KR20040030114A - Cyclic amine compound - Google Patents

Abstract

본 발명은 일반식(1)The present invention is formula (1)

〔식중, R¹, R²및 R³는 각각 독립하여 수소원자, 알콕시기 등을 나타내고;[Wherein, R ¹ , R ² and R ³ each independently represent a hydrogen atom, an alkoxy group or the like;

W¹및 W²는 같거나 다른 것으로서, N 또는 CH를 나타내고;W ¹ and W ² are the same or different and represent N or CH;

X는 O, NR⁴, CONR⁴또는 NR⁴CO를 나타내고;X represents O, NR ⁴ , CONR ⁴ or NR ⁴ CO;

R⁴는 수소원자, 알킬기, 아릴기, 헤테로아릴기, 아랄킬기, 또는 헤테로아랄킬기 등을 나타내고;R ⁴ represents a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, an aralkyl group, a heteroaralkyl group, or the like;

l, m 및 n은 각각 0 또는 1의 수를 나타낸다]l, m and n each represent a number of 0 or 1]

로 표시되는 환상 아민 화합물, 그의 염 또는 이들의 수화물을 제공한다.Provided are cyclic amine compounds, salts thereof, or hydrates thereof.

본 발명 화합물은 세포 접착 및/또는 세포 침윤을 저해하고, 항천식약, 항알레르기약, 항류머티즘약, 항동맥경화약, 항염증제 및 항쉐그렌 증후군약 등으로서 유용하다.The compounds of the present invention inhibit cell adhesion and / or cell infiltration and are useful as anti-asthmatic drugs, anti-allergic drugs, anti-rheumatic drugs, anti-arteriosclerosis drugs, anti-inflammatory agents, anti-Segren's syndrome drugs and the like.

Description

환상 아민 화합물{CYCLIC AMINE COMPOUND}Cyclic amine compound {CYCLIC AMINE COMPOUND}

각종 염증성 질환에 있어서, 염증 부위로의 백혈구의 침윤이 발견된다. 예를 들면, 천식환자의 기관지로의 호산구의 침윤(Ohkawara Y. et. al., Am. J. Respir. Cell Mol. Biol. 12, 4-12(1995)), 동맥경화증의 혈관으로의 마크로파아지나 T세포의 침윤(Sakai A. et. al., Arterioscler Thromb. Vase. Biol. 17, 310-316(1997)), 아토피성 피부염 환자(Wakita H. et. al., J. Cutan. Pathol. 21, 33-39(1994)) 또는 접촉 피부염 환자의 피부로의 T세포, 호산구의 침윤(Satoh T. et. al., Eur. J. Immunol. 27, 85 -91(1997)) 및 만성 관절 류머티즘환자의 관절활막으로의 각종 백혈구의 침윤(Tak PP. et. al., Clin. Immunol. Immunopathol. 77, 236-242(1995))등이 보고되고 있다.In various inflammatory diseases, infiltration of leukocytes into the site of inflammation is found. For example, infiltration of eosinophils into the bronchus of asthma patients (Ohkawara Y. et. Al., Am. J. Respir. Cell Mol. Biol. 12, 4-12 (1995)), macrophages of atherosclerosis into blood vessels Infiltration of phage or T cells (Sakai A. et. Al., Arterioscler Thromb. Vase. Biol. 17, 310-316 (1997)), patients with atopic dermatitis (Wakita H. et. Al., J. Cutan. Pathol 21, 33-39 (1994)) or T cells into the skin of patients with contact dermatitis, eosinophil infiltration (Satoh T. et. Al., Eur. J. Immunol. 27, 85-91 (1997)) and chronic Invasion of various leukocytes into the synovial synovial membrane of arthritic rheumatism patients (Tak PP. Et. Al., Clin. Immunol. Immunopathol. 77, 236-242 (1995)) has been reported.

장기 특이적 자기면역 질환인 쉐그렌 증후군에 대해서는, 백혈구가 침샘이나 눈물샘으로 침윤하여 샘조직이 파괴되어 샘으로부터의 분비액이 부족하게 되고, 그 결과 눈의 건조나 입의 건조 등의 증상이 일으켜지고 있다(Fox RI et al.: "Sjogren's syndrome: proposed critical for classification" Arthritis Rheum. 29, 557-585(1986)) .For Scheren's syndrome, an organ-specific autoimmune disease, leukocytes infiltrate into salivary or lacrimal glands, destroying gland tissue, resulting in a lack of secretion from the glands, resulting in dry eyes and dry mouth. Fox RI et al .: "Sjogren's syndrome: proposed critical for classification" Arthritis Rheum. 29, 557-585 (1986).

이들 백혈구의 침윤은 염증 국소에서 산생되는 사이토카인, 케모카인, 리피드 및 보체 등에 의해 야기된다(Albelda SM. et al., FASE B J. 8, 504-512(1994)). 활성화한 혈류중의 백혈구는 동일하게 활성화된 혈관내피 세포와 롤링(rolling) 또는 테이터링(tethering)으로 불리는 상호작용을 통하여 혈관내피 세포와 접착(adhesion)한다. 그런 다음, 혈관내피를 통과하여(transmigration), 염증부위로 침윤한다(Springer TA. et al., Annu.Rev.Physiol. 57, 827-872(1995)). 이 과정에서의 백혈구와 혈관내피 세포와의 접착에는 사이토카인 등의 자극에 의해 세포 표면에 발현하는 이뮤노글로블린 수퍼패밀리(ICAM-1, VCAM-1 등), 셀렉틴 패밀리(E- 셀렉틴 등), 인테그린 패밀리(LFA-1, VLA-4 등) 및 CD44 등의 각종 세포 접착분자가 중요한 역할을 하고 있으며(臨床免疫(Clinical Immune), 30, Suppl. 18(1998)), 병태와 세포 접착분자의 발현항진과의 관련성이 지적되고 있다.Infiltration of these leukocytes is caused by cytokines, chemokines, lipids and complements produced locally in inflammatory areas (Albelda SM. Et al., FASE B J. 8, 504-512 (1994)). Leukocytes in activated blood flow adhere to vascular endothelial cells through an interaction called rolling or tethering with the same activated vascular endothelial cells. It is then transmigration and infiltrated into the inflammatory site (Springer TA. Et al., Annu. Rev. Physiol. 57, 827-872 (1995)). In this process, immunoglobulin superfamily (ICAM-1, VCAM-1, etc.), a selectin family (E-selectin, etc.) expressed on the surface of cells by stimulation with cytokines, etc. Cell adhesion molecules such as integrin family (LFA-1, VLA-4, etc.) and CD44 play an important role (Clinical Immune, 30, Suppl. 18 (1998)). Association with hyperexpression has been pointed out.

따라서, 세포 접착 또는 세포 침윤을 저해할 수가 있는 약제는 기관지 천식, 피부염, 비염, 결막염 등의 알레르기 질환, 만성 관절 류머티즘, 신장염, 쉐그렌 증후군, 염증성 장질환, 당뇨병, 동맥경화증 등의 자기면역 질환이나 만성 염증성질환 등의 예방약 및 치료약으로서 유효한 것으로 생각된다. 사실, LFA-1, Mac-1, VLA-4 등의 백혈구 측의 세포 접착분자에 대한 항체 또는 그의 리간드로 되는 혈관내피 세포 측의 ICAM-l, VCAM-1, P-셀렉틴, E-셀렉틴 등에 대한 항체가 각종 동물 병태 모델에서 백혈구의 염증 국소로의 침윤을 억제하는 것이 보고되고 있다. 예를 들면, VCAM-1과 그의 카운터 수용체인 VLA-4에 대한 중화 항체는 당뇨병을 자연 발병하는 NOD 마우스 모델에서 그의 발증을 지연시킬 수 있다(Michie SA. et al., Curr. Top. Microbiol. Immunol. 231, 65-83(1998)). 또한, VLA-4, 또는 ICAM-1과 그의 카운터 수용체 LFA-1에 대한 항체는 기니어 피그 또는 마우스 알레르기성 결막염 모델에 있어서 호산구의 침윤을 억제하고(Ebihara et al., Current Eye Res. 19, 20-25(1999), Whitcup SM. et al., C1in. Immunol. 93, 107-113(1999)), VCAM-1에 대한 단일 클론 항체는 마우스 DSS 유도성 대장염 모델에서 백혈구 침윤을 억제하여 대장염의 발증을 지연시키는 것이 보고되어 있다(Soriano A. et al., Lab. Invest. 80, 1541-1551(2000)). 또한, 항 VLA-4 항체, 항 CD44 항체는 마우스 콜라겐 유도성 관절염 모델에서 그의 발증을 억제시킨다(Zeidler A. et al., Autoimmunity, 21, 245-252(1995)). 또한, 이들 세포 접착분자를 결손시킨 마우스에 있어서도 염증 모델의 시험과 동일하게 백혈구의 염증 조직으로의 침윤의 억제가 관찰된다(Bendjelloul F. et al., C1in. Exp. Immunol. 119, 57-63(2000), Wolyniec WW. et al., Am. J. Respir. Cell Mol. Biol. 18, 777-785(1998), Bullard DC. et al., J. Immunol. 157, 3153-3158(1996)).Therefore, agents that can inhibit cell adhesion or cell infiltration are allergic diseases such as bronchial asthma, dermatitis, rhinitis, conjunctivitis, chronic arthritis, nephritis, Siegren's syndrome, inflammatory bowel disease, diabetes mellitus, arteriosclerosis, etc. And prophylactic and therapeutic drugs such as chronic inflammatory diseases. In fact, ICAM-1, VCAM-1, P-selectin, E-selectin, etc., on the vascular endothelial cell side, which are antibodies or a ligand thereof against the cell adhesion molecules on the leukocyte side such as LFA-1, Mac-1, VLA-4, etc. It has been reported that Korean antibodies inhibit infiltration of leukocytes into inflammatory sites in various animal condition models. For example, neutralizing antibodies to VCAM-1 and its counter receptor, VLA-4, may delay its onset in NOD mouse models that naturally develop diabetes (Michie SA. Et al., Curr. Top. Microbiol. Immunol. 231, 65-83 (1998). In addition, antibodies to VLA-4, or ICAM-1 and its counter receptor LFA-1, inhibit eosinophil infiltration in guinea pig or mouse allergic conjunctivitis models (Ebihara et al., Current Eye Res. 19, 20-25 (1999), Whitcup SM. Et al., C 1 in. Immunol. 93, 107-113 (1999)), monoclonal antibodies against VCAM-1 inhibit colitis by inhibiting leukocyte infiltration in a mouse DSS-induced colitis model Has been reported to delay the onset of (Soriano A. et al., Lab. Invest. 80, 1541-1551 (2000)). In addition, anti-VLA-4 antibodies, anti-CD44 antibodies inhibit their development in mouse collagen-induced arthritis models (Zeidler A. et al., Autoimmunity, 21, 245-252 (1995)). In addition, inhibition of infiltration of leukocytes into inflammatory tissues was observed in mice lacking these cell adhesion molecules (Bendjelloul F. et al., C1in. Exp. Immunol. 119, 57-63) in the same manner as in the inflammation model test. (2000), Wolyniec WW. Et al., Am. J. Respir. Cell Mol. Biol. 18, 777-785 (1998), Bullard DC. Et al., J. Immunol. 157, 3153-3158 (1996) ).

그러나, 항체류를 이용한 개발에는 항체가 펩티드성 고분자이기 때문에, 경구투여가 곤란할 뿐만 아니고, 항원성에 의한 알레르기 반응 등의 부작용의 가능성을 문제점으로서 생각된다.However, in the development using antibodies, since the antibody is a peptidic polymer, oral administration is difficult, and the possibility of side effects such as an allergic reaction due to antigenicity is considered as a problem.

이에 대해, 경구투여화를 목표로 한 각종의 저분자의 세포 접착 저해작용 화합물이 보고되고 있다. 벤조티오펜 유도체(Boschelli DH. et al., J. Med. Chem. 38, 4597-4614(1995)), 나프탈렌 유도체(일본국 특개평 10-147568호 공보), 히드록시벤조산 유도체(일본국 특개평 10-182550호 공보), 리그난류(일본국 특개평 10-67656호 공보), 2-치환 벤조티아졸 유도체(일본국 특개 2000-086641호 공보), 축합 피라진 화합물(일본국 특개 2000-319277호 공보), 2,6-디알킬-4-실릴페놀(일본국 특표 2000-509070호 공보) 등이 있으나, 반드시 충분히 목적을 달성하고 있지 않는 상황이다. 일본국 특개평 9-143075호 공보, 일본국 특개평 11-92282호 공보, WO 02/20477에 기재되어 있는 환상 디아민 화합물에 있어서는 충분한 세포 접착 저해작용을 나타내는 것은 아니고, 또한 활성의 향상이 요망되고 있다.On the other hand, various low molecular weight cell adhesion inhibitory compounds aimed at oral administration have been reported. Benzothiophene derivatives (Boschelli DH. Et al., J. Med. Chem. 38, 4597-4614 (1995)), naphthalene derivatives (Japanese Patent Laid-Open No. 10-147568), hydroxybenzoic acid derivatives (Japanese Patent Publication No. 10-182550), lignans (JP-A-10-67656), 2-substituted benzothiazole derivatives (JP-A-2000-086641), condensed pyrazine compounds (JP-A-2000-319277) And 2,6-dialkyl-4-silylphenol (Japanese Patent Application Laid-Open No. 2000-509070), but there are situations where the purpose is not sufficiently achieved. The cyclic diamine compounds described in Japanese Patent Application Laid-Open No. 9-143075, Japanese Patent Application Laid-Open No. 11-92282, and WO 02/20477 do not exhibit sufficient cell adhesion inhibitory activity, and further improvement in activity is desired. have.

따라서, 본 발명은 세포 접착 및 세포 침윤 저해작용을 가지며, 또한 우수한 항천식 작용, 항알레르기 작용, 항류머티즘 작용, 항동맥경화 작용, 항염증 작용 및 항쉐그렌 증후군 작용을 가지는 물질을 제공하는 것을 목적으로 한다.Accordingly, an object of the present invention is to provide a substance having cell adhesion and cell invasion inhibitory activity, and also having an excellent anti-asthmatic action, antiallergic action, antirheumatic action, anti-arteriosclerosis action, anti-inflammatory action and anti-Shegren's syndrome action. It is done.

본 발명은 세포 접착 저해작용 및 세포 침윤 저해작용을 가지며, 항천식제, 항알레르기제, 항류머티즘제, 항동맥경화제, 항염증제, 항쉐그렌 증후군제(anti-Sjogren's syndrome agents) 등으로서 유용한 신규 환상 아민 화합물 및 이를 함유하는 의약에 관한 것이다.The present invention has a novel cyclic amine having an inhibitory effect on cell adhesion and cell infiltration, and is useful as an asthma agent, an antiallergic agent, an antirheumatic agent, an antiarterial agent, an anti-inflammatory agent, an anti-Sjogren's syndrome agents, and the like. It relates to a compound and a medicine containing the same.

이러한 실정을 감안하여 본 발명자들은 세포 접착 및 세포 침윤을 저해하는 물질을 얻기 위하여 예의 연구한 결과, 환상 아민의 양단에, 각각, 페닐-피리딜기, 또는 디페닐기를 가지는 하기 일반식(1)에서 표시되는 화합물이 우수한 세포 접착저해작용 및 세포 침윤 저해작용을 가지며, 항알레르기제, 항천식제, 항류머티즘제, 항동맥경화제, 항염증제, 항쉐그렌 증후군제로서 유용한 것을 발견하고, 본 발명을 완성하게 되었다.In view of such a situation, the present inventors earnestly studied to obtain a substance that inhibits cell adhesion and cell infiltration, and as a result, in the following general formula (1) having a phenyl-pyridyl group or a diphenyl group at each end of the cyclic amine, The compounds to be displayed have excellent cell adhesion inhibitory effect and cell invasion inhibitory activity, and are found to be useful as anti-allergic, anti-asthmatic, antirheumatic, anti-arteriosclerosis, anti-inflammatory, and anti-Segren's syndrome agents. It became.

즉, 본 발명은 일반식(1)That is, the present invention is of general formula (1)

[식중, R¹, R²및 R³는 각각 독립하여 수소원자, 할로겐원자, 히드록시기, 알킬기, 할로겐 치환 알킬기, 알콕시기, 알킬티오기, 카르복실기, 알콕시카르보닐기 또는 알카노일기를 나타내고;[Wherein, R ¹ , R ² and R ³ each independently represent a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group, a halogen substituted alkyl group, an alkoxy group, an alkylthio group, a carboxyl group, an alkoxycarbonyl group or an alkanoyl group;

w¹및 w²는 각각 독립하여 N 또는 CH를 나타내고;w ¹ and w ² each independently represent N or CH;

X는 O, NR⁴, CONR⁴또는 NR⁴CO를 나타내고;X represents O, NR ⁴ , CONR ⁴ or NR ⁴ CO;

R⁴는 수소원자, 알킬기, 알케닐기, 알키닐기, 치환 혹은 무치환 아릴기, 치환 혹은 무치환 헤테로아릴기, 치환 혹은 무치환 아랄킬기, 또는 치환 혹은 무치환 헤테로아랄킬기를 나타내고;R ⁴ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted heteroaralkyl group;

l, m 및, n은 각각 0 또는 1의 수를 나타낸다]l, m and n each represent a number of 0 or 1]

로 표시되는 환상 아민 화합물, 그의 산부가염 또는 이들의 수화물을 제공하는 것이다.It is to provide cyclic amine compounds, acid addition salts thereof, or hydrates thereof.

또한, 본 발명은 상기 환상 아민, 그의 산부가염 또는 이들의 수화물을 유효 성분으로 하는 의약을 제공하는 것이다.Moreover, this invention provides the medicine which uses the said cyclic amine, its acid addition salt, or hydrate thereof as an active ingredient.

또한, 본 발명은 상기 환상 아민, 그의 산부가염 또는 이들의 수화물 및 약학적으로 허용되는 담체를 함유하는 의약 조성물을 제공하는 것이다.Moreover, this invention provides the pharmaceutical composition containing the said cyclic amine, its acid addition salt or its hydrate, and a pharmaceutically acceptable carrier.

또한, 본 발명은 상기 환상 아민, 그의 산부가염 또는 이들의 수화물의 의약제조를 위한 사용을 제공하는 것이다.The present invention also provides a use for the pharmaceutical preparation of the cyclic amines, acid addition salts thereof or hydrates thereof.

또한, 본 발명은 상기 환상 아민, 그 염 또는 이들의 수화물의 유효량을 필요로 하는 환자에게 투여하는 것을 특징으로 하는 세포 접착 및/또는 세포 침윤에 기인하는 질환의 처치 방법을 제공하는 것이다.The present invention also provides a method for treating a disease caused by cell adhesion and / or cell infiltration, which is administered to a patient in need of an effective amount of the cyclic amine, salts thereof or hydrates thereof.

[발명을 실시하기 위한 최선의 형태]Best Mode for Carrying Out the Invention

본 발명의 화합물은 환상 아민의 양단에, 각각, 페닐-피리딜기, 또는 비페닐기를 가지는 것을 특징으로 한다. 이와 같은 구조를 가지는 화합물이 우수한 세포 접착 저해작용 및 세포 침윤 저해작용을 가지는 것은 전혀 알려지지 않았다.The compound of the present invention is characterized by having a phenyl-pyridyl group or a biphenyl group at both ends of the cyclic amine. It is not known at all that the compound having such a structure has excellent cell adhesion inhibition and cell invasion inhibition.

일반식(1) 중, R¹∼R³로 표시되는 할로겐원자에는 불소 원자, 염소원자, 브롬 원자, 요드원자를 들 수 있다.In general formula (1), the halogen atom represented by R <^1> -R <^3> can mention a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

R¹∼R⁴로 표시되는 알킬기로서는 C₁-C₈의 직쇄, 분기쇄 또는 환상의 알킬기를 들 수 있으며, C₁-C₈-직쇄 또는 분기쇄 알킬기로서는 예를 들면, 메틸, 에틸, 프로필, 부틸, 펜틸, 헥실, 헵틸, 옥틸 등을 들 수 있고, C₃-C₈환상 알킬기로서는, 예를 들면, 시클로프로필, 시클로부틸, 시클로펜틸, 시클로헥실, 시클로헥실메틸, 시클로헥실에틸 등을 들 수 있다. 이 중, 메틸, 에틸, n-프로필, 이소프로필, n-부틸 등의 C₁-C₆-알킬기가 특히 바람직하다.Examples of the alkyl group represented by R ¹ to R ⁴ include a C ₁ -C ₈ straight, branched or cyclic alkyl group. Examples of the C ₁ -C ₈ -linear or branched alkyl group include methyl, ethyl and propyl. And butyl, pentyl, hexyl, heptyl, octyl and the like. Examples of the C ₃ -C ₈ cyclic alkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, and the like. Can be mentioned. Among them, C ₁ -C ₆ such as methyl, ethyl, n- propyl, isopropyl, n- butyl - an alkyl group is particularly preferred.

R¹∼R³로 표시되는 할로겐 치환 알킬기로서는1∼3개의 할로겐원자가 치환한 C₁-C₈-알킬기를 들 수 있으며, 이 중 트리플루오로메틸, 2,2,2-트리플루오로메틸 등의 1∼3개의 할로겐원자가 치환한 C₁-C₆-알킬기가 특히 바람직하다.Examples of the halogen substituted alkyl group represented by R ¹ to R ³ include a C ₁ -C ₈ -alkyl group substituted with ¹ to ³ halogen atoms, among which trifluoromethyl, 2,2,2-trifluoromethyl, and the like. Particularly preferred is a C ₁ -C ₆ -alkyl group substituted with 1 to 3 halogen atoms of.

알콕시기로서는 C₁-C₈의 직쇄, 분기쇄 또는 환상의 알콕시기를 들 수 있으며, C₁-C₈-직쇄 또는 분기쇄의 알콕시기로서는, 예를 들면, 메톡시, 에톡시, n-프로폭시, 이소프로폭시, n-부톡시, 이소부톡시, sec-부톡시, tert-부톡시, 펜틸옥시, 헥실옥시 등을 들 수 있고, C₃-C₈-시클로알킬옥시기로서는 예를 들면, 시클로프로필옥시, 시클로부틸옥시, 시클로펜틸옥시, 시클로헥실옥시, 시클로헥실메틸옥시, 시클로헥실에틸옥시 등을 들 수 있다. 이 중, 메톡시, 에톡시, n-프로폭시, 이소프로폭시, n-부톡시 등의 C₁-C₆-알콕시기가 특히 바람직하다.Examples of the alkoxy group include C ₁ -C ₈ straight, branched or cyclic alkoxy groups, and examples of C ₁ -C ₈ -linear or branched alkoxy groups include methoxy, ethoxy and n-pro. propoxy, isopropoxy, n- butoxy, isobutoxy, sec- butoxy, tert- butoxy, pentyloxy, hexyloxy and the like, C ₃ -C ₈ - cycloalkyloxy groups as, for example, , Cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclohexylmethyloxy, cyclohexylethyloxy, etc. are mentioned. Among them, methoxy, ethoxy, n- propoxy, isopropoxy, C ₁ -C _6, such as n- butoxy-alkoxy group is particularly preferred.

알킬티오기로서는 C₁-C₈-알킬티오기를 들 수 있으며, 예를 들면, 메틸티오, 에틸티오, n-프로필티오, 이소프로필티오 등의 C₁-C₆-알킬티오기가 바람직하다.Examples of the alkylthio group include C ₁ -C ₈ -alkylthio groups, and for example, C ₁ -C ₆ -alkylthio groups such as methylthio, ethylthio, n-propylthio, and isopropylthio are preferable.

알콕시카르보닐기로서는 C₁-C₆알콕시카르보닐기를 들 수 있으며, 예를 들면메톡시카르보닐, 에톡시카르보닐, tert-부톡시카르보닐 등의 C₁-C₆알콕시카르보닐기가 바람직하다.As the alkoxycarbonyl group may be mentioned C ₁ -C ₆ alkoxycarbonyl group, for example methoxycarbonyl, ethoxycarbonyl, tert- butoxycarbonyl is preferred, such as the C ₁ -C ₆ alkoxycarbonyl group.

알카노일기로서는 C₁-C₆-알카노일기를 들 수 있으며, 예를 들면, 아세틸, 프로피오닐, 부티릴, 이소부티릴 등의 C₁-C₄알카노일기가 바람직하다.Examples of the alkanoyl group include C ₁ -C ₆ -alkanoyl groups, and for example, C ₁ -C ₄ alkanoyl groups such as acetyl, propionyl, butyryl and isobutyryl are preferable.

R⁴로 표시되는 알케닐기로서는 C₃-C₈-알케닐기를 들 수 있으며, 예를 들면, 2-프로페닐, 3-부테닐 등의 C₃-C₆알케닐기가 바람직하다.Examples of the alkenyl group represented by R ⁴ include C ₃ -C ₈ -alkenyl groups, and for example, C ₃ -C ₆ alkenyl groups such as 2-propenyl and 3-butenyl are preferable.

알키닐기로서는 C₃-C₈-알키닐기를 들 수 있으며, 예를 들면, 2-프로피닐, 3-부티닐 등의 C₃-C₆-알키닐기가 바람직하다.Examples of the alkynyl group include C ₃ -C ₈ -alkynyl groups, and for example, C ₃ -C ₆ -alkynyl groups such as 2-propynyl and 3-butynyl are preferable.

R⁴로 표시되는 아릴기로서는 C₆-C₁₄아릴기를 들 수 있으며, 예를 들면, 페닐, 나프틸, 안트릴, 인데닐, 인다닐, 5,6,7,8-테트라히드로나프틸기 등이 바람직하다.Examples of the aryl group represented by R ⁴ include a C ₆ -C ₁₄ aryl group, for example, a phenyl, naphthyl, anthryl, indenyl, indanyl, 5,6,7,8-tetrahydronaphthyl group, and the like. This is preferred.

R⁴로 표시되는 헤테로아릴기로서는 질소 원자를 1∼4개 함유하는 5 또는 6원환으로 이루어진 헤테로아릴기를 들 수 있으며, 예를 들면, 이미다졸릴기, 피리딜기, 피리미디닐기 등이 바람직하다. R⁴로 표시되는 아랄킬기로서는 C₆-C₁₄-아릴-C-C₆-알킬기를 들 수 있으며, 예를 들면, 벤질, 나프틸메틸, 페닐에틸, 페닐프로필 등의 페닐-C-C₆-알킬 또는 나프틸-C₁-C₆-알킬기 등을 들 수 있다. R⁴로 표시되는 헤테로아랄킬기로서는 질소 원자를 1∼4개 함유하는 5 또는 6원환으로 이루어진 헤테로아릴-C₁-C₆-알킬기를 들 수 있으며, 예를 들면, 이미다졸릴 C₁-C₆-알킬기, 피리딜 C₁-C₆-알킬기, 피리미디닐 C₁-C₆-알킬기 등을 들 수 있다.As a heteroaryl group represented by R <^4> , the heteroaryl group which consists of 5 or 6 membered rings containing 1-4 nitrogen atoms is mentioned, For example, an imidazolyl group, a pyridyl group, a pyrimidinyl group, etc. are preferable. . Examples of the aralkyl group represented by R ⁴ include a C ₆ -C ₁₄ -aryl-CC ₆ -alkyl group. For example, phenyl-CC ₆ -alkyl or naph, such as benzyl, naphthylmethyl, phenylethyl, or phenylpropyl. naphthyl -C ₁ -C ₆ - alkyl group and the like can be given. Examples of the heteroaralkyl group represented by R ⁴ include a heteroaryl-C ₁ -C ₆ -alkyl group consisting of a 5 or 6 membered ring containing 1 to 4 nitrogen atoms. For example, imidazolyl C ₁ -C ₆ there may be mentioned alkyl groups such as - alkyl group, a pyridyl C ₁ -C ₆ - alkyl, pyrimidinyl C ₁ -C _6.

이들 아릴기, 헤테로아릴기, 아랄킬기, 또는 헤테로아랄킬기에 치환될 수 있는 기로서는 알킬기, 알콕시기, 할로겐 치환 알콕시기, 알킬티오기, 알킬술피닐기, 알킬술포닐기, 할로겐원자, 니트로기, 아미노기, 아세틸아미노기, 트리플루오로메틸기 및 알킬렌디옥시기로부터 선택된 1∼3개의 기 또는 원자를 들 수 있다. 여기서 알킬기, 알콕시기 및 알킬티오기로서는 전기 R¹∼R³에서 설명한 것과 같은 것을 들 수 있다. 알킬술피닐기 및 알킬술포닐기의 알킬기로서는 C₁-C₃-알킬기, 특히 메틸기, 에틸기, n-프로필기 및 이소프로필기를 들 수 있다. 할로겐 치환 알콕시기로서는 1∼3개의 할로겐원자가 치환한 C₁-C₈알콕시기, 특히, 트리플루오로메톡시기, 2,2,2-트리플루오르에톡시기 등을 들 수 있고, 1∼3개의 할로겐원자가 치환한 C₁-C₄-알콕시기가 바람직하다. 알킬렌디옥시기로서는 C₁-C₃알킬렌디옥시기, 예를 들면 메틸렌디옥시기, 에틸렌디옥시기, 프로필렌디옥시기를 들 수 있다.Examples of the group which may be substituted with these aryl groups, heteroaryl groups, aralkyl groups, or heteroaralkyl groups include alkyl groups, alkoxy groups, halogen substituted alkoxy groups, alkylthio groups, alkylsulfinyl groups, alkylsulfonyl groups, halogen atoms, nitro groups, 1 to 3 groups or atoms selected from amino group, acetylamino group, trifluoromethyl group and alkylenedioxy group. Examples of the alkyl group, alkoxy group and alkylthio group include those described above for R ¹ to R ³ . Alkylsulfinyl group and the alkyl group in the alkylsulfonyl group C ₁ -C ₃ - alkyl group may be mentioned, in particular, methyl group, ethyl group, n- propyl group and an isopropyl group. Examples of the halogen-substituted alkoxy group include C ₁ -C ₈ alkoxy groups substituted with _{1 to} 3 halogen atoms, particularly trifluoromethoxy groups, 2,2,2-trifluoroethoxy groups, and the like. Preferred is a C ₁ -C ₄ -alkoxy group substituted by a halogen atom. Examples of the alkylenedioxy group include a C ₁ -C ₃ alkylenedioxy group, for example, a methylenedioxy group, an ethylenedioxy group, and a propylenedioxy group.

X로서는 NR⁴가 바람직하고, 더욱이 R⁴가 치환 또는 비치환 C₆-C_l4-아릴기 또는 1∼4개의 질소 원자를 함유하는 5 또는 6원환의 치환 또는 비치환 헤테로아릴기인경우가 바람직하다. 식(1)에서 X가 NR⁴인 화합물은 후술하는 시험예 1에 나타난 바와 같이, 특히 강한 세포 접착 저해작용을 가진다.As X is preferably NR ^4, further R ⁴ is a substituted or unsubstituted C ₆ -C _l4 - it is preferred if the aryl group or from 1 to 4 nitrogen atoms substituted or unsubstituted heteroaryl group of a 5 or 6-membered ring containing an . In Formula (1), the compound whose X is NR ⁴ has a particularly strong cell adhesion inhibitory effect, as shown in Test Example 1 described later.

R^l, R²및 R³는 각각 페닐기의 3,4 및 5위치에 결합하고 있는 것이 바람직하다. 이 때, R^l및 R³(즉, 페닐기상의 3위치 및 5위치)는 알콕시기 또는 할로겐원자가 특히 바람직하다. 또, R²(즉, 페닐기상의 4위)치는 수소원자, 할로겐원자, 히드록시기, 알킬기, 할로겐 치환 알킬기, 알콕시기, 알킬티오기, 카르복실기, 알콕시카르보닐기 또는 알카노일기가 바람직하다.It is preferable that R <^1> , R <^2> and R <^3> are couple | bonded with the 3,4 and 5 position of a phenyl group, respectively. At this time, R ¹ and R ³ (ie, 3 and 5 positions on the phenyl group) are particularly preferably an alkoxy group or a halogen atom. R ² (that is, the fourth position on the phenyl group) value is preferably a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group, a halogen substituted alkyl group, an alkoxy group, an alkylthio group, a carboxyl group, an alkoxycarbonyl group or an alkanoyl group.

l은 0 또는 1을 나타내지만, 1이 보다 바람직하다.1 represents 0 or 1, but 1 is more preferable.

W^l는 N이 바람직하다. 또한, W²는 N이 바람직하다.W ¹ is preferably N. In addition, W ² is preferably N.

식(1)의 화합물 중, X가 NR⁴이고, R⁴가 치환 또는 비치환 C₆-C_l4아릴기 또는 1∼4개의 질소 원자를 함유하는 5 또는 6원환의 치환 또는 비치환의 헤테로아릴기인 화합물이 바람직하다. 더욱이 R⁴는 할로겐원자, 알킬기, 알콕시기, 알킬티오기, 트리플루오로메틸기 및 알킬렌디옥시기로부터 선택되는 1 또는 2개의 기 또는 원자가 치환하고 있어도 좋은 페닐기 또는 피리딜기가 특히 바람직하다.Of the compounds of formula (1), X is NR ^4, and, R ⁴ is a substituted or unsubstituted C ₆ -C _l4 aryl group, or 1 to 4 nitrogen atoms substituted or unsubstituted 5- or 6-membered ring of the heteroaryl group containing a Compound is preferred. Furthermore, R ⁴ is particularly preferably a phenyl group or a pyridyl group which may be substituted by one or two groups or atoms selected from halogen atoms, alkyl groups, alkoxy groups, alkylthio groups, trifluoromethyl groups and alkylenedioxy groups.

본 발명 화합물(1)의 산부가염으로서는 약학상 허용되는 염이면 특히 제한되지 않으나, 예를 들면 염산염, 브롬화수소산염, 요드화수소산염, 황산염, 인산염과 같은 광산의 산부가염; 벤조산염, 메탄설폰산염, 에탄설폰산염, 벤젠술폰산염, p-톨루엔술폰산염, 옥살산염, 말레인산염, 푸말산염, 타르타르산염, 시트르산염, 아세트산염과 같은 유기산의 산부가염을 들 수가 있다.The acid addition salt of the compound (1) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples thereof include acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate; Acid addition salts of organic acids such as benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, oxalate, maleate, fumarate, tartarate, citrate, acetate.

또한, 본 발명 화합물(1)은 수화물로 대표되는 용매화물의 형태로 존재 할 수 있으며, 이 용매화물도 본 발명에 포함된다.The compound (1) of the present invention may also exist in the form of a solvate represented by a hydrate, which is also included in the present invention.

본 발명 화합물(1)은 하기에 표시되는 A법∼L법으로 따라 제조할 수 있다.The compound (1) of the present invention can be produced by the A method to the L method shown below.

합성법 A: 식(1)에 있어서, l= 1, m=0, n=1, X=CONR⁴로 표시되는 화합물Synthesis Method A: A compound represented by formula (1) wherein l = 1, m = 0, n = 1, X = CONR ⁴

(식중, W¹W², R¹, R², R³, R⁴는 전술한 바와 같고, W³는 W^l또는 W²와 같은 의미를 나타내고, B는 할로겐원자, 메탄술포닐옥시기, 또는 p-톨루엔술포닐옥시기 등의 이탈기를 나타낸다.)Wherein W ¹ W ² , R ¹ , R ² , R ³ , and R ⁴ are as described above, W ³ represents the same meaning as W ¹ or W ^2, and B is a halogen atom, a methanesulfonyloxy group, or leaving groups such as p-toluenesulfonyloxy group.)

화합물(2)과 N-(2-니트로)벤젠술포닐아민 유도체(3)를 반응시켜, 화합물(4)을 얻을 수 있다. 이것을 탄산칼륨 등의 염기 존재하, 티오페놀로 처리하고, 2-니트로벤젠술포닐기를 제거하여 아민체(5)를 얻는다. 또한, R⁴= H의 경우는 화합물(2)을 프탈이미드칼륨과 반응시켜, 프탈이미드 유도체(6)에 유도하고, 이어서 히드라진으로 처리함으로서 대응하는 아민체(5)를 얻을 수 있다.Compound (4) can be obtained by making compound (2) and N- (2-nitro) benzenesulfonylamine derivative (3) react. This is treated with thiophenol in the presence of a base such as potassium carbonate, and the 2-nitrobenzenesulfonyl group is removed to obtain an amine (5). In the case of R ⁴ = H, the corresponding amine 5 can be obtained by reacting compound (2) with potassium phthalimide to induce the phthalimide derivative (6) and then treating with hydrazine.

한편, 화합물(2)과 에틸 이소니페코티네이트(7)를 탄산칼륨 등의 염기 존재하, 아세토니트릴, N,N-디메틸포름아미드(DMF), 디메틸술폭시드(DMSO), 테트라히드로푸란(THF), 디옥산, 톨루엔, 벤젠 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 실온에서 하룻밤 반응시킴으로서 화합물(8)을 얻을 수 있다. 다시, 화합물(8)을 통상의 알칼리 가수분해에 의해 카르복실산체(9)를 얻을 수 있다.On the other hand, compound (2) and ethyl isonipecotinate (7) were added to acetonitrile, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and tetrahydrofuran in the presence of a base such as potassium carbonate. In a solvent such as THF), dioxane, toluene and benzene, the compound (8) can be obtained by reacting overnight at 0 ° C to reflux for several hours to several days, preferably at room temperature. Again, the carboxylic acid compound 9 can be obtained by normal alkali hydrolysis of the compound (8).

카르복실산체(9)와 아민체(5)를 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드·염산염(수용성 카르보디이미드), 2-(1H-벤조트리아졸-1-일)-1,1,3,3-테트라메틸우로늄 헥사플루오로포스페이트(HBTU) 등의 탈수 축합제를 이용하고, 클로로포름, 디클로로에탄, THF, 디옥산, 아세토니트릴 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 실온에서 12시간 반응시킴으로서목적물(1A)을 얻을 수 있다.Carboxylic acid (9) and amine (5) are 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (water-soluble carbodiimide), 2- (1H-benzotriazol-1-yl 0 deg. C to 1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and the like in a solvent such as chloroform, dichloroethane, THF, dioxane and acetonitrile The objective 1A can be obtained by reacting at reflux for several hours to several days, preferably at room temperature for 12 hours.

합성법 B: 식(1)에 있어서, l = 1, m=0, n=1, x= O로 표시되는 화합물Synthesis Method B: Compound represented by l = 1, m = 0, n = 1, x = O in Formula (1)

(식중, B, W¹W², R¹, R², R³는 전술한 바와 같고, J는 벤질옥시카르보닐기, tert-부톡시카르보닐기, 아세틸기, 벤조일기, 벤질기 등의 보호기를 나타낸다.)(Wherein, B, W ¹ W ^2, R ^1, R ^2, R ³ are as defined above, J represents a protecting group such as benzyloxycarbonyl group, tert- butoxycarbonyl group, an acetyl group, a benzoyl group, a benzyl group. )

반응식중, "W²→ W¹"는 화합물(2)에서 W²를 W¹로 변경한 화합물을 이용하는 것을 의미한다. 이하 반응식에 대해서도 같다.In the scheme, "W ² → W ¹ " means using a compound obtained by changing W ² to W ¹ in Compound (2). The same applies to the following scheme.

아미노기를 보호한 4-히드록시피페리딘체(10)와 화합물(2)를 수소화나트륨 및 요드화칼륨 존재하, DMF, DMSO 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 실온에서 2일간 반응시켜 화합물(11)을 얻을 수 있다. 화합물(11)의 보호기를 공지의 방법으로 제거하여 화합물(12)을 얻은 후, 화합물(12)과 화합물(2)을 탄산칼륨 등의 염기 존재하, 아세토니트릴, DMF, DMSO,THF, 디옥산 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 실온에서 4시간 반응시킴으로서 목적물(1B)을 얻을 수 있다.The 4-hydroxypiperidine body (10) and the compound (2) in which the amino group is protected are in the presence of sodium hydride and potassium iodide, in a solvent such as DMF and DMSO, for several hours to several days at 0 ° C to reflux temperature. Below, compound (11) can be obtained by making it react for 2 days at room temperature. After the protecting group of Compound (11) was removed by a known method to obtain Compound (12), Compound (12) and Compound (2) were dissolved in acetonitrile, DMF, DMSO, THF, dioxane in the presence of a base such as potassium carbonate. In a solvent such as the above, the target product 1B can be obtained by reacting the reaction at 0 ° C. to reflux for several hours to several days, preferably at room temperature for 4 hours.

합성법 C: 식(1)에 있어서, l= 1, m= 0, n= 0, X= NR⁴CO, R⁴= H, Me로 표시되는 화합물Synthesis Method C: Compound represented by formula (1) represented by l = 1, m = 0, n = 0, X = NR ⁴ CO, R ⁴ = H, Me

(식중, B, W¹W², R¹, R², R³는 전술한 바와 같고, R⁴는 수소원자 또는 메틸기를 나타낸다.)(Wherein B, W ¹ W ² , R ¹ , R ² , and R ³ are as described above, and R ⁴ represents a hydrogen atom or a methyl group.)

이소니페코타미드(13)와 화합물(2)을 탄산칼륨, 탄산나트륨 등의 염기 존재하, 아세토니트릴, DMF, DMSO, THF, 디옥산 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 실온에서 4시간 반응시킴으로서 화합물(14)를 얻을 수 있다. 이것을 호프만 전위반응에 걸어 아민체(15)를 얻을 수 있다.Isonipecotamide (13) and compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, in the presence of a base such as potassium carbonate or sodium carbonate at a temperature of 0 to reflux temperature for several hours to several The compound (14) can be obtained by making it react for 4 hours at room temperature preferably. This can be subjected to Hoffman potential reaction to obtain the amine 15.

한편, 화합물(14)을 에탄올중, 호프만 전위 반응시켜 카르바메이트체(16)를 얻을 수 있다. 화합물(16)을 수소화리튬알루미늄 등을 이용하는 환원 반응에 걸어 메틸아민체(17)를 얻을 수 있다.On the other hand, the carbamate body 16 can be obtained by carrying out Hofmann electric potential reaction of compound (14) in ethanol. The methylamine body 17 can be obtained by subjecting compound (16) to reduction reaction using lithium aluminum hydride or the like.

카르복실산체(18)와 아민체(15) 또는 메틸아민체(17)를 합성법 A의 축합반응과 동일하게 반응시킴으로써 목적물(1C)을 얻을 수 있다.The desired product (1C) can be obtained by reacting the carboxylic acid body 18 with the amine body 15 or the methylamine body 17 in the same manner as in the condensation reaction of Synthesis Method A.

합성법 D: 식(1)에 있어서, l= 1, m= 0, n= 1, X=NR⁴로 표시되는 화합물Synthesis Method D: Compound represented by Formula (1) represented by l = 1, m = 0, n = 1, X = NR ⁴

(식중, B, W¹W², R¹, R², R³는 전술한 바와 같고, R⁴는 알킬기, 알케닐기, 알키닐기, 아랄킬기 또는 헤테로아랄킬기를 나타낸다.)(Wherein B, W ¹ W ² , R ¹ , R ² , and R ³ are as described above, and R ⁴ represents an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group or a heteroaralkyl group.)

상기 아민체(15)와 2-니트로벤젠술포닐클로라이드(19)를 공지의 방법으로 반응시켜 화합물(20)을 얻을 수 있다. 이것에 화합물(2) 탄산칼륨 등 염기 존재하, 아세토니트릴, DMF, DMSO, THF, 디옥산 등의 용매중, 0℃ 내지 환류온도에서 수시간부터 수일간, 바람직하기로는 실온에서 4시간 반응시킴으로서 화합물(21)을 얻을 수 있다. 이것의 벤젠술포닐기를 합성법 A에 있어서의 화합물(4)의 경우와 동일하게 제거함으로서 목적물(R⁴= H)(1D)을 얻을 수 있다. 화합물(1D)을 R⁴-B와 탄산나트륨, 탄산수소나트륨, 탄산칼륨, 탄산세슘 등의 염기 존재하, 아세토니트릴, THF, 디옥산, 클로로포름, 디클로로메탄, DMF, DMSO 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 80℃에서 12시간 반응시킴으로서 목적물(1D')을 얻을 수 있다.Compound (20) can be obtained by reacting the amine (15) with 2-nitrobenzenesulfonyl chloride (19) by a known method. In a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc., in the presence of a base such as potassium carbonate (2), the reaction is carried out for several hours to several days at 0 ° C. to reflux temperature, preferably at room temperature for 4 hours. Compound (21) can be obtained. By removing this benzenesulfonyl group similarly to the case of the compound (4) in the synthesis method A, the target object (R ⁴ = H) (1D) can be obtained. Compound (1D) is 0 ° C in a solvent such as acetonitrile, THF, dioxane, chloroform, dichloromethane, DMF, DMSO in the presence of R ⁴ -B and bases such as sodium carbonate, sodium bicarbonate, potassium carbonate and cesium carbonate. To a reflux temperature of several hours to several days, preferably 12 hours at 80 ℃ can obtain the target (1D ').

한편, 전기 메틸아민체(17)와 화합물(2)을 탄산칼륨 등의 염기존재하, 아세토니트릴, DMF, DMSO, THF, 디옥산 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 실온에서 4시간 반응시킴으로서 목적물(R⁴= Me)(1D")를 얻을 수 있다.On the other hand, in the presence of a base such as potassium carbonate, the methylamine compound (17) and the compound (2) are present in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at 0 ° C. to reflux temperature for several hours to several days. For example, the target product (R ⁴ = Me) (1D ″) can be obtained by reacting at room temperature for 4 hours.

합성법 E: 식(1)에 있어서, l= 1, m= 0 또는 1, n= l, X= NR⁴로 표시되는 화합물Synthesis Method E: Compound represented by formula (1) represented by l = 1, m = 0 or 1, n = l, X = NR ⁴

(식중, B, J, W¹W², R¹, R², R³는 전술한 바와 같고, R⁴는 알킬기, 알케닐기, 알키닐기, 아랄킬기, 헤테로아랄킬기 등을 나타낸다.)(Wherein B, J, W ¹ W ² , R ¹ , R ² , and R ³ are as described above, and R ⁴ represents an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group, a heteroaralkyl group, and the like.)

환상의 아미노기를 보호한 아미노피페리딘 유도체(22)와 화합물(2)을 탄산칼륨 등의 염기 존재하, 아세토니트릴, DMF, DMSO, THF, 디옥산 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 실온에서 4시간 반응시킴으로서 화합물(23)을 얻을 수 있다. 이것에, R⁴-B를 탄산나트륨, 탄산수소나트륨, 탄산칼륨, 탄산세슘 등의 염기 존재하, 아세토니트릴, THF, 디옥산, 클로로포름, 디클로로에탄, DMF, DMSO 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 80℃에서 12시간 반응시킴으로서 화합물(24)을 얻을 수 있다. 화합물(24)의 보호기를 제거하고, 화합물(2)과 탄산칼륨 등의 염기 존재하, 아세토니트릴, DMF, DMSO, THF, 디옥산 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 실온에서 4시간 반응시킴으로서 화합물(1E)을 얻을 수 있다.The aminopiperidine derivative (22) and the compound (2) which protected the cyclic amino group were made to exist in a solvent, such as acetonitrile, DMF, DMSO, THF, and dioxane, in presence of a base, such as potassium carbonate, at 0 degreeC-reflux temperature. Compound (23) can be obtained by reacting for several hours to several days, preferably at room temperature for 4 hours. In the presence of a base such as sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, and R ⁴ -B, 0 ° C. to reflux in a solvent such as acetonitrile, THF, dioxane, chloroform, dichloroethane, DMF, and DMSO Compound (24) can be obtained by reacting at a temperature for several hours to several days, preferably at 80 DEG C for 12 hours. The protecting group of the compound (24) is removed, and in the presence of a base such as the compound (2) and potassium carbonate, in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, and the like at 0 ° C. to reflux temperature for several hours to several days. Preferably, compound (1E) can be obtained by making it react for 4 hours at room temperature.

