KR101271219B1 - Novel Hydantoin Derivatives and Uses Thereof - Google Patents

Novel Hydantoin Derivatives and Uses Thereof Download PDF

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KR101271219B1
KR101271219B1 KR1020110008329A KR20110008329A KR101271219B1 KR 101271219 B1 KR101271219 B1 KR 101271219B1 KR 1020110008329 A KR1020110008329 A KR 1020110008329A KR 20110008329 A KR20110008329 A KR 20110008329A KR 101271219 B1 KR101271219 B1 KR 101271219B1
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KR20120086957A (en
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김용철
이가은
박진희
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광주과학기술원
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Abstract

본 발명은 다양한 신규 하이단토인(Hydantoin) 유도체 화합물 및 이들을 유효성분으로 포함하는 P2X7 수용체 활성 억제용 조성물에 관한 것이다. 본 발명은 P2X7 수용체의 활성과 관련된 다양한 질환, 즉 만성 염증성 질환, 염증성 통증, 신경병성 통증, 자가면역 질환 또는 퇴행성 질환의 예방 또는 치료에 유용하게 이용될 수 있다.The present invention relates to various novel Hydantoin derivative compounds and compositions for inhibiting P2X 7 receptor activity comprising them as an active ingredient. The present invention can be usefully used for the prevention or treatment of various diseases related to the activity of the P2X 7 receptor, that is, chronic inflammatory disease, inflammatory pain, neuropathic pain, autoimmune disease or degenerative disease.

Description

신규한 하이단토인 유도체 및 이의 용도{Novel Hydantoin Derivatives and Uses Thereof}Novel Hydantoin Derivatives and Uses thereof {Novel Hydantoin Derivatives and Uses Thereof}

본 발명은 신규한 하이단토인 유도체 및 이의 P2X7 수용체의 활성과 관련된 질환의 예방 및 치료용도에 관한 것이다.
The present invention relates to the use of the novel hydantoin derivatives and their prevention and treatment for diseases associated with the activity of the P2X 7 receptor.

ATP(adenosine 5'-triphosphate)는 세포내에 일차원적인 에너지원으로 이용될 뿐만 아니라 세포외에도 미량 존재하며 세포내 다양한 생리적 기능에 관여하는 것으로 알려져 있는데, 특히 중추신경계 및 신경·평활근 시냅스에서 작용하는 중요한 전달물질이다. 세포 외액의 ATP와 같은 아데닌(adenine) 뉴클레오티드 및 아데노신(adenosine)의 작용은 세포 외막에 존재하는 수용체를 매개로 이루어지는데, 이러한 수용체를 퓨린성 수용체(퓨린ergic rceptor)라 한다. 아데노신과 AMP(adenosine monophosphate)의 작용이 우세한 P1 수용체는 다시 A1, A2 및 A3로, ADP와 ATP의 작용이 우세한 P2 수용체는 리간드-의존성(ligand-gated) 이온채널인 P2X와 G-단백과 연결된 P2Y로 나누어진다. 현재까지 포유류에서 클로닝된 P2X 수용체의 아형은 7개(P2X1 -7), P2Y 수용체의 아형은 8개(P2X1 -8)로 알려져 있다. 그 중 리간드 활동성 양이온 채널인 P2X 수용체들은 효현제 ATP의 직접적인 결합에 의해 활성화 되고 세포 외부의 Na+, Ca2 +과 같은 작은 양이온의 유입을 유도하며 근육 수축 유발(P2X1), 통증에 대한 감각 기능 담당(P2X3 or P2X2 /3), 척추로부터의 신경전달 관여(P2X2 ,4,6), 위 장관, 방관 및 흉선의 세포성장에 관여(P2X5), 세포사멸유도 및 염증반응 작용(P2X7) 등 다양한 생체기능의 조절에 관여한다고 보고하고 있다. P2X 수용체를 구성하는 단위체는 두 개의 세포막 통과부위(transmembrane region)를 갖는 세포막 단백이며 N-말단과 C-말단은 세포 내에 존재할 것으로 예상되는데, P2X7 수용체는 다른 P2X 수용체의 서브타입과 다르게 C-말단이 240 아미노산(a.a.) 만큼 더 길다(도 1).ATP (adenosine 5'-triphosphate) is not only used as a one-dimensional energy source in cells but also present in trace amounts outside the cells and is involved in various physiological functions in the cells. Especially, it is an important transporter acting in the central nervous system and nerve and smooth muscle synapses. It is a substance. The action of adenine nucleotides and adenosine, such as ATP in the extracellular fluid, is mediated by receptors present in the extracellular membrane, which are called purinergic receptors. The P1 receptors that dominate the action of adenosine and AMP (adenosine monophosphate) are A 1 , A 2, and A 3. The P2 receptors that dominate the action of ADP and ATP are the ligand-gated ion channels, P2X and G-. It is divided into P2Y linked to protein. Subsets of the P2X receptors in a mammal cloned to date, seven (P2X 1 -7), P2Y receptor subtypes are known as eight (P2X 1 -8). Among them, the ligand activity cation channel of P2X receptors are activated by a direct binding of the agonist ATP cell external Na +, sensory function to induce the influx of small cations and muscle contraction induced (P2X 1), pain such as Ca 2 + responsible (P2X 3 or P2X 2/3 ), neurotransmitters involved from the spine (P2X 2, 4,6), above the ministers, involved in cell growth of bladder and thymus (P2X 5), induce apoptosis and inflammatory activity ( P2X 7 ) is reported to be involved in the regulation of various biological functions. Units constituting the P2X receptors are membrane proteins with two membrane-pass region (transmembrane region) N- terminus and C- terminus there is expected to be present in the cell, P2X 7 receptors are different from the other subtypes of P2X receptors C- The terminal is longer by 240 amino acids (aa) (FIG. 1).

다른 P2X 수용체와 마찬가지로 P2X7 수용체는 내생(endogenous) ATP와 합성된 BzATP(2'(3')-O-(4-benzolybenzoly)adenosine 5'-triphospate)에 의한 짧은 자극으로 양이온 채널의 개방을 통한 일시적인 흐름(current)을 발생시킨다. 그러나 특이하게 다른 P2X 수용체와 달리 반복적이고 계속적인 효현제의 자극은 비선택적 포어의 형성을 통한 지속적인 흐름(current)를 발생시키고, 이 포어는 분자량이 900 Da까지의 큰 양이온들(ethidium bromide, propidium iodide, Yo-PRO-1 등)을 통과시킬 수 있다. 이러한 채널확장 과정과 관계되는 메커니즘은 P2X7 수용체의 C-말단 부분에 의해서라고 생각되어지고 있다. Like other P2X receptors, the P2X 7 receptor is a short stimulus by endogenous ATP and BzATP (2 '(3')-O- (4-benzolybenzoly) adenosine 5'-triphospate) synthesized through the opening of the cation channel. Generate a temporary current. However, unlike other P2X receptors, repetitive and continuous stimulation of the agonist produces a continuous current through the formation of non-selective pores, which are large cations (ethidium bromide, propidium iodide up to 900 Da). , Yo-PRO-1, etc.). The mechanism involved in this channel expansion process is thought to be due to the C-terminal portion of the P2X 7 receptor.

P2X7 수용체는 조혈계 세포(예: 비만세포(mast cells), 대식세포(macrophages), 섬유아세포(fibroblasts), 인간 단핵구 세포주 THP-1 등)에 분포하기 때문에 염증의 중재자로서 고려되어지는데, 특히, P2X7 수용체는 뇌와 말초의 대부분의 면역계 세포에서 발견되며, 그들의 활성은 세포투과화(Cell permeabilization), 세포사멸(apopatosis), 사이토카인 방출과 같은 다양한 다운스트림을 이끈다. 면역세포(immunocyte)의 선택적 발현 뿐 아니라, P2X7 수용체는 중추 신경계나 말초 신경계의 전연접부(presynaptic) 말단이나 인간 상피 랑거한스 세포와 같은 면역조절과 관계없는 세포에도 존재한다. P2X7 수용체는 microglia 세포에 풍부하게 존재하는데, 신경 손상으로 인한 통증의 발생할 때 중추신경계의 면역기전에 관여한다고 보고되고 있다. 알려진 바에 의하면, 신경이 손상되면 미세아교세포가 활성화 되는데, 이러한 활성화로 P2X7의 발현이 미세아교세포에서 증가하게 된다(도 2). 이 수용체는 일차 구심성 감각 신경세포나 성상세포(astrocyte)에서 분비되는 ATP에 의해 활성화되어, 세포내 칼슘을 증가시키고, p38 MAP 카이네이즈를 활성화시켜, 사이토카인이나 신경영양인자(neurotrophic facotr) 등을 방출시키게 되어, 통증을 발생시킨다고 한다. 또한, 활성화된 미세아교세포에서의 P2X7 수용체의 업-레귤레이션은 허혈 손상과 세포괴사(necrosis)와 관계된다고 보고되고 있다. 이에 본 발명자들은 P2X7 수용체의 효과적인 길항 활성을 가지는 화합물을 스크리닝함으로써 자가면역 질환과 염증성 질환 및 다양한 퇴행성 질환의 예방 또는 치료에 이용하고자 하였다.
P2X 7 receptors are considered as mediators of inflammation because they are distributed in hematopoietic cells (eg, mast cells, macrophages, fibroblasts, human monocyte line THP-1, etc.), in particular , P2X 7 receptors are found in most immune system cells in the brain and peripherals, and their activity leads to various downstream such as cell permeabilization, apoptosis, and cytokine release. In addition to selective expression of immune cells, P2X 7 receptors are also present in cells that are not involved in immunomodulation, such as the presynaptic end of the central or peripheral nervous system or human epidermal Langerhans cells. P2X 7 receptors are present in abundance in microglia cells and are reported to be involved in the central nervous system's immune mechanisms in the event of pain caused by nerve damage. As is known, when the nerves are damaged, microglia are activated, and this activation causes the expression of P2X 7 to increase in microglia (FIG. 2). This receptor is activated by ATP secreted by primary afferent sensory neurons or astrocytes, increasing intracellular calcium, activating p38 MAP kinase, and releasing cytokines and neurotrophic facotr. It is said to cause pain. In addition, up-regulation of P2X 7 receptor in activated microglia has been reported to be associated with ischemic damage and necrosis. Accordingly, the present inventors have screened a compound having an effective antagonistic activity of the P2X 7 receptor to be used for the prevention or treatment of autoimmune diseases, inflammatory diseases and various degenerative diseases.

본 명세서 전체에 걸쳐 다수의 논문 및 특허문헌이 참조되고 그 인용이 표시되어 있다. 인용된 논문 및 특허문헌의 개시 내용은 그 전체로서 본 명세서에 참조로 삽입되어 본 발명이 속하는 기술 분야의 수준 및 본 발명의 내용이 보다 명확하게 설명된다.
Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

본 발명자들은 면역기능 및 신경세포의 사멸에 중요한 영향을 하는 것으로 여겨지는 P2X7 수용체의 효과적인 길항제를 발굴함으로써 자가면역 질환과 염증성 질환 및 다양한 퇴행성 질환의 예방 또는 치료용 조성물을 개발하기 위하여 예의 연구 노력하였다. 그 결과 본 발명의 신규한 하이단토인 유도체가 P2X7 수용체의 활성을 매우 효과적으로 억제함을 발견함으로써, 본 발명을 완성하게 되었다.The present inventors have made diligent research efforts to develop compositions for the prevention or treatment of autoimmune diseases, inflammatory diseases and various degenerative diseases by discovering effective antagonists of P2X 7 receptors, which are believed to have important effects on immune function and neuronal cell death. It was. As a result, the present invention has been completed by discovering that the novel hydantoin derivative of the present invention inhibits the activity of the P2X 7 receptor very effectively.

따라서 본 발명의 목적은 신규한 하이단토인 유도체를 제공하는 데 있다.It is therefore an object of the present invention to provide novel hydantoin derivatives.

본 발명의 다른 목적은 만성 염증성 질환, 염증성 통증, 신경병성 통증, 자가면역 질환 또는 퇴행성 질환의 예방 또는 치료용 조성물을 제공하는 데 있다.Another object of the present invention to provide a composition for preventing or treating chronic inflammatory diseases, inflammatory pain, neuropathic pain, autoimmune diseases or degenerative diseases.

본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명, 청구범위 및 도면에 의해 보다 명확하게 된다.
Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

본 발명의 일 양태에 따르면, 본 발명은 하기의 화학식 1로 표시되는 하이단토인(Hydantoin) 유도체를 제공한다:According to one aspect of the invention, the present invention provides Hydantoin derivative represented by the following formula (1):

화학식 1Formula 1

Figure 112011006794440-pat00001
Figure 112011006794440-pat00001

상기 화학식에서, R1 및 R2는 각각 독립적으로 수소, 피페리딘, 피페리디닐 C1-C4 알킬, 퀴놀린, 이소퀴놀린, 퀴놀리닐 C1-C4 알킬 또는 이소퀴놀리닐 C1-C4 알킬이고, R3-R6는 각각 독립적으로 수소, 할로, 히드록시, 아미노, 니트로, 니트로소, 시아노, C1-C10 알킬, C2-C20 알케닐, C1-C10 알콕시, C2 -C20 알콕시알킬, C3 -20 알콕시알콕시알킬, 아릴, 헤테로아릴, 아릴알킬, 아릴알케닐 또는 알킬아릴이며, R7은 산소, NH 또는 C0-C4 알킬이고, R8은 설포닐(-S(O)2-) 또는 카르보닐(-C(O)-)이며, R9는 퀴놀린, 이소퀴놀린, 퀴놀리닐 C1-C4 알킬 또는 이소퀴놀리닐 C1-C4 알킬이고, n은 0-5의 정수이다. In the above formula, R 1 And each R 2 is independently hydrogen, piperidine, piperidinyl C 1 -C 4 alkyl, quinoline, isoquinoline, quinolinyl C 1 -C 4 alkyl or isoquinolinyl C 1 -C 4 alkyl, R 3 -R 6 are each independently hydrogen, halo, hydroxy, amino, nitro, nitroso, cyano, C 1 -C 10 alkyl, C 2 -C 20 Alkenyl, C 1 -C 10 Alkoxy, C 2 - C 20 alkoxyalkyl, C 3 -20 alkoxyalkoxy, aryl, heteroaryl, arylalkyl, aryl alkenyl, or alkyl aryl, R 7 is an oxygen, NH, or C 0 -C 4 alkyl, R 8 is sulfonyl (-S (O) 2- ) or carbonyl (-C (O)-), R 9 is quinoline, isoquinoline, quinolinyl C 1 -C 4 alkyl or isoquinolinyl C 1 -C 4 alkyl, n is an integer of 0-5.

본 발명자들은 면역기능 및 신경세포의 사멸에 중요한 영향을 하는 것으로 여겨지는 P2X7 수용체의 효과적인 길항제를 발굴함으로써 자가면역 질환과 염증성 질환 및 다양한 퇴행성 질환의 예방 또는 치료용 조성물을 개발하기 위하여 예의 연구 노력하였다. 그 결과 본 발명의 하이단토인 유도체가 P2X7 수용체의 활성을 매우 효과적으로 억제함을 발견하였다. The present inventors have made diligent research efforts to develop compositions for the prevention or treatment of autoimmune diseases, inflammatory diseases and various degenerative diseases by discovering effective antagonists of P2X 7 receptors, which are believed to have important effects on immune function and neuronal cell death. It was. As a result, it was found that the hydantoin derivative of the present invention inhibits the activity of the P2X 7 receptor very effectively.

본 명세서에서 용어“알킬”은 직쇄, 분쇄 또는 사이클릭 구조의 비치환 또는 치환된 포화 탄화수소기를 의미하며, 예를 들어, 메틸, 에틸, 프로필, 이소부틸, 펜틸, 헥실, 헵틸, 옥틸, 노닐, 데실, 운데실, 트리데실, 펜타데실 및 헵타데실, 사이클로프로필, 사이클로부틸 및 사이클로펜틸 등을 포함한다. C1-C4 알킬은 탄소수 1 내지 4의 알킬 유니트를 가지는 알킬기를, C1-C10 알킬은 탄소수 1 내지 10의 알킬 유니트를 가지는 알킬기를 각각 의미하며, C1-C4 또는 C1-C10 알킬이 치환된 경우 치환체의 탄소수는 포함되지 않은 것이다. As used herein, the term "alkyl" refers to an unsubstituted or substituted saturated hydrocarbon group of straight, pulverized or cyclic structure, for example methyl, ethyl, propyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, Decyl, undecyl, tridecyl, pentadecyl and heptadecyl, cyclopropyl, cyclobutyl and cyclopentyl and the like. C 1 -C 4 alkyl means an alkyl group having an alkyl unit having 1 to 4 carbon atoms, C 1 -C 10 alkyl means an alkyl group having an alkyl unit having 1 to 10 carbon atoms, respectively, and C 1 -C 4 Or when C 1 -C 10 alkyl is substituted, carbon number of the substituent is not included.

본 명세서에서 용어“피페리디닐 알킬”은 피페리딘기로 치환된 알킬기를 의미한다. 피페리디닐 C1-C4 알킬은 탄소수 1 내지 4의 피페리디닐 알킬 유니트를 가지는 피페리디닐 알킬기를 의미하며, 피페리디닐 C1-C4 알킬이 치환된 경우 치환체의 탄소수는 포함되지 않은 것이다.As used herein, the term “piperidinyl alkyl” refers to an alkyl group substituted with a piperidine group. Piperidinyl C 1 -C 4 Alkyl means a piperidinyl alkyl group having a piperidinyl alkyl unit having 1 to 4 carbon atoms, and piperidinyl C 1 -C 4 When alkyl is substituted, the carbon number of the substituent is not included.

본 명세서에서 용어“퀴놀리디닐 알킬”은 퀴놀린기로 치환된 알킬기를 의미한다. 퀴놀리디닐 C1-C4 알킬은 탄소수 1 내지 4의 퀴놀리디닐 알킬 유니트를 가지는 퀴놀리디닐 알킬기를 의미하며, 퀴놀리디닐 C1-C4 알킬이 치환된 경우 치환체의 탄소수는 포함되지 않은 것이다.As used herein, the term "quinolidinyl alkyl" refers to an alkyl group substituted with a quinoline group. Quinolidinyl C 1 -C 4 Alkyl means a quinolidinyl alkyl group having a quinolidinyl alkyl unit having 1 to 4 carbon atoms, and quinolidinyl C 1 -C 4 When alkyl is substituted, the carbon number of the substituent is not included.

본 명세서에서 용어“이소퀴놀리디닐 알킬”은 이소퀴놀린기로 치환된 알킬기를 의미한다. 이소퀴놀리디닐 C1-C4 알킬은 탄소수 1 내지 4의 이소퀴놀리디닐 알킬 유니트를 가지는 이소퀴놀리디닐 알킬기를 의미하며, 이소퀴놀리디닐 C1-C4 알킬이 치환된 경우 치환체의 탄소수는 포함되지 않은 것이다.As used herein, the term “isoquinolidinyl alkyl” refers to an alkyl group substituted with an isoquinoline group. Isoquinolidinyl C 1 -C 4 Alkyl means an isoquinolidinyl alkyl group having isoquinolidinyl alkyl units having 1 to 4 carbon atoms, and isoquinolidinyl C 1 -C 4 When alkyl is substituted, the carbon number of the substituent is not included.

본 명세서에서 용어“할로”는 할로겐족 원소를 나타내며, 예컨대, 플루오로, 클로로, 브로모 및 요오도를 포함한다.As used herein, the term “halo” refers to a halogen group element and includes, for example, fluoro, chloro, bromo and iodo.

본 명세서에서 용어 “알케닐”은 지정된 탄소수를 가지는 직쇄 또는 분쇄의 비치환 또는 치환된 불포화 탄화수소기를 나타내며, 예컨대, 에테닐, 비닐, 프로페닐, 알릴, 이소프로페닐, 부테닐, 이소부테닐, t-부테닐, n-펜테닐 및 n-헥세닐을 포함한다. 화학식 1에서, R3-R6 위치의 C2-C20 알케닐은 탄소수 2 내지 20의 알케닐 유니트를 가지는 알케닐기를 의미하며, C2-C20 알케닐이 치환된 경우 치환체의 탄소수는 포함되지 않은 것이다. As used herein, the term “alkenyl” refers to a straight-chain or branched unsubstituted or substituted unsaturated hydrocarbon group having the specified carbon number, for example ethenyl, vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, t -Butenyl, n -pentenyl and n -hexenyl. In Formula 1, C 2 -C 20 at the R 3 -R 6 position Alkenyl means an alkenyl group having an alkenyl unit having 2 to 20 carbon atoms. When C 2 -C 20 alkenyl is substituted, carbon atoms of the substituent are not included.

본 명세서에서 용어“알콕시”는 알코올에서 수소가 제거되어 형성된 라디칼을 의미하며, C2-C10 알콕시가 치환된 경우 치환체의 탄소수는 포함되지 않은 것이다. As used herein, the term “alkoxy” refers to a radical formed by the removal of hydrogen from an alcohol, and C 2 -C 10. When alkoxy is substituted, the carbon number of the substituent is not included.

본 명세서에서 용어“알콕시알킬”은 알콕시기로 치환된 알킬을 의미한다. C2-C20 알콕시알킬은 탄소수 2 내지 20의 알콕시알킬 유니트를 가지는 알콕시알킬기를 의미하며, C2-C20 알콕시알킬이 치환된 경우 치환체의 탄소수는 포함되지 않은 것이다.The term "alkoxyalkyl" used herein means alkyl substituted with an alkoxy group. C 2 -C 20 alkoxyalkyl means an alkoxyalkyl group having an alkoxyalkyl unit having 2 to 20 carbon atoms, and when C 2 -C 20 alkoxyalkyl is substituted, the carbon number of the substituent is not included.

본 명세서에서 용어“알콕시알콕시알킬”은 알콕시알콕시기로 치환된 알킬기(알콕시-알콕시-알킬-)를 의미한다. C3-C20 알콕시알콕시알킬은 탄소수 3 내지 20의 알콕시알콕시알킬 유니트를 가지는 알콕시알콕시알킬기를 의미하며, C3-C20 알콕시알콕시알킬이 치환된 경우 치환체의 탄소수는 포함되지 않은 것이다.The term "alkoxyalkoxyalkyl" used herein means an alkyl group (alkoxy-alkoxy-alkyl-) substituted with an alkoxyalkoxy group. C 3 -C 20 alkoxyalkoxyalkyl means an alkoxyalkoxyalkyl group having an alkoxyalkoxyalkyl unit having 3 to 20 carbon atoms, and when C 3 -C 20 alkoxyalkoxyalkyl is substituted, the carbon number of the substituent is not included.

본 명세서에서 용어“아릴”은 전체적으로 또는 부분적으로 불포화되고 방향성(aromaticity)를 가지는 치환 또는 비치환된 모노사이클릭 또는 폴리사이클릭 탄소 고리를 의미한다.As used herein, the term “aryl” refers to a substituted or unsubstituted monocyclic or polycyclic carbon ring that is wholly or partially unsaturated and has aromaticity.

