KR20030035592A - Melanocortin receptor agonists - Google Patents

Melanocortin receptor agonists Download PDF

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KR20030035592A
KR20030035592A KR1020010067706A KR20010067706A KR20030035592A KR 20030035592 A KR20030035592 A KR 20030035592A KR 1020010067706 A KR1020010067706 A KR 1020010067706A KR 20010067706 A KR20010067706 A KR 20010067706A KR 20030035592 A KR20030035592 A KR 20030035592A
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amino
heteroaryl
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이구
박희술
정원혁
안인애
유현주
임현주
박숙경
최덕영
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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 is a melanocortin 4 receptor(MC4R) agonist, to accelerate the function of the melanocortin 4 receiptor(MC4R) and to prevent and treat diseases associated with the MC4R such as obesity, diabetes and sexual disorder. 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, C1-8-alkyl, (CH2)n, (CH2)n-aryl or (CH2)n-heteroaryl in which R1 is hydrogen, C1-8-alkyl, (CH2)n-C3-7-cycloalkyl, (CH2)n-aryl or (CH2)n-heteroaryl, n is an integer of 1 to 7; B and E are independently hydrogen, C1-8-alkyl, (CH2)n-C3-7-cycloalkyl, (CH2)n-aryl, (CH2)n-heteroaryl, (CH2)n-heterocycle, (CH2)n-amino, (CH2)n-(alkyl)amino, (CH2)n-(dialkyl)amino, (CH2)n-amide(CONH2) or (CH2)n-O(CH2)aryl in which n is an integer of 0 to 7; C is (CH2)m-heteroaryl, (CH2)m-heterocycle, (CH2)m-NH-heteroaryl, (CH2)m-NH-heterocycle, (CH2)m-NH-(alkylsulfonyl), (CH2)m-NH-(arylsulfonyl), (CH2)m-NH-alkoxycarbonyl, (CH2)m-NH-alkylamino carbamoyl, (CH2)m-NH-C(O)-heteroaryl, (CH2)m-NH-C(O)-heterocycle, (CH2)m-NH-(CH2)m-heteroaryl, (CH2)m-NH-(CH2)m-heterocycle, (CH2)m-NH-C(O)-(CH2)m-heteroaryl, (CH2)m-NH-C(O)-(CH2)m-heterocycle, C(O)-heterocycle, (CH2)m-NH-alkylester, (CH2)m-NH-alkyl amide, alkoxycarbonyl, (CH2)m-O-(alkylsulfonyl), (CH2)m-O-(arylsulfonyl), alkylamino carbamoyl, hydroxyalkyl amino carbamoyl, arylamino carbamoyl or hydrogen which are substituted or unsubstituted by a substituent selected from the group consisting of halogen, C1-5 alkyl, trifluoromethyl, hydroxy, C1-3 alkyloxy, amino, (C1-3 alkyl)amino, (C1-3 alkyl)2amino, cyano, carboxy(CO2H), CO2-C1-3 alkyl, CONH2, amidine(C(NH)NH2), nitro and oxo(C=O) in which m is an integer of 0 to 2; D is piperidine, pyrrolidine, hexamethyleneimine, 2 or 3 oxo piperidine and hexamethyleneimine, pyrrolidine or dialkylamine; and Cy is C5-C7-aryl or C5-7 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 and oxo(C=O).

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, G 및 Cy는 하기 정의한 바와 같다.Wherein B, C, D, G and Cy 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 조절하는데 피부색소침착, 체온, 염증, 식욕, 행동조절기능 등이 알려져 있다 (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 and exhibits a physiological effect. Melanocortin peptides regulate various physiological phenomena according to affinity for each of the MCRs, and are known for skin pigmentation, body temperature, inflammation, appetite, and behavioral control (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 매개의 기능이 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 (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 식욕조절에서의 중요한 역할을 한다는 것을 증명해주고 있다 (Lu D, Willard D, et al., Nature 1994, 371(6500), 799; Huszar Det 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 mediating the 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 (Haskell-Luevano C, et al., Drug News 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, indicating that this receptor plays an important role in appetite control. (Lu D, Willard D, et al., Nature 1994, 371 (6500), 799; Huszar Det 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 이루어 지면서 주로 아미노산의 조합을 변화시킨 펩티드들과의 구조활성 상관관계를 통하여 연구되어졌다. 대표적인 MCR 항진 펩티드는 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) 로서, 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 (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 보였으며 (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 (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 (Benoit, SC, et al. J. Neuroscience 2000, 20, 3442).As the MCRs were found to be involved in the regulation of several important physiological phenomena, the active search for anti-inflammatory or antagonist was actively conducted, and the study was carried out through the structural activity correlation with peptides that changed the combination of amino acids. Representative MCR antigenic peptides are 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-Phe-Arg- Trp-Gly-Lys-Po-Val-NH 2 ) has a potent effect (Haskell-Luevano C, et al., J Med. Chem. 1997, 40, 1738). In particular, the MCR anti-peptide peptide MTII was absorbed by the subcutaneous injection route and then passed through the Blood Brain Barrier (BBB), showing effects on the central nervous system (Dorr RT, et al., Life Sci. 1996, 58 (20), 1777). In addition, this substance has been shown to be effective in clinical trials in men with 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 약효시험을 (High-throughput Screening) 통하거나, 조합화학을 이용하여 발굴된 MCR 항진제 물질이 최근 보고되었다 (WO 0110842, WO 0105401, WO 0123392, WO 0123887). 또한 성장호르몬 촉진제로서의 활성을 지닌 소분자 물질군으로부터 적절한 구조변화 연구를 통해 발굴된 MC4R에 선택적인 항진제 물질이 보고되었다 (WO 99/64002, WO 00/74679).Research into small-molecule MCR agonists is also actively underway. MCR adjuvant materials discovered through high-throughput screening or combinatorial chemistry from libraries of non-peptide small molecule materials have recently been reported (WO 0110842, WO 0105401, WO 0123392, WO 0123887). In addition, selective anti-inflammatory agents have been reported for MC4R, which has been discovered through appropriate structural change studies from small molecule groups with 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 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 earnestly researched to develop a new small molecule-type anti-diarrheal agent exhibiting anti-microbial-specific anti-inflammatory activity, and found that the compound of Formula 1 exhibits MC4R selective anti-inflammatory effect and completed the present invention.

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, 당뇨병 및 성기능 장애에 대한 예방 및 치료에 우수한 효과를 나타낸다.In particular, the compositions according to the invention show excellent effects in the prevention and treatment of obesity, diabetes and sexual dysfunction.

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]

상기식에서,In the above formula,

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

, ,

여기에서,From here,

A는 수소, COR1, CO2R1, SO2R1, SO2NHR1, SO2N(R1)2, PO(OR1)2, C1-8알킬, (CH2)n-아릴 또는 (CH2)n-헤테로아릴을 나타내고, 여기서 R1은 수소, C1-8알킬, (CH2)n-C3-7사이클로알킬, (CH2)n-아릴 또는 (CH2)n-헤테로아릴을 나타내며, n은 1 내지 7의 정수를 나타내며, 알킬, 아릴, 헤테로아릴은 할로겐, C1-5알킬, 트리플루오로메틸, 하이드록시, C1-3알킬옥시, 아미노, (C1-3알킬)아미노, (C1-3알킬)2아미노, 시아노, 카복시 (CO2H), 에스테르 (CO2-C1-3알킬), 아미드 (CONH2)로 이루어진 그룹 중에서 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 1-8 alkyl, (CH 2 ) n − Aryl or (CH 2 ) n -heteroaryl, wherein R 1 is hydrogen, C 1-8 alkyl, (CH 2 ) n -C 3-7 cycloalkyl, (CH 2 ) n -aryl or (CH 2 ) n -heteroaryl, n represents an integer from 1 to 7, alkyl, aryl, heteroaryl represents halogen, C 1-5 alkyl, trifluoromethyl, hydroxy, C 1-3 alkyloxy, amino, ( C 1-3 alkyl) amino, (C 1-3 alkyl) 2 amino, cyano, carboxy (CO 2 H), ester (CO 2 -C 1-3 alkyl), amide (CONH 2 ) Unsubstituted or substituted by 1 to 3 substituents;

B와 E는 각각 독립적으로, 수소, C1-8알킬, (CH2)n-C3-7사이클로알킬, (CH2)n-아릴, (CH2)n-헤테로아릴, (CH2)n-헤테로사이클, (CH2)n-아미노, (CH2)n-(알킬)아미노, (CH2)n-(디알킬)아미노, (CH2)n-아미드(CONH2) 또는 (CH2)n-O(CH2)아릴을 나타내고, 여기에 알킬, 사이클로알킬,아릴, 헤테로아릴, 헤테로사이클은 할로겐, C1-5알킬, 트리플루오로메틸, 하이드록시, C1-3알킬옥시, 아미노, (C1-3알킬)아미노, (C1-3알킬)2아미노, 시아노, 카복시 (CO2H), 에스테르 (CO2-C1-3알킬), 아미드 (CONH2), 아미딘 (C(NH)NH2), 니트로로 이루어진 그룹 중에서 선택된 1개 내지 3개의 치환체에 의해 치환되거나 비치환되고, n은 0 내지 7의 정수를 나타내며;B and E are each independently hydrogen, C 1-8 alkyl, (CH 2 ) n -C 3-7 cycloalkyl, (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, (CH 2 ) n -heterocycle, (CH 2 ) n -amino, (CH 2 ) n- (alkyl) amino, (CH 2 ) n- (dialkyl) amino, (CH 2 ) n -amide (CONH 2 ) or (CH 2 ) n- O (CH 2 ) aryl, wherein alkyl, cycloalkyl , aryl, heteroaryl, heterocycle is halogen, C 1-5 alkyl, trifluoromethyl, hydroxy, C 1-3 alkyloxy , Amino, (C 1-3 alkyl) amino, (C 1-3 alkyl) 2 amino, cyano, carboxy (CO 2 H), ester (CO 2 -C 1-3 alkyl), amide (CONH 2 ), Amidine (C (NH) NH 2 ), substituted or unsubstituted with one to three substituents selected from the group consisting of nitro, n represents an integer from 0 to 7;

C는 할로겐, C1-5알킬, 트리플루오로메틸, 하이드록시, C1-3알킬옥시, 아미노, (C1-3알킬)아미노, (C1-3알킬)2아미노, 시아노, 카복시(CO2H), CO2-C1-3알킬, CONH2, 아미딘(C(NH)NH2), 니트로 및 옥소 (C=O)로 이루어진 그룹 중에서 선택된 치환체(들)에 의해 치환되거나 비치환될 수 있는, (CH2)m-헤테로아릴, (CH2)m-헤테로사이클, (CH2)m-NH-헤테로아릴, (CH2)m-NH-헤테로사이클, (CH2)m-NH-(알킬설포닐), (CH2)m-NH-(아릴설포닐), (CH2)m-NH-알콕시카보닐, (CH2)m-NH-알킬아미노 카바모일, (CH2)m-NH-C(O)-헤테로아릴, (CH2)m-NH-C(O)-헤테로사이클, (CH2)m-NH-(CH2)m-헤테로아릴, (CH2)m-NH-(CH2)m-헤테로사이클, (CH2)m-NH-C(O)-(CH2)m-헤테로아릴, (CH2)m-NH-C(O)-(CH2)m-헤테로사이클, C(O)-헤테로사이클, (CH2)m-NH-알킬에스터, (CH2)m-NH-알킬 아마이드, 알콕시카보닐, (CH2)m-O-(알킬설포닐), (CH2)m-O-(아릴설포닐), 알킬아미노 카바모일, 하이드록시알킬 아미노 카바모일, 아릴아미노 카바모일 또는 수소를 나타내며, 여기서, 헤테로아릴은 고리안에 1- 4개의 N이나 O 또는 S를 함유하고 있는 원자수가 5 혹은 6, 7인 고리 방향족 화합물이고, 헤테로사이클은 고리안에 1-2개의 N, O 또는 S를 갖는 원자수가 5, 6 혹은 7인 고리 화합물이며, m은 0 내지 2의 정수를 나타내고;C is halogen, C 1-5 alkyl, trifluoromethyl, hydroxy, C 1-3 alkyloxy, amino, (C 1-3 alkyl) amino, (C 1-3 alkyl) 2 amino, cyano, carboxy Or substituted by substituent (s) selected from the group consisting of (CO 2 H), CO 2 -C 1-3 alkyl, CONH 2 , amidine (C (NH) NH 2 ), nitro and oxo (C═O) (CH 2 ) m -heteroaryl, (CH 2 ) m -heterocycle, (CH 2 ) m -NH-heteroaryl, (CH 2 ) m -NH-heterocycle, (CH 2 ) m- NH- (alkylsulfonyl), (CH 2 ) m -NH- (arylsulfonyl), (CH 2 ) m -NH-alkoxycarbonyl, (CH 2 ) m -NH-alkylamino carbamoyl, ( CH 2 ) m -NH-C (O) -heteroaryl, (CH 2 ) m -NH-C (O) -heterocycle, (CH 2 ) m -NH- (CH 2 ) m -heteroaryl, (CH 2) m -NH- (CH 2) m - heterocycle, (CH 2) m -NH- C (O) - (CH 2) m - heteroaryl, (CH 2) m -NH- C (O) - (CH 2) m - heterocyclyl, C (O) - heterocyclyl, (CH 2) m -NH- alkyl esters, (CH 2) m -NH- alkyl amide, alkoxy Carbonyl group, a (CH 2) m -O- (alkyl sulfonyl), (CH 2) m -O- (arylsulfonyl) alkylamino carbamoyl, hydroxy alkyl, amino-carbamoyl, aryl-amino-carbamoyl, or hydrogen Wherein heteroaryl is a ring aromatic compound having 5, 6, or 7 atoms containing 1-4 N, O or S in the ring, and heterocycle is 1-2 N, O or S in the ring A ring compound having 5, 6, or 7 atoms, and m represents an integer of 0 to 2;

D는 피페리딘, 피롤리딘, 헥사메틸렌이민, 2 혹은 3 옥소 피페리딘 및 헥사메틸렌이민, 피롤리딘 혹은 디알킬아민 그 자체나 이들의 치환된 유도체를 나타내며;D represents piperidine, pyrrolidine, hexamethyleneimine, 2 or 3 oxo piperidine and hexamethyleneimine, pyrrolidine or dialkylamine itself or substituted derivatives thereof;

Cy는 C1-C5-알킬, 할로겐, 트리플루오로메틸, 하이드록시, C1-C3-알킬옥시, 아미노, (C1-C3-알킬)아미노, 디(C1-C3-알킬)아미노 및 옥소(C=O) 및 니트로로 구성된 그룹 중에서 선택된 치환체(들)에 의해 치환되거나 비치환된, C5-C7-아릴 혹은 C5-7사이클로알킬을 나타낸다.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 5-7 cycloalkyl unsubstituted or substituted by substituent (s) selected from the group consisting of alkyl) amino and oxo (C═O) and nitro.

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

용어 아릴은 페닐, 나프틸 등을 포함하는 방향족 그룹을 의미한다.The term aryl means an aromatic group including phenyl, naphthyl and the like.

용어 헤테로아릴은 산소, 질소 및 황 중에서 선택된 헤테로원자를 함유하는 모노사이클릭 또는 비사이클릭 방향족 그룹을 의미한다. 모노사이클릭 헤테로아릴은 그 예가 티아졸, 옥사졸, 티오펜, 퓨란, 피롤, 이미다졸, 이소옥사졸, 피라졸, 트리아졸, 치아디아졸, 테트라졸, 옥사디아졸, 피리딘, 피디다진, 피리미딘, 피라진과 그와 유사한 그룹이지만 이들로 제한되는 것은 아니다. 비사이클릭 헤테로아릴은 그 예가 인돌, 벤조티오펜, 벤조퓨란, 벤즈이미다졸, 벤즈옥사졸, 벤즈이소옥사졸, 벤조티아졸, 벤즈치아디아졸, 벤즈트리아졸, 퀴놀린, 이소퀴놀린, 퓨린, 퓨로피리딘과 그와 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. Monocyclic heteroaryls include, for example, thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, pyrazole, triazole, chiadiazole, tetrazole, oxadiazole, pyridine, pyidazine, Pyrimidines, pyrazines and similar groups, but not limited to these. Bicyclic heteroaryls include, for example, indole, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzioxazole, benzothiazole, benzithiazole, benztriazole, quinoline, isoquinoline, purine, puro Pyridine and similar groups, but is not limited to these.

용어 헤테로사이클은 산소, 질소 및 황 중에서 선택된 헤테로원자를 함유하는 비방향족 모노사이클릭 또는 비사이클릭 그룹을 의미한다. 그 예는 피페리딘, 모폴린, 치아모폴린, 피롤리딘, 이미다졸리딘, 테트라히드로퓨란, 피페라진과 그와 유사한 그룹을 들 수 있지만 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, chimorpholine, 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, C1-8알킬, (CH2)n-아릴 또는 (CH2)n-헤테로아릴을 나타내며, R1이 수소, C1-8알킬, (CH2)n-아릴 또는 (CH2)n-C3-7사이클로알킬을 나타내고, 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 1-8 alkyl, (CH 2 ) n -aryl or (CH 2 ) n -heteroaryl, R 1 represents hydrogen, C 1-8 alkyl, (CH 2 ) n -aryl or (CH 2 ) n -C 3-7 cycloalkyl, n Represents an integer of 1 to 3, or

ii) B가 할로겐, C1-5알킬, 트리플루오로메틸, 하이드록시, C1-3알킬옥시, 아미노, (C1-3알킬)아미노, (C1-3알킬)2아미노로 이루어진 그룹 중에서 1개 내지 2개의 치환체에 의해 치환되거나 비치환된, 벤질, CH2피리딜, CH2피리미딜 또는 CH2-5환-헤테로아릴을 나타내거나,ii) B is a group consisting of halogen, C 1-5 alkyl, trifluoromethyl, hydroxy, C 1-3 alkyloxy, amino, (C 1-3 alkyl) amino, (C 1-3 alkyl) 2 amino Benzyl, CH 2 pyridyl, CH 2 pyrimidyl or CH 2 -5 ring-heteroaryl unsubstituted or substituted by 1 to 2 substituents in

iii) C가 할로겐, 메틸, 에틸, 메톡시, 에톡시, 하이드록시, 메틸아미노 또는 디메틸아미노에 의해 치환된, (CH2)m-헤테로아릴, (CH2)m-헤테로사이클, (CH2)m-NH-헤테로아릴, (CH2)m-NH-헤테로사이클, (CH2)m-NH-(알킬설포닐), (CH2)m-NH-아릴설포닐, (CH2)m-NH-알콕시카르보닐, (CH2)m-NH-알킬아미노카바모일, (CH2)m-NH-C(O)-헤테로아릴, (CH2)m-NH-C(O)-헤테로사이클, (CH2)m-NH-(CH2)m-헤테로아릴, (CH2)m-NH-(CH2)m-헤테로사이클, (CH2)m-NH-C(O)-(CH2)m-헤테로아릴, (CH2)m-NH-C(O)-(CH2)m-헤테로사이클, C(O)-헤테로사이클, 알콕시카보닐, 하이드록시알킬 아미노 카바모일, (CH2)m-O-(알킬설포닐), (CH2)m-O-(아릴설포닐), 알킬아미노 카바모일, 아릴아미노 카바모일을 나타내거나,iii) a C-substituted by halogen, methyl, ethyl, methoxy, ethoxy, hydroxy, methylamino or dimethylamino, (CH 2) m - heteroaryl, (CH 2) m - heterocycle, (CH 2 ) m -NH-heteroaryl, (CH 2 ) m -NH-heterocycle, (CH 2 ) m -NH- (alkylsulfonyl), (CH 2 ) m -NH-arylsulfonyl, (CH 2 ) m -NH-alkoxycarbonyl, (CH 2 ) m -NH-alkylaminocarbamoyl, (CH 2 ) m -NH-C (O) -heteroaryl, (CH 2 ) m -NH-C (O) -hetero Cycle, (CH 2 ) m -NH- (CH 2 ) m -heteroaryl, (CH 2 ) m -NH- (CH 2 ) m -heterocycle, (CH 2 ) m -NH-C (O)-( CH 2 ) m -heteroaryl, (CH 2 ) m -NH-C (O)-(CH 2 ) m -heterocycle, C (O) -heterocycle, alkoxycarbonyl, hydroxyalkyl amino carbamoyl, ( CH 2 ) m- O- (alkylsulfonyl), (CH 2 ) m- O- (arylsulfonyl), alkylamino carbamoyl, arylamino carbamoyl, or

iv) D는 피페리딘, 피롤리딘, 헥사메틸렌이민, 디알킬아민 그 자체 혹은 치환된 유도체를 나타내거나,iv) D represents piperidine, pyrrolidine, hexamethyleneimine, dialkylamine itself or substituted derivatives, or

v) E가 할로겐, 메틸, 에틸, 트리플루오로메틸, 하이드록시, 메톡시, 에톡시, 아미노, 메틸아미노, 디메틸아미노로 이루어진 그룹 중에서 선택된 1 내지 3개의 치환체에 의해 치환되거나 비치환된, C1-8알킬, (CH2)n-헤테로아릴, (CH2)n-헤테로사이클, (CH2)n-(알킬)아미노, (CH2)n-(디알킬)아미노 또는 (CH2)n-아미드(CONH2)를 나타내거나,v) C, wherein E is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino 1-8 alkyl, (CH 2 ) n -heteroaryl, (CH 2 ) n -heterocycle, (CH 2 ) n- (alkyl) amino, (CH 2 ) n- (dialkyl) amino or (CH 2 ) n -amide (CONH 2 ), or