합성법 F: 식(1)에 있어서, l= 1, m= 0, n=1, X=NR⁴로 표시되는 화합물Synthesis Method F: A compound represented by l = 1, m = 0, n = 1, X = NR ⁴ in formula (1)

(식중, B, W¹W², R¹, R², R³는 전술한 바와 같고, R⁴는 알킬기, 알케닐기, 알키닐기, 아랄킬기, 헤테로아랄킬기, 아릴기, 헤테로아릴기 등을 나타낸다.)Wherein B, W ¹ W ² , R ¹ , R ² , and R ³ are as described above, and R ⁴ represents an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group, a heteroaralkyl group, an aryl group, a heteroaryl group, or the like. Indicates.)

4-피페리돈에틸렌 케탈(26)과 화합물(2)을 탄산칼륨 등의 염기 존재하, 아세토니트릴, DMF, DMSO, THF, 디옥산 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 실온에서 4시간 반응시킴으로서, 화합물(27)을 얻고, 이것을 산으로 탈케탈화함으로써, 케톤체(28)를 얻을 수 있다.4-piperidone ethylene ketal (26) and compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, in the presence of a base such as potassium carbonate, at a temperature of 0 DEG C to reflux for several hours to several days Preferably, the compound (27) is obtained by reacting at room temperature for 4 hours, and the ketone body 28 can be obtained by deketalizing it with an acid.

한편, 4-피페리돈(29)에 화합물(2)을 탄산칼륨 등의 염기 존재하, 아세토니트릴, DMF, DMSO, THF, 디옥산 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 실온에서 4시간 반응시키는 것에 의해서도, 화합물(28)을 얻을 수 있다. 화합물(28)을 이용해 이하의 2개의 합성법으로, 아민 화합물(30)을 얻을 수 있다.On the other hand, the compound (2) in 4-piperidone (29) in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, for several hours to several days at 0 ℃ to reflux temperature Preferably, compound (28) can also be obtained by making it react at room temperature for 4 hours. Using the compound (28), the amine compound (30) can be obtained by the following two synthesis methods.

합성법 1: 화합물(28)을 톨루엔 또는 벤젠중, 몰리큘라 시이브스 존재하, 아민 화합물 R⁴-NH₂와 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 환류온도에서 12시간 반응시킨 후, 메탄올, 에탄올, 프로판올, 이소프로판올 등의 용매중, 수소화 붕소 나트륨, 수소화시아노붕소나트륨 등의 환원제와 0℃ 내지 환류온도에서 수분 내지 수일간, 바람직하기로는 실온에서 1시간 반응시킴으로서 아민 화합물(30)을 얻을 수 있다.Synthesis Method 1: Compound (28) was reacted in toluene or benzene in the presence of Molecular Sieves with amine compound R ⁴ -NH ₂ at 0 ° C to reflux for several hours to several days, preferably at reflux for 12 hours After the amine compound is reacted with a reducing agent such as sodium borohydride or sodium cyanoborohydride in a solvent such as methanol, ethanol, propanol or isopropanol, at a temperature of 0 ° C. to reflux for a few minutes to several days, preferably at room temperature for 1 hour. 30 can be obtained.

합성법 2: 화합물(28)과 아민 화합물 R⁴-NH₂를 디클로로메탄, 1,2-디클로로에탄, 메탄올, 에탄올 등의 용매중, 트리아세톡시 수소화붕소나트륨 등의 환원제의 존재하, 0℃ 내지 환류온도에서 수분 내지 수일간, 바람직하기로는 실온에서 4시간 반응시킴으로서, 아민 화합물(30)을 얻을 수 있다.Synthesis method 2: Compound (28) and amine compound R ⁴ -NH ₂ in a solvent such as dichloromethane, 1,2-dichloroethane, methanol, and ethanol, in the presence of a reducing agent such as sodium triacetoxy borohydride, from 0 ° C to An amine compound 30 can be obtained by reacting at reflux temperature for several minutes to several days, preferably at room temperature for 4 hours.

화합물(30)과 화합물(2)을 아세토니트릴, DMF, DMSO, THF, 디옥산 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 실온에서 4시간 반응시킴으로서, 목적물(1F)을 얻을 수 있다.Compound (30) and compound (2) were reacted in a solvent such as acetonitrile, DMF, DMSO, THF and dioxane at 0 ° C. to reflux for several hours to several days, preferably at room temperature for 4 hours, whereby 1F) can be obtained.

합성법 G: 식(1)에 있어서, l = 1, m= 0, n= 1, X=NR⁴로 표시되는 화합물Synthesis method G: a compound represented by formula (1) represented by l = 1, m = 0, n = 1, X = NR ⁴

(식중, B, J, W¹W², R¹, R², R³는 전술한 바와 같고, R⁴는 알킬기, 알케닐기, 알키닐기, 아랄킬기, 헤테로아랄킬기, 아릴기, 헤테로아릴기 등을 나타낸다.)Wherein B, J, W ¹ W ² , R ¹ , R ² , and R ³ are as described above, and R ⁴ is an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group, a heteroaralkyl group, an aryl group, a heteroaryl group Etc.)

아미노기를 보호한 4-피페리돈 유도체(31)와 아민 화합물 R⁴-NH₂를, 합성법 F에서의 화합물(30)의 합성과 동일하게 반응시켜 화합물(32)을 얻을 수 있다. 이것과 화합물(2)을 탄산칼륨 등의 염기 존재하, 아세토니트릴, DMF, DMSO, THF, 디옥산 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 실온에서 4시간 반응시킴으로서 화합물(33)을 얻을 수 있다. 이것의 보호기를 제거하여 화합물(34)을 얻은 후, 화합물(2)과 탄산칼륨 등의 염기 존재하, 아세토니트릴, DMF, DMSO, THF, 디옥산 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간,바람직하기로는 실온에서 4시간 반응시킴으로써 목적물(1G)를 얻을 수 있다.Compound (32) can be obtained by reacting an amino group-protected 4-piperidone derivative (31) with an amine compound R ⁴ -NH ₂ in the same manner as in the synthesis of Compound (30) in Synthesis Method F. This and the compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, in the presence of a base such as potassium carbonate, at a temperature of 0 ° C. to reflux for several hours to several days, preferably 4 hours at room temperature. Compound (33) can be obtained by reacting. After removing the protecting group to obtain the compound (34), in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane and the like in the presence of a base such as compound (2) and potassium carbonate, water at 0 ℃ to reflux temperature The target product (1G) can be obtained by making it react for 4 hours at room temperature preferably for several days.

합성법 H: 식(1)에 있어서, l= 0, m= 0, n= 1, X=NH로 표시되는 화합물Synthesis Method H: A compound represented by formula (1) represented by l = 0, m = 0, n = 1, X = NH

(식중, B, J, W¹W², R¹, R², R³는 전술한 바와 같다.)(Wherein B, J, W ¹ W ² , R ¹ , R ² , and R ³ are as described above).

환상의 아미노기를 보호한 3-아미노피롤리딘 유도체(35)에 2-니트로벤젠술포닐클로라이드(19)를 통상의 조건으로 반응시켜 벤젠술포닐 유도체(36)를 얻을 수 있다. 화합물(36)과 화합물(2)을 탄산칼륨 등의 염기 존재하, 아세토니트릴, DMF, DMSO, THF, 디옥산 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 실온에서 4시간 반응시킴으로서 화합물(37)을 얻을 수 있다. 이것의 아미노기 보호기를 제거하여 화합물(38)을 얻은 후, 화합물(2)와 탄산칼륨 등의 염기 존재하, 아세토니트릴, DMF, DMSO, THF, 디옥산 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 실온에서 4시간 반응시킴으로서 화합물(39)을 얻을 수 있다. 화합물(39)을 합성법 A의 화합물(5)의 합성의 경우와 동일하게 반응시켜 목적물(1H)을 얻을 수 있다.2-nitrobenzenesulfonyl chloride (19) can be reacted with the 3-aminopyrrolidine derivative (35) which protected the cyclic amino group on normal conditions, and the benzenesulfonyl derivative (36) can be obtained. Compound (36) and compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF and dioxane in the presence of a base such as potassium carbonate, at a temperature of 0 ° C. to reflux for several hours to several days, preferably room temperature Compound (37) can be obtained by reacting for 4 hours at. After the amino group protecting group was removed to obtain Compound (38), in the presence of a base such as Compound (2) and potassium carbonate, in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, and the like at 0 ° C to reflux temperature Compound (39) can be obtained by reacting for several hours to several days, preferably at room temperature for 4 hours. Compound (39) can be reacted in the same manner as in the synthesis of Compound (5) in Synthesis Method A to obtain the desired compound (1H).

합성법 I: 식(1)에 있어서, l= 0, m= 0, n= 1, X=NR⁴로 표시되는 화합물Synthesis Method I: A compound represented by formula (1) wherein l = 0, m = 0, n = 1, X = NR ⁴

(식중, B, J, W¹W², R¹, R², R³는 전술한 바와 같고, R⁴는 알킬기, 알케닐기, 알키닐기, 아랄킬기 등을 나타낸다.)(Wherein B, J, W ¹ W ² , R ¹ , R ² , and R ³ are as described above, and R ⁴ represents an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group, and the like.)

화합물(36)과 R⁴-B를 탄산나트륨, 탄산칼륨 등의 염기 존재하, 아세토니트릴, THF, 디옥산, 클로로포름, 디클로로에탄, DMF, DMSO 등의 용매중, 0℃ 내지 환류온도에서, 수시간 내지 수일간, 바람직하기로는 80℃에서 12시간 반응시킴으로써, 화합물(40)을 얻을 수 있다. 이것의 아미노기의 보호기를 제거하여 화합물(41)을 얻고, 이것에 화합물(2)을 탄산칼륨 등의 염기 존재하, 아세토니트릴, DMF, DMSO, THF, 디옥산 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 실온에서 4시간 반응시킴으로서 화합물(42)을 얻을 수 있다. 화합물(42)을 합성법 A에 있어서의 화합물(5)의 합성의 경우와 동일하게 반응시킴으로써, 화합물(43)을 얻을 수 있다. 이것에 화합물(2)을 탄산칼륨 등의 염기 존재하, 아세토니트릴, DMF, DMSO, THF, 디옥산 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 실온에서 4시간 반응시킴으로써 목적물(1Ⅰ)을 얻을 수 있다.Compound (36) and R ⁴ -B in a solvent such as acetonitrile, THF, dioxane, chloroform, dichloroethane, DMF, DMSO in the presence of a base such as sodium carbonate and potassium carbonate at a temperature of 0 ° C. to reflux for several hours Compound (40) can be obtained by making it react for several days, Preferably it is 12 hours at 80 degreeC. Compound (41) is obtained by removing the protecting group of this amino group, and compound (2) is added to this in a solvent such as acetonitrile, DMF, DMSO, THF and dioxane in the presence of a base such as potassium carbonate. Compound (42) can be obtained by reacting at a temperature for several hours to several days, preferably at room temperature for 4 hours. Compound (43) can be obtained by making compound (42) react similarly to the case of synthesis | combination of compound (5) in synthesis method A. Compound (2) is added thereto in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, in the presence of a base such as potassium carbonate, at a temperature of 0 ° C. to reflux for several hours to several days, preferably at room temperature for 4 hours. By reacting, target object (1I) can be obtained.

합성법 J: 식(1)에 있어서, R²= OH로 표시되는 화합물Synthesis method J: A compound represented by R <^2> = OH in Formula (1)

(식중, X, W¹W², R¹, R², R³, l, m, n은 전술한 바와 같다.)(Wherein X, W ¹ W ² , R ¹ , R ² , R ³ , l, m, n are as described above).

메톡시체(1J)에 요드화트리메틸실란을 톨루엔, 벤젠, 클로로포름, 디클로로메탄 등의 용매중, -25℃ 내지 환류온도에서 수분 내지 수일사이, 바람직하기로는 0℃에서 2시간 반응시킴으로서 목적물(1J ')을 얻을 수 있다.Trimethyl iodide to the methoxy body (1J) is reacted in a solvent such as toluene, benzene, chloroform, dichloromethane, at a temperature of −25 ° C. to reflux for a few minutes to several days, preferably 0 ° C. for 2 hours. ) Can be obtained.

합성법 K: 식(1)에 있어서, l= 1, m= 0, n=0, X=NR⁴CO로 표시되는 화합물Synthesis Method K: A compound represented by formula (1) wherein l = 1, m = 0, n = 0, X = NR ⁴ CO

(식중 B, J, W¹W², R¹, R², R³는 전술한 바와 같고, R⁴는 알킬, 알케닐, 알키닐, 아랄킬, 헤테로아랄킬, 아릴, 또는 헤테로아릴기를 나타낸다.)Wherein B, J, W ¹ W ² , R ¹ , R ² , and R ³ are as described above, and R ⁴ represents an alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, or heteroaryl group. .)

합성법 G에서 언급한 화합물(32)과 화합물(18)을 합성법 A에 있어서의 화합물(1A)의 합성과 같은 조건으로 반응시켜 화합물(44)을 얻을 수 있다. 화합물(44)의 보호기를 제거하여 화합물(45)로 한 후, 이것과 화합물(2)를 탄산칼륨 등의 염기 존재하, 아세토니트릴, DMF, DMSO, THF, 디옥산 등의 용매중, 0℃ 내지 환류온도에서 수시간 내지 수일간, 바람직하기로는 실온에서 4시간 반응시킴으로서 목적물(1K)을 얻을 수 있다.Compound (44) can be obtained by reacting compound (32) and compound (18) mentioned in Synthesis Method G under the same conditions as the synthesis of Compound (1A) in Synthesis Method A. After removing the protecting group of compound (44) to make compound (45), this and compound (2) were prepared in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, or the like in the presence of a base such as potassium carbonate, at 0 ° C. The target product (1K) can be obtained by reacting at a reflux temperature for several hours to several days, preferably at room temperature for 4 hours.

합성법 L: 식(1)에 있어서, l = 1, m= 0, n = 1, X= 알킬술포닐페닐아미노기로 표시되는 화합물Synthesis Method L: A compound represented by formula (1) represented by l = 1, m = 0, n = 1, X = alkylsulfonylphenylamino group

(식중 B, W¹W², R¹, R², R³는 전술한 바와 같다.)(Wherein B, W ¹ W ² , R ¹ , R ² , and R ³ are as described above).

합성법 G에 따라서 합성된 X가 알킬티오페닐아미노기인 화합물(34)를 공지의 방법에 따라, 3-클로로과벤조산, 과아세트산, 과산화수소 등의 산화제와 반응시켜 알킬술폭시드 유도체(46)를 얻었다. 화합물(46)을 화합물(2)을 탄산칼륨 등 염기 존재하, 아세토니트릴, DMF, DMSO, THF, 디옥산 등의 용매중, 0℃ 내지 환류온도에 있어서, 수시간 내지 수일간, 바람직하기로는 70℃에서, 하룻밤 반응시킴으로써, 목적의 화합물(1L)을 얻을 수 있다.Compound (34), wherein X synthesized according to Synthesis Method G was an alkylthiophenylamino group, was reacted with an oxidizing agent such as 3-chloroperbenzoic acid, peracetic acid, hydrogen peroxide, and the like to obtain an alkyl sulfoxide derivative (46). Compound (46) is a compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, in the presence of a base such as potassium carbonate, at a temperature of 0 ° C. to reflux temperature for several hours to several days, preferably The target compound (1L) can be obtained by reacting at 70 ° C overnight.

본 발명 화합물(1)은 상기 방법에 의해 얻을 수 있지만, 다시 필요에 따라 재결정법, 컬럼크로마토그래피 등의 통상의 정제 수단을 이용하여 정제 할 수 있다. 또, 필요에 따라서, 통상의 방법에 따라 전술한 소망의 염 또는 용매화물로 할 수도 있다.Although compound (1) of this invention can be obtained by the said method, it can refine | purify using normal purification means, such as a recrystallization method and column chromatography, if necessary again. Moreover, you may make it the above-mentioned desired salt or solvate according to a conventional method as needed.

또한, 화합물(1)이 부제탄소를 가지는 경우는 본 발명은 어느 입체 배치로 되는 이성체도 포함한다.In addition, when compound (1) has a subsidiary carbon, this invention also includes the isomer which becomes any three-dimensional arrangement.

이렇게 하여 얻어진 본 발명 화합물(1), 그의 염 또는 용매화물은 후기 시험예 1에 나타난 바와 같이, 우수한 세포 접착 저해작용을 나타내고, 사람을 포함한 동물의 세포 접착 또는 세포 침윤에 기인하는 질환, 예를 들면 천식, 알레르기, 류머티즘, 동맥경화, 염증, 쉐그렌 증후군 등의 치료 또는 예방용 의약으로서 유용하다.Compound (1) of the present invention thus obtained, a salt or solvate thereof exhibits excellent cell adhesion inhibitory action, as shown in later Test Example 1, and a disease caused by cell adhesion or cell invasion of animals including humans, for example. For example, it is useful as a medicament for the treatment or prophylaxis of asthma, allergies, rheumatism, arteriosclerosis, inflammation, and Sjogren's syndrome.

본 발명의 의약은 본 발명 화합물(1), 그의 염 또는 이들의 수화물을 유효 성분으로 하는 것이고, 이 투여 형태는 특히 한정되지 않고 치료 목적에 따라 적당 선택할 수 있으며, 예를 들면, 경구제, 주사제, 좌제, 연고제, 흡입제, 점안제, 점비제, 첩부제의 어느 것이라도 좋고, 이들의 투여 형태에 적합한 조성물은 약학적으로 허용되는 담체를 배합하고, 당업자에게 공지 관용의 제제 방법에 의해 제조할 수 있다.The medicament of the present invention contains the compound (1) of the present invention, a salt thereof, or a hydrate thereof as an active ingredient, and the dosage form is not particularly limited and can be appropriately selected depending on the therapeutic purpose. For example, oral or injection Any of suppositories, ointments, inhalants, eye drops, nasal drops, and patches may be used, and the composition suitable for these dosage forms may be prepared by formulating a pharmaceutically acceptable carrier and known in the art to those skilled in the art. have.

경구용 고형 제제를 조제하는 경우는 본 발명 화합물(1)에 부형제, 필요에 따라서 결합제, 붕괴제, 활택제, 착색제, 교미제, 교취제 등을 가한 후, 통상의 방법에 의해 정제, 피복 정제, 과립제, 산제, 캅셀제 등으로 제조할 수 있다. 그와 같은 첨가제로서는 당해 분야에서 일반적으로 사용되고 있는 것으로 좋고, 예를 들면, 부형제로서는 락토오즈, 백당, 염화나트륨, 포도당, 전분, 탄산칼슘, 카올린, 미결정 셀루로오즈, 규산 등을 들 수 있고, 결합제로서는 물, 에탄올, 프로판올, 단미시럽, 포도당액, 전분액, 젤라틴액, 카르복시메틸셀루로오즈, 히드록시프로필셀루로오즈, 히드록시프로필스타치, 메틸셀루로오즈, 에틸셀루로오즈, 쉘락, 인산칼슘, 폴리비닐피롤리돈 등을 들 수 있고, 붕괴제로서는 건조 전분, 알긴산나트륨, 칸텐말, 탄산수소나트륨, 탄산칼슘, 라우릴황산나트륨, 스테아린산모노글리세리드, 락토오즈 등을 들 수 있고, 활택제로서는 정제 탈크, 스테아린산염, 붕사, 폴리에틸렌글리콜 등을 들 수 있고, 교미제로서는 백당, 계피, 시트르산, 타르타르산 등을 예시할 수 있다.When preparing an oral solid preparation, an excipient, a binder, a disintegrant, a lubricant, a coloring agent, a coagulant, a odorant and the like are added to the compound (1) of the present invention, and then tablets, coated tablets, It can manufacture with a granule, a powder, a capsule, etc. As such additives, those commonly used in the art may be used. Examples of the excipient include lactose, white sugar, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid, and the like. Examples include water, ethanol, propanol, sweet syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, Calcium phosphate, polyvinylpyrrolidone, etc. are mentioned, As a disintegrating agent, dry starch, sodium alginate, cantenmal, sodium hydrogencarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride stearate, lactose, etc. are mentioned. Examples of the agent include purified talc, stearic acid salt, borax, polyethylene glycol, and the like, and examples of the copulating agent include white sugar, cinnamon, citric acid, tartaric acid, and the like. There.

경구용 액체 제제를 조제하는 경우는 본 발명 화합물(1)에 교미제, 완충제, 안정화제, 교취제 등을 더해 통상의 방법에 의해 내복액제, 시럽제, 에릭실제 등을 제조할 수 있다. 이 경우 교미제로서는 전술한 것으로 좋고, 완충제로서는 시트르산나트륨 등을 들 수 있고, 안정화제로서는 트라간트, 아라비아 검, 젤라틴 등을 들 수 있다.When preparing an oral liquid formulation, a compound, a buffer, a stabilizer, a odor agent, etc. can be added to the compound (1) of the present invention to prepare an oral solution, a syrup, an erythyl agent, or the like by a conventional method. In this case, as a mating agent, what was mentioned above is good, As a buffer, sodium citrate etc. are mentioned, As a stabilizer, a tragant, gum arabic, gelatin, etc. are mentioned.

주사제를 조제하는 경우는 본 발명 화합물(1)에 pH 조절제, 완충제, 안정화제, 등장화제, 국소 마취제 등을 첨가하여 통상의 방법에 의해 피하, 근육 및 정맥내 주사제를 제조할 수 있다. 이 경우, pH 조절 및 완충제로서는 시트르산나트륨, 아세트산나트륨, 인산나트륨 등을 들 수 있다. 안정화제로서는 피로아황산나트륨, EDTA, 티오글리콜산, 티오젖산 등을 들 수 있다. 국소 마취제로서는 염산 프로카인, 염산 리도카인 등을 들 수 있다. 등장화제로서는 염화나트륨, 포도당 등을 예시할 수 있다.When preparing an injection, a subcutaneous, intramuscular and intravenous injection can be prepared by conventional methods by adding a pH adjusting agent, a buffer, a stabilizer, an isotonic agent, a local anesthetic and the like to the compound (1) of the present invention. In this case, sodium citrate, sodium acetate, sodium phosphate, etc. are mentioned as a pH control and a buffer. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactate, and the like. Local anesthetics include procaine hydrochloride, lidocaine hydrochloride, and the like. Examples of the tonicity agent include sodium chloride and glucose.

좌약을 조제하는 경우는 본 발명 화합물(1)에 당업계에 있어 공지의 제제용 담체, 예를 들면, 폴리에틸렌 리콜, 라놀린, 카카오지방, 지방산 트리글리세라이드등을, 또한 필요에 따라서 트인(등록상표)과 같은 계면활성제 등을 가한 후, 통상의 방법에 의해 제조할 수가 있다.When preparing a suppository, the compound (1) of the present invention may be prepared by using a carrier for a preparation well known in the art, for example, polyethylene recall, lanolin, cacao fat, fatty acid triglyceride, etc. After adding surfactant, such as these, it can manufacture by a conventional method.

연고제를 조제하는 경우는 본 발명 화합물(1)에 통상 사용되는 기제, 안정제, 습윤제, 보존제 등이 필요에 따라 배합되고, 통상의 방법에 의해 혼합, 제제화된다. 기제로서는 유동 파라핀, 백색 바셀린, 경랍, 옥틸도데실알코올, 파라핀 등을 들 수 있다. 보존제로서는 메틸 p-히드록시벤조에이트, 에틸 p-히드록시벤조에이트, 에틸벤조에이트, 프로필 p-히드록시벤조에이트 등을 들 수 있다.When preparing an ointment, the base, stabilizer, wetting agent, preservative, etc. which are normally used for compound (1) of this invention are mix | blended as needed, and it mixes and formulates by a conventional method. Examples of the base include liquid paraffin, white petrolatum, meridians, octyldodecyl alcohol, paraffin and the like. Methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, ethyl benzoate, propyl p-hydroxybenzoate, etc. are mentioned as a preservative.

상기 이외로, 통상의 방법에 의해 흡입제, 점안제, 점비제로 할 수도 있다. 본 발명의 의약의 투여량은 연령, 체중, 증상, 투여 형태 및 투여 회수 등에 따라 다르지만, 통상은 성인에 대해서 본 발명 화합물(1)로서 1 일 1∼1000 mg를 1회 또는 수회 나누어 경구투여 또는 비경구 투여하는 것이 바람직하다.In addition to the above, inhalants, eye drops, and nasal drops can also be prepared by conventional methods. The dosage of the medicament of the present invention varies depending on age, weight, symptoms, dosage form, number of administrations, and the like, but is usually orally administered 1 to 1000 mg once or several times per day as the compound (1) of the present invention to adults. Parenteral administration is preferred.

실시예Example

이하, 실시예를 들어 본 발명을 상세하게 설명하지만, 본 발명은 이들로 한정되는 것은 아니다Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these.

제조예 1Preparation Example 1

에틸 2-(3,4,5-트리메톡시페닐)이소니코티네이트의 합성:Synthesis of ethyl 2- (3,4,5-trimethoxyphenyl) isonicotinate:

톨루엔(200㎖)과 THF(100㎖)의 혼합 용매에 3,4,5-트리메톡시페닐붕소산(20.10g)과 에틸 2-클로로이소니코티네이트(18.56g)를 현탁하고, 2M 탄산나트륨(200㎖)을 가했다. 이어서, 테트라키스(트리페닐포스핀)팔라듐(0)(5.78g)을 현탁액에 가하고, 아르곤 분위기하 90℃에서 하룻밤 교반했다. 혼합물에 에틸아세테이트를 가하여 추출하고, 유기층을 포화 식염수로 세정한 후, 무수 황산 마그네슘으로 건조하고, 감압 농축했다. 잔사를 실리카겔 컬럼크로마토그래피(헥산: 에틸아세테이트= 5: 1)로 정제하여 목적물을 얻었다.3,4,5-trimethoxyphenylboronic acid (20.10 g) and ethyl 2-chloroisonicotinate (18.56 g) were suspended in a mixed solvent of toluene (200 mL) and THF (100 mL), and 2M sodium carbonate ( 200 ml) was added. Then, tetrakis (triphenylphosphine) palladium (0) (5.78 g) was added to the suspension, and the mixture was stirred overnight at 90 ° C under argon atmosphere. Ethyl acetate was added to the mixture, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the target product.

수량: 27.99g(88%)Quantity: 27.99 g (88%)

^lH-NMR(400MHz, CDC1₃) δ: 1.45(t, 3H, J=7.0Hz), 3.92(s, 3H), 3.99(s, 6H), 4.46(q, 2H, J=7.0Hz), 7.30(s, 2H), 7.76(dd, 1H, J=5.1Hz, 1.6Hz), 8.24(dd, 1H, J=1.6Hz, 0.8Hz), 8.81(dd, 1H, J=5.1Hz, 0.8Hz) ^{l H-NMR (400MHz, CDC1} 3) δ: 1.45 (t, 3H, J = 7.0Hz), 3.92 (s, 3H), 3.99 (s, 6H), 4.46 (q, 2H, J = 7.0Hz), 7.30 (s, 2H), 7.76 (dd, 1H, J = 5.1 Hz, 1.6 Hz), 8.24 (dd, 1H, J = 1.6 Hz, 0.8 Hz), 8.81 (dd, 1H, J = 5.1 Hz, 0.8 Hz )

제조예 2Preparation Example 2

4-히드록시메틸-2-(3,4,5-트리메톡시페닐) 피리딘의 합성:Synthesis of 4-hydroxymethyl-2- (3,4,5-trimethoxyphenyl) pyridine:

에틸 2-(3,4,5-트리메톡시페닐)이소니코티네이트(24.57g)를 THF(200㎖)에 용해하고, 아르곤 분위기하, 수소화리튬알루미늄(2.94g)을 0℃에서 가했다. 혼합물을 0℃에서 1시간 교반한 후, 소량의 물과 황산나트륨을 반응액에 가하여 생긴 불용물을 세라이트로 여과하여 제거했다. 여액을 감압 농축하고, 조결정을 에틸아세테이트-헥산으로 재결정하여 목적물을 얻었다.Ethyl 2- (3,4,5-trimethoxyphenyl) isonicotinate (24.57 g) was dissolved in THF (200 mL), and lithium aluminum hydride (2.94 g) was added at 0 ° C under argon atmosphere. After the mixture was stirred at 0 ° C. for 1 hour, a small amount of water and sodium sulfate were added to the reaction solution, and the insolubles formed were filtered off with celite. The filtrate was concentrated under reduced pressure, and the crude crystals were recrystallized from ethyl acetate-hexane to obtain the target product.

수량: 17.53 g(82 %)Quantity: 17.53 g (82%)

¹H-NMR(400MHz, CDC1₃) δ: 3.90(s, 3H), 3.95(s, 6H), 4.79(s, 2H), 7.19(d, 1H, J=5.1Hz), 7.21(s, 2H), 7.66(s, 1H), 8.60(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 3.90 (s, 3H), 3.95 (s, 6H), 4.79 (s, 2H), 7.19 (d, 1H, J = 5.1 Hz), 7.21 (s, 2H ), 7.66 (s, 1 H), 8.60 (d, 1 H, J = 5.1 Hz)

제조예 3Preparation Example 3

4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘의 합성:Synthesis of 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine:

4-히드록시메틸-2-(3,4,5-트리메톡시페닐)피리딘(19.18g)을 클로로포름(100㎖)에 용해하고, 0℃에서 티오닐클로라이드(10.2㎖)를 가했다. 0℃에서 30분간, 다시 실온에서 4시간 교반했다. 반응액을 포화 탄산수소나트륨과 포화 식염수로 세정하고, 무수 황산나트륨으로 건조하고, 감압 농축했다. 결정성 잔사를 에틸아세테이트-헥산으로부터 재결정하여 담황색 결정성 분말로서 표기 화합물을 얻었다.4-hydroxymethyl-2- (3,4,5-trimethoxyphenyl) pyridine (19.18 g) was dissolved in chloroform (100 mL) and thionyl chloride (10.2 mL) was added at 0 ° C. It stirred at 0 degreeC for 30 minutes again at room temperature for 4 hours. The reaction solution was washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crystalline residue was recrystallized from ethyl acetate-hexane to obtain the title compound as a pale yellow crystalline powder.

수량: 18.24g(89%)Quantity: 18.24 g (89%)

¹H-NMR(400MHz, CDC1₃) δ: 3.91(s, 3H), 3.97(s, 6H), 4.61(s, 2H), 7.24(s, 2H), 7.26(d, 1H, J=5.1Hz), 7.68(s, 1H), 8.67(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 3.91 (s, 3H), 3.97 (s, 6H), 4.61 (s, 2H), 7.24 (s, 2H), 7.26 (d, 1H, J = 5.1 Hz ), 7.68 (s, 1 H), 8.67 (d, 1 H, J = 5.1 Hz)

제조예 4Preparation Example 4

N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]프탈이미드의 합성:Synthesis of N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] phthalimide:

4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(881mg)을 클로로포름(10㎖)에 용해하고, 이어서 프탈이미드칼륨(556mg)을 가했다. 혼합물을 실온에서 하룻밤 교반하고, 물을 가했다. 유기층을 분리 후, 수층을 클로로포름으로 추출했다. 유기층을 합하고, 무수 황산마그네슘으로 건조한 후, 감압 농축하여 표기 화합물을 백색 분말로서 얻었다.4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (881 mg) was dissolved in chloroform (10 mL), followed by addition of potassium phthalimide (556 mg). The mixture was stirred at rt overnight, and water was added. After separating an organic layer, the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the title compound as a white powder.

수량: 1.16g (96%)Quantity: 1.16g (96%)

제조예 5Preparation Example 5

4-아미노메틸-2-(3,4,5-트리메톡시페닐)피리딘의 합성:Synthesis of 4-aminomethyl-2- (3,4,5-trimethoxyphenyl) pyridine:

N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]프탈이미드(1.16g)를 에탄올(30㎖)에 현탁하고, 히드라진 1수화물(1㎖)을 가했다. 혼합물을 3시간 가열 환류했다. 방냉한 후, 불용물을 여과하여 제거하고, 여액을 감압 농축했다. 잔사를클로로포름에 용해해, 포화 탄산수소나트륨수, 식염수로 세정해, 무수 황산마그네슘으로 건조 후, 감압 농축하여 목적물을 담황색 유상물로서 얻었다.N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] phthalimide (1.16 g) was suspended in ethanol (30 mL), and hydrazine monohydrate (1 mL). Added. The mixture was heated to reflux for 3 hours. After allowing to cool, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform, washed with saturated sodium bicarbonate water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the target product as a pale yellow oil.

수량: 418mg (53%)Quantity: 418mg (53%)

제조예 6Preparation Example 6

에틸 1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘-4카르복실레이트의 합성:Synthesis of ethyl 1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine-4carboxylate:

에틸 피페리딘-4-카르복실레이트(514mg), 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(969mg), 탄산칼륨(452mg)을 아세토니트릴(20㎖)에 현탁하고, 실온에서 4시간 교반했다. 반응액을 감압 농축 후, 클로로포름과 물을 가하여 유기층을 분리했다. 수층을 클로로포름으로 추출하고, 유기층을 합하여 무수 황산마그네슘으로 건조했다. 감압 농축 후, 잔사를 실리카겔 컬럼크로마토그래피(헥산: 에틸아세테이트 =1: 1, 이어서 클로로포름: 메탄올 = 40: 1)로 정제하여 표기 화합물을 백색 프리즘 결정으로서 얻었다.Ethyl piperidine-4-carboxylate (514 mg), 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (969 mg), potassium carbonate (452 mg) to acetonitrile (20 mL) It was suspended in and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and then chloroform and water were added to separate an organic layer. The aqueous layer was extracted with chloroform, and the organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1, then chloroform: methanol = 40: 1) to obtain the title compound as white prism crystals.

수량: 1.20g (88%)Quantity: 1.20g (88%)

¹H-NMR(400MHz, CDC1₃) δ: 1.25(t, 3H, J=7.0Hz), 1.72-1.93(m, 4H), 2.10(t, 2H, J=9.8Hz), 2.27-2.35(m, 1H), 2.86(d, 2H, J=11.3Hz), 3.55(s, 2H),3.91(s, 3H), 3.98(s, 6H), 4.14(q, 2H, J=7.0Hz), 7.21(d, 1H, J=4.9Hz), 7.24(s, 2H), 7.63(s, 1H), 8.59(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.25 (t, 3H, J = 7.0 Hz), 1.72-1.93 (m, 4H), 2.10 (t, 2H, J = 9.8 Hz), 2.27-2.35 (m , 1H), 2.86 (d, 2H, J = 11.3 Hz), 3.55 (s, 2H), 3.91 (s, 3H), 3.98 (s, 6H), 4.14 (q, 2H, J = 7.0 Hz), 7.21 (d, 1H, J = 4.9 Hz), 7.24 (s, 2H), 7.63 (s, 1H), 8.59 (d, 1H, J = 5.1 Hz)

제조예 7Preparation Example 7

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘-4-카르복실산의 합성:Synthesis of 1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine-4-carboxylic acid:

에틸 1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]피페리딘-4-카르복실레이트(760mg)를 에탄올(10㎖)에 용해하고, 1M 수산화나트륨(10㎖)을 가했다. 혼합물을 실온에서 4시간 교반한 후, 감압하 에탄올을 증류하고, 잔사에 물 20㎖를 가했다. 5% 황산수소칼륨 수용액을 서서히 용액에 적하하고, pH를 7로 했다. 석출한 결정을 취하고, 이를 더 이상 정제하지 않고, 다음의 스텝에 이용했다.Ethyl 1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] piperidine-4-carboxylate (760 mg) is dissolved in ethanol (10 ml) and 1M sodium hydroxide (10 mL) was added. After the mixture was stirred at room temperature for 4 hours, ethanol was distilled off under reduced pressure, and 20 ml of water was added to the residue. A 5% aqueous potassium hydrogen sulfate solution was slowly added dropwise to the solution, and the pH was adjusted to 7. The precipitated crystals were taken out and used for the next step without further purification.

수량: 779mgQuantity: 779mg

실시예 1Example 1

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]-4-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸아미노카르보닐]피페리딘·말레인산염의 합성:1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] -4-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl ] Synthesis of methylaminocarbonyl] piperidine maleate:

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘-4-카르복실산(97mg)과 4-아미노메틸-2-(3,4,5-트리메톡시페닐)피리딘(68mg)을 아세토니트릴(5㎖)에 용해하고, 2-(1H-벤조트리아졸-1-일)-1,1,3,3-테트라메틸우로늄헥사플루오로포스페이트(95mg)를 가했다. 혼합물을 실온에서 12시간 교반하고, 감압 농축했다. 잔사를 클로로포름에 용해하고, 포화 탄산수소나트륨수, 포화 식염수로 세정하고, 무수 황산마그네슘으로 건조 후, 감압 농축했다. 잔사를 실리카겔 컬럼크로마토그래피(클로로포름: 메탄올= 40: 1∼20: 1)로 정제하여 표기 화합물을 유리 염기로서 얻었다. 이것을 메탄올에 용해한 후, 말레인산을 가하여 말레인산염으로 했다.1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine-4-carboxylic acid (97 mg) with 4-aminomethyl-2- (3,4 , 5-trimethoxyphenyl) pyridine (68 mg) was dissolved in acetonitrile (5 mL) and 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexa Fluorophosphate (95 mg) was added. The mixture was stirred at room temperature for 12 hours and concentrated under reduced pressure. The residue was dissolved in chloroform, washed with saturated sodium bicarbonate water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1-20: 1) to obtain the title compound as a free base. After dissolving this in methanol, maleic acid was added to make maleic acid salt.

수량: 93mg (49%)Quantity: 93mg (49%)

¹H-NMR(400MHz, 말레인산염으로서 측정, DMSO-d₆) δ: 1.87-2.01(m, 4H), 2.48-2.56(m, 1H), 2.78-2.86(m, 2H), 3.26-3.31(m, 2H), 3.78(s, 3H), 3.79(s, 3H), 3.87(s, 6H), 3.90(s, 6H), 4.15(s, 2H), 4.39(d, 2H, J=5.9Hz), 6.16(s, 2H), 7.16(d, 1H, J=5.9Hz), 7.35(s, 2H), 7.39(d, 1H, J=5.9Hz), 7.39(s, 2H), 7.73(s, 1H), 7.95(s, 1H), 8.15(d, 1H, J=5.9Hz), 8.54(d, 1H, J=4.9Hz), 8.68(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, measured as maleate, DMSO-d ₆ ) δ: 1.87-2.01 (m, 4H), 2.48-2.56 (m, 1H), 2.78-2.86 (m, 2H), 3.26-3.31 ( m, 2H), 3.78 (s, 3H), 3.79 (s, 3H), 3.87 (s, 6H), 3.90 (s, 6H), 4.15 (s, 2H), 4.39 (d, 2H, J = 5.9 Hz ), 6.16 (s, 2H), 7.16 (d, 1H, J = 5.9 Hz), 7.35 (s, 2H), 7.39 (d, 1H, J = 5.9 Hz), 7.39 (s, 2H), 7.73 (s , 1H), 7.95 (s, 1H), 8.15 (d, 1H, J = 5.9 Hz), 8.54 (d, 1H, J = 4.9 Hz), 8.68 (d, 1H, J = 4.9 Hz)

제조예 8Preparation Example 8

1-(벤질옥시카르보닐)-4-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸옥시]피페리딘의 합성:Synthesis of 1- (benzyloxycarbonyl) -4-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyloxy] piperidine

1-(벤질옥시카르보닐)-4-히드록시피페리딘(1.0g)을 DMF(20㎖)에 용해하고, 수소화나트륨(55% 광유 현탁액; 222mg)을 가하고, 실온에서 1시간 교반했다. 이어서, 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(1.37g)과 요드화칼륨(755mg)을 가하고, 70℃에서 하룻밤 교반했다. 반응액에 물을 가하고, 클로로포름으로 추출했다. 유기층을 포화 식염수로 세정, 무수 황산나트륨으로 건조 후, 감압 농축했다. 잔사를 실리카겔 컬럼크로마토그래피(클로로포름: 메탄올 =99: 1)로 정제하여 표기 화합물을 얻었다.1- (benzyloxycarbonyl) -4-hydroxypiperidine (1.0 g) was dissolved in DMF (20 mL), sodium hydride (55% mineral oil suspension; 222 mg) was added, and the mixture was stirred at room temperature for 1 hour. Subsequently, 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (1.37 g) and potassium iodide (755 mg) were added, and it stirred at 70 degreeC overnight. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 99: 1) to obtain the title compound.

수량 213mg (10%)Quantity 213mg (10%)

¹H-NMR(400MHz, CDC1₃) δ: 1.63(br, 2H), 1.89(br, 2H), 3.20-3.35(m, 2H), 3.57-3.68(m, 1H), 3.84-3.92(m, 5H), 3.94(s, 6H), 4.62(s, 2H), 5.11(s, 2H), 7.21-7.35(m, 8H), 7.61(s, 1H), 8.61(d, 1H, J=5.0Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.63 (br, 2H), 1.89 (br, 2H), 3.20-3.35 (m, 2H), 3.57-3.68 (m, 1H), 3.84-3.92 (m, 5H), 3.94 (s, 6H), 4.62 (s, 2H), 5.11 (s, 2H), 7.21-7.35 (m, 8H), 7.61 (s, 1H), 8.61 (d, 1H, J = 5.0Hz )

제조예 9Preparation Example 9

4-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸옥시]피페리딘의 합성:Synthesis of 4-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyloxy] piperidine:

1-(벤질옥시카르보닐)-4-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸옥시]피페리딘(213mg)을 메탄올(10㎖)에 용해하고, 40% 수산화칼륨 수용액(10㎖)을 가하고 100℃에서 3시간 교반했다. 감압 농축 후, 잔사에 물을 가하고, 클로로포름으로 추출했다. 유기층을 포화 식염수로 세정해, 무수 황산나트륨으로 건조 후, 감압 농축했다. 잔사를 실리카겔 컬럼크로마토그래피(클로로포름: 암모니아 포화 메탄올=20: 1)로 정제하여 표기 화합물을 얻었다.Dissolve 1- (benzyloxycarbonyl) -4-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyloxy] piperidine (213 mg) in methanol (10 mL) 40% potassium hydroxide aqueous solution (10 ml) was added, and it stirred at 100 degreeC for 3 hours. After concentration under reduced pressure, water was added to the residue, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ammonia saturated methanol = 20: 1) to obtain the title compound.

수량: 93mg (60%)Quantity: 93mg (60%)

¹H-NMR(400MHz, CDC1₃) δ: 1.55-1.68(m, 2H), 2.01(br, 2H), 2.67-2.72(m, 2H), 3.13-3.18(m, 2H), 3.50-3.60(m, 1H), 3.91(s, 3H), 3.97(s, 6H), 4.64(s, 2H), 7.22(d, 1H, J=4.3Hz), 7.24(s, 2H), 7.64(s, 1H), 8.63(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.55-1.68 (m, 2H), 2.01 (br, 2H), 2.67-2.72 (m, 2H), 3.13-3.18 (m, 2H), 3.50-3.60 ( m, 1H), 3.91 (s, 3H), 3.97 (s, 6H), 4.64 (s, 2H), 7.22 (d, 1H, J = 4.3 Hz), 7.24 (s, 2H), 7.64 (s, 1H ), 8.63 (d, 1H, J = 5.1 Hz)

실시예 2Example 2

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]-4-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸옥시]피페리딘·3염산염의 합성:1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] -4-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl ] Synthesis of methyloxy] piperidinetrichloride:

4-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸옥시]피페리딘(70mg), 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(22mg), 탄산칼륨(56mg)과 요드화칼륨(40mg)을 아세토니트릴(5㎖)에 현탁하고, 실온에서 5시간 교반했다. 혼합물을 감압 농축 후, 잔사에 물과 클로로포름을 가하고, 유기층을 분리했다. 수층을 클로로포름으로 추출해, 유기층을 맞추어 무수 황산마그네슘으로 건조했다. 감압 농축 후, 잔사를 실리카겔 컬럼크로마토그래피(클로로포름: 메탄올 =40: 1)로 정제하고, 얻어진 유리 염기를 통상의 방법에 의해 3염산염으로 했다.4-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyloxy] piperidine (70 mg), 4-chloromethyl-2- (3,4,5-trimeth The oxyphenyl) pyridine (22 mg), potassium carbonate (56 mg) and potassium iodide (40 mg) were suspended in acetonitrile (5 mL) and stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure, water and chloroform were added to the residue, and the organic layer was separated. The aqueous layer was extracted with chloroform, the organic layers were combined, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1) and the free base obtained was triturated by a conventional method.

수량: 42mg (39%)Quantity: 42mg (39%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.53-2.42(m, 6H), 2.80(br, 2H), 3.57(br, 3H), 3.88(s, 6H), 3.94(s, 6H), 3.95(s, 6H), 4.60(s, 2H), 7.18-7.24(m, 3H), 7.61(s, 2H), 8.58-8.61(m, 2H) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.53-2.42 (m, 6H), 2.80 (br, 2H), 3.57 (br, 3H), 3.88 (s, 6H), 3.94 (s , 6H), 3.95 (s, 6H), 4.60 (s, 2H), 7.18-7.24 (m, 3H), 7.61 (s, 2H), 8.58-8.61 (m, 2H)

제조예 10Preparation Example 10

(3S)-1-(tert-부톡시카르보닐)-3-(2-니트로벤젠술포닐아미노)피롤리딘의 합성:Synthesis of (3S) -1- (tert-butoxycarbonyl) -3- (2-nitrobenzenesulfonylamino) pyrrolidine:

(3S)-3-아미노-1-(tert-부톡시카르보닐)피롤리딘(404mg)과 트리에틸아민(220mg)의 THF(5㎖) 용액에 빙냉하, 2-니트로벤젠술포닐클로라이드(481mg)를 가하고, 실온에서 30분간 교반했다. 감압 농축 후, 잔사에 에틸아세테이트를 가하고, 물, 포화 식염수로 세정하고, 무수 황산나트륨으로 건조한 후, 감압 농축했다. 잔사를 실리카겔 컬럼크로마토그래피(클로로포름: 메탄올 =20: 1)로 정제하여 표기 화합물을 담황색 무정형 결정으로서 얻었다.(3S) -3-amino-1- (tert-butoxycarbonyl) pyrrolidine (404 mg) and triethylamine (220 mg) in THF (5 mL) solution under ice-cooling, 2-nitrobenzenesulfonyl chloride ( 481 mg) was added and stirred at room temperature for 30 minutes. After concentration under reduced pressure, ethyl acetate was added to the residue, washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain the title compound as a pale yellow amorphous crystal.

수량: 597mg (74%)Quantity: 597mg (74%)

¹H-NMR(400MHz, CDC1₃) δ: 1.44(s, 9H), 1.80-2.12(m, 2H), 3.14-3.44(m, 4H), 4.02(br, 1H), 5.48(d, 1H, J=7.2Hz), 7.77(t, 2H, J=4.4Hz), 7.87-7.90(m, 1H) 8.17-8.19(m, 1H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.44 (s, 9H), 1.80-2.12 (m, 2H), 3.14-3.44 (m, 4H), 4.02 (br, 1H), 5.48 (d, 1H, J = 7.2 Hz), 7.77 (t, 2H, J = 4.4 Hz), 7.87-7.90 (m, 1H) 8.17-8.19 (m, 1H)

제조예 11Preparation Example 11

(3S)-1-(tert-부톡시카르보닐)-3-[N-메틸-N-(2-니트로벤젠술포닐)아미노]피롤리딘의 합성:Synthesis of (3S) -1- (tert-butoxycarbonyl) -3- [N-methyl-N- (2-nitrobenzenesulfonyl) amino] pyrrolidine:

(3S)-1-(tert-부톡시카르보닐)-3-(2-니트로벤젠술포닐아미노)피롤리딘(371mg)과 탄산칼륨(138mg)을 아세토니트릴(10㎖)에 현탁하고, 요드화메틸(141mg)을 가하고, 60℃에서 2시간 교반했다. 반응액을 감압 농축하고, 에틸아세테이트를 가하고, 포화 탄산수소나트륨수, 포화 식염수로 세정한 후, 무수 황산나트륨으로 건조하고, 감압하 농축했다. 잔사를 실리카겔 컬럼크로마토그래피(헥산: 에틸아세테이트 = 2: 1)로 정제하여 표기 화합물을 황색 유상물로서 얻었다.(3S) -1- (tert-butoxycarbonyl) -3- (2-nitrobenzenesulfonylamino) pyrrolidine (371 mg) and potassium carbonate (138 mg) were suspended in acetonitrile (10 mL), and iodine Methyl chloride (141 mg) was added, and it stirred at 60 degreeC for 2 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the title compound as a yellow oil.

