KR20120063028A - Novel hydrazine derivatives and uses thereof - Google Patents

Novel hydrazine derivatives and uses thereof Download PDF

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KR20120063028A
KR20120063028A KR1020100124023A KR20100124023A KR20120063028A KR 20120063028 A KR20120063028 A KR 20120063028A KR 1020100124023 A KR1020100124023 A KR 1020100124023A KR 20100124023 A KR20100124023 A KR 20100124023A KR 20120063028 A KR20120063028 A KR 20120063028A
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KR101728898B1 (en
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김용철
이원길
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광주과학기술원
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    • C—CHEMISTRY; METALLURGY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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    • 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
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

PURPOSE: A novel hydrazine derivative compound and a composition containing the same are provided to prevent or treat varous diseases relating to a P2X7 receptor. CONSTITUTION: A hydradrazine derivative is denoted by chemical formula 1. A composition for preventing or treating chronic inflammatory diseases, inflammatory pain, neuropathic pain, autoimmune diseases, or degenerative diseases contains the hydrazine derivative as an active ingredient. The autoimmune diseases include rheumatoid arthritis, psoriasis, allergic dermatitis, multiple sclerosis, or asthma. The chronic inflammatory diseases are chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, glomerulonephritis, inflammatory bowel diseases(inflammation), Crohn's disease, ulcerative colitis, atherosclerosis, myoblastic leukemia, diabetes, burn, ischemic heart disease, stroke, or varicose vein.

Description

신규한 하이드라진 유도체 및 이의 용도{Novel Hydrazine Derivatives and Uses Thereof}Novel Hydrazine Derivatives and Uses Thereof

본 발명은 신규한 하이드라진 유도체 및 이의 P2X7 수용체의 활성과 관련된 질환의 예방 및 치료용도에 관한 것이다.
The present invention relates to the prevention and treatment of diseases related to the activity of the novel hydrazine derivatives and their P2X 7 receptor.

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

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

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

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 cited papers and patent documents are incorporated herein by reference in their entirety, and the level of the technical field to which the present invention belongs and the contents of the present invention are more clearly explained.

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

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

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

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

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

화학식 1Formula 1

Figure pat00001
Figure pat00001

상기 화학식에서, R1은 알킬, 알케닐, 할로알킬, -C(O)알킬, -C(O)할로알킬, -C(O)아릴알킬, -C(O)알킬할로아릴, -C(O)할로아릴, -C(O)O(알킬), -C(O)O(알킬아릴), -C(O)NH2, -C(O)N(H)(알킬), -C(O)N(알킬)2, -C(O)OH, 또는 -C(O)O알킬이고, R2는

Figure pat00002
(A1-A4는 각각 독립적으로 수소, 할로, 할로, 히드록시, 아미노, 니트로, 니트로소, 시아노, C1-C20 알킬, C2-C20 알케닐, C1-C20 알콕시, C2-C20 알콕시알킬, C3-30 알콕시알콕시알킬, 아릴, 헤테로아릴, 아릴알킬, 아릴알케닐 또는 알킬아릴이다),
Figure pat00003
(B1-B5는 각각 독립적으로 수소, 할로, 할로, 히드록시, 아미노, 니트로, 니트로소, 시아노, C1-C20 알킬, C2-C20 알케닐, C1-C20 알콕시, C2 -C20 알콕시알킬, C3 -30 알콕시알콕시알킬, 아릴, 헤테로아릴, 아릴알킬, 아릴알케닐 또는 알킬아릴) 또는 고리 내 질소가 알킬화된 이의 염(salt),
Figure pat00004
(C1-C2는 각각 독립적으로 수소, 할로, 할로, 히드록시, 아미노, 니트로, 니트로소, 시아노, C1-C20 알킬, C2-C20 알케닐, C1-C20 알콕시, C2 -C20 알콕시알킬, C3 -30 알콕시알콕시알킬, 아릴, 헤테로아릴, 아릴알킬, 아릴알케닐 또는 알킬아릴),
Figure pat00005
(D1-D2는 각각 독립적으로 수소, 할로, 할로, 히드록시, 아미노, 니트로, 니트로소, 시아노, C1-C20 알킬, C2-C20 알케닐, C1-C20 알콕시, C2 -C20 알콕시알킬, C3 -30 알콕시알콕시알킬, 아릴, 헤테로아릴, 아릴알킬, 아릴알케닐 또는 알킬아릴),
Figure pat00006
(E1-E6은 각각 독립적으로 수소, 할로, 할로, 히드록시, 아미노, 니트로, 니트로소, 시아노, C1-C20 알킬, C2-C20 알케닐, C1-C20 알콕시, C2 -C20 알콕시알킬, C3 -30 알콕시알콕시알킬, 아릴, 헤테로아릴, 아릴알킬, 아릴알케닐 또는 알킬아릴) 또는 고리 내 질소가 알킬화 된 이의 염(salt),
Figure pat00007
(F1-F6은 각각 독립적으로 수소, 할로, 할로, 히드록시, 아미노, 니트로, 니트로소, 시아노, C1-C20 알킬, C2-C20 알케닐, C1-C20 알콕시, C2 -C20 알콕시알킬, C3 -30 알콕시알콕시알킬, 아릴, 헤테로아릴, 아릴알킬, 아릴알케닐 또는 알킬아릴) 또는 고리 내 질소가 알킬화 된 이의 염(salt) 또는
Figure pat00008
(G1-G6은 각각 독립적으로 수소, 할로, 할로, 히드록시, 아미노, 니트로, 니트로소, 시아노, C1-C20 알킬, C2-C20 알케닐, C1-C20 알콕시, C2 -C20 알콕시알킬, C3 -30 알콕시알콕시알킬, 아릴, 헤테로아릴, 아릴알킬, 아릴알케닐 또는 알킬아릴) 또는 고리 내 질소가 알킬화 된 이의 염(salt)이다.Wherein R 1 is alkyl, alkenyl, haloalkyl, -C (O) alkyl, -C (O) haloalkyl, -C (O) arylalkyl, -C (O) alkylhaloaryl, -C (O) haloaryl, -C (O) O (alkyl), -C (O) O (alkylaryl), -C (O) NH 2 , -C (O) N (H) (alkyl), -C (O) N (alkyl) 2 , -C (O) OH, or -C (O) Oalkyl, R 2 is
Figure pat00002
(A 1 -A 4 are each independently hydrogen, halo, halo, hydroxy, amino, nitro, nitroso, cyano, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 1 -C 20 alkoxy , C 2 -C 20 alkoxyalkyl, C 3-30 alkoxyalkoxyalkyl, aryl, heteroaryl, arylalkyl, arylalkenyl or alkylaryl),
Figure pat00003
(B 1 -B 5 are each independently hydrogen, halo, halo, hydroxy, amino, nitro, nitroso, cyano, C 1 -C 20 alkyl, C 2 -C 20 Alkenyl, C 1 -C 20 Alkoxy, C 2 - C 20 Alkoxyalkyl, C 3 -30 alkoxyalkoxy, aryl, heteroaryl, arylalkyl, aryl alkenyl, or a salt thereof with an alkyl group) or a ring nitrogen is alkylated (salt),
Figure pat00004
(C 1 -C 2 are each independently hydrogen, halo, halo, hydroxy, amino, nitro, nitroso, cyano, C 1 -C 20 alkyl, C 2 -C 20 Alkenyl, C 1 -C 20 Alkoxy, C 2 - C 20 Alkoxyalkyl, C 3 -30 alkoxyalkoxy, aryl, heteroaryl, arylalkyl, arylalkenyl or alkylaryl),
Figure pat00005
(D 1 -D 2 are each independently hydrogen, halo, halo, hydroxy, amino, nitro, nitroso, cyano, C 1 -C 20 alkyl, C 2 -C 20 Alkenyl, C 1 -C 20 Alkoxy, C 2 - C 20 Alkoxyalkyl, C 3 -30 alkoxyalkoxy, aryl, heteroaryl, arylalkyl, arylalkenyl or alkylaryl),
Figure pat00006
(E 1 -E 6 are each independently hydrogen, halo, halo, hydroxy, amino, nitro, nitroso, cyano, C 1 -C 20 alkyl, C 2 -C 20 Alkenyl, C 1 -C 20 Alkoxy, C 2 - C 20 Alkoxyalkyl, C 3 -30 alkoxyalkoxy, aryl, heteroaryl, arylalkyl, aryl alkenyl, or a salt thereof with an alkyl group) or a ring nitrogen is alkylated (salt),
Figure pat00007
(F 1 -F 6 are each independently hydrogen, halo, halo, hydroxy, amino, nitro, nitroso, cyano, C 1 -C 20 alkyl, C 2 -C 20 Alkenyl, C 1 -C 20 Alkoxy, C 2 - C 20 Alkoxyalkyl, C 3 -30 alkoxyalkoxy, aryl, heteroaryl, arylalkyl, arylalkenyl or alkylaryl) or (salt), a salt thereof, a ring nitrogen is alkylated or
Figure pat00008
(G 1 -G 6 are each independently hydrogen, halo, halo, hydroxy, amino, nitro, nitroso, cyano, C 1 -C 20 alkyl, C 2 -C 20 Alkenyl, C 1 -C 20 Alkoxy, C 2 - C 20 Is alkoxyalkyl, C 3 -30 alkoxyalkoxy, aryl, heteroaryl, arylalkyl, arylalkenyl or alkylaryl) or a salt thereof The ring nitrogen is alkylated (salt).

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 하이드라진 유도체가 P2X7 수용체의 활성을 매우 효과적으로 억제함을 발견하였다. The present inventors have made diligent research efforts to develop compositions for the prevention or treatment of autoimmune diseases, inflammatory diseases and various degenerative diseases by discovering effective antagonists of P2X 7 receptors, which are believed to have important effects on immune function and neuronal cell death. It was. As a result, the hydrazine derivative of the present invention was found to inhibit the activity of the P2X 7 receptor very effectively.

본 명세서에서 용어 “알킬”은 직쇄, 분쇄 또는 사이클릭 구조의 비치환 또는 치환된 포화 탄화수소기를 의미하며, 예를 들어, 메틸, 에틸, 프로필, 이소부틸, 펜틸, 헥실, 헵틸, 옥틸, 노닐, 데실, 운데실, 트리데실, 펜타데실 및 헵타데실, 사이클로프로필, 사이클로부틸 및 사이클로펜틸 등을 포함한다. C1 -20 알킬은 탄소수 1 내지 20의 알킬 유니트를 가지는 알킬기를 의미하며, C1 -20 알킬이 치환된 경우 치환체의 탄소수는 포함되지 않은 것이다. 화학식 1에서, R2 위치의 C1 -20 알킬은 바람직하게는 C1 -15 알킬, 보다 바람직하게는 C1 -10 알킬이다.As used herein, the term "alkyl" refers to an unsubstituted or substituted saturated hydrocarbon group of straight, pulverized or cyclic structure, for example methyl, ethyl, propyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, Decyl, undecyl, tridecyl, pentadecyl and heptadecyl, cyclopropyl, cyclobutyl and cyclopentyl and the like. C 1 -20 alkyl having a carbon number in the case where means an alkyl group that has an alkyl unit having 1 to 20 carbon atoms, and, C 1 -20 alkyl-substituted substituent is not included. In formula 1, R to C 1 -20 alkyl at the 2-position is preferably a C 1 -15 alkyl, more preferably C 1 -10 alkyl.

본 명세서에서 용어 “알케닐”은 지정된 탄소수를 가지는 직쇄 또는 분쇄의 비치환 또는 치환된 불포화 탄화수소기를 나타내며, 예컨대, 에테닐, 비닐, 프로페닐, 알릴, 이소프로페닐, 부테닐, 이소부테닐, t-부테닐, n-펜테닐 및 n-헥세닐을 포함한다. 화학식 1에서, R2 위치의 C2 -20 알케닐은 탄소수 2 내지 20의 알케닐 유니트를 가지는 알케닐기를 의미하며, C2 -20 알케닐이 치환된 경우 치환체의 탄소수는 포함되지 않은 것이다. As used herein, the term “alkenyl” refers to a straight-chain or branched unsubstituted or substituted unsaturated hydrocarbon group having the specified carbon number, for example ethenyl, vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, t -Butenyl, n -pentenyl and n -hexenyl. In formula 1, R 2, C 2 -20 alkenyl position is not included in the carbon number of a substituent when the means alkenyl group having an alkenyl unit having 2 to 20 carbon atoms, the alkenyl-substituted C 2 -20 Al.

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

본 명세서에서 용어“할로알킬”은 할로겐족 원소로 치환된 알킬을 의미한다.As used herein, the term “haloalkyl” refers to alkyl substituted with a halogen group element.

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

본 명세서에서 용어 “할로아릴”은 할로겐족 원소로 치환된 아릴을 의미한다.As used herein, the term “haloaryl” refers to aryl substituted with a halogen group element.

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

본 명세서에서 용어 “알킬할로아릴”은 알킬기 및 할로겐족 원소로 치환된 아릴을 의미한다.As used herein, the term “alkylhaloaryl” refers to aryl substituted with an alkyl group and a halogen group element.

본 명세서에서 용어 “알콕시”는 알코올에서 수소가 제거되어 형성된 라디칼을 의마하며, C2 -20 알콕시가 치환된 경우 치환체의 탄소수는 포함되지 않은 것이다.The present specification the term "alkoxy" is a radical formed uima the hydrogen is removed from the alcohol in the carbon number of the C 2 -20 if the alkoxy is substituted with a substituent is not included.

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

본 명세서에서 용어“알콕시알콕시알킬”은 알콕시알콕시기로 치환된 알킬기(알콕시-알콕시-알킬-)를 의미한다. C3 -30 알콕시알콕시알킬은 탄소수 3 내지 30의 알콕시알콕시알킬 유니트를 가지는 알콕시알콕시알킬기를 의미하며, C2 -20 알콕시알콕시알킬이 치환된 경우 치환체의 탄소수는 포함되지 않은 것이다.The term "alkoxyalkoxyalkyl" used herein means an alkyl group (alkoxy-alkoxy-alkyl-) substituted with an alkoxyalkoxy group. C 3 -30 alkoxyalkoxy alkyl means a alkyl group having an alkoxy-alkoxy-alkoxy-alkoxy-alkyl units having 3 to 30, C 2 -20 carbon atoms, alkoxy alkoxy alkyl When a substituent is substituted is not included.

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

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

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

본 명세서에서 “고리 내 질소가 알킬화 된 이의 염(salt)”은 헤테로 방향족 분자의 고리 내 질소원자에 알킬화(alkylation)가 되어 질소에 양의 형식전하(formal charge)가 생겨 형성된 염을 의미한다. 이러한 양전하를 띄는 질소원자는 당업계에 염을 형성하는 것으로 알려진 어떠한 음이온과도 결합이 가능하며, 바람직하게는 할로겐 음이온과 결합하며, 가장 바람직하게는 I-와 결합한다.
As used herein, the term “salt thereof in which a nitrogen in a ring is alkylated” refers to a salt formed by alkylation of nitrogen atoms in a ring of a heteroaromatic molecule to form a positive formal charge in nitrogen. This positively charged nitrogen atom is capable of binding with any anion known in the art to form salts, preferably with halogen anions, most preferably with I − .

본 발명의 바람직한 구현예에 따르면, 본 발명의 화학식 1의 R1은 -C(O)알킬아릴, -C(O)알킬, -C(O)할로알킬, -C(O)O(아릴알킬) 또는 -C(O)알킬할로아릴이고, R2는

Figure pat00009
(A1-A4는 각각 독립적으로 수소, 할로겐 또는 알킬) 또는 고리 내 질소가 알킬화 된 이의 염(salt),
Figure pat00010
(B1-B5는 각각 독립적으로 수소, 할로겐 또는 알킬),
Figure pat00011
(C1-C2는 각각 독립적으로 수소, 할로겐 또는 알킬),
Figure pat00012
(D1-D2는 각각 독립적으로 수소, 할로겐 또는 알킬),
Figure pat00013
(E1-E6은 각각 독립적으로 수소, 할로겐 또는 알킬) 또는 고리 내 질소가 알킬화 된 이의 염(salt),
Figure pat00014
(F1-F6은 각각 독립적으로 수소, 할로겐 또는 알킬) 또는 고리 내 질소가 알킬화 된 이의 염(salt) 또는
Figure pat00015
(G1-G6은 각각 독립적으로 수소, 할로겐 또는 알킬이다) 또는 고리 내 질소가 알킬화 된 이의 염(salt)이다.
According to a preferred embodiment of the invention, R 1 of formula 1 of the present invention is -C (O) alkylaryl, -C (O) alkyl, -C (O) haloalkyl, -C (O) O (arylalkyl ) Or -C (O) alkylhaloaryl, R 2 is
Figure pat00009
(A 1 -A 4 are each independently hydrogen, halogen or alkyl) or a salt thereof in which the nitrogen in the ring is alkylated,
Figure pat00010
(B 1 -B 5 are each independently hydrogen, halogen or alkyl),
Figure pat00011
(C 1 -C 2 are each independently hydrogen, halogen or alkyl),
Figure pat00012
(D 1 -D 2 are each independently hydrogen, halogen or alkyl),
Figure pat00013
(E 1 -E 6 are each independently hydrogen, halogen or alkyl) or a salt thereof, wherein the nitrogen in the ring is alkylated,
Figure pat00014
(F 1 -F 6 are each independently hydrogen, halogen or alkyl) or a salt thereof in which the nitrogen in the ring is alkylated, or
Figure pat00015
(G 1 -G 6 are each independently hydrogen, halogen or alkyl) or a salt thereof in which the nitrogen in the ring is alkylated.