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

특히 바람직한 화학식 1의 화합물은 B가 할로겐, C1-3알킬, 트리플루오로메틸, 메톡시, 에톡시, 메틸아미노, 디메틸아미노로 이루어진 그룹 중에서 선택된 1 내지 2개의 치환체에 의해 치환되거나 비치환된 벤질 또는 피리딜을 나타내고; C가 할로겐, 메틸, 에틸, 메톡시, 에톡시, 하이드록시, 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, CH2-NH-C(O)-이미다졸, CH2-NH-C(O)-트리아졸, CH2-NH-C(O)-테트라졸, CH2-NH-C(O)-티아졸, CH2-NH-CH2-이미다졸, CH2-NH-CH2-트리아졸, CH2-NH-CH2-테트라졸, CH2-NH-CH2-티아졸, CH2-NH-CH2-이미다졸론, CH2-NH-CH2-옥사졸론, CH2-NH-CH2-다이아졸론, CH2-NH-알킬설포닐, CH2-NH-아릴설포닐, C(O)-피페리딘, C(O)-피페라진, CH2-NH-에스테르, 알콕시카보닐, 하이드록시알킬 아미노 카바모일, 알킬 혹은 아릴 아미노 카바모일, (CH2)m-O-(알킬설포닐), (CH2)m-O-(아릴설포닐)을 나타내고, ; D가 디알킬아민, 피페리딘, 피롤리딘, 헥사메틸렌이민과 그의 유도체를 나타내고; E가 할로겐, 메틸, 에틸, 트리플루오로메틸, 하이드록시, 메톡시, 에톡시, 아미노, 메틸아미노, 아미드 또는 디메틸아미노에 의해 치환된 C1-8알킬, (CH2)n-헤테로아릴, (CH2)n-헤테로사이클, (CH2)n-(알킬)아미노, (CH2)n-(디알킬)아미노 또는 (CH2)n-아미드(CONH2) (여기서, n은 0내지 2의 정수임)을 나타내고; Cy는 페닐 혹은 사이클로헥실을 나타낸다.Particularly preferred compounds of formula 1 are those wherein B is unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of halogen, C 1-3 alkyl, trifluoromethyl, methoxy, ethoxy, methylamino, dimethylamino Benzyl or pyridyl; CH 2 -pyrrole, CH 2 -imidazole, CH 2 -pyrazole, CH 2 -thiazole, wherein C is substituted by halogen, methyl, ethyl, methoxy, ethoxy, hydroxy, methylamino or dimethylamino, CH 2 -oxazole, CH 2 -triazole, CH 2 -tetrazole, CH 2 -pyridine, CH 2 -pyrimidine, CH 2 -pyrazine, CH 2 -NH-C (O) -imidazole, CH 2- NH-C (O) -triazole, CH 2 -NH-C (O) -tetrazole, CH 2 -NH-C (O) -thiazole, CH 2 -NH-CH 2 -imidazole, CH 2- NH-CH 2 -triazole, CH 2 -NH-CH 2 -tetrazole, CH 2 -NH-CH 2 -thiazole, CH 2 -NH-CH 2 -imidazolone, CH 2 -NH-CH 2- oxazolone, CH 2 -NH-CH 2 - diamond isothiazolone, CH 2 -NH- alkylsulfonyl, CH 2 -NH- arylsulfonyl, C (O) - piperidine, C (O) - piperazine, CH 2 -NH-ester, alkoxycarbonyl, hydroxyalkyl amino carbamoyl, alkyl or aryl amino carbamoyl, (CH 2 ) m -O- (alkylsulfonyl), (CH 2 ) m -O- (arylsulfonyl ),; D represents dialkylamine, piperidine, pyrrolidine, hexamethyleneimine and its derivatives; C 1-8 alkyl wherein E is substituted by halogen, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, amino, methylamino, amide or dimethylamino, (CH 2 ) n -heteroaryl, (CH 2 ) n -heterocycle, (CH 2 ) n- (alkyl) amino, (CH 2 ) n- (dialkyl) amino or (CH 2 ) n -amide (CONH 2 ), where n is 0 to An integer of 2); Cy represents phenyl or cyclohexyl.

G 가인 경우 본 발명에 따른 화학식 1의 대표적인 화합물에는 다음과 같은 화합물을 들 수 있다.G In the case of the representative compounds of the formula (1) according to the present invention include the following compounds.

G 가인 경우 본 발명에 따른 화학식 1의 대표적인 화합물에는 다음과 같은 화합물을 들 수 있다.G In the case of the representative compounds of the formula (1) according to the present invention include the following compounds.

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 B-아미노산 화합물을 하기 화학식 3의 화합물과 반응시키고 가수분해시켜 하기 화학식 4의 디펩티드 화합물을 형성하고, 화학식 4의 화합물을 하기 화학식 5의 피페리딘 유도체와 아미드-커플링반응시키고 탈보호화하여 하기 화학식 1a의 화합물을 제조하거나,(a) reacting and hydrolyzing a B-amino acid compound of formula (2) having a protecting group P introduced at the N-terminus with a compound of formula (3) to form a dipeptide compound of formula (4), wherein the compound of formula (4) is Amide-coupling and deprotection with a piperidine derivative of 5 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 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 in which A group is introduced 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,

화학식 1b 및 1d에서의 A는 앞에서 정의된 바와 동일하나, 단 수소는 제외되며,In Formulas 1b and 1d, A is the same as defined above, except for 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 요약하여 나타내었다.Methods (a) to (f) according to the invention are shown in summary in Schemes 1 to 4, respectively.

상기 방법 (a) 내지 (f)에서 각 단계의 반응은 바람직하게는 반응에 악영향을 끼치지 않는 통상적인 용매 중에서 수행될 수 있으며, 특히 바람직하게는 디메틸포름아미드, 디메틸아세트아미드, 테트라히드로푸란, 메틸렌클로라이드, 클로로포름 중에서 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 강산의 존재하에 수행하거나, 트리에틸아민, 디이소프로필에틸아민 (DIPEA) 등과 같은 아민 염기의 존재하에 수행하거나, 수소첨가반응을 사용하여 수행할 수 있다. 구체적인 반응조건은 문헌 (T.W. Green & G.M. Wuts Protective Groups in Organic Synthesis, Chapter 7, pp 309-405)에 기재된 내용을 참조할 수있다.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) and the like, or in the presence of an amine base such as triethylamine, diisopropylethylamine (DIPEA) or the like. And hydrogenation. Specific reaction conditions may be referred to those described in T.W. Green & G. M. Wuts Protective Groups in Organic Synthesis, Chapter 7, pp 309-405.

또한, 상기 반응식 1 내지 4의 커플링 반응에 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) 와 혼합된 상태로 사용하거나, 또는 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 것이 아니다.In addition, known coupling agents that may be used in the coupling reactions of Schemes 1 to 4 include dicyclohexylcarbodiimide (DCC) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC). , Carbodiimides such as 1,1'-dicarbonyldiimidazole (CDI) and mixed with 1-hydroxybenzotriazole (HOBT) or 1-hydroxy-7-azabenzotriazole (HOAT) Or bis- (2-oxo-3-oxazolidinyl) -phosphonic acid chloride (BOP-Cl), diphenylphosphoryl azide (DPPA), N- [dimethylamino-1H-1,2,3 -Triazole [4,5-b] pyridin-1-ylmethylene] -N-methylmethane aluminum (HATU) and the like can be used, but are 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.

본 발명의 화합물은 멜라노코틴 수용체에 대하여 우수한 항진작용을 나타내므로 본 발명은 또한, 약제학적으로 허용되는 담체와 함께 유효성분으로서 화학식 1의 화합물 또는 약제학적으로 허용되는 그의 염을 함유함을 특징으로 하는 멜라노코틴 수용체의 기능항진제 조성물을 제공한다. 특히, 본 발명에 따른 조성물은 비만, 당뇨 및 성기능 장애에 대한 예방 및 치료에 우수한 효과를 나타내나 이들 질병에만 제한되는 것은 아니다.Since the compound of the present invention exhibits excellent anticancer action against the melanocortin receptor, the present invention is also characterized by containing a compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier. It provides an anti-functional composition of the melanocortin receptor. In particular, the compositions according to the invention show excellent effects in the prevention and treatment of obesity, diabetes and sexual dysfunction, but are not limited to these diseases.

본 발명의 화합물을 임상적인 목적으로 투여시에 단일용량 또는 분리용량으로 숙주에게 투여될 총 일일용량은 체중 1㎏ 당 0.01 ㎎ 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, but the specific dose level for each patient 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 바람직 하나, 피부, 복강, 후강 및 직장을 경로하여 투여할 수 있다.The compounds of the present invention can be administered by any route as desired. Injection, oral and nasal administration are preferred, but can be administered by route of 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 하기 실시예에서 화합물의 명칭에 사용되는 약어와 용어의 설명은 다음과 같다.Explanation of the abbreviations and terms used in the names of the compounds in the above reaction schemes, the following preparation examples and examples are as follows.

EDC: 1-(3-디메틸아미노프로필)-3-에틸카보디이미드.염산염EDC: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide. Hydrochloride

HOBT: 하이드록시벤조트리아졸HOBT: hydroxybenzotriazole

Boc: t-부틸옥시카보닐Boc: t-butyloxycarbonyl

Ac: 아세틸Ac: Acetyl

Bn: 벤질Bn: Benzyl

DMF: 디메틸포름아미드DMF: Dimethylformamide

Cbz: 카보벤질옥시Cbz: carbobenzyloxy

THF: 테트라히드로퓨란THF: tetrahydrofuran

TFA: 트리플루오로아세트산TFA: trifluoroacetic acid

EtOAc: 에틸아세테이트EtOAc: ethyl acetate

DEAD: 디에틸아조디카복실레이트DEAD: diethylazodicarboxylate

MgSO4: 마그네슘설페이트MgSO 4 : magnesium sulfate

Et3N: 트리에틸아민Et 3 N: triethylamine

NH4Cl: 암모늄클로리드NH 4 Cl: ammonium chloride

CH3CN: 아세토니트릴CH 3 CN: acetonitrile

하기 제조예는 본 발명 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 inventive compound of the invention.

제조예 1 : N-Boc-4,4-(피페리딜, 메톡시카보닐)피페리딘Preparation Example 1 N-Boc-4,4- (piperidyl, methoxycarbonyl) piperidine

단계 A : N-Boc-4,4-(아미노, 메톡시카보닐)피페리딘Step A: N-Boc-4,4- (amino, methoxycarbonyl) piperidine

상업적으로 구입할 수 있는 N-Boc-4,4 아미노, 메틸카복실산을 디클로로메탄(2441.4 mg, 10 mmol)에 녹이고 다이아조메탄을 0oC에서 천천히 적가한다. 반응이 종결한 용액을 여과하고 감압 농축하여 표제의 화합물 (2530 mg, 98 %)을 수득하였다.Commercially available N-Boc-4,4 amino, methylcarboxylic acid is dissolved in dichloromethane (2441.4 mg, 10 mmol) and diazomethane is slowly added dropwise at 0 ° C. The reaction solution was filtered and concentrated under reduced pressure to give the title compound (2530 mg, 98%).

MS[M+H] = 259MS [M + H] = 259

단계 B : N-Boc-4,4-(피페리딜, 메톡시카보닐)피페리딘Step B: N-Boc-4,4- (piperidyl, methoxycarbonyl) piperidine

단계 A에서 얻은 N-Boc-4,4-(아미노, 메톡시카보닐)피페리딘(258.2 mg, 1 mmol)를 DMF (5 ml) 용매에 녹이고 그루타알데하이드(100.0 mg, 1 mmol)를 넣고, 나트륨트리아세톡시보로하이드라이드 (345 mg, 1.5 mmol)를 적가한 후 상온에서 2시간 동안 교반하였다. 반응이 끝난 용액을 무수 MgSO4로 건조시킨 후 여과하여 감압 농축하였다. 수득된 잔유물을 관 크로마토그라피 (용리액, MC/아세톤 = 2/3)로 정제하여 표제의 화합물을 수득하였다 (290.3 mg, 89 %).The N-Boc-4,4- (amino, methoxycarbonyl) piperidine (258.2 mg, 1 mmol) obtained in step A was dissolved in DMF (5 ml) solvent and glutaaldehyde (100.0 mg, 1 mmol) was added. Sodium triacetoxyborohydride (345 mg, 1.5 mmol) was added dropwise and stirred at room temperature for 2 hours. The reaction solution was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent, MC / acetone = 2/3) to give the title compound (290.3 mg, 89%).

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

제조예 2 : N-Boc-4,4-[(N,N-디메틸)아미노, 메톡시카보닐]-피페리딘Preparation Example 2 N-Boc-4,4-[(N, N-dimethyl) amino, methoxycarbonyl] -piperidine

제조예 1의 단계 A에서 얻은 N-Boc-4,4-(아미노, 메톡시카보닐)피페리딘 (258.2 mg, 1 mmol) 를 DMF (5 ml)에 녹이고 포르말린 을 넣고, 나트륨트리아세톡시보로하이드라이드 (345 mg, 1.5 mmol)를 적가한 후 상온에서 2시간 동안 교반하였다. 반응이 끝난 용액을 무수 MgSO4로 건조시킨 후 여과하여 감압 농축하였다. 수득된 잔유물을 관 크로마토그라피 (용리액, MC/아세톤 = 2/3)로 정제하여 표제의 화합물 (277.6 mg, 97 %)을 수득하였다.N-Boc-4,4- (amino, methoxycarbonyl) piperidine (258.2 mg, 1 mmol) obtained in step A of Preparation Example 1 was dissolved in DMF (5 ml), and formalin was added thereto, followed by sodium triacetoxybo. Lohydride (345 mg, 1.5 mmol) was added dropwise and stirred at room temperature for 2 hours. The reaction solution was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent, MC / acetone = 2/3) to afford the title compound (277.6 mg, 97%).

MS[M+H] = 287MS [M + H] = 287

제조예 3 : N-Boc-4,4-[피롤리딜, 메톡시카보닐]-피페리딘Preparation Example 3 N-Boc-4,4- [pyrrolidyl, methoxycarbonyl] -piperidine

제조예 1의 단계 A에서 얻은 N-Boc-4,4-(아미노, 메톡시카보닐)피페리딘 (258.2 mg, 1 mmol)를 DMF (5 ml)에 녹이고 트리에틸아민 (280 ml, 2 mmol)을 넣은 후, 디브로모부탄 (320.9 mg, 1.5 mmol)을 적가하여 70oC에서 12시간 교반시켰다. 반응이 종결된 용액을 EtOAc로 희석시키고 탄산수소나트륨과 HCl로 차례로 씻고 무수 MgSO4로 건조시킨 후 여과하여 감압 농축하였다. 수득된 잔유물을 관 크로마토그라피 (용리액, MC/아세톤 = 2/3)로 정제하여 표제의 화합물 (237.3 mg, 76 %)을 수득하였다.N-Boc-4,4- (amino, methoxycarbonyl) piperidine (258.2 mg, 1 mmol) obtained in step A of Preparation Example 1 was dissolved in DMF (5 ml) and triethylamine (280 ml, 2 mmol), and dibromobutane (320.9 mg, 1.5 mmol) was added dropwise and stirred at 70 ° C. for 12 hours. The reaction solution was diluted with EtOAc, washed successively with sodium bicarbonate and HCl, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent, MC / acetone = 2/3) to give the title compound (237.3 mg, 76%).

MS[M+H] = 313MS [M + H] = 313

제조예 4 : N-Boc-4,4-(헥사메틸렌 이민일, 메톡시카보닐)페페리딘Preparation Example 4 N-Boc-4,4- (hexamethylene iminyl, methoxycarbonyl) ferridine

제조예 1의 단계 A에서 얻은 N-Boc-4,4-(아미노, 메톡시카보닐) (258.2 mg, 1 mmol)와 디브로모헥산 (241.9 mg, 1 mmol)을 이용하여 제조예 3과 같은 방법으로 표제의 화합물 (241.6 mg, 71 %)을 수득하였다.Preparation Example 3 using N-Boc-4,4- (amino, methoxycarbonyl) (258.2 mg, 1 mmol) and dibromohexane (241.9 mg, 1 mmol) obtained in step A of Preparation Example 1 In the same manner the title compound (241.6 mg, 71%) was obtained.

MS[M+H] = 341MS [M + H] = 341

제조예 5 : N-Boc-4,4-[피페리딘1-일, (메탄술페이티딜)메틸]피페리딘Preparation Example 5 N-Boc-4,4- [piperidin1-yl, (methanesulfatidyl) methyl] piperidine

단계 A : N-Boc-4,4-[(5-브로모펜타노익)아마이드, 메톡시카보닐]피페리딘Step A: N-Boc-4,4-[(5-bromopentanoic) amide, methoxycarbonyl] piperidine

제조예 1의 단계 A와 같은 방법으로 얻은 N-Boc-4,4-(아미노, 메틸카복실릴)피페리딘 (5164 mg, 20 mmol)를 디클로로메탄 (40 ml)에 녹이고 트리에틸아민 (2800 ml)으로 용액을 염기화시켰다. 디클로로메탄에 녹인 5-브로모발레익산 (3600 mg, 20mmol)과 EDC (5073 mg, 26 mmol), HoBt (4053 mg, 30 mmol)를 차례로 넣고 상온에서 12시간 반응시켰다. 반응이 종결된 용액을 EtOAc로 희석시키고 탄산수소나트륨과 HCl로 차례로 씻고 무수 MgSO4로 건조시킨 후 여과하여 감압 농축하였다. 수득된 잔유물을 관 크로마토그라피 (용리액, EtOAc/n-헥산 = 3/2)로 정제하여 표제의 화합물 (7982 mg, 95 %)을 수득하였다.N-Boc-4,4- (amino, methylcarboxylyl) piperidine (5164 mg, 20 mmol) obtained in the same manner as in Step A of Preparation Example 1 was dissolved in dichloromethane (40 ml) and triethylamine (2800 ml) and the solution was basified. 5-Bromovaleic acid (3600 mg, 20 mmol) dissolved in dichloromethane, EDC (5073 mg, 26 mmol), and HoBt (4053 mg, 30 mmol) were added sequentially, followed by reaction at room temperature for 12 hours. The reaction solution was diluted with EtOAc, washed successively with sodium bicarbonate and HCl, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography (eluent, EtOAc / n-hexane = 3/2) to afford the title compound (7982 mg, 95%).