수량: 365mg (95%)Quantity: 365mg (95%)

¹H-NMR(400MHz, CDC1₃) δ: 1.44(s, 9H), 1.95(br, 1H), 2.09(br, 1H), 2.87(s, 3H), 3.20-3.31(m, 2H), 3.53(br, 2H), 4.58(br, 1H), 7.65(br, 1H), 7.71(br, 2H), 8.04(br, 1H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.44 (s, 9H), 1.95 (br, 1H), 2.09 (br, 1H), 2.87 (s, 3H), 3.20-3.31 (m, 2H), 3.53 (br, 2H), 4.58 (br, 1H), 7.65 (br, 1H), 7.71 (br, 2H), 8.04 (br, 1H)

제조예 12Preparation Example 12

(3S)-3-[N-메틸-N-(2-니트로벤젠술포닐)아미노]피롤리딘의 합성:Synthesis of (3S) -3- [N-methyl-N- (2-nitrobenzenesulfonyl) amino] pyrrolidine:

(3S)-1-(tert-부톡시카르보닐)-3-[N-메틸-N-(2-니트로벤젠술포닐)아미노]피롤리딘(365mg)을 디클로로메탄(25㎖)에 용해하고, 0℃에서 트리플루오로아세트산(1㎖)을 가하고, 실온에서 3시간 교반했다. 감압 농축 후, 클로로포름을 가하고, 포화 탄산수소나트륨 수용액, 포화 식염수로 세정한 후, 무수 황산나트륨으로 건조하고, 감압하 농축하여 표기 화합물을 황색 유상물로서 얻었다.(3S) -1- (tert-butoxycarbonyl) -3- [N-methyl-N- (2-nitrobenzenesulfonyl) amino] pyrrolidine (365 mg) was dissolved in dichloromethane (25 mL) Trifluoroacetic acid (1 ml) was added at 0 degreeC, and it stirred at room temperature for 3 hours. After concentration under reduced pressure, chloroform was added, washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound as a yellow oil.

수량: 135mg (50%)Quantity: 135mg (50%)

¹H-NMR(400MHz, CDC1₃) δ: 1.69-1.74(m, 1H), 1.95-2.02(m, 1H), 2.80(dd, 1H, J=11.7Hz, 5.7Hz), 2.84-2.91(m, 4H), 2.96-3.05(m, 1H), 3.10(dd, 1H, J=11.7Hz, 8.2Hz), 4.48-4.56(m, 1H), 7.61-7.63(m, 1H), 7.66-7.73(m, 2H), 8.01-8.04(m, 1H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.69-1.74 (m, 1H), 1.95-2.02 (m, 1H), 2.80 (dd, 1H, J = 11.7 Hz, 5.7 Hz), 2.84-2.91 (m , 4H), 2.96-3.05 (m, 1H), 3.10 (dd, 1H, J = 11.7 Hz, 8.2 Hz), 4.48-4.56 (m, 1H), 7.61-7.63 (m, 1H), 7.66-7.73 ( m, 2H), 8.01-8.04 (m, 1H)

제조예 13Preparation Example 13

(3S)-3-[N-메틸-N-(2-니트로벤젠술포닐)아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피롤리딘의 합성:(3S) -3- [N-methyl-N- (2-nitrobenzenesulfonyl) amino] -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] Synthesis of pyrrolidine:

(3S)-3-[N-메틸-N-(2-니트로벤젠술포닐)아미노]피롤리딘(135mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(139mg)을 실시예 2와 동일하게 처리하여 표기 화합물을 황색 무정형 결정으로서 얻었다.(3S) -3- [N-methyl-N- (2-nitrobenzenesulfonyl) amino] pyrrolidine (135 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (139 mg) was treated in the same manner as in Example 2 to obtain the title compound as a yellow amorphous crystal.

수율: 247mg (96%)Yield: 247 mg (96%)

¹H-NMR(400MHz, CDC1₃) δ: 1.80-1.87(m, 1H), 2.15-2.30(m, 2H), 2.52(dd, 1H, J=10.5Hz, 8.2Hz), 2.71(dd, 1H, J=10.5Hz, 8.2Hz), 2.90(dt, 1H, J=8.8Hz, 2.9Hz), 2.96(s, 3H), 3.53(d, 1H, J=13.9Hz), 3.68(d, 1H, J=13.9Hz), 3.90(s, 3H), 3.96(s, 6H), 4.61-4.68(m, 1H), 7.16(dd, 1H, J=4.9Hz, 1.2Hz), 7.21(s, 2H), 7.58-7.60(m, 2H), 7.64-7.69(m, 2H), 7.99-8.02(m, 1H), 8.58(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.80-1.87 (m, 1H), 2.15-2.30 (m, 2H), 2.52 (dd, 1H, J = 10.5 Hz, 8.2 Hz), 2.71 (dd, 1H , J = 10.5 Hz, 8.2 Hz), 2.90 (dt, 1H, J = 8.8 Hz, 2.9 Hz), 2.96 (s, 3H), 3.53 (d, 1H, J = 13.9 Hz), 3.68 (d, 1H, J = 13.9 Hz), 3.90 (s, 3H), 3.96 (s, 6H), 4.61-4.68 (m, 1H), 7.16 (dd, 1H, J = 4.9 Hz, 1.2 Hz), 7.21 (s, 2H) , 7.58-7.60 (m, 2H), 7.64-7.69 (m, 2H), 7.99-8.02 (m, 1H), 8.58 (d, 1H, J = 4.9 Hz)

제조예 14Preparation Example 14

(3S)-3-메틸아미노-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피롤리딘의 합성:Synthesis of (3S) -3-methylamino-1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] pyrrolidine:

(3S)-3-[N-메틸-N-(2-니트로벤젠술포닐)아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피롤리딘(242mg)을 아세토니트릴(5㎖)에 용해하고, 탄산칼륨(94mg), 티오페놀(75mg)을 가하고, 80℃에서 1시간 교반했다. 방냉 후, 에틸아세테이트를 가하고, 포화 탄산수소나트륨수, 물, 포화 식염수로 세정한 후, 무수 황산나트륨으로 건조, 감압 농축했다. 잔사를 실리카겔 분취 박층크로마토그래피(클로로포름: 메탄올= 20: 1)로 정제하여 표기 화합물을 황색 유상물로서 얻었다.(3S) -3- [N-methyl-N- (2-nitrobenzenesulfonyl) amino] -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] Pyrrolidine (242 mg) was dissolved in acetonitrile (5 mL), potassium carbonate (94 mg) and thiophenol (75 mg) were added, and the mixture was stirred at 80 ° C for 1 hour. After cooling, ethyl acetate was added, washed with saturated sodium bicarbonate water, water, and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel preparative thin layer chromatography (chloroform: methanol = 20: 1) to obtain the title compound as a yellow oil.

수량: 104mg (64%)Quantity: 104mg (64%)

¹H-NMR(400MHz, CDC1₃) δ: 1.32(br, 1H), 1.56-1.64(m, 1H), 2.11-2.17(m, 1H), 2.38(s, 3H), 2.44(dd, 1H, J=7.4Hz, 4.5Hz), 2.50-2.55(m, 1H), 2.66-2.75(m, 2H), 3.20-3.26(m, 1H), 3.66(s, 2H), 3.90(s, 3H), 3.97(s, 6H), 7.21(d, 1H, J=4.1Hz), 7.25(s, 2H), 7.64(s, 1H), 8.59(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.32 (br, 1H), 1.56-1.64 (m, 1H), 2.11-2.17 (m, 1H), 2.38 (s, 3H), 2.44 (dd, 1H, J = 7.4 Hz, 4.5 Hz), 2.50-2.55 (m, 1H), 2.66-2.75 (m, 2H), 3.20-3.26 (m, 1H), 3.66 (s, 2H), 3.90 (s, 3H), 3.97 (s, 6H), 7.21 (d, 1H, J = 4.1 Hz), 7.25 (s, 2H), 7.64 (s, 1H), 8.59 (d, 1H, J = 4.9 Hz)

실시예 3Example 3

(3S)-3-[N-메틸-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]-1-[[ 2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피롤리딘·4염산염의 합성:(3S) -3- [N-methyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1-[[2- (3,4 Synthesis of, 5-trimethoxyphenyl) pyridin-4-yl] methyl] pyrrolidine tetrahydrochloride:

(3S)-3-메틸아미노-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피롤리딘(104mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(85mg)을 실시예 2와 동일하게 반응시키고, 이어서, 4염산염으로 변환함으로서 표기 화합물을 황색 분말로서 얻었다.(3S) -3-methylamino-1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] pyrrolidine (104 mg) and 4-chloromethyl-2- ( The title compound was obtained as a yellow powder by reacting 3,4,5-trimethoxyphenyl) pyridine (85 mg) in the same manner as in Example 2 and then converting to tetrahydrochloride.

수량: 151mg (68%)Quantity: 151mg (68%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.89-1.92(m, 1H), 2.04-2.08(m, 1H), 2.18(s, 3H), 2.60-2.76(m, 4H), 3.25-3.29(m, 1H), 3.53(d, 1H, J=14.3Hz), 3.62(d, 1H, J=14.3Hz), 3.64(d, 1H, J=18.9Hz), 3.73(d, 1H, J=13.9Hz), 3.89(s, 6H), 3.95(s, 6H), 3.96(s, 6H), 7.20-7.21(m, 2H), 7.23(s, 2H), 7.24(s, 2H), 7.61(s, 1H), 7.65(s, 1H), 8.59(d, 1H, J=5.7Hz), 8.60(d, 1H, J=5.3Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.89-1.92 (m, 1H), 2.04-2.08 (m, 1H), 2.18 (s, 3H), 2.60-2.76 (m, 4H) , 3.25-3.29 (m, 1H), 3.53 (d, 1H, J = 14.3 Hz), 3.62 (d, 1H, J = 14.3 Hz), 3.64 (d, 1H, J = 18.9 Hz), 3.73 (d, 1H, J = 13.9 Hz), 3.89 (s, 6H), 3.95 (s, 6H), 3.96 (s, 6H), 7.20-7.21 (m, 2H), 7.23 (s, 2H), 7.24 (s, 2H ), 7.61 (s, 1H), 7.65 (s, 1H), 8.59 (d, 1H, J = 5.7 Hz), 8.60 (d, 1H, J = 5.3 Hz)

제조예 15Preparation Example 15

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘-4-카르복사미드의합성:Synthesis of 1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine-4-carboxamide:

피페리딘-4-카르복사미드(385mg)와 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(881mg)을 실시예 2와 동일하게 반응시켜 표기 화합물을 백색 침상 결정으로서 얻었다.Piperidine-4-carboxamide (385 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (881 mg) were reacted in the same manner as in Example 2 to give the title compound as a white needle. Obtained as a crystal.

수량: 1.01g (87%)Quantity: 1.01g (87%)

¹H-NMR(400MHz, CDC1₃) δ: 1.70-1.88(m, 4H), 2.01-2.23(m, 3H), 2.95(d, 2H, J=11.0Hz), 3.56(s, 2H), 3.90(s, 3H), 3.98(s, 6H), 5.46(d, 2H, J=16.3Hz), 7.21(d, 1H, J=5.0Hz), 7.24(s, 2H), 7.64(s, 1H), 8.59(d, 1H, J=5.0Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.70-1.88 (m, 4H), 2.01-2.23 (m, 3H), 2.95 (d, 2H, J = 11.0 Hz), 3.56 (s, 2H), 3.90 (s, 3H), 3.98 (s, 6H), 5.46 (d, 2H, J = 16.3 Hz), 7.21 (d, 1H, J = 5.0 Hz), 7.24 (s, 2H), 7.64 (s, 1H) , 8.59 (d, 1H, J = 5.0 Hz)

제조예 16Preparation Example 16

4-아미노-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:Synthesis of 4-amino-1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘-4-카르복사미드(192mg)를 아세토니트릴(50㎖)과 물(50㎖)의 혼합 용매에 용해하고, [비스(트리플루오로아세톡시)요드]벤젠(323mg)을 가했다. 혼합물을 실온에서 하룻밤 교반하고, 감압 농축했다. 잔사에 포화 탄산수소나트륨수를 가하여 알칼리성으로 하고, 클로로포름으로 추출했다. 클로로포름층을 포화 식염수로 세정, 무수 황산마그네슘으로 건조하고, 감압 농축했다. 얻을 수 있던 황색 유상물을 염산염으로 변환하고, 황색 분말을 얻었다. 표기 화합물은 더 이상의 정제는 실시하지 않고, 다음의 스텝에 이용했다.1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine-4-carboxamide (192 mg) was dissolved in acetonitrile (50 mL) and water (50 mL). ) And [bis (trifluoroacetoxy) iodide] benzene (323 mg) was added. The mixture was stirred at rt overnight, and concentrated under reduced pressure. Saturated sodium hydrogencarbonate water was added to the residue to make it alkaline and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained yellow oily substance was converted into the hydrochloride, and yellow powder was obtained. The title compound was used for the next step without further purification.

수량: 201mg (이론량)Quantity: 201mg (Theoretical quantity)

제조예 17Preparation Example 17

2-(3,4,5-트리메톡시페닐)이소니코틴산의 합성:Synthesis of 2- (3,4,5-trimethoxyphenyl) isonicotinic acid:

에틸 2-(3,4,5-트리메톡시페닐)이소니코티네이트(3.17g)를 에탄올(40㎖)에 용해하고, 10% 수산화칼륨(2.42㎖)을 가했다. 혼합물을 실온에서 5시간 교반하고, 감압 농축했다. 잔사에 소량의 물을 가하고, pH를 7에 조정하고, 석출한 백색 고체를 여과하여 취했다. 얻어진 표기 화합물은 더 이상의 정제는 실시하지 않고, 다음의 반응에 이용했다.Ethyl 2- (3,4,5-trimethoxyphenyl) isonicotinate (3.17 g) was dissolved in ethanol (40 mL) and 10% potassium hydroxide (2.42 mL) was added. The mixture was stirred at room temperature for 5 hours, and concentrated under reduced pressure. A small amount of water was added to the residue, the pH was adjusted to 7, and the precipitated white solid was collected by filtration. The title compound thus obtained was used for the next reaction without further purification.

수량: 2.60g(90%)Quantity: 2.60g (90%)

실시예 4Example 4

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]-4-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일] 카르보닐아미노]피페리딘·말레인산염의 합성:1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] -4-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl ] Carbonylamino] piperidine maleate synthesis:

2-(3,4,5-트리메톡시페닐)피리딘-4-카르복실산(72mg)과 4-아미노-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(117mg)을 실시예 1과 동일하게 반응시키고, 이어서, 말레인산염으로 함으로써 표기 화합물을 얻었다.2- (3,4,5-trimethoxyphenyl) pyridine-4-carboxylic acid (72 mg) with 4-amino-1-[[2- (3,4,5-trimethoxyphenyl) pyridine-4 -Yl] methyl] piperidine (117 mg) was reacted in the same manner as in Example 1, and then the maleic acid salt was used to obtain the title compound.

수량: 173mg (93%)Quantity: 173mg (93%)

¹H-NMR(400MHz, 말레인산염으로서 측정, DMSO-d₆) δ: 1.82-1.94(m, 2H), 2.03-2.08(m, 2H), 2.77-2.83(m, 2H), 3.20-3.27(m, 2H), 3.79(s, 6H), 3.90(s, 12H), 4.00(br, 1H), 4.06(s, 2H), 6.15(s, 2H), 7.36-7.38(m, 1H), 7.39(s, 2H), 7.41(s, 2H), 7.61-7.63(m, 1H), 7.90(s, 1H), 8.12(s, 1H), 8.27-8.32(m, 1H), 8.67(d, 1H, J=4.9Hz), 8.74(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, measured as maleate, DMSO-d ₆ ) δ: 1.82-1.94 (m, 2H), 2.03-2.08 (m, 2H), 2.77-2.83 (m, 2H), 3.20-3.27 ( m, 2H), 3.79 (s, 6H), 3.90 (s, 12H), 4.00 (br, 1H), 4.06 (s, 2H), 6.15 (s, 2H), 7.36-7.38 (m, 1H), 7.39 (s, 2H), 7.41 (s, 2H), 7.61-7.63 (m, 1H), 7.90 (s, 1H), 8.12 (s, 1H), 8.27-8.32 (m, 1H), 8.67 (d, 1H) , J = 4.9 Hz), 8.74 (d, 1H, J = 5.1 Hz)

제조예 18Preparation Example 18

4-(2-니트로벤젠술포닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘의 합성:Synthesis of 4- (2-nitrobenzenesulfonylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine:

4-아미노-1-[[ 2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(467mg)과 2-니트로벤젠술포닐클로라이드(244mg)를 제조예 10과 동일하게 반응시켜 표기 화합물을 얻었다.Preparation Example of 4-amino-1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (467 mg) and 2-nitrobenzenesulfonyl chloride (244 mg) The reaction was carried out in the same manner as 10 to obtain the title compound.

수량: 494mg (91%)Quantity: 494mg (91%)

제조예 19Preparation Example 19

4-[N-(2-니트로벤젠술포닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘의 합성:4- [N- (2-nitrobenzenesulfonyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1-[[2- ( Synthesis of 3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine:

4-(2-니트로벤젠술포닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(494mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(267mg)을 실시예 2와 동일하게 반응시켜 표기 화합물을 얻었다.4- (2-nitrobenzenesulfonylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (494 mg) and 4-chloromethyl- 2- (3,4,5-trimethoxyphenyl) pyridine (267 mg) was reacted in the same manner as in Example 2 to obtain the title compound.

수량: 443mg (61%)Quantity: 443mg (61%)

실시예 5Example 5

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]-4-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸아미노]피페리딘·2푸말산염의 합성:1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] -4-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl ] Synthesis of methylamino] piperidine-2 fumarate:

4-[N-(2-니트로벤젠술포닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(443mg)을 제조예 14와 동일하게 처리하여 표기 화합물을 2푸말산염으로서 얻었다.4- [N- (2-nitrobenzenesulfonyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1-[[2- ( 3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (443 mg) was treated in the same manner as in Production Example 14 to obtain the title compound as difumarate.

수량: 103mg (24%)Quantity: 103mg (24%)

¹H-NMR(400MHz, 2말레인산염으로서 측정, DMSO-d₆) δ: 1.44-1.53(m, 2H), 1.87-1.91(m, 2H), 2.15(t, 2H, J=1.1Hz), 2.57-2.64(m, 1H), 2.82-2.85(m, 2H), 3.59(s, 2H), 3.78(s, 6H), 3.89(s, 12H), 3.90(s, 2H), 6.63(s, 4H), 7.24(d, 1H, J=4.9Hz), 7.29(d, 1H, J=4.9), 7.35(s, 2H), 7.37(s, 2H), 7.76(s, 1H), 7.85(s, 1H), 8.53-8.56(m, 2H). ¹ H-NMR (400 MHz, measured as dimaleate, DMSO-d ₆ ) δ: 1.44-1.53 (m, 2H), 1.87-1.91 (m, 2H), 2.15 (t, 2H, J = 1.1 Hz), 2.57-2.64 (m, 1H), 2.82-2.85 (m, 2H), 3.59 (s, 2H), 3.78 (s, 6H), 3.89 (s, 12H), 3.90 (s, 2H), 6.63 (s, 4H), 7.24 (d, 1H, J = 4.9 Hz), 7.29 (d, 1H, J = 4.9), 7.35 (s, 2H), 7.37 (s, 2H), 7.76 (s, 1H), 7.85 (s , 1H), 8.53-8.56 (m, 2H).

제조예 20Preparation Example 20

4-(에톡시카르보닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘의 합성:Synthesis of 4- (ethoxycarbonylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine:

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘-4-카르복사미드(528mg)를 에탄올(10㎖)과 아세토니트릴(10㎖)에 용해하고, [비스(트리플루오로아세톡시) 요드]벤젠(884mg)을 가하고, 실온에서 하룻밤 교반했다. 혼합물을 감압 농축 후, 포화 탄산수소나트륨수를 가하고, 클로로포름으로 추출했다. 유기층을 포화 식염수로 세정하고, 무수 황산마그네슘으로, 건조하고, 감압 농축했다. 잔사를 실리카겔컬럼크로마토그래피(클로로포름: 메탄올 =20: 1)로 정제하여 표기 화합물을 얻었다.1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine-4-carboxamide (528 mg) was diluted with ethanol (10 mL) and acetonitrile (10 mL). ), [Bis (trifluoroacetoxy) iodide] benzene (884 mg) was added, and it stirred at room temperature overnight. The mixture was concentrated under reduced pressure, saturated sodium bicarbonate water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain the title compound.

수량: 566mg (96%)Quantity: 566mg (96%)

¹H-NMR(400MHz, CDC1₃) δ: 1.21(t, 3H, J=7.0Hz), 1.40-1.51(m, 2H), 1.92(d, 2H, J=10.9Hz), 2.15(t, 2H, J=10.9Hz), 2.78(d, 2H, J=11.6Hz), 3.52(br, 3H), 3.87(s, 3H), 3.94(s, 6H), 4.07(q, 2H, J=7.0Hz), 4.56(br, 1H), 7.17(d, 1H, J=4.9Hz), 7.21(s, 2H), 7.59(s, 1H), 8.56(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.21 (t, 3H, J = 7.0 Hz), 1.40-1.51 (m, 2H), 1.92 (d, 2H, J = 10.9 Hz), 2.15 (t, 2H , J = 10.9 Hz), 2.78 (d, 2H, J = 11.6 Hz), 3.52 (br, 3H), 3.87 (s, 3H), 3.94 (s, 6H), 4.07 (q, 2H, J = 7.0 Hz ), 4.56 (br, 1H), 7.17 (d, 1H, J = 4.9 Hz), 7.21 (s, 2H), 7.59 (s, 1H), 8.56 (d, 1H, J = 5.1 Hz)

제조예 21Preparation Example 21

4-(메틸아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘의합성:Synthesis of 4- (methylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine:

아르곤 분위기하, 수소화리튬알루미늄(100mg)을 무수 THF(50㎖)에 현탁하고, 0℃에서, 4-(에톡시카르보닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(566mg)의 무수 THF(50㎖) 용액을 서서히 적하했다. 혼합물을 하룻밤 가열 환류하고, 방냉 후 포화 염화암모늄 수용액을 가했다. 발포가 종료된 후, 에틸아세테이트로 추출하고, 유기층을 포화 식염수로 세정하고, 무수 황산나트륨으로 건조한 후, 감압 농축했다. 잔사를 실리카겔 컬럼크로마토그래피(클로로포름: 암모니아 포화 메탄올 = 9: 1)로 정제하여 표기 화합물을 얻었다.Lithium aluminum hydride (100 mg) was suspended in anhydrous THF (50 mL) in an argon atmosphere, and 4- (ethoxycarbonylamino) -1-[[2- (3,4,5-trimeth) at 0 ° C. Anhydrous THF (50 mL) solution of oxyphenyl) pyridin-4-yl] methyl] piperidine (566 mg) was slowly added dropwise. The mixture was heated to reflux overnight, and after cooling, saturated aqueous ammonium chloride solution was added. After foaming was completed, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ammonia saturated methanol = 9: 1) to obtain the title compound.

수량: 379mg (78%)Quantity: 379mg (78%)

¹H-NMR(400MHz, CDC1₃) δ: 1.36-1.46(m, 2H), 1.89(d, 2H, J=12.5Hz), 2.10(dt, 2H, J=11.5Hz, 1.1Hz), 2.35-2.43(m, 1H), 2.43(s, 3H), 2.86(d, 2H, J=11.6Hz), 3.56(s, 2H), 3.90(s, 3H), 3.97(s, 6H), 7.21(d, 1H, J=5.1Hz), 7.24(s, 2H), 7.64(s, 1H), 8.59(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.36-1.46 (m, 2H), 1.89 (d, 2H, J = 12.5 Hz), 2.10 (dt, 2H, J = 11.5 Hz, 1.1 Hz), 2.35- 2.43 (m, 1H), 2.43 (s, 3H), 2.86 (d, 2H, J = 11.6 Hz), 3.56 (s, 2H), 3.90 (s, 3H), 3.97 (s, 6H), 7.21 (d , 1H, J = 5.1Hz), 7.24 (s, 2H), 7.64 (s, 1H), 8.59 (d, 1H, J = 4.9Hz)

제조예 22Preparation Example 22

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]-4-피페리돈 에틸렌 케탈의합성:Synthesis of 1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone ethylene ketal:

4-피페리돈 에틸렌 케탈(12.0g)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(12.3g)을 실시예 2와 동일하게 반응시켜 표기 화합물을 얻었다.4-piperidone ethylene ketal (12.0 g) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (12.3 g) were reacted in the same manner as in Example 2 to obtain the title compound.

수량:19.0g(이론량)Quantity: 19.0 g (theoretical quantity)

¹H-NMR(400MHz, CDC1₃) δ: 1.68(t, 4H, J=5.6Hz), 2.48(br, 4H), 3.50(s, 2H), 3.82(s, 3H), 3.86(s, 4H), 3.88(s, 6H), 7.13(d, 1H, J=4.9Hz), 7.17(s, 2H), 7.57(s, 1H), 8.51(d, 1H, J=4.9Hz). ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.68 (t, 4H, J = 5.6 Hz), 2.48 (br, 4H), 3.50 (s, 2H), 3.82 (s, 3H), 3.86 (s, 4H ), 3.88 (s, 6H), 7.13 (d, 1H, J = 4.9 Hz), 7.17 (s, 2H), 7.57 (s, 1H), 8.51 (d, 1H, J = 4.9 Hz).

제조예 23Preparation Example 23

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4일]메틸]-4-피페리돈의 합성:Synthesis of 1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4yl] methyl] -4-piperidone:

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]-4-피페리돈 에틸렌 케탈(19.0g)을 THF(200㎖)에 용해하고, 1M 염산(200㎖)을 가했다. 혼합물을 90℃에서 하룻밤 교반한 후, 2M 수산화나트륨으로 중화하고, 에틸아세테이트로 추출했다. 유기층을 포화 식염수로 세정하고, 무수 황산나트륨으로 건조하고, 감압 농축했다.잔사를 실리카겔 컬럼크로마토그래피(클로로포름: 메탄올 =40:1)로 정제하여 표기 화합물을 얻었다.1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone ethylene ketal (19.0 g) was dissolved in THF (200 mL), and 1M hydrochloric acid ( 200 ml) was added. The mixture was stirred at 90 ° C. overnight, then neutralized with 2M sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1) to obtain the title compound.

수량: 15.0g(75%)Quantity: 15.0 g (75%)

¹H-NMR(400MHz, CDC1₃) δ: 2.48(t, 4H, J=6.1Hz), 2.79(t, 4H, J=6.0Hz), 3.69(s, 2H), 3.89(s, 3H), 3.96(s, 6H), 7.24(s, 2H), 7.26(d, 1H, J=4.9Hz), 7.66(s, 1H), 8.62(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 2.48 (t, 4H, J = 6.1 Hz), 2.79 (t, 4H, J = 6.0 Hz), 3.69 (s, 2H), 3.89 (s, 3H), 3.96 (s, 6H), 7.24 (s, 2H), 7.26 (d, 1H, J = 4.9 Hz), 7.66 (s, 1H), 8.62 (d, 1H, J = 4.9 Hz)

제조예 24Preparation Example 24

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]-4-피페리돈의 합성:Synthesis of 1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone:

4-피페리돈 염산염 1수화물(3.07g)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(2.94g)을 실시예 2와 동일하게 반응시켜 표기 화합물을 얻었다.4-piperidone hydrochloride monohydrate (3.07 g) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (2.94 g) were reacted in the same manner as in Example 2 to obtain the title compound.

수량: 3.55g(99%)Quantity: 3.55g (99%)

제조예 25Preparation Example 25

4-(메틸아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘의 합성:Synthesis of 4- (methylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine:

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]-4-피페리돈(1.00g)을 1,2-디클로로에탄(60㎖)에 용해하고, 30% 메틸아민에탄올 용액(750mg)과 트리아세톡시 수소화붕소나트륨(1.66g)을 가하고, 실온에서 3시간 교반했다. 혼합물에 물을 가하고, 감압 농축하고, 잔사에 물을 가하고 클로로포름으로 추출했다. 유기층을 포화 식염수로 세정 후, 무수 황산나트륨으로 건조하고, 감압 농축했다. 잔사를 실리카겔 컬럼크로마토그래피(클로로포름: 메탄올 =40: 1)로 정제하고, 표기 화합물을 황색 유상물로서 얻었다.Dissolve 1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone (1.00 g) in 1,2-dichloroethane (60 mL), 30% methylamine ethanol solution (750 mg) and sodium triacetoxy borohydride (1.66 g) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture, concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1) to obtain the title compound as a yellow oil.

수량: 640mg (62%)Quantity: 640mg (62%)

제조예 26Preparation Example 26

에틸 3-(3,4,5-트리메톡시페닐)벤조에이트의 합성:Synthesis of ethyl 3- (3,4,5-trimethoxyphenyl) benzoate:

3,4,5-트리메톡시페닐보론산(3.7g)과 에틸 3-브로모벤조에이트(4.02g)를 제조예 1과 동일하게 반응시켜 표기 화합물을 얻었다.3,4,5-trimethoxyphenylboronic acid (3.7 g) and ethyl 3-bromobenzoate (4.02 g) were reacted in the same manner as in Production Example 1 to obtain the title compound.

수량: 5.09g(92%)Quantity: 5.09 g (92%)

¹H-NMR(400MHz, CDC1₃) δ: 1.42(t, 3H, J=7.1Hz), 3.90(s, 3H), 3.94(s, 6H), 4.41(q, 2H, J=7.1Hz), 6.79(s, 2H), 7.50(t, 1H, J=7.8Hz), 7.73(dt, 1H, J=7.1Hz, 1.5Hz), 8.01(dt, 1H, J=7.8Hz, 1.4Hz), 8.23(t, 1H, J=1.8Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.42 (t, 3H, J = 7.1 Hz), 3.90 (s, 3H), 3.94 (s, 6H), 4.41 (q, 2H, J = 7.1 Hz), 6.79 (s, 2H), 7.50 (t, 1H, J = 7.8 Hz), 7.73 (dt, 1H, J = 7.1 Hz, 1.5 Hz), 8.01 (dt, 1H, J = 7.8 Hz, 1.4 Hz), 8.23 (t, 1H, J = 1.8 Hz)

제조예 27Preparation Example 27

3-(3,4,5-트리메톡시페닐)벤조산의 합성:Synthesis of 3- (3,4,5-trimethoxyphenyl) benzoic acid:

에틸 3-(3,4,5-트리메톡시페닐)벤조에이트(1.19g)를 제조예 17과 동일하게 처리하여 표기 화합물을 얻었다.Ethyl 3- (3,4,5-trimethoxyphenyl) benzoate (1.19 g) was treated in the same manner as in Production Example 17 to obtain the title compound.

수량: 986mg (91%)Quantity: 986mg (91%)

실시예 6Example 6

4-[N-메틸-N-[3-(3,4,5-트리메톡시페닐)벤조일]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2염산염의 합성:4- [N-methyl-N- [3- (3,4,5-trimethoxyphenyl) benzoyl] amino] -1-[[2- (3,4,5-trimethoxyphenyl) pyridine-4 Synthesis of -yl] methyl] piperidine-dihydrochloride:

3-(3,4,5-트리메톡시페닐)벤조산(1.03g)과 4-(메틸아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리지-4-일]메틸]피페리딘(1.32g)을 실시예 1과 동일하게 반응시켜표기 화합물을 2염산염으로서 얻었다.3- (3,4,5-trimethoxyphenyl) benzoic acid (1.03 g) and 4- (methylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyrizi-4- Il] methyl] piperidine (1.32 g) was reacted in the same manner as in Example 1 to obtain the title compound as a dihydrochloride salt.

수량: 1.44g (57%)Quantity: 1.44g (57%)

¹H-NMR(400MHz, 2염산염으로서 측정, DMSO-d₆) δ: 1.89(d, 2H, J=11.7Hz), 2.54-2.62(m, 2H), 2.89(s, 3H), 3.09(t, 2H, J=12.7Hz), 3.43(d, 2H, J=14.4Hz), 3.76(s, 3H), 3.78(s, 3H), 3.88(s, 6H), 3.91(s, 6H), 4.34(br, 3H), 6.91(s, 2H), 7.33(d, 1H, J=7.6Hz), 7.47-7.51(m, 2H), 7.54(s, 2H), 7.60(s, 1H), 7.71(d, 1H, J=7.8Hz), 8.55(s, 1H), 8.68(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, measured as dihydrochloride, DMSO-d ₆ ) δ: 1.89 (d, 2H, J = 11.7 Hz), 2.54-2.62 (m, 2H), 2.89 (s, 3H), 3.09 (t , 2H, J = 12.7 Hz, 3.43 (d, 2H, J = 14.4 Hz), 3.76 (s, 3H), 3.78 (s, 3H), 3.88 (s, 6H), 3.91 (s, 6H), 4.34 (br, 3H), 6.91 (s, 2H), 7.33 (d, 1H, J = 7.6 Hz), 7.47-7.51 (m, 2H), 7.54 (s, 2H), 7.60 (s, 1H), 7.71 ( d, 1H, J = 7.8 Hz, 8.55 (s, 1H), 8.68 (d, 1H, J = 5.1 Hz)

실시예 7Example 7

4-[N-메틸-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2푸말산염의 합성:4- [N-methyl-N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] -1-[[2- (3,4,5-tri Synthesis of methoxyphenyl) pyridin-4-yl] methyl] piperidine-2-fumarate:

4-(메틸아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(135mg)과 5-클로로메틸-3-(3,4,5-트리메톡시페닐)피리딘(107mg)을 실시예 2와 동일하게 반응시켜 표기 화합물을 2푸말산염으로서 얻었다.4- (methylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (135 mg) and 5-chloromethyl-3- (3, 4,5-trimethoxyphenyl) pyridine (107 mg) was reacted in the same manner as in Example 2 to obtain the title compound as difumarate.

수량: 180mg (58%)Quantity: 180mg (58%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.69-1.73(m, 2H), 1.82-1.85(m, 2H), 2.03-2.08(m, 2H), 2.25(s, 3H), 2.48-2.51(m, 1H), 2.97-2.99(m, 2H), 3.56(s, 2H), 3.67(s, 2H), 3.90(s, 3H), 3.91(s, 3H), 3.94(s, 6H), 3.98(s, 6H), 6.76(s, 2H), 7.22(d, 1H, J=5.1Hz), 7.24(s, 2H), 7.62(s, 1H), 7.80(s, 1H), 8.50(d, 1H, J=2.0Hz), 8.60(d, 1H, J=4.3Hz), 8.69(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.69-1.73 (m, 2H), 1.82-1.85 (m, 2H), 2.03-2.08 (m, 2H), 2.25 (s, 3H) , 2.48-2.51 (m, 1H), 2.97-2.99 (m, 2H), 3.56 (s, 2H), 3.67 (s, 2H), 3.90 (s, 3H), 3.91 (s, 3H), 3.94 (s , 6H), 3.98 (s, 6H), 6.76 (s, 2H), 7.22 (d, 1H, J = 5.1Hz), 7.24 (s, 2H), 7.62 (s, 1H), 7.80 (s, 1H) , 8.50 (d, 1H, J = 2.0 Hz), 8.60 (d, 1H, J = 4.3 Hz), 8.69 (d, 1H, J = 5.1 Hz)

제조예 28Preparation Example 28

1-브로모-4-클로로-3,5-디메톡시 벤젠의 합성:Synthesis of 1-bromo-4-chloro-3,5-dimethoxy benzene:

4-브로모-2,6-디메톡시아닐린(232mg)의 6.0M 염산(2.5㎖) 현탁액에 크래시 얼음을 가하고, 아질산나트륨(97mg)을 물(2.0㎖)에 용해한 것을 서서히 적하했다. 혼합물을 30분간 빙욕 중에서 교반하고, 염화동(495㎖)의 농염산(2.0㎖) 용액을 가했다. 실온에서 30분간, 다시 10℃에서 2시간 교반했다. 반응 혼합물을 에틸아세테이트로 추출한 후, 유기층을 포화 탄산수소나트륨 용액과 물로 세정하고, 무수 황산나트륨으로 건조시켰다. 감압 농축 후, 잔사를 실리카겔 컬럼크로마토그래피(헥산: 에틸아세테이트 =10:1)로 정제하여 표기 화합물을 백색 분말로서 얻었다.Crash ice was added to a 6.0M hydrochloric acid (2.5 mL) suspension of 4-bromo-2,6-dimethoxyaniline (232 mg), and a solution of sodium nitrite (97 mg) dissolved in water (2.0 mL) was slowly added dropwise. The mixture was stirred in an ice bath for 30 minutes, and a concentrated hydrochloric acid (2.0 mL) solution of copper chloride (495 mL) was added. It stirred at room temperature for 30 minutes again at 10 degreeC for 2 hours. After the reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated sodium bicarbonate solution and water, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the title compound as a white powder.

수량: 230mg (92%)Quantity: 230mg (92%)

제조예 29Preparation Example 29

4-클로로-3,5-디메톡시페닐붕소산의 합성:Synthesis of 4-chloro-3,5-dimethoxyphenylboronic acid:

드라이아이스-메탄올 욕으로 냉각한 무수 THF(2㎖)에 아르곤 분위기하에서 n-부틸리튬의 1.57M 헥산 용액(0.8㎖)을 적하하고, 이어서, 1-브로모-4-클로로-3,5-디메톡시벤젠(160mg)의 무수 THF(2㎖) 용액을 적하했다. 혼합물을 20분간 드라이아이스-메탄올 욕중에서 교반하고, 붕산트리이소프로필(0.18㎖)을 가하고, 다시 20분간 교반했다. 다시 실온에서 1시간 교반했다. 0℃에서, 4M 염산으로 반응액의 pH를 3으로 조정하고, 다시 0℃에서 1시간 교반했다. 반응액을 에틸아세테이트로 추출하고, 유기층을 포화 식염수로 세정한 후 무수 황산나트륨으로 건조시켰다. 감압 농축 후, 잔사를 에틸아세테이트 헥산으로부터 재결정시켜 표기 화합물의 백색 분말을 얻었다.To anhydrous THF (2 ml) cooled in a dry ice-methanol bath, 1.57 M hexane solution (0.8 ml) of n-butyllithium was added dropwise under argon atmosphere, followed by 1-bromo-4-chloro-3,5- Anhydrous THF (2 mL) solution of dimethoxybenzene (160 mg) was added dropwise. The mixture was stirred in a dry ice-methanol bath for 20 minutes, triisopropyl borate (0.18 mL) was added and stirred for 20 minutes. It stirred at room temperature again for 1 hour. At 0 degreeC, pH of the reaction liquid was adjusted to 3 with 4 M hydrochloric acid, and it stirred at 0 degreeC again for 1 hour. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was recrystallized from ethyl acetate hexane to obtain a white powder of the title compound.

수량: 90mg (66%)Quantity: 90mg (66%)

제조예 30Preparation Example 30

에틸 2-(4클로로-3,5-디메톡시페닐)이소니코티네이트의 합성:Synthesis of ethyl 2- (4chloro-3,5-dimethoxyphenyl) isonicotinate:

4-클로로-3,5-디메톡시페닐붕소산(7.45g)과 에틸 2-클로로이소니코티네이트(6.39g)를 제조예 1과 동일하게 처리하여 표기 화합물을얻었다.4-chloro-3,5-dimethoxyphenylboronic acid (7.45 g) and ethyl 2-chloroisonicotinate (6.39 g) were treated in the same manner as in Preparation Example 1 to obtain the title compound.

수량; 8.55g(77%)Quantity; 8.55 g (77%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(t, 3H, J=7.3Hz), 4.03(s, 6H), 4.45(q, 2H, J=7.3Hz), 7.32(s, 2H), 7.80(d, 1H, J=5.1Hz), 8.27(s, 1H), 8.83(d, 1H, J=5.0Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (t, 3H, J = 7.3 Hz), 4.03 (s, 6H), 4.45 (q, 2H, J = 7.3 Hz), 7.32 (s, 2H), 7.80 (d, 1H, J = 5.1 Hz), 8.27 (s, 1H), 8.83 (d, 1H, J = 5.0 Hz)

제조예 31Preparation Example 31

2-(4-클로로-3,5-디메톡시페닐)이소니코틴산의 합성:Synthesis of 2- (4-chloro-3,5-dimethoxyphenyl) isonicotinic acid:

에틸 2-(4-클로로-3,5-디메톡시페닐)이소니코티네이트(8.55g)를 에탄올(80㎖)에 용해하고, 2M 수산화나트륨(100㎖)을 가했다. 혼합물을 가열 환류하 30분간 교반하고, 감압하 에탄올을 증류하고, 용액에 1M 염산을 가하여 중화했다. 석출한 고체를 에틸아세테이트/THF(3/1)의 혼합 용매에 용해하고, 무수 황산나트륨으로 건조하고, 감압 농축하여 표기 화합물을 얻었다.Ethyl 2- (4-chloro-3,5-dimethoxyphenyl) isonicotinate (8.55 g) was dissolved in ethanol (80 mL) and 2M sodium hydroxide (100 mL) was added. The mixture was stirred under reflux for 30 minutes, ethanol was distilled off under reduced pressure, and neutralized by adding 1M hydrochloric acid to the solution. The precipitated solid was dissolved in a mixed solvent of ethyl acetate / THF (3/1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound.

수량: 7.20g (92%)Quantity: 7.20g (92%)

¹H-NMR(400MHz, CDC1₃) δ: 4.02(s, 6H), 7.34(s, 2H), 7.83(d, 1H, J=4.9Hz), 7.84(s, 1H), 8.82(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 4.02 (s, 6H), 7.34 (s, 2H), 7.83 (d, 1H, J = 4.9 Hz), 7.84 (s, 1H), 8.82 (d, 1H , J = 4.9Hz)

제조예 32Preparation Example 32

2-(4-클로로-3,5-디메톡시페닐)-4-히드록시메틸 피리딘의 합성:Synthesis of 2- (4-chloro-3,5-dimethoxyphenyl) -4-hydroxymethyl pyridine:

2-(4-클로로-3,5-디메톡시페닐)이소니코틴산(7.20g)과 트리에틸아민(5.6㎖)을 THF(70㎖)에 용해하고, 0℃에서 에틸 클로로포르메이트(2.8㎖)를 가했다. 실온에서 1시간 교반한 후, 불용물을 여과하여 제거했다. 여액에 수소화붕소나트륨(1.25g)의 수용액(4㎖)을 가하고, 실온에서 1시간 교반했다. 감압 농축한 후, 잔사에 물을 가하고 클로로포름으로 추출하고, 유기층을 포화 식염수로 세정하고, 무수 황산나트륨으로 건조한 후, 감압 농축했다. 잔사를 실리카겔 컬럼크로마토그래피(클로로포름: 메탄올 =20: 1∼15:1)로 정제하여 표기 화합물을 얻었다.2- (4-chloro-3,5-dimethoxyphenyl) isonicotinic acid (7.20 g) and triethylamine (5.6 mL) were dissolved in THF (70 mL) and ethyl chloroformate (2.8 mL) at 0 ° C. Added. After stirring for 1 hour at room temperature, insolubles were removed by filtration. An aqueous solution (4 ml) of sodium borohydride (1.25 g) was added to the filtrate, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, water was added to the residue, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1-15: 1) to obtain the title compound.

수량: 4.10g (60%)Quantity: 4.10g (60%)

¹H-NMR(400MHz, CDC1₃+DMSO-d₆) δ: 4.01(s, 6H), 4.76(s, 2H), 7.20-7.35(m, 3H), 7.78(s, 1H), 8.62(s, 1H) ¹ H-NMR (400 MHz, CDC1 ₃ + DMSO-d ₆ ) δ: 4.01 (s, 6H), 4.76 (s, 2H), 7.20-7.35 (m, 3H), 7.78 (s, 1H), 8.62 (s , 1H)

제조예 33Preparation Example 33

2-(4-클로로-3,5-디메톡시페닐)-4-클로로메틸피리딘의 합성:Synthesis of 2- (4-chloro-3,5-dimethoxyphenyl) -4-chloromethylpyridine:

2-(4-클로로-3,5-디메톡시페닐)-4-히드록시메틸피리딘(4.10g)을 클로로포름(20㎖)에 용해하고, 티오닐클로라이드(5.5㎖)를 가하고, 70℃에서 1시간 교반했다. 감압하 농축한 후, 잔사를 포화 탄산수소나트륨 수용액으로 중화하고, 에틸아세테이트로 추출했다. 유기층을 물, 포화 식염수로 세정하고, 무수 황산마그네슘으로 건조, 감압 농축하여 표기 화합물을 얻었다.2- (4-Chloro-3,5-dimethoxyphenyl) -4-hydroxymethylpyridine (4.10 g) is dissolved in chloroform (20 mL), thionyl chloride (5.5 mL) is added, and 1 at 70 ° C. It stirred for hours. After concentration under reduced pressure, the residue was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound.

수량:4.20g (96%)Quantity: 4.20g (96%)

¹H-NMR(400MHz, CDC1₃) δ: 4.02(s, 6H), 4.63(s, 2H), 7.26(s, 2H), 7.29(d, 1H, J=4.9Hz), 7.72(s, 1H), 8.69(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 4.02 (s, 6H), 4.63 (s, 2H), 7.26 (s, 2H), 7.29 (d, 1H, J = 4.9 Hz), 7.72 (s, 1H ), 8.69 (d, 1H, J = 4.9 Hz)

제조예 34Preparation Example 34

1-[[ 2-(4-클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]피페리딘-4-카르복사미드의 합성:Synthesis of 1-[[2- (4-chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] piperidine-4-carboxamide:

피페리딘-4-카르복사미드(301mg)와 2-(4-클로로-3,5-디메톡시페닐)-4-클로로메틸 피리딘(600mg)을 실시예 2와 동일하게 반응시켜 표기 화합물을 얻었다.Piperidine-4-carboxamide (301 mg) and 2- (4-chloro-3,5-dimethoxyphenyl) -4-chloromethyl pyridine (600 mg) were reacted in the same manner as in Example 2 to obtain the title compound. .

수량: 743mg (95%)Quantity: 743mg (95%)

¹H-NMR(400MHz, CDC1₃) δ: 1.75-1.90(m, 4H), 2.07-2.25(m, 3H), 2.94(d, 2H, J=11.6Hz), 3.57(s, 2H), 4.02(s, 6H), 7.24-7.31(m, 3H), 7.67(s, 1H), 8.61(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.75-1.90 (m, 4H), 2.07-2.25 (m, 3H), 2.94 (d, 2H, J = 11.6 Hz), 3.57 (s, 2H), 4.02 (s, 6H), 7.24-7.31 (m, 3H), 7.67 (s, 1H), 8.61 (d, 1H, J = 5.1 Hz)

제조예 35Preparation 35

1-[[2-(4-클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]-4-(에톡시카르보닐아미노)피페리딘의 합성:Synthesis of 1-[[2- (4-chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] -4- (ethoxycarbonylamino) piperidine

1-[[2-(4-클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]피페리딘-4-카르복사미드(743mg)를 제조예 20과 동일하게 처리하여 표기 화합물을 얻었다.1-[[2- (4-chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] piperidine-4-carboxamide (743 mg) was treated in the same manner as in Production Example 20 to obtain the title compound. Got.