본 발명의 보다 바람직한 구현예에 따르면, 본 발명의 하이드라진 유도체는 하기의 화학식 2 내지 51로 표시되는 화합물로 구성된 군으로부터 선택된다.According to a more preferred embodiment of the present invention, the hydrazine derivative of the present invention is selected from the group consisting of compounds represented by the following formula (2) to (51).

화학식 2 화학식 3Formula 2 Formula 3

Figure pat00016
Figure pat00017

Figure pat00016
Figure pat00017

화학식 4 화학식 5Formula 4 Formula 5

Figure pat00018
Figure pat00019

Figure pat00018
Figure pat00019

화학식 6 화학식 7Formula 6 Formula 7

Figure pat00020
Figure pat00021

Figure pat00020
Figure pat00021

화학식 8 화학식 9Formula 8 Formula 9

Figure pat00022
Figure pat00023

Figure pat00022
Figure pat00023

화학식 10 화학식 11Formula 10 Formula 11

Figure pat00024
Figure pat00025

Figure pat00024
Figure pat00025

화학식 12 화학식 13 Chemical Formula 12 Chemical Formula 13

Figure pat00026
Figure pat00027

Figure pat00026
Figure pat00027

화학식 14 화학식 15Formula 14 Formula 15

Figure pat00028
Figure pat00029

Figure pat00028
Figure pat00029

화학식 16 화학식 17Formula 16 Formula 17

Figure pat00030
Figure pat00031

Figure pat00030
Figure pat00031

화학식 18 화학식 19Formula 18 Formula 19

Figure pat00032
Figure pat00033

Figure pat00032
Figure pat00033

화학식 20 화학식 21Chemical Formula 20 Chemical Formula 21

Figure pat00034
Figure pat00035

Figure pat00034
Figure pat00035

화학식 22 화학식 23Chemical Formula 22 Chemical Formula 23

Figure pat00036
Figure pat00037

Figure pat00036
Figure pat00037

화학식 24 화학식 25Chemical Formula 24 Chemical Formula 25

Figure pat00038
Figure pat00039

Figure pat00038
Figure pat00039

화학식 26 화학식 27Formula 26 Formula 27

Figure pat00040
Figure pat00041

Figure pat00040
Figure pat00041

화학식 28 화학식 29Chemical Formula 28 Chemical Formula 29

Figure pat00042
Figure pat00043

Figure pat00042
Figure pat00043

화학식 30 화학식 31Chemical Formula 30 Chemical Formula 31

Figure pat00044
Figure pat00045

Figure pat00044
Figure pat00045

화학식 32 화학식 33Chemical Formula 32 Chemical Formula 33

Figure pat00046
Figure pat00047

Figure pat00046
Figure pat00047

화학식 34 화학식 35Chemical Formula 34 Chemical Formula 35

Figure pat00048
Figure pat00049

Figure pat00048
Figure pat00049

화학식 36 화학식 37Formula 36 Formula 37

Figure pat00050
Figure pat00051

Figure pat00050
Figure pat00051

화학식 38 화학식 39Formula 38 Formula 39

Figure pat00052
Figure pat00053

Figure pat00052
Figure pat00053

화학식 40 화학식 41Formula 40 Formula 41

Figure pat00054
Figure pat00055

Figure pat00054
Figure pat00055

화학식 42 화학식 43Chemical Formula 42 Chemical Formula 43

Figure pat00056
Figure pat00057

Figure pat00056
Figure pat00057

화학식 44 화학식 45Formula 44 Formula 45

Figure pat00058
Figure pat00059

Figure pat00058
Figure pat00059

화학식 46 화학식 47Chemical Formula 47 Chemical Formula 47

Figure pat00060
Figure pat00061

Figure pat00060
Figure pat00061

화학식 48 화학식 49Chemical Formula 48 Chemical Formula 49

Figure pat00062
Figure pat00063

Figure pat00062
Figure pat00063

화학식 50 화학식 51Chemical Formula 50 Chemical Formula 51

Figure pat00064
Figure pat00065

Figure pat00064
Figure pat00065

가장 바람직하게는, 본 발명의 하이드라진 유도체는 상기의 화학식 5, 6, 10, 11, 12, 13, 15, 18, 20, 21, 22, 23, 24, 28, 30 및 51으로 표시되는 화합물로 이루어진 군으로부터 선택된다. 본 발명에 따르면, 상기 나열한 16가지 화합물은 P2X7 수용체의 다운-레귤레이션에 있어서 매우 낮은 IC50 값을 가진다. 따라서 이들은 P2X7 활성과 관련된 다양한 질환의 효과적인 치료 조성물로 이용될 수 있다. Most preferably, the hydrazine derivatives of the present invention are the compounds represented by the formulas 5, 6, 10, 11, 12, 13, 15, 18, 20, 21, 22, 23, 24, 28, 30 and 51. Selected from the group consisting of: According to the invention, the 16 compounds listed above have very low IC 50 values for down-regulation of the P2X 7 receptor. So these are P2X 7 It can be used as an effective therapeutic composition for various diseases related to activity.

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

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

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

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

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

본 발명의 바람직한 구현예에 따르면, 본 발명의 조성물로 예방 또는 치료되는 자가면역 질환은 류마티스 관절염, 건선, 알러지성 피부염, 다발성 경화증 및 천식으로 구성된 군으로부터 선택되는 질환이다. According to a preferred embodiment of the present invention, the autoimmune disease to be prevented or treated with the composition of the present invention is a disease selected from the group consisting of rheumatoid arthritis, psoriasis, allergic dermatitis, multiple sclerosis and asthma.

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

본 발명의 바람직한 구현예에 따르면, 본 발명의 조성물로 예방 또는 치료되는 퇴행성 질환은 알츠하이머 병, 수막염, 골다공증 및 퇴행성 관절염으로 구성된 군으로부터 선택되는 질환이다.
According to a preferred embodiment of the present invention, the degenerative disease to be prevented or treated with the composition of the present invention is 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 compositions for inhibiting P2X 7 receptor activity comprising the same as an active ingredient.

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

도 1은 P2X1 -6 및 P2X7 수용체의 분자해부학적 위치를 나타낸 그림(도 1a) 및 P2X7 수용체가 ATP에 의해 활성화되어 세가지 다른 형태(채널의 개방, 채널의 폐쇄 및 포어형성)를 띄는 모습을 나타낸 그림이다(Curr . Med . Chem 14:1505-1523(2007)).
도 2는 척수에서의 퓨린작동성(Purinergic) 신호전달의 모식도를 나타낸 그림이다(Nature Review Drug Discovery 7:575-590(2008)).
도 3은 BzATP에 의해 증가하는 IL-1β의 양이 상기 합성예 45번의 유도체의 농도에 의존적으로 감소함을 나타내는 그림이다. 모든 값은 3번의 실험에 대한 평균±표준편차 값이다.
도 4는 hP2X7-발현 HEK 293 세포에서 BzATP와 KN62의 영향을 나타낸 그림이다. BzATP를 처리하자 농도 의존적 에티듐 브로마이드가 축적되었으며(EC50 = 3.67 μM, 도 4a), 4 μM BzATP를 처리 한 후에 KN62를 처리하자 농도 의존적으로 에티듐 브로마이드의 축적이 저해되었다(IC50 = 389 nM, 도 4b).Figure 1 is a stand -6 P2X 1 and P2X 7 receptors picture (Fig. 1a) showing the molecular and anatomical location of the P2X 7 receptor is activated by ATP in three different forms (the opening of the channel, the closed pores and the formation of the channel) Figure shows the appearance ( Curr . Med . Chem 14: 1505-1523 (2007).
2 is a diagram showing a schematic diagram of purinergic signaling in the spinal cord ( Nature Review Drug Discovery 7: 575-590 (2008).
3 is a graph showing that the amount of IL-1β increased by BzATP decreases depending on the concentration of the derivative of Synthesis Example 45. All values are mean ± standard deviation values for three experiments.
4 shows the effect of BzATP and KN62 on hP2X 7 -expressing HEK 293 cells. Treatment with BzATP resulted in concentration dependent ethidium bromide accumulation (EC 50 = 3.67 μM, FIG. 4A), and treatment with KN62 after treatment with 4 μM BzATP inhibited concentration dependent ethidium bromide accumulation (IC 50 = 389). nM, Figure 4b).

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. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. .

실시예Example

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

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

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

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

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

P2X7 수용체의 새로운 길항제 선도물질 발굴을 위하여 한국화합물 은행으로부터 9,000여종의 다양한 골격구조의 대표 화합물 라이브러리를 제공받아 이로부터 hP2X7 수용체에 길항효과를 가지는 물질에 대한 탐색을 진행했으며, 1μM 농도에서 50 % 이하의 염료축적 저해활성을 보이는 화합물 약 3종의 대표 골격을 발굴하였다. 해당 골격을 갖는 유도체 라이브러리 5,000 여종을 한국화합물 은행에서 다시 제공받아 hP2X7-발현 HEK 293 세포에서 BzATP을 처리하여 포어를 형성 시킨 후에 최종 선도물질 1개를 선별하였다.
P2X antagonist lead compound for new excavations 7 receptor compounds Bank of Korea received from the representative compound library provides a variety of species from which the skeleton of the 9000 hP2X 7 We searched for a substance that had an antagonistic effect on the receptor, and discovered a representative skeleton of about three compounds that showed dye accumulation inhibitory activity of less than 50% at 1 μM concentration. About 5,000 derivative libraries with the backbone were provided by the Korea Compound Bank and treated with BzATP in hP2X 7 -expressing HEK 293 cells to form pores, and then one final leader was selected.

합성 모식도 1Synthetic schematic diagram 1 aa

Figure pat00066
Figure pat00066

a시약 및 반응조건: (a) 하이드라진 수화물(hydrazine hydrate), n-BuOH, 90℃; (b) EDC, DIPEA, HCA(hydrocinnamic acid), DCM, RT; (c) 3-페닐프로피온알데하이드, 소듐 사이아노보로하이드라이드, DCE 용해 1% AcOH, RT; (d) 포름알데하이드, 소듐 사이아노보로하이드라이드, DCE 용해 1% AcOH, RT; (e) EDC, DIPEA, HCA, DCM, RT; (f)TEA, 하이드로신나모일 클로라이드(Hydrocinnamoyl chloride), DCM, RT
a reagents and reaction conditions: (a) hydrazine hydrate, n-BuOH, 90 ° C .; (b) EDC, DIPEA, hydrocinnamic acid (HCA), DCM, RT; (c) 3-phenylpropionaldehyde, sodium cyanoborohydride, DCE dissolved 1% AcOH, RT; (d) formaldehyde, sodium cyanoborohydride, DCE dissolved 1% AcOH, RT; (e) EDC, DIPEA, HCA, DCM, RT; (f) TEA, Hydrocinnamoyl chloride, DCM, RT

합성 모식도 2Synthetic schematic diagram 2 aa

Figure pat00067
Figure pat00067

a시약 및 반응조건: (a) 하이드라진 수화물, n-BuOH, 90-100 °C; (b) EDC, DIPEA, HCA, DCM, RT
 a reagents and reaction conditions: (a) hydrazine hydrate, n-BuOH, 90-100 ° C .; (b) EDC, DIPEA, HCA, DCM, RT

합성 모식도 3Synthetic schematic diagram 3 aa

Figure pat00068
Figure pat00068

a시약 및 반응조건: (a) 벤질 클로로카르복세이트, DCM, RT; (b) EDC, DIPEA, 산 화합물, DCM 또는 DMF, RT; (c) 카르보닐 디이미다졸, TEA, DCM, RT; (d) 아이오도메탄(Iodomethan), 메탄올, 70℃ (e) 벤질아민, TEA, RT
 a reagents and reaction conditions: (a) benzyl chlorocarboxate, DCM, RT; (b) EDC, DIPEA, acid compound, DCM or DMF, RT; (c) carbonyl diimidazole, TEA, DCM, RT; (d) Iodomethan, methanol, 70 ° C. (e) Benzylamine, TEA, RT

합성 모식도 4Synthetic schematic diagram 4 aa

Figure pat00069
Figure pat00069

a시약 및 반응조건: (a) 하이드라진 수화물, EtOH, 60-70℃; (b) TEA, 하이드로신나모일 클로라이드(hydrocinnamoyl chloride), DCM, RT
 a reagents and reaction conditions: (a) hydrazine hydrate, EtOH, 60-70 ° C .; (b) TEA, hydrocinnamoyl chloride, DCM, RT

합성 모식도 5Synthetic Schematic 5 aa

Figure pat00070
Figure pat00070

a시약 및 반응조건: (a) 하이드라진 수화물, EtOH, 60-70℃; (b) TEA, 하이드로신나모일 클로라이드, DCM, RT
 a reagents and reaction conditions: (a) hydrazine hydrate, EtOH, 60-70 ° C .; (b) TEA, hydrocinnamoyl chloride, DCM, RT

리드 화합물(1)의 하이드라자이드 골격에 다양한 치환체의 도입Introduction of various substituents on the hydrazide skeleton of lead compound ( 1 ) 화합물compound XX YY R1 R 1 IC50 (nM) a IC 50 (nM) a 1One NHNH NHNH H    H 653±166653 ± 166 22 NHNH HH <20% b <20% b 33 NHNH NHNH CH3 CH 3 <20% b <20% b 44 <20% b <20% b 55 <20% b <20% b 66 <20% b <20% b

Figure pat00071
Figure pat00071

a Number of determinations ≥ 3. b % inhibition at concentration 10 μM and number of determination ≥ 3.
 a Number of determinations ≥ 3. b% inhibition at concentration 10 μM and number of determination ≥ 3.

리드 화합물(1)의 피리딘(피리딘)골격에 다양한 치환체의 도입.Introduction of various substituents on the pyridine (pyridine) backbone of lead compound ( 1 ). 화합물compound XX YY IC50 (μM) a IC 50 (μM) a 1One NN ClCl 0.65±0.170.65 ± 0.17 77 CC ClCl 1.39±0.231.39 ± 0.23 88 NN HH <20% b <20% b 99 NN FF <20% b <20% b 1010 CC FF <20% b <20% b 1111 CC CH3 CH 3 0.90±0.080.90 ± 0.08

Figure pat00072
Figure pat00072

a Number of determinations ≥ 3. b % inhibition at concentration 10 μM and number of determination ≥ 3.
 a Number of determinations ≥ 3. b% inhibition at concentration 10 μM and number of determination ≥ 3.

리드 화합물(1)의 R1 위치에 다양한 방향족(Aromatic Group) 도입Introduction of various aromatic groups at the R 1 position of the lead compound ( 1 ) 화합물compound XX R1 R 1 R2 R 2 IC50 (nM) a IC 50 (nM) a 1212 (CH2)2(p-fluoroPh)(CH 2 ) 2 (p-fluoroPh) 902±245902 ± 245 1313 (CH2)2(p-chloroPh)(CH 2 ) 2 (p-chloroPh) 1065±1191065 ± 119 1414 (CH2)2Tol(CH 2 ) 2 Tol 1362±2231362 ± 223 1515 (CH2)2(p-methoxyPh)(CH 2 ) 2 (p-methoxyPh) 1450±3271450 ± 327 1616 CH2(p-chloroPh)CH 2 (p-chloroPh) 615±27615 ± 27 1717 (CH2)2(p-hydroxyPh)(CH 2 ) 2 (p-hydroxyPh) <20% b <20% b 1818 PhPh <20% b <20% b 1919 CH2PhCH 2 Ph 1124±831124 ± 83 2020 (CH2)3Ph(CH 2 ) 3 Ph 765±57765 ± 57 2121 (CH2)4Ph(CH 2 ) 4 Ph 1203±2231203 ± 223 2222 (CH2)5Ph(CH 2 ) 5 Ph 1933±711933 ± 71 2323 (CH2)6Ph(CH 2 ) 6 Ph 948±229948 ± 229 2424 OO PhPh 371±132371 ± 132 2525 NHNH PhPh <20% b <20% b 2626 (E)-CHCHPh(E) -CHCHPh <20% b <20% b 2727 1,2,3,4,-Tetrahydronaphthyl-2-1,2,3,4, -Tetrahydronaphthyl-2- 1124±1411124 ± 141 2828 Indanyl-2-Indanyl-2- 4213±824213 ± 82 2929 Benzocyclobutyl-1-Benzocyclobutyl-1- 319±14319 ± 14 3030 1H-Indene-2-1H-Indene-2- <20% b <20% b 3131 CH2Naphthyl-1-CH 2 Naphthyl-1- <20% b <20% b 3232 CH2Naphthyl-2-CH 2 Naphthyl-2- <20% b <20% b 3333 CH2CH2Naphthyl-2-CH 2 CH 2 Naphthyl-2- 1161±188 1161 ± 188 3434 (CH2)2Pyridyl(CH 2 ) 2 Pyridyl <20% b <20% b 3535 Indole-2-Indole-2- <20% b <20% b

Figure pat00073
Figure pat00073

a Number of determinations ≥ 3. b % inhibition at concentration 10 μM and number of determination ≥ 3.
 a Number of determinations ≥ 3. b% inhibition at concentration 10 μM and number of determination ≥ 3.