MS[M+H] = 422MS [M + H] = 422

단계 B : N-Boc-4,4-[(2-피페리디논-1-일), 메틸카복실릴]피페리딘Step B: N-Boc-4,4-[(2-piperidinone-1-yl), methylcarboxylyl] piperidine

가지달린 둥근플라스크에 NaH (520 mg, 13 mmol, 60 %)를 넣고 질소치환을 한 후 THF (40 ml)를 넣고 단계 A에서 얻은 N-Boc-4,4-[(5-브로모펜타노익)아마이드, 메틸카복실릴]피페리딘 (4201 mg, 10 mmol)을 무수 THF (5 ml) 에 녹여 0oC에서 천천히 적가하였다. 30분 뒤 상온으로 올린 뒤 2시간을 더 교반시켰다. 반응이 종결된 용액에 증류수를 소량 넣고 10분 정도 교반시킨 후 무수 MgSO4로 건조시키고여과하였다. 남은 유기 용액을 감압 농축하고 잔유물을 관 크로마토그라피 (용리액, EtOAc/n-헥산 = 1/4)로 정제하여 표제의 화합물 (3062 mg, 90 %)을 수득하였다.NaH (520 mg, 13 mmol, 60%) was added to a round flask equipped with nitrogen, and nitrogen-substituted, THF (40 ml) was added, and N-Boc-4,4-[(5-bromopentanoic obtained in step A) was added. ) Amide, methylcarboxyl] piperidine (4201 mg, 10 mmol) was dissolved in anhydrous THF (5 ml) and slowly added dropwise at 0 ° C. After 30 minutes, the temperature was raised to room temperature, followed by further stirring for 2 hours. After the reaction was completed, a small amount of distilled water was added thereto, stirred for about 10 minutes, dried over anhydrous MgSO 4 , and filtered. The remaining organic solution was concentrated under reduced pressure and the residue was purified by column chromatography (eluent, EtOAc / n-hexane = 1/4) to afford the title compound (3062 mg, 90%).

MS[M+H] = 341MS [M + H] = 341

단계 C : N-Boc-4,4-[(피페리딘-2-온-1-일), 하이드록시메틸]피페리딘Step C: N-Boc-4,4-[(piperidin-2-one-1-yl), hydroxymethyl] piperidine

단계 B에서 얻은 N-Boc-4,4-[(2-피페리디논-1-일), 메틸카복실릴]피페리딘 (1000 mg, 3.0 mmol)를 메탄올 (10 ml)에 녹이고 나트륨보로하이드라이드 (345 mg, 9 mmol)와 LiCl을 넣고 상온에서 24시간 교반하였다. 반응이 종결된 용액을 감압 농축하고 EtOAc로 희석시킨 후 물로 씻어 준 다음 무수 MgSO4로 건조시키고 여과하였다. 남은 유기 용액을 감압 농축하고 잔유물을 관 크로마토그라피 (용리액, EtOAc/n-헥산 = 4/1)로 정제하여 표제의 화합물 (759 mg, 81 %)을 수득하였다.N-Boc-4,4-[(2-piperidinone-1-yl), methylcarboxylyl] piperidine (1000 mg, 3.0 mmol) obtained in step B was dissolved in methanol (10 ml) and sodium borohydride. Hydride (345 mg, 9 mmol) and LiCl were added and stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, diluted with EtOAc, washed with water, dried over anhydrous MgSO 4 , and filtered. The remaining organic solution was concentrated under reduced pressure and the residue was purified by column chromatography (eluent, EtOAc / n-hexane = 4/1) to afford the title compound (759 mg, 81%).

MS[M+H] = 313MS [M + H] = 313

단계 D : N-Boc-4,4-[피페리딘-2-온-1-일, (메탄술페이티딜)메틸]피페리딘Step D: N-Boc-4,4- [piperidin-2-one-1-yl, (methanesulfatidyl) methyl] piperidine

단계 C에서 얻은 N-Boc-4,4-[(2-피페리디논-1-일), 하이드록시메틸]피페리딘 (500 mg, 1.6 mmol)를 디클로로메탄 (6 ml)에 녹이고 트리에틸아민 (450 ml, 3.2 mmol)으로 염기화시킨 후 메탄설포닐클로라이드 (220 mg, 1.9 mmol)를 천천히 적가하여 상온에서 4시간 동안 교반하였다. 반응이 종결된 용액을 디클로로메탄으로 희석시킨 후 HCl 수용액으로 씻어 준 다음 무수 MgSO4로 건조시키고 여과하여 감압 농축하였다. 잔유물을 관 크로마토그라피 (용리액, EtOAc/n-헥산 = 3/2)로 정제하여 표제의 화합물 (612 mg, 98 %)을 수득하였다.N-Boc-4,4-[(2-piperidinone-1-yl), hydroxymethyl] piperidine (500 mg, 1.6 mmol) obtained in step C was dissolved in dichloromethane (6 ml) and triethyl After basifying with amine (450 ml, 3.2 mmol), methanesulfonylchloride (220 mg, 1.9 mmol) was slowly added dropwise and stirred at room temperature for 4 hours. The reaction solution was diluted with dichloromethane, washed with HCl aqueous solution, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc / n-hexane = 3/2) to afford the title compound (612 mg, 98%).

MS[M+H] = 391MS [M + H] = 391

단계 E : N-Boc-4,4-[피페리딘-1-일, (메탄술페이티딜)메틸]피페리딘Step E: N-Boc-4,4- [piperidin-1-yl, (methanesulfatidyl) methyl] piperidine

단계 D에서 얻은 N-Boc-4,4-[피페리딘-2-온-1-일, (메탄술페이티딜)메틸]피페리딘 (100 mg, 0.26 mmol)을 무수 THF (10 ml)에 넣고 LAH (36.4 mg, 1.04 mmol)을 적가하여 상온에서 4시간 동안 교반하였다. 반응이 종결된 용액에 증류수를 넣고 2시간 동안 교반하였다. 흰색 침전이 충분히 생기면 EtOA로 추출하고 무수 MgSO4로 건조시키고 여과하여 감압 농축하였다. 잔유물을 관 크로마토그라피 (용리액, EtOAc/n-헥산 = 3/2)로 정제하여 표제의 화합물 (65.5 mg, 67 %)을 수득하였다.N-Boc-4,4- [piperidin-2-one-1-yl, (methanesulfatidyl) methyl] piperidine (100 mg, 0.26 mmol) obtained in step D was dried with anhydrous THF (10 ml). LAH (36.4 mg, 1.04 mmol) was added dropwise and stirred at room temperature for 4 hours. Distilled water was added to the solution terminated and stirred for 2 hours. When sufficient white precipitate formed, the mixture was extracted with EtOA, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc / n-hexane = 3/2) to afford the title compound (65.5 mg, 67%).

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

제조예 6 : N-Boc-4,4-[피페리딘1-일, (이소프로필술페이티딜)메틸]피페리딘Preparation Example 6 N-Boc-4,4- [piperidin1-yl, (isopropylsulfatidyl) methyl] piperidine

제조예 5의 단계 C와 같이 얻을 수 있는 N-Boc-4,4-[(피페리딘-2-온-1-일), 하이드록시메틸]피페리딘 (100 mg, 0.32 mmol)와 이소프로필설포닐클로라이드(54.8 mg, 0.38 mmol)를 이용하여 제조예 5의 단계 D, E와 같은 방법으로 표제 화합물 (89.2 mg, 69 %)을 얻었다.N-Boc-4,4-[(piperidin-2-one-1-yl), hydroxymethyl] piperidine (100 mg, 0.32 mmol) and isoform obtained as in Step C of Preparation Example 5 Propylsulfonylchloride (54.8 mg, 0.38 mmol) was used to obtain the title compound (89.2 mg, 69%) in the same manner as in Steps D and E of Preparation Example 5.

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

제조예 7 : N-Boc-4,4-[피페리딘 1-일, (벤젠술페이티딜)메틸]피페리딘Preparation Example 7 N-Boc-4,4- [piperidin 1-yl, (benzenesulfatidyl) methyl] piperidine

제조예 5의 단계 C에서 얻은 N-Boc-4,4-[(피페리디딘-2-온-1-일), 하이드록시메틸]피페리딘 (100 mg, 0.32 mmol)와 벤젠설포닐클로라이드 (67.8 mg, 0.38 mmol)를 이용하여 제조예 5의 단계 D, E와 같은 방법으로 표제 화합물 (88.34 mg, 63 %)을 얻었다.N-Boc-4,4-[(piperidinin-2-one-1-yl), hydroxymethyl] piperidine (100 mg, 0.32 mmol) and benzenesulfonylchloride obtained in step C of Preparation Example 5 (67.8 mg, 0.38 mmol) was used to give the title compound (88.34 mg, 63%) in the same manner as in Steps D and E of Preparation Example 5.

MS[M+H] = 439MS [M + H] = 439

제조예 8 : N-Boc-4,4-[피페리딘-1-일, (피페리딘-1-일)카보닐] 피페리딘Preparation Example 8 N-Boc-4,4- [piperidin-1-yl, (piperidin-1-yl) carbonyl] piperidine

제조예 1에서 얻은 N-Boc-4,4-(피페리딘-1-일, 메톡시카보닐)피페리딘 (100 mg, 0.31 mmol)을 DMF (10 ml)에 녹이고 피페리딘 (52.8 mg, 0.62 mmol)을 적가하여 100oC에서 24시간 교반하였다. 반응이 종결된 용액을 EtOAc로 희석시키고 탄산수소나트륨과 HCl 수용액으로 차례로 씻은 다음 무수 MgSO4로 건조시키고 여과하여 감압 농축하였다. 잔유물을 관 크로마토그라피 (용리액, EtOAc/n-헥산 = 1/1)로 정제하여 표제의 화합물 (95.1 mg, 78 %)을 수득하였다.N-Boc-4,4- (piperidin-1-yl, methoxycarbonyl) piperidine (100 mg, 0.31 mmol) obtained in Preparation Example 1 was dissolved in DMF (10 ml) and piperidine (52.8 mg, 0.62 mmol) was added dropwise and stirred at 100 ° C. for 24 hours. The reaction solution was diluted with EtOAc, washed sequentially with sodium bicarbonate and HCl aqueous solution, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc / n-hexane = 1/1) to afford the title compound (95.1 mg, 78%).

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

제조예 9 : N-Boc-4,4-[피페리딘-1-일, (1,2,4-트리아졸-1-일)메틸]피페리딘Preparation Example 9 N-Boc-4,4- [piperidin-1-yl, (1,2,4-triazol-1-yl) methyl] piperidine

제조예 5의 단계 E와 같은 방법으로 얻은 N-Boc-4,4-[피페리딘-1-일, (메탄술페이티딜)메틸]피페리딘 (390.50 mg, 1 mmol)을 DMF (5 ml)에 녹이고 나트륨으로 치환된 1,2,4-트리아졸 (136.6 mg, 1.5 mmol)을 적가한 다음 100oC에서 24시간 교반하였다. 반응이 종결된 용액을 EtOAc로 희석시키고 탄산수소나트륨과 HCl 수용액으로 차례로 씻은 다음 무수 MgSO4로 건조시키고 여과하여 감압 농축하였다. 잔유물을 관 크로마토그라피 (용리액, EtOAc/n-헥산 = 3/2)로 정제하여 표제의 화합물 (307.3 mg, 88 %) 을 수득하였다.N-Boc-4,4- [piperidin-1-yl, (methanesulfatidyl) methyl] piperidine (390.50 mg, 1 mmol) obtained in the same manner as in Step E of Preparation Example 5 was dissolved in DMF (5 ml, and 1,2,4-triazole (136.6 mg, 1.5 mmol) substituted with sodium were added dropwise and stirred at 100 ° C. for 24 hours. The reaction solution was diluted with EtOAc, washed sequentially with sodium bicarbonate and HCl aqueous solution, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc / n-hexane = 3/2) to afford the title compound (307.3 mg, 88%).

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

제조예 10 : N-Boc-4,4-[피페리딘-1-일, (1,2,3-트리아졸-1-일)메틸]피페리딘Preparation Example 10 N-Boc-4,4- [piperidin-1-yl, (1,2,3-triazol-1-yl) methyl] piperidine

제조예 5의 단계 E와 같은 방법으로 얻은 N-Boc-4,4-[피페리딘-1-일, (메탄술페이티딜)메틸]피페리딘 (390.50 mg, 1 mmol)과 나트륨이소펜톡사이드 (165.2 mg, 1.5 mmol)와 1,2,3-트리아졸 (207.2mg, 3 mmol)를 이용하여 제조예 9와 같은 방법으로 표제의 화합물 (288.7 mg, 83 %)을 수득하였다.N-Boc-4,4- [piperidin-1-yl, (methanesulfatidyl) methyl] piperidine (390.50 mg, 1 mmol) and sodium isopentoke obtained by the same method as in Step E of Preparation Example 5 The title compound (288.7 mg, 83%) was obtained by the same method as Preparation Example 9 using side (165.2 mg, 1.5 mmol) and 1,2,3-triazole (207.2 mg, 3 mmol).

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

제조예 11 : N-Boc-4,4-[피페리딘-1-일, (테트라졸-1-일)메틸]피페리딘Preparation Example 11 N-Boc-4,4- [piperidin-1-yl, (tetrazol-1-yl) methyl] piperidine

단계 A : N-Boc-4,4-[피페리딘-1-일, 하이드록시메틸]피페리딘Step A: N-Boc-4,4- [piperidin-1-yl, hydroxymethyl] piperidine

제조예 5의 단계 C와 같은 방법으로 얻은 N-Boc-4,4-[피페리딘-2-온-1-일, 하이드록시메틸]피페리딘 (312.4 mg, 1 mmol)을 이용하여 제조예 5의 단계 E와 같은 방법으로 표제의 화합물 (259.4 mg, 87 %)을 수득하였다.Prepared using N-Boc-4,4- [piperidin-2-one-1-yl, hydroxymethyl] piperidine (312.4 mg, 1 mmol) obtained in the same manner as in Step C of Preparation Example 5. In the same manner as in Step E of Example 5, the title compound (259.4 mg, 87%) was obtained.

MS[M+H] = 299MS [M + H] = 299

단계 B : N-Boc-4,4-[피페리딘-1-일, (테트라졸-1-일)메틸]피페리딘Step B: N-Boc-4,4- [piperidin-1-yl, (tetrazol-1-yl) methyl] piperidine

단계 A에서 얻은 N-Boc-4,4-[피페리딘-1-일, 하이드록시메틸]피페리딘 (200 mg, 0.67 mmol)을 무수 THF (5 ml)에 녹이고 트리페닐포스핀 (261.1 mg, 1 mmol)과 테트라졸, DEAD를 차례로 적가한 다음 상온에서 4시간동안 교반하였다. 반응이 종결된 용액을 감압 농축하고 잔유물을 관 크로마토그라피 (용리액, EtOAc/n-헥산 = 1/1)로 정제하여 표제의 화합물 (192.4 mg, 82 %)을 수득하였다.N-Boc-4,4- [piperidin-1-yl, hydroxymethyl] piperidine (200 mg, 0.67 mmol) obtained in step A was dissolved in dry THF (5 ml) and triphenylphosphine (261.1) mg, 1 mmol), tetrazole and DEAD were added dropwise, followed by stirring at room temperature for 4 hours. The solution was terminated under reduced pressure and the residue was purified by column chromatography (eluent, EtOAc / n-hexane = 1/1) to afford the title compound (192.4 mg, 82%).

MS[M+H] = 351MS [M + H] = 351

제조예 12 : N-Boc-4,4-[피페리딘-1-일, (1-메틸-테트라졸-5-일)] 피페리딘Preparation Example 12 N-Boc-4,4- [piperidin-1-yl, (1-methyl-tetrazol-5-yl)] piperidine

단계 A : N-Boc-4,4-(피페리딘-1-일, 사이아노메틸)피페리딘Step A: N-Boc-4,4- (piperidin-1-yl, cyanomethyl) piperidine

제조예 5의 단계 E와 같은 방법으로 얻은 N-Boc-4,4-[피페리딘-1-일, (메탄술페이티딜)메틸]피페리딘 (376.2 mg, 1 mmol)을 DMF (5 ml)에 녹이고 나트륨사이아나이드 (148.5 mg, 3 mmol)를 적가한 다음 100oC에서 24시간 교반하였다. 반응이 종결된 용액을 EtOAc로 희석시키고 탄산수소나트륨과 HCl 수용액으로 차례로 씻은 다음 무수 MgSO4로 건조시키고 여과하여 감압 농축하였다. 잔유물을 관 크로마토그라피 (용리액, EtOAc/n-헥산 = 1/4)로 정제하여 표제의 화합물 (282.7 mg, 92 %)을 수득하였다.N-Boc-4,4- [piperidin-1-yl, (methanesulfatidyl) methyl] piperidine (376.2 mg, 1 mmol) obtained in the same manner as in Step E of Preparation Example 5 was dissolved in DMF (5 ml) and sodium cyanide (148.5 mg, 3 mmol) were added dropwise and stirred at 100 ° C. for 24 hours. The reaction solution was diluted with EtOAc, washed sequentially with sodium bicarbonate and HCl aqueous solution, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc / n-hexane = 1/4) to afford the title compound (282.7 mg, 92%).

MS[M+H] = 308MS [M + H] = 308

단계 B : N-Boc-4,4-[피페리딘-1-일, (테트라졸-5-일)메틸]피페리딘Step B: N-Boc-4,4- [piperidin-1-yl, (tetrazol-5-yl) methyl] piperidine

단계 A에서 얻은 N-Boc-4,4-(피페리딘-1-일, 사이아노메틸)피페리딘 (250 mg, 0.81 mmol)을 DMF (5 ml)에 녹이고 나트륨아자이드 (265.3 mg, 4.1 mmol)와 암모니움클로라이드를 넣고 90oC에서 24시간 교반하였다. 반응이 종결된 용액을 EtOAc로 희석시키고 탄산수소나트륨과 HCl 수용액으로 차례로 씻은 다음 무수 MgSO4로 건조시키고 여과하여 감압 농축하였다. 잔유물을 관 크로마토그라피 (용리액, MC/MeOH = 9/1)로 정제하여 표제의 화합물 (246.8 mg, 87 %)을 수득하였다.N-Boc-4,4- (piperidin-1-yl, cyanomethyl) piperidine (250 mg, 0.81 mmol) obtained in step A was dissolved in DMF (5 ml) and sodium azide (265.3 mg, 4.1 mmol) and ammonium chloride were added and stirred at 90 ° C. for 24 hours. The reaction solution was diluted with EtOAc, washed sequentially with sodium bicarbonate and HCl aqueous solution, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, MC / MeOH = 9/1) to afford the title compound (246.8 mg, 87%).

MS[M+H] = 351MS [M + H] = 351

단계 C : N-Boc-4,4-[피페리딘-1-일, (1-메틸-테트라졸-5-일)]피페리딘Step C: N-Boc-4,4- [piperidin-1-yl, (1-methyl-tetrazol-5-yl)] piperidine

단계 B에서 얻은 N-Boc-4,4-[피페리딘-1-일, (테트라졸-5-일)메틸]피페리딘(200 mg, 0.57 mmol)를 DMF에 녹인 후 트리에틸아민 (160 ml, 1.14 mmol)으로 염기화시킨 후 아이오도메탄 (162.1 mg, 1.14 mmol)을 적가하여 70oC에서 교반하였다. 반응이 종결된 용액을 EtOAc과 증류수로 희석시키고 EtOAc로 추출한 다음 무수 MgSO4로 건조시키고 여과하여 감압 농축하였다. 잔유물을 관 크로마토그라피 (용리액, MC/MeOH = 3/1)로 정제하여 표제의 화합물 (185.1 mg, 89 %)을 수득하였다.N-Boc-4,4- [piperidin-1-yl, (tetrazol-5-yl) methyl] piperidine (200 mg, 0.57 mmol) obtained in step B was dissolved in DMF and then triethylamine ( 160 ml, 1.14 mmol) was added and iodomethane (162.1 mg, 1.14 mmol) was added dropwise and stirred at 70 ° C. The reaction solution was diluted with EtOAc and distilled water, extracted with EtOAc, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, MC / MeOH = 3/1) to afford the title compound (185.1 mg, 89%).

MS[M+H] = 365MS [M + H] = 365

제조예 13 : N-Boc-4,4-[피페리딘-1-일, (1-아미노-트리아졸일)]피페리딘Preparation Example 13 N-Boc-4,4- [piperidin-1-yl, (1-amino-triazolyl)] piperidine

제조예 5의 단계 E와 같은 방법으로 얻을 수 있는 N-Boc-4,4-[피페리딘-1-일, (메탄술페이티딜)메틸]피페리딘 (202.1 mg, 0.5 mmol)과 아미노트리아졸을 이용하여 제조예 10과 같은 방법으로 표제 화합물 (122.1 mg, 67 %)을 수득하였다.N-Boc-4,4- [piperidin-1-yl, (methanesulfatidyl) methyl] piperidine (202.1 mg, 0.5 mmol) and amino obtained in the same manner as in Step E of Preparation Example 5 Triazole was used to obtain the title compound (122.1 mg, 67%) in the same manner as in Preparation 10.

