KR101732732B1 - Novel Uracil Derivatives and Uses Thereof - Google Patents

Novel Uracil Derivatives and Uses Thereof Download PDF

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KR101732732B1
KR101732732B1 KR1020110010204A KR20110010204A KR101732732B1 KR 101732732 B1 KR101732732 B1 KR 101732732B1 KR 1020110010204 A KR1020110010204 A KR 1020110010204A KR 20110010204 A KR20110010204 A KR 20110010204A KR 101732732 B1 KR101732732 B1 KR 101732732B1
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김용철
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광주과학기술원
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

본 발명은 다양한 신규 우리실(uracil) 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 uracil derivative compounds and a composition for inhibiting P2X 7 receptor activity comprising these as an active ingredient. The present invention can be usefully used for the prevention or treatment of various diseases related to the activity of P2X 7 receptor, i.e., chronic inflammatory diseases, inflammatory pain, neuropathic pain, autoimmune diseases or degenerative diseases.

Description

신규한 우라실 유도체 및 이의 용도{Novel Uracil Derivatives and Uses Thereof}Novel Uracil Derivatives and Uses Thereof < RTI ID = 0.0 >

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

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).It is known that ATP (adenosine 5'-triphosphate) is not only used as a one-dimensional energy source within a cell but also exists in a very small amount outside the cell and is involved in various physiological functions in the cell. Especially, important transduction in the central nervous system and neuron / smooth muscle synapse Material. The action of adenine nucleotides and adenosine, such as extracellular ATP, is mediated through receptors in the extracellular membrane, which are called purinergic receptors. P2 receptors predominantly functioning as adenosine and AMP (adenosine monophosphate), A 1 , A 2 and A 3 , and ADP and ATP predominantly function as P2 receptor ligand-gated ion channels P2X and G- And P2Y linked to protein. To date, the subtypes of P2X receptors cloned from mammals have been known to be 7 (P2X 1 -7 ), and the subtypes of P2Y receptor 8 (P2X 1 -8 ). Among them, P2X receptors, which are ligand active cation channels, are activated by direct binding of ATP, and induce the inflow of small cations such as Na + and Ca 2 + outside the cells. They induce muscle contraction (P2X 1 ) 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 ), and the like. Units constituting the P2X receptors are membrane proteins with two membrane passage region (transmembrane region) C- and N- terminal ends there is expected to be present in the cell, P2X 7 receptors are different from the other subtypes of P2X receptors C- 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 produced by endogenous ATP and synthesized BzATP (2 '(3') - O- (4-benzolybenzoly) adenosine 5'-triphospate) Causing a momentary current. Unlike the other P2X receptors, however, the repetitive and continuous stimulation of the agonist produces a continuous current through the formation of non-selective pores, and this pore contains large cations (ethidium bromide, propidium iodide , 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 monocytic cell line THP-1, etc.) , P2X 7 receptors are found in most of the brain and peripheral immune system cells and their activity leads to various downstreams such as cell permeabilization, apopatosis, and cytokine release. In addition to the selective expression of immunocytes, the P2X 7 receptor is also present in cells that are not involved in immunomodulation, such as the presynaptic terminal of the central nervous system or peripheral nervous system, or human epithelial langerhans cells. P2X 7 receptors are abundantly present in microglia cells, and they are reported to be involved in the central nervous system immunity mechanism when pain caused by nerve injury occurs. As far as is known, when the nerve is damaged there is activated microglia, such as activating the expression of P2X 7 is increased in microglia (Fig. 2). This receptor is activated by ATP secreted from primary afferent sensory neurons or astrocyte, increasing intracellular calcium, activating p38 MAP kinase and releasing cytokines or neurotrophic facotrs And it is said to cause pain. In addition, up-regulation of P2X 7 receptor in activated microglial cells has been reported to be associated with ischemic injury and necrosis. Thus, the present inventors was to use in the prevention or treatment of autoimmune diseases and inflammatory diseases, and various degenerative diseases by screening a compound having effective antagonistic activity of the P2X 7 receptor.

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 우리실 유도체가 P2X7 수용체의 활성을 매우 효과적으로 억제함을 발견함으로써, 본 발명을 완성하게 되었다.The present inventors have conducted intensive studies to develop compositions for the prevention or treatment of autoimmune diseases, inflammatory diseases and various degenerative diseases by identifying effective antagonists of P2X 7 receptors which are considered to have important effects on immune function and neuronal cell death Respectively. As a result, by our room derivatives of the present invention it found to be highly effective in inhibiting the activity of the P2X 7 receptor, thereby completing the present invention.

따라서 본 발명의 목적은 신규한 우라실 유도체를 제공하는 데 있다.Accordingly, an object of the present invention is to provide a novel uracil derivative.

본 발명의 다른 목적은 만성 염증성 질환, 염증성 통증, 신경병성 통증, 자가면역 질환 또는 퇴행성 질환의 예방 또는 치료용 조성물을 제공하는 데 있다.It is another object of the present invention to provide a composition for the prophylaxis or treatment of 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 우라실(uracil) 유도체를 제공한다:According to one aspect of the present invention, there is provided a uracil derivative represented by the following formula (1): < EMI ID =

화학식 1Formula 1

Figure 112011008191173-pat00001
Figure 112011008191173-pat00001

상기 화학식에서, R1은 수소, C1-C4 알킬이고, R2는 수소, C1-C4 알킬, 아실(-C(O)-X, X는 알킬), 아릴, 또는 아릴 C1-C4 알킬이며, R3는 산소, NH 또는 C0-C4 알킬이고, R4는 설포닐(-S(O)2-) 또는 카르보닐(-C(O)-)이며, R5는 헤테로아릴, n은 0-5의 정수이다.Wherein R 1 is hydrogen, C 1 -C 4 alkyl and R 2 is hydrogen, C 1 -C 4 alkyl, acyl (-C (O) -X, X is alkyl), aryl, or aryl C 1 and -C 4 alkyl, R 3 is oxygen, NH or C 0 -C 4 alkyl, R 4 is a sulfonyl (-S (O) 2 -) or carbonyl (-C (O) -), and, R 5 Is heteroaryl, and 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 우리실 유도체가 P2X7 수용체의 활성을 매우 효과적으로 억제함을 발견하였다. The present inventors have conducted intensive studies to develop compositions for the prevention or treatment of autoimmune diseases, inflammatory diseases and various degenerative diseases by identifying effective antagonists of P2X 7 receptors which are considered to have important effects on immune function and neuronal cell death Respectively. As a result, we room derivatives of the invention were found to be highly effective in inhibiting the activity of the P2X 7 receptor.

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, 헵타데실, 사이클로프로필, 사이클로부틸, 사이클로펜틸 및 다양한 바이사이클로알킬 및 트리사이클로알킬 등을 포함한다. C1-C4 알킬은 탄소수 1 내지 4의 알킬 유니트를 가지는 알킬기를 의미하며, 상기 화학식에서 R3을 지시하면서 기재된 C0 알킬은 탄소수가 없는 경우로서 페닐기와 R4가 직접 결합한 경우를 의미하고, C1-C4 또는 C0-C4 알킬이 치환된 경우 치환체의 탄소수는 포함되지 않은 것이다. As used herein, the term " alkyl " means an unsubstituted or substituted saturated hydrocarbon group of linear, branched or cyclic structure, and includes, for example, methyl, ethyl, propyl, isobutyl, pentyl, hexyl, heptyl, Decyl, undecyl, tridecyl, pentadecyl, heptadecyl, cyclopropyl, cyclobutyl, cyclopentyl, and various bicycloalkyl and tricycloalkyl. C 1 -C 4 alkyl means an alkyl group having an alkyl unit having 1 to 4 carbon atoms, and in the above formula, C 0 alkyl denoting R 3 means a case where the number of carbon atoms is absent and a phenyl group and R 4 are directly bonded to each other , C 1 -C 4 Or when the C 0 -C 4 alkyl is substituted, the number of carbon atoms of the substituent is not included.

본 명세서에서 용어“알콕시”는 알코올에서 수소가 제거되어 형성된 라디칼을 의미한다. The term " alkoxy " as used herein means a radical formed by removing hydrogen from an alcohol.

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 " means a substituted or unsubstituted monocyclic or polycyclic carbon ring that is totally or partially unsaturated and has aromaticity.

본 명세서에서 용어“아릴알킬”은 아릴기로 치환된 알킬을 의미한다. 아릴 C1-C4 알킬은 아릴기로 치환된 탄소수 1 내지 4의 알킬 유니트를 의미한다. As used herein, the term " arylalkyl " means an alkyl substituted with an aryl group. Aryl C 1 -C 4 alkyl means an alkyl unit having from 1 to 4 carbon atoms substituted with an aryl group.

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 " means a heterocyclic aromatic group containing a hetero atom, oxygen, sulfur or nitrogen, in the ring. 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 optionally substituted with various substituents at various positions, for example, halo, hydroxy, nitro, cyano, C 1 -C 4 Substituted or unsubstituted straight or branched chain alkyl, C 1 -C 4 Lt; / RTI > may be substituted by straight chain or branched alkoxy.

본 발명의 바람직한 구현예에 따르면, 본 발명의 화학식 1의 R1은 수소이고, 상기 R3는 산소 또는 NH이며, 상기 R4는 설포닐(-S(O)2-)이다.According to a preferred embodiment of the present invention, R 1 in the formula (1) of the present invention is hydrogen, R 3 is oxygen or NH, and R 4 is sulfonyl (-S (O) 2 -).

본 발명의 바람직한 구현예에 따르면, 본 발명의 화학식 1의 R5가 지시하는 헤테로아릴은 퀴놀린 또는 이소퀴놀린이다. According to a preferred embodiment of the present invention, the heteroaryl indicated by R < 5 > in the formula (I) of the present invention is quinoline or isoquinoline.

본 발명의 바람직한 구현예에 따르면, 본 발명의 화학식 1의 R2가 지시하는 아실(-C(O)-X, X는 알킬 또는 알콕시)에서 상기 알킬은 C1-C6 직쇄 또는 분쇄 알킬, C5-C7 사이클로알킬, C5-C7 사이클로알킬 C1-C4 알킬, C8-C14 브릿지드(bridged) 바이사이클로알킬, C10-C16 브릿지드 트리사이클로알킬, 또는 브릿지드 C10-C16 트리사이클로알킬 C1-C4 알킬이다.According to a preferred embodiment of the present invention, in the acyl (-C (O) -X, where X is alkyl or alkoxy) indicated by R 2 in the formula 1 of the present invention, the alkyl is C 1 -C 6 linear or branched alkyl, C 5 -C 7 cycloalkyl, C 5 -C 7 Cycloalkyl C 1 -C 4 alkyl, C 8 -C 14 Bridged bicycloalkyl, C 10 -C 16 Bridged tricycloalkyl, or bridged C 10 -C 16 Tree is cycloalkyl C 1 -C 4 alkyl.

본 명세서에서 용어“브릿지드(bridged) 바이사이클로알킬”또는“브릿지드 트리사이클로알킬”은 2개 이상의 브릿지헤드(bridge head) 탄소와 1개 이상의 탄소 브릿지(carbon bridge)를 가져 2개 또는 3개의 환형구조가 융합된 사이클로알킬 구조를 의미한다. As used herein, the term " bridged bicycloalkyl " or " bridged tricycloalkyl " refers to bridged bicycloalkyl having two or more bridge head carbon and one or more carbon bridges, Means a cycloalkyl structure in which the cyclic structure is fused.

