KR20050045927A - Melanocortin receptor agonists - Google Patents

Melanocortin receptor agonists Download PDF

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KR20050045927A
KR20050045927A KR1020040092245A KR20040092245A KR20050045927A KR 20050045927 A KR20050045927 A KR 20050045927A KR 1020040092245 A KR1020040092245 A KR 1020040092245A KR 20040092245 A KR20040092245 A KR 20040092245A KR 20050045927 A KR20050045927 A KR 20050045927A
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amino
cyclohexyl
alkyl
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boc
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이구
박희술
안인애
유현주
최성필
최덕영
임현주
권오환
콘도유타카
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주식회사 엘지생명과학
야마노우치세이야쿠 가부시키가이샤
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Abstract

본 발명은 멜라노코틴 수용체에 대한 항진활성이 우수한 하기 화학식 1의 화합물, 약제학적으로 허용되는 그의 염, 수화물, 용매화물 또는 이성체, 및 이를 유효성분으로 함유함을 특징으로 하는 멜라노코틴 수용체의 기능항진제 조성물에 관한 것이다:The present invention provides a compound of formula (1) having excellent anti-inflammatory activity against melanocytes, pharmaceutically acceptable salts, hydrates, solvates or isomers thereof, and a melanocortin receptor's anti-functional agent, comprising the same as an active ingredient. Regarding the composition:

상기 식에서 R1, R2, R3, R4, 및 R5는 명세서에 정의한 바와 같다.Wherein R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in the specification.

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]

상기 식에서 R1, R2, R3, R4, 및 R5는 하기 정의한 바와 같다.Wherein R 1 , R 2 , R 3 , R 4 , and R 5 are as defined below.

본 발명은 또한, 상기 화학식 1의 화합물을 유효성분으로 함유함을 특징으로 하는 멜라노코틴 수용체의 기능항진제 조성물, 특히 구체적으로는 비만, 당뇨, 염증 및 발기부전증에 대한 예방 및 치료용 조성물에 관한 것이다. The present invention also relates to a composition for inhibiting melanchotin receptors, characterized in that it contains the compound of Formula 1 as an active ingredient, in particular, a composition for preventing and treating obesity, diabetes, inflammation and erectile dysfunction. .

프로-오피오멜라노코틴(pro-opiomelanocortin, POMC)은 POMC 유전자에서 유래하며, 뇌의 시상하부, 하수체, 뇌간 등에서 주로 발현되고 번역 후 효소적 수식에 의해 α-멜라닌 세포 자극 호르몬(melanocyte stimulating hormone, MSH), β-MSH, γ-MSH, 부신피질 자극 호르몬(adrenocorticotrophic hormone) 등의 신경 펩티드가 되어 생리효과를 나타낸다. 멜라노코틴 펩티드들은 MCR들 각각에 대한 친화력에 따라 여러 가지 생리현상을 조절하며, 이러한 생리현상으로는 피부색소침착, 체온, 염증, 식욕, 행동조절기능 등이 알려져 있다(참조: Mountjoy KG, et al., Mol Cell Endocrinol 1997, 128, 171; Haskell-Luevano C. et al., Drug News Perspect 1999, 12, 197; Wikberg, JES, et al., Pharmacol Res 2000, 42, 393).Pro-opiomelanocortin (POMC) is derived from the POMC gene and is mainly expressed in the hypothalamus, pituitary gland, and brain stem of the brain and is a melanocyte stimulating hormone by post-translational enzymatic modification. , MSH), β-MSH, γ-MSH, adrenal cortical stimulating hormone (adrenocorticotrophic hormone), such as neuropeptides exhibit a physiological effect. Melanocortin peptides regulate a variety of physiological phenomena according to affinity for each of the MCRs, such as skin pigmentation, body temperature, inflammation, appetite, behavioral control is known (Mountjoy KG, et al. , Mol Cell Endocrinol 1997, 128, 171; Haskell-Luevano C. et al., Drug News Perspect 1999, 12, 197; Wikberg, JES, et al., Pharmacol Res 2000, 42, 393).

멜라노코틴 수용체(melanocortin receptor, MCR)들은 G-단백질 짝지움 수용체에 속하며 현재까지 모두 5가지 종류가 밝혀져 있다. MCR 1은 멜라닌 세포, 대식세포에서 발현되며 멜라닌 세포에서는 멜라닌 색소를 조절함으로써 피부와 모발의 색을 결정한다. MCR 2는 부신과 지방조직에서 발현되며 부신에서의 부신피질 자극 호르몬에 의한 부신호르몬 분비조절의 매개기능이 잘 알려져 있다. MCR 3, 4 및 5는 신경 말단뿐만 아니라 뇌에서도 발현되어 행동, 학습, 기억, 식욕, 신경의 발생과 재생 등에 대한 효과로 나타나는 멜라노코틴 펩티드들에 의한 중추 신경 작용을 매개하는 것으로 생각되고 있다. 현재까지 MCR 3은 발기부전 및 염증반응, MCR 4는 비만 및 당뇨병에 관여한다고 알려져 있고, 각 수용체의 작용 특이성에 대한 연구가 활발하게 이루어지고 있다 (참조: MacNeil DJ, et al., Eur J Pharmacol 2002, 450, 93). 그 결과, 비만이 활발히 진행된 사람에서의 유전학적 연구에서 MCR 4가 깊이 관여됨을 알았고, MCR 4가 제거된 유전자 변이 마이스(knockout mice)가 과식에 의해 비만으로 발전함을 보여주어 이 수용체가 식욕조절에서 중요한 역할을 한다는 것을 증명해주고 있다 (참조: Lu D, Willard D, et al., Nature 1994, 371(6500), 799; Huszar D et al., Cell 1997, 88(1), 131; Hinney A, et al., J Clin Endocrinol Metab 1990, 84(4), 1483).Melanocortin receptors (MCRs) belong to the G-protein mating receptor and all five types have been identified to date. MCR 1 is expressed in melanocytes and macrophages. In melanocytes, the color of skin and hair is determined by regulating melanin pigment. MCR 2 is expressed in the adrenal and adipose tissues and is well known for the mediating function of parasignal secretion by adrenal cortical stimulating hormone in the adrenal glands. MCRs 3, 4, and 5 are thought to mediate central nervous activity by melanocytes, which are expressed not only in the nerve endings but also in the brain, resulting in effects on behavior, learning, memory, appetite, nerve development and regeneration. To date, it is known that MCR 3 is involved in erectile dysfunction and inflammatory response, MCR 4 is involved in obesity and diabetes, and studies on the specificity of action of each receptor have been actively conducted (see MacNeil DJ, et al., Eur J Pharmacol). 2002, 450, 93). As a result, genetic studies in active obese people found that MCR 4 was deeply involved, and that MCR 4-knockout mice developed obesity due to overeating, suggesting that this receptor is an appetite regulator. (Lud, Willard D, et al., Nature 1994, 371 (6500), 799; Huszar D et al., Cell 1997, 88 (1), 131; Hinney A). , et al., J Clin Endocrinol Metab 1990, 84 (4), 1483).

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

소분자 MCR 항진제에 대한 발굴과 이들의 생리학적 연구도 최근에 활발히 진행되고 있다. 비펩티드성 소분자 물질의 라이브러리로부터 고효율 약효시험(High-throughput Screening)을 통하거나, 조합화학을 이용하여 발굴된 MCR 항진제 물질이 최근 보고되었다(참조: WO 01/10842, WO 01/05401, WO 01/23392, WO 01/23887). 특히, 머크(Merck)사는 성장호르몬 촉진제로서의 활성을 지닌 소분자 물질로부터 적절한 구조변화 연구를 통해 발굴된 MC4R에 선택적인 우수한 항진제 물질을 보고하였는데(참조: WO 99/64002, WO 00/74679), 이 물질을 쥐(rat)에 주사로 투여한 동물시험에서 발기를 유발하는 효능이 검정되었다(참조: Sebhat, IK, et al., J Med Chem 2002, 45, 4589). 머크사는 그 후 유사한 구조의 소분자 MCR 항진제들을 발굴하였으며(참조: WO 01/55109, WO 01/70337, WO 01/70708, WO 02/081443, WO 02/15909, WO 02/068387), 이와 유사한 구조를 지니는 소분자 MCR 항진제들도 다른 여러 연구 그룹들에 의해 보고되었다(참조: WO 02/059095, WO 02/059107, WO 02/059117, WO 02/059108, WO 02/085925, WO 03/009847, WO 03/009850, WO 02/018327). 또한, 최근에 발굴된 MC1R 에 선택적인 소분자 항진제는 쥐(mouse)를 사용한 동물시험에서 항감염 효능이 검정되었다(참조: Herpin, TF, et al., J Med Chem 2003, 46, 1123). The discovery of small molecule MCR agonists and their physiological studies have been actively conducted in recent years. Recently reported MCR adjuvant materials have been reported from high-throughput screening or combinatorial chemistry from libraries of non-peptide small molecule materials (see WO 01/10842, WO 01/05401, WO 01). / 23392, WO 01/23887. In particular, Merck has reported an excellent anti-inflammatory agent selective for MC4R that has been discovered through appropriate structural change studies from small molecule materials with activity as growth hormone promoters (WO 99/64002, WO 00/74679). Efficacy of inducing erection has been assayed in animal studies in which rats have been injected by rat (Sebhat, IK, et al., J Med Chem 2002, 45, 4589). Merck has then discovered small molecule MCR adjuvants of similar structure (see WO 01/55109, WO 01/70337, WO 01/70708, WO 02/081443, WO 02/15909, WO 02/068387) and similar structures. Small molecule MCR adjuvants with have been reported by several other research groups (see WO 02/059095, WO 02/059107, WO 02/059117, WO 02/059108, WO 02/085925, WO 03/009847, WO). 03/009850, WO 02/018327). In addition, recently discovered small molecule anti-inflammatory agents selective for MC1R have been tested for anti-infective efficacy in animal studies using mice (Herpin, TF, et al., J Med Chem 2003, 46, 1123).

그러나 전술한 펩티드성 MCR 항진제는 그 분자적 특성으로 인해 경구용 제제로서 사용할 수 없는 커다란 한계를 지니고 있다. 또한, 머크사의 물질뿐 아니라 현재까지 보고된 소분자 MCR 항진제도 경구흡수성 및 그 효능에 있어서 개선되어야만 의약으로서 사용될 가능성이 있다. 따라서 본 발명의 목적은 새로운 구조의 소분자 MCR 항진제를 제공하는 것이며 이들은 비만, 당뇨 및 성기능 장애에 대한 예방 및 치료 목적으로 사용될 수 있다. However, the peptidic MCR agonists described above have great limitations due to their molecular properties that cannot be used as oral preparations. In addition, Merck's substances as well as small molecule MCR agonists reported to date are likely to be used as medicaments only when improved in oral absorptivity and its efficacy. It is therefore an object of the present invention to provide new molecule small molecule MCR agonists, which can be used for the prevention and treatment of obesity, diabetes and sexual dysfunction.

구체적으로, 본 발명은 MCR들에 대한 항진 효능, 특히 MC4R에 대한 선택적인 항진 효능이 뛰어난 화학식 1의 화합물, 그의 약제학적으로 허용되는 염, 수화물, 용매화물, 및 이성체를 제공하는 것을 목적으로 한다.In particular, it is an object of the present invention to provide a compound of formula (1), pharmaceutically acceptable salts, hydrates, solvates, and isomers that are excellent in antimicrobial potency against MCRs, in particular selective antigenic potency against MC4R. .

본 발명은 또한, 약제학적으로 허용되는 담체와 함께 유효성분으로서 화학식 1의 화합물, 그의 약제학적으로 허용되는 염, 수화물, 용매화물, 또는 이성체를 함유함을 특징으로 하는 멜라노코틴 수용체의 기능항진제 조성물을 제공함을 목적으로 한다. The present invention also provides a melanocortin receptor hyperfunctional composition comprising a compound of formula 1, a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof as an active ingredient together with a pharmaceutically acceptable carrier. The purpose is to provide.

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

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

[화학식 1][Formula 1]

상기 식에서,Where

R1은 수소,R 1 is hydrogen,

-(CH2)p-R6,-(CH 2 ) p -R 6 ,

-(CH2)p-CO-R6,-(CH 2 ) p -CO-R 6 ,

-(CH2)p-SO2-R6,-(CH 2 ) p -SO 2 -R 6 ,

-CO-(CH2)p-R6을 나타내며,-CO- (CH 2 ) p -R 6 ,

여기서 here

p는 독립적으로 0, 1, 2 또는 3을 나타내고, p independently represents 0, 1, 2 or 3,

R6은 각각 C1-C6-알킬, 할로겐, 아미노, C1-C6-알킬아미노, 디(C1-C6-알킬)아미노, 하이드록시, C1-C8-알콕시, 트리플루오로메톡시, C1-C6-알킬카보닐, 아릴카보닐, C1-C6-알콕시카보닐, 카바모일, C1-C6-알킬설포닐, 아릴설포닐, 카복시, 시아노 및 옥소로 구성된 그룹으로부터 선택된 치환체에 의해 일치환 또는 다치환되거나 비치환된 C1-C10-알킬, C3-C8-사이클로알킬, 헤테로사이클, 아릴, 헤테로아릴, 아미노, 또는 하이드록시를 나타내며,R 6 is C 1 -C 6 -alkyl, halogen, amino, C 1 -C 6 -alkylamino, di (C 1 -C 6 -alkyl) amino, hydroxy, C 1 -C 8 -alkoxy, trifluoro Methoxy, C 1 -C 6 -alkylcarbonyl, arylcarbonyl, C 1 -C 6 -alkoxycarbonyl, carbamoyl, C 1 -C 6 -alkylsulfonyl, arylsulfonyl, carboxy, cyano and oxo Mono- or poly-substituted or unsubstituted C 1 -C 10 -alkyl, C 3 -C 8 -cycloalkyl, heterocycle, aryl, heteroaryl, amino, or hydroxy by a substituent selected from the group consisting of:

-(CH2)p- 그룹에서 수소원자는 R6에 의해 대체될 수 있고,The hydrogen atom in the-(CH 2 ) p -group can be replaced by R 6 ,

R2는 수소,R 2 is hydrogen,

C1-C8-알킬, 또는C 1 -C 8 -alkyl, or

C3-C7-사이클로알킬을 나타내거나,C 3 -C 7 -cycloalkyl, or

R2와 R1 그룹은 이들이 붙어 있는 원자와 더불어 4 내지 8의 단일환 또는 이환을 형성할 수 있으며, 여기에 O, S, N-C1-C4-알킬로 이루어진 그룹 중에서 선택된 헤테로 원자가 추가로 삽입될 수 있고,The R 2 and R 1 groups together with the atoms to which they are attached may form a 4 to 8 monocyclic or bicyclic ring, to which an additional hetero atom selected from the group consisting of O, S and NC 1 -C 4 -alkyl is further inserted Can be,

R3는 각각 C1-C6-알킬, 할로겐, 아미노, C1-C6-알킬아미노, 디(C1-C6-알킬)아미노, 하이드록시, C1-C8-알콕시, C1-C6-알킬카보닐, 아릴카보닐, C1-C6-알콕시카보닐, 카바모일, C1-C6-알킬설포닐, 아릴설포닐, 시아노 및 옥소로 구성된 그룹으로부터 선택된 치환체에 의해 일치환 내지 삼치환되거나 비치환된R 3 is C 1 -C 6 -alkyl, halogen, amino, C 1 -C 6 -alkylamino, di (C 1 -C 6 -alkyl) amino, hydroxy, C 1 -C 8 -alkoxy, C 1 to alkylsulfonyl, arylsulfonyl, cyano, and substituents selected from the group consisting of oxo - -C 6 - alkylcarbonyl, arylcarbonyl, C 1 -C 6 - alkoxycarbonyl, carbamoyl, C 1 -C 6 Mono- to tri-substituted or unsubstituted by

-C1-C8-알킬,-C 1 -C 8 -alkyl,

-(CH2)q-C3-C7-사이클로알킬,-(CH 2 ) q -C 3 -C 7 -cycloalkyl,

-(CH2)q-페닐 또는-(CH 2 ) q -phenyl or

-(CH2)q-헤테로아릴을 나타내며,-(CH 2 ) q -heteroaryl,

여기서 here

q는 독립적으로 0, 1, 2 또는 3을 나타내고, q independently represents 0, 1, 2 or 3,

R4는 페닐, 사이클로헥실, 또는 -NR7R8을 나타내고,R 4 represents phenyl, cyclohexyl, or —NR 7 R 8 ,

여기에서 R7 및 R8은 각각 독립적으로 C1-C6-알킬, -(CH2 )q-C3-C7-사이클로알킬, -(CH2)q-페닐, 또는 -(CH2)q-헤테로아릴을 나타내거나(여기서 q는 상기 정의된 바와 같다), 이들이 부착되어 있는 질소원자와 함께 O, S, 또는 N-(C1-C4-알킬)을 포함할 수 있는 4- 내지 8-원의 단일환 또는 이환을 형성할 수 있으며, 이들은 C1-C6-알킬, 할로겐, 아미노, C1-C6-알킬아미노, 디(C1-C6 -알킬)아미노, 하이드록시, C1-C8-알콕시, 트리플루오로메톡시, C1-C6-알킬카보닐, 아릴카보닐, C1 -C6-알콕시카보닐, 카바모일, C1-C6-알킬설포닐, 아릴설포닐, 카복시, 시아노 및 옥소로 구성된 그룹으로부터 선택된 치환체에 의해 일치환 또는 다치환되거나 비치환되고,Wherein R 7 and R 8 are each independently C 1 -C 6 -alkyl,-(CH 2 ) q -C 3 -C 7 -cycloalkyl,-(CH 2 ) q -phenyl, or-(CH 2 ) q - 4 to which may include - (alkyl C 1 -C 4), or indicate a heteroaryl O, S, N- or together with the nitrogen atom (wherein q is as defined above) which they are attached It may form an 8-membered monocyclic or bicyclic, which is C 1 -C 6 -alkyl, halogen, amino, C 1 -C 6 -alkylamino, di (C 1 -C 6 -alkyl) amino, hydroxy , C 1 -C 8 -alkoxy, trifluoromethoxy, C 1 -C 6 -alkylcarbonyl, arylcarbonyl, C 1 -C 6 -alkoxycarbonyl, carbamoyl, C 1 -C 6 -alkylsulfonyl Mono- or poly-substituted or unsubstituted by a substituent selected from the group consisting of arylsulfonyl, carboxy, cyano and oxo,

R5는 -(CH2)o-R9,R 5 is-(CH 2 ) o -R 9 ,

-(CH2)o-COR9, 또는-(CH 2 ) o -COR 9 , or

-(CH2)o-C(O)N(R9)(R10) 을 나타내며,-(CH 2 ) o -C (O) N (R 9 ) (R 10 ),

여기서 here

o는 독립적으로 0, 1, 2, 또는 3을 나타내고, o independently represents 0, 1, 2, or 3,

R9 및 R10은 각각 독립적으로 수소, 아미노, 하이드록시, C1-C6-알킬, C1-C6-알콕시, C3-C7-사이클로알킬, 페닐, 헤테로사이클, 또는 헤테로아릴을 나타내고, 수소를 제외한 이들은 각각 C1-C6-알킬, 할로겐, 아미노, C1-C6-알킬아미노, 디(C1-C6-알킬)아미노, 하이드록시, C1-C8-알콕시, 트리플루오로메톡시, C1-C6 -알킬카보닐, 아릴카보닐, C1-C6-알콕시카보닐, 카바모일, C1-C6-알킬설포닐, 아릴설포닐, C3-C6-사이클로알킬, C2-C8-알카노일, C1-C6-알킬설파모일, 카복시, 시아노 및 옥소로 구성된 그룹 중에서 선택된 1개 내지 3개의 치환체에 의해 치환되거나 비치환되고,R 9 and R 10 each independently represent hydrogen, amino, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 7 -cycloalkyl, phenyl, heterocycle, or heteroaryl Except hydrogen, these are C 1 -C 6 -alkyl, halogen, amino, C 1 -C 6 -alkylamino, di (C 1 -C 6 -alkyl) amino, hydroxy, C 1 -C 8 -alkoxy , Trifluoromethoxy, C 1 -C 6 -alkylcarbonyl, arylcarbonyl, C 1 -C 6 -alkoxycarbonyl, carbamoyl, C 1 -C 6 -alkylsulfonyl, arylsulfonyl, C 3- Unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of C 6 -cycloalkyl, C 2 -C 8 -alkanoyl, C 1 -C 6 -alkylsulfamoyl, carboxy, cyano and oxo,

R9 및 R10은 이들이 부착되어 있는 질소원자와 함께 O, S, 또는 N-(C1-C 4-알킬)을 포함할 수 있는 4- 내지 8-원의 단일환 또는 이환을 형성할 수 있다.R 9 and R 10 may form a 4- to 8-membered monocyclic or bicyclic which may include O, S, or N- (C 1 -C 4 -alkyl) with the nitrogen atom to which they are attached have.

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

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

용어 "헤테로아릴"은 질소원자, 산소원자 및 황원자로 구성된 그룹으로부터 선택된 1 내지 2개의 헤테로원자를 포함하고, 벤조 또는 C3-C8-사이클로알킬과 융합될 수 있는 방향족 3 내지 6원 환을 의미하고, 모노사이클릭 헤테로아릴의 예로는 티아졸, 옥사졸, 티오펜, 퓨란, 피롤, 이미다졸, 이소옥사졸, 피라졸, 트리아졸, 티아디아졸, 테트라졸, 옥사디아졸, 피리딘, 피리다진, 피리미딘, 피라진 및 이와 유사한 그룹을 들 수 있으나 이들로 제한되는 것은 아니며, 비사이클릭 헤테로아릴의 예로는 인돌, 벤조티오펜, 벤조퓨란, 벤즈이미다졸, 벤족사졸, 벤즈이속사졸, 벤즈티아졸, 벤즈티아디아졸, 벤즈트리아졸, 퀴놀린, 이소퀴놀린, 퓨린, 퓨로피리딘 및 이와 유사한 그룹을 들 수 있으나 이들로 제한되는 것은 아니다.The term "heteroaryl" includes an aromatic 3-6 membered ring containing 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms and which can be fused with benzo or C 3 -C 8 -cycloalkyl Examples of monocyclic heteroaryl include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, pyrazole, triazole, thiadiazole, tetrazole, oxadiazole, pyridine, Pyridazines, pyrimidines, pyrazines and similar groups, including but not limited to, examples of bicyclic heteroaryls include indole, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, Benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine, puropyridine and similar groups, but is not limited thereto.

용어 "헤테로사이클"은 질소원자, 산소원자 및 황원자로 구성된 그룹으로부터 선택된 1 내지 2개의 헤테로원자를 포함하며, 벤조 또는 C3-C8-사이클로알킬과 융합될 수 있는 포화 3 내지 6원 환을 의미하고, 그 예로는 피페리딘, 모폴린, 티아모폴린, 피롤리딘, 이미다졸리딘, 테트라하이드로퓨란, 피페라진 및 이와 유사한 그룹을 들 수 있으나 이들로 제한되는 것은 아니다.The term "heterocycle" includes one to two heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms, and refers to a saturated three to six membered ring which can be fused with benzo or C 3 -C 8 -cycloalkyl. Examples include, but are not limited to, piperidine, morpholine, thiamorpholine, pyrrolidine, imidazolidine, tetrahydrofuran, piperazine and similar groups.

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

ⅰ) R1이 수소, -(CH2)p-R6, -(CH2)p-CO-R 6 또는 -(CH2)p-SO2-R6 을 나타내고, 여기에서 p는 상기 정의된 바와 같고,Iii) R 1 represents hydrogen,-(CH 2 ) p -R 6 ,-(CH 2 ) p -CO-R 6 or-(CH 2 ) p -SO 2 -R 6 , where p is the above definition As it is,

또한, R1이 -CO-(CH2)q-R6 을 나타내고, 여기에서 q는 상기 정의된 바와 같은 화합물,In addition, R 1 represents -CO- (CH 2 ) q -R 6 , wherein q is a compound as defined above,

ii) R2가 수소 또는 C1-C6-알킬을 나타내는 화합물,ii) a compound in which R 2 represents hydrogen or C 1 -C 6 -alkyl,

iii) R3가 각각 할로겐, 시아노, 카복시, 하이드록시, C1-C4-알킬, C1 -C8-알콕시, 아미노, C1-C4-알킬아미노 및 디(C1-C4-알킬)아미노로 구성된 그룹으로부터 선택된 치환체에 의해 일치환 내지 삼치환되거나 비치환된 -(CH2)q-C3-C7 -사이클로알킬, -(CH2)q-페닐 또는 -(CH2)q-헤테로아릴을 나타내고, 여기에서 q는 상기 정의된 바와 같은 화합물,iii) R 3 is halogen, cyano, carboxy, hydroxy, C 1 -C 4 -alkyl, C 1 -C 8 -alkoxy, amino, C 1 -C 4 -alkylamino and di (C 1 -C 4 alkyl) by a substituent selected from the group consisting of amino mono- to tri-substituted or unsubstituted - (CH 2) q -C 3 -C 7 - cycloalkyl, - (CH 2) q-phenyl, or - (CH 2 ) q -heteroaryl, wherein q is a compound as defined above,

iv) R4가 페닐, 사이클로헥실, C1-C4-알킬아미노, 디(C1-C4 -알킬)아미노, 피롤리딘일, 피페리딘일 또는 아제핀일을 나타내며, 여기에서 C1-C4-알킬, 피롤리디닐, 피페리디닐 또는 아제피닐은 할로겐, 하이드록시, C1-C4-알킬, C1-C 4-알콕시, 아미노, C1-C4-알킬아미노 및 디(C1-C4-알킬)아미노로 구성된 그룹으로부터 선택된 치환체에 의해 일치환 내지 삼치환되거나 비치환되는 화합물,iv) R 4 represents phenyl, cyclohexyl, C 1 -C 4 -alkylamino, di (C 1 -C 4 -alkyl) amino, pyrrolidinyl, piperidinyl or azepinyl, wherein C 1 -C 4 -alkyl, pyrrolidinyl, piperidinyl or azefinyl is halogen, hydroxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, amino, C 1 -C 4 -alkylamino and di ( Mono- to tri-substituted or unsubstituted by a substituent selected from the group consisting of C 1 -C 4 -alkyl) amino,

v) R5가 C1-C6-알킬, -(CH2)o-헤테로아릴, -(CH 2)o-헤테로사이클, -COR9, -C(O)N(R9)(R10), -(CH2)O-OR11, -(CH2) o-NHR11, 또는 -(CH2)O-N(R11)(R12)를 나타내며, 여기에서 헤테로사이클은 하이드록시, C1-C4-알킬, C1-C4-알콕시, 아미노, C1-C4-알킬아미노, 디(C1-C4-알킬)아미노, 및 옥소로 구성된 그룹으로부터 선택된 치환체에 의해 일치환 내지 삼치환되거나 비치환되고, R9 및 R10은 상기 정의된 바와 같고, R11 및 R12는 각각 독립적으로 C1-C6-알킬, C3-C6-사이클로알킬, C2-C8-알카노일, C1-C6-알킬설포닐, C1-C6-알킬설파모일, 또는 아릴설포닐을 나타내며 o는 상기 정의된 바와 같은 화합물이다.v) R 5 is C 1 -C 6 -alkyl,-(CH 2 ) o -heteroaryl,-(CH 2 ) o -heterocycle, -COR 9 , -C (O) N (R 9 ) (R 10 ),-(CH 2 ) O -OR 11 ,-(CH 2 ) o -NHR 11 , or-(CH 2 ) O -N (R 11 ) (R 12 ) wherein the heterocycle is hydroxy, Work by a substituent selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, amino, C 1 -C 4 -alkylamino, di (C 1 -C 4 -alkyl) amino, and oxo. Substituted to trisubstituted or unsubstituted, R 9 and R 10 are as defined above and R 11 and R 12 are each independently C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 2- C 8 -alkanoyl, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -alkylsulfamoyl, or arylsulfonyl and o is a compound as defined above.

본 발명에 따른 화학식 1의 화합물에서도 특히 바람직한 화합물은Particularly preferred compounds in the compound of formula 1 according to the present invention are

i) R1이 수소 또는 -(CH2)p-R6 을 나타내고, 여기에서 p는 상기 정의된 바와 같은 화합물,i) R 1 represents hydrogen or — (CH 2 ) p —R 6 , wherein p is a compound as defined above,

ii) R3가 각각 할로겐, 시아노, 하이드록시, C1-C4-알콕시, 트리플루오로메톡시 및 C1-C4-알킬로 구성된 그룹으로부터 선택된 치환체에 의해 일치환 내지 삼치환되거나 비치환된 -CH2-사이클로헥실 또는 -CH2-페닐을 나타내는 화합물,ii) R 3 are each halogen, cyano, hydroxy, C 1 -C 4 - alkoxy, trifluoromethoxy, and C 1 -C 4 - substituted one substituents of which are selected from the group consisting of alkyl to tri-substituted or unsubstituted It represents a phenyl compound, - a -CH 2 - or -CH 2 -cyclohexyl

iii) R5가 -(CH2)0-1-헤테로아릴, -(CH2)0-1-헤테로사이클, -C(O)N(R9)(R10), -CH2-OR11, -(CH2)0-1-NHR11 또는 -(CH2) 0-1-N(R11)(R12)를 나타내고, 여기에서 R9, R10, R11 및 R12는 상기 정의된 바와 같은 화합물이다.iii) R 5 is- (CH 2 ) 0-1 -heteroaryl,-(CH 2 ) 0-1 -heterocycle , -C (O) N (R 9 ) (R 10 ), -CH 2 -OR 11 ,-(CH 2 ) 0-1 -NHR 11 or-(CH 2 ) 0-1 -N (R 11 ) (R 12 ), wherein R 9 , R 10 , R 11 and R 12 are the above definitions Compound as shown.