MS[M+H] = 365MS [M + H] = 365

제조예 14 : N-벤질-4,4-[피페리딘-1-일, (아세틸아미노)메틸]피페리딘Preparation Example 14 N-benzyl-4,4- [piperidin-1-yl, (acetylamino) methyl] piperidine

단계 A : N-벤질-4,4-[피페리딘-1-일, (아미노)메틸]피페리딘Step A: N-benzyl-4,4- [piperidin-1-yl, (amino) methyl] piperidine

N-벤질-4-시아노-4-(1-피페리디노)-피페리딘 (1647 mg, 5.79 mmol)을 이용하여 제조예 5의 단계 E와 같은 방법으로 표제의 화합물 (1630 mg, 97 %)을 수득하였다.Using the N-benzyl-4-cyano-4- (1-piperidino) -piperidine (1647 mg, 5.79 mmol) in the same manner as in Step E of Preparation Example 5, the title compound (1630 mg, 97 %) Was obtained.

MS[M+H]=288MS [M + H] = 288

단계 B : N-벤질-4,4-[피페리딘-1-일, (아세틸아미노)메틸]피페리딘Step B: N - benzyl-4,4- [piperidin-1-yl, (acetylamino) methyl] piperidine

단계 A에서 얻은 N-벤질-4,4-[피페리딘-1-일, (아미노)메틸]피페리딘 (410 mg, 1.43 mmol)을 CH2Cl25 ml에 녹이고 Et3N (0.3 ml, 2.14 mmol)과 아세틸클로라이드 (0.15 ml, 2.14 mmol)을 0oC에서 적가하고 동 온도에서 20분 교반하였다. 반응이 종결된 용액에 1N 염산을 가하고 유기층을 CH2Cl2로 추출하여 무수 MgSO4로 건조하여 감압 농축하여 표제 화합물 (395 mg, 수율 85 %)을 수득하였다.N-benzyl-4,4- [piperidin-1-yl, (amino) methyl] piperidine (410 mg, 1.43 mmol) obtained in step A was dissolved in 5 ml of CH 2 Cl 2 and Et 3 N (0.3 ml, 2.14 mmol) and acetylchloride (0.15 ml, 2.14 mmol) were added dropwise at 0 ° C. and stirred at the same temperature for 20 minutes. 1N hydrochloric acid was added to the reaction solution, the organic layer was extracted with CH 2 Cl 2 , dried over anhydrous MgSO 4 , and concentrated under reduced pressure to obtain the title compound (395 mg, yield 85%).

MS[M+H]=330MS [M + H] = 330

제조예 15 : NPreparation Example 15 N -- 벤질-4,4-[피페리딘-1-일, (이소프로필설포닐아미노)메틸]피페리딘Benzyl-4,4- [piperidin-1-yl, (isopropylsulfonylamino) methyl] piperidine

제조예 14의 단계 A에서 얻은 N-벤질-4,4-[피페리딘-1-일, (아미노)메틸]피페리딘 (116 mg, 0.34 mmol)을 디클로로메탄 (1.4 ml)에 녹인 후 트리에틸아민 (100 ml, 0.68 mmol)을 넣어 염기화시킨다. 이소프로필설포닐클로라이드 (60 ㎕, 0.52 mmol) 을 0oC 천천히 적가하고 동 온도에서 20분 동안 교반한 후 증류수 (2 ml)를 넣어주고 디클로로메탄으로 희석한 다음 1N HCl로 씻어 주고 무수 MgSO4로 건조하여 감압 농축하였다. 얻어진 잔유물을 관 크로마토그라피 (용리액, MC/메탄올 = 9/1)로 정제하여 표제의 화합물 (107 mg, 수율 88 %)을 수득하였다.N-benzyl-4,4- [piperidin-1-yl, (amino) methyl] piperidine (116 mg, 0.34 mmol) obtained in step A of Preparation Example 14 was dissolved in dichloromethane (1.4 ml). Triethylamine (100 ml, 0.68 mmol) is added and basified. Isopropylsulfonyl chloride (60 μl, 0.52 mmol) was slowly added dropwise at 0 o C, stirred for 20 minutes at the same temperature, distilled water (2 ml) was diluted with dichloromethane, washed with 1N HCl and anhydrous MgSO 4 It was dried over and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent, MC / methanol = 9/1) to give the title compound (107 mg, yield 88%).

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

제조예 16 : NPreparation Example 16 N -- 벤질-4,4-[피페리딘-1-일, CHBenzyl-4,4- [piperidin-1-yl, CH 22 NHC(O)-(1,2,4-트리아졸-1-일)]피페리딘NHC (O)-(1,2,4-triazol-1-yl)] piperidine

단계 A : N-벤질-4,4-(피페리딘-1-일, CH2NHC(O)Cl)피페리딘Step A: N - benzyl-4,4- (piperidin-1-yl, CH 2 NHC (O) Cl) piperidine

제조예 14의 단계 A에서 얻은 N-벤질-4,4-[피페리딘-1-일, (아미노)메틸]피페리딘 (331.5 mg, 1 mmol)을 디클로로메탄 (5 ml)에 녹이고 트리에틸아민 (280 ml, 2 mmol)으로 염기화시키고 포스젠을 적가한 다음 상온에서 24시간 교반하였다. 반응이 종결된 용액을 여과하여 표제 화합물 (390.3 mg, 94 %)을 수득하였다.N-benzyl-4,4- [piperidin-1-yl, (amino) methyl] piperidine (331.5 mg, 1 mmol) obtained in step A of Preparation Example 14 was dissolved in dichloromethane (5 ml), and The mixture was basified with ethylamine (280 ml, 2 mmol) and phosgene was added dropwise and stirred at room temperature for 24 hours. The solution which terminated the reaction was filtered to give the title compound (390.3 mg, 94%).

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

단계 B : N-벤질-4,4-[피페리딘-1-일, CH2NHC(O)-(1,2,4-트리아졸-1-일)]피페리딘Step B: N - benzyl-4,4- [piperidin-1-yl, CH 2 NHC (O)-(1,2,4-triazol-1-yl)] piperidine

단계 A에서 얻은 N-벤질-4,4-(피페리딘-1-일, CH2NHC(O)Cl)피페리딘 (200 mg, 0.5 mmol)을 이용하여 제조예 9와 같은 방법으로 표제의 화합물 (193.7 mg, 89 %)을 수득하였다.Using the N - benzyl-4,4- (piperidin-1-yl, CH 2 NHC (O) Cl) piperidine (200 mg, 0.5 mmol) obtained in step A in the same manner as in Preparation Example 9 Compound (193.7 mg, 89%) was obtained.

MS[M+H] = 383MS [M + H] = 383

제조예 17 : NPreparation Example 17 N -- 벤질-4,4-[피페리딘-1-일, CHBenzyl-4,4- [piperidin-1-yl, CH 22 NHC(O)-(1,2,4-트리아졸-1-일)]피페리딘NHC (O)-(1,2,4-triazol-1-yl)] piperidine

제조예 14의 단계 A와 같은 방법으로 얻을 수 있는 N-벤질-4,4-[피페리딘-1-일, (아미노)메틸]피페리딘 (331.5 mg, 1 mmol)과 1,2,3-트리아졸, 나트륨이소펜톡사이드를 이용하여 제조예 16의 단계 B와 같은 방법으로 표제 화합물 (201 mg, 81 %) 을 합성하였다.N-benzyl-4,4- [piperidin-1-yl, (amino) methyl] piperidine (331.5 mg, 1 mmol) and 1,2, obtained by the same method as in Step A of Preparation Example 14; The title compound (201 mg, 81%) was synthesized in the same manner as in Step B of Preparation Example 16 using 3-triazole, sodium isopentoside.

MS[M+H] = 383MS [M + H] = 383

제조예 18 : NPreparation Example 18 -- Boc-4,4-[피롤리딘-1-일, (메탄술페이티딜)메틸]피페리딘Boc-4,4- [pyrrolidin-1-yl, (methanesulfatidyl) methyl] piperidine

단계 A : N-Boc-4,4-[피롤리딘-1-일, 하이드록시메틸]피페리딘Step A: N - Boc-4,4- [pyrrolidin-1-yl, hydroxymethyl] piperidine

제조예 3에서 얻은 N-Boc-4,4-[피롤리딘-1-일, 메톡시카보닐]피페리딘 (1561mg, 5 mmol)을 이용하여 제조예 5의 단계 C와 같은 방법으로 표제의 화합물 (952.7 mg, 67 mmol)을 수득하였다.Using N - Boc-4,4- [pyrrolidin-1-yl, methoxycarbonyl] piperidine (1561 mg, 5 mmol) obtained in Preparation Example 3 in the same manner as in Step C of Preparation Example 5 Compound (952.7 mg, 67 mmol) was obtained.

MS[M+H] = 285MS [M + H] = 285

단계 B : N-Boc-4,4-[피롤리딘-1-일, (메탄술페이티딜)메틸]피페리딘Step B: N - Boc-4,4- [pyrrolidin-1-yl, (methanesulfatidyl) methyl] piperidine

단계 A에서 얻은 N-Boc-4,4-[피롤리딘-1-일, 하이드록시메틸]피페리딘 (853.2 mg, 3 mmol)을 이용하여 제조예 5의 단계 D와 같은 방법으로 표제 화합물 (1022 mg, 94 %)을 얻었다.The title compound in the same manner as in Step D of Preparation Example 5 using N - Boc-4,4- [pyrrolidin-1-yl, hydroxymethyl] piperidine (853.2 mg, 3 mmol) obtained in Step A. (1022 mg, 94%) was obtained.

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

제조예 19 : N-Boc-4,4-[피롤리딘-1-일, (1,2,4-트리아졸-1-일)메틸]피페리딘Preparation Example 19 N-Boc-4,4- [pyrrolidin-1-yl, (1,2,4-triazol-1-yl) methyl] piperidine

제조예 18에서 얻은 N-Boc-4,4-[피롤리딘-1-일, (메탄술페이티딜)메틸]피페리딘 (362.5 mg, 1 mmol)을 이용하여 제조예 9와 같은 방법으로 표제 화합물 (305.3 mg, 91 %)을 얻었다.In the same manner as in Preparation Example 9, using N-Boc-4,4- [pyrrolidin-1-yl, (methanesulfatidyl) methyl] piperidine (362.5 mg, 1 mmol) obtained in Preparation Example 18. The title compound (305.3 mg, 91%) was obtained.

MS[M+H] = 336MS [M + H] = 336

제조예 20 : N-Boc-4,4-[피롤리딘-1-일, (1,2,3-트리아졸-1-일)메틸]피페리딘Preparation Example 20 N-Boc-4,4- [pyrrolidin-1-yl, (1,2,3-triazol-1-yl) methyl] piperidine

제조예 18에서 얻은 N-Boc-4,4-[피롤리딘-1-일, (메탄술페이티딜)메틸]피페리딘 (362.5 mg, 1 mmol) 및 1,2,3-트리아졸을 이용하여 제조예 9와 같은 방법으로 표제 화합물 (300.3 mg, 89 %)을 얻었다.N-Boc-4,4- [pyrrolidin-1-yl, (methanesulfatidyl) methyl] piperidine (362.5 mg, 1 mmol) and 1,2,3-triazole obtained in Preparation Example 18 were prepared. In the same manner as in Preparation Example 9, the title compound (300.3 mg, 89%) was obtained.

MS[M+H] = 336MS [M + H] = 336

제조예 21 : N-Boc-4,4-[피롤리딘-1-일, (테트라졸-1-일)메틸]피페리딘Preparation Example 21 N-Boc-4,4- [pyrrolidin-1-yl, (tetrazol-1-yl) methyl] piperidine

제조예 18의 단계 A에서 얻은 N-Boc-4,4-[피롤리딘-1-일, 하이드록시메틸]피페리딘 (284.4 mg, 1 mmol )과 테트라졸 (70.1 mg, 1 mmol)을 이용하여 제조예 11의 단계 B와 같은 방법으로 표제 화합물 (275.8 mg, 82 %)을 얻었다.N-Boc-4,4- [pyrrolidin-1-yl, hydroxymethyl] piperidine (284.4 mg, 1 mmol) and tetrazole (70.1 mg, 1 mmol) obtained in step A of Preparation Example 18 were prepared. To obtain the title compound (275.8 mg, 82%) in the same manner as in Step B of Preparation Example 11.

MS[M+H] = 337MS [M + H] = 337

제조예 22 : N-Boc-4,4-[피롤리딘-1-일, (1-메틸-테트라졸-5-일)메틸]피페리딘Preparation Example 22 N-Boc-4,4- [pyrrolidin-1-yl, (1-methyl-tetrazol-5-yl) methyl] piperidine

제조예 18의 단계 B 에서 얻은 N-Boc-4,4-[피롤리딘-1-일, (메탄술페이티딜)메틸]피페리딘 (362.5 mg, 1 mmol)를 이용하여 제조예 12와 같은 방법으로 표제 화합물 (206.8 mg, 59 %)을 얻었다.Preparation Example 12 was prepared using N-Boc-4,4- [pyrrolidin-1-yl, (methanesulfatidyl) methyl] piperidine (362.5 mg, 1 mmol) obtained in Step B of Preparation Example 18. In the same manner the title compound (206.8 mg, 59%) was obtained.

MS[M+H] = 351MS [M + H] = 351

제조예 23: NPreparation Example 23 N -- Boc-4,4-[디메틸아미노, (메탄술페이티딜)메틸]피페리딘Boc-4,4- [dimethylamino, (methanesulfetidyl) methyl] piperidine

단계 A: N-Boc-4,4-[디메틸아미노, 하이드록시메틸]피페리딘Step A: N-Boc-4,4- [dimethylamino, hydroxymethyl] piperidine

제조예 2에서 얻은 N-Boc-4,4-[디메틸아미노, 메톡시카보닐]피페리딘 (1431 mg, 5 mmol)을 이용하여 제조예 5의 단계 C와 같은 방법으로 표제의 화합물 (1175 mg, 91 mmol)을 수득하였다Using the N-Boc-4,4- [dimethylamino, methoxycarbonyl] piperidine (1431 mg, 5 mmol) obtained in Preparation Example 2 in the same manner as in Step C of Preparation Example 5, the title compound (1175) mg, 91 mmol) was obtained.

MS[M+H] = 259MS [M + H] = 259

단계 B : N-Boc-4,4-[디메틸아미노, (메탄술페이티딜)메틸]피페리딘Step B: N-Boc-4,4- [dimethylamino, (methanesulfatidyl) methyl] piperidine

단계 A에서 얻은N-Boc-4,4-[디메틸아미노, 메톡시카보닐]피페리딘 (775.2 mg, 3mmol)을 이용 제조예 5의 단계 D와 같은 방법으로 표제 화합물 (994.1 mg, 91 %)을 얻었다.Using the N- Boc-4,4- [dimethylamino, methoxycarbonyl] piperidine (775.2 mg, 3 mmol) obtained in step A in the same manner as in step D of Preparation Example 5, the title compound (994.1 mg, 91% )

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

제조예 24 : N-Boc-4,4-[디메틸아미노, (1,2,4-트리아졸-1-일)메틸]피페리딘Preparation Example 24 N-Boc-4,4- [dimethylamino, (1,2,4-triazol-1-yl) methyl] piperidine

제조예 23에서 얻은 N-Boc-4,4-[디메틸아미노, (메탄술페이티딜)메틸]피페리딘 (352.5 mg, 1 mmol)을 이용하여 제조예 9와 같은 방법으로 표제 화합물 (259.9 mg, 84 %)을 얻었다.Using the N-Boc-4,4- [dimethylamino, (methanesulfatidyl) methyl] piperidine (352.5 mg, 1 mmol) obtained in Preparation Example 23, the title compound (259.9 mg was prepared in the same manner as in Preparation Example 9. , 84%).

MS[M+H] = 310MS [M + H] = 310

제조예 25 : N-Boc-4,4-[디메틸아미노-1-일, (1,2,3-트리아졸-1-일)메틸]피페리딘Preparation Example 25 N-Boc-4,4- [dimethylamino-1-yl, (1,2,3-triazol-1-yl) methyl] piperidine

제조예 23에서 얻은 N-Boc-4,4-[디메틸아미노, (메탄술페이티딜)메틸]피페리딘 (352.5 mg, 1 mmol)및 1,2,3-트리아졸을 이용하여 제조예 9와 같은 방법으로 표제 화합물 (289.0 mg, 93 %)을 얻었다.Preparation Example 9 using N-Boc-4,4- [dimethylamino, (methanesulfatidyl) methyl] piperidine (352.5 mg, 1 mmol) and 1,2,3-triazole obtained in Preparation Example 23 In the same manner as the title compound (289.0 mg, 93%).

MS[M+H] = 310MS [M + H] = 310

제조예 26 : N-Boc-4,4-[디메틸아미노, (테트라졸-1-일)메틸]피페리딘Preparation Example 26 N-Boc-4,4- [dimethylamino, (tetrazol-1-yl) methyl] piperidine

제조예 23의 단계 A에서 얻은 N-Boc-4,4-[디메틸아미노, 하이드록시메틸]피페리딘 (258.4 mg, 1 mmol)과 테트라졸 (70.1 mg, 1 mmol)을 이용하여 제조예 11의 단계 B와 같은 방법으로 표제 화합물 (270.0 mg, 87 %)을 얻었다.Preparation Example 11 using N-Boc-4,4- [dimethylamino, hydroxymethyl] piperidine (258.4 mg, 1 mmol) and tetrazole (70.1 mg, 1 mmol) obtained in step A of Preparation Example 23 The title compound (270.0 mg, 87%) was obtained in the same manner as in step B.

MS[M+H] = 311MS [M + H] = 311

제조예 27 : N-Boc-4,4-[피롤리딘-1-일, (1-메틸-테트라졸-5-일)메틸]피페리딘Preparation Example 27 N-Boc-4,4- [pyrrolidin-1-yl, (1-methyl-tetrazol-5-yl) methyl] piperidine

제조예 23의 단계 B 에서 얻은 N-Boc-4,4-[디메틸아미노, (메탄술페이티딜)메틸]피페리딘 (352.2 mg, 1 mmol)를 이용하여 제조예 12와 같은 방법으로 표제 화합물 (197.9 mg, 61 %)을 얻었다.Using the N-Boc-4,4- [dimethylamino, (methanesulfatidyl) methyl] piperidine (352.2 mg, 1 mmol) obtained in step B of Preparation Example 23 in the same manner as in Preparation Example 12 (197.9 mg, 61%) was obtained.

MS[M+H] = 325MS [M + H] = 325

제조예 28 : NPreparation Example 28 N -- Boc-4,4-[헥사메틸렌이민일, (메탄술페이티딜)메틸]피페리딘Boc-4,4- [hexamethyleneiminyl, (methanesulfetidyl) methyl] piperidine

단계 A : N-Boc-4,4-[헥사메틸렌이민일, 하이드록시메틸]피페리딘Step A: N-Boc-4,4- [hexamethyleneiminyl, hydroxymethyl] piperidine

제조예 4에서 얻은 N-Boc-4,4-[헥사메틸렌이민일, 메톡시카보닐]피페리딘 (1701 mg, 5 mmol)을 이용하여 제조예 5의 단계 C와 같은 방법으로 표제의 화합물 (1312 mg, 84 mmol)을 수득하였다Using the N-Boc-4,4- [hexamethyleneiminyl, methoxycarbonyl] piperidine (1701 mg, 5 mmol) obtained in Preparation Example 4 in the same manner as in Step C of Preparation Example 5, 1312 mg, 84 mmol) was obtained.

MS[M+H] = 313MS [M + H] = 313

단계 B : N-Boc-4,4-[헥사메틸렌이민일, (메탄술페이티딜)메틸]피페리딘Step B: N-Boc-4,4- [hexamethyleneiminyl, (methanesulfatidyl) methyl] piperidine

단계 A에서 얻은 N-Boc-4,4-[헥사메틸렌이민일, 하이드록시메틸]피페리딘 (937.5 mg, 3mmol)을 이용하여 제조예 5의 단계 D와 같은 방법으로 표제 화합물 (1034 mg, 92 %)을 얻었다.Using the N - Boc-4,4- [hexamethyleneiminyl, hydroxymethyl] piperidine (937.5 mg, 3 mmol) obtained in step A in the same manner as in Step D of Preparation Example 5, the title compound (1034 mg, 92 %) Was obtained.