본 발명의 바람직한 구현예에 따르면, 본 발명의 우라실 유도체는 하기의 화학식 2 내지 36로 표시되는 화합물로 구성된 군으로부터 선택된다:According to a preferred embodiment of the present invention, the uracil derivatives of the present invention are selected from the group consisting of the compounds represented by the following formulas (2) to (36)

화학식 2 화학식 3         (2)

Figure 112011008191173-pat00002
Figure 112011008191173-pat00003

Figure 112011008191173-pat00002
Figure 112011008191173-pat00003

화학식 4 화학식 5         (4)

Figure 112011008191173-pat00004
Figure 112011008191173-pat00005

Figure 112011008191173-pat00004
Figure 112011008191173-pat00005

화학식 6 화학식 7        (6)

Figure 112011008191173-pat00006
Figure 112011008191173-pat00007

Figure 112011008191173-pat00006
Figure 112011008191173-pat00007

화학식 8 화학식 9          (8)

Figure 112011008191173-pat00008
Figure 112011008191173-pat00009
Figure 112011008191173-pat00008
Figure 112011008191173-pat00009

화학식 10 화학식 11         (10)

Figure 112011008191173-pat00010
Figure 112011008191173-pat00011

Figure 112011008191173-pat00010
Figure 112011008191173-pat00011

화학식 12 화학식 13        (12)

Figure 112011008191173-pat00012
Figure 112011008191173-pat00013

Figure 112011008191173-pat00012
Figure 112011008191173-pat00013

화학식 14 화학식 15(14)

Figure 112011008191173-pat00014
Figure 112011008191173-pat00015

Figure 112011008191173-pat00014
Figure 112011008191173-pat00015

화학식 16 화학식 17   (16)

Figure 112011008191173-pat00016
Figure 112011008191173-pat00017

Figure 112011008191173-pat00016
Figure 112011008191173-pat00017

화학식 18 화학식 19(18)

Figure 112011008191173-pat00018
Figure 112011008191173-pat00019

Figure 112011008191173-pat00018
Figure 112011008191173-pat00019

화학식 20 화학식 21       (20)

Figure 112011008191173-pat00020
Figure 112011008191173-pat00021

Figure 112011008191173-pat00020
Figure 112011008191173-pat00021

화학식 22 화학식 23(22)

Figure 112011008191173-pat00022
Figure 112011008191173-pat00023

Figure 112011008191173-pat00022
Figure 112011008191173-pat00023

화학식 24 화학식 25       (24)

Figure 112011008191173-pat00024
Figure 112011008191173-pat00025

Figure 112011008191173-pat00024
Figure 112011008191173-pat00025

화학식 26 화학식 27 (26)

Figure 112011008191173-pat00026
Figure 112011008191173-pat00027

Figure 112011008191173-pat00026
Figure 112011008191173-pat00027

화학식 28 화학식 29       (28)

Figure 112011008191173-pat00028
Figure 112011008191173-pat00029

Figure 112011008191173-pat00028
Figure 112011008191173-pat00029

화학식 30 화학식 31(30)

Figure 112011008191173-pat00030
Figure 112011008191173-pat00031

Figure 112011008191173-pat00030
Figure 112011008191173-pat00031

화학식 32 화학식 33       (32)

Figure 112011008191173-pat00032
Figure 112011008191173-pat00033

Figure 112011008191173-pat00032
Figure 112011008191173-pat00033

화학식 34 화학식 35(34)

Figure 112011008191173-pat00034
Figure 112011008191173-pat00035

Figure 112011008191173-pat00034
Figure 112011008191173-pat00035

화학식 36       Formula 36

Figure 112011008191173-pat00036
Figure 112011008191173-pat00036

본 발명의 보다 바람직한 구현예에 따르면, 본 발명의 우라실 유도체는 상기의 화학식 10, 13 내지 21 및 24 내지 36으로 표시되는 화합물로 이루어진 군으로부터 선택된다.According to a more preferred embodiment of the present invention, the uracil derivatives of the present invention are selected from the group consisting of the compounds represented by the above formulas (10), (13) to (21) and (24) to (36).

본 발명에 따르면, 상기 나열한 16가지 화합물은 P2X7 수용체의 다운-레귤레이션에 있어서 동일한 농도(10μM)를 투여하였을 때 매우 높은 억제율(% Inhibition)을 가진다. 따라서 이들은 P2X7 활성과 관련된 다양한 질환의 효과적인 치료 조성물로 이용될 수 있다. According to the present invention, the 16 compounds listed have a very high% inhibition when administered at the same concentration (10 μM) in the down-regulation of the P2X 7 receptor. Therefore, they P2X 7 Can be used as an effective therapeutic composition for a variety of diseases associated with activity.

본 발명의 다른 양태에 따르면 본 발명은 본 발명의 우라실 유도체를 유효성분으로 포함하는 만성 염증성 질환, 염증성 통증 또는 신경병성 통증의 예방 또는 치료용 조성물을 제공한다.According to another aspect of the present invention, there is provided a composition for preventing or treating chronic inflammatory diseases, inflammatory pain or neuropathic pain comprising the uracil 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 manufactured from a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations include, but are not limited to, 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 can be administered orally or parenterally, and in the case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, muscle 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 composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of excipients, powders, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.

본 발명의 바람직한 구현예에 따르면, 본 발명의 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 of the present invention is selected from the group consisting of chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, glomerulonephritis, inflammatory bowel disease (Inflammation), Crohn's disease, ulcerative colitis, atherosclerosis, myoblastic leukaemia, diabetes, burns, ischemic heart disease, stroke, meningitis, and varices Lt; / RTI >

본 발명의 또 다른 양태에 따르면 본 발명은 본 발명의 우라실 유도체를 유효성분으로 포함하는 자가면역 질환의 예방 또는 치료용 조성물을 제공한다.According to still another aspect of the present invention, there is provided a composition for preventing or treating an autoimmune disease comprising the uracil derivative of the present invention as an active ingredient.

바람직하게는, 본 발명의 자가면역 질환은 류마티스 관절염, 건선, 알러지성 피부염, 다발성 경화증 및 천식으로 구성된 군으로부터 선택되는 질환이다.
Preferably, the autoimmune disease of the present invention is a disease selected from the group consisting of rheumatoid arthritis, psoriasis, allergic dermatitis, multiple sclerosis and asthma.

본 발명의 또 다른 양태에 따르면 본 발명은 본 발명의 우라실 유도체를 유효성분으로 포함하는 퇴행성 질환의 예방 또는 치료용 조성물을 제공한다.According to still another aspect of the present invention, there is provided a composition for preventing or treating a degenerative disease comprising the uracil derivative of the present invention as an active ingredient.

바람직하게는, 본 발명의 퇴행성 질환은 알츠하이머 병, 수막염, 골다공증 및 퇴행성 관절염으로 구성된 군으로부터 선택되는 질환이다.
Preferably, the degenerative disease of the present invention is a disease selected from the group consisting of Alzheimer'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 하이드라진 유도체 화합물 및 이들을 유효성분으로 포함하는 P2X7 수용체 활성 억제용 조성물을 제공한다.(a) The present invention provides various novel hydrazine derivative compounds and a composition for inhibiting P2X 7 receptor activity comprising these 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 used to various conditions, that is useful for the prevention or treatment of chronic inflammatory conditions, inflammatory pain, neuropathic pain, autoimmune diseases or degenerative diseases associated with the activity of the P2X 7 receptor.

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).FIG. 1 shows (A) the molecular anatomical location of the molecular topology of the P2X 1 -6 and P2X 7 receptors (FIG. 1A) and FIG. 1B showing the P2X 7 receptor activated by ATP and having three different forms : Channel opening, channel closure and pore formation ( Curr . Med . Chem . 2007,14, 1505-1523).
Figure 2 shows Purinergic signaling in the spinal cord ( Nature Review Drug Discovery , 2008, 7, 575-590).
3 is a graph showing the effect of BzATP and KN62 on hP2X 7 -expressing HEK 293 cells. Treatment of BzATP resulted in concentration dependent accumulation of thiodium bromide (EC 50 = 3.67 μM, FIG. 3a), treatment of 4 μM BzATP followed by KN62 inhibited the accumulation of ethidium bromide in a concentration dependent manner (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 Studies on the death of cells using permanent cell lines and inhibitory compound activity

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 A number of permanent cell lines were obtained through selection and continuous cultivation. 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 obtained are ATP-dependent, leading to apoptosis, enabling rapid screening of antagonists that inhibit the activity of P2X 7 receptors through cell-based assays.

P2XP2X 77 영구세포주를 이용한 세포의 저해 화합물 활성 연구 Studies on Inhibitory Compounds 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 been shown to stimulate the surface of the cell by continuous stimulation of the agonist with substances with a molecular weight of up to 900 Da (eg choline, 100 Da, methylglucamine, 190 Da, ethidium, 314 Da), YO-PRO-1 (376 Da), propidium (414 Da), and lucifer yellow (467 Da). To this feature on the basis of my hP2X 7 selective agonists of ATP and 2'and via the 3'-O-benzoyl-benzoly- ATP pores formed by treating (BzATP) DNA binding fluorescent dye is ethidium bromide in the cell By measuring the degree of measurement through a fluorescent reader, we were able to search for antagonists to the P2X 7 receptor. Dependent concentration of intracellular dye accumulation in BzATP using THP-1 cells, which are endogenous P2X 7 receptors on the cell surface, and cell lines (hP2X 7 -expressing HEK 293 cells) that have permanently expressed hP2X 7 receptors As shown in Fig. 3. In addition, APT or by handling the BzATP which is said to have an antagonistic effect is reported with respect to the P2X 7 receptors, 1- [N, O-bis ( 1,5-isoquinolinesulphonyl) -N-methyl-L-tyrosyl] that after forming the fore- 4-phenylpiperizine (KN62) was treated in a concentration-dependent manner to obtain degree of inhibition of dye accumulation as shown in FIG. 3B.

화합물 라이브러리 및 유도체에 대한 활성검색Active 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 우라실 유도체 도출하였다. 합성된 우라실 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.
In order to discover new drug candidates for the new skeleton of the P2X7 receptor, a new compound of various modifications to the already reported P2X7 receptor antagonist 'KN62' of the tyrosine skeleton was designed and a novel novel uraacyl derivative of the skeleton was derived. The synthesized uracil derivatives were treated with BzATP in hP2X7-expressing HEK 293 cells to form pores, and their antagonistic effects were investigated. Derivatives having a P2X7 receptor antagonistic effect, which was equivalent to or superior to the conventional antagonist KN62, were selected.

합성 모식도 1Synthetic pattern diagram 1 aa

Figure 112011008191173-pat00037
Figure 112011008191173-pat00037

a시약 및 반응조건: (a) 1-(bromomethyl)-4-nitrobenzene 또는 (4-(bromomethyl)phenoxy)(tert-butyl)dimethylsilane, NaH, LiBr, DMF, DMSO, RT; (b) substituted piperazine, NaHCO3, EtOH, microwave reaction; (c) H2 gas, Pt(IV)oxide, MeOH, RT; (d) AcCl, MeOH, 0℃, (e) 5-isoquinolinesulfonyl chloride, TEA, DCM, RT a Reagents and reaction conditions: (a) 1- (bromomethyl) -4-nitrobenzene or (4- (bromomethyl) phenoxy) tert-butyl dimethylsilane, NaH, LiBr, DMF, DMSO, RT; (b) substituted piperazine, NaHCO 3 , EtOH, microwave reaction; (c) H 2 gas, Pt (IV) oxide, MeOH, RT; (d) AcCl, MeOH, 0 ° C, (e) 5-isoquinolinesulfonyl chloride, TEA, DCM, RT

합성 모식도 2Synthetic pattern diagram 2 aa

Figure 112011008191173-pat00038
Figure 112011008191173-pat00038

a시약 및 반응조건: (a) 20% piperidine, DCM, RT; (b) acyclicalkyl, mono-, or polycycloalky carboxylic acid, 혹은 치환된 benzoic acid, EDC·HCl, TEA, DCM, RT
 a Reagents and reaction conditions: (a) 20% piperidine, DCM, RT; (b) acyclicalkyl, mono-, or polycycloalky carboxylic acid, or substituted benzoic acid, EDC · HCl, TEA, DCM, RT

우라실Uracil 유도체 중간체의 대표 합성법 Representative synthetic methods for derivative intermediates

하기의 화합물 (4a)를 예시로 하여 기술된 합성모식도 1의 과정을 통해 얻어진 우라실 유도체의 중간체의 대표합성법을 기술한다.
A representative synthesis method of the intermediate of the uracil derivative obtained through the process of the synthetic scheme 1 described below with reference to the following compound (4a) will be described.

합성예1Synthesis Example 1 :1-(4-( : 1- (4- ( terttert -- 부틸디메틸실릴옥시Butyldimethylsilyloxy )벤질)-6-) Benzyl) -6- 클로로피리미딘Chloropyrimidine -2,4(1-2,4 (1 HH ,3, 3 HH )-) - 디온Dion (1a) (1a)

6-클로로우라실(2.76 g, 18.8 mmol)를 무수 DMF:DMSO = 6:1의 비율의 용매 50 ml에 용해시켰다. 혼합액을 얼음중탕(ice bath) 하에서 NaH(753 mg, 18.8 mmol)를 가하고 30분간 반응시킨 후, 브롬화 리튬(LiBr, 1.30 g, 15.1 mmol)을 첨가하여 상온에서 15분 간 교반시켰다. 다음으로 (4-(브로모메틸)페녹시)(tert-부틸)디메틸실란(5.67 g, 18.8 mmol)을 가한 후 상온에서 30분간 교반시켰다. 반응이 종료되었음을 확인한 후, 염화암모늄 포화용액을 가하고 충분히 교반시킨 후 반응을 중단시키고 회전식 증발(rotary evaporation)을 하여 건조시켰다. 이를 염화암모늄 포화 용액을 이용하여 산성화시킨 후, 클로로포름으로 추출한 뒤에, 무수 MgSO4로 건조, 여과하고 나서 회전식 증발을 시켰다. 화합물의 정제는 컬럼 크로마토그래피(에틸 아세테이트:n-헥산 = 1:2.5)로 정제하여 흰색의 결정을 얻었다; 수율: 74.3%, 1H NMR(400 MHz, CDCl3) δ: 7.23(2H, d, J=8.4 Hz), 6.80(2H, d, J=8.4Hz), 5.88(1H, s), 5.16(2H, s), 0.96(9H, s), 0.17(6H, s). ESI[M-H]- : 364.80.
6-Chlorouracil (2.76 g, 18.8 mmol) was dissolved in 50 ml of anhydrous DMF: DMSO = 6: 1 solvent. The mixture was stirred for 30 minutes with NaH (753 mg, 18.8 mmol) in an ice bath, followed by addition of lithium bromide (LiBr, 1.30 g, 15.1 mmol) and the mixture was stirred at room temperature for 15 minutes. Then, (4- (bromomethyl) phenoxy) (tert-butyl) dimethylsilane (5.67 g, 18.8 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. After confirming that the reaction was completed, a saturated ammonium chloride solution was added and stirred sufficiently, then the reaction was stopped and rotary evaporated to dryness. The residue was acidified with saturated ammonium chloride solution, extracted with chloroform, dried over anhydrous MgSO 4 , filtered, and rotary evaporated. Purification of the compound was purified by column chromatography (ethyl acetate: n-hexane = 1: 2.5) to obtain white crystals; Yield: 74.3%, 1 H NMR ( 400 MHz, CDCl 3) δ: 7.23 (2H, d, J = 8.4 Hz), 6.80 (2H, d, J = 8.4Hz), 5.88 (1H, s), 5.16 ( 2H, s), 0.96 (9H, s), 0.17 (6H, s). ESI [MH] < - & gt ;: 364.80.

