KR20030035589A - Melanocortin receptor agonists - Google Patents

Melanocortin receptor agonists Download PDF

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KR20030035589A
KR20030035589A KR1020010067702A KR20010067702A KR20030035589A KR 20030035589 A KR20030035589 A KR 20030035589A KR 1020010067702 A KR1020010067702 A KR 1020010067702A KR 20010067702 A KR20010067702 A KR 20010067702A KR 20030035589 A KR20030035589 A KR 20030035589A
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boc
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이구
박희술
정원혁
안인애
유현주
최덕영
심동섭
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주식회사 엘지생명과학
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

PURPOSE: Provided are a melanocortin 4 receptor(MC4R) agonist and a composition for containing the same, to accelerate the function of the melanocortin 4 receiptor(MC4R), so as to prevent and treat diseases associated with the MC4R such as obesity, penile erection disorder, diabetes and inflammation. CONSTITUTION: Compounds functioning as a melanocortin 4 receptor(MC4R) agonist are represented by formula(1), wherein A is hydrogen, COR1, CO2R1, SO2R1, SO2NHR1, SO2N(R1)2, PO(OR1)2, C1-C8-alkyl, (CH2)n-C5-C7-aryl, or (CH2)n-C5-C7-heteroaryl in which R1 is hydrogen, C1-C8-alkyl, (CH2)n-C3-C7-cycloalkyl, (CH2)n-C5-C7-aryl or (CH2)n-C5-C7-heteroaryl and n is an integer of 1 to 7; B and E are independently hydrogen, C1-C8-alkyl, (CH2)n-C3-C7-cycloalkyl, (CH2)n-C5-C7-aryl, (CH2)n-C5-C7-heteroaryl, (CH2)n-C5-C7-heterocycle or (CH2)n-O(CH2)-C5-C7-aryl in which n is an integer of 1 to 7; Cy is C5-C7-aryl or C5-C7-cycloalkyl which is substituted or unsubstituted by a substituent selected from the group consisting of C1-C5-alkyl, halogen, trifluoromethyl, hydroxy, C1-C3-alkyloxy, amino, (C1-C3-alkyl)amino, di(C1-C3-alkyl)amino, oxo(C=O) and nitro; C is hydrogen, COR1, CO2R1, SO2R1, SO2NHR1, (CH2)m-C1-C8-alkylsulfonyl, (CH2)m-C1-C8-alkoxycarbonyl, amide(CONH2), (CH2)m-C1-C8-alkylcarbamoyl, C(O)-C5-C7-heteroaryl, (CO)-C5-C7-heterocycle, C(O)-(CH2)m-C5-C7-heteroaryl, C(O)-(CH2)m-C5-C7-heterocycle, (CH2)m-C5-C7-heteroaryl or (CH2)m-C5-C7-heterocycle in which R1 is C1-C8-alkyl or C5-C7-aryl and m is an integer of 0 to 2; and D is C5-C10-alkyl, (CH2)m-C5-C7-cycloalkyl, (CH2)m-C5-C7-aryl, (CH2)m-C5-C7-heterocycloalkyl I which m is an integer of 0 to 2.

Description

멜라노코틴 수용체의 항진제 {Melanocortin receptor agonists}Melanocortin receptor agonists

본 발명은 멜라노코틴 수용체에 대한 항진활성이 우수한 하기 화학식 1의 화합물, 약제학적으로 허용되는 그의 염, 수화물, 용매화물 및 이성체에 관한 것이다:The present invention relates to a compound of formula (1), a pharmaceutically acceptable salt, hydrate, solvate and isomer thereof having excellent anti-tumor activity against the melanocortin receptor:

[화학식 1][Formula 1]

상기식에서 B, C, D 및 G는 하기 정의한 바와 같다.In the above formula, B, C, D and G are as defined below.

본 발명은 또한, 상기 화학식 1의 화합물을 유효성분으로 함유함을 특징으로 하는 멜라노코틴 수용체의 기능항진제 조성물에 관한 것이다.The present invention also relates to a melanocortin receptor antagonist composition comprising the compound of Formula 1 as an active ingredient.

프로-오피오멜라노코틴(pro-opiomelanocortin, POMC)은 POMC 유전자에서 유래하며, 뇌의 시상하부, 하수체, 뇌간 등에서 주로 발현되고 번역 후 효소적 수식에 의해 α-멜라닌 세포 자극 호르몬(melanocyte stimulating hormone, MSH), β-MSH, γ-MSH, 부신피질 자극 호르몬(adrenocorticotrophic hormone) 등의 신경 펩티드가 되어 생리효과를 나타낸다. 멜라노코틴 펩티드들은 MCR들 각각에 대한 친화력에 따라 여러 가지 생리현상을 조절하며, 이러한 생리현상으로는 피부색소침착, 체온, 염증, 식욕, 행동조절기능 등이 알려져 있다(참조: Mountjoy KG, et al., Mol Cell Endocrinol 1997, 128, 171).Pro-opiomelanocortin (POMC) is derived from the POMC gene, and is mainly expressed in the hypothalamus, pituitary gland, and brain stem of the brain and is a melanocyte stimulating hormone by post-translational enzymatic modification. , MSH), β-MSH, γ-MSH, adrenal cortical stimulating hormone (adrenocorticotrophic hormone), such as neuropeptides exhibit a physiological effect. Melanocortin peptides regulate a variety of physiological phenomena according to affinity for each of the MCRs, such as skin pigmentation, body temperature, inflammation, appetite, behavioral control is known (Mountjoy KG, et al. , Mol Cell Endocrinol 1997, 128, 171).

멜라노코틴 수용체(melanocortin receptor, MCR)들은 G-단백질 수용체에 속하며 현재까지 모두 5가지 종류가 밝혀져 있다. MCR 1은 멜라닌세포, 대식세포에서 발현되며 멜라닌세포에서는 멜라닌 색소를 조절함으로써 피부와 모발의 색을 결정한다. MCR 2는 부신과 지방조직에서 발현되며 부신에서의 부신피질 자극 호르몬에 의한 부신호르몬 분비조절의 매개기능이 잘 알려져 있다. MCR 3, 4 및 5는 신경 말단뿐만 아니라 뇌에서도 발현되어 행동, 학습, 기억, 식욕, 신경의 발생과 재생 등에 대한 효과로 나타나는 멜라노코틴 펩티드들에 의한 중추 신경 작용을 매개하는 것으로 생각되고 있다. 현재까지 MCR 3은 발기부전 및 염증반응, MCR 4는 비만 및 당뇨병에 관여한다고 알려져 있으나, 각 수용체의 작용 특이성에 대한 연구가 아직 미흡한 실정이다(참조: Haskell-Luevano C, et al., Drug News Perspect 1999, 12, 197). 이 중 특히 MCR 4와 비만과의 관계에 대해서 많은 연구가 이루어졌다. 비만이 활발히 진행된 사람에서의 유전학적 연구에서 MCR 4가 깊이 관여됨을 알았고, MCR 4가 제거된 녹아웃 마이스(knockout mice)가 과식에 의해 비만으로 발전함을 보여주어 이 수용체가 식욕조절에서 중요한 역할을 한다는 것을 증명해주고 있다 (참조: Lu D, Willard D, et al., Nature 1994, 371(6500), 799; Huszar D et al., Cell 1997, 88(1), 131; Hinney A, et al., J Clin Endocrinol Metab 1990, 84(4),1483).Melanocortin receptors (MCRs) belong to the G-protein receptor and all five types have been identified to date. MCR 1 is expressed in melanocytes and macrophages, and in melanocytes, the color of skin and hair is determined by controlling melanin pigment. MCR 2 is expressed in the adrenal and adipose tissues and is well known for the mediating function of parasignal secretion by adrenal cortical stimulating hormone in the adrenal glands. MCRs 3, 4, and 5 are thought to mediate central nervous activity by melanocytes, which are expressed not only in the nerve endings but also in the brain, resulting in effects on behavior, learning, memory, appetite, nerve development and regeneration. To date, MCR 3 is known to be involved in erectile dysfunction and inflammatory response, and MCR 4 is involved in obesity and diabetes, but studies on the specificity of action of each receptor are still insufficient (see Haskell-Luevano C. Perspect 1999, 12, 197). In particular, much research has been conducted on the relationship between MCR 4 and obesity. Genetic studies in actively active obesity have shown that MCR 4 is deeply involved and that knockout mice without MCR 4 have been developed into obesity by overeating, which plays an important role in appetite control. (See Lu D, Willard D, et al., Nature 1994, 371 (6500), 799; Huszar D et al., Cell 1997, 88 (1), 131; Hinney A, et al. , J Clin Endocrinol Metab 1990, 84 (4), 1483).

이처럼 MCR들이 여러 가지 중요한 생리현상의 조절에 관련되어 있음이 밝혀지면서 항진 물질 또는 길항 물질에 대한 탐색이 활발히 이루어졌고, 주로 아미노산의 조합을 변화시킨 펩티드들의 구조활성 상관관계를 통해 연구되어졌다. 대표적인 MCR 항진 펩티드로는 NDP-MSH(Ac-Ser-Tyr-Ser-Nle-Glu-His-DPhe-Arg-Trp-Gly- Lys-Po-Val-NH2)와 MTⅡ(Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2)를 들 수 있고, 이들은 MCR 1, 3, 4, 5에 대해 α-MSH(Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp- Gly-Lys-Po-Val-NH2)보다 강력한 효력을 나타낸다(참조: Haskell-Luevano C, et al., J Med Chem 1997, 40, 1738). 특히 상기 MCR 항진 펩티드 MTⅡ는 피하주사 경로로 흡수된 후 Blood Brain Barrier(BBB)를 통과하여 중추신경계에 대한 효과도 나타내었으며(참조: Dorr RT, et al., Life Sci 1996, 58(20), 1777), 뿐만 아니라 이 물질은 발기를 유발하는 효능을 지니고 있어 최근에 정신적 발기부전을 겪고 있는 남성을 대상으로 한 임상실험에서 효능이 있는 것으로 보고되었다(참조: Wessels, et al. Urology, 2000, 56, 641: Wessels, et al. J. Urol., 1998, 160, 389). 최근에는 소분자형 펩티드도 MC4R에 대해 우수한 항진 효능을 보였으며, 이 물질이 동물실험에서 식욕을 억제하는 효능을 가진다고 보고되었다(참조: Benoit, SC, et al. J. Neuroscience 2000, 20, 3442).As MCRs are found to be involved in the regulation of several important physiological phenomena, the search for anti-inflammatory or antagonists has been actively conducted, mainly through the structural activity correlation of peptides with varying amino acid combinations. Representative MCR agonistic peptides include NDP-MSH (Ac-Ser-Tyr-Ser-Nle-Glu-His-DPhe-Arg-Trp-Gly- Lys-Po-Val-NH 2 ) and MTII (Ac-Nle-c [ Asp-His-DPhe-Arg-Trp-Lys] -NH 2 ), these are α-MSH (Ac-Ser-Tyr-Ser-Met-Glu-His-) for MCR 1, 3, 4, 5 Phe-Arg-Trp-Gly-Lys-Po-Val-NH 2 ) (see Haskell-Luevano C, et al., J Med Chem 1997, 40, 1738). In particular, the MCR anti-binding peptide MTII was also absorbed by the subcutaneous injection route and then passed through the Blood Brain Barrier (BBB) to show effects on the central nervous system (Dorr RT, et al., Life Sci 1996, 58 (20), In addition, the substance has been shown to be effective in clinical trials in men who have recently suffered from erectile dysfunction due to its efficacy in inducing erection (Wessels, et al. Urology, 2000, 56, 641: Wessels, et al. J. Urol., 1998, 160, 389). In recent years, small molecule peptides have also been shown to have good antitumor efficacy against MC4R, and this substance has been reported to have an appetite suppressant effect in animal experiments (Benoit, SC, et al. J. Neuroscience 2000, 20, 3442). .

소분자 MCR 항진제에 대한 연구도 최근에 활발히 진행되고 있다. 비펩티드성 소분자 물질의 라이브러리로부터 고효율 약효시험(High-throughput Screening)을 통하거나, 조합화학을 이용하여 발굴된 MCR 항진제 물질이 최근 보고되었다(참조: WO 01/10842, WO 01/05401, WO 01/23392, WO 01/23887). 또한 성장호르몬 촉진제로서의 활성을 지닌 소분자 물질군으로부터 적절한 구조변화 연구를 통해 발굴된 MC4R에 선택적인 항진제 물질이 보고되었다(참조: WO 99/64002, WO 00/74679).Research into small-molecule MCR agonists is also actively underway. Recently reported MCR adjuvant materials have been reported from high-throughput screening or combinatorial chemistry from libraries of non-peptide small molecule materials (see WO 01/10842, WO 01/05401, WO 01). / 23392, WO 01/23887. In addition, selective anti-inflammatory agents have been reported for MC4R discovered through appropriate structural change studies from a group of small molecule substances having activity as growth hormone promoters (WO 99/64002, WO 00/74679).

따라서, MCR들에 작용하며 각각에 특이성을 보이는 새로운 소분자형 항진물질의 탐색 및 선별에 대한 많은 연구가 필요하다.Therefore, much research is needed on the screening and selection of new small-molecule-type agonists that act on MCRs and are specific to each.

이에 본 발명자들은 특정 MCR에 특이적인 항진활성을 보이는 새로운 소분자형 항진물질을 개발하고자 예의 연구한 결과, 하기 화학식 1의 화합물이 MC4R 선택적으로 항진효능을 나타냄을 발견하고 본 발명을 완성하게 되었다.Accordingly, the present inventors have intensively researched to develop a new small molecule type anti-diarrheal substance that exhibits specific anti-inflammatory activity specific to MCR. As a result, the present inventors have found that the compound represented by the following Chemical Formula 1 selectively exhibits anti-tumor efficacy.

따라서, 본 발명은 MC4R에 대한 선택적인 항진 효능이 뛰어난 화학식 1의 화합물, 그의 약제학적으로 허용되는 염, 수화물, 용매화물, 및 이성체를 제공하는 것을 목적으로 한다.Accordingly, it is an object of the present invention to provide a compound of formula (1), pharmaceutically acceptable salts, hydrates, solvates, and isomers thereof, which are excellent in selective antifungal efficacy against MC4R.

본 발명은 또한, 약제학적으로 허용되는 담체와 함께 유효성분으로서 화학식 1의 화합물을 함유함을 특징으로 하는 멜라노코틴 수용체의 기능항진제 조성물을 제공함을 목적으로 한다.It is another object of the present invention to provide a melanocortin receptor antagonist composition comprising a compound of formula 1 as an active ingredient together with a pharmaceutically acceptable carrier.

특히, 본 발명에 따른 조성물은 비만, 발기부전증, 당뇨병, 및 염증에 대한 예방 및 치료에 우수한 효과를 나타낸다.In particular, the compositions according to the invention exhibit excellent effects in the prevention and treatment of obesity, erectile dysfunction, diabetes, and inflammation.

본 발명은 하기 화학식 1의 화합물, 약제학적으로 허용되는 그의 염, 수화물, 용매화물 및 이성체 화합물을 제공한다.The present invention provides compounds of formula 1, pharmaceutically acceptable salts, hydrates, solvates and isomeric compounds thereof.

[화학식 1][Formula 1]

상기식에서In the above formula

G는 하기 구조중 하나를 나타내고:G represents one of the following structures:

여기에서From here

A는 수소, COR1, CO2R1, SO2R1, SO2NHR1, SO2N(R1)2, PO(OR1)2, C1-C8-알킬, (CH2)n-C5-C7-아릴, 또는 (CH2)n-C5-C7-헤테로아릴을 나타내고, 여기서 R1은 수소, C1-C8-알킬, (CH2)n-C3-C7-사이클로알킬, (CH2)n-C5-C7-아릴, 또는 (CH2)n-C5-C7-헤테로아릴을 나타내며, n은 1 내지 7의 정수를 나타내고, 알킬, 사이클로알킬, 아릴 또는 헤테로아릴은 할로겐, C1-C5-알킬, 트리플루오로메틸, 하이드록시, C1-C3-알킬옥시,아미노, (C1-C3-알킬)아미노, 디(C1-C3-알킬)아미노, 시아노, 카복시(CO2H), 에스테르(CO2-C1-C3-알킬) 및 아미드(CONH2)로 구성된 그룹중에서 선택된 1 내지 3개의 치환체에 의해 치환되거나 비치환되며,A is hydrogen, COR 1 , CO 2 R 1 , SO 2 R 1 , SO 2 NHR 1 , SO 2 N (R 1 ) 2 , PO (OR 1 ) 2 , C 1 -C 8 -alkyl, (CH 2 ) n- C 5 -C 7 -aryl, or (CH 2 ) n -C 5 -C 7 -heteroaryl, wherein R 1 is hydrogen, C 1 -C 8 -alkyl, (CH 2 ) n -C 3 -C 7 -cycloalkyl, (CH 2 ) n -C 5 -C 7 -aryl, or (CH 2 ) n -C 5 -C 7 -heteroaryl, n represents an integer from 1 to 7, and alkyl , Cycloalkyl, aryl or heteroaryl is halogen, C 1 -C 5 -alkyl, trifluoromethyl, hydroxy, C 1 -C 3 -alkyloxy, amino, (C 1 -C 3 -alkyl) amino, di 1-3 substituents selected from the group consisting of (C 1 -C 3 -alkyl) amino, cyano, carboxy (CO 2 H), ester (CO 2 -C 1 -C 3 -alkyl) and amide (CONH 2 ) Substituted or unsubstituted by

B 및 E는 각각 독립적으로 수소, C1-C8-알킬, (CH2)n-C3-C7-사이클로알킬, (CH2)n-C5-C7-아릴, (CH2)n-C5-C7-헤테로아릴, (CH2)n-C5-C7-헤테로사이클 또는 (CH2)n-O(CH2)-C5-C7-아릴을 나타내고, 여기서 알킬, 사이클로알킬, 아릴, 헤테로아릴 또는 헤테로사이클은 할로겐, C1-C5-알킬, 트리플루오로메틸, 하이드록시, C1-C3-알킬옥시, 아미노, (C1-C3-알킬)아미노, 디(C1-C3-알킬)아미노, 시아노, 카복시(CO2H), 에스테르(CO2-C1-C3-알킬), 아미드(CONH2), 아미딘(C(NH)NH2), 니트로 및 페닐로 구성된 그룹중에서 선택된 1 내지 3개의 치환체에 의해 치환되거나 비치환되며, n은 1 내지 7의 정수를 나타내고,B and E are each independently hydrogen, C 1 -C 8 -alkyl, (CH 2 ) n -C 3 -C 7 -cycloalkyl, (CH 2 ) n -C 5 -C 7 -aryl, (CH 2 ) n- C 5 -C 7 -heteroaryl, (CH 2 ) n -C 5 -C 7 -heterocycle or (CH 2 ) n -O (CH 2 ) -C 5 -C 7 -aryl, wherein alkyl , Cycloalkyl, aryl, heteroaryl or heterocycle is halogen, C 1 -C 5 -alkyl, trifluoromethyl, hydroxy, C 1 -C 3 -alkyloxy, amino, (C 1 -C 3 -alkyl) Amino, di (C 1 -C 3 -alkyl) amino, cyano, carboxy (CO 2 H), ester (CO 2 -C 1 -C 3 -alkyl), amide (CONH 2 ), amidine (C (NH ) NH 2 ), substituted or unsubstituted by 1 to 3 substituents selected from the group consisting of phenyl, n represents an integer of 1 to 7,

Cy는 C1-C5-알킬, 할로겐, 트리플루오로메틸, 하이드록시, C1-C3-알킬옥시, 아미노, (C1-C3-알킬)아미노, 디(C1-C3-알킬)아미노, 옥소(C=O) 및 니트로로 구성된 그룹중에서 선택된 치환체에 의해 치환되거나 비치환된 C5-C7-아릴 또는 C5-C7-사이클로알킬을 나타내며,Cy is C 1 -C 5 -alkyl, halogen, trifluoromethyl, hydroxy, C 1 -C 3 -alkyloxy, amino, (C 1 -C 3 -alkyl) amino, di (C 1 -C 3- C 5 -C 7 -aryl or C 5 -C 7 -cycloalkyl unsubstituted or substituted by a substituent selected from the group consisting of alkyl) amino, oxo (C═O) and nitro,

C는 수소, COR1, CO2R1, SO2R1, SO2NHR1, (CH2)m-C1-C8-알킬설포닐, (CH2)m-C1-C8-알콕시카보닐, 아미드(CONH2), (CH2)m-C1-C8-알킬카바모일, C(O)-C5-C7-헤테로아릴, C(O)-C5-C7-헤테로사이클, C(O)-(CH2)m-C5-C7-헤테로아릴, C(O)-(CH2)m-C5-C7-헤테로사이클, (CH2)m-C5-C7-헤테로아릴 또는 (CH2)m-C5-C7-헤테로사이클을 나타내고, 여기서, R1은 C1-C8-알킬 또는 C5-C7-아릴을 나타내며, 헤테로아릴은 고리안에 1 개 내지 4개의 질소원자 또는 산소 또는 황원자를 포함할 수 있고, 헤테로사이클은 고리안에 1 또는 2개의 질소원자 또는 산소 또는 황원자를 포함할 수 있으며, 헤테로아릴 또는 헤테로사이클은 할로겐, C1-C3-알킬, 트리플루오로메틸, 니트로, 하이드록시, C1-C3-알킬옥시, 아미노, (C1-C3-알킬)아미노, 디(C1-C3-알킬)아미노 및 옥소(C=O)로 구성된 그룹중에서 선택된 치환체에 의해 치환되거나 비치환되고, 여기서 m은 0 내지 2의 정수를 나타내며,C is hydrogen, COR 1 , CO 2 R 1 , SO 2 R 1 , SO 2 NHR 1 , (CH 2 ) m -C 1 -C 8 -alkylsulfonyl, (CH 2 ) m -C 1 -C 8- Alkoxycarbonyl, amide (CONH 2 ), (CH 2 ) m -C 1 -C 8 -alkylcarbamoyl, C (O) -C 5 -C 7 -heteroaryl, C (O) -C 5 -C 7 -Heterocycle, C (O)-(CH 2 ) m -C 5 -C 7 -heteroaryl, C (O)-(CH 2 ) m -C 5 -C 7 -heterocycle, (CH 2 ) m- C 5 -C 7 -heteroaryl or (CH 2 ) m -C 5 -C 7 -heterocycle, wherein R 1 represents C 1 -C 8 -alkyl or C 5 -C 7 -aryl, hetero Aryl may contain 1 to 4 nitrogen atoms or oxygen or sulfur atoms in the ring, heterocycle may contain 1 or 2 nitrogen atoms or oxygen or sulfur atoms in the ring, heteroaryl or heterocycle may be halogen, C 1 -C 3 -alkyl, trifluoromethyl, nitro, hydroxy, C 1 -C 3 -alkyloxy, amino, (C 1 -C 3 -alkyl) amino, di (C 1 -C 3 -alkyl) Amino Oxo (C = O) substituted by a substituent selected from the group consisting of and or unsubstituted ring, wherein m is an integer from 0 to 2,

D는 C5-C10-알킬, (CH2)m-C5-C7-사이클로알킬, (CH2)m-C5-C7-아릴, (CH2)m-C5-C7-헤테로사이클로알킬을 나타내고, 여기서 m은 0 내지 2의 정수를 나타낸다.D is C 5 -C 10 -alkyl, (CH 2 ) m -C 5 -C 7 -cycloalkyl, (CH 2 ) m -C 5 -C 7 -aryl, (CH 2 ) m -C 5 -C 7 -Heterocycloalkyl, where m represents an integer from 0 to 2.

본 발명에 따른 화학식 1의 화합물의 치환기에 대한 정의에서 용어 "알킬"은 단독으로 또는 "알킬옥시"와 같이 조합하여 사용되는 경우에 각각 직쇄 또는 측쇄 탄화수소 라디칼을 의미하며, 용어 "사이클로알킬"은 사이클로헥실을 포함한 환상 알킬을 의미한다.The term "alkyl" in the definition of the substituent of the compound of formula 1 according to the invention, when used alone or in combination with "alkyloxy" means a straight or branched chain hydrocarbon radical, respectively, and the term "cycloalkyl" It means cyclic alkyl including cyclohexyl.

용어 "아릴"은 페닐, 나프틸 등을 포함하는 방향족 그룹을 의미한다.The term "aryl" refers to an aromatic group including phenyl, naphthyl and the like.

용어 "헤테로아릴"은 산소, 질소 및 황 중에서 선택된 헤테로원자를 함유하는 모노사이클릭 또는 비사이클릭 방향족 그룹을 의미한다. 모노사이클릭 헤테로아릴의 예로는 티아졸, 옥사졸, 티오펜, 퓨란, 피롤, 이미다졸, 이소옥사졸, 피라졸, 트리아졸, 티아디아졸, 테트라졸, 옥사디아졸, 피리딘, 피리다진, 피리미딘, 피라진 및 이와 유사한 그룹을 들 수 있으나 이들로 제한되는 것은 아니다. 비사이클릭 헤테로아릴의 예로는 인돌, 벤조티오펜, 벤조퓨란, 벤즈이미다졸, 벤족사졸, 벤즈이속사졸, 벤즈티아졸, 벤즈티아디아졸, 벤즈트리아졸, 퀴놀린, 이소퀴놀린, 퓨린, 퓨로피리딘 및 이와 유사한 그룹을 들 수 있으나 이들로 제한되는 것은 아니다.The term "heteroaryl" means a monocyclic or bicyclic aromatic group containing a heteroatom selected from oxygen, nitrogen and sulfur. Examples of monocyclic heteroaryl include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, pyrazole, triazole, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, Pyrimidine, pyrazine and similar groups, but is not limited to these. Examples of bicyclic heteroaryl include indole, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine, puropyridine And similar groups, but is not limited thereto.

용어 헤테로사이클은 산소, 질소 및 황 중에서 선택된 헤테로원자를 함유하는 비방향족 모노사이클릭 또는 비사이클릭 그룹을 의미한다. 그 예로는 피페리딘, 모폴린, 티아모폴린, 피롤리딘, 이미다졸리딘, 테트라하이드로퓨란, 피페라진 및 이와 유사한 그룹을 들 수 있으나 이들로 제한되는 것은 아니다.The term heterocycle means a non-aromatic monocyclic or bicyclic group containing a heteroatom selected from oxygen, nitrogen and sulfur. Examples include, but are not limited to, piperidine, morpholine, thiamorpholine, pyrrolidine, imidazolidine, tetrahydrofuran, piperazine and similar groups.