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

본 발명에 따른 화합물은 또한 약제학적으로 허용되는 염을 형성할 수 있다. 이러한 약제학적으로 허용되는 염에는 약제학적으로 허용되는 음이온을 함유하는 무독성 산부가염을 형성하는 산, 예를 들면 염산, 황산, 질산, 인산, 브롬화수소산, 요오드화수소산 등과 같은 무기산, 타타르산, 포름산, 시트르산, 아세트산, 트리클로로아세트산, 트리플루오로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산 등과 같은 유기 카본산, 메탄설폰산, 벤젠설폰산, p-톨루엔설폰산 또는 나프탈렌설폰산 등과 같은 설폰산 등에 의해 형성된 산부가염, 특히 바람직하게는 황산, 메탄설폰산 또는 할로겐화수소산 등에 의해 형성된 산부가염이 포함된다. 본 발명에 따른 화학식 1의 화합물은 통상적인 방법에 의해 그의 염으로 전환시킬 수 있다.The compounds according to the invention can also form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, Organic carbon acids such as citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc., sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid Acid addition salts formed by, and the like, particularly preferably acid addition salts formed by sulfuric acid, methanesulfonic acid or hydrochloric acid and the like. The compound of formula 1 according to the present invention can be converted to its salts by conventional methods.

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

한편, 본 발명에 따른 화학식 1의 화합물은 하기 반응식 1 내지 7에 도시한 바와 같은 방법으로 제조할 수 있다. 하기 반응식에서 화합물(3), (6), (10), (11), (12), (14), (18), (20) 및 (31)은 화학식 1 화합물의 전형적인 화합물들을 나타낸다.On the other hand, the compound of formula 1 according to the present invention can be prepared by the method as shown in the reaction schemes 1 to 7. Compounds (3), (6), (10), (11), (12), (14), (18), (20) and (31) in the following schemes represent typical compounds of the compound of formula (1).

먼저, 화합물(3)은 반응식 1에 나타낸 바와 같이 아미노기가 보호된 아미노산 화합물(1)(P는 보호기를 나타내며, BOC, Cbz, Fmoc 등을 나타낸다)을 피페리딘 화합물(2)와 일반적인 아미드 결합 방법에 따라 반응시켜 제조할 수 있다. 출발물질인 보호된 아미노산 화합물(1)은 상업적으로 구입 가능하며, 문헌에 공지된 방법에 따라 제조할 수도 있다(참조: Williams, R. M., Synthesis of Optically Active a-Amino Acids, Pergamon Press: Oxford, 1989). 또한, 피페리딘 화합물(2)은 상업적으로 구입할 수 있는 물질로부터 합성할 수 있으며, 제조법은 하기 본 명세서를 참조할 수 있다. First, compound (3) binds an amino acid compound (1) (P represents a protecting group and BOC, Cbz, Fmoc, etc.) with an amino group protected as shown in Scheme 1 to piperidine compound (2) in general. It can manufacture by reacting according to a method. Protected amino acid compounds (1) as starting materials are commercially available and may be prepared according to methods known in the literature (William, RM, Synthesis of Optically Active a-Amino Acids, Pergamon Press: Oxford, 1989). ). In addition, the piperidine compound (2) can be synthesized from commercially available materials, the preparation of which can be referred to the following specification.

화합물(6) (R1=Ac, Ms 등)은 하기 반응식 2에 나타낸 바와 같이 아미노 그룹이 아실화, 알킬화, 또는 설포닐화된 아미노산 유도체(5)를 피페리딘 화합물(2)과 커플링 반응시켜 제조할 수 있다. 또한, 아미노산 유도체(5)는 아미노산 알킬 에스테르를 염기 존재하에 아실화, 알킬화, 또는 설포닐화시킨 후 염기 존재하에 가수분해함으로써 합성할 수 있다.Compound (6) (R 1 = Ac, Ms, etc.) is a coupling reaction of an amino group acylated, alkylated, or sulfonylated amino acid derivative (5) with piperidine compound (2) as shown in Scheme 2 below. Can be prepared. The amino acid derivative (5) can also be synthesized by acylating, alkylating, or sulfonylating the amino acid alkyl ester in the presence of a base and then hydrolyzing in the presence of a base.

화합물(10), (11), 및 (12) (R2=H, R1=카보닐 포함 그룹)는 하기 반응식 3에 나타낸 바와 같이 보호된 아미노산 유도체(7), (8) (화합물(8)에서 Cy는 피롤리딘, 아제티딘, 아지리딘, 피페리딘 등을 나타낸다), 또는 (9)를 반응식 1에서 제조한 화합물(3)과 커플링 반응시켜 제조할 수 있다. 보호된 화합물(7), (8), 및 (9)는 상업적으로 구입이 가능하거나, 상업적으로 구입가능한 아미노산으로부터 보호화 반응과 가수분해 반응을 거쳐 제조할 수 있다.Compounds (10), (11), and (12) (R 2 = H, R 1 = carbonyl containing group) are protected amino acid derivatives (7), (8) (Compound (8) Cy) may represent pyrrolidine, azetidine, aziridine, piperidine, or the like), or (9) by coupling reaction with compound (3) prepared in Scheme 1. Protected compounds (7), (8), and (9) can be prepared from commercially available or commercially available amino acids via protection and hydrolysis reactions.

화합물(14)는 하기 반응식 4에 나타낸 바와 같이 반응식 1에서 제조한 화합물(3)과 보호된 아미노 알데히드 화합물(13)의 환원성 아미노 반응을 통해 제조될 수 있다. 환원성 아미노 반응은 반응시약으로 NaHB(OAc)3 또는 NaBH3CN을 사용할 수 있고, 용매로 DCE, DMF, 메탄올, DCM 등을 사용할 수 있으나, 단 이들로 제한되는 것은 아니다. 보호된 아미노 알데히드 화합물(13)은 상업적으로 구입이 가능한 아미노산으로부터 티오에스테르의 환원반응 또는 아미노 알콜의 산화반응과 같이 공지된 방법으로 합성할 수 있으나, 단 이들로 제한되는 것은 아니다.Compound (14) can be prepared through a reducing amino reaction of Compound (3) prepared in Scheme 1 with protected amino aldehyde compound (13), as shown in Scheme 4 below. The reducing amino reaction may use NaHB (OAc) 3 or NaBH 3 CN as a reaction reagent and DCE, DMF, methanol, DCM, etc. may be used as a solvent, but is not limited thereto. The protected amino aldehyde compound (13) can be synthesized by known methods such as, but not limited to, reduction of thioester or oxidation of amino alcohol from commercially available amino acids.

하기 반응식 5는 화합물(18), (19), 및 (20)을 제조하는 방법을 나타내고 있다. 화합물(3)에 니트로벤젠설포닐 클로라이드를 사용하여 니트로벤젠설포닐 그룹을 도입시킨 화합물(15)(참조: Tetrahedron Letters, 1995, 36, 6373-6374)에 대해 알킬화 또는 환원성 아미노 반응을 통하여 화합물(17)로 전환시킬 수 있다. 보호된 화합물(16)에서 Q는 아미노알킬 또는 알킬화된 아미노알킬을 나타내며, X는 할로겐을 나타낸다. 화합물(19)는 다시 화합물(17)로부터 환원성 아미노 반응을 수행하여 제조할 수 있고, 화합물(19)에 다시 알킬화 반응을 수행하면 화합물(20)으로 전환될 수 있다.Scheme 5 below shows a method for producing compounds (18), (19), and (20). Compound (3) was introduced to nitrobenzenesulfonyl group using nitrobenzenesulfonyl chloride (15) (see Tetrahedron Letters , 1995 , 36 , 6373-6374) through alkylation or reductive amino reactions 17). In protected compound (16), Q represents aminoalkyl or alkylated aminoalkyl and X represents halogen. Compound (19) may be prepared by performing a reductive amino reaction from compound (17), and may be converted to compound (20) by performing an alkylation reaction on compound (19) again.

4,4-이중 치환된 피페리딘 유도체(21)는 공지 문헌에 따라 합성할 수 있으며, 화합물(23)과 같이 옥사졸린에 의해 치환된 화합물은 4,4-이중 치환된 피페리딘 유도체(21)로부터 합성할 수 있다. 즉, 화합물(21)의 아실할라이드 그룹을 아민과 커플링 반응시켜 화합물(22)를 제조할 수 있으며, 이 화합물로부터 포스겐을 이용한 고리화 반응을 통하여 화합물(23)의 옥사졸린 치환된 피페리딘 유도체를 합성할 수 있다.The 4,4-disubstituted piperidine derivative (21) can be synthesized according to the known literature, and the compound substituted with oxazoline like compound (23) is a 4,4-disubstituted piperidine derivative ( 21). That is, compound 22 may be prepared by coupling an acyl halide group of compound 21 with an amine, and an oxazoline substituted piperidine of compound 23 may be prepared by cyclization using phosgene from the compound. Derivatives can be synthesized.

한편, 피페리딘 환의 4번 위치에 피페리딘이 치환된 피페리딘 유도체는 하기 반응식 7의 방법에 따라 제조할 수 있다. 피페리딘 카복실산 화합물(24)는 문헌에 공지된 방법에 따라 합성할 수 있으며, 아미드 연결 반응을 통하여 화합물(25)를 합성하고, 다시 고리화 반응을 통하여 화합물(26)을 합성할 수 있다. 이때, 고리화 반응은 디알데히드 또는 디할로알칸 화합물을 이용하여 환원성 아미노 반응과 알킬화 반응을 통하여 수행할 수 있다. 또한, 화합물(29)는 화합물(24)로부터 화합물(23)을 합성할 때와 동일한 방법으로 화합물(28)을 합성하고, 다시 고리화 반응을 수행하여 얻을 수 있다. Meanwhile, the piperidine derivative in which piperidine is substituted at position 4 of the piperidine ring may be prepared according to the method of Scheme 7 below. The piperidine carboxylic acid compound (24) can be synthesized according to a method known in the literature, and the compound (25) can be synthesized through an amide linkage reaction, and the compound (26) can be synthesized through a cyclization reaction. In this case, the cyclization reaction may be carried out through a reducing amino reaction and an alkylation reaction using a dialdehyde or dihaloalkane compound. In addition, the compound (29) can be obtained by synthesizing the compound (28) in the same manner as the synthesis of the compound (23) from the compound (24), and performing a cyclization reaction again.

4번위치에 알콜 혹은 아민 으로 치환된 카보닐 화합물은 반응식 8에서와 같이 합성 할 수 있다. 화합물과 (3)과 (2')을 아미드 커플링 반응을 하고 화합물(2')의 카복시산을 산클로라이드로 변환시키면 화합물 (30)과 같은 화합물을 얻을 수 있다. 다시 아민 화합물을 이용 화합물 (30)과 아미드 커플링 반응과 탈보호화 반응을 수행하여 화합물 (31)을 얻을 수 있다. A carbonyl compound substituted with an alcohol or an amine at position 4 can be synthesized as in Scheme 8. Compounds (3) and (2 ') are subjected to an amide coupling reaction, and the carboxylic acid of compound (2') is converted into an acid chloride, thereby obtaining a compound similar to compound (30). Compound (31) can be obtained by carrying out an amide coupling reaction and deprotection reaction with compound (30) using an amine compound.

상기 각 방법에 있어서 각 단계의 반응은 바람직하게는 반응에 악영향을 끼치지 않는 통상적인 용매 중에서 수행될 수 있으며, 특히 바람직하게는 디메틸포름아미드, 디메틸아세트아미드, 테트라하이드로푸란, 메틸렌클로라이드, 및 클로로포름 중에서 선택된 1종 이상의 용매를 사용할 수 있으나, 단 이들로 제한되는 것은 아니다. The reaction of each step in each of the above methods may preferably be carried out in a conventional solvent which does not adversely affect the reaction, particularly preferably dimethylformamide, dimethylacetamide, tetrahydrofuran, methylene chloride, and chloroform One or more solvents selected from among them may be used, but they are not limited thereto.

탈보호화 반응은 염산, 트리플루오로아세트산 등과 같은 강산의 존재하에서 수행하거나, 트리에틸아민, 디이소프로필에틸아민 등과 같은 아민 염기의 존재하에서 수행하거나, 수소첨가 반응을 사용하여 수행할 수 있다. 구체적인 반응 조건은 문헌(참조: T. W. Green & G. M. Wuts Protective Groups in Organic Synthesis, Chapter 7, pp309-405)에 기재된 내용을 참조할 수 있다.The deprotection reaction can be carried out in the presence of a strong acid such as hydrochloric acid, trifluoroacetic acid or the like, in the presence of an amine base such as triethylamine, diisopropylethylamine or the like, or by using a hydrogenation reaction. Specific reaction conditions may be referred to those described in T. W. Green & G. M. Wuts Protective Groups in Organic Synthesis, Chapter 7, pp309-405.

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

일반적인 혼합물의 분리는 칼럼 크로마토그래피를 사용하고 최종 화합물의 경우 재결정이나 노말 또는 리버스 상태의 HPLC(Waters, Delta Pack, 300x50 mm I.D., C18 5㎛, 100A)를 통하여 분리할 수 있다. 재결정이나 HPLC를 통해 정제하는 경우, 트리플루오로아세트산염의 형태로 화합물을 얻을 수 있으며, 염산염을 얻고자 하는 경우에는 이온교환 수지를 이용할 수 있다. Separation of common mixtures can be carried out using column chromatography and, for final compounds, by recrystallization or normal or reversed HPLC (Waters, Delta Pack, 300 × 50 mm I.D., C18 5 μm, 100 A). In the case of recrystallization or purification through HPLC, a compound can be obtained in the form of trifluoroacetic acid salt, and an ion exchange resin can be used in case of obtaining hydrochloride.

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

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

본 발명의 화합물을 임상적인 목적으로 투여시에 단일용량 또는 분리용량으로 숙주에게 투여될 총 일일용량은 체중 1㎏ 당 0.01 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 to 10 mg / kg body weight, but specific dose levels for individual patients may be used. The specific compound, the weight of the patient, sex, health condition, diet, the time of administration of the drug, the method of administration, the rate of excretion, drug mixing and the severity of the disease may be changed.

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

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

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

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

Ac 아세틸Ac acetyl

BOC tert-부톡시카보닐BOC tert-butoxycarbonyl

Bn 벤질Bn benzyl

Bu 부틸Bu butyl

CBZ(Cbz) 벤질옥시카보닐CBZ (Cbz) benzyloxycarbonyl

c-Hep 사이클로헵틸c-Hep cycloheptyl

c-Hex 사이클로헥실c-Hex cyclohexyl

c-Pen 사이클로펜틸c-Pen cyclopentyl

DCC 디사이클로헥실카보디이미드DCC dicyclohexylcarbodiimide

DCE 디클로로에탄DCE dichloroethane

DCM 디클로로메탄DCM dichloromethane

Dic 데카하이드로이소퀴놀린-3-카복실산 Dic decahydroisoquinoline-3-carboxylic acid

DIPEA 디이소프로필에틸아민DIPEA diisopropylethylamine

DMAP 4-디메틸아미노피리딘DMAP 4-dimethylaminopyridine

DMF N,N-디메틸포름아미드DMF N, N-dimethylformamide

EDC 1-(3-디메틸아미노프로필)-3-에틸카보디이미드 염산염EDC 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

Fmoc 9-플루오레닐메톡시카보닐Fmoc 9-fluorenylmethoxycarbonyl

Hex 헥산Hex Hexane

HOBt 1-하이드록시벤조트리아졸HOBt 1-hydroxybenzotriazole

HPLC 고효율 액체 크로마토그래피(high performance liquid chromatography)HPLC high performance liquid chromatography

i-Bu 이소부틸i-Bu isobutyl

i-Pr 이소프로필i-Pr Isopropyl

Imz 이미다졸Imz imidazole

LAH 리튬알루미늄하이드라이드LAH Lithium Aluminum Hydride

Ms 메탄설포닐Ms methanesulfonyl

Ph 페닐Ph phenyl

Phe 페닐알라닌 Phe Phenylalanine

Pid 피페리딘Pid piperidine

Pro 프롤린Pro Proline

Pyd 피롤리딘Pyd pyrrolidine

TEA 트리에틸아민TEA triethylamine

Tez 테트라졸Tez tetrazole

TFA 트리플루오로아세트산TFA trifluoroacetic acid

Tic 1,2,3,4-테트라하이드로이소퀴놀린-3-카복실산Tic 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

TPAP 테트라프로필암모늄 퍼루테네이트TPAP tetrapropylammonium perruthenate

Trz 트리아졸 Trz Triazole

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

제조예 1: 4-사이클로헥실-4-(t-부틸카바모일)피페리딘Preparation Example 1 4-cyclohexyl-4- (t-butylcarbamoyl) piperidine

단계 A: 1-BOC-4-사이클로헥실-4-(t-부틸카바모일)피페리딘Step A: 1-BOC-4-cyclohexyl-4- (t-butylcarbamoyl) piperidine

4-사이클로헥실-4-피페리딘카복실산(311 mg, 1 mmol)을 DMF(3 ㎖)에 녹이고 DIPEA(0.348 ㎖, 2 mmol)를 적가하여 용액을 염기화하였다. 반응액에 EDC(600 mg, 1.3 mmol), HOBT(230 mg, 1.5 mmol), 및 t-부틸아민(0.137 ㎖, 1.3 mmol)을 차례로 첨가하였다. 반응물을 상온에서 6시간 교반한 후 DMF를 감압 증류하여 제거하고, 포화 탄산수소나트륨 수용액을 넣어 희석하였다. EtOAc로 유기물을 추출하고 탄산수소나트륨 수용액과 1N 염산 수용액으로 씻어주었다. 유기용액은 MgSO4로 건조하고 여과한 후 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산 =1/1)로 정제하여 표제화합물(350 mg, 94 %)을 수득하였다.4-cyclohexyl-4-piperidinecarboxylic acid (311 mg, 1 mmol) was dissolved in DMF (3 mL) and the solution was basified by dropwise addition of DIPEA (0.348 mL, 2 mmol). EDC (600 mg, 1.3 mmol), HOBT (230 mg, 1.5 mmol), and t-butylamine (0.137 mL, 1.3 mmol) were added sequentially to the reaction solution. After the reaction was stirred at room temperature for 6 hours, DMF was distilled off under reduced pressure, and diluted with saturated aqueous sodium hydrogen carbonate solution. The organics were extracted with EtOAc and washed with aqueous sodium bicarbonate solution and 1N hydrochloric acid solution. The organic solution was dried over 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 (350 mg, 94%).

MS[M+H] = 367(M+1)MS [M + H] = 367 (M + 1)

단계 B: 4-사이클로헥실-4-(t-부틸카바모일)피페리딘Step B: 4-cyclohexyl-4- (t-butylcarbamoyl) piperidine

단계 A에서 얻은 1-BOC-4-사이클로헥실-4-(t-부틸카바모일)피페리딘(300 mg, 0.818 mmol)을 DCM(2 ㎖)에 녹이고 TFA(2 ㎖)를 적가한 후 상온에서 30분 동안 교반하였다. 반응이 종결되면 반응물을 감압 농축하여 표제화합물의 TFA염(235 mg, 90 %)을 수득하였다. 1-BOC-4-cyclohexyl-4- (t-butylcarbamoyl) piperidine (300 mg, 0.818 mmol) obtained in step A was dissolved in DCM (2 mL) and TFA (2 mL) was added dropwise, followed by room temperature. Stir for 30 minutes. At the end of the reaction, the reaction was concentrated under reduced pressure to give TFA salt of the title compound (235 mg, 90%).

MS[M+H] = 267(M+1)MS [M + H] = 267 (M + 1)

제조예 2-8: Preparation Example 2-8:

4-사이클로헥실-4-피페리딘카복실산을 제조예 1과 동일한 방법으로 반응시켜 하기 화합물을 수득하였다. 4-cyclohexyl-4-piperidinecarboxylic acid was reacted in the same manner as in Preparation Example 1 to obtain the following compound.

제조예 9: 4-사이클로헥실-4-[(4,4-디메틸)옥사졸린-2-일]피페리딘Preparation Example 9 4-cyclohexyl-4-[(4,4-dimethyl) oxazolin-2-yl] piperidine

단계 A: 1-BOC-4-사이클로헥실-4-피페리딘카복실클로라이드Step A: 1-BOC-4-cyclohexyl-4-piperidinecarboxylate

4-사이클로헥실-4-피페리딘카복실산(3.11 g, 10 mmol)을 DCM(30 ㎖)에 녹이고 옥살릴클로라이드(1.40 g, 11 mmol)를 적가하였다. 반응물을 상온에서 3시간동안 교반한 후 용매를 감압 증류하여 제거하고 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=1/4)로 정제하여 표제화합물(3.06 g, 94 %)을 수득하였다. 4-cyclohexyl-4-piperidinecarboxylic acid (3.11 g, 10 mmol) was dissolved in DCM (30 mL) and oxalylchloride (1.40 g, 11 mmol) was added dropwise. After the reaction was stirred at room temperature for 3 hours, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: EtOAc / n-hexane = 1/4) to obtain the title compound (3.06 g, 94%). It was.

MS[M+H] = 307 (M+1)MS [M + H] = 307 (M + 1)

단계 B: 1-BOC-4-사이클로헥실-4-[(2-하이드록시-1,1-디메틸)에틸카바모일]피페리딘Step B: 1-BOC-4-cyclohexyl-4-[(2-hydroxy-1,1-dimethyl) ethylcarbamoyl] piperidine

1-BOC-4-사이클로헥실-4-피페리딘카복실클로라이드와 2-아미노-2-메틸-1-프로판올을 제조예 1의 단계 A와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4-piperidinecarboxylchloride and 2-amino-2-methyl-1-propanol were reacted in the same manner as in Step A of Preparation Example 1 to obtain the title compound.

MS[M+H] = 383 (M+1)MS [M + H] = 383 (M + 1)

단계 C: 1-BOC-4-사이클로헥실-4-[(4,4-디메틸)옥사졸린-2-일]피페리딘Step C: 1-BOC-4-cyclohexyl-4-[(4,4-dimethyl) oxazolin-2-yl] piperidine

단계 B에서 수득한 1-BOC-4-사이클로헥실-4-[(2-하이드록시-1,1-디메틸)에틸카바모일]피페리딘(382 mg, 1 mmol)을 DCM(5 ㎖)에 녹이고 DIPEA(0.348 ㎖, 2 mmol)와 DMAP(25 mg, 0.2 mmol)를 적가한 후 포스겐(2.5 M 톨루엔 용액, 2 ㎖)을 천천히 적가하였다. 반응물을 상온에서 2시간 동안 교반한 후 감압 농축하고 수득된 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=2/1)로 정제하여 표제화합물(328 mg, 90 %)을 수득하였다. 1-BOC-4-cyclohexyl-4-[(2-hydroxy-1,1-dimethyl) ethylcarbamoyl] piperidine (382 mg, 1 mmol) obtained in step B was added to DCM (5 mL). After dissolving DIPEA (0.348 mL, 2 mmol) and DMAP (25 mg, 0.2 mmol) were added dropwise, phosgene (2.5 M toluene solution, 2 mL) was slowly added dropwise. The reaction was stirred at room temperature for 2 hours, concentrated under reduced pressure and the residue obtained was purified by column chromatography (eluent: EtOAc / n-hexane = 2/1) to give the title compound (328 mg, 90%).

MS[M+H] = 365 (M+1)MS [M + H] = 365 (M + 1)

단계 D: 4-사이클로헥실-4-[(4,4-디메틸)옥사졸린-2-일]피페리딘Step D: 4-cyclohexyl-4-[(4,4-dimethyl) oxazolin-2-yl] piperidine

단계 C에서 얻은 1-BOC-4-사이클로헥실-4-[(4,4-디메틸)옥사졸린-2-일]피페리딘을 제조예 1의 단계 B와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4-[(4,4-dimethyl) oxazolin-2-yl] piperidine obtained in step C was reacted in the same manner as in step B of Preparation Example 1 to obtain the title compound. It was.

MS[M+H] = 265 (M+1)MS [M + H] = 265 (M + 1)

제조예 10: 4-사이클로헥실-4-(옥사졸린-2-일)피페리딘Preparation Example 10 4-cyclohexyl-4- (oxazolin-2-yl) piperidine

클로로 1-BOC-4-사이클로헥실-4-피페리딘카복실레이트와 아미노에탄올을 제조예 9에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. Chloro 1-BOC-4-cyclohexyl-4-piperidinecarboxylate and aminoethanol were reacted in the same manner as in Preparation Example 9 to obtain the title compound.

MS[M+H] = 237 (M+1)MS [M + H] = 237 (M + 1)

제조예 11: 4-사이클로헥실-4-[(4,4-디메틸)티오옥사졸린-2-일]피페리딘Preparation Example 11 4-cyclohexyl-4-[(4,4-dimethyl) thiooxazolin-2-yl] piperidine

단계 A: 1-BOC-4-사이클로헥실-4-[(4,4-디메틸)티오옥사졸린-2-일]피페리딘Step A: 1-BOC-4-cyclohexyl-4-[(4,4-dimethyl) thiooxazolin-2-yl] piperidine

제조예 9의 단계 C에서 수득한 1-BOC-4-사이클로헥실-4-[(4,4-디메틸)옥사졸린-2-일]피페리딘(382 mg, 1 mmol)을 톨루엔(10 ㎖)에 녹이고 로웨슨 시약(Lawesson's reagent; 330 mg, 3 mmol)을 적가하였다. 반응물을 120℃에서 2시간 동안 교반한 후 침전물을 셀라이트로 여과하고 남은 여액을 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: DCM/MeOH=19/1)로 정제하여 표제화합물(304 mg, 80%)을 수득하였다. 1-BOC-4-cyclohexyl-4-[(4,4-dimethyl) oxazolin-2-yl] piperidine (382 mg, 1 mmol) obtained in step C of Preparation Example 9 was diluted with toluene (10 mL). ) Was added dropwise to Lawesson's reagent (330 mg, 3 mmol). The reaction was stirred at 120 ° C. for 2 hours, then the precipitate was filtered through celite and the remaining filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: DCM / MeOH = 19/1) to give the title compound (304 mg, 80%).

MS[M+H] = 381 (M+1)MS [M + H] = 381 (M + 1)

단계 B: 4-사이클로헥실-4-[(4,4-디메틸)티오옥사졸린-2-일]피페리딘Step B: 4-cyclohexyl-4-[(4,4-dimethyl) thiooxazolin-2-yl] piperidine

단계 A에서 얻은 1-BOC-4-사이클로헥실-4-[(4,4-디메틸)티오옥사졸린-2-일]피페리딘을 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. The 1-BOC-4-cyclohexyl-4-[(4,4-dimethyl) thiooxazolin-2-yl] piperidine obtained in Step A was reacted in the same manner as in Step B of Preparation Example 1 to obtain the title compound. Obtained.

MS[M+H] = 281 (M+1)MS [M + H] = 281 (M + 1)

제조예 12: 4-사이클로헥실-4-(티오옥사졸린-2-일)피페리딘Preparation Example 12 4-cyclohexyl-4- (thiooxazolin-2-yl) piperidine

1-BOC-4-(사이클로헥실)-4-[(2-하이드록시에틸)카바모일]피페리딘을 제조예 11에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4- (cyclohexyl) -4-[(2-hydroxyethyl) carbamoyl] piperidine was reacted in the same manner as in Preparation Example 11 to obtain the title compound.

MS[M+H] = 253 (M+1)MS [M + H] = 253 (M + 1)

제조예 13: 메틸 4-사이클로헥실-4-피페리딘카복실레이트Preparation Example 13 Methyl 4-cyclohexyl-4-piperidinecarboxylate

단계 A: 메틸 1-BOC-4-사이클로헥실-4-피페리딘카복실레이트Step A: Methyl 1-BOC-4-cyclohexyl-4-piperidinecarboxylate

1-BOC-4-사이클로헥실-4-피페리딘카복실산(311 mg, 1 mmol)을 DMF(5 ㎖)에 녹이고 K2CO3(414 mg, 3 mmol)를 첨가한 다음 메틸요오다이드(0.183 ㎖, 1.2 mmol)를 적가하였다. 반응물을 상온에서 3시간동안 교반시킨 후 감압 하에 용액을 농축하고 잔류물을 1N 염산 수용액으로 희석하였다. 유기물을 EtOAc로 추출하고, 추출한 유기용액을 MgSO4로 건조시킨 후 여과하고 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=1/10)로 정제하여 표제화합물(109 mg, 95 %)을 수득하였다.Dissolve 1-BOC-4-cyclohexyl-4-piperidinecarboxylic acid (311 mg, 1 mmol) in DMF (5 mL), add K 2 CO 3 (414 mg, 3 mmol), and then add methyl iodide ( 0.183 mL, 1.2 mmol) was added dropwise. The reaction was stirred at room temperature for 3 hours, then the solution was concentrated under reduced pressure and the residue was diluted with 1N aqueous hydrochloric acid solution. The organics were extracted with EtOAc, and the extracted organic solution was dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-hexane = 1/10) to give the title compound (109 mg, 95%).