수량:887mg (이론량)Quantity: 887mg (theoretical quantity)

¹H-NMR(400MHz, CDC1₃) δ: 1.24(t, 3H, J=7.1Hz), 1.43-1.59(m, 2H), 1.96(d, 2H, J=11.4Hz), 2.19(t, 2H, J=11.0Hz), 2.82(d, 2H, J=11.5Hz), 3.56(s, 2H), 4.02(s, 6H), 4.10(q, 2H, J=7.1Hz), 7.26(s, 2H), 7.66(s, 1H), 7.71(dd, 1H, J=5.6Hz, 1.0Hz), 8.6(dd, 1H, J=4.9Hz, 0.5Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.24 (t, 3H, J = 7.1 Hz), 1.43-1.59 (m, 2H), 1.96 (d, 2H, J = 11.4 Hz), 2.19 (t, 2H , J = 11.0 Hz), 2.82 (d, 2H, J = 11.5 Hz), 3.56 (s, 2H), 4.02 (s, 6H), 4.10 (q, 2H, J = 7.1 Hz), 7.26 (s, 2H ), 7.66 (s, 1H), 7.71 (dd, 1H, J = 5.6 Hz, 1.0 Hz), 8.6 (dd, 1H, J = 4.9 Hz, 0.5 Hz)

제조예 36Preparation Example 36

1-[[2-(4-클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]-4메틸아미노피페리딘의 합성:Synthesis of 1-[[2- (4-chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] -4methylaminopiperidine:

1-[[2-(4-클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]-4-(에톡시카르보닐아미노)피페리딘(887mg)을 제조예 21과 동일하게 처리하여 표기 화합물을 얻었다.1-[[2- (4-chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] -4- (ethoxycarbonylamino) piperidine (887 mg) was prepared in the same manner as in Production Example 21. The treatment gave the title compound.

수량: 195mg (27%)Quantity: 195mg (27%)

¹H-NMR(400MHz, CDC1₃) δ: 1.35-1.49(m, 2H), 1.89(d, 2H, J=12.4Hz), 2.11(t, 2H, J=9.4Hz), 2.38-2.45(m, 1H), 2.44(s, 3H), 2.87(d, 2H, J=10.7Hz), 3.57(s, 2H), 4.02(s, 6H), 7.23-7.29(m, 3H), 7.68(s, 1H), 8.61(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.35-1.49 (m, 2H), 1.89 (d, 2H, J = 12.4 Hz), 2.11 (t, 2H, J = 9.4 Hz), 2.38-2.45 (m , 1H), 2.44 (s, 3H), 2.87 (d, 2H, J = 10.7Hz), 3.57 (s, 2H), 4.02 (s, 6H), 7.23-7.29 (m, 3H), 7.68 (s, 1H), 8.61 (d, 1H, J = 4.9 Hz)

실시예 8Example 8

1-[[2-(4-클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]-4-[N-[[2-(4-클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]-N-메틸아미노]피페리딘·4염산염의 합성:1-[[2- (4-chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] -4- [N-[[2- (4-chloro-3,5-dimethoxyphenyl) Synthesis of pyridin-4-yl] methyl] -N-methylamino] piperidine tetrahydrochloride:

1-[[2-(4-클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]-4-메틸아미노피페리딘(195mg)과 2-(4-클로로-3,5-디메톡시페닐)-4-클로로메틸피리딘(152mg)을 실시예 2와 동일하게 반응시켜 얻어진 유리 염기를 4염산염으로 변환하여 표기 화합물을 황색 분말로서 얻었다.1-[[2- (4-chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] -4-methylaminopiperidine (195 mg) and 2- (4-chloro-3,5- The free base obtained by reacting dimethoxyphenyl) -4-chloromethylpyridine (152 mg) similarly to Example 2 was converted into tetrahydrochloride, and the title compound was obtained as a yellow powder.

수량: 300mg (75%)Quantity: 300mg (75%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.60-1.90(m, 4H), 2.06(t, 2H, J=11.7Hz), 2.26(s, 3H), 2.45-2.55(m, 1H), 2.97(d, 2H, J=11.3Hz), 3.57(s, 2H), 3.67(s, 2H), 4.01(s, 6H), 4.02(s, 6H), 7.24-7.28(m, 6H), 7.65(s, 1H), 7.67(s, 1H), 8.61(d, 1H, J=5.4Hz), 8.62(d, 1H, J=5.4Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.60-1.90 (m, 4H), 2.06 (t, 2H, J = 11.7 Hz), 2.26 (s, 3H), 2.45-2.55 (m , 1H), 2.97 (d, 2H, J = 11.3 Hz), 3.57 (s, 2H), 3.67 (s, 2H), 4.01 (s, 6H), 4.02 (s, 6H), 7.24-7.28 (m, 6H), 7.65 (s, 1H), 7.67 (s, 1H), 8.61 (d, 1H, J = 5.4 Hz), 8.62 (d, 1H, J = 5.4 Hz)

제조예 37Preparation Example 37

4-(p-아니시디노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘의 합성:Synthesis of 4- (p-anisidino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine:

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]-4-피페리돈(2.17g)을 톨루엔(40㎖)에 용해하고, p-아니시딘(900mg)과 몰리큘라 시이브스 4A(6.0g)를 가하고, 하룻밤 환류했다. 몰리큘라 시이브스를 여과하여 제거하고, 여액을 감압 농축하고, 잔사를 에탄올(40㎖)에 용해했다. 수소화붕소나트륨(276mg)을 가하고, 실온에서 2시간 교반했다. 혼합물을 감압 농축하고, 물을 가하고, 에틸아세테이트로 추출했다. 유기층을 포화 식염수로 세정하고, 무수 황산나트륨으로 건조 후, 감압 농축했다. 잔사를 실리카겔 컬럼크로마토그래피(클로로포름: 메탄올 = 50: 1)로 정제하여 표기 화합물을 얻었다.1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone (2.17 g) is dissolved in toluene (40 mL), and p-anisidine ( 900 mg) and Molycula Sieves 4A (6.0 g) were added and refluxed overnight. The molecular sieves were removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in ethanol (40 mL). Sodium borohydride (276 mg) was added and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to obtain the title compound.

수량: 1.56g(55%)Quantity: 1.56 g (55%)

¹H-NMR(400MHz, CDC1₃) δ: 1.48(br, 2H), 2.05(br, 2H), 2.20(br, 2H), 2.86(br, 2H), 3.23(s, 1H), 3.58(s, 2H), 3.74(s, 3H), 3.91(s, 3H), 3.97(s, 6H), 6.58(d, 2H, J=8.8Hz), 6.77(d, 2H, J=9.0Hz), 7.22(d, 1H, J=5.1Hz), 7.26(s, 2H), 7.64(s, 1H), 8.59(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.48 (br, 2H), 2.05 (br, 2H), 2.20 (br, 2H), 2.86 (br, 2H), 3.23 (s, 1H), 3.58 (s , 2H), 3.74 (s, 3H), 3.91 (s, 3H), 3.97 (s, 6H), 6.58 (d, 2H, J = 8.8 Hz), 6.77 (d, 2H, J = 9.0 Hz), 7.22 (d, 1H, J = 5.1 Hz), 7.26 (s, 2H), 7.64 (s, 1H), 8.59 (d, 1H, J = 4.9 Hz)

제조예 38Preparation Example 38

에틸 2-(3,4,5-트리메톡시페닐)니코티네이트의 합성:Synthesis of ethyl 2- (3,4,5-trimethoxyphenyl) nicotinate:

3,4,5-트리메톡시페닐붕소산(694mg)과 에틸 2-클로로니코티네이트(608mg)를 제조예 1과 동일하게 반응시켜 표기 화합물을 얻었다.3,4,5-trimethoxyphenylboronic acid (694 mg) and ethyl 2-chloronicotinate (608 mg) were reacted in the same manner as in Production Example 1 to obtain the title compound.

수량: 799mg (77%)Quantity: 799mg (77%)

¹H-NMR(400MHz, CDC1₃) δ: 1.10(t, 3H, J=7.2Hz), 3.89(s, 9H), 4.19(q,2H, J=7.2Hz), 6.79(s, 2H), 7.34(dd, 1H, J=7.8Hz, 4.8Hz), 8.06(dd, 1H, J=7.8Hz, 1.7Hz), 8.75(dd, 1H, J=4.8Hz, 1.7Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.10 (t, 3H, J = 7.2 Hz), 3.89 (s, 9H), 4.19 (q, 2H, J = 7.2 Hz), 6.79 (s, 2H), 7.34 (dd, 1H, J = 7.8 Hz, 4.8 Hz), 8.06 (dd, 1H, J = 7.8 Hz, 1.7 Hz), 8.75 (dd, 1H, J = 4.8 Hz, 1.7 Hz)

제조예 39Preparation Example 39

3-히드록시메틸-2-(3,4,5-트리메톡시페닐)피리딘의 합성:Synthesis of 3-hydroxymethyl-2- (3,4,5-trimethoxyphenyl) pyridine:

에틸 2-(3,4,5-트리메톡시페닐)니코티네이트(468mg)를 제조예 2와 동일하게 처리하여 표기 화합물을 얻었다.Ethyl 2- (3,4,5-trimethoxyphenyl) nicotinate (468 mg) was treated in the same manner as in Production Example 2 to obtain the title compound.

수량: 293mg (72%)Quantity: 293mg (72%)

¹H-NMR(400MHz, CDC1₃) δ: 3.90(s, 9H), 4.72(S, 2H), 6.83(s, 2H), 7.32(dd, 1H, J=7.9Hz, 4.8Hz), 7.92(dd, 1H, J=7.9Hz, 1.7Hz), 8.62(dd, 1H, J=4.8Hz, 1.7Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 3.90 (s, 9H), 4.72 (S, 2H), 6.83 (s, 2H), 7.32 (dd, 1H, J = 7.9 Hz, 4.8 Hz), 7.92 ( dd, 1H, J = 7.9 Hz, 1.7 Hz), 8.62 (dd, 1H, J = 4.8 Hz, 1.7 Hz)

제조예 40Preparation Example 40

3-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘의 합성:Synthesis of 3-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine:

3-히드록시메틸-2-(3,4,5-트리메톡시페닐)피리딘(293mg)을 제조예 3과 동일하게 반응시켜 표기 화합물을 얻었다.3-hydroxymethyl-2- (3,4,5-trimethoxyphenyl) pyridine (293 mg) was reacted in the same manner as in Production Example 3 to obtain the title compound.

수량: 311mg(이론량)Quantity: 311 mg (theoretical amount)

실시예 9Example 9

4-[N-(4-메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-3-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (4-methoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-3-yl] methyl] amino] -1-[[2- (3 Synthesis of, 4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

4-(p-아니시디노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(139mg)과 3-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(114mg)을 아세토니트릴(5㎖)에 용해하고, 탄산칼륨(83mg)과 요드화칼륨(63mg)을 가하고, 70℃에서 하룻밤 교반했다. 혼합물을 감압 농축 후, 잔사를 클로로포름에 용해하고, 물, 포화 식염수로 세정하고, 무수 황산마그네슘으로 건조 후, 감압 농축했다. 잔사를 실리카겔 컬럼크로마토그래피(에테르: 메탄올 =20:1)로 정제하고, 얻어진 유리 염기를 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (p-anisidino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (139 mg) and 3-chloromethyl-2- ( 3,4,5-trimethoxyphenyl) pyridine (114 mg) was dissolved in acetonitrile (5 mL), potassium carbonate (83 mg) and potassium iodide (63 mg) were added, and the mixture was stirred at 70 ° C. overnight. The mixture was concentrated under reduced pressure, the residue was dissolved in chloroform, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ether: methanol = 20: 1), and the title compound was obtained as a yellow powder using the obtained free base as trichloride.

수량: 16mg (8%)Quantity: 16mg (8%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.60(br, 2H), 1.77(br, 2H), 2.09(br, 2H), 2.93(br, 2H), 3.45(br, 1H), 3.54(s, 2H), 3.73(s, 3H), 3.90(s, 6H), 3.91(s, 6H), 3.96(s, 6H), 4.34(s, 2H), 6.65(d, 2H, J=9.0Hz), 6.71(s, 2H), 6.74(d, 2H, J=9.0Hz), 7.16-7.19(m, 2H), 7.22(s, 2H), 7.55(s, 1H), 7.79(d, 1H, J=7.0Hz), 8.50(br, 1H), 8.58(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.60 (br, 2H), 1.77 (br, 2H), 2.09 (br, 2H), 2.93 (br, 2H), 3.45 (br, 1H ), 3.54 (s, 2H), 3.73 (s, 3H), 3.90 (s, 6H), 3.91 (s, 6H), 3.96 (s, 6H), 4.34 (s, 2H), 6.65 (d, 2H, J = 9.0Hz), 6.71 (s, 2H), 6.74 (d, 2H, J = 9.0Hz), 7.16-7.19 (m, 2H), 7.22 (s, 2H), 7.55 (s, 1H), 7.79 ( d, 1H, J = 7.0 Hz, 8.50 (br, 1H), 8.58 (d, 1H, J = 4.9 Hz)

실시예 10Example 10

4-[N-(4메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (4methoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1-[[2- (3, Synthesis of 4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrihydrochloride:

4-(4-아니시디노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(1.56g)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(1.08g)을 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (4-anisidino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (1.56 g) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (1.08 g) was reacted in the same manner as in Example 9 to obtain the title compound as a yellow powder using trihydrochloride as a free base.

수량: 1.17g (40%)Quantity: 1.17g (40%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.68-1.97(m, 4H), 2.09-2.23(m, 2H), 2.98(br, 2H), 3.54-3.66(m, 3H), 3.73(s, 3H), 3.89(s, 3H), 3.90(s, 3H), 3.93(s, 6H), 3.96(s, 6H), 4.45(s, 2H), 6.74(d, 2H, J=9.2Hz), 6.79(d, 2H, J=9.2Hz), 7.15(s, 2H), 7.16-7.21(m, 2H), 7.23(s, 2H), 7.57(s, 1H), 7.60(s, 1H), 8.54(d, 1H, J=5.1Hz), 8.59(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.68-1.97 (m, 4H), 2.09-2.23 (m, 2H), 2.98 (br, 2H), 3.54-3.66 (m, 3H) , 3.73 (s, 3H), 3.89 (s, 3H), 3.90 (s, 3H), 3.93 (s, 6H), 3.96 (s, 6H), 4.45 (s, 2H), 6.74 (d, 2H, J = 9.2 Hz), 6.79 (d, 2H, J = 9.2 Hz), 7.15 (s, 2H), 7.16-7.21 (m, 2H), 7.23 (s, 2H), 7.57 (s, 1H), 7.60 (s , 1H), 8.54 (d, 1H, J = 5.1 Hz), 8.59 (d, 1H, J = 4.9 Hz)

제조예 41Preparation Example 41

3-(3,4,5-트리메톡시페닐)벤질 알코올의 합성:Synthesis of 3- (3,4,5-trimethoxyphenyl) benzyl alcohol:

에틸 3-(3,4,5-트리메톡시페닐)벤조에이트(5.09g)를 제조예 2와 동일하게 처리하여 표기 화합물을 얻었다.Ethyl 3- (3,4,5-trimethoxyphenyl) benzoate (5.09 g) was treated in the same manner as in Production Example 2 to obtain the title compound.

수량: 4.25g (97%)Quantity: 4.25g (97%)

¹H-NMR(400MHz, CDC1₃) δ: 1.87(t, 1H, J=6.0Hz), 3.89(s, 3H), 3.92(s, 6H), 4.76(d, 1H, J=5.6Hz), 6.77(s, 2H), 7.34(d, 1H, J=7.4Hz), 7.42(t, 1H, J=7.5Hz), 7.48(d, 1H, J=7.6Hz), 7.55(s, 1H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.87 (t, 1H, J = 6.0 Hz), 3.89 (s, 3H), 3.92 (s, 6H), 4.76 (d, 1H, J = 5.6 Hz), 6.77 (s, 2H), 7.34 (d, 1H, J = 7.4 Hz), 7.42 (t, 1H, J = 7.5 Hz), 7.48 (d, 1H, J = 7.6 Hz), 7.55 (s, 1H)

제조예 42Preparation Example 42

3-(3,4,5-트리메톡시페닐)벤질클로라이드의 합성:Synthesis of 3- (3,4,5-trimethoxyphenyl) benzylchloride:

3-(3,4,5-트리메톡시페닐)벤질알코올(1.21g)을 제조예 3과 동일하게 처리하여 표기 화합물을 얻었다.3- (3,4,5-trimethoxyphenyl) benzyl alcohol (1.21 g) was treated in the same manner as in Production Example 3 to obtain the title compound.

수량: 893mg (69%)Quantity: 893mg (69%)

¹H-NMR(400MHz, CDC1₃) δ: 3.87(s, 3H), 3.90(s, 6H), 4.62(s, 2H), 6.75(s, 2H), 7.33(d, 1H, J=7.6Hz), 7.39(t, 1H, J=7.7Hz), 7.48(d, 1H, J=7.6Hz), 7.54(s, 1H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 3.87 (s, 3H), 3.90 (s, 6H), 4.62 (s, 2H), 6.75 (s, 2H), 7.33 (d, 1H, J = 7.6 Hz ), 7.39 (t, 1H, J = 7.7 Hz), 7.48 (d, 1H, J = 7.6 Hz), 7.54 (s, 1H)

실시예 11Example 11

4-[N-(4-메톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2염산염의 합성:4- [N- (4-methoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] -1-[[2- (3,4,5-trimeth Synthesis of oxyphenyl) pyridin-4-yl] methyl] piperidine dihydrochloride:

4-(p-아니시디노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(139mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(114mg)를 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 2 염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (p-anisidino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (139 mg) and 3- (3,4,5 Trimethoxyphenyl) benzylchloride (114 mg) was reacted in the same manner as in Example 9 to obtain the title compound as a yellow powder using dihydrochloride as the free base.

수량: 52mg (22%)Quantity: 52mg (22%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDCl₃) δ: 1.77-1.92(m, 5H), 2.14-2.20(m, 2H), 2.95-3.00(m, 2H), 3.58(s, 2H), 3.72(s, 3H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.96(s, 6H), 4.47(s, 2H), 6.70(s, 2H), 6.74-6.83(m, 4H), 7.20(d, 1H, J=7.4Hz), 7.23(s, 2H), 7.25-7.27(m, 1H), 7.33(t, 1H, J=7.4Hz), 7.38(d, 1H, J=8.7Hz), 7.43(s, 1H), 7.62(s, 1H), 8.59(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, measured as free base, CDCl ₃ ) δ: 1.77-1.92 (m, 5H), 2.14-2.20 (m, 2H), 2.95-3.00 (m, 2H), 3.58 (s, 2H) , 3.72 (s, 3H), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.96 (s, 6H), 4.47 (s, 2H), 6.70 (s, 2H), 6.74-6.83 (m, 4H), 7.20 (d, 1H, J = 7.4 Hz), 7.23 (s, 2H), 7.25-7.27 (m, 1H), 7.33 (t, 1H, J = 7.4 Hz), 7.38 (d, 1H, J = 8.7 Hz), 7.43 (s, 1H), 7.62 (s, 1H), 8.59 (d, 1H, J = 5.1 Hz)

제조예 43Preparation Example 43

에틸 6-(3,4,5-트리메톡시페닐)니코티네이트의 합성:Synthesis of ethyl 6- (3,4,5-trimethoxyphenyl) nicotinate:

3,4,5-트리메톡시페닐붕소산(1.16g)과 에틸 6-클로로니코티네이트(1.02g)를 제조예 1과 동일하게 반응시켜 표기 화합물을 얻었다.3,4,5-trimethoxyphenylboronic acid (1.16 g) and ethyl 6-chloronicotinate (1.02 g) were reacted in the same manner as in Production Example 1 to obtain the title compound.

수량: 1.42g(82%)Quantity: 1.42 g (82%)

¹H-NMR(400MHz, CDCl₃) δ: 1.43(t, 3H, J=7.2Hz), 3.92(s, 3H), 3.98(s, 6H), 4.44(q, 2H, J=7.2Hz), 7.32(s, 2H), 7.76(d, 1H, J=8.3Hz), 8.33(dd, 1H, J=8.2Hz, 2.2Hz), 9.26(d, 1H, J=2.2Hz) ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43 (t, 3H, J = 7.2 Hz), 3.92 (s, 3H), 3.98 (s, 6H), 4.44 (q, 2H, J = 7.2 Hz), 7.32 (s, 2H), 7.76 (d, 1H, J = 8.3 Hz), 8.33 (dd, 1H, J = 8.2 Hz, 2.2 Hz), 9.26 (d, 1H, J = 2.2 Hz)

제조예 44Preparation Example 44

5-히드록시메틸-2-(3,4,5-트리메톡시페닐)피리딘의 합성:Synthesis of 5-hydroxymethyl-2- (3,4,5-trimethoxyphenyl) pyridine:

에틸 6-(3,4,5-트리메톡시페닐)니코티네이트(658mg)를 제조예 2와 동일하게 처리하여 표기 화합물을 얻었다.Ethyl 6- (3,4,5-trimethoxyphenyl) nicotinate (658 mg) was treated in the same manner as in Production Example 2 to obtain the title compound.

수량: 482mg (85%)Quantity: 482mg (85%)

¹H-NMR(400MHz, CDC1₃) δ: 3.91(s, 3H), 3.97(s, 6H), 4.76(s, 2H), 7.23(s, 2H), 7.68(d, 1H, J=7.4Hz), 7.78(dd, 1H, J=7.4Hz, 2.3Hz), 8.63(d, 1H, J=2.3Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 3.91 (s, 3H), 3.97 (s, 6H), 4.76 (s, 2H), 7.23 (s, 2H), 7.68 (d, 1H, J = 7.4 Hz ), 7.78 (dd, 1H, J = 7.4 Hz, 2.3 Hz), 8.63 (d, 1H, J = 2.3 Hz)

제조예 45Preparation Example 45

5-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘의 합성:Synthesis of 5-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine:

5-히드록시메틸-2-(3,4,5-트리메톡시페닐)피리딘(685mg)을 제조예 3과 동일하게 처리하여 표기 화합물을 얻었다.5-hydroxymethyl-2- (3,4,5-trimethoxyphenyl) pyridine (685 mg) was treated in the same manner as in Production Example 3 to obtain the title compound.

수량: 787mg (이론량)Quantity: 787mg (Theoretical quantity)

실시예 12Example 12

4-[N-(4-메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (4-methoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] -1-[[2- (3 Synthesis of, 4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

4-(p-아니시디노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(139mg)과 5-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(114mg)을 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (p-anisidino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (139 mg) and 5-chloromethyl-2- ( Using the free base obtained by reacting 3,4,5-trimethoxyphenyl) pyridine (114 mg) in the same manner as in Example 9, the title compound was obtained as a yellow powder.

수량: 13mg (5%)Quantity: 13mg (5%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.76(br, 2H), 1.88(br, 2H), 2.14(br, 2H), 2.97(br, 2H), 3.51(br, 1H), 3.57(s, 2H), 3.72(s, 3H), 3.89(s, 3H), 3.90(s, 3H), 3.94(s, 6H), 3.96(s, 6H), 4.42(s, 2H), 6.78(br, 4H), 7.20(br, 3H), 7.23(s, 2H), 7.57-7.70(m, 3H), 8.58-8.60(m, 2H) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.76 (br, 2H), 1.88 (br, 2H), 2.14 (br, 2H), 2.97 (br, 2H), 3.51 (br, 1H ), 3.57 (s, 2H), 3.72 (s, 3H), 3.89 (s, 3H), 3.90 (s, 3H), 3.94 (s, 6H), 3.96 (s, 6H), 4.42 (s, 2H) , 6.78 (br, 4H), 7.20 (br, 3H), 7.23 (s, 2H), 7.57-7.70 (m, 3H), 8.58-8.60 (m, 2H)

제조예 46Preparation Example 46

에틸 5-(3,4,5-트리메톡시페닐)니코티네이트의 합성:Synthesis of ethyl 5- (3,4,5-trimethoxyphenyl) nicotinate:

3,4,5-트리메톡시페닐붕소산(6.36g)과 에틸 5-브로모니코티네이트(6.90g)를 제조예 1과 동일하게 반응시켜 표기 화합물을 얻었다.3,4,5-trimethoxyphenylboronic acid (6.36 g) and ethyl 5-bromonicotinate (6.90 g) were reacted in the same manner as in Production Example 1 to obtain the title compound.

수량: 7.19g (76%)Quantity: 7.19g (76%)

¹H-NMR(400MHz, CDC1₃) δ: 1.44(t, 3H, J=7.1Hz), 3.91(s, 3H), 3.95(s, 6H), 4.46(q, 2H, J=7.1Hz), 6.79(s, 2H), 8.44(t, 1H, J=2.1Hz), 8.96(d, 1H, J=2.1Hz), 9.18(d, 1H, J=1.8Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.44 (t, 3H, J = 7.1 Hz), 3.91 (s, 3H), 3.95 (s, 6H), 4.46 (q, 2H, J = 7.1 Hz), 6.79 (s, 2H), 8.44 (t, 1H, J = 2.1 Hz), 8.96 (d, 1H, J = 2.1 Hz), 9.18 (d, 1H, J = 1.8 Hz)

제조예 47Preparation 47

3-히드록시메틸-5-(3,4,5-트리메톡시페닐)피리딘의 합성:Synthesis of 3-hydroxymethyl-5- (3,4,5-trimethoxyphenyl) pyridine:

에틸 5-(3,4,5-트리메톡시페닐)니코티네이트(7.19g)를 제조예 2와 동일하게 처리하여 표기 화합물을 얻었다.Ethyl 5- (3,4,5-trimethoxyphenyl) nicotinate (7.19 g) was treated in the same manner as in Production Example 2 to obtain the title compound.

수량: 3.83g(61%)Quantity: 3.83 g (61%)

¹H-NMR(400MHz, CDC1₃) δ: 3.88(s, 3H), 3.89(s, 6H), 4.39(br, 1H), 4.80(s, 2H), 6.72(s, 2H), 7.89(t, 1H, J=1.2Hz), 8.47(d, 1H, J=2.1Hz), 8.63(d, 1H, J=2.2Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 3.88 (s, 3H), 3.89 (s, 6H), 4.39 (br, 1H), 4.80 (s, 2H), 6.72 (s, 2H), 7.89 (t , 1H, J = 1.2 Hz, 8.47 (d, 1H, J = 2.1 Hz), 8.63 (d, 1H, J = 2.2 Hz)

제조예 48Preparation Example 48

3-클로로메틸-5-(3,4,5-트리메톡시페닐)피리딘의 합성:Synthesis of 3-chloromethyl-5- (3,4,5-trimethoxyphenyl) pyridine:

3-히드록시메틸-5-(3,4,5-트리메톡시페닐)피리딘(2.85g)을 제조예 3과 동일하게 처리하여 표기 화합물을 얻었다.3-hydroxymethyl-5- (3,4,5-trimethoxyphenyl) pyridine (2.85 g) was treated in the same manner as in Production Example 3 to obtain the title compound.

수량: 1.97g(65%)Quantity: 1.97 g (65%)

¹H-NMR(400MHz, CDC1₃) δ: 3.90(s, 3H), 3.94(s, 6H), 4.67(s, 2H), 6.75(s, 2H), 7.87(t, 1H, J=2.1Hz), 8.59(d, 1H, J=2.0Hz), 8.76(d, 1H, J=2.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 3.90 (s, 3H), 3.94 (s, 6H), 4.67 (s, 2H), 6.75 (s, 2H), 7.87 (t, 1H, J = 2.1 Hz ), 8.59 (d, 1H, J = 2.0 Hz), 8.76 (d, 1H, J = 2.1 Hz)

실시예 13Example 13

4-[N-(4-메톡시페닐)-N-[[5-(3,4,5-트리메톡시페닐)피리딘-3-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (4-methoxyphenyl) -N-[[5- (3,4,5-trimethoxyphenyl) pyridin-3-yl] methyl] amino] -1-[[2- (3 Synthesis of, 4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

4-(4-아니시디노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(139mg)과 3-클로로메틸-5-(3,4,5-트리메톡시페닐)피리딘(114mg)을 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (4-anisidino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (139 mg) and 3-chloromethyl-5- ( Using the free base obtained by reacting 3,4,5-trimethoxyphenyl) pyridine (114 mg) in the same manner as in Example 9, the title compound was obtained as a yellow powder.

수량: 14mg (5%)Quantity: 14mg (5%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ : 1.73-1.75(m, 2H), 1.88(d, 2H, J=11.3Hz), 2.13(t, 2H, J=11.3Hz), 2.96(d, 2H, J=11.5Hz), 3.50(br, 1H), 3.55(s, 2H), 3.72(s, 3H), 3.88(s, 3H), 3.89(s, 9H), 3.96(s, 6H), 4.45(s, 2H), 6.65(s, 2H), 6.76(d, 2H, J=9.6Hz), 6.80(d, 2H, J=9.4Hz), 7.20(d, 1H, J=5.3Hz), 7.22(s, 2H), 7.59(s, 1H), 7.67(s, 1H), 8.50(s, 1H), 8.59(d, 1H, J=4.7Hz), 8.62(s, 1H) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.73-1.75 (m, 2H), 1.88 (d, 2H, J = 11.3 Hz), 2.13 (t, 2H, J = 11.3 Hz), 2.96 (d, 2H, J = 11.5 Hz), 3.50 (br, 1H), 3.55 (s, 2H), 3.72 (s, 3H), 3.88 (s, 3H), 3.89 (s, 9H), 3.96 (s , 6H), 4.45 (s, 2H), 6.65 (s, 2H), 6.76 (d, 2H, J = 9.6 Hz), 6.80 (d, 2H, J = 9.4 Hz), 7.20 (d, 1H, J = 5.3 Hz), 7.22 (s, 2H), 7.59 (s, 1H), 7.67 (s, 1H), 8.50 (s, 1H), 8.59 (d, 1H, J = 4.7 Hz), 8.62 (s, 1H)

제조예 49Preparation 49

4-요드-2,6-디메톡시페놀의 합성:Synthesis of 4-iod-2,6-dimethoxyphenol:

5-요드-1,2,3-트리메톡시벤젠(3.2g)을 1,2-디클로로에탄(40㎖)에 용해하고, 염화알루미늄(1.6g)을 가했다. 혼합물을 60℃에서 4시간 교반한 후, 감압 농축했다. 잔사에 1M 수산화나트륨 용액을 가하고, 에테르로 세정했다. 이어서 수층을 산성으로 해 클로로포름으로 추출하고, 이어서, 포화 식염수로 세정했다. 유기층을 무수 황산마그네슘으로 건조 후, 감압하 농축하여 표기 화합물을 백색결정성 분말로서 얻었다.5-iod-1,2,3-trimethoxybenzene (3.2 g) was dissolved in 1,2-dichloroethane (40 mL) and aluminum chloride (1.6 g) was added. The mixture was stirred at 60 ° C. for 4 hours, and then concentrated under reduced pressure. 1M sodium hydroxide solution was added to the residue, and the mixture was washed with ether. The aqueous layer was then acidified, extracted with chloroform, and then washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the title compound as a white crystalline powder.

수량: 1.0g (31%)Quantity: 1.0g (31%)

제조예 50Preparation 50

5-요드-2-이소프로폭시-1,3-디메톡시벤젠의 합성:Synthesis of 5-iod-2-isopropoxy-1,3-dimethoxybenzene:

4-요드-2,6-디메톡시페놀(1.0g)과 탄산칼륨(983mg)을 DMF(10㎖)에 현탁하고, 2-요드프로판(507㎖)을 가했다. 혼합물을 60℃에서 3시간 교반하고, 감압 농축했다. 잔사에 에틸아세테이트와 물을 가하고 유기층을 분리하고, 포화 식염수로 세정, 무수 황산나트륨으로 건조했다. 감압 농축 후, 잔사를 실리카겔 컬럼크로마토그래피(헥산: 에틸아세테이트 = 5: 1)로 정제하여 표기 화합물을 얻었다.4-iod-2,6-dimethoxyphenol (1.0 g) and potassium carbonate (983 mg) were suspended in DMF (10 mL), and 2-iodine propane (507 mL) was added. The mixture was stirred at 60 ° C. for 3 hours, and concentrated under reduced pressure. Ethyl acetate and water were added to the residue, the organic layer was separated, washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the title compound.

수량: 788mg (72%)Quantity: 788mg (72%)

제조예 51Preparation Example 51

4-이소프로폭시-3,5-디메톡시페닐붕소산의 합성:Synthesis of 4-isopropoxy-3,5-dimethoxyphenylboronic acid:

5-요드-2-이소프로폭시-1,3-디메톡시벤젠(2.25g)을 제조예 29와 동일하게 처리하여 표기 화합물을 얻었다.5-iod-2-isopropoxy-1,3-dimethoxybenzene (2.25 g) was treated in the same manner as in Production Example 29 to obtain the title compound.

수량: 1.23g(74%)Quantity: 1.23 g (74%)

제조예 52Preparation Example 52

에틸 2-(4-이소프로폭시-3,5-디메톡시페닐)이소니코티네이트의 합성:Synthesis of ethyl 2- (4-isopropoxy-3,5-dimethoxyphenyl) isonicotinate:

4-이소프로폭시 3,5-디메톡시페닐붕소산(1.23g)과 에틸 2-클로로 이소니코티네이트(0.95g)를 제조예 1과 동일하게 반응시켜 표기 화합물을 얻었다.4-isopropoxy 3,5-dimethoxyphenylboronic acid (1.23 g) and ethyl 2-chloro isonicotinate (0.95 g) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.

수량: 1.57g (89%)Quantity: 1.57g (89%)

¹H-NMR(400MHz, CDC1₃) δ: 1.33(d, 6H, J=4.9Hz), 1.44(t, 3H, J=7.1Hz),3.95(s, 6H), 4.42-4.49(m, 3H), 7.29(s, 2H), 7.75(dd, 1H, J=4.9Hz, 1.4Hz), 8.24(s, 1H), 8.80(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.33 (d, 6H, J = 4.9 Hz), 1.44 (t, 3H, J = 7.1 Hz), 3.95 (s, 6H), 4.42-4.49 (m, 3H ), 7.29 (s, 2H), 7.75 (dd, 1H, J = 4.9 Hz, 1.4 Hz), 8.24 (s, 1H), 8.80 (d, 1H, J = 4.9 Hz)

제조예 53Preparation Example 53

4-히드록시메틸-2-(4-이소프로폭시-3,5-디메톡시페닐)피리딘의 합성:Synthesis of 4-hydroxymethyl-2- (4-isopropoxy-3,5-dimethoxyphenyl) pyridine:

수소화리튬알루미늄(190mg)을 THF(20㎖)에 현탁하고, 빙냉하 아르곤 분위기하에서 에틸 2-(4-이소프로폭시-3,5-디메톡시페닐)이소니코티네이트(1.57g)의 THF(30㎖)의 용액을 적하했다. 혼합물을 0℃에서 30분간 교반하고, 포화 염화 암모늄 수용액을 가했다. 에틸아세테이트로 추출한 후, 유기층을 포화 식염수로 세정하고, 무수 황산나트륨으로 건조한 후, 감압 농축했다. 잔사를 실리카겔 컬럼크로마토그래피(헥산: 에틸아세테이트 =3:1, 이어서 클로로포름: 메탄올 =15:1)로 정제하여 표기 화합물을 얻었다.Lithium aluminum hydride (190 mg) was suspended in THF (20 mL), and THF (1.57 g) of ethyl 2- (4-isopropoxy-3,5-dimethoxyphenyl) isonicotinate was dissolved in an argon atmosphere under ice-cooling. 30 ml) was added dropwise. The mixture was stirred at 0 ° C. for 30 minutes and saturated aqueous ammonium chloride solution was added. After extraction with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1, then chloroform: methanol = 15: 1) to obtain the title compound.

수량: 1.31g(95%)Quantity: 1.31 g (95%)

¹H-NMR(400MHz, CDC1₃) δ: 1.32(d, 6H, J=6.1Hz), 3.93(s, 6H), 4.45(quint, 1H, J=6.1Hz), 4.81(s, 2H), 7.20(d, 1H, J=5.1Hz), 7.23(s, 2H), 7.68(s, 1H), 8.62(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.32 (d, 6H, J = 6.1 Hz), 3.93 (s, 6H), 4.45 (quint, 1H, J = 6.1 Hz), 4.81 (s, 2H), 7.20 (d, 1H, J = 5.1 Hz), 7.23 (s, 2H), 7.68 (s, 1H), 8.62 (d, 1H, J = 5.1 Hz)

제조예 54Preparation Example 54

4-클로로메틸-2-(3,5-디메톡시-4-이소프로폭시페닐)피리딘의 합성:Synthesis of 4-chloromethyl-2- (3,5-dimethoxy-4-isopropoxyphenyl) pyridine:

4-히드록시메틸-2-(4-이소프로폭시-3,5-디메톡시페닐)피리딘(1.49g)을 제조예 3과 동일하게 처리하여 표기 화합물을 얻었다.4-hydroxymethyl-2- (4-isopropoxy-3,5-dimethoxyphenyl) pyridine (1.49 g) was treated in the same manner as in Production Example 3 to obtain the title compound.

수량: 1.33g(84%)Quantity: 1.33 g (84%)

¹H-NMR(400MHz, CDC1₃) δ: 1.32(d, 6H, J=6.2Hz), 3.94(s, 6H), 4.45(quint, 1H, J=6.1Hz), 4.61(s, 2H), 7.23-7.26(m, 3H), 7.69(s, 1H), 8.66(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.32 (d, 6H, J = 6.2 Hz), 3.94 (s, 6H), 4.45 (quint, 1H, J = 6.1 Hz), 4.61 (s, 2H), 7.23-7.26 (m, 3H), 7.69 (s, 1H), 8.66 (d, 1H, J = 5.1 Hz)

제조예 55Preparation Example 55

1-[[ 2-(4-이소프로폭시-3,5-디메톡시페닐)피리딘-4-일]메틸]-4-피페리돈 에틸렌 케탈의 합성:Synthesis of 1-[[2- (4-isopropoxy-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone ethylene ketal:

4-클로로메틸-2-(4-이소프로폭시-3,5-디메톡시페닐)피리딘(643mg)과 4-피페리돈 에틸렌 케탈(287mg)을 실시예 2와 동일하게 반응시켜 표기 화합물을 얻었다.4-Chloromethyl-2- (4-isopropoxy-3,5-dimethoxyphenyl) pyridine (643 mg) and 4-piperidone ethylene ketal (287 mg) were reacted in the same manner as in Example 2 to obtain the title compound.

수량: 818mg (95%)Quantity: 818mg (95%)

¹H-NMR(400MHz, CDC1₃) δ: 1.32(d, 6H, J=6.1Hz), 1.78(t, 4H, J=5.7Hz), 2.57(br, 4H), 3.49(s, 4H), 3.59(s, 2H), 3.94(s, 6H), 4.44(quint, 1H, J=6.1Hz), 7.21(d, 1H, J=5.1Hz), 7.23(s, 2H), 7.65(s, 1H), 8.59(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.32 (d, 6H, J = 6.1 Hz), 1.78 (t, 4H, J = 5.7 Hz), 2.57 (br, 4H), 3.49 (s, 4H), 3.59 (s, 2H), 3.94 (s, 6H), 4.44 (quint, 1H, J = 6.1 Hz), 7.21 (d, 1H, J = 5.1 Hz), 7.23 (s, 2H), 7.65 (s, 1H ), 8.59 (d, 1H, J = 5.1 Hz)

제조예 56Preparation Example 56

1-[[2-(4-이소프로폭시-3,5-디메톡시페닐)피리딘-4-일]메틸]-4-피페리돈의 합성:Synthesis of 1-[[2- (4-isopropoxy-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone:

1-[[2-(4이소프로폭시-3,5-디메톡시페닐)피리딘-4-일]메틸]-4-피페리돈 에틸렌 케탈(818mg)을 제조예 23과 동일하게 처리하여 표기 화합물을 얻었다.1-[[2- (4isopropoxy-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone ethylene ketal (818 mg) was treated in the same manner as in Production Example 23 to obtain the title compound. Got it.

수량: 717mg (98%)Quantity: 717mg (98%)

¹H-NMR(400MHz, CDC1₃) δ : 1.32(d, 6H, J=6.2Hz), 2.50(t, 4H, J=6.1Hz), 2.81(t, 4H, J=6.1Hz), 3.69(s, 2H), 3.95(s, 6H), 4.45(quint, 1H, J=6.2Hz), 7.24(s, 2H), 7.25-7.27(m, 1H), 7.68(s, 1H), 8.63(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.32 (d, 6H, J = 6.2 Hz), 2.50 (t, 4H, J = 6.1 Hz), 2.81 (t, 4H, J = 6.1 Hz), 3.69 ( s, 2H), 3.95 (s, 6H), 4.45 (quint, 1H, J = 6.2 Hz), 7.24 (s, 2H), 7.25-7.27 (m, 1H), 7.68 (s, 1H), 8.63 (d , 1H, J = 5.1Hz)

제조예 57Preparation Example 57

4-(p-아니시디노)-1-[[2-(4이소프로폭시-3,5-디메톡시페닐)피리딘-4-일]메틸]피페리딘의 합성:Synthesis of 4- (p-anisidino) -1-[[2- (4isopropoxy-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] piperidine:

1-[[2-(4-이소프로폭시-3,5-디메톡시페닐)피리딘-4-일]메틸]-4-피페리돈(350mg)과 p-아니시딘(123mg)을 제조예 37과 동일하게 처리하여 표기 화합물을 얻었다.1-[[2- (4-isopropoxy-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone (350 mg) and p-anisidine (123 mg) were prepared in Preparation Example 37 The same process was performed to obtain the title compound.

수량: 307mg (69%)Quantity: 307mg (69%)

¹H-NMR(400MHz, CDC1₃) δ: 1.32(d, 6H, J=6.3Hz), 1.46-1.52(m, 2H), 2.00-2.24(m, 2H), 2.22(t, 2H, J=11.1Hz), 2.86(d, 2H, J=12.1Hz), 3.18-3.28(m, 1H), 3.58(s, 2H), 3.74(s, 3H), 3.94(s, 6H), 4.40(quint, 1H, J=6.3Hz), 6.58(d, 2H, J=6.6Hz), 6.78(d, 2H, J=6.6Hz), 7.20(d, 1H, J=5.1Hz), 7.24(s, 2H), 7.64(s, 1H), 8.59(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.32 (d, 6H, J = 6.3 Hz), 1.46-1.52 (m, 2H), 2.00-2.24 (m, 2H), 2.22 (t, 2H, J = 11.1 Hz), 2.86 (d, 2H, J = 12.1 Hz), 3.18-3.28 (m, 1H), 3.58 (s, 2H), 3.74 (s, 3H), 3.94 (s, 6H), 4.40 (quint, 1H, J = 6.3 Hz, 6.58 (d, 2H, J = 6.6 Hz), 6.78 (d, 2H, J = 6.6 Hz), 7.20 (d, 1H, J = 5.1 Hz), 7.24 (s, 2H) , 7.64 (s, 1 H), 8.59 (d, 1 H, J = 5.1 Hz)

실시예 14Example 14

1-[[2-(4-이소프로폭시-3,5-디메톡시페닐)피리딘-4-일]메틸]-4-[N-[[2-(4이소프로폭시-3,5-디메톡시페닐)피리딘-4-일]메틸]-N-(4메톡시페닐)아미노]피페리딘·3염산염의 합성:1-[[2- (4-isopropoxy-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] -4- [N-[[2- (4isopropoxy-3,5-dimeth Synthesis of oxyphenyl) pyridin-4-yl] methyl] -N- (4methoxyphenyl) amino] piperidinetrichloride:

4-(p-아니시디노)-1-[[2-(4-이소프로폭시-3,5-디메톡시페닐)피리딘-4-일]메틸]피페리딘(307mg)과 4-클로로메틸-2-(4-이소프로폭시-3.5-디메톡시페닐)피리딘(201mg)을 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (p-anisidino) -1-[[2- (4-isopropoxy-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] piperidine (307 mg) with 4-chloromethyl- The title compound was obtained as a yellow powder using tri-hydrochloride as a free base obtained by reacting 2- (4-isopropoxy-3.5-dimethoxyphenyl) pyridine (201 mg) in the same manner as in Example 9.

수량: 230mg (46%)Quantity: 230mg (46%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.31(d, 6H, J=3.3Hz), 1.32(d, 6H, J=6.8Hz), 1.70-1.92(m, 4H), 2.10-2.20(m, 2H), 2.92-3.01(m, 2H), 3.56(s, 2H), 3.73(s, 3H), 3.85-3.95(m, 1H), 3.90(s, 6H), 3.93(s, 6H), 4.39-4.49(m, 4H), 6.73(d, 2H, J=4.8Hz), 6.78(d, 2H, J=4.8Hz), 7.14(s, 2H), 7.15-7.20(m, 2H), 7.23(s, 2H), 7.58(s, 1H), 7.60(s, 1H), 8.53(d, 1H, J=5.1Hz), 8.58(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.31 (d, 6H, J = 3.3 Hz), 1.32 (d, 6H, J = 6.8 Hz), 1.70-1.92 (m, 4H), 2.10-2.20 (m, 2H), 2.92-3.01 (m, 2H), 3.56 (s, 2H), 3.73 (s, 3H), 3.85-3.95 (m, 1H), 3.90 (s, 6H), 3.93 ( s, 6H), 4.39-4.49 (m, 4H), 6.73 (d, 2H, J = 4.8 Hz), 6.78 (d, 2H, J = 4.8 Hz), 7.14 (s, 2H), 7.15-7.20 (m , 2H), 7.23 (s, 2H), 7.58 (s, 1H), 7.60 (s, 1H), 8.53 (d, 1H, J = 5.1 Hz), 8.58 (d, 1H, J = 5.1 Hz)

제조예 58Preparation 58

4-벤질아미노-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘의 합성:Synthesis of 4-benzylamino-1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine:

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]-4-피페리돈(1.40g)과 벤질아민(0.51g)을 제조예 37과 동일하게 처리하여 표기 화합물을 얻었다.1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone (1.40 g) and benzylamine (0.51 g) were treated in the same manner as in Preparation Example 37 To obtain the title compound.

수량: 1.20g (68%)Quantity: 1.20g (68%)

¹H-NMR(400MHz, CDC1₃) δ: 1.40-1.60(m, 2H), 1.88-2.09(m, 5H), 2.54(br, 1H), 2.82-2.85(m, 2H), 3.52(s, 2H), 3.80(s, 2H), 3.89(s, 3H), 3.95(s, 6H), 7.18-7.31(m, 8H), 7.64(s, 1H), 8.57(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.40-1.60 (m, 2H), 1.88-2.09 (m, 5H), 2.54 (br, 1H), 2.82-2.85 (m, 2H), 3.52 (s, 2H), 3.80 (s, 2H), 3.89 (s, 3H), 3.95 (s, 6H), 7.18-7.31 (m, 8H), 7.64 (s, 1H), 8.57 (d, 1H, J = 5.1Hz )

실시예 15Example 15

4-[N-벤질-N-[[2-(3,4,5-트리메톡시페닐)피리딘-3-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·4염산염의 합성:4- [N-benzyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-3-yl] methyl] amino] -1-[[2- (3,4,5-tri Synthesis of methoxyphenyl) pyridin-4-yl] methyl] piperidine tetrahydrochloride:

4-벤질아미노-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(134mg)과 3-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(114mg)을 실시예 9와 동일하게반응시켜 얻어진 유리 염기를 4염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4-benzylamino-1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (134 mg) and 3-chloromethyl-2- (3,4, 5-trimethoxyphenyl) pyridine (114 mg) was reacted in the same manner as in Example 9 to obtain the title compound as a yellow powder using tetrahydrochloride as a free base.

