3 mg, 0.210 mmol)을 건조된 THF (2 ml)에 용해시킨 후 상온에서 48시간 동안 반응하였다 반응 혼합물을 찬 얼음물로 종결하고 에틸아세테이트로 추출하였다. 용매를 무수 황산마그네슘으로 건조하여 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=8:1)하여 표제 화합물 (74.1 mg 반응수율: 92.8 %, 무색 액체)을 얻었다.The compound prepared in step 4 (63.1 mg, 0.187 mmol), tert -butyldimethylsilyl chloride (32.1 mg, 0.210 mmol) and imidazole (14.3 mg, 0.210 mmol) were dissolved in dried THF (2 ml). After reacting for 48 hours at room temperature The reaction mixture was terminated with cold ice water and extracted with ethyl acetate. The solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (hexane: ethyl acetate = 8: 1) to obtain the title compound (74.1 mg reaction yield: 92.8%, colorless liquid).

1H NMR(400MHz, CDCl3): δ 7.11(d, J=2.8Hz, 2H), 7.09(d, J=2.8Hz, 2H), 4.16(m, 4H), 3.71(m, 2H), 3.64(m, 2H), 3.03(m, 2H), 2.57(m, 2H), 1.57-1.75(m, 5H), 1.25(m, 6H), 0.88(s, 9H), 0.03(s, 6H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.11 (d, J = 2.8 Hz, 2H), 7.09 (d, J = 2.8 Hz, 2H), 4.16 (m, 4H), 3.71 (m, 2H), 3.64 (m, 2H), 3.03 (m, 2H), 2.57 (m, 2H), 1.57-1.75 (m, 5H), 1.25 (m, 6H), 0.88 (s, 9H), 0.03 (s, 6H).

단계 6: 2-(2-{4-[3-(Step 6: 2- (2- {4- [3- ( tert-tert- 부틸-디메틸-실라닐옥시)-프로필]-페닐}-에틸)-말로닉 엑시드 모노에틸 에스터의 합성 Synthesis of Butyl-dimethyl-silanyloxy) -propyl] -phenyl} -ethyl) -malonic acid monoethyl ester

Figure 112006049660803-pat00170
Figure 112006049660803-pat00170

상기 제 5단계와 같은 방법으로 제조한 화합물 (1.2 g, 2.760 mmol)을 에탄올 (25 ml)에 용해시키고 온도를 0 ℃로 낮춘 다음 에탄올 (5 ml)에 용해시킨 수산화나트륨 (160 mg, 2.760 mmol)을 천천히 첨가시킨 후 상온에서 36시간 동안 반응하였다. 반응 혼합물을 찬 얼음물로 낮추고 1N 염산 수용액으로 중화시킨 다음 에틸아세테이트로 추출하였다. 용매를 무수 황산마그네슘으로 건조하고 감압 농축하여 잔여물을 건조하여 표제 화합물 (710 mg, 반응 수율: 63.4 %, 흰 고체)을 얻었다. Sodium hydroxide (160 mg, 2.760 mmol) dissolved in ethanol (25 ml) and dissolved in ethanol (5 ml) after dissolving the compound (1.2 g, 2.760 mmol) prepared in the same manner as in the fifth step. ) Was slowly added and reacted at room temperature for 36 hours. Lowering the reaction mixture with cold ice water and was neutralized with 1 N hydrochloric acid solution and extracted with ethyl acetate. The solvent was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to dry the residue to give the title compound (710 mg, reaction yield: 63.4%, white solid).

1H NMR(400MHz, CDCl3): δ 7.14(d, J=2.8Hz, 2H), 7.11(d, J=2.8Hz, 2H), 4.16(q, 2H), 3.71(m, 2H), 3.64(m, 2H), 3.03(m, 2H), 2.57(m, 2H), 1.60-1.76(m, 5H), 1.20(t, 3H), 0.89(s, 9H), 0.06(s, 6H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.14 (d, J = 2.8 Hz, 2H), 7.11 (d, J = 2.8 Hz, 2H), 4.16 (q, 2H), 3.71 (m, 2H), 3.64 (m, 2H), 3.03 (m, 2H), 2.57 (m, 2H), 1.60-1.76 (m, 5H), 1.20 (t, 3H), 0.89 (s, 9H), 0.06 (s, 6H).

단계 7: 에틸 4-{4-[3-(Step 7: ethyl 4- {4- [3- ( terttert -부틸-디메틸-실라닐옥시)-프로필]-페닐}-2-메틸렌 부티릭 엑시드 에틸 에스터의 합성-Butyl-dimethyl-silanyloxy) -propyl] -phenyl} -2-methylene butyric acid ethyl ester

Figure 112006049660803-pat00171
Figure 112006049660803-pat00171

상기 제 6단계에서 제조한 화합물 (710 mg, 1.746 mmol)을 디에틸아민 (0.199 ml, 1.920 mmol) 용해시킨 후 온도를 0 ℃로 낮춘 다음 37 % 포름아미드수용액 0.2 ml 첨가 후 상온에서 11시간 동안 반응하였다 반응 혼합물을 찬 얼음물로 종결하고 에틸아세테이트로 추출 후 포화 중탄산나트륨으로 유기층을 씻어준다. 용매를 무수 황산마그네슘으로 건조하여 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=4:1)하여 표제 화합물 (500.0 mg 반응수율: 73.3 %, 무색 액체)을 얻었다.After dissolving the compound (710 mg, 1.746 mmol) prepared in step 6 of diethylamine (0.199 ml, 1.920 mmol), the temperature was lowered to 0 ° C., followed by addition of 0.2 ml of aqueous 37% formamide solution for 11 hours at room temperature. The reaction mixture was terminated with cold ice water, extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate. The solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (500.0 mg reaction yield: 73.3%, colorless liquid).

1H NMR(400MHz, CDCl3): δ 7.12(d, J=6.8Hz, 2H), 7.09(d, J=6.8Hz, 2H), 6.15(s, 1H), 5.43(s, 1H), 4.16(q, 2H), 3.78(m, 2H), 3.64(m, 2H), 3.03(m, 2H), 2.45(m, 2H), 1.70-1.64(m, 5H), 1.20(t, 3H), 0.88(s, 9H), 0.04(s, 6H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.12 (d, J = 6.8 Hz, 2H), 7.09 (d, J = 6.8 Hz, 2H), 6.15 (s, 1H), 5.43 (s, 1H), 4.16 (q, 2H), 3.78 (m, 2H), 3.64 (m, 2H), 3.03 (m, 2H), 2.45 (m, 2H), 1.70-1.64 (m, 5H), 1.20 (t, 3H), 0.88 (s, 9 H), 0.04 (s, 6 H).

단계 8: 2-(2-{4-[4-(Step 8: 2- (2- {4- [4- ( terttert -부틸-디메틸-실라닐옥시)-부틸]-페닐}-에틸)-4-(디에톡시-포스포릴)-펜타디오익 엑시드 디에틸 에스터의 합성Synthesis of -butyl-dimethyl-silanyloxy) -butyl] -phenyl} -ethyl) -4- (diethoxy-phosphoryl) -pentadioic acid diethyl ester

Figure 112006049660803-pat00172
Figure 112006049660803-pat00172

트리에틸포스포노아세테이트 (1.1 ml, 3.840 mmol)을 건조된 THF (25 ml)에 용해시키고 0 ℃로 온도를 낮춘 후 60 % 소듐하이드라이드 (154 mg, 3.840 mmol)을 천천히 넣어 1시간 동안 교반하였다. 반응 혼합물에 상기 제 7단계에서 제조한 화합물 (500 mg, 1.280 mmol)을 건조된 THF (3 ml)에 용해시켜 넣고 상온에서 24시간 동안 반응하였다. 찬 얼음물로 반응을 종결하고 염화암모늄 수용액으로 씻은 다음 에틸아세테이트로 추출하였다. 용매를 무수 황산마그네슘으로 건조하여 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=1:1)하여 표제 화합물 (580 mg, 반응 수율: 63.2 %, 무색 액체)을 얻었다.Triethylphosphonoacetate (1.1 ml, 3.840 mmol) was dissolved in dried THF (25 ml), the temperature was lowered to 0 ° C., and 60% sodium hydride (154 mg, 3.840 mmol) was slowly added thereto and stirred for 1 hour. . In the reaction mixture, the compound (500 mg, 1.280 mmol) prepared in step 7 was dissolved in dried THF (3 ml) and reacted at room temperature for 24 hours. The reaction was terminated with cold ice water, washed with aqueous ammonium chloride solution and extracted with ethyl acetate. The solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound (580 mg, reaction yield: 63.2%, colorless liquid).

1H NMR(400MHz, CDCl3): δ 7.14(d, J=6.8Hz, 2H), 7.10(d, J=6.8Hz, 2H), 4.16(m, 8H), 3.79(m, 2H), 3.65(m, 2H), 3.03(m, 2H), 2.55(m, 3H), 2.45(m, 2H), 1.64-1.70(m, 5H), 1.20(m, 12H), 0.88(s, 9H), 0.02(s, 6H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.14 (d, J = 6.8 Hz, 2H), 7.10 (d, J = 6.8 Hz, 2H), 4.16 (m, 8H), 3.79 (m, 2H), 3.65 (m, 2H), 3.03 (m, 2H), 2.55 (m, 3H), 2.45 (m, 2H), 1.64-1.70 (m, 5H), 1.20 (m, 12H), 0.88 (s, 9H), 0.02 (s, 6 H).

단계 9: 2-[2-(4-메톡시벤질옥시)-4-메틸벤질리덴]-4-[4-(4-Step 9: 2- [2- (4-methoxybenzyloxy) -4-methylbenzylidene] -4- [4- (4- terttert -부틸디메틸실릴부틸)펜에틸] 펜타디오익 엑시드 디에틸 에스터의 합성-Butyldimethylsilylbutyl) phenethyl] Synthesis of pentadioic acid diethyl ester

Figure 112006049660803-pat00173
Figure 112006049660803-pat00173

상기 제 8단계에서 제조한 화합물 (580 g, 0.809 mmol)을 건조된 THF (20 ml)에 용해시키고 t-리튬부톡사이드 (1M THF 용액: 1.05 ml, 1.05 mmol)을 넣어 30분 동안 반응하였다. 반응 혼합물에 2-(4-메톡시-벤질록시)-4-메틸-벤즈알데히드 (673 mg, 0.674 mmol)을 넣고 상온에서 18시간 동안 반응 한 다음 찬 얼음물로 반응을 종결하고 에틸아세테이트로 추출하였다. 용매를 무수 황산마그네슘으로 건조하여 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=5:1)하여 표제 화합물 (340 mg, 반응 수율: 73.7 %, 무색 액체)을 얻었다.The compound (580 g, 0.809 mmol) prepared in step 8 was dissolved in dried THF (20 ml), and t -lithium butoxide (1 M THF solution: 1.05 ml, 1.05 mmol) was added and reacted for 30 minutes. . 2- (4-methoxy-benzyloxy) -4-methyl-benzaldehyde (673 mg, 0.674 mmol) was added to the reaction mixture, which was reacted at room temperature for 18 hours. The reaction was terminated with cold ice water and extracted with ethyl acetate. The solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (hexane: ethyl acetate = 5: 1) to obtain the title compound (340 mg, reaction yield: 73.7%, colorless liquid).

1H NMR(400MHz, CDCl3): δ 7.87(s, 1H), 7.45(m, 2H), 7.38(m, 2H), 7.13(m, 4H), 6.82(m, 3H), 5.29(s, 2H), 4.22(q, 2H), 4.00(q, 2H), 3.79(s, 3H), 3.25(m, 2H), 2.83(m, 1H), 2.68(t, 2H), 2.50(t, 2H), 2.29(s, 3H), 1.48-1.60(m, 7H), 1.34(t, 3H), 1.25(m, 3H), 1.11(t, 3H), 0.88(s, 9H), 0.02(s, 6H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.87 (s, 1H), 7.45 (m, 2H), 7.38 (m, 2H), 7.13 (m, 4H), 6.82 (m, 3H), 5.29 (s, 2H), 4.22 (q, 2H), 4.00 (q, 2H), 3.79 (s, 3H), 3.25 (m, 2H), 2.83 (m, 1H), 2.68 (t, 2H), 2.50 (t, 2H ), 2.29 (s, 3H), 1.48-1.60 (m, 7H), 1.34 (t, 3H), 1.25 (m, 3H), 1.11 (t, 3H), 0.88 (s, 9H), 0.02 (s, 6H).