본 발명에 따른 화학식 1의 화합물에서도 바람직한 화합물은Preferred compounds in the compound of formula 1 according to the present invention

i) A가 수소, COR1, CO2R1, SO2R1, SO2NHR1, SO2N(R1)2, PO(OR1)2, C1-C8-알킬, (CH2)n-C5-C7-아릴, 또는 (CH2)n-C5-C7-헤테로아릴을 나타내고, 여기서 R1이 수소, C1-C8-알킬, (CH2)n-C3-C7-사이클로알킬, 또는 (CH2)n-C5-C7-아릴을 나타내며, n은 1 내지 3의 정수를 나타내거나,i) A is hydrogen, COR 1 , CO 2 R 1 , SO 2 R 1 , SO 2 NHR 1 , SO 2 N (R 1 ) 2 , PO (OR 1 ) 2 , C 1 -C 8 -alkyl, (CH 2 ) n -C 5 -C 7 -aryl, or (CH 2 ) n -C 5 -C 7 -heteroaryl, wherein R 1 is hydrogen, C 1 -C 8 -alkyl, (CH 2 ) n − C 3 -C 7 -cycloalkyl, or (CH 2 ) n -C 5 -C 7 -aryl, n represents an integer of 1 to 3, or

ⅱ) B가 벤질, CH2-피리딜, CH2-피리미딜, 또는 CH2-5환-헤테로아릴을 나타내고, 여기에서 아릴 또는 헤테로아릴은 할로겐, C1-C5-알킬, 트리플루오로메틸, 하이드록시, C1-C3-알킬옥시, 아미노, (C1-C3-알킬)아미노, 디(C1-C3-알킬)아미노, 시아노, 카복시(CO2H), 에스테르(CO2-C1-C3-알킬), 아미드(CONH2), 아미딘(C(NH)NH2), 니트로 및 페닐로 구성된 그룹중에서 선택된 1 또는 2개의 치환체에 의해 치환되거나 비치환되거나,Ⅱ) B is benzyl, CH 2 - alkyl, trifluoromethyl-pyridyl, CH 2-pyrimidyl, or CH 2 -5 exchange - represents a heteroaryl, aryl or heteroaryl, where is halogen, C 1 -C 5 Methyl, hydroxy, C 1 -C 3 -alkyloxy, amino, (C 1 -C 3 -alkyl) amino, di (C 1 -C 3 -alkyl) amino, cyano, carboxy (CO 2 H), ester Unsubstituted or substituted by one or two substituents selected from the group consisting of (CO 2 -C 1 -C 3 -alkyl), amide (CONH 2 ), amidine (C (NH) NH 2 ), nitro and phenyl; ,

특히 바람직하게는 할로겐, C1-C3-알킬, 트리플루오로메틸, 메톡시, 에톡시, 메틸아미노 및 디메틸아미노로 구성된 그룹중에서 선택된 1 또는 2개의 치환체에 의해 치환되거나 비치환된 벤질 또는 CH2-피리딜을 나타내거나,Particularly preferably benzyl or CH unsubstituted or substituted by one or two substituents selected from the group consisting of halogen, C 1 -C 3 -alkyl, trifluoromethyl, methoxy, ethoxy, methylamino and dimethylamino 2 -pyridyl, or

ⅲ) C가 할로겐, 메틸, 에틸, 트리플루오로메틸, 하이드록시, 메톡시, 에톡시, 아미노, 메틸아미노 또는 디메틸아미노에 의해 치환된 (CH2)m-C5-C7-헤테로아릴을 나타내고, m이 0 내지 2의 정수를 나타내거나,Iii) C is a (CH 2 ) m -C 5 -C 7 -heteroaryl substituted by halogen, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, amino, methylamino or dimethylamino M represents an integer of 0 to 2, or

특히 바람직하게는 할로겐, 메틸, 에틸, 메톡시, 에톡시, 메틸아미노 또는 디메틸아미노에 의해 치환된 CH2-피롤, CH2-이미다졸, CH2-피라졸, CH2-티아졸, CH2-옥사졸, CH2-트리아졸, CH2-테트라졸, CH2-피리딘, CH2-피리미딘, CH2-피라진 또는 CH2-트리아진을 나타내거나,Particularly preferably halogen, methyl, ethyl, methoxy, ethoxy, methylamino or dimethylamino in the CH 2 substituted by-pyrrole, CH 2-imidazole, CH 2 - pyrazole, CH 2-thiazole, CH 2 -Oxazole, CH 2 -triazole, CH 2 -tetrazole, CH 2 -pyridine, CH 2 -pyrimidine, CH 2 -pyrazine or CH 2 -triazine, or

C가 C1-C8-알킬설포닐, C5-C7-아릴설포닐, (CH2)m-C1-C8-알킬설포닐, (CH2)m- C1-C8-알콕시카보닐, 아미드(CONH2), 또는 (CH2)m-C1-C8-알킬카바모일을 나타내고, m은 0 내지 2의 정수를 나타내거나,C is C 1 -C 8 -alkylsulfonyl, C 5 -C 7 -arylsulfonyl, (CH 2 ) m -C 1 -C 8 -alkylsulfonyl, (CH 2 ) m -C 1 -C 8- Alkoxycarbonyl, amide (CONH 2 ), or (CH 2 ) m -C 1 -C 8 -alkylcarbamoyl, m represents an integer from 0 to 2, or

C가 C(O)-이미다졸, C(O)-트리아졸, C(O)-티아졸, C(O)-옥사졸, C(O)-테트라졸, C(O)-피리딘, C(O)-피라진, C(O)-트리아진, CH2-C(O)-이미다졸, CH2-C(O)-트리아졸, CH2-C(O)-테트라졸, CH2-C(O)-티아졸, CH2-CH2-이미다졸, CH2-CH2-트리아졸, CH2-CH2-테트라졸, CH2-CH2-티아졸, CH2-CH2-이미다졸론, CH2-CH2-옥사졸론, CH2-CH2-디아졸론을 나타내거나,C is C (O) -imidazole, C (O) -triazole, C (O) -thiazole, C (O) -oxazole, C (O) -tetrazole, C (O) -pyridine, C (O) -pyrazine, C (O) -triazine, CH 2 -C (O) -imidazole, CH 2 -C (O) -triazole, CH 2 -C (O) -tetrazole, CH 2- C (O) -thiazole, CH 2 -CH 2 -imidazole, CH 2 -CH 2 -triazole, CH 2 -CH 2 -tetazole, CH 2 -CH 2 -thiazole, CH 2 -CH 2- Imidazolone, CH 2 -CH 2 -oxazolone, CH 2 -CH 2 -diazolone, or

ⅳ) D가 C5-C10-알킬 또는 (CH2)m-C5-C7-사이클로알킬을 나타내고, 여기서 m은 0 내지 2의 정수를 나타내거나,Iii) D represents C 5 -C 10 -alkyl or (CH 2 ) m -C 5 -C 7 -cycloalkyl, wherein m represents an integer from 0 to 2, or

ⅴ) E가 CH2-C3-C7-사이클로알킬, CH2-C5-C7-아릴, CH2-C5-C7-헤테로아릴 또는 CH2-C5-C7-헤테로사이클을 나타내고, 사이클로알킬, 아릴, 헤테로아릴 또는 헤테로사이클은 할로겐, C1-C5-알킬, 트리플루오로메틸, 하이드록시, C1-C3-알킬옥시, 아미노, (C1-C3-알킬)아미노, 디(C1-C3-알킬)아미노, 시아노, 카복시(CO2H), 에스테르(CO2-C1-C3-알킬), 아미드(CONH2), 아미딘(C(NH)NH2), 니트로 및 페닐로 구성된 그룹중에서 선택된 1 내지 3개의 치환체에 의해 치환되거나 비치환되거나,Iii) E is CH 2 -C 3 -C 7 -cycloalkyl, CH 2 -C 5 -C 7 -aryl, CH 2 -C 5 -C 7 -heteroaryl or CH 2 -C 5 -C 7 -heterocycle Cycloalkyl, aryl, heteroaryl or heterocycle is halogen, C 1 -C 5 -alkyl, trifluoromethyl, hydroxy, C 1 -C 3 -alkyloxy, amino, (C 1 -C 3- Alkyl) amino, di (C 1 -C 3 -alkyl) amino, cyano, carboxy (CO 2 H), ester (CO 2 -C 1 -C 3 -alkyl), amide (CONH 2 ), amidine (C (NH) NH 2 ), unsubstituted or substituted by one to three substituents selected from the group consisting of nitro and phenyl,

특히 바람직하게는 CH2-C5-C7-헤테로아릴 또는 CH2-C5-C7-헤테로사이클을 나타내고, 여기서 헤테로아릴 또는 헤테로사이클은 할로겐, 메틸, 에틸, 트리플루오로메틸, 하이드록시, 메톡시, 에톡시, 아미노, 메틸아미노 및 디메틸아미노로 구성된 그룹중에서 선택된 1 내지 3개의 치환체에 의해 치환되거나 비치환되거나,Particularly preferably CH 2 -C 5 -C 7 -heteroaryl or CH 2 -C 5 -C 7 -heterocycle, wherein the heteroaryl or heterocycle is halogen, methyl, ethyl, trifluoromethyl, hydroxy Or unsubstituted or substituted by one to three substituents selected from the group consisting of methoxy, ethoxy, amino, methylamino and dimethylamino,

ⅵ) Cy가 페닐 또는 사이클로헥실을 나타내는 화합물이다.V) Cy is a compound representing phenyl or cyclohexyl.

보다 특히 바람직한 화합물은 A가 수소, COR1, CO2R1, SO2R1, SO2NHR1, SO2N(R1)2, PO(OR1)2, C1-C8-알킬, (CH2)n-C5-C7-아릴, 또는 (CH2)n-C5-C7-헤테로아릴을 나타내고, 여기서 R1이 수소, C1-C8-알킬, (CH2)n-C3-C7-사이클로알킬, 또는 (CH2)n- C5-C7-아릴을 나타내며, n은 1 내지 3의 정수를 나타내고; B가 할로겐, C1-C3-알킬, 트리플루오로메틸, 메톡시, 에톡시, 메틸아미노 및 디메틸아미노로 구성된 그룹중에서 선택된 1 또는 2개의 치환체에 의해 치환되거나 비치환된 벤질 또는 CH2-피리딜을 나타내며; C가 할로겐, 메틸, 에틸, 메톡시, 에톡시, 메틸아미노 또는 디메틸아미노에 의해 치환된 CH2-피롤, CH2-이미다졸, CH2-피라졸, CH2-티아졸, CH2-옥사졸, CH2-트리아졸, CH2-테트라졸, CH2-피리딘, CH2-피리미딘, CH2-피라진 또는 CH2-트리아진을 나타내거나, C1-C8-알킬설포닐, C5-C7-아릴설포닐, (CH2)m-C1-C8-알킬설포닐, (CH2)m-C1-C8-알콕시카보닐, 아미드(CONH2), 또는 (CH2)m-C1-C8-알킬카바모일을 나타내고, m은 0 내지 2의 정수를 나타내거나, C(O)-이미다졸, C(O)-트리아졸, C(O)-티아졸, C(O)-옥사졸, C(O)-테트라졸, C(O)-피리딘, C(O)-피라진, C(O)-트리아진, CH2-C(O)-이미다졸, CH2-C(O)-트리아졸, CH2-C(O)-테트라졸, CH2-C(O)-티아졸, CH2-CH2-이미다졸, CH2-CH2-트리아졸, CH2-CH2-테트라졸, CH2-CH2-티아졸, CH2-CH2-이미다졸론, CH2-CH2-옥사졸론, CH2-CH2-디아졸론을 나타내고; D가 C5-C10-알킬 또는 (CH2)m-C5-C7-사이클로알킬을 나타내며, 여기서 m은 0 내지 2의 정수를 나타내고; E가 할로겐, 메틸, 에틸, 트리플루오로메틸, 하이드록시, 메톡시, 에톡시, 아미노, 메틸아미노 및 디메틸아미노로 구성된 그룹중에서 선택된 1 내지 3개의 치환체에 의해 치환되거나 비치환된 CH2-이미다졸, CH2-피라졸, CH2-티아졸, CH2-옥사졸, CH2-트리아졸, CH2-피리딘, CH2-1-피페리딘 또는 CH2-1-헥사메틸렌이민을 나타내며; Cy가 페닐 또는 사이클로헥실을 나타내는 화합물이다.More particularly preferred compounds are those in which A is hydrogen, COR 1 , CO 2 R 1 , SO 2 R 1 , SO 2 NHR 1 , SO 2 N (R 1 ) 2 , PO (OR 1 ) 2 , C 1 -C 8 -alkyl , (CH 2 ) n -C 5 -C 7 -aryl, or (CH 2 ) n -C 5 -C 7 -heteroaryl, wherein R 1 is hydrogen, C 1 -C 8 -alkyl, (CH 2 ) n- C 3 -C 7 -cycloalkyl, or (CH 2 ) n -C 5 -C 7 -aryl, n represents an integer from 1 to 3; Benzyl or CH 2 -unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, C 1 -C 3 -alkyl, trifluoromethyl, methoxy, ethoxy, methylamino and dimethylamino Pyridyl; C is halogen, methyl, ethyl, methoxy, ethoxy, methylamino or dimethylamino in the CH 2 substituted by-pyrrole, CH 2-imidazole, CH 2 - pyrazole, CH 2-thiazole, CH 2 - oxazole Sol, CH 2 -triazole, CH 2 -tetrazole, CH 2 -pyridine, CH 2 -pyrimidine, CH 2 -pyrazine or CH 2 -triazine, or C 1 -C 8 -alkylsulfonyl, C 5 -C 7 -arylsulfonyl, (CH 2 ) m -C 1 -C 8 -alkylsulfonyl, (CH 2 ) m -C 1 -C 8 -alkoxycarbonyl, amide (CONH 2 ), or (CH 2 ) m- C 1 -C 8 -alkylcarbamoyl, m represents an integer of 0 to 2, or C (O) -imidazole, C (O) -triazole, C (O) -thiazole , C (O) -oxazole, C (O) -tetrazole, C (O) -pyridine, C (O) -pyrazine, C (O) -triazine, CH 2 -C (O) -imidazole, CH 2 -C (O) -triazole, CH 2 -C (O) -tetrazole, CH 2 -C (O) -thiazole, CH 2 -CH 2 -imidazole, CH 2 -CH 2 -triazole , CH 2 -CH 2 -tetrazole, CH 2 -CH 2 -thiazole, CH 2 -CH 2 -imidazolone, CH 2 -CH 2 -oxazolone, CH 2 -CH 2 -diazolone; D represents C 5 -C 10 -alkyl or (CH 2 ) m -C 5 -C 7 -cycloalkyl, wherein m represents an integer from 0 to 2; CH 2 -alternatively unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, amino, methylamino and dimethylamino Dazole, CH 2 -pyrazole, CH 2 -thiazole, CH 2 -oxazole, CH 2 -triazole, CH 2 -pyridine, CH 2-1 -piperidine or CH 2-1 -hexamethyleneimine ; Cy is a compound representing phenyl or cyclohexyl.

본 발명에 따른 화학식 1의 대표적인 화합물에는 다음 표 1에 표시된 화합물이 포함된다.Representative compounds of Formula 1 according to the present invention include the compounds shown in Table 1 below.

본 발명에 따른 화학식 1의 대표적인 화합물에는 또한, 다음 표 2에 표시된 화합물이 포함된다.Representative compounds of Formula 1 according to the present invention also include compounds shown in Table 2 below.

본 발명에 따른 화합물은 또한 약제학적으로 허용되는 염을 형성할 수 있다. 이러한 약제학적으로 허용되는 염에는 약제학적으로 허용되는 음이온을 함유하는 무독성 산부가염을 형성하는 산, 예를 들면 염산, 황산, 질산, 인산, 브롬화수소산, 요오드화수소산 등과 같은 무기산, 타타르산, 포름산, 시트르산, 아세트산, 트리클로로아세트산, 트리플루오로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산 등과 같은 유기 카본산, 메탄설폰산, 벤젠설폰산, p-톨루엔설폰산 또는 나프탈렌설폰산 등과 같은 설폰산 등에 의해 형성된 산부가염, 특히 바람직하게는 황산, 메탄설폰산 또는 할로겐화수소산 등에 의해 형성된 산부가염이 포함된다.The compounds according to the invention can also form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, Organic carbon acids such as citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc., sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid Acid addition salts formed by, and the like, particularly preferably acid addition salts formed by sulfuric acid, methanesulfonic acid or hydrochloric acid and the like.

한편, 본 발명에 따른 화합물들은 비대칭 탄소중심을 가질 수 있으므로 R 또는 S 이성체, 라세미 화합물, 부분입체이성체 혼합물 및 개개 부분입체이성체로서 존재할 수 있으며, 이들 모든 이성체 및 혼합물은 본 발명의 범위에 포함된다.On the other hand, the compounds according to the invention may have an asymmetric carbon center and therefore may exist as R or S isomers, racemic compounds, diastereomeric mixtures and individual diastereomers, all of these isomers and mixtures being included in the scope of the invention. do.

한편, 본 발명에 따른 화학식 1의 화합물은On the other hand, the compound of formula 1 according to the present invention

(a) N-말단에 보호기 P가 도입된 하기 화학식 2의 화합물을 하기 화학식 3의 화합물과 반응시키고 가수분해시켜 하기 화학식 4의 디펩티드 화합물을 형성하고, 화학식 4의 화합물을 하기 화학식 5의 피페리딘 유도체와 아미드-커플링 반응시키 고 탈보호화하여 하기 화학식 1a의 화합물을 제조하거나,(a) reacting a compound of formula (2) having a protecting group P introduced at the N-terminus with a compound of formula (3) and hydrolyzing to form a dipeptide compound of formula (4), wherein the compound of formula (4) is An amide-coupling reaction with a ferridine derivative and deprotection to prepare a compound of formula

(b) N-말단에 보호기 P'가 도입된 하기 화학식 6의 화합물을 화학식 5의 피페리딘 유도체와 아미드-커플링 반응시키고 탈보호화하여 하기 화학식 7의 화합물을 형성하고, 화학식 7의 화합물을 화학식 2의 화합물과 반응시키고 탈보호화하여 화학식 1a의 화합물을 제조하거나,(b) an amide-coupling reaction and deprotection of a compound of formula (6) having a protecting group P ′ introduced at the N-terminus with a piperidine derivative of formula (5) to form a compound of formula (7); Reacting with a compound of formula 2 and deprotecting to prepare a compound of formula 1a, or

(c) 화학식 1a의 화합물에 A' 그룹을 도입시키는 커플링 반응을 수행하여 하기 화학식 1b의 화합물을 수득하거나,(c) conducting a coupling reaction in which the A 'group is introduced into the compound of Formula 1a to obtain a compound of Formula 1b

(d) N-말단에 보호기 P가 도입된 하기 화학식 8의 화합물을 화학식 3의 화합물과 반응시키고 가수분해시켜 하기 화학식 9의 디펩티드 화합물을 형성하고, 화학식 9의 화합물을 화학식 5의 피페리딘 유도체와 아미드-커플링 반응시키고 탈보호화하여 하기 화학식 1c의 화합물을 제조하거나,(d) reacting and hydrolyzing the compound of formula 8 having the protecting group P introduced at the N-terminus with the compound of formula 3 to form a dipeptid compound of formula 9, wherein the compound of formula 9 is a piperidine of formula 5 An amide-coupling reaction with a derivative and deprotection to prepare a compound of Formula 1c

(e) 화학식 6의 화합물을 화학식 5의 피페리딘 유도체와 아미드-커플링 반응시키고 탈보호화하여 하기 화학식 10의 화합물을 형성하고, 화학식 10의 화합물을 화학식 8의 화합물과 반응시키고 탈보호화하여 화학식 1c의 화합물을 제조하거나,(e) amide-coupling a compound of formula 6 with a piperidine derivative of formula 5 and deprotecting to form a compound of formula 10, wherein the compound of formula 10 is reacted with a compound of formula 8 and deprotected to Preparing a compound of 1c, or

(f) 화학식 1c의 화합물에 A' 그룹을 도입시키는 커플링 반응을 수행하여 하기 화학식 1d의 화합물을 수득함을 특징으로 하여 제조할 수 있다.(f) a coupling reaction of introducing the A 'group into the compound of Formula 1c may be performed to obtain a compound of Formula 1d.

상기식에서,In the above formula,

Cy, A, B, C, D 및 E는 각각 앞에서 정의한 바와 같고,Cy, A, B, C, D and E are as defined above,

A'는 A와 동일하나, 단 수소는 제외되며,A 'is the same as A, except hydrogen

P 및 P'는 각각 독립적으로 아미노보호기, 바람직하게는 t-부톡시카보닐 (Boc), 벤질옥시카보닐(Cbz) 또는 플루오레닐메톡시카보닐(Fmoc)을 나타낸다.P and P 'each independently represent an aminoprotecting group, preferably t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or fluorenylmethoxycarbonyl (Fmoc).

본 발명에 따른 방법 (a) 내지 (f)를 각각 하기 반응식 1 내지 4에 요약하여나타내었다.Methods (a) to (f) according to the present invention are summarized in the following schemes 1 to 4, respectively.

상기 방법 (a) 내지 (f)에서 각 단계의 반응은 바람직하게는 반응에 악영향을 끼치지 않는 통상적인 용매중에서 수행될 수 있으며, 특히 바람직하게는 디메틸포름아미드, 디메틸아세트아미드, 테트라하이드로푸란, 메틸렌클로라이드 및 클로로포름중에서 선택된 1종 이상의 용매를 사용할 수 있으나, 단 이들로 제한되는 것은 아니다.The reaction of each step in the above methods (a) to (f) may preferably be carried out in a conventional solvent which does not adversely affect the reaction, particularly preferably dimethylformamide, dimethylacetamide, tetrahydrofuran, One or more solvents selected from methylene chloride and chloroform may be used, but is not limited thereto.

아미노 그룹의 탈보호기화 반응은 염산(HCl), 트리플루오로아세트산(TFA) 등과 같은 강산 존재하에 수행하거나, 트리에틸아민, 디이소프로필에틸아민(DIPEA) 등과 같은 아민 염기의 존재하에 수행하거나, 수소첨가반응을 사용하여 수행할 수 있다. 구체적인 반응조건은 문헌(참조: T.W. Green & G.M. Wuts, "Protective Groups in Organic Synthesis", Chapter 7, pp309-405)에 기재된 내용을 참조할 수 있다.The deprotection reaction of the amino group is carried out in the presence of a strong acid such as hydrochloric acid (HCl), trifluoroacetic acid (TFA) or the like, or in the presence of an amine base such as triethylamine, diisopropylethylamine (DIPEA), or the like. It can be carried out using a hydrogenation reaction. Specific reaction conditions may be referred to those described in T.W. Green & G.M. Wuts, "Protective Groups in Organic Synthesis", Chapter 7, pp309-405.

또한, 커플링반응에 사용될 수 있는 공지의 커플링제로는 디사이클로헥실카보디이미드(DCC), 1-(3-디메틸아미노프로필)-3-에틸카보디이미드(EDC), 1,1'-디카보닐디이미다졸(CDI) 등의 카보이미드류를 1-하이드록시벤조트리아졸(HOBT) 또는 1-하이드록시-7-아자벤조트리아졸(HOAT)과 혼합된 상태로 사용하거나, 비스-(2-옥소-3-옥사졸리디닐)-포스핀산 클로라이드(BOP-Cl), 디페닐포스포릴아지드(DPPA), N-[디메틸아미노-1H-1,2,3-트리아졸[4,5-b]피리딘-1-일메틸렌]-N-메틸메탄아미늄(HATU) 등을 사용할 수 있으나, 단 이들로 제한되는 것은 아니다.In addition, known coupling agents that can be used in the coupling reaction include dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC), 1,1'- Carbonimides, such as dicarbonyldiimidazole (CDI), are used in a mixed state with 1-hydroxybenzotriazole (HOBT) or 1-hydroxy-7-azabenzotriazole (HOAT), or bis- ( 2-oxo-3-oxazolidinyl) -phosphinic chloride (BOP-Cl), diphenylphosphoryl azide (DPPA), N- [dimethylamino-1H-1,2,3-triazole [4,5 -b] pyridin-1-ylmethylene] -N-methylmethanealuminum (HATU) or the like may be used, but is not limited thereto.

본 발명의 방법에 따라 제조된 화학식 1의 화합물은 통상적인 방법에 의해 그의 염으로 전환시킬 수 있다.Compounds of formula (1) prepared according to the process of the invention can be converted to their salts by conventional methods.

상기한 본 발명의 방법에 따른 반응이 완결된 후에 생성물은 통상적인 후처리 방법, 예를들면 크로마토그래피, 재결정화 등의 방법에 의해 분리 및 정제할 수있다.After completion of the reaction according to the process of the invention described above, the product can be separated and purified by conventional post-treatment methods such as chromatography, recrystallization and the like.

본 발명의 화합물은 멜라노코틴 수용체에 대하여 우수한 항진작용을 나타내므로 본 발명은 또한, 약제학적으로 허용되는 담체와 함께 유효성분으로서 화학식 1의 화합물을 함유함을 특징으로 하는 멜라노코틴 수용체의 기능항진제 조성물을제공한다. 특히, 본 발명에 따른 조성물은 비만, 발기부전증, 당뇨병, 및 염증에 대한 예방 및 치료에 우수한 효과를 나타내나 이들 질병에만 제한되는 것은 아니다.Since the compound of the present invention exhibits excellent anticancer activity against the melanocortin receptor, the present invention also contains a compound of formula (1) as an active ingredient with a pharmaceutically acceptable carrier. To provide. In particular, the compositions according to the invention show excellent effects in the prevention and treatment of obesity, erectile dysfunction, diabetes, and inflammation, but are not limited to these diseases.

본 발명의 화합물을 임상적인 목적으로 투여시에 단일용량 또는 분리용량으로 숙주에게 투여될 총 일일용량은 체중 1㎏ 당 0.01mg 내지 10㎎의 범위가 바람직하나, 개개 환자에 대한 특이적인 용량 수준은 사용될 특정 화합물, 환자의 체중, 성, 건강상태, 식이, 약제의 투여시간, 투여방법, 배설률, 약제혼합 및 질환의 중증도 등에 따라 변화될 수 있다.The total daily dose to be administered to the host in a single dose or in separate doses when administering a compound of the present invention for clinical purposes is preferably in the range of 0.01 mg to 10 mg per kg of body weight. It may vary depending on the particular compound to be used, the weight of the patient, sex, health condition, diet, time of administration of the drug, method of administration, rate of excretion, drug mixing and severity of the disease.

본 발명의 화합물은 목적하는 바에 따라 어떠한 경로로도 투여될 수 있다. 주사, 경구 및 비강 투여가 바람직하나, 피부, 복강, 후강 및 직장을 통하여 투여할 수도 있다.The compounds of the present invention can be administered by any route as desired. Injection, oral and nasal administration are preferred, but can also be administered through the skin, abdominal cavity, larynx and rectum.

주사용 제제, 예를들면 멸균 주사용 수성 또는 유성 현탁액은 공지된 기술에 따라 적합한 분산제, 습윤제, 또는 현탁제를 사용하여 제조할 수 있다. 이를 위해 사용될 수 있는 용매에는 물, 링거액 및 등장성 NaCl 용액이 있으며, 멸균 고정오일도 통상적으로 용매 또는 현탁 매질로서 사용한다. 모노-, 디-글리세라이드를 포함하여 어떠한 무자극성 고정오일도 이러한 목적으로 사용될 수 있으며, 또한 올레산과 같은 지방산도 주사용 제제에 사용할 수 있다.Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, can be prepared using suitable dispersing agents, wetting agents, or suspending agents according to known techniques. Solvents that can be used for this are water, Ringer's solution and isotonic NaCl solution, and sterile fixed oils are also commonly used as solvents or suspending media. Any non-irritating fixed oil may be used for this purpose, including mono- and diglycerides, and fatty acids such as oleic acid may also be used in the preparation of injectables.

경구투여용 고체투여 형태로는 캅셀제, 정제, 환제, 산제 및 입제가 있으며, 특히 캅셀제와 정제가 유용하다. 정제 및 환제는 장피제로 제조하는 것이 바람직하다. 고체투여 형태는 본 발명에 따른 화학식 1의 활성화합물을 수크로오즈, 락토오즈, 전분 등과 같은 하나 이상의 불활성 희석제 및 마그네슘 스테아레이트와 같은 윤활제, 붕해제, 결합제 등과 같은 담체와 혼합시켜 제조할 수 있다.Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. Particularly, capsules and tablets are useful. Tablets and pills are preferably prepared with enteric agents. Solid dosage forms can be prepared by mixing the active compound of formula 1 according to the invention with one or more inert diluents such as sucrose, lactose, starch and the like and a carrier such as a lubricant, disintegrant, binder, etc., such as magnesium stearate .

상기 반응식, 하기 제조예 및 실시예에서 화합물의 명칭에 사용되는 약어와 용어의 설명은 다음과 같다.Explanation of abbreviations and terms used in the names of the compounds in the above reaction schemes, preparation examples and examples are as follows.

EDC: 1-(3-디메틸아미노프로필)-3-에틸카보디이미드·염산EDC: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloric acid

HOBT: 하이드록시벤조트리아졸HOBT: hydroxybenzotriazole

Boc: t-부톡시카보닐Boc: t-butoxycarbonyl

Ac: 아세틸Ac: Acetyl

Bn: 벤질Bn: Benzyl

DMF: 디메틸포름아미드DMF: Dimethylformamide

Cbz: 벤질옥시카보닐Cbz: benzyloxycarbonyl

THF: 테트라하이드로퓨란THF: Tetrahydrofuran

TFA: 트리플루오로아세트산TFA: trifluoroacetic acid

EtOAc: 에틸아세테이트EtOAc: ethyl acetate

DEAD: 디에틸아조디카복실레이트DEAD: diethylazodicarboxylate

MgSO4: 황산마그네슘MgSO 4 : Magnesium Sulfate

Et3N: 트리에틸아민Et 3 N: triethylamine

NH4Cl: 염화암모늄NH 4 Cl: ammonium chloride

CH3CN: 아세토니트릴CH 3 CN: acetonitrile

MCPBA: 메타클로로퍼벤조산MCPBA: metachloroperbenzoic acid

CDI: 디카보닐디이미다졸CDI: dicarbonyldiimidazole

하기 제조예는 본 발명에 따른 실시예 화합물의 합성에 필요한 중간체 제조를 보다 구체적으로 설명한다.The following preparations more specifically illustrate the preparation of intermediates required for the synthesis of the example compounds according to the invention.

제조예 1: N-Boc-4-[N,N-(사이클로헥실, 메탄설포닐)아미노]피페리딘Preparation Example 1 N-Boc-4- [N, N- (cyclohexyl, methanesulfonyl) amino] piperidine

단계 A : N-Boc-4-피페리디논Step A: N-Boc-4-piperidinone

4-피페리디논(HCl염, 1.35g, 10mmol)을 디클로로메탄(30㎖)에 녹이고, 트리에틸아민(2.8㎖, 20mmol)을 넣은 후 디-t-부틸 디카보네이트(2190mg, 10mmol)를 넣고 상온에서 4시간동안 교반하였다. 반응이 종결된 용액에 1N HCl을 넣고 중화시킨후 EtOAc(50㎖ x 4)로 추출하여 무수 MgSO4로 건조한 다음 여과하여 감압 농축하였다. 잔유물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=1/5, v/v)로 정제하여 표제화합물(1853mg, 수율 93%)을 수득하였다.Dissolve 4-piperidinone (HCl salt, 1.35 g, 10 mmol) in dichloromethane (30 mL), add triethylamine (2.8 mL, 20 mmol), add di-t-butyl dicarbonate (2190 mg, 10 mmol) Stir at room temperature for 4 hours. After the reaction was completed, 1N HCl was added, neutralized, extracted with EtOAc (50 mL × 4), dried over anhydrous MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-hexane = 1/5, v / v) to afford the title compound (1853 mg, 93% yield).

MS [M+H] = 200MS [M + H] = 200

단계 B : N-Boc-4-[N-(사이클로헥실)아미노]피페리딘Step B: N-Boc-4- [N- (cyclohexyl) amino] piperidine

단계 A에서 얻은 N-Boc-4-피페리디논(996.25mg, 5mmol)과 사이클로헥실아민 (495.9mg, 5mmol)을 디클로로에탄(15㎖)에 넣고 교반하였다. 5분쯤후에 NaBH(OAc)3(1590mg, 7.5mmol)를 넣고 상온에서 2시간 동안 교반하였다. 반응이 종결된 후 디클로로메탄(40㎖)으로 희석시키고 포화 탄산수소나트륨 수용액으로 씻어 주고 무수 MgSO4로 건조한 다음 여과하여 감압 농축하였다. 잔유물을 칼럼 크로마토그래피(용리액: MC/MeOH=9/1, v/v)로 정제하여 표제화합물(1200mg, 수율 85%)을 수득하였다.N-Boc-4-piperidinone (996.25 mg, 5 mmol) and cyclohexylamine (495.9 mg, 5 mmol) obtained in step A were added to dichloroethane (15 mL) and stirred. After about 5 minutes NaBH (OAc) 3 (1590mg, 7.5mmol) was added and stirred for 2 hours at room temperature. After completion of the reaction, the mixture was diluted with dichloromethane (40 ml), washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: MC / MeOH = 9/1, v / v) to afford the title compound (1200 mg, yield 85%).