리드 화합물(1)의 R1 위치에 다양한 비방향족(Aromatic Group) 도입.Introduction of various Aromatic Groups at the R 1 position of the lead compound ( 1 ). 화합물compound R1 R 1 IC50 (nM) a IC 50 (nM) a 3636 (CH2)8CH3-(CH 2 ) 8 CH 3- 4943.1 ±256.34943.1 ± 256.3 3737 (CH2)2cyclopentyl(CH 2 ) 2 cyclopentyl 378.5±28.7378.5 ± 28.7 3838 (CH2)2cyclo헥실(CH 2 ) 2 cyclohexyl 131.8±54.6131.8 ± 54.6 3939 CH2cycloheptylCH 2 cycloheptyl 198.5 ±43.3198.5 ± 43.3 4040 CH2cyclohexylCH 2 cyclohexyl 730.2 ±142.1 730.2 ± 142.1 4141 (CH2)3cyclohexyl(CH 2 ) 3 cyclohexyl 360.1 ±38.5 360.1 ± 38.5 4242 CH2Adanmantyl-1-CH 2 Adanmantyl-1- 335.3±41.0335.3 ± 41.0 4343 Adanmantyl-1-Adanmantyl-1- 77.4±27.977.4 ± 27.9 4444 (3-Bromoadamantyl)-1-(3-Bromoadamantyl) -1- 4.91±0.514.91 ± 0.51 4545 (3,5-dimethyladamantyl)-1-(3,5-dimethyladamantyl) -1- 12.6±0.5512.6 ± 0.55 4646 Noradmantyl-1-Noradmantyl-1- 1384±3271384 ± 327 4747 Norbornanyl-2-Norbornanyl-2- 2801.6 ±469.9 2801.6 ± 469.9 4848 CH2Norbornanyl-2-CH 2 Norbornanyl-2- 208.7 ±21.4 208.7 ± 21.4 4949 (5-Norbornenyl)-2-(5-Norbornenyl) -2- <20% b <20% b 5050 42.0 ±1.942.0 ± 1.9

Figure pat00074
Figure pat00074

a Number of determinations ≥ 3. b % inhibition at concentration 10 μM and number of determination ≥ 3.
 a Number of determinations ≥ 3. b% inhibition at concentration 10 μM and number of determination ≥ 3.

퓨린e-하이드라자이드의 R1 위치에 다양한 치환체 도입.Introduction of various substituents at the R 1 position of the purine e-hydrazide. 화합물compound XX RR R2 R 2 IC50 (nM) a IC 50 (nM) a 5151 HH (CH2)2Phenyl(CH 2 ) 2 Phenyl <20% b <20% b 5252 HH (CH2)2Cyclohexyl(CH 2 ) 2 Cyclohexyl <50% b <50% b 5353 HH (3,5-dimethyladamantyl)(3,5-dimethyladamantyl) 2.88±0.122.88 ± 0.12 5454 ClCl (CH2)2Phenyl(CH 2 ) 2 Phenyl <50% b <50% b 5555 ClCl Adanmantyl-1-Adanmantyl-1- >50% b > 50% b 5656 ClCl (3,5-dimethyladamantyl)-1-(3,5-dimethyladamantyl) -1- >50% b > 50% b 5757 (CH2)2Cyclohexyl(CH 2 ) 2 Cyclohexyl <50% b <50% b 5858 Adanmantyl-1-Adanmantyl-1- <20% b <20% b 5959 (3,5-dimethyladamantyl)-1-(3,5-dimethyladamantyl) -1- <50% b <50% b

Figure pat00075
Figure pat00075

a Number of determinations ≥ 3. b % inhibition at concentration 10 μM and number of determination ≥ 3.
 a Number of determinations ≥ 3. b% inhibition at concentration 10 μM and number of determination ≥ 3.

퀴놀린e-하이드라자이드의 R1 위치에 다양한 치환체 도입.Introduction of various substituents at the R 1 position of quinoline e-hydrazide. 화합물compound XX RR IC50 (nM) a IC 50 (nM) a 6060 ClCl (CH2)2Cyclohexyl(CH 2 ) 2 Cyclohexyl <20% b <20% b 6161 ClCl (CH2)2Phenyl(CH 2 ) 2 Phenyl 374±83.2a 374 ± 83.2 a 6262 HH (CH2)2Phenyl(CH 2 ) 2 Phenyl <50% b <50% b 6363 HH (3,5-dimethyladamantyl)(3,5-dimethyladamantyl) 6464 HH (CH2)2Phenyl(CH 2 ) 2 Phenyl <50% b <50% b 6565 HH (3,5-dimethyladamantyl)(3,5-dimethyladamantyl) <50% b <50% b 6666 HH (CH2)2Phenyl(CH 2 ) 2 Phenyl <50% b <50% b 6767 HH (3,5-dimethyladamantyl)(3,5-dimethyladamantyl) <50% b <50% b

Figure pat00076
Figure pat00076

a Number of determinations ≥ 3. b % inhibition at concentration 10 μM and number of determination ≥ 3.
 a Number of determinations ≥ 3. b% inhibition at concentration 10 μM and number of determination ≥ 3.

페닐 하이드라진 또는 피리디닐 하이드라진 중간체의 대표 합성법Representative synthesis of phenyl hydrazine or pyridinyl hydrazine intermediate

3,5-디클로로-4-하이드라지노피리딘 외 모든 하이드라진기를 갖는 중간체 합성법Synthesis of Intermediates Having 3,5-Dichloro-4-hydrazinopyridine and All Hydrazine Groups

3,5-디클로로-4-아이오도피리딘(4.0g, 14.6 mmol)과 하이드라진 수화물(1.5 ml, 29.3 mmol) n-부탄올 또는 에탄올(100.0 ml)에 녹였다. 혼합액은 80℃에서14-18시간 반응시켰다. 회전 농축기(rotary evaporator)를 이용하여 건조시켜 얻은 잔여물(residue)을 EA(Ethyl Acetate)에 녹인 후, NaHCO2 포화 용액으로 반응 용액을 추출하였다. 추출된 EA 용액은 소듐 설페이트를 이용하여 무수화 과정을 거치고 필터하여 걸러 얻은 유기 용매를 건조한다. 실리카겔(silica gel)을 이용한 컬럼을 수행하여 정제를 하며 각각의 중간체를 50-80% 수득율로 얻는다.
It was dissolved in 3,5-dichloro-4-iodopyridine (4.0 g, 14.6 mmol) and hydrazine hydrate (1.5 ml, 29.3 mmol) n-butanol or ethanol (100.0 ml). The mixed solution was reacted at 80 ° C for 14-18 hours. The residue obtained by drying using a rotary evaporator was dissolved in EA (Ethyl Acetate), and the reaction solution was extracted with a saturated NaHCO 2 solution. The extracted EA solution is anhydrous using sodium sulfate and filtered to dry the organic solvent obtained by filtration. Purification is performed by column with silica gel to obtain each intermediate in 50-80% yield.

합성예 1:Synthesis Example 1: N'-(3, 5-디클로로피리딘-4-일)-3-페닐프로판하이드라자이드N '-(3, 5-dichloropyridin-4-yl) -3-phenylpropanehydrazide

3,5-디클로로-4-하이드라지노피리딘(20.0 mg, 0.1 mmol)과 하이드로신나몰산(하이드로신나몰산)(28.0 mg, 0.2 mmol)을 무수 디클로로메탄(DCM, 2.0 ml)에 용해시켰다. 혼합액에 EDC(43.1 mg, 0.2 mmol)와 디이소프로필에틸라민(DIPEA, 29 μl, 0.2 mmol)을 첨가하여 상온에서 30분간 반응시켰다. 반응 후, DCM을 회전 농축기(rotary evaporator )를 이용하여 건조시키며, 남은 잔여물(residue)은 EA(Ethyl Acetate)에 녹인 후, NaHCO2 포화 용액으로 추출하였다. 추출된 EA 용액은 소듐 설페이트를 이용하여 무수화 과정을 거치고 필터하여 걸러 얻은 유기 용매를 건조하였다. 실리카겔(silica gel)을 이용한 컬럼을 수행하여 정제된 최종 산물 (1)을 88.4% 수득율로 얻었다.3,5-Dichloro-4-hydrazinopyridine (20.0 mg, 0.1 mmol) and hydrocinnamic acid (hydrocinnamolic acid) (28.0 mg, 0.2 mmol) were dissolved in anhydrous dichloromethane (DCM, 2.0 ml). EDC (43.1 mg, 0.2 mmol) and diisopropylethylamine (DIPEA, 29 μl, 0.2 mmol) were added to the mixed solution, and reacted at room temperature for 30 minutes. After the reaction, DCM was dried using a rotary evaporator, and the remaining residue was dissolved in EA (Ethyl Acetate) and extracted with saturated NaHCO 2 solution. The extracted EA solution was filtered through anhydrous solution using sodium sulfate and filtered to dry the organic solvent. Columns were run on silica gel to give the purified final product ( 1 ) in 88.4% yield.

Mp: 149-151°C. 1H NMR (CDCl3, 300MHz, δ ppm, J in Hz) 8.28 (2H, S), 7.61 (1H, d, J= 3.3 Hz), 7.31-6.83 (5H, m), 6.82 (1H, d, J = 3.9 Hz), 2.97 (2H, t, J = 7.7 Hz), 2.55 (2H, t, J = 7.5 Hz). 13C NMR δ: ESI [M + H] = 311.9.
Mp: 149-151 ° C. 1 H NMR (CDCl 3 , 300 MHz, δ ppm, J in Hz) 8.28 (2H, S), 7.61 (1H, d, J = 3.3 Hz), 7.31-6.83 (5H, m), 6.82 (1H, d, J = 3.9 Hz), 2.97 (2H, t, J = 7.7 Hz), 2.55 (2H, t, J = 7.5 Hz). 13 C NMR δ: ESI [M + H] = 311.9.

합성예Synthetic example 2: 2: N-(3, 5-N- (3, 5- 디클로로피리딘Dichloropyridine -4-일)-3--4-yl) -3- 페닐프로파나마이드Phenylpropanamide

4-아미노-3,5-디클로로피리딘(16.3 mg, 0.1 mmol)과 하이드로신나몰산(28.0 mg ,0.2 mmol)을 무수 디클로로메탄(DCM, 2.0 ml)에 녹인다. 혼합액에 EDC (43.1 mg, 0.2 mmol)와 디이소프로필에틸아민 (DIPEA, 29 μl, 0.2 mmol)를 첨가하여 상온에서 30분간 반응시켰다. 반응 후, DCM을 회전 농축기(rotary evaporator )를 이용하여 건조시키고, 남은 잔여물(residue)은 EA(Ethyl Acetate)에 녹인 후, NaHCO2 포화 용액으로 추출하였다. 추출된 EA 용액은 소듐 설페이트를 이용하여 무수화 과정을 거치고 필터하여 걸러 얻은 유기 용매를 건조시켰다. 실리카겔(silica gel)을 이용한 컬럼을 수행하여 정제된 최종 산물 (2)을 93.3% 수득율로 얻었다.Dissolve 4-amino-3,5-dichloropyridine (16.3 mg, 0.1 mmol) and hydrocinnamolic acid (28.0 mg, 0.2 mmol) in anhydrous dichloromethane (DCM, 2.0 ml). EDC (43.1 mg, 0.2 mmol) and diisopropylethylamine (DIPEA, 29 μl, 0.2 mmol) were added to the mixture, and the mixture was reacted at room temperature for 30 minutes. After the reaction, DCM was dried using a rotary evaporator, and the residue was dissolved in EA (Ethyl Acetate) and extracted with saturated NaHCO 2 solution. The extracted EA solution was filtered through anhydrous solution using sodium sulfate and filtered to dry the organic solvent. A column using silica gel was carried out to obtain a purified final product ( 2 ) in 93.3% yield.

1HNMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.63 (2H, S), 7.30-7.17 (5H, m), 2.98 (2H, t, J = 7.6 Hz), 2.85 (2H, t, J = 7.4 Hz). 13C NMR δ: 172.5, 148.9, 142.2, 140.0, 132.1, 128.5, 126.3, 39.3, 30.2. ESI [M + H] = 296.0.
 1 HNMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.63 (2H, S), 7.30-7.17 (5H, m), 2.98 (2H, t, J = 7.6 Hz), 2.85 (2H, t, J = 7.4 Hz). 13 C NMR δ: 172.5, 148.9, 142.2, 140.0, 132.1, 128.5, 126.3, 39.3, 30.2. ESI [M + H] = 296.0.

합성예Synthetic example 3: 3: N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-N--4-yl) -N- 메틸methyl -3--3- 페닐프로판하이드라자이드Phenylpropanehydrazide

3,5-디클로로-4-하이드라지노피리딘(50.0 mg, 0.3 mmol)과 포름알데하이드(14.0 μl, 0.4 mmol)를 무수 DCM(2.0 ml)에 녹인 다음 아세트산(20 μl)를 첨가하였다. 혼합된 용액은 상온에서 30분 간 반응시킨 후, 소듐 사이아노보로하이드라이드(27.0 mg, 0.4 mmol)를 첨가하여 반응을 2시간 동안 상온에서 지속시켰다. 소금물(소금물)(10.0 ml)과 반응용액을 혼합하여 소듐 사이아노보로하이드라이드의 반응성을 제거하여 DCM을 추가하여 물질을 추출하였다. 추출된 EA 용액은 소듐 설페이트를 이용하여 무수화 과정을 거치고 여과하여 걸러 얻은 유기 용매를 건조시켰다. 실리카겔(silica gel)을 이용한 컬럼을 수행하여 51.9% 수득율로 중간체(3,5-디클로로-4-(2-메틸하이드라지닐)피리딘)를 얻었다. 정제된 중간체(19.3 mg, 0.1 mmo)l는 하이드로신나몰산(28.0 mg ,0.2 mmol)과 무수 디클로로메탄(DCM, 2.0 ml)에 용해시켰다. 혼합액에 EDC (43.1 mg, 0.2 mmol)와 디이소프로필에틸아민(DIPEA, 29 μl, 0.2 mmol)를 첨가하여 상온에서 30분간 반응시켰다. 반응 후, DCM을 회전 농축기(rotary evaporator)를 이용하여 건조시키고, 남은 잔여물은 (EA)(Ethyl Acetate)에 녹인 후, NaHCO2 포화 용액으로 추출하였다. 추출된 EA 용액은 소듐 설페이트를 이용하여 무수화 과정을 거치고 여과하여 걸러 얻은 유기 용매를 건조한다. 실리카겔(silica gel)을 이용한 컬럼을 수행하여 정제된 최종 산물 (3)을 79.8% 수득율로 얻었다.3,5-dichloro-4-hydrazinopyridine (50.0 mg, 0.3 mmol) and formaldehyde (14.0 μl, 0.4 mmol) were dissolved in anhydrous DCM (2.0 ml) and acetic acid (20 μl) was then added. The mixed solution was allowed to react at room temperature for 30 minutes, and then sodium cyanoborohydride (27.0 mg, 0.4 mmol) was added to maintain the reaction at room temperature for 2 hours. Brine (salt) (10.0 ml) and the reaction solution was mixed to remove the sodium cyanoborohydride reactivity was added DCM to extract the material. The extracted EA solution was filtered through anhydrous solution using sodium sulfate and filtered to dry the organic solvent. A column using silica gel was performed to obtain intermediate (3,5-dichloro-4- (2-methylhydrazinyl) pyridine) in 51.9% yield. Purified intermediate (19.3 mg, 0.1 mmol) was dissolved in hydrocinnamolic acid (28.0 mg, 0.2 mmol) and anhydrous dichloromethane (DCM, 2.0 ml). EDC (43.1 mg, 0.2 mmol) and diisopropylethylamine (DIPEA, 29 μl, 0.2 mmol) were added to the mixture, and the mixture was reacted at room temperature for 30 minutes. After the reaction, DCM was dried using a rotary evaporator, and the remaining residue was dissolved in (EA) (Ethyl Acetate) and extracted with saturated NaHCO 2 solution. The extracted EA solution is filtered through anhydrous solution using sodium sulfate and filtered to dry the organic solvent obtained. A column using silica gel was performed to obtain the purified final product ( 3 ) in 79.8% yield.

Mp: 113-115 °C. 1H NMR (CDCl3, 400MHz, δ ppm, Jin Hz) 8.28 (2H, s), 7.31-7.18 (5H, m), 6.49 (1H, s), 3.06 (3H, s), 2.98 (2H, t, J = 7.4 Hz), 2.67 (2H, t, J = 7.8 Hz). 13C NMR δ: 194.0, 153.8, 151.5, 149.7, 135.6, 135.5, 133.0, 123.3, 20.1, 18.9, 14.0. ESI [M + H] = 325.8.
Mp: 113-115 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.28 (2H, s), 7.31-7.18 (5H, m), 6.49 (1H, s), 3.06 (3H, s), 2.98 (2H, t, J = 7.4 Hz), 2.67 (2H, t, J = 7.8 Hz). 13 C NMR δ: 194.0, 153.8, 151.5, 149.7, 135.6, 135.5, 133.0, 123.3, 20.1, 18.9, 14.0. ESI [M + H] = 325.8.