단계10: 2-(2-히드록시-4-메틸벤질리덴)-4-[4-(4-Step 10: 2- (2-hydroxy-4-methylbenzylidene) -4- [4- (4- terttert -부틸디메틸실릴부틸)펜에틸]펜타디오익 엑시드 디에틸 에스터과 2-(2-히드록시-4-메틸벤질리덴)-4-[4-(4-히드로록시부틸)펜에틸]펜타디오익 엑시드 디에틸 에스터의 합성-Butyldimethylsilylbutyl) phenethyl] pentadiic acid diethyl ester with 2- (2-hydroxy-4-methylbenzylidene) -4- [4- (4-hydroxybutyl) phenethyl] pentadiic acid Synthesis of Diethyl Ester

Figure 112006049660803-pat00174
Figure 112006049660803-pat00174

상기 제 9단계에서 제조한 화합물 (340 mg, 0.495 mmol)을 1,4-디옥산 (3 ml)에 용해시킨 후 0 ℃로 온도를 낮추고 4 N 염산 용액 (1.4 ml, 7.0 mmol)을 넣어 상온에서 24시간 동안 반응하였다. 반응 혼합물을 찬 얼음물로 종결하고 에틸아세테이트로 추출하여 용매를 무수 황산마그네슘으로 건조한 다음 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=2:1)하여 표제 화합물 A (178 mg, 노란 액체)와 표제 화합물 B (117 mg, 노란 액체)를 얻었다.After dissolving the compound (340 mg, 0.495 mmol) prepared in step 9 in 1,4-dioxane (3 ml), the temperature was lowered to 0 ° C. and 4N hydrochloric acid solution (1.4 ml, 7.0 mmol) was added to room temperature. Reaction was carried out for 24 hours. The reaction mixture was terminated with cold ice water, extracted with ethyl acetate, the solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and the residue was subjected to column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound A (178 mg, yellow liquid). ) And the title compound B (117 mg, yellow liquid).

1H NMR(400MHz, CDCl3): δ 7.87(s, 1H), 7.44(d, J=8.0Hz, 2H), 7.33(d, J=8.2Hz, 2H), 6.72(m, 3H), 4.12(q, 2H), 4.01(q, 2H), 3.79(s, 3H), 3.25(m, 2H), 2.83(m, 1H), 2.68(t, 2H), 2.50(t, 2H), 2.29(s, 3H), 1.48-1.61(m, 7H), 1.34(t, 3H), 1.25(m, 3H), 1.10(t, 3H), 0.86(s, 9H), 0.03(s, 6H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.87 (s, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 6.72 (m, 3H), 4.12 (q, 2H), 4.01 (q, 2H), 3.79 (s, 3H), 3.25 (m, 2H), 2.83 (m, 1H), 2.68 (t, 2H), 2.50 (t, 2H), 2.29 ( s, 3H), 1.48-1.61 (m, 7H), 1.34 (t, 3H), 1.25 (m, 3H), 1.10 (t, 3H), 0.86 (s, 9H), 0.03 (s, 6H).

1H NMR(400MHz, CDCl3): δ 7.86(s, 1H), 7.49(d, J=8.3Hz, 2H), 7.32(d, J=8.0Hz, 2H), 6.72(m, 3H), 4.12(q, 2H), 4.00(m, 2H), 3.79(s, 3H), 3.24(t, 2H), 2.83(m, 1H), 2.68(t, 2H), 2.50(t, 2H), 2.29(s, 3H), 1.51-1.63(m, 7H), 1.36(t, 3H), 1.19(m, 3H), 1.13(t, 3H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.86 (s, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 6.72 (m, 3H), 4.12 (q, 2H), 4.00 (m, 2H), 3.79 (s, 3H), 3.24 (t, 2H), 2.83 (m, 1H), 2.68 (t, 2H), 2.50 (t, 2H), 2.29 ( s, 3H), 1.51-1.63 (m, 7H), 1.36 (t, 3H), 1.19 (m, 3H), 1.13 (t, 3H).

단계 11: 4-[4-(4-Step 11: 4- [4- (4- trettret -부틸디메틸실릴부틸)페닐]-2-[(7-메틸-2-옥소-2H-크로멘-3-일)메틸]부티릭 엑시드 에틸 에스터과 4-[4-(4-히드록시부틸)페닐]-2-[(7-메틸-2-옥소-2H-크로멘-3-일)메틸]부티릭 엑시드 에틸 에스터의 합성-Butyldimethylsilylbutyl) phenyl] -2-[(7-methyl-2-oxo-2H-chromen-3-yl) methyl] butyric acid ethyl ester and 4- [4- (4-hydroxybutyl) phenyl ] -2-[(7-methyl-2-oxo-2H-chromen-3-yl) methyl] butyric acid ethyl ester

Figure 112006049660803-pat00175
Figure 112006049660803-pat00175

상기 제 10단계에서 제조한 화합물 A와 B의 혼합물(295 mg)을 자일렌 (10 ml)에 용해시켜 봉인 튜브 (sealed tube)를 사용하여 130 ℃에서 72시간 동안 반응하였다. 반응 혼합물을 상온으로 낮춘 후 용매를 감압 농축하여 제거하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트 =4:1)하여 표제 화합물 C (각 111.3 mg)와 표제 화합물 D(92.7 mg, 무색 액체)를 얻었다.The mixture of Compounds A and B (295 mg) prepared in step 10 was dissolved in xylene (10 ml) and reacted at 130 ° C. for 72 hours using a sealed tube. After cooling the reaction mixture to room temperature, the solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound C (111.3 mg each) and the title compound D (92.7 mg, colorless liquid). Got.

1H NMR(400MHz, CDCl3): δ 7.65(s, 1H), 7.43(s, 1H), 7.38(d, J=8.8Hz, 1H), 7.28(d, J=8.2Hz, 1H), 7.07(d, J=8.4Hz, 2H), 6.81(d, J=8.0Hz, 2H), 4.12(q, 2H), 4.01(q, 2H), 3.79(s, 3H), 3.25(m, 2H), 2.88(m, 1H), 2.68(t, 2H), 2.50(t, 2H), 2.29(s, 3H), 1.46-1.61(m, 7H), 1.36(t, 3H), 1.25(m, 3H), 1.10(m, 3H), 0.88(s, 9H), 0.04(s, 6H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.65 (s, 1 H), 7.43 (s, 1 H), 7.38 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.0 Hz, 2H), 4.12 (q, 2H), 4.01 (q, 2H), 3.79 (s, 3H), 3.25 (m, 2H) , 2.88 (m, 1H), 2.68 (t, 2H), 2.50 (t, 2H), 2.29 (s, 3H), 1.46-1.61 (m, 7H), 1.36 (t, 3H), 1.25 (m, 3H ), 1.10 (m, 3H), 0.88 (s, 9H), 0.04 (s, 6H).

1H NMR(400MHz, CDCl3): δ 7.60(s, 1H), 7.46(s, 1H), 7.41(d, J=8.6Hz, 1H), 7.28(d, J=8.2Hz, 1H), 7.07(d, J=8.4Hz, 2H), 6.83(d, J=8.0Hz, 2H), 4.12(q, 2H), 4.01(q, 2H), 3.79(s, 3H), 3.24(t, 2H), 2.83(m, 1H), 2.68(t, 2H), 2.50(t, 2H), 2.29(s, 3H), 1.51-1.63(m, 7H), 1.36(t, 3H), 1.19(m, 3H), 1.13(t, 3H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.60 (s, 1 H), 7.46 (s, 1 H), 7.41 (d, J = 8.6 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 4.12 (q, 2H), 4.01 (q, 2H), 3.79 (s, 3H), 3.24 (t, 2H) , 2.83 (m, 1H), 2.68 (t, 2H), 2.50 (t, 2H), 2.29 (s, 3H), 1.51-1.63 (m, 7H), 1.36 (t, 3H), 1.19 (m, 3H ), 1.13 (t, 3 H).

단계12: 4-[4-(4-히드록시부틸)펜에칠]-2[(7-메칠-2-옥소-2H크로멘-3-일)메칠]부티릭 에세드 에칠 에스터의 합성Step 12: Synthesis of 4- [4- (4-hydroxybutyl) phenethyl] -2 [(7-methyl-2-oxo-2Hchromen-3-yl) methyl] butyric ester ethyl ester

Figure 112006049660803-pat00176
Figure 112006049660803-pat00176

상기 제 11단계에서 제조한 화합물 C와 D의 혼합물 (204 mg)을 1,4-디옥산 (3 ml)에 용해시킨 후 0 ℃로 온도를 낮추고 4 N 염산 용액 (1.4 ml, 7.0 mmol)을 넣어 상온에서 24시간 동안 반응하였다. 반응 혼합물을 찬 얼음물로 종결하고 에틸아세테이트로 추출하여 용매를 무수 황산마그네슘으로 건조한 다음 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=1:1)하여 표제 화합물 (180 mg, 노란 액체)을 얻었다.The mixture of Compounds C and D (204 mg) prepared in step 11 was dissolved in 1,4-dioxane (3 ml), and then the temperature was lowered to 0 ° C. and 4N hydrochloric acid solution (1.4 ml, 7.0 mmol) was added. The reaction was carried out at room temperature for 24 hours. The reaction mixture was terminated with cold ice water, extracted with ethyl acetate, the solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (180 mg, yellow liquid). Got.

1H NMR(400MHz, CDCl3): δ 7.61(s, 1H), 7.45(s, 1H), 7.41(d, J=8.8Hz, 1H), 7.28(d, J=8.6Hz, 1H), 7.07(d, J=8.4Hz, 2H), 6.83(d, J=8.0Hz, 2H), 4.12(q, 2H), 4.01(q, 2H), 3.79(s, 3H), 3.24(t, 2H), 2.83(m, 1H), 2.68(t, 2H), 2.50(t, 2H), 2.29(s, 3H), 1.50-1.64(m, 7H), 1.36(m, 3H), 1.19(m, 3H), 1.11(t, 3H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.61 (s, 1H), 7.45 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 4.12 (q, 2H), 4.01 (q, 2H), 3.79 (s, 3H), 3.24 (t, 2H) , 2.83 (m, 1H), 2.68 (t, 2H), 2.50 (t, 2H), 2.29 (s, 3H), 1.50-1.64 (m, 7H), 1.36 (m, 3H), 1.19 (m, 3H ), 1.11 (t, 3 H).

단계 13: 4-(4-(3-포밀프로필)페닐)-2-[(7-메틸-2-옥소-2H-크로멘-3-일)메틸]부티릭 엑시드 에틸 에스터의 합성Step 13: Synthesis of 4- (4- (3-formylpropyl) phenyl) -2-[(7-methyl-2-oxo-2H-chromen-3-yl) methyl] butyric acid ethyl ester

Figure 112006049660803-pat00177
Figure 112006049660803-pat00177

상기 제 12단계에서 제조한 화합물 (108 mg, 0.247 mmol)을 디클로로메탄 (10 ml)에 용해시킨 후 피리디늄 디클로메이트 (279.2 mg, 0.742 mmol)과 460 mg의 실리카겔을 넣은 후 상온에서 6시간 동안 반응하였다. 반응 혼합물을 관 크로마토그래피 (헥산:에틸아세테이트 =1:1)하여 표제 화합물 (102 mg, 반응 수율: 95.0 %, 무색 고체)을 얻었다.The compound prepared in step 12 (108 mg, 0.247 mmol) was dissolved in dichloromethane (10 ml), pyridinium dichloromate (279.2 mg, 0.742 mmol) and 460 mg of silica gel were added, followed by 6 hours at room temperature. Reaction. The reaction mixture was subjected to column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (102 mg, reaction yield: 95.0%, colorless solid).

1H NMR(400MHz, CDCl3): δ 10.34(s, 1H), 7.64(s, 1H), 7.50(s, 1H), 7.41(d, J=8.8Hz, 1H), 7.31(d, J=8.6Hz, 1H), 7.11(d, J=8.4Hz, 2H), 6.83(d, J=8.0Hz, 2H), 4.12(q, 2H), 4.01(q, 2H), 3.79(s, 3H), 3.24(t, 2H), 2.83(m, 1H), 2.60(t, 2H), 2.50(t, 2H), 2.29(s, 3H), 1.68(m, 1H), 1.63(m, 2H), 1.58(m, 2H), 1.36(m, 3H), 1.19(m, 3H), 1.11(t, 3H). 1 H NMR (400 MHz, CDCl 3 ): δ 10.34 (s, 1H), 7.64 (s, 1H), 7.50 (s, 1H), 7.41 (d, J = 8.8Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 4.12 (q, 2H), 4.01 (q, 2H), 3.79 (s, 3H) , 3.24 (t, 2H), 2.83 (m, 1H), 2.60 (t, 2H), 2.50 (t, 2H), 2.29 (s, 3H), 1.68 (m, 1H), 1.63 (m, 2H), 1.58 (m, 2H), 1.36 (m, 3H), 1.19 (m, 3H), 1.11 (t, 3H).