수량: 43mg 17%)Quantity: 43mg 17%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.63(br, 4H), 1.97(br, 2H), 2.39(br, 1H), 2.88(br, 2H), 3.49(s, 2H), 3.57(s, 2H), 3.68(s, 2H), 3.86(s, 6H), 3.88(s, 3H), 3.90(s, 3H), 3.96(s, 6H), 6.60(s, 2H), 7.17(d, 1H, J=5.1Hz), 7.22-7.29(m, 8H), 7.56(s, 1H), 8.02(d, 1H, J=8.0Hz), 8.50(d, 1H, J=6.4Hz), 8.58(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.63 (br, 4H), 1.97 (br, 2H), 2.39 (br, 1H), 2.88 (br, 2H), 3.49 (s, 2H ), 3.57 (s, 2H), 3.68 (s, 2H), 3.86 (s, 6H), 3.88 (s, 3H), 3.90 (s, 3H), 3.96 (s, 6H), 6.60 (s, 2H) , 7.17 (d, 1H, J = 5.1 Hz), 7.22-7.29 (m, 8H), 7.56 (s, 1H), 8.02 (d, 1H, J = 8.0 Hz), 8.50 (d, 1H, J = 6.4 Hz), 8.58 (d, 1H, J = 5.1 Hz)

실시예 16Example 16

4-[N-벤질-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·4염산염의 합성:4- [N-benzyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1-[[2- (3,4,5-tri Synthesis of methoxyphenyl) pyridin-4-yl] methyl] piperidine tetrahydrochloride:

4-벤질아미노-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(230mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(158mg)을 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 4염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4-benzylamino-1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (230 mg) and 4-chloromethyl-2- (3,4, 5-trimethoxyphenyl) pyridine (158 mg) was reacted in the same manner as in Example 9 to obtain the title compound as a yellow powder using tetrahydrochloride as the free base.

수량: 172mg (47%)Quantity: 172mg (47%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.69-1.85(m, 4H), 1.93-1.99(m, 2H), 2.56(br, 1H), 2.93-3.00(m, 2H), 3.51(s, 2H), 3.71(s, 2H), 3.74(s, 2H), 3.90(s, 6H), 3.96(s, 6H), 3.96(s, 6H), 7.18-7.32(m, 9H), 7.38(d, 2H, J=7.1Hz), 7.59(s, 1H), 7.68(s, 1H), 8.56(d, 1H, J=5.1Hz), 8.60(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.69-1.85 (m, 4H), 1.93-1.99 (m, 2H), 2.56 (br, 1H), 2.93-3.00 (m, 2H) , 3.51 (s, 2H), 3.71 (s, 2H), 3.74 (s, 2H), 3.90 (s, 6H), 3.96 (s, 6H), 3.96 (s, 6H), 7.18-7.32 (m, 9H ), 7.38 (d, 2H, J = 7.1 Hz), 7.59 (s, 1H), 7.68 (s, 1H), 8.56 (d, 1H, J = 5.1 Hz), 8.60 (d, 1H, J = 5.1 Hz )

실시예 17Example 17

4-[N-벤질-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N-benzyl-N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] -1-[[2- (3,4,5-trimethoxyphenyl) pyridine-4 Synthesis of -yl] methyl] piperidinetrichloride:

4-벤질아미노-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(134mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(114mg)를 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4-benzylamino-1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (134 mg) and 3- (3,4,5-trimethoxy The title compound was obtained as a yellow powder using phenyl) benzyl chloride (114 mg) in the same manner as in Example 9 with trihydrochloride as the free base.

수량: 47mg (18%)Quantity: 47mg (18%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ:1.70-1.86(m, 4H), 1.96(br,2H), 2.59(br, 1H), 2.94(br, 2H), 3.51(s, 2H), 3.70(s, 2H), 3.74(s, 2H), 3.89(s, 3H), 3.90(s, 3H), 3.92(s, 6H), 3.96(s, 6H), 6.75(s, 2H), 7.18-7.30(m, 6H), 7.35-7.40(m, 5H), 7.56(s, 1H), 7.60(s, 1H), 8.58(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.70-1.86 (m, 4H), 1.96 (br, 2H), 2.59 (br, 1H), 2.94 (br, 2H), 3.51 (s , 2H), 3.70 (s, 2H), 3.74 (s, 2H), 3.89 (s, 3H), 3.90 (s, 3H), 3.92 (s, 6H), 3.96 (s, 6H), 6.75 (s, 2H), 7.18-7.30 (m, 6H), 7.35-7.40 (m, 5H), 7.56 (s, 1H), 7.60 (s, 1H), 8.58 (d, 1H, J = 5.1 Hz)

실시예 18Example 18

4-[N-벤질-N-[[2-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·4염산염의 합성:4- [N-benzyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] -1-[[2- (3,4,5-tri Synthesis of methoxyphenyl) pyridin-4-yl] methyl] piperidine tetrahydrochloride:

4-벤질아미노-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(134mg)과 5-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(114mg)을 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 4염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4-benzylamino-1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (134 mg) and 5-chloromethyl-2- (3,4, 5-Trimethoxyphenyl) pyridine (114 mg) was reacted in the same manner as in Example 9 to obtain the title compound as a yellow powder using tetrahydrochloride as the free base.

수량: 44mg (17%)Quantity: 44mg (17%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.81(br, 4H), 1.96(br, 2H), 2.55(br, 1H), 2.96(br, 2H), 3.52(s, 2H), 3.69(s, 4H), 3.89(s, 6H), 3.95(s, 6H), 3.96(s, 6H), 7.19-7.32(m, 8H), 7.36-7.38(m, 2H), 7.61(d, 2H, J=7.6Hz), 7.69-7.73(m, 1H), 8.59(d, 1H, J=4.9Hz), 8.63(s, 1H) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.81 (br, 4H), 1.96 (br, 2H), 2.55 (br, 1H), 2.96 (br, 2H), 3.52 (s, 2H ), 3.69 (s, 4H), 3.89 (s, 6H), 3.95 (s, 6H), 3.96 (s, 6H), 7.19-7.32 (m, 8H), 7.36-7.38 (m, 2H), 7.61 ( d, 2H, J = 7.6 Hz), 7.69-7.73 (m, 1H), 8.59 (d, 1H, J = 4.9 Hz), 8.63 (s, 1H)

실시예 19Example 19

4-[N-벤질-N-[[5-(3,4,5-트리메톡시페닐)피리딘-3-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·4염산염의 합성:4- [N-benzyl-N-[[5- (3,4,5-trimethoxyphenyl) pyridin-3-yl] methyl] amino] -1-[[2- (3,4,5-tri Synthesis of methoxyphenyl) pyridin-4-yl] methyl] piperidine tetrahydrochloride:

4-벤질아미노-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(134mg)과 3-클로로메틸-5-(3,4,5-트리메톡시페닐)피리딘(114mg)을 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 4염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4-benzylamino-1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (134 mg) and 3-chloromethyl-5- (3,4, 5-Trimethoxyphenyl) pyridine (114 mg) was reacted in the same manner as in Example 9 to obtain the title compound as a yellow powder using tetrahydrochloride as the free base.

수량: 26mg (10%)Quantity: 26mg (10%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.83(br, 4H), 1.97(br, 2H), 2.58(br, 1H), 2.95(br, 2H), 3.53(s, 2H), 3.71(s, 2H), 3.75(s, 2H), 3.90(s, 6H), 3.93(s, 6H), 3.96(s, 6H), 6.74(s, 2H), 7.19-7.30(m, 6H), 7.36(d, 2H, J=6.8Hz), 7.60(s, 1H), 7.79(s, 1H), 8.54(s, 1H), 8.59(d, 1H, J=5.1Hz), 8.64(s, 1H) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.83 (br, 4H), 1.97 (br, 2H), 2.58 (br, 1H), 2.95 (br, 2H), 3.53 (s, 2H ), 3.71 (s, 2H), 3.75 (s, 2H), 3.90 (s, 6H), 3.93 (s, 6H), 3.96 (s, 6H), 6.74 (s, 2H), 7.19-7.30 (m, 6H), 7.36 (d, 2H, J = 6.8 Hz), 7.60 (s, 1H), 7.79 (s, 1H), 8.54 (s, 1H), 8.59 (d, 1H, J = 5.1 Hz), 8.64 ( s, 1 H)

제조예 59Preparation Example 59

1-(tert-부톡시카르보닐)-4-[N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노메틸]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4- [N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] aminomethyl] piperidine

1-(tert-부톡시카르보닐)-4-아미노메틸피페리딘(200mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(183mg)을 실시예 2와 동일하게 반응시켜 표기 화합물을 황색 유상물로서 얻었다.1- (tert-butoxycarbonyl) -4-aminomethylpiperidine (200mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (183mg) The reaction was carried out in the same manner to obtain the title compound as a yellow oil.

수량: 264mg (90%)Quantity: 264mg (90%)

¹H-NMR(400MHz, CDC1₃) δ: 1.12-1.27(m, 3H), 1.45(s, 9H), 1.60(br, 1H), 1.74(d, 2H, J=12.9Hz), 2.54(d, 2H, J=6. 6Hz), 2.69(br, 2H), 3.87(s, 2H), 3.90(s, 3H), 3.97(s, 6H), 4.03-4.14(m, 2H), 7.20(d, 1H, J=3.9Hz), 7.24(s, 2H), 7.65(s, 1H), 8.60(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.12-1.27 (m, 3H), 1.45 (s, 9H), 1.60 (br, 1H), 1.74 (d, 2H, J = 12.9 Hz), 2.54 (d , 2H, J = 6.1 Hz, 2.69 (br, 2H), 3.87 (s, 2H), 3.90 (s, 3H), 3.97 (s, 6H), 4.03-4.14 (m, 2H), 7.20 (d , 1H, J = 3.9Hz), 7.24 (s, 2H), 7.65 (s, 1H), 8.60 (d, 1H, J = 4.9Hz)

제조예 60Preparation Example 60

1-(tert-부톡시카르보닐)-4-[N-메틸-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노메틸]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N-methyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] aminomethyl] piperidine Synthesis of:

1-(tert-부톡시카르보닐)-4-[N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노메틸]피페리딘(264mg)을 제조예 11과 동일하게 처리하여 표기 화합물을 황색 유상물로서 얻었다.1- (tert-butoxycarbonyl) -4- [N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] aminomethyl] piperidine (264 mg) The same process as in Production Example 11 was carried out to obtain the title compound as a yellow oil.

수량: 157mg (58%)Quantity: 157mg (58%)

¹H-NMR(400MHz, CDC1₃) δ: 1.00-1.09(m, 2H), 1.43(s, 9H), 1.65-1.70(m, 1H), 1.79(d, 2H, J=12.7Hz), 2.21(d, 2H, J=7.4Hz), 2.23(s, 3H), 2.69(br, 2H), 3.52(s, 2H), 3.89(s, 3H), 3.96(s, 6H), 4.07-4.13(m, 2H), 7.20(d, 1H, J=4.9Hz), 7.24(s, 2H), 7.64(s, 1H), 8.58(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.00-1.09 (m, 2H), 1.43 (s, 9H), 1.65-1.70 (m, 1H), 1.79 (d, 2H, J = 12.7 Hz), 2.21 (d, 2H, J = 7.4 Hz), 2.23 (s, 3H), 2.69 (br, 2H), 3.52 (s, 2H), 3.89 (s, 3H), 3.96 (s, 6H), 4.07-4.13 ( m, 2H), 7.20 (d, 1H, J = 4.9 Hz), 7.24 (s, 2H), 7.64 (s, 1H), 8.58 (d, 1H, J = 5.1 Hz)

제조예 61Preparation Example 61

4-[N-메틸-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노메틸]피페리딘의 합성:Synthesis of 4- [N-methyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] aminomethyl] piperidine:

1-(tert-부톡시카르보닐)-4-[N-메틸-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노메틸]피페리딘(152mg)을 제조예 12와 동일하게 처리하여 표기 화합물을 황색결정으로서 얻었다.1- (tert-butoxycarbonyl) -4- [N-methyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] aminomethyl] piperidine (152 mg) was treated in the same manner as in Preparation Example 12 to obtain the title compound as yellow crystals.

수량: 105mg (88%)Quantity: 105mg (88%)

¹H-NMR(400MHz, CDC1₃) δ: 1.00-1.10(m, 2H), 1.60-1.68(m, 1H), 1.80(d, 2H, J=12.5Hz), 2.03(br, 1H), 2.20(d, 2H, J=8.4Hz), 2.21(s, 3H), 2.58(dt, 2H, J=12.1Hz, 2.1Hz), 3.05(d, 2H, J=12.1Hz), 3.51(s, 2H), 3.89(s, 3H), 3.95(s, 6H), 7.20(d, 1H, J=5.1Hz), 7.24(s, 2H), 7.65(s, 1H), 8.57(d, 1H, J=5.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.00-1.10 (m, 2H), 1.60-1.68 (m, 1H), 1.80 (d, 2H, J = 12.5 Hz), 2.03 (br, 1H), 2.20 (d, 2H, J = 8.4 Hz), 2.21 (s, 3H), 2.58 (dt, 2H, J = 12.1 Hz, 2.1 Hz), 3.05 (d, 2H, J = 12.1 Hz), 3.51 (s, 2H ), 3.89 (s, 3H), 3.95 (s, 6H), 7.20 (d, 1H, J = 5.1 Hz), 7.24 (s, 2H), 7.65 (s, 1H), 8.57 (d, 1H, J = 5.9 Hz)

실시예 20Example 20

4-[N-메틸-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노메틸]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2옥살산염의 합성:4- [N-methyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] aminomethyl] -1-[[2- (3,4,5- Synthesis of trimethoxyphenyl) pyridin-4-yl] methyl] piperidine dioxalate:

4-[N-메틸-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노메틸]피페리딘(96mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(73mg)을 실시예 2와 동일하게 반응시키고, 이어서, 2 옥살산염으로 하여 표기 화합물을 무색 분말로서 얻었다.4- [N-methyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] aminomethyl] piperidine (96 mg) with 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (73 mg) was reacted in the same manner as in Example 2, and then, as a dioxalate, the title compound was obtained as a colorless powder.

수량: 109mg (40%)Quantity: 109mg (40%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.19-1.27(m, 2H), 1.56(br, 1H), 1.81(d, 2H, J=11.1Hz), 1.99-2.04(m, 2H), 2.23(s, 5H), 2.88(d, 2H, J=11.1Hz), 3.53(s, 4H), 3.89(s, 3H), 3.90(s, 3H), 3.94(s, 6H), 3.96(s, 6H), 7.20(br, 2H), 7.23(s, 4H), 7.61(s, 1H), 7.64(s, 1H), 8.58(d, 2H, J=4.9Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.19-1.27 (m, 2H), 1.56 (br, 1H), 1.81 (d, 2H, J = 11.1 Hz), 1.99-2.04 (m , 2H), 2.23 (s, 5H), 2.88 (d, 2H, J = 11.1Hz), 3.53 (s, 4H), 3.89 (s, 3H), 3.90 (s, 3H), 3.94 (s, 6H) , 3.96 (s, 6H), 7.20 (br, 2H), 7.23 (s, 4H), 7.61 (s, 1H), 7.64 (s, 1H), 8.58 (d, 2H, J = 4.9Hz)

제조예 62Preparation Example 62

4-(3,5-디메톡시페닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4일]메틸]피페리딘의 합성:Synthesis of 4- (3,5-dimethoxyphenylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4yl] methyl] piperidine:

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]-4-피페리돈(1.40g)과 3,5-디메톡시아닐린(722mg)을 제조예 37과 동일하게 반응시켜 표기 화합물을 얻었다.Preparation Example 37 of 1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone (1.40 g) and 3,5-dimethoxyaniline (722 mg) The reaction was carried out in the same manner as to obtain the title compound.

수량: 800mg (41%)Quantity: 800mg (41%)

¹H-NMR(400MHz, CDC1₃) δ: 1.40-1.90(m, 2H), 1.95-2.50(m, 4H), 2.93(br, 2H), 3.31(br, 1H), 3.65(br, 2H), 3.72(s, 6H), 3.88(s, 3H), 3.96(s, 6H), 5.76(s, 2H), 5.85(s, 1H), 7.20-7.35(m, 3H), 7.73(br, 1H), 8.60(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.40-1.90 (m, 2H), 1.95-2.50 (m, 4H), 2.93 (br, 2H), 3.31 (br, 1H), 3.65 (br, 2H) , 3.72 (s, 6H), 3.88 (s, 3H), 3.96 (s, 6H), 5.76 (s, 2H), 5.85 (s, 1H), 7.20-7.35 (m, 3H), 7.73 (br, 1H ), 8.60 (d, 1H, J = 4.9 Hz)

실시예 21Example 21

4-[N-(3,5-디메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-3-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (3,5-dimethoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-3-yl] methyl] amino] -1-[[2- Synthesis of (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

4-(3,5-디메톡시페닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(148mg)과 3-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(114mg)을 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (3,5-dimethoxyphenylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (148 mg) and 3-chloromethyl The title compound was obtained as a yellow powder by using the free base obtained by reacting -2- (3,4,5-trimethoxyphenyl) pyridine (114 mg) in the same manner as in Example 9.

수량: 29mg (11%)Quantity: 29mg (11%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.60-1.63(m, 2H), 1.79(d, 2H, J=11.7Hz), 2.13(t, 2H, J=11.4Hz), 2.94(d, 2H, J=11.3Hz), 3.54(s, 2H), 3.71(s, 6H), 3.78-3.84(m, 1H), 3.90(s, 3H), 3.91(s, 6H), 3.92(s, 3H), 3.96(s, 6H), 4.41(s, 2H), 5.84(s, 2H), 6.72(s, 2H), 7.09-7.24(m, 5H), 7.53(s, 1H), 7.71(d, 1H, J=6.6Hz), 8.51(dd, 1H, J=4.7Hz, 1.6Hz), 8.59(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.60-1.63 (m, 2H), 1.79 (d, 2H, J = 11.7 Hz), 2.13 (t, 2H, J = 11.4 Hz), 2.94 (d, 2H, J = 11.3 Hz), 3.54 (s, 2H), 3.71 (s, 6H), 3.78-3.84 (m, 1H), 3.90 (s, 3H), 3.91 (s, 6H), 3.92 (s, 3H), 3.96 (s, 6H), 4.41 (s, 2H), 5.84 (s, 2H), 6.72 (s, 2H), 7.09-7.24 (m, 5H), 7.53 (s, 1H), 7.71 (d, 1H, J = 6.6 Hz), 8.51 (dd, 1H, J = 4.7 Hz, 1.6 Hz), 8.59 (d, 1H, J = 4.9 Hz)

제조예 63Preparation Example 63

에틸 2-(3,4,5-트리메톡시페닐)벤조에이트의 합성:Synthesis of ethyl 2- (3,4,5-trimethoxyphenyl) benzoate:

3,4,5-트리메톡시페닐붕소산(649mg)과 에틸 2-브로모 벤조에이트(479mg)를 제조예 1과 동일하게 반응시켜 표기 화합물을 얻었다.3,4,5-trimethoxyphenylboronic acid (649 mg) and ethyl 2-bromo benzoate (479 mg) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.

수량: 655mg (69%)Quantity: 655mg (69%)

¹H-NMR(400MHz, CDC1₃) δ: 1.04(t, 3H, J=7.2Hz), 3.86(s, 6H), 3.89(s, 3H), 4.12(q, 2H, J=7.2Hz), 6.54(s, 2H), 7.40-7.42(m, 2H), 7.51(t, 1H, J=7.8Hz), 7.77(d, 1H, J=6.8Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.04 (t, 3H, J = 7.2 Hz), 3.86 (s, 6H), 3.89 (s, 3H), 4.12 (q, 2H, J = 7.2 Hz), 6.54 (s, 2H), 7.40-7.42 (m, 2H), 7.51 (t, 1H, J = 7.8 Hz), 7.77 (d, 1H, J = 6.8 Hz)

제조예 64Preparation Example 64

2-(3,4,5-트리메톡시페닐)벤질알코올의 합성:Synthesis of 2- (3,4,5-trimethoxyphenyl) benzyl alcohol:

에틸 2-(3,4,5-트리메톡시페닐)벤조에이트(655mg)를 제조예 2와 동일하게 처리하여 표기 화합물을 얻었다.Ethyl 2- (3,4,5-trimethoxyphenyl) benzoate (655 mg) was treated in the same manner as in Production Example 2 to obtain the title compound.

수량: 630mg (이론량)Quantity: 630mg (Theoretical quantity)

¹H-NMR(400MHz, CDC1₃) δ: 3.85(s, 6H), 3.90(s, 3H), 4.61(s, 2H), 6.61(s, 2H), 7.26-7.39(m, 3H), 7.53(d, 1H, J=6.8Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 3.85 (s, 6H), 3.90 (s, 3H), 4.61 (s, 2H), 6.61 (s, 2H), 7.26-7.39 (m, 3H), 7.53 (d, 1H, J = 6.8 Hz)

제조예 65Preparation 65

2-(3,4,5-트리메톡시페닐)벤질클로라이드의 합성:Synthesis of 2- (3,4,5-trimethoxyphenyl) benzylchloride:

2-(3,4,5-트리메톡시페닐)벤질알코올(630mg)을 제조예 3과 동일하게 처리하여 표기 화합물을 얻었다.2- (3,4,5-trimethoxyphenyl) benzyl alcohol (630 mg) was treated in the same manner as in Preparation Example 3 to obtain the title compound.

수량: 615mg (이론량)Quantity: 615mg (Theoretical quantity)

¹H-NMR(400MHz, CDC1₃) δ: 3.87(s, 6H), 3.90(s, 3H), 4.53(s, 2H), 6.66(s, 2H), 7.29-7.32(m, 1H), 7.34-7.39(m, 2H), 7.50-7.52(m, 1H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 3.87 (s, 6H), 3.90 (s, 3H), 4.53 (s, 2H), 6.66 (s, 2H), 7.29-7.32 (m, 1H), 7.34 -7.39 (m, 2H), 7.50-7.52 (m, 1H)

실시예 22Example 22

4-[N-(3,5-디메톡시페닐)-N-[2-(3,4,5-트리메톡시페닐)벤질]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2염산염의 합성:4- [N- (3,5-dimethoxyphenyl) -N- [2- (3,4,5-trimethoxyphenyl) benzyl] amino] -1-[[2- (3,4,5- Synthesis of trimethoxyphenyl) pyridin-4-yl] methyl] piperidine dihydrochloride:

4-(3,5-디메톡시페닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(148mg)과 2-(3,4,5-트리메톡시페닐)벤질클로라이드(114mg)를 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 2염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (3,5-dimethoxyphenylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (148 mg) and 2- (3 The title compound was obtained as a yellow powder using the free base obtained by reacting 4,5-trimethoxyphenyl) benzyl chloride (114 mg) in the same manner as in Example 9.

수량: 20mg (8%)Quantity: 20mg (8%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.50-1.90(m, 4H), 2.05-2.20(m, 2H), 2.92(br, 2H), 3.52(br, 3H), 3.68(s, 6H), 3.85(s, 6H), 3.88(s, 3H), 3.89(s, 3H), 3.94(s, 6H), 4.31(s, 2H), 5.85(br, 3H), 6.52(s, 2H), 7.05-7.27(m, 6H), 7.34(s, 1H), 7.51(s, 1H), 8.56(s, 1H) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.50-1.90 (m, 4H), 2.05-2.20 (m, 2H), 2.92 (br, 2H), 3.52 (br, 3H), 3.68 (s, 6H), 3.85 (s, 6H), 3.88 (s, 3H), 3.89 (s, 3H), 3.94 (s, 6H), 4.31 (s, 2H), 5.85 (br, 3H), 6.52 ( s, 2H), 7.05-7.27 (m, 6H), 7.34 (s, 1H), 7.51 (s, 1H), 8.56 (s, 1H)

실시예 23Example 23

4-[N-(3,5-디메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (3,5-dimethoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1-[[2- Synthesis of (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

4-(3,5-디메톡시페닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(148mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(114mg)을 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (3,5-dimethoxyphenylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (148 mg) and 4-chloromethyl The title compound was obtained as a yellow powder by using the free base obtained by reacting -2- (3,4,5-trimethoxyphenyl) pyridine (114 mg) in the same manner as in Example 9.

수량: 40mg (18%)Quantity: 40mg (18%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.68-1.90(m, 4H), 2.12-2.22(m, 2H), 2.94-3.02(m, 2H), 3.57(s, 2H), 3.71(s, 6H), 3.81-3.83(m, 1H), 3.89(s, 3H), 3.90(s, 3H), 3.93(s, 6H), 3.96(s, 6H), 4.52(s, 2H), 5.89-5.94(m, 3H), 7.14(d, 1H, J=5.3Hz), 7.16(s, 2H), 7.20(d, 1H, J=3.7Hz), 7.22(s, 2H), 7.54-7.60(m, 2H), 8.55(d, 1H, J=5.1Hz), 8.59(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.68-1.90 (m, 4H), 2.12-2.22 (m, 2H), 2.94-3.02 (m, 2H), 3.57 (s, 2H) , 3.71 (s, 6H), 3.81-3.83 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.93 (s, 6H), 3.96 (s, 6H), 4.52 (s, 2H ), 5.89-5.94 (m, 3H), 7.14 (d, 1H, J = 5.3 Hz), 7.16 (s, 2H), 7.20 (d, 1H, J = 3.7 Hz), 7.22 (s, 2H), 7.54 -7.60 (m, 2H), 8.55 (d, 1H, J = 5.1 Hz), 8.59 (d, 1H, J = 5.1 Hz)

실시예 24Example 24

4-[N-(3,5-디메톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2염산염의 합성:4- [N- (3,5-dimethoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] -1-[[2- (3,4,5- Synthesis of trimethoxyphenyl) pyridin-4-yl] methyl] piperidine dihydrochloride:

4-(3,5-디메톡시페닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(148mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(114mg)를 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 2염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (3,5-dimethoxyphenylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (148 mg) and 3- (3 The title compound was obtained as a yellow powder using the free base obtained by reacting 4,5-trimethoxyphenyl) benzyl chloride (114 mg) in the same manner as in Example 9.

수량: 41mg (16%)Quantity: 41mg (16%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.78-1.88(m, 4H), 2.16(t, 2H, J=10.7Hz), 2.96(d, 2H, J=11.3Hz), 3.56(s, 2H), 3.70(s, 6H), 3.73-3.84(m, 1H), 3.87(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.95(s, 6H), 4.54(s, 2H), 5.95(s, 2H), 6.71(s, 2H), 7.19-7.26(m, 4H), 7.31-7.39(m, 3H), 7.42(s, 1H), 7.59(s, 1H), 8.58(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.78-1.88 (m, 4H), 2.16 (t, 2H, J = 10.7 Hz), 2.96 (d, 2H, J = 11.3 Hz), 3.56 (s, 2H), 3.70 (s, 6H), 3.73-3.84 (m, 1H), 3.87 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.95 (s, 6H) , 4.54 (s, 2H), 5.95 (s, 2H), 6.71 (s, 2H), 7.19-7.26 (m, 4H), 7.31-7.39 (m, 3H), 7.42 (s, 1H), 7.59 (s , 1H), 8.58 (d, 1H, J = 4.9 Hz)

실시예 25Example 25

4-[N-(3,5-디메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (3,5-dimethoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] -1-[[2- Synthesis of (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

4-(3,5-디메톡시페닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(148mg)과 5클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(114mg)을 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (3,5-dimethoxyphenylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (148 mg) and 5 chloromethyl- The title compound was obtained as a yellow powder by using the free base obtained by reacting 2- (3,4,5-trimethoxyphenyl) pyridine (114 mg) in the same manner as in Example 9.

수량: 23mg (10%)Quantity: 23mg (10%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.64(br, 2H), 1.82(br, 2H), 2.10(br, 2H), 2.94(br, 2H), 3.48-3.60(m, 3H), 3.64(s, 6H), 3.82(s, 3H), 3.83(s, 3H), 3.87(s, 6H), 3.90(s, 6H), 4.46(s, 2H), 5.85(br, 3H), 7.05-7.24(m, 6H), 7.53-7.54(m, 2H), 8.51(s, 1H), 8.54(br, 1H) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.64 (br, 2H), 1.82 (br, 2H), 2.10 (br, 2H), 2.94 (br, 2H), 3.48-3.60 (m , 3H), 3.64 (s, 6H), 3.82 (s, 3H), 3.83 (s, 3H), 3.87 (s, 6H), 3.90 (s, 6H), 4.46 (s, 2H), 5.85 (br, 3H), 7.05-7.24 (m, 6H), 7.53-7.54 (m, 2H), 8.51 (s, 1H), 8.54 (br, 1H)

제조예 66Preparation 66

에틸 4-(3,4,5-트리메톡시페닐)벤조에이트의 합성:Synthesis of ethyl 4- (3,4,5-trimethoxyphenyl) benzoate:

3,4,5-트리메톡시페닐붕소산(2.01g)과 에틸 4-브로모벤조에이트(2.29g)를 제조예 1과 동일하게 반응시켜 표기 화합물을 얻었다.3,4,5-trimethoxyphenylboronic acid (2.01 g) and ethyl 4-bromobenzoate (2.29 g) were reacted in the same manner as in Production Example 1 to obtain the title compound.

수량: 2.99g(95%)Quantity: 2.99 g (95%)

¹H-NMR(400MHz, CDC1₃) δ: 1.42(t, 3H, J=7.2Hz), 3.90(s, 3H), 3.94(s, 6H), 4.38(q, 2H, J=7.2Hz), 6.81(s, 2H), 7.62(d, 2H, J=8.2Hz), 8.10(d, 2H, J=8.2Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.42 (t, 3H, J = 7.2 Hz), 3.90 (s, 3H), 3.94 (s, 6H), 4.38 (q, 2H, J = 7.2 Hz), 6.81 (s, 2H), 7.62 (d, 2H, J = 8.2 Hz), 8.10 (d, 2H, J = 8.2 Hz)

제조예 67Preparation Example 67

4-(3,4,5-트리메톡시페닐)벤질알코올의 합성:Synthesis of 4- (3,4,5-trimethoxyphenyl) benzyl alcohol:

에틸 4-(3,4,5-트리메톡시페닐)벤조에이트(2.99g)를 제조예 2와 동일하게 처리하여 표기 화합물을 얻었다.Ethyl 4- (3,4,5-trimethoxyphenyl) benzoate (2.99 g) was treated in the same manner as in Production Example 2 to obtain the title compound.

수량: 1.83g (71%)Quantity: 1.83g (71%)

제조예 68Preparation Example 68

4-(3,4,5-트리메톡시페닐)벤질클로라이드의 합성:Synthesis of 4- (3,4,5-trimethoxyphenyl) benzylchloride:

4-(3,4,5-트리메톡시페닐)벤질알코올(1.83g)을 제조예 3과 동일하게 처리하여 표기 화합물을 얻었다.4- (3,4,5-trimethoxyphenyl) benzyl alcohol (1.83 g) was treated in the same manner as in Production Example 3 to obtain the title compound.

수량: 1.65g(84%)Quantity: 1.65 g (84%)

¹H-NMR(400MHz, CDC1₃) δ: 3.90(s, 3H), 3.93(s, 6H), 4.65(s, 2H), 6.77(s, 2H), 7.46(d, 2H, J=8.0Hz), 7.55(d, 2H, J=8.0Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 3.90 (s, 3H), 3.93 (s, 6H), 4.65 (s, 2H), 6.77 (s, 2H), 7.46 (d, 2H, J = 8.0 Hz ), 7.55 (d, 2H, J = 8.0 Hz)

실시예 26Example 26

4-[N-(3,5디메톡시페닐)-N-[4-(3,4,5-트리메톡시페닐)벤질]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2염산염의 합성:4- [N- (3,5dimethoxyphenyl) -N- [4- (3,4,5-trimethoxyphenyl) benzyl] amino] -1-[[2- (3,4,5-tri Synthesis of methoxyphenyl) pyridin-4-yl] methyl] piperidine dihydrochloride:

4-(3,5-디메톡시페닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(148mg)과 4-(3,4,5-트리메톡시페닐)벤질클로라이드(114mg)를 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 2염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (3,5-dimethoxyphenylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (148 mg) and 4- (3 The title compound was obtained as a yellow powder using the free base obtained by reacting 4,5-trimethoxyphenyl) benzyl chloride (114 mg) in the same manner as in Example 9.

수량: 35mg (14%)Quantity: 35mg (14%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.80-1.89(m, 4H), 2.17(br, 2H), 3.57(s, 2H), 3.70(s, 6H), 3.77-3.84(m, 1H), 3.87(s, 3H), 3.90(s, 3H), 3.91(s, 6H), 3.96(s, 6H), 4.52(s, 2H), 5.93(s, 2H), 6.74(s, 2H), 7.19-7.22(m, 4H), 7.31(d, 2H, J=8.2Hz), 7.46(d, 2H, J=8.2Hz), 7.60(s, 1H), 8.59(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.80-1.89 (m, 4H), 2.17 (br, 2H), 3.57 (s, 2H), 3.70 (s, 6H), 3.77-3.84 (m, 1H), 3.87 (s, 3H), 3.90 (s, 3H), 3.91 (s, 6H), 3.96 (s, 6H), 4.52 (s, 2H), 5.93 (s, 2H), 6.74 ( s, 2H), 7.19-7.22 (m, 4H), 7.31 (d, 2H, J = 8.2 Hz), 7.46 (d, 2H, J = 8.2 Hz), 7.60 (s, 1H), 8.59 (d, 1H , J = 5.1 Hz)

제조예 69Preparation Example 69

4-(3,4-메틸렌디옥시페닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘의 합성:Synthesis of 4- (3,4-methylenedioxyphenylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine:

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]-4-피페리돈(1.40g)과 3,4-메틸렌디옥시아닐린(646mg)을 제조예 37과 동일하게 반응시켜 표기 화합물을 얻었다.Preparation Example of 1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone (1.40 g) and 3,4-methylenedioxyaniline (646 mg) In the same manner as in 37, the title compound was obtained.

수량: 810mg (43%)Quantity: 810mg (43%)

¹H-NMR(400MHz, CDC1₃) δ: 1.63(br, 2H), 2.02-2.60(m, 4H), 2.80-3.15(m, 2H), 3.25(br, 1H), 3.70(br, 2H), 3.88(s, 3H), 3.96(s, 6H), 5.83(s, 2H),6.02(d, 1H, J=8.3Hz), 6.22(s, 1H), 6.61(d, 1H, J=8.3Hz), 7.18-7.28(m, 3H), 7.64(br, 1H), 8.60(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.63 (br, 2H), 2.02-2.60 (m, 4H), 2.80-3.15 (m, 2H), 3.25 (br, 1H), 3.70 (br, 2H) , 3.88 (s, 3H), 3.96 (s, 6H), 5.83 (s, 2H), 6.02 (d, 1H, J = 8.3Hz), 6.22 (s, 1H), 6.61 (d, 1H, J = 8.3 Hz), 7.18-7.28 (m, 3H), 7.64 (br, 1H), 8.60 (d, 1H, J = 4.9 Hz)

실시예 27Example 27

4-[N-(3,4-메틸렌디옥시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-3일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (3,4-methylenedioxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-3yl] methyl] amino] -1-[[2- Synthesis of (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

4-(3,4-메틸렌디옥시페닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(119mg)과 3-클로로메틸-2-(3,4,5-트리메톡시페닐)피리지(114mg)를 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (3,4-methylenedioxyphenylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (119 mg) and 3-chloro The title compound was obtained as a yellow powder by using the free base obtained by reacting methyl-2- (3,4,5-trimethoxyphenyl) pyrige (114 mg) in the same manner as in Example 9.

수량: 30mg (14%)Quantity: 30mg (14%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.45-2.25(m, 6H), 2.90(br, 2H), 3.40(br, 1H), 3.55(br, 2H), 3.87(s, 3H), 3.88(s, 9H), 3.93(s, 6H), 4.28(s, 2H), 5.82(s, 2H), 6.10(br, 1H), 6.28(s, 1H), 6.58(d, 1H,J=8.4Hz), 6.67(s, 2H), 7.12-7.30(m, 4H), 7.52(br, 1H), 7.75(br, 1H), 8.51(br, 1H), 8.57(br, 1H) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.45-2.25 (m, 6H), 2.90 (br, 2H), 3.40 (br, 1H), 3.55 (br, 2H), 3.87 (s , 3H), 3.88 (s, 9H), 3.93 (s, 6H), 4.28 (s, 2H), 5.82 (s, 2H), 6.10 (br, 1H), 6.28 (s, 1H), 6.58 (d, 1H, J = 8.4 Hz), 6.67 (s, 2H), 7.12-7.30 (m, 4H), 7.52 (br, 1H), 7.75 (br, 1H), 8.51 (br, 1H), 8.57 (br, 1H )

실시예 28Example 28

4-[N-(3,4-메틸렌디옥시페닐)-N-[2-(3,4,5-트리메톡시페닐)벤질]아미노-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2염산염의 합성:4- [N- (3,4-methylenedioxyphenyl) -N- [2- (3,4,5-trimethoxyphenyl) benzyl] amino-1-[[2- (3,4,5- Synthesis of trimethoxyphenyl) pyridin-4-yl] methyl] piperidine dihydrochloride:

4-(3,4-메틸렌디옥시페닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(119mg)과 2-(3,4,5-트리메톡시페닐)벤질클로라이드(114mg)를 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 2염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (3,4-methylenedioxyphenylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (119 mg) and 2- ( 3,4,5-trimethoxyphenyl) benzylchloride (114 mg) was reacted in the same manner as in Example 9 to obtain the title compound as a yellow powder using dihydrochloride as a free base.

수량: 13mg (6%)Quantity: 13mg (6%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.61(br, 2H), 1.78(br, 2H), 2.10(br, 2H), 2.91(br, 2H), 3.50-3.54(m, 3H), 3.87(s, 6H), 3.90(s, 3H), 3.92(s, 3H), 3.99(s, 6H), 4.26(s, 2H), 5.82(s, 2H), 6.12(d, 1H, J=8.6Hz), 6.32(s, 1H), 6.53(s, 2H), 6.62(d, 1H, J=8.6Hz), 7.17-7.26(m, 6H), 7.42(br,1H), 7.55(s, 1H), 8.58(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.61 (br, 2H), 1.78 (br, 2H), 2.10 (br, 2H), 2.91 (br, 2H), 3.50-3.54 (m , 3H), 3.87 (s, 6H), 3.90 (s, 3H), 3.92 (s, 3H), 3.99 (s, 6H), 4.26 (s, 2H), 5.82 (s, 2H), 6.12 (d, 1H, J = 8.6 Hz), 6.32 (s, 1H), 6.53 (s, 2H), 6.62 (d, 1H, J = 8.6 Hz), 7.17-7.26 (m, 6H), 7.42 (br, 1H), 7.55 (s, 1 H), 8.58 (d, 1 H, J = 4.9 Hz)

실시예 29Example 29

4-[N-(3,4-메틸렌디옥시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (3,4-methylenedioxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1-[[2 Synthesis of-(3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

4-(3,4-메틸렌디옥시페닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4일]메틸]피페리딘(119mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(114mg)을 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (3,4-methylenedioxyphenylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4yl] methyl] piperidine (119 mg) and 4-chloromethyl The title compound was obtained as a yellow powder by using the free base obtained by reacting -2- (3,4,5-trimethoxyphenyl) pyridine (114 mg) in the same manner as in Example 9.

수량: 52mg (25%)Quantity: 52mg (25%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.60-1.95(m, 4H), 2.20(br, 2H), 3.00(br, 2H), 3.58(br, 3H), 3.86(s, 3H), 3.87(s, 3H), 3.91(s, 6H), 3.94(s, 6H), 4.41(s, 2H), 5.82(s, 2H), 6.17(d, 1H, J=8.4Hz), 6.39(s, 1H), 6.62(d, 1H, J=8.4Hz), 7.12-7.13(m, 3H), 7.18(d, 1H, J=4.1Hz), 7.23(br,2H), 7.54(br, 2H), 8.51(br, 1H, J=5.1Hz), 8.57(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.60-1.95 (m, 4H), 2.20 (br, 2H), 3.00 (br, 2H), 3.58 (br, 3H), 3.86 (s , 3H), 3.87 (s, 3H), 3.91 (s, 6H), 3.94 (s, 6H), 4.41 (s, 2H), 5.82 (s, 2H), 6.17 (d, 1H, J = 8.4 Hz) , 6.39 (s, 1H), 6.62 (d, 1H, J = 8.4Hz), 7.12-7.13 (m, 3H), 7.18 (d, 1H, J = 4.1Hz), 7.23 (br, 2H), 7.54 ( br, 2H), 8.51 (br, 1H, J = 5.1 Hz), 8.57 (d, 1H, J = 4.9 Hz)

실시예 30Example 30

4-[N-(3,4-메틸렌디옥시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2염산염의 합성:4- [N- (3,4-methylenedioxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] -1-[[2- (3,4,5 Synthesis of -trimethoxyphenyl) pyridin-4-yl] methyl] piperidine dihydrochloride:

4-(3,4-메틸렌디옥시페닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(119mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(114mg)를 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 2염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (3,4-methylenedioxyphenylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (119 mg) and 3- ( 3,4,5-trimethoxyphenyl) benzylchloride (114 mg) was reacted in the same manner as in Example 9 to obtain the title compound as a yellow powder using dihydrochloride as a free base.

수량: 58mg (29%)Quantity: 58mg (29%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.60-1.97(m, 4H), 2.15(br, 2H), 3.00(br, 2H), 3.58(br, 3H), 3.86(s, 3H), 3.88(s, 9H), 3.94(s, 6H), 4.43(s, 2H), 5.81(s, 2H), 6.21(br, 1H), 6.42(s, 1H), 6.62(d, 1H, J=8.4Hz), 6.69(s, 2H), 7.18(d, 1H, J=4.9Hz), 7.22-7.39(m, 6H), 7.60(br, 1H), 8.57(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.60-1.97 (m, 4H), 2.15 (br, 2H), 3.00 (br, 2H), 3.58 (br, 3H), 3.86 (s , 3H), 3.88 (s, 9H), 3.94 (s, 6H), 4.43 (s, 2H), 5.81 (s, 2H), 6.21 (br, 1H), 6.42 (s, 1H), 6.62 (d, 1H, J = 8.4 Hz, 6.69 (s, 2H), 7.18 (d, 1H, J = 4.9 Hz), 7.22-7.39 (m, 6H), 7.60 (br, 1H), 8.57 (d, 1H, J = 4.9 Hz)

실시예 31Example 31

4-[N-(3,4-메틸렌디옥시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (3,4-methylenedioxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] -1-[[2 Synthesis of-(3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

4-(3,4-메틸렌디옥시페닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(119mg)과 5-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(114mg)을 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (3,4-methylenedioxyphenylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (119 mg) and 5-chloro The title compound was obtained as a yellow powder by using the free base obtained by reacting methyl-2- (3,4,5-trimethoxyphenyl) pyridine (114 mg) in the same manner as in Example 9.

수량: 69mg (27%)Quantity: 69mg (27%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.71-1.88(m, 4H), 2.14(d, 2H, J=11.2Hz), 2.97(d, 2H, J=11.5Hz), 3.45-3.52(m, 1H), 3.56(s, 2H), 3.89(s, 3H), 3.90(s, 3H), 3.94(s, 6H), 3.96(s, 6H), 4.12(s, 2H), 5.85(s, 2H), 6.24(dd, 1H, J=8.5Hz, 2.5Hz), 6.45(d, 1H, J=2.4Hz), 6.64(d, 1H, J=8.5Hz), 7.20-7.21(m, 1H), 7.21(s, 2H), 7.23(s, 2H), 7.58-7.65(m, 3H), 8.57(d, 1H,J=1.5Hz), 8.59(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.71-1.88 (m, 4H), 2.14 (d, 2H, J = 11.2 Hz), 2.97 (d, 2H, J = 11.5 Hz), 3.45-3.52 (m, 1H), 3.56 (s, 2H), 3.89 (s, 3H), 3.90 (s, 3H), 3.94 (s, 6H), 3.96 (s, 6H), 4.12 (s, 2H) , 5.85 (s, 2H), 6.24 (dd, 1H, J = 8.5 Hz, 2.5 Hz), 6.45 (d, 1H, J = 2.4 Hz), 6.64 (d, 1H, J = 8.5 Hz), 7.20-7.21 (m, 1H), 7.21 (s, 2H), 7.23 (s, 2H), 7.58-7.65 (m, 3H), 8.57 (d, 1H, J = 1.5 Hz), 8.59 (d, 1H, J = 4.9 Hz)

실시예 32Example 32

4-[N-(3,4-메틸렌디옥시페닐)-N-[4-(3,4,5-트리메톡시페닐)벤질]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2염산염의 합성:4- [N- (3,4-methylenedioxyphenyl) -N- [4- (3,4,5-trimethoxyphenyl) benzyl] amino] -1-[[2- (3,4,5 Synthesis of -trimethoxyphenyl) pyridin-4-yl] methyl] piperidine dihydrochloride:

4-(3,4-메틸렌디옥시페닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(119mg)과 4-(3,4,5-트리메톡시페닐)벤질클로라이드(114mg)를 실시예 9와 동일하게 반응시켜 얻어진 유리 염기를 2염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (3,4-methylenedioxyphenylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (119 mg) and 4- ( 3,4,5-trimethoxyphenyl) benzylchloride (114 mg) was reacted in the same manner as in Example 9 to obtain the title compound as a yellow powder using dihydrochloride as a free base.

수량: 29mg (14%)Quantity: 29mg (14%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.62-2.00(m, 4H), 2.20(br, 2H), 2.99(br, 2H), 3.58(br, 3H), 3.86(s, 3H), 3.87(s, 3H), 3.88(s, 6H), 3.89(s, 6H), 4.41(s, 2H), 5.82(s, 2H), 6.19(d, 1H, J=8.6Hz), 6.39(s, 1H), 6.63(d, 1H, J=8.4Hz), 6.72(s, 2H), 7.18(d, 1H, J=5.1Hz), 7.23(s, 2H), 7.29(d, 2H, J=8.0Hz), 7.43(d, 2H, J=8.2Hz), 7.60(br, 1H), 8.57(d, 1H,J=4.9Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.62-2.00 (m, 4H), 2.20 (br, 2H), 2.99 (br, 2H), 3.58 (br, 3H), 3.86 (s , 3H), 3.87 (s, 3H), 3.88 (s, 6H), 3.89 (s, 6H), 4.41 (s, 2H), 5.82 (s, 2H), 6.19 (d, 1H, J = 8.6Hz) , 6.39 (s, 1H), 6.63 (d, 1H, J = 8.4 Hz), 6.72 (s, 2H), 7.18 (d, 1H, J = 5.1 Hz), 7.23 (s, 2H), 7.29 (d, 2H, J = 8.0Hz), 7.43 (d, 2H, J = 8.2Hz), 7.60 (br, 1H), 8.57 (d, 1H, J = 4.9Hz)

제조예 70Preparation 70

4-[N-메틸-N-[(2-니트로벤젠)술포닐]아미노메틸]-2-(3,4,5-트리메톡시페닐)피리딘의 합성Synthesis of 4- [N-methyl-N-[(2-nitrobenzene) sulfonyl] aminomethyl] -2- (3,4,5-trimethoxyphenyl) pyridine

4-클로로메틸-2-(3.4.5-트리메톡시페닐)피리딘(232mg), N-메틸-2-니트로벤젠 술폰아미드(171mg)와 탄산칼륨(138mg)을 아세토니트릴(10㎖)에 현탁하고, 실온에서 하룻밤 교반했다. 혼합물을 감압 농축 후, 잔사를 클로로포름에 용해하고, 포화 탄산수소나트륨과 포화 식염수로 세정하고, 무수 황산마그네슘으로 건조한 후, 감압하 농축하여 표기 화합물을 얻었다.4-Chloromethyl-2- (3.4.5-trimethoxyphenyl) pyridine (232 mg), N-methyl-2-nitrobenzene sulfonamide (171 mg) and potassium carbonate (138 mg) are suspended in acetonitrile (10 ml). And it stirred at room temperature overnight. The mixture was concentrated under reduced pressure, the residue was dissolved in chloroform, washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound.