본 명세서에서 용어“헤테로아릴”은 헤테로원자로서 고리 내에 산소, 황 또는 질소를 포함하는 헤테로사이클릭 방향족기를 의미한다. 바람직하게는, 헤테로원자는 질소이다. 헤테로원자의 개수는 1-4이며, 바람직하게는 1-2이다. 헤테로아릴에서 아릴은 바람직하게는 모노아릴 또는 비아릴이다. 헤테로아릴은 다양한 위치에서 다양한 치환체에 의해 치환될 수 있으며, 예컨대, 할로, 히드록시, 니트로, 시아노, C1-C4 치환 또는 비치환된 직쇄 또는 가지쇄 알킬, C1-C4 직쇄 또는 가지쇄 알콕시에 의해 치환될 수 있다.As used herein, the term “heteroaryl” refers to a heterocyclic aromatic group containing oxygen, sulfur or nitrogen in the ring as a heteroatom. Preferably, the heteroatom is nitrogen. The number of heteroatoms is 1-4, preferably 1-2. In heteroaryl aryl is preferably monoaryl or biaryl. Heteroaryl may be substituted by various substituents at various positions, such as halo, hydroxy, nitro, cyano, C 1 -C 4 Substituted or unsubstituted straight or branched chain alkyl, C 1 -C 4 It may be substituted by straight chain or branched alkoxy.

본 명세서에서 용어 “아릴알킬”은 아릴기로 치환된 알킬을 의미한다.The term "arylalkyl" used herein means alkyl substituted with an aryl group.

본 명세서에서 용어 “아릴아케닐”은 아릴기로 치환된 아케닐을 의미한다.As used herein, the term “arylakenyl” refers to akenyl substituted with an aryl group.

본 명세서에서 용어 “알킬아릴”은 알킬기로 치환된 아릴을 의미한다.The term "alkylaryl" used herein means aryl substituted with an alkyl group.

본 발명의 바람직한 구현예에 따르면, 본 발명의 화학식 1의 R7은 산소이다.According to a preferred embodiment of the invention, R 7 in formula 1 of the present invention is oxygen.

본 발명의 바람직한 구현예에 따르면, 본 발명의 화학식 1의 R8은 설포닐(-S(O)2-)이다.According to a preferred embodiment of the invention, R 8 of formula 1 of the present invention is sulfonyl (-S (O) 2- ).

본 발명의 바람직한 구현예에 따르면, 본 발명의 화학식 1의 R1 또는 R2의 피페리딘 또는 피페리디닐 C1-C4 알킬은 고리 내 질소가 아실기 또는 페닐 C1-C4 알킬로 치환된다.
According to a preferred embodiment of the invention, R 1 of formula 1 of the present invention Or the piperidine or piperidinyl C 1 -C 4 alkyl of R 2 is substituted with an acyl group or phenyl C 1 -C 4 alkyl with nitrogen in the ring.

본 발명의 보다 바람직한 구현예에 따르면, 본 발명의 하이단토인 유도체는 하기의 화학식 2 내지 43으로 표시되는 화합물로 구성된 군으로부터 선택된다:According to a more preferred embodiment of the present invention, the hydantoin derivative of the present invention is selected from the group consisting of compounds represented by the following formulas 2 to 43:

화학식 2 화학식 3       Formula 2 Formula 3

Figure 112011006794440-pat00002
Figure 112011006794440-pat00003

Figure 112011006794440-pat00002
Figure 112011006794440-pat00003

화학식 4 화학식 5       Formula 4 Formula 5

Figure 112011006794440-pat00004
Figure 112011006794440-pat00005

Figure 112011006794440-pat00004
Figure 112011006794440-pat00005

화학식 6 화학식 7 Formula 6 Formula 7

Figure 112011006794440-pat00006
Figure 112011006794440-pat00007

Figure 112011006794440-pat00006
Figure 112011006794440-pat00007

화학식 8 화학식 9      Formula 8 Formula 9

Figure 112011006794440-pat00008
Figure 112011006794440-pat00009
Figure 112011006794440-pat00008
Figure 112011006794440-pat00009

화학식 10 화학식 11      Formula 10 Formula 11

Figure 112011006794440-pat00010
Figure 112011006794440-pat00011

Figure 112011006794440-pat00010
Figure 112011006794440-pat00011

화학식 12 화학식 13Chemical Formula 12 Chemical Formula 13

Figure 112011006794440-pat00012
Figure 112011006794440-pat00013

Figure 112011006794440-pat00012
Figure 112011006794440-pat00013

화학식 14 화학식 15      Formula 14 Formula 15

Figure 112011006794440-pat00014
Figure 112011006794440-pat00015

Figure 112011006794440-pat00014
Figure 112011006794440-pat00015

화학식 16 화학식 17      Formula 16 Formula 17

Figure 112011006794440-pat00016
Figure 112011006794440-pat00017

Figure 112011006794440-pat00016
Figure 112011006794440-pat00017

화학식 18 화학식 19       Formula 18 Formula 19

Figure 112011006794440-pat00018
Figure 112011006794440-pat00019

Figure 112011006794440-pat00018
Figure 112011006794440-pat00019

화학식 20 화학식 21      Chemical Formula 20 Chemical Formula 21

Figure 112011006794440-pat00020
Figure 112011006794440-pat00021

Figure 112011006794440-pat00020
Figure 112011006794440-pat00021

화학식 22 화학식 23      Chemical Formula 22 Chemical Formula 23

Figure 112011006794440-pat00022
Figure 112011006794440-pat00023

Figure 112011006794440-pat00022
Figure 112011006794440-pat00023

화학식 24 화학식 25      Chemical Formula 24 Chemical Formula 25

Figure 112011006794440-pat00024
Figure 112011006794440-pat00025

Figure 112011006794440-pat00024
Figure 112011006794440-pat00025

화학식 26 화학식 27      Formula 26 Formula 27

Figure 112011006794440-pat00026
Figure 112011006794440-pat00027

Figure 112011006794440-pat00026
Figure 112011006794440-pat00027

화학식 28 화학식 29      Chemical Formula 28 Chemical Formula 29

Figure 112011006794440-pat00028
Figure 112011006794440-pat00029

Figure 112011006794440-pat00028
Figure 112011006794440-pat00029

화학식 30 화학식 31      Chemical Formula 30 Chemical Formula 31

Figure 112011006794440-pat00030
Figure 112011006794440-pat00031

Figure 112011006794440-pat00030
Figure 112011006794440-pat00031

화학식 32 화학식 33      Chemical Formula 32 Chemical Formula 33

Figure 112011006794440-pat00032
Figure 112011006794440-pat00033

Figure 112011006794440-pat00032
Figure 112011006794440-pat00033

화학식 34 화학식 35      Chemical Formula 34 Chemical Formula 35

Figure 112011006794440-pat00034
Figure 112011006794440-pat00035
Figure 112011006794440-pat00034
Figure 112011006794440-pat00035

화학식 36 화학식 37      Formula 36 Formula 37

Figure 112011006794440-pat00036
Figure 112011006794440-pat00037

Figure 112011006794440-pat00036
Figure 112011006794440-pat00037

화학식 38 화학식 39      Formula 38 Formula 39

Figure 112011006794440-pat00038
Figure 112011006794440-pat00039

Figure 112011006794440-pat00038
Figure 112011006794440-pat00039

화학식 40 화학식 41      Formula 40 Formula 41

Figure 112011006794440-pat00040
Figure 112011006794440-pat00041
Figure 112011006794440-pat00040
Figure 112011006794440-pat00041

화학식 42 화학식 43      Chemical Formula 42 Chemical Formula 43

Figure 112011006794440-pat00042
Figure 112011006794440-pat00043

Figure 112011006794440-pat00042
Figure 112011006794440-pat00043

화학식 44 화학식 45      Formula 44 Formula 45

Figure 112011006794440-pat00044
Figure 112011006794440-pat00045

Figure 112011006794440-pat00044
Figure 112011006794440-pat00045

화학식 46Formula 46

Figure 112011006794440-pat00046

Figure 112011006794440-pat00046

가장 바람직하게는, 본 발명의 하이단토인 유도체는 상기의 화학식 13, 14, 25 내지 27, 29 내지 33, 36, 38 내지 43, 45 및 46으로 표시되는 화합물로 이루어진 군으로부터 선택된다.Most preferably, the hydantoin derivative of the present invention is selected from the group consisting of the compounds represented by the above formulas (13), (14), (25)-(27), (29)-(33), (36), (38)-(43), (45) and (46).

본 발명에 따르면, 상기 나열한 16가지 화합물은 P2X7 수용체의 다운-레귤레이션에 있어서 매우 낮은 IC50 값을 가진다. 따라서 이들은 P2X7 활성과 관련된 다양한 질환의 효과적인 치료 조성물로 이용될 수 있다.
According to the present invention, the 16 compounds listed above have a very low IC 50 in down-regulation of the P2X 7 receptor. Value. So these are P2X 7 It can be used as an effective therapeutic composition for various diseases related to activity.

본 발명의 다른 양태에 따르면, 본 발명은 본 발명의 하이단토인 유도체를 유효성분으로 포함하는 만성 염증성 질환, 염증성 통증, 신경병성 통증, 자가면역 질환 또는 퇴행성 질환의 예방 또는 치료용 조성물을 제공한다.According to another aspect of the present invention, the present invention provides a composition for the prevention or treatment of chronic inflammatory disease, inflammatory pain, neuropathic pain, autoimmune disease or degenerative disease comprising the hydantoin derivative of the present invention as an active ingredient. .

본 발명의 조성물이 약제학적 조성물로 제조되는 경우, 본 발명의 약제학적 조성물은 약제학적으로 허용되는 담체를 포함한다. 본 발명의 약제학적 조성물에 포함되는 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약제학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. 적합한 약제학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences (19th ed., 1995)에 상세히 기재되어 있다.When the composition of the present invention is made into a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers included in the pharmaceutical compositions of the present invention are those commonly used in the preparation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like It doesn't happen. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).

본 발명의 약제학적 조성물은 경구 또는 비경구 투여할 수 있으며, 비경구 투여인 경우에는 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 경피 투여 등으로 투여할 수 있다. The pharmaceutical composition of the present invention may be administered orally or parenterally, and in the case of parenteral administration, it may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, or the like.

본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 본 발명의 약제학적 조성물의 1일 투여량은 예컨대 0.001-100 ㎎/㎏이다.The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . The daily dosage of the pharmaceutical composition of the present invention is, for example, 0.001-100 mg / kg.

본 발명의 약제학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액, 시럽제 또는 유화액 형태이거나 엑스제, 산제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.The pharmaceutical compositions of the present invention may be prepared in unit dose form by formulating with a pharmaceutically acceptable carrier and / or excipient according to methods which can be easily carried out by those skilled in the art. Or may be prepared by incorporation into a multi-dose container. The formulation may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of extracts, powders, powders, granules, tablets or capsules, and may further comprise dispersants or stabilizers.

본 발명의 바람직한 구현예에 따르면, 본 발명의 조성물로 예방 또는 치료되는 자가면역 질환은 류마티스 관절염, 건선, 알러지성 피부염, 다발성 경화증, 자가 면역성 뇌척수염, 자가 면역성 빈혈, 전신성 홍반성 루푸스 및 천식으로 구성된 군으로부터 선택되는 질환이다.According to a preferred embodiment of the invention, the autoimmune disease to be prevented or treated with the composition of the present invention consists of rheumatoid arthritis, psoriasis, allergic dermatitis, multiple sclerosis, autoimmune encephalomyelitis, autoimmune anemia, systemic lupus erythematosus and asthma Disease selected from the group.

본 발명의 바람직한 구현예에 따르면, 본 발명의 조성물로 예방 또는 치료되는 만성 염증성 질환은 만성폐쇄성 폐질환(chronic obstructive pulmonary disease), 기도 과민성 질환(airways hyper-responsiveness), 폐혈성 쇼크(septic shock), 사구체 신염, 염증성 장질환(염증), 크론병(Crohn's disease), 궤양잘록창자염(ulcerative colitis), 아테롬성 동맥경화증, 골수아구 세포성 백혈병(myoblastic leukaemia), 당뇨, 화상, 허혈성 심장질환, 뇌졸중, 수막염 및 정맥류로 구성된 군으로부터 선택되는 질환이다. According to a preferred embodiment of the present invention, the chronic inflammatory disease prevented or treated with the composition of the present invention is chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock , Glomerulonephritis, inflammatory bowel disease (inflammatory), Crohn's disease, ulcerative colitis, atherosclerosis, myoblastic leukaemia, diabetes, burns, ischemic heart disease, stroke , Meningitis and varicose veins.

본 발명의 바람직한 구현예에 따르면, 본 발명의 조성물로 예방 또는 치료되는 퇴행성 질환은 알츠하이머 병, 루게릭병, 수막염, 골다공증 및 퇴행성 관절염으로 구성된 군으로부터 선택된다.
According to a preferred embodiment of the present invention, the degenerative disease to be prevented or treated with the composition of the present invention is selected from the group consisting of Alzheimer's disease, Lou Gehrig's disease, meningitis, osteoporosis and degenerative arthritis.

본 발명의 특징 및 이점을 요약하면 다음과 같다:The features and advantages of the present invention are summarized as follows:

(a) 본 발명은 다양한 신규 하이단토인 유도체 화합물 및 이들을 유효성분으로 포함하는 P2X7 수용체 활성 억제용 조성물을 제공한다.(a) The present invention provides various novel hydantoin derivative compounds and compositions for inhibiting P2X 7 receptor activity comprising the same as an active ingredient.

(b) 본 발명은 P2X7 수용체의 활성과 관련된 다양한 질환, 즉 만성 염증성 질환, 염증성 통증, 신경병성 통증, 자가면역 질환 또는 퇴행성 질환의 예방 또는 치료에 유용하게 이용될 수 있다.
(b) The present invention can be usefully used for the prevention or treatment of various diseases related to the activity of the P2X 7 receptor, that is, chronic inflammatory disease, inflammatory pain, neuropathic pain, autoimmune disease or degenerative disease.

도 1은 (A) The molecular topology of the P2X1 -6 및 P2X7 수용체의 분자해부학적 위치를 나타낸 그림(도 1a) 및 P2X7 수용체가 ATP에 의해 활성화되어 세가지 다른 형태를 띄는 모습을 나타낸 그림이다: 채널의 개방, 채널의 폐쇄 및 포어형성 (Curr . Med . Chem . 2007,14,1505-1523).
도 2는 척수에서의 퓨린작동성(Purinergic) 신호전달을 나타낸 그림이다(Nature Review Drug Discovery , 2008, 7, 575-590)
도 3은 hP2X7-발현 HEK 293 세포에서 BzATP와 KN62의 영향을 나타낸 그림이다. BzATP를 처리하자 농도 의존적 에티듐 브로마이드가 축적되었으며(EC50 = 3.67 μM, 도 3a), 4 μM BzATP를 처리 한 후에 KN62를 처리하자 농도 의존적으로 에티듐 브로마이드의 축적이 저해되었다(IC50 = 389 nM, 도 3b).Figure 1 (A) The molecular topology of the P2X 1 and P2X -6 illustration showing the anatomic location of the molecules 7 receptor (Fig. 1a) and the P2X 7 receptor is activated by ATP illustration showing a state stands out the three different types Is: channel opening, channel closure and pore formation ( Curr . Med . Chem . 2007, 14, 1505-1523).
2 is a diagram showing Purinergic signaling in the spinal cord ( Nature Review Drug Discovery , 2008, 7, 575-590)
3 shows the effect of BzATP and KN62 on hP2X 7 -expressing HEK 293 cells. Treatment with BzATP resulted in concentration-dependent ethidium bromide accumulation (EC 50 = 3.67 μM, FIG. 3A), and treatment with KN62 after treatment with 4 μM BzATP inhibited concentration-dependent accumulation of ethidium bromide (IC 50 = 389). nM, Figure 3b).

이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

실시예Example

P2XP2X 77 영구세포주를 이용한 세포의 사멸연구 및 저해화합물 활성연구 Apoptosis and Inhibitory Compound Activity Studies Using Permanent Cell Lines

P2X7의 영구적 발현 세포주는 고등동물 발현벡터인 pcDNA3.1에 삽입한 인간 P2X7을 리포펙타민(Invitrogen)을 이용하여 HEK293 세포 내로 전달하고, Neor 유전자를 이용하여 형질전환된 세포를 배양하여 선택하고 지속적인 배양을 통해 다수의 영구 세포주를 확보하였다. ATP에 농도 의존적으로 사멸하는 세포주를 선택하여 인간 P2X7 수용체를 영구적으로 발현하는 세포주를 확립하였고, hP2X7 수용체의 발현여부 및 정도는 hP2X7 수용체에 대한 항체를 이용한 웨스턴 블롯팅으로 확인하였다. 이와 같이 확보한 세포주들은 ATP 의존적으로 세포 사멸을 일으킴으로, P2X7 수용체의 활성을 저해하는 길항물질들을 세포기반 분석(cell-based assay)을 통해 빠르게 탐색할 수 있게 되었다.
P2X 7 expression of the permanent cell line is transferred into the human P2X 7 inserted into higher animal expression vector pcDNA3.1 using the lipofectamine (Invitrogen), and HEK293 cells, by using the Neo r gene culturing a cell transformed with Multiple permanent cell lines were obtained through selection and continued culture. Was concentration-dependent manner by selecting a cell line death in the ATP establish a cell line permanently expressing the human P2X 7 receptors, the expression status and the degree of hP2X 7 receptor was confirmed by Western blotting using antibodies against the hP2X 7 receptor. The cell lines thus secured ATP-dependent cell death, allowing the rapid detection of antagonists that inhibit P2X 7 receptor activity through cell-based assays.

P2XP2X 77 영구세포주를 이용한 세포의 저해 화합물 활성 연구 Inhibitory Activity of Cells Using Permanent Cell Lines

P2X7 수용체는 다른 P2X 수용체와 달리 지속적인 아고니스트의 자극에 의해 세포 표면에 분자량 900Da 이하의 물질[예를 들어 콜린(choline, 100 Da), 메틸글루카민(methylglucamine, 190 Da), 에티디움(ethidium, 314 Da), YO-PRO-1 (376 Da), 프로피디움(propidium, 414 Da), 루시퍼 옐로우(lucifer yellow, 467 Da)]이 통과할 수 있는 큰 포어를 형성하였다. 이 특징을 기초로 하여 hP2X7 에 선택적인 아고니스트인 ATP와 2’and 3’-O-benzoyl-benzoly-ATP(BzATP)를 처리하여 형성된 포어를 통해 DNA 결합 형광염료인 에티디움 브로마이드의 세포내 측적 정도를 형광 리더를 통하여 측정함으로써 P2X7 수용체에 대한 길항제를 탐색할 수 있었다. 세포 표면에 내생적인 P2X7 수용체를 가지는 인간 단핵구 세포주인 THP-1 세포와 hP2X7 수용체를 영구발현한 세포주(hP2X7-발현 HEK 293 세포)를 이용하여 BzATP에 대한 농도의존적인 세포내 염료 축적정도를 도 3과 같이 얻었다. 또한 APT 혹은 BzATP를 처리하여 포어를 형성시킨 후에 P2X7 수용체에 대하여 길항 효과를 가진다고 보고가 되어 있는 1-[N,O-bis(1,5-isoquinolinesulphonyl) -N-methyl-L-tyrosyl]-4-phenylpiperizine(KN62)를 농도 의존적으로 처리하여 염료 축적의 저해 정도를 도 3b와 같이 얻었다.
P2X 7 Receptors, unlike other P2X receptors, have a molecular weight of 900 Da or less (for example, choline (100 Da), methylglucamine (190 Da), ethidium (314)) on the cell surface due to continuous agonist stimulation. Da), YO-PRO-1 (376 Da), propidium (414 Da), lucifer yellow (467 Da)] formed large pores through which they could pass. Based on this feature, intracellular cytoplasm of ethidium bromide, a DNA-binding fluorescent dye, was formed through treatment of hP2X 7 selective agonist ATP with 2'and 3'-O-benzoyl-benzoly-ATP (BzATP). By measuring the degree of measurement through a fluorescence reader, it was possible to search for antagonists for the P2X 7 receptor. Level-dependent intracellular dye accumulation for BzATP using THP-1 cells, human monocyte cell lines with endogenous P2X 7 receptors on the cell surface, and cell lines permanently expressing hP2X 7 receptors (hP2X 7 -expressing HEK 293 cells) Was obtained as shown in FIG. 3. In addition, 1- [N, O-bis (1,5-isoquinolinesulphonyl) -N-methyl-L-tyrosyl]-which has been reported to have an antagonistic effect on P2X 7 receptor after treatment with APT or BzATP to form pores. Treatment of 4-phenylpiperizine (KN62) concentration-dependently obtained the degree of inhibition of dye accumulation as shown in Figure 3b.

화합물 라이브러리 및 유도체에 대한 활성검색Activity search for compound libraries and derivatives

P2X7 수용체의 새로운 골격의 신약후보물질 발굴을 위하여 이미 보고된 P2X7 수용체 길항제‘티로신(tyrosine) 골격의 KN62’에 대한 다양한 변형의 새로운 화합물을 설계하여 전혀 새로운 골격의 신규한 하이단토인 유도체 도출하였다. 합성된 하이단토인 유도체들은 hP2X7-발현 HEK 293 세포에서 BzATP을 처리하여 포어를 형성 시킨 후에 길항효과를 조사하였으며, 이중 기존의 길항제인 KN62와 동등하거나 훨씬 우수한 P2X7 수용체 길항 효과를 가지는 유도체들을 선별하였다.
Already reported a P2X 7 receptor antagonist derived, tyrosine (tyrosine) KN62 skeleton "to design new compounds of various modifications stage novel high completely new skeleton hydantoin derivatives of the for the candidate drug discovery of a new skeleton of the P2X 7 receptor It was. The synthesized hydantoin derivatives hP2X 7 - the expression We investigated the antagonistic effects after the processing of BzATP in HEK 293 cells form the pores, a double existing derivative having equal or more excellent P2X 7 receptor antagonistic effect and the antagonist KN62 Screened.