합성예Synthetic example 4: 4: 3, 5-3, 5- 디클로로Dichloro -4-(2-(3--4- (2- (3- 페닐프로필Phenylpropyl )) 하이드라지닐Hydrazinyl )피리딘Pyridine

3,5-디클로로-4-하이드라지노피리딘(35.6 mg, 0.2 mmol)을 3-페닐프로피온알데하이드(40.0 μl, 0.3 mmol)와 함께 무수 DCM(2.0 ml)에 녹인 다음 아세트산(20 μl)를 참가하였다. 혼합된 용액은 상온에서 30분간 반응시킨 후, 소듐 사이아노보로하이드라이드(27.0 mg, 0.4 mmol)를 첨가하여 반응을 2시간 동안 상온에서 지속시켰다. 소금물(10.0 ml)과 반응용액을 혼합하여 소듐 사이아노보로하이드라이드의 반응성을 제거하여 DCM을 추가하여 물질을 추출하였다. 추출된 EA 용액은 소듐 설페이트를 이용하여 무수화 과정을 거치고 필터하여 걸러 얻은 유기 용매를 건조시켰다. 실리카겔(silica gel)을 이용한 컬럼을 수행하여 99.0% 수득율로 최종 산물(4)를 얻었다.Dissolve 3,5-dichloro-4-hydrazinopyridine (35.6 mg, 0.2 mmol) in 3- DCM propionaldehyde (40.0 μl, 0.3 mmol) in dry DCM (2.0 ml), followed by acetic acid (20 μl). It was. The mixed solution was allowed to react at room temperature for 30 minutes and then sodium cyanoborohydride (27.0 mg, 0.4 mmol) was added to maintain the reaction at room temperature for 2 hours. Brine (10.0 ml) and the reaction solution was mixed to remove the reactivity of sodium cyanoborohydride and DCM was added to extract the material. The extracted EA solution was filtered through anhydrous solution using sodium sulfate and filtered to dry the organic solvent. A column using silica gel was performed to give the final product (4) in 99.0% yield.

1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.22 (2H, s), 7.28-7.14 (5H, m), 6.09 (1H, br), 4.31 (1H, d, J = 4.8 Hz), 2.83-2.78 (2H, m), 2.66 (2H, t, J = 7.8 Hz), 1.81-1.74 (2H, m). 13C NMR δ: 181.6, 154.5, 152.6, 147.3, 132.9, 132.8, 130.2, 122.6, 48.8, 29.0, 24.3. ESI [M + H] = 297.3.
 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.22 (2H, s), 7.28-7.14 (5H, m), 6.09 (1H, br), 4.31 (1H, d, J = 4.8 Hz) , 2.83-2.78 (2H, m), 2.66 (2H, t, J = 7.8 Hz), 1.81-1.74 (2H, m). 13 C NMR δ: 181.6, 154.5, 152.6, 147.3, 132.9, 132.8, 130.2, 122.6, 48.8, 29.0, 24.3. ESI [M + H] = 297.3.

합성예Synthetic example 5: 5: N'N ' -(2--(2- 클로로피리딘Chloropyridine -4-일)-3--4-yl) -3- 페닐프로판하이드라자이드Phenylpropanehydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 68.0% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 68.0%.

1H NMR (CDCl3, 400MHz, δ ppm, Jin Hz) 8.20 (1H. s), 7.88 (1H, d, J = 5.7 Hz), 7.36-7.20 (5H, m), 6.99 (1H, s), 6.46 (1H, d, J = 2.1 Hz), 6.28 (1H, dd, J = 5.7 Hz, 1.8Hz), 3.20 (2H, t, J = 5.7 Hz), 2.59 (2H, t, J = 7.2 Hz). ESI [M + H] = 276.0.
 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.20 (1H.s), 7.88 (1H, d, J = 5.7 Hz), 7.36-7.20 (5H, m), 6.99 (1H, s) , 6.46 (1H, d, J = 2.1 Hz), 6.28 (1H, dd, J = 5.7 Hz, 1.8 Hz), 3.20 (2H, t, J = 5.7 Hz), 2.59 (2H, t, J = 7.2 Hz ). ESI [M + H] = 276.0.

합성예Synthetic example 6: 6: N'N ' -(2,6--(2,6- 디클로로피리딘Dichloropyridine -4-일)-3--4-yl) -3- 페닐프로판하이드라자이드Phenylpropanehydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 88.6% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 88.6%.

1H NMR (CDCl3, 400MHz, δ ppm, Jin Hz) 7.36-7.21 (5H, m), 6.99 (1H, br), 6.45 (2H, s), 6.34 (1H, br), 3.04 (2H, t, J = 7.2 Hz), 2.61 (2H, t, J = 7.8 Hz). ESI [M + H] = 311.9.
 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 7.36-7.21 (5H, m), 6.99 (1H, br), 6.45 (2H, s), 6.34 (1H, br), 3.04 (2H, t, J = 7.2 Hz), 2.61 (2H, t, J = 7.8 Hz). ESI [M + H] = 311.9.

합성예Synthetic example 7: 7: N'N ' -(2, 6--(2, 6- 디클로로페닐Dichlorophenyl )-3-) -3- 페닐프로판하이드라자이드Phenylpropanehydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 83.2% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, whereby 83.2% yield was obtained.

1H NMR (CDCl3, 300MHz, δ ppm, J in Hz) 7.57 (1H, d, J = 4.8 Hz), 7.29-7.14 (7H, m), 6.91 (1H, t, J = 8.1 Hz), 6.80 (1H, d, J = 5.1 Hz), 2.95 (2H, t, J = 7.7 Hz), 2.49 (2H, t, J = 7.8 Hz). 13C NMR δ: 180.0, 147.0, 146.3, 133.8, 133.5, 133.1, 131.0, 130.6, 128.5, 32.1, 27.1. ESI [M + H] = 311.0.
 1 H NMR (CDCl 3 , 300 MHz, δ ppm, J in Hz) 7.57 (1H, d, J = 4.8 Hz), 7.29-7.14 (7H, m), 6.91 (1H, t, J = 8.1 Hz), 6.80 (1H, d, J = 5.1 Hz), 2.95 (2H, t, J = 7.7 Hz), 2.49 (2H, t, J = 7.8 Hz). 13 C NMR δ: 180.0, 147.0, 146.3, 133.8, 133.5, 133.1, 131.0, 130.6, 128.5, 32.1, 27.1. ESI [M + H] = 311.0.

합성예Synthetic example 8: 8: 3-3- 페닐Phenyl -- N'N ' -(피리딘-4-일)-(Pyridin-4-yl) 프로판하이드라자이드Propanehydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 48.7% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 48.7%.

1H NMR (CDCl3, 300MHz, δ ppm, J in Hz) 7.57 (1H, br), 7.34-7.11 (7H, m), 6.91 (1H, br), 6.45 (2H, d, J = 7.6 Hz), 2.45 (2H, t, J = 7.6 Hz), 2.26 (2H, t, J = 7.6 Hz). ESI [M + H] = 242.4.
 1 H NMR (CDCl 3 , 300 MHz, δ ppm, J in Hz) 7.57 (1H, br), 7.34-7.11 (7H, m), 6.91 (1H, br), 6.45 (2H, d, J = 7.6 Hz) , 2.45 (2H, t, J = 7.6 Hz), 2.26 (2H, t, J = 7.6 Hz). ESI [M + H] = 242.4.

합성예Synthetic example 9: 9: N'N ' -(3,5--(3,5- 디플루오로피리딘Difluoropyridine -4-일)-3--4-yl) -3- 페닐프로판하이드라자이드Phenylpropanehydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 51.4% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 51.4%.

1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.15 (2H, s), 7.36 (1H, br), 7.30-7.16 (5H, m), 6.39 (1H, s), 2.97 (2H, t, J = 7.6 Hz), 2.53 (2H, t, J = 7.4 Hz). ESI [M + H] = 278.0.
 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.15 (2H, s), 7.36 (1H, br), 7.30-7.16 (5H, m), 6.39 (1H, s), 2.97 (2H, t, J = 7.6 Hz), 2.53 (2H, t, J = 7.4 Hz). ESI [M + H] = 278.0.

합성예Synthetic example 10: 10: N'N ' -(2,6--(2,6- 디플루오로페닐Difluorophenyl )-3-) -3- 페닐프로판하이드라자이드Phenylpropanehydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 83.7% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, whereby 83.7% yield was obtained.

Mp: 119-121 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 7.59 (1H, d, J= 5.2 Hz), 7.29-7.16 (5H, m), 6.91-6.81 (3H, m), 6.41-6.39 (1H, m), 2.96 (2H, t, J = 7.8 Hz), 2.48 (2H, t, J = 7.8 Hz). ESI [M + H] = 277.2.
Mp: 119-121 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 7.59 (1H, d, J = 5.2 Hz), 7.29-7.16 (5H, m), 6.91-6.81 (3H, m), 6.41-6.39 ( 1H, m), 2.96 (2H, t, J = 7.8 Hz), 2.48 (2H, t, J = 7.8 Hz). ESI [M + H] = 277.2.

합성예Synthetic example 11:  11: N'N ' -(2,6--(2,6- 디메틸페닐Dimethylphenyl )-3-) -3- 페닐프로판하이드라자이드Phenylpropanehydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 93.4% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 93.4%.

Mp: 78-80 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 7.26-7.11 (6H, m), 6.96 (2H, d, J= 7.2 Hz), 6.90-6.86 (1H, m), 6.09 (1H, d, J = 3.6 Hz), 2.93 (2H, d, J = 7.6 Hz), 2.42 (2H, d, J = 7.6 Hz), 2.31 (3H, s). ESI [M + H] = 268.9.
Mp: 78-80 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 7.26-7.11 (6H, m), 6.96 (2H, d, J = 7.2 Hz), 6.90-6.86 (1H, m), 6.09 (1H, d, J = 3.6 Hz), 2.93 (2H, d, J = 7.6 Hz), 2.42 (2H, d, J = 7.6 Hz), 2.31 (3H, s). ESI [M + H] = 268.9.

합성예Synthetic example 12: 12: N'N ' -(3, 5--(3, 5- 디클로로피리딘Dichloropyridine -4-일)-3-(4--4-yl) -3- (4- 플루오로페닐Fluorophenyl )) 프로판하이드라자이드Propanehydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 83.6% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, whereby 83.6% yield was obtained.

Mp: 182-184 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.28 (2H, s), 7.58 (1H, d, J = 3.6 Hz), 7.12-7.09 (2H, m), 6.96-6.92 (2H, m), 6.80 (1H, d, J = 4.0 Hz), 2.93 (2H, t, J = 7.4 Hz), 2.50 (2H, t, J = 7.6 Hz). ESI [M + H] = 328.9
Mp: 182-184 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.28 (2H, s), 7.58 (1H, d, J = 3.6 Hz), 7.12-7.09 (2H, m), 6.96-6.92 (2H, m), 6.80 (1H, d, J = 4.0 Hz), 2.93 (2H, t, J = 7.4 Hz), 2.50 (2H, t, J = 7.6 Hz). ESI [M + H] = 328.9

합성예Synthetic example 13: 13: 3-(4-3- (4- 클로로페닐Chlorophenyl )-) - N'N ' -(3, 5--(3, 5- 디클로로피리딘Dichloropyridine -4-일)-4- days) 프로판하이드라자이드Propanehydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 86.0% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 86.0%.

Mp: 172-174 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.46 (1H, d, J = 4.0 Hz), 7.22 (2H, d, J = 8.4 Hz), 7.08 (2H, d, J = 8.8 Hz), 6.80 (1H, d, J = 4.0 Hz), 2.93 (2H, t, J = 7.4 Hz), 2.50 (2H, t, J = 7.4 Hz). ESI [M + H] = 346.9.
Mp: 172-174 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.46 (1H, d, J = 4.0 Hz), 7.22 (2H, d, J = 8.4 Hz), 7.08 (2H , d, J = 8.8 Hz), 6.80 (1H, d, J = 4.0 Hz), 2.93 (2H, t, J = 7.4 Hz), 2.50 (2H, t, J = 7.4 Hz). ESI [M + H] = 346.9.

합성예Synthetic example 14: 14: N'N ' -(3, 5--(3, 5- 디클로로피리딘Dichloropyridine -4-일)-3-p--4-yl) -3-p- 톨릴프로판하이드라자이드Tolylpropanehydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 86.0% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 86.0%.

Mp: 185-187 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.28 (2H, s), 7.51 (1H, d, J = 3.6 Hz), 7.10-7.04 (4H, m), 6.82 (1H, d, J = 4.0 Hz), 2.92 (2H, t, J = 7.8 Hz), 2.51 (2H, t, J= 7.6 Hz), 2.31 (3H, s). ESI [M + H] = 326.0.
Mp: 185-187 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.28 (2H, s), 7.51 (1H, d, J = 3.6 Hz), 7.10-7.04 (4H, m), 6.82 (1H, d, J = 4.0 Hz), 2.92 (2H, t, J = 7.8 Hz), 2.51 (2H, t, J = 7.6 Hz), 2.31 (3H, s). ESI [M + H] = 326.0.

합성예Synthetic example 15: 15: N'N ' -(3, 5--(3, 5- 디클로로피리딘Dichloropyridine -4-일)-3-(4--4-yl) -3- (4- 메톡시페닐Methoxyphenyl )) 프로판하이드라자이드Propanehydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 86.0% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 86.0%.

Mp: 148-150 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.28 (2H, s), 7.52 (1H,d, J= 4.0 Hz), 7.07 (2H, d, J= 6.4 Hz), 6.80 (2H, d, J= 6.4 Hz), 2.90 (2H, t, J= 7.6 Hz), 2.50 (2H, t, J= 7.6 Hz). ESI [M + H] = 342.0.
Mp: 148-150 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.28 (2H, s), 7.52 (1H, d, J = 4.0 Hz), 7.07 (2H, d, J = 6.4 Hz), 6.80 (2H , d, J = 6.4 Hz), 2.90 (2H, t, J = 7.6 Hz), 2.50 (2H, t, J = 7.6 Hz). ESI [M + H] = 342.0.

합성예Synthetic example 16: 16: 2-(4-2- (4- 클로로페닐Chlorophenyl )-) - N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-4- days) 아세토하이드라자이드Acetohydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 86.0% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 86.0%.

1H NMR (CDCl3, 400MHz, δ ppm, Jin Hz) 8.29 (2H, s), 7.63 (1H, br), 7.33-7.24 (4H, m), 6.79 (1H, br), 3.59 (2H, s). ESI [M + H] = 332.0.
 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.63 (1H, br), 7.33-7.24 (4H, m), 6.79 (1H, br), 3.59 (2H, s). ESI [M + H] = 332.0.

합성예Synthetic example 17:  17: N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-3-(4--4-yl) -3- (4- 하이드록시페닐Hydroxyphenyl )) 프로판하이드라Propanehydra 자이드Zayed

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 92.6% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 92.6%.

Mp: 154-156 °C. 1H NMR (CDCl3, 400MHz, δ ppm, Jin Hz) 10.12 (1H, s), 9.14 (1H, s), 8.20 (2H, s), 8.14 (1H, s), 6.95 (2H, d, J = 8.4 Hz), 6.62 (2H, d, J = 8.0 Hz), 2.67 (2H, t, J = 7.8 Hz), 2.35 (2H, t, J = 7.8 Hz). ESI [M + H] = 328.0.
Mp: 154-156 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 10.12 (1H, s), 9.14 (1H, s), 8.20 (2H, s), 8.14 (1H, s), 6.95 (2H, d, J = 8.4 Hz), 6.62 (2H, d, J = 8.0 Hz), 2.67 (2H, t, J = 7.8 Hz), 2.35 (2H, t, J = 7.8 Hz). ESI [M + H] = 328.0.

합성예Synthetic example 18: 18: N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-4- days) 벤조하이드라자이드Benzohydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 90.4% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 90.4%.

Mp: 160-162 °C. 1HNMR (CDCl3, 400MHz, δ ppm, J in Hz) 9.00 (1H, s), 8.27 (2H, S), 7.80 (2H, d, J = 7.2 Hz), 7.54 (1H, t, J = 7.6 Hz), 7.44 (2H, t, J= 7.6 Hz), 7.07 (1H, s). ESI [M + H] = 283.9
Mp: 160-162 ° C. 1 HNMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 9.00 (1H, s), 8.27 (2H, S), 7.80 (2H, d, J = 7.2 Hz), 7.54 (1H, t, J = 7.6 Hz), 7.44 (2H, t, J = 7.6 Hz), 7.07 (1H, s). ESI [M + H] = 283.9

합성예Synthetic example 19:  19: N'N ' -(3, 5--(3, 5- 디클로로피리딘Dichloropyridine -4-일)-2--4-yl) -2- 페닐아세토하이드라자이드Phenylacetohydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 77.8% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 77.8%.

Mp: 216-218 °C. 1H NMR (CDCl3, 400MHz, δ ppm, Jin Hz) 8.24 (2H, S), 7.96 (1H, s), 7.38-7.27 (5H, m), 6.80 (1H, s), 3.59 (2H, s). ESI [M + H] = 298.0.
Mp: 216-218 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.24 (2H, S), 7.96 (1H, s), 7.38-7.27 (5H, m), 6.80 (1H, s), 3.59 (2H, s). ESI [M + H] = 298.0.

합성예Synthetic example 20: 20: N'N ' -(3, 5--(3, 5- 디클로로피리딘Dichloropyridine -4-일)-4--4-yl) -4- 페닐부탄하이드라자이드Phenylbutanehydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 91.2% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 91.2%.