합성예Synthetic example 2 : (9 2: (9 HH -- 플루오렌Fluorene -9-일)-9-yl) 메틸methyl 4-(3-(4-( 4- (3- (4- ( terttert -- 부틸디메틸부틸디메틸실릴옥시Butyl dimethylbutyldimethylsilyloxy ) 벤질)-2,6-) Benzyl) -2,6- 디옥소Dioxo -1,2,3,6-테-1,2,3,6-te 트라하이드로Trahidro 피리미딘-4-일)피페라진-1-Pyrimidin-4-yl) piperazin-l- 카르복실레이트Carboxylate (2a): (2a):

중간체 화합물 1a(795 mg, 2.17 mmol)와 (9H-플루오렌-9-일)메틸 피페라진-1-카르복실레이트(802 mg, 2.60 mmol)를 무수 EtOH에 용해시켰다. 혼합액에 NaHCO3(910 mg, 10.8 mmol)를 가한 후 마이크로웨이브 반응기를 이용하여 120 ℃에서 30분간 반응시켰다. 반응이 종료되었음을 확인한 후, 회전식 증발을 하여 농축시켰다. 이를 염화암모늄 포화 용액을 이용하여 산성화 시킨 후, 클로로포름으로 추출한 뒤, 무수 MgSO4로 건조, 여과한 후 회전식 증발을 하였다. 화합물의 정제는 컬럼 크로마토그래피(메탄올:클로로포름 = 1:50)로 정제하여 흰색의 결정을 얻었다; 수율: 88.9%, 1H NMR(400 MHz, CDCl3) δ: 8.04(1H, s), 7.77(2H, d, J=7.6 Hz), 7.55(2H, d, J=6.8 Hz), 7.42(2H, t, J=7.6 Hz), 7.33(2H, t, J=7.6 Hz), 7.09(2H, d, J=8.4 Hz), 6.79(2H, d, J=8.8 Hz), 5.20(1H, d, J=2.0 Hz), 4.96(2H, s), 4.54(2H, d, J=6.0 Hz), 4.23(1H, t, J=6.0 Hz), 3.37(4H, brs), 2.68(4H, brs), 0.95(9H, s), 0.17(6H, s). ESI[M+H]+ : 639.40.
Intermediate compound 1a (795 mg, 2.17 mmol) and - a (9 H-fluoren-9-yl) methyl piperazine-1-carboxylate (802 mg, 2.60 mmol) was dissolved in anhydrous EtOH. NaHCO 3 (910 mg, 10.8 mmol) was added to the mixture, and the mixture was reacted at 120 ° C for 30 minutes using a microwave reactor. After confirming that the reaction was completed, the reaction mixture was concentrated by rotary evaporation. The mixture was acidified with saturated ammonium chloride solution, extracted with chloroform, dried over anhydrous MgSO 4 , filtered, and rotary evaporated. Purification of the compound was purified by column chromatography (methanol: chloroform = 1: 50) to obtain white crystals; Yield: 88.9%, 1 H NMR ( 400 MHz, CDCl 3) δ: 8.04 (1H, s), 7.77 (2H, d, J = 7.6 Hz), 7.55 (2H, d, J = 6.8 Hz), 7.42 ( (2H, d, J = 7.6 Hz), 7.33 (2H, t, J = 7.6 Hz), 7.09 (2H, d, J = 2.0 Hz), 4.96 (2H, s), 4.54 (2H, d, J = 6.0 Hz), 4.23 brs), 0.95 (9H, s), 0.17 (6H, s). ESI [M + H] < + >: 639.40.

합성예Synthetic example 3 : (9 3: (9 HH -- 플루오렌Fluorene -9-일)-9-yl) 메틸methyl 4-(3-(4- 4- (3- (4- 하이드록시벤질Hydroxybenzyl )-2,6-) -2,6- 디옥소Dioxo -1,2,3,6- -1,2,3,6- 테트라하이드로피리미딘Tetrahydropyrimidine -4-일)피페라진-1-Yl) piperazin-l- 카르복실레이트Carboxylate (3a):  (3a):

얼음중탕 하에서, 10 ml 무수 MeOH에 아세틸 클로라이드(362 ml, 5.09 mmol)를 천천히 적가한 후, 10분 동안 저어주었다. 중간체 화합물 2a(325 mg, 0.509 mmol)를 가하고 실온에서 충분히 교반시켰다. 반응이 종료되었음을 확인한 후, 반응을 중단시키고 회전식 증발을 하여 건조시켰다. 이를 소듐 비카보네이트 포화 용액을 이용하여 염기화시킨 후, 클로로포름으로 추출한 뒤, 무수 MgSO4로 건조, 여과한 후 회전식 증발을 하였다. 화합물의 정제는 컬럼 크로마토그래피(메탄올:클로로포름 = 1:30)로 정제하여 흰색의 결정을 얻었다; 수율: 98.6%, 1H NMR(400 MHz, CDCl3) δ: 8.50(1H, s), 7.77(2H, d, J=7.6 Hz), 7.55(2H, d, J=7.2 Hz), 7.42(2H, t, J=7.6 Hz), 7.33(2H, t, J=7.2 Hz), 7.08(2H, d, J=8.8 Hz), 6.76(2H, d, J=8.4 Hz), 5.20(1H, s), 4.94(2H, s), 4.55(2H, d, J=5.6 Hz), 4.23(1H, t, J=6.0 Hz), 3.39(4H, brs), 2.72(4H, brs). ESI[M-H]- : 523.27.
Under an ice bath, acetyl chloride (362 ml, 5.09 mmol) was slowly added dropwise to 10 ml anhydrous MeOH and stirred for 10 min. Intermediate compound 2a (325 mg, 0.509 mmol) was added and stirred well at room temperature. After confirming the completion of the reaction, the reaction was stopped and rotary evaporated to dryness. The residue was basified with saturated sodium bicarbonate solution, extracted with chloroform, dried over anhydrous MgSO 4 , filtered, and rotary evaporated. Purification of the compound was purified by column chromatography (methanol: chloroform = 1: 30) to give white crystals; Yield: 98.6%, 1 H NMR ( 400 MHz, CDCl 3) δ: 8.50 (1H, s), 7.77 (2H, d, J = 7.6 Hz), 7.55 (2H, d, J = 7.2 Hz), 7.42 ( (2H, d, J = 7.6 Hz), 7.33 (2H, t, J = 7.2 Hz), 7.08 s), 4.94 (2H, s), 4.55 (2H, d, J = 5.6 Hz), 4.23 (1H, t, J = 6.0 Hz), 3.39 (4H, brs), 2.72 (4H, ESI [MH] < - & gt ;: 523.27.

합성예Synthetic example 4 : (9 4: (9 HH -- 플루오렌Fluorene -9-일)-9-yl) 메틸methyl 4-(3-(4-(이소퀴놀린-5-일 4- (3- (4- (isoquinolin-5-yl 설포닐옥시Sulfonyloxy )벤질) -2,6-디옥소-1,2,3,6-) Benzyl) -2,6-dioxo-1,2,3,6- 테트라하이드로피리미딘Tetrahydropyrimidine -4-일)피페라진-1-Yl) piperazin-l- 카르복실레이트Carboxylate (4a)(4a)

중간체 화합물 3a(315 mg, 0.600 mmol)을 무수 DCM에 넣고 용해시켰다. 혼합액에 5-이소퀴놀린설포닐 클로라이드·HCl(190.3 mg, 0.721 mmol)와 TEA(100 ml, 0.721 mmol)를 가한 후, 상온에서 2시간 동안 교반시켰다. 반응이 종료되었음을 확인한 후, 염화 암모늄 포화 용액을 이용하여 산성화 시킨 후 DCM으로 추출한 뒤, 무수 MgSO4로 건조, 여과한 후 회전식 증발을 하였다. 화합물의 정제는 컬럼 크로마토그래피(메탄올:클로로포름 = 1:45)로 정제하여 흰색의 결정을 얻었다; 수율: 54.0%, 1H NMR(400 MHz, CDCl3) δ: 9.41(1H, s), 8.81(1H, d, J=6.0 Hz), 8.53(1H, d, J=6.0 Hz), 8.28-8.25(2H, m), 7.77(2H, d, J=7.6 Hz), 7.64(1H, t, J=7.6Hz), 7.55(2H, d, J=7.6 Hz), 7.42(2H, t, J=7.2 Hz), 7.31(2H, t, J=7.6 Hz), 7.06(2H, d, J=8.8 Hz), 6.85(2H, d, J=8.4 Hz), 5.19(1H, s), 4.92(2H, s), 4.56(2H, d, J=6.0 Hz), 4.23(1H, t, J=6.0 Hz), 3.30(4H, brs), 2.63(4H, brs). ESI[M+H]+ : 716.27.
Intermediate compound 3a (315 mg, 0.600 mmol) was dissolved in anhydrous DCM. 5-isoquinoline sulfonyl chloride · HCl (190.3 mg, 0.721 mmol) and TEA (100 ml, 0.721 mmol) were added to the mixture, followed by stirring at room temperature for 2 hours. After confirming the completion of the reaction, the reaction mixture was acidified with saturated ammonium chloride solution, extracted with DCM, dried over anhydrous MgSO 4 , filtered, and rotary evaporated. Purification of the compound was purified by column chromatography (methanol: chloroform = 1: 45) to obtain white crystals; Yield: 54.0%, 1 H NMR ( 400 MHz, CDCl 3) δ: 9.41 (1H, s), 8.81 (1H, d, J = 6.0 Hz), 8.53 (1H, d, J = 6.0 Hz), 8.28- (2H, t, J = 7.6 Hz), 7.65 (2H, d, J = = 7.2 Hz), 7.31 (2H, t, J = 7.6 Hz), 7.06 (2H, d, J = 8.8 Hz), 6.85 2H, s), 4.56 (2H, d, J = 6.0Hz), 4.23 (1H, t, J = 6.0Hz), 3.30 (4H, brs), 2.63 (4H, brs). ESI [M + H] < + >: 716.27.

하기의 화합물 (6a)를 예시로 하여 기술된 합성모식도 2의 과정을 통해 얻어진 우라실 유도체의 중간체의 대표합성법을 기술한다.
A representative synthesis method of the intermediate of the uracil derivative obtained through the process of the synthetic scheme 2 described below with reference to the following compound (6a) will be described.

합성예Synthetic example 5 : 4-((2,4- 5: 4 - ((2,4- 디옥소Dioxo -6-(피페라진-1--6- (piperazin-l- ylyl )-3,4-) -3,4- 디하이드로피리미딘Dihydropyrimidine -1(2-1 (2 HH )-일) 메틸)) -Yl) methyl) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (5a) (5a)

2 ml의 피페리딘을 무수 8 ml의 무수 DCM에 가하여, 20 % 피페리딘 혼합액을 만들었다. 이 혼합액에 중간체 화합물 4a(195 mg, 0.395 mmol)을 넣고, 상온에서 30분 동안 교반시켰다. 반응이 종료되었음을 확인한 후, 염화 암모늄 포화 용액을 이용하여 산성화 시킨 후 DCM으로 추출한 뒤, 무수 MgSO4로 건조, 여과한 후 회전식 증발을 하였다. 화합물의 정제는 컬럼 크로마토그래피(메탄올:클로로포름 = 1:5)로 정제하여 흰색의 결정을 얻었다; 수율: 92.9%, 1H NMR(400 MHz, CDCl3) δ: 9.41(1H, s), 8.79(1H, d, J=6.4 Hz), 8.51(1H, d, J=6.0 Hz), 8.29-8.26(2H, m), 7.66(1H, t, J=8.0 Hz), 7.09(2H, d, J=8.8 Hz), 6.83(2H, d, J=8.4 Hz), 5.22(1H, s), 4.93(2H, s), 3.30(4H, m), 2.63(4H, m). ESI[M+H]+ : 494.26
2 ml of piperidine was added to anhydrous 8 ml of anhydrous DCM to make a 20% piperidine mixed solution. To this mixture was added intermediate compound 4a (195 mg, 0.395 mmol) and the mixture was stirred at room temperature for 30 minutes. After confirming the completion of the reaction, the reaction mixture was acidified with saturated ammonium chloride solution, extracted with DCM, dried over anhydrous MgSO 4 , filtered, and rotary evaporated. Purification of the compound was purified by column chromatography (methanol: chloroform = 1: 5) to obtain white crystals; Yield: 92.9%, 1 H NMR ( 400 MHz, CDCl 3) δ: 9.41 (1H, s), 8.79 (1H, d, J = 6.4 Hz), 8.51 (1H, d, J = 6.0 Hz), 8.29- D, J = 8.8 Hz), 6.83 (2H, d, J = 8.4 Hz), 5.22 (1H, s), 8.26 4.93 (2H, s), 3.30 (4H, m), 2.63 (4H, m). ESI [M + H] < + >: 494.26