합성 모식도 1Synthetic schematic diagram 1 aa

Figure 112011006794440-pat00047
Figure 112011006794440-pat00047

a시약 및 반응조건: (a) i) KOCN, H2O, pyridine, 90°C, 3h, ii) conc.HCl, AcOH, 120°C, 1h 30min, (b) isoquinoline sulfonyl chloride, HCl, NaH, THF, rt, 5h, (c) R1-OSO2Me, CsHCO3, DMF, 50℃, 24h
 a Reagent and reaction conditions: (a) i) KOCN, H 2 O, pyridine, 90 ° C, 3h, ii) conc.HCl, AcOH, 120 ° C, 1h 30min, (b) isoquinoline sulfonyl chloride, HCl, NaH , THF, rt, 5h, (c) R 1 -OSO 2 Me, CsHCO 3 , DMF, 50 ° C., 24h

합성 모식도 2Synthetic schematic diagram 2 aa

Figure 112011006794440-pat00048
Figure 112011006794440-pat00048

a시약 및 반응조건: (a) isoquinoline sulfonyl chloride.HCl, NaH, THF, rt, 5h, (b) 20% TFA, DCM, rt, 3h, (c) R2CHO, NaBH(OAc)3, DCE, rt, 4h, (d) KOCN, AcOH, rt, 5h, (e) R2-OSO2Me, CsHCO3, DMF, 50℃, 24h
 a Reagent and reaction conditions: (a) isoquinoline sulfonyl chloride.HCl, NaH, THF, rt, 5h, (b) 20% TFA, DCM, rt, 3h, (c) R 2 CHO, NaBH (OAc) 3 , DCE , rt, 4h, (d) KOCN, AcOH, rt, 5h, (e) R 2 -OSO 2 Me, CsHCO 3 , DMF, 50 ° C., 24h

합성 모식도 3Synthetic schematic diagram 3 aa

Figure 112011006794440-pat00049
Figure 112011006794440-pat00049

a시약 및 반응조건: (a) 20% TFA, DCM, 0℃¡, 1h, (b) R3-Cl, TEA, DCM, rt, 2h, or R3COOH, TEA, EDC, DCM, 2h, or R3-COH, NaBH(OAC)3, DMF, rt, 24h, (c) Diazomethane, MeOH, 0℃, 1h
 a Reagent and reaction conditions: (a) 20% TFA, DCM, 0 ° C., 1 h, (b) R 3 -Cl, TEA, DCM, rt, 2h, or R 3 COOH, TEA, EDC, DCM, 2h, or R3-COH, NaBH (OAC) 3 , DMF, rt, 24h, (c) Diazomethane, MeOH, 0 ° C, 1h

Figure 112011006794440-pat00050
Figure 112011006794440-pat00050

하이단토인(Hydantoin)골격에 다양한 치환체의 도입Introduction of various substituents on Hydantoin skeleton 화합물compound R1 R 1 R2 R 2 IC50 a(nM)IC 50 a (nM) KN62 (양성대조군)KN62 (Yangseong Control Group) 150±22 nM150 ± 22 nM 22 HH HH NAb NA b 3a3a isoquinolin-5-yl methylisoquinolin-5-yl methyl HH 1220 ± 17001220 ± 1700 3b3b 1-Boc-4-piperidinylmethyl1-Boc-4-piperidinylmethyl HH 7720 ± 23007720 ± 2300 6a6a HH isoquinolin-5-ylmethylisoquinolin-5-ylmethyl 3820 ± 9703820 ± 970 6c6c HH 1-Boc-4-piperidinylmethyl1-Boc-4-piperidinylmethyl 800 ± 15800 ± 15 7a7a 1-Boc-4-piperidinylmethyl1-Boc-4-piperidinylmethyl isoquinolin-5-ylmethylisoquinolin-5-ylmethyl 1210 ± 6501210 ± 650 7b7b isoquinolin-5-ylmethylisoquinolin-5-ylmethyl 1-Boc-4-piperidinylmethyl1-Boc-4-piperidinylmethyl 1970 ± 1701970 ± 170 7c7c isoquinolin-5-ylmethylisoquinolin-5-ylmethyl 1- PhCH2-4-piperidinylmethyl1- PhCH 2-4 -piperidinylmethyl 8860 ± 19008860 ± 1900 7d7d quinolin-5-ylmethylquinolin-5-ylmethyl 1- PhCH2-4-piperidinylmethyl1- PhCH 2-4 -piperidinylmethyl 2690 ± 4702690 ± 470 7e7e PhCH2 PhCH 2 1- PhCH2-4-piperidinylmethyl1- PhCH 2-4 -piperidinylmethyl 6080 ± 11006080 ± 1100 6e6e HH 1- PhCH2-4-piperidinylmethyl1- PhCH 2-4 -piperidinylmethyl 1820 ± 3601820 ± 360

aIC50(50% 억제 농도, 50% inhibitory concentrations)는 농도-반응 곡선으로부터 얻었다. 데이터 값들은 평균±표준편차로 표현하였다. 모든 실험은 최소 3-11회 반복하였다. a IC 50 (50% inhibitory concentrations) was obtained from the concentration-response curve. Data values are expressed as mean ± standard deviation. All experiments were repeated at least 3-11 times.

b활성없음(No activity). 실험은 hP2X7-발현 HEK293 세포를 이용한 ethidium+ 축적 분석을 통하여 수행하였다.
 b No activity. Experiments were performed via ethidium + accumulation assay using hP2X 7 -expressing HEK293 cells.

Figure 112011006794440-pat00051
Figure 112011006794440-pat00051

하이단토인(Hydantoin)의 피페리디닐(piperidinyl)골격에 다양한 치환체의 도입Introduction of various substituents on the piperidinyl skeleton of Hydantoin 화합물compound nn R3 R 3 IC50(nM) a IC 50 (nM) a KN62 (양성대조군)KN62 (Yangseong Control Group) 150±22 nM150 ± 22 nM 6b6b 00 Boc Boc 355 ± 150355 ± 150 9a9a 00 PhCH2 PhCH 2 63% inhibition 63% inhibition 9b9b 00 PhCO PhCO 629 ± 120629 ± 120 6c6c 1One BocBoc 800±148800 ± 148 10a10a 1One PhCO PhCO 794 ± 100794 ± 100 6d6d 22 BocBoc 1010 ± 1101010 ± 110 11a11a 22 PhCH2 PhCH 2 33% inhibition33% inhibition 11b11b 22 PhCOPhCO 49% inhibition49% inhibition

aIC50(50% 억제 농도, 50% inhibitory concentrations)는 농도-반응 곡선으로부터 얻었다. 데이터 값들은 평균±표준편차로 표현하였다. 모든 실험은 최소 3-11회 반복하였다. a IC 50 (50% inhibitory concentrations) was obtained from the concentration-response curve. Data values are expressed as mean ± standard deviation. All experiments were repeated at least 3-11 times.

b활성없음(No activity). 실험은 hP2X7-발현 HEK293 세포를 이용한 ethidium+ 축적 분석을 통하여 수행하였다.
 b No activity. Experiments were performed via ethidium + accumulation assay using hP2X 7 -expressing HEK293 cells.

Figure 112011006794440-pat00052
Figure 112011006794440-pat00052

피페리디닐(piperidinyl)의 R3 위치에 다양한 지방족(Aliphatic Group) 도입Introduction of various aliphatic groups at the R 3 position of piperidinyl 화합물compound R1 R 1 R3 R 3 IC50 (nM) a IC 50 (nM) a KN62 (양성대조군)KN62 (Yangseong Control Group) 150±22 nM150 ± 22 nM 8a8a HH HH NAb NA b 9c9c HH EtCOEtCO 1190 ± 15001190 ± 1500 9d9d HH i-PrCO i -PrCO 7220 ± 11007220 ± 1100 9e9e HH tBuCO t BuCO 5650 ± 8005650 ± 800 9f9f HH n-PrCO n -PrCO 8770 ± 5408770 ± 540 9g9g HH 2-Me-PrCO2-Me-PrCO 4890 ± 7104890 ± 710 9h9h HH c-C6H11CO c -C 6 H 11 CO 144 ± 27144 ± 27 9i9i HH 1-adamantylCO1-adamantylCO 23.3 ± 2.423.3 ± 2.4 1212 MeMe 1-adamantylCO1-adamantylCO 67% inhibition67% inhibition 9j9j HH 1-adamantylmethyl1-adamantylmethyl 13% inhibition13% inhibition 9k9k HH 1-adamantylacetylCO1-adamantylacetylCO 84.4 ± 1284.4 ± 12 9l9l HH 3-Br-1-adamatnylCO3-Br-1-adamatnylCO 29.9 ± 4.729.9 ± 4.7 9m9m HH (3,5-diMe)-1-adamantylCO(3,5-diMe) -1-adamantylCO 99.4 ± 1799.4 ± 17 9n9n HH 3- noradamantylCO3- noradamantylCO 68.6 ± 1368.6 ± 13 9o9o HH 2-norbornanylacetylCO2-norbornanylacetylCO 109 ± 3.5109 ± 3.5

aIC50(50% 억제 농도, 50% inhibitory concentrations)는 농도-반응 곡선으로부터 얻었다. 데이터 값들은 평균±표준편차로 표현하였다. 모든 실험은 최소 3-11회 반복하였다. a IC 50 (50% inhibitory concentrations) was obtained from the concentration-response curve. Data values are expressed as mean ± standard deviation. All experiments were repeated at least 3-11 times.

b활성없음(No activity). 실험은 hP2X7-발현 HEK293 세포를 이용한 ethidium+ 축적 분석을 통하여 수행하였다.
 b No activity. Experiments were performed via ethidium + accumulation assay using hP2X 7 -expressing HEK293 cells.

Figure 112011006794440-pat00053
Figure 112011006794440-pat00053

피페리디닐(piperidinyl)의 R3 위치에 다양한 방향족(Aromatic Group) 도입Introduction of various aromatic groups at the R 3 position of piperidinyl compdcompd R3 R 3 IC50 (nM) a IC 50 (nM) a KN62 (양성대조군)KN62 (Yangseong Control Group) 150±22 nM150 ± 22 nM 9p9p (3, 4-di(MeO)2)PhCO(3, 4-di (MeO) 2 ) PhCO 3870 ± 5703870 ± 570 9q9q (4-F)PhCO(4-F) PhCO 666 ± 68666 ± 68 9r9r (3,4-diF)PhCO(3,4-diF) PhCO 255 ± 60255 ± 60 9s9s (2-Cl)PhCO(2-Cl) PhCO 70% inhibition70% inhibition 9t9t (3-Cl)PhCO(3-Cl) PhCO 230 ± 17230 ± 17 9u9u (4-Cl)PhCO(4-Cl) PhCO 143 ± 22143 ± 22 9v9v (3,4-diCl)PhCO(3,4-diCl) PhCO 79% inhibition79% inhibition 9w9w (3,4-diCl)PhCH2 (3,4-diCl) PhCH 2 244 ± 22244 ± 22 9x9x (2-F-4-Cl)PhCO(2-F-4-Cl) PhCO 423±24.4423 ± 24.4 9y9y (3-CF3-4-Cl)PhCO(3-CF 3 -4-Cl) PhCO 81.7 ± 1881.7 ± 18

aIC50(50% 억제 농도, 50% inhibitory concentrations)는 농도-반응 곡선으로부터 얻었다. 데이터 값들은 평균±표준편차로 표현하였다. 모든 실험은 최소 3-11회 반복하였다. a IC 50 (50% inhibitory concentrations) was obtained from the concentration-response curve. Data values are expressed as mean ± standard deviation. All experiments were repeated at least 3-11 times.

b활성없음(No activity). 실험은 hP2X7-발현 HEK293 세포를 이용한 ethidium+ 축적 분석을 통하여 수행하였다.
 b No activity. Experiments were performed via ethidium + accumulation assay using hP2X 7 -expressing HEK293 cells.

Figure 112011006794440-pat00054
Figure 112011006794440-pat00054

5-아이소퀴놀린 메틸(5-isoquinoline methyl)의 X 위치에 다양한 치환체 도입Introduction of various substituents at the X position of 5-isoquinoline methyl compdcompd XX IC50 (nM) a IC 50 (nM) a KN62 (양성대조군)KN62 (Yangseong Control Group) 150±22 nM150 ± 22 nM 13a13a SO2 SO 2 400 ± 52400 ± 52 13b13b COCO 602 ± 29602 ± 29

aIC50(50% 억제 농도, 50% inhibitory concentrations)는 농도-반응 곡선으로부터 얻었다. 데이터 값들은 평균±표준편차로 표현하였다. 모든 실험은 최소 3-11회 반복하였다. a IC 50 (50% inhibitory concentrations) was obtained from the concentration-response curve. Data values are expressed as mean ± standard deviation. All experiments were repeated at least 3-11 times.

b활성없음(No activity). 실험은 hP2X7-발현 HEK293 세포를 이용한 ethidium+ 축적 분석을 통하여 수행하였다.
 b No activity. Experiments were performed via ethidium + accumulation assay using hP2X 7 -expressing HEK293 cells.

하이단토인Hydantoin (( HydantoinHydantoin ) 대표 합성법Representative Synthesis

화합물 2를 예시로 모식도 1에 의해 얻어진 하이단토인 유도체의 대표합성법은 다음과 같다:Representative synthesis method of the hydantoin derivative obtained by Scheme 1 with Compound 2 as an example is as follows:

합성예Synthetic example 1 : 4-((2,5- 1: 4-((2,5- 디옥소이미다졸리딘Dioximidazolidine -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (2) (2)

(A) O-벤질-L-티로신(2 g, 7.37 mmol)과 시안산 칼륨(1.49 g, 18.43 mmol)을 피리딘(1ml)과 물(100.0 ml)에 용해시켰다. 혼합액은 90℃에서 3시간 반응시키고, 클로로포름을 넣어 유기층과 물층을 분리하였다. 분리한 물층에 con.HCl과 아세트산을 첨가하고, 이 혼합액을 다시 90℃에서 1시간 30분간 반응시켰다. 반응 후, 주위의 온도로 냉각하고 물로 세척하면서 필터하여 걸러 얻은 유기 용매를 건조시켰다. 컬럼 없이 중간체 화합물 1을 약 50.4%의 수득율로 흰색 고체를 얻었다. (A) O-benzyl-L-tyrosine (2 g, 7.37 mmol) and potassium cyanate (1.49 g, 18.43 mmol) were dissolved in pyridine (1 ml) and water (100.0 ml). The mixed solution was reacted at 90 ° C. for 3 hours, chloroform was added thereto, and the organic layer and the water layer were separated. Con.HCl and acetic acid were added to the separated water layer, and the mixture was reacted at 90 ° C for 1 hour and 30 minutes. After the reaction, the organic solvent obtained by filtration was dried while cooling to ambient temperature and washing with water. Intermediate compound 1 was obtained without a column at about 50.4% yielding a white solid.

(B) 정제된 화합물 1(1.2 g, 40 mmol)과 NaH(696 mg, 16 mmol)를 무수 THF(Tetrahydrofuran, 50 ml)에 용해시켰다. 10분 후, 혼합액에 5-이소퀴놀린 설폰산(3.8 g, 12 mmol)을 첨가하여 상온에서 5시간 반응시켰다. 반응 후, THF를 회전 농축기(rotary evaporator)를 이용하여 증발시키고, 남은 잔여물(residue)은 EA(Ethyl Acetate)에 녹인 후, 염화암모늄 포화 수용액으로 추출하였다. 추출된 EA 용액은 황산나트륨을 이용하여 무수화과정을 거친 뒤, 농축하였다. 실리카겔(silica gel)을 이용한 컬럼을 수행하여 정제된 연노란색 고체를 약 80.2% 수득하였다. (B) Purified Compound 1 (1.2 g, 40 mmol) and NaH (696 mg, 16 mmol) were dissolved in anhydrous THF (Tetrahydrofuran, 50 ml). After 10 minutes, 5-isoquinoline sulfonic acid (3.8 g, 12 mmol) was added to the mixed solution and reacted at room temperature for 5 hours. After the reaction, THF was evaporated using a rotary evaporator, and the remaining residue was dissolved in EA (Ethyl Acetate) and extracted with saturated aqueous ammonium chloride solution. The extracted EA solution was anhydrous using sodium sulfate and concentrated. A column using silica gel was performed to yield about 80.2% of a purified pale yellow solid.

1H NMR(400MHz, CDCl3) δ (ppm); 10.411(s, NH), 9.562(s, H=1), 8.824(d, J=6.0Hz, H=1), 8.592(d, J=8.4Hz, H=1), 8.365(d, J=6.0Hz, H=1), 8.265(d, J= 7.2Hz, H=1), 7.813(t, J= 8.0Hz, H=2),7.079(d, J=8.4Hz, H=2), 6.795(d, J=8.4Hz, H=2), 4.237(t, J=Hz, H=1), 2.859(m, H=2), HRMS(FAB) C19H15N3O5S : calcd 398.0811, found 460.1402
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 10.411 (s, NH), 9.562 (s, H = 1), 8.824 (d, J = 6.0 Hz, H = 1), 8.592 (d, J = 8.4 Hz, H = 1), 8.365 (d, J = 6.0 Hz, H = 1), 8.265 (d, J = 7.2 Hz, H = 1), 7.813 (t, J = 8.0 Hz, H = 2), 7.079 (d, J = 8.4 Hz, H = 2), 6.795 (d, J = 8.4 Hz, H = 2), 4.237 (t, J = Hz, H = 1), 2.859 (m, H = 2), HRMS (FAB) C 19 H 15 N 3 O 5 S: calcd 398.0811, found 460.1402

화합물 3를 예시로 모식도 1에 의해 얻어진 하이단토인 유도체의 대표합성법은 다음과 같다:Representative synthesis method of the hydantoin derivative obtained by Scheme 1 with Compound 3 as an example is as follows:

합성예Synthetic example 2 : 4-((1-(이소퀴놀린-5-일  2: 4-((1- (isoquinolin-5-yl 메틸methyl )-2,5-) -2,5- 디옥소이미다졸리딘Dioximidazolidine -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (3a) (3a)

화합물 2(50.0 mg, 0.1 mmol)와 CsHCO3(48 mg, 0.25 mmol)를 무수 DMF(Di메틸formamide, 5.0 ml)에 녹인 다음 5-(메틸설포닐메틸)이소퀴놀린(60 mg, 0.25 mmol)을 첨가하였다. 혼합된 용액은 50℃에서 24시간 반응시킨다. 반응 후, DMF을 회전 농축기(rotary evaporator)를 이용하여 증발 시키며, 남은 잔여물(residue)은 Ethyl Acetate(EA)에 녹인 후, 염화암모늄 포화 수용액으로 추출하였다. 추출된 EA 용액은 황산나트륨을 이용하여 무수화 과정을 거치고, 농축하였다. 실리카겔(silica gel)을 이용한 컬럼을 수행하여 정제된 최종 산물을 43.7% 수득율로 얻었다.
Compound 2 (50.0 mg, 0.1 mmol) and CsHCO 3 (48 mg, 0.25 mmol) were dissolved in anhydrous DMF (Dimethylformamide, 5.0 ml) and then 5- (methylsulfonylmethyl) isoquinoline (60 mg, 0.25 mmol) Was added. The mixed solution is reacted at 50 ° C for 24 hours. After the reaction, the DMF was evaporated using a rotary evaporator, and the residue was dissolved in Ethyl Acetate (EA) and extracted with saturated aqueous ammonium chloride solution. The extracted EA solution was anhydrous using sodium sulfate and concentrated. A column using silica gel was performed to give a purified final product in 43.7% yield.

1H NMR(400MHz, CDCl3) δ (ppm); 9.414(s, H=1), 9.229(s, H=1,), 8.829(d, J=6.0Hz, H=1), 8.557(d, J=5.6Hz, H=1), 8.530(d, J=6Hz, H=1), 8.291(d, J=8Hz, H=1),8.234(d, J=7.2Hz, H=1), 8.055(d, J=6Hz, H=1), 7.918(d, J=8Hz, H=1), 7.649(t, J=8Hz, H=1), 7.585(d, J=7.2Hz, H=1), 7.515(t, J=8Hz, H=1), 6.945(d, J=8.8Hz, H=2), 6.651(d, J=8.8 H=2), 5.003(bq, J=14.8Hz, H=2), 4.229(m, H=1), 3.116(dd, J=14.4Hz, H=1), 2.837(dd, J=14.4Hz, H=1), HRMS(FAB) C29H22N4O5S : calcd 539.1389, found 539.1393
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.414 (s, H = 1), 9.229 (s, H = 1,), 8.829 (d, J = 6.0 Hz, H = 1), 8.557 (d, J = 5.6 Hz, H = 1), 8.530 (d , J = 6 Hz, H = 1), 8.291 (d, J = 8 Hz, H = 1), 8.234 (d, J = 7.2 Hz, H = 1), 8.055 (d, J = 6 Hz, H = 1), 7.918 (d, J = 8 Hz, H = 1), 7.649 (t, J = 8 Hz, H = 1), 7.585 (d, J = 7.2 Hz, H = 1), 7.515 (t, J = 8 Hz, H = 1), 6.945 (d, J = 8.8 Hz, H = 2), 6.651 (d, J = 8.8 H = 2), 5.003 (bq, J = 14.8 Hz, H = 2), 4.229 (m, H = 1 ), 3.116 (dd, J = 14.4 Hz, H = 1), 2.837 (dd, J = 14.4 Hz, H = 1), HRMS (FAB) C 29 H 22 N 4 O 5 S: calcd 539.1389, found 539.1393

합성예Synthetic example 3:  3: terttert -부틸 4-((4-(4-(이소퀴놀린-5-일 -Butyl 4-((4- (4- (isoquinolin-5-yl 설포닐옥시Sulfonyloxy ))벤질)-2,5-)) Benzyl) -2,5- 디옥소이미다졸리딘Dioximidazolidine -1-일)-1 day) 메틸methyl )피페리딘-1-) Piperidin-l- 카르복실레이트Carboxylate (3b) (3b)

합성예 2와 동일한 대표 합성법으로 수행하였으며, 80.6% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis Example 2, and obtained at a yield of 80.6%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.454(s, H=1), 8.819(d, J=6.4Hz, H=1,), 8.572(d, J=6.4Hz, H=1), 8.336(q, J=4.4Hz, H=2), 7.710(t, J=8Hz, H=1), 7.079(d, J=8.4Hz, H=2), 6.854(d, J=8.4Hz, H=2), 4.208(m, H=1), 4.035(m, H=2), 3.298(m, H=2), 3.171(dd, J=14.4Hz, H=1), 2.859(dd, J=14.4Hz, H=1), 2.606(m, H=2), 1.746(m, H=2), 1.431(s, H=9), 1.348(m, H=2), HRMS(FAB) C30H34N4O7S : calcd 595.2226, found 595.2223
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.454 (s, H = 1), 8.819 (d, J = 6.4 Hz, H = 1,), 8.572 (d, J = 6.4 Hz, H = 1), 8.336 (q, J = 4.4 Hz, H = 2 ), 7.710 (t, J = 8 Hz, H = 1), 7.079 (d, J = 8.4 Hz, H = 2), 6.854 (d, J = 8.4 Hz, H = 2), 4.208 (m, H = 1 ), 4.035 (m, H = 2), 3.298 (m, H = 2), 3.171 (dd, J = 14.4 Hz, H = 1), 2.859 (dd, J = 14.4 Hz, H = 1), 2.606 ( m, H = 2), 1.746 (m, H = 2), 1.431 (s, H = 9), 1.348 (m, H = 2), HRMS (FAB) C 30 H 34 N 4 O 7 S: calcd 595.2226 , found 595.2223

화합물 6을 예시로 모식도 2에 의해 얻어진 hydantoin 유도체 및 중간체의 대표합성법은 다음과 같다:
Representative synthesis of the hydantoin derivatives and intermediates obtained by Scheme 2 with Compound 6 as an example is as follows:

합성예Synthetic example 4: 4-((3-(이소퀴놀린-5-일  4: 4-((3- (isoquinolin-5-yl 메틸methyl )-2,5-) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (6a) (6a)

(A) Boc-Tyr-OMe (2 g, 6.8 mmol)과 NaH(813.6 mg, 20.4 mmol)를 무수 THF (Tetrahydrofuran, 75 ml)에 녹인 다음, 10분 후 5-(메틸설포닐메틸)이소퀴놀린(4.5 mg, 17 mmol)을 첨가하였다. 혼합된 용액을 상온에서 5시간 반응시켰다. 반응 후, THF를 회전 농축기(rotary evaporator)를 이용하여 증발시키고, 남은 잔여물은 EA(Ethyl Acetate)에 녹인 후, 염화암모늄 포화 수용액으로 추출하였다. 추출된 DCM 용액은 황산나트륨을 이용하여 무수화 과정을 거치고, 농축하였다. 실리카겔을 이용한 컬럼을 수행하여 정제된 중간체(메틸 2-(tert-부톡시카르보닐아미노)-3-(4-(나프탈렌-1-일 설포닐옥시)페닐)프로파노에이트)를 약 80.2% 수득율로 획득하였다. (A) Boc-Tyr-OMe (2 g, 6.8 mmol) and NaH (813.6 mg, 20.4 mmol) were dissolved in anhydrous THF (Tetrahydrofuran, 75 ml) and after 10 minutes 5- (methylsulfonylmethyl) isoquinoline (4.5 mg, 17 mmol) was added. The mixed solution was reacted at room temperature for 5 hours. After the reaction, THF was evaporated using a rotary evaporator, and the remaining residue was dissolved in EA (Ethyl Acetate) and extracted with saturated aqueous ammonium chloride solution. The extracted DCM solution was anhydrous using sodium sulfate and concentrated. Performing a column using silica gel yielded about 80.2% of purified intermediate (methyl 2- (tert-butoxycarbonylamino) -3- (4- (naphthalen-1-yl sulfonyloxy) phenyl) propanoate) Obtained.