Mp: 117-119 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.30 (2H, s), 7.51 (1H, d, J = 4.0 Hz), 7.30-7.15 (5H, m), 6.81 (1H, d, J = 4.4 Hz), 2.65 (2H, t, J = 7.4 Hz), 2.22 (2H, t, J = 7.4 Hz), 2.02-1.95 (2H, m). ESI [M + H] = 325.9.
Mp: 117-119 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.30 (2H, s), 7.51 (1H, d, J = 4.0 Hz), 7.30-7.15 (5H, m), 6.81 (1H, d, J = 4.4 Hz), 2.65 (2H, t, J = 7.4 Hz), 2.22 (2H, t, J = 7.4 Hz), 2.02-1.95 (2H, m). ESI [M + H] = 325.9.

합성예Synthetic example 21:  21: N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-5--4-yl) -5- 페닐펜탄하이드라자이드Phenylpentanehydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 80.7% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 80.7%.

Mp: 118-120 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.30 (2H, s), 7.49 (1H, d, J = 4.0 Hz), 7.29-7.14 (5H, m), 6.83 (1H, d, J = 3.6 Hz), 2.61 (2H, t, J = 7.2 Hz), 2.23 (2H, t, J= 7.2 Hz), 1.69-1.62 (4H, m). ESI [M - H] = 337.7.
Mp: 118-120 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.30 (2H, s), 7.49 (1H, d, J = 4.0 Hz), 7.29-7.14 (5H, m), 6.83 (1H, d, J = 3.6 Hz), 2.61 (2H, t, J = 7.2 Hz), 2.23 (2H, t, J = 7.2 Hz), 1.69-1.62 (4H, m). ESI [M-H] = 337.7.

합성예Synthetic example 22: 22: N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-6--4-yl) -6- 페닐헥산하이드라자이드Phenylhexanehydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 71.7% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 71.7%.

Mp: 128-130 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.71 (1H, d, J= 2.4 Hz), 7.28-7.25 (2H, m), 7.19-7.14 (3H, m), 6.83 (1H, d, J = 3.2 Hz), 2.58 (2H, t, J = 7.6 Hz), 2.21 (2H, t, J = 7.4 Hz), 1.68-1.61 (4H, m), 1.38-1.24 (2H, m). ESI [M + H] = 363.6
Mp: 128-130 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.71 (1H, d, J = 2.4 Hz), 7.28-7.25 (2H, m), 7.19-7.14 (3H, m), 6.83 (1H, d, J = 3.2 Hz), 2.58 (2H, t, J = 7.6 Hz), 2.21 (2H, t, J = 7.4 Hz), 1.68-1.61 (4H, m), 1.38- 1.24 (2H, m). ESI [M + H] = 363.6

합성예Synthetic example 23: 23: N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-7--4-yl) -7- 페닐헵탄하이드라자이드Phenylheptane hydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 80.7% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 80.7%.

Mp: 131-133 °C. 1H NMR (CDCl3, 400MHz, δ ppm, Jin Hz) 8.29 (2H, s), 7.77 (1H, s), 7.28-7.24 (2H, m), 7.18-7.14 (3H, m), 6.83 (1H, d, J = 2.8 Hz), 2.57 (2H, t, J = 7.6 Hz), 2.20 (2H, t, J = 7.6 Hz), 1.64-1.57 (4H, m), 1.33-1.31 (4H, m). ESI [M + H] = 368.0
Mp: 131-133 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.77 (1H, s), 7.28-7.24 (2H, m), 7.18-7.14 (3H, m), 6.83 ( 1H, d, J = 2.8 Hz, 2.57 (2H, t, J = 7.6 Hz), 2.20 (2H, t, J = 7.6 Hz), 1.64-1.57 (4H, m), 1.33-1.31 (4H, m ). ESI [M + H] = 368.0

합성예Synthetic example 24: 24: 벤질 2-(3, 5-Benzyl 2- (3, 5- 디클로로피리딘Dichloropyridine -4-일)-4- days) 하이드라진카르복실레이트Hydrazinecarboxylate

3,5-디클로로-4-하이드라지노피리딘 (17.8 mg, 0.1 mmol)과 벤질 카르보노클로리데이트(34.6 μl ,0.2 mmol)을 무수 DCM (2.0 ml)에 용해시켰다. 혼합액에 트리에틸아민(TEA, 20 μl, 0.2 mmol)을 첨가하여 상온에서 30분간 반응시켰다. 반응 후, DCM 1 ml로 희석한 다음 NaHCO2 포화 용액으로 추출하였다. 추출된 DCM 용액은 소듐 설페이트를 이용하여 무수화 과정을 거치고 필터하여 걸러 얻은 유기 용매를 건조시켰다. 실리카겔(silica gel)을 이용한 컬럼을 수행하여 정제된 최종 산물 (24)을 71.0 % 수득율로 얻었다.3,5-Dichloro-4-hydrazinopyridine (17.8 mg, 0.1 mmol) and benzyl carnochloridate (34.6 μl, 0.2 mmol) were dissolved in anhydrous DCM (2.0 ml). Triethylamine (TEA, 20 μl, 0.2 mmol) was added to the mixed solution and reacted at room temperature for 30 minutes. After the reaction, the mixture was diluted with 1 ml of DCM and extracted with saturated NaHCO 2 solution. The extracted DCM solution was filtered through anhydrous solution using sodium sulfate and filtered to dry the organic solvent. A column using silica gel was performed to obtain the purified final product (24) in 71.0% yield.

1H NMR (CDCl3, 300MHz, δ ppm, Jin Hz) 8.29 (2H, s), 7.71 (1H, s), 7.36-7.21 (5H, m), 6.80 (1H, s), 3.58 (2H, s). ESI [M + H] = 312.9.
 1 H NMR (CDCl 3 , 300 MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.71 (1H, s), 7.36-7.21 (5H, m), 6.80 (1H, s), 3.58 (2H, s). ESI [M + H] = 312.9.

합성예Synthetic example 25: 25: N-벤질-2-(3,5-N-benzyl-2- (3,5- 디클로로피리딘Dichloropyridine -4-일)-4- days) 하이드라진카르복사마이드Hydrazine Carboxamide

N'-(2,6-디클로로피리딘-4-일)-3-페닐프로판하이드라진(34.6 mg, 0.2 mmol)을 카르보닐 디이미다졸(36.4 mg, 0.4 mmol)과 함께 무수 DCM (2.0 ml)에 녹인다. 반응 용액에 트리에틸아민(TEA, 40 μl, 0.4 mmol)을 첨가하여 상온에서 60분간 반응시켰다. 생성된 침전물을 필터로 받아서 DCM으로 2회 세척한 후 건조하여 중간체(N'-(3,5-디클로로피리딘-4-일)-1H-이미다졸-1-카보하이드라자이드)를 76 % 수득율로 획득하였다. 중간체(46.5 mg, 0.17 mmol)을 벤질아민(36.5 μl, 0.3 mmol)와 함께 무수 디메틸포르마이미드(DMF, 2.0 ml)에 용해시켰다. 반응 용액에 TEA(35.0 μl, 0.4 mmol)를 첨가하여 상온에서 2시간동안 반응시켰다. 반응 후, DCM을 회전 농축기(rotary evaporator)를 이용하여 건조시키며, 남은 잔여물은 EA(Ethyl Acetate)에 녹인 후, NaHCO2 포화 용액으로 추출하였다. 추출된 EA 용액은 소듐 설페이트를 이용하여 무수화 과정을 거치고 필터하여 걸러 얻은 유기 용매를 건조시켰다. 실리카겔(silica gel)을 이용한 컬럼을 수행하여 정제된 최종 산물을 65.0% 수득율로 얻었다.N '-(2,6-dichloropyridin-4-yl) -3-phenylpropanehydrazine (34.6 mg, 0.2 mmol) was added to anhydrous DCM (2.0 ml) together with carbonyl diimidazole (36.4 mg, 0.4 mmol). Dissolve. Triethylamine (TEA, 40 μl, 0.4 mmol) was added to the reaction solution and allowed to react at room temperature for 60 minutes. The resulting precipitate was taken as a filter, washed twice with DCM and dried to yield 76% of an intermediate (N ′-(3,5-dichloropyridin-4-yl) -1H-imidazole-1-carbohydrazide). Obtained. The intermediate (46.5 mg, 0.17 mmol) was dissolved in anhydrous dimethylformamide (DMF, 2.0 ml) with benzylamine (36.5 μl, 0.3 mmol). TEA (35.0 μl, 0.4 mmol) was added to the reaction solution and reacted at room temperature for 2 hours. After the reaction, DCM was dried using a rotary evaporator, and the remaining residue was dissolved in EA (Ethyl Acetate) and extracted with saturated NaHCO 2 solution. The extracted EA solution was filtered through anhydrous solution using sodium sulfate and filtered to dry the organic solvent. Columns were run on silica gel to give a purified final product in 65.0% yield.

Mp: 215-217 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.18 (2H, s), 7.39 (1H, br), 7.28-7.18 (5H, m), 6.97(1H, s), 6.10(1H, t, J = 5.0 Hz), 4.37 (2H, d, J = 4.8 Hz). ESI [M + H] = 312.9.
Mp: 215-217 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.18 (2H, s), 7.39 (1H, br), 7.28-7.18 (5H, m), 6.97 (1H, s), 6.10 (1H, t, J = 5.0 Hz), 4.37 (2H, d, J = 4.8 Hz). ESI [M + H] = 312.9.

합성예Synthetic example 26:  26: N'N ' -(3, 5--(3, 5- 디클로로피리딘Dichloropyridine -4-일)-4- days) 신나모하이드라자이드Cinnamohydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 77.9% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 77.9%.

Mp: 184-186 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.33 (2H,s), 7.71 (1H, d, J= 16.0 Hz), 7.68 (1H, d, J= 4.0 Hz), 7.53-7.38 (5H, m), 7.01 (1H, d, J = 4.0 Hz), 6.42 (1H, d, J = 15.6 Hz). ESI [M + H] = 309.0.
Mp: 184-186 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.33 (2H, s), 7.71 (1H, d, J = 16.0 Hz), 7.68 (1H, d, J = 4.0 Hz), 7.53-7.38 (5H, m), 7.01 (1H, d, J = 4.0 Hz), 6.42 (1H, d, J = 15.6 Hz). ESI [M + H] = 309.0.

합성예Synthetic example 27:  27: N'N ' -(3, 5--(3, 5- 디클로로피리딘Dichloropyridine -4-일)-1,2,3,4--4-yl) -1,2,3,4- 테트라하이드로나프탈렌Tetrahydronaphthalene -2--2- 카보하이드라자이드Carbohydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 77.9% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 77.9%.

Mp: 219-211 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 9.15 (2H, s), 8.48 (1H, d, J = 4.8 Hz), 7.67-7.56 (4H, m), 7.36 (1H, d, J= 4.8 Hz), 3.05-2.84 (4H, m), 2.64-2.61 (1H, m), 2.14-1.87 (2H, m). ESI [M + H] = 337.9.
Mp: 219-211 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 9.15 (2H, s), 8.48 (1H, d, J = 4.8 Hz), 7.67-7.56 (4H, m), 7.36 (1H, d, J = 4.8 Hz), 3.05-2.84 (4H, m), 2.64-2.61 (1H, m), 2.14-1.87 (2H, m). ESI [M + H] = 337.9.

합성예Synthetic example 28: 28: N'N ' -(3, 5--(3, 5- 디클로로피리딘Dichloropyridine -4-일)-2, 3--4-yl) -2, 3- 디하이드로Dihydro -1H--1H- 인딘Indine -2--2- 카보하이드라자이드Carbohydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 69.8% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 69.8%.

Mp: 237-239 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.31 (2H, s), 7.68 (1H, d, J = 3.2 Hz), 7.22-7.16 (4H, m), 6.86 (1H, d, J = 4.0 Hz), 3.26-3.18 (5H, m). ESI [M + H] = 323.9.
Mp: 237-239 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.31 (2H, s), 7.68 (1H, d, J = 3.2 Hz), 7.22-7.16 (4H, m), 6.86 (1H, d, J = 4.0 Hz), 3.26-3.18 (5H, m). ESI [M + H] = 323.9.

합성예Synthetic example 29: 29: N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-1,2--4-yl) -1,2- 디하이드로사이클로부타벤젠Dihydrocyclobutabenzene -1--One- 카보하이드라자이드Carbohydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 69.8% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 69.8%.

Mp: 237-239 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.31 (2H, s), 8.01 (1H, d, J = 4.0 Hz), 7.32-7.30 (2H, m), 7.22 (1H, t, J = 4.0 Hz), 7.17 (1H, d, J = 4.0 Hz), 6.85 (1H, d, J = 4.0 Hz). 4.30-4.28 (1H, m), 3.60 (1H, dd, J = 14.0, 6.4 Hz), 3.397 (1H, J = 14.2, 2.4 Hz). ESI [M + H] = 309.3.
Mp: 237-239 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.31 (2H, s), 8.01 (1H, d, J = 4.0 Hz), 7.32-7.30 (2H, m), 7.22 (1H, t, J = 4.0 Hz), 7.17 (1H, d, J = 4.0 Hz), 6.85 (1H, d, J = 4.0 Hz). 4.30-4.28 (1H, m), 3.60 (1H, doublet of doublets, J = 14.0, 6.4 Hz), 3.397 (1H, J = 14.2, 2.4 Hz). ESI [M + H] = 309.3.

합성예Synthetic example 30:  30: N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-1H--4-yl) -1H- 인딘Indine -3--3- 카보하이드라자이드Carbohydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 68.4% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 68.4%.

Mp: 202-204 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.34 (2H, s), 8.10 (1H, d, J = 3.6 Hz), 7.89 (1H, d, J = 7.6 Hz), 7.50 (1H, d, J= 7.6 Hz), 7.34-7.26 (2H, m), 7.14 (1H, t, J = 2.0 Hz), 7.06 (1H, d, J = 3.6 Hz), 3.56 (2H, d, J = 1.6 Hz). ESI [M + H] = 321.6.
Mp: 202-204 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.34 (2H, s), 8.10 (1H, d, J = 3.6 Hz), 7.89 (1H, d, J = 7.6 Hz), 7.50 (1H , d, J = 7.6 Hz), 7.34-7.26 (2H, m), 7.14 (1H, t, J = 2.0 Hz), 7.06 (1H, d, J = 3.6 Hz), 3.56 (2H, d, J = 1.6 Hz). ESI [M + H] = 321.6.

합성예Synthetic example 31:  31: N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-2-(나프탈렌-1-일)-4-yl) -2- (naphthalen-1-yl) 아세토하이드라자이드Acetohydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 71.1% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 71.1%.

Mp: 221-223 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.47 (1H, br), 8.11 (2H, s), 7.91-7.76 (3H, m), 7.49-7.37 (4H, m), 6.84 (1H, br), 3.99 (2H, s). ESI [M + H] = 347.5.
Mp: 221-223 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.47 (1H, br), 8.11 (2H, s), 7.91-7.76 (3H, m), 7.49-7.37 (4H, m), 6.84 ( 1H, br), 3.99 (2H, s). ESI [M + H] = 347.5.

합성예Synthetic example 32:  32: N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-2-(나프탈렌-2-일)-4-yl) -2- (naphthalen-2-yl) 아세토하이드라자이드Acetohydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 80.5% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, whereby 80.5% yield was obtained.

Mp: 240-242 °C. 1H NMR (CDCl3, 400MHz, δ ppm, Jin Hz) 10.47 (1H, s), 8.24 (1H, s), 7.86-7.81 (4H, m), 7.47-7.40 (3H, m), 3.64 (2H, s). ESI [M + H] = 347.6.
Mp: 240-242 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 10.47 (1H, s), 8.24 (1H, s), 7.86-7.81 (4H, m), 7.47-7.40 (3H, m), 3.64 ( 2H, s). ESI [M + H] = 347.6.

합성예Synthetic example 33:  33: N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-3-(나프탈렌-1-일)-4-yl) -3- (naphthalen-1-yl) 프로판하이드라자이드Propanehydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 90.0% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 90.0%.

Mp: 206-208 °C. 1H NMR (CDCl3, 400MHz, δ ppm, Jin Hz) 8.39 (1H, br), 8.21 (2H, s), 7.99-7.96 (1H, m), 7.85-7.83 (1H, m), 7.71 (1H, d, J = 8.4 Hz), 7.48-7.45 (2H, m), 7.34 (1H, t, J = 7.6 Hz), 7.27 (1H, d, J = 6.8 Hz), 6.82 (1H, br), 3.39 (2H, t, J = 7.8 Hz), 2.62 (2H, t, J = 7.6 Hz). ESI [M + H] = 361.3
Mp: 206-208 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.39 (1H, br), 8.21 (2H, s), 7.99-7.96 (1H, m), 7.85-7.83 (1H, m), 7.71 ( 1H, d, J = 8.4 Hz), 7.48-7.45 (2H, m), 7.34 (1H, t, J = 7.6 Hz), 7.27 (1H, d, J = 6.8 Hz), 6.82 (1H, br), 3.39 (2H, t, J = 7.8 Hz), 2.62 (2H, t, J = 7.6 Hz). ESI [M + H] = 361.3

합성예Synthetic example 34: 34: N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-2-(피리딘-4-일)-4-yl) -2- (pyridin-4-yl) 아세토하이드라자이드Acetohydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 81.2% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 81.2%.