단계 14: 2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(4-피페리딘-1-일-부틸)-페닐]-부티릭 엑시드 에틸 에스터의 합성Step 14: 2- (7-Methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (4-piperidin-1-yl-butyl) -phenyl] -butyric acid Synthesis of Ethyl Ester

Figure 112006049660803-pat00178
Figure 112006049660803-pat00178

상기 제 13단계에서 제조한 화합물 (102 mg, 0.235 mmol)과 피페리딘 (40 mg, 0.470 mmol)을 디클로로메탄 (3 ml)에 용해시킨 후 0 ℃로 온도를 낮추고 소듐보로하이드라이드 (18 mg, 0.470 mmol)을 넣어 상온에서 24시간 동안 반응하였다. 반응 혼합물을 찬 얼음물로 종결하고 에틸아세테이트로 추출하여 용매를 무수 황산마그네슘으로 건조한 다음 감압 농축하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=1:2)하여 표제 화합물 (87 mg, 반응 수율: 73.5 %, 노란액체)을 얻었다.The compound (102 mg, 0.235 mmol) and piperidine (40 mg, 0.470 mmol) prepared in step 13 were dissolved in dichloromethane (3 ml), and the temperature was lowered to 0 ° C. and sodium borohydride (18 mg, 0.470 mmol) was added and reacted at room temperature for 24 hours. The reaction mixture was terminated with cold ice water, extracted with ethyl acetate, the solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and the residue was purified by column chromatography (hexane: ethyl acetate = 1: 2) to give the title compound (87 mg, reaction yield: 73.5%, yellow liquid).

1H NMR(400MHz, CDCl3): δ 7.65(s, 1H), 7.50(s, 1H), 7.40(d, J=8.0Hz, 1H), 7.33(d, J=8.6Hz, 1H), 7.21(d, J=8.4Hz, 2H), 6.87(d, J=8.0Hz, 2H), 4.13(q, 2H), 4.01(q, 2H), 3.79(s, 3H), 3.24(t, 2H), 2.83(m, 1H), 2.60(t, 2H), 2.55(m, 4H), 2.35(m, 2H), 2.50(t, 2H), 2.29(s, 3H), 1.58-1.68(m, 5H), 1.36(m, 3H), 1.19(m, 3H), 1.11(t, 3H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.65 (s, 1H), 7.50 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.0 Hz, 2H), 4.13 (q, 2H), 4.01 (q, 2H), 3.79 (s, 3H), 3.24 (t, 2H) , 2.83 (m, 1H), 2.60 (t, 2H), 2.55 (m, 4H), 2.35 (m, 2H), 2.50 (t, 2H), 2.29 (s, 3H), 1.58-1.68 (m, 5H ), 1.36 (m, 3H), 1.19 (m, 3H), 1.11 (t, 3H).

단계15Step 15 : : NN -히드록시-2-[(7--Hydroxy-2-[(7- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일)-3 days) 메틸methyl ]-4-4-[4-] -4-4- [4-

(피페리딘-1-일) 부틸] 페닐부탄아미드의 합성

Figure 112006049660803-pat00179
(Piperidin-1-yl) butyl] Synthesis of Phenylbutanamide
Figure 112006049660803-pat00179

상기 제 14단계에서 제조한 화합물 (87 mg, 0.173 mmol)을 메탄올에 용해된 1.76M NH2OH HCl (0.50 ml, 0.864 mmol)을 넣어 상온에서 하루 동안 반응하였다. 반응 혼합물을 감압 농축하여 용매를 제거 하고 잔여물을 관 크로마토그래피 (헥산:에틸아세테이트=1:1)하여 표제 화합물 (32.5 mg, 반응 수율: 38.3 %, 흰 고체)을 얻었다.The compound (87 mg, 0.173 mmol) prepared in step 14 was added 1.76 M NH 2 OH HCl (0.50 ml, 0.864 mmol) dissolved in methanol, and reacted at room temperature for one day. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was subjected to column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (32.5 mg, reaction yield: 38.3%, white solid).

1H NMR(400MHz, CDCl3): δ 9.81(s, 1H), 8.69(s, 1H), 7.64(s, 1H), 7.40(s, 1H), 7.39(d, J=8.6Hz, 1H), 7.25(d, J=8.6Hz, 1H), 7.08(d, J=8.2Hz, 2H), 6.81(d, J=8.3Hz, 2H), 3.92(t, J=8.2Hz, 2H), 2.66(m, 3H), 2.53(m, 4H), 2.40(s, 3H), 2.34(m, 6H), 1.82(m, 2H), 1.46-1.49m, 4H), 1.33-1.40(m, 2H). 1 H NMR (400 MHz, CDCl 3 ): δ 9.81 (s, 1H), 8.69 (s, 1H), 7.64 (s, 1H), 7.40 (s, 1H), 7.39 (d, J = 8.6Hz, 1H) , 7.25 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 8.2 Hz, 2H), 6.81 (d, J = 8.3 Hz, 2H), 3.92 (t, J = 8.2 Hz, 2H), 2.66 (m, 3H), 2.53 (m, 4H), 2.40 (s, 3H), 2.34 (m, 6H), 1.82 (m, 2H), 1.46-1.49m, 4H), 1.33-1.40 (m, 2H) .

단계 16: Step 16: NN -히드록시-2-[(7--Hydroxy-2-[(7- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일)-3 days) 메틸methyl ]-4-4-[4-(피페리딘-1-일)부틸]페닐부탄아미드 ] -4-4- [4- (piperidin-1-yl) butyl] phenylbutanamide 하이드로클로라이드의Hydrochloride 합성 synthesis

상기 제 15단계에서 제조한 화합물 (32.5 mg, 0.066 mmol)을 1,4-디옥산 (1 ml)에 용해시킨 후 4 N 염산 용액 (1.6 ml, 6.624 mmol)을 넣어 상온에서 24시간 동안 반응하였다. 반응 혼합물 중에 생긴 고체를 걸러 1,4-디옥산과 에틸아세테이트로 씻은 후 건조하여 표제 화합물 (25.4 mg, 흰 고체)을 얻었다.The compound (32.5 mg, 0.066 mmol) prepared in step 15 was dissolved in 1,4-dioxane (1 ml), and 4 N hydrochloric acid solution (1.6 ml, 6.624 mmol) was added thereto and reacted at room temperature for 24 hours. . The solid formed in the reaction mixture was filtered, washed with 1,4-dioxane and ethyl acetate and dried to obtain the title compound (25.4 mg, white solid).

1H NMR(400MHz, DMSO): δ10.38(br, 1H), 8.69(br, 1H), 7.65(s, 1H), 7.43(s, 1H), 7.38(d, J=8.8Hz, 1H), 7.28(d, J=8.2Hz, 1H), 7.07(d, J=8.4Hz, 2H), 6.81(d, J=8.0Hz, 2H), 3.92(t, J=8.0Hz, 2H), 2.67(m, 3H), 2.55(m, 4H), 2.35(s, 3H), 2.33(m, 6H), 1.80-1.83(m, 2H), 1.46-1.48m, 4H), 1.35-1.37(m, 2H). 1 H NMR (400 MHz, DMSO): δ 10.38 (br, 1 H), 8.69 (br, 1 H), 7.65 (s, 1 H), 7.43 (s, 1 H), 7.38 (d, J = 8.8 Hz, 1 H), 7.28 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.0 Hz, 2H), 3.92 (t, J = 8.0 Hz, 2H), 2.67 ( m, 3H), 2.55 (m, 4H), 2.35 (s, 3H), 2.33 (m, 6H), 1.80-1.83 (m, 2H), 1.46-1.48m, 4H, 1.35-1.37 (m, 2H ).

상기 실시예의 반응을 이용하여 하기와 같은 화합물들을 제조하였다.The following compounds were prepared using the reaction of the above example.

실시예Example 117.  117. NN -히드록시-2-Hydroxy-2- 메틸methyl -3-(2-옥소-2H--3- (2-oxo-2H- 크로멘Chromen -3-일)-3 days) 프로피온아미드Propionamide

실시예Example 118. 2-벤질-N-히드록시-3-(6- 118. 2-benzyl-N-hydroxy-3- (6- 메틸methyl -2-옥소-2H--2-oxo-2H- 크로멘Chromen -3-일)--3 days)- 프로피온아미드Propionamide

실시예 Example 화학구조Chemical structure NMR 스펙트럼 데이터 (1H 혹은 13C)NMR spectral data ( 1 H or 13 C) 117117

Figure 112006049660803-pat00180
Figure 112006049660803-pat00180
13C-NMR (CD3OD, 400MHz) δ174.8, 163.4, 154.7, 142.6, 132.3, 129.1, 127.6, 125.7, 120.9, 117.2, 37.6, 36.2, 18.3.13 C-NMR (CD 3 OD, 400 MHz) δ 174.8, 163.4, 154.7, 142.6, 132.3, 129.1, 127.6, 125.7, 120.9, 117.2, 37.6, 36.2, 18.3. 118118
Figure 112006049660803-pat00181
Figure 112006049660803-pat00181
 1H-NMR (CD3OD, 400MHz) δ 7.62(s, 1H), 7.33-7.15(m, 8H), 2.99-2.76(m, 5H), 2.36(s, 3H).1 H-NMR (CD 3 OD, 400 MHz) δ 7.62 (s, 1H), 7.33-7.15 (m, 8H), 2.99-2.76 (m, 5H), 2.36 (s, 3H).

실시예Example 119.  119. NN -히드록시-3-(6--Hydroxy-3- (6- 메톡시Methoxy -2-옥소-2-2-oxo-2 HH -- 크로멘Chromen -3-일)--3 days)- 아크릴아미드의Acrylamide 합성의 합성 Synthesis synthesis

Figure 112006049660803-pat00182
Figure 112006049660803-pat00182

단계 1: 글루타코닉 액시드 디에틸 에스테르의 합성Step 1: Synthesis of Glutaconic Acid Diethyl Ester

글루타코닉 액시드 (1 g, 9.7 mmol)를 에탄올 (20 ml)에 용해시킨 후 촉매량의 황산을 적가 하여 12시간 환류하였다. 종결된 반응 혼합물의 용매를 감압 농축하여 제거한 다음 에틸아세테이트에 용해시키고 유기용매 층을 포화 탄산나트륨으로 씻어준 후 무수 황산나트륨으로 건조하여 용매를 감압 농축하여 표제화합물 (1.3 g, 반응수율: 90 %, 흰색고체)을 얻었다.Glutaconic acid (1 g, 9.7 mmol) was dissolved in ethanol (20 ml) and then refluxed for 12 hours with the addition of a catalytic amount of sulfuric acid. The solvent of the reaction mixture was concentrated under reduced pressure, and then dissolved in ethyl acetate. The organic solvent layer was washed with saturated sodium carbonate, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give the title compound (1.3 g, reaction yield: 90%, white). Solid).

단계 2: 3-(6-메톡시-2-옥소-2Step 2: 3- (6-methoxy-2-oxo-2 HH -크로멘-3-일)-아크릴릭 액시드 에틸 에스테르의 합성Synthesis of -chromen-3-yl) -acrylic acid ethyl ester

2-히드록시-5-메톡시벤즈알데히드 (300 mg, 2 mmol)와 글루타코닉 액시드 디에틸 에스테르 (372 mg, 2 mmol)를 에탄올 (10 ml)에 용해시키고 촉매량의 피페리딘을 적가하였다. 6시간 동안 환류하여 반응하였다. 용매를 감압 농축하여 잔여물을 관 크로마토그래피 (에틸아세테이트:헥산=1:9)하여 표제화합물 (280 mg, 반응수율: 51 %, 노란색 고체)을 얻었다.2-hydroxy-5-methoxybenzaldehyde (300 mg, 2 mmol) and glutaconic acid diethyl ester (372 mg, 2 mmol) were dissolved in ethanol (10 ml) and a catalytic amount of piperidine was added dropwise. . The reaction was carried out at reflux for 6 hours. The solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate: hexane = 1: 9) to obtain the title compound (280 mg, reaction yield: 51%, yellow solid).