MS [M+H] = 283MS [M + H] = 283

단계 C : N-Boc-4-[N,N-(사이클로헥실, 메탄설포닐)아미노]피페리딘Step C: N-Boc-4- [N, N- (cyclohexyl, methanesulfonyl) amino] piperidine

단계 B에서 얻은 N-Boc-4-[N-(사이클로헥실)아미노]피페리딘(282.4mg, 1 mmol)을 디클로로메탄(5㎖)에 녹이고 트리에틸아민(280㎖, 2mmol)을 넣어 염기화 시켰다. 이 용액에 메탄설포닐클로라이드(137.52mg, 1.2mmol)를 넣고 상온에서 1시간 30분 동안 교반하였다. 반응이 종결된 후 1N HCl 수용액(5㎖)으로 중화시키고 디클로로메탄(20㎖ x 3)으로 추출하였다. 추출한 용액을 무수 MgSO4로 건조한 다음 여과하여 감압 농축하였다. 잔유물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산= 1/3, v/v)로 정제하여 표제화합물(312.5mg, 수율 94%)을 수득하였다.N-Boc-4- [N- (cyclohexyl) amino] piperidine (282.4 mg, 1 mmol) obtained in step B was dissolved in dichloromethane (5 mL) and triethylamine (280 mL, 2 mmol) was added to the base. Mad. Methanesulfonyl chloride (137.52mg, 1.2mmol) was added to the solution and stirred at room temperature for 1 hour 30 minutes. After the reaction was terminated, the mixture was neutralized with a 1N HCl aqueous solution (5 mL) and extracted with dichloromethane (20 mL x 3). The extracted solution was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-hexane = 1/3, v / v) to give the title compound (312.5 mg, yield 94%).

MS [M+H] = 333MS [M + H] = 333

제조예 2: N-Boc-4-[N,N-(사이클로헥실, 이소프로필설포닐)아미노]피페리딘Preparation Example 2 N-Boc-4- [N, N- (cyclohexyl, isopropylsulfonyl) amino] piperidine

제조예 1의 단계 B에서 얻은 1-N-Boc-4-[N-(사이클로헥실)아미노]피페리딘 (282.4mg, 1mmol)과 이소프로필설포닐클로라이드(171.2mg, 1.2mmol)를 이용하여 제조예 1의 단계 C와 같은 방법으로 표제화합물(338.1mg, 수율 85%)을 수득하였다.Using 1-N-Boc-4- [N- (cyclohexyl) amino] piperidine (282.4 mg, 1 mmol) and isopropylsulfonyl chloride (171.2 mg, 1.2 mmol) obtained in step B of Preparation Example 1 The title compound (338.1 mg, yield 85%) was obtained in the same manner as in Step C of Preparation Example 1.

MS [M+H] = 389MS [M + H] = 389

제조예 3: N-Boc-4-[N,N-(사이클로헥실, 벤젠설포닐)아미노]피페리딘Preparation Example 3 N-Boc-4- [N, N- (cyclohexyl, benzenesulfonyl) amino] piperidine

제조예 1의 단계 B에서 얻은 N-Boc-4-[N-(사이클로헥실)아미노]피페리딘 (282.4mg, 1mmol)과 벤젠설포닐클로라이드(211.9mg, 1.2mmol)를 이용하여 제조예 1의 단계 C와 같은 방법으로 표제화합물(338.1mg, 수율 80%)을 수득하였다.Preparation Example 1 using N-Boc-4- [N- (cyclohexyl) amino] piperidine (282.4 mg, 1 mmol) and benzenesulfonylchloride (211.9 mg, 1.2 mmol) obtained in step B of Preparation Example 1 The title compound (338.1 mg, yield 80%) was obtained in the same manner as step C of.

MS [M+H] = 423MS [M + H] = 423

제조예 4: N-Boc-4-{N,N-[사이클로헥실, (2-메탄설포닐에틸)]아미노}피페리딘Preparation Example 4 N-Boc-4- {N, N- [cyclohexyl, (2-methanesulfonylethyl)] amino} piperidine

단계 A : N-Boc-4-{N,N-[사이클로헥실, (2-메틸티오)에틸]아미노}피페리딘Step A: N-Boc-4- {N, N- [cyclohexyl, (2-methylthio) ethyl] amino} piperidine

NaH(96mg, 2.4mmol, 60%)를 가지달린 둥근 플라스크에 넣고 질소치환을 한다음 제조예 1의 단계 B에서 얻은 1-N-Boc-4-[N-(사이클로헥실)아미노]피페리딘 (564.8mg, 2mmol)을 무수 THF(10㎖)에 녹여 0℃에서 천천히 적가하였다. 동 온도에서 30분 동안 교반하였다. 클로로에틸 메틸 술파이드(265.5mg, 2.4mmol)를 무수 THF(3㎖)에 녹인 후 0℃에서 천천히 적가하고 상온에서 12시간 교반하였다. 반응이 종결된 용액에 증류수를 넣고 EtOAc로 희석한 다음 무수 MgSO4로 건조시켰다. 용액을 여과하고 감압농축한 다음, 잔유물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=3/1, v/v)로 정제하여 표제화합물(438.7mg, 수율 60%)을 수득하였다.Into a round flask with NaH (96 mg, 2.4 mmol, 60%) and nitrogen-substituted, 1-N-Boc-4- [N- (cyclohexyl) amino] piperidine obtained in step B of Preparation Example 1 (564.8 mg, 2 mmol) was dissolved in anhydrous THF (10 mL) and slowly added dropwise at 0 ° C. Stirred at the same temperature for 30 minutes. Chloroethyl methyl sulfide (265.5 mg, 2.4 mmol) was dissolved in anhydrous THF (3 mL), and slowly added dropwise at 0 ° C, and stirred at room temperature for 12 hours. Distilled water was added to the finished solution, diluted with EtOAc, and dried over anhydrous MgSO 4 . The solution was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: EtOAc / n-hexane = 3/1, v / v) to give the title compound (438.7 mg, yield 60%).

MS [M+H] = 357MS [M + H] = 357

단계 B : N-Boc-4-{N,N-[사이클로헥실, (2-메탄설포닐)에틸]아미노}피페리딘Step B: N-Boc-4- {N, N- [cyclohexyl, (2-methanesulfonyl) ethyl] amino} piperidine

단계 A에서 얻은 N-Boc-{4-[N,N-사이클로헥실, (2-메틸티오)에틸]아미노}피페리딘(356.6mg, 1mmol)을 디클로로메탄(5㎖)에 녹이고 MCPBA(526.7mg, 3mmol)를 적가하여 상온에서 4시간동안 교반하였다. 반응이 종결된 용액에 황산나트륨 (150mg) 을 넣고 30분 동안 교반한다음 EtOAc(20㎖ x 4)로 추출하였다. 추출한 용액을 MgSO4로 건조한 다음 여과하고 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=7/1, v/v)로 정제하여 표제화합물(291.4mg, 수율 75%)을 수득하였다.N-Boc- {4- [N, N-cyclohexyl, (2-methylthio) ethyl] amino} piperidine (356.6 mg, 1 mmol) obtained in step A was dissolved in dichloromethane (5 mL) and MCPBA (526.7) mg, 3 mmol) was added dropwise and stirred at room temperature for 4 hours. Sodium sulfate (150 mg) was added to the reaction solution and the mixture was stirred for 30 minutes, and then extracted with EtOAc (20 mL x 4). The extracted solution was dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-hexane = 7/1, v / v) to give the title compound (291.4 mg, yield 75%).

MS [M+H] = 389MS [M + H] = 389

제조예 5: N-Boc-{4-[N,N-(사이클로헥실, 메톡시카보닐메틸)아미노]피페리딘Preparation Example 5 N-Boc- {4- [N, N- (cyclohexyl, methoxycarbonylmethyl) amino] piperidine

제조예 1의 단계 B에서 얻은 1-N-Boc-4-[N-(사이클로헥실)아미노]피페리딘 (282.43mg, 1mmol)과 메틸브로모아세테이트(183.6mg, 1.2mmol)를 이용하여 제조예 4의 단계 A와 같은 방법으로 표제화합물(333.2mg, 수율 94%)을 합성하였다.Prepared using 1-N-Boc-4- [N- (cyclohexyl) amino] piperidine (282.43mg, 1mmol) and methylbromoacetate (183.6mg, 1.2mmol) obtained in step B of Preparation Example 1 The title compound (333.2 mg, yield 94%) was synthesized in the same manner as Step A of Example 4.

MS [M+H] = 355MS [M + H] = 355

제조예 6: N-Boc-4-{N,N-[사이클로헥실, (메톡시카보닐)에틸]아미노}피페리딘Preparation Example 6 N-Boc-4- {N, N- [cyclohexyl, (methoxycarbonyl) ethyl] amino} piperidine

제조예 1의 단계 B에서 얻은 N-Boc-4-[N-(사이클로헥실)아미노]피페리딘 (282.43mg, 1mmol), 메틸 아크릴레이트(130.4mg, 1.5mmol) 및 나트륨메톡사이드 (162.9mg, 3mmol)를 무수 THF(10㎖)에 녹인 후 상온에서 24시간 교반하였다. 반응이 종결된 용액을 감압응축하고, EtOAc로 희석하고, HCl로 씻어내고, 무수 MgSO4로 건조한 다음 여과하고 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=2/3, v/v)로 정제하여 표제화합물(298.5mg, 수율 81%)을 수득하였다.N-Boc-4- [N- (cyclohexyl) amino] piperidine (282.43 mg, 1 mmol), methyl acrylate (130.4 mg, 1.5 mmol) and sodium methoxide (162.9 mg) obtained in step B of Preparation Example 1 , 3 mmol) was dissolved in anhydrous THF (10 mL) and stirred at room temperature for 24 hours. The reaction was terminated under reduced pressure, diluted with EtOAc, washed with HCl, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-hexane = 2/3, v / v) to give the title compound (298.5 mg, yield 81%).

MS [M+H] = 334MS [M + H] = 334

제조예 7: N-Boc-4-{N,N-[사이클로헥실, (피페리딘-1-일)카보닐메틸]아미노}피페리딘Preparation Example 7 N-Boc-4- {N, N- [cyclohexyl, (piperidin-1-yl) carbonylmethyl] amino} piperidine

제조예 5에서 얻은 N-Boc-4-{N,N-(사이클로헥실, (메톡시카보닐)메틸)아미노}피페리딘 (177.2mg, 0.5mmol)을 DMF(5㎖)에 녹이고 피페리딘(85.2mg, 1mmol)을 적가한 다음 90℃에서 24시간 교반하였다. 반응이 종결된 용액을 EtOAc로 희석한 다음 탄산수소나트륨과 HCl로 차례로 씻어내고 무수 MgSO4로 건조한 다음 여과하고 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=3/2, v/v)로 정제하여 표제화합물(142.6mg, 수율 78%)을 수득하였다.N-Boc-4- {N, N- (cyclohexyl, (methoxycarbonyl) methyl) amino} piperidine (177.2 mg, 0.5 mmol) obtained in Preparation Example 5 was dissolved in DMF (5 mL) and piperi Dean (85.2 mg, 1 mmol) was added dropwise and stirred at 90 ° C. for 24 hours. The reaction solution was diluted with EtOAc, washed sequentially with sodium bicarbonate and HCl, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-hexane = 3/2, v / v) to give the title compound (142.6 mg, yield 78%).

MS [M+H] = 366MS [M + H] = 366

제조예 8: N-Boc-4-{N,N-[사이클로헥실, (이미다졸-1-일)카보닐]아미노}피페리딘Preparation Example 8 N-Boc-4- {N, N- [cyclohexyl, (imidazol-1-yl) carbonyl] amino} piperidine

제조예 1의 단계 B에서 얻은 1-N-Boc-4-[(N-사이클로헥실)아미노]피페리딘 (282.4mg, 1mmol)을 디클로로메탄(5㎖)에 녹이고 CDI(194.6mg, 1.2mmol)를 적가한 다음 상온에서 24시간 교반하였다. 반응이 종결된 용액을 디클로로메탄으로 희석하고 물로 씻어준다음 무수 MgSO4로 건조하고 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: MC/MeOH=10/1, v/v)로 정제하여 표제화합물(323.8mg, 수율 86%) 을 수득하였다.1-N-Boc-4-[(N-cyclohexyl) amino] piperidine (282.4 mg, 1 mmol) obtained in step B of Preparation Example 1 was dissolved in dichloromethane (5 mL) and CDI (194.6 mg, 1.2 mmol). ) Was added dropwise and stirred at room temperature for 24 hours. The reaction solution was diluted with dichloromethane, washed with water, dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: MC / MeOH = 10/1, v / v) to give the title compound (323.8 mg, yield 86%).

MS [M+H] = 377MS [M + H] = 377

제조예 9: N-Boc-4-{N,N-[사이클로헥실, (이미다졸-1-일)메틸]아미노}피페리딘Preparation Example 9 N-Boc-4- {N, N- [cyclohexyl, (imidazol-1-yl) methyl] amino} piperidine

제조예 8에서 얻은 N-Boc-4-{N,N-[사이클로헥실, (이미다졸-1-일)카보닐]아미노}피페리딘(188.3mg, 0.5mmol)을 정제한 THF(10㎖)에 넣고 LAH(70mg, 2mmol)를 0℃에서 적가하여 6시간동안 교반하였다. 반응이 종결된 용액을 EtOAc로 희석하고 물을 넣은 다음 다시 2시간동안 교반하였다. 하얀 침전물이 생기면 셀라이트에 여과하고 무수 MgSO4로 건조한 다음 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: MC/MeOH=7/1, v/v)로 정제하여 표제화합물(130.5mg, 수율 72%)을 수득하였다.THF (10 mL) which purified N-Boc-4- {N, N- [cyclohexyl, (imidazol-1-yl) carbonyl] amino} piperidine (188.3 mg, 0.5 mmol) obtained in Preparation Example 8. ) And LAH (70mg, 2mmol) was added dropwise at 0 ℃ and stirred for 6 hours. The reaction solution was diluted with EtOAc, water was added and stirred for 2 hours. When a white precipitate formed, it was filtered through celite, dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: MC / MeOH = 7/1, v / v) to afford the title compound (130.5 mg, yield 72%).

MS [M+H] = 363MS [M + H] = 363

제조예 10: N-Boc-4-{N,N-[사이클로헥실, (1-메틸-이미다졸-4-일)메틸]아미노}피페리딘Preparation Example 10 N-Boc-4- {N, N- [cyclohexyl, (1-methyl-imidazol-4-yl) methyl] amino} piperidine

제조예 1의 단계 B에서 얻은 1-N-Boc-4-[N-(사이클로헥실)아미노]피페리딘 (282.4mg, 1mmol)과 1-메틸이미다졸-4-카보알데하이드(110.1mg, 1mmol)를 이용하여 제조예 1 의 단계 B와 같은 방법으로 표제화합물(312.6mg, 수율 83%)을 수득하였다.1-N-Boc-4- [N- (cyclohexyl) amino] piperidine (282.4 mg, 1 mmol) and 1-methylimidazole-4-carboaldehyde (110.1 mg, obtained in Step B of Preparation Example 1) 1 mmol) was used to obtain the title compound (312.6 mg, 83% yield) in the same manner as in Step B of Preparation Example 1.

MS [M+H] = 377MS [M + H] = 377

제조예 11: N-Boc-4-{N,N-[사이클로헥실, (1,2,4-트리아졸-1-일)아세틸]아미노}피페리딘Preparation Example 11 N-Boc-4- {N, N- [cyclohexyl, (1,2,4-triazol-1-yl) acetyl] amino} piperidine

단계 A : N-Boc-4-[N,N-(사이클로헥실, 브로모아세틸)아미노]피페리딘Step A: N-Boc-4- [N, N- (cyclohexyl, bromoacetyl) amino] piperidine

제조예 1의 단계 B에서 얻은 N-Boc-4-[N-(사이클로헥실)아미노]피페리딘 (282.4 mg, 1mmol)을 THF(5㎖)에 녹이고 트리에틸아민(280㎖, 2mmol)을 넣어 염기화시켰다. 이 용액에 브로모아세틸브로마이드(241.3mg, 1.2mmol)를 0℃에서 천천히 첨가하고 온도를 상온으로 올려 6시간 동안 교반하였다. 반응이 종결된 후 1N HCl로 중화하고 EtOAc(10㎖ x 3)로 추출한 다음 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=1/4, v/v)로 정제하여 표제화합물(383.2mg, 수율 95%)을 수득하였다.N-Boc-4- [N- (cyclohexyl) amino] piperidine (282.4 mg, 1 mmol) obtained in step B of Preparation Example 1 was dissolved in THF (5 mL), and triethylamine (280 mL, 2 mmol) was added. Put and basified. Bromoacetylbromide (241.3 mg, 1.2 mmol) was slowly added to this solution at 0 ° C., and the temperature was raised to room temperature and stirred for 6 hours. After the reaction was terminated, the mixture was neutralized with 1N HCl, extracted with EtOAc (10 mL × 3), and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-hexane = 1/4, v / v) to give the title compound (383.2 mg, yield 95%).

MS [M+H] = 404MS [M + H] = 404

단계 B : N-Boc-4-{N,N-[사이클로헥실, (1,2,4-트리아졸-1-일)아세틸]아미노}피페리딘Step B: N-Boc-4- {N, N- [cyclohexyl, (1,2,4-triazol-1-yl) acetyl] amino} piperidine

단계 A 에서 얻은 N-Boc-4-[N,N-(사이클로헥실, 브로모아세틸)아미노]피페리딘(191.6mg, 0.5mmol)과 나트륨으로 치환된 1,2,4-트리아졸(91.1mg, 1mmol)을 DMF (10㎖)에 녹이고 100℃에서 24시간 동안 교반시켰다. 반응이 종결된 후 EtOAc로 희석시키고 포화 탄산수소나트륨 수용액 및 HCl로 차례로 씻고 무수 MgSO4로 건조한 다음 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=2/3, v/v)로 정제하여 표제화합물(176.2mg, 수율 90%)을 수득하였다.1,2,4-triazole (91.1) substituted with N-Boc-4- [N, N- (cyclohexyl, bromoacetyl) amino] piperidine (191.6 mg, 0.5 mmol) and sodium obtained in step A mg, 1 mmol) was dissolved in DMF (10 mL) and stirred at 100 ° C. for 24 h. After completion of the reaction, the mixture was diluted with EtOAc, washed successively with saturated aqueous sodium hydrogen carbonate solution and HCl, dried over anhydrous MgSO 4, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-hexane = 2/3, v / v) to give the title compound (176.2 mg, yield 90%).

MS [M+H] = 392MS [M + H] = 392

제조예 12: N-Boc-4-{N,N-[사이클로헥실, (1,2,4-트리아졸-1-일)에틸]아미노}피페리딘Preparation Example 12 N-Boc-4- {N, N- [cyclohexyl, (1,2,4-triazol-1-yl) ethyl] amino} piperidine

제조예 11에서 얻은 N-Boc-4-{N,N-[사이클로헥실, (1,2,4-트리아졸-1-일)아세틸]아미노}피페리딘(195.8mg, 0.5mmol)을 이용하여 제조예 9와 같은 방법으로 표제 화합물(169.92mg, 수율 90%)을 수득하였다.Using N-Boc-4- {N, N- [cyclohexyl, (1,2,4-triazol-1-yl) acetyl] amino} piperidine (195.8 mg, 0.5 mmol) obtained in Preparation Example 11 In the same manner as in Preparation Example 9, the title compound (169.92 mg, yield 90%) was obtained.

MS [M+H] = 378MS [M + H] = 378

제조예 13: N-Boc-4-{N,N-[사이클로헥실, (1,2,3-트리아졸-2-일)아세틸]아미노}피페리딘Preparation Example 13: N-Boc-4- {N, N- [cyclohexyl, (1,2,3-triazol-2-yl) acetyl] amino} piperidine

제조예 11의 단계 A에서 얻은 N-Boc-4-[N,N-(사이클로헥실, 브로모아세틸)아미노]피페리딘(191.6mg, 0.5mmol), 1,2,3-트리아졸(70mg, 1mmol) 및 나트륨 이소펜톡사이드(220.2mg, 4mmol)를 이용하여 제조예 11의 단계 B와 같은 방법으로 표제 화합물(169.1mg, 수율 86%)을 수득하였다.N-Boc-4- [N, N- (cyclohexyl, bromoacetyl) amino] piperidine (191.6 mg, 0.5 mmol), 1,2,3-triazole (70 mg) obtained in step A of Preparation Example 11 , 1 mmol) and sodium isopentoside (220.2 mg, 4 mmol) to give the title compound (169.1 mg, yield 86%) in the same manner as in Step B of Preparation Example 11.

MS [M+H] = 392MS [M + H] = 392

제조예 14: N-Boc-4-{N,N-[사이클로헥실, (1,2,4-트리아졸-1-일)카보닐]아미노}피페리딘Preparation Example 14 N-Boc-4- {N, N- [cyclohexyl, (1,2,4-triazol-1-yl) carbonyl] amino} piperidine

단계 A : N-Boc-4-[N,N-(사이클로헥실, 클로로카보닐)아미노]피페리딘Step A: N-Boc-4- [N, N- (cyclohexyl, chlorocarbonyl) amino] piperidine

제조예 1의 단계 B에서 얻은 N-Boc-4-[N-(사이클로헥실)아미노]피페리딘 (282.43mg, 1mmol)을 디클로로메탄(10㎖)에 녹이고 트리에틸아민(280㎖, 2mmol)을 넣어 염기화시킨 후 포스겐(534㎖, 1mmol, 20% 톨루엔 용액)을 천천히 첨가하였다. 반응물을 상온에서 24시간 교반하였다. 반응이 종결된 후 트리에틸아민 HCl염을 제거하기 위해 여과하고 감압 농축하여 표제화합물(310.4mg, 수율 90%)을 수득하였다.N-Boc-4- [N- (cyclohexyl) amino] piperidine (282.43 mg, 1 mmol) obtained in step B of Preparation Example 1 was dissolved in dichloromethane (10 mL) and triethylamine (280 mL, 2 mmol) Phosphogen (534 ml, 1 mmol, 20% toluene solution) was added slowly. The reaction was stirred at room temperature for 24 hours. After the reaction was terminated, filtered to remove triethylamine HCl salt and concentrated under reduced pressure to give the title compound (310.4 mg, 90% yield).

MS [M+H] = 347MS [M + H] = 347

단계 B : N-Boc-4-{N,N-[사이클로헥실, (1,2,4-트리아졸-1-일)카보닐]아미노}피페리딘Step B: N-Boc-4- {N, N- [cyclohexyl, (1,2,4-triazol-1-yl) carbonyl] amino} piperidine

단계 A에서 얻은 N-Boc-4-[N,N-(사이클로헥실, 클로로카보닐)아미노]피페리딘(173mg, 0.5mmol)을 DMF(10㎖)에 녹이고 나트륨으로 치환된 1,2,4-트리아졸(91.1 mg, 1mmol)을 첨가하여 100℃에서 24시간 교반하였다. 반응이 종결된 후 EtOAc로 희석하고 탄산수소나트륨과 HCl로 각각 씻어준 다음 무수 MgSO4로 건조하고 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: 아세톤/MC=2/3, v/v)로 정제하여 표제화합물(166.1mg, 수율 88%)을 수득하였다.N-Boc-4- [N, N- (cyclohexyl, chlorocarbonyl) amino] piperidine (173 mg, 0.5 mmol) obtained in step A was dissolved in DMF (10 mL) and substituted with sodium 1,2, 4-triazole (91.1 mg, 1 mmol) was added and stirred at 100 ° C. for 24 hours. After completion of the reaction, the mixture was diluted with EtOAc, washed with sodium hydrogen carbonate and HCl, respectively, dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: acetone / MC = 2/3, v / v) to give the title compound (166.1 mg, yield 88%).

MS [M+H] = 378MS [M + H] = 378

제조예 15: N-Boc-4-{N,N-[사이클로헥실, (1,2,4-트리아졸-1-일)메틸]아미노}피페리딘Preparation Example 15 N-Boc-4- {N, N- [cyclohexyl, (1,2,4-triazol-1-yl) methyl] amino} piperidine

제조예 14에서 얻은 N-Boc-{4-[N,N-사이클로헥실, (1,2,4-트리아졸-1-일)카보닐]아미노}피페리딘(188.8mg, 0.5mmol)을 이용하여 제조예 9와 같은 방법으로 표제화합물(158.1mg, 수율 87%)을 수득하였다.N-Boc- {4- [N, N-cyclohexyl, (1,2,4-triazol-1-yl) carbonyl] amino} piperidine (188.8 mg, 0.5 mmol) obtained in Preparation Example 14 was prepared. Using the same method as in Preparation Example 9 to obtain the title compound (158.1 mg, yield 87%).

MS [M+H] = 364MS [M + H] = 364

제조예 16: 4-{사이클로헥실[(1-트리틸-1,2,4-트리아졸일)카보닐]아미노}피페리딘Preparation Example 16 4- {cyclohexyl [(1-trityl-1,2,4-triazolyl) carbonyl] amino} piperidine

단계 A: 1-트리틸-1,2,4-트리아졸-5-카보알데히드Step A: 1-trityl-1,2,4-triazole-5-carboaldehyde

1-트리틸-1,2,4-트리아졸(1.0g, 3.2mmol)을 무수 THF(100㎖)에 녹이고 N,N,N',N'-테트라메틸에틸렌디아민(0.48㎖, 3.2mmol)을 적가하였다. 혼합물을 -78℃로 냉각시킨 후 n-부틸리튬(1.6N 헥산 용액, 2.2㎖, 3.52mmol)을 천천히 적가하였다. 1시간 교반한 후 무수 DMF(0.36㎖, 4.6mmol)를 적가하고 -30℃로 승온시켰다. 30분간 교반한 후 물 1㎖를 적가하였다. NH4Cl 수용액(50㎖)과 소금물(50㎖)로 세척한 후 무수 MgSO4로 건조하고 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=2/1, v/v)로 정제하여 표제화합물(0.8g, 수율 74%)을 수득하였다.Dissolve 1-trityl-1,2,4-triazole (1.0 g, 3.2 mmol) in dry THF (100 mL) and N, N, N ', N'-tetramethylethylenediamine (0.48 mL, 3.2 mmol) Was added drop wise. The mixture was cooled to −78 ° C. and n-butyllithium (1.6N hexane solution, 2.2 mL, 3.52 mmol) was slowly added dropwise. After stirring for 1 hour, anhydrous DMF (0.36 mL, 4.6 mmol) was added dropwise and the temperature was raised to -30 ° C. After stirring for 30 minutes, 1 ml of water was added dropwise. Washed with aqueous NH 4 Cl solution (50 mL) and brine (50 mL), dried over anhydrous MgSO 4 and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: EtOAc / n-hexane = 2/1, v / v) to give the title compound (0.8 g, yield 74%).

MS (M+H) = 340MS (M + H) = 340

단계 B: 1-트리틸-1,2,4-트리아졸-3-카보알데히드Step B: 1-trityl-1,2,4-triazole-3-carboaldehyde

1-트리틸-1,2,4-트리아졸-5-카보알데히드(1g, 2.95mmol)를 무수 CH2Cl2(6㎖)에 녹이고 TFA(0.1㎖)를 천천히 적가하였다. 실온에서 14 시간 교반한 후 감압 농축하여 표제화합물(0.95g, 수율 95%)을 수득하였다.1-trityl-1,2,4-triazole-5-carboaldehyde (1 g, 2.95 mmol) was dissolved in anhydrous CH 2 Cl 2 (6 mL) and TFA (0.1 mL) was slowly added dropwise. After stirring for 14 hours at room temperature, the mixture was concentrated under reduced pressure to obtain the title compound (0.95 g, yield 95%).

MS (M+H) = 340MS (M + H) = 340

단계 C: 메틸 1-트리틸-1,2,4-트리아졸-3-카복실레이트Step C: Methyl 1-trityl-1,2,4-triazole-3-carboxylate

산화망간(MnO2, 2.6g, 29.9mmol), 소듐시아나이드(NaCN, 0.58g, 11.80mmol) 및 아세트산(0.17㎖, 2.95mmol)을 메탄올(60㎖)에 적가한 후 실온에서 1시간 교반하였다. 여기에 단계 B에서 수득한 화합물(1g, 2.95mmol)을 염화메틸렌(10㎖)에 녹여서 적가하고 실온에서 2시간 반응하였다. 반응 종료후 휘발성 물질을 저온에서감압증류하고 에틸아세테이트(20㎖)로 희석하고 포화 탄산수소나트륨 수용액 및 소금물로 차례로 세척한 후 무수 MgSO4로 건조하고 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=3/7, v/v)로 정제하여 표제화합물(0.75g, 수율 68%)을 수득하였다.Manganese oxide (MnO 2 , 2.6 g, 29.9 mmol), sodium cyanide (NaCN, 0.58 g, 11.80 mmol) and acetic acid (0.17 mL, 2.95 mmol) were added dropwise to methanol (60 mL), followed by stirring at room temperature for 1 hour. . The compound (1 g, 2.95 mmol) obtained in step B was dissolved in methylene chloride (10 ml) and added dropwise thereto, followed by reaction at room temperature for 2 hours. After completion of the reaction, the volatiles were distilled under reduced pressure at low temperature, diluted with ethyl acetate (20 ml), washed sequentially with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-hexane = 3/7, v / v) to give the title compound (0.75 g, yield 68%).