(B) 중간체(475.5 mg, 0.98 mmol)을 TFA(Trifluoroaceticacid, 6 ml)와 함께 무수 DCM(dichloromethane, 30 ml)에 녹여 실온에서 3시간 반응시켰다. 반응 후, TFA를 회전 농축기(rotary evaporator)를 이용하여 증발시키고, 남은 잔여물은 DCM에 녹인 후, 소듐비카보네이트 포화 수용액으로 추출하였다. 추출된 DCM 용액은 황산나트륨을 이용하여 무수화 과정을 거치고, 농축하였다. 실리카겔(silica gel)을 이용한 컬럼을 수행하여 정제된 중간체 화합물 4를 약 90.5% 수득율로 획득한다. (B) The intermediate (475.5 mg, 0.98 mmol) was dissolved in anhydrous DCM (dichloromethane, 30 ml) with TFA (Trifluoroacetic acid, 6 ml) and reacted at room temperature for 3 hours. After the reaction, TFA was evaporated using a rotary evaporator, and the remaining residue was dissolved in DCM and extracted with saturated aqueous sodium bicarbonate solution. The extracted DCM solution was anhydrous using sodium sulfate and concentrated. A column using silica gel is performed to obtain purified intermediate compound 4 in about 90.5% yield.

(C) 화합물 4(312.8 mg, 0.82 mmol)와 NaBH(OAC)3(343.4 mg, 1.62 mmol)을 무수 1,2-디클로로에탄(DCE, 25ml)에 넣고, 이소퀴놀린-5-카르복살데하이드(넣고1.0 mg, 1.22 mmol)와 아세트산넨고2.6 ml, 1.62 mmol)을 첨가하였다. 이 반응액을 실온에서 4시간 반응시킨 후, 혼합물을 EA로 희석하고 포화된 염화암모늄 수용액으로 2회 및 염수로 1회 추출하였고, 황산나트륨으로 건조시킨 후 감압 하에서 농축하였다. 실리카겔(silica gel)을 이용한 컬럼을 수행하여 정제된 중간체를 72.4%의 수득율로 획득하였다. (C) Compound 4 (312.8 mg, 0.82 mmol) and NaBH (OAC) 3 (343.4 mg, 1.62 mmol) were added to anhydrous 1,2-dichloroethane (DCE, 25 ml) and isoquinoline-5-carboxaldehyde (1.0 mg, 1.22 mmol) and 2.6 ml of 1.6 mg, 1.62 mmol) were added. After the reaction solution was reacted for 4 hours at room temperature, the mixture was diluted with EA, extracted twice with saturated aqueous ammonium chloride solution and once with brine, dried over sodium sulfate, and concentrated under reduced pressure. A column using silica gel was carried out to obtain purified intermediates with a yield of 72.4%.

(D) 화합물 5(98mg, 0.19mmol)와 시안산 칼륨(75.34 mg, 0.93 mmol)을 아세트산(15ml)에 용해시켰다. 이 혼합액을 실온에서 5시간 반응시킨 후, 아세트산을 회전 농축기를 이용하여 증발시키고, 남은 잔여물은 DCM에 녹인 후, 소듐비카보네이트 포화 수용액으로 추출하였다. 추출된 DCM 용액은 황산나트륨을 이용하여 무수화 과정을 거친 뒤 농축하였다. 실리카겔을 이용한 컬럼을 수행하여 최종 산물을 76.3%의 수득율로 획득하였다.(D) Compound 5 (98 mg, 0.19 mmol) and potassium cyanate (75.34 mg, 0.93 mmol) were dissolved in acetic acid (15 ml). After the reaction mixture was allowed to react at room temperature for 5 hours, acetic acid was evaporated using a rotary concentrator, and the remaining residue was dissolved in DCM and extracted with saturated aqueous sodium bicarbonate solution. The extracted DCM solution was concentrated through anhydrous treatment with sodium sulfate. The column was run with silica gel to give the final product in 76.3% yield.

1H NMR(400MHz, CDCl3) δ (ppm); 9.415(s, H=1), 9.289(s, H=1), 8.814(d, J=6Hz, H=1), 8.576(d, J=6Hz, H=1), 8.532(d, J=6Hz, H=1), 8.300(m, H=2), 7.996(d, J=8.4Hz, H=1), 7.811(d, J=6Hz, H=1), 7.671(t, J=8Hz, H=1), 7.561(t, J=7.2Hz, H=1), 7.364(d, J=7.2Hz, H=1), 6.956(d, J=6.8Hz, H=2), 6.804(d, J=8.4Hz, H=2), 5.484(bd, J=14.8Hz, H=1), 4.367(bd, J=15.2Hz, H=1), 3.776(t, J=4.8Hz, H=1), 3.047(d, J=4.8Hz, H=2), HRMS(FAB) C29H22N4O5S : calcd 539.1389, found 539.1391
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.415 (s, H = 1), 9.289 (s, H = 1), 8.814 (d, J = 6 Hz, H = 1), 8.576 (d, J = 6 Hz, H = 1), 8.532 (d, J = 6 Hz, H = 1, 8.300 (m, H = 2), 7.996 (d, J = 8.4 Hz, H = 1), 7.811 (d, J = 6 Hz, H = 1), 7.671 (t, J = 8 Hz , H = 1), 7.561 (t, J = 7.2 Hz, H = 1), 7.364 (d, J = 7.2 Hz, H = 1), 6.956 (d, J = 6.8 Hz, H = 2), 6.804 ( d, J = 8.4 Hz, H = 2), 5.484 (bd, J = 14.8 Hz, H = 1), 4.367 (bd, J = 15.2 Hz, H = 1), 3.776 (t, J = 4.8 Hz, H = 1), 3.047 (d, J = 4.8 Hz, H = 2), HRMS (FAB) C 29 H 22 N 4 O 5 S: calcd 539.1389, found 539.1391

합성예Synthetic example 5: 5: terttert -부틸-4-((5-(4-(이소퀴놀린-5-일 -Butyl-4-((5- (4- (isoquinolin-5-yl 설포닐옥시Sulfonyloxy )벤질)-2,4-) Benzyl) -2,4- 디옥소이미다졸리딘Dioximidazolidine -1-일) 피페리딘-1--1-yl) piperidine-1- 카르복실레이트Carboxylate (6b) (6b)

합성예 4와 동일한 대표 합성법으로 수행하였으며, 80.9% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis Example 4, and obtained at a yield of 80.9%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.406(s, H=1), 8.797(d, J=6Hz, 1H), 8.515(d, J=6.0Hz, H=1), 8.293(d, J=8.4Hz, H=1), 8.260(d, J=7.6Hz, H=1), 7.668(t, J=7.6Hz, H=1), 7.003(d, J=8.4Hz, H=2), 6.799(d, J=8.4Hz, H=2), 4.195(t, J=4.4Hz, H=1), 3.743(m, H=1), 3.051(m, H=2), 2.898(m, H=1), 2.620(m, H=2), 1.430(s, H=9), 1.260(t, J=7.2Hz, H=2), 1.101(m, H=2), HRMS(FAB) C29H32N4O7S : calcd 581.2070, found 581.2072
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.406 (s, H = 1), 8.797 (d, J = 6 Hz, 1H), 8.515 (d, J = 6.0 Hz, H = 1), 8.293 (d, J = 8.4 Hz, H = 1), 8.260 ( d, J = 7.6 Hz, H = 1), 7.668 (t, J = 7.6 Hz, H = 1), 7.003 (d, J = 8.4 Hz, H = 2), 6.799 (d, J = 8.4 Hz, H = 2), 4.195 (t, J = 4.4 Hz, H = 1), 3.743 (m, H = 1), 3.051 (m, H = 2), 2.898 (m, H = 1), 2.620 (m, H = 2), 1.430 (s, H = 9), 1.260 (t, J = 7.2 Hz, H = 2), 1.101 (m, H = 2), HRMS (FAB) C 29 H 32 N 4 O 7 S: calcd 581.2070, found 581.2072

합성예Synthetic example 6 :  6: terttert -부틸-4-((5-(4-(이소퀴놀린-5-일 -Butyl-4-((5- (4- (isoquinolin-5-yl 설포닐옥시Sulfonyloxy )벤질)-2,4-) Benzyl) -2,4- 디옥소이미다졸리딘Dioximidazolidine -1-일)-1 day) 메틸methyl ) 피페리딘-1-) Piperidine-1- 카르복실레이트Carboxylate (6c) (6c)

합성예 4와 동일한 대표 합성법으로 수행하였으며, 82.1% 수득율로 수득하였다.The synthesis was carried out in the same representative manner as in Synthesis example 4, whereby 82.1% yield was obtained.

1H NMR(400MHz, CDCl3) δ (ppm); 9.407(s, H=1), 8.802(d, J=6.0Hz, H=1), 8.525(d, J=6.8Hz, H=1), 8.290(d, J=8.4Hz, H=1), 8.256(d, J=7.6Hz, H=1), 7.649(t, J=8.0Hz, H=1), 7.037(d, J=8.4Hz, H=5), 6.803(d, J=8.4Hz, H=2), 4.198(t, J=4.8Hz, H=2), 3.409(m, H=1), 3.146(qd, J=14.8Hz, H=2), 2.566(m, H=2), 1.947(qd, J=4.4Hz, H=1), 1.778(m, H=2), 1.592(m, H=4), 1.421(s, H=9), HRMS(FAB) C30H35N4O7S : calcd 595.2226, found 595.2223
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.407 (s, H = 1), 8.802 (d, J = 6.0 Hz, H = 1), 8.525 (d, J = 6.8 Hz, H = 1), 8.290 (d, J = 8.4 Hz, H = 1) , 8.256 (d, J = 7.6 Hz, H = 1), 7.649 (t, J = 8.0 Hz, H = 1), 7.037 (d, J = 8.4 Hz, H = 5), 6.803 (d, J = 8.4 Hz, H = 2), 4.198 (t, J = 4.8 Hz, H = 2), 3.409 (m, H = 1), 3.146 (qd, J = 14.8 Hz, H = 2), 2.566 (m, H = 2), 1.947 (qd, J = 4.4 Hz, H = 1), 1.778 (m, H = 2), 1.592 (m, H = 4), 1.421 (s, H = 9), HRMS (FAB) C 30 H 35 N 4 O 7 S: calcd 595.2226, found 595.2223

합성예Synthetic example 7 :  7: terttert -부틸-4-(2-(5-(4-(이소퀴놀린-5-일 -Butyl-4- (2- (5- (4- (isoquinolin-5-yl 설포닐옥시Sulfonyloxy )벤질)-2,4-) Benzyl) -2,4- 디옥소이미다졸리딘Dioximidazolidine -1-일)에틸) 피페리딘-1--1-yl) ethyl) piperidine-1- 카르복실레이트Carboxylate (6d) (6d)

합성예 4와 동일한 대표 합성법으로 수행하였으며, 75.8% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis Example 4, and obtained at a yield of 75.8%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.406(s, H=1), 8.797(d, J=6Hz, H=1,), 8.515(d, J=6.0Hz, H=1), 8.293(d, J=8.4Hz, H=1), 8.260(d, J=7.1Hz, H=1), 7.668(t, J=7.6Hz, H=2), 7.003(d, J=8.4Hz, H=2), 6.799(d, J=8.4Hz, H=2), 4.195(t, J=4.4Hz, H=1), 4.134(m, H=2), 3.743(m, H=1) 3.051(s, H=2), 2.898(m, H=1), 2.620(m, H=2), 1.655(m, H=4), 1.430(s, H=9), 1.309(t, J=7.2Hz, H=1), 1.101(m, H=2), HRMS(FAB) C3131H36N4O7S : calcd 609.2383, found 609.2381
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.406 (s, H = 1), 8.797 (d, J = 6 Hz, H = 1,), 8.515 (d, J = 6.0 Hz, H = 1), 8.293 (d, J = 8.4 Hz, H = 1) , 8.260 (d, J = 7.1 Hz, H = 1), 7.668 (t, J = 7.6 Hz, H = 2), 7.003 (d, J = 8.4 Hz, H = 2), 6.799 (d, J = 8.4 Hz, H = 2), 4.195 (t, J = 4.4 Hz, H = 1), 4.134 (m, H = 2), 3.743 (m, H = 1) 3.051 (s, H = 2), 2.898 (m , H = 1), 2.620 (m, H = 2), 1.655 (m, H = 4), 1.430 (s, H = 9), 1.309 (t, J = 7.2 Hz, H = 1), 1.101 (m , H = 2), HRMS (FAB) C31 31 H 36 N 4 O 7 S: calcd 609.2383, found 609.2381

합성예Synthetic example 8 : 4-((3-((1- 8: 4-((3-((1- 벤질피페리딘Benzylpiperidine -4-일)Yl) 메틸methyl )-2,5-) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (6e)(6e)

합성예 4와 동일한 대표 합성법으로 수행하였으며, 74.7% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis Example 4, and obtained at a yield of 74.7%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.396(s, H=1), 8.796(d, J=6.4Hz, H=1), 8.519(d, J=6.0Hz, H=1), 8.272(d, J=8.4Hz, H=1), 8.243(d, J=7.2Hz, H=1), 7.649(t, J=8.0Hz, H=1), 7.323(m, H=5), 6.989(d, J=8.4Hz, H=2), 6.784(d, J=8.8Hz, H=2), 4.192(d, J=4.4Hz, H=1), 3.569(m, H=3), 3.053(d, J=4.4Hz, H=2), 2.873(d, J=10Hz, H=2), 2.728(dd, J=13.6Hz, H=1), 1.934(m, H=3), 1.502(m, H=2), 1.303(m, H=2), HRMS(FAB) C32H32N4O5S : calcd 585.2172, found 585.2174
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.396 (s, H = 1), 8.796 (d, J = 6.4 Hz, H = 1), 8.519 (d, J = 6.0 Hz, H = 1), 8.272 (d, J = 8.4 Hz, H = 1) , 8.243 (d, J = 7.2 Hz, H = 1), 7.649 (t, J = 8.0 Hz, H = 1), 7.323 (m, H = 5), 6.989 (d, J = 8.4 Hz, H = 2 ), 6.784 (d, J = 8.8 Hz, H = 2), 4.192 (d, J = 4.4 Hz, H = 1), 3.569 (m, H = 3), 3.053 (d, J = 4.4 Hz, H = 2), 2.873 (d, J = 10 Hz, H = 2), 2.728 (dd, J = 13.6 Hz, H = 1), 1.934 (m, H = 3), 1.502 (m, H = 2), 1.303 ( m, H = 2), HRMS (FAB) C 32 H 32 N 4 O 5 S: calcd 585.2172, found 585.2174

합성예 9 : tert -부틸-4-((3-이소퀴놀린-5-일 메틸 )-4-(4-(이소퀴놀린-5-일 설포닐옥시 )벤질)-2,5- 디옥소이미다졸리딘 -1-일) 메틸 ) 피페리딘-1- 카르복실레이트(7a) Synthesis Example 9 tert -Butyl-4-((3-isoquinolin-5-yl methyl ) -4- (4- (isoquinolin-5-yl sulfonyloxy ) benzyl) -2,5 -dioxoimida Zolidin- 1 - yl) methyl ) piperidine-1- carboxylate (7a)

4-((3-(이소퀴놀린-5-일메틸)-2,5-디옥소이미다졸린-4-yl)메틸)페닐 이소퀴놀린-5-설포네이트(50 mg, 0.09 mmol)과 tert-부틸 4-((메틸설포닐옥시)메틸)피페리딘-1-카르복실레이트(54.5 mg, 0.19 mmol) 및 탄산칼륨(49.5 mg, 0.36 mmol)을 DMF(15 ml)에 첨가하였다. 24시간 후에 DMF를 회전 농축기를 이용하여 증발 시키며, 남은 잔여물은 EA 및 염화암모늄에 첨가하여 추출하였다. 황산나트륨으로 건조시키고 감압 하에서 농축하여 실리카겔을 이용한 컬럼을 수행하였다. 최종 산물을 70.7%의 수득율로 획득하였다.4-((3- (isoquinolin-5-ylmethyl) -2,5-dioxoimidazoline-4-yl) methyl) phenyl isoquinolin-5-sulfonate (50 mg, 0.09 mmol) and tert- Butyl 4-((methylsulfonyloxy) methyl) piperidine-1-carboxylate (54.5 mg, 0.19 mmol) and potassium carbonate (49.5 mg, 0.36 mmol) were added to DMF (15 ml). After 24 hours, DMF was evaporated using a rotary concentrator and the remaining residue was extracted by addition to EA and ammonium chloride. After drying over sodium sulfate and concentration under reduced pressure, a column using silica gel was performed. The final product was obtained at a yield of 70.7%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.426(s, H=1), 9.289(s, H=1), 8.830(d, J=6.0Hz, H=1), 8.554(t, J=6.4Hz, H=2), 8.309(dd, J=3.6Hz, H=2), 7.996(d, J=8.4Hz, H=1), 7.802(d, J=6.0Hz, H=1), 7.674(t, J=8.0Hz, H=1), 7.563(t, J=3.6Hz, H=1), 7.368(d, J=6.8Hz, H=1), 6.962(d, J=8.8Hz, H=2), 6.822(d, J=8.4Hz, H=2), 5.573(d, J=15.2Hz, H=1), 4.414(d, J=15.2Hz, H=1), 3.980(m, H=2), 3.688(t, J=4.8Hz, H=2), 3.234(m, H=2), 3.045(m, H=2), 2.513(m, H=2), 1.653(m, H=2), 1.442(s, H=9), 0.968(m, H=3), HRMS(FAB) C40H41N5O7S : calcd 736.2805, found 736.2807
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.426 (s, H = 1), 9.289 (s, H = 1), 8.830 (d, J = 6.0 Hz, H = 1), 8.554 (t, J = 6.4 Hz, H = 2), 8.309 (dd, J = 3.6 Hz, H = 2), 7.996 (d, J = 8.4 Hz, H = 1), 7.802 (d, J = 6.0 Hz, H = 1), 7.674 (t, J = 8.0 Hz, H = 1 ), 7.563 (t, J = 3.6 Hz, H = 1), 7.368 (d, J = 6.8 Hz, H = 1), 6.962 (d, J = 8.8 Hz, H = 2), 6.822 (d, J = 8.4 Hz, H = 2), 5.573 (d, J = 15.2 Hz, H = 1), 4.414 (d, J = 15.2 Hz, H = 1), 3.980 (m, H = 2), 3.688 (t, J = 4.8 Hz, H = 2), 3.234 (m, H = 2), 3.045 (m, H = 2), 2.513 (m, H = 2), 1.653 (m, H = 2), 1.442 (s, H = 9), 0.968 (m, H = 3), HRMS (FAB) C 40 H 41 N 5 O 7 S: calcd 736.2805, found 736.2807

합성예 10 : tert -부틸 4-((3-(이소퀴놀린-5- yl메틸 )-5-(4-(이소퀴놀린-5-일 설포닐옥시 )벤질)-2,4- 디옥소이미다졸린 -1-일) 메틸 )피페리딘-1- 카르복실레이트 (7b) Synthesis Example 10 tert -Butyl 4-((3- (isoquinolin-5- ylmethyl ) -5- (4- (isoquinolin-5 - yl sulfonyloxy ) benzyl) -2,4 -dioxoimida Sleepy- 1 - yl) methyl ) piperidine-1 -carboxylate (7b)

합성예 8과 동일한 대표 합성법으로 수행하였으며, 68.3% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis Example 8, and obtained at a yield of 68.3%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.420(s, H=1), 9.021(s, H=1), 8.874(d, J=6.0Hz, H=1), 8.521(d, J=6.0Hz, H=2), 8.277(d, J=8.4Hz, H=1), 8.161(d, J=7.6Hz, H=1), 7.991(d, J=5.6Hz, H=1), 7.875(d, J=7.6Hz, H=1), 7.624(t, J=8.0Hz, H=1), 7.444(m, H=2), 6.727(d, J=8.4Hz, H=2), 6.361(d, J=8.4Hz, H=2), 4.914(qd, J=14.8Hz, H=2), 4.158(m, H=2), 3.638(m, H=1), 3.001(m, H=2), 2.817(d, J=5.6Hz, H=1), 2.620(m, H=2), 1.707(m, H=4), 1.431(s, H=9), 1.153(qd, J=12.4Hz, H=2), HRMS(FAB) C40H41N5O7S : calcd 736.2805, found 736.2803
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.420 (s, H = 1), 9.021 (s, H = 1), 8.874 (d, J = 6.0 Hz, H = 1), 8.521 (d, J = 6.0 Hz, H = 2), 8.277 (d, J = 8.4 Hz, H = 1), 8.161 (d, J = 7.6 Hz, H = 1), 7.991 (d, J = 5.6 Hz, H = 1), 7.875 (d, J = 7.6 Hz, H = 1 ), 7.624 (t, J = 8.0 Hz, H = 1), 7.444 (m, H = 2), 6.727 (d, J = 8.4 Hz, H = 2), 6.361 (d, J = 8.4 Hz, H = 2), 4.914 (qd, J = 14.8 Hz, H = 2), 4.158 (m, H = 2), 3.638 (m, H = 1), 3.001 (m, H = 2), 2.817 (d, J = 5.6 Hz, H = 1), 2.620 (m, H = 2), 1.707 (m, H = 4), 1.431 (s, H = 9), 1.153 (qd, J = 12.4 Hz, H = 2), HRMS (FAB) C 40 H 41 N 5 O 7 S: calcd 736.2805, found 736.2803

합성예Synthetic example 11 : 4-((3-((1- 11: 4-((3-((1- 벤질피페리딘Benzylpiperidine -4-일)Yl) 메틸methyl )-1-(이소퀴놀린-5-일 ) -1- (isoquinolin-5-yl 메틸methyl )-2,5-) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)메틸) -4-yl) methyl) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (7c)(7c)

합성예 8과 동일한 대표 합성법으로 수행하였으며, 59.1% 수득율로 수득하였다.It carried out by the same representative synthesis method as Synthesis Example 8, and obtained in a 59.1% yield.