MS[M+H] = 375MS [M + H] = 375

제조예 29 : N-Boc-4,4-[헥사메틸렌이민일, (1,2,4-트리아졸-1-일)메틸]피페리딘Preparation Example 29 N-Boc-4,4- [hexamethyleneiminyl, (1,2,4-triazol-1-yl) methyl] piperidine

제조예 28에서 얻은 N-Boc-4,4-[헥사메틸렌이민일, (메탄술페이티딜)메틸]피페리딘 (374.5 mg, 1 mmol)을 이용하여 제조예 9와 같은 방법으로 표제 화합물 (305.3 mg, 84 %)을 얻었다.Using the N-Boc-4,4- [hexamethyleneiminyl, (methanesulfatidyl) methyl] piperidine (374.5 mg, 1 mmol) obtained in Preparation Example 28 in the same manner as in Preparation Example 9, the title compound (305.3 mg, 84%).

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

제조예 30 : N-Boc-4,4-[헥사메틸렌이민일, (1,2,3-트리아졸-1-일)메틸]피페리딘Preparation Example 30 N-Boc-4,4- [hexamethyleneiminyl, (1,2,3-triazol-1-yl) methyl] piperidine

제조예 28에서 얻은 N-Boc-4,4-[헥사메틸렌이민일, (메탄술페이티딜)메틸]피페리딘 (374.5 mg, 1 mmol)및 1,2,3-트리아졸을 이용하여 제조예 9와 같은 방법으로 표제 화합물 (288.1 mg, 79 %)을 얻었다.Preparation Example Using N-Boc-4,4- [hexamethyleneiminyl, (methanesulfetidyl) methyl] piperidine (374.5 mg, 1 mmol) and 1,2,3-triazole obtained in Preparation Example 28 In the same manner as 9, the title compound (288.1 mg, 79%) was obtained.

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

제조예 31 : N-Boc-4,4-[헥사메틸렌이민일, (테트라졸-1-일)메틸]피페리딘Preparation Example 31 N-Boc-4,4- [hexamethyleneiminyl, (tetrazol-1-yl) methyl] piperidine

제조예 28의 단계 A에서 얻은 N-Boc-4,4-[헥사메틸렌이민일, 하이드록시메틸]피페리딘 (312.5 mg, 1mmol )과 테트라졸 (70.1 mg, 1 mmol)을 이용 제조예 11의 단계 B와 같은 방법으로 표제 화합물 (331.7 mg, 91 %)을 얻었다.N-Boc-4,4- [hexamethyleneiminyl, hydroxymethyl] piperidine (312.5 mg, 1 mmol) and tetrazole (70.1 mg, 1 mmol) obtained in step A of Preparation Example 28 were used. In the same manner as in step B, the title compound (331.7 mg, 91%) was obtained.

MS[M+H] = 365MS [M + H] = 365

제조예 32 : N-Boc-4,4-[헥사메틸렌이민일, (1-메틸-테트라졸-5-일)메틸]피페리딘Preparation Example 32 N-Boc-4,4- [hexamethyleneiminyl, (1-methyl-tetrazol-5-yl) methyl] piperidine

제조예 28의 단계 B에서 얻은 N-Boc-4,4-[헥사메틸렌이민일, (메탄술페이티딜)메틸]피페리딘 (374.5 mg, 1 mmol)를 이용하여 제조예 12와 같은 방법으로 표제 화합물 (208.2 mg, 55 %)을 얻었다.Using N-Boc-4,4- [hexamethyleneiminyl, (methanesulfetidyl) methyl] piperidine (374.5 mg, 1 mmol) obtained in step B of Preparation Example 28 in the same manner as in Preparation 12 Compound (208.2 mg, 55%) was obtained.

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

제조예 33 : BOC-도데실하이드로이소퀴놀릭 산Preparation Example 33 BOC-dodecylhydroisoquinolinic acid

단계 A : D-테트라하이드로이소퀴놀릭 메틸에스터Step A: D-tetrahydroisoquinolic methylester

메탄올 용액 (30 ml)에 아세틸클로라이드 (1.57 ml, 10 mmol)를 넣고 30분 정도 교반한다. 상업적으로 구입한 N-BOC-테트라하이드로이소퀴놀릭 산 (2773 mg, 10 mmol)를 메탄올 (5 ml)에 녹여 천천히 적가한 다음 상온에서 30분 정도 교반한다. 반응이 종결된 용액을 감압 농축하여 표제화합물의 HCl염 (2207 mg, 92 %)을 수득하였다.Add acetyl chloride (1.57 ml, 10 mmol) to methanol solution (30 ml) and stir for 30 minutes. Commercially purchased N-BOC-tetrahydroisoquinolinic acid (2773 mg, 10 mmol) is dissolved in methanol (5 ml) and slowly added dropwise, followed by stirring at room temperature for 30 minutes. The solution was terminated under reduced pressure to give HCl salt (2207 mg, 92%) of the title compound.

MS[M+H] = 192MS [M + H] = 192

단계 B : 도데실하이드로이소퀴놀릭 메틸에스터Step B: Dodecylhydroisoquinolinic Methyl Ester

단계 A에서 얻은 D-테트라하이드로이소퀴놀릭 메틸에스터 (1138 mg, 5 mmol)를 메탄올 (40 ml)에 녹인 후 진한 HCl (10 ml)과 PtO2(750 ml)를 적가한 후 수소반응기 (45 psi)에서 3일동안 반응시킨다. 반응이 종결된 용액을 감압 농축하여 표제 화합물의 HCl염 (1023 mg, 87 %)을 얻었다.The D-tetrahydroisoquinolinic methyl ester (1138 mg, 5 mmol) obtained in step A was dissolved in methanol (40 ml), and concentrated HCl (10 ml) and PtO 2 (750 ml) were added dropwise followed by hydrogen reactor (45 psi) for 3 days. The solution was terminated under reduced pressure to give HCl salt (1023 mg, 87%) of the title compound.

MS[M+H] = 198MS [M + H] = 198

단계 C: N-Boc-도데실하이드로이소퀴놀릭 메틸에스터Step C: N-Boc-dodecylhydroisoquinolic methylester

단계 B에서 얻은 NH-도데실하이드로이소퀴놀릭 메틸에스터 (934.8 mg, 4 mmol)를 디클로로메탄 (15 ml)에 녹이고 트리에틸아민 (1.12 ml, 8 mmol)으로 염기화시킨 후 디-t-부틸 디카보네이트 (520 mg, 4 mmol)를 적가하여 상온에서 6시간 교반하였다. 반응이 종결된 용액을 디클로로메탄으로 희석하고 1N HCl로 씻어 주고 무수 MgSO4로 건조시키고 여과하여 감압 농축하였다. 잔유물을 관 크로마토그라피 (용리액, EtOAc/n-헥산 = 1/4)로 정제하여 표제의 화합물 (1064 mg, 89 %)을 수득하였다.The NH-dodecylhydroisoquinolinic methyl ester (934.8 mg, 4 mmol) obtained in step B was dissolved in dichloromethane (15 ml) and basified with triethylamine (1.12 ml, 8 mmol) followed by di-t-butyl Dicarbonate (520 mg, 4 mmol) was added dropwise and stirred at room temperature for 6 hours. The reaction solution was diluted with dichloromethane, washed with 1N HCl, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc / n-hexane = 1/4) to afford the title compound (1064 mg, 89%).

MS[M+H] = 298MS [M + H] = 298

단계 D : BOC-도데실하이드로이소퀴놀릭산Step D: BOC-dodecylhydroisoquinolic acid

단계 C에서 얻은 N-Boc-도데실하이드로이소퀴놀릭 메틸에스터 (892 mg, 3 mmol)를 THF (12 ml)와 증류수용액 (3 ml)에 녹이고 LiOH (350 mg, 10 mmol)를 넣고 상온에서 6시간 동안 교반하였다. 반응이 종결된 용액을 EtOAc로 희석하고 HCl로 씻어 준 다음 무수 MgSO4로 건조시키고 여과하여 감압 농축하였다. 잔유물을 관 크로마토그라피 (용리액, EtOAc/n-헥산 = 1/4)로 정제하여 표제의 화합물 (790 mg, 93 %)을 수득하였다.N-Boc-dodecylhydroisoquinolinic methyl ester (892 mg, 3 mmol) obtained in step C was dissolved in THF (12 ml) and distilled solution (3 ml), and LiOH (350 mg, 10 mmol) was added thereto at room temperature. Stir for 6 hours. The reaction solution was 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 = 1/4) to afford the title compound (790 mg, 93%).

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

제조예 34 : N-Boc-(1-Boc-5-메틸)히스티딘Preparation Example 34 N-Boc- (1-Boc-5-methyl) histidine

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

Boc-5-메틸-4-(하이드록시메틸)이미다졸 (1.6 g, 7.54 mmol)을 CH2Cl2(150 ml)에 녹인 후, 사브롬화탄소 (CBr4, 3.0 g, 9.05 mmol)을 적가한 다음 트리페닐포스핀 (PPh3, 2.4 g, 9.15 mmol)을 조금씩 적가하였다. 실온에서 8시간 교반한 다음 감압 농축하였다. 수득된 잔유물을 관 크로마토그라피 (용리액, EtOAc/n-헥산 = 1/4)로 정제하여 표제의 화합물 (0.79 g, 38%) 을 수득하였다.Boc-5-methyl-4- (hydroxymethyl) imidazole (1.6 g, 7.54 mmol) was dissolved in CH 2 Cl 2 (150 ml), and carbon tetrabromide (CBr 4 , 3.0 g, 9.05 mmol) was added dropwise. Triphenylphosphine (PPh 3 , 2.4 g, 9.15 mmol) was then added dropwise. After stirring for 8 hours at room temperature, the mixture was concentrated under reduced pressure. The residue obtained was purified by column chromatography (eluent, EtOAc / n-hexane = 1/4) to afford the title compound (0.79 g, 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 (0.2 g, 0.53 mmol)을 무수 에탄올 1 ml에 녹이고 소듐에톡사이드 (2N 에탄올 용액, 0.32 ml, 0.64 mmol)을 적가한 후 실온에서 1시간 교반한 후, 여기에 1-Boc-5-메틸-4-(브로모메틸)이미다졸 (0.16 g, 0.59 mmol)을 넣고 실온에서 2시간 교반하고, 90 ℃에서 2시간 교반하였다. 여기에 수산화나트륨 수용액 (1N, 1.1 ml, 1.1 mmol)을 넣고 90 ℃에서 5시간 교반한 다음 감압 농축하였다. 잔유물에 EtOAc을 넣고 묽은 염산으로 pH를 5에 맞추었다. 유기층을 분리하고 EtOAc으로 2번 더 추출하였다. 유기층을 모아 소금물로 씻은 다음 무수 MgSO4로 건조하고 감압 농축하여 표제의 화합물 (0.1 g, 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, and stirred at room temperature for 1 hour. 1-Boc-5-methyl-4- (bromomethyl) imidazole (0.16 g, 0.59 mmol) was added thereto, stirred at room temperature for 2 hours, and stirred at 90 ° C 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, 46%).

MS[M+H] =370MS [M + H] = 370

제조예 35 : N-Boc-(2-메틸)히스티딘Preparation Example 35 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 (5.9 g, 13 mmol)을 THF (100 ml)에 녹인 용액을 0 ℃로 냉각시키고, 여기에 n-부틸리튬 (1.6 N 헥산 용액, 8.94 ml, 14.3 mmol)을 적가한 다음 30분 동안 교반하였다. 여기에 요드메탄 (2.13 mg, 15 mmol)을 적가하고 혼합액을 실온에서 30분간 더 교반한 후, 테트라부틸암모늄플루오리드 (1N THF용액, 26 ml, 26 mmol)을 적가하였다. 생성된 혼합액을 EtOAc에 희석시키고 소금물로 씻은 다음 무수 MgSO4로 건조하고 감압 농축하였다. 수득된 잔유물을 EtOAc에서 재결정하여 표제의 화합물 (3.2 g, 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. Iodine (2.13 mg, 15 mmol) was added dropwise thereto, and the mixed solution was further stirred at room temperature for 30 minutes, and then 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 obtained residue was recrystallized in EtOAc to give the title compound (3.2 g, 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 34의 단계 A, B와 동일한 방법으로반응을 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 34 to obtain the title compound (yield: 54%).

MS[M+H] = 270MS [M + H] = 270

제조예 36 : N-Boc-3-(1-트리틸이미다졸-2-일)알라닌Preparation Example 36 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 (2.1 g, 6.2 mmol)을 메탄올 21 ml에 녹이고 소듐보로히드리드 (NaBH4, 0.23 g, 6.2 mmol)을 조금씩 적가하고 실온에서 4시간 교반한 다음 감압 농축하였다. 잔유물에 CH2Cl2를 넣고 NH4Cl 수용액으로 닦고 유기층을 분리하여 무수 MgSO4로 건조하고 감압 농축하였다. 수득된 잔유물을 관 크로마토그라피 (용리액, EtOAc/n-헥산 = 1/1)로 정제하여 표제의 화합물 (1.4 g, 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 residue obtained was purified by column chromatography (eluent, EtOAc / n-hexane = 1/1) to afford the title compound (1.4 g, 67%).

MS[M+H] =341MS [M + H] = 341

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

단계 A에서 수득한 화합물로부터 제조예 34의 단계 A와 동일한 방법으로 반응을 수행하여 표제화합물 (0.8 g, 76%)을 수득하였다.The reaction was carried out from the compound obtained in Step A in the same manner as in Step A of Preparation Example 34 to obtain the title compound (0.8 g, 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 34의 단계 B와 동일한 방법으로 반응을 수행하여 표제화합물 (0.23 g, 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 34 to obtain the title compound (0.23 g, 47%).

MS[M+H] = 498MS [M + H] = 498

제조예 37 : N-Boc-3-(1-트리틸-4-메틸이미다졸-2-일)알라닌Preparation Example 37 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 (1.04 g, 3.2 mmol)을 무수 THF (30 ml)에 녹이고 N,N,N',N'-테트라메틸에틸렌디아민 (0.48 ml, 3.2 mmol)을 적가하고 78 ℃으로 냉각 후 n-부틸리튬 (1.6 N 헥산 용액, 2.2 ml, 3.52 mmol)을 천천히 적가하였다. 1시간 교반 후 무수 DMF (0.36 ml, 4.6 mmol)을 적가하고 30 ℃으로 승온하고 30분간 교반 후 물 1 ml을 적가하였다. NH4Cl 수용액 (50 ml)과 소금물 (50 ml)로 닦은 후 무수 MgSO4로 건조하고 감압 농축하였다. 수득된 잔유물을 관 크로마토그라피 (용리액, EtOAc/n-헥산 = 2/1) 로 정제하여 표제의 화합물 (0.53 g, 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. After cooling to 78 ° C., n-butyllithium (1.6 N 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, the temperature was raised to 30 ° C, and after stirring for 30 minutes, 1 ml of water was added dropwise. After washing with aqueous NH 4 Cl solution (50 ml) and brine (50 ml), dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue obtained was purified by column chromatography (eluent, EtOAc / n-hexane = 2/1) to afford the title compound (0.53 g, 47%).

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 36의 단계 A와 동일한 방법으로 환원반응, 제조예 34의 단계 A와 동일한 방법으로 브롬화 반응을 차례로 수행하여 표제화합물을 수득하였다 (0.42 g, 수율: 61 %).From the compound obtained in Step A, the reduction reaction was carried out in the same manner as in Step A of Preparation Example 36, and the bromination reaction was carried out in the same manner as in Step A of Preparation Example 34, to obtain the title compound (0.42 g, yield: 61%). .

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 34의 단계 B와 동일한 방법으로 반응을 수행하여 표제화합물 (0.17 g, 56%)을 수득하였다.The reaction was carried out from the compound obtained in Step B in the same manner as in Step B of Preparation Example 34 to obtain the title compound (0.17 g, 56%).

MS[M+H] = 512MS [M + H] = 512

제조예 38 : N-아세틸-3-(이미다졸-1-일)알라닌Preparation Example 38 N-acetyl-3- (imidazol-1-yl) alanine

이 화합물은 기술논문 (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 described in the technical paper (Tetrahedron 1995, 51 (30), 8355).

제조예 39 : N-Boc-3-(1-트리틸-1,2,4-트리아졸-3-일)알라닌Preparation Example 39 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

1,2,4-트리아졸로부터 제조예 37의 단계 A와 동일한 방법으로 반응을 수행하여 표제화합물 (4.53 g, 87 %)을 수득하였다.The reaction was carried out from 1,2,4-triazole in the same manner as in Step A of Preparation Example 37 to obtain the title compound (4.53 g, 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 (1 g, 2.95 mmol)을 무수 CH2Cl2(6 ml)에 녹이고 TFA (0.1 ml)을 천천히 적가한 후 실온에서 14 시간 교반한 다음 감압 농축하여 표제의 화합물 (0.95 g, 95 %)을 수득하였다.Dissolve 1-trityl-1,2,4-triazole-5-carboaldehyde (1 g, 2.95 mmol) in anhydrous CH 2 Cl 2 (6 ml) and slowly add dropwise TFA (0.1 ml) to room temperature. After stirring for time, the mixture was concentrated under reduced pressure to give the title compound (0.95 g, 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 36의 단계 A와 동일한 방법으로 환원반응, 제조예 34의 단계 A와 동일한 방법으로 브롬화 반응을 차례로 수행하여 표제화합물 (0.83 g, 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 36, and the bromination reaction was carried out in the same manner as in Step A of Preparation Example 34, to obtain the title compound (0.83 g, 67%).

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

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

단계 C에서 수득한 화합물로부터 제조예 34의 단계 B와 동일한 방법으로 반응을 수행하여 표제화합물 (0.21 g, 61 %)을 수득하였다.The reaction was carried out from the compound obtained in Step C in the same manner as in Step B of Preparation Example 34, to obtain the title compound (0.21 g, 61%).

MS[M+H] = 499MS [M + H] = 499

제조예 40 : N-Boc-3-(2-아미노피리딘-5-일)알라닌Preparation Example 40 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 (1.9 g, 7.6 mmol)을 무수 THF (30 ml)에 녹이고 0 ℃으로 낮춘 후 리튬 알루미늄히드리드 (LiAlH4, 0.31 g, 7.6 mmol)를 조금씩 적가한 후, 실온으로 승온하여 교반하였다. 6시간후 0 ℃으로 낮추고 물 (1 ml)을 적가하고, 이를 Celite로 여과하고 여과액을 감압 농축하였다. 수득된 잔유물을 관 크로마토그라피 (용리액, EtOAc/n-헥산 = 2/1)로 정제하여 표제의 화합물 (1.25 g, 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., followed by lithium aluminum hydride (LiAlH 4 , 0.31 g, 7.6 mmol). After dropwise addition, the mixture was heated to room temperature and stirred. After 6 hours, the mixture was lowered to 0 ° C. and water (1 ml) was added dropwise, which 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) to give the title compound (1.25 g, 74%).

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 34의 단계 A와 동일한 방법으로 반응을 수행하여 표제화합물 (0.29 g, 78 %)을 수득하였다.The reaction was carried out from the compound obtained in Step A in the same manner as in Step A of Preparation Example 34 to obtain the title compound (0.29 g, 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 34의 단계 B와 동일한 방법으로 반응을 수행하여 표제화합물 (0.19 g, 93%)을 수득하였다.The reaction was carried out from the compound obtained in Step B in the same manner as in Step B of Preparation Example 34 to obtain the title compound (0.19 g, 93%).

MS[M+H] = 382MS [M + H] = 382

제조예 41 : N-Boc-3-(2-아미노피리딘-3-일)알라닌Preparation Example 41 N-Boc-3- (2-aminopyridin-3-yl) alanine

메틸 N-Boc-2-아미노피리딘-3-카복실레이트 화합물로부터 제조예 40과 동일한 방법으로 반응을 수행하여 표제화합물 (0.15 g, 56%)을 수득하였다.The reaction was carried out in the same manner as in Preparation Example 40 from the methyl N-Boc-2-aminopyridine-3-carboxylate compound to obtain the title compound (0.15 g, 56%).