1H-NMR (400MHz, CDCl3) 1.33(t, J=6.8Hz, 3H), 3.86(s, 3H), 4.27(dd, J=14, 6.8Hz, 2H), 6.95(d, J=3.2Hz, 1H), 7.10(d, J=15.6Hz, 1H), 7.16(dd, J=9.2, 3.2Hz, 1H), 7.28(d, J=9.2Hz, 1H), 7.56(d, J=16.4Hz, 1H), 7.82(s, 1H) 1 H-NMR (400 MHz, CDCl 3 ) 1.33 (t, J = 6.8 Hz, 3H), 3.86 (s, 3H), 4.27 (dd, J = 14, 6.8 Hz, 2H), 6.95 (d, J = 3.2 Hz, 1H), 7.10 (d, J = 15.6 Hz, 1H), 7.16 (dd, J = 9.2, 3.2 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 7.56 (d, J = 16.4 Hz, 1H), 7.82 (s, 1H)

단계 3: 3-(6-메톡시-2-옥소-2Step 3: 3- (6-methoxy-2-oxo-2 HH -크로멘-3-일)-아크릴릭 액시드의 합성Synthesis of -chromen-3-yl) -acrylic acid

상기 2단계에서 제조한 화합물 (55 mg, 0.12 mmol)을 메탄올 (1 ml)에 녹인 후 1 M 수산화나트륨 수용액 1 ml를 넣고 실온에서 2시간 동안 교반하였다. 반응이 종결된 후 2 M 염산으로 pH=3으로 산성화 한 후 에틸아세테이트로 추출한 후 무수 황산나트륨으로 건조시키고 용매를 감압 농축하여 표제화합물 (45 mg, 반응수율: 92 %, 노란색고체)을 얻었다. The compound prepared in step 2 (55 mg, 0.12 mmol) was dissolved in methanol (1 ml), 1 ml of 1 M aqueous sodium hydroxide solution was added thereto, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was acidified to pH = 3 with 2M hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain the title compound (45 mg, reaction yield: 92%, yellow solid).

단계 4: Step 4: NN -히드록시-3-(6-메톡시-2-옥소-2-Hydroxy-3- (6-methoxy-2-oxo-2 HH -크로멘-3-일)-아크릴아미드의 합성 Synthesis of -chromen-3-yl) -acrylamide

상기 3단계에서 제조한 화합물 (50 mg, 0.20 mmol), 펜타플루오로페놀 (39 mg, 0.209 mmol), 4-디메틸아미노피리딘 (25 mg, 0.209 mmol)을 질소 하 실온에서 디클로로메탄 (1 ml)에 녹인 후 1-(3-디메틸아미노프로필)-3-메틸카르보이미드 히드로클로리드 (EDCI; 40 mg, 0.209 mmol)를 천천히 넣어준 다음 실온에서 2시간 동안 교반하였다. 반응을 완결되면 반응용액을 1N 염산, 포화 탄산나트륨, 소금물로 씻어준 뒤 무수 황산나트륨으로 건조한 다음 용매를 감압 농축하였다. 정제 과정 없이 혼합물을 디클로로메탄(1ml)에 용해시킨 후 트리에틸아민 (0.1 ml, 0.76 mmol) NH2OHㆍHCl(52.8 mg, 0.76 mmol)을 넣어주고 실온에서 3시간 교반하였다. 반응이 종결된 후 포화 암모늄클로라이드 용액으로 씻어준 다음 유기 용매 층을 무수 황산나트륨으로 건조한 다음 용매를 감압 농축하였다. 관 크로마토그래피 (디클로로메탄/메탄올=9/1)로 정제하여 표제화합물 (12 mg, 반응수율: 38 %, 노란색고체)을 얻었다.Compound (50 mg, 0.20 mmol), pentafluorophenol (39 mg, 0.209 mmol), 4-dimethylaminopyridine (25 mg, 0.209 mmol) prepared in step 3 above was diluted with dichloromethane (1 ml) at room temperature under nitrogen. After dissolving in 1- (3-dimethylaminopropyl) -3-methylcarbodiimide hydrochloride (EDCI; 40 mg, 0.209 mmol) was added slowly and stirred at room temperature for 2 hours. After completing the reaction the reaction solution was concentrated under reduced pressure, a 1 N hydrochloric acid to a dried solvent, back over anhydrous sodium sulfate gave saturated sodium carbonate, washed with brine. After the mixture was dissolved in dichloromethane (1 ml) without purification, triethylamine (0.1 ml, 0.76 mmol) NH 2 OH.HCl (52.8 mg, 0.76 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was washed with saturated ammonium chloride solution, the organic solvent layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Purification by column chromatography (dichloromethane / methanol = 9/1) afforded the title compound (12 mg, reaction yield: 38%, yellow solid).

1H-NMR (400MHz, DMSO) 3.81(s, 3H), 7.03(d, J=15.6Hz, 1H), 7.23-7.39(m, 4H), 8.30(s, 1H), 9.12(s, 1H), 10.95(s, 1H) 1 H-NMR (400 MHz, DMSO) 3.81 (s, 3H), 7.03 (d, J = 15.6 Hz, 1H), 7.23-7.39 (m, 4H), 8.30 (s, 1H), 9.12 (s, 1H) , 10.95 (s, 1H)

실험예Experimental Example 1.  One. TNFTNF -α 전환효소 (-α convertase ( TACETACE )활성 측정Activity measurement

TACE (R&D Systems, Minneapolis, MN, U.S.A)의 효소활성은 25 ℃에서 합성 형광 반응기인 Mca-Pro-Leu-Ala-Gln-Ala-Val-Dpa-Arg-Ser-Ser-Ser-Agr-NH2 (Mca: [7-methoxycoumarin-4-yl] acetyl Dpa: N-3-[2,4-dinitrophenyl]- L-2,3-diaminopropionyl, R&D Systems, Minneapolis, MN, U.S.A)을 이용하여 측정하였다. 효소반응 후 만들어지는 형광물질을 퍼킨-엘머 (Perkin-Elmer) 분광광도계 LS50B (방법 1) 또는 퍼긴-엘머(Perkin-Elmer) Wallac 2100 EnVisionTM Microplate Reader (방법 2)를 이용하여 형광도를 측정하여 비약재 투여군과 비교하여 활성 억제도를 측정하였다. 효소반응의 결과 형광반응기인 Mca 생성물이 형광을 나타내며, 이를 흥분 파장인 324 nm (방법 1) 또는 340 nm (방법 2)에서 흡수하여 형광 발광인 420 nm (방법 1) 또는 400 nm (방법 2)에서 측정하였고 이는 효소의 활성도와 밀접한 연관을 지닌다. 실험결과를 하기 표 8에 나타내었다 (표에서 AA는 IC50's<0.1μM, A는 IC50's<0.3μM, B는 IC50's<0.5μM 및 C는 IC50's>0.5μM을 의미한다). 하기 표 8 (방법 1)과 표 9 (방법 2)에 나타난 바와 같이 본 발명의 화합물들이 우수한 TNF-α 전환효소 (TACE)에 대한 억제작용을 가짐을 확인할 수 있었다.The enzymatic activity of TACE (R & D Systems, Minneapolis, MN, USA) was synthesized at 25 ° C. with Mca-Pro-Leu-Ala-Gln-Ala-Val-Dpa-Arg-Ser-Ser-Ser-Agr-NH2 ( Mca: [7-methoxycoumarin-4-yl] acetyl Dpa: N- 3- [2,4-dinitrophenyl] -L-2,3-diaminopropionyl, R & D Systems, Minneapolis, MN, USA). The fluorescent material produced after the enzyme reaction was measured for fluorescence using a Perkin-Elmer spectrophotometer LS50B (Method 1) or a Perkin-Elmer Wallac 2100 EnVision TM Microplate Reader (Method 2). Inhibition of activity was measured in comparison with the non-medical administration group. As a result of the enzymatic reaction, the Mca product, which is a fluorescence reactor, exhibits fluorescence, which is absorbed at an excitation wavelength of 324 nm (method 1) or 340 nm (method 2) and fluorescence emission of 420 nm (method 1) or 400 nm (method 2). This is closely related to enzyme activity. The experimental results are shown in Table 8 below (AA in the IC 50 's <0.1 μM, A in the IC 50 ' s <0.3 μM, B in the IC 50 's <0.5 μM and C in the IC 50 's> 0.5 μM). As shown in Table 8 (Method 1) and Table 9 (Method 2), it was confirmed that the compounds of the present invention had an excellent inhibitory effect on TNF-α convertase (TACE).

실시예Example TACE 저해활성TACE inhibitory activity 실시예Example TACE 저해활성TACE inhibitory activity 22 AAAA 33 AA 44 AAAA 55 AA 66 AAAA 77 AAAA 88 AAAA 99 AA 1010 AA 1111 AA 1212 AA 1313 AAAA 1414 AA 1515 AA 1616 AAAA 1717 AAAA 1818 AAAA 1919 AAAA 2020 AAAA 2121 AAAA 2222 AAAA 2323 CC 2424 AA 2626 AA 2727 BB 2828 AA 2929 CC 3030 AAAA 3131 AAAA 3232 AA 3333 AAAA 3434 AA 3535 AAAA 3636 AAAA 3737 AAAA 3838 AAAA 3939 AAAA 4040 AAAA 4141 AAAA 4242 AAAA 4343 AAAA 4444 AAAA 4545 AA

실시예Example TACE 저해활성TACE inhibitory activity 실시예Example TACE 저해활성TACE inhibitory activity 110110 AAAA 112112 AAAA 113113 AAAA 116116 AAAA

실험예Experimental Example 2. 세포활성 측정 ( 2. Measurement of cell activity TNFTNF -α)-α)

세포배양액에 축적되는 TNF-α의 양을 측정함으로써, 본 발명의 화합물들의 TNF-α생성 억제능력을 실험하였다. 상기 실험에서는 마우스 마이크로파아지 세포주의 하나인 Raw 264.7 세포 (ATTC, 미국)를 이용하였다.By measuring the amount of TNF-α accumulated in the cell culture, the ability of the compounds of the present invention to inhibit TNF-α production was examined. In this experiment, Raw 264.7 cells (ATTC, USA), one of the mouse microphage cell lines, were used.

마우스의 마크로파아지 세포주인 RAW 264.7 세포를 10% 소 태아 혈청 (fetal bovine serum; FBS)을 포함하는 DMEM/HG 배지에서 배양하였다. RAW 264.7 세포를 96 웰 플레이트(96 well plate)에 세포를 5 % CO2, 37 ℃의 배양 조건하에서 5×105 cells/㎖로 24h 배양한 후, 적절한 농도의 화합물을 세포에 처리하였다(0.1-10 μM). 세포에 화합물을 처리함과 동시에 리포폴리사카라이드 (최종 농도 1 ㎍/㎖ (Sigma, 미국))를 처리하여 세포를 활성화시켰다. 리포폴리사카라이드와 화합물을 처리하고 24시간 후에 세포 배양액을 수집하였다. 수집된 세포배양액에 존재하는 TNF-α의 양을 ELISA 분석 키트 (Biosource international, ELISA assay kit, USA)를 사용하여 정량하였다. 실험결과를 하기 표 10에 나타내었다 (표에서 AA는 IC50's<1μM, A는 IC50's<5μM, B는 IC50's<10μM 및 C는 IC50's>10μM을 의미한다). 하기 표 10에 나타난 바와 같이 대식세포로부터의 TNF-α의 생산능에 미치는 화합물들의 영향을 측정한 결과, 본 발명의 화합물들이 우수한 TNF-α 생산 억제 활성을 가짐을 확인할 수 있었다. RAW 264.7 cells, the macrophage cell line of mice, were cultured in DMEM / HG medium containing 10% fetal bovine serum (FBS). RAW 264.7 cells were incubated in 96 well plates for 24h at 5 × 10 5 cells / ml under culture conditions of 5% CO 2 , 37 ° C., and then the compounds of appropriate concentration were treated with the cells (0.1 -10 μM). Cells were activated by treatment with lipopolysaccharides (final concentration 1 μg / ml (Sigma, USA)) while the cells were treated with the compound. Cell cultures were collected 24 hours after lipopolysaccharide and compound treatment. The amount of TNF-α present in the collected cell culture was quantified using an ELISA assay kit (Biosource international, ELISA assay kit, USA). The experimental results are shown in Table 10 (AA in the table IC 50 's <1 μM, A means IC 50 ' s <5 μM, B means IC 50 's <10 μM and C means IC 50 's> 10 μM) ). As shown in Table 10 below, the effect of compounds on the production capacity of TNF-α from macrophages was measured. As a result, it was confirmed that the compounds of the present invention had excellent TNF-α production inhibitory activity.