1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.59 (2H, d, J= 5.6 Hz), 8.30 (2H, s), 7.68 (1H, br), 7.23 (2H, d, J = 6.0 Hz), 6.82 (1H, d, J = 3.2 Hz), 3.59 (2H, s). ESI [M + H] = 298.2.
 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.59 (2H, d, J = 5.6 Hz), 8.30 (2H, s), 7.68 (1H, br), 7.23 (2H, d, J = 6.0 Hz), 6.82 (1H, d, J = 3.2 Hz), 3.59 (2H, s). ESI [M + H] = 298.2.

합성예Synthetic example 35:  35: N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-1H-인돌-2--4-yl) -1H-indole-2- 카보하이드라자이드Carbohydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 94.0% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 94.0%.

Mp: 273-275 °C. 1H NMR (CDCl3, 400MHz, δ ppm, Jin Hz) 11.65 (1H, s), 10.77 (1H, s), 8.52 (1H, s), 8.24 (2H, s), 7.62 (1H, d, J = 8.4 Hz), 7.40 (1H, d, J = 8.4 Hz), 7.22 (1H, s), 7.17(1H, t, J = 7.8 Hz), 7.03 (1H, t, J = 7.6 Hz). ESI [M + H] = 322.6.
Mp: 273-275 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 11.65 (1H, s), 10.77 (1H, s), 8.52 (1H, s), 8.24 (2H, s), 7.62 (1H, d, J = 8.4 Hz), 7.40 (1H, d, J = 8.4 Hz), 7.22 (1H, s), 7.17 (1H, t, J = 7.8 Hz), 7.03 (1H, t, J = 7.6 Hz). ESI [M + H] = 322.6.

합성예 36: N' -(3,5- 디클로로피리딘 -4-일) 데칸하이드라자이드(146): Synthesis Example 36 N ' -(3,5- dichloropyridin- 4-yl) decanhydrazide (146):

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 84.3% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 84.3%.

Mp: 181-183 °C. 1HNMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.70 (1H, d, J = 3.2 Hz), 5.83 (1H, d, J = 3.6 Hz), 2.21 (2H, t, J= 7.6 Hz), 1.67-1.60 (2H, m), 1.26-1.23 (12H, m), 0.86 (3H, t, J = 6.8 Hz). ESI [M + H] = 333.3.
Mp: 181-183 ° C. 1 HNMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.70 (1H, d, J = 3.2 Hz), 5.83 (1H, d, J = 3.6 Hz), 2.21 (2H, t, J = 7.6 Hz), 1.67-1.60 (2H, m), 1.26-1.23 (12H, m), 0.86 (3H, t, J = 6.8 Hz). ESI [M + H] = 333.3.

합성예Synthetic example 37: 3- 37: 3- 사이클로펜틸Cyclopentyl -- N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-4- days) 프로판하이드라자이드Propanehydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 92.9% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 92.9%.

Mp: 181-183 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.69 (1H, d, J = 3.6 Hz), 6.83 (1H, d, J = 3.6 Hz), 2.23 (2H, t, J= 7.6 Hz), 1.76-1.48 (11H, m). ESI [M + H] = 303.6.
Mp: 181-183 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.69 (1H, d, J = 3.6 Hz), 6.83 (1H, d, J = 3.6 Hz), 2.23 (2H , t, J = 7.6 Hz), 1.76-1.48 (11H, m). ESI [M + H] = 303.6.

합성예Synthetic example 38: 3- 38: 3- 사이클로헥실Cyclohexyl -- N'N ' -(3, 5--(3, 5- 디클로로피리딘Dichloropyridine -4-일)-4- days) 프로판하이드라자이드Propanehydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 90.3% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 90.3%.

Mp: 198-200 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.30 (2H, s), 7.55 (1H, d, J = 3.6 Hz), 6.84 (1H, d, J = 3.6 Hz), 2.23 (2H, t, J= 7.8 Hz), 1.68-1.62 (5H, m), 1.52 (2H, q, J = 7.6 Hz), 1.23-1.12 (4H, m), 0.90-0.81 (2H, m). ESI [M + H] = 318.0.
Mp: 198-200 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.30 (2H, s), 7.55 (1H, d, J = 3.6 Hz), 6.84 (1H, d, J = 3.6 Hz), 2.23 (2H , t, J = 7.8 Hz), 1.68-1.62 (5H, m), 1.52 (2H, q, J = 7.6 Hz), 1.23-1.12 (4H, m), 0.90-0.81 (2H, m). ESI [M + H] = 318.0.

합성예Synthetic example 39: 39: 2-2- 사이클로헵틸Cycloheptyl -- N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-4- days) 아세토하이드라자이드Acetohydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 79.3% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 79.3%.

Mp: 181-183 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.59 (1H, d, J = 3.6 Hz), 6.85 (1H, d, J= 3.6 Hz), 2.21-1.89 (6H, m), 1.54-1.47 (3H, m), 1.28-1.05 (6H, m). ESI [M + H] = 317.0
Mp: 181-183 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.59 (1H, d, J = 3.6 Hz), 6.85 (1H, d, J = 3.6 Hz), 2.21-1.89 (6H, m), 1.54-1.47 (3H, m), 1.28-1.05 (6H, m). ESI [M + H] = 317.0

합성예Synthetic example 40: 2- 40: 2- 사이클로헥실Cyclohexyl -- N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-4- days) 아세토하이드라자이드Acetohydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 77.8% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 77.8%.

Mp: 193-195 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.30 (2H, s), 7.60 (1H, s), 6.85 (1H, d, J= 2.8 Hz), 2.08 (2H, d, J = 6.8 Hz), 1.83-1.61 (5H, m), 1.28-1.00 (4H, m), 0.98-0.88 (2H, m). ESI [M + H] = 303.8.
Mp: 193-195 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.30 (2H, s), 7.60 (1H, s), 6.85 (1H, d, J = 2.8 Hz), 2.08 (2H, d, J = 6.8 Hz), 1.83-1.61 (5H, m), 1.28-1.00 (4H, m), 0.98-0.88 (2H, m). ESI [M + H] = 303.8.

합성예Synthetic example 41: 4- 41: 4- 사이클로헥실Cyclohexyl -- N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-4- days) 부탄하이드라자이드Butanehydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 76.7% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 76.7%.

Mp: 159-161 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.58 (1H, d, J = 3.2 Hz), 6.83 (1H, d, J = 4.0 Hz), 2.19 (2H, t, J= 7.6 Hz), 1.81-1.55 (9H, m), 1.32-1.07 (4H, m), 0.98-0.78 (2H, m). ESI [M + H] = 312.9.
Mp: 159-161 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.58 (1H, d, J = 3.2 Hz), 6.83 (1H, d, J = 4.0 Hz), 2.19 (2H , t, J = 7.6 Hz), 1.81-1.55 (9H, m), 1.32-1.07 (4H, m), 0.98-0.78 (2H, m). ESI [M + H] = 312.9.

합성예Synthetic example 42:  42: N'N ' -(3, 5--(3, 5- 디클로로피리딘Dichloropyridine -4-일)-2--4-yl) -2- 아다만틸아세토하이드라자이드Adamantyl Acetohydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 90.0% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 90.0%.

Mp: 195-197 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.52 (1H, d, J = 4.0 Hz), 6.90 (1H, d, J= 4.0 Hz), 1.96 (5H, br), 1.69-1.59 (12H, m). ESI [M + H] = 355.9.
Mp: 195-197 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.52 (1H, d, J = 4.0 Hz), 6.90 (1H, d, J = 4.0 Hz), 1.96 (5H , br), 1.69-1.59 (12H, m). ESI [M + H] = 355.9.

합성예Synthetic example 43:  43: N'N ' -(3, 5--(3, 5- 디클로로피리딘Dichloropyridine -4-일)-2--4-yl) -2- 아다만틸하이드라자이드Adamantylhydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 89.9% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, whereby 89.9% yield was obtained.

Mp: 207-209 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.30 (2H, s), 7.82 (1H, d, J = 4.0 Hz), 6.83 (1H, d, J= 4.0 Hz), 2.05-2.01 (3H, m), 1.93-1.88 (6H, m), 1.77-1.68 (6H, m). ESI [M + H] = 341.9.
Mp: 207-209 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.30 (2H, s), 7.82 (1H, d, J = 4.0 Hz), 6.83 (1H, d, J = 4.0 Hz), 2.05-2.01 (3H, m), 1.93-1.88 (6H, m), 1.77-1.68 (6H, m). ESI [M + H] = 341.9.

합성예Synthetic example 44:  44: N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-3--4-yl) -3- 브로모아다만틸하이드라자이드Bromoadamantylhydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 78.7% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 78.7%.

Mp: 214-216 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.31 (2H, s), 7.78 (1H, d, J = 4.0 Hz), 6.79 (1H, d, J= 4.0 Hz), 2.46 (2H, s), 2.36-2.24 (6H, m), 1.73-1.55 (6H, m). ESI [M + H] = 419.9.
Mp: 214-216 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.31 (2H, s), 7.78 (1H, d, J = 4.0 Hz), 6.79 (1H, d, J = 4.0 Hz), 2.46 (2H , s), 2.36-2.24 (6H, m), 1.73-1.55 (6H, m). ESI [M + H] = 419.9.

합성예Synthetic example 45:  45: N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-3,5--4-yl) -3,5- 디메틸아다만틸하이드라자이드Dimethyladamantylhydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 93.1% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 93.1%.

Mp: 162-164 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.82 (1H, d, J = 4.0 Hz), 6.79 (1H, d, J = 4.4 Hz0 m), 1.71 (2H, d, J = 2.8 Hz), 1.51 (4H, q, J = 12.8 Hz), 1.51 (4H, q, J = 10.6 Hz), 1.36-1.15 (2H, m), 0.85 (6H, s). ESI [M + H] = 369.8.
Mp: 162-164 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.82 (1H, d, J = 4.0 Hz), 6.79 (1H, d, J = 4.4 Hz 0 m), 1.71 ( 2H, d, J = 2.8 Hz), 1.51 (4H, q, J = 12.8 Hz), 1.51 (4H, q, J = 10.6 Hz), 1.36-1.15 (2H, m), 0.85 (6H, s). ESI [M + H] = 369.8.

합성예Synthetic example 46: 46: N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-2--4-yl) -2- nor아다만틸하이드라자이드noradamantylhydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 71.3% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 71.3%.

Mp: 198-200 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.30 (2H, s), 7.74 (1H, d, J = 4.0 Hz), 6.85 (1H, d, J = 3.6 Hz), 2.70 (1H, t, J= 6.6 Hz), 2.33 (2H, br), 2.01-1.99 (2H, m), 1.48-1.66 (4H, m), 1.64-1.59 (4H, m). ESI [M + H] = 328.0.
Mp: 198-200 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.30 (2H, s), 7.74 (1H, d, J = 4.0 Hz), 6.85 (1H, d, J = 3.6 Hz), 2.70 (1H , t, J = 6.6 Hz), 2.33 (2H, br), 2.01-1.99 (2H, m), 1.48-1.66 (4H, m), 1.64-1.59 (4H, m). ESI [M + H] = 328.0.

합성예Synthetic example 47:  47: N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-4- days) 비사이클로Bicyclo [2.2.1]헵탄-2-[2.2.1] heptan-2- 카보하이드라Carbohydra 자이드Zayed

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 84.3% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 84.3%.

Mp: 180-182 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.31 (2H, s), 7.60 (1H, d, J = 3.6 Hz), 6.84 (1H, d, J= 4.0 Hz), 2.68-2.64 (1H, m), 2.48-2.26 (3H, m), 1.65-1.27 (7H, m). ESI [M + H] = 301.7.
Mp: 180-182 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.31 (2H, s), 7.60 (1H, d, J = 3.6 Hz), 6.84 (1H, d, J = 4.0 Hz), 2.68-2.64 (1H, m), 2.48-2.26 (3H, m), 1.65-1.27 (7H, m). ESI [M + H] = 301.7.

합성예Synthetic example 48: 48: 2-(2-( 비사이클로[2.2.1]헵탄Bicyclo [2.2.1] heptane -2-일)--2 days)- N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-4- days) 아세토Aceto 하이드라자이드Hydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 80.1% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, whereby 80.1% yield was obtained.

Mp: 173-175 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.30 (2H, s), 7.55 (1H, d, J = 3.6 Hz), 6.86 (1H, d, J = 4.0 Hz), 2.13 (2H, d, J= 7.6 Hz), 2.04-1.99 (1H, m), 1.72-1.40 (8H, m), 1.24-1.09 (2H, m). ESI [M + H] = 315.7.
Mp: 173-175 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.30 (2H, s), 7.55 (1H, d, J = 3.6 Hz), 6.86 (1H, d, J = 4.0 Hz), 2.13 (2H , d, J = 7.6 Hz), 2.04-1.99 (1H, m), 1.72-1.40 (8H, m), 1.24-1.09 (2H, m). ESI [M + H] = 315.7.

합성예Synthetic example 49: 49: N'N ' -(3,5--(3,5- 디클로로피리딘Dichloropyridine -4-일)-4- days) 비사이클로Bicyclo [2.2.1][2.2.1] 헵타Hepta -5-엔-2--5-en-2- 카보Cabo 하이드라자이드Hydrazide

합성예 1과 동일한 대표 합성법을 통하여 합성을 수행하였으며, 69.0% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 1, and obtained at a yield of 69.0%.

Mp: 186-188 °C. 1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.57 (1H, d, J = 4.0 Hz), 6.80 (1H, d, J = 4.0 Hz), 6.22 (1H, q, J = 3.0 Hz), 5.93 (1H, q, J= 3.0 Hz), 3.18 (1H, br), 2.94-2.88 (2H, m), 1.98-1.91 (1H, m), 1.58-1.24 (3H, m). ESI [M + H] = 299.7.
Mp: 186-188 ° C. 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.29 (2H, s), 7.57 (1H, d, J = 4.0 Hz), 6.80 (1H, d, J = 4.0 Hz), 6.22 (1H , q, J = 3.0 Hz), 5.93 (1H, q, J = 3.0 Hz), 3.18 (1H, br), 2.94-2.88 (2H, m), 1.98-1.91 (1H, m), 1.58-1.24 ( 3H, m). ESI [M + H] = 299.7.

합성예Synthetic example 50: 3,5- 50: 3,5- 디클로로Dichloro -1--One- 메틸methyl -4-(2-(3.5--4- (2- (3.5- 디메틸아다만타닐카르보닐Dimethyladamantylcarbonyl ) ) 하이드라지닐Hydrazinyl )) 피리디늄Pyridinium

합성예 45의 중간체(73.6 mg, 0.2 mmol)를 아이오도메탄(과량)와 함께 무수메탄올(3ml)에 용해시켰다. 혼합액을 60℃에서 12 시간 반응 후, 에테르 (10ml)로 희석하여 추출되는 물질을 여과하고 에테르(10ml)로 2회 세척하여 63.2 % 수득율로 획득하였다The intermediate of Synthesis Example 45 (73.6 mg, 0.2 mmol) was dissolved in anhydrous methanol (3 ml) with iodomethane (excess). After the reaction mixture was reacted at 60 ° C. for 12 hours, the extracted material was diluted with ether (10 ml), filtered and washed twice with ether (10 ml) to obtain 63.2% yield.

1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 10.25 (1H, s), 9.82 (1H, s), 8.79 (2H, s), 3.93 (3H, s), 2.06-2.03 (1H, m), 1.66 (2H, d, J = 2.4 Hz), 1.45 (4H, q, J = 13.0 Hz), 1.30 (4H, q, J = 10.8 Hz), 1.14-1.07 (2H, m), 0.79 (6H, s). ESI [M + H] = 384.0.
 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 10.25 (1H, s), 9.82 (1H, s), 8.79 (2H, s), 3.93 (3H, s), 2.06-2.03 (1H, m), 1.66 (2H, d, J = 2.4 Hz), 1.45 (4H, q, J = 13.0 Hz), 1.30 (4H, q, J = 10.8 Hz), 1.14-1.07 (2H, m), 0.79 ( 6H, s). ESI [M + H] = 384.0.

합성예Synthetic example 51: 3- 51: 3- 페닐Phenyl -- N'N ' -(7H-퓨린-6-일)-(7H-purin-6-day) 프로판하이드라자이드Propanehydrazide

합성예 24와 동일한 대표 합성법을 통하여 합성을 수행하였으며, 77.4% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 24, and obtained at a yield of 77.4%.

1H NMR (DMSO, 400MHz, δ ppm, J in Hz) 9.84 (1H, br), 9.30 (1H, br), 8.28 (1H, s), 8.13 (1H, s), 7.27-7.24 (5H, m), 2.98 (2H, t, J = 7.8 Hz), 2.66 (2H, t, J = 8.0 Hz). ESI [M + H] = 283.1.
 1 H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 9.84 (1H, br), 9.30 (1H, br), 8.28 (1H, s), 8.13 (1H, s), 7.27-7.24 (5H, m ), 2.98 (2H, t, J = 7.8 Hz), 2.66 (2H, t, J = 8.0 Hz). ESI [M + H] = 283.1.