MS[M+H] = 326 (M+1)MS [M + H] = 326 (M + 1)

단계 B: 메틸 4-사이클로헥실-4-피페리딘카복실레이트Step B: Methyl 4-cyclohexyl-4-piperidinecarboxylate

단계 A에서 수득한 메틸 1-BOC-4-사이클로헥실-4-피페리딘카복실레이트를 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. The methyl 1-BOC-4-cyclohexyl-4-piperidinecarboxylate obtained in step A was reacted in the same manner as in step B of Preparation Example 1 to obtain the title compound.

MS[M+H] = 226 (M+1)MS [M + H] = 226 (M + 1)

제조예 14: 1-BOC-4-사이클로헥실-4-피페리딘메탄올Preparation Example 14 1-BOC-4-cyclohexyl-4-piperidinemethanol

제조예 13의 단계 A에서 수득한 메틸 1-BOC-4-사이클로헥실-4-피페리딘카복실레이트(3.25 g, 10 mmol)를 둥근 가지 달린 플라스크에 넣고 THF(30 ㎖)를 첨가하였다. 반응온도를 0℃로 내리고 LAH(759 mg, 20 mmol)를 적가한 후 다시 반응온도를 상온으로 올렸다. 반응물을 상온에서 2시간동안 교반한 후 반응온도를 다시 0℃로 내리고 물을 천천히 적가하였다. 기체가 더 이상 발생하지 않을 때까지 반응물을 교반하고 유기물을 EtOAc로 추출한 후 추출한 유기 용액을 MgSO4로 건조하고 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=1/1)로 정제하여 표제화합물을 수득하였다.Methyl 1-BOC-4-cyclohexyl-4-piperidinecarboxylate (3.25 g, 10 mmol) obtained in step A of Preparation Example 13 was placed in a round flask with THF (30 mL). The reaction temperature was lowered to 0 ° C., LAH (759 mg, 20 mmol) was added dropwise, and the reaction temperature was raised to room temperature. After the reaction was stirred at room temperature for 2 hours, the reaction temperature was lowered to 0 ° C. and water was slowly added dropwise. The reaction was stirred until no more gas was generated, the organics were extracted with EtOAc, and the extracted organic solution was dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-hexane = 1/1) to afford the title compound.

MS[M+H] = 298 (M+1)MS [M + H] = 298 (M + 1)

제조예 15: 1-BOC-4-사이클로헥실-4-피페리딘알데히드Preparation Example 15 1-BOC-4-cyclohexyl-4-piperidinealdehyde

제조예 14에서 수득한 1-BOC-4-사이클로헥실-4-피페리딘메탄올(892 mg, 3 mmol)을 DCM(10 ㎖)에 녹이고 반응온도를 0℃로 내린 후 4-메틸모폴린-N-옥사이드 (351 mg, 3 mmol)와 TPAP(25 mg)를 적가하였다. 반응물을 상온에서 3시간 동안 교반한 후 플로리실과 셀라이트로 여과하였다. 수득된 잔류물을 MgSO4로 건조하고 감압 농축하여 표제화합물을 수득하였다.1-BOC-4-cyclohexyl-4-piperidinemethanol (892 mg, 3 mmol) obtained in Preparation Example 14 was dissolved in DCM (10 mL), and the reaction temperature was decreased to 0 ° C., followed by 4-methylmorpholine- N-oxide (351 mg, 3 mmol) and TPAP (25 mg) were added dropwise. The reaction was stirred at room temperature for 3 hours and then filtered through Florisil and Celite. The obtained residue was dried over MgSO 4 and concentrated under reduced pressure to give the title compound.

MS[M+H] = 296(M+1)MS [M + H] = 296 (M + 1)

제조예 16: 4-사이클로헥실-4-[(1-하이드록시)이소부틸]피페리딘Preparation Example 16 4-cyclohexyl-4-[(1-hydroxy) isobutyl] piperidine

단계 A: 1-BOC-4-사이클로헥실-4-[(1-하이드록시)이소부틸]피페리딘Step A: 1-BOC-4-cyclohexyl-4-[(1-hydroxy) isobutyl] piperidine

가지달린 둥근 플라스크에 제조예 15에서 수득한 1-BOC-4-사이클로헥실-4-피페리딘알데히드(295 mg, 1 mmol)를 넣고 질소 치환을 한 다음 THF(5 ㎖)를 적가하였다. 반응온도를 0℃로 낮추고 이소프로필 마그네슘 클로라이드(2.5 M 헥산 용액, 1 ㎖)를 적가하였다. 30분 후에 반응온도를 상온으로 올리고 3시간 더 교반하였다. 반응이 종결되면 포화 암모늄클로라이드 수용액을 넣고 유기물을 EtOAc로 추출한 후 추출된 유기용액을 MgSO4로 건조하고 여과하여 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=1/2)로 정제하여 표제화합물을 수득하였다.1-BOC-4-cyclohexyl-4-piperidinealdehyde (295 mg, 1 mmol) obtained in Preparation Example 15 was added to a round flask equipped with nitrogen, and substituted with nitrogen, and THF (5 mL) was added dropwise. The reaction temperature was lowered to 0 ° C. and isopropyl magnesium chloride (2.5 M hexane solution, 1 mL) was added dropwise. After 30 minutes, the reaction temperature was raised to room temperature and further stirred for 3 hours. Upon completion of the reaction, saturated aqueous ammonium chloride solution was added, the organics were extracted with EtOAc, and the extracted organic solution was dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-hexane = 1/2) to afford the title compound.

MS[M+H] = 340(M+1)MS [M + H] = 340 (M + 1)

단계 B: 4-사이클로헥실-4-[(1-하이드록시)이소부틸]피페리딘Step B: 4-cyclohexyl-4-[(1-hydroxy) isobutyl] piperidine

단계 A에서 수득한 1-BOC-4-사이클로헥실-4-[(1-하이드록시)이소부틸]피페리딘을 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4-[(1-hydroxy) isobutyl] piperidine obtained in step A was reacted in the same manner as in step B of Preparation Example 1 to obtain the title compound.

MS[M+H] = 240(M+1)MS [M + H] = 240 (M + 1)

제조예 17: 4-사이클로헥실-4-(이소부티릴)피페리딘Preparation Example 17 4-cyclohexyl-4- (isobutyryl) piperidine

단계 A: 1-BOC-4-사이클로헥실-4-(이소부티릴)피페리딘Step A: 1-BOC-4-cyclohexyl-4- (isobutyryl) piperidine

제조예 16의 단계 A에서 얻은 1-BOC-4-사이클로헥실-4-[(1-하이드록시)이소부틸]피페리딘(200 mg, 0.59 mmol)을 가지달린 둥근 플라스크에 넣고 질소 치환을 한 후 옥살릴클로라이드(0.052 ㎖, 0.590 mmol)를 적가하였다. 반응온도를 -78℃로 내리고 온도가 -50℃ 이상 오르지 않게 하면서 DMSO(0.042 ㎖)를 적가하였다. 반응액을 30분 동안 교반한 후 TEA(0.248 ㎖, 2 mmol)를 적가하고 반응온도를 상온으로 올린 다음 포화 암모늄클로라이드 수용액을 첨가하였다. 유기물을 DCM으로 추출하여 MgSO4로 건조하고 여액을 감압농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산 = 1/2)로 정제하여 표제화합물(177 mg, 89 %)을 수득하였다.1-BOC-4-cyclohexyl-4-[(1-hydroxy) isobutyl] piperidine (200 mg, 0.59 mmol) obtained in step A of Preparation Example 16 was placed in a round flask equipped with nitrogen and replaced with nitrogen. Oxalyl chloride (0.052 mL, 0.590 mmol) was then added dropwise. The reaction temperature was lowered to −78 ° C. and DMSO (0.042 mL) was added dropwise while the temperature did not rise above −50 ° C. After stirring the reaction solution for 30 minutes, TEA (0.248 mL, 2 mmol) was added dropwise, the reaction temperature was raised to room temperature, and saturated aqueous ammonium chloride solution was added. The organics were extracted with DCM, dried over MgSO 4 and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-hexane = 1/2) to give the title compound (177 mg, 89%).

MS[M+H] = 338 (M+1)MS [M + H] = 338 (M + 1)

단계 B: 4-사이클로헥실-4-(이소부티릴)피페리딘Step B: 4-cyclohexyl-4- (isobutyryl) piperidine

제조예 17의 단계 A에서 수득한 1-BOC-4-사이클로헥실-4-(이소부티릴)피페리딘을 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다.1-BOC-4-cyclohexyl-4- (isobutyryl) piperidine obtained in Step A of Preparation Example 17 was reacted in the same manner as in Step B of Preparation Example 1 to obtain the title compound.

MS[M+H] = 238 (M+1)MS [M + H] = 238 (M + 1)

제조예 18: 4-사이클로헥실-4-[(4,4-디메틸옥사졸리딘-2-온-3-일)메틸]피페리딘Preparation 18: 4-cyclohexyl-4-[(4,4-dimethyloxazolidin-2-one-3-yl) methyl] piperidine

단계 A: 1-BOC-4-사이클로헥실-4-{N-[(2-하이드록시-1,1-디메틸)에틸]이미노}피페리딘Step A: 1-BOC-4-cyclohexyl-4- {N-[(2-hydroxy-1,1-dimethyl) ethyl] imino} piperidine

제조예 15에서 수득한 1-BOC-4-사이클로헥실-4-피페리딘알데히드(590 mg, 2 mmol)와 2-하이드록시-1,1-디메틸에틸아민(178 mg, 2 mmol)을 톨루엔(10 ㎖)에 녹이고 아세트산(0.05 ㎖)을 적가하였다. 반응물질을 90℃에서 딘스탁 장치를 이용하여 8시간 동안 교반하여 생성되는 물을 제거하였다. 반응이 종결되면 반응액을 감압 농축하고 잔류물을 아세트산에 다시 녹인 다음 PtO2를 첨가하여 수소 조건하에서 12시간 동안 교반하였다. 반응이 종결되면 셀라이트로 여과하고 반응액을 감압 농축하여 표제화합물을 수득하였다.1-BOC-4-cyclohexyl-4-piperidinealdehyde (590 mg, 2 mmol) and 2-hydroxy-1,1-dimethylethylamine (178 mg, 2 mmol) obtained in Preparation Example 15 were toluene. (10 mL) and acetic acid (0.05 mL) was added dropwise. The reaction mass was stirred at 90 ° C. for 8 hours using a Deanstock apparatus to remove the resulting water. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was dissolved in acetic acid again, and PtO 2 was added thereto, followed by stirring for 12 hours under hydrogen conditions. After the reaction was completed, the mixture was filtered through celite and the reaction solution was concentrated under reduced pressure to obtain the title compound.

MS[M+H] = 367 (M+1)MS [M + H] = 367 (M + 1)

단계 B: 1-BOC-4-사이클로헥실-4-[(4,4-디메틸옥사졸리딘-2-온-3-일)메틸]피페리딘Step B: 1-BOC-4-cyclohexyl-4-[(4,4-dimethyloxazolidin-2-one-3-yl) methyl] piperidine

단계 A에서 수득한 1-BOC-4-사이클로헥실-4-{N-[(2-하이드록시-1,1-디메틸)에틸]이미노}피페리딘을 제조예 9의 단계 C에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다.1-BOC-4-cyclohexyl-4- {N-[(2-hydroxy-1,1-dimethyl) ethyl] imino} piperidine obtained in step A was prepared in the same manner as in step C of Preparation Example 9. Reaction was carried out to give the title compound.

MS[M+H] = 395 (M+1)MS [M + H] = 395 (M + 1)

단계 C: 4-사이클로헥실-4-[(4,4-디메틸옥사졸리딘-2-온-3-일)메틸]피페리딘Step C: 4-cyclohexyl-4-[(4,4-dimethyloxazolidin-2-one-3-yl) methyl] piperidine

단계 B에서 수득한 1-BOC-4-사이클로헥실-4-[(4,4-디메틸옥사졸리딘-2-온-3-일)메틸]피페리딘을 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다.1-BOC-4-cyclohexyl-4-[(4,4-dimethyloxazolidin-2-on-3-yl) methyl] piperidine obtained in step B was prepared in the same manner as in step B of Preparation Example 1. Reaction was carried out to give the title compound.

MS[M+H] = 295(M+1)MS [M + H] = 295 (M + 1)

제조예 19: 4-사이클로헥실-4-[(옥사졸리딘-2-온-3-일)메틸]피페리딘Preparation Example 19 4-cyclohexyl-4-[(oxazolidin-2-one-3-yl) methyl] piperidine

제조예 15에서 수득한 1-BOC-4-사이클로헥실-4-피페리딘알데히드를 제조예 18에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다.1-BOC-4-cyclohexyl-4-piperidinealdehyde obtained in Preparation Example 15 was reacted in the same manner as in Preparation Example 18, to obtain the title compound.

MS[M+H] = 267 (M+1)MS [M + H] = 267 (M + 1)

제조예 20: 4-사이클로헥실-4-[(N-메톡시)이미닐]피페리딘Preparation Example 20 4-cyclohexyl-4-[(N-methoxy) iminyl] piperidine

단계 A: 1-BOC-4-사이클로헥실-4-[(N-메톡시)이미닐]피페리딘Step A: 1-BOC-4-cyclohexyl-4-[(N-methoxy) iminyl] piperidine

제조예 15에서 수득한 1-BOC-4-사이클로헥실-4-피페리딘알데히드(295 mg, 1 mmol)와 메톡시아민(94 mg, 2 mmol)을 톨루엔(10 ㎖)에 녹이고 아세트산(1-2 방울)을 적가한 다음, 딘스탁 장치를 하고 90℃에서 8시간 교반하였다. 반응이 종결되면 반응물을 포화 암모늄클로라이드 수용액에 넣고 유기물을 EtOAc로 추출한 후 추출한 유기 용액을 MgSO4로 건조하고 여과하여 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=9/1)로 정제하여 표제화합물을 수득하였다.1-BOC-4-cyclohexyl-4-piperidinealdehyde (295 mg, 1 mmol) and methoxyamine (94 mg, 2 mmol) obtained in Preparation Example 15 were dissolved in toluene (10 mL) and acetic acid (1 -2 drops) was added dropwise, followed by a Deanstock apparatus and stirred at 90 ° C for 8 hours. After the reaction was completed, the reaction mixture was poured into a saturated aqueous ammonium chloride solution, the organics were extracted with EtOAc, and the extracted organic solution was dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-hexane = 9/1) to afford the title compound.

MS[M+H] = 325 (M+1)MS [M + H] = 325 (M + 1)

단계 B: 4-사이클로헥실-4-[(N-메톡시)이미닐]피페리딘Step B: 4-cyclohexyl-4-[(N-methoxy) iminyl] piperidine

단계 A에서 수득한 1-BOC-4-사이클로헥실-4-[(N-메톡시)이미닐]피페리딘을 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다.1-BOC-4-cyclohexyl-4-[(N-methoxy) iminyl] piperidine obtained in step A was reacted in the same manner as in step B of Preparation Example 1 to obtain the title compound.

MS[M+H] = 225 (M+1)MS [M + H] = 225 (M + 1)

제조예 21: 4-사이클로헥실-4-[(메탄설포닐옥시)메틸]피페리딘Preparation Example 21 4-cyclohexyl-4-[(methanesulfonyloxy) methyl] piperidine

단계 A: 1-BOC-4-사이클로헥실-4-[(메탄설포닐옥시)메틸]피페리딘Step A: 1-BOC-4-cyclohexyl-4-[(methanesulfonyloxy) methyl] piperidine

제조예 14에서 수득한 1-BOC-4-사이클로헥실-4-피페리딘메탄올(2.97 g, 10 mmol)을 DCM(60 ㎖)에 녹이고 TEA(2.8 ㎖, 20 mmol)를 적가한 다음 메탄설포닐클로라이드(3.11 ㎖, 20 mmol)를 천천히 적가하였다. 반응물을 상온에서 1시간 동안 교반한 후 포화 암모늄클로라이드 수용액을 첨가하고 유기물은 DCM과 EtOAc로 추출하였다. 추출한 유기 용액은 MgSO4로 건조하고 여과하여 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-Hex=1/9)로 정제하여 표제화합물(1.55 g, 96 %)을 수득하였다.1-BOC-4-cyclohexyl-4-piperidinemethanol (2.97 g, 10 mmol) obtained in Preparation Example 14 was dissolved in DCM (60 mL), and TEA (2.8 mL, 20 mmol) was added dropwise, followed by methanesulphate. Ponylchloride (3.11 mL, 20 mmol) was added slowly dropwise. After the reaction was stirred at room temperature for 1 hour, saturated aqueous ammonium chloride solution was added, and the organics were extracted with DCM and EtOAc. The extracted organic solution was dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-Hex = 1/9) to afford the title compound (1.55 g, 96%).

MS[M+H] = 323 (M+1)MS [M + H] = 323 (M + 1)

단계 B: 4-사이클로헥실-4-[(메탄설포닐옥시)메틸]피페리딘Step B: 4-cyclohexyl-4-[(methanesulfonyloxy) methyl] piperidine

단계 A에서 수득한 1-BOC-4-사이클로헥실-4-[(메탄설포닐옥시)메틸]피페리딘을 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다.1-BOC-4-cyclohexyl-4-[(methanesulfonyloxy) methyl] piperidine obtained in step A was reacted in the same manner as in step B of Preparation Example 1 to obtain the title compound.

MS[M+H] = 276 (M+1)MS [M + H] = 276 (M + 1)

제조예 22: 1,2,3-트리아졸-1-카보닐클로라이드Preparation Example 22 1,2,3-triazole-1-carbonyl chloride

1,2,3-트리아졸(207 mg, 3 mmol)과 DMAP(366 mg, 3 mmol)를 DCM(10 ㎖)에 녹이고 포스겐(25 % 톨루엔 용액, 3 ㎖)을 적가한 후 상온에서 30분 동안 교반하였다. 생성된 침전물을 여과하고 여액을 감압 농축하여 표제화합물을 수득하였다. 1,2,3-triazole (207 mg, 3 mmol) and DMAP (366 mg, 3 mmol) are dissolved in DCM (10 mL) and phosgene (25% toluene solution, 3 mL) is added dropwise, followed by 30 minutes at room temperature. Was stirred. The resulting precipitate was filtered and the filtrate was concentrated under reduced pressure to give the title compound.

MS[M+H] = 132 (M+1)MS [M + H] = 132 (M + 1)

제조예 23: 1,2,4-트리아졸-1-카보닐클로라이드Preparation Example 23 1,2,4-triazole-1-carbonyl chloride

1,2,4-트리아졸을 제조예 22에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1,2,4-triazole was reacted in the same manner as in Production Example 22 to obtain the title compound.

MS[M+H] = 132 (M+1)MS [M + H] = 132 (M + 1)

제조예 24: 1,3-이미다졸-1-카보닐클로라이드Preparation Example 24 1,3-imidazole-1-carbonylchloride

1,3-이미다졸을 제조예 22에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1,3-imidazole was reacted in the same manner as in Preparation Example 22 to obtain the title compound.

MS[M+H] = 131 (M+1)MS [M + H] = 131 (M + 1)

제조예 25: 1-BOC-4-사이클로헥실-4-(아미노메틸)피페리딘Preparation Example 25 1-BOC-4-cyclohexyl-4- (aminomethyl) piperidine

단계 A: 1-BOC-4-사이클로헥실-4-(아지도메틸)피페리딘Step A: 1-BOC-4-cyclohexyl-4- (azidomethyl) piperidine

제조예 21의 단계 A에서 수득한 1-BOC-4-사이클로헥실-4-[(메탄설포닐옥시)메틸]피페리딘(1.88g, 5 mmol)과 아지도나트륨(1.32 g, 20 mmol)을 DMF(20 ㎖)에 녹이고 반응용액을 90℃로 4시간동안 가열하였다. 반응이 종결되면 감압 증류하여 DMF를 제거하고 잔류물을 물로 희석한 다음 유기물을 EtOAc로 추출하였다. 추출한 유기 용액을 MgSO4로 건조하고 여과하여 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=1/15)로 정제하여 표제화합물(1.55 g, 96 %)을 수득하였다.1-BOC-4-cyclohexyl-4-[(methanesulfonyloxy) methyl] piperidine (1.88 g, 5 mmol) and azido sodium (1.32 g, 20 mmol) obtained in step A of Preparation Example 21 Was dissolved in DMF (20 mL) and the reaction solution was heated to 90 ° C. for 4 h. After the reaction was completed, the mixture was distilled under reduced pressure to remove DMF, the residue was diluted with water, and the organics were extracted with EtOAc. The extracted organic solution was dried over MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: EtOAc / n-hexane = 1/15) to give the title compound (1.55 g, 96%).

MS[M+H] = 323 (M+1)MS [M + H] = 323 (M + 1)

단계 B: 1-BOC-4-사이클로헥실-4-(아미노메틸)피페리딘Step B: 1-BOC-4-cyclohexyl-4- (aminomethyl) piperidine

단계 A에서 수득한 1-BOC-4-사이클로헥실-4-(아지도메틸)피페리딘(1.0 g, 3.10 mmol)을 메탄올에 녹이고 Pd/C(200 mg)를 적가한 후 수소 조건으로 바꾸고 12시간 교반하였다. 반응이 종결되면 셀라이트로 여과하고 여액을 감압 농축하여 표제화합물을 수득하였다. Dissolve 1-BOC-4-cyclohexyl-4- (azidomethyl) piperidine (1.0 g, 3.10 mmol) obtained in step A in methanol, add Pd / C (200 mg) dropwise, and change to hydrogen. Stir for 12 hours. After the reaction was completed, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain the title compound.

MS[M+H] = 297 (M+1)MS [M + H] = 297 (M + 1)

제조예 26: 4-사이클로헥실-4-{[(사이클로헥실메틸)아미노]메틸}피페리딘Preparation 26: 4-cyclohexyl-4-{[(cyclohexylmethyl) amino] methyl} piperidine

단계 A: 1-BOC-4-사이클로헥실-4-[(사이클로헥실아미노)메틸]피페리딘Step A: 1-BOC-4-cyclohexyl-4-[(cyclohexylamino) methyl] piperidine

제조예 25에서 수득한 1-BOC-4-사이클로헥실-4-(아미노메틸)피페리딘(296 mg, 1 mmol)과 사이클로헥사논(98.3 mg, 1.0 mmol)을 DCE(5 ㎖)에 녹이고 NaBH(OAc)3 (678 mg, 3.2 mmol)를 천천히 적가하였다. 반응용액을 상온에서 4시간 동안 교반하고 포화 탄산수소나트륨 수용액을 첨가하고 유기물을 DCM으로 추출하였다. 추출한 유기 용액을 MgSO4로 건조하고 여과하여 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: MeOH/EtOAc/n-헥산=1/4/4)로 정제하여 표제화합물을 수득하였다.1-BOC-4-cyclohexyl-4- (aminomethyl) piperidine (296 mg, 1 mmol) and cyclohexanone (98.3 mg, 1.0 mmol) obtained in Preparation Example 25 were dissolved in DCE (5 mL). NaBH (OAc) 3 (678 mg, 3.2 mmol) was slowly added dropwise. The reaction solution was stirred at room temperature for 4 hours, saturated aqueous sodium hydrogen carbonate solution was added, and the organics were extracted with DCM. The extracted organic solution was dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography (eluent: MeOH / EtOAc / n-hexane = 1/4/4) to afford the title compound.

MS[M+H] = 379 (M+1)MS [M + H] = 379 (M + 1)

단계 B: 1-BOC-4-사이클로헥실-4-{[(사이클로헥실(메틸)아미노)메틸]피페리딘Step B: 1-BOC-4-cyclohexyl-4-{[(cyclohexyl (methyl) amino) methyl] piperidine

단계 A에서 수득한 1-BOC-4-사이클로헥실-4-[(사이클로헥실아미노)메틸]피페리딘과 포르말린을 단계 A에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. The title compound was obtained by reacting 1-BOC-4-cyclohexyl-4-[(cyclohexylamino) methyl] piperidine and formalin obtained in step A in the same manner as in step A.

MS[M+H] = 393(M+1)MS [M + H] = 393 (M + 1)

단계 C: 4-사이클로헥실-4-{[(사이클로헥실(메틸)아미노)메틸]피페리딘Step C: 4-cyclohexyl-4-{[(cyclohexyl (methyl) amino) methyl] piperidine

단계 B에서 수득한 1-BOC-4-사이클로헥실-4-{[(사이클로헥실(메틸)아미노)메틸]피페리딘을 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4-{[(cyclohexyl (methyl) amino) methyl] piperidine obtained in step B was reacted in the same manner as in step B of Preparation Example 1 to obtain the title compound. .

MS[M+H] = 293(M+1)MS [M + H] = 293 (M + 1)

제조예 27-37:Preparation Example 27-37:

1-BOC-4-사이클로헥실-4-피페리딘메탄올, 1-BOC-4-사이클로헥실-4-(아미노메틸)피페리딘 및 1-BOC-4-사이클로헥실-4-[(사이클로헥실아미노)메틸]피페리딘을 제조예 21에서와 동일한 방법으로 반응시켜 하기 화합물을 수득하였다. 1-BOC-4-cyclohexyl-4-piperidinemethanol, 1-BOC-4-cyclohexyl-4- (aminomethyl) piperidine and 1-BOC-4-cyclohexyl-4-[(cyclohexyl Amino) methyl] piperidine was reacted in the same manner as in Preparation Example 21 to obtain the following compound.

제조예 38: 4-사이클로헥실-4-[(1,2,4-트리아졸-1-일)메틸]피페리딘Preparation 38: 4-cyclohexyl-4-[(1,2,4-triazol-1-yl) methyl] piperidine

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

1-BOC-4-사이클로헥실-4-[(메탄설포닐옥시)메틸]피페리딘(375 mg, 1 mmol)과 1,2,4-트리아졸 나트륨염(273 mg, 3 mmol)을 DMF(10 ㎖)에 녹이고 90-100℃ 사이에서 12시간 교반하였다. 반응이 종결된 후 감압 증류를 통하여 DMF를 제거하고 포화 암모늄클로라이드 수용액을 첨가하여 유기물을 EtOAc로 추출하였다. 추출한 유기용액을 마그네슘 설페이트로 건조하고 여과하여 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: 아세톤/DCM=3/1)로 정제하여 표제화합물(313 mg, 90 %)을 수득하였다. 1-BOC-4-cyclohexyl-4-[(methanesulfonyloxy) methyl] piperidine (375 mg, 1 mmol) and 1,2,4-triazole sodium salt (273 mg, 3 mmol) were converted into DMF. (10 mL) and stirred for 12 h between 90-100 ° C. After completion of the reaction, DMF was removed by distillation under reduced pressure, and the organics were extracted with EtOAc by adding saturated aqueous ammonium chloride solution. The extracted organic solution was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: acetone / DCM = 3/1) to give the title compound (313 mg, 90%).

MS[M+H] = 349(M+1)MS [M + H] = 349 (M + 1)

단계 B: 4-사이클로헥실-4-[(1,2,4-트리아졸-1-일)메틸]피페리딘Step B: 4-cyclohexyl-4-[(1,2,4-triazol-1-yl) methyl] piperidine

단계 A에서 수득한 1-BOC-4-사이클로헥실-4-[(1,2,4-트리아졸-1-일)메틸]피페리딘을 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4-[(1,2,4-triazol-1-yl) methyl] piperidine obtained in step A was reacted in the same manner as in step B of Preparation Example 1 The title compound was obtained.

MS[M+H] = 249 (M+1)MS [M + H] = 249 (M + 1)

제조예 39: 4-사이클로헥실-4-[(1,2,3-트리아졸-1-일)메틸]피페리딘Preparation Example 39 4-cyclohexyl-4-[(1,2,3-triazol-1-yl) methyl] piperidine

단계 A: 1-BOC-4-사이클로헥실-4-[(1,2,3-트리아졸-1-일)메틸]피페리딘Step A: 1-BOC-4-cyclohexyl-4-[(1,2,3-triazol-1-yl) methyl] piperidine

1-BOC-4-사이클로헥실-4-[(메탄설포닐옥시)메틸]피페리딘(375 mg, 1 mmol)과 1,2,3-트리아졸(205 mg, 3 mmol)을 DMF(10 ㎖)에 녹이고 나트륨이소펜톡사이드(220 mg, 2 mmol)를 첨가한 다음 반응물을 90-100℃ 사이에서 12시간 교반하였다. 반응이 종결된 후 감압 증류하여 DMF를 제거하고 포화 암모늄클로라이드 수용액을 첨가하여 유기물을 EtOAc로 추출하였다. 추출한 유기용액을 마그네슘 설페이트로 건조하고 여과하여 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: 아세톤/DCM=3/1)로 정제하여 표제화합물(292 mg, 84 %)을 수득하였다. 1-BOC-4-cyclohexyl-4-[(methanesulfonyloxy) methyl] piperidine (375 mg, 1 mmol) and 1,2,3-triazole (205 mg, 3 mmol) were added to DMF (10 ML) and sodium isopentoside (220 mg, 2 mmol) were added and the reaction stirred between 90-100 ° C. for 12 hours. After the reaction was completed, the mixture was distilled under reduced pressure to remove DMF, and the organics were extracted with EtOAc by adding an aqueous saturated ammonium chloride solution. The extracted organic solution was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: acetone / DCM = 3/1) to give the title compound (292 mg, 84%).