실시예Example TNF-α 저해활성   TNF-α Inhibitory Activity 실시예Example TNF-α 저해활성  TNF-α Inhibitory Activity 1One AAAA 22 AAAA 33 BB 44 AAAA 55 AA 66 AAAA 77 AA 88 AA 99 BB 1010 AAAA 1111 AA 1212 CC 1313 AAAA 1414 BB 1616 AAAA 1717 AAAA 1818 AAAA 1919 AA 2020 CC 2121 CC 2424 AA 2525 AA 2626 BB 2828 AA 2929 CC 3030 CC 3131 BB 3232 AA 3333 AAAA 3434 AA 3535 CC 3636 AA 3737 AA 3838 AA 3939 AA 4040 AAAA 4141 AAAA 4242 AA 4343 AAAA 4444 CC 4545 CC 4646 AA 4747 CC 4848 AA 4949 CC 5050 CC 5151 AAAA 5252 BB 5353 AAAA 5454 AAAA 5555 AAAA 5656 AAAA 5757 AA 5858 AAAA 5959 AAAA 6060 AAAA 6161 AAAA 6262 CC 6363 AAAA 6464 AAAA 6565 AAAA 6666 AA 6767 BB 6868 AA 6969 AAAA 7070 CC 7171 AAAA 7272 AAAA 7373 AAAA 7474 AAAA 7575 AAAA 7676 AAAA 7777 AA 7878 AAAA 7979 AAAA 8080 AAAA 8181 AA 8282 AAAA 8383 AAAA 8484 AA 8585 AAAA 8686 AA 8787 AAAA 8888 CC 9090 AAAA 9191 AAAA 9292 AAAA 9393 AAAA

실시예Example TNF-α 저해활성   TNF-α Inhibitory Activity 실시예Example TNF-α 저해활성  TNF-α Inhibitory Activity 9494 AAAA 9595 AAAA 9696 AAAA 9797 AAAA 9898 AAAA 9999 AAAA 100100 AAAA 101101 AA 102102 AAAA 103103 AAAA 104104 AAAA 105105 AAAA 106106 AAAA 107107 AA 108108 AA 109109 AAAA 110110 AAAA 111111 AAAA 112112 AAAA 113113 AAAA 114114 CC 115115 CC 116116 AAAA 117117 AAAA 118118 AAAA 119119 CC

실험예Experimental Example 3. 마우스를 이용한  3. Using Mouse TNFTNF -α 억제 실험-α inhibition experiment

7~9주령 수컷 BALB/c계 마우스 (Japan SLC, Inc.)에서 혈액 내에 존재하는 TNF-α의 양을 측정하였다. 리포폴리사카라이드 (10 ug/마우스, sigma, L-2880)를       The amount of TNF-α present in blood was measured in 7- to 9-week-old male BALB / c mice (Japan SLC, Inc.). Lipopolysaccharide (10 ug / mouse, sigma, L-2880)

복강투여하여 염증을 유발하였다. 실험 전 마우스는 리포폴리사카라이드 투여 기준 24시간 전에 절식을 하였다. 적절한 농도의 화합물을 경구투여(0.2ml/마우스)하고 30분 후 리포폴리사카리드를 투여하였다. 리포폴리사카라이드 투여 90분경과 후에 마우스 심장으로부터 채혈하여 혈청을 분리하였다. TNF-a의 양을 분리한 혈청을 이용하여 ELISA 분석키트 (Biosource International, USA)로 정량하였다. 하기 표 11 내지 12 및 도 1 내지 2에 나타난 바와 같이 마우스를 이용한 TNF-α의 생산능에 미치는 경구투여한 화합물들의 영향을 측정한 결과, 본 발명의 화합물들이 우수한 TNF-α 생산 억제 활성을 가짐을 확인할 수 있었다.Intraperitoneal administration causes inflammation. Mice were fasted 24 hours prior to the baseline of lipopolysaccharide administration. Lipopolysaccharide was administered 30 min after oral administration of the appropriate concentration of compound (0.2 ml / mouse). 90 minutes after lipopolysaccharide administration, blood was collected from mouse hearts to separate serum. The amount of TNF-a was quantified by ELISA assay kit (Biosource International, USA) using the separated serum. As shown in Tables 11 to 12 and FIGS. 1 and 2, the effects of orally administered compounds on the production capacity of TNF-α using a mouse were determined. I could confirm it.

GroupGroup TypeType LPS con. (㎍/mouse)+ LPS con. (Μg / mouse) + pg/㎖pg / ml meanmean stdev.stdev. % of control++ % of control ++ Inhibition (%)Inhibition (%) LPS control LPS control serum serum 10 10 1598.21598.2 1599.21599.2 1371.21371.2 926.5926.5 988.7988.7 1675.51675.5 1359.881359.88 328.47328.47 100100 LPS + 실시예113** 10mg/kg LPS + Example 113 ** 10 mg / kg serum serum 10 10 562.8562.8 516.7516.7 675.9675.9 675.9675.9 607.81607.81 80.8380.83 44.7044.70 55.3055.30 LPS + 실시예113*8 30mg/kg LPS + Example 113 * 8 30 mg / kg serum serum 10 10 233.1233.1 229.3229.3 177.5177.5 177.5177.5 184.1184.1 137.9137.9 189.89189.89 35.9535.95 14.0014.00 86.0086.00 LPS + 실시예113** 100mg/kg LPS + Example 113 ** 100 mg / kg serum serum 10 10 36.236.2 54.154.1 54.154.1 31.531.5 31.531.5 41.4441.44 11.6811.68 3.053.05 96.9596.95 * 동물 : BALB /c, 9w, Male ** 실시예 113용액 -> 0.2㎖/M, 경구투여 + 용매 : 100 % saline ++ ED50 : 6.026 ㎎/㎏ * Animal: BALB / c, 9w, Male ** Example 113 solution- > 0.2ml / M , oral administration + solvent: 100% saline ++ ED50 : 6.026 mg / kg

GroupGroup TypeType con. (㎍/mouse)+con. (Μg / mouse) + pg/㎖pg / ml meanmean stdev.stdev. % of control++ % of control ++ inhibition (%)inhibition (%) LPS control LPS control serum serum 10 10 1676.01676.0 1604.51604.5 1921.41921.4 1278.61278.6 1620.131620.13 265.04265.04 100100 LPS + 실시예110** 30mg/kg LPS + Example 110 ** 30 mg / kg serum serum 10 10 884.5884.5 879.3879.3 611.4611.4 914.7914.7 822.49822.49 141.59141.59 50.7750.77 49.2349.23 LPS + 실시예111 30mg/kg LPS + Example 111 30 mg / kg serum serum 10 10 597.2597.2 795.6795.6 589.5589.5 435.6435.6 604.48604.48 147.57147.57 37.3137.31 62.6962.69 LPS + 실시예112 30mg/kg LPS + Example 112 30 mg / kg serumserum 1010 589.5589.5 526.4526.4 388.6388.6 887.1887.1 597.88597.88 210.25210.25 36.9036.90 63.163.1 * 동물 : BALB /c, 7w, Male ** 화합물 용액 -> 0.2㎖/M, 경구투여 + 용매 : EtOH : DW = 4:96 * Animal: BALB / c, 7w, Male ** Compound Solution-> 0.2ml / M , oral administration + Solvent: EtOH : DW = 4:96

실험예Experimental Example 4. 정맥투여  4. Intravenous administration 급성독성시험Acute Toxicity Test

실험동물로 5주된 체중 25 내지 30g의 ICR 마우스(SPF, 생산업체: 한국 코아텍(사))를 각각의 시험 화합물 당 암수 각각을 사용하였다. 각 그룹당 실험동물 10 마리(암수 각 5마리)로 구성된 그룹(T2, T3, T4 및 T5)을 지정하고, 상기 실시예 113에서 제조한 화합물을 이용하여 급성 독성을 측정하였다. 또한, 하기 표 13에 나타내어진 용량으로 실험동물에게 상기 실시예 113에서 제조한 화합물을 H2O 100%에 용해하여 정맥주사 후 7일 동안 일반증상 및 사망동물의 관찰과 체중변화를 관찰하였다 (도 3 내지 4). 대조군(T1)으로 상기 실시예 113에서 제조한 화합물을 제외한 용매제만을 투여한 그룹에 대해서도 상기와 동일한 실험을 수행하여 사망동물과 체중변화를 표 13에 나타내었다.ICR mice (SPF, produced by KOATETECH Co., Ltd.), weighing 25 to 30 g, 5 weeks old, were used for each test compound. Groups (T2, T3, T4, and T5) consisting of 10 experimental animals (5 male and female) in each group were designated, and acute toxicity was measured using the compound prepared in Example 113 above. In addition, the compounds prepared in Example 113 were dissolved in 100% H 2 O to the experimental animals at the doses shown in Table 13 to observe the general symptoms and the weight change of animals and dead animals for 7 days after intravenous injection ( 3-4). The same experiment was performed for the group administered only the solvent except for the compound prepared in Example 113 as the control (T1), and the dead animals and the weight change are shown in Table 13.

그룹group 동물수The number of animals 투여용량 (mg/kg)Dosage (mg / kg) 시험일(사망)Examination date (death) 1One 22 33 44 55 66 77 총계sum T1T1 1010 용매제Solvent 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10 T2T2 1010 5050 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10 T3T3 1010 100100 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10 T4T4 1010 150150 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10 T5T5 1010 200200 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10 0/100/10

상기 표 13에서 나타내는바와 같이 200mg/kg을 투여한 군의 사망한 3마리의 개체는 정맥주사 후 2시간이내에 사망하였으며 뚜렷한 특성은 나타나지 않았다. 생존하는 개체들은 200mg/kg에서 2일 동안 약간의 먹이 섭취가 감소하고 털빛이 거친 등의 증상을 나타냈으나 그 후 완전히 회복하였으며 체중이 지속적으로 증가하였다. 다른 그룹의 개체들은 먹이섭취나 움직임, 털빛 등 모든 상태가 양호하였으며 체중도 지속적으로 증가하였다. 이상의 결과를 볼 때 200mg/kg정도의 높은 농도에서도 독성이 거의 없는 것으로 나타나고 있다.As shown in Table 13, three dead individuals of the group administered 200 mg / kg died within 2 hours after intravenous injection and did not show any obvious characteristics. Surviving subjects showed a slight decrease in food intake and a rough hairy symptom at 200 mg / kg for 2 days, but then completely recovered and gained weight continuously. Other groups were in good condition, including food intake, movement, and hair color, and their weight continued to increase. The above results show that there is little toxicity even at the high concentration of 200mg / kg.

실험예 5. 카라기난 유도된 렛트의 부종억제시험Experimental Example 5. Swell inhibition test of carrageenan induced rats

실험동물로 스프라그-돌리(Sprague- Dawley)계의 체중 150g 정도의 5주령 웅성 흰쥐 (SPF, 생산업체: 한국 코아텍(사))를 사용하였다. 각 그룹 당 5마리의 실험동물을 사용하여 T1, T2, T3 및 T4의 네 그룹으로 지정하였다. 부종을 유발하고 약물의 효과를 관찰하기 위하여 약물을 조제하였다. 대조약물인 인도메타신(indomethacin)은 DMSO(dimethylsulfoxide)와 트윈(Tween) 80과 물(H2O)을 1:4:95의 비율로 섞은 용액에, 실시예 113의 약물은 에탄올과 PEG(polyethylene glycol)400과 물(H2O)을 5:20:75의 비율로 섞은 용액에 녹여서 사용하였다. 대조그룹인 용매그룹(T1)은 실시예 113의 약물을 녹인 용매와 동일한 용매를 사용하였다. 각 그룹에 부종을 유발하기 전에 용매(T1), 10mg/kg의 인도메타신(T2), 30mg/kg의 실시예 113의 약물(T3), 100mg/kg의 실시예 113의 약물(T4)을 복강투여하고 30분 후에 생리 식염수(saline)에 녹인 2% 카라기난(carragenan, Sigma, c-1013)액 100ul를 왼쪽 뒷다리의 안쪽 발목에 투여하여 부종을 유발하였다. 부종의 정도를 측정하기 위하여 캘리퍼(Vernier's caliper)를 사용하여 뒤꿈치의 두께를 측정하였다. 측정된 두께는 최대로 부종이 유발된 상태의 값에서 부종 유발 전의 값을 제외한 값을 100으로 환산하여 그 비교 값으로 나타내었으며(수학식 1참조) 부종은 유발 후 6시간에서 가장 뚜렷하게 관찰되었다(도 5). As a test animal, a 5-week-old male rat (SPF, producer: Korea Koatech Co., Ltd.) of 150g body weight of Sprague-Dawley system was used. Five experimental animals in each group were used to assign four groups of T1, T2, T3 and T4. Drugs were prepared to cause edema and observe the effects of the drugs. In contrast, indomethacin (indomethacin) is a solution of DMSO (dimethylsulfoxide), Tween 80 and water (H 2 O) in a ratio of 1: 4: 95, and the drug of Example 113 is ethanol and PEG ( Polyethylene glycol) 400 and water (H 2 O) were dissolved in a mixed solution of 5:20:75 and used. As a control group, solvent group (T1), the same solvent as the solvent in Example 113 was used. Before inducing edema in each group, solvent (T1), 10 mg / kg of indomethacin (T2), 30 mg / kg of Example 113 (T3), 100 mg / kg of Example 113 (T4) Thirty minutes after intraperitoneal administration, 100ul of 2% carragenan (Sigma, c-1013) solution dissolved in saline was administered to the inner ankle of the left hind leg to induce edema. To determine the degree of edema, the thickness of the heel was measured using a Vernier's caliper. The measured thickness was expressed as the comparison value of the value of the state in which the edema was induced to the maximum value before induction of edema (see Equation 1). Edema was most clearly observed at 6 hours after the induction. 5).