합성예Synthetic example 52: 3- 52: 3- 사이클로헥실Cyclohexyl -- N'N ' -(7H-퓨린-6-일)-(7H-purin-6-day) 프로판하이드라자이드Propanehydrazide

합성예 24와 동일한 대표 합성법을 통하여 합성을 수행하였으며, 84.7% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 24, and obtained at an yield of 84.7%.

1H NMR (DMSO, 400MHz, δ ppm, J in Hz) 9.83 (1H, br), 9.30 (1H, br), 8.19 (1H, s), 8.14 (1H, s), 2.17 (2H, t, J = 7.6 Hz), 1.69-1.56 (5H, m), 1.41 (2H, q, J = 7.4 Hz), 1.18-1.03 (4H, m), 0.82 (2H, q, J = 11.2 Hz). ESI [M + H] = 289.1
 1 H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 9.83 (1H, br), 9.30 (1H, br), 8.19 (1H, s), 8.14 (1H, s), 2.17 (2H, t, J = 7.6 Hz), 1.69-1.56 (5H, m), 1.41 (2H, q, J = 7.4 Hz), 1.18-1.03 (4H, m), 0.82 (2H, q, J = 11.2 Hz). ESI [M + H] = 289.1

합성예Synthetic example 53:  53: N'N ' -(7H-퓨린-6-일)3,5--(7H-purin-6-yl) 3,5- 디메틸아다만타닐하이드라자이드Dimethyladamantanylhydrazide

합성예 24와 동일한 대표 합성법을 통하여 합성을 수행하였으며, 81.3% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 24, and obtained at 81.3% yield.

1H NMR (DMSO, 400MHz, δ ppm, J in Hz) 9.48 (1H, br), 9.13 (1H, br), 8.17 (1H, s), 8.11 (1H, s), 2.05 (1H, s), 1.69 (2H, s), 1.49 (4H, q, J = 13.4 Hz), 1.30 (4H, q, J = 11.2 Hz), 1.10 (2H, s), 0.80 (6H, s),. ESI [M + H] = 341.3
 1 H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 9.48 (1H, br), 9.13 (1H, br), 8.17 (1H, s), 8.11 (1H, s), 2.05 (1H, s), 1.69 (2H, s), 1.49 (4H, q, J = 13.4 Hz), 1.30 (4H, q, J = 11.2 Hz), 1.10 (2H, s), 0.80 (6H, s) ,. ESI [M + H] = 341.3

합성예Synthetic example 54:  54: N'N ' -(2--(2- 클로로Chloro -7H-퓨린-6-일)-3--7H-purin-6-yl) -3- 페닐프로판하이드라자이드Phenylpropanehydrazide

합성예 24와 동일한 대표 합성법을 통하여 합성을 수행하였으며, 68.7% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 24, and obtained at a yield of 68.7%.

1H NMR (DMSO, 400MHz, δ ppm, J in Hz) 10.02 (1H, br), 9.58 (1H, br), 8.19 (1H, s), 7.28-7.14 (5H, m), 2.86 (2H, t, J = 7.6 Hz), 2.49 (2H, t, J = 7.8 Hz). ESI [M + H] = 317.3.
 1 H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 10.02 (1H, br), 9.58 (1H, br), 8.19 (1H, s), 7.28-7.14 (5H, m), 2.86 (2H, t , J = 7.6 Hz), 2.49 (2H, t, J = 7.8 Hz). ESI [M + H] = 317.3.

합성예Synthetic example 55:  55: N'N ' -(2--(2- 클로로Chloro -7H-퓨린-6-일)-7H-purin-6-day) 아다만타닐하이드라자이드Adamantanylhydrazide

합성예 24와 동일한 대표 합성법을 통하여 합성을 수행하였으며, 66.7% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 24, and obtained at a yield of 66.7%.

1H NMR (DMSO, 400MHz, δ ppm, J in Hz) 9.56 (1H, br), 9.31 (1H, br), 8.12 (1H, s), zt0r). ESI [M + H] = 347.4
 1 H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 9.56 (1H, br), 9.31 (1H, br), 8.12 (1H, s), zt0r). ESI [M + H] = 347.4

합성예Synthetic example 56:  56: N'N ' -(2--(2- 클로로Chloro -7H-퓨린-6-일)3,5--7H-purin-6-yl) 3,5- 디메틸아다만타닐하이드라자이드Dimethyladamantanylhydrazide

합성예 24와 동일한 대표 합성법을 통하여 합성을 수행하였으며,80.9% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 24, and obtained at an yield of 80.9%.

1H NMR (DMSO, 400MHz, δ ppm, J in Hz) 9.51 (1H, br), 9.16 (1H, br), 8.15 (1H, s), 2.04 (1H, s), 1.70 (2H, s), 1.49 (4H, q, J = 13.2 Hz), 1.29 (4H, q, J = 10.8 Hz), 1.10 (2H, s), 0.79 (6H, s),. ESI [M + H] = 375.3
 1 H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 9.51 (1H, br), 9.16 (1H, br), 8.15 (1H, s), 2.04 (1H, s), 1.70 (2H, s), 1.49 (4H, q, J = 13.2 Hz), 1.29 (4H, q, J = 10.8 Hz), 1.10 (2H, s), 0.79 (6H, s). ESI [M + H] = 375.3

합성예Synthetic example 57: 3- 57: 3- 사이클로헥실Cyclohexyl -- N'N ' -(7H-퓨린-2-일)-(7H-purin-2-yl) 프로판하이드라자이드Propanehydrazide

합성예 24와 동일한 대표 합성법을 통하여 합성을 수행하였으며,62.3% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 24, and obtained at a yield of 62.3%.

1H NMR (DMSO, 400MHz, δ ppm, J in Hz) 9.74 (1H, s), 8.90 (1H, br), 8.72 (1H, s), 8.30 (1H, br), 2.13 (2H, t, J = 7.8 Hz), 1.68-1.57 (5H, m), 1.40 (2H, q, J = 7.4 Hz), 1.14-1.09 (4H, m), 0.82 (2H, q, J = 11.0 Hz). ESI [M + H] = 289.1
 1 H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 9.74 (1H, s), 8.90 (1H, br), 8.72 (1H, s), 8.30 (1H, br), 2.13 (2H, t, J = 7.8 Hz), 1.68-1.57 (5H, m), 1.40 (2H, q, J = 7.4 Hz), 1.14-1.09 (4H, m), 0.82 (2H, q, J = 11.0 Hz). ESI [M + H] = 289.1

합성예Synthetic example 58:  58: N'N ' -(7H-퓨린-2-일)-(7H-purin-2-yl) 아다만타닐하이드라자이드Adamantanylhydrazide

합성예 24와 동일한 대표 합성법을 통하여 합성을 수행하였으며,85.4% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 24, and obtained at a yield of 85.4%.

1H NMR (DMSO, 400MHz, δ ppm, J in Hz) 9.34 (1H, s), 8.65 (1H, s), 8.43 (1H, br), 8.10 (1H, br), 1.95 (3H, br), 1.85 (6H, br), 1.62 (6H, br). ESI [M + H] = 313.4
 1 H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 9.34 (1H, s), 8.65 (1H, s), 8.43 (1H, br), 8.10 (1H, br), 1.95 (3H, br), 1.85 (6 H, br), 1.62 (6 H, br). ESI [M + H] = 313.4

합성예Synthetic example 59:  59: N'N ' -(7H-퓨린-2-일)3,5--(7H-purin-2-yl) 3,5- di메틸아다만타닐하이드라자이드dimethyladamantanylhydrazide

합성예 24와 동일한 대표 합성법을 통하여 합성을 수행하였으며,76.8% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 24, and obtained at a yield of 76.8%.

1H NMR (CDCl3, 400MHz, δ ppm, J in Hz) 8.68 (1H, s), 8.47 (1H, br), 8.11 (1H, br), 7.90 (1H, s), 2.13 (1H, t, J = 3.0 Hz), 1.77 (2H, s), 1.55 (4H, q, J = 12.4 Hz), 1.32 (4H, q, J = 11.0 Hz), 1.15 (2H, s), 0.79 (6H, s),. ESI [M + H] = 341.4
 1 H NMR (CDCl 3 , 400 MHz, δ ppm, J in Hz) 8.68 (1H, s), 8.47 (1H, br), 8.11 (1H, br), 7.90 (1H, s), 2.13 (1H, t, J = 3.0 Hz), 1.77 (2H, s), 1.55 (4H, q, J = 12.4 Hz), 1.32 (4H, q, J = 11.0 Hz), 1.15 (2H, s), 0.79 (6H, s) ,. ESI [M + H] = 341.4

합성예Synthetic example 60:  60: N'N ' -(7--(7- 클로로퀴놀린Chloroquinoline -4-일)- 3,5--4-yl) -3,5- di메틸아다만타닐하이드라자이드dimethyladamantanylhydrazide

합성예 24와 동일한 대표 합성법을 통하여 합성을 수행하였으며,80.4% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 24, and obtained at an yield of 80.4%.

1H NMR (DMSO, 400MHz, δ ppm, J in Hz) 9.86 (1H, s), 9.23 (1H, s), 8.45 (1H, d, J = 5.2 Hz), 8.25 (1H, d, J = 8.8 Hz ), 7.84 (1H, s), 7.50 (1H, d, J = 8.8 Hz), 2.00 (1H, s), 1.68 (2H, s),1.44 (4H, q, J = 13.2 Hz), 1.20 (4H, q, J = 10.8 Hz), 1.02 (2H, s), 0.80 (6H, s),. ESI [M + H] = 385.0
 1 H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 9.86 (1H, s), 9.23 (1H, s), 8.45 (1H, d, J = 5.2 Hz), 8.25 (1H, d, J = 8.8 Hz), 7.84 (1H, s), 7.50 (1H, d, J = 8.8 Hz), 2.00 (1H, s), 1.68 (2H, s), 1.44 (4H, q, J = 13.2 Hz), 1.20 ( 4H, q, J = 10.8 Hz), 1.02 (2H, s), 0.80 (6H, s). ESI [M + H] = 385.0

합성예Synthetic example 61:  61: N'N ' -(7--(7- 클로로퀴놀린Chloroquinoline -4-일)-3--4-yl) -3- 페닐프로판하이드라자이드Phenylpropanehydrazide

합성예 24와 동일한 대표 합성법을 통하여 합성을 수행하였으며,84.0% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 24, and obtained at an yield of 84.0%.

1H NMR (DMSO, 400MHz, δ ppm, J in Hz) 9.86 (1H, s), 9.23(1H, s), 8.45(1H, d, J = 5.2 Hz), 8.25 (1H, d, J = 8.8 Hz), 7.84 (1H, s), 7.50 (1H, d, J = 8.8 Hz), 6.53 (1H, d, J= 4.8 Hz). ESI [M + H] = 370.1
 1 H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 9.86 (1H, s), 9.23 (1H, s), 8.45 (1H, d, J = 5.2 Hz), 8.25 (1H, d, J = 8.8 Hz), 7.84 (1H, s), 7.50 (1H, d, J = 8.8 Hz), 6.53 (1H, d, J = 4.8 Hz). ESI [M + H] = 370.1

합성예Synthetic example 62: 62: 3-3- 페닐Phenyl -- N'N ' -(퀴놀린-4-일)-(Quinolin-4-yl) 프로판하이드라자이드Propanehydrazide

합성예 24와 동일한 대표 합성법을 통하여 합성을 수행하였으며,44.7% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 24, and obtained at a yield of 44.7%.

1H NMR (DMSO, 400MHz, δ ppm, J in Hz) 9.91 (1H, s), 9.06 (1H, s), 8.30 (1H, d, J = 5.2 Hz), 8.16 (1H, d, J = 8.4 Hz), 7.80 (1H, d J = 8.4 Hz), 7.61 (1H, t, J = 7.6 Hz), 7.42 (1H, t, J = 7.6 Hz), 7.33-7.23 (5H, m), 6.18 (1H, d, J = 5.2 Hz), 2.90 (2H, t, J = 7.6 Hz), 2.57 (2H, t, J = 7.6 Hz). ESI [M + H] = 292.4
 1 H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 9.91 (1H, s), 9.06 (1H, s), 8.30 (1H, d, J = 5.2 Hz), 8.16 (1H, d, J = 8.4 Hz), 7.80 (1H, d J = 8.4 Hz), 7.61 (1H, t, J = 7.6 Hz), 7.42 (1H, t, J = 7.6 Hz), 7.33-7.23 (5H, m), 6.18 (1H) , d, J = 5.2 Hz), 2.90 (2H, t, J = 7.6 Hz), 2.57 (2H, t, J = 7.6 Hz). ESI [M + H] = 292.4

합성예Synthetic example 63: 3- 63: 3- 페닐Phenyl -- N'N ' -(퀴놀린-3-일)-(Quinolin-3-yl) 프로판하이드라자이드Propanehydrazide

합성예 24와 동일한 대표 합성법을 통하여 합성을 수행하였으며,68.2% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 24, and obtained at a yield of 68.2%.

1H NMR (DMSO, 400MHz, δ ppm, J in Hz) 11.60 (1H, s) 8.43 (1H, s), 7.87 (1H, s), 7.75 (1H, d, J = 7.2 Hz), 7.24 (5H, m), 7.15 (2H, m), 7.08 (1H, t, J = 8Hz), 6.80(1H, s), 2.94 (2H, t, J = 8 Hz), 2.67 (2H, t, J = 8 Hz). ESI [M + H] = 292.4
 1 H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 11.60 (1H, s) 8.43 (1H, s), 7.87 (1H, s), 7.75 (1H, d, J = 7.2 Hz), 7.24 (5H , m), 7.15 (2H, m), 7.08 (1H, t, J = 8 Hz), 6.80 (1H, s), 2.94 (2H, t, J = 8 Hz), 2.67 (2H, t, J = 8 Hz). ESI [M + H] = 292.4

합성예Synthetic example 64:  64: N'N ' -(퀴놀린-3-일)-3,5--(Quinolin-3-yl) -3,5- 디메틸아다만타닐카보하이드라자이드Dimethyl adamantanyl carbohydrazide

합성예 24와 동일한 대표 합성법을 통하여 합성을 수행하였으며,63.3% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 24, and obtained at a yield of 63.3%.

1H NMR (DMSO, 400MHz, δ ppm, J in Hz) 11.14 (1H, s), 10.21 (1H, s), 8.71 (1H, d, J = 8 Hz), 7.66 (1H, s), 7.63 (1H, d, J = 8 Hz), 7.30 (1H, t, J = 8 Hz), 7.10 (1H, d, J = 8 Hz), 6.70 (1H, s), 2.16 (1H, m),1.85 (2H, d, J = 4 Hz), 1.64 (4H, q, J = 12.4 Hz), 1.38 ( 4H, q, J = 11.0 Hz), 1.18 (2H, s), 0.86 (6H, s). ESI [M + H] = 350.3
 1 H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 11.14 (1H, s), 10.21 (1H, s), 8.71 (1H, d, J = 8 Hz), 7.66 (1H, s), 7.63 ( 1H, d, J = 8 Hz), 7.30 (1H, t, J = 8 Hz), 7.10 (1H, d, J = 8 Hz), 6.70 (1H, s), 2.16 (1H, m), 1.85 ( 2H, d, J = 4 Hz), 1.64 (4H, q, J = 12.4 Hz), 1.38 (4H, q, J = 11.0 Hz), 1.18 (2H, s), 0.86 (6H, s). ESI [M + H] = 350.3

합성예Synthetic example 65: 3- 65: 3- 페닐Phenyl -- N'N ' -(퀴놀린-2-일)-(Quinolin-2-yl) 프로판하이드라자이드Propanehydrazide

합성예 24와 동일한 대표 합성법을 통하여 합성을 수행하였으며, 71.6% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 24, and obtained at a yield of 71.6%.

1H NMR (DMSO, 400MHz, δ ppm, J in Hz) 9.85 (1H, s), 8.75 (1H, s), 7.94 (1H, d, J = 9.2 Hz), 7.68 (1H, d, J = 7.6 Hz), 7.51-7.50 (2H, m), 7.26-7.19 (6H, m) 6.67 (1H, d, J = 8 Hz), 2.88 (2H, t, J = 8 Hz), 2.51 (2H, t, J = 8Hz). ESI [M + H] = 292.4
 1 H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 9.85 (1H, s), 8.75 (1H, s), 7.94 (1H, d, J = 9.2 Hz), 7.68 (1H, d, J = 7.6 Hz), 7.51-7.50 (2H, m), 7.26-7.19 (6H, m) 6.67 (1H, d, J = 8 Hz), 2.88 (2H, t, J = 8 Hz), 2.51 (2H, t, J = 8 Hz). ESI [M + H] = 292.4

합성예Synthetic example 66:  66: N'N ' -(퀴놀린-2-일)-3,5--(Quinolin-2-yl) -3,5- 디메틸아다만타닐카보하이드라자이드Dimethyl adamantanyl carbohydrazide

합성예 24와 동일한 대표 합성법을 통하여 합성을 수행하였으며, 72.5% 수득율로 수득하였다.Synthesis was carried out through the same representative synthesis method as in Synthesis Example 24, and obtained at a yield of 72.5%.