수량: 362mg (97%)Quantity: 362mg (97%)

제조예 71Preparation Example 71

4-(N-메틸아미노메틸)-2-(3,4,5-트리메톡시페닐)피리딘의 합성:Synthesis of 4- (N-methylaminomethyl) -2- (3,4,5-trimethoxyphenyl) pyridine:

4-[N-메틸-N-[(2-니트로벤젠)술포닐]아미노메틸]-2-(3,4,5-트리메톡시페닐)피리딘(691mg)과 탄산칼륨(203mg)을 아세토니트릴(20㎖)에 현탁하고, 티오페놀(228㎕)을 가했다. 혼합물을 50℃에서 하룻밤 교반하고, 감압하 농축했다. 잔사를 클로로포름에 용해하고, 포화 탄산수소나트륨과 포화 식염수로 세정하고, 무수 황산마그네슘상에서 건조한 후, 감압하 농축했다. 얻어진 잔사를 실리카겔 컬럼크로마토그래피(클로로포름: 메탄올 =40: 1∼10: 1)로 정제하고, 표기 화합물을 얻었다.4- [N-methyl-N-[(2-nitrobenzene) sulfonyl] aminomethyl] -2- (3,4,5-trimethoxyphenyl) pyridine (691 mg) and potassium carbonate (203 mg) were acetonitrile It was suspended in (20 ml), and thiophenol (228 µl) was added. The mixture was stirred at 50 ° C. overnight and concentrated under reduced pressure. The residue was dissolved in chloroform, washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1-10: 1) to obtain the title compound.

수량: 356mg (84%)Quantity: 356mg (84%)

실시예 33Example 33

4-[N-메틸-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노카르보닐]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4일]메틸]피페리딘·말레인산염의 합성:4- [N-methyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] aminocarbonyl] -1-[[2- (3,4,5 Synthesis of -trimethoxyphenyl) pyridin-4yl] methyl] piperidine maleate:

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘-4-카르복실산(98mg)과 4-(N-메틸아미노메틸)-2-(3,4,5-트리메톡시페닐)피리딘(73mg)을 실시예 1과 동일하게 처리하여 표기 화합물을 말레인산염으로서 얻었다.1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine-4-carboxylic acid (98 mg) and 4- (N-methylaminomethyl) -2 -(3,4,5-trimethoxyphenyl) pyridine (73 mg) was treated in the same manner as in Example 1 to obtain the title compound as maleate.

수량: 145mg (75%)Quantity: 145mg (75%)

¹H-NMR(400MHz, 말레인산으로서 측정, DMSO-d₆) δ: 1.89-1.97(m, 4H), 2.75-2.96(m, 3H), 3.03(s, 3H), 3.27(d, 2H, J=12.0Hz), 3.78(s, 3H), 3.79(s,3H), 3.87(s, 6H), 3.90(s, 6H), 4.09(s, 2H), 4.64(s, 2H), 6.14(s, 2H), 7.09(d, 1H, J=5.0Hz), 7.33(s, 2H), 7.37(d, 1H, J=5.0Hz), 7.38(s, 2H), 7.65(s, 1H), 7.90(s, 1H), 8.57(d, 1H, J=5.0Hz), 8.67(d, 1H, J=5.0Hz) ¹ H-NMR (400 MHz, measured as maleic acid, DMSO-d ₆ ) δ: 1.89-1.97 (m, 4H), 2.75-2.96 (m, 3H), 3.03 (s, 3H), 3.27 (d, 2H, J = 12.0 Hz), 3.78 (s, 3H), 3.79 (s, 3H), 3.87 (s, 6H), 3.90 (s, 6H), 4.09 (s, 2H), 4.64 (s, 2H), 6.14 (s , 2H), 7.09 (d, 1H, J = 5.0 Hz), 7.33 (s, 2H), 7.37 (d, 1H, J = 5.0 Hz), 7.38 (s, 2H), 7.65 (s, 1H), 7.90 (s, 1H), 8.57 (d, 1H, J = 5.0 Hz), 8.67 (d, 1H, J = 5.0 Hz)

제조예 72Preparation Example 72

(3S)-1-(tert-부톡시카르보닐)-3-[N-[(2-니트로벤젠)술포닐]-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피롤리딘의 합성:(3S) -1- (tert-butoxycarbonyl) -3- [N-[(2-nitrobenzene) sulfonyl] -N-[[2- (3,4,5-trimethoxyphenyl) pyridine Synthesis of -4-yl] methyl] amino] pyrrolidine:

(3S)-1-(tert-부톡시카르보닐)-3-[(2-니트로벤젠)술포닐아미노]피롤리딘(72mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(57mg)을 실시예 2와 동일하게 반응시켜 표기 화합물을 무색 무정형 결정으로서 얻었다.(3S) -1- (tert-butoxycarbonyl) -3-[(2-nitrobenzene) sulfonylamino] pyrrolidine (72 mg) with 4-chloromethyl-2- (3,4,5-tri Methoxyphenyl) pyridine (57 mg) was reacted in the same manner as in Example 2 to obtain the title compound as colorless amorphous crystals.

수량: 103mg (85%)Quantity: 103mg (85%)

제조예 73Preparation Example 73

(3S)-3-[N-[(2-니트로벤젠)술포닐]-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피롤리딘의 합성:(3S) -3- [N-[(2-nitrobenzene) sulfonyl] -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] pyrroli Dean's Synthesis:

(3S)-1-(tert-부톡시카르보닐)-3-[N-[(2-니트로벤젠)술포닐]-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피롤리딘(103mg)을 제조예 12와 동일하게 처리하여 표기 화합물의 황색 무정형 결정을 얻었다.(3S) -1- (tert-butoxycarbonyl) -3- [N-[(2-nitrobenzene) sulfonyl] -N-[[2- (3,4,5-trimethoxyphenyl) pyridine -4-yl] methyl] amino] pyrrolidine (103 mg) was treated in the same manner as in Production Example 12 to obtain a yellow amorphous crystal of the title compound.

수량: 72mg (84%)Quantity: 72mg (84%)

¹H-NMR(400MHz, CDC1₃) δ: 1.66-1.75(m, 1H), 2.03-2.05(m, 1H), 2.78-2.85(m, 2H), 3.00-3.10(m, 2H), 3.39(br, 1H), 3.90(s, 3H), 3.96(s, 6H), 4.59-4.67(m, 1H), 4.70(s, 2H), 7.13-7.18(m, 1H), 7.20(s, 2H), 7.52-7.64(m, 4H), 7.95(dd, 1H, J=7.9Hz, 1.1Hz), 8.52(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.66-1.75 (m, 1H), 2.03-2.05 (m, 1H), 2.78-2.85 (m, 2H), 3.00-3.10 (m, 2H), 3.39 ( br, 1H), 3.90 (s, 3H), 3.96 (s, 6H), 4.59-4.67 (m, 1H), 4.70 (s, 2H), 7.13-7.18 (m, 1H), 7.20 (s, 2H) , 7.52-7.64 (m, 4H), 7.95 (dd, 1H, J = 7.9 Hz, 1.1 Hz), 8.52 (d, 1H, J = 5.1 Hz)

제조예 74Preparation Example 74

(3S)-3-[N-[(2-니트로벤젠)술포닐]-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]-1[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피롤리딘의 합성:(3S) -3- [N-[(2-nitrobenzene) sulfonyl] -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1 Synthesis of [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] pyrrolidine:

(3S)-3-[N-[(2-니트로벤젠)술포닐]-N-[[21(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피롤리딘(72mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(40mg)을 실시예 2와 동일하게 반응시켜 표기 화합물을 황색 무정형 결정으로서 얻었다.(3S) -3- [N-[(2-nitrobenzene) sulfonyl] -N-[[21 (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] pyrrolidine (72 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (40 mg) were reacted in the same manner as in Example 2 to obtain the title compound as a yellow amorphous crystal.

수량: 97mg (91%)Quantity: 97mg (91%)

¹H-NMR(400MHz, CDC1₃) δ: 1.59(br, 1H), 1.80-1.90(m, 1H), 2.20-2.30(m, 2H), 2.55(dd, 1H, J=10.5Hz, 8.2Hz), 2.78(dd, 1H, J=10.6Hz, 3.2Hz), 2.87(t, 1H, J=7.2Hz), 3.50(d, 1H, J=13.7Hz), 3.64(d, 1H, J=7.2Hz), 3.89(s, 3H), 3.90(s, 3H), 3.92(s, 6H), 3.93(s, 6H), 4.83(d, 2H, J=4.5Hz), 7.07(d, 1H, J=5.1Hz), 7.10(d, 1H, J=4.9Hz), 7.15(s, 2H), 7.17(s, 2H), 7.41-7.45(m, 1H), 7.50-7.55(m, 3H), 7.61(s, 1H), 7.81(d, 1H, J=7.4Hz), 8.45(d, 1H, J=4.9Hz), 8.51(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.59 (br, 1H), 1.80-1.90 (m, 1H), 2.20-2.30 (m, 2H), 2.55 (dd, 1H, J = 10.5 Hz, 8.2 Hz ), 2.78 (dd, 1H, J = 10.6 Hz, 3.2 Hz), 2.87 (t, 1H, J = 7.2 Hz), 3.50 (d, 1H, J = 13.7 Hz), 3.64 (d, 1H, J = 7.2 Hz), 3.89 (s, 3H), 3.90 (s, 3H), 3.92 (s, 6H), 3.93 (s, 6H), 4.83 (d, 2H, J = 4.5 Hz), 7.07 (d, 1H, J) = 5.1 Hz), 7.10 (d, 1H, J = 4.9 Hz), 7.15 (s, 2H), 7.17 (s, 2H), 7.41-7.45 (m, 1H), 7.50-7.55 (m, 3H), 7.61 (s, 1H), 7.81 (d, 1H, J = 7.4 Hz), 8.45 (d, 1H, J = 4.9 Hz), 8.51 (d, 1H, J = 5.1 Hz)

실시예 34Example 34

(3S)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]-3-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸아미노]피롤리딘·3염산염의 합성:(3S) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] -3-[[2- (3,4,5-trimethoxyphenyl) pyridine Synthesis of -4-yl] methylamino] pyrrolidinetrichloride:

(3S)-3-[N-(2-니트로벤젠술포닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피롤리딘(97mg)을 제조예 14와 동일하게 처리하고, 이어서 통상의 방법에 따라 3염산염으로 하여 표기 화합물의 황색 분말을 얻었다.(3S) -3- [N- (2-nitrobenzenesulfonyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1- [ [2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] pyrrolidine (97 mg) was treated in the same manner as in Production Example 14, and then designated as trihydrochloride according to a conventional method. A yellow powder of the compound was obtained.

수량: 80mg (89%)Quantity: 80mg (89%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.71(br, 2H), 2.19-2.21(m, 1H), 2.52-2.55(m, 2H), 2.73-2.77(m, 2H), 3.39(br, 1H), 3.66(d, 1H, J=13.7Hz), 3.71(d, 1H, J=13.9Hz), 3.82(s, 2H), 3.90(s, 6H), 3.95(s, 12H), 7.18-7.21(m, 2H), 7.23(s, 2H), 7.24(s, 2H), 7.63(s, 2H), 8.59(d, 1H, J=4.3Hz), 8.60(d, 1H, J=4.3Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.71 (br, 2H), 2.19-2.21 (m, 1H), 2.52-2.55 (m, 2H), 2.73-2.77 (m, 2H) , 3.39 (br, 1H), 3.66 (d, 1H, J = 13.7 Hz), 3.71 (d, 1H, J = 13.9 Hz), 3.82 (s, 2H), 3.90 (s, 6H), 3.95 (s, 12H), 7.18-7.21 (m, 2H), 7.23 (s, 2H), 7.24 (s, 2H), 7.63 (s, 2H), 8.59 (d, 1H, J = 4.3 Hz), 8.60 (d, 1H , J = 4.3Hz)

실시예 35Example 35

4-[3-(3,4,5-트리메톡시페닐)벤조일아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·말레인산염의 합성:4- [3- (3,4,5-trimethoxyphenyl) benzoylamino] -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine Synthesis of Maleate:

3-(3,4,5-트리메톡시페닐) 벤조산(69mg)과 4-아미노-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(114mg)을 실시예 1과 동일하게 반응시키고, 이어서, 말레인산염으로 하여 표기 화합물을 얻었다.3- (3,4,5-trimethoxyphenyl) benzoic acid (69 mg) and 4-amino-1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] py Ferridine (114 mg) was reacted in the same manner as in Example 1, and then the title compound was obtained as maleic acid salt.

수량: 100mg (56%)Quantity: 100mg (56%)

¹H-NMR(400MHz, 말레인산염으로서 측정, DMSO-d₆) δ: 1.85-2.10(m, 4H), 2.77-2.93(m, 2H), 3.20-3.31(m, 2H), 3.77(s, 3H), 3.79(s, 3H), 3.89(s, 6H), 3.91(s, 6H), 3.98-4.07(m, 1H), 4.13(s, 2H), 6.15(s, 2H), 6.94(s, 2H), 7.40-7.52(m, 4H), 7.73-7.80(m, 2H), 8.02-8.10(m, 3H), 8.67-8.68(m, 1H) ¹ H-NMR (400 MHz, measured as maleate, DMSO-d ₆ ) δ: 1.85-2.10 (m, 4H), 2.77-2.93 (m, 2H), 3.20-3.31 (m, 2H), 3.77 (s, 3H), 3.79 (s, 3H), 3.89 (s, 6H), 3.91 (s, 6H), 3.98-4.07 (m, 1H), 4.13 (s, 2H), 6.15 (s, 2H), 6.94 (s , 2H), 7.40-7.52 (m, 4H), 7.73-7.80 (m, 2H), 8.02-8.10 (m, 3H), 8.67-8.68 (m, 1H)

실시예 36Example 36

4-[N-메틸-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·4염산염의 합성:4- [N-methyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1-[[2- (3,4,5-tri Synthesis of methoxyphenyl) pyridin-4-yl] methyl] piperidine tetrahydrochloride:

4-(메틸아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(2.67g)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(2.12g)을 실시예 2와 동일하게 반응시키고, 이어서 4염산염으로 하여 표기 화합물을 얻었다.4- (methylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (2.67 g) and 4-chloromethyl-2- (3 , 4,5-trimethoxyphenyl) pyridine (2.12 g) was reacted in the same manner as in Example 2, followed by tetrahydrochloride to obtain the title compound.

수량: 2.55g(46%)Quantity: 2.55 g (46%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.66-1.74(m, 2H), 1.82(d,2H, J=10.7Hz), 2.04(t, 2H, J=11.0Hz), 2.25(s, 3H), 2.45-2.51(m, 1H), 2.98(d, 2H, J=11.7Hz), 3.55(s, 2H), 3.66(s, 2H), 3.90(s, 3H), 3.91(s, 3H), 3.96(s, 6H), 3.97(s, 6H), 7.21-7.23(m, 2H), 7.24(s, 2H), 7.25(s, 2H), 7.62(s, 1H), 7.63(s, 1H), 8.59(d, 1H, J=5.1Hz), 8.60(d, 1H, J=5.3Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.66-1.74 (m, 2H), 1.82 (d, 2H, J = 10.7 Hz), 2.04 (t, 2H, J = 11.0 Hz), 2.25 (s, 3H), 2.45-2.51 (m, 1H), 2.98 (d, 2H, J = 11.7Hz), 3.55 (s, 2H), 3.66 (s, 2H), 3.90 (s, 3H), 3.91 (s, 3H), 3.96 (s, 6H), 3.97 (s, 6H), 7.21-7.23 (m, 2H), 7.24 (s, 2H), 7.25 (s, 2H), 7.62 (s, 1H), 7.63 (s, 1H), 8.59 (d, 1H, J = 5.1 Hz), 8.60 (d, 1H, J = 5.3 Hz)

제조예 75Preparation 75

1-(에톡시카르보닐)-4-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸아미노]피페리딘의 합성:Synthesis of 1- (ethoxycarbonyl) -4-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methylamino] piperidine:

1-(에톡시카르보닐)피페리딘(341mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(300mg)을 실시예 2와 동일하게 반응시켜 표기 화합물을 얻었다.1- (ethoxycarbonyl) piperidine (341mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (300mg) were reacted in the same manner as in Example 2 to obtain the title compound. Got it.

수량: 438mg (이론량)Quantity: 438mg (Theoretical quantity)

¹H-NMR(400MHz, CDC1₃) δ: 1.25(t, 3H, J=7.1Hz), 1.27-1.34(m, 2H), 1.60(br, 1H), 1.90(d, 2H, J=10.9Hz), 2.67-2.72(m, 1H), 2.87(t, 2H, J=11.5Hz), 3.90(s, 3H), 3.91(br, 2H), 3.96(s, 6H), 4.09(br, 2H), 4.12(q, 2H, J=7.0Hz), 7.21(d, 1H, J=3.5Hz), 7.24(s, 2H), 7.65(s, 1H), 8.59(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.25 (t, 3H, J = 7.1 Hz), 1.27-1.34 (m, 2H), 1.60 (br, 1H), 1.90 (d, 2H, J = 10.9 Hz ), 2.67-2.72 (m, 1H), 2.87 (t, 2H, J = 11.5 Hz), 3.90 (s, 3H), 3.91 (br, 2H), 3.96 (s, 6H), 4.09 (br, 2H) , 4.12 (q, 2H, J = 7.0 Hz), 7.21 (d, 1H, J = 3.5 Hz), 7.24 (s, 2H), 7.65 (s, 1H), 8.59 (d, 1H, J = 4.9 Hz)

제조예 76Preparation Example 76

1-(에톡시카르보닐)-4-[N-메틸-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:Synthesis of 1- (ethoxycarbonyl) -4- [N-methyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine

1-(에톡시카르보닐)-4-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸아미노]피페리딘(438mg)을 제조예 11과 동일하게 처리하여 표기 화합물을 황색 유상물로서 얻었다.Treated 1- (ethoxycarbonyl) -4-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methylamino] piperidine (438 mg) in the same manner as in Preparation Example 11 The title compound was obtained as a yellow oil.

수량: 235mg (52%)Quantity: 235mg (52%)

¹H-NMR(400MHz, CDC1₃) δ: 1.26(t, 3H, J=7.1Hz), 1.42-1.57(m, 2H), 1.82(d, 2H, J=11.9Hz), 2.24(s, 3H), 2.59-2.65(m, 1H), 2.75(t, 2H, J=12.0Hz), 3.65(s, 2H), 3.90(s, 3H), 3.97(s, 6H), 4.13(q, 2H, J=7.0Hz), 4.23(br, 2H), 7.22(dd, 1H, J=5.0Hz, 1.3Hz), 7.24(s, 2H), 7.63(s, 1H), 8.59(d, 1H, J=4.5Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.26 (t, 3H, J = 7.1 Hz), 1.42-1.57 (m, 2H), 1.82 (d, 2H, J = 11.9 Hz), 2.24 (s, 3H ), 2.59-2.65 (m, 1H), 2.75 (t, 2H, J = 12.0 Hz), 3.65 (s, 2H), 3.90 (s, 3H), 3.97 (s, 6H), 4.13 (q, 2H, J = 7.0 Hz), 4.23 (br, 2H), 7.22 (dd, 1H, J = 5.0 Hz, 1.3 Hz), 7.24 (s, 2H), 7.63 (s, 1H), 8.59 (d, 1H, J = 4.5 Hz)

제조예 77Preparation Example 77

4-[N-메틸-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:Synthesis of 4- [N-methyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine:

1-(에톡시카르보닐)-4-[N-메틸-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(100mg)을 에탄올(2㎖)에 용해하고, 4M 수산화나트륨(8㎖)을 가하고, 110℃에서 하룻밤 교반했다. 혼합물을 클로로포름으로 추출하고, 물, 포화 식염수로 세정하고, 무수 황산나트륨으로 건조하고, 감압 농축했다. 잔사를 실리카겔 컬럼크로마토그래피(클로로포름: 메탄올 =20:1)로 정제하여 표기 화합물을 황색 유상물로서 얻었다.1- (ethoxycarbonyl) -4- [N-methyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine (100 mg) Was dissolved in ethanol (2 mL), 4M sodium hydroxide (8 mL) was added, and the mixture was stirred at 110 ° C overnight. The mixture was extracted with chloroform, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain the title compound as a yellow oil.

수량: 73mg (88%)Quantity: 73mg (88%)

¹H-NMR(400MHz, CDC1₃) δ: 1.50-1.55(m, 2H), 1.84(d, 2H, J=12.0Hz), 1.99(br, 1H), 2.25(s, 3H), 2.55-2.63(m, 3H), 3.16(d, 2H, J=12.2Hz), 3.65(s, 2H), 3.90(s, 3H), 3.97(s, 6H), 7.22(d, 1H, J=6.1Hz), 7.24(s, 2H), 7.64(s, 1H), 8.58(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.50-1.55 (m, 2H), 1.84 (d, 2H, J = 12.0 Hz), 1.99 (br, 1H), 2.25 (s, 3H), 2.55-2.63 (m, 3H), 3.16 (d, 2H, J = 12.2 Hz), 3.65 (s, 2H), 3.90 (s, 3H), 3.97 (s, 6H), 7.22 (d, 1H, J = 6.1 Hz) , 7.24 (s, 2H), 7.64 (s, 1H), 8.58 (d, 1H, J = 5.1 Hz)

실시예 37Example 37

4-[N-메틸-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·4염산염의 합성:4- [N-methyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1-[[2- (3,4,5-tri Synthesis of methoxyphenyl) pyridin-4-yl] methyl] piperidine tetrahydrochloride:

4-[N-메틸-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(73mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(58mg)을 실시예 2와 동일하게 반응시키고, 이어서 4염산염으로 하여 표기 화합물을 얻었다.4- [N-methyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine (73 mg) and 4-chloromethyl-2- ( 3,4,5-trimethoxyphenyl) pyridine (58 mg) was reacted in the same manner as in Example 2, followed by tetrahydrochloride to obtain the title compound.

수량: 126mg (84%)Quantity: 126mg (84%)

실시예 38Example 38

4-[N-메틸-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2푸말산염의 합성:4- [N-methyl-N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] -1-[[2- (3,4,5-trimethoxyphenyl) pyridine-4 Synthesis of -yl] methyl] piperidine-2-fumarate:

4-(메틸아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(111mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(88mg)를 실시예 2와 동일하게 반응시켜, 이어서 2푸말산염으로 하여 표기 화합물을 얻었다.4- (methylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (111 mg) and 3- (3,4,5-tri Methoxyphenyl) benzyl chloride (88 mg) was reacted in the same manner as in Example 2, followed by difumarate to obtain the title compound.

수량: 59mg (23%)Quantity: 59mg (23%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.70-1.77(m, 2H), 1.85-1.87(m, 2H), 2.03-2.08(m, 2H), 2.27(s, 3H), 2.55-2.59(m, 1H), 2.98(d, 2H, J=11.3Hz), 3.56(s, 2H), 3.69(s, 2H), 3.89(s, 3H), 3.90(s, 3H), 3.93(s, 6H), 3.98(s, 6H), 6.79(s, 2H), 7.22(d, 1H, J=4.9Hz), 7.28(s, 2H), 7.31(d, 1H, J=7.6Hz), 7.38(t, 1H, J=7.4Hz), 7.45(d, 1H, J=7.6Hz), 7.51(s, 1H), 7.63(s,1H), 8.60(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.70-1.77 (m, 2H), 1.85-1.87 (m, 2H), 2.03-2.08 (m, 2H), 2.27 (s, 3H) , 2.55-2.59 (m, 1H), 2.98 (d, 2H, J = 11.3 Hz), 3.56 (s, 2H), 3.69 (s, 2H), 3.89 (s, 3H), 3.90 (s, 3H), 3.93 (s, 6H), 3.98 (s, 6H), 6.79 (s, 2H), 7.22 (d, 1H, J = 4.9Hz), 7.28 (s, 2H), 7.31 (d, 1H, J = 7.6Hz ), 7.38 (t, 1H, J = 7.4 Hz), 7.45 (d, 1H, J = 7.6 Hz), 7.51 (s, 1H), 7.63 (s, 1H), 8.60 (d, 1H, J = 5.1 Hz )

실시예 39Example 39

1-[[2-(4-히드록시-3.5-디메톡시페닐)피리딘-4-일]메틸]-4-[N-[[2-(4-히드록시-3,5-디메톡시페닐)피리딘-4-일]메틸]-N-메틸아미노]피페리딘·4염산염의 합성:1-[[2- (4-hydroxy-3.5-dimethoxyphenyl) pyridin-4-yl] methyl] -4- [N-[[2- (4-hydroxy-3,5-dimethoxyphenyl) Synthesis of pyridin-4-yl] methyl] -N-methylamino] piperidine tetrahydrochloride:

4-[N-메틸-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4일]메틸]아미노]-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(100mg)을 염화 메틸렌(5㎖)에 용해하고, 0℃ 요드화트리메틸실란(173㎕)을 가하고, 0℃에서 2시간, 다시 실온에 되돌려 밤새 교반했다. 0℃에서 소량의 물, 에틸아세테이트, 포화 탄산나트륨 수용액을 가하고, 유기층을 분리했다. 유기층을 포화 식염수로 세정한 후, 황산마그네슘으로 건조하고, 감압하 농축했다. 얻어진 잔사를 실리카겔 분취 박층크로마토그래피 실리카겔(클로로포름: 암모니아 포화 메탄올= 15: 1)에서 정제하고, 염산염으로 하여 표기 화합물을 얻었다.4- [N-methyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4yl] methyl] amino] -N-[[2- (3,4,5-trimeth Toxyphenyl) pyridin-4-yl] methyl] piperidine (100 mg) was dissolved in methylene chloride (5 mL), and 0 ° C trimethyl iodide (173 µl) was added, followed by 2 hours at 0 ° C. Turn back and stir overnight. A small amount of water, ethyl acetate, and saturated aqueous sodium carbonate solution were added at 0 ° C., and the organic layer was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography silica gel (chloroform: ammonia saturated methanol = 15: 1) to obtain the title compound as a hydrochloride salt.

수량: 50 mg (52.3%)Quantity: 50 mg (52.3%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.68-1.89(m, 4H), 2.03-2.12(m, 2H), 2.26(s, 3H), 2.48-2.60(m, 1H), 2.98-3.05(m, 2H), 3.57(s, 2H),3.65(s, 2H), 3.94(s, 6H), 3.95(s, 6H), 7.16-7.19(m, 2H), 7.26(s, 2H), 7.27(s, 2H), 7.62-7.68(m, 2H), 8.56(d, 1H, J=5.3Hz), 8.58(d, 1H, J=5.2Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.68-1.89 (m, 4H), 2.03-2.12 (m, 2H), 2.26 (s, 3H), 2.48-2.60 (m, 1H) , 2.98-3.05 (m, 2H), 3.57 (s, 2H), 3.65 (s, 2H), 3.94 (s, 6H), 3.95 (s, 6H), 7.16-7.19 (m, 2H), 7.26 (s , 2H), 7.27 (s, 2H), 7.62-7.68 (m, 2H), 8.56 (d, 1H, J = 5.3 Hz), 8.58 (d, 1H, J = 5.2 Hz)

제조예 78Preparation Example 78

1-(에톡시카르보닐)-4-[N-에틸-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:Synthesis of 1- (ethoxycarbonyl) -4- [N-ethyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine

1-(에톡시카르보닐)-4-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸아미노]피페리딘(400mg)을 아세토니트릴(5㎖)에 용해하고, 탄산칼륨(13mg)과 요드화에틸(145mg)을 가하고, 봉관중 80℃에서 2시간 교반했다. 반응액을 감압 농축하고, 에틸아세테이트를 가하고, 물, 포화 식염수로 세정하고, 황산나트륨으로 건조했다. 감압 농축 후, 실리카겔 컬럼크로마토그래피(클로로포름: 메탄올 =30: 1)로 분리하여 표기 화합물을 황색 유상물로서 얻었다.1- (ethoxycarbonyl) -4-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methylamino] piperidine (400 mg) in acetonitrile (5 mL) It melt | dissolved, potassium carbonate (13 mg) and ethyl iodide (145 mg) were added, and it stirred at 80 degreeC in sealing pipe for 2 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, washed with water and brine, and dried over sodium sulfate. After concentration under reduced pressure, the residue was separated by silica gel column chromatography (chloroform: methanol = 30: 1) to obtain the title compound as a yellow oil.

수량: 242mg (57%)Quantity: 242mg (57%)

¹H-NMR(400MHz, CDC1₃) δ: 1.04(t, 3H, J=7.1Hz), 1.25(t, 3H, J=7.1Hz), 1.43-1.52(m, 2H), 1.79(d, 2H, J=11.5Hz), 2.60(q, 2H, J=7.0Hz), 2.66-2.76(m, 3H), 3.70(s, 2H), 3.90(s, 3H), 3.97(s, 6H), 4.12(q, 2H, J=7.0Hz), 4.20(br,2H), 7.23(s, 2H), 7.26(d, 1H, J=5.7Hz) 7.67(s, 1H), 8.58(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.04 (t, 3H, J = 7.1 Hz), 1.25 (t, 3H, J = 7.1 Hz), 1.43-1.52 (m, 2H), 1.79 (d, 2H , J = 11.5 Hz), 2.60 (q, 2H, J = 7.0 Hz), 2.66-2.76 (m, 3H), 3.70 (s, 2H), 3.90 (s, 3H), 3.97 (s, 6H), 4.12 (q, 2H, J = 7.0Hz), 4.20 (br, 2H), 7.23 (s, 2H), 7.26 (d, 1H, J = 5.7Hz) 7.67 (s, 1H), 8.58 (d, 1H, J = 4.9 Hz)

제조예 79Preparation Example 79

4-[N-에틸-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:Synthesis of 4- [N-ethyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine:

1-(에톡시카르보닐)-4-[N-에틸-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4일]메틸]아미노]피페리딘(242mg)을 제조예 77과 동일하게 처리하여 표기 화합물을 황색 유상물로서 얻었다.1- (ethoxycarbonyl) -4- [N-ethyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4yl] methyl] amino] piperidine (242 mg) The same process as in Preparation Example 77 was carried out to obtain the title compound as a yellow oil.

수량: 150mg (74%)Quantity: 150mg (74%)

¹H-NMR(400MHz, CDC1₃) δ: 1.02(t, 3H, J=7.0Hz), 1.43-1.52(m, 2H), 1.70(br, 1H), 1.79(d, 2H, J=12.3Hz), 2.53-2.67(m, 5H), 3.13(d, 2H, J=11.9Hz), 3.71(s, 2H), 3.90(s, 3H), 3.97(s, 6H), 7.24(s, 2H), 7.27(d, 1H, J=5.1Hz), 7.68(s, 1H), 8.57(d, 1H, J=4.3Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.02 (t, 3H, J = 7.0 Hz), 1.43-1.52 (m, 2H), 1.70 (br, 1H), 1.79 (d, 2H, J = 12.3 Hz ), 2.53-2.67 (m, 5H), 3.13 (d, 2H, J = 11.9 Hz), 3.71 (s, 2H), 3.90 (s, 3H), 3.97 (s, 6H), 7.24 (s, 2H) , 7.27 (d, 1H, J = 5.1 Hz), 7.68 (s, 1H), 8.57 (d, 1H, J = 4.3 Hz)

실시예 40Example 40

4-[N-에틸-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·4염산염의 합성:4- [N-ethyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1-[[2- (3,4,5-tri Synthesis of methoxyphenyl) pyridin-4-yl] methyl] piperidine tetrahydrochloride:

4-[N-에틸-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(65mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(50mg)을 실시예 2와 동일하게 반응시켜, 이어서 4염산염으로 하여 표기 화합물을 얻었다.4- [N-ethyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine (65 mg) and 4-chloromethyl-2- ( 3,4,5-trimethoxyphenyl) pyridine (50 mg) was reacted in the same manner as in Example 2, followed by tetrahydrochloride to obtain the title compound.

수량: 121mg (90%)Quantity: 121mg (90%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.03(t, 3H, J=7.1Hz), 1.64-1.69(m, 2H), 1.77(d, 2H, J=10.7Hz), 2.01(t, 2H, J=10.8Hz), 2.55-2.64(m, 3H), 2.95(d, 2H, J=11.1Hz), 3.53(s, 2H), 3.71(s, 2H), 3.90(s, 6H), 3.97(s, 12H), 7.20-7.27(m, 6H), 7.60(s, 1H), 7.68(s, 1H), 8.57(d, 1H, J=4.9Hz), 8.59(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.03 (t, 3H, J = 7.1 Hz), 1.64-1.69 (m, 2H), 1.77 (d, 2H, J = 10.7 Hz), 2.01 (t, 2H, J = 10.8 Hz), 2.55-2.64 (m, 3H), 2.95 (d, 2H, J = 11.1 Hz), 3.53 (s, 2H), 3.71 (s, 2H), 3.90 (s , 6H), 3.97 (s, 12H), 7.20-7.27 (m, 6H), 7.60 (s, 1H), 7.68 (s, 1H), 8.57 (d, 1H, J = 4.9 Hz), 8.59 (d, 1H, J = 5.1Hz)

제조예 80Preparation Example 80

4-(시클로헥실아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4일]메틸]피페리딘의 합성:Synthesis of 4- (cyclohexylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4yl] methyl] piperidine:

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]-4-피페리돈(400mg)과 시클로헥실아민(134mg)을 제조예 37과 동일하게 반응시켜 표기 화합물을 얻었다.1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone (400 mg) and cyclohexylamine (134 mg) were reacted in the same manner as in Preparation Example 37. The title compound was obtained.

수량: 342mg (69%)Quantity: 342mg (69%)

¹H-NMR(400MHz, CDC1₃) δ: 1.05-1.30(m, 6H), 1.38-1.52(m, 2H), 1.53-1.80(m, 3H), 1.87(br, 4H), 2.07(t, 2H, J=10.7Hz), 2.59(br, 2H), 3.54(s, 2H), 3.90(s, 3H), 3.97(s, 6H), 7.19(d, 1H, J=4.9Hz). 7.24(s, 2H), 7.64(s, 1H), 8.58(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.05-1.30 (m, 6H), 1.38-1.52 (m, 2H), 1.53-1.80 (m, 3H), 1.87 (br, 4H), 2.07 (t, 2H, J = 10.7 Hz, 2.59 (br, 2H), 3.54 (s, 2H), 3.90 (s, 3H), 3.97 (s, 6H), 7.19 (d, 1H, J = 4.9 Hz). 7.24 (s, 2H), 7.64 (s, 1H), 8.58 (d, 1H, J = 4.9 Hz)

실시예 41Example 41

4-[N-시클로헥실-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·4염산염의 합성:4- [N-cyclohexyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1-[[2- (3,4,5- Synthesis of trimethoxyphenyl) pyridin-4-yl] methyl] piperidine tetrahydrochloride:

4-(시클로헥실아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(342mg)과 4클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(252mg)을 실시예 9와 동일하게 반응시키고, 이어서, 4염산염으로 하여 표기 화합물을 얻었다.4- (cyclohexylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (342 mg) and 4chloromethyl-2- (3, 4,5-trimethoxyphenyl) pyridine (252 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as tetrahydrochloride.

수량: 55mg (8%)Quantity: 55mg (8%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.0.-1.39(m, 6H), 1.58-1.88(m, 8H), 2.07(br, 2H), 2.61(br, 2H), 2.96(br, 2H), 3.57(br, 2H), 3.85(s, 2H), 3.90(s, 3H), 3.91(s, 3H), 3.97(s, 12H), 7.19-7.28(m, 6H), 7.70(br, 2H), 8.56(d, 1H, J=5.1Hz), 8.60(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.0.-1.39 (m, 6H), 1.58-1.88 (m, 8H), 2.07 (br, 2H), 2.61 (br, 2H), 2.96 (br, 2H), 3.57 (br, 2H), 3.85 (s, 2H), 3.90 (s, 3H), 3.91 (s, 3H), 3.97 (s, 12H), 7.19-7.28 (m, 6H) , 7.70 (br, 2H), 8.56 (d, 1H, J = 5.1 Hz), 8.60 (d, 1H, J = 5.1 Hz)

제조예 81Preparation Example 81

4-아닐리노-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘의 합성:Synthesis of 4-anilino-1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine:

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]-4-피페리돈(1.1g)과 아닐린(344mg)을 제조예 37과 동일하게 반응시켜 표기 화합물을 얻었다.1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone (1.1 g) and aniline (344 mg) were reacted in the same manner as in Production Example 37 to indicate The compound was obtained.

수량: 1.09g(81%)Quantity: 1.09 g (81%)

¹H-NMR(400MHz, CDC1₃) δ: 1.53(br, 2H), 2.02-2.13(m, 2H), 2.16-2.32(m, 2H), 2.86(br, 2H), 3.32(br, 1H), 3.59(s, 2H), 3.88(s, 3H), 3.95(s, 6H), 6.57(d, 2H, J=8.6Hz), 6.66(t, 1H, J=7.3Hz), 7.14(t, 2H, J=7.9Hz), 7.20-7.24(m, 5H), 7.65(br, 1H), 8.59(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.53 (br, 2H), 2.02-2.13 (m, 2H), 2.16-2.32 (m, 2H), 2.86 (br, 2H), 3.32 (br, 1H) , 3.59 (s, 2H), 3.88 (s, 3H), 3.95 (s, 6H), 6.57 (d, 2H, J = 8.6 Hz), 6.66 (t, 1H, J = 7.3 Hz), 7.14 (t, 2H, J = 7.9 Hz), 7.20-7.24 (m, 5H), 7.65 (br, 1H), 8.59 (d, 1H, J = 5.1 Hz)

실시예 42Example 42

4-[N-페닐-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N-phenyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1-[[2- (3,4,5-tri Synthesis of methoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

4-아닐리노-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(1.64g)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(1.33g)을 실시예 9와 동일하게 반응시키고, 이어서, 3염산염으로 하여 표기 화합물을 얻었다.4-anilino-1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (1.64 g) and 4-chloromethyl-2- (3,4 , 5-trimethoxyphenyl) pyridine (1.33 g) was reacted in the same manner as in Example 9, and then the title compound was obtained as trihydrochloride.

수량: 635mg (20%)Quantity: 635mg (20%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.60-2.00(m, 4H), 2.10-2.35(m, 2H), 2.99(br, 2H), 3.58(br, 3H), 3.86(s, 3H), 3.88(s, 3H), 3.90(s, 6H), 3.94(s, 6H), 4.52(s, 2H), 6.66-6.78(m, 3H), 7.13-7.28(m, 8H), 7.54(br, 2H), 8.52(d, 1H, J=5.1Hz), 8.58(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.60-2.00 (m, 4H), 2.10-2.35 (m, 2H), 2.99 (br, 2H), 3.58 (br, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 3.90 (s, 6H), 3.94 (s, 6H), 4.52 (s, 2H), 6.66-6.78 (m, 3H), 7.13-7.28 (m, 8H ), 7.54 (br, 2H), 8.52 (d, 1H, J = 5.1 Hz), 8.58 (d, 1H, J = 4.9 Hz)

제조예 82Preparation Example 82

1-[[2-(4-클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]-4-피페리돈 에틸렌 케탈의 합성:Synthesis of 1-[[2- (4-chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone ethylene ketal:

4-피페리돈 에틸렌 케탈(573mg)과 2-(4-클로로-3,5-디메톡시페닐)-4-클로로메틸피리딘(1.199)을 실시예 2와 동일하게 반응시켜 표기 화합물을 얻었다.4-Piperidone ethylene ketal (573 mg) and 2- (4-chloro-3,5-dimethoxyphenyl) -4-chloromethylpyridine (1.199) were reacted in the same manner as in Example 2 to obtain the title compound.

수량:1.67g (이론량)Quantity: 1.67g (theoretical quantity)

¹H-NMR(400MHz, CDC1₃) δ: 1.78(t, 4H, J=5.6Hz), 2.58(br, 4H), 3.61(s, 2H), 3.67(s, 4H), 4.02(s, 6H), 7.25-7.29(m, 3H), 7.68(s, 1H), 8.61(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.78 (t, 4H, J = 5.6 Hz), 2.58 (br, 4H), 3.61 (s, 2H), 3.67 (s, 4H), 4.02 (s, 6H ), 7.25-7.29 (m, 3H), 7.68 (s, 1H), 8.61 (d, 1H, J = 4.9 Hz)

제조예 83Preparation Example 83

1-[[2-(4클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]-4-피페리돈의 합성:Synthesis of 1-[[2- (4chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone:

1-[[2-(4-클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]-4-피페리돈 에틸렌 케탈(1.67g)을 제조예 23과 동일하게 처리하여 표기 화합물을 얻었다.1-[[2- (4-chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone ethylene ketal (1.67 g) was treated in the same manner as in Production Example 23 to obtain the title compound. Got it.

수량: 1.29g (89%)Quantity: 1.29g (89%)

¹H-NMR(400MHz, CDC1₃) δ: 2.50(t, 4H, J=5.8Hz), 2.81(t, 4H, J=5.8Hz), 3.71(s, 2H), 4.02(s, 6H), 7.26(s, 2H), 7.33(d, 1H, J=4.3Hz), 7.70(s, 1H), 8.66(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 2.50 (t, 4H, J = 5.8 Hz), 2.81 (t, 4H, J = 5.8 Hz), 3.71 (s, 2H), 4.02 (s, 6H), 7.26 (s, 2H), 7.33 (d, 1H, J = 4.3 Hz), 7.70 (s, 1H), 8.66 (d, 1H, J = 4.9 Hz)

제조예 84Preparation Example 84

4-아닐리노-1-[[2-(4-클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]피페리딘의 합성:Synthesis of 4-anilino-1-[[2- (4-chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] piperidine:

1-[[2-(4-클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]-4-피페리돈(600mg)과 아닐린(0.18㎖)을 제조예 37과 동일하게 처리하여 표기 화합물을 얻었다.1-[[2- (4-chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone (600 mg) and aniline (0.18 mL) were treated in the same manner as in Preparation Example 37. The title compound was obtained.

수량: 465mg (63%)Quantity: 465mg (63%)

¹H-NMR(400MHz, CDC1₃) δ: 1.49-1.69(m, 2H), 2.08(d, 2H, J=7.8Hz), 2.23(t, 2H, J=9.3Hz), 2.87(d, 2H, J=7.8Hz) 3.34(br, 1H), 3.60(s, 2H), 4.02(s, 6H), 6.60(d, 2H, J=7.6Hz), 6.69(t, 1H, J=7.3Hz), 7.10-7.20(m, 2H), 7.20-7.30(m, 3H), 7.67(s, 1H), 8.62(d, 1H, J=5.2Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.49-1.69 (m, 2H), 2.08 (d, 2H, J = 7.8 Hz), 2.23 (t, 2H, J = 9.3 Hz), 2.87 (d, 2H , J = 7.8 Hz) 3.34 (br, 1H), 3.60 (s, 2H), 4.02 (s, 6H), 6.60 (d, 2H, J = 7.6 Hz), 6.69 (t, 1H, J = 7.3 Hz) , 7.10-7.20 (m, 2H), 7.20-7.30 (m, 3H), 7.67 (s, 1H), 8.62 (d, 1H, J = 5.2 Hz)

실시예 43Example 43

1-[[2-(4-클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]-4-[N-[[2-(4-클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]-N-페닐아미노]피페리딘·3염산염의 합성:1-[[2- (4-chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] -4- [N-[[2- (4-chloro-3,5-dimethoxyphenyl) Synthesis of pyridin-4-yl] methyl] -N-phenylamino] piperidine trihydrochloride:

4-아닐리노-1-[[2-(4-클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]피페리딘(230mg)과 2-(4-클로로-3,5-디메톡시페닐)-4클로로메틸 피리딘(157mg)을 실시예 9와 동일하게 반응시키고, 이어서, 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4-anilino-1-[[2- (4-chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] piperidine (230 mg) and 2- (4-chloro-3,5- Dimethoxyphenyl) -4chloromethyl pyridine (157 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a yellow powder as trihydrochloride.

수량: 104mg (24%)Quantity: 104mg (24%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.70-1.85(m, 4H), 2.20(t, 2H, J=2.3Hz), 3.00(d, 2H, J=1.3Hz), 3.59(s, 2H), 3.96(s, 6H), 4.00(s, 6H), 4.56(s, 2H), 6.65-6.78(m, 3H), 7.16(s, 2H), 7.18-7.28(m, 6H), 7.59(s, 1H), 7.62(s, 1H), 8.57(d, 1H, J=5.1Hz), 8.57(d, 1H, J=4.8Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.70-1.85 (m, 4H), 2.20 (t, 2H, J = 2.3 Hz), 3.00 (d, 2H, J = 1.3 Hz), 3.59 (s, 2H), 3.96 (s, 6H), 4.00 (s, 6H), 4.56 (s, 2H), 6.65-6.78 (m, 3H), 7.16 (s, 2H), 7.18-7.28 (m, 6H), 7.59 (s, 1H), 7.62 (s, 1H), 8.57 (d, 1H, J = 5.1 Hz), 8.57 (d, 1H, J = 4.8 Hz)

제조예 85Preparation Example 85

4-(p-아니시디노)-1-[[2-(4-클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]피페리딘의 합성:Synthesis of 4- (p-anisidino) -1-[[2- (4-chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] piperidine:

1-[[2-(4-클로로-3,5디메톡시페닐)피리딘-4-일]메틸]-4-피페리돈(690mg)과 p-아니시딘(283mg)을 제조예 37과 동일하게 처리하여 표기 화합물을 얻었다.1-[[2- (4-chloro-3,5dimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone (690 mg) and p-anisidine (283 mg) were treated in the same manner as in Preparation Example 37 To obtain the title compound.

수량: 646mg (72%)Quantity: 646mg (72%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45-1.55(m, 2H), 2.05(d, 2H, J=11.7Hz), 2.20(t, 2H, J=11.2Hz), 2.87(d, 2H, J=11.7Hz), 3.20-3.35(m, 1H), 3.59(s, 2H), 3.74(s, 2H), 4.02(s, 6H), 6.58(d, 2H, J=8.7Hz), 6.77(d, 2H, J=8.7Hz), 7.25-7.28(m, 3H), 7.67(s, 1H), 8.62(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45-1.55 (m, 2H), 2.05 (d, 2H, J = 11.7 Hz), 2.20 (t, 2H, J = 11.2 Hz), 2.87 (d, 2H , J = 11.7 Hz), 3.20-3.35 (m, 1H), 3.59 (s, 2H), 3.74 (s, 2H), 4.02 (s, 6H), 6.58 (d, 2H, J = 8.7 Hz), 6.77 (d, 2H, J = 8.7 Hz), 7.25-7.28 (m, 3H), 7.67 (s, 1H), 8.62 (d, 1H, J = 4.9 Hz)

실시예 44Example 44

1-[[2-(4-클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]-4-[N-[[2-(4-클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]-N-(4메톡시페닐)아미노]피페리딘·3염산염의 합성:1-[[2- (4-chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] -4- [N-[[2- (4-chloro-3,5-dimethoxyphenyl) Synthesis of pyridin-4-yl] methyl] -N- (4methoxyphenyl) amino] piperidinetrichloride:

4-(p-아니시디노)-1-[[2-(4-클로로-3,5-디메톡시페닐)피리딘-4-일]메틸]피페리딘(271mg)과 2-(4-클로로-3,5-디메톡시페닐)-4-클로로메틸 피리딘(173mg)을 실시예 9와 동일하게 반응시키고, 이어서, 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (p-anisidino) -1-[[2- (4-chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] piperidine (271 mg) and 2- (4-chloro- 3,5-dimethoxyphenyl) -4-chloromethyl pyridine (173 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a yellow powder as trihydrochloride.

수량: 324mg (67%)Quantity: 324mg (67%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.65-1.90(m, 4H), 2.16(t, 2H, J=10.4Hz), 2.97(d, 2H, J=7.5Hz), 3.54-3.60(m, 1H), 3.58(s, 2H), 3.73(s, 3H), 3.97(s, 6H), 4.00(s, 6H), 4.46(s, 2H), 6.74(d, 2H, J=9.4Hz), 6.79(d, 2H, J=9.4Hz), 7.16(s, 2H), 7.20-7.29(m, 4H), 7.59(s, 1H), 7.62(s, 1H), 8.56(d, 1H, J=4.8Hz), 8.60(d, 1H, J=4.8Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.65-1.90 (m, 4H), 2.16 (t, 2H, J = 10.4 Hz), 2.97 (d, 2H, J = 7.5 Hz), 3.54-3.60 (m, 1H), 3.58 (s, 2H), 3.73 (s, 3H), 3.97 (s, 6H), 4.00 (s, 6H), 4.46 (s, 2H), 6.74 (d, 2H, J = 9.4 Hz), 6.79 (d, 2H, J = 9.4 Hz), 7.16 (s, 2H), 7.20-7.29 (m, 4H), 7.59 (s, 1H), 7.62 (s, 1H), 8.56 ( d, 1H, J = 4.8 Hz, 8.60 (d, 1H, J = 4.8 Hz)

제조예 86Preparation 86

4-(3-메틸티오아닐리노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘의 합성:Synthesis of 4- (3-methylthioanilino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine:

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]-4-피페리돈(1.40g)과 3-메틸티오아닐린(655mg)을 제조예 37과 동일하게 처리하여 표기 화합물을 얻었다.1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone (1.40 g) and 3-methylthioaniline (655 mg) were the same as in Preparation Example 37. Treatment to obtain the title compound.