MS (M+H) = 370MS (M + H) = 370

단계 D: 1-트리틸-1,2,4-트리아졸-3-카르복실산Step D: 1-trityl-1,2,4-triazole-3-carboxylic acid

단계 C에서 수득한 화합물(0.3g, 0.81mmol)을 메탄올(10㎖)에 녹이고 1N LiOH(1.6㎖, 1.62mmol)을 적가한 후 실온에서 3시간 교반하였다. 반응 종료후 휘발성 물질을 감압 증류하고 0.1N HCl로 pH를 5로 조절한 후 에틸아세테이트(10㎖)로 2회 추출하였다. 무수 MgSO4로 건조하고 감압 농축하여 표제화합물(0.29g, 수율 100%)을 수득하였다.The compound (0.3 g, 0.81 mmol) obtained in step C was dissolved in methanol (10 mL), 1N LiOH (1.6 mL, 1.62 mmol) was added dropwise, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the volatiles were distilled under reduced pressure, the pH was adjusted to 5 with 0.1 N HCl, and extracted twice with ethyl acetate (10 mL). Drying over anhydrous MgSO 4 and concentration under reduced pressure gave the title compound (0.29 g, yield 100%).

MS (M+H) = 356MS (M + H) = 356

단계 E: N-Boc-4-{N,N-[사이클로헥실,(1-트리틸-1,2,4-트리아졸-3-일)카보닐]아미노}피페리딘Step E: N-Boc-4- {N, N- [cyclohexyl, (1-trityl-1,2,4-triazol-3-yl) carbonyl] amino} piperidine

N-Boc-(4-사이클로헥실아미노)피페리딘(0.4g, 1.42mmol)을 DMF(10㎖)에 녹이고 여기에 단계 D에서 수득한 화합물(0.5g, 1.42mmol), HATU(0.65g, 1.70mmol) 및 Et(iPr)2N(0.62㎖, 3.54mmol)을 가하였다. 반응액을 실온에서 6시간 동안 교반하였다. 반응이 완결된 용액을 포화 염화암모늄 수용액, 포화 탄산수소나트륨 수용액 및 소금물로 차례로 세척한 후 무수 MgSO4로 건조하고 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=2/3, v/v)로 정제하여 표제화합물 (0.52g, 수율 60%)을 수득하였다.N-Boc- (4-cyclohexylamino) piperidine (0.4 g, 1.42 mmol) was dissolved in DMF (10 mL) and the compound obtained in step D (0.5 g, 1.42 mmol), HATU (0.65 g, 1.70 mmol) and Et (iPr) 2 N (0.62 mL, 3.54 mmol) were added. The reaction was stirred at room temperature for 6 hours. The reaction solution was washed sequentially with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-hexane = 2/3, v / v) to give the title compound (0.52 g, yield 60%).

MS (M+H) = 620MS (M + H) = 620

단계 F: 4-{N,N-[사이클로헥실,(1-트리틸-1,2,4-트리아졸-3-일)카보닐]아미노}피페리딘Step F: 4- {N, N- [cyclohexyl, (1-trityl-1,2,4-triazol-3-yl) carbonyl] amino} piperidine

단계 E에서 얻어진 화합물(0.2g, 0.32mmol)을 CH2Cl2(10㎖)에 녹이고 트리이소프로필실란((iPr)3SiH, 74㎕, 0.96mmol)과 TFA(2㎖)를 가한 다음 용액을 실온에서 2시간 동안 교반하였다. 반응이 완결된 용액을 감압 농축하여 표제화합물의 TFA염(0.15g, 수율 94%)을 수득하였다.The compound (0.2 g, 0.32 mmol) obtained in step E was dissolved in CH 2 Cl 2 (10 mL), triisopropylsilane ((iPr) 3 SiH, 74 μl, 0.96 mmol) and TFA (2 mL) were added, followed by the solution. Was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give TFA salt (0.15 g, 94% yield) of the title compound.

MS (M+H) = 278MS (M + H) = 278

제조예 17: 4-{N,N-[사이클로헥실,(1-메틸-1,2,4-트리아졸-3-일)카보닐]아미노}피페리딘Preparation 17: 4- {N, N- [cyclohexyl, (1-methyl-1,2,4-triazol-3-yl) carbonyl] amino} piperidine

단계 A: N-Boc-4-{N,N-[사이클로헥실, (1,2,4-트리아졸-3-일)카보닐]아미노}피페리딘Step A: N-Boc-4- {N, N- [cyclohexyl, (1,2,4-triazol-3-yl) carbonyl] amino} piperidine

제조예 16의 단계 E에서 수득한 N-Boc-4-{N,N-[사이클로헥실, (1-트리틸-1,2,4-트리아졸-3-일)카보닐]아미노}피페리딘(0.3g, 0.48mmol)을 CH2Cl2(3㎖)에 녹이고 트리이소프로필실란((iPr)3SiH, 0.20㎖, 0.96mmol)과 TFA(0.15㎖, 1.92mmol)를 가한 다음 용액을 실온에서 6시간 동안 교반하였다. 반응이 완결된 후, 포화 탄산수소나트륨 수용액 및 소금물로 차례로 세척한 후 무수 MgSO4로 건조하고 감압 농축하여 표제화합물(0.13g, 수율 72%)을 수득하였다.N-Boc-4- {N, N- [cyclohexyl, (1-trityl-1,2,4-triazol-3-yl) carbonyl] amino} piperi obtained from step E of Preparation Example 16 Dean (0.3 g, 0.48 mmol) was dissolved in CH 2 Cl 2 (3 mL), triisopropylsilane ((iPr) 3 SiH, 0.20 mL, 0.96 mmol) and TFA (0.15 mL, 1.92 mmol) were added. Stir at room temperature for 6 hours. After completion of the reaction, the mixture was washed sequentially with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous MgSO 4 , and concentrated under reduced pressure to obtain the title compound (0.13 g, 72% yield).

MS (M+H) = 378MS (M + H) = 378

단계 B: N-Boc-4-{N,N-[사이클로헥실, (1-메틸-1,2,4-트리아졸-3일)카보닐]아미노}피페리딘Step B: N-Boc-4- {N, N- [cyclohexyl, (1-methyl-1,2,4-triazol-3yl) carbonyl] amino} piperidine

단계 A에서 수득한 화합물(0.1g, 0.27mmol)을 DMF(2㎖)에 녹이고 MeI(50㎕, 0.80mmol)과 2N NaOH(0.4㎖, 0.8mmol)을 가한 후 실온에서 4시간 반응하였다. 반응이 완결된 후 감압증류하여 휘발성 물질을 제거하고 잔류물을 칼럼 크로마토그래피 (용리액: EtOAc/n-헥산=2/3, v/v)로 정제하여 표제화합물(82mg, 수율 78%)을 수득하였다.The compound (0.1 g, 0.27 mmol) obtained in step A was dissolved in DMF (2 mL), MeI (50 μl, 0.80 mmol) and 2N NaOH (0.4 mL, 0.8 mmol) were added, and the mixture was reacted at room temperature for 4 hours. After completion of the reaction, the product was distilled under reduced pressure to remove volatiles, and the residue was purified by column chromatography (eluent: EtOAc / n-hexane = 2/3, v / v) to obtain the title compound (82 mg, yield 78%). It was.

MS (M+H) = 392MS (M + H) = 392

단계 C: 4-{N,N-[사이클로헥실, (1-메틸-1,2,4-트리아졸-3-일)카보닐]아미노}피페리딘Step C: 4- {N, N- [cyclohexyl, (1-methyl-1,2,4-triazol-3-yl) carbonyl] amino} piperidine

단계 B에서 수득한 화합물(82mg, 0.21mmol)로부터 제조예 16의 단계 F와 동일한 방법으로 표제화합물(85mg, 수율 100%)을 수득하였다.The title compound (85 mg, yield 100%) was obtained from the compound (82 mg, 0.21 mmol) obtained in step B in the same manner as in Step F of Preparation Example 16.

MS (M+H) = 292MS (M + H) = 292

제조예 18: 2-메틸테트라졸-5-카복실산Preparation Example 18 2-methyltetrazole-5-carboxylic acid

논문(참조: JOC 1966, 31, 3849)에 기재된 방법과 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다.The reaction was carried out in the same manner as described in the paper (JoC 1966, 31, 3849) to obtain the title compound.

제조예 19: N-Boc-4-{N,N-[사이클로헥실, (1-메틸-1,2,4-트리아졸-3-일)메틸]아미노}피페리딘Preparation Example 19 N-Boc-4- {N, N- [cyclohexyl, (1-methyl-1,2,4-triazol-3-yl) methyl] amino} piperidine

제조예 17의 단계 B에서 얻은 N-Boc-4-{N,N-[사이클로헥실, (1-메틸-1,2,4-트리아졸-3-일)카보닐]아미노}피페리딘(195.8mg, 0.5mmol)을 이용하여 제조예 9와 같은 방법으로 표제화합물( 171.8mg, 수율 91%)을 수득하였다.N-Boc-4- {N, N- [cyclohexyl, (1-methyl-1,2,4-triazol-3-yl) carbonyl] amino} piperidine obtained in step B of Preparation Example 17 195.8 mg, 0.5 mmol) was used to obtain the title compound (171.8 mg, yield 91%) in the same manner as in Preparation Example 9.

MS (M+H) = 378MS (M + H) = 378

제조예 20: N-Boc-4-{N,N-[사이클로헥실, (1,2,3-트리아졸-2-일)에틸]아미노}피페리딘Preparation Example 20 N-Boc-4- {N, N- [cyclohexyl, (1,2,3-triazol-2-yl) ethyl] amino} piperidine

제조예 13에서 합성한 N-Boc-4-{N,N-[사이클로헥실, (1,2,3-트리아졸-2-일) 아세틸]아미노}피페리딘(188.8mg, 0.5mmol)을 이용하여 제조예 9와 같은 방법으로 표제화합물(156.3mg, 수율 86%)을 수득하였다.N-Boc-4- {N, N- [cyclohexyl, (1,2,3-triazol-2-yl) acetyl] amino} piperidine (188.8 mg, 0.5 mmol) synthesized in Preparation Example 13 was prepared. Using the same method as in Preparation Example 9 to obtain the title compound (156.3 mg, yield 86%).

MS (M+H) = 364MS (M + H) = 364

제조예 21: N-Boc-4-{N,N-[사이클로헥실, (테트라졸-5-일)메틸]아미노}피페리딘Preparation Example 21 N-Boc-4- {N, N- [cyclohexyl, (tetrazol-5-yl) methyl] amino} piperidine

논문(참조: JMC 1996, 39, 842)에 기재된 방법과 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다.The reaction was carried out in the same manner as described in the paper (see JMC 1996, 39, 842) to obtain the title compound.

제조예 22: N-Boc-4-{N,N-[사이클로헥실, (4-메틸-테트라졸-5-일)메틸카보닐]아미노}피페리딘Preparation Example 22 N-Boc-4- {N, N- [cyclohexyl, (4-methyl-tetrazol-5-yl) methylcarbonyl] amino} piperidine

단계 A : 에틸-(테트라졸-5-일)아세테이트Step A: Ethyl- (tetrazol-5-yl) acetate

상업적으로 구입한 에틸시아노아세테이트(565.6mg, 5mmol)를 DMF(20㎖)에 녹이고 트리부틸틴 아자이드(2004.6mg, 6mmol)를 적가하여 100℃에서 24시간 교반하였다. 반응이 종결된 용액을 여과하고 EtOAc(30㎖)로 희석하고 탄산수소나트륨과 HCl로 차례로 세척하였다. 무수 MgSO4로 건조하여 여과한 다음 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=10/1, v/v)로 정제하여 표제화합물(577.8mg, 수율 74%)을 수득하였다.Commercially purchased ethylcyanoacetate (565.6 mg, 5 mmol) was dissolved in DMF (20 mL), and tributyltin azide (2004.6 mg, 6 mmol) was added dropwise and stirred at 100 ° C. for 24 hours. The reaction solution was filtered, diluted with EtOAc (30 mL) and washed sequentially with sodium bicarbonate and HCl. Dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-hexane = 10/1, v / v) to give the title compound (577.8 mg, yield 74%).

MS [M+H] = 157MS [M + H] = 157

단계 B: 에틸-[(1-메틸)-테트라졸-5-일]아세테이트Step B: Ethyl-[(1-methyl) -tetrazol-5-yl] acetate

단계 A에서 합성한 에틸-(테트라졸-5-일)아세테이트(312.3mg, 2mmol)를 DMF (10㎖)에 녹이고 트리에틸아민(280㎖, 2mmol)으로 염기화시킨 후 요오드화메탄(340.6, 2.4mmol)을 적가하여 상온에서 6시간 교반시켰다. 반응이 종결된 용액을 여과하고 EtOAc로 희석하고 탄산수소나트륨과 HCl로 차례로 세척하였다. 무수 MgSO4로 건조하여 여과한 다음 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=5/1, v/v)로 정제하여 표제화합물(299.6mg, 수율 88%)을 수득하였다.Ethyl- (tetrazol-5-yl) acetate (312.3 mg, 2 mmol) synthesized in step A was dissolved in DMF (10 mL) and basified with triethylamine (280 mL, 2 mmol), followed by methane iodide (340.6, 2.4). mmol) was added dropwise and stirred at room temperature for 6 hours. The reaction was terminated by filtration, diluted with EtOAc and washed sequentially with sodium bicarbonate and HCl. Dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-hexane = 5/1, v / v) to give the title compound (299.6 mg, yield 88%).

MS [M+H] = 157MS [M + H] = 157

단계 C : (1-메틸-테트라졸-5-일)아세트산Step C: (1-Methyl-tetrazol-5-yl) acetic acid

단계 B에서 얻은 에틸-(1-메틸-테트라졸-5-일)아세테이트(170.2mg, 1mmol)를 THF(4㎖)와 물(1㎖) 용액에 녹이고 NaOH(120mg, 3mmol)를 적가한 다음 상온에서 4시간동안 교반하였다. 반응이 종결된 용액을 감압 농축하고 잔류물을 EtOAc로 희석하고 HCl로 중화한 다음 EtOAc로 추출하였다. 추출한 유기용액을 무수 MgSO4로 건조하여 여과한 다음 감압 농축하여 표제화합물(116.5mg, 수율 82%)을 수득하였다.The ethyl- (1-methyl-tetrazol-5-yl) acetate (170.2 mg, 1 mmol) obtained in step B was dissolved in a solution of THF (4 mL) and water (1 mL), and NaOH (120 mg, 3 mmol) was added dropwise. Stir at room temperature for 4 hours. After completion of the reaction, the solution was concentrated under reduced pressure, and the residue was diluted with EtOAc, neutralized with HCl, and extracted with EtOAc. The extracted organic solution was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure to obtain the title compound (116.5 mg, yield 82%).

MS [M+H] = 143MS [M + H] = 143

단계 D: 1-N-Boc-4-{N,N-[사이클로헥실, (4-메틸-테트라졸-5-일)메틸카보닐]아미노}피페리딘Step D: 1-N-Boc-4- {N, N- [cyclohexyl, (4-methyl-tetrazol-5-yl) methylcarbonyl] amino} piperidine

단계 C에서 합성한 (4-메틸-테트라졸-5-일)아세트산(100mg, 0.70mmol)과 제조예 1의 단계 B에서 합성한 1-N-Boc-[4-(N-사이클로헥실)아미노]피페리딘(197.7 mg, 0.7mmol)을 이용하여 제조예 16의 단계 E와 같은 방법으로 표제화합물(227.6mg, 수율 80%)을 수득하였다.(4-Methyl-tetrazol-5-yl) acetic acid (100 mg, 0.70 mmol) synthesized in step C and 1-N-Boc- [4- (N-cyclohexyl) amino synthesized in step B of Preparation Example 1 ] The title compound (227.6 mg, yield 80%) was obtained by the same method as Step E of Preparation Example 16 using piperidine (197.7 mg, 0.7 mmol).

MS [M+H] = 407MS [M + H] = 407

제조예 23: N-Boc-4-{N,N-[사이클로헥실, (4-메틸-테트라졸-5-일)에틸]아미노}피페리딘Preparation Example 23 N-Boc-4- {N, N- [cyclohexyl, (4-methyl-tetrazol-5-yl) ethyl] amino} piperidine

제조예 22에서 얻은 1-N-Boc-4-{N,N-[사이클로헥실, (4-메틸-테트라졸-5-일)메틸카보닐]아미노}피페리딘(100mg, 0.44mmol)을 이용하여 제조예 9와 같은 방법으로 표제화합물(155.5mg, 수율 90%)을 합성하였다.1-N-Boc-4- {N, N- [cyclohexyl, (4-methyl-tetrazol-5-yl) methylcarbonyl] amino} piperidine (100 mg, 0.44 mmol) obtained in Preparation Example 22 was prepared. Using the same method as in Preparation Example 9 to obtain the title compound (155.5mg, 90% yield).

MS [M+H] = 393MS [M + H] = 393

제조예 24: N-Boc-4-{N,N-[사이클로헥실, (4-메틸-테트라졸-5-일)에틸카보닐]아미노}피페리딘Preparation Example 24 N-Boc-4- {N, N- [cyclohexyl, (4-methyl-tetrazol-5-yl) ethylcarbonyl] amino} piperidine

에틸(시아노)프로피올레이트를 이용하여 제조예 22와 같은 방법으로 표제화합물을 수득하였다(수율 46%).The title compound was obtained in the same manner as in Preparation Example 22 using ethyl (cyano) propiolate (yield 46%).

MS [M+H] = 421MS [M + H] = 421

제조예 25: N-Boc-4-{N,N-[사이클로헥실, (4-메틸-테트라졸-5-일)프로필]아미노}피페리딘Preparation Example 25 N-Boc-4- {N, N- [cyclohexyl, (4-methyl-tetrazol-5-yl) propyl] amino} piperidine

제조예 24에서 합성한 N-Boc-{4-[N,N-사이클로헥실, (4-메틸-테트라졸-5-일)에틸카보닐]아미노}피페리딘(210.3mg, 0.5mmol)을 이용하여 제조예 9와 같은 방법으로 표제화합물(182.9mg, 수율 90%)을 수득하였다.N-Boc- {4- [N, N-cyclohexyl, (4-methyl-tetrazol-5-yl) ethylcarbonyl] amino} piperidine (210.3 mg, 0.5 mmol) synthesized in Preparation Example 24 was prepared. Using the same method as in Preparation Example 9 to obtain the title compound (182.9 mg, 90% yield).

MS [M+H] = 407MS [M + H] = 407

제조예 26: N-Boc-4-{N,N-[사이클로헥실, (테트라졸-1-일)아세틸]아미노}피페리딘Preparation Example 26 N-Boc-4- {N, N- [cyclohexyl, (tetrazol-1-yl) acetyl] amino} piperidine

제조예 1의 단계 B에서 합성한 N-Boc-[4-(N-사이클로헥실)아미노]피페리딘 (282.43mg, 1mmol)과 1-테트라졸 아세트산(128.10mg, 1mmol)을 이용하여 제조예 16의 단계 E와 같은 방법으로 표제화합물(349.3mg, 수율 89%)을 수득하였다.Preparation Example using N-Boc- [4- (N-cyclohexyl) amino] piperidine (282.43 mg, 1 mmol) and 1-tetrazol acetic acid (128.10 mg, 1 mmol) synthesized in step B of Preparation Example 1 In the same manner as in Step E of 16, the title compound (349.3 mg, yield 89%) was obtained.

MS [M+H] = 393MS [M + H] = 393

제조예 27: N-Boc-4-{N,N-[사이클로헥실, (테트라졸-1-일)에틸]아미노}피페리딘Preparation Example 27 N-Boc-4- {N, N- [cyclohexyl, (tetrazol-1-yl) ethyl] amino} piperidine

제조예 26에서 얻은 N-Boc-{4-[N,N-사이클로헥실, (테트라졸-1-일)아세틸]아미노}피페리딘(146.3mg, 0.5mmol)을 이용하여 제조예 9와 같은 방법으로 표제화합물(172.2mg, 수율 91%)을 수득하였다.N-Boc- {4- [N, N-cyclohexyl, (tetrazol-1-yl) acetyl] amino} piperidine (146.3 mg, 0.5 mmol) obtained in Preparation Example 26 was used. The title compound (172.2 mg, yield 91%) was obtained by the method.

MS [M+H] = 379MS [M + H] = 379

제조예 28: N-Boc-4-{N,N-[사이클로헥실, (하이드록시)에틸]아미노}피페리딘Preparation Example 28 N-Boc-4- {N, N- [cyclohexyl, (hydroxy) ethyl] amino} piperidine

제조예 5에서 얻은 N-Boc-4-{N,N-[사이클로헥실, (메톡시카보닐)메틸]아미노}피페리딘(177.2mg, 0.5mmol)을 이용하여 제조예 9와 같은 방법으로 표제화합물 (146.9mg, 수율 90%)을 수득하였다.In the same manner as in Preparation Example 9, using N-Boc-4- {N, N- [cyclohexyl, (methoxycarbonyl) methyl] amino} piperidine (177.2 mg, 0.5 mmol) obtained in Preparation Example 5 The title compound (146.9 mg, yield 90%) was obtained.

MS [M+H] = 327MS [M + H] = 327

제조예 29: N-Boc-4-{N,N-[사이클로헥실, (메탄술페이트)에틸]아미노}피페리딘Preparation Example 29 N-Boc-4- {N, N- [cyclohexyl, (methanesulfate) ethyl] amino} piperidine

제조예 28에서 얻은 N-Boc-4-{N,N-[사이클로헥실, (하이드록시)에틸]아미노}피페리딘(70mg, 0.21mmol)을 이용하여 제조예 1의 단계 C와 같은 방법으로 표제화합물(84 mg, 수율 97%)을 수득하였다.Using N-Boc-4- {N, N- [cyclohexyl, (hydroxy) ethyl] amino} piperidine (70 mg, 0.21 mmol) obtained in Preparation Example 28 in the same manner as in Step C of Preparation Example 1 The title compound (84 mg, yield 97%) was obtained.

MS [M+H] = 405MS [M + H] = 405

제조예 30: N-Boc-4-{N,N-[사이클로헥실, (4-피리딜)카보닐]아미노}피페리딘Preparation Example 30 N-Boc-4- {N, N- [cyclohexyl, (4-pyridyl) carbonyl] amino} piperidine

제조예 1의 단계 B에서 합성한 N-Boc-4-[N-(사이클로헥실)아미노]피페리딘 (282.4mg, 1mmol)과 4-피리딘카복시산(123.1mg, 1mmol)을 이용하여 제조예 16의 단계 E와 같은 방법으로 표제화합물(356.5mg, 수율 92%)을 수득하였다.Preparation Example using N-Boc-4- [N- (cyclohexyl) amino] piperidine (282.4mg, 1mmol) and 4-pyridinecarboxylic acid (123.1mg, 1mmol) synthesized in Step B of Preparation Example 1 In the same manner as in Step E of 16, the title compound (356.5 mg, yield 92%) was obtained.

MS [M+H] = 388MS [M + H] = 388

제조예 31: N-Boc-4-[N,N-(사이클로헥실, 3-피리딜카보닐)아미노]피페리딘Preparation Example 31 N-Boc-4- [N, N- (cyclohexyl, 3-pyridylcarbonyl) amino] piperidine

제조예 1의 단계 B에서 합성한 N-Boc-4-[N-(사이클로헥실)아미노]피페리딘 (282.4mg, 1mmol)과 3-피리딘카복시산(123.1mg, 1mmol)을 이용하여 제조예 16의 단계 E와 같은 방법으로 표제화합물(352.6mg, 수율 91%)을 수득하였다.Preparation Example using N-Boc-4- [N- (cyclohexyl) amino] piperidine (282.4 mg, 1 mmol) and 3-pyridinecarboxylic acid (123.1 mg, 1 mmol) synthesized in step B of Preparation Example 1 The title compound (352.6 mg, yield 91%) was obtained in the same manner as in Step E of 16.

MS [M+H] = 388MS [M + H] = 388

제조예 32: N-Boc-4-[N,N-(사이클로헥실, 2-피리딜카보닐)아미노]피페리딘Preparation Example 32 N-Boc-4- [N, N- (cyclohexyl, 2-pyridylcarbonyl) amino] piperidine

제조예 1의 단계 B에서 합성한 N-Boc-4-[N-(사이클로헥실)아미노]피페리딘 (282.4mg, 1mmol)과 2-피리딘카복시산(123.1mg, 1mmol)을 이용하여 제조예 16의 단계 E와 같은 방법으로 표제화합물(352.5mg, 수율 91%)을 수득하였다.Preparation Example Using N-Boc-4- [N- (cyclohexyl) amino] piperidine (282.4mg, 1mmol) and 2-pyridinecarboxylic acid (123.1mg, 1mmol) synthesized in Step B of Preparation Example 1 The title compound (352.5 mg, yield 91%) was obtained in the same manner as in Step E of 16.

MS [M+H] = 388MS [M + H] = 388

제조예 33: N-Boc-4-{N,N-[사이클로헥실, (4-피리딜)메틸]아미노}피페리딘Preparation Example 33 N-Boc-4- {N, N- [cyclohexyl, (4-pyridyl) methyl] amino} piperidine

제조예 30에서 합성한 N-Boc-4-[N,N-(사이클로헥실, 4-피리딜카보닐)아미노]피페리딘(193.8mg, 0.5mg)을 이용하여 제조예 9와 같은 방법으로 표제화합물(165.7 mg, 수율 89%)을 수득하였다.In the same manner as in Preparation Example 9, using N-Boc-4- [N, N- (cyclohexyl, 4-pyridylcarbonyl) amino] piperidine (193.8 mg, 0.5 mg) synthesized in Preparation Example 30. The title compound (165.7 mg, yield 89%) was obtained.

MS [M+H] = 374MS [M + H] = 374

제조예 34: N-Boc-4-{N,N-[사이클로헥실, (3-피리딜)메틸]아미노}피페리딘Preparation Example 34 N-Boc-4- {N, N- [cyclohexyl, (3-pyridyl) methyl] amino} piperidine

제조예 31에서 합성한 N-Boc-4-[N,N-(사이클로헥실, 3-피리딜카보닐)아미노]피페리딘(193.8mg, 0.5mg)을 이용하여 제조예 9와 같은 방법으로 표제화합물(165.7 mg, 수율 89%)을 수득하였다.Using N-Boc-4- [N, N- (cyclohexyl, 3-pyridylcarbonyl) amino] piperidine (193.8 mg, 0.5 mg) synthesized in Preparation Example 31 in the same manner as in Preparation Example 9 The title compound (165.7 mg, yield 89%) was obtained.

MS [M+H] = 374MS [M + H] = 374

제조예 35: N-Boc-4-{N,N-[사이클로헥실, (2-피리딜)메틸]아미노}피페리딘Preparation 35: N-Boc-4- {N, N- [cyclohexyl, (2-pyridyl) methyl] amino} piperidine

제조예 32에서 합성한 N-Boc-4-[N,N-(사이클로헥실, 2-피리딜카보닐)아미노]피페리딘(193.8mg, 0.5mg)을 이용하여 제조예 9와 같은 방법으로 표제화합물(171.2 mg, 수율 92%)을 수득하였다.Using N-Boc-4- [N, N- (cyclohexyl, 2-pyridylcarbonyl) amino] piperidine (193.8 mg, 0.5 mg) synthesized in Preparation Example 32 in the same manner as in Preparation Example 9 The title compound (171.2 mg, yield 92%) was obtained.

MS [M+H] = 374MS [M + H] = 374

제조예 36: N-Boc-4-{N,N-[사이클로헥실, (피라진-2-일)카보닐]아미노}피페리딘Preparation Example 36 N-Boc-4- {N, N- [cyclohexyl, (pyrazin-2-yl) carbonyl] amino} piperidine

제조예 1의 단계 B에서 합성한 N-Boc-4-[N-(사이클로헥실)아미노]피페리딘 (282.4mg, 1mmol)과 2-피라진카복시산(124.0mg, 1mmol)을 이용하여 제조예 16의 단계 E와 같은 방법으로 표제화합물(352.6mg, 수율 91%)을 수득하였다.Preparation Example using N-Boc-4- [N- (cyclohexyl) amino] piperidine (282.4 mg, 1 mmol) and 2-pyrazinecarboxylic acid (124.0 mg, 1 mmol) synthesized in step B of Preparation Example 1 The title compound (352.6 mg, yield 91%) was obtained in the same manner as in Step E of 16.

MS [M+H] = 388MS [M + H] = 388

제조예 37: N-Boc-4-{N,N-[사이클로헥실, (피라진-2-일)메틸]아미노}피페리딘Preparation Example 37 N-Boc-4- {N, N- [cyclohexyl, (pyrazin-2-yl) methyl] amino} piperidine

제조예 36에서 합성한 N-Boc-4-{N,N-[사이클로헥실, (피라진-2-일)카보닐]아미노}피페리딘(194.2mg, 0.5mmol)을 이용하여 제조예 9와 같은 방법으로 표제화합물(170.3mg, 수율 91%)을 수득하였다.Preparation Example 9 was prepared using N-Boc-4- {N, N- [cyclohexyl, (pyrazin-2-yl) carbonyl] amino} piperidine (194.2 mg, 0.5 mmol) synthesized in Preparation Example 36. In the same manner to give the title compound (170.3 mg, 91% yield).