Figure 112006049660803-pat00183
Figure 112006049660803-pat00183

각 약물의 저해효과를 6시간과 24시간에 관찰하여 그 결과를 도 6와 표 14에 나타내었다. 6시간에서 부종만 유발시킨 대조군에 비해 대조약물인 10mg/kg의 인도메타신을 투여한 그룹은 15%, 30mg/kg의 실시예 113의 약물을 투여한 그룹은 8%, 100mg/kg의 실시예 113의 약물을 투여한 그룹은 20%의 저해효과를 나타내었다. 24 시간에 관찰했을 때는 각각 4%, 14%, 35%의 저해효과를 나타내었다.The inhibitory effect of each drug was observed at 6 hours and 24 hours, and the results are shown in FIGS. 6 and 14. 15% of the group receiving 10 mg / kg of indomethacin as a control compared to the control group that induced edema at 6 hours, and 8% of the group receiving the drug of Example 113 of 8% and 100 mg / kg of the example 113 The group administered 113 drugs showed an inhibitory effect of 20%. When observed at 24 hours, the inhibitory effect was 4%, 14% and 35%, respectively.

각 시간대에서 측정한 뒤꿈치 두께의 비율표Percent table of heel thickness measured at each time zone 그룹group 6시간6 hours 24시간24 hours T1T1 100.0100.0 100.0100.0 T2T2 85.485.4 95.895.8 T3T3 92.092.0 86.486.4 T4T4 79.679.6 65.465.4

본 발명에 따른 화합물은 종양 괴사 인자-α 전환효소 (TNF-α converting enzyme)에 대해 강한 저해활성을 나타냄으로써, 이를 포함하는 조성물은 염증 질환, 특히 관절염의 치료를 위한 약제로써 이용가능하다.The compound according to the present invention exhibits a strong inhibitory activity against tumor necrosis factor-α converting enzyme (TNF-α converting enzyme), whereby the composition comprising the same can be used as a medicament for the treatment of inflammatory diseases, especially arthritis.

Claims (12)