MS[M+H] = 382MS [M + H] = 382

제조예 42 : N-Boc-3-(피페리딘-1-일)알라닌Preparation Example 42 N-Boc-3- (piperidin-1-yl) alanine

단계 A : (S)-N-Boc -디아미노프로피오닉 에시드 메틸에스테르Step A: (S) -N-Boc-diaminopropionic acid methylester

(S)-N-Boc-(NCbz)-디아미노프로피오닉 에시드 (990 mg, 26.6 mmol), 포타슘카보네이트 (11 g, 79.8 mmol) 및 요오드메탄 (4.9 ml, 79.8 mmol)을 DMF (100 ml) 에 녹이고, 실온에서 12 시간 교반한다. 반응액을 EtOAc로 희석한 후, 물과 소금물로 각각 2번 씻은 후, 무수 MgSO4로 건조하고 감압 농축하였다. 얻어진 잔유물을 THF (100 ml)에 녹인 후 10% Pd/C (100 mg)를 가하고 수소풍선 하에서 4시간 동안 교반하였다. 반응액을 Celite로 여과하고 여과액을 감압 농축하여 표제의 화합물 (4.6 g, 79 %) 을 수득하였다.(S) -N-Boc- (NCbz) -diaminopropionic acid (990 mg, 26.6 mmol), potassium carbonate (11 g, 79.8 mmol) and iodomethane (4.9 ml, 79.8 mmol) were added to DMF (100 ml). It is dissolved in and stirred at room temperature for 12 hours. The reaction solution was diluted with EtOAc, washed twice with water and brine, then 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 (4.6 g, 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-디아미노프로피오닉 에시드 메틸에스테르 (1.78 g, 8.2 mmol), 25 % 글루타르알데히드 용액 (3.9 g, 9.8 mmol) 및 소디움트리아세톡시보로하이드라이드 [NaHB(OAc)3, 2.6 g, 12.3 mmol]을 디클로로에탄 (50 ml)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. 잔유물을 관 크로마토그래피로 정제하여 N-Boc-3-(피페리딘-1-일)알라닌 메틸에스테르 (590 mg, 2 mmol)를 수득하였다. 이 물질을 메탄올:물(2:1) 용액에 녹이고 리튬하이드록시드 (500 mg, 21 mmol)을 가한 다음 상온에서 5시간동안 교반하고 반응액을 감압증류하여 표제화합물 (1.5 g, 66 %)을 수득하였다.(S) -N-Boc-diaminopropionic acid methylester (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] were dissolved in dichloroethane (50 ml) and the mixture 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, stirred at room temperature for 5 hours, and the reaction mixture was distilled under reduced pressure to give the title compound (1.5 g, 66%). Obtained.

MS[M+H] = 273MS [M + H] = 273

제조예 43 : N-Boc-3-(4-메틸-피페리딘-1-일)알라닌Preparation Example 43 N-Boc-3- (4-methyl-piperidin-1-yl) alanine

제조예 42의 단계 A에서 수득한 화합물 (650 mg, 2.9 mmol), 1,5-다이브로모-3-메틸펜탄(1.3 ml, 8.7 mmol) 및 Et3N (1.2 ml, 8.7 mmol)을 DMF (20 ml)에 녹여 실온에서 약 15시간 동안 교반하였다. 반응액을 EtOAc로 희석한 후, 포화 탄산수소나트륨 수용액 및 소금물로 차례로 씻고 무수 MgSO4로 건조한 다음 감압 농축하였다. 잔유물을 관 크로마토그래피로 정제하여 N-Boc-3-(4-메틸-피페리딘-1-일)알라닌 메틸에스테르 (590 mg, 2 mmol)를 수득하였다. 이 물질을 메탄올:물 (2:1) 용액에 녹이고 리튬하이드록시드 (150 mg, 6 mmol)로 가수분해하여 표제화합물 (480 mg, 55%)을 얻었다.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 42 were diluted with DMF ( 20 ml) 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 taken up in a methanol: water (2: 1) solution and hydrolyzed with lithium hydroxide (150 mg, 6 mmol) to give the title compound (480 mg, 55%).

MS[M+H] = 287MS [M + H] = 287

제조예 44 : N-Boc-3-(헥사메틸렌이민-1-일)알라닌Preparation Example 44 N-Boc-3- (hexamethyleneimin-1-yl) alanine

1,6-다이브로모헥산 (0.2 ml, 1.32 mmol)으로부터 제조예 43과 동일한 방법으로 반응을 수행하여 표제화합물 (23 mg, 수율: 18 %) 을 수득하였다.The reaction was carried out in the same manner as in Preparation Example 43 from 1,6-dibromohexane (0.2 ml, 1.32 mmol) to obtain the title compound (23 mg, yield: 18%).

MS[M+H] = 287MS [M + H] = 287

제조예 45 : 4-사이클로헥실-4-(1,2,3-트리아졸-2-일메틸)피페리딘Preparation Example 45 4-cyclohexyl-4- (1,2,3-triazol-2-ylmethyl) piperidine

N-Boc-4-사이클로헥실-4-(메틸설포닐옥시메틸)피페리딘 (187.8 mg, 0.5 mmol, 제조 참조: WO 00/74679)을 DMF (3 ml) 에 녹이고 여기에 1,2,3-트리아졸 (103.7 mg, 1.5 mmol)과 소듐아이소펜톡사이드 (273.4 mg, 2.5 mmol) 를 넣고 용액을 90oC 에서 24 시간 교반하였다. 반응이 완결된 용액을 0.5 N 염산 용액, 포화 탄산수소나트륨 수용액 및 소금물로 차례로 씻고 무수 MgSO4로 건조한 다음 감압 농축하였다. 잔유물을 관 크로마토그라피 (용리액, EtOAc/n-헥산 = 1/3)로 정제하여 N-Boc-4-사이클로헥실-4-(1,2,3-트리아졸-2-일메틸)피페리딘 (136.7 mg, 수율: 78 %)을 수득하였다. 얻어진 잔유물을 CH2Cl2(4 ml)에 녹이고 TFA (2 ml)를 가한 다음 용액을 실온에서 2시간 동안 교반하였다. 반응이 완결된 용액을 감압 농축하여 표제화합물의 TFA염 (128.4 mg, 90 %)을 수득하였다.N-Boc-4-cyclohexyl-4- (methylsulfonyloxymethyl) piperidine (187.8 mg, 0.5 mmol, see preparation: WO 00/74679) is dissolved in DMF (3 ml) and added 1,2, 3-triazole (103.7 mg, 1.5 mmol) and sodium isopentoside (273.4 mg, 2.5 mmol) were added thereto, and the solution was stirred at 90 ° C. for 24 hours. The reaction was completed, the solution was washed sequentially with 0.5 N 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 = 1/3) to give N-Boc-4-cyclohexyl-4- (1,2,3-triazol-2-ylmethyl) piperidine (136.7 mg, yield: 78%) was obtained. The residue obtained was taken up in CH 2 Cl 2 (4 ml), TFA (2 ml) was added and the solution stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give TFA salt (128.4 mg, 90%) of the title compound.

MS[M+H] = 249MS [M + H] = 249

제조예 46 : N-Boc-(3-N-Boc)히스티딜 메틸-4-Cl-페닐알라닌Preparation Example 46 N-Boc- (3-N-Boc) histidyl methyl-4-Cl-phenylalanine

단계 A : 메틸-4-Cl-페닐알라닌Step A: Methyl-4-Cl-phenylalanine

아세틸클로라이드 (755 mg, 10 mmol)를 메탄올 (30 ml)에 녹이고 30분정도 교반한다. N-Boc-4-Cl-페닐알라닌 (2998 mg, 10 mmol)을 넣고 3시간 정도 교반한다. 반응이 완결된 후 감압하에 메탄올을 날려 보내고 표제 화합물의 HCl 염 (2427 mg, 97 %)을 얻었다.Acetylchloride (755 mg, 10 mmol) is dissolved in methanol (30 ml) and stirred for 30 minutes. Add N-Boc-4-Cl-phenylalanine (2998 mg, 10 mmol) and stir for 3 hours. After completion of the reaction the methanol was blown off under reduced pressure to give HCl salt (2427 mg, 97%) of the title compound.

MS[M+H] = 535MS [M + H] = 535

단계 B : N-Boc-(3-N-Boc) 히스티딜 메틸-4-Cl-페닐알라닌 메틸에스터Step B: N-Boc- (3-N-Boc) histidyl methyl-4-Cl-phenylalanine methylester

단계 A에서 얻은 메틸-4-Cl-페닐알라닌 HCl염 (2251 mg, 9 mmol)을 DMF (30 ml) 용매에 녹이고 트라이에틸아민 (2520 ml, 18 mmol)으로 용액을 염기화시킨다. N-Boc(3-N-Boc)히스티딘 (3198 mg, 9 mmol), EDC (2281 mg, 11.7 mmol), Hobt (1822 mg, 13.5 mmol)를 넣고 상온에서 4시간동안 교반한다. 반응액을 EtOAc로 희석한 후, 포화 탄산수소나트륨 수용액 및 HCl로 차례로 씻고 무수 MgSO4로 건조한 다음 감압 농축하였다. 잔유물을 관 크로마토그래피 (용리액, EtOAc/n-헥산 = 3/2)로 정제하여 N-Boc-(3-N-Boc)히스티딜 메틸-4-Cl-페닐알라닌 (4466 mg, 90 %)을 수득하였다.Methyl-4-Cl-phenylalanine HCl salt (2251 mg, 9 mmol) obtained in step A is dissolved in DMF (30 ml) solvent and the solution is 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) to give N-Boc- (3-N-Boc) histidyl methyl-4-Cl-phenylalanine (4466 mg, 90%). It was.

MS[M+H] = 552MS [M + H] = 552

단계 C : N-Boc-(3-N-Boc) 히스티딜 메틸-4-Cl-페닐알라닌Step C: N-Boc- (3-N-Boc) histidyl methyl-4-Cl-phenylalanine

단계 B에서 얻은 N-Boc-(3-N-Boc) 히스티딜 메틸-4-Cl-페닐알라닌 (4408 mg, 8 mmol)를 메탄올 (40 ml)과 물 (10 ml) 용액에 녹이고 LiOH (852 mg, 24 mmol )을 첨가한 후 상온에서 2시간 동안 교반하고 HCl로 중화하여 N-Boc-(3-N-Boc) 히스티딜4-Cl-페닐알라닌 (3781 mg, 88 %)을 수득하였다. 수득한 화합물을 디클로로메탄(30 ml)에 녹이고 트리플루오르아세틱 산을 적가하여 상온에서 2시간 동안 교반하였다. 반응이 종결된 용액을 감압 응축하여 표지 화합물의 TFA 염을 수득하였다.The N-Boc- (3-N-Boc) histidyl methyl-4-Cl-phenylalanine (4408 mg, 8 mmol) obtained in step B was dissolved in a solution of methanol (40 ml) and water (10 ml) and LiOH (852 mg , 24 mmol) was added thereto, stirred at room temperature for 2 hours, and neutralized with HCl to obtain N-Boc- (3-N-Boc) histidyl4-Cl-phenylalanine (3781 mg, 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 a TFA salt of the labeling compound.

MS[M+H] = 337MS [M + H] = 337

제조예 47 : N-Boc-(테트라하이드로이소퀴놀릭에시드)-4-Cl-페닐알라닌Preparation Example 47 N-Boc- (tetrahydroisoquinolic acid) -4-Cl-phenylalanine

제조예 46의 단계 A와 같은 방법으로 얻을 수 있는 메틸-4-Cl-페닐알라닌 (2251 mg, 9 mmol)과 N-Boc-(테트라하이드로이소퀴놀릭)에시드 (2478 mg, 9 mmol)를 이용하여 표지의 화합물의 TFA염을 수득하였다 (수득률 82 %).Using methyl-4-Cl-phenylalanine (2251 mg, 9 mmol) and N-Boc- (tetrahydroisoquinolinic) acid (2478 mg, 9 mmol) obtained in the same manner as in Step A of Preparation Example 46 TFA salt of the compound of the label was obtained (yield 82%).

MS[M+H] = 359MS [M + H] = 359

본 발명의 화합물들은 하기 실시예에 의거하여 보다 구체적으로 설명된다. 그러나, 이들 실시예는 본 발명에 대한 이해를 돕기 위한 것일 뿐, 어떤 의미로든 본 발명의 범위가 이들로 한정되는 것은 아니다.The compounds of the present invention are explained in more detail based on the following examples. However, these examples are only for the understanding of the present invention, and the scope of the present invention in any sense is not limited thereto.

실시예 1 : (R)-테트라하이드로이소퀸리닐일-(R)-(4-클로로페닐)알라닐-[4-사이클로헥실-4-[(1,2,4-트리아졸-1-일)메틸]]피페리디드 2TFA염Example 1 (R) -tetrahydroisoquininylyl- (R)-(4-chlorophenyl) alanyl- [4-cyclohexyl-4-[(1,2,4-triazol-1-yl) Methyl]] piperidide 2TFA salt

단계 A : 4,4-[(1-피페리딘-1-일), (1,2,4-트리아졸-1-일)메틸]피페리딘Step A: 4,4-[(1-piperidin-1-yl), (1,2,4-triazol-1-yl) methyl] piperidine

제조예 9와 같은 방법으로 합성한 N-Boc-4,4-[(1-피페리딘-1-일), (1,2,4-트리아졸-1-일)메틸]피페리딘 (350.24 mg, 1 mmol)을 디클로로메탄 (4 ml)에 녹이고 트리플루오르아세트산 (2 ml)를 적가하여 2시간동안 교반 하였다. 반응이 종결된 용액을 감압 농축하여 표제 화합물 (239.4 mg, 수율: 96 %)을 수득하였다.N-Boc-4,4-[(1-piperidin-1-yl), (1,2,4-triazol-1-yl) methyl] piperidine synthesized in the same manner as in Preparation Example 9 350.24 mg, 1 mmol) was dissolved in dichloromethane (4 ml) and trifluoroacetic acid (2 ml) was added dropwise and stirred for 2 hours. The solution was terminated under reduced pressure to give the title compound (239.4 mg, yield: 96%).

MS[M+H] = 250MS [M + H] = 250

단계 B : (R)-테트라하이드로이소퀸리닐일-(R)-(4-클로로페닐)알라닐-[4-사이클로헥실-4-[(1,2,4-트리아졸-1-일)메틸]]피페리디드 2TFA염Step B: (R) -Tetrahydroisoquininylyl- (R)-(4-chlorophenyl) alanyl- [4-cyclohexyl-4-[(1,2,4-triazol-1-yl) methyl Piperidide 2TFA salt

단계 A에서 합성한 4,4-[(1-피페리딘-1-일), (1,2,4-트리아졸-1-일)메틸]피페리딘 (100 mg, 0.42 mmol)를 DMF (3 ml)에 녹이고, 트리에틸아민을 적가하여 염기화시키고 제조예 47에서 합성한 N-Boc-(R)-(테트라하이드로이소퀴놀릭 에시드)-(R)-4-Cl-페닐알라닌 (191.7 mg, 0.42 mmol), EDC (106.5 mg, 0.55 mmol), HOBT (85.1 mg, 0.63 mmol) 및 Et3N (117.6 ml, 0.84 mmol)을 가한 다음 용액을 실온에서 12시간 동안 교반하였다. 반응이 완결된 용액을 0.5 N 염산 용액, 포화 탄산수소나트륨 수용액 및 소금물로 차례로 씻고 무수 MgSO4로 건조한 다음 감압 농축하였다. 잔유물을 관 크로마토그라피 (용리액, EtOAc/n-헥산 = 3/2)로 정제하여 Boc-보호기가 있는 표제화합물 263.5 mg (수율 91%)을 수득하였다. 얻어진 잔유물을 CH2Cl2(4 ml)에 녹이고 TFA (2 ml)를 가한 다음 용액을 실온에서 1시간 동안 교반하였다. 반응이 완결된 용액을 감압 농축하여 분취용 HPLC (용리액, TFA 0.1% 포함된 물/아세토니트릴 = 65/35 -> 30/70 (부피/부피))로 정제하여 표제화합물의 염 (202.7 mg, 수율: 91%)을 수득하였다.4,4-[(1-piperidin-1-yl), (1,2,4-triazol-1-yl) methyl] piperidine (100 mg, 0.42 mmol) synthesized in Step A was purified by DMF. N-Boc- (R)-(tetrahydroisoquinolinic acid)-(R) -4-Cl-phenylalanine (191.7), which was dissolved in (3 ml) and basified by dropwise addition of triethylamine. mg, 0.42 mmol), EDC (106.5 mg, 0.55 mmol), HOBT (85.1 mg, 0.63 mmol) and Et 3 N (117.6 ml, 0.84 mmol) were added and the solution was stirred at rt for 12 h. The reaction was completed, the solution was washed sequentially with 0.5 N 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) to give 263.5 mg (91% yield) of the title compound with Boc-protecting group. The residue obtained was taken up in CH 2 Cl 2 (4 ml), TFA (2 ml) was added and the solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and purified by preparative HPLC (eluent, water / acetonitrile containing 0.1% TFA = 65/35-> 30/70 (volume / volume)) to obtain the salt of the title compound (202.7 mg, Yield 91%).

MS[M+H] = 589MS [M + H] = 589

실시예 2 : 아세틸-(R)-테트라이소퀴놀릭-(R)-(4-클로로페닐)알라닐-[4-사이클로헥실-4-[(1,2,4-트리아졸-1-일)메틸]]피페리디드 TFA염Example 2: Acetyl- (R) -Tetraisoquinolic- (R)-(4-chlorophenyl) alanyl- [4-cyclohexyl-4-[(1,2,4-triazol-1-yl ) Methyl]] piperidide TFA salt

실시예 1에서 수득한 화합물 (100.0 mg, 0.17 mmol)을 DMF (3 ml) 에 녹이고 여기에 빙초산 (10.2 g, 0.17 mmol), EDC (43.1 mg, 0.22 mmol), HOBT (34.4 mg, 0.26 mmol) 및 Et3N (47.6 ml, 0.34 mmol)을 가한 다음 용액을 실온에서 12시간 동안 교반하였다. 반응액을 바로 감압 농축한 다음 잔유물을 분취용 HPLC (용리액, TFA 0.1% 포함된 물/아세토니트릴 = 65/35 -> 55/45 (부피/부피))로 정제하여 표제화합물 (94.4 mg, 수율: 88%)을 수득하였다.The compound obtained in Example 1 (100.0 mg, 0.17 mmol) was dissolved in DMF (3 ml), to which was glacial acetic acid (10.2 g, 0.17 mmol), EDC (43.1 mg, 0.22 mmol), HOBT (34.4 mg, 0.26 mmol) And Et 3 N (47.6 ml, 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 (volume / volume)) to obtain the title compound (94.4 mg, yield). : 88%) was obtained.

MS[M+H] = 632MS [M + H] = 632

실시예 3 - 50Examples 3-50

하기 표에 서술된 실시예 화합물들 (G =이고, A = H일 경우) 은, 중간체 제조예 1-47 에서 합성되어진 N 말단이 보호된 아미노산과 또는 상업화된 아미노산으로부터 실시예 1과 동일한 방법으로 반응을 수행하여 수득하였다. 그 외 실시예의 화합물은 (A = H 아닐 경우), 실시예 2 와 동일한 방법으로 반응을 수행하여 수득하였다.Example compounds described in the table below (G = , And A = H) was obtained by carrying out the reaction in the same manner as in Example 1 from the N-terminal protected amino acid synthesized in Intermediate Preparation Example 1-47 or a commercialized amino acid. The compounds of the other examples (if not A = H) were obtained by carrying out the reaction in the same manner as in Example 2.