합성예Synthetic example 6 : 4-((2,4- 6: 4 - ((2,4- 디옥소Dioxo -6-(4--6- (4- 피발로일피페라진Pivaloylpiperazine -1-일)-3,4--1-yl) -3,4- 디하이드로피리미딘Dihydropyrimidine -1(2H)-일) -1 (2H) -yl) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6a):  (6a):

중간체 화합물 5a(30 mg, 0.061 mmol)와 피발산(pivalic acid, 7.46 mg, 0.073 mmol)를 무수 DCM에 넣고 용해시켰다. 이 혼합액에 EDC·HCl(13.9 mg, 0.073mmol)와 TEA(10.2 ml, 0.073 mmol)를 차례로 가한 후, 1시간 동안 교반시켰다. 반응이 종료되었음을 확인한 후, 염화 암모늄 포화 용액을 이용하여 산성화 시킨 후 DCM으로 추출한 뒤, 무수 MgSO4로 건조, 여과한 후 회전식 증발을 하였다. 화합물의 정제는 컬럼 크로마토그래피(메탄올:클로로포름 = 1:50)로 정제하여 흰색의 결정을 얻었다; 수율: 93.5%, 1H NMR(400 MHz, CDCl3) δ: 9.42(1H, s), 8.81(1H, d, J=5.6 Hz), 8.70(1H, s), 8.52(1H, d, J=6.0 Hz), 8.31-8.27(2H, m), 7.68(1H, t, J=7.8 Hz), 7.09(2H, d, J=8.8 Hz), 6.86(2H, d, J=8.0 Hz), 5.22(1H, s), 4.96(2H, s), 3.62(4H, brs), 2.79(4H, brs), 1.26(9H, s).
Intermediate compound 5a (30 mg, 0.061 mmol) and pivalic acid (7.46 mg, 0.073 mmol) were dissolved in anhydrous DCM. EDC · HCl (13.9 mg, 0.073 mmol) and TEA (10.2 ml, 0.073 mmol) were successively added to the mixture, followed by stirring for 1 hour. After confirming the completion of the reaction, the reaction mixture was acidified with saturated ammonium chloride solution, extracted with DCM, dried over anhydrous MgSO 4 , filtered, and rotary evaporated. Purification of the compound was purified by column chromatography (methanol: chloroform = 1: 50) to obtain white crystals; Yield: 93.5%, 1 H NMR ( 400 MHz, CDCl 3) δ: 9.42 (1H, s), 8.81 (1H, d, J = 5.6 Hz), 8.70 (1H, s), 8.52 (1H, d, J = 6.0 Hz), 8.31-8.27 (2H, m), 7.68 (1H, t, J = 7.8 Hz), 7.09 (2H, d, J = 8.8 Hz), 6.86 5.22 (1H, s), 4.96 (2H, s), 3.62 (4H, brs), 2.79 (4H, brs), 1.26 (9H, s).

합성예Synthetic example 7 : 4-((2,4- 7: 4 - ((2,4- 디옥소Dioxo -6-(4--6- (4- 페닐피페라진Phenylpiperazine -1-일)-3,4--1-yl) -3,4- 디하이드로피리미딘Dihydropyrimidine -1 (2-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (4b):  (4b):

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 92.4% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and was obtained with a yield of 92.4%.

1H NMR(400 MHz, DMSO) δ: 11.2(1H, s), 9.55(1H, s), 8.81(1H, d, J=5.6 Hz), 8.58(1H, d, J=8.4 Hz), 8.35(1H, d, J=6.0 Hz), 8.28(1H, d, J=7.6 Hz), 7.77(1H, t, J=7.6 Hz), 7.22(2H, m), 7.10(2H, d, J=8.4 Hz), 6.89(2H, d, J=8.8 Hz), 6.83(3H, m), 5.18(1H, s), 4.86(2H, s), 3.01(4H, brs), 2.85(4H, brs).
 1 H NMR (400 MHz, DMSO ) δ: 11.2 (1H, s), 9.55 (1H, s), 8.81 (1H, d, J = 5.6 Hz), 8.58 (1H, d, J = 8.4 Hz), 8.35 (1H, d, J = 7.6 Hz), 7.72 (1H, d, J = 6.0 Hz), 8.28 (2H, s), 3.01 (4H, brs), 2.85 (4H, brs) .

합성예Synthetic example 8 : 4-((6-(4-(2- 8: 4 - ((6- (4- (2- 플루오로페닐Fluorophenyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4--3,4- 디하이드로Dihydro 피리미딘-1(2 Pyrimidin-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (4c)  (4c)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 65.9% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 65.9%.

1H NMR(400 MHz, DMSO) δ: 11.2(1H, s), 9.54(1H, s), 8.82(1H, d, J=6.0 Hz), 8.56(1H, d, J=8.4 Hz), 8.35(1H, d, J=6.0 Hz), 8.28(1H, d, J=7.6 Hz), 7.76(1H, t, J=7.8 Hz), 7.15-7.07(4H, m), 6.99-6.92(2H, m), 6.84(2H, d, J=8.4 Hz), 5.19(1H, s), 4.86(2H, s), 2.88(8H, brs).
 1 H NMR (400 MHz, DMSO ) δ: 11.2 (1H, s), 9.54 (1H, s), 8.82 (1H, d, J = 6.0 Hz), 8.56 (1H, d, J = 8.4 Hz), 8.35 (1H, d, J = 6.0 Hz), 8.28 (1H, d, J = 7.6 Hz), 7.76 (1H, t, J = 7.8 Hz), 7.15-7.07 m), 6.84 (2H, d, J = 8.4 Hz), 5.19 (1H, s), 4.86 (2H, s), 2.88 (8H, brs).

합성예Synthetic example 9 : 4-((6-(4-(4- 9: 4 - ((6- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4--3,4- 디하이드로Dihydro 피리미딘-1(2 Pyrimidin-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (4d)  (4d)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 84.9% 수득율로 수득하였다. Synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 84.9%.

1H NMR(400 MHz, CDCl3) δ: 9.39(1H, s), 8.76(1H, d, J=6.0 Hz), 8.50(1H, d, J=6.4 Hz), 8.29-8.27(2H, m), 7.65(1H, t, J=7.8 Hz), 7.08(2H, d, J=8.4 Hz), 6.96-6.94(2H, m), 6.85-6.80(4H, m), 5.23(1H, s), 4.96(2H, s), 3.07(4H, brs), 2.97(4H, brs).
 1 H NMR (400 MHz, CDCl 3) δ: 9.39 (1H, s), 8.76 (1H, d, J = 6.0 Hz), 8.50 (1H, d, J = 6.4 Hz), 8.29-8.27 (2H, m (2H, m), 6.85-6.80 (4H, m), 5.23 (1H, s), 7.65 (1H, t, J = 7.8Hz) , 4.96 (2H, s), 3.07 (4H, brs), 2.97 (4H, brs).

합성예Synthetic example 10 : 4-((2,4- 10: 4 - ((2,4- 디옥소Dioxo -6-(4-(3-(-6- (4- (3- ( 트리플루오로메틸Trifluoromethyl )) 페닐Phenyl )피페라진-1-일)-3,4- ) Piperazin-1-yl) -3,4- 디하이드로피리미딘Dihydropyrimidine -1(2-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (4e) (4e)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 59.8% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 59.8%.

1H NMR(400 MHz, CDCl3) δ: 9.41(1H, s), 8.81(1H, d, J=6.0 Hz), 8.52(1H, d, J=6.4 Hz), 8.29(2H, d, J=8.0 Hz), 8.16(1H, s), 7.66(1H, t, J=7.8 Hz), 7.40(1H, t, J=7.8 Hz), 7.17(1H, d, J=7.6 Hz), 7.11(2H, d, J=8.4 Hz), 7.06(1H, d, J=8.4 Hz), 6.87(2H, d, J=8.4 Hz), 5.30(1H, s), 4.99(2H, s), 3.22(4H, brs), 3.00(4H, brs).
 1 H NMR (400 MHz, CDCl 3) δ: 9.41 (1H, s), 8.81 (1H, d, J = 6.0 Hz), 8.52 (1H, d, J = 6.4 Hz), 8.29 (2H, d, J = 8.0 Hz), 8.16 (1H, s), 7.66 (1H, t, J = 7.8 Hz), 7.40 (1H, t, J = 7.8 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.06 (1H, d, J = 8.4 Hz), 6.87 4H, br s), 3.00 (4H, br s).

합성예Synthetic example 11 : 4-((2,4- 11: 4 - ((2,4- 디옥소Dioxo -6-(4-o--6- (4-o- 톨릴피페라진Tolylpiperazine -1-일)-3,4--1-yl) -3,4- 디하이드로피리미딘Dihydropyrimidine -1 (2-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (4f):  (4f):

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 78.3% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and was obtained with a yield of 78.3%.

1H NMR(400 MHz, CDCl3) δ: 9.41(1H, s), 8.81(1H, d, J=6.0 Hz), 8.53(1H, d, J=6.0 Hz), 8.31(1H, s), 8.28-8.25(2H, m), 7.63(1H, t, J=7.8 Hz), 7.21-7.16(2H, m), 7.13(2H, d, J=8.4 Hz), 7.06(1H, J=7.4 Hz), 6.98(1H, d, J=7.6 Hz), 6.86(2H, d, J=8.8 Hz), 5.29(1H, s), 4.99(2H, s), 2.99(4H, brs), 2.91(4H, brs), 2.28(3H, s).
 1 H NMR (400 MHz, CDCl 3) δ: 9.41 (1H, s), 8.81 (1H, d, J = 6.0 Hz), 8.53 (1H, d, J = 6.0 Hz), 8.31 (1H, s), J = 7.4 Hz), 7.21-7.16 (2H, m), 7.13 (2H, d, J = 8.4 Hz), 7.06 ), 6.98 (1H, d, J = 7.6 Hz), 6.86 (2H, d, J = 8.8 Hz), 5.29 (1H, s), 4.99 , brs), 2.28 (3H, s).

합성예Synthetic example 12 : 4-((6-(4- 12: 4 - ((6- (4- 벤질피페라진Benzylpiperazine -1-일)-2,4--1-yl) -2, 4- 디옥소Dioxo -3,4--3,4- 디하이드로피리미딘Dihydropyrimidine -1 (2-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (4g) (4g)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 84.5% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis procedure as in Synthesis Examples 1 to 6, and was obtained with a yield of 84.5%.

1H NMR(400 MHz, CDCl3) δ: 9.40(1H, s), 8.80(1H, d, J=6.4 Hz), 8.52(1H, d, J=6.0 Hz), 8.27-8.23(3H, m), 7.60(1H, t, J=7.6 Hz), 7.37-7.25(5H, m), 7.08(2H, d, J=8.4 Hz), 6.83(2H, d, J=8.8 Hz), 5.21(1H, s), 4.91(2H, s), 3.51(2H, s), 2.84(4H, m), 2.45(4H, brs).
1 H NMR (400 MHz, CDCl 3) δ: 9.40 (1H, s), 8.80 (1H, d, J = 6.4 Hz), 8.52 (1H, d, J = 6.0 Hz), 8.27-8.23 (3H, m ), 7.60 (1H, t, J = 7.6 Hz), 7.37-7.25 (5H, m), 7.08 (2H, d, J = 8.4 Hz), 6.83 , 4.91 (2H, s), 3.51 (2H, s), 2.84 (4H, m), 2.45 (4H, brs).

합성예Synthetic example 13 : 4-((6-(4-(4- 13: 4 - ((6- (4- (4- 플루오로벤질Fluorobenzyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4--3,4- 디하이드로Dihydro 피리미딘-1(2 Pyrimidin-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (4h)  (4h)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 76.9% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 76.9%.

1H NMR(400 MHz, CDCl3) δ: 9.41(1H, s), 8.81(1H, d, J=6.4 Hz), 8.52(1H, d, J=6.0 Hz), 8.33(1H, s), 7.28(2H, d, J=7.6 Hz), 7.63(1H, t, J=7.8 Hz), 7.27(2H, m), 7.09(2H, d, J=8.4 Hz), 7.03(1H, t, J=8.6 Hz), 6.84(2H, d, J=8.8 Hz), 5.21(1H, s), 4.91(2H, s), 3.47(2H, s), 2.85(4H, m), 2.44(4H, brs).
1 H NMR (400 MHz, CDCl 3) δ: 9.41 (1H, s), 8.81 (1H, d, J = 6.4 Hz), 8.52 (1H, d, J = 6.0 Hz), 8.33 (1H, s), (2H, d, J = 8.4 Hz), 7.03 (1H, t, J), 7.28 (2H, d, J = 7.6 Hz), 7.63 (2H, s), 2.85 (4H, m), 2.44 (4H, brs) ).