삭제delete 삭제delete 하기 일반식 (II)의 구조를 갖는 화합물, 또는 이의 약리학적으로 허용가능한 염: A compound having the structure of formula (II): or a pharmacologically acceptable salt thereof:
Figure 112007070232409-pat00188
Figure 112007070232409-pat00188
 R1는 -NHOH 이고; n은 0 내지 3의 정수이고; X는 C 원자이고; R2 내지 R6은 각각 독립적으로 수소원자, 할로겐, 아민, C1 내지 C4의 저급 알킬기, C1 내지 C4의 알켄일기 또는 C1 내지 C4의 저급 알콕시기로부터 선택된 하나이상의 치환기이고; R8 및 A3은 각각 독립적으로 수소원자 또는 수소원자, 니트로, 할로겐, 아민, 아세트아미드, 카보 아미드, 또는 페닐기로 치환되거나 비치환된 C1 내지 C20의 쇄상, 가지상 알킬기, 알켄일기, 알키닐기, 알콕시기이며, 단 R8 및 A3가 동시에 수소원자는 아니며;R 1 is -NHOH; n is an integer from 0 to 3; X is a C atom; R 2 to R 6 are each independently at least one substituent selected from a hydrogen atom, a halogen, an amine, a C 1 to C 4 lower alkyl group, a C 1 to C 4 alkenyl group or a C 1 to C 4 lower alkoxy group; R 8 and A 3 are each independently a hydrogen atom or a C 1 to C 20 chain, branched alkyl group, alkenyl group unsubstituted or substituted with a hydrogen atom, a nitro, halogen, amine, acetamide, carboamide, or phenyl group; An alkynyl group and an alkoxy group, provided that R 8 and A 3 are not hydrogen atoms at the same time; (
Figure 112007070232409-pat00189
) 점선은 이중결합 또는 단일결합을 의미한다. (
Figure 112007070232409-pat00189
) Dashed line means double bond or single bond. 제 3항에 있어서, 상기 일반식 (II) 화합물은 According to claim 3, wherein the general formula (II) compound 2-(2-옥소-2H-크로멘-3-일메틸)-펜트-4-에노익 엑시드 히드록시아미드, N-히드록시-2-메틸-3-(6-메틸-2-옥소-2H-크로멘-3-일)-프로피온아미드, 2-(7-메톡시-2-옥소-2H-크로멘-3-일메틸)-펜트-4-에노익 엑시드 히드록시아미드, 2-(6-메톡시-2-옥소-2H-크로멘-3-일메틸)-펜트-4-에노익 엑시드 히드록시아미드, N-히드록시-3-(7-메톡시-2-옥소-2H-크로멘-3-일)-2-메틸-프로피온아미드, N-히드록시-2-메틸-3-(7-메틸-2-옥소-2H-크로멘-3-일)-프로피온아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-펜트-4-에노익 엑시드 히드록시아미드, 2-벤질-N-히드록시-3-(6-메톡시-2-옥소-2H-크로멘-3-일)-프로피온아미드, 2-벤질-N-히드록시-3-(2-옥소-2H-크로멘-3-일)-프로피온아미드, 2-벤질-N-히드록시-3-(7-메톡시-2-옥소-2H-크로멘-3-일)-프로 피온아미드, 3-(7-플루오로-2-옥소-2H-크로멘-3-일)-N-히드록시-2-메틸-프로피온아미드, 3-(7-클로로-2-옥소-2H-크로멘-3-일)-N-히드록시-2-메틸-프로피온아미드, 2-벤질-3-(7-클로로-2-옥소-2H-크로멘-3-일)-N-히드록시-프로피온아미드, 2-벤질-N-히드록시-3-(7-메틸-2-옥소-2H-크로멘-3-일)-프로피온아미드, 2-벤질-3-(7-플루오로-2-옥소-2H-크로멘-3-일)-N-히드록시-프로피온아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-6-페닐-헥사노익 엑시드 히드록시아미드, 4-메틸-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-펜타노익 엑시드 히드록시아미드, N-히드록시-3-메틸-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-도데카노익 엑시드 히드록시아미드, 3-(7-플루오로-6-메틸-2-옥소-2H-크로멘-3-일)-N-히드록시-2-메틸-프로피온아미드, N-히드록시-2-메틸-3-(2-옥소-2H-크로멘-3-일)프로피온아미드, 2-벤질-N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-프로피온아미드, N-히드록시-3-(6-메톡시-2-옥소-2H-크로멘-3-일)-아크릴아미드, 또는 N-히드록시-2,2-디메틸-3-(6-메틸-옥소-2H-크로멘-3-일)-프로피온아미드인 화합물.2- (2-oxo-2H-chromen-3-ylmethyl) -pent-4-enoic acid hydroxyamide, N -hydroxy-2-methyl-3- (6-methyl-2-oxo-2H -Cromen-3-yl) -propionamide, 2- (7-methoxy-2-oxo-2H-chromen-3-ylmethyl) -pent-4-enoic acid hydroxyamide, 2- (6 -Methoxy-2-oxo-2H-chromen-3-ylmethyl) -pent-4-enoic acid hydroxyamide, N -hydroxy-3- (7-methoxy-2-oxo-2H-chrome Men-3-yl) -2-methyl-propionamide, N -hydroxy-2-methyl-3- (7-methyl-2-oxo-2H-chromen-3-yl) -propionamide, 2- ( 6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -pent-4-enoic acid hydroxyamide, 2-benzyl- N -hydroxy-3- (6-methoxy-2-oxo -2H-chromen-3-yl) -propionamide, 2-benzyl- N -hydroxy-3- (2-oxo-2H-chromen-3-yl) -propionamide, 2-benzyl- N -hydroxy Roxy-3- (7-methoxy-2-oxo-2H-chromen-3-yl) -propionamide, 3- (7-fluoro-2-oxo-2H-chromen-3-yl)- N -hydroxy-2-meth Tyl-propionamide, 3- (7-chloro-2-oxo-2H-chromen-3-yl) -N -hydroxy-2-methyl-propionamide, 2-benzyl-3- (7-chloro-2 -Oxo-2H-chromen-3-yl) -N -hydroxy-propionamide, 2-benzyl- N -hydroxy-3- (7-methyl-2-oxo-2H-chromen-3-yl) -Propionamide, 2-benzyl-3- (7-fluoro-2-oxo-2H-chromen-3-yl) -N -hydroxy-propionamide, 2- (6-methyl-2-oxo-2H -Cromen-3-ylmethyl) -6-phenyl-hexanoic acid hydroxyamide, 4-methyl-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -pentanoic acid Hydroxyamide, N -hydroxy-3-methyl-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide, 2- (6-methyl-2-oxo-2H -Cromen-3-ylmethyl) -dodecanoic acid hydroxyamide, 3- (7-fluoro-6-methyl-2-oxo-2H-chromen-3-yl) -N -hydroxy-2 -Methyl-propionamide, N -hydroxy-2-methyl-3- (2-oxo-2H-chromen-3-yl) propionamide, 2-benzyl-N-hydroxy-3- (6 -Methyl-2-oxo-2H-chromen-3-yl) -propionamide, N -hydroxy-3- (6-methoxy-2-oxo- 2H -chromen-3-yl) -acrylamide Or N -hydroxy-2,2-dimethyl-3- (6-methyl-oxo-2H-chromen-3-yl) -propionamide. 하기 일반식 (III)의 구조를 갖는 화합물, 또는 이의 약리학적으로 허용가능한 염 :A compound having the structure of formula (III), or a pharmacologically acceptable salt thereof:
Figure 112007070232409-pat00190
Figure 112007070232409-pat00190
 R1는 -NHOH이고; n은 0 내지 3의 정수이고; m은 1 내지 10의 정수이고; X는 탄소원자이고; R2 내지 R6은 각각 독립적으로 수소원자, 할로겐, 아민, C1 내지 C4의 저급 알킬기, C1 내지 C4의 저급 알켄일기 또는 C1 내지 C4의 저급 알콕시기로부터 선택된 하나이상의 치환기이며; A1은 각각 독립적으로 니트로, 할로겐 아민, 아세트아미드, 카보 아미드, 히드록시기, 아세틸기, 아세톡시기, C1 내지 C5의 알킬카보닐기, C1 내지 C5의 알킬에스테르기 또는, C1 내지 C5의 알콕시기, C1 내지 C5의 디알킬아민, C1 내지 C5의 모노알킬아민 또는 아민기로 치환된 C1 내지 C20의 쇄상, 가지상 알킬기, 알켄일기, 알키닐기 및 알콕시기로부터 선택된 하나이상의 치환기이다. R 1 is -NHOH; n is an integer from 0 to 3; m is an integer from 1 to 10; X is a carbon atom; R 2 to R 6 are each independently at least one substituent selected from a hydrogen atom, a halogen, an amine, a C 1 to C 4 lower alkyl group, a C 1 to C 4 lower alkenyl group or a C 1 to C 4 lower alkoxy group ; A 1 is each independently nitro, halogen amine, acetamide, carbonamide, hydroxy group, acetyl group, acetoxy group, C 1 to C 5 alkylcarbonyl group, C 1 to C 5 alkyl ester group, or C 1 to C 1 to C 20 chain, branched alkyl, alkenyl, alkynyl and alkoxy groups substituted with C 5 alkoxy groups, C 1 to C 5 dialkylamines, C 1 to C 5 monoalkylamines or amine groups At least one substituent selected from. 제 5항에 있어서, 상기 일반식 (III) 화합물은 The compound of claim 5, wherein the general formula (III) compound N-히드록시-4-(4-히드록시-페닐)-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 6-[4-(3-히드록시-프로폭시)-페닐]-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-헥사노익 엑시드 히드록시아미드, 6-[4-(3-메톡시-프로폭시)-페닐]-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-헥사노익 엑시드 히드록시아미드, 아세틱 엑시드 4-[3-히드록시카바모일-4-(6-메틸-2-옥소-2H-크로멘-3-일)-부틸]-페닐 에스터, 2-[3-(2-디메틸아미노-에톡시)-벤질]-N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-프로피온아미드, 4-[4-(3-디메틸아미노-프로폭시)-페닐]-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 5-[3-(3-디메틸아미노-프로폭시)-페닐]-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-펜탄오익 엑시드 히드록시아미드, 5-[4-(3-디메틸아미노-프로폭시)-페닐]-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-펜탄오익 엑시드 히드록시아미드, 4-[4-(2-디메틸아미노-에톡시)-페닐]-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일-메틸)-부틸아미드, 4-[4-(2-디에틸아미노-에톡시)-페닐]-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 4-[4-(2-디이소프로필아미노-에톡시)-페닐]-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 6-[4-(3-디메틸아미노-프로폭시)-페닐]-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-헥사노익 엑시드 히드록시아미드, 4-[4-(3-디메틸아미노-프로폭시)-페닐]-N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 4-(4-부트-2-일옥시-페닐)-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 4-[4-(2-디에틸아미노-에톡시)-페닐]-N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 2-(7-클로로-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-디메틸아미노프로폭시)페 닐]-N-히드록시-부틸아미드, 4-[4-(3-디메틸아미노-프로폭시)-페닐]-2-(7-플루오로-2-옥소-2H-크로멘-3-일메틸)-N-히드록시-부틸아미드, (4-[4-(3-디메틸아미노-프로필아미노)-페닐]-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 4-[4-(2-디에틸아미노-에톡시)-페닐]-N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드 하이드로클로라이드, 또는 {2-[4-(2-디에틸아미노-에톡시)-페닐]-에틸}-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-아민-N-카르보하이드록사믹 엑시드 인 화합물. N -hydroxy-4- (4-hydroxy-phenyl) -2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide, 6- [4- (3-hydroxy Hydroxy-propoxy) -phenyl] -2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -hexanoic acid hydroxyamide, 6- [4- (3-methoxy-prop Foxy) -phenyl] -2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -hexanoic acid hydroxyamide, acetic acid 4- [3-hydroxycarbamoyl-4- (6-Methyl-2-oxo-2H-chromen-3-yl) -butyl] -phenyl ester, 2- [3- (2-dimethylamino-ethoxy) -benzyl] -N -hydroxy-3- (6-Methyl-2-oxo-2H-chromen-3-yl) -propionamide, 4- [4- (3-dimethylamino-propoxy) -phenyl] -N -hydroxy-2- (6- Methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide, 5- [3- (3-dimethylamino-propoxy) -phenyl] -2- (6-methyl-2-oxo-2H -Cromen-3-ylmethyl) -pentanoic acid hydroxyamide, 5- [4- (3-dimethylamino-propoxy) -phenyl] -2- (6-methyl-2-oxo-2H-chromen -3-ylmethyl) -pentaneoic Exe hydroxyamide, 4- [4- (2-dimethylamino-ethoxy) -phenyl] -N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-yl-methyl) -Butylamide, 4- [4- (2-diethylamino-ethoxy) -phenyl] -N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl)- Butylamide, 4- [4- (2-diisopropylamino-ethoxy) -phenyl] -N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl)- Butylamide, 6- [4- (3-dimethylamino-propoxy) -phenyl] -2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -hexanoic acid hydroxyamide, 4- [4- (3-Dimethylamino-propoxy) -phenyl] -N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide, 4- (4-But-2-yloxy-phenyl) -N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide, 4- [4- (2 -Diethylamino-ethoxy) -phenyl] -N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide, 2- (7-chloro-2 -Oxo-2H-chromen-3-ylmethyl) -4- [4- (3-dime Tylaminopropoxy) phenyl] -N -hydroxy-butylamide, 4- [4- (3-dimethylamino-propoxy) -phenyl] -2- (7-fluoro-2-oxo-2H-chrome Men-3-ylmethyl) -N -hydroxy-butylamide, (4- [4- (3-dimethylamino-propylamino) -phenyl] -N -hydroxy-2- (6-methyl-2-oxo -2H-chromen-3-ylmethyl) -butylamide, 4- [4- (2-diethylamino-ethoxy) -phenyl] -N -hydroxy-2- (7-methyl-2-oxo- 2H-chromen-3-ylmethyl) -butylamide hydrochloride, or {2- [4- (2-diethylamino-ethoxy) -phenyl] -ethyl}-(7-methyl-2-oxo-2H -Cromen-3-ylmethyl) -amine- N -carbohydroxyxamic acid phosphorus compound. 하기 일반식 (IV)의 구조를 갖는 화합물 또는 이의 약리학적으로 허용가능한 염:A compound having the structure of Formula (IV): or a pharmacologically acceptable salt thereof:
Figure 112007070232409-pat00191
Figure 112007070232409-pat00191
 상기 식에서In the above formula R1는 -NHOH 이고; n은 0 내지 3의 정수이고; m은 1 내지 10의 정수이고; X는 탄소원자이고; R2 내지 R6은 각각 독립적으로 수소원자, 히드록시기, 할로겐, C1 내지 C4의 저급 알킬기, C1 내지 C4의 알켄일기 또는 C1 내지 C4의 저급 알콕시기로부터 선택된 하나이상의 치환기이며; P 치환기는 하나 이상의 R'치환기로 임의로 치환 가능한 5 내지 7원의 시클릭환, 아릴 방향환, 헤테로 복소환 또는 이들이 상호 융합되거나 직접 연결된 환이며, 여기에서 R'는 수소원자, 할로겐, C1 내지 C5의 디알킬아민, C1 내지 C5의 모노알킬아민, 아민, 아세트아미드, 아세톡시기, 히드록시기, 카보아미드, 카보닐기, C1 내지 C10의 알킬기, 알켄일기 또는 알콕시기이며; Y는 O, N. 또는 C 원자이며; o는 1 내지 6의 정수이다. R 1 is -NHOH; n is an integer from 0 to 3; m is an integer from 1 to 10; X is a carbon atom; R 2 to R 6 each independently represent a hydrogen atom, a hydroxy group, a halogen, C 1 to C 4 lower alkyl group, C 1 to C 4 of the alkenyl group or C 1 to C 4 lower alkoxy group is one or more substituents selected from the; P substituent is a 5 to 7 membered cyclic ring, an aryl aromatic ring, a hetero heterocyclic ring or a ring in which they are mutually fused or directly linked to one or more R 'substituents, wherein R' is a hydrogen atom, halogen, C 1 to C 5 of dialkyl amines, mono-alkyl amines of C 1 to C 5, amine, acetamide, acetoxy group, hydroxyl group, carbonyl amide, carbonyl group, C 1 to C 10 alkyl group, alkenyl group or alkoxy group of; Y is O, N. or C atom; o is an integer from 1 to 6. 제 7항에 있어서, 상기 일반식 (IV) 화합물은 8. The compound of claim 7, wherein the compound of formula (IV) 2-(4-벤질옥시-벤질)-N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-프로피온아미드, 4-(4-벤질옥시-페닐)-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 2-(3-벤질옥시-벤질)-N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-프로피온아미드, 4-(3-벤질옥시-페닐)-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[3-(3-피리딘-4-일-프로폭시)-벤질]-프로피온아미드, 5-{4-[3-(4-디메틸아미노-페닐)-프로폭시]-페닐}-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-펜타노익 엑시드 히드록시아미드, 4-{4-[3-(4-아미노페닐)-프로폭시]-페닐}-N-히드록시-2-(6-메틸-2-옥소-2H-크 로멘-3-일메틸)-부틸아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[4-(2-피페리딘-1-일-에톡시)-벤질]-프로피온아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-메틸-퀴놀린-4-일-메톡시)-페닐]-부틸아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[4-(2-모르폴린-4-일-에톡시)-벤질]-프로피온아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[4-(3-모르폴린-4-일-프로폭시)-벤질]-프로피온아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[4-(3-피리딘-4-일-프로폭시)-벤질]-프로피온아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[3-(3-모르폴린-4-일-프로폭시)-벤질]-프로피온아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-피페리딘-1-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-피리딘-4-일-프로폭시)-페닐]-부틸아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[4-(3-피페리딘-1-일-프로폭시)-벤질]-프로피온아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-모르폴린-4-일-프로폭시)-페닐]-부틸아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[3-(2-모르폴린-4-일-에톡시)-벤질]-프로피온아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(3-피페리딘-1-일-프로폭시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(2-피리딘-1-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(3-모르폴린-4-일-프로폭시)-페닐]-부틸아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2- [3-(2-피페리딘-1-일-에톡시)-벤질]-프로피온아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[3-(3-피페리딘-1-일-프로폭시)-벤질]-프로피온아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(3-피리딘-4-일-프로폭시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(2-메틸-퀴놀린-4-일-메톡시)-페닐]-부틸아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[3-(2-메틸-퀴놀린-4-일-메톡시)-벤질]-프로피온아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(4-피리딘-4-일-부톡시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-피리딘-4-일-에톡시)-페닐]-부틸아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[4-(4-피리딘-4-일-부톡시)-벤질]-프로피온아미드, N-히드록시-3-(6-메틸-2-옥소-2H-크로멘-3-일)-2-[3-(4-피리딘-4-일-부톡시)-벤질]-프로피온아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-피페리딘-1-일-프로폭시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[4-(2-피페리딘-1-일-에톡시)-페닐]-펜타노익 