1H NMR(400MHz, CDCl3) δ (ppm); 10.325(s, NH), 9.413(s, H=1), 9.202(s, H=1), 8.858(d, J=6.0Hz, H=1), 8.505(d, J=6.0Hz, H=2), 8.280(d, J=8.4Hz, H=1), 8.160(d, J=7.2Hz, H=1), 7.977(d, J==7.2Hz, H=1), 7877(d, J=7.6Hz, H=1), 7.624(t, J=8.0Hz, H=1), 7.526(m, H=2), 7.446(m, H=5), 6.71), 6.71),0Hz, H=2), 6.3580(d, J=8.4Hz, H2), 4.837(qd, J=14.8Hz, H=2), 4.201(t, J=4.0 J=14.8Hz, H691(m, H=4), 3.016 (m, H=4), 1.975(m, H=2), 1.761(m, H=4), 1.256(m, H=2), HRMS(FAB) C42H39N5O5S : calcd 726.2750, found 726.2753
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 10.325 (s, NH), 9.413 (s, H = 1), 9.202 (s, H = 1), 8.858 (d, J = 6.0 Hz, H = 1), 8.505 (d, J = 6.0 Hz, H = 2), 8.280 (d, J = 8.4 Hz, H = 1), 8.160 (d, J = 7.2 Hz, H = 1), 7.977 (d, J == 7.2 Hz, H = 1), 7877 (d, J = 7.6 Hz, H = 1), 7.624 (t, J = 8.0 Hz, H = 1), 7.526 (m, H = 2), 7.446 (m, H = 5), 6.71), 6.71), 0 Hz, H = 2), 6.3580 (d, J = 8.4 Hz, H2), 4.837 (qd, J = 14.8 Hz, H = 2), 4.201 (t, J = 4.0 J = 14.8 Hz, H691 (m, H = 4 ), 3.016 (m, H = 4), 1.975 (m, H = 2), 1.761 (m, H = 4), 1.256 (m, H = 2), HRMS (FAB) C 42 H 39 N 5 O 5 S: calcd 726.2750, found 726.2753

합성예Synthetic example 12 : 4-((3-((1- 12: 4-((3-((1- 벤질피페리딘Benzylpiperidine -4-일)Yl) 메틸methyl )-2,5-) -2,5- 디옥소Dioxo -1-(퀴놀린-5-일 -1- (quinolin-5-yl 메틸methyl )) 이미다졸리딘Imidazolidine -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (7d)(7d)

합성예 8과 동일한 대표 합성법으로 수행하였으며, 62.9% 수득율로 수득하였다.
The synthesis was carried out in the same manner as in Synthesis Example 8, and obtained at a yield of 62.9%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.643(s, H=1), 9.405(s, H=1), 8.891(d, J=6.4Hz, H=2), 8.547(d, J=6.4Hz, H=2), 8.258(d, J=8.0Hz, H=1), 8.187(d, J=6.0Hz, H=1), 8.021(d, J=8.4Hz, H=1), 7.611(t, J=8.0Hz, H=1), 7.541(t, J=7.2Hz, H=3), 7.375(m, H=1), 7.305(m, H=5), 6.728(d, J=8.8Hz, H=2), 6.407(d, J=8.8Hz, H=2), 4.137(t, J=4.4Hz, H=2), 3.629(m, H=2), 3.492(d, J=9.2Hz, H=2), 2.991(d, J=4.4Hz, H=2), 2.823(m, H=2), 1.727(m, H=2), 1.521(mH=4), 1.263(m, H=2), HRMS(FAB) C42H39N5O5S : calcd 726.2750, found 726.2753
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.643 (s, H = 1), 9.405 (s, H = 1), 8.891 (d, J = 6.4 Hz, H = 2), 8.547 (d, J = 6.4 Hz, H = 2), 8.258 (d, J = 8.0 Hz, H = 1), 8.187 (d, J = 6.0 Hz, H = 1), 8.021 (d, J = 8.4 Hz, H = 1), 7.611 (t, J = 8.0 Hz, H = 1 ), 7.541 (t, J = 7.2 Hz, H = 3), 7.375 (m, H = 1), 7.305 (m, H = 5), 6.728 (d, J = 8.8 Hz, H = 2), 6.407 ( d, J = 8.8 Hz, H = 2), 4.137 (t, J = 4.4 Hz, H = 2), 3.629 (m, H = 2), 3.492 (d, J = 9.2 Hz, H = 2), 2.991 (d, J = 4.4 Hz, H = 2), 2.823 (m, H = 2), 1.727 (m, H = 2), 1.521 (mH = 4), 1.263 (m, H = 2), HRMS (FAB ) C 42 H 39 N 5 O 5 S: calcd 726.2750, found 726.2753

합성예Synthetic example 13 : 4-((1-벤질-3-((1- 13: 4-((1-benzyl-3-((1- 벤질피페리딘Benzylpiperidine -4-일)Yl) 메틸methyl )-2,5-) -2,5- 디옥소이미다졸린Dioxoimidazoline -4--4- ylyl )) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (7e) (7e)

합성예 8과 동일한 대표 합성법으로 수행하였으며, 63.8% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis Example 8, and obtained at a yield of 63.8%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.413(s, H=1), 8.841(d, J=6.4Hz, H=1), 8.542(d, J=6.4Hz, H=1), 8.270(d, J=8.0Hz, H=1), 8.204(d, J=7.6Hz, H=1), 7.629(t, J=7.6Hz, H=1), 7.301(m, H=5), 7.170(t, J=3.6Hz, H=3), 7.043(q, J=3.6Hz, H=3), 6.804(d, J=8.8Hz, H=2), 6.562(d, J=8.8Hz, H=2), 4.424(bq, J=14.8Hz, H=2), 4.134(t, J=4.4Hz, H=1), 3.601(m, H=1), 3.469(s, H=2), 3.085(qd, J= 14.8Hz, H=2), 2.851(bd, J=10.8Hz, H=2), 2.770(dd, J=14.4Hz, H=1), 2.027(d, J=8.0Hz, H=1), 1.927(q, J=10.8Hz, H=2), 1.496(t, J=8.0Hz, H=2), 1.301(m, H=2), HRMS(FAB) C39H38N4O5S : calcd 675.2641, found 675.2639
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.413 (s, H = 1), 8.841 (d, J = 6.4 Hz, H = 1), 8.542 (d, J = 6.4 Hz, H = 1), 8.270 (d, J = 8.0 Hz, H = 1) , 8.204 (d, J = 7.6 Hz, H = 1), 7.629 (t, J = 7.6 Hz, H = 1), 7.301 (m, H = 5), 7.170 (t, J = 3.6 Hz, H = 3 ), 7.043 (q, J = 3.6 Hz, H = 3), 6.804 (d, J = 8 Hz, H = 2), 6.562 (d, J = 8 Hz, H = 2), 4.424 (bq, J = 14.8 Hz, H = 2), 4.134 (t, J = 4.4 Hz, H = 1), 3.601 (m, H = 1), 3.469 (s, H = 2), 3.085 (qd, J = 14.8 Hz, H = 2), 2.851 (bd, J = 10.8 Hz, H = 2), 2.770 (dd, J = 14.4 Hz, H = 1), 2.027 (d, J = 8.0 Hz, H = 1), 1.927 (q, J = 10.8 Hz, H = 2), 1.496 (t, J = 8.0 Hz, H = 2), 1.301 (m, H = 2), HRMS (FAB) C 39 H 38 N 4 O 5 S: calcd 675.2641, found 675.2639

화합물 8을 예시로 모식도 3에 의해 얻어진 하이단토인 유도체의 대표합성법은 다음과 같다:Representative synthesis method of the hydantoin derivative obtained by Scheme 3 with Compound 8 as an example is as follows:

합성예Synthetic example 14 : 4-((2,5- 14: 4-((2,5- 디옥소Dioxo -3-(피페리딘-4-일)-3- (piperidin-4-yl) 이미다졸린Imidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (8a) (8a)

화합물 6b(150 mg, 0.26 mmol)를 TFA(Trifluoroaceticacid, 2.4 ml)와 함께 무수 DCM(12ml)에 녹여 0℃에서 1시간 반응시켰다. 반응 후, TFA를 회전 농축기를 이용하여 증발시키고, 남은 잔여물은 DCM에 녹인 후, 탄산칼륨 포화 수용액으로 추출하였다. 추출된 DCM 용액은 황산나트륨을 이용하여 무수화 과정을 거치고 농축하였다. 실리카겔을 이용한 컬럼을 수행하여 정제된 화합물을 약 85.2%의 수득율로 획득하였다. Compound 6b (150 mg, 0.26 mmol) was dissolved in anhydrous DCM (12 ml) with TFA (Trifluoroacetic acid, 2.4 ml) and reacted at 0 ° C. for 1 hour. After the reaction, TFA was evaporated using a rotary concentrator, and the remaining residue was dissolved in DCM and extracted with saturated aqueous potassium carbonate solution. The extracted DCM solution was concentrated using anhydrous solution using sodium sulfate. A column using silica gel was carried out to obtain purified compound in a yield of about 85.2%.

1H NMR(400MHz, DMSO) δ (ppm); 9.559(s, H=1), 8.824(d, J=6.0Hz, H=1), 8.586(d, J=8.0Hz, H=1), 8.361(d, J=6.0Hz, H=1), 8.253(d, J=7.6Hz, H=1), 7.801(t, J=8.0Hz, H=1), 7.079(d, J=7.6Hz, H=2), 6.790(d, J=7.2Hz, H=2), 4.330(t, J=4.4Hz, H=1), 3.129(m, H=1), 2.978(qd, J=14.8Hz, H=2), 2.875(m, H=2), 2.258(m, H=2), 1.855(qd, J=12.0Hz, H=1), 1.574(m, H=2), 1.371(m, H=1), HRMS(FAB) C24H24N4O5S : calcd 481.1546, found 481.1543
 1 H NMR (400 MHz, DMSO) δ (ppm); 9.559 (s, H = 1), 8.824 (d, J = 6.0 Hz, H = 1), 8.586 (d, J = 8.0 Hz, H = 1), 8.361 (d, J = 6.0 Hz, H = 1) , 8.253 (d, J = 7.6 Hz, H = 1), 7.801 (t, J = 8.0 Hz, H = 1), 7.079 (d, J = 7.6 Hz, H = 2), 6.790 (d, J = 7.2 Hz, H = 2), 4.330 (t, J = 4.4 Hz, H = 1), 3.129 (m, H = 1), 2.978 (qd, J = 14.8 Hz, H = 2), 2.875 (m, H = 2), 2.258 (m, H = 2), 1.855 (qd, J = 12.0 Hz, H = 1), 1.574 (m, H = 2), 1.371 (m, H = 1), HRMS (FAB) C 24 H 24 N 4 O 5 S: calcd 481.1546, found 481.1543

화합물 9를 예시로 모식도 3에 의해 얻어진 하이단토인 유도체의 대표합성법은 다음과 같다.Representative synthesis method of the hydantoin derivative obtained by the schematic diagram with the example of compound 9 is as follows.

합성예Synthetic example 15 : 4-((3-(1- 15: 4-((3- (1- 벤질피페리딘Benzylpiperidine -4-일)-2,5--4-yl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (9a) (9a)

화합물 8a(28.4 mg, 0.06 mmol)를 벤즈알데하이드(7.2 μl, 0.07 mmol) 및 소듐 트리아세톡시보로하이드라이드(25 mg, 0.12mmol)을 DMF(7ml)에 첨가하여 실온에서 24시간 반응시켰다. 반응 후, DMF를 회전 농축기를 이용하여 증발시키며, 남은 잔여물은 EA에 용해시킨 후, 염화암모늄 포화 수용액으로 추출하였다. 추출된 EA 용액은 황산나트륨을 이용하여 무수화과정을 거치고, 농축하였다. 실리카겔을 이용한 컬럼을 수행하여 정제된 최종 산물을 70.7%의 수득율로 획득하였다.Compound 8a (28.4 mg, 0.06 mmol) was added benzaldehyde (7.2 μl, 0.07 mmol) and sodium triacetoxyborohydride (25 mg, 0.12 mmol) to DMF (7 ml) and allowed to react at room temperature for 24 hours. After the reaction, DMF was evaporated using a rotary concentrator, and the remaining residue was dissolved in EA and extracted with saturated aqueous ammonium chloride solution. The extracted EA solution was anhydrous using sodium sulfate and concentrated. A column using silica gel was performed to obtain a purified final product with a yield of 70.7%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.396(s, H=1), 8.796(d, J=6.4Hz, H=1), 8.519(d, J=6.0Hz, H=1), 8.272(d, J=8.4Hz, H=1), 8.243(d, J=7.2Hz, H=1), 7.649(t, J=8.0Hz, H=1), 7.323(m, H=5), 6.989(d, J=8.4Hz, H=2), 6.784(d, J=8.8Hz, H=2), 4.192(d, J=4.4Hz, H=1), 3.569(m, H=1), 3.053(d, J=4.4Hz, H=2), 2.873(d, J=10Hz, H=2), 2.728(dd, J=13.6Hz, H=1), 1.934(m, H=3), 1.502(m, H=2), 1.303(m, H=2), HRMS(FAB) C31H30N4O5S : calcd 571.2172, found 571,2174
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.396 (s, H = 1), 8.796 (d, J = 6.4 Hz, H = 1), 8.519 (d, J = 6.0 Hz, H = 1), 8.272 (d, J = 8.4 Hz, H = 1) , 8.243 (d, J = 7.2 Hz, H = 1), 7.649 (t, J = 8.0 Hz, H = 1), 7.323 (m, H = 5), 6.989 (d, J = 8.4 Hz, H = 2 ), 6.784 (d, J = 8.8 Hz, H = 2), 4.192 (d, J = 4.4 Hz, H = 1), 3.569 (m, H = 1), 3.053 (d, J = 4.4 Hz, H = 2), 2.873 (d, J = 10 Hz, H = 2), 2.728 (dd, J = 13.6 Hz, H = 1), 1.934 (m, H = 3), 1.502 (m, H = 2), 1.303 ( m, H = 2), HRMS (FAB) C 31 H 30 N 4 O 5 S: calcd 571.2172, found 571,2174

합성예Synthetic example 16 : 4-((3-(1- 16: 4-((3- (1- 벤조일피페리딘Benzoylpiperidine -4--4- ylyl )-2,5-) -2,5- 디옥소이미다졸린Dioxoimidazoline -4--4- ylyl )) 메틸methyl )) 페닐Phenyl 이소퀴놀린e-5- Isoquinoline e-5- 설포네이트Sulfonate (9b) (9b)

화합물 8a(50mg, 0.10 mmol)를 벤조산(15.2 mg, 0.12 mmol) 및 EDC(29.9 mg, 0.16mmol), TEA(Triethanolamine, 21.7 ul, 0.16 mmol)을 DCM(7ml)에 넣고 2시간 실온에서 반응시켰다. 반응 후, 혼합물을 DCM으로 희석하고 탄산칼륨 포화 수용액으로 추출하였다. 추출된 DCM 용액은 황산나트륨을 이용하여 무수화 과정을 거치고, 농축하였다. 실리카겔을 이용한 컬럼을 수행하여 정제된 최종 산물을 약 70% 수득율로 획득하였다. Compound 8a (50 mg, 0.10 mmol) was added benzoic acid (15.2 mg, 0.12 mmol), EDC (29.9 mg, 0.16 mmol) and TEA (Triethanolamine, 21.7 ul, 0.16 mmol) in DCM (7 ml) and reacted at room temperature for 2 hours. . After the reaction, the mixture was diluted with DCM and extracted with saturated aqueous potassium carbonate solution. The extracted DCM solution was anhydrous using sodium sulfate and concentrated. The column was run with silica gel to obtain the purified final product in about 70% yield.

1H NMR(400MHz, CDCl3) δ (ppm); 9.396(s, H=1), 8.780(s, H=1), 8.516(d, J=5.6Hz, H=1), 8.271(s, NH), 8.251(d, J=7.2Hz, H=2), 7.652(t, J=8.0Hz, H=1), 7.476(m, H=5), 7.038(d, J=8.4Hz, H=2), 6.807(d, J=8.4Hz, H=2), 4.806(m, H=1), 4.210(t, J=4.8Hz, H=1), 4.134(qd, J=6.8Hz, H=1), 3.843(m, H=1), 3.470(t, J=10.8Hz, H=1), 3.154(qd, J=14.8Hz, H=1), 2.877(m, H=2), 1.892(m, H=2), 1.259(t, J=6.8Hz, H=1), HRMS(FAB) C31H29O6N4S : calcd 585.1808, found 585.1810
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.396 (s, H = 1), 8.780 (s, H = 1), 8.516 (d, J = 5.6 Hz, H = 1), 8.271 (s, NH), 8.251 (d, J = 7.2 Hz, H = 2), 7.652 (t, J = 8.0 Hz, H = 1), 7.476 (m, H = 5), 7.038 (d, J = 8.4 Hz, H = 2), 6.807 (d, J = 8.4 Hz, H = 2), 4.806 (m, H = 1), 4.210 (t, J = 4.8 Hz, H = 1), 4.134 (qd, J = 6.8 Hz, H = 1), 3.843 (m, H = 1), 3.470 (t, J = 10.8 Hz, H = 1), 3.154 (qd, J = 14.8 Hz, H = 1), 2.877 (m, H = 2), 1.892 (m, H = 2), 1.259 (t, J = 6.8 Hz, H = 1), HRMS (FAB) C 31 H 29 O 6 N 4 S: calcd 585.1808, found 585.1810

합성예Synthetic example 17 : 4-((2,5- 17: 4-((2,5- 디옥소Dioxo -3-(1--3- (1- 프로피오닐피페리딘Propionylpiperidine -4-일)Yl) 이미다졸리딘Imidazolidine -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (9c) (9c)

화합물 8a(50mg, 0.10 mmol)를 프로피오닐 클로라이드(11 μl, 0.13 mmol) 및 TEA(Triethanolamine, 14.5 μl, 0.10 mmol)을 DCM(7ml)에 첨가하여 실온에서 2시간 반응시켰다. 반응 후, 혼합물을 DCM으로 희석하고 염화암모늄 포화 수용액으로 추출하였다. 추출된 DCM 용액은 황산나트륨을 이용하여 무수화 과정을 거치고, 농축하였다. 실리카겔을 이용한 컬럼을 수행하여 정제된 최종 산물을 89.7%의 수득율로 획득하였다. Compound 8a (50 mg, 0.10 mmol) was added propionyl chloride (11 μl, 0.13 mmol) and TEA (Triethanolamine, 14.5 μl, 0.10 mmol) to DCM (7 ml) and allowed to react at room temperature for 2 hours. After the reaction, the mixture was diluted with DCM and extracted with saturated aqueous ammonium chloride solution. The extracted DCM solution was anhydrous using sodium sulfate and concentrated. A column using silica gel was carried out to obtain a purified final product with a yield of 89.7%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.388(s, H=1), 8.774(d, J=6.0Hz, H=1), 8.500(d, J=6.0Hz,H=1), 8.284(q, J=8.4Hz, H=2), 7.651(t, J=7.6Hz, H=1), 7.024(s, J=7.2Hz, H=2), 6.784(d, J=7.2Hz, H=2), 4.738(bt, J=12.4Hz, H=1), 4.172(d, J=3.2Hz, H=1), 3.901(bd, J=12.4Hz, H=1), 3.457(bt, J=11.2Hz, H=1), 3.119(bq, J=14.4Hz, H=2), 2.931(bq, J=15.2Hz, H=1), 2.397(m, H=3), 1.959(m, H=1), 1.780(m, H=2), 1.685(m, H=1), 1.122(t, J=7.2Hz ,H=3), HRMS(FAB) C27H28N4O6S : calcd 537.1808, found 537.1808
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.388 (s, H = 1), 8.774 (d, J = 6.0 Hz, H = 1), 8.500 (d, J = 6.0 Hz, H = 1), 8.284 (q, J = 8.4 Hz, H = 2) , 7.651 (t, J = 7.6 Hz, H = 1), 7.024 (s, J = 7.2 Hz, H = 2), 6.784 (d, J = 7.2 Hz, H = 2), 4.738 (bt, J = 12.4 Hz, H = 1), 4.172 (d, J = 3.2 Hz, H = 1), 3.901 (bd, J = 12.4 Hz, H = 1), 3.457 (bt, J = 11.2 Hz, H = 1), 3.119 (bq, J = 14.4 Hz, H = 2), 2.931 (bq, J = 15.2 Hz, H = 1), 2.397 (m, H = 3), 1.959 (m, H = 1), 1.780 (m, H = 2), 1.685 (m, H = 1), 1.122 (t, J = 7.2 Hz, H = 3), HRMS (FAB) C 27 H 28 N 4 O 6 S: calcd 537.1808, found 537.1808

합성예Synthetic example 18 : 4-((3-((1- 18: 4-((3-((1- 이소부티릴피페리딘Isobutyryl Piperidine -4-일)Yl) 메틸methyl )-2,5-) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5-설 Isoquinoline-5-sul 포네이Fornay 트 (9d)(9d)

합성예 17과 동일한 대표합성법으로 수행하였으며, 92.7% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 17, and obtained at a yield of 92.7%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.401(s, H=1), 8.791(d, J=6.5Hz, H=1), 8.513(d, J=6.0Hz, H=1), 8.347(s, NH), 8.292(d, J=8.4Hz, H=1), 8.244(d, J=7.2Hz, H=1), 7.661(t, J=8.0Hz, H=1), 7.032(d, J=8.4Hz, H=2), 6.799(, H=1), 8.347(s, NH)768(bt, J=10 8.244(d, J=7.279(s44(d, J=7.000(bd, J=11.6Hz, H=1), 3.458(s, H=1), 3.139(m, H=2), 2.953(bq, J=12Hz, H=1), 2.793(m, H=1), 2.408(m, H=1), 2.024(m, H=4), 1.102(s, H=6), HRMS(FAB) C28H30N4O6S : calcd 551.1964, found 551.1963
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.401 (s, H = 1), 8.791 (d, J = 6.5 Hz, H = 1), 8.513 (d, J = 6.0 Hz, H = 1), 8.347 (s, NH), 8.292 (d, J = 8.4 Hz, H = 1), 8.244 (d, J = 7.2 Hz, H = 1), 7.661 (t, J = 8.0 Hz, H = 1), 7.032 (d, J = 8.4 Hz, H = 2), 6.799 (, H = 1), 8.347 (s, NH) 768 (bt, J = 10 8.244 (d, J = 7.279 (s44 (d, J = 7.000 (bd, J = 11.6Hz, H = 1), 3.458 (s, H = 1), 3.139 (m, H = 2), 2.953 (bq, J = 12 Hz, H = 1), 2.793 (m, H = 1), 2.408 (m, H = 1), 2.024 ( m, H = 4), 1.102 (s, H = 6), HRMS (FAB) C 28 H 30 N 4 O 6 S: calcd 551.1964, found 551.1963

합성예Synthetic example 19 : 4-((2,5- 19: 4-((2,5- 디옥소Dioxo -3-(1--3- (1- 피발로일피페리딘Fivaloylpiperidine -4-일)Yl) 이미다졸리딘Imidazolidine -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (9e) (9e)

합성예 17과 동일한 대표합성법으로 수행하였으며, 94.6% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 17, and obtained at a yield of 94.6%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.406(s, H=1), 8.797(d, J=6.0Hz, H=1), 8.519(d, J=6.4Hz, H=1), 8.293(q, J=8.0Hz, H=2), 7.665(t, J=8.0Hz, H=1), 7.031(s, J=8.4Hz, H=2), 6.803(d, J=8.4Hz, H=2), 4.540(bt, J=14.8Hz, H=2), 4.193(t, J=4.4Hz, H=1), 3.498(m, H=1), 3.133(qd, J=10.0Hz, H=2), 2.662(bt, J=12.0Hz, H=2), 1.951(qd, J=3.2Hz, H=1), 1.807(m, H=2), 1.665(m, H=1), 1.258(s, H=9), HRMS(FAB) C29H32N4O6S : calcd 565.2121, found 565.2125
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.406 (s, H = 1), 8.797 (d, J = 6.0 Hz, H = 1), 8.519 (d, J = 6.4 Hz, H = 1), 8.293 (q, J = 8.0 Hz, H = 2) , 7.665 (t, J = 8.0 Hz, H = 1), 7.031 (s, J = 8.4 Hz, H = 2), 6.803 (d, J = 8.4 Hz, H = 2), 4.540 (bt, J = 14.8 Hz, H = 2), 4.193 (t, J = 4.4 Hz, H = 1), 3.498 (m, H = 1), 3.133 (qd, J = 10.0 Hz, H = 2), 2.662 (bt, J = 12.0 Hz, H = 2), 1.951 (qd, J = 3.2 Hz, H = 1), 1.807 (m, H = 2), 1.665 (m, H = 1), 1.258 (s, H = 9), HRMS (FAB) C 29 H 32 N 4 O 6 S: calcd 565.2121, found 565.2125

합성예Synthetic example 20 : 4-((3-((1- 20: 4-((3-((1- 부티릴피페리딘Butyryl Piperidine -4-일)Yl) 메틸methyl )-2,5-) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (9f) (9f)

합성예 17과 동일한 대표합성법으로 수행하였으며, 83.0% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 17, and the yield was obtained at 83.0% yield.