MS[M+H] = 349(M+1)MS [M + H] = 349 (M + 1)

단계 B: 4-사이클로헥실-4-[(1,2,3-트리아졸-1-일)메틸]피페리딘Step B: 4-cyclohexyl-4-[(1,2,3-triazol-1-yl) methyl] piperidine

단계 A에서 수득한 1-BOC-4-사이클로헥실-4-[(1,2,3-트리아졸-1-일)메틸]피페리딘을 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4-[(1,2,3-triazol-1-yl) methyl] piperidine obtained in step A was reacted in the same manner as in step B of Preparation Example 1 The title compound was obtained.

MS[M+H] = 249(M+1)MS [M + H] = 249 (M + 1)

제조예 40: 4-사이클로헥실-4-[(테트라졸-1-일)메틸]피페리딘Preparation 40: 4-cyclohexyl-4-[(tetrazol-1-yl) methyl] piperidine

1-BOC-4-사이클로헥실-4-[(메탄설포닐옥시)메틸]피페리딘과 테트라졸을 제조예 39에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4-[(methanesulfonyloxy) methyl] piperidine and tetrazole were reacted in the same manner as in Preparation Example 39 to obtain the title compound.

MS[M+H] = 250(M+1)MS [M + H] = 250 (M + 1)

제조예 41: 4-사이클로헥실-4-{[(1-메틸)테트라졸-5-일]메틸}피페리딘Preparation Example 41 4-cyclohexyl-4-{[(1-methyl) tetrazol-5-yl] methyl} piperidine

단계 A: 1-BOC-4-사이클로헥실-4-(시아노메틸)피페리딘Step A: 1-BOC-4-cyclohexyl-4- (cyanomethyl) piperidine

1-BOC-4-사이클로헥실-4-[(메탄설포닐옥시)메틸]피페리딘(375 mg, 1 mmol)과 나트륨시아나이드(153 mg, 3 mmol)를 DMF(5 ㎖)에 녹이고 24시간 동안 100℃에서 교반하였다. 반응이 종결되면 반응물을 EtOAc로 희석시키고 1N 염산 수용액을 첨가하였다. 유기물을 EtOAc로 추출하고 추출한 유기용액을 포화 탄산수소나트륨 수용액으로 씻어준 다음 MgSO4로 건조하고 여과한 후 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=1/3)로 정제하여 표제화합물을 수득하였다.1-BOC-4-cyclohexyl-4-[(methanesulfonyloxy) methyl] piperidine (375 mg, 1 mmol) and sodium cyanide (153 mg, 3 mmol) were dissolved in DMF (5 mL) and 24 Stir at 100 ° C for hours. At the end of the reaction the reaction was diluted with EtOAc and 1N aqueous hydrochloric acid solution was added. The organics were extracted with EtOAc and the extracted organic solution was washed with saturated aqueous sodium hydrogen carbonate solution, dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography (eluent: EtOAc / n-hexane = 1/3) to afford the title compound.

MS[M+H] = 306(M+1)MS [M + H] = 306 (M + 1)

단계 B: 1-BOC-4-사이클로헥실-4-{[(1-메틸)테트라졸-5-일]메틸}피페리딘Step B: 1-BOC-4-cyclohexyl-4-{[(1-methyl) tetrazol-5-yl] methyl} piperidine

단계 A에서 수득한 1-BOC-4-사이클로헥실-4-(시아노메틸)피페리딘(250 mg, 0.82 mmol), 나트륨아지드(195 mg, 3 mmol), 및 암모늄클로라이드(132 mg, 3 mmol)를 DMF에 녹이고 90℃에서 24시간 교반하였다. 반응이 종결되면 반응용액을 EtOAc로 희석시키고 1N 염산과 포화 탄산수소나트륨 수용액으로 씻어주었다. 남은 유기 용액을 MgSO4로 건조시키고 여과한 후 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: 아세톤/DCM=3/1)로 정제하여 표제화합물을 수득하였다.1-BOC-4-cyclohexyl-4- (cyanomethyl) piperidine (250 mg, 0.82 mmol), sodium azide (195 mg, 3 mmol) obtained in step A, and ammonium chloride (132 mg, 3 mmol) was dissolved in DMF and stirred at 90 ° C. for 24 hours. Upon completion of the reaction, the reaction solution was diluted with EtOAc and washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution. The remaining organic solution was dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography (eluent: acetone / DCM = 3/1) to afford the title compound.

MS[M+H] = 350(M+1)MS [M + H] = 350 (M + 1)

단계 C: 4-사이클로헥실-4-{[(1-메틸)테트라졸-5-일]메틸}피페리딘Step C: 4-cyclohexyl-4-{[(1-methyl) tetrazol-5-yl] methyl} piperidine

단계 B에서 수득한 1-BOC-4-사이클로헥실-4-{[(1-메틸)테트라졸-5-일]메틸}피페리딘을 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4-{[(1-methyl) tetrazol-5-yl] methyl} piperidine obtained in step B was reacted in the same manner as in step B of Preparation Example 1 to obtain the title The compound was obtained.

MS[M+H] = 250(M+1)MS [M + H] = 250 (M + 1)

제조예 42: 4-사이클로헥실-4-[(2-피롤리디논-1-일)메틸]피페리딘Preparation 42: 4-cyclohexyl-4-[(2-pyrrolidinone-1-yl) methyl] piperidine

단계 A: 1-BOC-4-사이클로헥실-4-[(2-피롤리디논-1-일)메틸]피페리딘Step A: 1-BOC-4-cyclohexyl-4-[(2-pyrrolidinone-1-yl) methyl] piperidine

50 ㎖ 가지달린 둥근 플라스크에 NaH(60 % 미네랄 오일, 60 mg, 1.5 mmol)를 넣고 질소 치환을 한 후 THF(5 ㎖)를 넣고 반응물을 0℃로 낮추었다. THF(1 ㎖)에 녹인 2-피롤리디논(102 mg, 1.2 mmol)을 천천히 적가한 후 0℃에서 30분 정도 교반 하고 1-BOC-4-사이클로헥실-4-[(메탄설포닐옥시)메틸]피페리딘(375 mg, 1 mmol)을 THF(1 ㎖)에 녹여서 천천히 적가하였다. 30분 후에 반응물의 온도를 상온으로 올리고 상온에서 5시간 더 교반하였다. 반응이 종결되었을 때 포화 암모늄클로라이드 수용액을 첨가하고 유기물은 EtOAc로 추출하였다. 추출한 유기 용액을 MgSO4로 건조하고 여과하여 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=1/2)로 정제하여 표제화합물(255 mg, 70 %)을 수득하였다.NaH (60% mineral oil, 60 mg, 1.5 mmol) was added to a 50 mL round flask equipped with nitrogen, and THF (5 mL) was added thereto, followed by lowering the reaction to 0 ° C. 2-pyrrolidinone (102 mg, 1.2 mmol) dissolved in THF (1 mL) was slowly added dropwise, stirred at 0 ° C. for 30 minutes, and then 1-BOC-4-cyclohexyl-4-[(methanesulfonyloxy) Methyl] piperidine (375 mg, 1 mmol) was dissolved slowly in THF (1 mL) and slowly added dropwise. After 30 minutes, the temperature of the reaction was raised to room temperature, and further stirred at room temperature for 5 hours. At the end of the reaction, saturated aqueous ammonium chloride solution was added and the organics were extracted with EtOAc. The extracted organic solution was dried over MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: EtOAc / n-hexane = 1/2) to give the title compound (255 mg, 70%).

MS[M+H] = 365(M+1)MS [M + H] = 365 (M + 1)

단계 B: 4-사이클로헥실-4-[(2-피롤리디논-1-일)메틸]피페리딘Step B: 4-cyclohexyl-4-[(2-pyrrolidinone-1-yl) methyl] piperidine

단계 A에서 수득한 1-BOC-4-사이클로헥실-4-[(2-피롤리디논-1-일)메틸]피페리딘을 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4-[(2-pyrrolidinone-1-yl) methyl] piperidine obtained in Step A was reacted in the same manner as in Step B of Preparation Example 1 to obtain the title compound. Obtained.

MS[M+H] = 265(M+1)MS [M + H] = 265 (M + 1)

제조예 43: 4-사이클로헥실-4-[(디메틸아미노)메틸]피페리딘Preparation Example 43 4-cyclohexyl-4-[(dimethylamino) methyl] piperidine

단계 A: 1-BOC-4-사이클로헥실-4-[(디메틸아미노)메틸]피페리딘Step A: 1-BOC-4-cyclohexyl-4-[(dimethylamino) methyl] piperidine

1-BOC-4-사이클로헥실-4-(아미노메틸)피페리딘과 포르말린을 제조예 26에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4- (aminomethyl) piperidine and formalin were reacted in the same manner as in Production Example 26 to obtain the title compound.

MS[M+H] = 325(M+1)MS [M + H] = 325 (M + 1)

단계 B: 4-사이클로헥실-4-[(디메틸아미노)메틸]피페리딘Step B: 4-cyclohexyl-4-[(dimethylamino) methyl] piperidine

단계 A에서 수득한 1-BOC-4-사이클로헥실-4-[(디메틸아미노)메틸]피페리딘을 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4-[(dimethylamino) methyl] piperidine obtained in step A was reacted in the same manner as in step B of Preparation Example 1 to obtain the title compound.

MS[M+H] = 225(M+1)MS [M + H] = 225 (M + 1)

제조예 44: 4-사이클로헥실-4-{[메틸(사이클로헥실)아미노]메틸}피페리딘Preparation Example 44 4-cyclohexyl-4-{[methyl (cyclohexyl) amino] methyl} piperidine

단계 A: 1-BOC-4-사이클로헥실-4-{[메틸(사이클로헥실)아미노]메틸}피페리딘Step A: 1-BOC-4-cyclohexyl-4-{[methyl (cyclohexyl) amino] methyl} piperidine

1-BOC-4-사이클로헥실-4-{[(사이클로헥실)아미노]메틸}피페리딘과 포르말린을 제조예 26에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4-{[(cyclohexyl) amino] methyl} piperidine was reacted with formalin in the same manner as in Production Example 26 to obtain the title compound.

MS[M+H] = 393(M+1)MS [M + H] = 393 (M + 1)

단계 B: 4-사이클로헥실-4-[(메틸(사이클로헥실)아미노)메틸]피페리딘Step B: 4-cyclohexyl-4-[(methyl (cyclohexyl) amino) methyl] piperidine

단계 A에서 수득한 1-BOC-4-사이클로헥실-4-{[메틸(사이클로헥실)아미노]메틸}피페리딘을 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4-{[methyl (cyclohexyl) amino] methyl} piperidine obtained in step A was reacted in the same manner as in step B of Preparation Example 1 to obtain the title compound.

MS[M+H] = 293(M+1)MS [M + H] = 293 (M + 1)

제조예 45: 1-BOC-4-사이클로헥실-4-아미노피페리딘Preparation Example 45 1-BOC-4-cyclohexyl-4-aminopiperidine

단계 A: 1-BOC-4-사이클로헥실-4-(벤질옥시카보닐아미노)피페리딘Step A: 1-BOC-4-cyclohexyl-4- (benzyloxycarbonylamino) piperidine

1-BOC-4-사이클로헥실-4-피페리딘카복실산(3.1 g, 10 mmol)과 TEA(2.8 ㎖, 20 mmol)를 THF에 넣고 DPPA(디페닐포스포릴아지드, 2.6 g, 12 mmol)를 적가한 후 반응물을 70℃에서 24시간 교반하였다. 반응액을 감압 증류하여 THF를 제거하고 톨루엔(10 ㎖)과 벤질알콜(1.5 ㎖)을 적가한 후 100℃에서 24시간 교반하였다. 반응이 종결된 후 감압 증류하여 용매를 제거하고 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=1/5)로 정제하여 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4-piperidinecarboxylic acid (3.1 g, 10 mmol) and TEA (2.8 mL, 20 mmol) were added to THF and DPPA (diphenylphosphoryl azide, 2.6 g, 12 mmol) After the dropwise addition, the reaction was stirred at 70 ° C for 24 hours. The reaction solution was distilled under reduced pressure to remove THF, and toluene (10 mL) and benzyl alcohol (1.5 mL) were added dropwise, followed by stirring at 100 ° C for 24 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography (eluent: EtOAc / n-hexane = 1/5) to obtain the title compound.

MS[M+H] = 417(M+1)MS [M + H] = 417 (M + 1)

단계 B: 1-BOC-4-사이클로헥실-4-아미노피페리딘Step B: 1-BOC-4-cyclohexyl-4-aminopiperidine

단계 A에서 수득한 1-BOC-4-사이클로헥실-4-(벤질옥시카보닐아미노)피페리딘(2.1 g, 5 mmol)을 메탄올(30 ㎖)에 녹이고 Pd/C(200 mg)를 적가한 후 수소 조건 하의 상온에서 12시간 교반하였다. 반응이 종결되었을 때 셀라이트로 여과하고 감압 농축하여 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4- (benzyloxycarbonylamino) piperidine (2.1 g, 5 mmol) obtained in step A was dissolved in methanol (30 mL) and Pd / C (200 mg) was added dropwise. After stirring, the mixture was stirred at room temperature under hydrogen conditions for 12 hours. When the reaction was terminated, filtered through celite and concentrated under reduced pressure to give the title compound.

MS[M+H] = 283(M+1)MS [M + H] = 283 (M + 1)

제조예 46: 4-사이클로헥실-4-(디메틸아미노)피페리딘Preparation 46: 4-cyclohexyl-4- (dimethylamino) piperidine

단계 A: 1-BOC-4-사이클로헥실-4-(디메틸아미노)피페리딘Step A: 1-BOC-4-cyclohexyl-4- (dimethylamino) piperidine

제조예 45의 단계 B에서 수득한 1-BOC-4-사이클로헥실-4-아미노피페리딘과 포르말린을 제조예 26에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4-aminopiperidine and formalin obtained in Step B of Preparation Example 45 were reacted in the same manner as in Preparation Example 26 to obtain the title compound.

MS[M+H] = 311(M+1)MS [M + H] = 311 (M + 1)

단계 B: 4-사이클로헥실-4-(디메틸아미노)피페리딘Step B: 4-cyclohexyl-4- (dimethylamino) piperidine

단계 A에서 수득한 1-BOC-4-사이클로헥실-4-(디메틸아미노)피페리딘을 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4- (dimethylamino) piperidine obtained in step A was reacted in the same manner as in step B of Preparation Example 1 to obtain the title compound.

MS[M+H] = 211(M+1)MS [M + H] = 211 (M + 1)

제조예 47: 4-사이클로헥실-4-(아세틸아미노)피페리딘Preparation Example 47 4-cyclohexyl-4- (acetylamino) piperidine

1-BOC-4-사이클로헥실-4-아미노피페리딘과 초산을 제조예 1에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4-aminopiperidine and acetic acid were reacted in the same manner as in Preparation Example 1 to obtain the title compound.

MS[M+H] = 225(M+1)MS [M + H] = 225 (M + 1)

제조예 48: 4-사이클로헥실-4-[이소프로필(메틸)아미노]피페리딘Preparation Example 48 4-cyclohexyl-4- [isopropyl (methyl) amino] piperidine

단계 A: 1-BOC-4-사이클로헥실-4-[(이소프로필)아미노]피페리딘Step A: 1-BOC-4-cyclohexyl-4-[(isopropyl) amino] piperidine

1-BOC-4-사이클로헥실-4-아미노피페리딘과 아세톤을 제조예 26에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4-aminopiperidine and acetone were reacted in the same manner as in Preparation Example 26 to obtain the title compound.

MS[M+H] = 325(M+1)MS [M + H] = 325 (M + 1)

단계 B: 1-BOC-4-사이클로헥실-4-[이소프로필(메틸)아미노]피페리딘Step B: 1-BOC-4-cyclohexyl-4- [isopropyl (methyl) amino] piperidine

1-BOC-4-사이클로헥실-4-[(이소프로필)아미노]피페리딘과 포르말린을 제조예 26에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4-[(isopropyl) amino] piperidine and formalin were reacted in the same manner as in Production Example 26 to obtain the title compound.

MS[M+H] = 339(M+1)MS [M + H] = 339 (M + 1)

단계 C: 4-사이클로헥실-4-[이소프로필(메틸)아미노]피페리딘Step C: 4-cyclohexyl-4- [isopropyl (methyl) amino] piperidine

1-BOC-4-사이클로헥실-4-[이소프로필(메틸)아미노]피페리딘을 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4-cyclohexyl-4- [isopropyl (methyl) amino] piperidine was reacted in the same manner as in Step B of Preparation Example 1 to obtain the title compound.

MS[M+H] = 239(M+1)MS [M + H] = 239 (M + 1)

제조예 49: (2R)-N-메탄설포닐-(4-클로로페닐)알라닌Preparation 49: (2R) -N-methanesulfonyl- (4-chlorophenyl) alanine

단계 A: (2R)-N-메탄설포닐-(4-클로로페닐)알라닌 메틸에스테르Step A: (2R) -N-methanesulfonyl- (4-chlorophenyl) alanine methylester

(2R)-(4-클로로페닐)알라닌 메틸에스테르(213 mg, 1.00 mmol)를 DCM(5 ㎖)에 녹이고 TEA(280 ㎖, 2.00 mmol)를 적가한 다음, 메탄설포닐클로라이드를 0℃에서 적가하였다. 30분 후에 감압 증류하여 DCM을 제거하고 EtOAc로 희석시킨 후 1N HCl로 씻어주었다. 추출된 유기용액을 MgSO4로 건조시킨 후 감압 농축하고 칼럼 크로마토그래피(용리액: MeOH/CHCl3=1/25)로 정제하여 표제화합물(280 mg, 96.1 %)을 수득하였다.(2R)-(4-chlorophenyl) alanine methyl ester (213 mg, 1.00 mmol) was dissolved in DCM (5 mL), TEA (280 mL, 2.00 mmol) was added dropwise, and methanesulfonylchloride was added dropwise at 0 ° C. It was. After 30 minutes distillation under reduced pressure to remove DCM, diluted with EtOAc and washed with 1N HCl. The extracted organic solution was dried over MgSO 4 , concentrated under reduced pressure, and purified by column chromatography (eluent: MeOH / CHCl 3 = 1/25) to obtain the title compound (280 mg, 96.1%).

MS [M+H] = 292(M+1)MS [M + H] = 292 (M + 1)

단계 B: (2R)-N-메탄설포닐-(4-클로로페닐)알라닌Step B: (2R) -N-methanesulfonyl- (4-chlorophenyl) alanine

단계 A에서 얻은 (2R)-N-메탄설포닐-(4-클로로페닐)알라닌 메틸에스테르를 물/메탄올(5 ㎖, 1/1)에 녹인 후 LiOH(70.0 mg, 2.00 mmol)를 적가하였다. 반응물을 상온에서 3시간 동안 교반한 후 반응용액을 감압 농축하고 1N HCl 수용액으로 희석시킨 후 EtOAc로 유기물을 추출하였다. 추출한 유기 용액을 감압 농축하여 표제화합물을 수득하였다(179 mg, 94.3 %). (2R) -N-methanesulfonyl- (4-chlorophenyl) alanine methylester obtained in step A was dissolved in water / methanol (5 mL, 1/1) and LiOH (70.0 mg, 2.00 mmol) was added dropwise. After the reaction was stirred at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure, diluted with a 1N HCl aqueous solution, and the organics were extracted with EtOAc. The extracted organic solution was concentrated under reduced pressure to give the title compound (179 mg, 94.3%).

MS [M+H] = 278(M+1)MS [M + H] = 278 (M + 1)

제조예 50: (2R)-N-아세틸-(4-클로로페닐)알라닌Preparation 50: (2R) -N-acetyl- (4-chlorophenyl) alanine

(2R)-(4-클로로페닐)알라닌 메틸에스테르와 초산 무수물을 제조예 49 에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. (2R)-(4-chlorophenyl) alanine methyl ester and acetic anhydride were reacted in the same manner as in Preparation Example 49 to obtain the title compound.

MS [M+H] = 240(M+1)MS [M + H] = 240 (M + 1)

제조예 51: (2R)-N-디메틸카바모일-(4-클로로페닐)알라닌Preparation Example 51 (2R) -N-dimethylcarbamoyl- (4-chlorophenyl) alanine

(2R)-(4-클로로페닐)알라닌 메틸에스테르와 클로로디메틸 카바메이트를 제조예 49 에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다.(2R)-(4-chlorophenyl) alanine methyl ester and chlorodimethyl carbamate were reacted in the same manner as in Preparation Example 49 to obtain the title compound.

MS [M+H] = 269(M+1)MS [M + H] = 269 (M + 1)

제조예 52: (2R)-N-BOC-프롤린 카복시알데히드Preparation 52: (2R) -N-BOC-proline carboxyaldehyde

단계 A: (2R)-N-BOC-프롤린 티오에스테르Step A: (2R) -N-BOC-Proline Thioester

DCC(2.55 g, 12.4 mmol), DMAP(100 mg), 및 EtSH(0.71 g, 11.1 mmol)를 DCM에 녹이고 DCM(30 ㎖)에 녹인 (2R)-N-BOC-프롤린(3.00 g, 9.52 mmol)을 적가하였다. 반응물을 30분 동안 상온에서 교반시킨 후 침전물은 셀라이트로 여과하였다. 남은 여과액을 MgSO4로 건조시키고 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/Hex=1/4)로 정제하여 표제화합물(2.34 g, 95.2 %)을 수득하였다.(2R) -N-BOC-proline (3.00 g, 9.52 mmol) dissolved in DCC (2.55 g, 12.4 mmol), DMAP (100 mg), and EtSH (0.71 g, 11.1 mmol) in DCM and DCM (30 mL) ) Was added dropwise. The reaction was stirred at room temperature for 30 minutes and then the precipitate was filtered through celite. The remaining filtrate was dried over MgSO 4 and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: EtOAc / Hex = 1/4) to give the title compound (2.34 g, 95.2%).

MS[M+H] = 260(M+1)MS [M + H] = 260 (M + 1)

단계 B: (2R)-N-BOC-프롤린 카복시알데히드Step B: (2R) -N-BOC-proline carboxyaldehyde

단계 A에서 얻은 (2R)-N-BOC-프롤린 티오에스테르를 아세톤에 녹이고 트리에틸실란(5.39 g, 46.3 mmol)과 Pd/C(100 mg)를 0℃에서 적가하였다. 기포발생이 멈추면 반응물의 온도를 상온으로 올리고 30분 정도 더 교반하였다. 반응이 종결되면 셀라이트로 여과하고 여액을 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/Hex=1/2)로 정제하여 표제화합물(1.43g, 93.2 %)을 얻었다. (2R) -N-BOC-proline thioester obtained in step A was dissolved in acetone and triethylsilane (5.39 g, 46.3 mmol) and Pd / C (100 mg) were added dropwise at 0 ° C. When bubble generation stopped, the temperature of the reaction was raised to room temperature and stirred for about 30 minutes. After the reaction was completed, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: EtOAc / Hex = 1/2) to give the title compound (1.43 g, 93.2%).

MS[M+H] = 200(M+1)MS [M + H] = 200 (M + 1)

제조예 53: (2R)-N-메틸-프롤린 카복시알데히드 Preparation 53: (2R) -N-methyl-proline carboxyaldehyde

단계 A: (2R)-N-메틸-프롤린 메틸에스테르Step A: (2R) -N-Methyl-Proline Methylester

(2R)-프롤린 메틸에스테르(1.20g, 10.0 mmol)를 DMF(30 ㎖)에 녹이고 포르말린(37% in water, 1.12 ㎖, 15.0 mmol)을 적가한 다음 NaBH(OAc)3(4.20g, 20.0 mmol)를 적가하였다. 반응이 종결되었을 때 반응물을 감압 농축하고, 잔류물을 NaHCO3(30 ㎖)로 희석하고 EtOAc로 추출하였다. 추출한 유기용액을 MgSO4로 건조한 후 감압 농축시킨 다음 수득된 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/Hex=4/1)로 정제하여 표제화합물(1.33g, 93.0 %)을 수득하였다.(2R) -proline methyl ester (1.20 g, 10.0 mmol) was dissolved in DMF (30 mL), formalin (37% in water, 1.12 mL, 15.0 mmol) was added dropwise, followed by NaBH (OAc) 3 (4.20 g, 20.0 mmol). ) Was added dropwise. At the end of the reaction, the reaction was concentrated under reduced pressure, and the residue was diluted with NaHCO 3 (30 mL) and extracted with EtOAc. The extracted organic solution was dried over MgSO 4 , concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: EtOAc / Hex = 4/1) to obtain the title compound (1.33 g, 93.0%).

MS[M+H] = 144(M+1)MS [M + H] = 144 (M + 1)

단계 B: (2R)-N-메틸-프롤린 카복시알데히드Step B: (2R) -N-Methyl-Proline Carboxyaldehyde

단계 A에서 얻은 (2R)-N-메틸-프롤린 메틸에스테르를 제조예 49의 단계 B 및 제조예 52에서와 동일한 방법으로 반응시켜 표제화합물을 얻었다.(2R) -N-methyl-proline methylester obtained in step A was reacted in the same manner as in Step B and Preparation Example 52 of Preparation Example 49 to obtain the title compound.

MS[M+H] = 114(M+1)MS [M + H] = 114 (M + 1)

제조예 54-62:Preparation Example 54-62:

여러가지 아미노산 메틸에스테르를 제조예 26 또는 제조예 49 및 제조예 52에서와 동일한 방법으로 반응시켜 하기 화합물을 수득하였다.Various amino acid methyl esters were reacted in the same manner as in Production Example 26 or Production Example 49 and Production Example 52 to obtain the following compounds.

제조예 63: 1-BOC-아지리딘-2-카복실산Preparation Example 63 1-BOC-aziridine-2-carboxylic acid

단계 A: 메틸 1-벤질-2-아지리딘카복실레이트Step A: Methyl 1-benzyl-2-aziridinecarboxylate

메틸-2,3-디브로모프로피올레이트(92.50 g, 10.0 mmol)와 K2CO3(4.10 g, 30.0 mmol)를 녹인 아세토니트릴(30 ㎖) 용액에 벤질아민(1.20 ㎖, 11 mmol)을 적가하였다. 반응물을 상온에서 4시간 교반한 후 포화 암모늄클로라이드 수용액으로 반응을 종결시켰다. 유기물을 EtOAc(50 ㎖ x 3)로 추출해낸 다음 MgSO4로 건조하고 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/Hex=2/1)로 정제하여 표제화합물(1.62g, 85.0 %)을 수득하였다.Benzylamine (1.20 mL, 11 mmol) in an acetonitrile (30 mL) solution of methyl-2,3-dibromopropiolate (92.50 g, 10.0 mmol) and K 2 CO 3 (4.10 g, 30.0 mmol) Was added drop wise. The reaction was stirred at room temperature for 4 hours and then quenched with saturated aqueous ammonium chloride solution. The organics were extracted with EtOAc (50 mL x 3), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / Hex = 2/1) to give the title compound (1.62 g, 85.0%).

MS[M+H] = 192(M+1)MS [M + H] = 192 (M + 1)

단계 B: 메틸 1-BOC-2-아지리딘카복실레이트Step B: Methyl 1-BOC-2-aziridinecarboxylate

단계 A에서 얻은 메틸 1-벤질-2-아지리딘카복실레이트(1.00 g, 5.23 mmol)와 디-t-부틸디카보네이트(1.34 g, 5.75 mmol)를 메탄올(20 ㎖)에 녹인 후 Pd/C(300 mg)를 적가하였다. 반응물을 수소 조건으로 바꾼 다음 상온에서 24시간 교반하였다. 반응이 종결되었을 때 셀라이트로 여과하고 여액을 감압 농축하였다. 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/Hex=2/1)로 정제하여 표제화합물(985 mg, 91.0 %)을 수득하였다. Methyl 1-benzyl-2-aziridinecarboxylate (1.00 g, 5.23 mmol) and di-t-butyldicarbonate (1.34 g, 5.75 mmol) obtained in step A were dissolved in methanol (20 mL) and then Pd / C ( 300 mg) was added dropwise. The reaction was changed to hydrogen conditions and stirred at room temperature for 24 hours. At the end of the reaction, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / Hex = 2/1) to give the title compound (985 mg, 91.0%).

MS[M+H] = 202(M+1)MS [M + H] = 202 (M + 1)

단계 C: 1-BOC-2-아지리딘카복실산Step C: 1-BOC-2-aziridinecarboxylic acid

단계 B에서 얻은 메틸 1-BOC-2-아지리딘카복실레이트를 제조예 49의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 합성하였다. The title compound was synthesized by reacting methyl 1-BOC-2-aziridinecarboxylate obtained in step B in the same manner as in step B of Preparation Example 49.