합성예Synthetic example 14 :  14: terttert -부틸 4-(3-(4-(이소퀴놀린-5--Butyl 4- (3- (4- (isoquinolin-5- 일설포닐옥시1-sulfonyloxy )벤질)-2,6-) Benzyl) -2,6- 디옥소Dioxo -1,2,3,6- -1,2,3,6- 테트라하이드로피리미딘Tetrahydropyrimidine -4-일)피페라진-1-Yl) piperazin-l- 카르복실레이트Carboxylate (6b) (6b)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 57.5% 수득율로 수득하였다. Synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 57.5%.

1H NMR(400 MHz, CDCl3) δ: 9.42(1H, s), 8.80(1H, d, J=6.4 Hz), 8.52(1H, d, J=6.4 Hz), 8.31-8.27(2H, m), 7.68(1H, t, J=7.8 Hz), 7.08(2H, d, J=8.4 Hz), 6.86(2H, d, J=8.4 Hz), 5.22(1H, s), 4.94(2H, s), 3.41(4H, brs), 2.7(4H, brs), 1.45(9H, s).
1 H NMR (400 MHz, CDCl 3) δ: 9.42 (1H, s), 8.80 (1H, d, J = 6.4 Hz), 8.52 (1H, d, J = 6.4 Hz), 8.31-8.27 (2H, m D, J = 8.4 Hz), 5.22 (1H, s), 4.94 (2H, s), 7.68 (1H, ), 3.41 (4H, br s), 2.7 (4H, br s), 1.45 (9H, s).

합성예Synthetic example 15 : 4-((6-(4-( 15: 4 - ((6- (4- ( 사이클로헥산카르보닐Cyclohexanecarbonyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4 --3,4- 디하이드로피리미딘Dihydropyrimidine -1(2-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6c) (6c)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 78.6% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis procedure as in Synthesis Examples 1 to 6, and was obtained with a yield of 78.6%.

1H NMR(400 MHz, CDCl3) δ: 9.42(1H, s), 8.94(1H, s), 8.81(1H, d, J=6.4 Hz), 8.52(1H, d, J=6.4 Hz), 8.31-8.27(2H, m), 7.68(1H, t, J=7.8 Hz), 7.08(2H, d, J=8.8 Hz), 6.86(2H, d, J=8.8 Hz), 5.22(1H, s), 4.96(2H, s), 3.49(4H, brs), 2.80(4H, m), 2.40(1H, m), 1.80-1.24(10H, m).
1 H NMR (400 MHz, CDCl 3) δ: 9.42 (1H, s), 8.94 (1H, s), 8.81 (1H, d, J = 6.4 Hz), 8.52 (1H, d, J = 6.4 Hz), (2H, d, J = 8.8 Hz), 5.22 (1H, s), 8.31-8.27 (2H, m), 7.68 ), 4.96 (2H, s), 3.49 (4H, brs), 2.80 (4H, m), 2.40 (1H, m), 1.80-1.24 (10H, m).

합성예Synthetic example 16 : 4-((6-(4-(2- 16: 4 - ((6- (4- (2- 사이클로헥실아세틸Cyclohexyl acetyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4 --3,4- 디하이드로피리미딘Dihydropyrimidine -1(2-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6d) (6d)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 71.8% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis procedure as in Synthesis Examples 1 to 6, and the yield was 71.8%.

1H NMR(400 MHz, CDCl3) δ: 9.42(1H, s), 8.87(1H, s), 8.76(1H, d, J=6.4 Hz), 8.52(1H, d, J=6.4 Hz), 8.31-8.27(2H, m), 7.69(1H, t, J=7.6Hz), 7.08(2H, d, J=8.4 Hz), 6.86(2H, d, J=8.4 Hz), 5.23(1H, s), 4.96(2H, s), 3.47(4H, brs), 2.19(4H, m), 2.19(2H, d, J=6.8 Hz), 1.80-0.86(11H, m).
1 H NMR (400 MHz, CDCl 3) δ: 9.42 (1H, s), 8.87 (1H, s), 8.76 (1H, d, J = 6.4 Hz), 8.52 (1H, d, J = 6.4 Hz), (2H, d, J = 8.4 Hz), 5.23 (1H, s), 8.31-8.27 (2H, m), 7.69 ), 4.96 (2H, s), 3.47 (4H, brs), 2.19 (4H, m), 2.19 (2H, d, J = 6.8 Hz), 1.80-0.86 (11H, m).

합성예Synthetic example 17 : 4-((6-(4-(1- 17: 4 - ((6- (4- (1- 아다만틸카르보닐Adamantylcarbonyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4- -3,4- 디하이드로피리미딘Dihydropyrimidine -1(2-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6e)  (6e)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 92.9% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 92.9%.

1H NMR(400 MHz, CDCl3) δ: 9.42(1H, s), 8.80(1H, d, J=5.6 Hz), 8.52(1H, d, J=6.4 Hz), 8.31-8.27(2H, m), 8.01(1H, s), 7.68(1H, t, J=7.8 Hz), 7.08(2H, d, J=8.4 Hz), 6.87(2H, d, J=8.4 Hz), 5.21(1H, s), 4.96(2H, s), 3.69(4H, brs), 2.79(4H, brs), 2.04-1.52(15H, m).
1 H NMR (400 MHz, CDCl 3) δ: 9.42 (1H, s), 8.80 (1H, d, J = 5.6 Hz), 8.52 (1H, d, J = 6.4 Hz), 8.31-8.27 (2H, m D, J = 8.4 Hz), 8.01 (1H, s), 7.68 (1H, t, J = 7.8 Hz), 7.08 ), 4.96 (2H, s), 3.69 (4H, brs), 2.79 (4H, brs), 2.04-1.52 (15H, m).

합성예Synthetic example 18 : 4-((6-(4-(1- 18: 4 - ((6- (4- (1- 아다만틸아세틸Adamantylacetyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4- -3,4- 디하이드로피리미딘Dihydropyrimidine -1(2-1 (2 HH )-일)메틸)) -Yl) methyl) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6f): (6f):

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 71.4% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 71.4%.

1H NMR(400 MHz, CDCl3) δ: 9.42(1H, s), 8.80(1H, d, J=6 Hz), 8.52(1H, d, J=6.4 Hz), 8.31-8.27(2H, m), 7.68(1H, t, J=7.8 Hz), 7.08(2H, d, J=8.0 Hz), 6.86(2H, d, J=8.8 Hz), 5.23(1H, s), 4.96(2H, s), 3.53(4H, brs), 2.81(4H, brs), 2.13(2H, s), 1.96-1.61(15H, m).
1 H NMR (400 MHz, CDCl 3) δ: 9.42 (1H, s), 8.80 (1H, d, J = 6 Hz), 8.52 (1H, d, J = 6.4 Hz), 8.31-8.27 (2H, m ), 7.68 (1H, d, J = 7.8 Hz), 7.08 (2H, d, J = 8.0 Hz), 6.86 ), 3.53 (4H, brs), 2.81 (4H, brs), 2.13 (2H, s), 1.96-1.61 (15H, m).

합성예Synthetic example 19 : 4-((6-(4-(3- 19: 4 - ((6- (4- (3- 브로모Bromo -1--One- 아다만틸카르보닐Adamantylcarbonyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo - 3,4-- 3,4- 디하이드로피리미딘Dihydropyrimidine -1(2-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6g)  (6g)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 93.5% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 93.5%.

1H NMR(400 MHz, DMSO) δ: 11.2(1H, s), 9.59(1H, s), 8.85(1H, d, J=6 Hz), 8.62(1H, d, J=8.0 Hz), 8.39(1H, d, J=6.0 Hz), 8.32(1H, d, J=6.0 Hz), 7.84(1H, t, J=7.8 Hz), 7.14(2H, d, J=8.4 Hz), 6.86(2H, d, J=8.4 Hz), 5.15(1H, s), 4.87(2H, s), 3.53(4H, brs), 2.71(4H, brs), 1.96-1.66(14H, m).
1 H NMR (400 MHz, DMSO ) δ: 11.2 (1H, s), 9.59 (1H, s), 8.85 (1H, d, J = 6 Hz), 8.62 (1H, d, J = 8.0 Hz), 8.39 (2H, d, J = 8.4 Hz), 6.86 (2H, d, J = 6.0 Hz), 8.32 (d, J = 8.4Hz), 5.15 (1H, s), 4.87 (2H, s), 3.53 (4H, brs), 2.71 (4H, brs), 1.96-1.66 (14H, m).

합성예Synthetic example 20 : 4-((6-(4-(3,5-디메틸-1- 20: 4 - ((6- (4- (3,5-Dimethyl-1- 아다만틸카르보닐Adamantylcarbonyl )피페라진-1-일)-2,4- ) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4--3,4- 디하이드로피리미딘Dihydropyrimidine -1(2-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6h)  (6h)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 89.9% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 89.9%.

1H NMR(400 MHz, DMSO) δ: 11.12(1H, s), 9.56(1H, s), 8.82(1H, d, J=6.0 Hz), 8.59(1H, d, J=8.4 Hz), 8.35(1H, d, J=6.0 Hz), 8.29(1H, d, J=7.2 Hz), 7.81(1H, t, J=8.0 Hz), 7.11(2H, d, J=8.4 Hz), 6.84(2H, d, J=8.8 Hz), 5.13(1H, s), 4.84(2H, s), 3.49(4H, brs), 2.68(4H, brs), 2.00(1H, s), 1.66(2H, s), 1.50-1.19(8H, m), 1.07(2H, s), 0.76(6H, s).
 1 H NMR (400 MHz, DMSO ) δ: 11.12 (1H, s), 9.56 (1H, s), 8.82 (1H, d, J = 6.0 Hz), 8.59 (1H, d, J = 8.4 Hz), 8.35 (1H, d, J = 6.0 Hz), 8.29 (1H, d, J = 7.2 Hz), 7.81 (d, J = 8.8 Hz), 5.13 (1H, s), 4.84 (2H, s), 3.49 (4H, brs), 2.68 , 1.50-1.19 (8H, m), 1.07 (2H, s), 0.76 (6H, s).

합성예Synthetic example 21 : 4-((6-(4-(3- 21: 4 - ((6- (4- (3- 노르아다만틸카르보닐Noradamantylcarbonyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4- -3,4- 디하이드로피리미딘Dihydropyrimidine -1(2-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6i)  (6i)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 85.5% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 85.5%.

1H NMR(400 MHz, DMSO) δ: 11.12(1H, s), 9.56(1H, s), 8.82(1H, d, J=6.0Hz), 8.59(1H, d, J=8.4 Hz), 8.35(1H, d, J=6.0 Hz), 8.29(1H, d, J=7.6 Hz), 7.81(1H, t, J=8.0 Hz), 7.12(2H, d, J=8.0 Hz), 6.84(2H, d, J=8.4 Hz), 5.13(1H, s), 4.85(2H, s), 3.42(4H, brs), 2.71(5H, m), 2.19(2H, s), 1.94-1.47(10H, m).
1 H NMR (400 MHz, DMSO ) δ: 11.12 (1H, s), 9.56 (1H, s), 8.82 (1H, d, J = 6.0Hz), 8.59 (1H, d, J = 8.4 Hz), 8.35 (2H, d, J = 8.0 Hz), 6.84 (2H, d, J = 6.0 Hz), 8.29 (1H, d, J = 7.6 Hz), 7.81 (d, J = 8.4 Hz), 5.13 (1H, s), 4.85 (2H, s), 3.42 (4H, brs), 2.71 (2H, s), 1.94-1.47 m).

합성예Synthetic example 22 : 4-((6-(4-(2- 22: 4 - ((6- (4- (2- 노르보나닐카르보닐Norbornanylcarbonyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4- -3,4- 디하이드로피리미딘Dihydropyrimidine -1(2-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6j)  (6j)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 70.4% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 70.4%.

1H NMR(400 MHz, CDCl3) δ: 9.42(1H, s), 9.32(1H, s), 8.81(1H, d, J=6.0 Hz), 8.52(1H, d, J=6.0 Hz), 8.31-8.27(2H, m), 7.68(1H, t, J=7.8 Hz), 7.09(2H, d, J=8.4 Hz), 6.86(2H, d, J=8.4 Hz), 5.22(1H, s), 4.96(2H, s), 3.54(4H, brs), 2.76(4H, brs), 2.33-1.17(11H, m).
1 H NMR (400 MHz, CDCl 3) δ: 9.42 (1H, s), 9.32 (1H, s), 8.81 (1H, d, J = 6.0 Hz), 8.52 (1H, d, J = 6.0 Hz), (2H, d, J = 8.4 Hz), 5.22 (1H, s), 7.31-8.27 ), 4.96 (2H, s), 3.54 (4H, brs), 2.76 (4H, brs), 2.33-1.17 (11H, m).

합성예Synthetic example 23 : 4-((6-(4-(2- 23: 4 - ((6- (4- (2- 노르보나닐아세틸Norbornanylacetyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4- -3,4- 디하이드로피리미딘Dihydropyrimidine -1(2-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6k) :  (6k):

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 85.3% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis procedure as in Synthesis Examples 1 to 6, and the yield was 85.3%.