1H NMR(400MHz, CDCl3) δ (ppm); 9.401(s, H=1), 8.789(d, J=6.0 H=1), 8.512(d, J=6.0Hz, H=1), 8.453(s, NH), 8.291(d, J=8.0Hz, H=1), 8.245(d, J=7.2Hz, H=1), 7.661(t, J=8.0Hz, H=1), 7.031(d, J=8.4Hz, H=2), 6.799(d, J=8.4Hz, H=2), 4.755(bt, J=12.0Hz, H=1), 4.180(d, J=4.4Hz, H=1), 3.923(d, J=12.4Hz, H=1), 3.467(t, J=9.2Hz, H=1), 3.130(bq, J=14.4Hz, H=2), 2.940(bq, J=13.6Hz, H=1), 2.403(bt, J=11.6Hz, H=1), 2.276(t, J=7.6Hz, H=2), 1.960(bt, J=13.2Hz, H=1), 1.813(m, H=5), 0.960(t, J=7.2Hz, H=3), HRMS(FAB) C28H30N4O6S : calcd 551.1964, found 551.1962
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.401 (s, H = 1), 8.789 (d, J = 6.0 H = 1), 8.512 (d, J = 6.0 Hz, H = 1), 8.453 (s, NH), 8.291 (d, J = 8.0 Hz , H = 1), 8.245 (d, J = 7.2 Hz, H = 1), 7.661 (t, J = 8.0 Hz, H = 1), 7.031 (d, J = 8.4 Hz, H = 2), 6.799 ( d, J = 8.4 Hz, H = 2), 4.755 (bt, J = 12.0 Hz, H = 1), 4.180 (d, J = 4.4 Hz, H = 1), 3.923 (d, J = 12.4 Hz, H = 1), 3.467 (t, J = 9.2 Hz, H = 1), 3.130 (bq, J = 14.4 Hz, H = 2), 2.940 (bq, J = 13.6 Hz, H = 1), 2.403 (bt, J = 11.6 Hz, H = 1), 2.276 (t, J = 7.6 Hz, H = 2), 1.960 (bt, J = 13.2 Hz, H = 1), 1.813 (m, H = 5), 0.960 (t , J = 7.2 Hz, H = 3), HRMS (FAB) C 28 H 30 N 4 O 6 S: calcd 551.1964, found 551.1962

합성예Synthetic example 21 : 4-((3-(1-(3- 21: 4-((3- (1- (3- 메틸부타노일Methylbutanoyl )피페리딘-4-일)-2,5-) Piperidin-4-yl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5-설 Isoquinoline-5-sul 포네이Fornay 트 (9g)(9 g)

합성예 17과 동일한 대표합성법으로 수행하였으며, 74.4% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 17, and obtained at a yield of 74.4%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.339(s, H=1), 8.787(d, J=5.6Hz H=1), 8.511(d, J=6.0Hz, H=1), 8.460(s, NH), 8.290(d, J=8.0Hz, H=1), 8.245(d, J=7.6Hz, H=1), 7.661(t, J=7.6Hz, H=1), 7.031(d, J=8.4Hz, H=2), 6.798(d, J=8.4Hz, H=2), 4.769(t, J=13.2Hz, H=1), 4.178(s, H=1), 3.942(d, J=13.2Hz, H=1), 3.449(t, J=11.6Hz, H=1), 3.131(q, J=15.2Hz, H=2), 2.942(q, J=13.2Hz, H=1), 2.404(q, J=12.0Hz, H=1), 2.192(d, J=6.4Hz, H=2), 2.110(q, J=7.2Hz, H=1), 1.955(m, H=4), 0.951(d, J=6.4Hz, H=6), HRMS(FAB) C29H32N4O6S : calcd 565.2121, found 565.2123
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.339 (s, H = 1), 8.787 (d, J = 5.6 Hz H = 1), 8.511 (d, J = 6.0 Hz, H = 1), 8.460 (s, NH), 8.290 (d, J = 8.0 Hz, H = 1), 8.245 (d, J = 7.6 Hz, H = 1), 7.661 (t, J = 7.6 Hz, H = 1), 7.031 (d, J = 8.4 Hz, H = 2), 6.798 (d, J = 8.4 Hz, H = 2), 4.769 (t, J = 13.2 Hz, H = 1), 4.178 (s, H = 1), 3.942 (d, J = 13.2 Hz, H = 1), 3.449 (t, J = 11.6 Hz, H = 1), 3.131 (q, J = 15.2 Hz, H = 2), 2.942 (q, J = 13.2 Hz, H = 1), 2.404 (q, J = 12.0 Hz , H = 1), 2.192 (d, J = 6.4 Hz, H = 2), 2.110 (q, J = 7.2 Hz, H = 1), 1.955 (m, H = 4), 0.951 (d, J = 6.4 Hz, H = 6), HRMS (FAB) C 29 H 32 N 4 O 6 S: calcd 565.2121, found 565.2123

합성예Synthetic example 22 : 4-((3-((1-( 22: 4-((3-((1- ( cyclohexanecarbonylcyclohexanecarbonyl )) piperidinpiperidine -4--4- ylyl )) 메틸methyl )-2,5-) -2,5- 디옥소이미다졸린Dioxoimidazoline -4--4- ylyl )) 메틸methyl )) 페닐Phenyl 이소퀴놀린e-5- Isoquinoline e-5- 설포네이트Sulfonate (9h) (9h)

합성예 17과 동일한 대표합성법으로 수행하였으며, 78.0% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 17, and obtained at a yield of 78.0%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.397(s, H=1), 8.786(d, J=5.6Hz, H=1), 8.508(d, J=5.6Hz, H=1), 8.289(d, J=8.4Hz, NH=1), 8.239(d, J=7.6Hz, H=1), 7.659(t, J=8.4Hz, H=1), 7.031(d, J=8.4Hz, H=2), 6.794(d, J=8.4Hz, H=2), 4.754(t, J=13.2Hz, H=1), 4.175(s, H=1), 3.979(d, J=12.8Hz, H=1), 3.485(t, J=11.6Hz, H=1), 3.133(q, J=15.2Hz, H=2), 2.933(q, J=12.0Hz, H=1), 2.452(t, J=11.6Hz, H=1), 2.354(m, H=1), 2.018(m, H=8), 1.491(m, H=2), 1.255(m, H=4), HRMS(FAB) C31H34N4O6S : calcd 591.2277, found 591.2276
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.397 (s, H = 1), 8.786 (d, J = 5.6 Hz, H = 1), 8.508 (d, J = 5.6 Hz, H = 1), 8.289 (d, J = 8.4 Hz, NH = 1) , 8.239 (d, J = 7.6 Hz, H = 1), 7.659 (t, J = 8.4 Hz, H = 1), 7.031 (d, J = 8.4 Hz, H = 2), 6.794 (d, J = 8.4 Hz, H = 2), 4.754 (t, J = 13.2 Hz, H = 1), 4.175 (s, H = 1), 3.979 (d, J = 12.8 Hz, H = 1), 3.485 (t, J = 11.6 Hz, H = 1), 3.133 (q, J = 15.2 Hz, H = 2), 2.933 (q, J = 12.0 Hz, H = 1), 2.452 (t, J = 11.6 Hz, H = 1), 2.354 (m, H = 1), 2.018 (m, H = 8), 1.491 (m, H = 2), 1.255 (m, H = 4), HRMS (FAB) C 31 H 34 N 4 O 6 S: calcd 591.2277, found 591.2276

합성예Synthetic example 23 : 4-((3-(1- 23: 4-((3- (1- 아다만탄카르보닐피페리딘Adamantanecarbonylpiperidine -4-일)-2,5--4-yl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4--4- ylyl )) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5-설 Isoquinoline-5-sul 포네이Fornay 트 (9i)(9i)

합성예 17과 동일한 대표합성법으로 수행하였으며, 78.8% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 17, and obtained at a yield of 78.8%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.395(s, H=1), 8.784(d, J=5.6Hz, H=1), 8.511(d, J=6.0Hz, H=2), 8.285(d, J=8.0Hz, H=1), 8.234(d, J=7.6Hz, H=1), 7.655(t, J=8.0Hz, H=1), 7.027(d, J=8.4Hz, H=2), 6.787(d, J=8.0Hz, H=2), 4.625(bt, J=12.8Hz, H=2), 4.183(t, J=4.4Hz, H=1), 3.537(bt, J=12.4Hz, H=1), 3.127(qd, J=14.8Hz, H=2), 2.629(t, J=12.4Hz, H=2), 2.017(s, H=3), 1.949(s, H=6), 1.831(m, H=10), HRMS(FAB) C35H39O6N4S : calcd 643.2590, found643.2593
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.395 (s, H = 1), 8.784 (d, J = 5.6 Hz, H = 1), 8.511 (d, J = 6.0 Hz, H = 2), 8.285 (d, J = 8.0 Hz, H = 1) , 8.234 (d, J = 7.6 Hz, H = 1), 7.655 (t, J = 8.0 Hz, H = 1), 7.027 (d, J = 8.4 Hz, H = 2), 6.787 (d, J = 8.0 Hz, H = 2), 4.625 (bt, J = 12.8 Hz, H = 2), 4.183 (t, J = 4.4 Hz, H = 1), 3.537 (bt, J = 12.4 Hz, H = 1), 3.127 (qd, J = 14.8 Hz, H = 2), 2.629 (t, J = 12.4 Hz, H = 2), 2.017 (s, H = 3), 1.949 (s, H = 6), 1.831 (m, H = 10), HRMS (FAB) C 35 H 39 O 6 N 4 S: calcd 643.2590, found643.2593

합성예Synthetic example 24 : 4-((3-(1- 24: 4-((3- (1- 아다만틸메틸피페리딘Adamantylmethylpiperidine -4-일)-2,5--4-yl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (9j) (9j)

합성예 15와 동일한 대표합성법으로 수행하였으며, 72.4% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 15, and obtained in a yield of 72.4%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.408(s, H=1), 8.799(d, J=6.0Hz H=1), 8.517(d, J=6.4Hz, H=1), 8.300(t, J=10.8Hz, H=2), 7.992(s, NH), 7.672(t, J=8.4Hz, H=1), 7.046(d, J=8.4Hz, H=2), 6.832(d, J=12.0Hz, H=2), 4.530(t, J=10.8Hz, H=1), 4.200(q, J=4,4Hz, H=1), 3.690(m, H=1), 3.465(t, J=11.6Hz, H=1), 3.140(m, H=3), 2.489(m, H=1), 2.081(s, H=2), 2.015(m, H= 19), HRMS(FAB) C35H40N4O5S : calcd , found
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.408 (s, H = 1), 8.799 (d, J = 6.0 Hz H = 1), 8.517 (d, J = 6.4 Hz, H = 1), 8.300 (t, J = 10.8 Hz, H = 2), 7.992 (s, NH), 7.672 (t, J = 8.4 Hz, H = 1), 7.046 (d, J = 8.4 Hz, H = 2), 6.832 (d, J = 12.0 Hz, H = 2), 4.530 (t, J = 10.8 Hz, H = 1), 4.200 (q, J = 4,4 Hz, H = 1), 3.690 (m, H = 1), 3.465 (t, J = 11.6 Hz, H = 1) , 3.140 (m, H = 3), 2.489 (m, H = 1), 2.081 (s, H = 2), 2.015 (m, H = 19), HRMS (FAB) C35H40N4O5S: calcd, found

합성예Synthetic example 25 : 4-((3-(1- 25: 4-((3- (1- 아다만타일아세틸피페리딘Adamantylacetylpiperidine -4-일)-2,5--4-yl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4--4- ylyl )) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5-설 Isoquinoline-5-sul 포네이Fornay 트 (9k)(9k)

합성예 16과 동일한 대표합성법으로 수행하였으며, 70.2% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 16, and obtained at a yield of 70.2%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.409(s, H=1), 8.798(d, J=6.0Hz, H=1), 8.520(d, J=6.0Hz, H=1), 8.296(d, J=8.4Hz, H=1), 8.257(d, J=7.6Hz, H=1), 7.966(s, NH=1), 7.668(t, J=7.6,H=1), 7.032(d, J=8.8Hz, H=2), 6.805(d, J=8.4Hz, H=2), 4.830(bt, J=12.0Hz, H=1), 4.200(q, J=5.2Hz, H=1), 4.038(bd, J=12.4Hz, H=1), 3.496(m, H=1), 3.150(dd, J=4.8Hz, H=1), 3.050(m, H=1), 2.979(m, H=1), 2.410(m, H=1), 2.206(m, H=19), HRMS(FAB) C36H40N4O6S : calcd 657.2747, found 657.2744
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.409 (s, H = 1), 8.798 (d, J = 6.0 Hz, H = 1), 8.520 (d, J = 6.0 Hz, H = 1), 8.296 (d, J = 8.4 Hz, H = 1) , 8.257 (d, J = 7.6 Hz, H = 1), 7.966 (s, NH = 1), 7.668 (t, J = 7.6, H = 1), 7.032 (d, J = 8.8 Hz, H = 2) , 6.805 (d, J = 8.4 Hz, H = 2), 4.830 (bt, J = 12.0 Hz, H = 1), 4.200 (q, J = 5.2 Hz, H = 1), 4.038 (bd, J = 12.4 Hz, H = 1), 3.496 (m, H = 1), 3.150 (dd, J = 4.8 Hz, H = 1), 3.050 (m, H = 1), 2.979 (m, H = 1), 2.410 ( m, H = 1), 2.206 (m, H = 19), HRMS (FAB) C 36 H 4 0N 4 O 6 S: calcd 657.2747, found 657.2744

합성예Synthetic example 26 : 4-((3-(3- 26: 4-((3- (3- 브로모아다만틸카르보닐피페리딘Bromoadamantylcarbonylpiperidine -4-일)-2,5--4-yl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (9l) (9l)

합성예 16과 동일한 대표합성법으로 수행하였으며, 55.6% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 16, and the yield was obtained at 55.6%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.413(s, H=1), 8.800(d, J=6.4Hz, H=1), 8.522(d, J=6.4Hz, H=1), 8.305(q, J=8.4Hz, H=2), 7.804(s, NH), 7.672(t, J=8.0Hz, H=1), 7.038(d, J=8.4Hz, H=2), 6.822(d, J=8.8Hz, H=2), 4.572(t, J=6.8Hz, H=2), 4.197(t, J=5.2Hz, H=1), 3.477(m, H=1), 3.144(qd, J=14.8Hz, H=2), 2.655(t, J=8.4Hz, H=2), 2.531(s, H=2), 2.348(bt, J=14.8Hz, H=4), 2.216(s, H=2), 2.026(m, H=6), 1.784(m, H=5), HRMS(FAB) C35H37BrN4O6S : calcd 723.1681, found 723.1755
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.413 (s, H = 1), 8.800 (d, J = 6.4 Hz, H = 1), 8.522 (d, J = 6.4 Hz, H = 1), 8.305 (q, J = 8.4 Hz, H = 2) , 7.804 (s, NH), 7.672 (t, J = 8.0 Hz, H = 1), 7.038 (d, J = 8.4 Hz, H = 2), 6.822 (d, J = 8.8 Hz, H = 2), 4.572 (t, J = 6.8 Hz, H = 2), 4.197 (t, J = 5.2 Hz, H = 1), 3.477 (m, H = 1), 3.144 (qd, J = 14.8 Hz, H = 2) , 2.655 (t, J = 8.4 Hz, H = 2), 2.531 (s, H = 2), 2.348 (bt, J = 14.8 Hz, H = 4), 2.216 (s, H = 2), 2.026 (m , H = 6), 1.784 (m, H = 5), HRMS (FAB) C 35 H 37 BrN 4 O 6 S: calcd 723.1681, found 723.1755

합성예Synthetic example 27 : 4-((3-(3,5- 27: 4-((3- (3,5- 디메틸아다만탄카르보닐피페리딘Dimethyladamantanecarbonylpiperidine -4-일)-2,5--4-yl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (9m) (9m)

합성예 16과 동일한 대표합성법으로 수행하였으며, 76.0% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 16, and obtained at a yield of 76.0%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.405(s, H=1), 8.798(d, J=6.0Hz, H=1), 8.521(d, J=6.0Hz, H=1), 8.293(d, J=8.4Hz, H=1), 8.250(d, J=7.6Hz, H=1), 7.913(s, NH), 7.664(t, J=8.0Hz, H=1), 7.030(d, J=7.6Hz, H=2), 6.802(d, J=7.6Hz, H=2), 4.607(bt, J=14.0Hz, H=2), 4.191(t, J=3.6Hz, H=1), 3.529(bt, J=11.2Hz, H=1), 3.140(qd, J=14.0Hz, H=2), 2.630(bt, J=12Hz, H=2), 2.111(s, H=1), 1.911(q, J=11.2Hz, H=1), 1.779(s, H=4), 1.665(m, H=6), 1.336(m, H=7), 0.831(s, H=6), HRMS(FAB) C37H42N4O6S : calcd 671.2903, found 671.2900
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.405 (s, H = 1), 8.798 (d, J = 6.0 Hz, H = 1), 8.521 (d, J = 6.0 Hz, H = 1), 8.293 (d, J = 8.4 Hz, H = 1) , 8.250 (d, J = 7.6 Hz, H = 1), 7.913 (s, NH), 7.664 (t, J = 8.0 Hz, H = 1), 7.030 (d, J = 7.6 Hz, H = 2), 6.802 (d, J = 7.6 Hz, H = 2), 4.607 (bt, J = 14.0 Hz, H = 2), 4.191 (t, J = 3.6 Hz, H = 1), 3.529 (bt, J = 11.2 Hz , H = 1), 3.140 (qd, J = 14.0 Hz, H = 2), 2.630 (bt, J = 12 Hz, H = 2), 2.111 (s, H = 1), 1.911 (q, J = 11.2 Hz , H = 1), 1.779 (s, H = 4), 1.665 (m, H = 6), 1.336 (m, H = 7), 0.831 (s, H = 6), HRMS (FAB) C 37 H 42 N 4 O 6 S: calcd 671.2903, found 671.2900

합성예Synthetic example 28 : 4-((3-(1-(3- 28: 4-((3- (1- (3- 노라다만탄카르보닐Noradamantancarbonyl )피페리딘-4-일)-2,5-) Piperidin-4-yl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (9n) (9n)

합성예 16과 동일한 대표합성법으로 수행하였으며, 84.5% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 16, and the yield was obtained at 84.5%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.402(s, H=1), 8.793(d, J=6.0Hz, H=1), 8.516(d, J=5.6Hz, H=1), 8.291(d, J=8.4Hz, H=1), 8.240(d, J=7.2Hz, H=1), 7.661(t, J=8.4Hz, H=1), 7.031(d, J=8.4Hz, H=2), 6.796(d, J=8.4Hz, H=2), 4.194(t, J=4.8Hz, H=1), 3.528(t, J=12.0Hz, H=1), 3.140(bq, J=15.2Hz, H=2), 2.734(t, J=6.0Hz, H=1), 2.290(s, H=2), 2.045(m, H=16), HRMS(FAB) C34H36N4O6S : calcd 629.2434, found 629.2431
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.402 (s, H = 1), 8.793 (d, J = 6.0 Hz, H = 1), 8.516 (d, J = 5.6 Hz, H = 1), 8.291 (d, J = 8.4 Hz, H = 1) , 8.240 (d, J = 7.2 Hz, H = 1), 7.661 (t, J = 8.4 Hz, H = 1), 7.031 (d, J = 8.4 Hz, H = 2), 6.796 (d, J = 8.4 Hz, H = 2), 4.194 (t, J = 4.8 Hz, H = 1), 3.528 (t, J = 12.0 Hz, H = 1), 3.140 (bq, J = 15.2 Hz, H = 2), 2.734 (t, J = 6.0 Hz, H = 1), 2.290 (s, H = 2), 2.045 (m, H = 16), HRMS (FAB) C 34 H 36 N 4 O 6 S: calcd 629.2434, found 629.2431

합성예Synthetic example 29 : 4-((3-(1-(2- 29: 4-((3- (1- (2- 노보나닐아세틸Nobonanylacetyl )피페리딘-4-일)-2,5-) Piperidin-4-yl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4--4- ylyl )) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (9o) (9o)

합성예 16과 동일한 대표합성법으로 수행하였으며, 87.2% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 16, and the yield was obtained at 87.2% yield.