MS [M+H] = 373MS [M + H] = 373

제조예 38: N-Boc-4-{N,N-[사이클로헥실, (트리아진-2-일)카보닐]아미노}피페리딘Preparation Example 38 N-Boc-4- {N, N- [cyclohexyl, (triazin-2-yl) carbonyl] amino} piperidine

제조예 1의 단계 B에서 합성한 N-Boc-4-[N-(사이클로헥실)아미노]피페리딘 (282.4mg, 1mmol)과 2-트리아진카복시산(125.0mg, 1mmol)을 이용하여 제조예 16의 단계 E와 같은 방법으로 표제화합물(342.5mg, 수율 88%)을 수득하였다.Prepared using N-Boc-4- [N- (cyclohexyl) amino] piperidine (282.4 mg, 1 mmol) and 2-triazinecarboxylic acid (125.0 mg, 1 mmol) synthesized in step B of Preparation Example 1 The title compound (342.5 mg, yield 88%) was obtained by the same method as Step E of Example 16.

MS [M+H] = 390MS [M + H] = 390

제조예 39: N-Boc-4-{N,N-[사이클로헥실, (트리아진-2-일)메틸]아미노}피페리딘Preparation Example 39 N-Boc-4- {N, N- [cyclohexyl, (triazin-2-yl) methyl] amino} piperidine

제조예 38에서 합성한 N-Boc-4-{N,N-[사이클로헥실, (트리아진-2-일)카보닐]아미노}피페리딘(194.6mg, 0.5mmol)을 이용하여 제조예 28과 같은 방법으로 표제화합물(172.6mg, 수율 92%)을 수득하였다.Preparation Example 28 using N-Boc-4- {N, N- [cyclohexyl, (triazin-2-yl) carbonyl] amino} piperidine (194.6 mg, 0.5 mmol) synthesized in Preparation Example 38 In the same manner as the title compound (172.6 mg, yield 92%) was obtained.

MS [M+H] = 376MS [M + H] = 376

제조예 40: N-Boc-4-{N,N-[사이클로헥실, (1,3-아미노티아졸)-2-일]아미노}피페리딘Preparation Example 40 N-Boc-4- {N, N- [cyclohexyl, (1,3-aminothiazol) -2-yl] amino} piperidine

단계 A: N-Boc-4-{N-[(1,3-아미노티아졸)-2-일]아미노}피페리딘Step A: N-Boc-4- {N-[(1,3-aminothiazol) -2-yl] amino} piperidine

2-아미노-1,3-아미노티아졸(100.0mg, 1mmol)과 N-Boc-4-피페리디논(199.1 mg, 1mmol)을 이용하여 제조예 1의 단계 B와 같은 방법으로 표제화합물(249.2mg, 수율 88%)을 합성하였다.Using the 2-amino-1,3-aminothiazole (100.0 mg, 1 mmol) and N-Boc-4-piperidinone (199.1 mg, 1 mmol) in the same manner as in Step B of Preparation Example 1, the title compound (249.2 mg, yield 88%).

MS [M+H] = 284MS [M + H] = 284

단계 B: N-Boc-4-{N,N-[사이클로헥실,(1,3-아미노티아졸)-2-일]아미노}피페리딘Step B: N-Boc-4- {N, N- [cyclohexyl, (1,3-aminothiazol) -2-yl] amino} piperidine

단계 A에서 얻은 N-Boc-4-{N-[(1,3-아미노티아졸)-2-일]아미노}피페리딘 (141.6mg, 0.5mmol)과 사이클로헥사논(49.0mg, 0.5mmol)을 이용하여 제조예 1의 단계 B와 같은 방법으로 표제화합물(171.6mg, 수율 94%)을 합성하였다.N-Boc-4- {N-[(1,3-aminothiazol) -2-yl] amino} piperidine (141.6 mg, 0.5 mmol) and cyclohexanone (49.0 mg, 0.5 mmol) obtained in step A ) Was synthesized in the same manner as in Step B of Preparation Example 1 (171.6 mg, yield 94%).

MS [M+H] = 366MS [M + H] = 366

제조예 41: N-Boc-4-{N,N-[사이클로헥실, (1,3-아미노티아졸-4-일)카보닐]아미노}피페리딘Preparation Example 41 N-Boc-4- {N, N- [cyclohexyl, (1,3-aminothiazol-4-yl) carbonyl] amino} piperidine

제조예 1의 단계 B에서 합성한 1-N-Boc-4-[N-(사이클로헥실)아미노]피페리딘 (282.4mg, 1mmol)과 1,3-아미노티아졸-4-카복시산(129.0mg, 1mmol)을 이용하여 제조예 16의 단계 E와 같은 방법으로 표제화합물(369.6mg, 수율 94%)을 합성하였다.1-N-Boc-4- [N- (cyclohexyl) amino] piperidine (282.4 mg, 1 mmol) and 1,3-aminothiazole-4-carboxylic acid (129.0) synthesized in Step B of Preparation Example 1 mg, 1 mmol) to synthesize the title compound (369.6 mg, yield 94%) in the same manner as in Step E of Preparation Example 16.

MS [M+H] = 394MS [M + H] = 394

제조예 42: N-Boc-4-{N,N-[사이클로헥실, (1,3-아미노티아졸-4-일)메틸]아미노}피페리딘Preparation Example 42 N-Boc-4- {N, N- [cyclohexyl, (1,3-aminothiazol-4-yl) methyl] amino} piperidine

제조예 41에서 합성한 N-Boc-4-{N,N-[사이클로헥실, (1,3-아미노티아졸-4-일)카보닐]아미노}피페리딘(196.6mg, 0.5mmol)을 이용하여 제조예 9와 같은 방법으로 표제화합물(180.1mg, 수율 95%)을 합성하였다.N-Boc-4- {N, N- [cyclohexyl, (1,3-aminothiazol-4-yl) carbonyl] amino} piperidine (196.6 mg, 0.5 mmol) synthesized in Preparation Example 41 was prepared. Using the same method as in Preparation Example 9 to obtain the title compound (180.1mg, 95% yield).

MS [M+H] = 380MS [M + H] = 380

제조예 43: N-Boc-4-{N,N-[사이클로헥실, (1,3-옥사졸-5-일)카보닐]아미노}피페리딘Preparation Example 43 N-Boc-4- {N, N- [cyclohexyl, (1,3-oxazol-5-yl) carbonyl] amino} piperidine

제조예 1의 단계 B에서 합성한 N-Boc-[4-(N-사이클로헥실)아미노]피페리딘 (282.4mg, 1mmol)과 1,3-옥사졸-5-카복시산(113.0mg, 1mmol)을 이용하여 제조예 16의 단계 E와 같은 방법으로 표제화합물(354.6mg, 수율 94%)을 합성하였다.N-Boc- [4- (N-cyclohexyl) amino] piperidine (282.4 mg, 1 mmol) and 1,3-oxazole-5-carboxylic acid (113.0 mg, 1 mmol) synthesized in step B of Preparation Example 1 ) Was synthesized in the same manner as in Step E of Preparation Example 16 (354.6 mg, yield 94%).

MS [M+H] = 378MS [M + H] = 378

제조예 44: N-Boc-4-{N,N-[사이클로헥실, (이미다졸-2-온-4-일)메틸]아미노} 피페리딘Preparation Example 44 N-Boc-4- {N, N- [cyclohexyl, (imidazol-2-one-4-yl) methyl] amino} piperidine

제조예 1의 단계 B에서 합성한 1-N-Boc-(4-N-사이클로헥실)아미노피페리딘(282.4mg, 1mmol)과 이미다졸-2-온-4-카복시알데하이드(112.3mg, 1mmol)를 이용하여 제조예 1의 단계 B와 같은 방법으로 표제화합물(295.0mg, 수율 78%)을 합성하였다.1-N-Boc- (4-N-cyclohexyl) aminopiperidine (282.4 mg, 1 mmol) and imidazole-2-one-4-carboxyaldehyde (112.3 mg, 1 mmol) synthesized in step B of Preparation Example 1 ) Was synthesized in the same manner as in Step B of Preparation Example 1 (295.0 mg, yield 78%).

MS [M+H] = 379MS [M + H] = 379

제조예 45: N-Boc-4-{N,N-[사이클로헥실, 2-(이미다졸-2-온-4-일)에틸]아미노} 피페리딘Preparation 45: N-Boc-4- {N, N- [cyclohexyl, 2- (imidazol-2-one-4-yl) ethyl] amino} piperidine

제조예 1의 단계 B에서 합성한 N-Boc-4-[N-(사이클로헥실)아미노]피페리딘 (282.43mg, 1mmol)과 4-(2-클로로에틸)-이미다졸-2-온(175.2mg, 1.2mmol)을 이용 하여 제조예 4의 단계 A와 같은 방법으로 표제화합물(255.0mg, 수율 65%)을 합성하였다.N-Boc-4- [N- (cyclohexyl) amino] piperidine (282.43 mg, 1 mmol) and 4- (2-chloroethyl) -imidazol-2-one synthesized in Step B of Preparation Example 1 175.2 mg, 1.2 mmol) was synthesized in the same manner as in Step A of Preparation Example 4 (255.0 mg, yield 65%).

MS [M+H] = 393MS [M + H] = 393

제조예 46: N-Boc-4-[N,N-(사이클로헥실, 티아디아졸-2-일)아미노]피페리딘Preparation Example 46 N-Boc-4- [N, N- (cyclohexyl, thiadiazol-2-yl) amino] piperidine

아미노 티아디아졸, N-Boc-피페리디논 및 사이클로헥사논을 사용하여 제조예 40과 같은 방법으로 표제화합물(수율 68%)을 합성하였다.The title compound (yield 68%) was synthesized in the same manner as in Preparation Example 40 using amino thiadiazole, N-Boc-piperidinone, and cyclohexanone.

MS [M+H] = 367MS [M + H] = 367

제조예 47: N-Boc-4-[N,N-(사이클로헥실, 2-(옥사졸리딘-3-일)에틸)아미노]피페리딘Preparation Example 47 N-Boc-4- [N, N- (cyclohexyl, 2- (oxazolidin-3-yl) ethyl) amino] piperidine

제조예 1의 단계 B에서 얻은 N-Boc-4-[N-(사이클로헥실)아미노]피페리딘 (282.4mg, 1mmol)과 3-(2-클로로에틸)옥사졸리딘(131.0mg, 1mmol)을 이용하여 제조예 4의 단계 A와 같은 방법으로 표제화합물(256.5mg, 수율 68%)을 합성하였다.N-Boc-4- [N- (cyclohexyl) amino] piperidine (282.4 mg, 1 mmol) and 3- (2-chloroethyl) oxazolidine (131.0 mg, 1 mmol) obtained in step B of Preparation Example 1 The title compound (256.5 mg, yield 68%) was synthesized in the same manner as in Step A of Preparation Example 4, respectively.

MS [M+H] = 350MS [M + H] = 350

제조예 48: N-Boc-4-{N,N-[사이클로펜틸, (1,2,4-트리아졸-1-일)카보닐]아미노}피페리딘Preparation 48: N-Boc-4- {N, N- [cyclopentyl, (1,2,4-triazol-1-yl) carbonyl] amino} piperidine

단계 A: N-Boc-4-(N-사이클로펜틸아미노)피페리딘Step A: N-Boc-4- (N-cyclopentylamino) piperidine

제조예 1의 단계 A에서 합성한 N-Boc-피페리디논(987mg, 10mmol)과 사이클로펜틸아민(851mg, 10mmol)을 이용하여 제조예 1의 단계 B와 같은 방법으로 표제화합물(2333mg, 수율 87%)을 합성하였다.Using the N-Boc-piperidinone (987mg, 10mmol) and cyclopentylamine (851mg, 10mmol) synthesized in Step A of Preparation Example 1 in the same manner as in Step B of Preparation Example 1 (2333mg, Yield 87 %) Was synthesized.

MS [M+H] = 269MS [M + H] = 269

단계 B: N-Boc-4-{N,N-[사이클로펜틸, (1,2,4-트리아졸-1-일)카보닐]아미노} 피페리딘Step B: N-Boc-4- {N, N- [cyclopentyl, (1,2,4-triazol-1-yl) carbonyl] amino} piperidine

단계 A에서 합성한 N-Boc-4-(N-사이클로펜틸아미노)피페리딘(536.4mg, 2mmol)을 이용하여 제조예 14와 같은 방법으로 표제화합물(336.9mg, 수율 64%)을 합성하였다.Using the N-Boc-4- (N-cyclopentylamino) piperidine (536.4 mg, 2 mmol) synthesized in Step A, the title compound (336.9 mg, yield 64%) was synthesized in the same manner as in Preparation Example 14. .

MS [M+H] =364MS [M + H] = 364

제조예 49: N-Boc-4-{N,N-[사이클로펜틸, (1,2,4-트리아졸-1-일)아세틸]아미노}피페리딘Preparation 49: N-Boc-4- {N, N- [cyclopentyl, (1,2,4-triazol-1-yl) acetyl] amino} piperidine

제조예 48의 단계 A에서 합성한 N-Boc-4-[N-(사이클로펜틸)아미노]피페리딘을 이용하여 제조예 11과 같은 방법으로 표제화합물(수율 52%)을 합성하였다.The title compound (yield 52%) was synthesized in the same manner as in Preparation Example 11, using N-Boc-4- [N- (cyclopentyl) amino] piperidine synthesized in Step A of Preparation Example 48.

MS [M+H] = 379MS [M + H] = 379

제조예 50: N-Boc-4-{N,N-[사이클로펜틸, (테트라졸-1-일)아세틸]아미노}피페리딘Preparation 50: N-Boc-4- {N, N- [cyclopentyl, (tetrazol-1-yl) acetyl] amino} piperidine

제조예 48의 단계 A에서 합성한 N-Boc-4-[N-(사이클로펜틸)아미노]피페리딘 (268.2mg, 1mmol)과 1-테트라졸 아세트산(128.1mg, 1mmol)을 이용하여 제조예 26과 같은 방법으로 표제화합물(355.5mg, 수율 94%)을 합성하였다.Preparation Example Using N-Boc-4- [N- (cyclopentyl) amino] piperidine (268.2mg, 1mmol) and 1-tetrazol acetic acid (128.1mg, 1mmol) synthesized in Step A of Preparation Example 48 In the same manner as in 26, the title compound (355.5 mg, yield 94%) was synthesized.

MS [M+H] = 379MS [M + H] = 379

제조예 51: N-Boc-4-{N,N-[이소프로필, (1,2,4-트리아졸-1-일)카보닐]아미노}피페리딘Preparation Example 51 N-Boc-4- {N, N- [isopropyl, (1,2,4-triazol-1-yl) carbonyl] amino} piperidine

단계 A: N-Boc-4-[N-(이소프로필)아미노]피페리딘Step A: N-Boc-4- [N- (isopropyl) amino] piperidine

제조예 1의 단계 A에서 합성한 N-Boc-피페리디논(996.3mg, 5mmol)과 이소프로필아민(298.5mg, 5mmol)을 이용하여 제조예 1의 단계 B와 같은 방법으로 표제화합물(1126mg, 수율 93%)을 합성하였다.Using the N-Boc-piperidinone (996.3mg, 5mmol) and isopropylamine (298.5mg, 5mmol) synthesized in Step A of Preparation Example 1 in the same manner as in Step B of Preparation Example 1 (1126mg, Yield 93%).

MS [M+H] = 243MS [M + H] = 243

단계 B: N-Boc-4-{N,N-[이소프로필, (1,2,4-트리아졸-1-일)카보닐]아미노}피페리딘Step B: N-Boc-4- {N, N- [isopropyl, (1,2,4-triazol-1-yl) carbonyl] amino} piperidine

단계 A에서 합성한 N-Boc-4-[N-(이소프로필)아미노]피페리딘(242.2mg, 2mmol)을 이용하여 제조예 14와 같은 방법으로 표제화합물(210.7mg, 수율 60%)을 합성하였다.Using the N-Boc-4- [N- (isopropyl) amino] piperidine (242.2 mg, 2 mmol) synthesized in Step A, the title compound (210.7 mg, yield 60%) was obtained in the same manner as in Preparation Example 14. Synthesized.

MS [M+H] = 338MS [M + H] = 338

제조예 52: N-Boc-4-{N,N-[이소프로필, (1,2,4-트리아졸-1-일)아세틸]아미노}피페리딘Preparation Example 52 N-Boc-4- {N, N- [isopropyl, (1,2,4-triazol-1-yl) acetyl] amino} piperidine

제조예 51의 단계 A에서 합성한 N-Boc-4-[N-(이소프로필)아미노]피페리딘 (242.2mg, 1mmol)을 이용하여 제조예 11과 같은 방법으로 표제화합물(209.1mg, 수율 62%)을 합성하였다.Using the N-Boc-4- [N- (isopropyl) amino] piperidine (242.2 mg, 1 mmol) synthesized in Step A of Preparation Example 51 in the same manner as in Preparation Example 11, the title compound (209.1 mg, yield) 62%) was synthesized.

MS [M+H] = 352MS [M + H] = 352

제조예 53: N-Boc-4-{N,N-[이소프로필, (테트라졸-1-일)아세틸]아미노}피페리딘Preparation Example 53 N-Boc-4- {N, N- [isopropyl, (tetrazol-1-yl) acetyl] amino} piperidine

제조예 51의 단계 A에서 합성한 N-Boc-4-[N-(이소프로필)아미노]피페리딘 (242.2mg, 1mmol)을 이용하여 제조예 26과 같은 방법으로 표제화합물(324.0mg, 수율 92%)을 합성하였다.Using the N-Boc-4- [N- (isopropyl) amino] piperidine (242.2 mg, 1 mmol) synthesized in Step A of Preparation Example 51 in the same manner as in Preparation Example 26, the title compound (324.0 mg, yield) 92%) was synthesized.

MS [M+H] = 353MS [M + H] = 353

제조예 54: N-Boc-4-{N,N-[이소프로필, (1,2,4-트리아졸-1-일)에틸]아미노}피페리딘Preparation 54: N-Boc-4- {N, N- [isopropyl, (1,2,4-triazol-1-yl) ethyl] amino} piperidine

제조예 52에서 합성한 N-Boc-4-{N,N-[이소프로필, (1,2,4-트리아졸-1-일)아세틸]아미노}피페리딘(175.6mg, 0.5mmol)을 이용하여 제조예 9와 같은 방법으로 표제화합물(150.1mg, 수율 89%)을 수득하였다.N-Boc-4- {N, N- [isopropyl, (1,2,4-triazol-1-yl) acetyl] amino} piperidine (175.6 mg, 0.5 mmol) synthesized in Preparation Example 52 was prepared. Using the same method as in Preparation Example 9 to obtain the title compound (150.1 mg, 89% yield).

MS [M+H] = 338MS [M + H] = 338

제조예 55: N-Boc-4-{N,N-[사이클로헵틸, (1,2,4-트리아졸-1-일)카보닐]아미노}피페리딘Preparation 55: N-Boc-4- {N, N- [cycloheptyl, (1,2,4-triazol-1-yl) carbonyl] amino} piperidine

단계 A: N-Boc-4-[N-(사이클로헵틸)아미노]피페리딘Step A: N-Boc-4- [N- (cycloheptyl) amino] piperidine

제조예 1의 단계 A에서 합성한 N-Boc-4-피페리디논(966.3mg, 5mmol)과 사이클로헵틸아민(565.5mg, 5mmol)을 이용하여 제조예 1의 단계 B와 같은 방법으로 표제화합물(1362.8mg, 수율 92%)을 합성하였다.Using the title compound (N-Boc-4-piperidinone (966.3 mg, 5 mmol) and cycloheptylamine (565.5 mg, 5 mmol) synthesized in step A of Preparation Example 1 in the same manner as in Step B of Preparation Example 1 1362.8 mg, yield 92%).

단계 B: N-Boc-4-{N,N-[사이클로헵틸, (1,2,4-트리아졸-1-일)카보닐]아미노}피페리딘Step B: N-Boc-4- {N, N- [cycloheptyl, (1,2,4-triazol-1-yl) carbonyl] amino} piperidine

단계 A에서 합성한 1-N-Boc-4-[N-(사이클로헵틸)아미노]피페리딘(296.3mg,1mmol)을 이용하여 제조예 14와 같은 방법으로 표제화합물(258.2mg, 수율 66%)을 합성하였다.Using the 1-N-Boc-4- [N- (cycloheptyl) amino] piperidine (296.3 mg, 1 mmol) synthesized in step A in the same manner as in Preparation Example 14, the title compound (258.2 mg, yield 66%. ) Was synthesized.

MS [M+H] = 297MS [M + H] = 297

제조예 56: N-Boc-4-N,N-[사이클로헵틸, (1,2,4-트리아졸-1-일)아세틸]아미노피페리딘Preparation Example 56 N-Boc-4-N, N- [cycloheptyl, (1,2,4-triazol-1-yl) acetyl] aminopiperidine

제조예 55의 단계 A에서 합성한 N-Boc-4-[N-(사이클로헵틸)아미노]피페리딘 (296.5mg, 1mmol)을 이용하여 제조예 11과 같은 방법으로 표제화합물(405.3mg, 수율 62%)을 합성하였다.Using the N-Boc-4- [N- (cycloheptyl) amino] piperidine (296.5 mg, 1 mmol) synthesized in Step A of Preparation Example 55 in the same manner as in Preparation Example 11, the title compound (405.3 mg, yield) 62%) was synthesized.

MS [M+H] = 406MS [M + H] = 406

제조예 57: N-Boc-4-{N,N-[사이클로헵틸, (테트라졸-1-일)아세틸]아미노}피페리딘Preparation Example 57 N-Boc-4- {N, N- [cycloheptyl, (tetrazol-1-yl) acetyl] amino} piperidine

제조예 55의 단계 A에서 합성한 N-Boc-4-[N-(사이클로헵틸)아미노]피페리딘 (296.5mg, 1mmol)을 이용하여 제조예 26과 같은 방법으로 표제화합물(276.3mg, 수율 68%)을 합성하였다.Using the N-Boc-4- [N- (cycloheptyl) amino] piperidine (296.5 mg, 1 mmol) synthesized in Step A of Preparation Example 55 in the same manner as in Preparation Example 26, the title compound (276.3 mg, yield) 68%) was synthesized.

MS [M+H] = 407MS [M + H] = 407

제조예 58: N-Boc-4-{N,N-[사이클로헥산메틸, (1,2,4-트리아졸-1-일)카보닐]아미노}피페리딘Preparation 58: N-Boc-4- {N, N- [cyclohexanemethyl, (1,2,4-triazol-1-yl) carbonyl] amino} piperidine

단계 A: N-Boc-4-[N-(사이클로헥산메틸)아미노]피페리딘Step A: N-Boc-4- [N- (cyclohexanemethyl) amino] piperidine

제조예 1의 단계 A에서 합성한 N-Boc-4-피페리디논(996.3mg, 5mmol)과 사이클로헥산메틸아민(565.6mg, 5mmol)을 이용하여 제조예 1의 단계 B와 같은 방법으로 표제화합물(1363mg, 수율 92%)을 합성하였다.Using the N-Boc-4-piperidinone (996.3mg, 5mmol) and cyclohexanemethylamine (565.6mg, 5mmol) synthesized in Step A of Preparation Example 1 in the same manner as in Step B of Preparation Example 1 (1363 mg, yield 92%) was synthesized.

MS [M+H] = 297MS [M + H] = 297

단계 B: N-Boc-4-{N,N-[사이클로헥산메틸, (1,2,4-트리아졸-1-일)카보닐]아미노}피페리딘Step B: N-Boc-4- {N, N- [cyclohexanemethyl, (1,2,4-triazol-1-yl) carbonyl] amino} piperidine

단계 A에서 합성한 N-Boc-4-[N-(사이클로헥산메틸)아미노]피페리딘(296.3 mg, 1mmol)을 이용하여 제조예 14와 같은 방법으로 표제화합물(316.9mg, 수율 91%) 을 합성하였다.Using the N-Boc-4- [N- (cyclohexanemethyl) amino] piperidine (296.3 mg, 1 mmol) synthesized in Step A, the title compound (316.9 mg, 91% yield) in the same manner as in Preparation Example 14 Was synthesized.

MS [M+H] = 392MS [M + H] = 392

제조예 59: N-Boc-4-{N,N-[사이클로헥산메틸, (1,2,4-트리아졸-1-일)아세틸]아미노}피페리딘Preparation Example 59 N-Boc-4- {N, N- [cyclohexanemethyl, (1,2,4-triazol-1-yl) acetyl] amino} piperidine

제조예 58의 단계 A에서 합성한 N-Boc-4-[N-(사이클로헥산메틸)아미노]피페리딘(296.3mg, 1mmol)을 이용하여 제조예 11과 같은 방법으로 표제화합물(263.4 mg, 수율 65%)을 합성하였다.Using the N-Boc-4- [N- (cyclohexanemethyl) amino] piperidine (296.3 mg, 1 mmol) synthesized in Step A of Preparation Example 58 in the same manner as in Preparation Example 11, the title compound (263.4 mg, Yield 65%).

MS [M+H] = 406MS [M + H] = 406

제조예 60: N-Boc-4-{N,N-[사이클로헥산메틸, (테트라졸-1-일)아세틸]아미노}피페리딘Preparation Example 60 N-Boc-4- {N, N- [cyclohexanemethyl, (tetrazol-1-yl) acetyl] amino} piperidine

제조예 58의 단계 A에서 합성한 N-Boc-4-[N-(사이클로헥산메틸)아미노]피페리딘(296.3mg, 1mmol)을 이용하여 제조예 26과 같은 방법으로 표제화합물(256.0 mg, 수율 63%)을 합성하였다.Using the N-Boc-4- [N- (cyclohexanemethyl) amino] piperidine (296.3 mg, 1 mmol) synthesized in step A of Preparation Example 58, the title compound (256.0 mg, Yield 63%).

MS [M+H] = 407MS [M + H] = 407

제조예 61: N-Boc-4-{N,N-[사이클로헥산메틸, (1,2,4-트리아졸-1-일)에틸]아미노}피페리딘Preparation Example 61 N-Boc-4- {N, N- [cyclohexanemethyl, (1,2,4-triazol-1-yl) ethyl] amino} piperidine

제조예 59에서 합성한 N-Boc-4-{N,N-[사이클로헥산메틸, (1,2,4-트리아졸-1-일)아세틸]아미노}피페리딘(100.0mg, 0.25mmol)을 이용하여 제조예 9와 같은 방법으로 표제화합물(91.9mg, 수율 94%)을 합성하였다.N-Boc-4- {N, N- [cyclohexanemethyl, (1,2,4-triazol-1-yl) acetyl] amino} piperidine (100.0 mg, 0.25 mmol) synthesized in Preparation Example 59 Using the same method as in Preparation Example 9 was synthesized the title compound (91.9mg, 94% yield).

MS [M+H] = 392MS [M + H] = 392

제조예 62: N-Boc-4-{N,N-[사이클로헥산메틸, (테트라졸-1-일)에틸]아미노}피페리딘Preparation 62: N-Boc-4- {N, N- [cyclohexanemethyl, (tetrazol-1-yl) ethyl] amino} piperidine

제조예 60에서 합성한 N-Boc-4-{N,N-[사이클로헥산메틸, (테트라졸-1-일)아세틸]아미노}피페리딘(100mg, 0.25mmol)을 이용하여 제조예 9와 같은 방법으로 표제화합물(90.2mg, 수율 92%)을 합성하였다.Preparation Example 9 using N-Boc-4- {N, N- [cyclohexanemethyl, (tetrazol-1-yl) acetyl] amino} piperidine (100 mg, 0.25 mmol) synthesized in Preparation Example 60; In the same manner, the title compound (90.2 mg, yield 92%) was synthesized.

MS [M+H] = 393MS [M + H] = 393

제조예 63: N-Boc-(1-Boc-5-메틸)히스티딘Preparation Example 63 N-Boc- (1-Boc-5-methyl) histidine

단계 A: 1-Boc-5-메틸-4-(브로모메틸)이미다졸Step A: 1-Boc-5-methyl-4- (bromomethyl) imidazole

1-Boc-5-메틸-4-(하이드록시메틸)이미다졸(1.6g, 7.54mmol)을 CH2Cl2(150㎖)에 녹인 후, 사브롬화탄소(CBr4, 3.0g, 9.05mmol)을 적가한 다음 트리페닐포스핀 (PPh3, 2.4g, 9.15mmol)을 조금씩 적가하였다. 실온에서 8시간 교반한 다음 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=1/4, v/v) 로 정제하여 표제화합물(0.79g, 수율 38%)을 수득하였다.Dissolve 1-Boc-5-methyl-4- (hydroxymethyl) imidazole (1.6 g, 7.54 mmol) in CH 2 Cl 2 (150 mL), and then carbon tetrabromide (CBr 4 , 3.0 g, 9.05 mmol) Was added dropwise and triphenylphosphine (PPh 3 , 2.4 g, 9.15 mmol) was added dropwise. After stirring for 8 hours at room temperature, the mixture was concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: EtOAc / n-hexane = 1/4, v / v) to give the title compound (0.79 g, yield 38%).