엑시드 히드록시아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[4-(3-피페리딘-1-일-프로폭시)-페닐]-펜타노익 엑시드 히드록시아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[4-(3-모르폴린-4-일-프로폭시)-페닐]-펜타노익 엑시드 히드록시아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[3-(2-모르폴린-4-일-에톡시)-페닐]-펜타노익 엑시드 히드록시아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[3-(3-모르폴린-4-일-프로폭시)-페닐]-펜타노익 엑시드 히 드록시아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[3-(2-피페리딘-1-일-에톡시)-페닐]-펜탄오익 엑시드 히드록시아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[3-(3-피페리딘-1-일-프로폭시)-페닐]-펜타노익 엑시드 히드록시아미드, 4-{3-[3-(4-디메틸아미노-페닐)-프로폭시]-페닐}-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-5-[4-(2-모르폴린-4-일-에톡시)-페닐]-펜타노익 엑시드 히드록시아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-피롤-1-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-{4-[2-(2-옥소-피롤리딘-1-일)-에톡시]-페닐}-부틸아미드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(2-피페리딘-1-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(3-피페리딘-1-일-프로폭시)-페닐]-부틸아미드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[3-(3-모르폴린-4-일-프로폭시)-페닐]-부틸아미드, 4-[4-(3-[1,4']바이피페리디닐-1'-일-프로폭시)-페닐]-N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-모르폴린-4-일-프로폭시)-페닐]-부틸아미드, 2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-6-[4-(3-피페리딘-1-일-프로폭시)-페닐]-헥사노익 엑시드 히드록시아미드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-피페리딘-1-일-프로폭시)-페닐]-부틸아미 드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-피페리딘-1-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-{4-[3-(4-메틸-피페라진-1-일)-프로폭시]-페닐}-부틸아미드, N-히드록시-4-(4-3-[4-(2-히드록시-에틸)-피페라진-1-일]-프로폭시-페닐)-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-부틸아미드, 2-(7-플루오로-2-옥소-2H-크로멘-3-일메틸)-N-히드록시-4-[4-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드, 2-(7-클로로-2-옥소-2H-크로멘-3-일메틸)-N-히드록시-4-[4-(3-피페리딘-1-일-프로폭시)-페닐]-부틸아미드, 2-(7-클로로-2-옥소-2H-크로멘-3-일메틸)-N-히드록시-4-[4-(3-모르폴린-4-일-프로폭시)-페닐]-부틸아미드, 2-(7-플루오로-2-옥소-2H-크로멘-3-일메틸)-N-히드록시-4-[4-(3-피페리딘-1-일-프로폭시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-피롤리딘-1-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-{4-[2-(4-메틸-피페라진-1-일)-에톡시]-페닐}-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-피페라진-1-일-에톡시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-{4-[3-(4-옥소-피페리딘-1-일)-프로폭시]-페닐}-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-피롤리딘-1-일-프로폭시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-{4-[3-(4-메틸-피페라진-1-일)-프로폭시]-페닐}-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-피페라진-1-일-프로폭시)-페닐]-부틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-모르폴린-4-일-프로필아미노)-페닐]-부 틸아미드, N-히드록시-2-(6-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-피페리딘-1-일-프로필아미노)-페닐]-부틸아미드, 2-(7-플루오로-2-옥소-2H-크로멘-3-일메틸)-N-히드록시-4-[4-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드 하이드로클로라이드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(2-모르폴린-4-일-에톡시)-페닐]-부틸아미드 하이드로클로라이드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-모르폴린-4-일-프로폭시)-페닐]-부틸아미드 하이드로클로라이드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(3-피페리딘-1-일-프로폭시)-페닐]-부틸아미드 하이드로클로라이드, N-히드록시-2-(7-메틸-2-옥소-2H-크로멘-3-일메틸)-4-[4-(4-피페리딘-1-일-부틸)-페닐]-부틸아미드 하이드로크로라이드인 화합물2- (4-benzyloxy-benzyl) -N -hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -propionamide, 4- (4-benzyloxy-phenyl) N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide, 2- (3-benzyloxy-benzyl) -N -hydroxy-3- ( 6-Methyl-2-oxo-2H-chromen-3-yl) -propionamide, 4- (3-benzyloxy-phenyl) -N -hydroxy-2- (6-methyl-2-oxo-2H- Chromen-3-ylmethyl) -butylamide, N -hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [3- (3-pyridine-4- Yl-propoxy) -benzyl] -propionamide, 5- {4- [3- (4-dimethylamino-phenyl) -propoxy] -phenyl} -2- (6-methyl-2-oxo-2H-chrome Men-3-ylmethyl) -pentanoic acid hydroxyamide, 4- {4- [3- (4-aminophenyl) -propoxy] -phenyl} -N -hydroxy-2- (6-methyl-2 -Oxo-2H-chromen-3-ylmethyl) -butylamide, N -hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [4- (2 -piperidin-1-yl-ethoxy) -benzyl] -propionamide, N-hydroxy-2- (6-methyl-2-oxide -2H- chromene-3-ylmethyl) -4- [4- (2-methyl-quinolin-4-yl-methoxy) phenyl] butylamide, N-hydroxy-3- (6-methyl- 2-oxo-2H-chromen-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -propionamide, N -hydroxy-3- (6-methyl -2-oxo-2H-chromen-3-yl) -2- [4- (3-morpholin-4-yl-propoxy) -benzyl] -propionamide, N -hydroxy-3- (6- Methyl-2-oxo-2H-chromen-3-yl) -2- [4- (3-pyridin-4-yl-propoxy) -benzyl] -propionamide, N -hydroxy-3- (6- Methyl-2-oxo-2H-chromen-3-yl) -2- [3- (3-morpholin-4-yl-propoxy) -benzyl] -propionamide, N -hydroxy-2- (6 -Methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -butylamide, N -hydroxy-2 -(6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (3-pyridin-4-yl-propoxy) -phenyl] -butylamide, N -hydroxy- 3- (6-Methyl-2-oxo-2H-chromen-3-yl) -2- [4- (3-piperidin-1-yl-propoxy) -benzyl] -propionamide, N -hydride rock 2- (6-methyl-2-oxo -2H- chromene-3-yl) -4- [4- (3-morpholin-4-yl-propoxy) -phenyl] butylamide, N - Hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [3- (2-morpholin-4-yl-ethoxy) -benzyl] -propionamide, N -Hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (3-piperidin-1-yl-propoxy) -phenyl] -butyl Amide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (2-pyridin-1-yl-ethoxy) -phenyl]- Butylamide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (2-morpholin-4-yl-ethoxy) -phenyl ] -Butylamide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (3-morpholin-4-yl-propoxy) -Phenyl] -butylamide, N -hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [3- (2-piperidin-1-yl-e) Methoxy) -benzyl] -propionamide, N -hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [3- (3-piperidin-1-yl -Propoxy) -benzyl] -propionami , N-hydroxy-2- (6-methyl-2-oxo -2H- chromene-3-ylmethyl) -4- [3- (3-pyridin-4-yl-propoxy) -phenyl] -butyl Amide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (2-methyl-quinolin-4-yl-methoxy) -phenyl ] -Butylamide, N -hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [3- (2-methyl-quinolin-4-yl-methoxy) -Benzyl] -propionamide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (4-pyridin-4-yl-butoxy ) -Phenyl] -butylamide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (2-pyridin-4-yl-e) Methoxy) -phenyl] -butylamide, N -hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [4- (4-pyridin-4-yl-part Methoxy) -benzyl] -propionamide, N -hydroxy-3- (6-methyl-2-oxo-2H-chromen-3-yl) -2- [3- (4-pyridin-4-yl-part Methoxy) -benzyl] -propionamide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (3-piperidine-1- Mono-propoxy) -phenyl] -butyl Amide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -Butylamide, 2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -penta Norick acid hydroxyamide, 2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [4- (3-piperidin-1-yl-propoxy) -phenyl] -Pentanoic acid hydroxyamide, 2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [4- (3-morpholin-4-yl-propoxy) -phenyl ] -Pentanoic acid hydroxyamide, 2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [3- (2-morpholin-4-yl-ethoxy)- Phenyl] -pentanoic acid hydroxyamide, 2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [3- (3-morpholin-4-yl-propoxy) -Phenyl] -pentanoic acid hydroxyamide, 2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [3- (2-piperidin-1-yl- Ethoxy) -phenyl] -pentanoic acid hydroxyamide, 2- (6-methyl-2-jade -2H-chromen-3-ylmethyl) -5- [3- (3-piperidin-1-yl-propoxy) -phenyl] -pentanoic acid hydroxyamide, 4- {3- [3- (4-Dimethylamino-phenyl) -propoxy] -phenyl} -N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide, 2- (6 -Methyl-2-oxo-2H-chromen-3-ylmethyl) -5- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -pentanoic acid hydroxyamide, N -hydroxy Oxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (2-pyrrole-1-yl-ethoxy) -phenyl] -butylamide, N − Hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- {4- [2- (2-oxo-pyrrolidin-1-yl) -ethoxy] -Phenyl} -butylamide, N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (2-piperidin-1-yl- Ethoxy) -phenyl] -butylamide, N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (3-piperidine-1 -Yl-propoxy) -phenyl] -butylamide, N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (2-morpholine -4 -Yl-ethoxy) -phenyl] -butylamide, N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [3- (3-morpholine 4-yl-propoxy) -phenyl] -butylamide, 4- [4- (3- [1,4 '] bipiperidinyl-1'-yl-propoxy) -phenyl] -N -hydroxy -2- (6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -butylamide, N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-yl Methyl) -4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -butylamide, N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3 -Ylmethyl) -4- [4- (3-morpholin-4-yl-propoxy) -phenyl] -butylamide, 2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl ) -6- [4- (3-piperidin-1-yl-propoxy) -phenyl] -hexanoic acid hydroxyamide, N -hydroxy-2- (7-methyl-2-oxo-2H- Chromen-3-ylmethyl) -4- [4- (3-piperidin-1-yl-propoxy) -phenyl] -butylamide, N -hydroxy-2- (7-methyl-2- Oxo-2H-chromen-3-ylmethyl) -4- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -butylamide, N -hydroxy-2- (7-methyl -2- Bovine -2H- chromene-3-ylmethyl) -4- {4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} butylamide, N-hydroxy-4 -(4-3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy-phenyl) -2- (7-methyl-2-oxo-2H-chromen-3- Monomethyl) -butylamide, 2- (7-fluoro-2-oxo-2H-chromen-3-ylmethyl) -N -hydroxy-4- [4- (2-morpholin-4-yl- Ethoxy) -phenyl] -butylamide, 2- (7-chloro-2-oxo-2H-chromen-3-ylmethyl) -N -hydroxy-4- [4- (3-piperidine-1 -Yl-propoxy) -phenyl] -butylamide, 2- (7-chloro-2-oxo-2H-chromen-3-ylmethyl) -N -hydroxy-4- [4- (3-morpholine 4-yl-propoxy) -phenyl] -butylamide, 2- (7-fluoro-2-oxo-2H-chromen-3-ylmethyl) -N -hydroxy-4- [4- (3 -Piperidin-1-yl-propoxy) -phenyl] -butylamide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4 -(2-Pyrrolidin-1-yl-ethoxy) -phenyl] -butylamide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4 -{4- [2- (4- Butyl-piperazin-1-yl) -ethoxy] -phenyl} butylamide, N-hydroxy-2- (6-methyl-2-oxo -2H- chromene-3-ylmethyl) -4- [ 4- (2-piperazin-1-yl-ethoxy) -phenyl] -butylamide, N -hydroxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4 -{4- [3- (4-oxo-piperidin-1-yl) -propoxy] -phenyl} -butylamide, N -hydroxy-2- (6-methyl-2-oxo-2H-chrome Men-3-ylmethyl) -4- [4- (3-pyrrolidin-1-yl-propoxy) -phenyl] -butylamide, N -hydroxy-2- (6-methyl-2-oxo- 2H-chromen-3-ylmethyl) -4- {4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -butylamide, N -hydroxy-2- ( 6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (3-piperazin-1-yl-propoxy) -phenyl] -butylamide, N -hydroxy-2 -(6-Methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (3-morpholin-4-yl-propylamino) -phenyl] -butylamide, N -hydride Oxy-2- (6-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (3-piperidin-1-yl-propylamino) -phenyl] -butylamide, 2-( 7-fluoro-2-oxo-2H-chromen-3-ylmethyl) -N -hydroxy-4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -butylamide hydro Chloride, N-hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -Butylamide hydrochloride, N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (3-morpholin-4-yl-propoxy ) -Phenyl] -butylamide hydrochloride, N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (3-piperidine-1 -Yl-propoxy) -phenyl] -butylamide hydrochloride, N -hydroxy-2- (7-methyl-2-oxo-2H-chromen-3-ylmethyl) -4- [4- (4- Piperidin-1-yl-butyl) -phenyl] -butylamide hydrochloride 제3항, 제5항 및 제7항에 기재된 일반식 (Ⅱ) 내지 일반식 (IV) 화합물을 유효성분으로 함유하는 관절염 및 염증성 질환의 치료 및 예방용 약학 조성물.A pharmaceutical composition for the treatment and prophylaxis of arthritis and inflammatory diseases, comprising the compounds of formulas (II) to (IV) according to claims 3, 5 and 7 as an active ingredient. 삭제delete 제 9항에 있어서, 상기 관절염은 류마티스성 관절염 (rheumatoid arthritis), 척추성 관절염 (spondyloarthopathies), 통풍(gout), 골관절염 (osteoarthritis), 전신성 홍반성 루푸스 (systemic lupus erythematosus) 또는 유년기 관절염 (juvenile arthritis)인 약학조성물.10. The arthritis of claim 9, wherein the arthritis is rheumatoid arthritis, spondyloarthopathies, gout, osteoarthritis, systemic lupus erythematosus or juvenile arthritis. Phosphorus pharmaceutical composition. 제 9항에 있어서, 상기 염증성 질환은 근육염 (myositis), 치은염 (gingivitis), 활막염 (synovitis), 강직성 척추염 (ankylosing spondylitis), 활액낭염 (burstitis), 화상 (burns), 상처, 염증성 대장질환 (inflammatory bowel disease), 크론병 (Crohn's disease), 제 1형 당뇨병 (Type I diabetes), 건선 (Psoriasis)으로 이루어진 군으로 선택되는 염증성 질환인 약학조성물.The method of claim 9, wherein the inflammatory disease is myositis, gingivitis, synovitis, ankylosing spondylitis, burstitis, burns, wounds, inflammatory bowel disease pharmaceutical composition, which is an inflammatory disease selected from the group consisting of disease, Crohn's disease, Type I diabetes, and Psoriasis.
KR1020060065157A 2005-07-12 2006-07-12 Novel Chromen-2-one based hydroxamic acid derivatives having anti-inflammatory activity, the preparation thereof and a composition containing the same for treating inflammatory disease KR100794515B1 (en)

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