MS[M+H] = 188(M+1)MS [M + H] = 188 (M + 1)

제조예 64: 1-BOC-2-아지리딘카복시알데히드Preparation Example 64 1-BOC-2-aziridinecarboxyaldehyde

1-BOC-아지리딘-2-카복실산을 제조예 52에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-aziridine-2-carboxylic acid was reacted in the same manner as in Preparation Example 52 to obtain the title compound.

MS[M+H] = 172(M+1)MS [M + H] = 172 (M + 1)

제조예 65: 메틸 1-BOC-4-아미노-4-피페리딘카복실레이트Preparation 65: Methyl 1-BOC-4-amino-4-piperidinecarboxylate

1-BOC-4-아미노-4-피페리딘카복실산(2.00 g, 8.2 mmol)을 메탄올(300 ㎖)과 DCM(300 ㎖)에 녹이고 디아조메탄을 상온에서 반응용액의 색깔이 엷은 노란색으로 될 때까지 적가하였다. 반응물을 상온에서 30분 더 교반한 후 감압 농축하여 표제화합물을 수득하였다. Dissolve 1-BOC-4-amino-4-piperidinecarboxylic acid (2.00 g, 8.2 mmol) in methanol (300 mL) and DCM (300 mL), and change the color of the reaction solution to pale yellow at room temperature. Dropwise until The reaction was stirred for 30 minutes at room temperature and then concentrated under reduced pressure to give the title compound.

MS[M+H] = 393(M+1)MS [M + H] = 393 (M + 1)

제조예 66: 1-BOC-4-(Cbz-아미노)-4-피페리딘카복실산Preparation 66: 1-BOC-4- (Cbz-amino) -4-piperidinecarboxylic acid

제조예 65에서 수득한 메틸 1-BOC-4-아미노-4-피페리딘카복실레이트(1.29 g, 5 mmol)를 물(10 ㎖)과 디옥산(10 ㎖)에 녹이고 Na2CO3(1N 수용액, 10 ㎖)를 적가 한 후 CbzCl(1.5 ㎖, 10 mmol)를 천천히 적가하였다. 반응물을 상온에서 6시간 동안 교반하였다. 반응이 종결되면 감압 증류하여 용매를 제거하고 1N 염산으로 희석시킨 후 유기물을 EtOAc로 추출하였다. 추출한 유기 용액을 MgSO4로 건조하고 여과하여 표제화합물을 수득하였다.Methyl 1-BOC-4-amino-4-piperidinecarboxylate (1.29 g, 5 mmol) obtained in Preparation Example 65 was dissolved in water (10 mL) and dioxane (10 mL), followed by Na 2 CO 3 (1N). Aqueous solution, 10 mL) was added dropwise and CbzCl (1.5 mL, 10 mmol) was added dropwise. The reaction was stirred at room temperature for 6 hours. After the reaction was completed, the mixture was distilled under reduced pressure to remove the solvent, diluted with 1N hydrochloric acid, and the organics were extracted with EtOAc. The extracted organic solution was dried over MgSO 4 and filtered to give the title compound.

MS[M+H] = 379(M+1)MS [M + H] = 379 (M + 1)

제조예 67: 4-(피페리딘-1-일)-4-(디메틸카바모일)피페리딘Preparation Example 67 4- (piperidin-1-yl) -4- (dimethylcarbamoyl) piperidine

단계 A: 1-BOC-4-(Cbz-아미노)-4-(디메틸카바모일)피페리딘Step A: 1-BOC-4- (Cbz-amino) -4- (dimethylcarbamoyl) piperidine

1-BOC-4-(Cbz-아미노)-피페리딘카복실산과 디메틸아민을 제조예 1의 단계 A에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4- (Cbz-amino) -piperidinecarboxylic acid and dimethylamine were reacted in the same manner as in Step A of Preparation Example 1 to obtain the title compound.

MS[M+H] = 406(M+1)MS [M + H] = 406 (M + 1)

단계 B: 1-BOC-4-아미노-4-(디메틸카바모일)피페리딘Step B: 1-BOC-4-amino-4- (dimethylcarbamoyl) piperidine

단계 A에서 수득한 1-BOC-4-(Cbz-아미노)-4-(디메틸카바모일)피페리딘을 제조예 45의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4- (Cbz-amino) -4- (dimethylcarbamoyl) piperidine obtained in step A was reacted in the same manner as in step B of Preparation Example 45 to obtain the title compound.

MS[M+H] = 272(M+1)MS [M + H] = 272 (M + 1)

단계 C: 1-BOC-4-(피페리딘-1-일)-4-(디메틸카바모일)피페리딘Step C: 1-BOC-4- (piperidin-1-yl) -4- (dimethylcarbamoyl) piperidine

단계 B에서 수득한 1-BOC-4-아미노-4-(디메틸카바모일)피페리딘(1.35 g, 5 mmol)과 글루타알데히드(25 % 수용액, 6 ㎖)를 DMF에 녹이고 NaBH(OAc)3 (2.1 g, 10 mmol)를 적가한 후 상온에서 4시간 동안 교반하였다. 반응이 종결되면 감압 증류하여 DMF를 제거하고 포화 탄산수소나트륨 수용액으로 희석시킨 후 유기물을 EtOAc로 추출하였다. 추출한 유기 용액을 MgSO4로 건조하고 여과하여 감압 농축하였다. 수득한 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/n-헥산=2/1)로 정제하여 표제화합물(1.51 g, 91.0 %)을 수득하였다.1-BOC-4-amino-4- (dimethylcarbamoyl) piperidine (1.35 g, 5 mmol) and glutaaldehyde (25% aqueous solution, 6 mL) obtained in step B were dissolved in DMF and NaBH (OAc) 3 (2.1 g, 10 mmol) was added dropwise and stirred at room temperature for 4 hours. After the reaction was completed, the mixture was distilled under reduced pressure to remove DMF, diluted with saturated aqueous sodium hydrogen carbonate solution, and the organics were extracted with EtOAc. The extracted organic solution was dried over MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: EtOAc / n-hexane = 2/1) to give the title compound (1.51 g, 91.0%).

MS[M+H] = 340(M+1)MS [M + H] = 340 (M + 1)

단계 D: 4-(피페리딘-1-일)-4-(디메틸카바모일)피페리딘Step D: 4- (piperidin-1-yl) -4- (dimethylcarbamoyl) piperidine

단계 C에서 수득한 1-BOC-4-(피페리딘-1-일)-4-(디메틸카바모일)피페리딘을 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4- (piperidin-1-yl) -4- (dimethylcarbamoyl) piperidine obtained in step C was reacted in the same manner as in step B of Preparation Example 1 to obtain the title compound. .

MS[M+H] = 240(M+1)MS [M + H] = 240 (M + 1)

제조예 68-76: Preparation Example 68-76:

제조예 67과 동일한 방법으로 반응시켜 하기 화합물들을 수득하였다. In the same manner as in Preparation 67, the following compounds were obtained.

제조예 77: 4-(피페리딘-1-일)-4-[4,4-(디메틸)옥사졸린-2-일]피페리딘Preparation Example 77 4- (piperidin-1-yl) -4- [4,4- (dimethyl) oxazolin-2-yl] piperidine

단계 A: 1-BOC-4-(Cbz-아미노)-4-{[(2-하이드록시-1,1-디메틸)에틸]카바모일}피페리딘Step A: 1-BOC-4- (Cbz-amino) -4-{[(2-hydroxy-1,1-dimethyl) ethyl] carbamoyl} piperidine

1-BOC-4-(Cbz-아미노)-4-피페리딘카복실산과 2-아미노-2-메틸-1-프로판올을 제조예 1의 단계 A에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4- (Cbz-amino) -4-piperidinecarboxylic acid and 2-amino-2-methyl-1-propanol were reacted in the same manner as in Step A of Preparation Example 1 to obtain the title compound.

MS[M+H] = 450(M+1)MS [M + H] = 450 (M + 1)

단계 B: 1-BOC-4-(Cbz-아미노)-4-[4,4-(디메틸)옥사졸린-2-일]피페리딘Step B: 1-BOC-4- (Cbz-amino) -4- [4,4- (dimethyl) oxazolin-2-yl] piperidine

단계 A에서 수득한 1-BOC-4-(Cbz-아미노)-4-{[(2-하이드록시-1,1-디메틸)에틸]카바모일}피페리딘을 제조예 9의 단계 C에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4- (Cbz-amino) -4-{[(2-hydroxy-1,1-dimethyl) ethyl] carbamoyl} piperidine obtained in step A was prepared in step C of Preparation Example 9. The reaction was carried out in the same manner to obtain the title compound.

MS[M+H] = 432(M+1)MS [M + H] = 432 (M + 1)

단계 C: 1-BOC-4-아미노-4-[4,4-(디메틸)옥사졸린-2-일]피페리딘Step C: 1-BOC-4-amino-4- [4,4- (dimethyl) oxazolin-2-yl] piperidine

단계 B에서 수득한 1-BOC-4-(Cbz-아미노)-4-[4,4-(디메틸)옥사졸린-2-일]피페리딘을 제조예 45의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다.Reaction of 1-BOC-4- (Cbz-amino) -4- [4,4- (dimethyl) oxazolin-2-yl] piperidine obtained in step B in the same manner as in step B of Preparation Example 45 To give the title compound.

MS[M+H] = 298(M+1)MS [M + H] = 298 (M + 1)

단계 D: 1-BOC-4-(피페리딘-1-일)-4-(4,4-(디메틸)옥사졸린-2-일)피페리딘Step D: 1-BOC-4- (piperidin-1-yl) -4- (4,4- (dimethyl) oxazolin-2-yl) piperidine

단계 C에서 수득한 1-BOC-4-아미노-4-(4,4-(디메틸)옥사졸린-2-일)피페리딘을 제조예 67의 단계 C에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다.The title compound was reacted by reacting 1-BOC-4-amino-4- (4,4- (dimethyl) oxazolin-2-yl) piperidine obtained in step C in the same manner as in step C of Preparation Example 67. Obtained.

MS[M+H] = 366(M+1)MS [M + H] = 366 (M + 1)

단계 E: 4-(피페리딘-1-일)-4-[4,4-(디메틸)옥사졸린-2-일]피페리딘Step E: 4- (piperidin-1-yl) -4- [4,4- (dimethyl) oxazolin-2-yl] piperidine

단계 D에서 수득한 1-BOC-4-(피페리딘-1-일)-4-(4,4-(디메틸)옥사졸린-2-일)피페리딘을 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다.1-BOC-4- (piperidin-1-yl) -4- (4,4- (dimethyl) oxazolin-2-yl) piperidine obtained in step D was prepared in step B of Preparation Example 1 The reaction was carried out in the same manner to obtain the title compound.

MS[M+H] = 266(M+1)MS [M + H] = 266 (M + 1)

제조예 78: 4-(피페리딘-1-일)-4-(옥사졸린-2-일)피페리딘Preparation 78: 4- (piperidin-1-yl) -4- (oxazolin-2-yl) piperidine

1-BOC-4-(Cbz-아미노)-4-피페리딘카복실산과 아미노에탄올을 제조예 77에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. The title compound was obtained by reacting 1-BOC-4- (Cbz-amino) -4-piperidinecarboxylic acid and aminoethanol in the same manner as in Preparation Example 77.

MS[M+H] = 238(M+1)MS [M + H] = 238 (M + 1)

제조예 79: 메틸 4-(피페리딘-1-일)-4-피페리딘카복실레이트Preparation Example 79 Methyl 4- (piperidin-1-yl) -4-piperidinecarboxylate

단계 A: 메틸 1-BOC-4-(피페리딘-1-일)-4-피페리딘카복실레이트Step A: Methyl 1-BOC-4- (piperidin-1-yl) -4-piperidinecarboxylate

메틸 1-BOC-4-아미노-4-피페리딘카복실레이트를 제조예 67의 단계 C에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. Methyl 1-BOC-4-amino-4-piperidinecarboxylate was reacted in the same manner as in Step C of Preparation Example 67 to obtain the title compound.

MS[M+H] = 327(M+1)MS [M + H] = 327 (M + 1)

단계 B: 메틸 4-(피페리딘-1-일)-4-피페리딘카복실레이트Step B: Methyl 4- (piperidin-1-yl) -4-piperidinecarboxylate

단계 A에서 수득한 메틸 1-BOC-4-(피페리딘-1-일)-4-피페리딘카복실레이트를 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. The methyl 1-BOC-4- (piperidin-1-yl) -4-piperidinecarboxylate obtained in step A was reacted in the same manner as in step B of Preparation Example 1 to obtain the title compound.

MS[M+H] = 227(M+1)MS [M + H] = 227 (M + 1)

제조예 80: 1-BOC-4-(피페리딘-1-일)-4-(하이드록시메틸)피페리딘Preparation 80: 1-BOC-4- (piperidin-1-yl) -4- (hydroxymethyl) piperidine

메틸 1-BOC-4-(피페리딘-1-일)-4-피페리딘카복실레이트를 제조예 14에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. Methyl 1-BOC-4- (piperidin-1-yl) -4-piperidinecarboxylate was reacted in the same manner as in Preparation Example 14 to obtain the title compound.

MS[M+H] = 299(M+1)MS [M + H] = 299 (M + 1)

제조예 81: 1-BOC-4-(피페리딘-1-일)-4-피페리딘카복시알데히드Preparation Example 81 1-BOC-4- (piperidin-1-yl) -4-piperidinecarboxyaldehyde

1-BOC-4-(피페리딘-1-일)-4-(하이드록시메틸)피페리딘을 제조예 15에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4- (piperidin-1-yl) -4- (hydroxymethyl) piperidine was reacted in the same manner as in Preparation Example 15 to obtain the title compound.

MS[M+H] = 297(M+1)MS [M + H] = 297 (M + 1)

제조예 82: 4-(피페리딘-1-일)-4-[(1-하이드록시)이소부틸]피페리딘Preparation Example 82 4- (piperidin-1-yl) -4-[(1-hydroxy) isobutyl] piperidine

1-BOC-4-(피페리딘-1-일)-4-피페리딘카복시알데히드와 이소프로필마그네슘브로마이드를 제조예 16에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4- (piperidin-1-yl) -4-piperidinecarboxyaldehyde and isopropylmagnesium bromide were reacted in the same manner as in Preparation Example 16 to obtain the title compound.

MS[M+H] = 241(M+1)MS [M + H] = 241 (M + 1)

제조예 83: 4-(피페리딘-1-일)-4-(이소부티릴)피페리딘Preparation Example 83 4- (piperidin-1-yl) -4- (isobutyryl) piperidine

4-(피페리딘-1-일)-4-[(1-하이드록시)이소부틸]피페리딘을 제조예 17에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 4- (Piperidin-1-yl) -4-[(1-hydroxy) isobutyl] piperidine was reacted in the same manner as in Preparation Example 17 to obtain the title compound.

MS[M+H] = 239(M+1)MS [M + H] = 239 (M + 1)

제조예 84: 4-(피롤리딘-1-일)-4-(디메틸카바모일)피페리딘Preparation Example 84 4- (Pyrrolidin-1-yl) -4- (dimethylcarbamoyl) piperidine

단계 A: 1-BOC-4-(피롤리딘-1-일)-4-(디메틸카바모일)피페리딘Step A: 1-BOC-4- (pyrrolidin-1-yl) -4- (dimethylcarbamoyl) piperidine

1-BOC-4-아미노-4-(디메틸카바모일)피페리딘(542 mg, 2 mmol)과 TEA(0.560 ㎖, 4 mmol)를 DMF(10 ㎖)에 녹이고 디브로모부탄(473 mg, 1.1 mmol)을 적가한 후 반응물을 80-90℃로 12시간 가열하였다. 반응이 종결되면 감압 증류하여 DMF를 제거하고 포화 탄산수소나트륨 수용액으로 잔류물을 희석한 후 유기물을 EtOAc로 추출하였다. 추출한 유기 용액을 MgSO4로 건조하고 여과하여 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/Hex=3/1)로 정제하여 표제화합물(520 mg, 80.0 %)을 수득하였다.Dissolve 1-BOC-4-amino-4- (dimethylcarbamoyl) piperidine (542 mg, 2 mmol) and TEA (0.560 mL, 4 mmol) in DMF (10 mL) and dibromobutane (473 mg, 1.1 mmol) was added dropwise and the reaction was heated to 80-90 ° C. for 12 hours. After the reaction was completed, the mixture was distilled under reduced pressure to remove DMF, the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the organics were extracted with EtOAc. The extracted organic solution was dried over MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: EtOAc / Hex = 3/1) to give the title compound (520 mg, 80.0%).

MS[M+H] = 326(M+1)MS [M + H] = 326 (M + 1)

단계 B: 4-(피롤리딘-1-일)-4-(디메틸카바모일)피페리딘Step B: 4- (Pyrrolidin-1-yl) -4- (dimethylcarbamoyl) piperidine

단계 A에서 수득한 1-BOC-4-(피롤리딘-1-일)-4-(디메틸카바모일)피페리딘을 제조예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. 1-BOC-4- (pyrrolidin-1-yl) -4- (dimethylcarbamoyl) piperidine obtained in step A was reacted in the same manner as in step B of Preparation Example 1 to obtain the title compound. .

MS[M+H] = 226(M+1)MS [M + H] = 226 (M + 1)

제조예 85-97: Preparation Example 85-97:

1-BOC-4-(Cbz-아미노)-4-피페리딘카복실산을 제조예 67 또는 84에서와 동일한 방법으로 반응시켜 하기 화합물을 수득하였다. 1-BOC-4- (Cbz-amino) -4-piperidinecarboxylic acid was reacted in the same manner as in Preparation Example 67 or 84 to obtain the following compound.

제조예 98: 프탈이미노에틸 아민Preparation Example 98: Phthaliminoethyl Amine

단계 A: 2-프탈이미노-1-BOC-아미노에탄Step A: 2-phthalimino-1-BOC-aminoethane

상업적으로 구입 가능한 N-BOC-에틸렌 디아민(1.6 g, 10 mmol)과 (Et)3N(2.8 ㎖, 20 mmol)을 DCM(30 ㎖)에 녹이고 무수 프탈산(1.63 g, 11 mmol)을 첨가한 다음 상온에서 4시간 동안 교반 하였다. 반응이 종결 되면 포화 1N HCl 수용액을 첨가하고 유기물을 EtOAc로 추출한 후 MgSO4로 건조하고 여과하여 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/Hex=1/4)로 정제하여 표제화합물(1.60 g, 84.0 %)을 수득하였다.Commercially available N-BOC-ethylene diamine (1.6 g, 10 mmol) and (Et) 3 N (2.8 mL, 20 mmol) were dissolved in DCM (30 mL) and phthalic anhydride (1.63 g, 11 mmol) was added. Then stirred at room temperature for 4 hours. Upon completion of the reaction, saturated 1N HCl aqueous solution was added, the organics were extracted with EtOAc, dried over MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: EtOAc / Hex = 1/4) to give the title compound (1.60 g, 84.0%).

MS[M+H] = 291(M+1)MS [M + H] = 291 (M + 1)

단계 B: 프탈이미노에틸 아민Step B: Phthaliminoethyl Amine

단계 A에서 수득한 2-프탈이미노-1-BOC-아미노에탄(1.0 g, 3.43 mmol)을 DCM(5 ㎖)에 넣고 TFA(5 ㎖)를 첨가 하였다. 반응이 종결 되면 용매와 TFA를 감압하에 제거하고 추가의 정제 없이 다음 반응에 사용하였다. 2-phthalimino-1-BOC-aminoethane (1.0 g, 3.43 mmol) obtained in step A was added to DCM (5 mL) and TFA (5 mL) was added. Upon completion of the reaction, solvent and TFA were removed under reduced pressure and used for the next reaction without further purification.

MS[M+H] = 191(M+1)MS [M + H] = 191 (M + 1)

제조예 99: 2-프탈이미노-1-메틸아미노에탄Preparation Example 99 2-phthalimino-1-methylaminoethane

단계 A: 2-프탈이미노-1-메틸(N-BOC)아미노에탄Step A: 2-phthalimino-1-methyl (N-BOC) aminoethane

제조예 98의 단계 A에서 수득한 2-프탈이미노-1-BOC-아미노에탄(291 mg, 1 mmol)를 NaH(80 mg, 60 % in mineral oil, 2 mmol)를 녹인 THF(3 ㎖) 용액에 0 oC에서 천천히 첨가하고 반응온도를 상온으로 올려 12시간 동안 교반 하였다. 반응이 종결 되면 포화 NH4Cl수용액을 첨가하고 유기물을 EtOAc로 추출한 후 MgSO4로 건조하고 여과하여 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/Hex=1/5)로 정제하여 표제화합물(198 mg, 64%)을 수득하였다.2-phthalimino-1-BOC-aminoethane (291 mg, 1 mmol) obtained in step A of Preparation Example 98 was dissolved in NaH (80 mg, 60% in mineral oil, 2 mmol), THF (3 mL). The solution was slowly added at 0 ° C. and the reaction temperature was raised to room temperature and stirred for 12 hours. Upon completion of the reaction, saturated aqueous NH 4 Cl solution was added, the organics were extracted with EtOAc, dried over MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: EtOAc / Hex = 1/5) to give the title compound (198 mg, 64%).

MS[M+H] = 305(M+1)MS [M + H] = 305 (M + 1)

단계 B: 2-프탈이미노-1-메틸아미노에탄Step B: 2-phthalimino-1-methylaminoethane

단계 A에서 수득한 2-프탈이미노-1-메틸(N-BOC)아미노에탄을 이용하여 제조예 98의 단계 B와 같은 방법으로 표제 화합물을 수득하였다. The title compound was obtained in the same manner as in Step B of Preparation Example 98 using 2-phthalimino-1-methyl (N-BOC) aminoethane obtained in Step A.

MS[M+H] = 205(M+1)MS [M + H] = 205 (M + 1)

제조예 100: (3S)-1-(4-나이트로벤젠설포닐)-3-아미노-피롤리딘Preparation 100: (3S) -1- (4-nitrobenzenesulfonyl) -3-amino-pyrrolidine

단계 A: (3S)-1-(4-나이트로벤젠설포닐)-3-BOC-아미노-피롤리딘Step A: (3S) -1- (4-Nitrobenzenesulfonyl) -3-BOC-amino-pyrrolidine

3-BOC-아미노-피롤리딘(372 mg, 2 mmol)을 DCM(10 ㎖)에 녹이고 Et3N(0.56 ㎖, 4 mmol)과 4-니트로벤젠설포닐클로라이드(487.4 mg, 2.2 mmol)를 첨가한 후 상온에서 12시간 동안 교반 하였다. 반응이 종결 되면 포화 NH4Cl수용액을 넣고 유기물을 EtOAc로 추출한 후 MgSO4로 건조하고 여과하여 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/Hex=1/7)로 정제하여 표제화합물(697 mg, 94%)을 수득하였다.3-BOC-amino-pyrrolidine (372 mg, 2 mmol) was dissolved in DCM (10 mL) and Et 3 N (0.56 mL, 4 mmol) and 4-nitrobenzenesulfonylchloride (487.4 mg, 2.2 mmol) were added. After addition, the mixture was stirred at room temperature for 12 hours. Upon completion of the reaction, saturated aqueous NH 4 Cl solution was added, the organics were extracted with EtOAc, dried over MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: EtOAc / Hex = 1/7) to give the title compound (697 mg, 94%).

MS[M+H] = 372(M+1)MS [M + H] = 372 (M + 1)

단계 B: (3S)-1-(4-나이트로벤젠설포닐)-3-아미노-피롤리딘Step B: (3S) -1- (4-Nitrobenzenesulfonyl) -3-amino-pyrrolidine

단계 A에서 수득한 (3S)-1-(4-나이트로벤젠설포닐)-3-BOC-아미노-피롤리딘을 이용하여 제조예 98의 단계 B와 같이 반응시켜 표제 화합물을 수득하였다. The reaction was carried out in the same manner as in Step B of Preparation Example 98 using (3S) -1- (4-nitrobenzenesulfonyl) -3-BOC-amino-pyrrolidine obtained in Step A to obtain the title compound.

MS[M+H] = 272(M+1)MS [M + H] = 272 (M + 1)

본 발명의 화합물을 하기 실시예에 의거하여 보다 구체적으로 설명한다. 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: (2R)-2-아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 TFA 염Example 1: (2R) -2-amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) propionamide TFA salt

단계 A: (2R)-2-(BOC-아미노)-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드Step A: (2R) -2- (BOC-amino) -N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl Propionamide

4-사이클로헥실-4-(t-부틸카바모일)피페리딘(HCl 염, 917 mg, 3.30 mmol)을 DMF(30 ㎖)에 녹이고 DIPEA(1.15 ㎖, 6.70 mmol)를 적가하여 반응용액을 염기화한 다음, EDC(845 mg, 4.30 mmol), HOBT(668 mg, 5.00 mmol) 및 (2R)-N-BOC-(4-클로로페닐)알라닌을 차례로 적가하였다. 반응물을 상온에서 12시간 교반하였다. 반응이 종결되었을 때 감압 증류하여 DMF를 제거하고 잔류물에 EtOAc를 첨가하여 희석시킨 후 포화 탄산수소나트륨 수용액과 1N 염산 수용액으로 씻어주었다. 남은 여액을 MgSO4로 건조하고 여과하여 감압 농축하였다. 수득한 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/Hex=2/1)로 정제하여 표제화합물(1.58 g, 93.9 %)을 수득하였다.4-cyclohexyl-4- (t-butylcarbamoyl) piperidine (HCl salt, 917 mg, 3.30 mmol) was dissolved in DMF (30 mL) and DIPEA (1.15 mL, 6.70 mmol) was added dropwise to give a reaction solution. Then, EDC (845 mg, 4.30 mmol), HOBT (668 mg, 5.00 mmol) and (2R) -N-BOC- (4-chlorophenyl) alanine were added dropwise sequentially. The reaction was stirred at room temperature for 12 hours. At the end of the reaction, distillation was carried out under reduced pressure to remove DMF, and the residue was diluted with EtOAc. The mixture was washed with saturated aqueous sodium bicarbonate solution and 1N hydrochloric acid solution. The remaining filtrate was dried over MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: EtOAc / Hex = 2/1) to give the title compound (1.58 g, 93.9%).

MS[M+H] = 520(M+1)MS [M + H] = 520 (M + 1)

단계 B: (2R)-2-아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 TFA 염Step B: (2R) -2-Amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) propionamide TFA salt

단계 A에서 수득한 (2R)-2-(BOC-아미노)-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드(1.00 g, 1.93 mmol)를 DCM(7 ㎖)에 녹이고 TFA(7 ㎖)를 적가한 후 상온에서 30분 동안 교반하였다. 반응 용액을 감압 증류하여 용매를 제거하고 수득한 잔류물을 HPLC로 분류하여 표제화합물(TFA 염, 979 mg, 95.1 %)을 수득하였다. (2R) -2- (BOC-amino) -N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- (4- obtained in Step A Chlorophenyl) propionamide (1.00 g, 1.93 mmol) was dissolved in DCM (7 mL) and TFA (7 mL) was added dropwise, followed by stirring at room temperature for 30 minutes. The reaction solution was distilled under reduced pressure to remove the solvent, and the obtained residue was partitioned by HPLC to obtain the title compound (TFA salt, 979 mg, 95.1%).

MS[M+H] = 420(M+1)MS [M + H] = 420 (M + 1)

실시예 2: (2R)-2-[((2R)-피롤리딘-2-일)카보닐]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 TFA 염Example 2: (2R) -2-[((2R) -pyrrolidin-2-yl) carbonyl] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperi Din-1-yl} -3- (4-chlorophenyl) propionamide TFA salt

단계 A: (2R)-2-[((2R)-1-BOC-피롤리딘-2-일)카보닐]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드Step A: (2R) -2-[((2R) -1-BOC-pyrrolidin-2-yl) carbonyl] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl) ] Piperidin-1-yl} -3- (4-chlorophenyl) propionamide

실시예 1에서 수득한 (2R)-2-아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드(TFA 염, 100 mg, 0.188 mmol)를 DMF(3 ㎖)에 녹이고 DIPEA(66.1 ㎖, 0.381 mmol)를 적가하여 반응용액을 염기화하였다. 여기에 EDC(48.7 mg, 0.252 mmol), HOBT(43.6 mg, 0.322 mmol) 및 (2R)-N-BOC-프롤린(40.9 mg, 0.190 mmol)을 차례로 적가한 후 반응물을 상온에서 12시간 교반시켰다. 반응이 종결되었을 때 감압 증류하여 DMF를 제거하고 잔류물에 EtOAc를 첨가하여 희석시킨 후 포화 탄산수소나트륨 수용액과 1N 염산 수용액으로 씻어주었다. 남은 여액을 MgSO4로 건조하고 여과하여 감압 농축하였다. 수득한 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/Hex=2/1)로 정제하여 표제화합물(107 g, 90.8 %)을 수득하였다.(2R) -2-amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) obtained in Example 1 Propionamide (TFA salt, 100 mg, 0.188 mmol) was dissolved in DMF (3 mL) and DIPEA (66.1 mL, 0.381 mmol) was added dropwise to basify the reaction solution. EDC (48.7 mg, 0.252 mmol), HOBT (43.6 mg, 0.322 mmol) and (2R) -N-BOC-proline (40.9 mg, 0.190 mmol) were added dropwise thereto followed by stirring the reaction at room temperature for 12 hours. At the end of the reaction, distillation was carried out under reduced pressure to remove DMF, and the residue was diluted with EtOAc. The mixture was washed with saturated aqueous sodium bicarbonate solution and 1N hydrochloric acid solution. The remaining filtrate was dried over MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: EtOAc / Hex = 2/1) to give the title compound (107 g, 90.8%).