실시예 51 : (S)-히스티딜-(R)-(4-클로로페닐)알라닐-[4-사이클로헥실-4-[(1,2,4-트리아졸-1-일)메틸]]피페리디드 2TFA염Example 51: (S) -Histidyl- (R)-(4-chlorophenyl) alanyl- [4-cyclohexyl-4-[(1,2,4-triazol-1-yl) methyl]] Piperidide 2TFA salt

실시예 1의 단계 A에서 합성한 4,4-[(1-피페리딘-1-일), (1,2,4-트리아졸-1-일)메틸]피페리딘 (100 mg, 0.42 mmol)를 DMF (3 ml)에 녹이고 트리에틸아민을 적가하여 염기화시키고 제조예 46에서 얻은 N-Boc-(S)-(3-Boc)-히스티딜메틸-(R)-4-Cl-알라닌 (225.5 mg, 0.42 mmol), EDC (106.5 mg, 0.55 mmol), HOBT (85.1 mg, 0.63 mmol) 및 Et3N (117.6 ml, 0.84 mmol)을 가한 다음 용액을 실온에서 12시간 동안 교반하였다. 반응이 완결된 용액을 0.5 N 염산 용액, 포화 탄산수소나트륨 수용액 및 소금물로 차례로 씻고 무수 MgSO4로 건조한 다음 감압 농축하였다. 잔유물을 관 크로마토그라피 (용리액, EtOAc/n-헥산 = 3/2)로 정제하여 Boc-보호기가 있는 표제화합물 287.0 mg (수율 89%)을 수득하였다. 얻어진 잔유물을 CH2Cl2(4 ml)에 녹이고 TFA (2 ml)를 가한 다음 용액을 실온에서 1시간 동안 교반하였다. 반응이 완결된 용액을 감압 농축하여 분취용 HPLC (용리액, TFA 0.1% 포함된 물/아세토니트릴 = 65/35 -> 30/70 (부피/부피))로 정제하여 표제화합물의 염 (106.8 mg, 수율: 89 %)을 수득하였다.4,4-[(1-piperidin-1-yl), (1,2,4-triazol-1-yl) methyl] piperidine synthesized in Step A of Example 1 (100 mg, 0.42 mmol) was dissolved in DMF (3 ml) and basified by dropwise addition of triethylamine. N-Boc- (S)-(3-Boc) -histidylmethyl- (R) -4-Cl- obtained in Preparation 46 Alanine (225.5 mg, 0.42 mmol), EDC (106.5 mg, 0.55 mmol), HOBT (85.1 mg, 0.63 mmol) and Et 3 N (117.6 ml, 0.84 mmol) were added and the solution was stirred at rt for 12 h. The reaction was completed, the solution was washed sequentially with 0.5 N 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) to give 287.0 mg (89% yield) of the title compound with Boc-protecting group. The residue obtained was taken up in CH 2 Cl 2 (4 ml), TFA (2 ml) was added and the solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and purified by preparative HPLC (eluent, water / acetonitrile containing 0.1% TFA = 65/35-> 30/70 (volume / volume)) to obtain the salt of the title compound (106.8 mg, Yield: 89%).

MS[M+H] = 567MS [M + H] = 567

실시예 52 : 아세틸-(S)-히스티딜-(R)-(4-클로로페닐)알라닐-[4-사이클로헥실-4-[(1,2,4-트리아졸-1-일)메틸]]피페리디드 TFA염Example 52 Acetyl- (S) -Histidyl- (R)-(4-chlorophenyl) alanyl- [4-cyclohexyl-4-[(1,2,4-triazol-1-yl) methyl Piperidide TFA Salt

실시예 51에서 수득한 화합물 (80.0 mg, 0.14 mmol) 을 DMF (3 ml) 에 녹이고 여기에 빙초산 (16.8 g, 0.28 mmol), EDC (70.3 g, 0.36 mmol), HOBT (56.7 g, 0.42 mmol) 및 Et3N (78.4 ml, 0.56 mmol)을 가한 다음 용액을 실온에서 12시간 동안 교반하였다. 반응액을 바로 감압 농축한 다음 잔유물을 분취용 HPLC (용리액, TFA 0.1% 포함된 물/아세토니트릴 = 65/35 -> 55/45 (부피/부피))로 정제하여 표제화합물 (68.4 mg, 수율: 88 %)을 수득하였다.The compound obtained in Example 51 (80.0 mg, 0.14 mmol) was dissolved in DMF (3 ml), to which was glacial acetic acid (16.8 g, 0.28 mmol), EDC (70.3 g, 0.36 mmol), HOBT (56.7 g, 0.42 mmol) And Et 3 N (78.4 ml, 0.56 mmol) were added and the solution was stirred at rt for 12 h. 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-> 55/45 (volume / volume)) to obtain the title compound (68.4 mg, yield). : 88%) was obtained.

MS[M+H] = 609MS [M + H] = 609

실시예 53 - 106Examples 53-106

하기 표에 서술된 실시예 화합물들 (G =이고, A = H일 경우)은, 중간체 제조예 1-47에서 합성되어진 N 말단이 보호된 아미노산과 또는 상업화된 아미노산으로부터 실시예 51과 동일한 방법으로 반응을 수행하여 수득하였다. 그 외 실시예의 화합물은 (A = H 아닐 경우), 실시예 52와 동일한 방법으로 반응을 수행하여 수득하였다.Example compounds described in the table below (G = And A = H) were obtained by carrying out the reaction in the same manner as in Example 51 from the N-terminal protected amino acid synthesized in Intermediate Preparation Example 1-47 or a commercialized amino acid. The compounds of the other examples (if not A = H) were obtained by carrying out the reaction in the same manner as in Example 52.

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

본 발명의 화합물은 하기 설명하는 A, B 및 C 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 were evaluated by measuring the agonistic activity against the activity of the melanocortin receptor (MCR) and the binding capacity to MCR according to the methods A, B and C described below.

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

본 발명의 화합물에 대한 MCR 항진제로서의 활성을 측정하는 방법 중의 하나로서 세포 내 cAMP 함량의 증가에 비례하는 표지 유전자 (예, 루시퍼라제)의 발현 양을 측정하였다.As one of the methods for measuring the activity as an MCR agonist against the compounds of the present invention, the amount of expression of a label gene (eg, luciferase) in proportion to the increase in the cAMP content in the cell 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 세포주들은 6% CO2가 존재하는 37oC 항온 배양기에서 선택 배지(10% 열-불활성화된 소 태자 혈청(Gibco/BRL), 100 unit/ml 페니실린(Gibco/BRL), 100 unit/ml 스트렙토마이신(Gibco/BRL), 200 ug/ml 제네티신(G418) (Gibco/BRL)을 함유한 DMEM(Dulbecco's Modified Eagles Medium)을 사용하여 배양하였다. 직경 100 mm 배양접시에 세포가 전체면적의 70% 정도가 되었을 때 10 ml의 Ca++과 Mg++이 함유되지 않은 인산완충액(Phosphate Buffered Saline : PBS)으로 1회 세척한 다음, 0.05% 트립신과 0.53 mM EDTA를 함유한 PBS용액 3 ml을 가하였다. 상기 트립신/EDTA 용액을 제거하고 37oC 항온 배양기에서 1분간 배양한 뒤 10 ml의 선택배지에 다시 현탁시키고 1500 rpm에서 5분간 원심분리하였다. 상층액을 제거한 뒤 침전된 세포들을 5 ml의 페놀레드 (Phenol Red)가 함유되지 않은 선택배지로 다시 현탁시켰다. 상기 세포현탁액을 96-웰 발광측정기 (Luminometer)용 세포 배양 판 (Costar)의 각 웰에 100 ㎕의 배양액에 5 X 104세포가 되도록 첨가한 뒤 6% CO2가 존재하는 37oC 항온 배양기에서 18시간 동안 배양하였다. 상기 배양액을 사용하여 각 단계별 농도로 희석시킨 MCR 항진제 (실시예 화합물)를 최종 DMSO 농도가 1 %를 넘지 않게 처리한 다음 6% CO2가 존재하는 37oC 항온 배양기에서 5시간 동안 배양하였다. 각 웰에 50 ㎕의 Bright-Glo 루시페라제 시약 (Promega)를 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 ㎛의 NDP-MSH처리에 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 selected in 37 ° C. incubator with 6% CO 2 in selection medium (10% heat-inactivated fetal bovine serum (Gibco / BRL), 100 unit / ml penicillin (Gibco / BRL), 100 unit / ml). Cultured using Dulbecco's Modified Eagles Medium (DMEM) containing streptomycin (Gibco / BRL), 200 ug / ml Geneticin (G418) (Gibco / BRL) Cells were prepared in a 100 mm diameter dish. At about 70%, wash once with 10 ml of Ca ++ and Mg ++ phosphate buffer (PBS), then 3 ml of PBS solution containing 0.05% trypsin and 0.53 mM EDTA. The trypsin / EDTA solution was removed and incubated for 1 minute in a 37 ° C. incubator, then re-suspended in 10 ml of selection medium and centrifuged at 1500 rpm for 5 minutes. It was resuspended in a selection medium that did not contain 5 ml of phenol red. Solution to a 96-well luminescence meter (Luminometer) cell culture plate 18 eseo 37 o C constant temperature incubator to 5 X 10 4 cells is a back 6% CO 2 was added to the culture medium in the presence 100 ㎕ to each well of (Costar) for The culture medium was used to treat the MCR adjuvants (Example compound) diluted to each step concentration to a final DMSO concentration of no greater than 1% and then in a 37 ° C. incubator with 6% CO 2. Each well was treated with 50 μl of Bright-Glo Luciferase Reagent (Promega), and then allowed to stand at room temperature for 15 minutes, followed by Luminometer (Luminometer, Victor). The amount of luminescence induced by the antidiarrheal agent diluted at each step concentration was converted into a% value relative to the amount indicated by NDP-MSH treatment of 10 μm. EC 50 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 발명의 화합물이 MCR 항진제로서의 활성을 측정하는 또 다른 방법으로서 세포내 cAMP 함량의 증가를 측정하였다.As another method of measuring the activity of the compounds of the present invention as MCR agonists, an increase in 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 ml의 배양액에 2 x 105세포가 되도록 첨가한 뒤 6% CO2가 존재하는 37oC 항온 배양기에서 24시간 동안 배양하였다. 각 웰의 배지를 제거하고 0.5 ml의 차가운 DMEM으로 1회 세척해 주었다. 500 ㎛ IBMX(이소부틸메틸잔틴)를 함유한 DMEM 200 ㎕를 사용하여 단계별 농도로 희석시킨 MCR 항진제 (실시예 화합물) 를 최종 DMSO 농도가 1 %를 넘지 않게 처리한 다음 6% CO2가 존재하는 37oC 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 placed in 1 ml of culture per well of a 24-well cell culture plate (Costar). x 10 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 cold DMEM. MCR adjuvants (Example compounds) diluted to 200 μl DMEM containing 500 μm IBMX (isobutylmethylxanthine) at a stepwise concentration were treated with a final DMSO concentration of no greater than 1% and then with 6% CO 2 present. Incubated for 30 minutes in a 37 ° C. incubator. The content of cAMP in each cell was measured using the Amersham cAMP measurement kit (TRK432).

좀 더 상세하게 서술하면, 각 웰에 14.4 ㎕의 6 M PCA (60%)를 가하고 10분 동안 얼음에 방치한 다음 200 ㎕씩을 취하여 미세원심분리튜브로 옮겼다. 여기에 11 ㎕의 5M KOH / 1M 트리스를 가하여 중화시킨 뒤 12,000 rpm으로 1분간 원심분리 시켰다. 상층액 50 ㎕를 취한 후 50 ㎕의3H 으로 표지된 cAMP (0.9 pmol, 0.025uCi)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 4oC에서 12,000 rpm으로 3분간 원심분리하였다. 상층액 200 ㎕를 취한 후 신틸레이션(scintillation) 바이알에 넣고 5 ml의 신틸런트(scintillant)를 가한 다음 방사능을 측정하였다.In more detail, 14.4 μl of 6 M PCA (60%) was added to each well, left on ice for 10 minutes, and then 200 μl was transferred to the 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 uCi) 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 into a scintillation vial, 5 ml of scintillant was added, and radioactivity was measured.