수량: 1.01g (54%)Quantity: 1.01g (54%)

¹H-NMR(400MHz, CDC1₃) δ: 1.44-1.60(m, 2H), 1.98-2.10(m, 2H), 2.23(br, 2H), 2.42(s, 3H), 2.88(br, 2H), 3.30(br, 1H), 3.59(s, 2H), 3.88(s, 3H), 3.95(s, 6H), 6.35(d, 1H, J=7.6Hz), 6.47(s, 1H), 6.55(d, 1H, J=8.6Hz), 7.05(t, 1H, J=7.9Hz), 7.20(d, 1H, J=4.9Hz), 7.24(s, 2H), 7.68(br, 1H), 8.58(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.44-1.60 (m, 2H), 1.98-2.10 (m, 2H), 2.23 (br, 2H), 2.42 (s, 3H), 2.88 (br, 2H) , 3.30 (br, 1H), 3.59 (s, 2H), 3.88 (s, 3H), 3.95 (s, 6H), 6.35 (d, 1H, J = 7.6 Hz), 6.47 (s, 1H), 6.55 ( d, 1H, J = 8.6 Hz), 7.05 (t, 1H, J = 7.9 Hz), 7.20 (d, 1H, J = 4.9 Hz), 7.24 (s, 2H), 7.68 (br, 1H), 8.58 ( d, 1H, J = 4.9 Hz)

실시예 45Example 45

4-[N-(3-메틸티오페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-3-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (3-methylthiophenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-3-yl] methyl] amino] -1-[[2- (3 Synthesis of, 4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

4-(3-메틸티오아닐리노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(143mg)과 3-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(114mg)을 실시예 9와 동일하게 반응시키고, 이어서, 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (3-methylthioanilino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (143 mg) with 3-chloromethyl-2 -(3,4,5-trimethoxyphenyl) pyridine (114 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a yellow powder as trihydrochloride.

수량: 45mg (18%)Quantity: 45mg (18%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.58-1.71(s, 2H), 1.79(d, 2H, J=10.7Hz), 2.16(t, 2H, J=11.2Hz), 2.38(s, 3H), 2.96(d, 2H, J=11.2Hz), 3.56(s, 3H), 3.68-3.97(m, 1H), 3.90(s, 3H), 3.92(s, 9H), 3.96(s, 9H), 4.42(s, 2H), 6.45(d, 1H, J=8.3Hz), 6.52(s, 1H), 6.61(d, 1H, J=7.3Hz), 6.74(s, 2H), 7.11(t, 1H, J=8.1Hz), 7.15-7.26(m, 4H), 7.54(s, 1H), 7.68(d, 1H, J=7.8Hz), 8.53(d, 1H, J=3.2Hz), 8.59(d, 1H, J=4.8Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.58-1.71 (s, 2H), 1.79 (d, 2H, J = 10.7 Hz), 2.16 (t, 2H, J = 11.2 Hz), 2.38 (s, 3H), 2.96 (d, 2H, J = 11.2Hz), 3.56 (s, 3H), 3.68-3.97 (m, 1H), 3.90 (s, 3H), 3.92 (s, 9H), 3.96 (s, 9H), 4.42 (s, 2H), 6.45 (d, 1H, J = 8.3 Hz), 6.52 (s, 1H), 6.61 (d, 1H, J = 7.3 Hz), 6.74 (s, 2H) , 7.11 (t, 1H, J = 8.1 Hz), 7.15-7.26 (m, 4H), 7.54 (s, 1H), 7.68 (d, 1H, J = 7.8 Hz), 8.53 (d, 1H, J = 3.2 Hz), 8.59 (d, 1H, J = 4.8 Hz)

실시예 46Example 46

4-[N-(3-메틸티오페닐)-N-[2-(3,4,5-트리메톡시페닐)벤질]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2염산염의 합성:4- [N- (3-methylthiophenyl) -N- [2- (3,4,5-trimethoxyphenyl) benzyl] amino] -1-[[2- (3,4,5-trimeth Synthesis of oxyphenyl) pyridin-4-yl] methyl] piperidine dihydrochloride:

4-(3-메틸티오아닐리노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(143mg)과 2-(3,4,5-트리메톡시페닐)벤질클로라이드(114mg)를 실시예 9와 동일하게 반응시키고, 이어서, 2염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (3-methylthioanilino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (143 mg) and 2- (3,4 , 5-trimethoxyphenyl) benzylchloride (114 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a yellow powder as a dihydrochloride.

수량: 51mg (23%)Quantity: 51mg (23%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.56-1.73(m, 2H), 1.78-1.87(m, 2H), 2.10-2.20(m, 2H), 2.38(s, 3H), 2.91-2.98(m, 2H), 3.55(s, 2H), 3.70-3.80(m, 1H), 3.88(s, 6H), 3.90(s, 3H), 3.92(s, 3H), 3.96(s, 6H), 4.35(s, 2H), 6.47(d, 1H, J=8.2Hz), 6.53-6.62(m, 5H), 7.09(t, 1H, J=8.0Hz), 7.18-7.40(m, 6H), 7.54(s, 1H), 8.58(d, 1H, J=4.7Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.56-1.73 (m, 2H), 1.78-1.87 (m, 2H), 2.10-2.20 (m, 2H), 2.38 (s, 3H) , 2.91-2.98 (m, 2H), 3.55 (s, 2H), 3.70-3.80 (m, 1H), 3.88 (s, 6H), 3.90 (s, 3H), 3.92 (s, 3H), 3.96 (s , 6H), 4.35 (s, 2H), 6.47 (d, 1H, J = 8.2 Hz), 6.53-6.62 (m, 5H), 7.09 (t, 1H, J = 8.0 Hz), 7.18-7.40 (m, 6H), 7.54 (s, 1H), 8.58 (d, 1H, J = 4.7 Hz)

실시예 47Example 47

4-[N-(3-메틸티오페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·푸말산염의 합성:4- [N- (3-methylthiophenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1-[[2- (3 Synthesis of, 4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine fumarate:

4-(3-메틸티오아닐리노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(143mg)과 4-클로로메틸 2-(3,4,5-트리메톡시페닐)피리딘(114mg)을 실시예 9와 동일하게 반응시키고, 이어서, 푸말산염으로 하여 표기 화합물을 백색 분말로서 얻었다.4- (3-methylthioanilino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (143 mg) with 4-chloromethyl 2- (3,4,5-trimethoxyphenyl) pyridine (114 mg) was reacted in the same manner as in Example 9, and then, the fumarate was used to obtain the title compound as a white powder.

수량: 14mg (5%)Quantity: 14mg (5%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.76-1.86(m, 5H), 2.17-2.23(m, 2H), 2.39(s, 3H), 2.97-3.00(m, 2H), 3.58(s, 2H), 3.89(s, 3H), 3.90(s, 3H), 3.93(s, 6H), 3.96(s, 6H), 4.54(s, 2H), 6.47-6.50(m, 1H), 6.63(s, 1H), 6.64(s, 1H), 7.10-7.15(m, 2H), 7.15(s, 2H), 7.20-7.21(m, 1H), 7.22(s, 2H), 7.55(s, 1H), 7.59(s, 1H), 8.56(d, 1H, J=5.1Hz), 8.59(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.76-1.86 (m, 5H), 2.17-2.23 (m, 2H), 2.39 (s, 3H), 2.97-3.00 (m, 2H) , 3.58 (s, 2H), 3.89 (s, 3H), 3.90 (s, 3H), 3.93 (s, 6H), 3.96 (s, 6H), 4.54 (s, 2H), 6.47-6.50 (m, 1H ), 6.63 (s, 1H), 6.64 (s, 1H), 7.10-7.15 (m, 2H), 7.15 (s, 2H), 7.20-7.21 (m, 1H), 7.22 (s, 2H), 7.55 ( s, 1H), 7.59 (s, 1H), 8.56 (d, 1H, J = 5.1 Hz), 8.59 (d, 1H, J = 5.1 Hz)

실시예 48Example 48

4-[N-(3-메틸티오페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2염산염의 합성:4- [N- (3-methylthiophenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] -1-[[2- (3,4,5-trimeth Synthesis of oxyphenyl) pyridin-4-yl] methyl] piperidine dihydrochloride:

4-(3-메틸티오아닐리노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(143mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(114mg)를 실시예 9와 동일하게 반응시키고, 이어서, 2염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (3-methylthioanilino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (143 mg) and 3- (3,4 , 5-trimethoxyphenyl) benzylchloride (114 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a yellow powder as a dihydrochloride.

수량: 60mg (24%)Quantity: 60mg (24%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.65-1.91(m, 4H), 2.18(t, 2H, J=10.5Hz), 2.38(s, 3H), 2.97(d, 2H, J=10.9Hz), 3.58(s, 2H), 3.70-3.85(m, 1H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.96(s, 6H), 4.56(s, 2H), 6.52(d, 1H, J=8.4Hz), 6.59(d, 1H, J=7.6Hz), 6.65(s, 1H), 6.72(s, 2H), 7.10(t, 2H, J=8.0Hz), 7.19-7.25(m, 4H), 7.31-7.42(m, 3H), 7.60(s, 1H), 8.59(d, 1H, J=7.8Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.65-1.91 (m, 4H), 2.18 (t, 2H, J = 10.5 Hz), 2.38 (s, 3H), 2.97 (d, 2H , J = 10.9 Hz), 3.58 (s, 2H), 3.70-3.85 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.96 (s, 6H) , 4.56 (s, 2H), 6.52 (d, 1H, J = 8.4 Hz), 6.59 (d, 1H, J = 7.6 Hz), 6.65 (s, 1H), 6.72 (s, 2H), 7.10 (t, 2H, J = 8.0Hz), 7.19-7.25 (m, 4H), 7.31-7.42 (m, 3H), 7.60 (s, 1H), 8.59 (d, 1H, J = 7.8Hz)

실시예 49Example 49

4-[N-(3-메틸티오페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (3-methylthiophenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] -1-[[2- (3 Synthesis of, 4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

4-(3-메틸티오아닐리노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(143mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(114mg)를 실시예 9와 동일하게 반응시키고, 이어서, 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (3-methylthioanilino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (143 mg) and 3- (3,4 , 5-trimethoxyphenyl) benzylchloride (114 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a yellow powder as trihydrochloride.

수량: 22mg (9%)Quantity: 22mg (9%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.50-2.05(m, 4H), 2.20(br, 2H), 2.37(s, 3H), 3.05(br, 2H), 3.50-3.70(br, 3H), 3.86(s, 3H), 3.87(s, 3H), 3.92(s, 6H), 3.95(s, 6H), 4.52(s, 2H), 6.49(d, 1H, J=8.3Hz), 6.62(br, 2H), 7.09(t, 1H, J=8.2Hz), 7.18-7.30(m, 6H), 7.58(s, 2H), 8.54(br, 1H), 8.60(br, 1H) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.50-2.05 (m, 4H), 2.20 (br, 2H), 2.37 (s, 3H), 3.05 (br, 2H), 3.50-3.70 (br, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 3.92 (s, 6H), 3.95 (s, 6H), 4.52 (s, 2H), 6.49 (d, 1H, J = 8.3 Hz), 6.62 (br, 2H), 7.09 (t, 1H, J = 8.2 Hz), 7.18-7.30 (m, 6H), 7.58 (s, 2H), 8.54 (br, 1H), 8.60 (br, 1H )

실시예 50Example 50

4-[N-(3-메틸티오페닐)-N-[4-(3,4,5-트리메톡시페닐)벤질]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2염산염의 합성:4- [N- (3-methylthiophenyl) -N- [4- (3,4,5-trimethoxyphenyl) benzyl] amino] -1-[[2- (3,4,5-trimeth Synthesis of oxyphenyl) pyridin-4-yl] methyl] piperidine dihydrochloride:

4-(3-메틸티오아닐리노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(143mg)과 4-(3,4,5-트리메톡시페닐)벤질클로라이드(114mg)를 실시예 9와 동일하게 반응시키고, 이어서, 2염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (3-methylthioanilino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (143 mg) and 4- (3,4 , 5-trimethoxyphenyl) benzylchloride (114 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a yellow powder as a dihydrochloride.

수량: 57mg (22%)Quantity: 57mg (22%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.58-1.83(m, 4H), 2.20(t, 2H, J=11.3Hz), 2.39(s, 3H), 2.98(d, 2H, J=11.1Hz), 3.58(s, 2H), 3.88(s, 3H), 3.90(s, 3H), 3.91(s, 6H), 3.96(s, 6H), 4.53(s, 2H), 6.51(dd, 1H, J=8.4Hz, 2.4Hz), 6.60(d, 1H, J=8.0Hz), 6.64(s, 1H), 6.75(s, 2H), 7.10(t, 1H, J=8.1Hz), 7.24-7.33(m, 4H), 7.47(d, 2H, J=8.0Hz), 7.61(s, 1H), 8.59(d, 1H, J=5.0Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.58-1.83 (m, 4H), 2.20 (t, 2H, J = 11.3 Hz), 2.39 (s, 3H), 2.98 (d, 2H , J = 11.1 Hz), 3.58 (s, 2H), 3.88 (s, 3H), 3.90 (s, 3H), 3.91 (s, 6H), 3.96 (s, 6H), 4.53 (s, 2H), 6.51 (dd, 1H, J = 8.4Hz, 2.4Hz), 6.60 (d, 1H, J = 8.0Hz), 6.64 (s, 1H), 6.75 (s, 2H), 7.10 (t, 1H, J = 8.1Hz ), 7.24-7.33 (m, 4H), 7.47 (d, 2H, J = 8.0 Hz), 7.61 (s, 1H), 8.59 (d, 1H, J = 5.0 Hz)

제조예 87Preparation 87

4-프로파길아미노-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘의 합성:Synthesis of 4-propargylamino-1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine:

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]-4-피페리돈(400mg)과 프로파길아민(80mg)을 제조예 25와 동일하게 처리하여 표기 화합물을 얻었다.1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone (400 mg) and propargylamine (80 mg) were treated in the same manner as in Production Example 25. The title compound was obtained.

수량: 227mg (63%)Quantity: 227mg (63%)

¹H-NMR(400MHz, CDC1₃) δ: 1.38-1.51(m, 2H), 1.83-1.86(m, 3H), 2.10-2.15(m, 2H), 2.21(s, 1H), 2.74(br, 1H), 2.83-2.87(m, 2H), 3.45(s, 2H), 3.56(s, 2H), 3.89(s, 3H), 3.96(s, 6H), 7.19(d, 1H, J=4.9Hz), 7.24(s, 2H),7.65(s, 1H), 8.58(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.38-1.51 (m, 2H), 1.83-1.86 (m, 3H), 2.10-2.15 (m, 2H), 2.21 (s, 1H), 2.74 (br, 1H), 2.83-2.87 (m, 2H), 3.45 (s, 2H), 3.56 (s, 2H), 3.89 (s, 3H), 3.96 (s, 6H), 7.19 (d, 1H, J = 4.9 Hz ), 7.24 (s, 2H), 7.85 (s, 1H), 8.58 (d, 1H, J = 4.9 Hz)

실시예 51Example 51

4-[N-프로파길-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·4염산염의 합성:4- [N-propargyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1-[[2- (3,4,5- Synthesis of trimethoxyphenyl) pyridin-4-yl] methyl] piperidine tetrahydrochloride:

4-프로파길아미노-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(227mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(226mg)을 실시예 9와 동일하게 반응시키고, 이어서, 4염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4-propargylamino-1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (227 mg) and 4-chloromethyl-2- (3,4 , 5-trimethoxyphenyl) pyridine (226 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a yellow powder as tetrahydrochloride.

수량:128mg (23%)Quantity: 128mg (23%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.48-2.40(m, 7H), 2.72(br, 1H), 3.02(br, 2H), 3.39(s, 2H), 3.64(br, 2H), 3.84(s, 2H), 3.91(s, 6H), 3.98(s, 6H), 3.99(s, 6H), 7.22-7.29(m, 6H), 7.66(br, 2H), 8.60(d, 1H, J=4.9Hz), 8.62(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.48-2.40 (m, 7H), 2.72 (br, 1H), 3.02 (br, 2H), 3.39 (s, 2H), 3.64 (br , 2H), 3.84 (s, 2H), 3.91 (s, 6H), 3.98 (s, 6H), 3.99 (s, 6H), 7.22-7.29 (m, 6H), 7.66 (br, 2H), 8.60 ( d, 1H, J = 4.9 Hz), 8.62 (d, 1H, J = 4.9 Hz)

제조예 88Preparation Example 88

4-(5-인다닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘의 합성:Synthesis of 4- (5-indanylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine:

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]-4-피페리돈(1.40g)과 5-아미노인덴(680mg)을 제조예 37과 동일하게 처리하여 표기 화합물을 얻었다.1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone (1.40 g) and 5-aminoindene (680 mg) were the same as in Preparation Example 37. Treatment to obtain the title compound.

수량: 1.22g (59%)Quantity: 1.22g (59%)

¹H-NMR(400MHz, CDC1₃) δ: 1.40-1.57(m, 2H), 2.00-2.15(m, 5H), 2.9-2.25(m, 2H), 2.77-2.93(m, 6H), 3.30(br, 1H), 3.58(s, 2H), 3.91(s, 3H), 3.97(s, 6H), 6.41(d, 1H, J=8.0Hz), 6.52(s, 1H), 7.01(d, 1H, J=8.0Hz), 7.21-7.26(m, 3H), 7.64(s, 1H), 8.60(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.40-1.57 (m, 2H), 2.00-2.15 (m, 5H), 2.9-2.25 (m, 2H), 2.77-2.93 (m, 6H), 3.30 ( br, 1H), 3.58 (s, 2H), 3.91 (s, 3H), 3.97 (s, 6H), 6.41 (d, 1H, J = 8.0 Hz), 6.52 (s, 1H), 7.01 (d, 1H , J = 8.0 Hz), 7.21-7.26 (m, 3H), 7.64 (s, 1H), 8.60 (d, 1H, J = 4.9 Hz)

실시예 52Example 52

4-[N-(인덴-5-일)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-3-일]메틸]아미노]-1 -[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (inden-5-yl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-3-yl] methyl] amino] -1-[[2- (3 Synthesis of, 4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

4-(5-인다닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(142mg)과 3-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(114mg)을 실시예 9와 동일하게 반응시키고, 이어서, 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (5-Indanylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (142 mg) and 3-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (114 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a yellow powder as trihydrochloride.

수량: 90mg (41%)Quantity: 90mg (41%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.54-1.67(m, 2H), 1.74-1.83(m, 2H), 1.98-2.07(m, 2H), 2.09-2.19(m, 2H), 2.77-2.84(m, 4H), 2.90-2.98(m, 2H), 3.55(s, 2H), 3.64-3.74(m, 1H), 3.90(s, 3H), 3.91(s, 6H), 3.92(s, 3H), 3.96(s, 6H), 4.41(s, 2H), 6.49(dd, 1H, J=8.2Hz, 2.4Hz), 6.59(s, 1H), 6.74(s, 2H), 7.04(d, 1H, J=8.2Hz), 7.15-7.20(m, 2H), 7.22(s, 2H), 7.54(s, 1H), 7.77(dd, 1H, J=7.8Hz, 1.4Hz), 8.52(dd, 1H, J=4.7Hz, 1.8Hz), 8.59(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.54-1.67 (m, 2H), 1.74-1.83 (m, 2H), 1.98-2.07 (m, 2H), 2.09-2.19 (m, 2H), 2.77-2.84 (m, 4H), 2.90-2.98 (m, 2H), 3.55 (s, 2H), 3.64-3.74 (m, 1H), 3.90 (s, 3H), 3.91 (s, 6H) , 3.92 (s, 3H), 3.96 (s, 6H), 4.41 (s, 2H), 6.49 (dd, 1H, J = 8.2Hz, 2.4Hz), 6.59 (s, 1H), 6.74 (s, 2H) , 7.04 (d, 1H, J = 8.2 Hz), 7.15-7.20 (m, 2H), 7.22 (s, 2H), 7.54 (s, 1H), 7.77 (dd, 1H, J = 7.8 Hz, 1.4 Hz) , 8.52 (dd, 1H, J = 4.7 Hz, 1.8 Hz), 8.59 (d, 1H, J = 5.1 Hz)

실시예 53Example 53

4-[N-(인덴-5-일-N-[2-(3,4,5-트리메톡시페닐)벤질]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2염산염의 합성:4- [N- (inden-5-yl-N- [2- (3,4,5-trimethoxyphenyl) benzyl] amino] -1-[[2- (3,4,5-trimethoxy Synthesis of Phenyl) pyridin-4-yl] methyl] piperidine dihydrochloride:

4-(5-인다닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(142mg)과 2-(3,4,5-트리메톡시페닐)벤질클로라이드(114mg)를 실시예 9와 동일하게 반응시키고, 이어서, 2염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (5-Indanylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (142 mg) and 2- (3,4, 5-trimethoxyphenyl) benzylchloride (114 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a yellow powder as a dihydrochloride.

수량: 115mg (47%)Quantity: 115mg (47%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.56-1.66(m, 2H), 1.80-1.83(m, 2H), 2.00-2.05(m, 2H), 2.11-2.18(m, 2H), 2.77-2.83(m, 4H), 2.92-2.95(m, 2H), 3.55(s, 2H), 3.72(br, 1H), 3.87(s, 6H), 3.90(s, 3H) 3.92(s, 3H), 3.96(s, 6H), 4.34(s, 2H), 6.49(d, 1H, J=8.3Hz), 6.56(s, 2H), 6.60(s, 1H), 7.02(d, 1H, J=8.3Hz), 7.17-7.27(m, 5H), 7.42-7.45(m, 1H), 7.54(s, 1H), 8.58(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.56-1.66 (m, 2H), 1.80-1.83 (m, 2H), 2.00-2.05 (m, 2H), 2.11-2.18 (m, 2H), 2.77-2.83 (m, 4H), 2.92-2.95 (m, 2H), 3.55 (s, 2H), 3.72 (br, 1H), 3.87 (s, 6H), 3.90 (s, 3H) 3.92 ( s, 3H), 3.96 (s, 6H), 4.34 (s, 2H), 6.49 (d, 1H, J = 8.3 Hz), 6.56 (s, 2H), 6.60 (s, 1H), 7.02 (d, 1H , J = 8.3 Hz), 7.17-7.27 (m, 5H), 7.42-7.45 (m, 1H), 7.54 (s, 1H), 8.58 (d, 1H, J = 4.9 Hz)

실시예 54Example 54

4-[N-(인덴-5-일)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (inden-5-yl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1-[[2- (3 Synthesis of, 4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

4-(5-인다닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(142mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(114mg)을 실시예 9와 동일하게 반응시키고, 이어서, 3염산염으로 하여 표기 화합물을 백색 분말로서 얻었다.4- (5-Indanylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (142 mg) with 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (114 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a white powder as trihydrochloride.

수량: 23mg (9%)Quantity: 23mg (9%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.60-1.95(m, 4H), 2.00(quint, 2H, J=7.3Hz), 2.20(br, 2H), 2.75-2.81(m, 4H), 2.99(br, 2H), 3.58(br, 2H), 3.77(s, 1H), 3.86(s, 3H), 3.87(s, 3H), 3.91(s, 6H), 3.94(s, 6H), 4.49(s, 2H), 6.51(d, 1H, J=8.3Hz), 6.62(s, 1H), 7.02(d, 1H, J=8.0Hz), 7.16(s, 2H), 7.18-7.22(m, 4H), 7.57(br, 2H), 8.52(d, 1H, J=4.9Hz), 8.57(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.60-1.95 (m, 4H), 2.00 (quint, 2H, J = 7.3 Hz), 2.20 (br, 2H), 2.75-2.81 (m , 4H), 2.99 (br, 2H), 3.58 (br, 2H), 3.77 (s, 1H), 3.86 (s, 3H), 3.87 (s, 3H), 3.91 (s, 6H), 3.94 (s, 6H), 4.49 (s, 2H), 6.51 (d, 1H, J = 8.3 Hz), 6.62 (s, 1H), 7.02 (d, 1H, J = 8.0 Hz), 7.16 (s, 2H), 7.18- 7.22 (m, 4H), 7.57 (br, 2H), 8.52 (d, 1H, J = 4.9 Hz), 8.57 (d, 1H, J = 4.9 Hz)

실시예 55Example 55

4-[N-(인덴-5-일)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2염산염의 합성:4- [N- (inden-5-yl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] -1-[[2- (3,4,5-trimeth Synthesis of oxyphenyl) pyridin-4-yl] methyl] piperidine dihydrochloride:

4-(5-인다닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(60mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(114mg)를 실시예 9와 동일하게 반응시키고, 이어서, 2염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (5-Indanylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (60 mg) and 3- (3,4, 5-trimethoxyphenyl) benzylchloride (114 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a yellow powder as a dihydrochloride.

수량: 18mg (19%)Quantity: 18mg (19%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.60-1.95(m, 4H), 2.00(quint, 2H, J=7.2Hz), 2.20(br, 2H), 2.75-2.81(m, 4H), 2.95(br, 2H), 3.60(br, 2H), 3.85(br, 1H, 3.86(s, 3H), 3.87(s, 6H), 3.88(s, 3H), 3.94(s, 6H), 4.51(s, 2H), 6.54(d, 1H, J=8.2Hz), 6.66(s, 1H), 6.70(s, 2H), 7.01(d, 1H, J=8.4Hz), 7.19(d, 1H, J=4.9Hz), 7.19-7.42(m, 6H), 8.59(br, 1H) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.60-1.95 (m, 4H), 2.00 (quint, 2H, J = 7.2 Hz), 2.20 (br, 2H), 2.75-2.81 (m , 4H), 2.95 (br, 2H), 3.60 (br, 2H), 3.85 (br, 1H, 3.86 (s, 3H), 3.87 (s, 6H), 3.88 (s, 3H), 3.94 (s, 6H ), 4.51 (s, 2H), 6.54 (d, 1H, J = 8.2 Hz), 6.66 (s, 1H), 6.70 (s, 2H), 7.01 (d, 1H, J = 8.4 Hz), 7.19 (d , 1H, J = 4.9 Hz), 7.19-7.42 (m, 6H), 8.59 (br, 1H)

실시예 56Example 56

4-[N-(인덴-5-일)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (inden-5-yl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] -1-[[2- (3 Synthesis of, 4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

4-(5-인다닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(143mg)과 5-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(114mg)을 실시예 9와 동일하게 반응시키고, 이어서, 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (5-Indanylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (143 mg) and 5-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (114 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a yellow powder as trihydrochloride.

수량: 138mg (63%)Quantity: 138mg (63%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.71-1.91(m, 4H), 1.98-2.06(m, 2H), 2.13-2.22(m, 2H), 2.76-2.84(m, 4H), 2.94-3.05(m, 2H), 3.57(s, 2H), 3.69-3.78(m, 1H), 3.89(s, 3H), 3.90(s, 3H), 3.94(s, 6H), 3.96(s, 6H), 4.50(s, 2H), 6.57(dd, 1H, J=8.2Hz, 2.3Hz), 6.67(s, 1H), 7.04(d, 1H, J=8.4Hz), 7.20-7.22(m, 1H), 7.22(s, 2H), 7.23(s, 2H), 7.57-7.62(m, 1H), 7.60(s, 1H), 7.65(dd, 1H, J=8.2Hz, 2.2Hz), 8.58-8.62(m, 2H) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.71-1.91 (m, 4H), 1.98-2.06 (m, 2H), 2.13-2.22 (m, 2H), 2.76-2.84 (m, 4H), 2.94-3.05 (m, 2H), 3.57 (s, 2H), 3.69-3.78 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.94 (s, 6H), 3.96 (s, 6H), 4.50 (s, 2H), 6.57 (dd, 1H, J = 8.2 Hz, 2.3 Hz), 6.67 (s, 1H), 7.04 (d, 1H, J = 8.4 Hz), 7.20-7.22 (m, 1H), 7.22 (s, 2H), 7.23 (s, 2H), 7.57-7.62 (m, 1H), 7.60 (s, 1H), 7.65 (dd, 1H, J = 8.2 Hz, 2.2 Hz) , 8.58-8.62 (m, 2H)

실시예 57Example 57

4-[N-(인덴-5-일)-N-[4-(3,4,5-트리메톡시페닐)벤질]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2염산염의 합성:4- [N- (inden-5-yl) -N- [4- (3,4,5-trimethoxyphenyl) benzyl] amino] -1-[[2- (3,4,5-trimeth Synthesis of oxyphenyl) pyridin-4-yl] methyl] piperidine dihydrochloride:

4-(5-인다닐아미노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(143mg)과 4-(3,4,5-트리메톡시페닐)벤질클로라이드(114mg)를 실시예 9와 동일하게 반응시키고, 이어서, 2염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (5-Indanylamino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (143 mg) and 4- (3,4, 5-trimethoxyphenyl) benzylchloride (114 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a yellow powder as a dihydrochloride.

수량: 95mg (39%)Quantity: 95mg (39%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.74-1.90(m, 4H), 2.01-2.06(m, 2H), 2.16-2.22(m, 2H), 2.78-2.84(m, 4H), 2.96-2.99(m, 2H), 3.58(s, 2H), 3.72(br, 1H), 3.88(s, 3H), 3.90(s, 3H), 3.91(s, 6H), 3.96(s, 6H), 4.51(s, 2H), 6.55(d, 1H, J=8.3Hz), 6.67(s, 1H), 6.72(s, 2H), 7.04(d, 1H, J=8.3Hz), 7.20(d, 1H, J=5.1Hz), 7.23(s, 2H), 7.35(d, 2H, J=8.1Hz), 7.47(d, 2H, J=8.1Hz), 7.61(s, 1H), 8.59(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.74-1.90 (m, 4H), 2.01-2.06 (m, 2H), 2.16-2.22 (m, 2H), 2.78-2.84 (m, 4H), 2.96-2.99 (m, 2H), 3.58 (s, 2H), 3.72 (br, 1H), 3.88 (s, 3H), 3.90 (s, 3H), 3.91 (s, 6H), 3.96 (s , 6H), 4.51 (s, 2H), 6.55 (d, 1H, J = 8.3 Hz), 6.67 (s, 1H), 6.72 (s, 2H), 7.04 (d, 1H, J = 8.3 Hz), 7.20 (d, 1H, J = 5.1 Hz), 7.23 (s, 2H), 7.35 (d, 2H, J = 8.1 Hz), 7.47 (d, 2H, J = 8.1 Hz), 7.61 (s, 1H), 8.59 (d, 1H, J = 4.9 Hz)

제조예 89Preparation Example 89

4-(4-부틸아닐리노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘의 합성:Synthesis of 4- (4-butylanilino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine:

1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]-4-피페리돈(1.24g)과 4-부틸아닐린(149mg)을 제조예 37과 동일하게 처리하여 표기 화합물을 얻었다.1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone (1.24 g) and 4-butylaniline (149 mg) were prepared in the same manner as in Preparation Example 37. The treatment gave the title compound.

수량: 1.23g (72%)Quantity: 1.23g (72%)

¹H-NMR(400MHz, CDC1₃) δ: 0.82(t, 3H, J=7.3Hz), 1.20-1.30(m, 2H), 1.38-1.50(m, 4H), 1.92-2.25(m, 4H), 2.40(t, 2H, J=7.7Hz), 2.77(br, 2H), 3.21(br, 1H), 3.50(s, 2H), 3.82(s, 3H), 3.89(s, 6H), 6.45(d, 2H, J=7.8Hz), 6.89(d, 2H, J=8.0Hz), 7.13(d, 1H, J=4.9Hz), 7.18(s, 2H), 7.58(s, 1H), 8.52(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 0.82 (t, 3H, J = 7.3 Hz), 1.20-1.30 (m, 2H), 1.38-1.50 (m, 4H), 1.92-2.25 (m, 4H) , 2.40 (t, 2H, J = 7.7 Hz), 2.77 (br, 2H), 3.21 (br, 1H), 3.50 (s, 2H), 3.82 (s, 3H), 3.89 (s, 6H), 6.45 ( d, 2H, J = 7.8 Hz, 6.89 (d, 2H, J = 8.0 Hz), 7.13 (d, 1H, J = 4.9 Hz), 7.18 (s, 2H), 7.58 (s, 1H), 8.52 ( d, 1H, J = 4.9 Hz)

실시예 58Example 58

4-[N-(4-부틸페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-3-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (4-butylphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-3-yl] methyl] amino] -1-[[2- (3, Synthesis of 4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrihydrochloride:

4-(4-부틸아닐리노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(147mg)과 3-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(114mg)을 실시예 9와 동일하게 반응시키고, 이어서, 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (4-butylanilino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (147 mg) and 3-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (114 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a yellow powder as trihydrochloride.

수량: 58mg (27%)Quantity: 58mg (27%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 0.91(t, 3H, J=7.3Hz), 1.32-1.35(m, 2H), 1.50-1.70(m, 4H), 1.75(br, 2H), 2.10-2.20(m, 2H), 2.49(t, 2H, J=7.6Hz), 2.95(br, 2H), 3.55(s, 2H), 3.70(br, 1H), 3.90(s, 3H), 3.91(s, 6H), 3.92(s, 3H), 3.96(s, 6H), 4.41(s, 2H), 6.59(d, 2H, J=8.8Hz), 6.74(s, 2H), 7.00(d, 2H, J=8.6Hz), 7.16-7.17(m, 1H), 7.19(d, 1H, J=4.9Hz), 7.22(s, 2H), 7.54(s, 1H), 8.59(d, 1H, J=7.5Hz), 8.52(br, 1H), 8.59(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 0.91 (t, 3H, J = 7.3 Hz), 1.32-1.35 (m, 2H), 1.50-1.70 (m, 4H), 1.75 (br) , 2H), 2.10-2.20 (m, 2H), 2.49 (t, 2H, J = 7.6 Hz), 2.95 (br, 2H), 3.55 (s, 2H), 3.70 (br, 1H), 3.90 (s, 3H), 3.91 (s, 6H), 3.92 (s, 3H), 3.96 (s, 6H), 4.41 (s, 2H), 6.59 (d, 2H, J = 8.8 Hz), 6.74 (s, 2H), 7.00 (d, 2H, J = 8.6 Hz), 7.16-7.17 (m, 1H), 7.19 (d, 1H, J = 4.9 Hz), 7.22 (s, 2H), 7.54 (s, 1H), 8.59 (d , 1H, J = 7.5 Hz), 8.52 (br, 1H), 8.59 (d, 1H, J = 4.9 Hz)

실시예 59Example 59

4-[N-(4-부틸페닐)-N-[2-(3,4,5-트리메톡시페닐)벤질]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2염산염의 합성:4- [N- (4-butylphenyl) -N- [2- (3,4,5-trimethoxyphenyl) benzyl] amino] -1-[[2- (3,4,5-trimethoxy Synthesis of Phenyl) pyridin-4-yl] methyl] piperidine dihydrochloride:

4-(4-부틸아닐리노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(147mg)과 2-(3,4,5-트리메톡시페닐)벤질클로라이드(114mg)를 실시예 9와 동일하게 반응시키고, 이어서, 2염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (4-butylanilino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (147 mg) and 2- (3,4, 5-trimethoxyphenyl) benzylchloride (114 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a yellow powder as a dihydrochloride.

수량: 59mg (24%)Quantity: 59mg (24%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 0.90(t, 3H, J=7.4Hz), 1.25-1.41(m, 2H), 1.48-1.75(m, 4H), 1.81(d, 2H, J=11.7Hz), 2.13(t, 2H, J=11.2Hz), 2.48(t, 2H, J=7.5Hz), 2.93(d, 2H, J=11.2Hz) 3.55(s, 2H), 3.65-3.80(m, 1H), 3.87(s, 6H), 3.90(s, 3H), 3.92(s, 1H), 3.96(s, 6H), 4.33(s, 2H), 6.56(s, 2H), 6.60(d, 2H, J=8.5Hz), 6.98(de, 2H, J=81.5Hz), 7.18(d, 1H, J=4.9Hz), 7.21(s, 2H), 7.20-7.37(m, 3H), 7.41(br, 1H), 7.54(s, 1H), 8.58(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 0.90 (t, 3H, J = 7.4 Hz), 1.25-1.41 (m, 2H), 1.48-1.75 (m, 4H), 1.81 (d , 2H, J = 11.7 Hz, 2.13 (t, 2H, J = 11.2 Hz), 2.48 (t, 2H, J = 7.5 Hz), 2.93 (d, 2H, J = 11.2 Hz) 3.55 (s, 2H) , 3.65-3.80 (m, 1H), 3.87 (s, 6H), 3.90 (s, 3H), 3.92 (s, 1H), 3.96 (s, 6H), 4.33 (s, 2H), 6.56 (s, 2H ), 6.60 (d, 2H, J = 8.5 Hz), 6.98 (de, 2H, J = 81.5 Hz), 7.18 (d, 1H, J = 4.9 Hz), 7.21 (s, 2H), 7.20-7.37 (m , 3H), 7.41 (br, 1H), 7.54 (s, 1H), 8.58 (d, 1H, J = 4.9 Hz)

실시예 60Example 60

4-[N-(4-부틸페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (4-butylphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1-[[2- (3, Synthesis of 4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrihydrochloride:

4-(4-부틸아닐리노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(196mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(129mg)을 실시예 9와 동일하게 반응시키고, 이어서, 3염산염으로 하여 표기 화합물을 백색 분말로서 얻었다.4- (4-butylanilino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (196 mg) with 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (129 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a white powder as trihydrochloride.

수량: 20mg (6%)Quantity: 20mg (6%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 0.88(t, 3H, J=7.3Hz), 1.20-1.35(m, 2H), 1.49-1.60(m, 2H), 1.62-2.02(m, 4H), 2.20(br, 2H), 2.46(t, 2H, J=7.3Hz), 3.05(br, 2H), 3.60(br, 3H), 3.87(s, 3H), 3.88(s, 3H), 3.90(s, 6H), 3.94(s, 6H), 4.49(s, 2H), 6.62(d, 2H), 6.98(d, 2H, J=8.3Hz), 7.13(s, 2H), 7.15-7.40(m, 4H), 7.55(br, 2H), 8.52(d, 1H, J=4.9Hz), 8.60(br, 1H) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 0.88 (t, 3H, J = 7.3 Hz), 1.20-1.35 (m, 2H), 1.49-1.60 (m, 2H), 1.62-2.02 (m, 4H), 2.20 (br, 2H), 2.46 (t, 2H, J = 7.3 Hz), 3.05 (br, 2H), 3.60 (br, 3H), 3.87 (s, 3H), 3.88 (s, 3H), 3.90 (s, 6H), 3.94 (s, 6H), 4.49 (s, 2H), 6.62 (d, 2H), 6.98 (d, 2H, J = 8.3 Hz), 7.13 (s, 2H), 7.15-7.40 (m, 4H), 7.55 (br, 2H), 8.52 (d, 1H, J = 4.9 Hz), 8.60 (br, 1H)

실시예 61Example 61

4-[N-(4-부틸페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2염산염의 합성:4- [N- (4-butylphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] -1-[[2- (3,4,5-trimethoxy Synthesis of Phenyl) pyridin-4-yl] methyl] piperidine dihydrochloride:

4-(4-부틸아닐리노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(147mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(114mg)를 실시예 9와 동일하게 반응시키고, 이어서, 2염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (4-butylanilino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (147 mg) and 3- (3,4, 5-trimethoxyphenyl) benzylchloride (114 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a yellow powder as a dihydrochloride.

수량: 102mg (42%)Quantity: 102mg (42%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 0.90(t, 3H, J=7.4Hz), 1.30-1.36(m, 2H), 1.48-1.56(m, 2H), 1.76-1.89(m, 4H), 2.19(br, 2H), 2.48(t, 2H, J=7.8Hz), 2.97(br, 2H), 3.58(s, 2H), 3.86(br, 1H), 3.88(s, 3H), 3.90(s, 3H), 3.95(s, 6H), 4.54(s, 2H), 6.68(d, 2H, J=8.6Hz), 6.72(s, 2H), 7.00(d, 2H, J=8.6Hz), 7.20-7.27(m, 2H), 7.23(s, 2H), 7.32-7.40(m, 2H), 7.44(s, 1H), 7.62(s, 1H), 8.59(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 0.90 (t, 3H, J = 7.4 Hz), 1.30-1.36 (m, 2H), 1.48-1.56 (m, 2H), 1.76-1.89 (m, 4H), 2.19 (br, 2H), 2.48 (t, 2H, J = 7.8 Hz), 2.97 (br, 2H), 3.58 (s, 2H), 3.86 (br, 1H), 3.88 (s, 3H), 3.90 (s, 3H), 3.95 (s, 6H), 4.54 (s, 2H), 6.68 (d, 2H, J = 8.6 Hz), 6.72 (s, 2H), 7.00 (d, 2H, J = 8.6 Hz), 7.20-7.27 (m, 2H), 7.23 (s, 2H), 7.32-7.40 (m, 2H), 7.44 (s, 1H), 7.62 (s, 1H), 8.59 (d, 1H, J = 5.1Hz)

실시예 62Example 62

4-[N-(4-부틸페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (4-butylphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] -1-[[2- (3, Synthesis of 4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrihydrochloride:

4-(4-부틸아닐리노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(147mg)과 5-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(114mg)을 실시예 9와동일하게 반응시키고, 이어서, 3염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (4-butylanilino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (147 mg) and 5-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (114 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a yellow powder as trihydrochloride.

수량: 65mg (21%)Quantity: 65mg (21%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 0.90(t, 3H, J=7.3Hz), 1.32-1.36(m, 2H), 1.50-1.54(m, 2H), 1.70-1.95(m, 4H), 2.17(br, 2H), 2.49(t, 2H, J=7.7Hz), 2.96(br, 2H), 3.58(s, 2H), 3.75(br, 1H), 3.89(s, 3H), 3.90(s, 3H), 3.94(s, 6H), 3.96(s, 6H), 4.50(s, 2H), 6.68(d, 2H, J=8.6Hz), 7.00(d, 2H, J=8.6Hz), 7.20-7.22(m, 3H), 7.23(s, 2H), 7.58-7.66(m, 3H), 8.59(br, 1H), 8.60(br, 1H) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 0.90 (t, 3H, J = 7.3 Hz), 1.32-1.36 (m, 2H), 1.50-1.54 (m, 2H), 1.70-1.95 (m, 4H), 2.17 (br, 2H), 2.49 (t, 2H, J = 7.7 Hz), 2.96 (br, 2H), 3.58 (s, 2H), 3.75 (br, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.94 (s, 6H), 3.96 (s, 6H), 4.50 (s, 2H), 6.68 (d, 2H, J = 8.6 Hz), 7.00 (d, 2H, J) = 8.6 Hz), 7.20-7.22 (m, 3H), 7.23 (s, 2H), 7.58-7.66 (m, 3H), 8.59 (br, 1H), 8.60 (br, 1H)

실시예 63Example 63

4-[N-(4-부틸페닐)-N-[4-(3,4,5-트리메톡시페닐)벤질]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘.2염산염의 합성:4- [N- (4-butylphenyl) -N- [4- (3,4,5-trimethoxyphenyl) benzyl] amino] -1-[[2- (3,4,5-trimethoxy Phenyl) pyridin-4-yl] methyl] piperidine. Synthesis of Dihydrochloride:

4-(4-부틸아닐리노)-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘(147mg)과 4-(3,4,5-트리메톡시페닐)벤질클로라이드(114mg)를 실시예 9와 동일하게 반응시키고, 이어서, 2염산염으로 하여 표기 화합물을 황색 분말로서 얻었다.4- (4-butylanilino) -1-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (147 mg) and 4- (3,4, 5-trimethoxyphenyl) benzylchloride (114 mg) was reacted in the same manner as in Example 9, and then the title compound was obtained as a yellow powder as a dihydrochloride.

수량: 82mg (33%)Quantity: 82mg (33%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 0.90(t, 3H, J=7.3Hz), 1.30-1.36(m, 2H), 1.51-1.55(m, 2H), 1.79-1.90(m, 4H), 2.18(br, 2H), 2.48(t, 2H, J=7.7Hz), 2.98(d, 2H, J=10.7Hz), 3.57(s, 2H), 3.72-3.85(m, 1H), 3.88(s, 3H), 3.90(s, 3H), 3.91(s, 6H), 3.96(s, 6H), 4.50(s, 2H), 6.66(d, 2H, J=8.8Hz), 6.75(s, 2H), 7.00(d, 2H, J=8.8Hz), 7.20(d, 1H, J=4.9Hz), 7.22(s, 2H), 7.33(d, 2H, J=8.2Hz), 7.47(d, 2H, J=8.2Hz), 7.61(s, 1H), 8.59(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 0.90 (t, 3H, J = 7.3 Hz), 1.30-1.36 (m, 2H), 1.51-1.55 (m, 2H), 1.79-1.90 (m, 4H), 2.18 (br, 2H), 2.48 (t, 2H, J = 7.7 Hz), 2.98 (d, 2H, J = 10.7 Hz), 3.57 (s, 2H), 3.72-3.85 (m, 1H), 3.88 (s, 3H), 3.90 (s, 3H), 3.91 (s, 6H), 3.96 (s, 6H), 4.50 (s, 2H), 6.66 (d, 2H, J = 8.8 Hz), 6.75 (s, 2H), 7.00 (d, 2H, J = 8.8Hz), 7.20 (d, 1H, J = 4.9Hz), 7.22 (s, 2H), 7.33 (d, 2H, J = 8.2Hz), 7.47 (d, 2H, J = 8.2 Hz), 7.61 (s, 1H), 8.59 (d, 1H, J = 5.1 Hz)

제조예 90Preparation 90

1-(4-피콜릴)-4-피페리돈의 합성:Synthesis of 1- (4-picolyl) -4-piperidone:

4-피페리돈 염산염 1수화물(922mg)과 4-피콜릴클로라이드 염산염(820mg)을 실시예 2와 동일하게 반응시켜 표기 화합물을 얻었다.4-piperidone hydrochloride monohydrate (922 mg) and 4-picolinyl chloride hydrochloride (820 mg) were reacted in the same manner as in Example 2 to obtain the title compound.

수량: 870mg (92%)Quantity: 870mg (92%)

¹H-NMR(400MHz, CDC1₃) δ: 2.46(t, 4H, J=5.9Hz), 2.74(t, 4H, J=6.2Hz), 3.61(s, 2H), 7.29(d, 2H, J=6.2Hz), 8.55(dd, 2H, J=6.2Hz, 1.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 2.46 (t, 4H, J = 5.9 Hz), 2.74 (t, 4H, J = 6.2 Hz), 3.61 (s, 2H), 7.29 (d, 2H, J = 6.2 Hz), 8.55 (dd, 2H, J = 6.2 Hz, 1.1 Hz)

제조예 91Preparation 91

1-(4-피콜릴)-4-(4-피콜릴아미노)피페리딘·4염산염의 합성:Synthesis of 1- (4-picolyl) -4- (4-picolylamino) piperidine tetrahydrochloride:

1-(41피콜릴)-4-피페리돈(870mg)과 4-피콜릴아민(497mg)을 제조예 37과 동일하게 반응시켰다. 목적물은 담갈색의 4염산염으로서 얻었다.1- (41picolyl) -4-piperidone (870 mg) and 4-picolylamine (497 mg) were reacted in the same manner as in Preparation Example 37. The target product was obtained as light brown tetrahydrochloride.