1H NMR(400 MHz, CDCl3) δ: 9.42(1H, s), 9.35(1H, s), 8.80(1H, d, J=6.0 Hz), 8.51(1H, d, J=6.0 Hz), 8.31-8.27(2H, m), 7.68(1H, t, J=7.8 Hz), 7.08(2H, d, J=8.8 Hz),6.85(2H, d, J=8.8 Hz), 5.23(1H, s), 4.96(2H, s), 3.46(4H, brs), 2.79(4H, m), 2.30-2.07(3H, m), 1.95-0.99(10H, m).
1 H NMR (400 MHz, CDCl 3) δ: 9.42 (1H, s), 9.35 (1H, s), 8.80 (1H, d, J = 6.0 Hz), 8.51 (1H, d, J = 6.0 Hz), (2H, d, J = 8.8 Hz), 5.23 (1H, s), 8.31-8.27 (2H, m), 7.68 ), 4.96 (2H, s), 3.46 (4H, brs), 2.79 (4H, m), 2.30-2.07 (3H, m), 1.95-0.99 (10H, m).

합성예Synthetic example 24 : 4-((6-(4- 24: 4 - ((6- (4- 벤조일피페라진Benzoylpiperazine -1-일)-2,4--1-yl) -2, 4- 디옥소Dioxo -3,4--3,4- 디하이드로피리미딘Dihydropyrimidine -1(2 -1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6l): (6l):

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 85.3% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis procedure as in Synthesis Examples 1 to 6, and the yield was 85.3%.

1H NMR(400 MHz, DMSO) δ: 11.1(1H, s), 9.54(1H, s), 8.82(1H, d, J=6.4 Hz), 8.55(1H, d, J=8.4 Hz), 8.35(1H, d, J=6.4 Hz), 8.26(1H, d, J=7.6 Hz), 7.74(1H, t, J=7.8 Hz), 7.11(2H, d, J=8.4 Hz),6.83(2H, d, J=8.4 Hz), 5.15(1H, s), 4.84(2H, s), 3.51(4H, brs), 2.74(4H, brs).
 1 H NMR (400 MHz, DMSO ) δ: 11.1 (1H, s), 9.54 (1H, s), 8.82 (1H, d, J = 6.4 Hz), 8.55 (1H, d, J = 8.4 Hz), 8.35 (1H, d, J = 6.4 Hz), 8.26 (1H, d, J = 7.6 Hz), 7.74 (d, J = 8.4 Hz), 5.15 (1H, s), 4.84 (2H, s), 3.51 (4H, brs), 2.74 (4H, brs).

합성예Synthetic example 25 : 4-((2,4- 25: 4 - ((2,4- 디옥소Dioxo -6-(4-(2--6- (4- (2- 페닐아세틸Phenylacetyl )피페라진-1-일)-3,4-) Piperazin-1-yl) -3,4- 디하이드Dihydro 로피리미딘Ropyrimidine -1(2-1 (2 HH )-일))-Work) 메틸methyl )페닐 이소퀴놀린-5-) Phenylisoquinoline-5- 설포네이트Sulfonate (6m): (6m):

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 80.4% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 80.4%.

1H NMR(400 MHz, CDCl3) δ: 9.42(1H, s), 8.80(1H, d, J=6.4 Hz), 8.52(1H, d, J=8.4 Hz), 8.30-8.26(2H, m), 7.67(1H, t, J=7.8 Hz), 7.34-7.19(5H, m), 7.04(2H, d, J=8.4 Hz), 6.83(2H, d, J=8.4 Hz), 5.13(1H, s), 4.91(2H, s), 3.73(2H, s), 3.42(4H, brs), 2.71(2H, s), 2.55(2H, s).
 1 H NMR (400 MHz, CDCl 3) δ: 9.42 (1H, s), 8.80 (1H, d, J = 6.4 Hz), 8.52 (1H, d, J = 8.4 Hz), 8.30-8.26 (2H, m (2H, d, J = 8.4 Hz), 7.67 (1H, t, J = 7.8 Hz), 7.34-7.19 (5H, m), 7.04 , 4.91 (2H, s), 3.73 (2H, s), 3.42 (4H, brs), 2.71 (2H, s), 2.55 (2H, s).

합성예Synthetic example 26 : 4-((6-(4-(2- 26: 4 - ((6- (4- (2- 클로로벤조일Chlorobenzoyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4--3,4- 디하이드로Dihydro 피리미딘-1(2 Pyrimidin-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6n):  (6n):

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 89.6% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis procedure as in Synthesis Examples 1 to 6, and the yield was 89.6%.

1H NMR(400 MHz, CDCl3) δ: 9.42(1H, s), 9.12(1H, s), 8.81(1H, d, J=6.4 Hz), 8.51(1H, d, J=6.0 Hz), 8.30-8.24(2H, m), 7.66(1H, t, J=7.8 Hz), 7.42-7.26(4H, m), 7.07(2H, d, J=8.8 Hz), 6.85(2H, d, J=8.4 Hz), 5.25(1H, s), 4.96(2H, s), 3.52(4H, brs), 2.86(4H, brs).
1 H NMR (400 MHz, CDCl 3) δ: 9.42 (1H, s), 9.12 (1H, s), 8.81 (1H, d, J = 6.4 Hz), 8.51 (1H, d, J = 6.0 Hz), D, J = 8.8 Hz), 6.85 (2H, d, J = 7.8 Hz), 7.42-7.26 (4H, m) 8.4 Hz), 5.25 (1H, s), 4.96 (2H, s), 3.52 (4H, brs), 2.86 (4H, brs).

합성예Synthetic example 27 : 4-((6-(4-(3- 27: 4 - ((6- (4- (3- 클로로벤조일Chlorobenzoyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4--3,4- 디하이드로Dihydro 피리미딘-1(2 Pyrimidin-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6o)  (6o)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 52.4% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 52.4%.

1H NMR(400 MHz, CDCl3) δ: 9.43(1H, s), 9.19(1H, s), 8.80(1H, d, J=6.4 Hz), 8.52(1H, d, J=5.6 Hz), 8.30-8.26(2H, m), 7.66(1H, t, J=7.8 Hz), 7.44-7.23(4H, m), 7.08(2H, d, J=8.8 Hz),6.86(2H, d, J=8.8 Hz), 5.25(1H, s), 4.97(2H, s), 3.47(2H, s), 2.81(4H, brs).
 1 H NMR (400 MHz, CDCl 3) δ: 9.43 (1H, s), 9.19 (1H, s), 8.80 (1H, d, J = 6.4 Hz), 8.52 (1H, d, J = 5.6 Hz), D, J = 8.8 Hz), 6.86 (2H, d, J = 7.8 Hz), 7.44-7.23 (4H, m) 8.8 Hz), 5.25 (1H, s), 4.97 (2H, s), 3.47 (2H, s), 2.81 (4H, brs).

합성예Synthetic example 28 : 4-((6-(4-(4- 28: 4 - ((6- (4- (4- 플루오로벤조일Fluorobenzoyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4- -3,4- 디하이드로피리미딘Dihydropyrimidine -1(2-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6p)  (6p)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 86.9% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 86.9%.

1H NMR(400 MHz, CDCl3) δ: 9.42(1H, s), 8.81(1H, d, J=6.0 Hz), 8.51(1H, d, J=6.0 Hz), 8.30-8.26(2H, m), 7.66(1H, t, J=7.8 Hz), 7.42-7.39(2H, m), 7.14-7.06(4H, m), 6.86(2H, d, J=8.8 Hz), 5.24(1H, s), 4.97(2H, s), 3.55(4H, brs), 2.80 (4H, brs).
 1 H NMR (400 MHz, CDCl 3) δ: 9.42 (1H, s), 8.81 (1H, d, J = 6.0 Hz), 8.51 (1H, d, J = 6.0 Hz), 8.30-8.26 (2H, m ), 7.66 (1H, t, J = 7.8Hz), 7.42-7.39 (2H, m), 7.14-7.06 (4H, m), 6.86 , 4.97 (2H, s), 3.55 (4H, brs), 2.80 (4H, brs).

합성예Synthetic example 29 : 4-((6-(4-(4- 29: 4 - ((6- (4- (4- 클로로벤조일Chlorobenzoyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4--3,4- 디하이드로Dihydro 피리미딘-1(2 Pyrimidin-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6q)  (6q)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 95.7% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 95.7%.

1H NMR(400 MHz, CDCl3) δ: 9.42(1H, s), 8.80(1H, d, J=6.0 Hz), 8.50(1H, d, J=6.0 Hz), 8.30-8.25(2H, m), 7.66(1H, t, J=7.8 Hz), 7.40(2H, d, J=8.0 Hz), 7.34(2H, d, J=8.4 Hz), 7.08(2H, d, J=8.8 Hz), 6.85(2H, d, J=8.8 Hz), 5.24(1H, s), 4.96(2H, s), 3.49(4H, brs), 2.79(4H, brs).
 1 H NMR (400 MHz, CDCl 3) δ: 9.42 (1H, s), 8.80 (1H, d, J = 6.0 Hz), 8.50 (1H, d, J = 6.0 Hz), 8.30-8.25 (2H, m ), 7.66 (1H, t, J = 7.8 Hz), 7.40 (2H, d, J = 8.0 Hz) 6.85 (2H, d, J = 8.8 Hz), 5.24 (1H, s), 4.96 (2H, s), 3.49 (4H, brs), 2.79 (4H, brs).

합성예Synthetic example 30 : 4-((6-(4-(4- 30: 4 - ((6- (4- (4- 브로모벤조일Bromobenzoyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4--3,4- 디하이드로Dihydro 피리미딘-1(2 Pyrimidin-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6r) (6r)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 57.9% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 57.9%.

1H NMR(400 MHz, CDCl3) δ: 9.42(1H, s), 9.17(1H, s), 8.79(1H, d, J=6.0 Hz), 8.51(1H, d, J=6.0 Hz), 8.30-8.25(2H, m), 7.66(1H, t, J=7.8Hz), 7.57(1H, d, J=8.4 Hz), 7.27(2H, d, J=8.4 Hz), 7.08(2H, d, J=8.4 Hz),6.86(2H, d, J=8.4 Hz), 5.24(1H, s), 4.96(2H, s), 3.49(4H, brs), 2.79(4H, brs).
 1 H NMR (400 MHz, CDCl 3) δ: 9.42 (1H, s), 9.17 (1H, s), 8.79 (1H, d, J = 6.0 Hz), 8.51 (1H, d, J = 6.0 Hz), (2H, d, J = 8.4 Hz), 7.08 (2H, d, J = (1H, d, J = 8.4 Hz), 6.86 (2H, d, J = 8.4 Hz), 5.24 (1H, s), 4.96 (2H, s), 3.49 (4H, brs)

합성예Synthetic example 31 : 4-((6-(4-(3,4- 31: 4 - ((6- (4- (3,4- 디플루오로벤조일Difluorobenzoyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4- -3,4- 디하이드로피리미딘Dihydropyrimidine -1(2-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6s)  (6s)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 78.0% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis procedure as in Synthesis Examples 1 to 6, and was obtained with a yield of 78.0%.

1H NMR(400 MHz, CDCl3) δ: 9.42(1H, s), 8.81(1H, d, J=6.0 Hz), 8.51(1H, d, J=5.6 Hz), 8.31-8.27(2H, m), 7.68(1H, t, J=7.8 Hz), 7.28-7.14(3H, m), 7.09(2H, d, J=8.4 Hz), 6.87(2H, d, J=8.8 Hz), 5.24(1H, s), 4.97(2H, s), 3.54(4H, brs), 2.81(4H, brs).
1 H NMR (400 MHz, CDCl 3) δ: 9.42 (1H, s), 8.81 (1H, d, J = 6.0 Hz), 8.51 (1H, d, J = 5.6 Hz), 8.31-8.27 (2H, m (2H, d, J = 8.4 Hz), 7.68 (1H, d, J = 7.8 Hz), 7.28-7.14 , s), 4.97 (2H, s), 3.54 (4H, brs), 2.81 (4H, brs).

합성예Synthetic example 32 : 4-((6-(4-(4- 32: 4 - ((6- (4- (4- 클로로Chloro -2--2- 플루오로벤조일Fluorobenzoyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4- -3,4- 디하이드로피리미딘Dihydropyrimidine -1(2-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6t)  (6t)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 65.3% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 65.3%.

1H NMR(400 MHz, CDCl3) δ: 9.42(1H, s), 8.81(1H, d, J=6.0 Hz), 8.53(1H, d, J=6.0 Hz), 8.31-8.27(2H, m), 8.14(1H, s), 7.68(1H, t, J=7.8 Hz), 7.37(1H, t, J=7.6 Hz), 7.23(1H), 7.17(1H, dd, J=9.2 Hz, J=1.6 Hz,), 7.09(1H, d, J=8.8 Hz), 6.87(2H, d, J=8.4 Hz), 5.24(1H, s), 4.97(2H, s), 3.33(4H, brs), 2.86(4H, m).
 1 H NMR (400 MHz, CDCl 3) δ: 9.42 (1H, s), 8.81 (1H, d, J = 6.0 Hz), 8.53 (1H, d, J = 6.0 Hz), 8.31-8.27 (2H, m ), 8.14 (1H, s), 7.68 (1H, t, J = 7.8 Hz), 7.37 (1H, t, J = 7.6 Hz), 7.23 (2H, s), 3.33 (4H, brs), 6.97 (2H, d, J = , 2.86 (4 H, m).