각 단계별 농도로 희석된 항진제에 의해 유도되는 cAMP의 양은 10 ㎛의 NDP-MSH처리에 의해 나타나는 양에 대한 상대적인 % 값으로 환산하였다. EC50는 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 into a% value relative to the amount indicated by the NDP-MSH treatment of 10 μm. EC 50 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 배양판 (Costar)의 각 웰당 100 ㎕의 배양액에 1 x 105세포가 되도록 첨가한 뒤 6% CO2가 존재하는 37oC 항온 배양기에서 48시간 동안 배양하였다. 각 웰의 배지를 제거하고 150 ㎕의 차가운 흡착용액 (binding buffer ; 50 mM 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 0.2 N NaOH 를 가하고 실온에서 15분 동안 방치하였다. 각 웰에 담긴 용액을 5 ml 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 1 × in 100 μl of culture per well of a 96-well cell culture plate (Costar). 10 5 cells were added and then incubated 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 adsorption solution (RPM 1640 containing 50 mM HEPES and 1% BSA). 100 μl of an adsorption solution containing 0.1 nM of 125 I-NDP-MSH (NEN NEX352) 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 0.2 N 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 5 uM NDP-MSH 존재하에서 의 0.1 nM125I-NDP-MSH의 비특이적 결합 양을 제외한 값을125I-NDP-MSH의 특이결합 양으로 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.The total binding amount when only 0.1 nM of 125 I-NDP-MSH was added, excluding the non-specific binding amount of 0.1 nM 125 I-NDP-MSH in the presence of 5 uM NDP-MSH, was specific for 125 I-NDP-MSH. Used as binding amount. 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. IC 50 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 MCR에 대한 항진효능 및 결합 효과를 나타내는 것으로 확인되었다. 이들은 특히 MC4R에 대해 우수한 항진 효능과 결합 효과를 보였으며, 0.005 μM 내지 10 μM의 EC50값과 0.01 μM 내지 50 μM의 IC50값을 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 antifungal and binding effects on each MCR. They showed particularly good anti-inflammatory and binding effects for MC4R, with EC 50 values of 0.005 μM to 10 μM and IC 50 values of 0.01 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] 상기식에서,In the above formula, G는 하기 구조중 하나를 나타내고:G represents one of the following structures: , , 여기에서,From here, A는 수소, COR1, CO2R1, SO2R1, SO2NHR1, SO2N(R1)2, PO(OR1)2, C1-8알킬, (CH2)n-아릴 또는 (CH2)n-헤테로아릴을 나타내고, 여기서 R1은 수소, C1-8알킬, (CH2)n-C3-7사이클로알킬, (CH2)n-아릴 또는 (CH2)n-헤테로아릴을 나타내며, n은 1 내지 7의 정수를 나타내며, 알킬, 아릴, 헤테로아릴은 할로겐, C1-5알킬, 트리플루오로메틸, 하이드록시, C1-3알킬옥시, 아미노, (C1-3알킬)아미노, (C1-3알킬)2아미노, 시아노, 카복시 (CO2H), 에스테르 (CO2-C1-3알킬), 아미드 (CONH2)로 이루어진 그룹 중에서 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 1-8 alkyl, (CH 2 ) n − Aryl or (CH 2 ) n -heteroaryl, wherein R 1 is hydrogen, C 1-8 alkyl, (CH 2 ) n -C 3-7 cycloalkyl, (CH 2 ) n -aryl or (CH 2 ) n -heteroaryl, n represents an integer from 1 to 7, alkyl, aryl, heteroaryl represents halogen, C 1-5 alkyl, trifluoromethyl, hydroxy, C 1-3 alkyloxy, amino, ( C 1-3 alkyl) amino, (C 1-3 alkyl) 2 amino, cyano, carboxy (CO 2 H), ester (CO 2 -C 1-3 alkyl), amide (CONH 2 ) Unsubstituted or substituted by 1 to 3 substituents; B와 E는 각각 독립적으로, 수소, C1-8알킬, (CH2)n-C3-7사이클로알킬, (CH2)n-아릴, (CH2)n-헤테로아릴, (CH2)n-헤테로사이클, (CH2)n-아미노, (CH2)n-(알킬)아미노, (CH2)n-(디알킬)아미노, (CH2)n-아미드(CONH2) 또는 (CH2)n-O(CH2)아릴을 나타내고, 여기에 알킬, 사이클로알킬,아릴, 헤테로아릴, 헤테로사이클은 할로겐, C1-5알킬, 트리플루오로메틸, 하이드록시, C1-3알킬옥시, 아미노, (C1-3알킬)아미노, (C1-3알킬)2아미노, 시아노, 카복시 (CO2H), 에스테르 (CO2-C1-3알킬), 아미드 (CONH2), 아미딘 (C(NH)NH2), 니트로로 이루어진 그룹 중에서 선택된 1개 내지 3개의 치환체에 의해 치환되거나 비치환되고, n은 0 내지 7의 정수를 나타내며;B and E are each independently hydrogen, C 1-8 alkyl, (CH 2 ) n -C 3-7 cycloalkyl, (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, (CH 2 ) n -heterocycle, (CH 2 ) n -amino, (CH 2 ) n- (alkyl) amino, (CH 2 ) n- (dialkyl) amino, (CH 2 ) n -amide (CONH 2 ) or (CH 2 ) n- O (CH 2 ) aryl, wherein alkyl, cycloalkyl , aryl, heteroaryl, heterocycle is halogen, C 1-5 alkyl, trifluoromethyl, hydroxy, C 1-3 alkyloxy , Amino, (C 1-3 alkyl) amino, (C 1-3 alkyl) 2 amino, cyano, carboxy (CO 2 H), ester (CO 2 -C 1-3 alkyl), amide (CONH 2 ), Amidine (C (NH) NH 2 ), substituted or unsubstituted with one to three substituents selected from the group consisting of nitro, n represents an integer from 0 to 7; C는 할로겐, C1-5알킬, 트리플루오로메틸, 하이드록시, C1-3알킬옥시, 아미노, (C1-3알킬)아미노, (C1-3알킬)2아미노, 시아노, 카복시(CO2H), CO2-C1-3알킬, CONH2, 아미딘(C(NH)NH2), 니트로 및 옥소 (C=O)로 이루어진 그룹 중에서 선택된 치환체(들)에 의해 치환되거나 비치환될 수 있는, (CH2)m-헤테로아릴, (CH2)m-헤테로사이클, (CH2)m-NH-헤테로아릴, (CH2)m-NH-헤테로사이클, (CH2)m-NH-(알킬설포닐),(CH2)m-NH-(아릴설포닐), (CH2)m-NH-알콕시카보닐, (CH2)m-NH-알킬아미노 카바모일, (CH2)m-NH-C(O)-헤테로아릴, (CH2)m-NH-C(O)-헤테로사이클, (CH2)m-NH-(CH2)m-헤테로아릴, (CH2)m-NH-(CH2)m-헤테로사이클, (CH2)m-NH-C(O)-(CH2)m-헤테로아릴, (CH2)m-NH-C(O)-(CH2)m-헤테로사이클, C(O)-헤테로사이클, (CH2)m-NH-알킬에스터, (CH2)m-NH-알킬 아마이드, 알콕시카보닐, (CH2)m-O-(알킬설포닐), (CH2)m-O-(아릴설포닐), 알킬아미노 카바모일, 하이드록시알킬 아미노 카바모일, 아릴아미노 카바모일 또는 수소를 나타내며, 여기서, 헤테로아릴은 고리안에 1- 4개의 N이나 O 또는 S를 함유하고 있는 원자수가 5 혹은 6, 7인 고리 방향족 화합물이고, 헤테로사이클은 고리안에 1-2개의 N, O 또는 S를 갖는 원자수가 5, 6 혹은 7인 고리 화합물이며, m은 0 내지 2의 정수를 나타내고;C is halogen, C 1-5 alkyl, trifluoromethyl, hydroxy, C 1-3 alkyloxy, amino, (C 1-3 alkyl) amino, (C 1-3 alkyl) 2 amino, cyano, carboxy Or substituted by substituent (s) selected from the group consisting of (CO 2 H), CO 2 -C 1-3 alkyl, CONH 2 , amidine (C (NH) NH 2 ), nitro and oxo (C═O) (CH 2 ) m -heteroaryl, (CH 2 ) m -heterocycle, (CH 2 ) m -NH-heteroaryl, (CH 2 ) m -NH-heterocycle, (CH 2 ) m- NH- (alkylsulfonyl), (CH 2 ) m -NH- (arylsulfonyl), (CH 2 ) m -NH-alkoxycarbonyl, (CH 2 ) m -NH-alkylamino carbamoyl, ( CH 2 ) m -NH-C (O) -heteroaryl, (CH 2 ) m -NH-C (O) -heterocycle, (CH 2 ) m -NH- (CH 2 ) m -heteroaryl, (CH 2) m -NH- (CH 2) m - heterocycle, (CH 2) m -NH- C (O) - (CH 2) m - heteroaryl, (CH 2) m -NH- C (O) - (CH 2) m - heterocyclyl, C (O) - heterocyclyl, (CH 2) m -NH- alkyl esters, (CH 2) m -NH- alkyl amide, alkoxy Carbonyl group, a (CH 2) m -O- (alkyl sulfonyl), (CH 2) m -O- (arylsulfonyl) alkylamino carbamoyl, hydroxy alkyl, amino-carbamoyl, aryl-amino-carbamoyl, or hydrogen Wherein heteroaryl is a ring aromatic compound having 5, 6, or 7 atoms containing 1-4 N, O or S in the ring, and heterocycle is 1-2 N, O or S in the ring A ring compound having 5, 6, or 7 atoms, and m represents an integer of 0 to 2; D는 피페리딘, 피롤리딘, 헥사메틸렌이민, 2 혹은 3 옥소 피페리딘 및 헥사메틸렌이민, 피롤리딘 혹은 디알킬아민 그 자체나 이들의 치환된 유도체를 나타내며;D represents piperidine, pyrrolidine, hexamethyleneimine, 2 or 3 oxo piperidine and hexamethyleneimine, pyrrolidine or dialkylamine itself or substituted derivatives thereof; Cy는 C1-C5-알킬, 할로겐, 트리플루오로메틸, 하이드록시, C1-C3-알킬옥시, 아미노, (C1-C3-알킬)아미노, 디(C1-C3-알킬)아미노 및 옥소(C=O) 및 니트로로 구성된 그룹 중에서 선택된 치환체(들)에 의해 치환되거나 비치환된, C5-C7-아릴 혹은 C5-7사이클로알킬을 나타낸다.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 5-7 cycloalkyl unsubstituted or substituted by substituent (s) selected from the group consisting of alkyl) amino and oxo (C═O) and nitro. 제 1항에 있어서, A는 수소, COR1, CO2R1, SO2R1, SO2NHR1, SO2N(R1)2, PO(OR1)2 , C1-8알킬, (CH2)n-아릴 또는 (CH2)n-헤테로아릴을 나타내며, R1은 수소, C1-8알킬, (CH2)n-아릴 또는 (CH2)n-C3-7사이클로알킬을 나타내고, n은 1 내지 3의 정수를 나타내는 화합물.The compound of claim 1, wherein A is hydrogen, COROne, CO2ROne, SO2ROne, SO2NHROne, SO2N (ROne)2, PO (OROne)2 , C1-8Alkyl, (CH2)n-Aryl or (CH2)nHeteroaryl, ROneSilver hydrogen, C1-8Alkyl, (CH2)n-Aryl or (CH2)n-C3-7A cycloalkyl, wherein n represents an integer of 1 to 3; 제 1항에 있어서, B는 할로겐, C1-5알킬, 트리플루오로메틸, 하이드록시, C1-3알킬옥시, 아미노, (C1-3알킬)아미노, (C1-3알킬)2아미노, 시아노, 카복시(CO2H), CO2-C1-3알킬, CONH2, 아미딘(C(NH)NH2), 니트로로 이루어진 그룹 중에서 선택된 1개 내지 2개의 치환체에 의해 치환되거나 비치환되는, 벤질, CH2-피리딜, CH2-피리미딜, 또는 CH2-5환-헤테로아릴인 화합물.The compound of claim 1, wherein B is halogen, C 1-5 alkyl, trifluoromethyl, hydroxy, C 1-3 alkyloxy, amino, (C 1-3 alkyl) amino, (C 1-3 alkyl) 2 Substituted by 1 to 2 substituents selected from the group consisting of amino, cyano, carboxy (CO 2 H), CO 2 -C 1-3 alkyl, CONH 2 , amidine (C (NH) NH 2 ), nitro , benzyl, or unsubstituted ring is CH 2-pyridyl, CH 2-pyrimidyl, or CH 2 -5 ring-heteroaryl compounds. 제 3항에 있어서, B는 할로겐, C1-3알킬, 트리플루오로메틸, 메톡시, 에톡시, 메틸아미노, 디메틸아미노로 이루어진 그룹 중에서 선택된 1개 내지 2개의 치환체에 의해 치환되거나 비치환된, 벤질 또는 CH2-피리딜인 화합물.The compound of claim 3, wherein B is unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of halogen, C 1-3 alkyl, trifluoromethyl, methoxy, ethoxy, methylamino, dimethylamino , Benzyl or CH 2 -pyridyl. 제 1항에 있어서, C는 할로겐, 메틸, 에틸, 트리플루오로메틸, 하이드록시,메톡시, 에톡시, 아미노, 메틸아미노 또는 디메틸아미노로 이루어진 그룹 중에서 선택된 치환체에 의해 치환된 (CH2)m-헤테로아릴인 화합물.The compound of claim 1, wherein C is (CH 2 ) m substituted with a substituent selected from the group consisting of halogen, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, amino, methylamino or dimethylamino A compound that is heteroaryl. 제 5항에 있어서, C는 할로겐, 메틸, 에틸, 메톡시, 에톡시, 메틸아미노 또는 디메틸아미노로 이루어진 그룹 중에서 선택된 치환체에 의해 치환된, CH2-피롤, CH2-이미다졸, CH2-피라졸, CH2-티아졸, CH2-옥사졸, CH2-트리아졸, CH2-테트라졸, CH2-피리딘, CH2-피리미딘, CH2-피라진 또는 CH2-트리아진인 화합물.6. CH 2 -pyrrole, CH 2 -imidazole, CH 2 -according to claim 5, wherein C is substituted by a substituent selected from the group consisting of halogen, methyl, ethyl, methoxy, ethoxy, methylamino or dimethylamino. A compound that is 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. 제 1항에 있어서, C는 수소, 알콕시카보닐, (CH2)m-O-(알킬설포닐), (CH2)m-O-(아릴설포닐), 알킬아미노 카바모일, 아릴아미노 카바모일, 하이드록시알킬 아미노 카바모일, C(O)-피페리딘, C(O)-피페라진, (CH2)m-NH-(알킬설포닐), (CH2)m-NH-아릴설포닐, (CH2)m-NH-알킬에스터, (CH2)m-NH-알킬아마이드, (CH2)m-NH-C(O)-트리아졸, (CH2)m-NH-C(O)-테트라졸, (CH2)m-NH-C(O)-이미다졸, (CH2)m-NH-C(O)-이미다졸-2-온, (CH2)m-NH-C(O)-옥사졸, (CH2)m-NH-C(O)-아미노사이아졸, (CH2)m-NH-C(O)-티오다이아졸론, (CH2)m-NH-C(O)-옥사졸론, (CH2)m-NH-(CH2)m-이미다졸, (CH2)m-NH-(CH2)m-트리아졸, (CH2)m-NH-(CH2)m-테트라졸, (CH2)m-NH-(CH2)m-아미노사이아졸, (CH2)m-NH-(CH2)m-옥사졸, (CH2)m-NH-(CH2)m-옥사졸론, (CH2)m-NH-C(O)-(CH2)m-이미다졸, (CH2)m-NH-C(O)-(CH2)m-트리아졸, (CH2)m-NH-C(O)-(CH2)m-테트라졸, (CH2)m-NH-C(O)-(CH2)m-아미노사이아졸, (CH2)m-NH-C(O)-(CH2)m-옥사졸, (CH2)m-NH-C(O)-(CH2)m-티오다이아졸론 또는 (CH2)m-NH-C(O)-(CH2)m-옥사졸론인 화합물.C is hydrogen, alkoxycarbonyl, (CH 2 ) m -O- (alkylsulfonyl), (CH 2 ) m -O- (arylsulfonyl), alkylamino carbamoyl, arylamino carba Moyl, hydroxyalkyl amino carbamoyl, C (O) -piperidine, C (O) -piperazine, (CH 2 ) m -NH- (alkylsulfonyl), (CH 2 ) m -NH-arylsul Ponyl, (CH 2 ) m -NH-alkylester, (CH 2 ) m -NH-alkylamide, (CH 2 ) m -NH-C (O) -triazole, (CH 2 ) m -NH-C ( O) -tetrazol, (CH 2 ) m -NH-C (O) -imidazole, (CH 2 ) m -NH-C (O) -imidazol-2-one, (CH 2 ) m -NH- C (O) -oxazole, (CH 2 ) m -NH-C (O) -aminothiazol, (CH 2 ) m -NH-C (O) -thiodiazolone, (CH 2 ) m -NH- C (O) -oxazolone, (CH 2 ) m -NH- (CH 2 ) m -imidazole, (CH 2 ) m -NH- (CH 2 ) m -triazole, (CH 2 ) m -NH- (CH 2 ) m -tetrazole, (CH 2 ) m -NH- (CH 2 ) m -aminothiazol, (CH 2 ) m -NH- (CH 2 ) m -oxazole, (CH 2 ) m- NH- (CH 2 ) m -oxazolone, (CH 2 ) m -NH-C (O)-(CH 2 ) m -imidazole, (CH 2 ) m -NH-C (O)-(CH 2 ) m - tree Sol, (CH 2) m -NH- C (O) - (CH 2) m - tetrazole, (CH 2) m -NH- C (O) - (CH 2) m - between amino azole, (CH 2 ) m -NH-C (O)-(CH 2 ) m -oxazole, (CH 2 ) m -NH-C (O)-(CH 2 ) m -thiodiazolone or (CH 2 ) m -NH- C (O)-(CH 2 ) m -oxazolone. 제 1항에 있어서, D는 피롤리딘, 피페리딘, 헥사메틸렌이민, 디알킬아민 그 자체이거나 이들의 치환된 유도체인 화합물A compound according to claim 1, wherein D is pyrrolidine, piperidine, hexamethyleneimine, dialkylamine itself or substituted derivatives thereof. 제 1항에 있어서, E는 C3-7알킬, CH2-C3-7사이클로알킬, CH2-아릴, (CH2)n-아미노, (CH2)n-(알킬)아미노, (CH2)n-(디알킬)아미노, (CH2)n-아미드(CONH2), CH2-헤테로아릴 또는 CH2-헤테로사이클인 화합물 (여기에서, 사이클로알킬, 아릴, 헤테로아릴, 헤테로사이클은 할로겐, C1-5알킬, 트리플루오로메틸, 하이드록시, C1-3알킬옥시, 아미노, (C1-3알킬)아미노, (C1-3알킬)2아미노, 시아노, 카복시(CO2H), -CO2-C1-3알킬, CONH2, 아미딘 (C(NH)NH2), 니트로로 이루어진 그룹 중에서 선택된 1개 내지 3개의 치환체에 의해 치환되거나 비치환됨).The compound of claim 1, wherein E is C 3-7 alkyl, CH 2 -C 3-7 cycloalkyl, CH 2 -aryl, (CH 2 ) n -amino, (CH 2 ) n- (alkyl) amino, (CH 2) n - (dialkyl) amino-, (CH 2) n - amide (CONH 2), CH 2 - heteroaryl or a CH 2 - heterocycle, a compound (wherein cycloalkyl, aryl, heteroaryl, heterocycle Halogen, C 1-5 alkyl, trifluoromethyl, hydroxy, C 1-3 alkyloxy, amino, (C 1-3 alkyl) amino, (C 1-3 alkyl) 2 amino, cyano, carboxy (CO 2 H), -CO 2 -C 1-3 alkyl, CONH 2 , amidine (C (NH) NH 2 ), substituted or unsubstituted by 1 to 3 substituents selected from the group consisting of nitro). 제 9항에 있어서, E는 CH2-헤테로아릴 또는 CH2-헤테로사이클 (여기서, 헤테로아릴 및 헤테로사이클은 할로겐, 메틸, 에틸, 트리플루오로메틸, 하이드록시, 메톡시, 에톡시, 아미노, 메틸아미노, 디메틸아미노로 이루어진 그룹 중에서 선택된 1개 내지 3개의 치환체에 의해 치환되거나 비치환됨)인 화합물.The compound of claim 9, wherein E is CH 2 -heteroaryl or CH 2 -heterocycle, wherein the heteroaryl and heterocycle are halogen, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, amino, Unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of methylamino and dimethylamino. 제 10항에 있어서, E는 할로겐, 메틸, 에틸, 트리플루오로메틸, 하이드록시, 메톡시, 에톡시, 아미노, 메틸아미노 또는 디메틸아미노로 이루어진 그룹 중에서 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-헥사메틸렌이민인 화합물.The compound of claim 10, wherein E is substituted or unsubstituted by one to three substituents selected from the group consisting of halogen, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, amino, methylamino or dimethylamino Ring, CH 2 -imidazole, CH 2 -pyrazole, CH 2 -thiazole, CH 2 -oxazole, CH 2 -triazole, CH 2 -pyridine, CH 2-1 -piperidine or CH 2- A compound that is 1-hexamethyleneimine. 제 1항에 있어서, Cy는 페닐 또는 사이클로헥실인 화합물.The compound of claim 1, wherein Cy is phenyl or cyclohexyl. 제 1항에 있어서, A는 수소, COR1, CO2R1, SO2R1, SO2NHR1, SO2N(R1)2, PO(OR1)2 , C1-8알킬, (CH2)n-아릴 또는 (CH2)n-헤테로아릴을 나타내며; R1은 수소, C1-8알킬, (CH2)n-아릴 또는 (CH2)n-C3-7사이클로알킬 (여기서, n은 1 내지 3의 정수임)을 나타내고; B는 할로겐, C1-3알킬, 트리플루오로메틸, 메톡시, 에톡시, 메틸아미노, 디메틸아미노로 이루어진 그룹 중에서 선택된 1개 내지 2개의 치환체에 의해 치환되거나 비치환된 벤질 또는 피리딜이고; C는 할로겐, 메틸, 에틸, 메톡시, 에톡시, 메틸아미노 또는 디메틸아미노로 이루어진 그룹 중에서 선택된 치환체에 의해 치환된, CH2-피롤, 알콕시카보닐, (CH2)m-O-(알킬설포닐), (CH2)m-O-(아릴설포닐), 알킬아미노 카바모일, 아릴 아미노 카바모일, 피페리딘 카바모일, CH2-이미다졸, CH2-피라졸, CH2-티아졸, CH2-옥사졸, CH2-트리아졸, CH2-테트라졸, CH2-피리딘, CH2-피리미딘, CH2-피라진, CH2-트리아진, (CH2)m-NH-(알킬설포닐), (CH2)m-NH-아릴설포닐, (CH2)m-NH-알킬에스터, (CH2)m-NH-알킬아마이드, (CH2)m-NH-C(O)-트리아졸, (CH2)m-NH-C(O)-테트라졸, (CH2)m-NH-C(O)-이미다졸, (CH2)m-NH-C(O)-이미다졸-2-온, (CH2)m-NH-C(O)-옥사졸, (CH2)m-NH-C(O)-아미노사이아졸, (CH2)m-NH-C(O)-티오다이아졸론, (CH2)m-NH-C(O)-옥사졸론, (CH2)m-NH-(CH2)m-이미다졸, (CH2)m-NH-(CH2)m-트리아졸, (CH2)m-NH-(CH2)m-테트라졸, (CH2)m-NH-(CH2)m-아미노사이아졸, (CH2)m-NH-(CH2)m-옥사졸, (CH2)m-NH-(CH2)m-옥사졸론, (CH2)m-NH-C(O)-(CH2)m-이미다졸, (CH2)m-NH-C(O)-(CH2)m-트리아졸, (CH2)m-NH-C(O)-(CH2)m-테트라졸, (CH2)m-NH-C(O)-(CH2)m-아미노사이아졸, (CH2)m-NH-C(O)-(CH2)m-옥사졸, (CH2)m-NH-C(O)-(CH2)m-티오다이아졸론 또는 (CH2)m-NH-C(O)-(CH2)m-옥사졸론을 나타내고; D는 피롤리딘, 피페리딘, 헥사메틸렌이민, 디알킬아민 그 자체이거나 그들의 치환된 유도체를 나타내고; E는 할로겐, 메틸, 에틸, 트리플루오로메틸, 하이드록시, 메톡시, 에톡시, 아미노, 메틸아미노 또는 디메틸아미노로 이루어진 그룹 중에서 선택된 치환체에 의해 치환되거나비치환된, CH2-이미다졸, CH2-피라졸, CH2-티아졸, CH2-옥사졸, CH2-트리아졸, CH2-피리딘, CH2-1-피페리딘, CH2-아미노, CH2-디메틸아미노, CH2-아미드 또는 CH2-1-헥사메틸렌이민을 나타내고; Cy는 페닐 혹은 사이클로헥실인 화합물.The compound of claim 1, wherein A is hydrogen, COROne, CO2ROne, SO2ROne, SO2NHROne, SO2N (ROne)2, PO (OROne)2 , C1-8Alkyl, (CH2)n-Aryl or (CH2)n-Heteroaryl; ROneSilver hydrogen, C1-8Alkyl, (CH2)n-Aryl or (CH2)n-C3-7Cycloalkyl, where n is an integer from 1 to 3; B is halogen, C1-3Benzyl or pyridyl unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of alkyl, trifluoromethyl, methoxy, ethoxy, methylamino, dimethylamino; C is CH, substituted by a substituent selected from the group consisting of halogen, methyl, ethyl, methoxy, ethoxy, methylamino or dimethylamino2-Pyrrole, alkoxycarbonyl, (CH2) m-O- (alkylsulfonyl), (CH2) m-O- (arylsulfonyl), alkylamino carbamoyl, aryl amino carbamoyl, piperidine carbamoyl, CH2Imidazole, CH2Pyrazole, CH2-Thiazole, CH2-Oxazole, CH2Triazole, CH2Tetrazole, CH2-Pyridine, CH2-Pyrimidine, CH2-Pyrazine, CH2Triazine, (CH2)m-NH- (alkylsulfonyl), (CH2)m-NH-arylsulfonyl, (CH2)m-NH-alkylester, (CH2)m-NH-alkylamides, (CH2)m-NH-C (O) -triazole, (CH2)m-NH-C (O) -tetrazole, (CH2)m-NH-C (O) -imidazole, (CH2)m-NH-C (O) -imidazol-2-one, (CH2)m-NH-C (O) -oxazole, (CH2)m-NH-C (O) -aminothiazol, (CH2)m-NH-C (O) -thiodiazolone, (CH2)m-NH-C (O) -oxazolone, (CH2)m-NH- (CH2)mImidazole, (CH2)m-NH- (CH2)m-Triazole, (CH2)m-NH- (CH2)mTetrazole, (CH2)m-NH- (CH2)mAminothiazol, (CH2)m-NH- (CH2)mOxazole, (CH2)m-NH- (CH2)mOxazolone, (CH2)m-NH-C (O)-(CH2)mImidazole, (CH2)m-NH-C (O)-(CH2)m-Triazole, (CH2)m-NH-C (O)-(CH2)mTetrazole, (CH2)m-NH-C (O)-(CH2)mAminothiazol, (CH2)m-NH-C (O)-(CH2)mOxazole, (CH2)m-NH-C (O)-(CH2)m-Thiodiazolone or (CH2)m-NH-C (O)-(CH2)mOxazolone; D represents pyrrolidine, piperidine, hexamethyleneimine, dialkylamine itself or substituted derivatives thereof; E is CH, unsubstituted or substituted by a substituent selected from the group consisting of halogen, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, amino, methylamino or dimethylamino2Imidazole, CH2Pyrazole, CH2-Thiazole, CH2-Oxazole, CH2Triazole, CH2-Pyridine, CH2-1-piperidine, CH2-Amino, CH2-Dimethylamino, CH2-Amide or CH2-1-hexamethyleneimine; Cy is phenyl or cyclohexyl. 제 1항에 있어서, 하기 표에 기술된 화합물로 이루어진 그룹 중에서 선택된 화합물.The compound of claim 1 selected from the group consisting of the compounds set forth in the table below. [표 1a]TABLE 1a [표 1b]TABLE 1b [표 1c]TABLE 1c [표 1d]TABLE 1d [표 1e]TABLE 1e [표 1f]TABLE 1f 제 1항에 있어서, 하기 표에 기술된 화합물로 이루어진 그룹 중에서 선택된 화합물.The compound of claim 1 selected from the group consisting of the compounds set forth in the table below. [표 2a]TABLE 2a [표 2b]TABLE 2b [표 2c]TABLE 2c [표 2d]Table 2d [표 2e]TABLE 2e [표 2f]TABLE 2f 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 반응시키고탈보호화하여 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: [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, A는 제1항에 정의된 바와 동일하나, 단 수소는 제외된다.A is the same 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: [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, A는 제1항에 정의된 바와 동일하나, 단 수소는 제외된다.A is the same as defined in claim 1 except for hydrogen. 약제학적으로 허용되는 담체와 함께 유효성분으로서 제 1항에 정의된 화학식 1의 화합물을 함유함을 특징으로 하는 멜라노코틴 수용체의 기능항진제 조성물.A functional anti-inflammatory composition of a melanocortin receptor, characterized in that it contains a compound of formula 1 as defined in claim 1 together with a pharmaceutically acceptable carrier. 제 16항에 있어서, 비만, 당뇨병 및 성기능 장애에 대한 예방 및 치료 효과를 나타내는 조성물.The composition of claim 16 which exhibits a prophylactic and therapeutic effect on obesity, diabetes and sexual dysfunction.
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Publication number Priority date Publication date Assignee Title
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