MS[M+H] = 617(M+1)MS [M + H] = 617 (M + 1)

단계 B: (2R)-2-[((2R)-피롤리딘-2-일)카보닐]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 TFA 염Step B: (2R) -2-[((2R) -Pyrrolidin-2-yl) carbonyl] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidine -1-yl} -3- (4-chlorophenyl) propionamide TFA salt

단계 A에서 수득한 (2R)-2-[((2R)-1-BOC-피롤리딘-2-일)카보닐]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드(50.0 mg, 0.081 mmol)를 DCM(2 ㎖)에 녹이고 TFA(2 ㎖)를 적가한 후 상온에서 한시간 동안 교반하였다. 반응이 종결되면 용매를 감압 증류하여 제거하고 수득한 잔류물을 HPLC로 정제하여 표제화합물(TFA 염, 50.0 mg, 98.2 %)을 수득하였다. (2R) -2-[((2R) -1-BOC-pyrrolidin-2-yl) carbonyl] amino-N-{[4-cyclohexyl-4- (t-butylcarba) obtained in step A Mole)] piperidin-1-yl} -3- (4-chlorophenyl) propionamide (50.0 mg, 0.081 mmol) in DCM (2 mL) and TFA (2 mL) dropwise added, followed by an hour at room temperature. Stirred. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue obtained was purified by HPLC to give the title compound (TFA salt, 50.0 mg, 98.2%).

MS[M+H] = 516(M+1)MS [M + H] = 516 (M + 1)

실시예 3: (2R)-2-[((2R)-피롤리딘-2-일)메틸]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염Example 3: (2R) -2-[((2R) -pyrrolidin-2-yl) methyl] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidine -1-yl} -3- (4-chlorophenyl) propionamide 2TFA salt

단계 A: (2R)-2-[((2R)-N-BOC-피롤리딘-2-일)-메틸]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드Step A: (2R) -2-[((2R) -N-BOC-pyrrolidin-2-yl) -methyl] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl) ] Piperidin-1-yl} -3- (4-chlorophenyl) propionamide

실시예 1에서 수득한 (2R)-2-아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드(TFA 염 형태, 100 mg, 0.191 mmol)와 (2R)-N-BOC-프롤린 카복시알데히드(37.9 mg, 0.191 mmol)를 DCE(5 ㎖)에 녹이고 NaBH(OAc)3(80.0 mg, 0.380 mmol)를 천천히 적가한 후 반응물을 상온에서 4시간 동안 교반하였다. 반응이 종결되면 포화 탄산수소나트륨 수용액을 첨가하고 유기물을 DCM과 EtOAc로 추출한 후 MgSO4로 건조하고 여과하여 감압 농축하였다. 수득된 잔류물을 칼럼 크로마토그래피(용리액: DCM/MeOH=9/1)로 정제하여 표제화합물(109 mg, 95.0 %)을 수득하였다.(2R) -2-amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) obtained in Example 1 Propionamide (TFA salt form, 100 mg, 0.191 mmol) and (2R) -N-BOC-proline carboxyaldehyde (37.9 mg, 0.191 mmol) were dissolved in DCE (5 mL) and NaBH (OAc) 3 (80.0 mg, 0.380). mmol) was slowly added dropwise and the reaction was stirred at room temperature for 4 hours. Upon completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added, the organics were extracted with DCM and EtOAc, dried over MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: DCM / MeOH = 9/1) to give the title compound (109 mg, 95.0%).

MS[M+H] = 603(M+1)MS [M + H] = 603 (M + 1)

단계 B: (2R)-2-[((2R)-피롤리딘-2-일)메틸]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염Step B: (2R) -2-[((2R) -Pyrrolidin-2-yl) methyl] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidine- 1-yl} -3- (4-chlorophenyl) propionamide 2TFA salt

단계 A에서 수득한 (2R)-2-[((2R)-N-BOC-피롤리딘-2-일)-메틸]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드를 실시예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. (2R) -2-[((2R) -N-BOC-pyrrolidin-2-yl) -methyl] amino-N-{[4-cyclohexyl-4- (t-butylcarba) obtained in step A Moyl)] piperidin-1-yl} -3- (4-chlorophenyl) propionamide was reacted in the same manner as in Step B of Example 1 to obtain the title compound.

MS[M+H] = 503(M+1)MS [M + H] = 503 (M + 1)

실시예 4: (2R)-2-{메틸[((2R)-피롤리딘-2-일)메틸]}아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염Example 4: (2R) -2- {methyl [((2R) -pyrrolidin-2-yl) methyl]} amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] Piperidin-1-yl} -3- (4-chlorophenyl) propionamide 2TFA salt

실시예 3의 단계 A에서 수득한 (2R)-2-[((2R)-N-BOC-피롤리딘-2-일)-메틸]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드와 포르말린을 실시예 3에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. (2R) -2-[((2R) -N-BOC-pyrrolidin-2-yl) -methyl] amino-N-{[4-cyclohexyl-4- (obtained in Step A of Example 3 t-butylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) propionamide was reacted with formalin in the same manner as in Example 3 to obtain the title compound.

MS[M+H] = 545(M+H)MS [M + H] = 545 (M + H)

실시예 5: (2R)-2-(디메틸)아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 TFA 염Example 5: (2R) -2- (dimethyl) amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl Propionamide TFA Salt

실시예 1에서 수득한 (2R)-2-아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 TFA 염과 포르말린을 실시예 3에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. (2R) -2-amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) obtained in Example 1 Propionamide TFA salt and formalin were reacted in the same manner as in Example 3 to obtain the title compound.

MS[M+H] = 476(M+1)MS [M + H] = 476 (M + 1)

실시예 6: (2R)-2-[1-(메틸)아제티딘-3-일]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염Example 6: (2R) -2- [1- (methyl) azetidin-3-yl] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidine-1- I} -3- (4-chlorophenyl) propionamide 2TFA salt

단계 A: (2R)-2-[1-(BOC)아제티딘-3-일]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 Step A: (2R) -2- [1- (BOC) azetidin-3-yl] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl } -3- (4-chlorophenyl) propionamide

실시예 1에서 수득한 (2R)-2-아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 TFA 염과 포르말린을 실시예 3의 단계 A에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. (2R) -2-amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) obtained in Example 1 Propionamide TFA salt and formalin were reacted in the same manner as in Step A of Example 3 to obtain the title compound.

MS[M+H] = 603(M+1)MS [M + H] = 603 (M + 1)

단계 B: (2R)-2-{Fmoc[1-(BOC)아제티딘-3-일]}아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드Step B: (2R) -2- {Fmoc [1- (BOC) azetidin-3-yl]} amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidine- 1-yl} -3- (4-chlorophenyl) propionamide

단계 A에서 수득한 (2R)-2-[1-(BOC)아제티딘-3-일]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드와 Fmoc 클로라이드를 제조예 98의 단계 A에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. (2R) -2- [1- (BOC) azetidin-3-yl] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidine-1 obtained in step A -Yl} -3- (4-chlorophenyl) propionamide and Fmoc chloride were reacted in the same manner as in Step A of Preparation Example 98 to obtain the title compound.

MS[M+H] = 825(M+1)MS [M + H] = 825 (M + 1)

단계 C: (2R)-2-[Fmoc(아제티딘-3-일)]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 TFA 염Step C: (2R) -2- [Fmoc (azetidin-3-yl)] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl}- 3- (4-chlorophenyl) propionamide TFA salt

단계 B에서 수득한 (2R)-2-{Fmoc[1-(BOC)아제티딘-3-일]}아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드를 실시예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물의 TFA 염을 수득하였다. (2R) -2- {Fmoc [1- (BOC) azetidin-3-yl]} amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperi obtained in step B Din-1-yl} -3- (4-chlorophenyl) propionamide was reacted in the same manner as in Step B of Example 1 to obtain a TFA salt of the title compound.

MS[M+H] = 725(M+1)MS [M + H] = 725 (M + 1)

단계 D: (2R)-2-{Fmoc[1-(메틸)아제티딘-3-일]}아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드Step D: (2R) -2- {Fmoc [1- (methyl) azetidin-3-yl]} amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidine- 1-yl} -3- (4-chlorophenyl) propionamide

단계 C에서 수득한 (2R)-2-[Fmoc(아제티딘-3-일)]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 TFA 염과 포르말린을 실시예 3의 단계 A에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. (2R) -2- [Fmoc (azetidin-3-yl)] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl obtained in step C } -3- (4-chlorophenyl) propionamide TFA salt was reacted with formalin in the same manner as in Step A of Example 3 to obtain the title compound.

MS[M+H] = 739(M+1)MS [M + H] = 739 (M + 1)

단계 E: (2R)-2-[1-(메틸)아제티딘-3-일]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염Step E: (2R) -2- [1- (methyl) azetidin-3-yl] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl } -3- (4-chlorophenyl) propionamide 2TFA salt

단계 D에서 수득한 (2R)-2-{Fmoc[1-(메틸)아제티딘-3-일]}아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드(71.1 mg, 1 mmol)를 50% 피페리딘-DMF(2 ㎖) 용액에 녹이고 상온에서 30분동안 교반하였다. 반응이 종결되면 용액을 감압 증류하여 DMF를 제거하고 잔류물을 HPLC로 정제하여 표제화합물의 TFA염(52 mg, 73.5 %)을 수득하였다. (2R) -2- {Fmoc [1- (methyl) azetidin-3-yl]} amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperi obtained in step D Din-1-yl} -3- (4-chlorophenyl) propionamide (71.1 mg, 1 mmol) was dissolved in 50% piperidine-DMF (2 mL) solution and stirred at room temperature for 30 minutes. After completion of the reaction, the solution was distilled under reduced pressure to remove DMF, and the residue was purified by HPLC to give TFA salt (52 mg, 73.5%) of the title compound.

MS[M+H] = 517(M+1)MS [M + H] = 517 (M + 1)

실시예 7-186: Examples 7-186:

하기 표에 서술된 실시예 화합물들은, 전술한 제조예에서 합성된 피페리딘 유도체로부터 실시예 1-6에서와 동일한 방법으로 반응을 수행하여 수득하였다.The example compounds described in the following table were obtained by carrying out the reaction in the same manner as in Example 1-6 from the piperidine derivatives synthesized in the above-described preparation.

실시예 187: (2R)-2-(아미노)-N-{[4-사이클로헥실-4-(아미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2HCl 염Example 187: (2R) -2- (amino) -N-{[4-cyclohexyl-4- (aminoethylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) propion Amide 2HCl Salt

단계 A: (2R)-2-(BOC-아미노)-N-{[4-사이클로헥실-4-(카복실릴)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드Step A: (2R) -2- (BOC-amino) -N-{[4-cyclohexyl-4- (carboxylyl)] piperidin-1-yl} -3- (4-chlorophenyl) propionamide

(2R)-N-BOC-4-Cl-Phe과 4-사이클로헥실-4-카복실릴피페리딘을 이용하여 실시예 1의 단계 A과 같은 방법으로 표제 화합물을 수득 하였다. The title compound was obtained in the same manner as Step A of Example 1 using (2R) -N-BOC-4-Cl-Phe and 4-cyclohexyl-4-carboxylylpiperidine.

MS[M+H] = 493(M+1)MS [M + H] = 493 (M + 1)

단계 B: (2R)-2-(BOC-아미노)-N-{[4-사이클로헥실-4-(클로로카보닐)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드Step B: (2R) -2- (BOC-amino) -N-{[4-cyclohexyl-4- (chlorocarbonyl)] piperidin-1-yl} -3- (4-chlorophenyl) propion amides

단계 A에서 수득한 (2R)-2-(BOC-아미노)-N-{[4-사이클로헥실-4-(카복실릴)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 (1.0 g, 2.03 mmol)를 DCM(10 ㎖)에 녹이고 옥살릴 클로라이드(0.26 ㎖, 3.10 mmol)과 DMF(촉매량)를 넣고 0 oC에서 30분 동안 교반 하였다. 반응이 종결 되면 용매를 감압하에 제거하고 칼럼 크로마토그래피(용리액: EtOAc/Hex=1/1)로 정제하여 표제화합물(705 mg, 68 %)을 수득하였다.(2R) -2- (BOC-amino) -N-{[4-cyclohexyl-4- (carboxylyl)] piperidin-1-yl} -3- (4-chlorophenyl) obtained in step A Propionamide (1.0 g, 2.03 mmol) was dissolved in DCM (10 mL) and oxalyl chloride (0.26 mL, 3.10 mmol) and DMF (catalyst amount) were added and stirred at 0 ° C. for 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure and purified by column chromatography (eluent: EtOAc / Hex = 1/1) to give the title compound (705 mg, 68%).

MS[M+H] = 511(M+1)MS [M + H] = 511 (M + 1)

단계 C: (2R)-2-(BOC-아미노)-N-{[4-사이클로헥실-4-(BOC-아미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드Step C: (2R) -2- (BOC-amino) -N-{[4-cyclohexyl-4- (BOC-aminoethylcarbamoyl)] piperidin-1-yl} -3- (4-chloro Phenyl) propionamide

단계 B에서 수득한 (2R)-2-(BOC-아미노)-N-{[4-사이클로헥실-4-(클로로카보닐)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드(511 mg, 1.0 mmol)를 DCM(5 mL)에 녹이고 (Et)3N(0.28 ㎖, 2.0 mmol)을 첨가 한 다음, N(BOC)-에틸렌 디아민(90 mg, 1.5 mmol)를 DCM(0.5 ㎖)에 녹여 첨가 한 후 상온에서 2시간 교반 하였다. 반응이 종결 되면 용매를 감압 하에 제거하고 칼럼 크로마토그래피(용리액: EtOAc/Hex=1/2)로 정제하여 표제화합물(578 mg, 91 %)을 수득하였다.(2R) -2- (BOC-amino) -N-{[4-cyclohexyl-4- (chlorocarbonyl)] piperidin-1-yl} -3- (4-chlorophenyl obtained in step B Propionamide (511 mg, 1.0 mmol) was dissolved in DCM (5 mL) and (Et) 3 N (0.28 mL, 2.0 mmol) was added, followed by N (BOC) -ethylene diamine (90 mg, 1.5 mmol). It was dissolved in DCM (0.5 ml) and added and stirred at room temperature for 2 hours. After completion of the reaction the solvent was removed under reduced pressure and purified by column chromatography (eluent: EtOAc / Hex = 1/2) to afford the title compound (578 mg, 91%).

MS[M+H] = 635(M+1)MS [M + H] = 635 (M + 1)

단계 D: (2R)-2-(아미노)-N-{[4-사이클로헥실-4-(아미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염. Step D: (2R) -2- (amino) -N-{[4-cyclohexyl-4- (aminoethylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) propionamide 2TFA salt.

단계 C에서 수득한 (2R)-2-(BOC-아미노)-N-{[4-사이클로헥실-4-(아미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드를 이용하여 실시예 1의 단계 B와 같은 방법으로 표제 화합물을 수득하였다. (2R) -2- (BOC-amino) -N-{[4-cyclohexyl-4- (aminoethylcarbamoyl)] piperidin-1-yl} -3- (4-chloro obtained in step C The title compound was obtained by the same method as Step B of Example 1 using phenyl) propionamide.

MS[M+H] = 435(M+1)MS [M + H] = 435 (M + 1)

단계 E: (2R)-2-(아미노)-N-{[4-사이클로헥실-4-(아미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2HCl 염Step E: (2R) -2- (amino) -N-{[4-cyclohexyl-4- (aminoethylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) propionamide 2HCl salt

단계 D에서 수득한 (2R)-2-(아미노)-N-{[4-사이클로헥실-4-(아미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염을 메탄올에 녹인후 염산으로 치환된 이온교환 수지를 통과시켜 표제 화합물을 수득하였다. (2R) -2- (amino) -N-{[4-cyclohexyl-4- (aminoethylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) obtained in step D The propionamide 2TFA salt was dissolved in methanol and passed through an ion exchange resin substituted with hydrochloric acid to afford the title compound.

MS[M+H] = 435(M+1)MS [M + H] = 435 (M + 1)

실시예 188: (2R)-2-(디메틸아미노)-N-{[4-사이클로헥실-4-(아미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2HCl 염Example 188: (2R) -2- (dimethylamino) -N-{[4-cyclohexyl-4- (aminoethylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) Propionamide 2HCl Salt

단계 A: (2R)-2-(BOC-아미노)-N-{[4-사이클로헥실-4-(프탈이미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드Step A: (2R) -2- (BOC-amino) -N-{[4-cyclohexyl-4- (phthaliminoethylcarbamoyl)] piperidin-1-yl} -3- (4-chloro Phenyl) propionamide

실시예 187의 단계 B에서 수득한 (2R)-2-(BOC-아미노)-N-{[4-사이클로헥실-4-(클로로카보닐)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드와 제조예 98에서 수득한 2-프탈이미노-1-아미노에탄을 이용하여 실시예 187의 단계 C와 같은 방법으로 표제 화합물을 수득하였다. (2R) -2- (BOC-amino) -N-{[4-cyclohexyl-4- (chlorocarbonyl)] piperidin-1-yl} -3- (obtained in Step B of Example 187 The title compound was obtained in the same manner as Step C of Example 187 using 4-chlorophenyl) propionamide and 2-phthalimino-1-aminoethane obtained in Preparation Example 98.

MS[M+H] = 665(M+1)MS [M + H] = 665 (M + 1)

단계 B: (2R)-2-(아미노)-N-{[4-사이클로헥실-4-(프탈이미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드Step B: (2R) -2- (amino) -N-{[4-cyclohexyl-4- (phthaliminoethylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) Propionamide

단계 A에서 수득한 (2R)-2-(BOC-아미노)-N-{[4-사이클로헥실-4-(프탈이미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드를 이용하여 실시예 1의 단계 B와 같은 방법으로 표제 화합물을 수득하였다. (2R) -2- (BOC-amino) -N-{[4-cyclohexyl-4- (phthaliminoethylcarbamoyl)] piperidin-1-yl} -3- (4) obtained in step A The title compound was obtained by the same method as Step B of Example 1 using -chlorophenyl) propionamide.

MS[M+H] = 565(M+1)MS [M + H] = 565 (M + 1)

단계 C: (2R)-2-(디메틸아미노)-N-{[4-사이클로헥실-4-(프탈이미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드Step C: (2R) -2- (Dimethylamino) -N-{[4-cyclohexyl-4- (phthaliminoethylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl Propionamide

단계 B에서 수득한 (2R)-2-(아미노)-N-{[4-사이클로헥실-4-(프탈이미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드를 이용하여 실시예 3에서와 같은 방법으로 표제 화합물을 수득하였다. (2R) -2- (amino) -N-{[4-cyclohexyl-4- (phthaliminoethylcarbamoyl)] piperidin-1-yl} -3- (4-chloro obtained in step B The title compound was obtained in the same manner as in Example 3 using phenyl) propionamide.

MS[M+H] = 593(M+1)MS [M + H] = 593 (M + 1)

단계 D: (2R)-2-(디메틸아미노)-N-{[4-사이클로헥실-4-(아미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염Step D: (2R) -2- (Dimethylamino) -N-{[4-cyclohexyl-4- (aminoethylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) propion Amide 2TFA Salt

단계 C에서 수득한 (2R)-2-(디메틸아미노)-N-{[4-사이클로헥실-4-(프탈이미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드(200 mg, 0.34 mmol)를 MeOH(5 ㎖)에 녹이고 하이드라진(0.10 ㎖, 3.64 mmol)을 첨가 하여 상온에서 12시간 동안 교반 하였다. 반응이 종결 되면 반응 용액을 감압 증류하여 용매를 제거하고 수득한 잔류물을 HPLC로 분류하여 표제화합물(TFA 염, 111 mg, 57.0 %)을 수득하였다. (2R) -2- (dimethylamino) -N-{[4-cyclohexyl-4- (phthaliminoethylcarbamoyl)] piperidin-1-yl} -3- (4- obtained in step C Chlorophenyl) propionamide (200 mg, 0.34 mmol) was dissolved in MeOH (5 mL) and hydrazine (0.10 mL, 3.64 mmol) was added and stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent, and the residue was classified by HPLC to obtain the title compound (TFA salt, 111 mg, 57.0%).

MS[M+H] = 463(M+1) MS [M + H] = 463 (M + 1)

단계 E: (2R)-2-(디메틸아미노)-N-{[4-사이클로헥실-4-(아미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2HCl 염Step E: (2R) -2- (Dimethylamino) -N-{[4-cyclohexyl-4- (aminoethylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) propion Amide 2HCl Salt

단계 D에서 수득한 (2R)-2-(디메틸아미노)-N-{[4-사이클로헥실-4-(아미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염를 이용하여 실시예 187의 단계 E와 같은 방법으로 표제 화합물을 수득하였다. (2R) -2- (dimethylamino) -N-{[4-cyclohexyl-4- (aminoethylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl obtained in step D The title compound was obtained by the same method as Step E of Example 187, using propionamide 2TFA salt.

MS[M+H] = 463(M+1)MS [M + H] = 463 (M + 1)

실시예 : 189 - 225Example: 189-225

하기 표에 서술된 실시예 화합물들은, 전술한 제조예에서 합성된 피페리딘 유도체로부터 실시예 187 및 188에서와 동일한 방법으로 반응을 수행하여 수득하였다.The example compounds described in the following table were obtained by carrying out the reaction in the same manner as in Examples 187 and 188 from the piperidine derivatives synthesized in the above-described preparation.

실시예 226: (2R)-2-(아미노)-N-{[4-사이클로헥실-4-(3-옥소아제티딘-1-일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2HCl 염Example 226: (2R) -2- (amino) -N-{[4-cyclohexyl-4- (3-oxoazetidin-1-yl)] piperidin-1-yl} -3- ( 4-chlorophenyl) propionamide 2HCl salt

단계 A: (2R)-2-(아미노)-N-{[4-사이클로헥실-4-(3-옥소아제티딘-1-일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염Step A: (2R) -2- (amino) -N-{[4-cyclohexyl-4- (3-oxoazetidin-1-yl)] piperidin-1-yl} -3- (4 -Chlorophenyl) propionamide 2TFA salt

실시예 204에서 수득한 (2R)-2-(BOC-아미노)-N-{[4-사이클로헥실-4-(3-하이드록시아제티딘-1-일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드(200 mg, 0.45 mmol)를 DCM(5 ㎖)에 녹이고 데스-마틴 시약(3.0 ㎖, 15 wt% in DCM, 10 mmol)을 첨가 한 후 상온에서 12시간 동안 교반 하였다. 반응이 종결 되면 포화 Na2S2O3 수용액을 넣고 침전 시킨후 여과하여 고형질을 제거 하였다. 잔류 유기 용액을 MgSO4로 건조한 후 용매를 감압하에 제거하고 수득한 잔류물을 HPLC로 분류하여 표제화합물(TFA 염, 203 mg, 81.0 %)을 수득하였다.(2R) -2- (BOC-amino) -N-{[4-cyclohexyl-4- (3-hydroxyazetidin-1-yl)] piperidin-1-yl} obtained in Example 204} Dissolve 3--3- (4-chlorophenyl) propionamide (200 mg, 0.45 mmol) in DCM (5 mL), add Dess-Martin reagent (3.0 mL, 15 wt% in DCM, 10 mmol), and then add 12 mL at room temperature. Stirred for hours. Upon completion of the reaction, saturated Na 2 S 2 O 3 aqueous solution was added, precipitated, and filtered to remove solids. The residual organic solution was dried over MgSO 4 , the solvent was removed under reduced pressure and the residue obtained was classified by HPLC to give the title compound (TFA salt, 203 mg, 81.0%).

MS[M+H] = 446(M+1)MS [M + H] = 446 (M + 1)

단계 B: (2R)-2-(아미노)-N-{[4-사이클로헥실-4-(3-옥소아제티딘-1-일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2HCl 염Step B: (2R) -2- (amino) -N-{[4-cyclohexyl-4- (3-oxoazetidin-1-yl)] piperidin-1-yl} -3- (4 -Chlorophenyl) propionamide 2HCl salt

단계 A에서 수득한 (2R)-2-(아미노)-N-{[4-사이클로헥실-4-(3-옥소아제티딘-1-일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염를 이용하여 실시예 187의 단계 E에서와 같은 방법으로 표제 화합물을 수득하였다. (2R) -2- (amino) -N-{[4-cyclohexyl-4- (3-oxoazetidin-1-yl)] piperidin-1-yl} -3-obtained in step A The title compound was obtained in the same manner as in Step E of Example 187 using (4-chlorophenyl) propionamide 2TFA salt.

MS[M+H] = 446(M+1)MS [M + H] = 446 (M + 1)

실시예 227: (2R)-2-(아미노)-N-{[4-사이클로헥실-4-(4-옥소피페리딘-1-일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2HCl 염Example 227: (2R) -2- (amino) -N-{[4-cyclohexyl-4- (4-oxopiperidin-1-yl)] piperidin-1-yl} -3- ( 4-chlorophenyl) propionamide 2HCl salt

실시예 207에서 수득한 (2R)-2-(아미노)-N-{[4-사이클로헥실-4-(4-하이드록시피페리딘-1-일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2HCl 염을 이용하여 실시예 226와 같은 방법으로 수행하여 표제 화합물을 수득하였다. (2R) -2- (amino) -N-{[4-cyclohexyl-4- (4-hydroxypiperidin-1-yl)] piperidin-1-yl} -obtained in Example 207 The title compound was obtained in the same manner as Example 226 using 3- (4-chlorophenyl) propionamide 2HCl salt.

MS[M+H] = 474(M+1)MS [M + H] = 474 (M + 1)

실시예 228: (2R)-2-[2-(디메틸아미노)에틸]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}}-3-(4-클로로페닐)프로피온아미드 2TFA 염Example 228: (2R) -2- [2- (dimethylamino) ethyl] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl}}- 3- (4-chlorophenyl) propionamide 2TFA salt

단계 A: (2R)-2-(2-니트로벤젠설포닐)아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드Step A: (2R) -2- (2-nitrobenzenesulfonyl) amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- ( 4-chlorophenyl) propionamide

실시예 1에서 수득한 (2R)-2-아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드(519 mg, 1 mmol)를 DMF(10 ㎖)에 녹이고 TEA(280 ㎖, 2 mmol)를 적가한 다음 2-니트로벤젠설포닐클로라이드(222 mg, 1.00 mmol)를 적가하였다. 반응물을 상온에서 4시간 동안 교반한 후 암모늄클로라이드 수용액을 첨가하고 유기물을 DCM과 EtOAc로 추출하였다. 추출한 유기용액을 MgSO4로 건조하고 여과한 다음 감압 농축하였다. 수득한 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/Hex=1/2)로 정제하여 표제화합물(570 mg, 90 %)을 수득하였다.(2R) -2-amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) obtained in Example 1 Propionamide (519 mg, 1 mmol) was dissolved in DMF (10 mL), TEA (280 mL, 2 mmol) was added dropwise and 2-nitrobenzenesulfonylchloride (222 mg, 1.00 mmol) was added dropwise. After the reaction was stirred at room temperature for 4 hours, an aqueous ammonium chloride solution was added, and the organics were extracted with DCM and EtOAc. The extracted organic solution was dried over MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: EtOAc / Hex = 1/2) to give the title compound (570 mg, 90%).

MS[M+H] = 633(M+1)MS [M + H] = 633 (M + 1)

단계 B: (2R)-2-{2-니트로벤젠설포닐-[2-(디메틸아미노)에틸]}아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드Step B: (2R) -2- {2-Nitrobenzenesulfonyl- [2- (dimethylamino) ethyl]} amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperi Din-1-yl} -3- (4-chlorophenyl) propionamide

단계 A에서 수득한 (2R)-2-(2-니트로벤젠설포닐)아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}}-3-(4-클로로페닐)프로피온아미드(500 mg, 0.79 mmol)를 DMF(5 ㎖)에 녹이고 K2CO3(280 mg, 2 mmol)를 적가한 후 2-(디메틸아미노)에틸 클로라이드(염산염, 125.9 mg, 1 mmol)를 적가하였다. 반응이 종결되면, 반응용액을 감압 증류하여 DMF를 제거하고 암모늄클로라이드 수용액을 첨가하고 유기물을 EtOAc로 추출하였다. 추출한 유기용액을 MgSO4로 건조하고 여과하여 감압 농축하였다. 수득한 잔류물을 칼럼 크로마토그래피(용리액: EtOAc/Hex=1/2)로 정제하여 표제화합물(511 mg, 92 %)을 수득하였다.(2R) -2- (2-nitrobenzenesulfonyl) amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl}} obtained in step A}- 3- (4-chlorophenyl) propionamide (500 mg, 0.79 mmol) was dissolved in DMF (5 mL) and K 2 CO 3 (280 mg, 2 mmol) was added dropwise, followed by 2- (dimethylamino) ethyl chloride (hydrochloride , 125.9 mg, 1 mmol) was added dropwise. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove DMF, an aqueous ammonium chloride solution was added, and the organics were extracted with EtOAc. The extracted organic solution was dried over MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: EtOAc / Hex = 1/2) to give the title compound (511 mg, 92%).