MS (M+H) = 276MS (M + H) = 276

단계 B: N-Boc-(1-Boc-5-메틸)히스티딘Step B: N-Boc- (1-Boc-5-methyl) histidine

N-Boc-디에틸 아미노말로네이트(0.2g, 0.53mmol)를 무수 에탄올 1㎖에 녹이고 소듐에톡사이드(2N 에탄올 용액, 0.32㎖, 0.64mmol)을 적가한 후 실온에서 1시간 교반하였다. 여기에 1-Boc-5-메틸-4-(브로모메틸)이미다졸(0.16g, 0.59mmol)을 넣고 실온에서 2시간 교반하고, 90℃에서 2시간 교반하였다. 여기에 수산화나트륨 수용액(1N, 1.1㎖, 1.1mmol)을 넣고 90℃에서 5시간 교반한 다음 감압 농축하였다. 잔류물에 EtOAc을 넣고 묽은 염산으로 pH를 5에 맞추었다. 유기층을 분리하고 EtOAc으로 2번 더 추출하였다. 유기층을 모아 소금물로 씻은 다음 무수 MgSO4로 건조하고 감압 농축하여 표제화합물(0.1g, 수율 46%)을 수득하였다.N-Boc-diethyl aminomalonate (0.2 g, 0.53 mmol) was dissolved in 1 mL of anhydrous ethanol, sodium ethoxide (2N ethanol solution, 0.32 mL, 0.64 mmol) was added dropwise, followed by stirring at room temperature for 1 hour. 1-Boc-5-methyl-4- (bromomethyl) imidazole (0.16g, 0.59mmol) was put there, and it stirred at room temperature for 2 hours, and it stirred at 90 degreeC for 2 hours. An aqueous sodium hydroxide solution (1N, 1.1 ml, 1.1 mmol) was added thereto, stirred at 90 ° C. for 5 hours, and then concentrated under reduced pressure. EtOAc was added to the residue and the pH was adjusted to 5 with diluted hydrochloric acid. The organic layer was separated and extracted twice more with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO 4 , and concentrated under reduced pressure to obtain the title compound (0.1 g, yield 46%).

MS (M+H) = 370MS (M + H) = 370

제조예 64: N-Boc-(2-메틸)히스티딘Preparation Example 64 N-Boc- (2-methyl) histidine

단계 A: 1-트리틸-2-메틸-4-(하이드록시메틸)이미다졸Step A: 1-trityl-2-methyl-4- (hydroxymethyl) imidazole

1-트리틸-4-[(t-부틸디메틸실릴옥시)메틸]이미다졸(5.9g, 13mmol)을 THF (100㎖)에 녹인 용액을 0℃로 냉각시키고, 여기에 n-부틸리튬(1.6N 헥산용액, 8.94 ㎖, 14.3mmol)을 적가한 다음 30분 동안 교반하였다. 여기에 요오드화메탄(2.13mg, 15mmol)을 적가하고 혼합액을 실온에서 30분간 더 교반한 후, 테트라부틸암모늄플루오라이드(1N THF 용액, 26㎖, 26mmol)을 적가하였다. 생성된 혼합액을 EtOAc에 희석시키고 소금물로 씻은 다음 무수 MgSO4로 건조하고 감압 농축하였다. 수득된 잔류물을 EtOAc에서 재결정하여 표제화합물(3.2g, 수율 70%)을 수득하였다.A solution of 1-trityl-4-[(t-butyldimethylsilyloxy) methyl] imidazole (5.9 g, 13 mmol) in THF (100 mL) was cooled to 0 ° C. and n-butyllithium (1.6 N hexane solution, 8.94 mL, 14.3 mmol) was added dropwise and stirred for 30 minutes. Methane iodide (2.13 mg, 15 mmol) was added dropwise thereto, the mixture was further stirred at room temperature for 30 minutes, and tetrabutylammonium fluoride (1N THF solution, 26 mL, 26 mmol) was added dropwise. The resulting mixture was diluted with EtOAc, washed with brine, dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The residue obtained was recrystallized in EtOAc to give the title compound (3.2 g, yield 70%).

MS (M+H) = 355MS (M + H) = 355

단계 B: N-Boc-(2-메틸)히스티딘Step B: N-Boc- (2-methyl) histidine

단계 A에서 수득한 화합물로부터 제조예 63의 단계 A, B와 동일한 방법으로 반응을 수행하여 표제화합물을 수득하였다(수율 54%).From the compound obtained in step A, the reaction was carried out in the same manner as in steps A and B of Preparation Example 63 to obtain the title compound (yield 54%).

MS (M+H) = 270MS (M + H) = 270

제조예 65: N-Boc-3-(1-트리틸이미다졸-2-일)알라닌Preparation 65: N-Boc-3- (1-tritylimidazol-2-yl) alanine

단계 A: 1-트리틸-2-(하이드록시메틸)이미다졸Step A: 1-trityl-2- (hydroxymethyl) imidazole

1-트리틸이미다졸-2-카보알데히드(2.1g, 6.2mmol)를 메탄올 21㎖에 녹이고 소듐보로하이드리드(NaBH4, 0.23g, 6.2mmol)를 조금씩 적가하고 실온에서 4시간 교반한 다음 감압 농축하였다. 잔류물에 CH2Cl2를 넣고 NH4Cl 수용액으로 닦은 다음 유기층을 분리하여 무수 MgSO4로 건조하고 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=1/1, v/v)로 정제하여 표제화합물(1.4g, 수율 67%)을 수득하였다.1-tritylimidazole-2-carboaldehyde (2.1 g, 6.2 mmol) was dissolved in 21 ml of methanol, and sodium borohydride (NaBH 4 , 0.23 g, 6.2 mmol) was added dropwise and stirred at room temperature for 4 hours. It was then concentrated under reduced pressure. CH 2 Cl 2 was added to the residue, followed by washing with an aqueous NH 4 Cl solution. The organic layer was separated, dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: EtOAc / n-hexane = 1/1, v / v) to give the title compound (1.4 g, yield 67%).

MS (M+H) = 341MS (M + H) = 341

단계 B: 1-트리틸-2-(브로모메틸)이미다졸Step B: 1-trityl-2- (bromomethyl) imidazole

단계 A에서 수득한 화합물로부터 제조예 63의 단계 A와 동일한 방법으로 반응을 수행하여 표제화합물(0.8g, 수율 76%)을 수득하였다.From the compound obtained in Step A, the reaction was carried out in the same manner as in Step A of Preparation Example 63, to obtain the title compound (0.8 g, yield 76%).

MS (M+H) = 404MS (M + H) = 404

단계 C: N-Boc-3-(1-트리틸이미다졸-2-일)알라닌Step C: N-Boc-3- (1-tritylimidazol-2-yl) alanine

단계 B에서 수득한 화합물로부터 제조예 63의 단계 B와 동일한 방법으로 반응을 수행하여 표제화합물(0.23g, 수율 47%)을 수득하였다.From the compound obtained in Step B, the reaction was carried out in the same manner as in Step B of Preparation Example 63, to obtain the title compound (0.23 g, yield 47%).

MS (M+H) = 498MS (M + H) = 498

제조예 66: N-Boc-3-(1-트리틸-4-메틸이미다졸-2-일)알라닌Preparation 66: N-Boc-3- (1-trityl-4-methylimidazol-2-yl) alanine

단계 A: 1-트리틸-1H-이미다졸-4-메틸-2-카보알데히드Step A: 1-trityl-1H-imidazole-4-methyl-2-carboaldehyde

1-트리틸-4-메틸이미다졸(1.04g, 3.2mmol)을 무수 THF(30㎖)에 녹이고 N,N,N',N'-테트라메틸에틸렌디아민(0.48㎖, 3.2mmol)을 적가한 다음 -78℃로 냉각시켰다. 여기에 n-부틸리튬(1.6N 헥산 용액, 2.2㎖, 3.52mmol)을 천천히 적가하였다. 1시간 교반한 후 무수 DMF(0.36㎖, 4.6mmol)를 적가하고 -30℃로 승온시켰다. 반응액을 30분간 교반하고 물 1㎖를 적가하였다. NH4Cl 수용액(50㎖)과 소금물(50㎖)로 닦은 후 무수 MgSO4로 건조하고 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=2/1, v/v)로 정제하여 표제화합물(0.53g, 수율 47%)을 수득하였다.Dissolve 1-trityl-4-methylimidazole (1.04 g, 3.2 mmol) in dry THF (30 mL) and add N, N, N ', N'-tetramethylethylenediamine (0.48 mL, 3.2 mmol) dropwise. Then cooled to -78 ° C. N-butyllithium (1.6N hexane solution, 2.2 ml, 3.52 mmol) was slowly added dropwise thereto. After stirring for 1 hour, anhydrous DMF (0.36 mL, 4.6 mmol) was added dropwise and the temperature was raised to -30 ° C. The reaction solution was stirred for 30 minutes and 1 ml of water was added dropwise. The mixture was washed with aqueous NH 4 Cl solution (50 mL) and brine (50 mL), dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: EtOAc / n-hexane = 2/1, v / v) to give the title compound (0.53 g, 47% yield).

MS (M+H) = 353MS (M + H) = 353

단계 B: 1-트리틸-2-(브로모메틸)-4-메틸이미다졸Step B: 1-trityl-2- (bromomethyl) -4-methylimidazole

단계 A에서 수득한 화합물로부터 제조예 65의 단계 A와 동일한 방법으로 환원반응, 제조예 63의 단계 A와 동일한 방법으로 브롬화 반응을 차례로 수행하여 표제화합물(0.42g, 수율 61%)을 수득하였다.From the compound obtained in Step A, the reduction reaction was carried out in the same manner as in Step A of Preparation Example 65, and the bromination reaction was performed in the same manner as in Step A of Preparation Example 63, to obtain the title compound (0.42 g, 61% yield).

MS (M+H) = 418MS (M + H) = 418

단계 C: N-Boc-3-(1-트리틸-4-메틸이미다졸-2-일)알라닌Step C: N-Boc-3- (1-trityl-4-methylimidazol-2-yl) alanine

단계 B에서 수득한 화합물로부터 제조예 63의 단계 B와 동일한 방법으로 반응을 수행하여 표제화합물(0.17g, 수율 56%)을 수득하였다.From the compound obtained in Step B, the reaction was carried out in the same manner as in Step B of Preparation Example 63, to obtain the title compound (0.17 g, yield 56%).

MS (M+H) = 512MS (M + H) = 512

제조예 67: N-아세틸-3-(이미다졸-1-일)알라닌Preparation Example 67 N-acetyl-3- (imidazol-1-yl) alanine

이 화합물은 문헌(Tetrahedron 1995, 51 (30), 8355)에 기재된 제조법과 동일한 방법으로 반응을 수행하여 수득하였다.This compound was obtained by carrying out the reaction in the same manner as the preparation described in Tetrahedron 1995, 51 (30), 8355.

제조예 68: N-Boc-3-(1-트리틸-1,2,4-트리아졸-3-일)알라닌Preparation Example 68 N-Boc-3- (1-trityl-1,2,4-triazol-3-yl) alanine

단계 A: 1-트리틸-1,2,4-트리아졸-5-카보알데히드Step A: 1-trityl-1,2,4-triazole-5-carboaldehyde

1-트리틸-1,2,4-트리아졸로부터 제조예 66의 단계 A와 동일한 방법으로 반응을 수행하여 표제화합물(4.53g, 수율 87%)을 수득하였다.The reaction was carried out from 1-trityl-1,2,4-triazole in the same manner as in Step A of Preparation Example 66 to obtain the title compound (4.53 g, yield 87%).

MS (M+H) = 340MS (M + H) = 340

단계 B: 1-트리틸-1,2,4-트리아졸-3-카보알데히드Step B: 1-trityl-1,2,4-triazole-3-carboaldehyde

1-트리틸-1,2,4-트리아졸-5-카보알데히드(1g, 2.95mmol)를 무수 CH2Cl2(6㎖)에 녹이고 TFA(0.1㎖)을 천천히 적가하였다. 반응액을 실온에서 14시간 교반한 후 감압 농축하여 표제화합물(0.95g, 수율 95%)을 수득하였다.1-trityl-1,2,4-triazole-5-carboaldehyde (1 g, 2.95 mmol) was dissolved in anhydrous CH 2 Cl 2 (6 mL) and TFA (0.1 mL) was slowly added dropwise. The reaction solution was stirred at room temperature for 14 hours, and then concentrated under reduced pressure to obtain the title compound (0.95 g, yield 95%).

MS (M+H) = 340MS (M + H) = 340

단계 C: 1-트리틸-3-(브로모메틸)-1,2,4-트리아졸Step C: 1-trityl-3- (bromomethyl) -1,2,4-triazole

단계 B에서 수득한 화합물로부터 제조예 65의 단계 A와 동일한 방법으로 환원반응, 제조예 63의 단계 A와 동일한 방법으로 브롬화 반응을 차례로 수행하여 표제화합물(0.83g, 수율 67%)을 수득하였다.From the compound obtained in Step B, the reduction reaction was carried out in the same manner as in Step A of Preparation Example 65, and the bromination reaction was carried out in the same manner as in Step A of Preparation Example 63, to obtain the title compound (0.83 g, yield 67%).

MS (M+H) = 405MS (M + H) = 405

단계 D: N-Boc-3-(1-트리틸-1,2,4-트리아졸-3-일)알라닌Step D: N-Boc-3- (1-trityl-1,2,4-triazol-3-yl) alanine

단계 C에서 수득한 화합물로부터 제조예 63의 단계 B와 동일한 방법으로 반응을 수행하여 표제화합물(0.21g, 수율 61%)을 수득하였다.From the compound obtained in Step C, the reaction was carried out in the same manner as in Step B of Preparation Example 63, to obtain the title compound (0.21 g, 61% yield).

MS (M+H) = 499MS (M + H) = 499

제조예 69: N-Boc-3-(2-아미노피리딘-5-일)알라닌Preparation Example 69 N-Boc-3- (2-aminopyridin-5-yl) alanine

단계 A: N-Boc-2-아미노-5-하이드록시메틸피리딘Step A: N-Boc-2-amino-5-hydroxymethylpyridine

메틸 N-Boc-2-아미노피리딘-5-카복실레이트(1.9g, 7.6mmol)를 무수 THF(30㎖)에 녹이고 0℃로 낮추었다. 리튬알루미늄하이드리드(LiAlH4, 0.31g, 7.6mmol)를 조금씩 적가한 후, 실온으로 승온하여 교반하였다. 6시간후 0℃로 낮추고 물(1㎖)을 적가하였다. 이를 셀라이트(Celite)로 여과하고 여액을 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=2/1, v/v)로 정제하여 표제화합물(1.25g, 수율 74%)을 수득하였다.Methyl N-Boc-2-aminopyridine-5-carboxylate (1.9 g, 7.6 mmol) was dissolved in anhydrous THF (30 mL) and lowered to 0 ° C. Lithium aluminum hydride (LiAlH 4 , 0.31 g, 7.6 mmol) was added dropwise thereto, and the temperature was raised to room temperature and stirred. After 6 hours the temperature was lowered to 0 ° C. and water (1 mL) was added dropwise. It was filtered through Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: EtOAc / n-hexane = 2/1, v / v) to give the title compound (1.25 g, 74% yield).

MS (M+H) = 225MS (M + H) = 225

단계 B: N-Boc-2-아미노-5-브로모메틸피리딘Step B: N-Boc-2-amino-5-bromomethylpyridine

단계 A에서 수득한 화합물로부터 제조예 63의 단계 A와 동일한 방법으로 반응을 수행하여 표제화합물(0.29g, 수율 78%)을 수득하였다.From the compound obtained in Step A, the reaction was carried out in the same manner as in Step A of Preparation Example 63, to obtain the title compound (0.29 g, yield 78%).

MS (M+H) = 288MS (M + H) = 288

단계 C: N-Boc-3-(2-아미노피리딘-5-일)알라닌Step C: N-Boc-3- (2-aminopyridin-5-yl) alanine

단계 B에서 수득한 화합물로부터 제조예 63의 단계 B와 동일한 방법으로 반응을 수행하여 표제화합물(0.19g, 수율 93%)을 수득하였다.From the compound obtained in Step B, the reaction was carried out in the same manner as in Step B of Preparation Example 63, to obtain the title compound (0.19 g, yield 93%).

MS (M+H) = 382MS (M + H) = 382

제조예 70: N-Boc-3-(2-아미노피리딘-3-일)알라닌Preparation Example 70 N-Boc-3- (2-aminopyridin-3-yl) alanine

메틸 N-Boc-2-아미노피리딘-3-카복실레이트 화합물로부터 제조예 69과 동일한 방법으로 반응을 수행하여 표제화합물(0.15g, 수율 56%)을 수득하였다.The reaction was carried out in the same manner as in Preparation 69 from methyl N-Boc-2-aminopyridine-3-carboxylate compound to give the title compound (0.15 g, 56% yield).

MS (M+H) = 382MS (M + H) = 382

제조예 71: N-Boc-3-(피페리딘-1-일)알라닌Preparation Example 71 N-Boc-3- (piperidin-1-yl) alanine

단계 A: (S)-N-Boc -디아미노프로피온산 메틸에스테르Step A: (S) -N-Boc-diaminopropionic acid methyl ester

(S)-N-Boc-(NCbz)-디아미노프로피온산(990mg, 26.6mmol), 포타슘카보네이트 (11g, 79.8mmol) 및 요오드화메탄(4.9㎖, 79.8mmol)을 DMF(100㎖)에 녹이고, 실온에서 12시간 교반하였다. 반응액을 EtOAc로 희석한 후, 물과 소금물로 각각 2회 씻고, 무수 MgSO4로 건조하고 감압 농축하였다. 얻어진 잔류물을 THF(100㎖)에 녹인 후 10% Pd/C(100mg)를 가하고 수소풍선 하에서 4시간 동안 교반하였다. 반응액을 셀라이트로 여과하고 여액을 감압 농축하여 표제화합물(4.6g, 수율 79%)을 수득하였다.(S) -N-Boc- (NCbz) -diaminopropionic acid (990 mg, 26.6 mmol), potassium carbonate (11 g, 79.8 mmol) and methane iodide (4.9 mL, 79.8 mmol) were dissolved in DMF (100 mL), and Stir at 12 h. The reaction solution was diluted with EtOAc, washed twice with water and brine, dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The obtained residue was dissolved in THF (100 mL), and then 10% Pd / C (100 mg) was added and stirred for 4 hours under a hydrogen balloon. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to give the title compound (4.6g, yield 79%).

MS (M+H) = 273MS (M + H) = 273

단계 B: N-Boc-3-(피페리딘-1-일)알라닌Step B: N-Boc-3- (piperidin-1-yl) alanine

(S)-N-Boc-디아미노프로피온산 메틸에스테르(1.78g, 8.2mmol), 25% 글루타르알데히드 용액(3.9g, 9.8mmol) 및 소듐트리아세톡시보로하이드라이드[NaHB(OAc)3, 2.6g, 12.3mmol]을 디클로로에탄(50㎖)에 녹여 혼합액을 실온에서 약 8시간 동안 교반하였다. 유기용매를 감압증류하여 제거한 다음, EtOAc에 녹여 포화 탄산수소나트륨 수용액 및 소금물로 차례로 씻고 무수 MgSO4로 건조한 다음 감압 농축하였다. 잔류물을 칼럼 크로마토그래피로 정제하여 N-Boc-3-(피페리딘-1-일)알라닌 메틸에스테르 (590mg, 2mmol)를 수득하였다. 이 물질을 메탄올:물 (2:1) 용액에 녹이고 리튬하이드록사이드 (500mg, 21mmol)을 가한 다음 상온에서 5시간동안 교반하고 반응액을 감압증류하여 표제화합물 (1.5g, 수율 66%)을 수득하였다.(S) -N-Boc-diaminopropionic acid methyl ester (1.78 g, 8.2 mmol), 25% glutaraldehyde solution (3.9 g, 9.8 mmol) and sodium triacetoxyborohydride [NaHB (OAc) 3 , 2.6 g, 12.3 mmol] was dissolved in dichloroethane (50 mL), and the mixed solution was stirred at room temperature for about 8 hours. The organic solvent was removed by distillation under reduced pressure, and then dissolved in EtOAc, washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous MgSO 4, and concentrated under reduced pressure. The residue was purified by column chromatography to give N-Boc-3- (piperidin-1-yl) alanine methylester (590 mg, 2 mmol). This material was dissolved in a methanol: water (2: 1) solution, lithium hydroxide (500 mg, 21 mmol) was added thereto, stirred at room temperature for 5 hours, and the reaction solution was distilled under reduced pressure to obtain the title compound (1.5 g, yield 66%). Obtained.

MS (M+H) = 245MS (M + H) = 245

제조예 72: N-Boc-3-(4-메틸-피페리딘-1-일)알라닌Preparation Example 72 N-Boc-3- (4-methyl-piperidin-1-yl) alanine

제조예 71의 단계 A에서 수득한 화합물(650mg,2.9mmol), 1.5-다이브로모-3-메틸펜탄(1.3㎖, 8.7mmol) 및 Et3N(1.2㎖, 8.7mmol)을 DMF(20㎖)에 녹여 실온에서 약 15시간 동안 교반하였다. 반응액을 EtOAc로 희석한 후, 포화 탄산수소나트륨 수용액 및 소금물로 차례로 씻고 무수 MgSO4로 건조한 다음 감압 농축하였다. 잔류물을 칼럼 크로마토그래피로 정제하여 N-Boc-3-(4-메틸-피페리딘-1-일)알라닌 메틸에스테르(590mg, 2mmol)를 수득하였다. 이 물질을 메탄올/물(2/1, v/v)의 혼합액에 녹이고 리튬하이드록사이드(150mg, 6mmol)로 가수분해하여 표제화합물 (480mg, 수율 55%)을 수득하였다.Compound (650 mg, 2.9 mmol), 1.5-dibromo-3-methylpentane (1.3 mL, 8.7 mmol) and Et 3 N (1.2 mL, 8.7 mmol) obtained in step A of Preparation Example 71 were diluted with DMF (20 mL). It was dissolved in and stirred at room temperature for about 15 hours. The reaction solution was diluted with EtOAc, washed sequentially with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous MgSO 4, and concentrated under reduced pressure. The residue was purified by column chromatography to give N-Boc-3- (4-methyl-piperidin-1-yl) alanine methylester (590 mg, 2 mmol). This material was dissolved in a mixture of methanol / water (2/1, v / v) and hydrolyzed with lithium hydroxide (150 mg, 6 mmol) to give the title compound (480 mg, yield 55%).

MS (M+H) = 287MS (M + H) = 287

제조예 73: N-Boc-3-(헥사메틸렌이민-1-일)알라닌Preparation Example 73 N-Boc-3- (hexamethyleneimin-1-yl) alanine

1,6-디브로모헥산(0.2㎖, 1.32mmol)으로 부터 제조예 72과 동일한 방법으로 반응을 수행하여 표제화합물(23mg, 수율 18%)을 수득하였다.The reaction was carried out in the same manner as in Preparation 72 from 1,6-dibromohexane (0.2 ml, 1.32 mmol) to obtain the title compound (23 mg, 18% yield).

MS (M+H) = 287MS (M + H) = 287

제조예 74: (S)-N-Boc-(3-N-Boc)히스티딜-(R)-4-Cl-페닐알라닌Preparation Example 74 (S) -N-Boc- (3-N-Boc) histidyl- (R) -4-Cl-phenylalanine

단계 A : (R)-4-Cl-페닐알라닌 메틸에스테르Step A: (R) -4-Cl-phenylalanine methylester

아세틸 클로라이드(755mg, 10mmol)를 메탄올(30㎖)에 녹이고 30분정도 교반하였다. N-Boc-4-Cl-페닐알라닌(2998mg, 10mmol)을 넣고 3시간 정도 교반하였다.반응이 완결된 후 감압하에 메탄올을 날려 보내고 표제화합물의 HCl염(2427mg, 수율 97%)을 수득하였다.Acetyl chloride (755 mg, 10 mmol) was dissolved in methanol (30 mL) and stirred for about 30 minutes. N-Boc-4-Cl-phenylalanine (2998 mg, 10 mmol) was added thereto and stirred for about 3 hours. After completion of the reaction, methanol was blown out under reduced pressure to obtain an HCl salt (2427 mg, 97% yield) of the title compound.

단계 B : (S)-N-Boc-(3-N-Boc)히스티딜-(R)-4-Cl-페닐알라닌 메틸에스테르Step B: (S) -N-Boc- (3-N-Boc) histidyl- (R) -4-Cl-phenylalanine methylester

단계 A 에서 얻은 (R)-4-Cl-페닐알라닌 메틸에스테르 HCl염(2251mg, 9mmol)을 DMF(30㎖) 용매에 녹이고 트리에틸아민(2520㎖, 18mmol)으로 용액을 염기화시켰다. N-Boc (3-N-Boc)히스티딘(3198mg, 9mmol), EDC(2281mg, 11.7mmol) 및 HOBT(1822mg, 13.5 mmol)를 넣고 상온에서 4시간동안 교반하였다. 반응액을 EtOAc로 희석한 후, 포화 탄산수소나트륨 수용액 및 HCl로 차례로 씻고 무수 MgSO4로 건조한 다음 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산= 3/2, v/v)로 정제하여 N-Boc-(3-N-Boc)히스티딜 메틸-4-Cl-페닐알라닌 메틸에스테르(4466mg, 수율 90%)를 수득하였다.(R) -4-Cl-phenylalanine methylester HCl salt (2251 mg, 9 mmol) obtained in step A was dissolved in DMF (30 mL) solvent and the solution was basified with triethylamine (2520 mL, 18 mmol). N-Boc (3-N-Boc) histidine (3198 mg, 9 mmol), EDC (2281 mg, 11.7 mmol) and HOBT (1822 mg, 13.5 mmol) were added thereto and stirred at room temperature for 4 hours. The reaction solution was diluted with EtOAc, washed successively with saturated aqueous sodium hydrogen carbonate solution and HCl, dried over anhydrous MgSO 4, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-hexane = 3/2, v / v) to give N-Boc- (3-N-Boc) histidyl methyl-4-Cl-phenylalanine methylester (4466 mg). , Yield 90%) was obtained.

MS [M+1] = 552MS [M + 1] = 552

단계 C: (S)-N-Boc-(3-N-Boc)-히스티딜-(R)-4-Cl-페닐알라닌Step C: (S) -N-Boc- (3-N-Boc) -histidyl- (R) -4-Cl-phenylalanine

단계 B에서 얻은 (S)-N-Boc-(3-N-Boc)-히스티딜-4-Cl-페닐알라닌 메틸에스터르(4408mg, 8mmol)를 메탄올(40㎖)과 물(10㎖) 용액에 녹이고 LiOH(852mg, 24mmol)을 가한 다음 상온에서 2시간 동안 교반하였다. HCl로 중화하여 (S)-N-Boc-(3-N-Boc)히스티딜-(R)-4-Cl-페닐알라닌 산(3781mg, 수율 88%)을 수득하였다. 수득한 화합물을 디클로로메탄(30㎖) 에 녹이고 트리플루오르아세트산을 적가하여 상온에서2시간동안 교반하였다. 반응이 종결된 용액을 감압 응축하여 표제화합물의 TFA 염을 수득하였다.(S) -N-Boc- (3-N-Boc) -histidyl-4-Cl-phenylalanine methylester (4408 mg, 8 mmol) obtained in step B was added to a solution of methanol (40 mL) and water (10 mL). After dissolving, LiOH (852 mg, 24 mmol) was added thereto, followed by stirring at room temperature for 2 hours. Neutralization with HCl afforded (S) -N-Boc- (3-N-Boc) histidyl- (R) -4-Cl-phenylalanine acid (3781 mg, yield 88%). The obtained compound was dissolved in dichloromethane (30 mL) and trifluoroacetic acid was added dropwise and stirred at room temperature for 2 hours. The solution terminated under reduced pressure was condensed under reduced pressure to give the TFA salt of the title compound.

MS [M+1] = 337MS [M + 1] = 337

제조예 75: (R)-N-Boc-(테트라하이드로이소퀴놀린산)-(R)-4-Cl-페닐알라닌Preparation Example 75 (R) -N-Boc- (tetrahydroisoquinoline acid)-(R) -4-Cl-phenylalanine

제조예 74의 단계 A와 같은 방법으로 얻은 (R)-4-Cl-페닐알라닌 메틸에스테르(2251mg, 9mmol)와 (R)-N-Boc-(테트라하이드로이소퀴놀린산)(2478mg, 9mmol)을 이용하여 제조예 74의 단계 B 및 C에 따라 표제화합물의 TFA염을 수득하였다(수율 82%).Using (R) -4-Cl-phenylalanine methyl ester (2251 mg, 9 mmol) and (R) -N-Boc- (tetrahydroisoquinoline acid) (2478 mg, 9 mmol) obtained in the same manner as in Step A of Preparation Example 74 The TFA salt of the title compound was obtained in accordance with Steps B and C of Preparation Example 74 (yield 82%).

MS [M+1] = 359MS [M + 1] = 359

본 발명의 화합물들은 하기 실시예에 의해 보다 구체적으로 설명된다. 그러나, 본 발명의 범위가 이들에 의해 어떤 식으로든 제한되는 것은 아니다.The compounds of the present invention are explained in more detail by the following examples. However, the scope of the present invention is not limited in any way by these.