합성예Synthetic example 33 : 4-((6-(4-(3,4- 33: 4 - ((6- (4- (3,4- 디클로로벤조일Dichlorobenzoyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4- -3,4- 디하이드로Dihydro 피리미딘-1(2 Pyrimidin-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6u)  (6u)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 27.6% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 27.6%.

1H NMR(400 MHz, CDCl3) δ: 9.42(1H, s), 8.80(1H, d, J=6.0 Hz), 8.76(1H, s), 8.52(1H, d, J=5.2 Hz), 8.31-8.25(2H, m), 7.67(1H, t, J=7.8 Hz), 7.52-7.49(2H, m), 7.24(1H, d, J=80 Hz), 7.08(2H, d, J=8.4 Hz), 6.88(2H, d, J=8.8 Hz), 5.24(1H, s), 4.97(2H, s), 3.50(4H, brs), 2.81(4H, brs).
 1 H NMR (400 MHz, CDCl 3) δ: 9.42 (1H, s), 8.80 (1H, d, J = 6.0 Hz), 8.76 (1H, s), 8.52 (1H, d, J = 5.2 Hz), D, J = 80 Hz), 7.08 (2H, d, J = 7.8 Hz), 7.52-7.49 (2H, m), 7.24 8.4 Hz), 6.88 (2H, d, J = 8.8 Hz), 5.24 (1H, s), 4.97 (2H, s), 3.50 (4H, brs), 2.81 (4H,

합성예Synthetic example 34 : 34: 4-((6-(4-(4-4 - ((6- (4- (4- 클로로Chloro -3--3- 플루오로벤조일Fluorobenzoyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo - 3,4-디- 3,4-di 하이드로피리Hydropy 미딘-1(2Middin-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6v) (6v)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 65.9% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 65.9%.

1H NMR(400 MHz, CDCl3) δ: 9.42(1H, s), 8.81(1H, d, J=6.0 Hz), 8.51(1H, d, J=5.6 Hz), 8.31-8.27(2H, m), 7.68(1H, t, J=8.0 Hz), 7.49(1H, t, J=7.6 Hz), 7.21-7.12(2H, m), 7.09(2H, d, J=8.0 Hz), 6.88(2H, d, J=8.8 Hz), 5.24(1H, s), 4.97(2H, s), 3.51(4H, brs), 2.81(4H, brs).
 1 H NMR (400 MHz, CDCl 3) δ: 9.42 (1H, s), 8.81 (1H, d, J = 6.0 Hz), 8.51 (1H, d, J = 5.6 Hz), 8.31-8.27 (2H, m ), 7.68 (1H, d, J = 8.0 Hz), 7.49 (1H, t, J = 7.6Hz), 7.21-7.12 (d, J = 8.8 Hz), 5.24 (1H, s), 4.97 (2H, s), 3.51 (4H, brs), 2.81 (4H, brs).

합성예Synthetic example 35 : 35: 4-((6-(4-(4-4 - ((6- (4- (4- 클로로Chloro -3-(-3- ( 트리플루오로메틸Trifluoromethyl )) 벤조일Benzoyl )피페라진-1-일)-2,4- ) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4--3,4- 디하이드로피리미딘Dihydropyrimidine -1(2-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6w) (6w)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 65.5% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis procedure as in Synthesis Examples 1 to 6, and was obtained with a yield of 65.5%.

1H NMR(400 MHz, DMSO) δ: 11.1(1H, s), 9.55(1H, s), 8.82(1H, d, J=6.0 Hz), 8.58 (1H, d, J=8.0 Hz), 8.35(1H, d, J=6.4 Hz), 8.28(1H, d, J=7.2 Hz), 7.83-7.68(4H, m), 7.12(2H, d, J=8.4 Hz), 6.83(2H, d, J=8.8 Hz), 5.14(1H, s), 4.84(2H, s), 3.53(4H, brs), 2.75(4H, brs).
 1 H NMR (400 MHz, DMSO ) δ: 11.1 (1H, s), 9.55 (1H, s), 8.82 (1H, d, J = 6.0 Hz), 8.58 (1H, d, J = 8.0 Hz), 8.35 (1H, d, J = 6.4 Hz), 8.28 (1H, d, J = 7.2 Hz), 7.83-7.68 (4H, m), 7.12 J = 8.8 Hz), 5.14 (1H, s), 4.84 (2H, s), 3.53 (4H, brs), 2.75 (4H, brs).

합성예Synthetic example 36 : 36: 4-((6-(4-(5-4 - ((6- (4- (5- 브로모Bromo -2--2- 클로로벤조일Chlorobenzoyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4- -3,4- 디하이드로피리미딘Dihydropyrimidine -1(2-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6x) (6x)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 57.6% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis procedure as in Synthesis Examples 1 to 6, and was obtained with a yield of 57.6%.

1H NMR(400 MHz, CDCl3) δ: 9.42(1H, s), 8.81(1H, d, J=5.2 Hz), 8.53 (1H, d, J=6.0 Hz), 7.33-7.27(2H, m),8.10(1H, s), 7.67(1H, t, J=7.8 Hz), 7.50-7.27(3H, m), 7.08(2H, d, J=8.4 Hz), 6.88(2H, d, J=8.8 Hz), 5.24(1H, s), 4.96(2H, s), 3.64(4H, brs), 2.87(4H, brs).
 1 H NMR (400 MHz, CDCl 3) δ: 9.42 (1H, s), 8.81 (1H, d, J = 5.2 Hz), 8.53 (1H, d, J = 6.0 Hz), 7.33-7.27 (2H, m D, J = 8.4 Hz), 6.88 (2H, d, J = 7.8 Hz), 7.50-7.27 (3H, m) 8.8 Hz), 5.24 (1H, s), 4.96 (2H, s), 3.64 (4H, brs), 2.87 (4H, brs).

합성예Synthetic example 37 :  37: NN -(4-((6-(4-(1-- (4 - ((6- (4- (1- 아다만틸카르보닐Adamantylcarbonyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4- -3,4- 디하이드로피리미딘Dihydropyrimidine -1(2-1 (2 HH )-일))-Work) 메틸methyl )) 페닐Phenyl 이소퀴놀린-5- Isoquinolin-5- 설포네이트Sulfonate (6y) (6y)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 53.6% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 53.6%.

1H NMR(400 MHz, CDCl3) δ: 10.0(1H, s), 9.42(1H, s), 8.81(1H, d, J=5.6 Hz), 8.53(1H, d, J=6.4 Hz), 8.33-8.27(2H, m), 8.01(1H, s), 7.67(1H, t, J=7.8 Hz), 7.08(2H, d, J=8.4 Hz), 6.88(2H, d, J=8.4 Hz), 5.23(1H, s), 4.96(2H, s), 3.65(4H, brs), 2.80(4H, brs), 2.05-1.53(15H, m).
 1 H NMR (400 MHz, CDCl 3) δ: 10.0 (1H, s), 9.42 (1H, s), 8.81 (1H, d, J = 5.6 Hz), 8.53 (1H, d, J = 6.4 Hz), (2H, d, J = 8.4 Hz), 7.08 (2H, d, J = 8.4 Hz), 8.33-8.27 (2H, m), 8.01 ), 5.23 (1H, s), 4.96 (2H, s), 3.65 (4H, brs), 2.80 (4H, brs), 2.05-1.53 (15H, m).

합성예Synthetic example 38 :  38: NN -(4-((6-(4-(1-- (4 - ((6- (4- (1- 아다만틸카르보닐Adamantylcarbonyl )피페라진-1-일)-2,4-) Piperazin-1-yl) -2,4- 디옥소Dioxo -3,4- -3,4- 디하이드로피리미딘Dihydropyrimidine -1(2-1 (2 HH )-) - ylyl )) 메틸methyl )) 페닐Phenyl )이소퀴놀린-5-) Isoquinolin-5- 카르복사마이드Carboxamide (6z) (6z)

합성예 1 내지 6과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 43.9% 수득율로 수득하였다. The synthesis was carried out by the same representative synthesis method as in Synthesis Examples 1 to 6, and the yield was 43.9%.

1H NMR(400 MHz, CDCl3) δ: 9.45(1H, s), 8.83(1H, d, J=5.6 Hz), 8.55(1H, d, J=6.4 Hz), 8.33-8.28(2H, m), 8.03(1H, s), 7.68(1H, t, J=7.8 Hz), 7.09(2H, d, J=8.4 Hz), 6.88(2H, d, J=8.4 Hz), 5.23(1H, s), 4.98(2H, s), 3.63(4H, brs), 2.78(4H, brs), 2.00-1.50(15H, m).
 1 H NMR (400 MHz, CDCl 3) δ: 9.45 (1H, s), 8.83 (1H, d, J = 5.6 Hz), 8.55 (1H, d, J = 6.4 Hz), 8.33-8.28 (2H, m (2H, d, J = 8.4 Hz), 8.03 (1H, s), 7.68 (1H, t, J = 7.8 Hz), 7.09 ), 4.98 (2H, s), 3.63 (4H, brs), 2.78 (4H, brs), 2.00-1.50 (15H, m).

Figure 112011008191173-pat00039
Figure 112011008191173-pat00039

우라실 유도체의 R1 위치에 치환된 페닐 또는 벤질기의 도입Introduction of a phenyl or benzyl group substituted at the R 1 position of the uracil derivative 화합물compound R1 R 1 10 μMa 농도에서 억제율 (%Inhibition)10 μM a Inhibition (% inhibition) KN62 (양성대조군)KN62 (positive control) 90.8±0.590.8 ± 0.5 4b4b PhPh 59.7±4.359.7 ± 4.3 4c4c 2-F-Ph2-F-Ph 13.2±9.013.2 ± 9.0 4d4d 4-F-Ph4-F-Ph 79.0±6.679.0 + - 6.6 4e4e 3-CF3-Ph 3-CF 3 -Ph 69.5±1.269.5 ± 1.2 4f4f 2-CH3-Ph2-CH 3 -Ph 69.1±3.869.1 ± 3.8 4g4g BenzylBenzyl 87.5±2.387.5 ± 2.3 4h4h 4-F-Benzyl4-F-Benzyl 93.4±1.893.4 ± 1.8

a실험은 hP2X 7 -발현 HEK293 세포를 이용한 ethidium+ 축적분석을 통해서 수행하였다. 억제율 값(% Inhibition values)은 BzATP 만에 의한 ethidium 최대축적량에 대한 상대적인 백분율로 표현하였다. 데이터 값은 평균±표준편차값으로 나타냈으며, 모든 실험은 최소 3-6번 반복하였다.
a Experiments were performed by ethidium + accumulation assay using hP2X 7 - expressing HEK293 cells. The percent inhibition values are expressed as a percentage relative to the maximum accumulation of ethidium by BzATP alone. Data values were expressed as mean ± standard deviation, and all experiments were repeated 3-6 times at least.

Figure 112011008191173-pat00040
Figure 112011008191173-pat00040

우라실 유도체의 R1 위치에 치환된 알킬 카르보닐, 모노- 혹은 폴리사이클로알킬 카르보닐기 도입Introduction of alkylcarbonyl, mono- or polycycloalkylcarbonyl substituted at the R 1 position of the uracil derivative 화합물compound ZZ R1 R 1 10 μMa 농도에서 억제율(%Inhibition)10 μM a Inhibition (% inhibition) KN62 (양성대조군)KN62 (positive control) 90.8±0.590.8 ± 0.5 5a5a OO HH 19.5±1.119.5 ± 1.1 6a6a OO tBuCO t BuCO 78.9±1.278.9 ± 1.2 6b6b OO BocBoc 70.5±3.570.5 ± 3.5 6c6c OO c-C6H11CO c -C 6 H 11 CO 90.2±2.590.2 ± 2.5 6d6d OO c-C6H11CH2CO c -C 6 H 11 CH 2 CO 92.4±8.092.4 ± 8.0 6e6e OO 1-adamantylCO1-adamantylCO 99.5±1.699.5 ± 1.6 6f6f OO 1-adamantylmethylCO1-adamantylmethylCO 99.0±1.899.0 ± 1.8 6g6g OO 3-Br-1-adamatnylCO3-Br-1-adamantylCO 99.8±1.399.8 ± 1.3 6h6h OO (3,5-diMe)-1-adamantylCO(3,5-dimethyl) -1-adamantylCO 98.6±1.498.6 ± 1.4 6i6i OO 3-noradamantylCO3-noradamantylCO 100±3100 ± 3 6j6j OO 2-norbornanylCO2-norbornanylCO 100±2100 ± 2 6k6k OO 2-norbornanylmethylCO2-norbornanylmethylCO 100±2100 ± 2

a실험은 hP2X 7 -발현 HEK293 세포를 이용한 ethidium+ 축적분석을 통해서 수행하였다. 억제율 값(% Inhibition values)은 BzATP 만에 의한 ethidium 최대축적량에 대한 상대적인 백분율로 표현하였다. 데이터 값은 평균±표준편차값으로 나타냈으며, 모든 실험은 최소 3-6번 반복하였다.
a Experiments were performed by ethidium + accumulation assay using hP2X 7 - expressing HEK293 cells. The percent inhibition values are expressed as a percentage relative to the maximum accumulation of ethidium by BzATP alone. Data values were expressed as mean ± standard deviation, and all experiments were repeated 3-6 times at least.