MS[M+H] = 703(M+1)MS [M + H] = 703 (M + 1)

단계 C: (2R)-2-[2-(디메틸아미노)에틸]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염Step C: (2R) -2- [2- (dimethylamino) ethyl] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) propionamide 2TFA salt

단계 B에서 수득한 (2R)-2-{2-니트로벤젠설포닐-[2-(디메틸아미노)에틸]}아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드(500 mg, 0.71 mmol)를 DMF(3 ㎖)에 녹이고 K2CO3(300 mg, 2 mmol)와 티오벤젠(210 ㎖, 0.429 mmol)을 적가하였다. 반응물을 상온에서 2시간 동안 교반하고 반응용액을 감압 증류하여 DMF를 제거한 후 잔류물을 물로 희석하고 유기물을 EtOAc로 추출하였다. 추출한 유기용액을 MgSO4로 건조하고 여과한 후 감압 농축하였다. 잔류물을 HPLC로 정제하여 표제화합물의 TFA 염(477 mg, 90 %)을 수득하였다.(2R) -2- {2-nitrobenzenesulfonyl- [2- (dimethylamino) ethyl]} amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] obtained in step B] Piperidin-1-yl} -3- (4-chlorophenyl) propionamide (500 mg, 0.71 mmol) was dissolved in DMF (3 mL), K 2 CO 3 (300 mg, 2 mmol) and thiobenzene (210 ML, 0.429 mmol) was added dropwise. The reaction was stirred at room temperature for 2 hours, the reaction solution was distilled under reduced pressure to remove DMF, the residue was diluted with water and the organics were extracted with EtOAc. The extracted organic solution was dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by HPLC to give TFA salt (477 mg, 90%) of the title compound.

MS[M+H] = 520(M+1)MS [M + H] = 520 (M + 1)

실시예 229: (2R)-2-[2-(메틸아미노)에틸]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염Example 229: (2R) -2- [2- (methylamino) ethyl] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3 -(4-chlorophenyl) propionamide 2TFA salt

단계 A: (2R)-2-{2-니트로벤젠설포닐-[2-(BOC-아미노)에틸]}아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드Step A: (2R) -2- {2-nitrobenzenesulfonyl- [2- (BOC-amino) ethyl]} amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] pi Ferridin-1-yl} -3- (4-chlorophenyl) propionamide

실시예 228의 단계 A에서 수득한 (2R)-(2-니트로벤젠설포닐)아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드와 N-BOC-아미노에틸 브로마이드를 실시예 228의 단계 B와 동일한 방법으로 반응시켜 표제화합물을 수득하였다.Obtained in Step A of Example 228 (2R)-(2-nitrobenzenesulfonyl) amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) Propionamide and N-BOC-aminoethyl bromide were reacted in the same manner as in Step B of Example 228 to obtain the title compound.

MS[M+H] = 727(M+1)MS [M + H] = 727 (M + 1)

단계 B: (2R)-2-[(N-메틸-N-BOC-아미노)에틸-(2-니트로벤젠설포닐)]아미노-N-[4-사이클로헥실-4-(t-부틸카바모일)피페리딘-1-일]-3-(4-클로로페닐)프로피온아미드Step B: (2R) -2-[(N-Methyl-N-BOC-amino) ethyl- (2-nitrobenzenesulfonyl)] amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl Piperidin-1-yl] -3- (4-chlorophenyl) propionamide

단계 A에서 수득한 (2R)-2-{2-니트로벤젠설포닐-[2-(BOC-아미노)에틸]}아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드와 요오도메탄을 실시예 228의 단계 B와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. (2R) -2- {2-nitrobenzenesulfonyl- [2- (BOC-amino) ethyl]} amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl) obtained in step A ] Piperidin-1-yl} -3- (4-chlorophenyl) propionamide and iodomethane were reacted in the same manner as in Step B of Example 228 to obtain the title compound.

MS[M+H] = 740(M+1)MS [M + H] = 740 (M + 1)

단계 C: (2R)-2-[(N-메틸-N-BOC-아미노)에틸]아미노-N-[4-사이클로헥실-4-(t-부틸카바모일)피페리딘-1-일]-3-(4-클로로페닐)프로피온아미드Step C: (2R) -2-[(N-Methyl-N-BOC-amino) ethyl] amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl] -3- (4-chlorophenyl) propionamide

단계 B에서 수득한 (2R)-2-[(N-메틸-N-BOC-아미노)에틸-(2-니트로벤젠설포닐)]아미노-N-[4-사이클로헥실-4-(t-부틸카바모일)피페리딘-1-일]-3-(4-클로로페닐)프로피온아미드를 실시예 228의 단계 C와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. (2R) -2-[(N-methyl-N-BOC-amino) ethyl- (2-nitrobenzenesulfonyl)] amino-N- [4-cyclohexyl-4- (t-butyl) obtained in step B Carbamoyl) piperidin-1-yl] -3- (4-chlorophenyl) propionamide was reacted in the same manner as in Step C of Example 228 to obtain the title compound.

MS[M+H] = 606(M+1)MS [M + H] = 606 (M + 1)

단계 D: (2R)-2-[2-(메틸아미노)에틸]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염Step D: (2R) -2- [2- (Methylamino) ethyl] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) propionamide 2TFA salt

단계 C에서 수득한 (2R)-2-[(N-메틸-N-BOC-아미노)에틸]아미노-N-[4-사이클로헥실-4-(t-부틸카바모일)피페리딘-1-일]-3-(4-클로로페닐)프로피온아미드를 실시예 1의 단계 B와 동일한 방법으로 반응시켜 표제화합물의 TFA 염을 수득하였다. (2R) -2-[(N-methyl-N-BOC-amino) ethyl] amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidine-1- obtained in step C Il] -3- (4-chlorophenyl) propionamide was reacted in the same manner as in Step B of Example 1 to obtain a TFA salt of the title compound.

MS[M+H] = 506(M+1)MS [M + H] = 506 (M + 1)

실시예 230: (2R)-2-(2-아미노에틸)아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염Example 230: (2R) -2- (2-aminoethyl) amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- (4 -Chlorophenyl) propionamide 2TFA salt

단계 A: (2R)-2-[2-(BOC-아미노)에틸]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드Step A: (2R) -2- [2- (BOC-amino) ethyl] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3 -(4-chlorophenyl) propionamide

실시예 229의 단계 A에서 수득한 (2R)-2-{2-니트로벤젠설포닐-[2-(BOC-아미노)에틸]}아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드를 실시예 228의 단계 C에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. (2R) -2- {2-nitrobenzenesulfonyl- [2- (BOC-amino) ethyl]} amino-N-{[4-cyclohexyl-4- (t-) obtained in step A of Example 229. Butylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) propionamide was reacted in the same manner as in Step C of Example 228 to obtain the title compound.

MS[M+H] = 563(M+1)MS [M + H] = 563 (M + 1)

단계 B: (2R)-2-(2-아미노에틸)아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염Step B: (2R) -2- (2-Aminoethyl) amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- (4- Chlorophenyl) propionamide 2TFA salt

단계 A에서 수득한 (2R)-2-[2-(BOC-아미노)에틸]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드를 실시예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. (2R) -2- [2- (BOC-amino) ethyl] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} obtained in step A 3- (4-chlorophenyl) propionamide was reacted in the same manner as in Step B of Example 1 to obtain the title compound.

MS[M+H] = 463(M+1)MS [M + H] = 463 (M + 1)

실시예 231: (2R)-2-[2-(아세틸아미노)에틸]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 TFA 염Example 231: (2R) -2- [2- (acetylamino) ethyl] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3 -(4-chlorophenyl) propionamide TFA salt

아세틸아미노에틸 브로마이드를 실시예 228에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. Acetylaminoethyl bromide was reacted in the same manner as in Example 228 to obtain the title compound.

MS[M+H] = 505(M+1)MS [M + H] = 505 (M + 1)

실시예 232: (2R)-2-{메틸-[2-(메틸아미노)에틸]}아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염Example 232: (2R) -2- {methyl- [2- (methylamino) ethyl]} amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidine-1- I} -3- (4-chlorophenyl) propionamide 2TFA salt

단계 A: (2R)-2-{메틸-[2-(BOC-아미노)에틸]}아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드Step A: (2R) -2- {methyl- [2- (BOC-amino) ethyl]} amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidine-1- Japanese} -3- (4-chlorophenyl) propionamide

실시예 230의 단계 A에서 수득한 (2R)-2-[2-(BOC-아미노)에틸]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드를 실시예 3의 단계 A에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. (2R) -2- [2- (BOC-amino) ethyl] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidine- obtained in Step A of Example 230 1-yl} -3- (4-chlorophenyl) propionamide was reacted in the same manner as in Step A of Example 3 to obtain the title compound.

MS[M+H] = 577(M+1)MS [M + H] = 577 (M + 1)

단계 B: (2R)-2-{메틸-[2-[메틸(BOC)아미노]에틸]}아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드Step B: (2R) -2- {methyl- [2- [methyl (BOC) amino] ethyl]} amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidine- 1-yl} -3- (4-chlorophenyl) propionamide

단계 A에서 수득한 (2R)-2-{메틸-[2-(BOC-아미노)에틸]}아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드를 제조예 42의 단계 A에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다.(2R) -2- {methyl- [2- (BOC-amino) ethyl]} amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidine- obtained in step A 1-yl} -3- (4-chlorophenyl) propionamide was reacted in the same manner as in Step A of Preparation Example 42 to obtain the title compound.

MS[M+H] = 591(M+1)MS [M + H] = 591 (M + 1)

단계 C: (2R)-2-{메틸-[2-(메틸아미노)에틸]}아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염Step C: (2R) -2- {methyl- [2- (methylamino) ethyl]} amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl } -3- (4-chlorophenyl) propionamide 2TFA salt

단계 B에서 수득한 (2R)-2-{메틸-[2-[메틸(BOC)아미노]에틸]}아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드를 실시예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. (2R) -2- {methyl- [2- [methyl (BOC) amino] ethyl]} amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperi obtained in step B Din-1-yl} -3- (4-chlorophenyl) propionamide was reacted in the same manner as in Step B of Example 1 to obtain the title compound.

MS[M+H] = 491(M+1)MS [M + H] = 491 (M + 1)

실시예 233: (2R)-2-{메틸-[2-(아미노)에틸]}아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염Example 233: (2R) -2- {methyl- [2- (amino) ethyl]} amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl } -3- (4-chlorophenyl) propionamide 2TFA salt

실시예 232의 단계 A에서 수득한 (2R)-2-{메틸-[2-(BOC-아미노)에틸]}아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드를 실시예 1의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. (2R) -2- {methyl- [2- (BOC-amino) ethyl]} amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] obtained in step A of Example 232 Piperidin-1-yl} -3- (4-chlorophenyl) propionamide was reacted in the same manner as in Step B of Example 1 to obtain the title compound.

MS[M+H] = 477(M+1)MS [M + H] = 477 (M + 1)

실시예 234: (2R)-2-(메틸)아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염Example 234: (2R) -2- (methyl) amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl Propionamide 2TFA Salt

단계 A: (2R)-2-[메틸-(2-니트로벤젠설포닐)]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드Step A: (2R) -2- [Methyl- (2-nitrobenzenesulfonyl)] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) propionamide

실시예 228의 단계 A에서 수득한 (2R)-2-(2-니트로벤젠설포닐)아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드를 제조예 228의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. (2R) -2- (2-nitrobenzenesulfonyl) amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidine-1- obtained in Step A of Example 228 Il} -3- (4-chlorophenyl) propionamide was reacted in the same manner as in Step B of Preparation Example 228 to obtain the title compound.

MS[M+H] = 619(M+1)MS [M + H] = 619 (M + 1)

단계 B: (2R)-2-(메틸)아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염Step B: (2R) -2- (methyl) amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl) Propionamide 2TFA Salt

단계 A에서 수득한 (2R)-2-[메틸-(2-니트로벤젠설포닐)]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드를 실시예 228의 단계 C에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. (2R) -2- [methyl- (2-nitrobenzenesulfonyl)] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidine-1- obtained in step A Il} -3- (4-chlorophenyl) propionamide was reacted in the same manner as in Step C of Example 228 to obtain the title compound.

MS[M+H] = 434(M+1)MS [M + H] = 434 (M + 1)

실시예 235-269Example 235-269

하기 표의 화합물들은 제조예에서 합성된 피페리딘 유도체를 이용하여 실시예 228-234에서와 동일한 방법으로 반응을 수행하여 수득하였다.The compounds in the following table were obtained by carrying out the reaction in the same manner as in Example 228-234 using the piperidine derivative synthesized in the Preparation.

실시예 270: (2R)-2-(디메틸아미노에틸)아미노-N-{[4-사이클로헥실-4-(아미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2HCl 염Example 270 (2R) -2- (dimethylaminoethyl) amino-N-{[4-cyclohexyl-4- (aminoethylcarbamoyl)] piperidin-1-yl} -3- (4-chloro Phenyl) propionamide 2HCl salt

단계 A: (2R)-2-(디메틸아미노에틸)아미노-N-{[4-사이클로헥실-4-(프탈이미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 Step A: (2R) -2- (Dimethylaminoethyl) amino-N-{[4-cyclohexyl-4- (phthaliminoethylcarbamoyl)] piperidin-1-yl} -3- (4- Chlorophenyl) propionamide

실시예 188의 단계 B에서 수득한 (2R)-2-(아미노)-N-{[4-사이클로헥실-4-(프탈이미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드를 이용하여 실시예 228과 같이 반응시키고 칼럼 크로마토그래피(용리액: EtOAc/Hex=4/1)를 이용하여 정제 하여 표제 화합물을 수득하였다.(2R) -2- (amino) -N-{[4-cyclohexyl-4- (phthaliminoethylcarbamoyl)] piperidin-1-yl} -3-obtained in step B of Example 188. The reaction was carried out as in Example 228 using (4-chlorophenyl) propionamide and purification using column chromatography (eluent: EtOAc / Hex = 4/1) to obtain the title compound.

MS[M+H] = 636(M+1)MS [M + H] = 636 (M + 1)

단계 B: (2R)-2-(디메틸아미노에틸)아미노-N-{[4-사이클로헥실-4-(아미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드 2TFA 염Step B: (2R) -2- (Dimethylaminoethyl) amino-N-{[4-cyclohexyl-4- (aminoethylcarbamoyl)] piperidin-1-yl} -3- (4-chlorophenyl Propionamide 2TFA Salt

단계 A에서 수득한 (2R)-2-(디메틸아미노에틸)아미노-N-{[4-사이클로헥실-4-(프탈이미노에틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드를 이용하여 실시예 188의 D 및 E와 같이 반응하여 표제 화합물을 수득하였다. (2R) -2- (dimethylaminoethyl) amino-N-{[4-cyclohexyl-4- (phthaliminoethylcarbamoyl)] piperidin-1-yl} -3- (obtained in step A) Reaction with Example 188 D and E using 4-chlorophenyl) propionamide to afford the title compound.

MS[M+H] = 506(M+1)MS [M + H] = 506 (M + 1)

실시예 : 271 - 280Example: 271-280

하기 표에 서술된 실시예 화합물들은, 전술한 제조예에서 합성된 피페리딘 유도체로부터 실시예 187 및 270에서와 동일한 방법으로 반응을 수행하여 수득하였다.The example compounds described in the following table were obtained by carrying out the reaction in the same manner as in Examples 187 and 270 from the piperidine derivatives synthesized in the above-described preparation.

실시예 281: (2R)-2-(카복시메틸)아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드Example 281: (2R) -2- (carboxymethyl) amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} -3- (4-chloro Phenyl) propionamide

실시예 259에서 수득한 (2R)-2-[(메톡시카보닐)메틸]아미노-N-{[4-사이클로헥실-4-(t-부틸카바모일)]피페리딘-1-일}-3-(4-클로로페닐)프로피온아미드를 제조예 49의 단계 B에서와 동일한 방법으로 반응시켜 표제화합물을 수득하였다. (2R) -2-[(methoxycarbonyl) methyl] amino-N-{[4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl} obtained in Example 259 The title compound was obtained by reacting -3- (4-chlorophenyl) propionamide in the same manner as in Step B of Preparation Example 49.

MS[M+H]= 506(M+1)MS [M + H] = 506 (M + 1)

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

A. 루시퍼라제(Luciferase) 발현도 측정A. Measurement of Luciferase Expression

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

먼저 각 서브타입(subtype)의 MCR 유전자와 CRE(cAMP Response Element) 조절하의 루시퍼라제 유전자(CRE-LUC)를 동시에 발현시키는 영구 발현 HEK(Human Embryonic Kidney) 세포주(HEK MC1R-Luc, MC3R-Luc, MC4R-Luc, 또는 MC5R-Luc)들을 구축하였다. 상기 세포주들을 6% CO2가 존재하는 37℃ 항온배양기에서 선택 배지(10% 열-불활성화된 소 태자 혈청(Gibco/BRL), 100unit/㎖ 페니실린(Gibco/BRL), 100unit/㎖ 스트렙토마이신(Gibco/BRL) 및 200㎍/㎖ 제네티신(G418)(Gibco/BRL)을 함유한 DMEM(Dulbecco's Modified Eagles Medium)을 사용하여 배양하였다. 직경 100mm 배양접시에 세포가 전체면적의 70% 정도가 되었을 때 10㎖의 Ca++와 Mg++이 함유되지 않은 인산완충액(Phosphate Buffered Saline; PBS)으로 1회 세척한 다음, 0.05% 트립신과 0.53mM EDTA를 함유한 PBS용액 3㎖를 가하였다. 상기 트립신/EDTA 용액을 제거하고 37℃ 항온 배양기에서 1분간 배양한 뒤 10㎖의 선택배지에 다시 현탁시키고 1500rpm에서 5분간 원심분리하였다. 상층액을 제거한 뒤 침전된 세포들을 5㎖의 페놀레드(Phenol Red)가 함유되지 않은 선택배지로 다시 현탁시켰다. 상기 세포현탁액을 96-웰 발광측정기(Luminometer)용 세포 배양 판(Costar)의 각 웰에 100㎕의 배양액에 5X104 세포가 되도록 첨가한 뒤 6% CO2가 존재하는 37℃ 항온 배양기에서 18시간 동안 배양하였다. 상기 배양액을 사용하여 각 단계별 농도로 희석시킨 MCR 항진제(실시예 화합물)를 최종 DMSO 농도가 1%를 넘지 않게 처리한 다음 6% CO2가 존재하는 37℃ 항온 배양기에서 5시간 동안 배양하였다. 각 웰에 50㎕의 Bright-Glo 루시퍼라제 시약(Promega)을 처리한 다음 15분간 상온에 방치한 뒤 발광측정기(Luminometer, Victor)를 사용하여 각 웰의 발광 정도(Luminescence)를 측정하였다. 각 단계별 농도로 희석된 항진제에 의해 유도되는 Luminescence양은 10 μM의 NDP-MSH 처리에 의해 나타나는 양에 대한 상대적인 % 값으로 환산하였다. EC50는 각 항진제에 의해 유도될 수 있는 최대 Luminescence양의 50%를 유도시키는 농도로 표시하였고 이 측정치는 통계 소프트웨어 (Prizm)를 사용하여 측정하였다.First, a permanently expressed human Embryonic Kidney (HEK) cell line (HEK MC1R-Luc, MC3R-Luc, which expresses the MCR gene of each subtype and the luciferase gene (CRE-LUC) under the control of the CAMP (cAMP Response Element) at the same time. MC4R-Luc, or MC5R-Luc) were constructed. The cell lines were treated with a selection medium (10% heat-inactivated fetal bovine serum (Gibco / BRL), 100 units / ml penicillin (Gibco / BRL), 100 units / ml streptomycin (C) in a 37 ° C. incubator with 6% CO 2. Cultured using Dulbecco's Modified Eagles Medium (DMEM) containing Gibco / BRL) and 200 μg / ml Geneticin (G418) (Gibco / BRL), 70% of the total area When rinsed once with 10 ml of Ca ++ and Mg ++ (Phosphate Buffered Saline; PBS), 3 ml of PBS solution containing 0.05% trypsin and 0.53 mM EDTA was added. The trypsin / EDTA solution was removed, incubated for 1 minute in a 37 ° C. incubator, then resuspended in 10 ml of selective medium and centrifuged for 5 minutes at 1500 rpm After removing the supernatant, the precipitated cells were removed in 5 ml of phenol red ( Phenol Red) was resuspended in a selective medium containing no cell suspension. 96-well luminescence meter (Luminometer) cell culture plate (Costar) 37 ℃ that the back 6% CO 2 added to the medium so as to have 5X10 4 cells present in the culture medium of 100㎕ to each well and incubated for 18 hours in a constant-temperature incubator. Using the culture solution, the MCR adjuvants (Example compound) diluted to each step concentration were treated so that the final DMSO concentration did not exceed 1%, and then incubated for 5 hours in a 37 ° C incubator in which 6% CO 2 was present. The wells were treated with 50 μl of Bright-Glo Luciferase Reagent (Promega), and then allowed to stand at room temperature for 15 minutes, followed by measuring the luminescence of each well using a luminometer (Luminometer, Victor). The amount of luminescence induced by the antidiarrheal agent diluted with was converted into a% value relative to the amount indicated by NDP-MSH treatment of 10 μM. EC50 was expressed as a concentration that induces 50% of the maximum amount of luminescence that can be induced by each antidiarrheal agent and this measurement was determined using statistical software (Prizm).

B. cAMP 측정B. cAMP measurement

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

먼저 상기 각 서브타입의 MCR 유전자를 발현시키는 영구 발현 HEK(Human Embryonic Kidney) 세포주(HEK MC1R, MC3R, MC4R, 또는 MC5R)들을 24-웰 세포 배양 판(Costar)의 각 웰당 1㎖의 배양액에 2X105 세포가 되도록 첨가한 뒤 6% CO2가 존재하는 37℃ 항온 배양기에서 24시간 동안 배양하였다. 각 웰의 배지를 제거하고 0.5㎖의 차가운 DMEM으로 1회 세척해 주었다. 500μM IBMX(이소부틸메틸잔틴)를 함유한 DMEM 200㎕를 사용하여 단계별 농도로 희석시킨 MCR 항진제(실시예 화합물)를 최종 DMSO 농도가 1%를 넘지 않게 처리한 다음 6% CO2가 존재하는 37℃ 항온 배양기에서 30분 동안 배양하였다. 각 세포 내 cAMP의 함량은 아머샴(Amersham) cAMP 측정 키트(TRK432)를 사용하여 측정하였다.First, a permanently expressed HEK (Human Embryonic Kidney) cell line (HEK MC1R, MC3R, MC4R, or MC5R) expressing the MCR gene of each subtype was 2X10 in 1 ml of culture medium per well of a 24-well cell culture plate (Costar). 5 cells were added and then incubated for 24 hours in a 37 ° C. incubator with 6% CO 2 . The medium of each well was removed and washed once with 0.5 ml of cold DMEM. MCR adjuvants (Example compound) 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 an incubator. The content of cAMP in each cell was measured using an Amersham cAMP measurement kit (TRK432).

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

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

C. 수용체 결합 시험C. Receptor Binding Test

상기 각 서브타입의 MCR 유전자를 발현시키는 영구 발현 HEK(Human Embryonic Kidney) 세포주(HEK MC1R, MC3R, MC4R, 또는 MC5R)들을 96-웰 세포 배양 판(Costar)의 각 웰당 100㎕의 배양액에 1X105 세포가 되도록 첨가한 뒤 6% CO2가 존재하는 37℃ 항온 배양기에서 48시간 동안 배양하였다. 각 웰의 배지를 제거하고 150㎕의 차가운 흡착 완충액(binding buffer; 50mM HEPES와 1% BSA를 함유한 DMEM)으로 1회 세척해 주었다. 0.1nM의 125I-NDP-MSH(NEN NEX352)와 단계별 농도로 희석시킨 MCR 항진제(실시예 화합물)를 함유한 100㎕의 흡착 완충액을 가한 후 실온에서 2시간동안 방치하였다. 배지 제거 후 200㎕의 차가운 흡착 완충액으로 1회 세척해 준 다음 150㎕의 0.2N NaOH를 가하고 실온에서 15분 동안 방치하였다. 각 웰에 담긴 용액을 5㎖ 시험관으로 옮긴 뒤 감마선 측정기(Wallac)로 방사능을 측정하였다.Permanent expressing HEK (Human Embryonic Kidney) cell lines (HEK MC1R, MC3R, MC4R, or MC5R) expressing the MCR gene of each subtype were added to 1 × 10 5 in 100 μl of culture medium per well of a 96-well cell culture plate (Costar). Cells were added and cultured for 48 hours in a 37 ° C. incubator with 6% CO 2 . The medium of each well was removed and washed once with 150 μl cold binding buffer (DMEM containing 50 mM HEPES and 1% BSA). 100 μl of adsorption buffer containing 125 n -NDP-MSH (NEN NEX352) of 0.1 nM and MCR antidiarrheal agent (Example compound) diluted to stepwise concentration was added and then left for 2 hours at room temperature. After removing the medium, the cells were washed once with 200 μl of cold adsorption buffer, and then 150 μl of 0.2N NaOH was added thereto and left at room temperature for 15 minutes. The solution contained in each well was transferred to a 5 ml test tube and radioactivity was measured by a gamma ray detector (Wallac).

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

이상 설명한 방법에 따라 측정한 결과, 본 발명의 실시예 화합물은 각 MCR 에 대한 항진효능 및 결합 효과를 나타내는 것으로 확인되었다. 이들은 특히 MC4R에 대해 우수한 항진 효능과 결합 효과를 보였으며 0.005 μM 내지 10 μM 의 EC50값과 0.01 μM 내지 50 μM 의 IC50 값을 나타내었다. 구체적으로 예를 들면, 실시예 화합물 1, 2 및 3은 MC4R에 대해 0.05 μM 내지 0.5 μM의 우수한 EC50 값과 0.1 μM 내지 0.5 μM의 우수한 IC50 값을 나타내었다. As a result of the measurement according to the method described above, it was confirmed that the example compound of the present invention exhibits anti-tumor effect and binding effect on each MCR. In particular, they showed good anti-inflammatory and binding effects on MC4R, and showed an EC50 value of 0.005 μM to 10 μM and an IC50 value of 0.01 μM to 50 μM. Specifically, for example, Example Compounds 1, 2 and 3 showed good EC50 values of 0.05 μM to 0.5 μM and good IC50 values of 0.1 μM to 0.5 μM for MC4R.

또한, 본 발명의 화합물은 하기 설명하는 D, E, F, G, H, 및 I의 방법에 따라 동물에서의 효능을 평가할 수 있다. In addition, the compounds of the present invention can assess efficacy in animals according to the methods of D, E, F, G, H, and I described below.

D. 절식동물모델에서의 사료섭취억제효과시험D. Feed Inhibition Effect Test in Fasting Animal Model

멜라노코틴 수용체 효능제의 식욕억제 효과는 절식마우스 모델에서 사료섭취억제효과를 측정하여 평가하였다. 시험동물은 수컷 ddY 마우스를 이용하며 케이지당 한마리씩 수용하였다. 시험전날, 기초 일일사료섭취량을 토대로 군당 7-10 마리씩 군분리하고 사료를 제거하여 절식시켰다. 절식은 시험물질투여 전 20시간이며, 이 기간동안 물은 자유섭취시켰다. 시험당일 아침 각 동물에 매체 또는 시험물질용액을 존데를 이용하여 위내투여하고, 1시간 경과 후 사료를 공급하였다. 사료공급후 1시간동안 섭취한 사료량을 측정하였다. 매체 투여군에서의 사료섭취량과 비교하여 사료섭취량에 미치는 시험물질의 영향을 평가하였다. The appetite suppression effect of the melanocortin receptor agonist was evaluated by measuring the feed intake inhibitory effect in the fasting mouse model. Test animals were housed one male per cage using male ddY mice. The day before the test, based on the basal daily feed intake was grouped 7-10 animals per group, and the diet was removed and fasted. Fasting was 20 hours prior to administration of the test material, during which time water was freely ingested. On the morning of the test, each animal was given a gastric or test substance solution intragastrically using sonde, and fed after 1 hour. The amount of feed consumed for 1 hour after feeding was measured. The effect of the test substance on the feed intake was evaluated in comparison with the feed intake in the media administration group.

E. 야간사료섭취 억제효과시험E. Night Feed Inhibition Effect Test

야행성인 설치류에서의 야간사료섭취억제효과는 수컷 ICR 마우스에서 시험하였다. 동물은 케이지당 한마리씩 사육하며 기초 일일사료섭취량을 토대로 군당 7-10마리씩 군분리하였다. 시험당일 야간기(夜間期) 시작 1시간 전 사료를 제거하고, 매체 또는 시험물질 용액을 존데를 사용하여 위내투여하였다. 소등 직후 사료를 공급하고 2시간째의 사료섭취량을 측정하였다. The effect of night feed intake in nocturnal rodents was tested in male ICR mice. Animals were bred one per cage and grouped 7-10 per group based on basal daily intake. The feed was removed 1 hour before the start of the night phase on the day of the test and the medium or test solution was intragastrically administered using sonde. Immediately after turning off the feed, the feed intake was measured at 2 hours.