실시예 1: (R)-테트라하이드로이소퀴놀리닉-(R)-(4-클로로페닐)알라닐 -[4-N,N-사이클로헥실, (1,2,4-트리아졸-1-일)아세틸]피페리디드 2TFA염Example 1: (R) -tetrahydroisoquinolinic- (R)-(4-chlorophenyl) alanyl- [4-N, N-cyclohexyl, (1,2,4-triazole-1- Acetyl) piperidide 2TFA salt

.2TFA .2TFA

제조예 11에서 합성한 N-Boc-4-{N,N-[사이클로헥실, (1,2,4-트리아졸-1-일)-아세틸]아미노}피페리딘(100mg, 0.255mmol)을 디클로로메탄(3㎖)에 녹이고 트리플루오로아세트산(1.5㎖)을 가한 다음 상온에서 1시간 동안 교반하였다. 반응이 종결된 용액을 감압 농축하여 4-{N,N-[사이클로헥실, (1,2,4-트리아졸-1-일)-아세틸]아미노}피페리딘의 TFA 염을 수득하였다. 4-{N,N-[사이클로헥실, (1,2,4-트리아졸-1-일)-아세틸]아미노}피페리딘의 TFA 염을 DMF에 녹이고 트리에틸아민(70㎕)을 넣어 염기화시켰다. 여기에 제조예 75에서 합성한 (R)-N-Boc-테트라하이드로이소퀴놀리닉-(R)-(4-클로로페닐)알라닐산(116.8mg, 0.255mmol), EDC(64.5 mg, 0.332mmol) 및 HOBT(51.7mg, 0.382mmol)를 가한 다음 용액을 실온에서 12시간 동안 교반하였다. 반응이 완결된 용액을 0.5N 염산 용액, 포화 탄산수소나트륨 수용액 및 소금물로 차례로 씻고 무수 MgSO4로 건조한 다음 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=3/2, v/v)로 정제하여 Boc-보호기가 있는 표제화합물 169.7mg(수율 91%)을 수득하였다. 얻어진 잔류물을 CH2Cl2(4㎖)에 녹이고 TFA(2㎖)를 가한 다음 용액을 실온에서 1시간 동안 교반하였다. 반응이 완결된 용액을 감압 농축하여 분취용 HPLC(용리액: TFA 0.1% 포함된 물/아세토니트릴=65/35 →40/60, v/v)로 정제하여 표제화합물(120.1mg, 수율 82%)을 수득하였다.N-Boc-4- {N, N- [cyclohexyl, (1,2,4-triazol-1-yl) -acetyl] amino} piperidine (100 mg, 0.255 mmol) synthesized in Preparation Example 11 was prepared. It was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1.5 mL) was added, followed by stirring at room temperature for 1 hour. The solution was terminated under reduced pressure to give a TFA salt of 4- {N, N- [cyclohexyl, (1,2,4-triazol-1-yl) -acetyl] amino} piperidine. TFA salt of 4- {N, N- [cyclohexyl, (1,2,4-triazol-1-yl) -acetyl] amino} piperidine was dissolved in DMF and triethylamine (70 μl) was added to the base. Mad. (R) -N-Boc-tetrahydroisoquinolinic- (R)-(4-chlorophenyl) alanyl acid (116.8 mg, 0.255 mmol) synthesized in Preparation Example 75, EDC (64.5 mg, 0.332 mmol) ) And HOBT (51.7 mg, 0.382 mmol) were added and the solution was stirred at room temperature for 12 hours. The completed solution was washed sequentially with 0.5N hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous MgSO 4, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-hexane = 3/2, v / v) to give 169.7 mg (91% yield) of the title compound with Boc-protecting group. The resulting residue was taken up in CH 2 Cl 2 (4 mL), TFA (2 mL) was added and the solution was stirred at rt for 1 h. The reaction solution was concentrated under reduced pressure and purified by preparative HPLC (eluent: water / acetonitrile containing 0.1% TFA = 65/35 → 40/60, v / v) to give the title compound (120.1 mg, yield 82%). Obtained.

MS (M+H) = 632MS (M + H) = 632

실시예 2: 아세틸-(R)-테트라하이드로이소퀴놀리닉-(R)-(4-클로로페닐)알라닐-[4-N,N-사이클로헥실, (1,2,4-트리아졸-1-일)-아세틸]피페리디드 TFA염Example 2: Acetyl- (R) -tetrahydroisoquinolinic- (R)-(4-chlorophenyl) alanyl- [4-N, N-cyclohexyl, (1,2,4-triazole- 1-yl) -acetyl] piperidide TFA salt

. TFA . TFA

실시예 1에서 수득한 화합물(100.0mg, 0.158mmol)을 DMF(3㎖)에 녹이고 여기에 빙초산(9.4mg, 0.158mmol), EDC(40.0mg, 0.21mmol), HOBT(32.0mg, 0.237mmol) 및 Et3N(78.4㎕, 0.56mmol)을 가한 다음 용액을 실온에서 12시간 동안 교반하였다. 반응액을 바로 감압 농축한 다음 잔류물을 분취용 HPLC(용리액: TFA 0.1% 포함된 물/아세토니트릴 = 65/35 →40/60, v/v)로 정제하여 표제화합물(89.4mg, 수율 82%)을 수득하였다.The compound obtained in Example 1 (100.0 mg, 0.158 mmol) was dissolved in DMF (3 mL), and glacial acetic acid (9.4 mg, 0.158 mmol), EDC (40.0 mg, 0.21 mmol), and HOBT (32.0 mg, 0.237 mmol) were added thereto. And Et 3 N (78.4 μl, 0.56 mmol) were added and the solution stirred at room temperature for 12 hours. The reaction mixture was concentrated directly under reduced pressure, and the residue was purified by preparative HPLC (eluent: water / acetonitrile containing 0.1% TFA = 65/35 → 40/60, v / v) to obtain the title compound (89.4 mg, yield 82). %) Was obtained.

MS (M+H) = 674MS (M + H) = 674

실시예 3 내지 57Examples 3 to 57

하기 표 3에 서술된 실시예 화합물중 A가 수소인 경우의 화합물은 중간체 제조예 1 내지 75에서 합성된 N 말단이 보호된 아미노산 또는 상업화된 아미노산으로부터 실시예 1과 동일한 방법으로 반응을 수행하여 수득하였다. 그 외 A가 수소가 아닌 실시예 화합물들은 실시예 1 또는 2와 동일한 방법으로 반응을 수행하여 수득하였다.In the example compounds described in Table 3 below, when A is hydrogen, the compound was obtained by carrying out the reaction in the same manner as in Example 1 from the N-terminal protected amino acid or commercialized amino acid synthesized in Intermediate Preparation Examples 1 to 75. It was. Other example compounds in which A is not hydrogen were obtained by carrying out the reaction in the same manner as in Example 1 or 2.

실시예 58: (S)-히스티딜-(R)-(4-클로로페닐)알라닐-[4-N,N-사이클로헥실, (1,2,4-트리아졸-1-일)아세틸] 피페리디드 2TFA염Example 58: (S) -Histidyl- (R)-(4-chlorophenyl) alanyl- [4-N, N-cyclohexyl, (1,2,4-triazol-1-yl) acetyl] Piperidide 2TFA salt

. 2TFA . 2TFA

제조예 11에서 합성한 N-Boc-4-{N,N-[사이클로헥실, (1,2,4-트리아졸-1-일)-아세틸]아미노}피페리딘(100mg, 0.255mmol)을 디클로로메탄(3㎖)에 녹이고 트리플루오로아세트산(1.5㎖)을 가한 다음 상온에서 1시간 동안 교반하였다. 반응이 종결된 용액을 감압 농축하여 4-{N,N-[사이클로헥실, (1,2,4-트리아졸-1-일)-아세틸]아미노}피페리딘의 TFA 염을 수득하였다. 4-{N,N-[사이클로헥실, (1,2,4-트리아졸-1-일)-아세틸]아미노}피페리딘의 TFA 염을 DMF에 녹이고 트리에틸아민(70㎕)을 넣어 염기화시켰다. 여기에 제조예 74에서 합성한 (S)-N-Boc-[(N-Boc)히스티딜]-(R)-(4-클로로페닐)알라닌(90.6mg, 0.255mmol), EDC(64.5mg, 0.332mmol) 및 HOBT(51.7mg,0.382mmol)를 가한 다음 용액을 실온에서 12시간 동안 교반하였다. 반응이 완결된 용액을 0.5N 염산 용액, 포화 탄산수소나트륨 수용액 및 소금물로 차례로 씻고 무수 MgSO4로 건조한 다음 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=3/2, v/v)로 정제하여 Boc-보호기가 있는 표제화합물 187.5mg(수율 94%)을 수득하였다. 얻어진 잔류물을 CH2Cl2(4㎖)에 녹이고 TFA(2㎖)를 가한 다음 용액을 실온에서 1시간 동안 교반하였다. 반응이 완결된 용액을 감압 농축하여 분취용 HPLC(용리액: TFA 0.1% 포함된 물/아세토니트릴=65/35 →40/60, v/v)로 정제하여 표제화합물(139.5mg, 수율 99%)의 TFA염을 수득하였다.N-Boc-4- {N, N- [cyclohexyl, (1,2,4-triazol-1-yl) -acetyl] amino} piperidine (100 mg, 0.255 mmol) synthesized in Preparation Example 11 was prepared. It was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1.5 mL) was added, followed by stirring at room temperature for 1 hour. The solution was terminated under reduced pressure to give a TFA salt of 4- {N, N- [cyclohexyl, (1,2,4-triazol-1-yl) -acetyl] amino} piperidine. TFA salt of 4- {N, N- [cyclohexyl, (1,2,4-triazol-1-yl) -acetyl] amino} piperidine was dissolved in DMF and triethylamine (70 μl) was added to the base. Mad. (S) -N-Boc-[(N-Boc) histidyl]-(R)-(4-chlorophenyl) alanine (90.6 mg, 0.255 mmol) synthesized in Production Example 74, EDC (64.5 mg, 0.332 mmol) and HOBT (51.7 mg, 0.382 mmol) were added and then the solution was stirred at room temperature for 12 hours. The completed solution was washed sequentially with 0.5N hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous MgSO 4, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-hexane = 3/2, v / v) to give 187.5 mg (yield 94%) of the title compound with Boc-protecting group. The resulting residue was taken up in CH 2 Cl 2 (4 mL), TFA (2 mL) was added and the solution was stirred at rt for 1 h. The reaction solution was concentrated under reduced pressure and purified by preparative HPLC (eluent: water / acetonitrile containing 0.1% TFA = 65/35 → 40/60, v / v) to give the titled compound (139.5mg, 99% yield). TFA salt of was obtained.

MS (M+H) = 567MS (M + H) = 567

실시예 59: 아세틸-(S)-히스티딜-(R)-(4-클로로페닐)알라닐-[4-N,N-사이클로헥실, (1,2,4-트리아졸-1-일)-아세틸]피페리디드 TFA염Example 59: Acetyl- (S) -Histidyl- (R)-(4-chlorophenyl) alanyl- [4-N, N-cyclohexyl, (1,2,4-triazol-1-yl) -Acetyl] piperidide TFA salt

. TFA . TFA

실시예 58에서 수득한 화합물(100.0mg, 0.17mmol)을 DMF(3㎖)에 녹이고 여기에 빙초산(10.2mg, 0.17mmol), EDC(43.1mg, 0.22mmol), HOBT(34.4mg, 0.26mmol) 및 Et3N(47.6㎕, 0.34mmol)을 가한 다음 용액을 실온에서 12시간 동안 교반하였다. 반응액을 바로 감압 농축한 다음 잔류물을 분취용 HPLC(용리액: TFA 0.1% 포함된 물/아세토니트릴 = 65/35 →55/45, v/v)로 정제하여 표제화합물(84.9mg, 수율 80%)을 수득하였다.The compound obtained in Example 58 (100.0 mg, 0.17 mmol) was dissolved in DMF (3 mL), and glacial acetic acid (10.2 mg, 0.17 mmol), EDC (43.1 mg, 0.22 mmol), and HOBT (34.4 mg, 0.26 mmol) were added thereto. And Et 3 N (47.6 μl, 0.34 mmol) were added and the solution stirred at room temperature for 12 hours. The reaction solution was concentrated directly under reduced pressure, and the residue was purified by preparative HPLC (eluent: water / acetonitrile containing 0.1% TFA = 65/35 → 55/45, v / v) to obtain the title compound (84.9 mg, yield 80). %) Was obtained.

MS (M+H) = 652MS (M + H) = 652

실시예 60 내지 124Examples 60-124

하기 표 4에 서술된 실시예 화합물중 A가 수소인 경우의 화합물은 중간체 제조예 1 내지 75에서 합성된 N 말단이 보호된 아미노산 또는 상업화된 아미노산으로부터 실시예 58과 동일한 방법으로 반응을 수행하여 수득하였다. 그 외 A가 수소가 아닌 실시예 화합물들은 실시예 59와 동일한 방법으로 반응을 수행하여 수득하였다.In the example compounds described in Table 4 below, when A is hydrogen, the compound was obtained by carrying out the reaction in the same manner as in Example 58 from the N-terminal protected amino acid or commercialized amino acid synthesized in Intermediate Preparation Examples 1 to 75. It was. Other example compounds in which A is not hydrogen were obtained by carrying out the reaction in the same manner as in Example 59.

실험예: 생리 활성 평가 (Biological Assays)Experimental Example: Biological Assays

본 발명의 화합물은 하기 설명하는 A, B 및 C의 방법에 따라 멜라노코틴 수용체(MCR)의 활성에 대한 항진능력(agonistic activity)과 MCR에 대한 결합능력을 측정하여 그 활성 정도를 평가하였다.Compounds of the present invention was evaluated by measuring the agonistic activity and the binding capacity to the MCR activity of the melanocyte inhibitor (MCR) according to the method of A, B and C described below.

A. 루시페라제(Luciferase) 발현도 측정A. Luciferase Expression Measurement

본 발명에 따른 화합물의 MCR 항진제로서의 활성을 측정하는 방법 중의 하나로서 세포내 cAMP 함량의 증가에 비례하는 표지유전자(예, 루시퍼라제)의 발현양을 측정하였다.As one of the methods for measuring the activity of the compound according to the present invention as an MCR agonist, the amount of expression of a label gene (eg, luciferase) in proportion to the increase in the intracellular cAMP content was measured.

먼저 각 서브타입(subtype)의 MCR 유전자와 CRE(cAMP Responsive Element) 조절하의 루시페라제 유전자(CRE-LUC)를 동시에 발현시키는 영구 발현 HEK(Human Embryonic Kidney) 세포주(HEK MC1R-Luc, MC3R-Luc, MC4R-Luc, 또는 MC5R-Luc)들을 구축하였다. 상기 세포주들을 6% CO2가 존재하는 37℃ 항온배양기에서 선택 배지(10% 열-불활성화된 소 태자 혈청(Gibco/BRL), 100unit/㎖ 페니실린(Gibco/BRL), 100unit/㎖ 스트렙토마이신(Gibco/BRL) 및 200㎍/㎖ 제네티신(G418)(Gibco/ BRL)을 함유한 DMEM(Dulbecco's Modified Eagles Medium)을 사용하여 배양하였다. 직경 100mm 배양접시에 세포가 전체면적의 70% 정도가 되었을 때 10㎖의 Ca++와 Mg++이 함유되지않은 인산완충액(Phosphate Buffered Saline; PBS)으로 1회 세척한 다음, 0.05% 트립신과 0.53mM EDTA를 함유한 PBS용액 3㎖를 가하였다. 상기 트립신/EDTA 용액을 제거하고 37℃ 항온 배양기에서 1분간 배양한 뒤 10㎖의 선택배지에 다시 현탁시키고 1500rpm에서 5분간 원심분리하였다. 상층액을 제거한 뒤 침전된 세포들을 5㎖의 페놀레드(Phenol Red)가 함유되지않은 선택배지로 다시 현탁시켰다. 상기 세포현탁액을 96-웰 발광측정기(Luminometer)용 세포 배양 판(Costar)의 각 웰에 100㎕의 배양액에 5X104세포가 되도록 첨가한 뒤 6% CO2가 존재하는 37℃ 항온 배양기에서 18시간 동안 배양하였다. 상기 배양액을 사용하여 각 단계별 농도로 희석시킨 MCR 항진제(실시예 화합물)를 최종 DMSO 농도가 1%를 넘지않게 처리한 다음 6% CO2가 존재하는 37℃ 항온 배양기에서 5시간 동안 배양하였다. 각 웰에 50㎕의 Bright-Glo 루시페라제 시약(Promega)을 처리한 다음 15분간 상온에 방치한 뒤 발광측정기(Luminometer, Victor)를 사용하여 각 웰의 발광 정도(Luminescence)를 측정하였다. 각 단계별 농도로 희석된 항진제에 의해 유도되는 Luminescence양은 10 μM의 NDP-MSH 처리에 의해 나타나는 양에 대한 상대적인 % 값으로 환산하였다. EC50는 각 항진제에 의해 유도될 수 있는 최대 Luminescence양의 50%를 유도시키는 농도로 표시하였고 이 측정치는 통계 소프트웨어 (Prizm)를 사용하여 측정하였다.First, a permanently expressed Human Embryonic Kidney (HEK) cell line (HEK MC1R-Luc, MC3R-Luc) expressing the MCR gene of each subtype and the luciferase gene (CRE-LUC) under the control of the cAMP Responsive Element (CRE) simultaneously. , MC4R-Luc, or MC5R-Luc) were constructed. The cell lines were treated with a selection medium (10% heat-inactivated fetal bovine serum (Gibco / BRL), 100 units / ml penicillin (Gibco / BRL), 100 units / ml streptomycin (C) in a 37 ° C. incubator with 6% CO 2. Cultured using Dulbecco's Modified Eagles Medium (DMEM) containing Gibco / BRL) and 200 μg / ml Geneticin (G418) (Gibco / BRL). When rinsed once with 10 ml of Ca ++ and Mg ++ (Phosphate Buffered Saline; PBS), 3 ml of PBS solution containing 0.05% trypsin and 0.53 mM EDTA was added. The trypsin / EDTA solution was removed, incubated for 1 minute in a 37 ° C. incubator, then resuspended in 10 ml of selective medium and centrifuged for 5 minutes at 1500 rpm After removing the supernatant, the precipitated cells were removed in 5 ml of phenol red ( Phenol Red) was resuspended in a selection-free medium. 96-well luminescence meter (Luminometer) cell culture plate (Costar) 37 ℃ that the back 6% CO 2 added to the medium so as to have 5X10 4 cells present in the culture medium of 100㎕ to each well and incubated for 18 hours in a constant-temperature incubator. Using the culture solution, the MCR adjuvants (Example compound) diluted to each step concentration were treated so that the final DMSO concentration did not exceed 1%, and then incubated for 5 hours in a 37 ° C incubator in which 6% CO 2 was present. The wells were treated with 50 μl of Bright-Glo Luciferase Reagent (Promega), and then allowed to stand at room temperature for 15 minutes, followed by measuring the luminescence of each well using a luminometer (Luminometer, Victor). Luminescence amount induced by the concentration-diluted antidiarrheal agent was converted into% value relative to the amount indicated by NDP-MSH treatment of 10 μM. EC50 was expressed as a concentration that induces 50% of the maximum amount of luminescence that can be induced by each antidiarrheal agent and this measurement was determined using statistical software (Prizm).

B. cAMP 측정B. cAMP measurement

본 발명에 따른 화합물의 MCR 항진제로서의 활성을 측정하는 또 다른 방법으로서 세포내 cAMP 함량의 증가를 측정하였다.As another method of measuring the activity of the compounds according to the invention as MCR agonists, an increase in the intracellular cAMP content was measured.

먼저 상기 각 서브타입의 MCR 유전자를 발현시키는 영구 발현 HEK(Human Embryonic Kidney) 세포주(HEK MC1R, MC3R, MC4R, 또는 MC5R)들을 24-웰 세포 배양 판(Costar)의 각 웰당 1㎖의 배양액에 2X105세포가 되도록 첨가한 뒤 6% CO2가 존재하는 37℃ 항온 배양기에서 24시간 동안 배양하였다. 각 웰의 배지를 제거하고 0.5㎖의 차가운 DMEM으로 1회 세척해 주었다. 500μM IBMX(이소부틸메틸잔틴)를 함유한 DMEM 200㎕를 사용하여 단계별 농도로 희석시킨 MCR 항진제(실시예 화합물)를 최종 DMSO농도가 1%를 넘지않게 처리한 다음 6% CO2가 존재하는 37℃ 항온 배양기에서 30분 동안 배양하였다. 각 세포 내 cAMP의 함량은 아머샴(Amersham) cAMP 측정 키트(TRK432)를 사용하여 측정하였다.First, a permanently expressed HEK (Human Embryonic Kidney) cell line (HEK MC1R, MC3R, MC4R, or MC5R) expressing the MCR gene of each subtype was 2X10 in 1 ml of culture medium per well of a 24-well cell culture plate (Costar). 5 cells were added and then incubated for 24 hours in a 37 ° C. incubator with 6% CO 2 . The medium of each well was removed and washed once with 0.5 ml of cold DMEM. MCR adjuvants (Example compounds) diluted to 200 μl with DMEM containing 500 μM IBMX (isobutylmethylxanthine) were treated with a final DMSO concentration of no more than 1%, followed by the presence of 6% CO 2. Incubated for 30 minutes in an incubator. The content of cAMP in each cell was measured using an Amersham cAMP measurement kit (TRK432).

좀 더 상세하게 서술하면, 각 웰에 14.4㎕의 6M PCA(60%)를 가하고 10분 동안 얼음에 방치한 다음 200㎕씩을 취하여 미세원심분리튜브로 옮겼다. 여기에 11㎕의 5M KOH/1M 트리스를 가하여 중화시킨 뒤 12,000rpm으로 1분간 원심분리하였다. 상층액 50㎕를 취한 후 50㎕의3H로 표지된 cAMP(0.9pmol, 0.025μCi)를 가하고 100㎕의 흡착 단백질(binding protein)을 첨가해 준 다음 5초간 흔들어 주었다. 2시간 동안 얼음에 방치한 후 100㎕의 활성탄(charcoal)을 가하고 4℃에서 12,000rpm으로 3분간 원심분리하였다. 상층액 200㎕를 취한 후 신틸레이션(scintillation) 바이알에 넣고 5㎖의 신틸런트(scintillant)를 가한 다음 방사능을 측정하였다.In more detail, 14.4 μl of 6M PCA (60%) was added to each well, left on ice for 10 minutes, and then 200 μl of each well was transferred to a microcentrifuge tube. 11 μl of 5M KOH / 1M Tris was added thereto, neutralized, and centrifuged at 12,000 rpm for 1 minute. After taking 50 μl of the supernatant, 50 μl of 3 H-labeled cAMP (0.9 pmol, 0.025 μCi) was added, and 100 μl of binding protein was added thereto, followed by shaking for 5 seconds. After standing on ice for 2 hours, 100 µl of activated charcoal (charcoal) was added and centrifuged at 12,000 rpm for 3 minutes at 4 ° C. 200 μl of the supernatant was taken and placed in a scintillation vial, 5 ml of scintillant was added, and radioactivity was measured.

각 단계별 농도로 희석된 항진제에 의해 유도되는 cAMP의 양은 10μM의 NDP-MSH 처리에 의해 나타나는 양에 대한 상대적인 % 값으로 환산하였다. EC50은 각 항진제에 의해 유도될 수 있는 최대 cAMP양의 50%를 유도시키는 농도로 표시하였고 이 측정치는 통계 소프트웨어 (Prizm)를 사용하여 측정하였다.The amount of cAMP induced by the antidiarrheal agent diluted at each step concentration was converted to a percentage value relative to the amount indicated by 10 μM NDP-MSH treatment. EC50 was expressed as a concentration that induces 50% of the maximum amount of cAMP that can be induced by each antidiarrheal agent and this measurement was determined using statistical software (Prizm).

C. 수용체 결합 시험C. Receptor Binding Test

상기 각 서브타입의 MCR 유전자를 발현시키는 영구 발현 HEK(Human Embryonic Kidney) 세포주(HEK MC1R, MC3R, MC4R, 또는 MC5R)들을 96-웰 세포 배양 판(Costar)의 각 웰당 100㎕의 배양액에 1X105세포가 되도록 첨가한 뒤 6% CO2가 존재하는 37℃ 항온 배양기에서 48시간 동안 배양하였다. 각 웰의 배지를 제거하고 150㎕의 차가운 흡착용액(binding buffer; 50mM HEPES와 1% BSA를 함유한 RPMI 1640)으로 1회 세척해 주었다. 0.1nM의125I-NDP-MSH(NEN NEX352)와 단계별 농도로 희석시킨 MCR 항진제(실시예 화합물)를 함유한 100㎕의 흡착용액을 가한 후 실온에서 2시간동안 방치하였다. 배지 제거 후 200㎕의 차가운 흡착용액으로 1회 세척해 준 다음 150㎕의 0.2N NaOH를 가하고 실온에서 15분 동안 방치하였다. 각 웰에 담긴 용액을 5㎖ 시험관으로 옮긴 뒤 감마선 측정기(Wallac)로 방사능을 측정하였다.Permanent expressing HEK (Human Embryonic Kidney) cell lines (HEK MC1R, MC3R, MC4R, or MC5R) expressing the MCR genes of each subtype were added to 1 × 10 5 in 100 μl of culture medium per well of a 96-well cell culture plate (Costar). Cells were added and cultured for 48 hours in a 37 ° C. incubator with 6% CO 2 . The medium of each well was removed and washed once with 150 μl of cold binding buffer (RPM 1640 containing 50 mM HEPES and 1% BSA). 100 μl of an adsorption solution containing 125 n -NDP-MSH (NEN NEX352) of 0.1 nM and MCR antidiarrheal agent (Example compound) diluted to stepwise concentration was added and then left at room temperature for 2 hours. After removing the medium, the solution was washed once with 200 μl of cold adsorption solution, and then 150 μl of 0.2N NaOH was added thereto and left at room temperature for 15 minutes. The solution contained in each well was transferred to a 5 ml test tube and radioactivity was measured by a gamma ray detector (Wallac).

0.1nM의125I-NDP-MSH만 첨가했을 때의 총 결합 양에서 5μM NDP-MSH 존재하에서의 0.1nM125I-NDP-MSH의 비특이적 결합 양을 제외한 값을125I-NDP-MSH의 특이결합양으로 사용하였다. 각 단계별 농도로 희석된 항진제에 의해 상기125I-NDP-MSH의 특이결합이 저해되는 정도를 측정하였다. IC50는 50%의125I-NDP-MSH 특이결합을 저해하는 각 항진제의 농도로 표시하였고 이 측정치는 통계 소프트웨어 (Prizm)를 사용하여 측정하였다.Total amount of binding when only 0.1 nM of 125 I-NDP-MSH was added, excluding the amount of non-specific binding of 0.1 nM 125 I-NDP-MSH in the presence of 5 μM NDP-MSH, specific binding amount of 125 I-NDP-MSH Used as. The degree to which the specific binding of 125 I-NDP-MSH was inhibited by the antidiarrheal agent diluted to each step concentration was measured. IC50 was expressed as the concentration of each anti-inhibitor that inhibited 50% of 125 I-NDP-MSH specific binding and this measurement was determined using statistical software (Prizm).

이상 설명한 방법에 따라 측정한 결과, 본 발명의 실시예 화합물은 각 MCR 에 대한 항진효능 및 결합 효과를 나타내는 것으로 확인 되었다. 이들은 특히 MC4R에 대해 우수한 항진 효능과 결합 효과를 보였으며 0.005 μM 내지 10 μM 의 EC50값과 0.005 μM 내지 50 μM 의 IC50 값을 나타내었다.As a result of the measurement according to the method described above, it was confirmed that the example compound of the present invention exhibits anti-tumor effect and binding effect on each MCR. In particular, they showed excellent anti-inflammatory and binding effects on MC4R, and showed an EC50 value of 0.005 μM to 10 μM and an IC50 value of 0.005 μM to 50 μM.