1H NMR(400MHz, CDCl3) δ (ppm); 9.402(s, H=1), 8.794(d, J=6.4Hz H=1), 8.515(d, J=6.0Hz, H=1), 8.293(d, J=8.4Hz, NH), 8.245(d, J=8.0Hz, H=1), 7.662(t, J=8.0Hz, H=1), 7.032(d, J=8.4Hz, H=2), 6.800(d, J=8.8Hz, H=2), 4.753(t, J=12.4Hz, H=1), 4.180(d, J=4.0, H=1), 3.929(d, J=13.2Hz, H=1), 3.470(m, H=1), 3.136(q, J=14.8Hz, H=2), 2.932(q, J=12.8Hz, H=1), 2.393(m, H=4), 1.994(m, H=5), 1.603(m, H=4), 1.287(m, H=5), HRMS(FAB) C33H36N4O6S : calcd 617.2434, found 617.2432
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.402 (s, H = 1), 8.794 (d, J = 6.4 Hz H = 1), 8.515 (d, J = 6.0 Hz, H = 1), 8.293 (d, J = 8.4 Hz, NH), 8.245 ( d, J = 8.0 Hz, H = 1), 7.662 (t, J = 8.0 Hz, H = 1), 7.032 (d, J = 8.4 Hz, H = 2), 6.800 (d, J = 8.8 Hz, H = 2), 4.753 (t, J = 12.4 Hz, H = 1), 4.180 (d, J = 4.0, H = 1), 3.929 (d, J = 13.2 Hz, H = 1), 3.470 (m, H = 1), 3.136 (q, J = 14.8 Hz, H = 2), 2.932 (q, J = 12.8 Hz, H = 1), 2.393 (m, H = 4), 1.994 (m, H = 5), 1.603 (m, H = 4), 1.287 (m, H = 5), HRMS (FAB) C 33 H 36 N 4 O 6 S: calcd 617.2434, found 617.2432

합성예Synthetic example 30 : 4-((3-(1-(3,4- 30: 4-((3- (1- (3,4- 디메톡시벤조일Dimethoxybenzoyl )피페리딘-4-일)-2,5-) Piperidin-4-yl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4--4- ylyl )) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (9p) (9p)

합성예 16과 동일한 대표합성법으로 수행하였으며, 70.8% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 16, and obtained in a yield of 70.8%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.397(s, H=1), 8.791(d, J=6.0Hz, H=1), 8.510(d, J=6.0Hz, H=1), 8.284(d, J=8.0Hz, H=1), 8.255(d, J=7.6Hz, H=1), 7.660(t, J=7.6Hz, H=1), 7.042(m, H=4), 6.862(d, J=8.4Hz, H=1), 6.810(d, J=8.4Hz, H=2), 4.209(t, J=4.8Hz, H=1), 3.895(s, H=6), 3.468(m, H=1), 3.148(bq, J=15.2Hz, H=2), 2.747(m, H=2), 2.601(m, H=2), 1.876(m, H=2), 1.631(m, H=2), HRMS(FAB) C33H32N4O8S : calcd 645.2019, found 645.2021
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.397 (s, H = 1), 8.791 (d, J = 6.0 Hz, H = 1), 8.510 (d, J = 6.0 Hz, H = 1), 8.284 (d, J = 8.0 Hz, H = 1) , 8.255 (d, J = 7.6 Hz, H = 1), 7.660 (t, J = 7.6 Hz, H = 1), 7.042 (m, H = 4), 6.862 (d, J = 8.4 Hz, H = 1 ), 6.810 (d, J = 8.4 Hz, H = 2), 4.209 (t, J = 4.8 Hz, H = 1), 3.895 (s, H = 6), 3.468 (m, H = 1), 3.148 ( bq, J = 15.2 Hz, H = 2), 2.747 (m, H = 2), 2.601 (m, H = 2), 1.876 (m, H = 2), 1.631 (m, H = 2), HRMS ( FAB) C 33 H 32 N 4 O 8 S: calcd 645.2019, found 645.2021

합성예Synthetic example 31 : 4-((3-(1-(4- 31: 4-((3- (1- (4- 플루오로벤조일Fluorobenzoyl )피페리딘-4-일)-2,5-) Piperidin-4-yl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (9q) (9q)

합성예 17과 동일한 대표합성법으로 수행하였으며, 72.7% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 17, and obtained at a yield of 72.7%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.413(s, H=1), 8.789(d, J=7.2Hz, H=1), 8.508(d, J=6.0Hz, H=1), 8.297(dd, J=8.0Hz, H=2), 8.118(t, J=5.6Hz, H=1), 7.675(t, J=8.0Hz, H=1), 7.399(t, J=8.0Hz, H=2), 7.092(t, J=9.2Hz, H=2), 7.005(d, J=8.8Hz, H=2), 6.807(d, J=8.8Hz, H=2), 4.212(t, J=4.8Hz, H=1), 3.587(m, H=1), 3.086(d, J=4.4Hz, H=2), 2.904(m, H=1), 3.086(qd, 14.4Hz, H=2), 1.813(m, H=1), 1.566(m, H=2), 1.240(m, H=2), HRMS(FAB) C31H27FN4O6S : calcd 603.1714, found 603.1711
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.413 (s, H = 1), 8.789 (d, J = 7.2 Hz, H = 1), 8.508 (d, J = 6.0 Hz, H = 1), 8.297 (dd, J = 8.0 Hz, H = 2) , 8.118 (t, J = 5.6 Hz, H = 1), 7.675 (t, J = 8.0 Hz, H = 1), 7.399 (t, J = 8.0 Hz, H = 2), 7.092 (t, J = 9.2 Hz, H = 2), 7.005 (d, J = 8.8 Hz, H = 2), 6.807 (d, J = 8.8 Hz, H = 2), 4.212 (t, J = 4.8 Hz, H = 1), 3.587 (m, H = 1), 3.086 (d, J = 4.4 Hz, H = 2), 2.904 (m, H = 1), 3.086 (qd, 14.4 Hz, H = 2), 1.813 (m, H = 1 ), 1.566 (m, H = 2), 1.240 (m, H = 2), HRMS (FAB) C 31 H 27 FN 4 O 6 S: calcd 603.1714, found 603.1711

합성예Synthetic example 32 : 4-((3-(1-(3,4- 32: 4-((3- (1- (3,4- 디플루오로벤조일Difluorobenzoyl )피페리딘-4-일)-2,5-) Piperidin-4-yl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (9r) (9r)

합성예 17과 동일한 대표합성법으로 수행하였으며, 80.6% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 17, and the yield was obtained at 80.6% yield.

1H NMR(400MHz, CDCl3) δ (ppm); 9.420(s, H=1), 8.794(d, J=5.6Hz, H=1), 8.521(d, J=6.4Hz, H=1), 8.310(t, J=8.4Hz, H=2), 7.766(s, H=1), 7.686(t, J=8.0Hz, H=1),7.235(m, H=3), 7.045(d, J=6.8Hz, H=2), 6.833(d, J=8.8Hz, H=2), 4.872(m, H=1), 4.212(t, J=4.8Hz, H=1), 3.956(m, H=1), 3.429(t, J=12.0Hz, H=1), 3.152(qd, 14.4Hz, H=2), 2.911(m, H=2), 2.080(m, H=2), 1.941(m, H=2), HRMS (FAB) C31H26F2N4O6S : calcd 621.1619, found 621.1621
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.420 (s, H = 1), 8.794 (d, J = 5.6 Hz, H = 1), 8.521 (d, J = 6.4 Hz, H = 1), 8.310 (t, J = 8.4 Hz, H = 2) , 7.766 (s, H = 1), 7.686 (t, J = 8.0 Hz, H = 1), 7.235 (m, H = 3), 7.045 (d, J = 6.8 Hz, H = 2), 6.833 (d , J = 8.8 Hz, H = 2), 4.872 (m, H = 1), 4.212 (t, J = 4.8 Hz, H = 1), 3.956 (m, H = 1), 3.429 (t, J = 12.0 Hz, H = 1), 3.152 (qd, 14.4 Hz, H = 2), 2.911 (m, H = 2), 2.080 (m, H = 2), 1.941 (m, H = 2), HRMS (FAB) C 31 H 26 F 2 N 4 O 6 S: calcd 621.1619, found 621.1621

합성예Synthetic example 33 : 4-((3-(1-(2- 33: 4-((3- (1- (2- 클로로벤조일Chlorobenzoyl )피페리딘-4-일)-2,5-) Piperidin-4-yl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4--4- ylyl )) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5-설 Isoquinoline-5-sul 포네이Fornay 트 (9s)(9s)

합성예 17과 동일한 대표합성법으로 수행하였으며, 71.2% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 17, and obtained at a yield of 71.2%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.377(s, H=1), 8.794(d, J=6.0Hz H=1), 8.516(d, J=5.6Hz, NH), 8.274(t, J=7.2Hz, H=2), 7.674(t, J=7.6Hz, H=1), 7.422(m, H=3), 7.041(d, J=7.0Hz, H=2), 6.790(d, J=7.2Hz, H=2), 4.932(m, H=1), 4.198(t, J=4.8Hz, H=1), 3.711(m, H=1), 3.505(t, J=13.6Hz, H=1), 3.148(m, H=4), 2.017(m, H=4), HRMS(FAB) C31H27ClN4O6S : calcd 619.1418, found 619.1415
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.377 (s, H = 1), 8.794 (d, J = 6.0 Hz H = 1), 8.516 (d, J = 5.6 Hz, NH), 8.274 (t, J = 7.2 Hz, H = 2), 7.674 ( t, J = 7.6 Hz, H = 1), 7.422 (m, H = 3), 7.041 (d, J = 7.0 Hz, H = 2), 6.790 (d, J = 7.2 Hz, H = 2), 4.932 (m, H = 1), 4.198 (t, J = 4.8 Hz, H = 1), 3.711 (m, H = 1), 3.505 (t, J = 13.6 Hz, H = 1), 3.148 (m, H = 4), 2.017 (m, H = 4), HRMS (FAB) C 31 H 27 ClN 4 O 6 S: calcd 619.1418, found 619.1415

합성예Synthetic example 34 : 4-((3-(1-(3- 34: 4-((3- (1- (3- 클로로벤조일Chlorobenzoyl )피페리딘-4-일)-2,5-) Piperidin-4-yl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5-설 Isoquinoline-5-sul 포네이Fornay 트 (9t)(9t)

합성예 17과 동일한 대표합성법으로 수행하였으며, 75.9% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 17, and obtained at a yield of 75.9%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.390(s, H=1), 8.782(d, J=5.6Hz H=1), 8.536(s, NH), 8.504(d, J=5.6Hz, H=1), 8.279(d, J=8.0Hz, H=1), 8.246(d, J=7.6Hz, H=1), 7.655(t, J=7.6Hz, H=1), 7.406(m, H=3), 7.036(d, J=7.1Hz, H=2), 6.805(d, J=7.2Hz, H=2), 4.824(m, H=1), 4.207(t, J=4.8Hz, H=1), 3.773(m, H=1), 3.416(t, J=12.0Hz, H=1), 3.146(qd, J=4.0Hz, H=2), 2.943(m, H=2), 2.065(m, H=4), HRMS(FAB) C31H27ClN4O6S : calcd 619.1418, found 619.1421
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.390 (s, H = 1), 8.782 (d, J = 5.6 Hz H = 1), 8.536 (s, NH), 8.504 (d, J = 5.6 Hz, H = 1), 8.279 (d, J = 8.0 Hz, H = 1), 8.246 (d, J = 7.6 Hz, H = 1), 7.655 (t, J = 7.6 Hz, H = 1), 7.406 (m, H = 3), 7.036 (d, J = 7.1 Hz, H = 2, 6.805 (d, J = 7.2 Hz, H = 2), 4.824 (m, H = 1), 4.207 (t, J = 4.8 Hz, H = 1), 3.773 (m, H = 1), 3.416 (t, J = 12.0 Hz, H = 1), 3.146 (qd, J = 4.0 Hz, H = 2), 2.943 (m, H = 2), 2.065 (m, H = 4), HRMS (FAB) C 31 H 27 ClN 4 O 6 S: calcd 619.1418, found 619.1421

합성예Synthetic example 35 : 4-((3-(1-(4- 35: 4-((3- (1- (4- 클로로벤조일Chlorobenzoyl )피페리딘-4-일)-2,5-) Piperidin-4-yl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5-설 Isoquinoline-5-sul 포네이Fornay 트 (9u)(9u)

합성예 17과 동일한 대표합성법으로 수행하였으며, 77.6% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 17, and obtained at a yield of 77.6%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.411(s, H=1), 8.779(s, H=1), 8.508(d, J=5.2Hz, H=1), 8.395(s, NH=1), 8.290(t, J=7.2Hz, H=2), 7.667(t, J=8.0Hz, H=1), 7.392(q, J=8.0Hz, H=4), 7.040(d, J=8.4Hz, H=2), 6.812(d, J=8.0Hz, H=2), 4.780(m, H=1), 4.204(t, J=4.8Hz, H=1), 3.806(m, H=1), 3.432(t, J=11.2Hz, H=1), 3.142(qd, J=14.4Hz, H=2), 3.041(d, J=3.6Hz, H=2), 2.115(m, H=4), HRMS(FAB) C31H27ClN4O6S : calcd 619.1418, found 619.1415
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.411 (s, H = 1), 8.779 (s, H = 1), 8.508 (d, J = 5.2 Hz, H = 1), 8.395 (s, NH = 1), 8.290 (t, J = 7.2 Hz, H = 2), 7.667 (t, J = 8.0 Hz, H = 1), 7.392 (q, J = 8.0 Hz, H = 4), 7.040 (d, J = 8.4 Hz, H = 2), 6.812 (d , J = 8.0 Hz, H = 2), 4.780 (m, H = 1), 4.204 (t, J = 4.8 Hz, H = 1), 3.806 (m, H = 1), 3.432 (t, J = 11.2 Hz, H = 1), 3.142 (qd, J = 14.4 Hz, H = 2), 3.041 (d, J = 3.6 Hz, H = 2), 2.115 (m, H = 4), HRMS (FAB) C 31 H 27 ClN 4 O 6 S: calcd 619.1418, found 619.1415

합성예Synthetic example 36 : 4-((3-((1-(3,4- 36: 4-((3-((1- (3,4- 디클로로벤조일Dichlorobenzoyl )피페리딘-4-일)) ≪ / RTI > piperidin-4-yl) 메틸methyl )-2,5-) -2,5- 디옥소이미다졸린Dioxoimidazoline -4--4- ylyl )) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (9v)  (9v)

합성예 16과 동일한 대표합성법으로 수행하였으며, 70.3% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 16, and obtained in a yield of 70.3%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.402(s, H=1), 8.792(d, J=6.4Hz, H=1), 8.510(d, J=6.4Hz, H=1), 8.293(d, J=7.6Hz, H=1), 7.669(t, J=8.0Hz, H=1), 7.497(d, J=8.0Hz, H=2), 7.242(dd, J=8.4Hz, H=2), 7.047(d, J=8.4Hz, H=2), 6.829(d, J=8.4Hz, H=2), 4.852(m, H=2), 4.207(t, J=4.8Hz, H=1), 3.413(m, H=1), 3.146(qd, J=6.4Hz, H=2), 2.071(m, H=2), 1.984(m, H=2), 1.642(m, H=2), HRMS(FAB) C31H26Cl2N4O6S : calcd 653.1028, found 653.1026
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.402 (s, H = 1), 8.792 (d, J = 6.4 Hz, H = 1), 8.510 (d, J = 6.4 Hz, H = 1), 8.293 (d, J = 7.6 Hz, H = 1) , 7.669 (t, J = 8.0 Hz, H = 1), 7.497 (d, J = 8.0 Hz, H = 2), 7.242 (dd, J = 8.4 Hz, H = 2), 7.047 (d, J = 8.4 Hz, H = 2), 6.829 (d, J = 8.4 Hz, H = 2), 4.852 (m, H = 2), 4.207 (t, J = 4.8 Hz, H = 1), 3.413 (m, H = 1), 3.146 (qd, J = 6.4 Hz, H = 2), 2.071 (m, H = 2), 1.984 (m, H = 2), 1.642 (m, H = 2), HRMS (FAB) C 31 H 26 Cl 2 N 4 O 6 S: calcd 653.1028, found 653.1026

합성예Synthetic example 37 : 4-((3-(1-(3,4- 37: 4-((3- (1- (3,4- 디클로로벤질Dichlorobenzyl )피페리딘-4-일)-2,5-) Piperidin-4-yl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (9w) (9w)

합성예 15와 동일한 대표합성법으로 수행하였으며, 68.1% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 15, and obtained in a yield of 68.1%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.395(s, H=1), 8.793(d, J=6.0Hz, H=1), 8.518(d, J=6.0Hz, H=1), 8.276(t, J=7.2Hz, H=2), 7.654(t, J=Hz, H=1), 7.576(s, NH), 7.405(s, H=1), 7.384(d, J=8.4Hz, H=1) 7.139(d, J=7.6Hz, H=1), 7.039(d, J=8.4Hz, H=2), 6.791(d, J=8.0Hz, H=2), 4.221(t, J=4.8Hz, H=1), 3.501(m, H=1), 3.416(s, H=2), 3.181(m, H=2), 2.006(m, H=4), 1.613(m, H=4), HRMS(FAB) C31H29O5N4Cl2S : calcd 639.1236, found 639.1232
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.395 (s, H = 1), 8.793 (d, J = 6.0 Hz, H = 1), 8.518 (d, J = 6.0 Hz, H = 1), 8.276 (t, J = 7.2 Hz, H = 2) , 7.654 (t, J = Hz, H = 1), 7.576 (s, NH), 7.405 (s, H = 1), 7.384 (d, J = 8.4 Hz, H = 1) 7.139 (d, J = 7.6 Hz, H = 1), 7.039 (d, J = 8.4 Hz, H = 2), 6.791 (d, J = 8.0 Hz, H = 2), 4.221 (t, J = 4.8 Hz, H = 1), 3.501 (m, H = 1), 3.416 (s, H = 2), 3.181 (m, H = 2), 2.006 (m, H = 4), 1.613 (m, H = 4), HRMS (FAB) C 31 H 29 O 5 N 4 Cl 2 S: calcd 639.1236, found 639.1232

합성예Synthetic example 38 : 4-((3-(1-(4- 38: 4-((3- (1- (4- 클로로Chloro -2--2- 플루오로벤조일Fluorobenzoyl )피페리딘-4-일)-2,5-) Piperidin-4-yl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (9x) (9x)

합성예 17와 동일한 대표합성법으로 수행하였으며, 82.8% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 17, and the yield was obtained at 82.8% yield.

1H NMR(400MHz, CDCl3) δ (ppm); 9.395(s, H=1), 8.773(s, H=1), 8.502(s, H=1), 8.444(s, H=1), 8.297(m, H=2), 7.647(q, J=4.0Hz, H=1), 7.360(t, J=7.6Hz, H=1), 7.222(d, J=8.0Hz, H=1), 7.139(d, J=6.4Hz, H=1) 7.035(d, J=8.0Hz, H=2), 6.811(t, J=6.4Hz, H=2), 4.844(t, J=12.8Hz, H=1), 4.191(s, H=1), 3.590(d, J=13.6Hz, H=1), 3.141(m, H=3), 2.641(m, H=1), 2.070(m, H=5), HRMS(FAB) C31H26ClFN4O6S : calcd 637.1324, found 637.1320
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.395 (s, H = 1), 8.773 (s, H = 1), 8.502 (s, H = 1), 8.444 (s, H = 1), 8.297 (m, H = 2), 7.647 (q, J = 4.0 Hz, H = 1), 7.360 (t, J = 7.6 Hz, H = 1), 7.222 (d, J = 8.0 Hz, H = 1), 7.139 (d, J = 6.4 Hz, H = 1) 7.035 (d, J = 8.0 Hz, H = 2), 6.811 (t, J = 6.4 Hz, H = 2), 4.844 (t, J = 12.8 Hz, H = 1), 4.191 (s, H = 1) , 3.590 (d, J = 13.6 Hz, H = 1), 3.141 (m, H = 3), 2.641 (m, H = 1), 2.070 (m, H = 5), HRMS (FAB) C 31 H 26 ClFN 4 O 6 S: calcd 637.1324, found 637.1320

합성예Synthetic example 39 : 4-((3-(1-(4- 39: 4-((3- (1- (4- 클로로Chloro -3-(-3- ( 트리플루오로메틸Trifluoromethyl )) 벤조일Benzoyl )피페리딘-4-일)-2,5-) Piperidin-4-yl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)메틸)-4-yl) methyl) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (9y) (9y)

합성예 16과 동일한 대표합성법으로 수행하였으며, 75.3% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 16, and obtained in a yield of 75.3%.