F. ob/ob 비만 마우스에서의 체중감소효과시험F. weight loss test in ob / ob obese mice

비만동물모델에서의 시험물질의 사료섭취억제 및 체중감소 효과는 8주령 수컷 ob/ob 마우스를 이용하여 평가하였다. 동물은 케이지당 한마리씩 사육하며 기초 일일사료섭취량을 토대로 군분리하였다. 매체 또는 시험물질 용액은 존데를 통하여 각 동물에 위내투여하며, 처치는 일일 일회 14일간 실시하였다. 사료섭취량과 체중은 매일 측정하며, 피하지방과 복강내 지방의 무게는 마지막 투약 후 부검하여 측정하였다. 혈중 당, 인슐린, 중성지질과 콜레스테롤, 간내 중성지질 함유량 등은 부검 직전 취한 혈액에서 정량하였다. UCP3 mRNA와 UCP1 mRNA의 발현율은 부검시 적출한 장딴지근과 Brown fat pad에서 각각 측정하였다. Feeding inhibitory and weight loss effects of test substances in obese animal models were evaluated using 8-week-old male ob / ob mice. Animals were bred one per cage and grouped based on basal daily intake. The medium or test solution was intragastrically administered to each animal via sonde and treatment was performed once daily for 14 days. Feed intake and body weight were measured daily, and subcutaneous fat and intraperitoneal fat were measured by autopsy after the last dose. Blood sugar, insulin, triglyceride and cholesterol, and triglyceride content in liver were quantified in blood taken just before autopsy. The expression rates of UCP3 mRNA and UCP1 mRNA were measured in the gastrocnemius muscle and Brown fat pad, respectively.

G. 고지질사료야기 비만마우스에서의 체중감소효과시험G. Weight loss test in obese mice

사람에서의 비만과 가장 유사한 특징을 보이는 고지질사료야기 비만마우스를 이용하여 시험물질의 사료섭취억제 및 체중감소 효과를 평가하였다. 실험동물은 4주령 C57BL/6 마우스에 60%kcal fat 사료를 8주 이상 공급하여 비만을 야기시켰다. 고지질사료야기 비만마우스는 케이지당 한마리씩 수용하며 기초 일일사료섭취량을 토대로 군분리하였다. 매체 또는 시험물질 용액은 존데를 통하여 각 동물에 위내투여하며, 처치는 일일 일회 14일간 실시하였다. 사료섭취량과 체중은 매일 측정하였다. 혈중 당, 인슐린, 랩틴, 중성지질과 콜레스테롤, 간내 중성지질 함유량 등은 부검 직전 취한 혈액에서 정량하였다. UCP3 mRNA와 UCP1 mRNA의 발현율은 부검시 적출한 장딴지근과 Brown fat pad에서 각각 측정하였다. High-fat dietary obese mice, which showed the most similar characteristics to obesity in humans, were used to evaluate the effects of feed intake inhibition and weight loss. Experimental animals were fed obese by feeding 60% kcal fat feed for more than 8 weeks to 4 weeks old C57BL / 6 mice. High-fat dietary obese mice were housed one per cage and grouped based on basal daily intake. The medium or test solution was intragastrically administered to each animal via sonde and treatment was performed once daily for 14 days. Feed intake and body weight were measured daily. Blood glucose, insulin, laptin, triglyceride and cholesterol, and triglyceride content in liver were quantified in blood taken just before autopsy. The expression rates of UCP3 mRNA and UCP1 mRNA were measured in the gastrocnemius muscle and Brown fat pad, respectively.

H. 급성염증모델에서의 항염증효과시험H. Anti-inflammatory effect test in acute inflammation model

항염증 효과는 결정야기 다형핵 중성구모집에 미치는 영향을 시험하여 평가하였다. 동물은 수컷 Balb/c 마우스를 이용하였다. 급성염증반응의 하나인 다형핵 중성구의 모집은 PBS 완충액(0.5 ㎖)에 현탁시킨 mono-sodium urea 결정(3 mg) 을 복강투여하여 야기시켰다. 매체 또는 시험물질 용액은 결정의 복강투여 1시간 전 존데를 통하여 위내투여하였다. 결정투여 6시간 후 시험동물을 CO2 가스에 노출/안락사시켰다. 복강에 3 ㎖의 PBS 완충액을 투여하여 복강내부를 충분히 세척한 후 회수하였다. 소량의 복강세척액을 Turk's solution (0.01% crystal violet in 3% acetic acid)으로 염색하고, 광학현미경과 혈구측정기를 이용하여 세포수를 종류별로 세었다. 이 때 다형핵 중성구의 수를 마우스당 (1~10)x106 까지 세었다. 매체군과 비교시 시험물질 투여군에서의 마우스당 다형핵 중성구의 수를 비교하여 항염증효과를 평가하였다.The anti-inflammatory effect was evaluated by testing the effect on the crystallographic polymorphonuclear neutrophil recruitment. The animals used male Balb / c mice. Recruitment of polymorphonuclear neutrophils, one of the acute inflammatory reactions, was caused by intraperitoneal administration of mono-sodium urea crystals (3 mg) suspended in PBS buffer (0.5 ml). The medium or test substance solution was intragastrically administered via Sonde 1 hour prior to intraperitoneal administration of the crystals. Six hours after crystal dosing, the test animals were exposed / relaxed to CO 2 gas. 3 ml of PBS buffer was administered to the abdominal cavity, and then the inner abdominal cavity was sufficiently washed and recovered. A small amount of peritoneal washing solution was stained with Turk's solution (0.01% crystal violet in 3% acetic acid), and the number of cells was counted by light microscopy and hemocytometer. The number of polymorphonuclear neutrophils was counted to (1-10) x10 6 per mouse. The anti-inflammatory effect was evaluated by comparing the number of polymorphonuclear neutrophils per mouse in the test substance administration group compared with the medium group.

I. 발기야기효과(Erectile effects)I. Erectile effects

시험물질의 발기야기효과는 수컷 SD 랫드에서의 발기 횟수를 측정하여 평가하였다. 각 동물은 관찰 상자 위에 놓인 2 리터 비이커에 한마리씩 넣어 관찰하며 시험시작 30분전부터 적응시켰다. 비이커에 적응한지 30분 후 매체 또는 시험물질 용액을 투여하였다. 투여 30분 후부터 1시간동안 하품, 기지개, 몸치장, 발기의 횟수를 측정하였다. 발기여부는 시험동물의 자세 (hip constriction, hip thrust, tiptoe posture)로 판단하였다. The erectile effect of the test substance was evaluated by measuring the number of erections in male SD rats. Each animal was placed in a 2-liter beaker placed on the observation box and observed for 30 minutes prior to the start of the test. The media or test solution was administered 30 minutes after adaptation to the beaker. The frequency of yawning, stretching, grooming and erection was measured for 1 hour from 30 minutes after administration. Erection was determined by the posture of the test animals (hip constriction, hip thrust, tiptoe posture).

이상 설명한 방법에 따라 측정한 결과, 본 발명의 실시예 화합물들은 MCR 에 대한 사료섭취와 체중감소는 물론 염증효과와 발기야기 효과를 나타내는 것으로 확인 되었다. 구체적으로 예를 들면, 절식야기 사료섭취억제효능 시험에서 실시예 화합물 1, 2 및 3을 10 내지 30 mg/kg 용량으로 경구 투여시 매체 대조군의 절식후 사료공급 1시간 사료섭취에 비하여 용량 상관적으로 20 내지 50%의 섭취 억제율을 보였으며, 야간사료섭취 억제효과시험에서는 동물의 정상적인 사료섭취를 억제하는 실시예 화합물들은 화합물의 체내흡수 및 약물지속시간에 따라, 야간주기 이후 수시간 동안 매체 대조군의 사료섭취에 비하여 용량 상관적으로 20 내지 40%의 억제율을 보였다. ob/ob 비만 마우스에서의 체중감소효과시험에서는, MC4R에 작용하여 사료섭취억제효과를 보이는 실시예 화합물들을 ob/ob 마우스에서 2-3주 경구 반복투여하여 체중감소 효과가 있는 경우, 용량 상관적 체중감소, 혈당감소, 간내 중성지질함유량의 감소, 복강내 지방 및 피하지방감소 등을 야기시켰다. 또한, 고지질사료야기 비만마우스에서의 체중감소 효과시험의 경우, MC4R에 작용하여 사료섭취 억제효과를 보이는 실시예 화합물들을 고지질사료야기 비만마우스에서 2 내지 3주 경구 반복투여하여 체중감소 효과가 있는 경우, 용량 상관적 체중감소, 혈당감소, 간내 중성지질 함유량의 감소, 복강내 지방 및 피하지방감소 등을 야기시켰다.As a result of measuring according to the method described above, it was confirmed that the example compounds of the present invention exhibited inflammatory and erectile effects as well as feed intake and weight loss for MCR. Specifically, for example, when orally administering Example Compounds 1, 2, and 3 at a dose of 10 to 30 mg / kg in a fasting feed inhibitory efficacy test, the dose control was correlated with a 1 hour feed intake after fasting of the medium control group. Ingestion inhibition rate of 20 to 50%, and in the night feed intake inhibitory effect test, the example compounds that inhibit the normal feed intake of animals according to the body absorption and drug duration of the compound, depending on the media control for several hours after the night cycle Dose correlation was 20-40% inhibition compared to feed intake. In the weight loss test in ob / ob obese mice, dose-related body weights were obtained when Example compounds that acted on MC4R and exhibited feed inhibition effect were administered orally repeated 2-3 weeks in ob / ob mice. Decreased blood glucose, decreased hepatic triglyceride content, decreased intraperitoneal fat and subcutaneous fat. In the case of weight loss test in obese mice, Example compound showing the effect of inhibiting feed intake was administered orally repeated two or three weeks in high-fat diet obese mice weight loss effect, dose-related weight loss, blood sugar reduction, hepatic triglyceride content, abdominal cavity It caused a decrease in fat and subcutaneous fat.

급성염증모델에서의 항염증효과시험에서는 급성염증모델에서 유효한 항염증효과를 보이는 경우 매체 대조군에 비하여 다형핵 중성구의 수를 용량 상관적으로 15~60% 감소시켰으며, 발기야기효과를 보이는 시험물질의 경우 1시간의 관찰기간동안 매체 대조군에 비하여 3~12배의 발기 횟수를 보였다.In the anti-inflammatory effect test in the acute inflammation model In the acute inflammation model, the effective anti-inflammatory effect was reduced by 15-60% of the number of polymorphonuclear neutrophils compared to the media control.In the case of test substance showing erectile effect, Compared with 3 ~ 12 times of erection.

Claims (15)

하기 화학식 1의 화합물, 약제학적으로 허용되는 그의 염, 수화물, 용매화물 및 이성체: Compounds of Formula 1, pharmaceutically acceptable salts, hydrates, solvates and isomers thereof: [화학식 1] [Formula 1] 상기 식에서,Where R1은 수소,R 1 is hydrogen, -(CH2)p-R6,-(CH 2 ) p -R 6 , -(CH2)p-CO-R6,-(CH 2 ) p -CO-R 6 , -(CH2)p-SO2-R6,-(CH 2 ) p -SO 2 -R 6 , -CO-(CH2)p-R6을 나타내며,-CO- (CH 2 ) p -R 6 , 여기서 here p는 독립적으로 0, 1, 2 또는 3을 나타내고, p independently represents 0, 1, 2 or 3, R6은 각각 C1-C6-알킬, 할로겐, 아미노, C1-C6-알킬아미노, 디(C1-C6-알킬)아미노, 하이드록시, C1-C8-알콕시, 트리플루오로메톡시, C1-C6-알킬카보닐, 아릴카보닐, C1-C6-알콕시카보닐, 카바모일, C1-C6-알킬설포닐, 아릴설포닐, 카복시, 시아노 및 옥소로 구성된 그룹으로부터 선택된 치환체에 의해 일치환 또는 다치환되거나 비치환된 C1-C10-알킬, C3-C8-사이클로알킬, 헤테로사이클, 아릴, 헤테로아릴, 아미노, 또는 하이드록시를 나타내며,R 6 is C 1 -C 6 -alkyl, halogen, amino, C 1 -C 6 -alkylamino, di (C 1 -C 6 -alkyl) amino, hydroxy, C 1 -C 8 -alkoxy, trifluoro Methoxy, C 1 -C 6 -alkylcarbonyl, arylcarbonyl, C 1 -C 6 -alkoxycarbonyl, carbamoyl, C 1 -C 6 -alkylsulfonyl, arylsulfonyl, carboxy, cyano and oxo Mono- or poly-substituted or unsubstituted C 1 -C 10 -alkyl, C 3 -C 8 -cycloalkyl, heterocycle, aryl, heteroaryl, amino, or hydroxy by a substituent selected from the group consisting of: -(CH2)p- 그룹에서 수소원자는 R6에 의해 대체될 수 있고,The hydrogen atom in the-(CH 2 ) p -group can be replaced by R 6 , R2는 수소,R 2 is hydrogen, C1-C8-알킬, 또는C 1 -C 8 -alkyl, or C3-C7-사이클로알킬을 나타내거나,C 3 -C 7 -cycloalkyl, or R2와 R1 그룹은 이들이 붙어 있는 원자와 더불어 4 내지 8의 단일환 또는 이환을 형성할 수 있으며, 여기에 O, S, N-C1-C4-알킬로 이루어진 그룹 중에서 선택된 헤테로 원자가 추가로 삽입될 수 있고,The R 2 and R 1 groups together with the atoms to which they are attached may form a 4 to 8 monocyclic or bicyclic ring, to which an additional hetero atom selected from the group consisting of O, S and NC 1 -C 4 -alkyl is further inserted Can be, R3는 각각 C1-C6-알킬, 할로겐, 아미노, C1-C6-알킬아미노, 디(C1-C6-알킬)아미노, 하이드록시, C1-C8-알콕시, C1-C6-알킬카보닐, 아릴카보닐, C1-C6-알콕시카보닐, 카바모일, C1-C6-알킬설포닐, 아릴설포닐, 카복시, 시아노 및 옥소로 구성된 그룹으로부터 선택된 치환체에 의해 일치환 내지 삼치환되거나 비치환된R 3 is C 1 -C 6 -alkyl, halogen, amino, C 1 -C 6 -alkylamino, di (C 1 -C 6 -alkyl) amino, hydroxy, C 1 -C 8 -alkoxy, C 1 -C 6 -alkylcarbonyl, arylcarbonyl, C 1 -C 6 -alkoxycarbonyl, carbamoyl, C 1 -C 6 -alkylsulfonyl, arylsulfonyl, carboxy, cyano and oxo Mono- to tri-substituted or unsubstituted by a substituent -C1-C8-알킬,-C 1 -C 8 -alkyl, -(CH2)q-C3-C7-사이클로알킬,-(CH 2 ) q -C 3 -C 7 -cycloalkyl, -(CH2)q-페닐 또는-(CH 2 ) q -phenyl or -(CH2)q-헤테로아릴을 나타내며,-(CH 2 ) q -heteroaryl, 여기서 here q는 독립적으로 0, 1, 2 또는 3을 나타내고, q independently represents 0, 1, 2 or 3, R4는 페닐, 사이클로헥실, 또는 -NR7R8을 나타내고,R 4 represents phenyl, cyclohexyl, or —NR 7 R 8 , 여기에서 R7 및 R8은 각각 독립적으로 C1-C6-알킬, -(CH2 )q-C3-C7-사이클로알킬, -(CH2)q-페닐, 또는 -(CH2)q-헤테로아릴을 나타내거나(여기서 q는 상기 정의된 바와 같다), 이들이 부착되어 있는 질소원자와 함께 O, S, 또는 N-(C1-C4-알킬)을 포함할 수 있는 4- 내지 8-원의 단일환 또는 이환을 형성할 수 있으며, 이들은 C1-C6-알킬, 할로겐, 아미노, C1-C6-알킬아미노, 디(C1-C6 -알킬)아미노, 하이드록시, C1-C8-알콕시, 트리플루오로메톡시, C1-C6-알킬카보닐, 아릴카보닐, C1 -C6-알콕시카보닐, 카바모일, C1-C6-알킬설포닐, 아릴설포닐, 카복시, 시아노 및 옥소로 구성된 그룹으로부터 선택된 치환체에 의해 일치환 또는 다치환되거나 비치환되고,Wherein R 7 and R 8 are each independently C 1 -C 6 -alkyl,-(CH 2 ) q -C 3 -C 7 -cycloalkyl,-(CH 2 ) q -phenyl, or-(CH 2 ) q - 4 to which may include - (alkyl C 1 -C 4), or indicate a heteroaryl O, S, N- or together with the nitrogen atom (wherein q is as defined above) which they are attached It may form an 8-membered monocyclic or bicyclic, which is C 1 -C 6 -alkyl, halogen, amino, C 1 -C 6 -alkylamino, di (C 1 -C 6 -alkyl) amino, hydroxy , C 1 -C 8 -alkoxy, trifluoromethoxy, C 1 -C 6 -alkylcarbonyl, arylcarbonyl, C 1 -C 6 -alkoxycarbonyl, carbamoyl, C 1 -C 6 -alkylsulfonyl Mono- or poly-substituted or unsubstituted by a substituent selected from the group consisting of arylsulfonyl, carboxy, cyano and oxo, R5는 -(CH2)o-R9,R 5 is-(CH 2 ) o -R 9 , -(CH2)o-COR9, 또는-(CH 2 ) o -COR 9 , or -(CH2)o-C(O)N(R9)(R10) 을 나타내며,-(CH 2 ) o -C (O) N (R 9 ) (R 10 ), 여기서 here o는 독립적으로 0, 1, 2, 또는 3을 나타내고, o independently represents 0, 1, 2, or 3, R9 및 R10은 각각 독립적으로 수소, 아미노, 하이드록시, C1-C6-알킬, C1-C6-알콕시, C3-C7-사이클로알킬, 페닐, 헤테로사이클, 또는 헤테로아릴을 나타내고, 수소를 제외한 이들은 각각 C1-C6-알킬, 할로겐, 아미노, C1-C6-알킬아미노, 디(C1-C6-알킬)아미노, 하이드록시, C1-C8-알콕시, 트리플루오로메톡시, C1-C6 -알킬카보닐, 아릴카보닐, C1-C6-알콕시카보닐, 카바모일, C1-C6-알킬설포닐, 아릴설포닐, C3-C6-사이클로알킬, C2-C8-알카노일, C1-C6-알킬설파모일, 카복시, 시아노 및 옥소로 구성된 그룹 중에서 선택된 1개 내지 3개의 치환체에 의해 치환되거나 비치환되고,R 9 and R 10 each independently represent hydrogen, amino, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 7 -cycloalkyl, phenyl, heterocycle, or heteroaryl Except hydrogen, these are C 1 -C 6 -alkyl, halogen, amino, C 1 -C 6 -alkylamino, di (C 1 -C 6 -alkyl) amino, hydroxy, C 1 -C 8 -alkoxy , Trifluoromethoxy, C 1 -C 6 -alkylcarbonyl, arylcarbonyl, C 1 -C 6 -alkoxycarbonyl, carbamoyl, C 1 -C 6 -alkylsulfonyl, arylsulfonyl, C 3- C 6 -cycloalkyl, Unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of C 2 -C 8 -alkanoyl, C 1 -C 6 -alkylsulfamoyl, carboxy, cyano and oxo, R9 및 R10은 이들이 부착되어 있는 질소원자와 함께 O, S, 또는 N-(C1-C 4-알킬)을 포함할 수 있는 4- 내지 8-원의 단일환 또는 이환을 형성할 수 있다.R 9 and R 10 may form a 4- to 8-membered monocyclic or bicyclic which may include O, S, or N- (C 1 -C 4 -alkyl) with the nitrogen atom to which they are attached have. 제1항에 있어서, R1이 수소, -(CH2)p-R6, -(CH2) p-CO-R6 또는 -(CH2)p-SO2-R6 을 나타내고, 여기에서 p는 제 1항에 정의된 바와 같은 화학식 1의 화합물, 약제학적으로 허용되는 그의 염, 수화물, 용매화물 및 이성체.The compound of claim 1, wherein R 1 represents hydrogen, — (CH 2 ) p —R 6 , — (CH 2 ) p —CO—R 6 or — (CH 2 ) p —SO 2 —R 6 , wherein p is a compound of formula 1 as defined in claim 1, a pharmaceutically acceptable salt, hydrate, solvate and isomer thereof. 제2항에 있어서, R1이 수소 또는 -(CH2)p-R6 을 나타내고, 여기에서 p는 제 1항에 정의된 바와 같은 화학식 1의 화합물, 약제학적으로 허용되는 그의 염, 수화물, 용매화물 및 이성체.The compound of claim 2, wherein R 1 represents hydrogen or — (CH 2 ) p —R 6 , wherein p is a compound of Formula 1 as defined in claim 1, a pharmaceutically acceptable salt thereof, a hydrate, Solvates and Isomers. 제1항에 있어서, R1이 -CO-(CH2)p-R6 을 나타내고, 여기에서 p는 제 1항에 정의된 바와 같은 화학식 1의 화합물, 약제학적으로 허용되는 그의 염, 수화물, 용매화물 및 이성체.The compound of claim 1, wherein R 1 represents —CO— (CH 2 ) p —R 6 , wherein p is a compound of Formula 1 as defined in claim 1, a pharmaceutically acceptable salt thereof, a hydrate, Solvates and Isomers. 제1항에 있어서, R2가 수소 또는 C1-C6-알킬을 나타내는 화학식 1의 화합물, 약제학적으로 허용되는 그의 염, 수화물, 용매화물 및 이성체.The compound of formula (1) according to claim 1, wherein R 2 represents hydrogen or C 1 -C 6 -alkyl, pharmaceutically acceptable salts, hydrates, solvates and isomers thereof. 제1항에 있어서, R3가 각각 할로겐, 시아노, 카복시, 하이드록시, C1-C4-알킬, C1-C8-알콕시, 아미노, C1-C4-알킬아미노 및 디(C1 -C4-알킬)아미노로 구성된 그룹으로부터 선택된 치환체에 의해 일치환 내지 삼치환되거나 비치환된 -(CH2)q-C3 -C7-사이클로알킬, -(CH2)q-페닐 또는 -(CH2)q-헤테로아릴을 나타내고, 여기에서 q는 제 1항에 정의된 바와 같은 화학식 1의 화합물, 약제학적으로 허용되는 그의 염, 수화물, 용매화물 및 이성체.The compound of claim 1, wherein R 3 is halogen, cyano, carboxy, hydroxy, C 1 -C 4 -alkyl, C 1 -C 8 -alkoxy, amino, C 1 -C 4 -alkylamino and di (C -(CH 2 ) q -C 3 -C 7 -cycloalkyl,-(CH 2 ) q -phenyl, mono- to tri-substituted or unsubstituted by a substituent selected from the group consisting of 1- C 4 -alkyl) amino, or -(CH 2 ) q -heteroaryl, wherein q is a compound of formula 1 as defined in claim 1, a pharmaceutically acceptable salt, hydrate, solvate and isomer thereof. 제6항에 있어서, R3가 각각 할로겐, 시아노, 하이드록시, C1-C4-알콕시, 트리플루오로메톡시 및 C1-C4-알킬로 구성된 그룹으로부터 선택된 치환체에 의해 일치환 내지 삼치환되거나 비치환된 -CH2-사이클로헥실 또는 -CH2-페닐을 나타내는 화학식 1의 화합물, 약제학적으로 허용되는 그의 염, 수화물, 용매화물 및 이성체.7. Monovalent to threefold according to claim 6, wherein R 3 is substituted by a substituent selected from the group consisting of halogen, cyano, hydroxy, C 1 -C 4 -alkoxy, trifluoromethoxy and C 1 -C 4 -alkyl, respectively. Compounds of formula (I), pharmaceutically acceptable salts, hydrates, solvates and isomers thereof, which represent substituted or unsubstituted -CH 2 -cyclohexyl or -CH 2 -phenyl. 제1항에 있어서, R4가 페닐, 사이클로헥실, C1-C4-알킬아미노, 디(C1 -C4-알킬)아미노, 피롤리딘일, 피페리딘일 또는 아제핀일을 나타내며, 여기에서 C1-C4-알킬, 피롤리디닐, 피페리디닐 또는 아제피닐은 할로겐, 하이드록시, C1-C4-알킬, C1 -C4-알콕시, 아미노, C1-C4-알킬아미노 및 디(C1-C4-알킬)아미노로 구성된 그룹으로부터 선택된 치환체에 의해 일치환 내지 삼치환되거나 비치환되는 화학식 1의 화합물, 약제학적으로 허용되는 그의 염, 수화물, 용매화물 및 이성체.The compound of claim 1, wherein R 4 represents phenyl, cyclohexyl, C 1 -C 4 -alkylamino, di (C 1 -C 4 -alkyl) amino, pyrrolidinyl, piperidinyl or azepinyl, wherein C 1 -C 4 -alkyl, pyrrolidinyl, piperidinyl or azefinyl is halogen, hydroxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, amino, C 1 -C 4 -alkyl A compound of formula (I), pharmaceutically acceptable salts, hydrates, solvates and isomers thereof, mono-, tri- or unsubstituted by a substituent selected from the group consisting of amino and di (C 1 -C 4 -alkyl) amino. 제1항에 있어서, R5가 C1-C6-알킬, -(CH2)o-헤테로아릴, -(CH2)o-헤테로사이클, -COR9, -C(O)N(R9)(R10), -(CH2)O-OR11, -(CH2)o-NHR11 또는 -(CH2)O-N(R11)(R 12)를 나타내며, 여기에서 헤테로사이클은 하이드록시, C1-C4-알킬, C1-C4-알콕시, 아미노, C1-C4-알킬아미노, 디(C1-C4-알킬)아미노, 및 옥소로 구성된 그룹으로부터 선택된 치환체에 의해 일치환 내지 삼치환되거나 비치환되고, R9 및 R10은 제1항에 정의된 바와 같고, R11 및 R12는 각각 독립적으로 C1-C6-알킬, C3-C 6-사이클로알킬, C2-C8-알카노일, C1-C6-알킬설포닐, C1-C6-알킬설파모일, 또는 아릴설포닐을 나타내며 o는 제1항에 정의된 바와 같은 화학식 1의 화합물, 약제학적으로 허용되는 그의 염, 수화물, 용매화물 및 이성체.The compound of claim 1, wherein R 5 is C 1 -C 6 -alkyl,-(CH 2 ) o -heteroaryl,-(CH 2 ) o -heterocycle, -COR 9 , -C (O) N (R 9 ) (R 10 ),-(CH 2 ) O -OR 11 ,-(CH 2 ) o -NHR 11 or-(CH 2 ) O -N (R 11 ) (R 12 ), wherein the heterocycle Substituents selected from the group consisting of hydroxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, amino, C 1 -C 4 -alkylamino, di (C 1 -C 4 -alkyl) amino, and oxo Mono- to tri-substituted or unsubstituted by R 9 and R 10 are as defined in claim 1, and R 11 and R 12 are each independently C 1 -C 6 -alkyl, C 3 -C 6- Cycloalkyl, C 2 -C 8 -alkanoyl, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -alkylsulfamoyl, or arylsulfonyl, where o is formula 1 as defined in claim 1 Of compounds, pharmaceutically acceptable salts, hydrates, solvates and isomers thereof. 제9항에 있어서, R5가 -(CH2)0-1-헤테로아릴, -(CH2)0-1 -헤테로사이클, -C(O)N(R9)(R10), -CH2-OR11, -(CH2)0-1-NHR 11 또는 -(CH2)0-1-N(R11)(R12)를 나타내고, 여기에서 R9, R10, R11 및 R12는 제 9항에 정의된 바와 같은 화학식 1의 화합물, 약제학적으로 허용되는 그의 염, 수화물, 용매화물 및 이성체. 10. The compound of claim 9, wherein R 5 is- (CH 2 ) 0-1 -heteroaryl,-(CH 2 ) 0-1 -heterocycle , -C (O) N (R 9 ) (R 10 ), -CH 2 -OR 11 ,-(CH 2 ) 0-1 -NHR 11 or-(CH 2 ) 0-1 -N (R 11 ) (R 12 ), wherein R 9 , R 10 , R 11 and R 12 is a compound of formula 1 as defined in claim 9, a pharmaceutically acceptable salt, hydrate, solvate and isomer thereof. 약제학적으로 허용되는 담체와 함께 유효성분으로서 제1항에 정의된 화학식 1의 화합물, 그의 약제학적으로 허용되는 염, 수화물, 용매화물, 또는 이성체를 함유함을 특징으로 하는 멜라노코틴 수용체의 기능항진제 조성물. Melanocyte inhibitors, characterized in that it contains a compound of formula (1), a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof as an active ingredient together with a pharmaceutically acceptable carrier. Composition. 제10항에 있어서, 비만의 예방 및 치료용 조성물. The composition for preventing and treating obesity according to claim 10. 제10항에 있어서, 당뇨의 예방 및 치료용 조성물. The composition of claim 10 for preventing and treating diabetes. 제10항에 있어서, 염증의 예방 및 치료용 조성물. The composition of claim 10 for preventing and treating inflammation. 제10항에 있어서, 발기부전증의 예방 및 치료용 조성물. The composition for preventing and treating erectile dysfunction according to claim 10.
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