Claims (23)

하기 화학식 1의 화합물, 약제학적으로 허용되는 그의 염, 수화물, 용매화물 및 이성체 화합물:Compounds of Formula 1, pharmaceutically acceptable salts, hydrates, solvates and isomeric compounds thereof: [화학식 1][Formula 1] 상기식에서In the above formula G는 하기 구조중 하나를 나타내고:G represents one of the following structures: 여기에서From here A는 수소, COR1, CO2R1, SO2R1, SO2NHR1, SO2N(R1)2, PO(OR1)2, C1-C8-알킬, (CH2)n-C5-C7-아릴, 또는 (CH2)n-C5-C7-헤테로아릴을 나타내고, 여기서 R1은 수소, C1-C8-알킬, (CH2)n-C3-C7-사이클로알킬, (CH2)n-C5-C7-아릴, 또는 (CH2)n-C5-C7-헤테로아릴을 나타내며, n은 1 내지 7의 정수를 나타내고, 알킬, 사이클로알킬, 아릴 또는 헤테로아릴은 할로겐, C1-C5-알킬, 트리플루오로메틸, 하이드록시, C1-C3-알킬옥시,아미노, (C1-C3-알킬)아미노, 디(C1-C3-알킬)아미노, 시아노, 카복시(CO2H), 에스테르(CO2-C1-C3-알킬) 및 아미드(CONH2)로 구성된 그룹중에서 선택된 1 내지 3개의 치환체에 의해 치환되거나 비치환되며,A is hydrogen, COR 1 , CO 2 R 1 , SO 2 R 1 , SO 2 NHR 1 , SO 2 N (R 1 ) 2 , PO (OR 1 ) 2 , C 1 -C 8 -alkyl, (CH 2 ) n- C 5 -C 7 -aryl, or (CH 2 ) n -C 5 -C 7 -heteroaryl, wherein R 1 is hydrogen, C 1 -C 8 -alkyl, (CH 2 ) n -C 3 -C 7 -cycloalkyl, (CH 2 ) n -C 5 -C 7 -aryl, or (CH 2 ) n -C 5 -C 7 -heteroaryl, n represents an integer from 1 to 7, and alkyl , Cycloalkyl, aryl or heteroaryl is halogen, C 1 -C 5 -alkyl, trifluoromethyl, hydroxy, C 1 -C 3 -alkyloxy, amino, (C 1 -C 3 -alkyl) amino, di 1-3 substituents selected from the group consisting of (C 1 -C 3 -alkyl) amino, cyano, carboxy (CO 2 H), ester (CO 2 -C 1 -C 3 -alkyl) and amide (CONH 2 ) Substituted or unsubstituted by B 및 E는 각각 독립적으로 수소, C1-C8-알킬, (CH2)n-C3-C7-사이클로알킬, (CH2)n-C5-C7-아릴, (CH2)n-C5-C7-헤테로아릴, (CH2)n-C5-C7-헤테로사이클 또는 (CH2)n-O(CH2)-C5-C7-아릴을 나타내고, 여기서 알킬, 사이클로알킬, 아릴, 헤테로아릴 또는 헤테로사이클은 할로겐, C1-C5-알킬, 트리플루오로메틸, 하이드록시, C1-C3-알킬옥시, 아미노, (C1-C3-알킬)아미노, 디(C1-C3-알킬)아미노, 시아노, 카복시(CO2H), 에스테르(CO2-C1-C3-알킬), 아미드(CONH2), 아미딘(C(NH)NH2), 니트로 및 페닐로 구성된 그룹중에서 선택된 1 내지 3개의 치환체에 의해 치환되거나 비치환되며, n은 1 내지 7의 정수를 나타내고,B and E are each independently hydrogen, C 1 -C 8 -alkyl, (CH 2 ) n -C 3 -C 7 -cycloalkyl, (CH 2 ) n -C 5 -C 7 -aryl, (CH 2 ) n- C 5 -C 7 -heteroaryl, (CH 2 ) n -C 5 -C 7 -heterocycle or (CH 2 ) n -O (CH 2 ) -C 5 -C 7 -aryl, wherein alkyl , Cycloalkyl, aryl, heteroaryl or heterocycle is halogen, C 1 -C 5 -alkyl, trifluoromethyl, hydroxy, C 1 -C 3 -alkyloxy, amino, (C 1 -C 3 -alkyl) Amino, di (C 1 -C 3 -alkyl) amino, cyano, carboxy (CO 2 H), ester (CO 2 -C 1 -C 3 -alkyl), amide (CONH 2 ), amidine (C (NH ) NH 2 ), substituted or unsubstituted by 1 to 3 substituents selected from the group consisting of phenyl, n represents an integer of 1 to 7, Cy는 C1-C5-알킬, 할로겐, 트리플루오로메틸, 하이드록시, C1-C3-알킬옥시, 아미노, (C1-C3-알킬)아미노, 디(C1-C3-알킬)아미노, 옥소(C=O) 및 니트로로 구성된 그룹중에서 선택된 치환체에 의해 치환되거나 비치환된 C5-C7-아릴 또는 C5-C7-사이클로알킬을 나타내며,Cy is C 1 -C 5 -alkyl, halogen, trifluoromethyl, hydroxy, C 1 -C 3 -alkyloxy, amino, (C 1 -C 3 -alkyl) amino, di (C 1 -C 3- C 5 -C 7 -aryl or C 5 -C 7 -cycloalkyl unsubstituted or substituted by a substituent selected from the group consisting of alkyl) amino, oxo (C═O) and nitro, C는 수소, COR1, CO2R1, SO2R1, SO2NHR1, (CH2)m-C1-C8-알킬설포닐, (CH2)m-C1-C8-알콕시카보닐, 아미드(CONH2), (CH2)m-C1-C8-알킬카바모일, C(O)-C5-C7-헤테로아릴, C(O)-C5-C7-헤테로사이클, C(O)-(CH2)m-C5-C7-헤테로아릴, C(O)-(CH2)m-C5-C7-헤테로사이클, (CH2)m-C5-C7-헤테로아릴 또는 (CH2)m-C5-C7-헤테로사이클을 나타내고, 여기서, R1은 C1-C8-알킬 또는 C5-C7-아릴을 나타내며, 헤테로아릴은 고리안에 1 내지 4개의 질소원자 또는 산소 또는 황원자를 포함할 수 있고, 헤테로사이클은 고리안에 1 또는 2개의 질소원자 또는 산소 또는 황원자를 포함할 수 있으며, 헤테로아릴 또는 헤테로사이클은 할로겐, C1-C3-알킬, 트리플루오로메틸, 니트로, 하이드록시, C1-C3-알킬옥시, 아미노, (C1-C3-알킬)아미노, 디(C1-C3-알킬)아미노 및 옥소(C=O)로 구성된 그룹중에서 선택된 치환체에 의해 치환되거나 비치환되고, 여기서 m은 0 내지 2의 정수를 나타내며,C is hydrogen, COR 1 , CO 2 R 1 , SO 2 R 1 , SO 2 NHR 1 , (CH 2 ) m -C 1 -C 8 -alkylsulfonyl, (CH 2 ) m -C 1 -C 8- Alkoxycarbonyl, amide (CONH 2 ), (CH 2 ) m -C 1 -C 8 -alkylcarbamoyl, C (O) -C 5 -C 7 -heteroaryl, C (O) -C 5 -C 7 -Heterocycle, C (O)-(CH 2 ) m -C 5 -C 7 -heteroaryl, C (O)-(CH 2 ) m -C 5 -C 7 -heterocycle, (CH 2 ) m- C 5 -C 7 -heteroaryl or (CH 2 ) m -C 5 -C 7 -heterocycle, wherein R 1 represents C 1 -C 8 -alkyl or C 5 -C 7 -aryl, hetero Aryl may contain 1 to 4 nitrogen atoms or oxygen or sulfur atoms in the ring, heterocycle may contain 1 or 2 nitrogen atoms or oxygen or sulfur atoms in the ring, heteroaryl or heterocycle may be halogen, C 1 -C 3 -alkyl, trifluoromethyl, nitro, hydroxy, C 1 -C 3 -alkyloxy, amino, (C 1 -C 3 -alkyl) amino, di (C 1 -C 3 -alkyl) amino And Cattle (C = O) substituted by a substituent selected from the group consisting of and or unsubstituted ring, wherein m is an integer from 0 to 2, D는 C5-C10-알킬, (CH2)m-C5-C7-사이클로알킬, (CH2)m-C5-C7-아릴, (CH2)m-C5-C7-헤테로사이클로알킬을 나타내고, 여기서 m은 0 내지 2의 정수를 나타낸다.D is C 5 -C 10 -alkyl, (CH 2 ) m -C 5 -C 7 -cycloalkyl, (CH 2 ) m -C 5 -C 7 -aryl, (CH 2 ) m -C 5 -C 7 -Heterocycloalkyl, where m represents an integer from 0 to 2. 제1항에 있어서, A가 수소, COR1, CO2R1, SO2R1, SO2NHR1, SO2N(R1)2, PO(OR1)2, C1-C8-알킬, (CH2)n-C5-C7-아릴, 또는 (CH2)n-C5-C7-헤테로아릴을 나타내고, 여기서 R1이 수소, C1-C8-알킬, (CH2)n-C3-C7-사이클로알킬, 또는 (CH2)n-C5-C7-아릴을 나타내며, n은 1 내지 3의 정수를 나타내는 화합물.The compound of claim 1, wherein A is hydrogen, COR 1 , CO 2 R 1 , SO 2 R 1 , SO 2 NHR 1 , SO 2 N (R 1 ) 2 , PO (OR 1 ) 2 , C 1 -C 8- Alkyl, (CH 2 ) n -C 5 -C 7 -aryl, or (CH 2 ) n -C 5 -C 7 -heteroaryl, wherein R 1 is hydrogen, C 1 -C 8 -alkyl, (CH 2 ) n- C 3 -C 7 -cycloalkyl, or (CH 2 ) n -C 5 -C 7 -aryl, where n represents an integer from 1 to 3. 제1항에 있어서, B가 벤질, CH2-피리딜, CH2-피리미딜, 또는 CH2-5환-헤테로아릴을 나타내고, 여기에서 아릴 또는 헤테로아릴은 할로겐, C1-C5-알킬, 트리플루오로메틸, 하이드록시, C1-C3-알킬옥시, 아미노, (C1-C3-알킬)아미노, 디(C1-C3-알킬)아미노, 시아노, 카복시(CO2H), 에스테르(CO2-C1-C3-알킬), 아미드(CONH2), 아미딘(C(NH)NH2), 니트로 및 페닐로 구성된 그룹중에서 선택된 1 또는 2개의 치환체에 의해 치환되거나 비치환된 화합물.The method of claim 1, wherein, B is benzyl, CH 2-pyridyl, CH 2-pyrimidyl, or CH 2 -5 exchange - represents a heteroaryl, aryl or heteroaryl are halogen, C 1 -C 5 here -alkyl , Trifluoromethyl, hydroxy, C 1 -C 3 -alkyloxy, amino, (C 1 -C 3 -alkyl) amino, di (C 1 -C 3 -alkyl) amino, cyano, carboxy (CO 2 Substituted by one or two substituents selected from the group consisting of H), ester (CO 2 -C 1 -C 3 -alkyl), amide (CONH 2 ), amidine (C (NH) NH 2 ), nitro and phenyl Or unsubstituted compounds. 제3항에 있어서, B가 할로겐, C1-C3-알킬, 트리플루오로메틸, 메톡시, 에톡시, 메틸아미노 및 디메틸아미노로 구성된 그룹중에서 선택된 1 또는 2개의 치환체에 의해 치환되거나 비치환된 벤질 또는 CH2-피리딜을 나타내는 화합물.The compound of claim 3, wherein B is unsubstituted or substituted by one or two substituents selected from the group consisting of halogen, C 1 -C 3 -alkyl, trifluoromethyl, methoxy, ethoxy, methylamino and dimethylamino Benzyl or CH 2 -pyridyl. 제1항에 있어서, C가 할로겐, 메틸, 에틸, 트리플루오로메틸, 하이드록시, 메톡시, 에톡시, 아미노, 메틸아미노 또는 디메틸아미노에 의해 치환된 (CH2)m-C5-C7-헤테로아릴을 나타내고 m이 0 내지 2의 정수를 나타내는 화합물.The compound of claim 1, wherein C is (CH 2 ) m -C 5 -C 7 substituted by halogen, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, amino, methylamino or dimethylamino. -A heteroaryl wherein m represents an integer from 0 to 2. 제5항에 있어서, 할로겐, 메틸, 에틸, 메톡시, 에톡시, 메틸아미노 또는 디메틸아미노에 의해 치환된 CH2-피롤, CH2-이미다졸, CH2-피라졸, CH2-티아졸, CH2-옥사졸, CH2-트리아졸, CH2-테트라졸, CH2-피리딘, CH2-피리미딘, CH2-피라진 또는 CH2-트리아진을 나타내는 화합물.The process of claim 5, wherein CH 2 -pyrrole, CH 2 -imidazole, CH 2 -pyrazole, CH 2 -thiazole substituted by halogen, methyl, ethyl, methoxy, ethoxy, methylamino or dimethylamino, CH 2 - oxazole, CH 2 - triazole, CH 2 - tetrazole, CH 2 - pyridine, CH 2 - pyrimidine, CH 2 - pyrazinyl, or CH 2 - compound representing triazine. 제1항에 있어서, C가 C1-C8-알킬설포닐, C5-C7-아릴설포닐, (CH2)m-C1-C8-알킬설포닐, (CH2)m- C1-C8-알콕시카보닐, 아미드(CONH2), 또는 (CH2)m-C1-C8-알킬카바모일을 나타내고, m은 0 내지 2의 정수를 나타내는 화합물.The compound of claim 1, wherein C is C 1 -C 8 -alkylsulfonyl, C 5 -C 7 -arylsulfonyl, (CH 2 ) m -C 1 -C 8 -alkylsulfonyl, (CH 2 ) m − C 1 -C 8 -alkoxycarbonyl, amide (CONH 2 ), or (CH 2 ) m -C 1 -C 8 -alkylcarbamoyl, wherein m represents an integer of 0 to 2. 제1항에 있어서, C가 C(O)-이미다졸, C(O)-트리아졸, C(O)-티아졸, C(O)-옥사졸, C(O)-테트라졸, C(O)-피리딘, C(O)-피라진, C(O)-트리아진, CH2-C(O)-이미다졸, CH2-C(O)-트리아졸, CH2-C(O)-테트라졸, CH2-C(O)-티아졸, CH2-CH2-이미다졸, CH2-CH2-트리아졸, CH2-CH2-테트라졸, CH2-CH2-티아졸, CH2-CH2-이미다졸론, CH2-CH2-옥사졸론, CH2-CH2-디아졸론을 나타내는 화합물.The compound of claim 1 wherein C is C (O) -imidazole, C (O) -triazole, C (O) -thiazole, C (O) -oxazole, C (O) -tetrazole, C ( O) -pyridine, C (O) -pyrazine, C (O) -triazine, CH 2 -C (O) -imidazole, CH 2 -C (O) -triazole, CH 2 -C (O)- Tetrazole, CH 2 -C (O) -thiazole, CH 2 -CH 2 -imidazole, CH 2 -CH 2 -triazole, CH 2 -CH 2 -tetrazole, CH 2 -CH 2 -thiazole, CH 2 -CH 2 - imidazolonyl, CH 2 -CH 2 - oxazolone, CH 2 -CH 2 - a compound represented by dia isothiazolone. 제1항에 있어서, D가 C5-C10-알킬 또는 (CH2)m-C5-C7-사이클로알킬을 나타내고, 여기서 m은 0 내지 2의 정수를 나타내는 화합물.The compound of claim 1, wherein D represents C 5 -C 10 -alkyl or (CH 2 ) m -C 5 -C 7 -cycloalkyl, wherein m represents an integer from 0 to 2. 8. 제1항에 있어서, E가 CH2-C3-C7-사이클로알킬, CH2-C5-C7-아릴, CH2-C5-C7-헤테로아릴 또는 CH2-C5-C7-헤테로사이클을 나타내고, 사이클로알킬, 아릴, 헤테로아릴 또는 헤테로사이클은 할로겐, C1-C5-알킬, 트리플루오로메틸, 하이드록시, C1-C3-알킬옥시, 아미노, (C1-C3-알킬)아미노, 디(C1-C3-알킬)아미노, 시아노, 카복시(CO2H), 에스테르(CO2-C1-C3-알킬), 아미드(CONH2), 아미딘(C(NH)NH2), 니트로 및 페닐로 구성된 그룹중에서 선택된 1 내지 3개의 치환체에 의해 치환되거나 비치환된 화합물.The compound of claim 1, wherein E is CH 2 -C 3 -C 7 -cycloalkyl, CH 2 -C 5 -C 7 -aryl, CH 2 -C 5 -C 7 -heteroaryl or CH 2 -C 5 -C 7 -heterocycle, cycloalkyl, aryl, heteroaryl or heterocycle represents halogen, C 1 -C 5 -alkyl, trifluoromethyl, hydroxy, C 1 -C 3 -alkyloxy, amino, (C 1 -C 3 -alkyl) amino, di (C 1 -C 3 -alkyl) amino, cyano, carboxy (CO 2 H), ester (CO 2 -C 1 -C 3 -alkyl), amide (CONH 2 ), A compound substituted or unsubstituted by one to three substituents selected from the group consisting of amidine (C (NH) NH 2 ), nitro and phenyl. 제10항에 있어서, E가 CH2-C5-C7-헤테로아릴 또는 CH2-C5-C7-헤테로사이클을 나타내고, 여기서 헤테로아릴 또는 헤테로사이클은 할로겐, 메틸, 에틸, 트리플루오로메틸, 하이드록시, 메톡시, 에톡시, 아미노, 메틸아미노 및 디메틸아미노로 구성된 그룹중에서 선택된 1 내지 3개의 치환체에 의해 치환되거나 비치환된 화합물.The compound of claim 10, wherein E represents CH 2 -C 5 -C 7 -heteroaryl or CH 2 -C 5 -C 7 -heterocycle, wherein the heteroaryl or heterocycle is halogen, methyl, ethyl, trifluoro A compound substituted or unsubstituted by one to three substituents selected from the group consisting of methyl, hydroxy, methoxy, ethoxy, amino, methylamino and dimethylamino. 제1항에 있어서, Cy가 페닐 또는 사이클로헥실을 나타내는 화합물.The compound of claim 1, wherein Cy represents phenyl or cyclohexyl. 제1항에 있어서, A가 수소, COR1, CO2R1, SO2R1, SO2NHR1, SO2N(R1)2, PO(OR1)2, C1-C8-알킬, (CH2)n-C5-C7-아릴, 또는 (CH2)n-C5-C7-헤테로아릴을 나타내고, 여기서 R1이 수소, C1-C8-알킬, (CH2)n-C3-C7-사이클로알킬, 또는 (CH2)n- C5-C7-아릴을 나타내며, n은 1 내지 3의 정수를 나타내고; B가 할로겐, C1-C3-알킬, 트리플루오로메틸, 메톡시, 에톡시, 메틸아미노 및 디메틸아미노로 구성된 그룹중에서 선택된 1 또는 2개의 치환체에 의해 치환되거나 비치환된 벤질 또는 CH2-피리딜을 나타내며; C가 할로겐, 메틸, 에틸, 메톡시, 에톡시, 메틸아미노 또는 디메틸아미노에 의해 치환된 CH2-피롤, CH2-이미다졸, CH2-피라졸, CH2-티아졸, CH2-옥사졸, CH2-트리아졸, CH2-테트라졸, CH2-피리딘, CH2-피리미딘, CH2-피라진 또는 CH2-트리아진을 나타내거나, C1-C8-알킬설포닐, C5-C7-아릴설포닐, (CH2)m-C1-C8-알킬설포닐, (CH2)m-C1-C8-알콕시카보닐, 아미드(CONH2), 또는 (CH2)m-C1-C8-알킬카바모일을 나타내고, m은 0 내지 2의 정수를 나타내거나, C(O)-이미다졸, C(O)-트리아졸, C(O)-티아졸, C(O)-옥사졸, C(O)-테트라졸, C(O)-피리딘, C(O)-피라진, C(O)-트리아진, CH2-C(O)-이미다졸, CH2-C(O)-트리아졸, CH2-C(O)-테트라졸, CH2-C(O)-티아졸, CH2-CH2-이미다졸, CH2-CH2-트리아졸, CH2-CH2-테트라졸, CH2-CH2-티아졸, CH2-CH2-이미다졸론, CH2-CH2-옥사졸론, CH2-CH2-디아졸론을 나타내고; D가 C5-C10-알킬 또는 (CH2)m-C5-C7-사이클로알킬을 나타내며, 여기서 m은 0 내지 2의 정수를 나타내고; E가 할로겐, 메틸, 에틸, 트리플루오로메틸, 하이드록시, 메톡시, 에톡시, 아미노, 메틸아미노 및 디메틸아미노로 구성된 그룹중에서 선택된 1 내지 3개의 치환체에 의해 치환되거나 비치환된 CH2-이미다졸, CH2-피라졸, CH2-티아졸, CH2-옥사졸, CH2-트리아졸, CH2-피리딘,CH2-1-피페리딘 또는 CH2-1-헥사메틸렌이민을 나타내며; Cy가 페닐 또는 사이클로헥실을 나타내는 화합물.The compound of claim 1, wherein A is hydrogen, COR 1 , CO 2 R 1 , SO 2 R 1 , SO 2 NHR 1 , SO 2 N (R 1 ) 2 , PO (OR 1 ) 2 , C 1 -C 8- Alkyl, (CH 2 ) n -C 5 -C 7 -aryl, or (CH 2 ) n -C 5 -C 7 -heteroaryl, wherein R 1 is hydrogen, C 1 -C 8 -alkyl, (CH 2 ) n- C 3 -C 7 -cycloalkyl, or (CH 2 ) n -C 5 -C 7 -aryl, n represents an integer from 1 to 3; Benzyl or CH 2 -unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, C 1 -C 3 -alkyl, trifluoromethyl, methoxy, ethoxy, methylamino and dimethylamino Pyridyl; C is halogen, methyl, ethyl, methoxy, ethoxy, methylamino or dimethylamino in the CH 2 substituted by-pyrrole, CH 2-imidazole, CH 2 - pyrazole, CH 2-thiazole, CH 2 - oxazole Sol, CH 2 -triazole, CH 2 -tetrazole, CH 2 -pyridine, CH 2 -pyrimidine, CH 2 -pyrazine or CH 2 -triazine, or C 1 -C 8 -alkylsulfonyl, C 5 -C 7 -arylsulfonyl, (CH 2 ) m -C 1 -C 8 -alkylsulfonyl, (CH 2 ) m -C 1 -C 8 -alkoxycarbonyl, amide (CONH 2 ), or (CH 2 ) m- C 1 -C 8 -alkylcarbamoyl, m represents an integer of 0 to 2, or C (O) -imidazole, C (O) -triazole, C (O) -thiazole , C (O) -oxazole, C (O) -tetrazole, C (O) -pyridine, C (O) -pyrazine, C (O) -triazine, CH 2 -C (O) -imidazole, CH 2 -C (O) -triazole, CH 2 -C (O) -tetrazole, CH 2 -C (O) -thiazole, CH 2 -CH 2 -imidazole, CH 2 -CH 2 -triazole , CH 2 -CH 2 -tetrazole, CH 2 -CH 2 -thiazole, CH 2 -CH 2 -imidazolone, CH 2 -CH 2 -oxazolone, CH 2 -CH 2 -diazolone; D represents C 5 -C 10 -alkyl or (CH 2 ) m -C 5 -C 7 -cycloalkyl, wherein m represents an integer from 0 to 2; CH 2 -alternatively unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, amino, methylamino and dimethylamino Dazole, CH 2 -pyrazole, CH 2 -thiazole, CH 2 -oxazole, CH 2 -triazole, CH 2 -pyridine, CH 2-1 -piperidine or CH 2-1 -hexamethyleneimine ; Cy represents phenyl or cyclohexyl. 제1항에 있어서, 하기 표에 기재된 화합물로 구성된 그룹중에서 선택된 화합물:The compound of claim 1 selected from the group consisting of compounds listed in the following table: 제1항에 있어서, 하기 표에 기재된 화합물로 구성된 그룹중에서 선택된 화합물:The compound of claim 1 selected from the group consisting of compounds listed in the following table: N-말단에 보호기 P가 도입된 하기 화학식 2의 화합물을 하기 화학식 3의 화합물과 반응시키고 가수분해시켜 하기 화학식 4의 디펩티드 화합물을 형성하고, 화학식 4의 화합물을 하기 화학식 5의 피페리딘 유도체와 아미드-커플링 반응시키고 탈보호화하여 하기 화학식 1a의 화합물을 제조함을 특징으로 하여 제1항에 정의된 화학식 1의 화합물을 제조하는 방법:The compound of formula (2) having the protecting group P introduced at the N-terminus is reacted with a compound of formula (3) and hydrolyzed to form a dipeptide compound of formula (4), and the compound of formula (4) is a piperidine derivative of formula (5) A process for preparing the compound of formula 1 as defined in claim 1, characterized in that the compound of formula 1a is prepared by amide-coupling reaction with deprotection. [화학식 2][Formula 2] [화학식 3][Formula 3] [화학식 4][Formula 4] [화학식 5][Formula 5] [화학식 1a][Formula 1a] 상기식에서,In the above formula, Cy, B, C 및 D는 각각 제1항에서 정의한 바와 같고,Cy, B, C and D are each as defined in claim 1, P는 아미노보호기를 나타낸다.P represents an aminoprotecting group. N-말단에 보호기 P'가 도입된 하기 화학식 6의 화합물을 하기 화학식 5의 피페리딘 유도체와 아미드-커플링 반응시키고 탈보호화하여 하기 화학식 7의 화합물을 형성하고, 화학식 7의 화합물을 하기 화학식 2의 화합물과 반응시키고 탈보호화하여 화학식 1a의 화합물을 제조함을 특징으로 하여 제1항에 정의된 화학식 1의 화합물을 제조하는 방법:An amide-coupling reaction and deprotection of a compound of formula (6) having a protecting group P ′ introduced at the N-terminus with a piperidine derivative of formula (5) to form a compound of formula (7), wherein the compound of formula (7) A process for preparing the compound of formula 1 as defined in claim 1 characterized in that the compound of formula 1a is prepared by reacting with and deprotecting the compound of formula 2 [화학식 6][Formula 6] [화학식 5][Formula 5] [화학식 7][Formula 7] [화학식 2][Formula 2] [화학식 1a][Formula 1a] 상기식에서,In the above formula, Cy, B, C 및 D는 각각 제1항에서 정의한 바와 같고,Cy, B, C and D are each as defined in claim 1, P 및 P'는 각각 독립적으로 아미노보호기를 나타낸다.P and P 'each independently represent an aminoprotecting group. 제16항 또는 제17항에서 수득된 화학식 1a의 화합물에 A' 그룹을 도입시키는 커플링 반응을 수행하여 하기 화학식 1b의 화합물을 제조함을 특징으로 하여 제1항에 정의된 화학식 1의 화합물을 제조하는 방법:A compound of formula 1 as defined in claim 1 is prepared by carrying out a coupling reaction in which A 'group is introduced into a compound of formula 1a obtained in claim 16 or 17 to prepare a compound of formula 1b. How to manufacture: [화학식 1b][Formula 1b] 상기식에서,In the above formula, Cy, B, C 및 D는 각각 제1항에서 정의한 바와 같고,Cy, B, C and D are each as defined in claim 1, A'는 제1항에 정의된 A와 동일하나, 단 수소는 제외된다.A 'is the same as A as defined in claim 1 except for hydrogen. N-말단에 보호기 P가 도입된 하기 화학식 8의 화합물을 하기 화학식 3의 화합물과 반응시키고 가수분해시켜 하기 화학식 9의 디펩티드 화합물을 형성하고, 화학식 9의 화합물을 하기 화학식 5의 피페리딘 유도체와 아미드-커플링 반응시키고 탈보호화하여 하기 화학식 1c의 화합물을 제조함을 특징으로 하여 제1항에 정의된 화학식 1의 화합물을 제조하는 방법:The compound of formula 8 having the protecting group P introduced at the N-terminus is reacted with a compound of formula 3 to be hydrolyzed to form a dipeptide compound of formula 9, and the compound of formula 9 is a piperidine derivative of formula 5 A process for preparing the compound of formula (I) as defined in claim 1 characterized in that the compound of formula (1c) is prepared by amide-coupling reaction with deprotection. [화학식 8][Formula 8] [화학식 3][Formula 3] [화학식 9][Formula 9] [화학식 5][Formula 5] [화학식 1c][Formula 1c] 상기식에서,In the above formula, B, C, D 및 E는 각각 제1항에서 정의한 바와 같고,B, C, D and E are each as defined in claim 1, P는 아미노보호기를 나타낸다.P represents an aminoprotecting group. 하기 화학식 6의 화합물을 하기 화학식 5의 피페리딘 유도체와 아미드-커플링 반응시키고 탈보호화하여 하기 화학식 10의 화합물을 형성하고, 화학식 10의 화합물을 하기 화학식 8의 화합물과 반응시키고 탈보호화하여 하기 화학식 1c의 화합물을 제조함을 특징으로 하여 제1항에 정의된 화학식 1의 화합물을 제조하는 방법:Amide-coupling and deprotecting a compound of Formula 6 with a piperidine derivative of Formula 5 to form a compound of Formula 10, and reacting a compound of Formula 10 with a compound of Formula 8 and deprotecting A process for preparing the compound of formula 1 as defined in claim 1 characterized in that the compound of formula 1c is prepared. [화학식 6][Formula 6] [화학식 5][Formula 5] [화학식 10][Formula 10] [화학식 8][Formula 8] [화학식 1c][Formula 1c] 상기식에서,In the above formula, B, C, D 및 E는 각각 제1항에서 정의한 바와 같고,B, C, D and E are each as defined in claim 1, P 및 P'는 각각 독립적으로 아미노보호기를 나타낸다.P and P 'each independently represent an aminoprotecting group. 제19항 또는 제20항에서 수득된 화학식 1c의 화합물에 A' 그룹을 도입시키는 커플링 반응을 수행하여 하기 화학식 1d의 화합물을 제조함을 특징으로 하여 제1항에 정의된 화학식 1의 화합물을 제조하는 방법:A compound of formula 1 as defined in claim 1 is prepared by carrying out a coupling reaction in which A 'group is introduced into a compound of formula 1c obtained in claim 19 or 20 to prepare a compound of formula 1d. How to manufacture: [화학식 1d][Formula 1d] 상기식에서,In the above formula, B, C, D 및 E는 각각 제1항에서 정의한 바와 같고,B, C, D and E are each as defined in claim 1, A'는 제1항에 정의된 A와 동일하나, 단 수소는 제외된다.A 'is the same as A as defined in claim 1 except for hydrogen. 약제학적으로 허용되는 담체와 함께 유효성분으로서 제1항에 정의된 화학식 1의 화합물을 함유함을 특징으로 하는 멜라노코틴 수용체의 기능항진제 조성물.A functional anti-diarrheal composition of a melanocortin receptor characterized in that it contains a compound of the formula (1) as defined in claim 1 together with a pharmaceutically acceptable carrier. 제22항에 있어서, 비만, 발기부전증, 당뇨병, 및 염증에 대한 예방 및 치료효과를 나타내는 조성물.23. The composition of claim 22, wherein the composition exhibits a prophylactic and therapeutic effect on obesity, erectile dysfunction, diabetes, and inflammation.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999064002A1 (en) * 1998-06-11 1999-12-16 Merck & Co., Inc. Spiropiperidine derivatives as melanocortin receptor agonists
WO2000074679A1 (en) * 1999-06-04 2000-12-14 Merck & Co., Inc. Substituted piperidines as melanocortin-4 receptor agonists
WO2001070337A1 (en) * 2000-03-23 2001-09-27 Merck & Co., Inc. Spiropiperidine derivatives as melanocortin receptor agonists
WO2001070708A1 (en) * 2000-03-23 2001-09-27 Merck & Co., Inc. Substituted piperidines as melanocortin receptor agonists

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999064002A1 (en) * 1998-06-11 1999-12-16 Merck & Co., Inc. Spiropiperidine derivatives as melanocortin receptor agonists
WO2000074679A1 (en) * 1999-06-04 2000-12-14 Merck & Co., Inc. Substituted piperidines as melanocortin-4 receptor agonists
WO2001070337A1 (en) * 2000-03-23 2001-09-27 Merck & Co., Inc. Spiropiperidine derivatives as melanocortin receptor agonists
WO2001070708A1 (en) * 2000-03-23 2001-09-27 Merck & Co., Inc. Substituted piperidines as melanocortin receptor agonists

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