Figure 112011008191173-pat00041
Figure 112011008191173-pat00041

우라실 유도체의 R1 위치에 방향성 혹은 치환된 벤조일기 도입Introduction of aromatic or substituted benzoyl group at the R 1 position of the uracil derivative 화합물compound ZZ R1 R 1 10 μMa 농도에서 억제율(%Inhibition)10 μM a Inhibition (% inhibition) KN62 (양성대조군)KN62 (positive control) 90.8±0.590.8 ± 0.5 4a4a OO FmocFmoc 55.8±2.555.8 ± 2.5 6l6l OO PhCOPhCO 87.8±2.487.8 ± 2.4 6m6m OO PhCH2COPhCH 2 CO 85.1±0.685.1 ± 0.6 6n6n OO (2-Cl)PhCO(2-Cl) PhCO 98.5±2.698.5 ± 2.6 6o6o OO (3-Cl)PhCO(3-Cl) PhCO 96.8±3.396.8 ± 3.3 6p6p OO (4-F)PhCO(4-F) PhCO 97.3±4.897.3 ± 4.8 6q6q OO (4-Cl)PhCO(4-Cl) PhCO 96.3±5.296.3 ± 5.2 6r6r OO (4-Br)PhCO(4-Br) PhCO 99.5±4.399.5 ± 4.3 6s6s OO (3,4-diF)PhCO(3,4-diF) PhCO 98.6±2.398.6 ± 2.3 6t6t OO (2-F-4-Cl)PhCO(2-F-4-Cl) PhCO 95.5±1.595.5 ± 1.5 6u6u OO (3,4-diCl)PhCO(3,4-diCl) PhCO 97.5±1.697.5 ± 1.6 6v6v OO (3-F-4-Cl)PhCO(3-F-4-Cl) PhCO 98.8±2.398.8 ± 2.3 6w6w OO (3-CF3-4-Cl)PhCO (3-CF 3 -4-Cl ) PhCO 102±1102 ± 1 6x6x OO (2-Cl-5-Br)PhCO(2-Cl-5-Br) PhCO 99.0±2.299.0 ± 2.2

a실험은 hP2X 7 -발현 HEK293 세포를 이용한 ethidium+ 축적분석을 통해서 수행하였다. 억제율 값(% Inhibition values)은 BzATP 만에 의한 ethidium 최대축적량에 대한 상대적인 백분율로 표현하였다. 데이터 값은 평균±표준편차값으로 나타냈으며, 모든 실험은 최소 3-6번 반복하였다. a Experiments were performed by ethidium + accumulation assay using hP2X 7 - expressing HEK293 cells. The percent inhibition values are expressed as a percentage relative to the maximum accumulation of ethidium by BzATP alone. Data values were expressed as mean ± standard deviation, and all experiments were repeated 3-6 times at least.

Figure 112011008191173-pat00042
Figure 112011008191173-pat00042

우라실 유도체의 Z 및 W 위치에 각각 아민기 및 설포닐기 또는 카르보닐기의 도입 Introduction of an amine group and a sulfonyl group or a carbonyl group at Z and W positions of the uracil derivative, respectively 화합물compound ZZ WW 10 μMa 농도에서 억제율(%Inhibition)10 μM a Inhibition (% inhibition) KN62 (양성대조군)KN62 (positive control) 90.8±0.590.8 ± 0.5 6y6y NHNH SO2 SO 2 95.5±2.395.5 ± 2.3 6z6z NHNH COCO 86.5±2.486.5 ± 2.4

a실험은 hP2X 7 -발현 HEK293 세포를 이용한 ethidium+ 축적분석을 통해서 수행하였다. 억제율 값(% Inhibition values)은 BzATP 만에 의한 ethidium 최대축적량에 대한 상대적인 백분율로 표현하였다. 데이터 값은 평균±표준편차값으로 나타냈으며, 모든 실험은 최소 3-6번 반복하였다.
a Experiments were performed by ethidium + accumulation assay using hP2X 7 - expressing HEK293 cells. The percent inhibition values are expressed as a percentage relative to the maximum accumulation of ethidium by BzATP alone. Data values were expressed as mean ± standard deviation, and all experiments were repeated 3-6 times at least.

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 (12)

하기의 화학식 1로 표시되는 우라실(uracil) 유도체:
[화학식 1]
Figure 112016125826634-pat00043

상기 화학식에서,
R1은 수소, C1-C4 알킬이고,
R2는 수소, C1-C4 알킬, 아실(-C(O)-X, X는 알킬 또는 알콕시), 아릴, 또는 아릴 C1-C4 알킬이며,
R3는 산소, NH 또는 C1-C4 알킬이고,
R4는 설포닐(-S(O)2-) 또는 카르보닐(-C(O)-)이며,
R5는 헤테로아릴이고,
n은 1-5의 정수이다.
A uracil derivative represented by the following formula (1):
[Chemical Formula 1]
Figure 112016125826634-pat00043

In the above formulas,
R 1 is hydrogen, C 1 -C 4 alkyl,
R 2 is hydrogen, C 1 -C 4 alkyl, acyl (-C (O) -X, X is alkyl or alkoxy), aryl, or aryl C 1 -C 4 alkyl,
R 3 is oxygen, NH or C 1 -C 4 alkyl,
R 4 is sulfonyl (-S (O) 2 -) or carbonyl (-C (O) -)
R < 5 > is heteroaryl,
n is an integer of 1-5.
제 1 항에 있어서, 상기 R1은 수소이고, 상기 R3는 산소 또는 NH이며, 상기 R4는 설포닐(-S(O)2-)인 것을 특징으로 하는 우라실 유도체.
The uracil derivative according to claim 1, wherein R 1 is hydrogen, R 3 is oxygen or NH, and R 4 is sulfonyl (-S (O) 2 -).
제 1 항에 있어서, 상기 헤테로아릴은 퀴놀린 또는 이소퀴놀린인 것을 특징으로 하는 우라실 유도체.
The uracil derivative according to claim 1, wherein the heteroaryl is quinoline or isoquinoline.
제 1 항에 있어서, 상기 아실(-C(O)-X, X는 알킬 또는 알콕시)에서 상기 알킬은 C1-C6 직쇄 또는 분쇄 알킬, C5-C7 사이클로알킬, C5-C7 사이클로알킬 C1-C4 알킬, C8-C14 브릿지드(bridged) 바이사이클로알킬, C10-C16 브릿지드 트리사이클로알킬, 또는 브릿지드 C10-C16 트리사이클로알킬 C1-C4 알킬인 것을 특징으로 하는 우라실 유도체.
The method of claim 1, wherein the acyl in the acyl (-C (O) -X, X is alkyl or alkoxy) is C 1 -C 6 straight or branched chain alkyl, C 5 -C 7 Cycloalkyl, C 5 -C 7 C 1 -C 4 alkyl, C 8 -C 14 bridged bicycloalkyl, C 10 -C 16 bridged tricycloalkyl, or bridged C 10 -C 16 tricycloalkyl C 1 -C 4 alkyl, Alkyl. ≪ / RTI >
제 1 항에 있어서, 상기 우라실 유도체는 하기의 화학식 2 내지 36으로 표시되는 화합물로 구성된 군으로부터 선택되는 것을 특징으로 하는 우라실 유도체:

화학식 2 화학식 3
Figure 112016125826634-pat00044
Figure 112016125826634-pat00045



화학식 4 화학식 5
Figure 112016125826634-pat00046
Figure 112016125826634-pat00047




화학식 6 화학식 7
Figure 112016125826634-pat00048
Figure 112016125826634-pat00049



화학식 8 화학식 9
Figure 112016125826634-pat00050
Figure 112016125826634-pat00051




화학식 10 화학식 11
Figure 112016125826634-pat00052
Figure 112016125826634-pat00053



화학식 12 화학식 13
Figure 112016125826634-pat00054
Figure 112016125826634-pat00055




화학식 14 화학식 15
Figure 112016125826634-pat00056
Figure 112016125826634-pat00057



화학식 16 화학식 17
Figure 112016125826634-pat00058
Figure 112016125826634-pat00059




화학식 18 화학식 19
Figure 112016125826634-pat00060
Figure 112016125826634-pat00061



화학식 20 화학식 21
Figure 112016125826634-pat00062
Figure 112016125826634-pat00063




화학식 22 화학식 23
Figure 112016125826634-pat00064
Figure 112016125826634-pat00065



화학식 24 화학식 25
Figure 112016125826634-pat00066
Figure 112016125826634-pat00067




화학식 26 화학식 27
Figure 112016125826634-pat00068
Figure 112016125826634-pat00069



화학식 28 화학식 29
Figure 112016125826634-pat00070
Figure 112016125826634-pat00071




화학식 30 화학식 31
Figure 112016125826634-pat00072
Figure 112016125826634-pat00073



화학식 32 화학식 33
Figure 112016125826634-pat00074
Figure 112016125826634-pat00075




화학식 34 화학식 35
Figure 112016125826634-pat00076
Figure 112016125826634-pat00077


화학식 36
Figure 112016125826634-pat00078

The uracil derivative according to claim 1, wherein the uracil derivative is selected from the group consisting of compounds represented by the following formulas (2) to (36):

(2)
Figure 112016125826634-pat00044
Figure 112016125826634-pat00045



(4)
Figure 112016125826634-pat00046
Figure 112016125826634-pat00047




(6)
Figure 112016125826634-pat00048
Figure 112016125826634-pat00049



(8)
Figure 112016125826634-pat00050
Figure 112016125826634-pat00051




(10)
Figure 112016125826634-pat00052
Figure 112016125826634-pat00053



(12)
Figure 112016125826634-pat00054
Figure 112016125826634-pat00055




(14)
Figure 112016125826634-pat00056
Figure 112016125826634-pat00057



(16)
Figure 112016125826634-pat00058
Figure 112016125826634-pat00059




(18)
Figure 112016125826634-pat00060
Figure 112016125826634-pat00061



(20)
Figure 112016125826634-pat00062
Figure 112016125826634-pat00063




(22)
Figure 112016125826634-pat00064
Figure 112016125826634-pat00065



(24)
Figure 112016125826634-pat00066
Figure 112016125826634-pat00067




(26)
Figure 112016125826634-pat00068
Figure 112016125826634-pat00069



(28)
Figure 112016125826634-pat00070
Figure 112016125826634-pat00071




(30)
Figure 112016125826634-pat00072
Figure 112016125826634-pat00073



(32)
Figure 112016125826634-pat00074
Figure 112016125826634-pat00075




(34)
Figure 112016125826634-pat00076
Figure 112016125826634-pat00077


Formula 36
Figure 112016125826634-pat00078

 제 5 항에 있어서, 상기 우라실 유도체는 상기의 화학식 10, 13 내지 21 및 24 내지 36으로 표시되는 화합물로 이루어진 군으로부터 선택되는 것을 특징으로 하는 우라실 유도체.
6. The uracil derivative according to claim 5, wherein the uracil derivative is selected from the group consisting of the compounds represented by the above formulas (10), (13) to (21) and (24) to (36).
제 1 항 내지 제 6 항 중 어느 한 항의 우라실 유도체를 유효성분으로 포함하는 만성 염증성 질환, 염증성 통증 또는 신경병성 통증의 예방 또는 치료용 조성물.
A composition for preventing or treating chronic inflammatory diseases, inflammatory pain or neuropathic pain comprising the uracil derivative of any one of claims 1 to 6 as an active ingredient.
제 7 항에 있어서, 상기 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 질환인 것을 특징으로 하는 조성물.
8. The method of claim 7, wherein the chronic inflammatory disease is selected from the group consisting of chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, glomerulonephritis, inflammatory bowel disease, A disease selected from the group consisting of Crohn's disease, ulcerative colitis, atherosclerosis, myoblastic leukaemia, diabetes, burn, ischemic heart disease, stroke, meningitis and varicose veins ≪ / RTI >
제 1 항 내지 제 6 항 중 어느 한 항의 우라실 유도체를 유효성분으로 포함하는 자가면역 질환의 예방 또는 치료용 조성물.
A composition for the prophylaxis or treatment of autoimmune diseases, comprising the uracil derivative of any one of claims 1 to 6 as an active ingredient.
제 9 항에 있어서, 상기 자가면역 질환은 류마티스 관절염, 건선, 알러지성 피부염, 다발성 경화증 및 천식으로 구성된 군으로부터 선택되는 질환인 것을 특징으로 하는 조성물.
10. The composition according to claim 9, wherein the autoimmune disease is a disease selected from the group consisting of rheumatoid arthritis, psoriasis, allergic dermatitis, multiple sclerosis and asthma.
제 1 항 내지 제 6 항 중 어느 한 항의 우라실 유도체를 유효성분으로 포함하는 퇴행성 질환의 예방 또는 치료용 조성물.
A composition for preventing or treating a degenerative disease, comprising the uracil derivative of any one of claims 1 to 6 as an active ingredient.
제 11 항에 있어서, 상기 퇴행성 질환은 알츠하이머 병, 수막염, 골다공증 및 퇴행성 관절염으로 구성된 군으로부터 선택되는 질환인 것을 특징으로 하는 조성물. 12. The composition according to claim 11, wherein the degenerative disease is a disease selected from the group consisting of Alzheimer's disease, meningitis, osteoporosis and degenerative arthritis.
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