1H NMR(400MHz, CDCl3) δ(ppm); 9.397(s, H=1), 8.784(d, J=6.0Hz H=1), 8.500(d, J=5.6Hz, H=1), 8.389(s, NH=1), 8.293(d, J=8.4Hz, H=1), 8.263(d, J=7.2Hz, H=1), 7.744(s, H=1), 7.668(t, J=8.0Hz, H=1), 7.568(d, J=8.4Hz, H=1), 7.519(d, J=8.0Hz, H=1), 7.046(d, J=8.4Hz, H=2), 6.823(d, J=8.0Hz, H=2), 4.802(m, H=1), 4.208(t, J=4.8Hz, H=1), 3.745(m, H=1), 3.407(t, J=12.0Hz, H=1), 3.146(m, H=2), 2.945(m, H=2), 2.167(m, H=4), HRMS(FAB) C32H26ClF3N4O6S : calcd 687.1292, found 687.1292
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.397 (s, H = 1), 8.784 (d, J = 6.0 Hz H = 1), 8.500 (d, J = 5.6 Hz, H = 1), 8.389 (s, NH = 1), 8.293 (d, J = 8.4 Hz, H = 1), 8.263 (d, J = 7.2 Hz, H = 1), 7.744 (s, H = 1), 7.668 (t, J = 8.0 Hz, H = 1), 7.568 (d, J = 8.4 Hz, H = 1), 7.519 (d, J = 8.0 Hz, H = 1), 7.046 (d, J = 8.4 Hz, H = 2), 6.823 (d, J = 8.0 Hz, H = 2 ), 4.802 (m, H = 1), 4.208 (t, J = 4.8 Hz, H = 1), 3.745 (m, H = 1), 3.407 (t, J = 12.0 Hz, H = 1), 3.146 ( m, H = 2), 2.945 (m, H = 2), 2.167 (m, H = 4), HRMS (FAB) C 32 H 26 ClF 3 N 4 O 6 S: calcd 687.1292, found 687.1292

합성예Synthetic example 40 : 4-((3-((1- 40: 4-((3-((1- 벤조일피페리딘Benzoylpiperidine -4-일)Yl) 메틸methyl )-2,5-) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (10a) (10a)

합성예 16과 동일한 대표합성법으로 수행하였으며, 95.0% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 16, and obtained in a yield of 95.0%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.410(s, H=1), 8.802(d, J=6.0Hz, H=1), 8.516(d, J=5.6Hz, H=1), 8.293(d, J=8.4Hz, H=1), 8.261(d, J=7.6Hz, H=1), 7.670(t, J=8.0Hz, H=1), 7.398(m, H=5), 7.010(d, J=8.4Hz, H=2), 6.817(d, J=8.4Hz, H=2), 4.697(m, H=1), 4.215(t, J=4.0Hz, H=1), 3.757(m, H=1), 3.591(q, J=10.4Hz, H=1), 3.079(d, J=6.4Hz, H=2), 2.938(m, H=1), 2.806(dd, J=5.6Hz, H=2), 1.817(m, H=2), 1.263(m, H=3), HRMS(FAB) C32H30N4O6S : calcd 599.964, found 599.1962
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.410 (s, H = 1), 8.802 (d, J = 6.0 Hz, H = 1), 8.516 (d, J = 5.6 Hz, H = 1), 8.293 (d, J = 8.4 Hz, H = 1) , 8.261 (d, J = 7.6 Hz, H = 1), 7.670 (t, J = 8.0 Hz, H = 1), 7.398 (m, H = 5), 7.010 (d, J = 8.4 Hz, H = 2 ), 6.817 (d, J = 8.4 Hz, H = 2), 4.697 (m, H = 1), 4.215 (t, J = 4.0 Hz, H = 1), 3.757 (m, H = 1), 3.591 ( q, J = 10.4 Hz, H = 1), 3.079 (d, J = 6.4 Hz, H = 2), 2.938 (m, H = 1), 2.806 (dd, J = 5.6 Hz, H = 2), 1.817 (m, H = 2), 1.263 (m, H = 3), HRMS (FAB) C 32 H 30 N 4 O 6 S: calcd 599.964, found 599.1962

합성예Synthetic example 41 : 4-((3-((1- 41: 4-((3-((1- 아다만탄카르보닐피페리딘Adamantanecarbonylpiperidine -4-일)Yl) 메틸methyl )-2,5-) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (10b) (10b)

합성예 16과 동일한 대표합성법으로 수행하였으며, 70.4% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 16, and obtained in a yield of 70.4%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.409(s, H=1), 8.800(d, J=6.4Hz, H=1), 8.518(d, J=6Hz, H=1), 8.298(d, J=8.4Hz, H=1), 8.257(d, J=7.6Hz, H=1), 7.676(t, J=8.4Hz, H=1), 7.007(d, J=8.4Hz, H=2), 6.809(d, J=8.8Hz, H=2), 4.510(bt, J=12.4Hz, H=2), 4.205(m, H=1), 3.557(m, H=1), 3.081(m, H=2), 2.757(m, H=2), 2.654(bd, J=12.4Hz, H=1), 2.010(s, H=3), 1.947(s, H=5), 1.692(s, H=5), 1.585(s, H=2), 1.544(bd, J=16.0Hz , H=1), 1.238(m, H=2), 1.107(m, H=2), HRMS(FAB) C36H40N4O6S : calcd 657.2747, found 657.2750
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.409 (s, H = 1), 8.800 (d, J = 6.4 Hz, H = 1), 8.518 (d, J = 6 Hz, H = 1), 8.298 (d, J = 8.4 Hz, H = 1), 8.257 (d, J = 7.6 Hz, H = 1), 7.676 (t, J = 8.4 Hz, H = 1), 7.007 (d, J = 8.4 Hz, H = 2), 6.809 (d, J = 8.8 Hz , H = 2), 4.510 (bt, J = 12.4 Hz, H = 2), 4.205 (m, H = 1), 3.557 (m, H = 1), 3.081 (m, H = 2), 2.757 (m , H = 2), 2.654 (bd, J = 12.4 Hz, H = 1), 2.010 (s, H = 3), 1.947 (s, H = 5), 1.692 (s, H = 5), 1.585 (s , H = 2), 1.544 (bd, J = 16.0 Hz, H = 1), 1.238 (m, H = 2), 1.107 (m, H = 2), HRMS (FAB) C 36 H 4 0N 4 O 6 S: calcd 657.2747, found 657.2750

합성예Synthetic example 42 : 4-((3-((1-(3,4- 42: 4-((3-((1- (3,4- 디메톡시벤조일Dimethoxybenzoyl )피페리딘-4-일)) ≪ / RTI > piperidin-4-yl) 메틸methyl )-2,5-) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (10c) (10c)

합성예 17과 동일한 대표합성법으로 수행하였으며, 51.7% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 17, and obtained at a yield of 51.7%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.403(s, H=1), 8.792(d, J=6.0Hz, H=1), 8.509(d, J=6.4Hz, H=1), 8.291(q, J=8.0Hz, H=2), 7.669(t, J=8.0Hz, H=1), 7.011(m, H=4), 6.846(d, J=8.4Hz, H=1), 6.808(d, J=8.4Hz, H=2), 4.210(t, J=4.4Hz, H=1), 3.829(s, H=6), 3.586(q, J=8.8Hz, H=1), 3.110(d, J=4.4Hz, H=2), 2.863(m, H=4), 1.793(m, H=2), 1.539(m, H=3), HRMS(FAB) C34H34N4O8S : calcd 659.2176, found 659.2179
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.403 (s, H = 1), 8.792 (d, J = 6.0 Hz, H = 1), 8.509 (d, J = 6.4 Hz, H = 1), 8.291 (q, J = 8.0 Hz, H = 2) , 7.669 (t, J = 8.0 Hz, H = 1), 7.011 (m, H = 4), 6.846 (d, J = 8.4 Hz, H = 1), 6.808 (d, J = 8.4 Hz, H = 2 ), 4.210 (t, J = 4.4 Hz, H = 1), 3.829 (s, H = 6), 3.586 (q, J = 8.8 Hz, H = 1), 3.110 (d, J = 4.4 Hz, H = 2), 2.863 (m, H = 4), 1.793 (m, H = 2), 1.539 (m, H = 3), HRMS (FAB) C 34 H 34 N 4 O 8 S: calcd 659.2176, found 659.2179

합성예Synthetic example 43 : 4-((3-(2-(1- 43: 4-((3- (2- (1- 벤조일피페리딘Benzoylpiperidine -4-일)에틸)-2,5--4-yl) ethyl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5-설포네이트 (11a) Isoquinoline-5-sulfonate (11a)

합성예 16과 동일한 대표합성법으로 수행하였으며, 72.5% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 16, and obtained at a yield of 72.5%.

1H NMR(400MHz, CDCl3) δ (ppm); ); 9.398(s, H=1), 8.786(d, J=6.0Hz, H=1), 8.504(d, J=5.6Hz, H=1) , 8.286(t, J=8.0Hz, H=2), 7.667(t, J=8.0Hz, H=1), 7.394(m, H=5), 7.009(d, J=8.0Hz, H=2), 6.807(d, J=8.8Hz, H=2), 4.195(t, J=4.0Hz, H=1), 3.746(m, H=2), 3.059(d, J=4.0Hz, H=2), 2.950(m, H=2), 1.851(m, H=4), 1.416(m, H=2), 1.260(t, J=7.2Hz, H=1), 1.207(m, H=2), HRMS(FAB) C33H32N4O6S : calcd 613.2121, found 613.2123
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); ); 9.398 (s, H = 1), 8.786 (d, J = 6.0 Hz, H = 1), 8.504 (d, J = 5.6 Hz, H = 1), 8.286 (t, J = 8.0 Hz, H = 2) , 7.667 (t, J = 8.0 Hz, H = 1), 7.394 (m, H = 5), 7.009 (d, J = 8.0 Hz, H = 2), 6.807 (d, J = 8.8 Hz, H = 2 ), 4.195 (t, J = 4.0 Hz, H = 1), 3.746 (m, H = 2), 3.059 (d, J = 4.0 Hz, H = 2), 2.950 (m, H = 2), 1.851 ( m, H = 4), 1.416 (m, H = 2), 1.260 (t, J = 7.2 Hz, H = 1), 1.207 (m, H = 2), HRMS (FAB) C 33 H 32 N 4 O 6 S: calcd 613.2121, found 613.2123

합성예Synthetic example 44 : 4-((3-(2-(1- 44: 4-((3- (2- (1- 벤질피페리딘Benzylpiperidine -4-일)에틸)-2,5--4-yl) ethyl) -2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (11b) (11b)

합성예 15와 동일한 대표합성법으로 수행하였으며, 79.1% 수득율로 수득하였다.The synthesis was carried out in the same manner as in Synthesis example 15, and obtained in a yield of 79.1%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.400(s, H=1), 8.789(d, J=6.0Hz, H=1), 8.512(d, J=6.0Hz, H=1), 8.281(t, J=7.6Hz, H=2), 7.991(s, NH) 7.657(t, J=8.0Hz, H=1), 7.294(m, H=5), 6.994(d, J=8.0Hz, H=2), 6.785(d, J=7.6Hz, H=2), 4.177(t, J=4.0Hz, H=1), 3.733(m, H=1), 3.523(s, H=2), 3.038(s, H=2), 2.908(m, H=3), 1.976(t, J=10.8Hz, H=2), 1.654(dd, J=10.4Hz, H=2), 1.427(m, H=5), HRMS(FAB) C33H34N4O5S : calcd 599.2328, found 599.2332
 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.400 (s, H = 1), 8.789 (d, J = 6.0 Hz, H = 1), 8.512 (d, J = 6.0 Hz, H = 1), 8.281 (t, J = 7.6 Hz, H = 2) , 7.991 (s, NH) 7.657 (t, J = 8.0 Hz, H = 1), 7.294 (m, H = 5), 6.994 (d, J = 8.0 Hz, H = 2), 6.785 (d, J = 7.6 Hz, H = 2), 4.177 (t, J = 4.0 Hz, H = 1), 3.733 (m, H = 1), 3.523 (s, H = 2), 3.038 (s, H = 2), 2.908 (m, H = 3), 1.976 (t, J = 10.8 Hz, H = 2), 1.654 (dd, J = 10.4 Hz, H = 2), 1.427 (m, H = 5), HRMS (FAB) C 33 H 34 N 4 O 5 S: calcd 599.2328, found 599.2332

합성예Synthetic example 45 : 4-((3-(1- 45: 4-((3- (1- 아다만탄카르보닐피페리딘Adamantanecarbonylpiperidine -4-일)-1-Yl) -1- 메틸methyl -2,5--2,5- 디옥소이미다졸린Dioxoimidazoline -4-일)Yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinoline-5- 설포네이트Sulfonate (12) (12)

0℃의 조건하에서 4-((3-(1-아다만탄카르보닐피페리딘-4-일)-2,5-디옥소이미다졸린-4-일)메틸)페닐 이소퀴놀린-5-설포네이트(10mg, 0.02mmol)가 녹아있는 메탄올(1ml)에 디아조메탄(12ml, 0.02mmol)을 첨가하여 1시간 반응시켰다. 반응 후, 매탄올을 회전 농축기를 이용하여 증발시키고, 추출 없이 실리카겔을 이용한 컬럼을 수행하여 정제된 최종산물(4-((3-(1-아다만탄카르보닐피페리딘-4-일)-1-메틸-2,5-디옥소이미다졸린-4-yl)메틸)페닐 이소퀴놀린-5-설포네이트)를 74.6%의 수득율로 수득하였다.4-((3- (1-adamantanecarbonylpiperidin-4-yl) -2,5-dioxoimidazolin-4-yl) methyl) phenyl isoquinoline-5- under conditions of 0 ° C To the methanol (1 ml) in which sulfonate (10 mg, 0.02 mmol) was dissolved, diazomethane (12 ml, 0.02 mmol) was added and reacted for 1 hour. After the reaction, the methanol was evaporated using a rotary concentrator and purified by column using silica gel without extraction to obtain the final product (4-((3- (1-adamantanecarbonylpiperidin-4-yl) -1-methyl-2,5-dioxoimidazoline-4-yl) methyl) phenyl isoquinoline-5-sulfonate) was obtained in a yield of 74.6%.

1H NMR(400MHz, CDCl3) δ (ppm); 9.415(s, H=1), 8.822(d, J=6.4Hz, H=1), 8.545(d, J=6.0Hz, H=1), 8.293(d, J=8.0Hz, H=1), 8.235(dd, J=7.6Hz, H=1), 7.657(t, J=8Hz, H=1), 6.998(d, J=8.4Hz, H=2), 6.797(dd, J=6.4Hz, H=2), 4.637(bt, J=13.6Hz, H=2), 4.118(m, H=1), 3.509(m, H=1), 3.104(qd, J=6.4Hz, H=2), 2.757(s, H=3), 2.633(bt, J=13.6Hz, H=2), 2.157(s, H=2), 2.029(s, H=3), 1.966(s, H=5), 1.796(m, H=2), 1.709(s, H=5), 1.670(m, H=2), HRMS(FAB) C36H40N4O6S : calcd 657.2747, found 657.2749 1 H NMR (400 MHz, CDCl 3 ) δ (ppm); 9.415 (s, H = 1), 8.822 (d, J = 6.4 Hz, H = 1), 8.545 (d, J = 6.0 Hz, H = 1), 8.293 (d, J = 8.0 Hz, H = 1) , 8.235 (dd, J = 7.6 Hz, H = 1), 7.657 (t, J = 8 Hz, H = 1), 6.998 (d, J = 8.4 Hz, H = 2), 6.797 (dd, J = 6.4 Hz , H = 2), 4.637 (bt, J = 13.6 Hz, H = 2), 4.118 (m, H = 1), 3.509 (m, H = 1), 3.104 (qd, J = 6.4 Hz, H = 2 ), 2.757 (s, H = 3), 2.633 (bt, J = 13.6 Hz, H = 2), 2.157 (s, H = 2), 2.029 (s, H = 3), 1.966 (s, H = 5 ), 1.796 (m, H = 2), 1.709 (s, H = 5), 1.670 (m, H = 2), HRMS (FAB) C 36 H 4 0N 4 O 6 S: calcd 657.2747, found 657.2749

이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (10)

하기의 화학식 1로 표시되는 하이단토인(Hydantoin) 유도체:
화학식 1
Figure 112012106908731-pat00055

상기 화학식에서, R1 및 R2는 각각 독립적으로 수소, 피페리딘, 피페리디닐 C1-C4 알킬, 퀴놀린, 이소퀴놀린, 퀴놀리닐 C1-C4 알킬 또는 이소퀴놀리닐 C1-C4 알킬이고, R3-R6는 수소이며, R7은 산소 또는 NH이고, R8은 설포닐(-S(O)2-) 또는 카르보닐(-C(O)-)이며, R9는 퀴놀린, 이소퀴놀린, 퀴놀리닐 C1-C4 알킬 또는 이소퀴놀리닐 C1-C4 알킬이고, n은 0-5의 정수이다.
Hydantoin derivative represented by Formula 1 below:
Formula 1
Figure 112012106908731-pat00055

In the above formula, R 1 and R 2 are each independently hydrogen, piperidine, piperidinyl C 1 -C 4 alkyl, quinoline, isoquinoline, quinolinyl C 1 -C 4 alkyl or isoquinolinyl C 1 -C 4 alkyl, R 3 -R 6 is hydrogen, R 7 is oxygen or NH, R 8 is sulfonyl (-S (O) 2- ) or carbonyl (-C (O)-), R 9 is quinoline, isoquinoline, quinolinyl C 1 -C 4 alkyl or isoquinolinyl C 1 -C 4 alkyl, n is an integer from 0-5.
제 1 항에 있어서, 상기 R7은 산소인 것을 특징으로 하는 하이단토인 유도체.
The hydantoin derivative according to claim 1, wherein R 7 is oxygen.
제 1 항에 있어서, 상기 R8은 설포닐(-S(O)2-)인 것을 특징으로 하는 하이단토인 유도체.
2. The hydantoin derivative according to claim 1, wherein R 8 is sulfonyl (-S (O) 2- ).
제 1 항에 있어서, 상기 R1 또는 R2의 피페리딘 또는 피페리디닐 C1-C4 알킬은 고리 내 질소가 아실기 또는 페닐 C1-C4 알킬로 치환된 것을 특징으로 하는 하이단토인 유도체.
The method of claim 1 , wherein the R 1 Or piperidine or piperidinyl C 1 -C 4 alkyl of R 2 is a hydantoin derivative characterized in that the nitrogen in the ring is substituted with an acyl group or phenyl C 1 -C 4 alkyl.
제 1 항에 있어서, 상기 하이단토인 유도체는 하기의 화학식 2 내지 46으로 표시되는 화합물로 구성된 군으로부터 선택되는 것을 특징으로 하는 하이단토인 유도체:
화학식 2 화학식 3
Figure 112012106908731-pat00056
Figure 112012106908731-pat00057


화학식 4 화학식 5
Figure 112012106908731-pat00058
Figure 112012106908731-pat00059


화학식 6 화학식 7
Figure 112012106908731-pat00060
Figure 112012106908731-pat00061


화학식 8 화학식 9
Figure 112012106908731-pat00062
Figure 112012106908731-pat00063


화학식 10 화학식 11
Figure 112012106908731-pat00064
Figure 112012106908731-pat00065



화학식 12 화학식 13
Figure 112012106908731-pat00066
Figure 112012106908731-pat00067


화학식 14 화학식 15
Figure 112012106908731-pat00068
Figure 112012106908731-pat00069


화학식 16 화학식 17
Figure 112012106908731-pat00070
Figure 112012106908731-pat00071


화학식 18 화학식 19
Figure 112012106908731-pat00072
Figure 112012106908731-pat00073


화학식 20 화학식 21
Figure 112012106908731-pat00074
Figure 112012106908731-pat00075


화학식 22 화학식 23
Figure 112012106908731-pat00076
Figure 112012106908731-pat00077


화학식 24 화학식 25
Figure 112012106908731-pat00078
Figure 112012106908731-pat00079


화학식 26 화학식 27
Figure 112012106908731-pat00080
Figure 112012106908731-pat00081


화학식 28 화학식 29
Figure 112012106908731-pat00082
Figure 112012106908731-pat00083


화학식 30 화학식 31
Figure 112012106908731-pat00084
Figure 112012106908731-pat00085


화학식 32 화학식 33
Figure 112012106908731-pat00086
Figure 112012106908731-pat00087


화학식 34 화학식 35
Figure 112012106908731-pat00088
Figure 112012106908731-pat00089

화학식 36 화학식 37
Figure 112012106908731-pat00090
Figure 112012106908731-pat00091


화학식 38 화학식 39
Figure 112012106908731-pat00092
Figure 112012106908731-pat00093


화학식 40 화학식 41
Figure 112012106908731-pat00094
Figure 112012106908731-pat00095

화학식 42 화학식 43
Figure 112012106908731-pat00096
Figure 112012106908731-pat00097


화학식 44 화학식 45
Figure 112012106908731-pat00098
Figure 112012106908731-pat00099


화학식 46
Figure 112012106908731-pat00100
[Claim 2] The hydantoin derivative of claim 1, wherein the hydantoin derivative is selected from the group consisting of compounds represented by the following Chemical Formulas 2 to 46:
(2)
Figure 112012106908731-pat00056
Figure 112012106908731-pat00057


(4)
Figure 112012106908731-pat00058
Figure 112012106908731-pat00059


(6)
Figure 112012106908731-pat00060
Figure 112012106908731-pat00061


Formula 8 Formula 9
Figure 112012106908731-pat00062
Figure 112012106908731-pat00063


(10)
Figure 112012106908731-pat00064
Figure 112012106908731-pat00065



Chemical Formula 12 Chemical Formula 13
Figure 112012106908731-pat00066
Figure 112012106908731-pat00067


Formula 14 Formula 15
Figure 112012106908731-pat00068
Figure 112012106908731-pat00069


Formula 16 Formula 17
Figure 112012106908731-pat00070
Figure 112012106908731-pat00071


Formula 18 Formula 19
Figure 112012106908731-pat00072
Figure 112012106908731-pat00073


Chemical Formula 20 Chemical Formula 21
Figure 112012106908731-pat00074
Figure 112012106908731-pat00075


Chemical Formula 22 Chemical Formula 23
Figure 112012106908731-pat00076
Figure 112012106908731-pat00077


Chemical Formula 24 Chemical Formula 25
Figure 112012106908731-pat00078
Figure 112012106908731-pat00079


Formula 26 Formula 27
Figure 112012106908731-pat00080
Figure 112012106908731-pat00081


Chemical Formula 28 Chemical Formula 29
Figure 112012106908731-pat00082
Figure 112012106908731-pat00083


Chemical Formula 30 Chemical Formula 31
Figure 112012106908731-pat00084
Figure 112012106908731-pat00085


(32)
Figure 112012106908731-pat00086
Figure 112012106908731-pat00087


(34)
Figure 112012106908731-pat00088
Figure 112012106908731-pat00089

(36)
Figure 112012106908731-pat00090
Figure 112012106908731-pat00091


(38)
Figure 112012106908731-pat00092
Figure 112012106908731-pat00093


Formula 40 Formula 41
Figure 112012106908731-pat00094
Figure 112012106908731-pat00095

Chemical Formula 42 Chemical Formula 43
Figure 112012106908731-pat00096
Figure 112012106908731-pat00097


Formula 44 Formula 45
Figure 112012106908731-pat00098
Figure 112012106908731-pat00099


Formula 46
Figure 112012106908731-pat00100
 제 5 항에 있어서, 상기 하이단토인 유도체는 상기의 화학식 13, 14, 25 내지 27, 29 내지 33, 36, 38 내지 43, 45 및 46으로 표시되는 화합물로 이루어진 군으로부터 선택되는 것을 특징으로 하는 하이단토인 유도체.
The method of claim 5, wherein the hydantoin derivative is characterized in that it is selected from the group consisting of the compounds represented by the formula 13, 14, 25 to 27, 29 to 33, 36, 38 to 43, 45 and 46 Hydantoin derivatives.
제 1 항 내지 제 6 항 중 어느 한 항의 하이단토인 유도체를 유효성분으로 포함하는 만성폐쇄성 폐질환(chronic obstructive pulmonary disease), 기도 과민성 질환(airways hyper-responsiveness), 폐혈성 쇼크(septic shock), 사구체 신염, 염증성 장질환, 크론병(Crohn's disease), 궤양잘록창자염(ulcerative colitis), 아테롬성 동맥경화증, 골수아구 세포성 백혈병(myoblastic leukaemia), 당뇨, 화상, 허혈성 심장질환, 뇌졸중 및 수막염 및 정맥류으로 구성된 군으로부터 선택되는 만성 염증성 질환; 염증성 통증; 신경병성 통증; 류마티스 관절염, 건선, 알러지성 피부염, 다발성 경화증 및 천식으로 구성된 군으로부터 선택되는 자가면역 질환; 또는 알츠하이머 병, 수막염 및 골다공증으로 구성된 군으로부터 선택되는 퇴행성 질환의 예방 또는 치료용 조성물.
Chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, comprising the hydantoin derivative of any one of claims 1 to 6 as an active ingredient, Glomerulonephritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, myoblastic leukaemia, diabetes, burns, ischemic heart disease, stroke and meningitis and varicose veins Chronic inflammatory diseases selected from the group consisting of; Inflammatory pain; Neuropathic pain; Autoimmune diseases selected from the group consisting of rheumatoid arthritis, psoriasis, allergic dermatitis, multiple sclerosis and asthma; Or Alzheimer's disease, meningitis and osteoporosis composition for the prevention or treatment of degenerative diseases selected from the group consisting of.
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US20030130273A1 (en) 2001-05-25 2003-07-10 Sheppeck James E. Hydantoins and related heterocycles as inhibitors of matrix metalloproteinases and/or TNF-alpha converting enzyme (TACE)
KR20070090924A (en) * 2004-12-17 2007-09-06 아스트라제네카 아베 Novel compounds

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Publication number Priority date Publication date Assignee Title
US20030130273A1 (en) 2001-05-25 2003-07-10 Sheppeck James E. Hydantoins and related heterocycles as inhibitors of matrix metalloproteinases and/or TNF-alpha converting enzyme (TACE)
KR20070090924A (en) * 2004-12-17 2007-09-06 아스트라제네카 아베 Novel compounds

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