1H NMR (DMSO, 400MHz, δ ppm, J in Hz) 9.47 (1H, s), 8.59 (1H, s), 7.98 (1H, d, J = 9.2 Hz), 7.67 (1H, d, J = 8 Hz), 7.51-7.48 (2H, m), 7.21 (1H, d, J = 8 Hz), 6.78 (1H, d, J = 8,8 Hz), 2.08-2.05 (1H, m), 1.72 (2H, d, J = 4Hz), 1.51 (4H, q, J = 40 Hz), 1.31 ( 4H, q, J = 36 Hz), 1.12 (1H, s), 0.81 (6H, s). ESI [M + H] = 350.3
 1 H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 9.47 (1H, s), 8.59 (1H, s), 7.98 (1H, d, J = 9.2 Hz), 7.67 (1H, d, J = 8 Hz), 7.51-7.48 (2H, m), 7.21 (1H, d, J = 8 Hz), 6.78 (1H, d, J = 8,8 Hz), 2.08-2.05 (1H, m), 1.72 (2H , d, J = 4 Hz), 1.51 (4H, q, J = 40 Hz), 1.31 (4H, q, J = 36 Hz), 1.12 (1H, s), 0.81 (6H, s). ESI [M + H] = 350.3

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. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

Claims (8)

하기의 화학식 1로 표시되는 하이드라진 유도체:
화학식 1
Figure pat00077

상기 화학식에서, R1은 알킬, 알케닐, 할로알킬, -C(O)알킬, -C(O)할로알킬, -C(O)아릴알킬, -C(O)알킬할로아릴, -C(O)할로아릴, -C(O)O(알킬), -C(O)O(알킬아릴), -C(O)NH2, -C(O)N(H)(알킬), -C(O)N(알킬)2, -C(O)OH, 또는 -C(O)O알킬이고, R2는
Figure pat00078
(A1-A4는 각각 독립적으로 수소, 할로, 할로, 히드록시, 아미노, 니트로, 니트로소, 시아노, C1-C20 알킬, C2-C20 알케닐, C1-C20 알콕시, C2-C20 알콕시알킬, C3 -30 알콕시알콕시알킬, 아릴, 헤테로아릴, 아릴알킬, 아릴알케닐 또는 알킬아릴이다),
Figure pat00079
(B1-B5는 각각 독립적으로 수소, 할로, 할로, 히드록시, 아미노, 니트로, 니트로소, 시아노, C1-C20 알킬, C2-C20 알케닐, C1-C20 알콕시, C2 -C20 알콕시알킬, C3 -30 알콕시알콕시알킬, 아릴, 헤테로아릴, 아릴알킬, 아릴알케닐 또는 알킬아릴) 또는 고리 내 질소가 알킬화된 이의 염(salt),
Figure pat00080
(C1-C2는 각각 독립적으로 수소, 할로, 할로, 히드록시, 아미노, 니트로, 니트로소, 시아노, C1-C20 알킬, C2-C20 알케닐, C1-C20 알콕시, C2 -C20 알콕시알킬, C3 -30 알콕시알콕시알킬, 아릴, 헤테로아릴, 아릴알킬, 아릴알케닐 또는 알킬아릴),
Figure pat00081
(D1-D2는 각각 독립적으로 수소, 할로, 할로, 히드록시, 아미노, 니트로, 니트로소, 시아노, C1-C20 알킬, C2-C20 알케닐, C1-C20 알콕시, C2 -C20 알콕시알킬, C3 -30 알콕시알콕시알킬, 아릴, 헤테로아릴, 아릴알킬, 아릴알케닐 또는 알킬아릴),
Figure pat00082
(E1-E6은 각각 독립적으로 수소, 할로, 할로, 히드록시, 아미노, 니트로, 니트로소, 시아노, C1-C20 알킬, C2-C20 알케닐, C1-C20 알콕시, C2 -C20 알콕시알킬, C3 -30 알콕시알콕시알킬, 아릴, 헤테로아릴, 아릴알킬, 아릴알케닐 또는 알킬아릴) 또는 고리 내 질소가 알킬화 된 이의 염(salt),
Figure pat00083
(F1-F6은 각각 독립적으로 수소, 할로, 할로, 히드록시, 아미노, 니트로, 니트로소, 시아노, C1-C20 알킬, C2-C20 알케닐, C1-C20 알콕시, C2 -C20 알콕시알킬, C3 -30 알콕시알콕시알킬, 아릴, 헤테로아릴, 아릴알킬, 아릴알케닐 또는 알킬아릴) 또는 고리 내 질소가 알킬화 된 이의 염(salt) 또는
Figure pat00084
(G1-G6은 각각 독립적으로 수소, 할로, 할로, 히드록시, 아미노, 니트로, 니트로소, 시아노, C1-C20 알킬, C2-C20 알케닐, C1-C20 알콕시, C2 -C20 알콕시알킬, C3 -30 알콕시알콕시알킬, 아릴, 헤테로아릴, 아릴알킬, 아릴알케닐 또는 알킬아릴) 또는 고리 내 질소가 알킬화 된 이의 염(salt)이다.
Hydrazine derivatives represented by Formula 1 below:
Formula 1
Figure pat00077

Wherein R 1 is alkyl, alkenyl, haloalkyl, -C (O) alkyl, -C (O) haloalkyl, -C (O) arylalkyl, -C (O) alkylhaloaryl, -C (O) haloaryl, -C (O) O (alkyl), -C (O) O (alkylaryl), -C (O) NH 2 , -C (O) N (H) (alkyl), -C (O) N (alkyl) 2 , -C (O) OH, or -C (O) Oalkyl, R 2 is
Figure pat00078
(A 1 -A 4 are each independently hydrogen, halo, halo, hydroxy, amino, nitro, nitroso, cyano, C 1 -C 20 alkyl, C 2 -C 20 Alkenyl, C 1 -C 20 Alkoxy, C 2- C 20 alkoxyalkyl, C 3 -30 alkoxyalkoxy, aryl, heteroaryl, arylalkyl, arylalkenyl or an alkyl group),
Figure pat00079
(B 1 -B 5 are each independently hydrogen, halo, halo, hydroxy, amino, nitro, nitroso, cyano, C 1 -C 20 alkyl, C 2 -C 20 Alkenyl, C 1 -C 20 Alkoxy, C 2 - C 20 Alkoxyalkyl, C 3 -30 alkoxyalkoxy, aryl, heteroaryl, arylalkyl, aryl alkenyl, or a salt thereof with an alkyl group) or a ring nitrogen is alkylated (salt),
Figure pat00080
(C 1 -C 2 are each independently hydrogen, halo, halo, hydroxy, amino, nitro, nitroso, cyano, C 1 -C 20 alkyl, C 2 -C 20 Alkenyl, C 1 -C 20 Alkoxy, C 2 - C 20 Alkoxyalkyl, C 3 -30 alkoxyalkoxy, aryl, heteroaryl, arylalkyl, arylalkenyl or alkylaryl),
Figure pat00081
(D 1 -D 2 are each independently hydrogen, halo, halo, hydroxy, amino, nitro, nitroso, cyano, C 1 -C 20 alkyl, C 2 -C 20 Alkenyl, C 1 -C 20 Alkoxy, C 2 - C 20 Alkoxyalkyl, C 3 -30 alkoxyalkoxy, aryl, heteroaryl, arylalkyl, arylalkenyl or alkylaryl),
Figure pat00082
(E 1 -E 6 are each independently hydrogen, halo, halo, hydroxy, amino, nitro, nitroso, cyano, C 1 -C 20 alkyl, C 2 -C 20 Alkenyl, C 1 -C 20 Alkoxy, C 2 - C 20 Alkoxyalkyl, C 3 -30 alkoxyalkoxy, aryl, heteroaryl, arylalkyl, aryl alkenyl, or a salt thereof with an alkyl group) or a ring nitrogen is alkylated (salt),
Figure pat00083
(F 1 -F 6 are each independently hydrogen, halo, halo, hydroxy, amino, nitro, nitroso, cyano, C 1 -C 20 alkyl, C 2 -C 20 Alkenyl, C 1 -C 20 Alkoxy, C 2 - C 20 Alkoxyalkyl, C 3 -30 alkoxyalkoxy, aryl, heteroaryl, arylalkyl, arylalkenyl or alkylaryl) or (salt), a salt thereof, a ring nitrogen is alkylated or
Figure pat00084
(G 1 -G 6 are each independently hydrogen, halo, halo, hydroxy, amino, nitro, nitroso, cyano, C 1 -C 20 alkyl, C 2 -C 20 Alkenyl, C 1 -C 20 Alkoxy, C 2 - C 20 Is alkoxyalkyl, C 3 -30 alkoxyalkoxy, aryl, heteroaryl, arylalkyl, arylalkenyl or alkylaryl) or a salt thereof The ring nitrogen is alkylated (salt).
제 1 항에 있어서, 상기 R1은 -C(O)알킬아릴, -C(O)알킬, -C(O)할로알킬, -C(O)O(아릴알킬) 또는 -C(O)알킬할로아릴이고, R2는 (A1-A4는 각각 독립적으로 수소, 할로겐 또는 알킬) 또는 고리 내 질소가 알킬화 된 이의 염(salt),
Figure pat00086
(B1-B5는 각각 독립적으로 수소, 할로겐 또는 알킬),
Figure pat00087
(C1-C2는 각각 독립적으로 수소, 할로겐 또는 알킬),
Figure pat00088
(D1-D2는 각각 독립적으로 수소, 할로겐 또는 알킬),
Figure pat00089
(E1-E6은 각각 독립적으로 수소, 할로겐 또는 알킬) 또는 고리 내 질소가 알킬화 된 이의 염(salt),
Figure pat00090
(F1-F6은 각각 독립적으로 수소, 할로겐 또는 알킬) 또는 고리 내 질소가 알킬화 된 이의 염(salt) 또는
Figure pat00091
(G1-G6은 각각 독립적으로 수소, 할로겐 또는 알킬이다) 또는 고리 내 질소가 알킬화 된 이의 염(salt)인 것을 특징으로 하는 하이드라진 유도체.
The compound of claim 1, wherein R 1 is —C (O) alkylaryl, —C (O) alkyl, —C (O) haloalkyl, —C (O) O (arylalkyl) or —C (O) alkyl Haloaryl, R 2 is (A 1 -A 4 are each independently hydrogen, halogen or alkyl) or a salt thereof in which the nitrogen in the ring is alkylated,
Figure pat00086
(B 1 -B 5 are each independently hydrogen, halogen or alkyl),
Figure pat00087
(C 1 -C 2 are each independently hydrogen, halogen or alkyl),
Figure pat00088
(D 1 -D 2 are each independently hydrogen, halogen or alkyl),
Figure pat00089
(E 1 -E 6 are each independently hydrogen, halogen or alkyl) or a salt thereof, wherein the nitrogen in the ring is alkylated,
Figure pat00090
(F 1 -F 6 are each independently hydrogen, halogen or alkyl) or a salt thereof in which the nitrogen in the ring is alkylated, or
Figure pat00091
(G 1 -G 6 are each independently hydrogen, halogen or alkyl) or a hydrazine derivative wherein the nitrogen in the ring is an alkylated salt thereof.
제 1 항에 있어서, 상기 하이드라진 유도체는 하기의 화학식 2 내지 51로 표시되는 화합물로 구성된 군으로부터 선택되는 것을 특징으로 하는 하이드라진 유도체.
화학식 2 화학식 3
Figure pat00092
Figure pat00093


화학식 4 화학식 5
Figure pat00094
Figure pat00095


화학식 6 화학식 7
Figure pat00096
Figure pat00097



화학식 8 화학식 9
Figure pat00098
Figure pat00099


화학식 10 화학식 11
Figure pat00100
Figure pat00101


화학식 12 화학식 13
Figure pat00102
Figure pat00103


화학식 14 화학식 15
Figure pat00104
Figure pat00105


화학식 16 화학식 17
Figure pat00106
Figure pat00107


화학식 18 화학식 19
Figure pat00108
Figure pat00109




화학식 20 화학식 21
Figure pat00110
Figure pat00111


화학식 22 화학식 23
Figure pat00112
Figure pat00113


화학식 24 화학식 25
Figure pat00114
Figure pat00115


화학식 26 화학식 27
Figure pat00116
Figure pat00117


화학식 28 화학식 29
Figure pat00118
Figure pat00119


화학식 30 화학식 31
Figure pat00120
Figure pat00121



화학식 32 화학식 33
Figure pat00122
Figure pat00123


화학식 34 화학식 35
Figure pat00124
Figure pat00125


화학식 36 화학식 37
Figure pat00126
Figure pat00127



화학식 38 화학식 39
Figure pat00128
Figure pat00129


화학식 40 화학식 41
Figure pat00130
Figure pat00131


화학식 42 화학식 43
Figure pat00132
Figure pat00133



화학식 44 화학식 45
Figure pat00134
Figure pat00135


화학식 46 화학식 47
Figure pat00136
Figure pat00137


화학식 48 화학식 49
Figure pat00138
Figure pat00139


화학식 50 화학식 51
Figure pat00140
Figure pat00141

The hydrazine derivative according to claim 1, wherein the hydrazine derivative is selected from the group consisting of compounds represented by the following Chemical Formulas 2 to 51.
Formula 2 Formula 3
Figure pat00092
Figure pat00093


Formula 4 Formula 5
Figure pat00094
Figure pat00095


Formula 6 Formula 7
Figure pat00096
Figure pat00097



Formula 8 Formula 9
Figure pat00098
Figure pat00099


Formula 10 Formula 11
Figure pat00100
Figure pat00101


Chemical Formula 12 Chemical Formula 13
Figure pat00102
Figure pat00103


Formula 14 Formula 15
Figure pat00104
Figure pat00105


Formula 16 Formula 17
Figure pat00106
Figure pat00107


Formula 18 Formula 19
Figure pat00108
Figure pat00109




Chemical Formula 20 Chemical Formula 21
Figure pat00110
Figure pat00111


Chemical Formula 22 Chemical Formula 23
Figure pat00112
Figure pat00113


Chemical Formula 24 Chemical Formula 25
Figure pat00114
Figure pat00115


Formula 26 Formula 27
Figure pat00116
Figure pat00117


Chemical Formula 28 Chemical Formula 29
Figure pat00118
Figure pat00119


Chemical Formula 30 Chemical Formula 31
Figure pat00120
Figure pat00121



Chemical Formula 32 Chemical Formula 33
Figure pat00122
Figure pat00123


Chemical Formula 34 Chemical Formula 35
Figure pat00124
Figure pat00125


Formula 36 Formula 37
Figure pat00126
Figure pat00127



Formula 38 Formula 39
Figure pat00128
Figure pat00129


Formula 40 Formula 41
Figure pat00130
Figure pat00131


Chemical Formula 42 Chemical Formula 43
Figure pat00132
Figure pat00133



Formula 44 Formula 45
Figure pat00134
Figure pat00135


Chemical Formula 47 Chemical Formula 47
Figure pat00136
Figure pat00137


Chemical Formula 48 Chemical Formula 49
Figure pat00138
Figure pat00139


Chemical Formula 50 Chemical Formula 51
Figure pat00140
Figure pat00141

 제 3 항에 있어서, 상기 하이드라진 유도체는 상기의 화학식 5, 6, 10, 11, 12, 13, 15, 18, 20, 21, 22, 23, 24, 28, 30 및 51으로 표시되는 화합물로 이루어진 군으로부터 선택되는 것을 특징으로 하는 하이드라진 유도체.
The method of claim 3, wherein the hydrazine derivative is made of a compound represented by the formula 5, 6, 10, 11, 12, 13, 15, 18, 20, 21, 22, 23, 24, 28, 30 and 51 Hydrazine derivatives, characterized in that selected from the group.
제 1 항 내지 제 4 항 중 어느 한 항의 하이드라진 유도체를 유효성분으로 포함하는 만성 염증성 질환, 염증성 통증, 신경병성 통증, 자가면역 질환 또는 퇴행성 질환의 예방 또는 치료용 조성물.
A composition for preventing or treating chronic inflammatory disease, inflammatory pain, neuropathic pain, autoimmune disease or degenerative disease comprising the hydrazine derivative of any one of claims 1 to 4 as an active ingredient.
제 5 항에 있어서, 상기 자가면역 질환은 류마티스 관절염, 건선, 알러지성 피부염, 다발성 경화증 및 천식으로 구성된 군으로부터 선택되는 질환인 것을 특징으로 하는 조성물.
6. The composition of claim 5, wherein the autoimmune disease is a disease selected from the group consisting of rheumatoid arthritis, psoriasis, allergic dermatitis, multiple sclerosis and asthma.
제 5 항에 있어서, 상기 만성 염증성 질환은 만성폐쇄성 폐질환(chronic obstructive pμlmonary disease), 기도 과민성 질환(airways hyper-responsiveness), 폐혈성 쇼크(septic shock), 사구체 신염, 염증성 장질환(염증), 크론 병(Crohn's disease), 궤양잘록창자염(μlcerative colitis), 아테롬성 동맥경화증, 골수아구 세포성 백혈병(myoblastic leukaemia), 당뇨, 화상, 허혈성 심장질환, 뇌졸중, 수막염 및 정맥류로 구성된 군으로부터 선택되는 질환인 것을 특징으로 하는 조성물.
The method of claim 5, wherein the chronic inflammatory disease is chronic obstructive pμlmonary 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 varicose veins The composition characterized in that the.
제 5 항에 있어서, 상기 퇴행성 질환은 알츠하이머 병, 수막염, 골다공증 및 퇴행성 관절염으로 구성된 군으로부터 선택되는 질환인 것을 특징으로 하는 조성물. 6. The composition of claim 5, 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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US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors

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US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors

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