수량: 363mg (19%)Quantity: 363mg (19%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.37-1.51(m, 2H), 1.82-1.90(m, 2H), 2.04(dt, 2H, J=11.6Hz, 2.7Hz), 2.44-2.55(m, 1H), 2.76-2.82(m, 2H), 3.47(s, 2H), 3.82(s, 2H), 7.23-7.26(m, 4H), 8.50-8.53(m, 4H) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.37-1.51 (m, 2H), 1.82-1.90 (m, 2H), 2.04 (dt, 2H, J = 11.6 Hz, 2.7 Hz), 2.44-2.55 (m, 1H), 2.76-2.82 (m, 2H), 3.47 (s, 2H), 3.82 (s, 2H), 7.23-7.26 (m, 4H), 8.50-8.53 (m, 4H)

제조예 92Preparation Example 92

4-(p-아니시디노)-1-(tert-부톡시카르보닐)피페리딘의 합성:Synthesis of 4- (p-anisidino) -1- (tert-butoxycarbonyl) piperidine:

1-(tert-부톡시카르보닐)-4-피페리돈(116g)과 p-아니시딘(68.3g)을 제조예 37과 동일하게 반응시키고 표기 화합물을 얻었다.1- (tert-butoxycarbonyl) -4-piperidone (116g) and p-anisidine (68.3g) were reacted in the same manner as in Preparation Example 37 to obtain the title compound.

수량: 125g (74%)Quantity: 125g (74%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.23-1.35(m, 2H), 1.46(s, 9H), 1.96-2.06(m, 2H), 2.83-2.96(m, 2H), 3.27-3.38(m, 1H), 3.74(s, 9H), 3.94-4.12(m, 2H), 6.58(d, 2H, J=9.0Hz), 6.77(d, 2H, J=9.0Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.23-1.35 (m, 2H), 1.46 (s, 9H), 1.96-2.06 (m, 2H), 2.83-2.96 (m, 2H) , 3.27-3.38 (m, 1H), 3.74 (s, 9H), 3.94-4.12 (m, 2H), 6.58 (d, 2H, J = 9.0 Hz), 6.77 (d, 2H, J = 9.0 Hz)

제조예 93Preparation Example 93

1-(tert-부톡시카르보닐)-4-[N-(4-메톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤조일]아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4- [N- (4-methoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzoyl] amino] piperidine :

4-(p-아니시디노)-1-(tert-부톡시카르보닐)피페리딘(613mg)과 3-(3,4,5-트리메톡시페닐)벤조산(577mg)을 실시예 1과 동일하게 반응시켜 표기 화합물을 얻었다.4- (p-anisidino) -1- (tert-butoxycarbonyl) piperidine (613 mg) and 3- (3,4,5-trimethoxyphenyl) benzoic acid (577 mg) in the same manner as in Example 1 Reaction was carried out to obtain the title compound.

수량:416mg (36%)Quantity: 416mg (36%)

제조예 94Preparation Example 94

4-[N-(4-메톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤조일]아미노]피페리딘·염산염의 합성:Synthesis of 4- [N- (4-methoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzoyl] amino] piperidine hydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4메톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤조일]아미노]피페리딘(416mg)을 에틸아세테이트(5㎖)에 용해하고, 4M 염화수소의 에틸아세테이트 용액(5㎖)을 가했다. 혼합물을 실온에서 4시간 교반하고, 생긴 침전을 여과하여 얻고, 이를 깔때기 상에서 에틸아세테이트로 씻고, 건조하여 표기 화합물을 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4methoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzoyl] amino] piperidine (416 mg) Was dissolved in ethyl acetate (5 ml), and an ethyl acetate solution (5 ml) of 4M hydrogen chloride was added. The mixture was stirred at room temperature for 4 hours, and the resulting precipitate was obtained by filtration, washed with ethyl acetate on a funnel and dried to obtain the title compound.

수량: 315mg (85%)Quantity: 315mg (85%)

실시예 64 내지 66Examples 64-66

이들 화합물은 4-[N-(4-메톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤조일]아미노]피페리딘·염산염과 제조예 3, 42, 48에서 얻어진 클로라이드체를 반응시킴으로서 얻었다. 얻어진 유리 염기는 염산염으로 하였다. 수율과 이들 유리 염기의NMR 데이터를 아래에 나타낸다.These compounds are 4- [N- (4-methoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzoyl] amino] piperidine hydrochloride and Preparation Examples 3, 42, 48 The chloride obtained in the above reaction was obtained by reacting. The obtained free base was made into hydrochloride. The yields and NMR data of these free bases are shown below.

제조예 95Preparation Example 95

1-(tert-부톡시카르보닐)-4-[N-(4-메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (4-methoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] Synthesis of Amino] piperidine:

4-(p-아니시디노)-1-(tert-부톡시카르보닐)피페리딘(2.21g)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(2.12g)을 실시예 9와 동일하게 반응시켜 표기 화합물을 얻었다.4- (p-anisidino) -1- (tert-butoxycarbonyl) piperidine (2.21g) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (2.12g ) Was reacted in the same manner as in Example 9 to obtain the title compound.

수량: 3.76g (93%)Quantity: 3.76g (93%)

¹H-NMR(400MHz, CDC1₃) δ: 1.40-1.64(m, 2H), 1.44(s, 9H), 1.82-1.91(m, 2H), 2.71-2.84(m, 2H), 3.62-3.73(m, 1H), 3.74(s, 3H), 3.89(s, 3H), 3.94(s, 6H), 4.10-4.30(m, 2H), 4.40(s, 2H), 6.76(d, 2H, J=9.4Hz), 6.79(d, 2H, J=9.8Hz), 7.14-7.19(m, 3H), 7.56(s, 1H), 8.55(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.40-1.64 (m, 2H), 1.44 (s, 9H), 1.82-1.91 (m, 2H), 2.71-2.84 (m, 2H), 3.62-3.73 ( m, 1H), 3.74 (s, 3H), 3.89 (s, 3H), 3.94 (s, 6H), 4.10-4.30 (m, 2H), 4.40 (s, 2H), 6.76 (d, 2H, J = 9.4 Hz), 6.79 (d, 2H, J = 9.8 Hz), 7.14-7.19 (m, 3H), 7.56 (s, 1H), 8.55 (d, 1H, J = 5.1 Hz)

제조예 96Preparation Example 96

4-[N-(4-메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (4-methoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(3.76g)을 제조예 94와 동일하게 처리하여 표기 화합물을 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4methoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino ] Piperidine (3.76 g) was treated in the same manner as in Preparation Example 94 to obtain the title compound.

수량: 3.77g (이론량)Quantity: 3.77g (Theory)

제조예 97Preparation Example 97

1-(tert-부톡시카르보닐)-4-[N-(4-메톡시페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (4-methoxyphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5yl] methyl] amino ] Synthesis of piperidine:

4-(p-아니시디노)-1-(tert-부톡시카르보닐)피페리딘(613mg)과 5-클로로메틸-3-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 황색 부정형 결정으로서 얻었다.4- (p-anisidino) -1- (tert-butoxycarbonyl) piperidine (613 mg) and 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) In the same manner as in Example 9, the title compound was obtained as yellow amorphous crystals.

수량: 159mg (14%)Quantity: 159mg (14%)

¹H-NMR(400MHz, CDC1₃) δ: 1.44(s, 9H), 1.50-1.65(m, 2H), 1.83-1.91(m, 2H), 2.70-2.84(m, 2H), 3.53-3.62(m, 1H), 3.73(s, 3H), 3.89(s, 3H), 3.91(s, 6H), 4.10-4.29(m, 2H), 4.41(s, 2H), 6.66(s, 2H), 6.76-6.84(m, 4H), 7.70(s, 1H), 8.49(s, 1H), 8.63(d, 1H, J=2.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.44 (s, 9H), 1.50-1.65 (m, 2H), 1.83-1.91 (m, 2H), 2.70-2.84 (m, 2H), 3.53-3.62 ( m, 1H), 3.73 (s, 3H), 3.89 (s, 3H), 3.91 (s, 6H), 4.10-4.29 (m, 2H), 4.41 (s, 2H), 6.66 (s, 2H), 6.76 -6.84 (m, 4H), 7.70 (s, 1H), 8.49 (s, 1H), 8.63 (d, 1H, J = 2.1 Hz)

제조예 98Preparation Example 98

4-[N-(4-메톡시페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (4-methoxyphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4메톡시페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘(159mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4methoxyphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino ] Piperidine (159 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a yellow powder.

수량: 142mg (94%)Quantity: 142mg (94%)

제조예 99Preparation Example 99

1-(tert-부톡시카르보닐)-4-[N-(4-메톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4- [N- (4-methoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine :

4-(p-아니시디노)-1-(tert-부톡시카르보닐)피페리딘(613mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(586mg)를 실시예 9와 동일하게 처리하여 표기 화합물을황색 부정형 결정으로서 얻었다.4- (p-anisidino) -1- (tert-butoxycarbonyl) piperidine (613 mg) and 3- (3,4,5-trimethoxyphenyl) benzylchloride (586 mg) The same treatment was carried out to obtain the title compound as a yellow amorphous crystal.

수량: 1.12g (90%)Quantity: 1.12g (90%)

¹H-NMR(400MHz, CDC1₃) δ: 1.44(s, 9H), 1.50-1.63(m, 2H), 1.82-1.91(m, 2H), 2.71-2.83(m, 2H), 3.69(tt, 1H, J=11.5Hz, 3.5Hz), 3.73(s, 3H), 3.88(s, 3H), 3.90(s, 6H), 4.10-4.28(m, 2H), 4.42(s, 2H), 6.71(s, 2H), 6.78(s, 4H), 7.24-7.28(m, 1H), 7.31-7.40(m, 2H), 7.42(s, 1H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.44 (s, 9H), 1.50-1.63 (m, 2H), 1.82-1.91 (m, 2H), 2.71-2.83 (m, 2H), 3.69 (tt, 1H, J = 11.5 Hz, 3.5 Hz), 3.73 (s, 3H), 3.88 (s, 3H), 3.90 (s, 6H), 4.10-4.28 (m, 2H), 4.42 (s, 2H), 6.71 ( s, 2H), 6.78 (s, 4H), 7.24-7.28 (m, 1H), 7.31-7.40 (m, 2H), 7.42 (s, 1H)

제조예 100Preparation Example 100

4-[N-(4-메톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘·염산염의 합성:Synthesis of 4- [N- (4-methoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine hydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-메톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘(1.12g)을 제조예 94와 동일하게 처리하여 표기 화합물을 황색 분말로 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-methoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine (1.12 g) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a yellow powder.

수량: 980mg (99%)Quantity: 980mg (99%)

실시예 67에서 71Examples 67 to 71

이들 화합물은 제조예 96, 98, 100에서 얻어진 아민체와 제조예 42와 48에서 얻어진 클로라이드체를 반응시킴으로서 얻어졌다. 얻어진 유리 염기는 염산염으로 하였다. 수율과 유리 염기의 NMR 데이터를 이하에 나타낸다.These compounds were obtained by reacting the amine bodies obtained in Production Examples 96, 98 and 100 and the chloride bodies obtained in Production Examples 42 and 48. The obtained free base was made into hydrochloride. The yield and NMR data of the free base are shown below.

제조예 101Preparation Example 101

1-(tert-부톡시카르보닐)-4-[(4-에톡시 페닐)아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4-[(4-ethoxy phenyl) amino] piperidine

1-(tert-부톡시카르보닐)-4-피페리돈(5.00g)과 p-페네티딘(3.28g)을 제조예 37과 동일하게 반응시켜 표기 화합물의 갈색 분말을 얻었다.1- (tert-butoxycarbonyl) -4-piperidone (5.00 g) and p-phenetidine (3.28 g) were reacted in the same manner as in Production Example 37 to obtain a brown powder of the title compound.

수량: 7.00g (91%)Quantity: 7.00g (91%)

¹H-NMR(400MHz, CDC1₃) δ: 1.21-1.31(m, 2H), 1.37(t, 3H, J=7.0Hz), 1.46(s, 9H), 1.97-2.05(m, 2H), 2.84-2.95(m, 2H), 3.28-3.37(m, 1H), 3.96(q,2H, J=7.0Hz), 3.99-4.10(m, 2H), 6.57(d, 2H, J=8.8Hz), 6.77(d, 2H, J=9.0Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.21-1.31 (m, 2H), 1.37 (t, 3H, J = 7.0 Hz), 1.46 (s, 9H), 1.97-2.05 (m, 2H), 2.84 -2.95 (m, 2H), 3.28-3.37 (m, 1H), 3.96 (q, 2H, J = 7.0 Hz), 3.99-4.10 (m, 2H), 6.57 (d, 2H, J = 8.8 Hz), 6.77 (d, 2H, J = 9.0 Hz)

제조예 102Preparation Example 102

1-(tert-부톡시카르보닐)-4-[N-(4-에톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (4-ethoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] Synthesis of Amino] piperidine:

1-(tert-부톡시카르보닐)-4-[(4-에톡시페닐)아미노]피페리딘(641mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 반응시켜 표기 화합물의 황색 부정형 결정을 얻었다.1- (tert-butoxycarbonyl) -4-[(4-ethoxyphenyl) amino] piperidine (641 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) was reacted in the same manner as in Example 9 to obtain yellow amorphous crystals of the title compound.

수량: 2.08g (94%)Quantity: 2.08g (94%)

¹H-NMR(400MHz, CDC1₃) δ: 1.36(t, 3H, J=7.9Hz), 1.44(s, 9H), 1.49-1.58(m, 2H), 1.82-1.92(m, 2H), 2.70-2.85(m, 2H), 3.62-3.72(m, 1H), 3.89(s, 3H), 3.94(s, 6H), 4.12-4.29(m, 2H), 4.39(s, 2H), 6.75(d, 2H, J=9.2Hz), 6.78(d, 2H, J=9.6Hz), 7.14-7.18(m, 3H), 7.55(s, 1H), 8.54(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.36 (t, 3H, J = 7.9 Hz), 1.44 (s, 9H), 1.49-1.58 (m, 2H), 1.82-1.92 (m, 2H), 2.70 -2.85 (m, 2H), 3.62-3.72 (m, 1H), 3.89 (s, 3H), 3.94 (s, 6H), 4.12-4.29 (m, 2H), 4.39 (s, 2H), 6.75 (d , 2H, J = 9.2 Hz, 6.78 (d, 2H, J = 9.6 Hz), 7.14-7.18 (m, 3H), 7.55 (s, 1H), 8.54 (d, 1H, J = 5.1 Hz)

제조예 103Preparation Example 103

4-[N-(4-에톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘·2염산염4- [N- (4-ethoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine dihydrochloride

1-(tert-부톡시카르보닐)-4-[N-(4-에톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(1.08g)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-ethoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] Amino] piperidine (1.08 g) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 1.01g (98%)Quantity: 1.01g (98%)

제조예 104Preparation Example 104

1-(tert-부톡시카르보닐)-4-[N-(4-에톡시페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (4-ethoxyphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] Synthesis of Amino] piperidine:

1-(tert-부톡시카르보닐)-4-[(4-에톡시페닐)아미노]피페리딘(641mg)과 5-클로로메틸-3-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[(4-ethoxyphenyl) amino] piperidine (641 mg) and 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) was reacted in the same manner as in Example 9 to obtain the title compound as pale yellow amorphous crystals.

수량: 452mg (39%)Quantity: 452mg (39%)

¹H-NMR(400MHz, CDC1₃) δ: 1.44(s, 9H), 1.50-1.60(m, 2H), 1.82-1.90(m, 1H), 2.68-2.82(m, 2H), 3.52-3.61(m, 1H), 3.88(s, 3H), 3.90(s, 6H), 3.94(q, 2H, J=7.0Hz), 4.10-4.25(m, 2H), 4.40(s, 2H), 6.66(s, 2H), 6.77(d, 2H, J=9.2Hz), 6.81(d, 2H, J=9.2Hz), 7.67(s, 1H), 8.49(d, 1H, J=2.0Hz), 8.62(d, 1H, J=2.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.44 (s, 9H), 1.50-1.60 (m, 2H), 1.82-1.90 (m, 1H), 2.68-2.82 (m, 2H), 3.52-3.61 ( m, 1H), 3.88 (s, 3H), 3.90 (s, 6H), 3.94 (q, 2H, J = 7.0 Hz), 4.10-4.25 (m, 2H), 4.40 (s, 2H), 6.66 (s , 2H), 6.77 (d, 2H, J = 9.2 Hz), 6.81 (d, 2H, J = 9.2 Hz), 7.67 (s, 1H), 8.49 (d, 1H, J = 2.0 Hz), 8.62 (d , 1H, J = 2.1 Hz)

제조예 105Preparation Example 105

4-[N-(4-에톡시페닐)-N-[[3-(3,4,5-복리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (4-ethoxyphenyl) -N-[[3- (3,4,5- compoundmethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-에톡시페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘(452mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-ethoxyphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] Amino] piperidine (452 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 380mg (88%)Quantity: 380mg (88%)

제조예 106Preparation Example 106

1-(tert-부톡시카르보닐)-4-[N-(4-에톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4- [N- (4-ethoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine :

1-(tert-부톡시카르보닐)-4-[(4-에톡시페닐)아미노]피페리딘(641mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(586mg)를 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[(4-ethoxyphenyl) amino] piperidine (641 mg) and 3- (3,4,5-trimethoxyphenyl) benzylchloride (586 mg) In the same manner as in Example 9, the title compound was obtained as light yellow amorphous crystals.

수량: 1.06g (92%)Quantity: 1.06g (92%)

¹H-NMR(400MHz, CDC1₃) δ: 1.36(t, 3H, J=7.0Hz), 1.44(s, 9H), 1.53-1.59(m, 2H), 1.83-1.91(m, 2H), 2.70-2.83(m, 2H), 3.64-3.73(m, 1H), 3.88(s, 3H), 3.90(s, 6H), 3.94(q, 2H, J=7.0Hz), 4.10-4.29(m, 2H), 4.41(s, 2H), 6.71(s, 2H), 6.76(s, 4H), 7.26(d, 1H, J=7.9Hz), 7.33(dd, 1H, J=7.4Hz, 7.4Hz), 7.38(d, 1H, J=7.6Hz), 7.42(s, 1H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.36 (t, 3H, J = 7.0 Hz), 1.44 (s, 9H), 1.53-1.59 (m, 2H), 1.83-1.91 (m, 2H), 2.70 -2.83 (m, 2H), 3.64-3.73 (m, 1H), 3.88 (s, 3H), 3.90 (s, 6H), 3.94 (q, 2H, J = 7.0 Hz), 4.10-4.29 (m, 2H ), 4.41 (s, 2H), 6.71 (s, 2H), 6.76 (s, 4H), 7.26 (d, 1H, J = 7.9 Hz), 7.33 (dd, 1H, J = 7.4 Hz, 7.4 Hz), 7.38 (d, 1 H, J = 7.6 Hz), 7.42 (s, 1 H)

제조예 107Preparation Example 107

4-[N-(4-에톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘·염산염의 합성:Synthesis of 4- [N- (4-ethoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine hydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-에톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘(1.06g)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-ethoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine (1.06 g) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 913mg (97%)Quantity: 913mg (97%)

실시예 72 내지 79Examples 72-79

이들 화합물은 제조예 103, 105, 107에서 얻어진 아민체와 제조예 3, 42, 48에서 얻어진 클로라이드체를 반응시킴으로서 얻었다. 얻어진 유리 염기는 염산염으로 하였다. 수율과 유리 염기의 NMR 데이터를 이하에 나타낸다.These compounds were obtained by reacting the amine bodies obtained in Production Examples 103, 105, and 107 with the chloride bodies obtained in Production Examples 3, 42, and 48. The obtained free base was made into hydrochloride. The yield and NMR data of the free base are shown below.

제조예 108Preparation Example 108

1-(tert-부톡시카르보닐)-4-[(4-부톡시페닐)아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4-[(4-butoxyphenyl) amino] piperidine

1-(tert-부톡시카르보닐)-4-피페리돈(5.00g)과 4-부톡시아닐린(3.95g)을 제조예 37과 동일하게 반응시켜 표기 화합물을 갈색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4-piperidone (5.00 g) and 4-butoxyaniline (3.95 g) were reacted in the same manner as in Production Example 37 to obtain the title compound as a brown powder.

수량: 6.91g (83%)Quantity: 6.91g (83%)

¹H-NMR(400MHz, CDC1₃) δ: 0.96(t, 3H, J=7.2Hz), 1.23-1.35(m, 2H), 1.42-1.53(m, 2H), 1.46(s, 9H), 1.68-1.76(m, 2H), 1.97-2.05(m, 2H), 2.84-2.95(m, 2H), 3.28-3.37(m, 1H), 3.88(t, 2H, J=6.6Hz), 3.96-4.12(m, 2H), 6.57(d, 2H, J=9.0Hz), 6.77(d, 2H, J=8.8Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 0.96 (t, 3H, J = 7.2 Hz), 1.23-1.35 (m, 2H), 1.42-1.53 (m, 2H), 1.46 (s, 9H), 1.68 -1.76 (m, 2H), 1.97-2.05 (m, 2H), 2.84-2.95 (m, 2H), 3.28-3.37 (m, 1H), 3.88 (t, 2H, J = 6.6 Hz), 3.96-4.12 (m, 2H), 6.57 (d, 2H, J = 9.0 Hz), 6.77 (d, 2H, J = 8.8 Hz)

제조예 109Preparation Example 109

1-(tert-부톡시카르보닐)-4-[N-(4-부톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (4-butoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] Synthesis of Amino] piperidine:

1-(tert-부톡시카르보닐)-4-[(4-부톡시페닐)아미노]피페리딘(696mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[(4-butoxyphenyl) amino] piperidine (696 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) was reacted in the same manner as in Example 9 to obtain the title compound as pale yellow amorphous crystals.

수량: 980mg (81%)Quantity: 980mg (81%)

¹H-NMR(400MHz, CDC1₃) δ: 0.95(t, 3H, J=7.4Hz), 1.40-1.50(m, 2H), 1.44(s, 9H), 1.67-1.76(m, 2H), 1.82-1.90(m, 2H), 1.82-1.90(m, 2H), 2.70-2.82(m, 2H), 3.61-3.71(m, 1H), 3.84-3.90(m, 5H), 3.94(s, 6H), 4.10-4.28(m,2H), 4.39(s, 2H), 6.74(d, 2H, J=9.4Hz), 6.78(d, 2H, J=9.4Hz), 7.14-7.18(m, 3H), 7.56(s, 1H), 8.54(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 0.95 (t, 3H, J = 7.4 Hz), 1.40-1.50 (m, 2H), 1.44 (s, 9H), 1.67-1.76 (m, 2H), 1.82 -1.90 (m, 2H), 1.82-1.90 (m, 2H), 2.70-2.82 (m, 2H), 3.61-3.71 (m, 1H), 3.84-3.90 (m, 5H), 3.94 (s, 6H) , 4.10-4.28 (m, 2H), 4.39 (s, 2H), 6.74 (d, 2H, J = 9.4 Hz), 6.78 (d, 2H, J = 9.4 Hz), 7.14-7.18 (m, 3H), 7.56 (s, 1 H), 8.54 (d, 1 H, J = 5.1 Hz)

제조예 110Preparation 110

4-[N-(4-부톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (4-butoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-부톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(980mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-butoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] Amino] piperidine (980 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a yellow powder.

수량: 926mg (99%)Quantity: 926mg (99%)

제조예 111Preparation Example 111

1-(tert-부톡시카르보닐)-4-[N-(4-부톡시페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘의 합성1- (tert-butoxycarbonyl) -4- [N- (4-butoxyphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] Amino] piperidine synthesis

1-(tert-부톡시카르보닐)-4-[(4-부톡시페닐)아미노]피페리딘(697mg)과 5-클로로메틸-3-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[(4-butoxyphenyl) amino] piperidine (697 mg) and 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) was reacted in the same manner as in Example 9 to obtain the title compound as pale yellow amorphous crystals.

수량: 485mg (40%)Quantity: 485mg (40%)

¹H-NMR(400MHz, CDC1₃) δ: 0.95(t, 3H, J=7.4Hz), 1.40-1.57(m, 2H), 1.44(s, 9H), 1.67-1.75(m, 2H), 1.82-1.90(m, 2H), 2.69-2.81(m, 2H), 3.51-3.60(m, 1H), 3.87(q, 2H, J=6.6Hz), 3.88(s, 3H), 3.90(s, 6H), 4.06-4.23(m, 2H), 4.39(s, 2H), 6.66(s, 2H), 6.77(d, 2H, J=9.2Hz), 6.81(d, 2H, J=9.2Hz), 6.81(d, 2H, J=9.4Hz), 7.67(s, 1H), 8.49(d, 1H, J=1.8Hz), 8.62(d, 1H, J=2.2Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 0.95 (t, 3H, J = 7.4 Hz), 1.40-1.57 (m, 2H), 1.44 (s, 9H), 1.67-1.75 (m, 2H), 1.82 -1.90 (m, 2H), 2.69-2.81 (m, 2H), 3.51-3.60 (m, 1H), 3.87 (q, 2H, J = 6.6 Hz), 3.88 (s, 3H), 3.90 (s, 6H ), 4.06-4.23 (m, 2H), 4.39 (s, 2H), 6.66 (s, 2H), 6.77 (d, 2H, J = 9.2 Hz), 6.81 (d, 2H, J = 9.2 Hz), 6.81 (d, 2H, J = 9.4 Hz), 7.67 (s, 1H), 8.49 (d, 1H, J = 1.8 Hz), 8.62 (d, 1H, J = 2.2 Hz)

제조예 112Preparation Example 112

4-[N-(4-부톡시페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (4-butoxyphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-부톡시페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘(485mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-butoxyphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] Amino] piperidine (485 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 456mg (98%)Quantity: 456mg (98%)

제조예 113Preparation Example 113

1-(tert-부톡시카르보닐)-4-[N-(4-부톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4- [N- (4-butoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine :

1-(tert-부톡시카르보닐)-4-[(4-부톡시페닐)아미노]피페리딘(697mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(586mg)를 실시예 9와 동일하게 처리하여 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[(4-butoxyphenyl) amino] piperidine (697 mg) and 3- (3,4,5-trimethoxyphenyl) benzylchloride (586 mg) The same procedure as in Example 9 was carried out to obtain the title compound as pale yellow amorphous crystals.

수량: 1.17g (97%)Quantity: 1.17g (97%)

¹H-NMR(400MHz, CDC1₃) δ: 0.95(t, 3H, J=7.3Hz), 1.40-1.61(m, 4H), 1.44(s, 9H), 1.67-1.75(m, 2H), 1.83-1.90(m, 2H), 2.70-2.83(m, 2H), 3.63-3.72(m, 2H), 3.87(q, 2H, J=6.6Hz), 3.88(s, 3H), 3.90(s, 6H), 4.09-4.28(m, 2H), 4.41(s, 2H), 6.70(s, 2H), 6.76(s, 4H), 7.26(d, 2H, J=8.0Hz), 7.33(t, 1H, J=7.6Hz), 7.38(d, 1H, J=7.3Hz), 7.42(s, 1H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 0.95 (t, 3H, J = 7.3 Hz), 1.40-1.61 (m, 4H), 1.44 (s, 9H), 1.67-1.75 (m, 2H), 1.83 -1.90 (m, 2H), 2.70-2.83 (m, 2H), 3.63-3.72 (m, 2H), 3.87 (q, 2H, J = 6.6 Hz), 3.88 (s, 3H), 3.90 (s, 6H ), 4.09-4.28 (m, 2H), 4.41 (s, 2H), 6.70 (s, 2H), 6.76 (s, 4H), 7.26 (d, 2H, J = 8.0 Hz), 7.33 (t, 1H, J = 7.6 Hz), 7.38 (d, 1 H, J = 7.3 Hz), 7.42 (s, 1 H)

제조예 114Preparation Example 114

4-[N-(4-부톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘·염산염의 합성:Synthesis of 4- [N- (4-butoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine hydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-부톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘(1.17g)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-butoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine (1.17 g) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 1.02g (98%)Quantity: 1.02g (98%)

실시예 80 내지 87Examples 80-87

이들 화합물은 제조예 110, 112, 114에서 얻어진 아민체와 제조예 3, 42, 48에서 얻어진 클로라이드체를 반응시킴으로서 얻어졌다. 얻어진 유리 염기는 염산염으로 하였다. 수율과 유리 염기의 NMR 데이터를 이하에 나타낸다.These compounds were obtained by reacting the amine bodies obtained in Production Examples 110, 112 and 114 with the chloride bodies obtained in Production Examples 3, 42 and 48. The obtained free base was made into hydrochloride. The yield and NMR data of the free base are shown below.

제조예 115Preparation Example 115

4-(m-아니시디노)-1-(tert-부톡시카르보닐)피페리딘의 합성:Synthesis of 4- (m-anisidino) -1- (tert-butoxycarbonyl) piperidine:

1-(tert-부톡시카르보닐)-4-피페리돈(4.78g)과 m-아니시딘(2.96g)을 제조예 37과 동일하게 반응시켜 표기 화합물을 얻었다.1- (tert-butoxycarbonyl) -4-piperidone (4.78 g) and m-anisidine (2.96 g) were reacted in the same manner as in Production Example 37 to obtain the title compound.

수량: 4.83g (66%)Quantity: 4.83g (66%)

¹H-NMR(400MHz, CDC1₃) δ: 1.20-1.39(m, 2H), 1.44(s, 9H), 1.99-2.05(m, 2H), 2.89(dt, 2H, J=13.5Hz, 2.2Hz), 3.33-3.44(m, 1H), 3.75(s, 3H), 3.96-4.07(m, 2H), 6.14(t, 1H, J=2.2Hz), 6.18-6.29(m, 2H), 7.05(t, 1H, J=8.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.20-1.39 (m, 2H), 1.44 (s, 9H), 1.99-2.05 (m, 2H), 2.89 (dt, 2H, J = 13.5 Hz, 2.2 Hz ), 3.33-3.44 (m, 1H), 3.75 (s, 3H), 3.96-4.07 (m, 2H), 6.14 (t, 1H, J = 2.2 Hz), 6.18-6.29 (m, 2H), 7.05 ( t, 1H, J = 8.1 Hz)

제조예 116Preparation Example 116

1-(tert-부톡시카르보닐)-4-[N-(3-메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (3-methoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] Synthesis of Amino] piperidine:

4-(m-아니시디노)-1-(tert-부톡시카르보닐)피페리딘(613mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색부정형 결정으로서 얻었다.4- (m-anisidino) -1- (tert-butoxycarbonyl) piperidine (613 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) In the same manner as in Example 9, the title compound was obtained as pale yellow amorphous crystals.

수량: 789mg (70%)Quantity: 789mg (70%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.50-1.67(m, 2H), 1.82-1.91(m, 2H), 2.74-2.87(m, 2H), 3.74(s, 3H), 3.88-3.98(m, 1H), 3.89(s, 3H), 3.94(s, 6H), 4.14-4.32(m, 2H), 4.48(s, 2H), 6.28(dd, 1H, J=2.2Hz, 2.2Hz), 6.31-6.37(m, 2H), 7.10-7.15(m, 2H), 7.16(s, 2H), 7.55(s, 1H), 8.56(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.50-1.67 (m, 2H), 1.82-1.91 (m, 2H), 2.74-2.87 (m, 2H), 3.74 (s, 3H), 3.88-3.98 (m, 1H), 3.89 (s, 3H), 3.94 (s, 6H), 4.14-4.32 (m, 2H), 4.48 (s, 2H), 6.28 (dd, 1H, J = 2.2 Hz, 2.2 Hz), 6.31-6.37 (m, 2H), 7.10-7.15 (m, 2H), 7.16 (s, 2H), 7.55 (s, 1H), 8.56 (d, 1H, J = 5.1 Hz)

제조예 117Preparation Example 117

4-[N-(3-메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (3-methoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(3-메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(789mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (3-methoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] Amino] piperidine (789 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 710mg (95%)Quantity: 710mg (95%)

제조예 118Preparation Example 118

1-(tert-부톡시카르보닐)-4-[N-(3-메톡시페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (3-methoxyphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] Synthesis of Amino] piperidine:

4-(m-아니시디노)-1-(tert-부톡시카르보닐)피페리딘(613mg)과 5-클로로메틸-3-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색 부정형 결정으로서 얻었다.4- (m-anisidino) -1- (tert-butoxycarbonyl) piperidine (613 mg) and 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) In the same manner as in Example 9, the title compound was obtained as light yellow amorphous crystals.

수량: 396mg (35%)Quantity: 396mg (35%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.54-1.66(m, 2H), 1.81-1.91(m, 2H), 2.73-2.87(m, 2H), 3.74(s, 3H), 3.87-3.93(m, 1H), 3.88(s, 3H), 3.90(s, 6H), 4.14-4.29(m, 2H), 4.51(s, 2H), 6.30-6.35(m, 2H), 6.38(d, 1H, J=7.2Hz), 6.68(s, 2H), 7.12(dd, 1H, J=8.8Hz, 8.8Hz), 7.66(s, 1H), 8.49(d, 1H, J=2.0Hz), 8.66(d, 1H, J=2.2Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.54-1.66 (m, 2H), 1.81-1.91 (m, 2H), 2.73-2.87 (m, 2H), 3.74 (s, 3H), 3.87-3.93 (m, 1H), 3.88 (s, 3H), 3.90 (s, 6H), 4.14-4.29 (m, 2H), 4.51 (s, 2H), 6.30-6.35 (m, 2H) , 6.38 (d, 1H, J = 7.2 Hz), 6.68 (s, 2H), 7.12 (dd, 1H, J = 8.8 Hz, 8.8 Hz), 7.66 (s, 1H), 8.49 (d, 1H, J = 2.0 Hz), 8.66 (d, 1H, J = 2.2 Hz)

제조예 119Preparation Example 119

4-[N-(3-메톡시페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (3-methoxyphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(3-메톡시페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘(396mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (3-methoxyphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] Amino] piperidine (396 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 348mg (92%)Quantity: 348mg (92%)

제조예 120Preparation Example 120

1-(tert-부톡시카르보닐)-4-[N-(3-메톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4- [N- (3-methoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine :

4-(m-아니시디노)-1-(tert-부톡시카르보닐)피페리딘(613mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(586mg)를 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색 부정형 결정으로 얻었다.4- (m-anisidino) -1- (tert-butoxycarbonyl) piperidine (613 mg) and 3- (3,4,5-trimethoxyphenyl) benzylchloride (586 mg) The reaction was carried out in the same manner to obtain the title compound as pale yellow amorphous crystals.

수량: 1.01g (90%)Quantity: 1.01g (90%)

¹H-NMR(400MHz, CDC1₃) δ: 1.44(s, 9H), 1.56-1.67(m, 2H), 1.83-1.91(m, 2H), 2.72-2.86(m, 2H), 3.73(s, 3H), 3.85-3.98(m, 1H), 3.88(s, 3H), 3.90(s, 6H), 4.12-4.30(m, 2H), 4.50(s, 2H), 6.27-6.34(m, 2H), 6.38(dd, 1H, J=8.2Hz, 2.4Hz), 6.72(s, 2H), 7.10(dd, 1H, J=8.2Hz, 8.2Hz), 7.21-7.27(m, 1H), 7.3217.43(m, 3H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.44 (s, 9H), 1.56-1.67 (m, 2H), 1.83-1.91 (m, 2H), 2.72-2.86 (m, 2H), 3.73 (s, 3H), 3.85-3.98 (m, 1H), 3.88 (s, 3H), 3.90 (s, 6H), 4.12-4.30 (m, 2H), 4.50 (s, 2H), 6.27-6.34 (m, 2H) , 6.38 (dd, 1H, J = 8.2 Hz, 2.4 Hz), 6.72 (s, 2H), 7.10 (dd, 1H, J = 8.2 Hz, 8.2 Hz), 7.21-7.27 (m, 1H), 7.3217.43 (m, 3 H)

제조예 121Preparation Example 121

4-[N-(3-메톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘·염산염의 합성:Synthesis of 4- [N- (3-methoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine hydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(3-메톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘(1.01g)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (3-methoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine (1.01 g) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 820mg (92%)Quantity: 820mg (92%)

실시예 88 내지 95Examples 88-95

이들의 화합물은 제조예 117, 119, 121에서 얻어진 아민체와 제조예 3, 42, 48에서 얻어진 클로라이드체를 반응시킴으로서 얻어졌다. 얻어진 유리 염기는 염산염으로 변환했다. 수율과 유리 염기의 NMR 데이터를 이하에 나타낸다.These compounds were obtained by making the amine bodies obtained in Production Examples 117, 119 and 121 react with the chloride bodies obtained in Production Examples 3, 42 and 48. The obtained free base was converted into hydrochloride. The yield and NMR data of the free base are shown below.

제조예 122Preparation Example 122

4-(o-아니시디노)-1-(tert-부톡시카르보닐)피페리딘의 합성:Synthesis of 4- (o-anisidino) -1- (tert-butoxycarbonyl) piperidine:

1-(tert-부톡시카르보닐)-4-피페리돈(4.78g)과 o-아니시딘(2.96g)을 제조예 37과 동일하게 반응시켜 표기 화합물을 얻었다.1- (tert-butoxycarbonyl) -4-piperidone (4.78g) and o-anisidine (2.96g) were reacted in the same manner as in Production Example 37 to obtain the title compound.

수량: 2.61g (36%)Quantity: 2.61g (36%)

¹H-NMR(400MHz, CDC1₃) δ: 1.31-1.41(m, 2H), 1.47(s, 9H), 2.00-2.08(m, 2H), 2.90-3.01(m, 2H), 3.38-3.47(m, 1H), 3.83(s, 3H), 4.00-4.21(m, 2H), 6.60-6.69(m, 2H), 6.76-6.89(m, 2H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.31-1.41 (m, 2H), 1.47 (s, 9H), 2.00-2.08 (m, 2H), 2.90-3.01 (m, 2H), 3.38-3.47 ( m, 1H), 3.83 (s, 3H), 4.00-4.21 (m, 2H), 6.60-6.69 (m, 2H), 6.76-6.89 (m, 2H)

제조예 123Preparation Example 123

1-(tert-부톡시카르보닐)-4-[N-(2-메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (2-methoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] Synthesis of Amino] piperidine:

4-(o-아니시디노)-1-(tert-부톡시카르보닐)피페리딘(613mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색 부정형 결정으로서 얻었다.4- (o-anisidino) -1- (tert-butoxycarbonyl) piperidine (613 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) In the same manner as in Example 9, the title compound was obtained as light yellow amorphous crystals.

수량: 763mg (68%)Quantity: 763mg (68%)

¹H-NMR(400MHz, CDC1₃) δ: 1.41-1.58(m, 2H), 1.44(s, 9H), 1.81-1.91(m, 2H), 2.62-2.78(m, 2H), 3.29(tt, 1H, J=7.6Hz, 3.7Hz), 3.86(s, 3H), 3.89(s, 3H), 3.95(s, 6H), 4.06-4.16(m, 2H), 4.37(s, 2H), 6.80(ddd, 1H, J=7.6Hz, 7.6Hz, 1.2Hz), 6.87(dd, 1H, J=8.5Hz, 1.0Hz), 7.00-7.06(m, 2H), 7.14(s, 2H), 7.20(dd, 1H, J=4.9Hz, 1.0Hz), 7.61(s, 1H), 8.49(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.41-1.58 (m, 2H), 1.44 (s, 9H), 1.81-1.91 (m, 2H), 2.62-2.78 (m, 2H), 3.29 (tt, 1H, J = 7.6 Hz, 3.7 Hz), 3.86 (s, 3H), 3.89 (s, 3H), 3.95 (s, 6H), 4.06-4.16 (m, 2H), 4.37 (s, 2H), 6.80 ( ddd, 1H, J = 7.6 Hz, 7.6 Hz, 1.2 Hz), 6.87 (dd, 1H, J = 8.5 Hz, 1.0 Hz), 7.00-7.06 (m, 2H), 7.14 (s, 2H), 7.20 (dd , 1H, J = 4.9Hz, 1.0Hz), 7.61 (s, 1H), 8.49 (d, 1H, J = 4.9Hz)

제조예 124Preparation Example 124

4-[N-(2-메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (2-methoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(2메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(763mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (2methoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino ] Piperidine (763 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 701mg (97%)Quantity: 701mg (97%)

제조예 125Preparation Example 125

1-(tert-부톡시카르보닐)-4-[N-(2메톡시페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (2methoxyphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino ] Synthesis of piperidine:

4-(o-아니시디노)-1-(tert-부톡시카르보닐)피페리딘(613mg)과 5-클로로메틸-3-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색부정형 결정으로서 얻었다.4- (o-anisidino) -1- (tert-butoxycarbonyl) piperidine (613 mg) and 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) In the same manner as in Example 9, the title compound was obtained as pale yellow amorphous crystals.

수량: 353mg (31%)Quantity: 353mg (31%)

¹H-NMR(400MHz, CDC1₃) δ: 1.44(s, 9H), 1.46-1.53(m, 2H), 1.82-1.91(m,2H), 2.62-2.78(m, 2H), 3.24-3.33(m, 1H), 3.83(s, 3H), 3.89(s, 3H), 3.91(s, 6H), 4.03-4.16(s, 2H), 4.37(s, 2H), 6.64(s, 2H), 6.79(ddd, 1H, J=7.6Hz, 7.6Hz, 1.2Hz), 6.84(dd, 1H, J=7.0Hz, 1.2Hz), 6.97-7.06(m, 2H), 7.68(dd, 1H, J=1.3Hz, 1.3Hz), 8.49(d, 1H, J=2.0Hz), 8.56(d, 1H, J=2.2Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.44 (s, 9H), 1.46-1.53 (m, 2H), 1.82-1.91 (m, 2H), 2.62-2.78 (m, 2H), 3.24-3.33 ( m, 1H), 3.83 (s, 3H), 3.89 (s, 3H), 3.91 (s, 6H), 4.03-4.16 (s, 2H), 4.37 (s, 2H), 6.64 (s, 2H), 6.79 (ddd, 1H, J = 7.6 Hz, 7.6 Hz, 1.2 Hz), 6.84 (dd, 1H, J = 7.0 Hz, 1.2 Hz), 6.97-7.06 (m, 2H), 7.68 (dd, 1H, J = 1.3 Hz, 1.3 Hz), 8.49 (d, 1H, J = 2.0 Hz), 8.56 (d, 1H, J = 2.2 Hz)

제조예 126Preparation Example 126

4-[N-(2메톡시페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (2methoxyphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(2메톡시페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘(353mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (2methoxyphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino ] Piperidine (353 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 312mg (93%)Quantity: 312mg (93%)

제조예 127Preparation Example 127

1-(tert-부톡시카르보닐)-4-[N-(2-메톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4- [N- (2-methoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine :

4-(o-아니시디노)-1-(tert-부톡시카르보닐)피페리딘(613mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(586mg)를 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색 부정형 결정으로 얻었다.4- (o-anisidino) -1- (tert-butoxycarbonyl) piperidine (613 mg) and 3- (3,4,5-trimethoxyphenyl) benzylchloride (586 mg) The reaction was carried out in the same manner to obtain the title compound as light yellow amorphous crystals.

수량: 1.12gQuantity: 1.12g

¹H-NMR(400MHz, CDC1₃) δ: 51.43(s, 9H), 1.46-1.57(m, 2H), 1.81-1.90(m, 2H), 2.61-2.76(m, 2H), 3.31(tt, 1H, J=11.1Hz, 3.3Hz), 3.84(s, 3H), 3.88(s, 3H), 3.91(s, 6H), 4.00-4.16(m, 2H), 4.36(s, 2H), 6.67(s, 2H), 6.78(t, 1H, J=7.3Hz), 6.85(d, 1H, J=7.9Hz), 6.96-7.03(m, 2H), 7.24-7.34(m, 3H), 7.43(s, 1H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 51.43 (s, 9H), 1.46-1.57 (m, 2H), 1.81-1.90 (m, 2H), 2.61-2.76 (m, 2H), 3.31 (tt, 1H, J = 11.1 Hz, 3.3 Hz), 3.84 (s, 3H), 3.88 (s, 3H), 3.91 (s, 6H), 4.00-4.16 (m, 2H), 4.36 (s, 2H), 6.67 ( s, 2H), 6.78 (t, 1H, J = 7.3 Hz), 6.85 (d, 1H, J = 7.9 Hz), 6.96-7.03 (m, 2H), 7.24-7.34 (m, 3H), 7.43 (s , 1H)

제조예 128Preparation Example 128

4-[N-(2-메톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘·염산염의 합성:Synthesis of 4- [N- (2-methoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine hydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(2-메톡시페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘(1.12g)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (2-methoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine (1.12 g) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 987mg (99%)Quantity: 987mg (99%)

실시예 96 내지 101Examples 96-101

이들의 화합물은 제조예 124, 126, 128에서 얻어진 아민체와 제조예 3, 48에서 얻어진 클로라이드체를 반응시킴으로서 얻어졌다. 얻어진 유리 염기는 염산염으로 하였다. 수율과 유리 염기의 NMR 데이터를 이하에 나타낸다.These compounds were obtained by making the amine body obtained by manufacture example 124, 126, 128, and the chloride body obtained by manufacture example 3, 48 react. The obtained free base was made into hydrochloride. The yield and NMR data of the free base are shown below.

제조예 129Preparation 129

1-(tert-부톡시카르보닐)-4-[(2,3-디메톡시페닐)아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4-[(2,3-dimethoxyphenyl) amino] piperidine

1-(tert-부톡시카르보닐)-4-피페리돈(4.78g)과 2,3-디메톡시아닐린(3.68g)을 제조예 37과 동일하게 반응시켜 표기 화합물을 얻었다.1- (tert-butoxycarbonyl) -4-piperidone (4.78g) and 2,3-dimethoxyaniline (3.68g) were reacted in the same manner as in Production Example 37 to obtain the title compound.

수량: 3.18g (39%)Quantity: 3.18g (39%)

¹H-NMR(400MHz, CDC1₃) δ: 1.29-1.42(m, 2H), 1.45(s, 9H), 1.97-2.03(m, 2H), 2.92(dt, 2H, J=13.5Hz, 2.2Hz), 3.38(dt, 1H, J=13.8Hz, 4.1Hz), 3.77(s, 3H), 3.82(s, 3H), 3.99-4.03(m, 2H), 4.17(m, 1H), 6.27-6.32(m, 2H), 6.88(t, 1H, J=8.4Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.29-1.42 (m, 2H), 1.45 (s, 9H), 1.97-2.03 (m, 2H), 2.92 (dt, 2H, J = 13.5 Hz, 2.2 Hz ), 3.38 (dt, 1H, J = 13.8 Hz, 4.1 Hz), 3.77 (s, 3H), 3.82 (s, 3H), 3.99-4.03 (m, 2H), 4.17 (m, 1H), 6.27-6.32 (m, 2H), 6.88 (t, 1H, J = 8.4 Hz)

제조예 130Preparation Example 130

1-(tert-부톡시카르보닐)-4-[N-(2,3-디메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (2,3-dimethoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] Synthesis of Methyl] amino] piperidine:

1-(tert-부톡시카르보닐)-4-[(2,3-디메톡시페닐)아미노]피페리딘(673mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[(2,3-dimethoxyphenyl) amino] piperidine (673 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl ) Pyridine (588 mg) was reacted in the same manner as in Example 9 to obtain the title compound as pale yellow amorphous crystals.

수량: 613mg (52%)Quantity: 613mg (52%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.56-1.70(m, 2H), 1.84-1.91(m, 2H), 2.62-2.76(m, 2H), 3.58(tt, 1H, J=11.8Hz, 3.6Hz), 3.83(s, 3H), 3.89(s, 6H), 3.93(s, 6H), 4.08-4.25(m, 2H), 4.35(s, 2H), 6.56-6.63(m, 2H), 6.86(t,1H, J=8.3Hz), 7.14(s, 2H), 7.17(dd, 1H, J=5.1Hz, 1.2Hz), 7.62(s, 1H), 8.50(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.56-1.70 (m, 2H), 1.84-1.91 (m, 2H), 2.62-2.76 (m, 2H), 3.58 (tt, 1H, J = 11.8Hz, 3.6Hz), 3.83 (s, 3H), 3.89 (s, 6H), 3.93 (s, 6H), 4.08-4.25 (m, 2H), 4.35 (s, 2H), 6.56- 6.63 (m, 2H), 6.86 (t, 1H, J = 8.3 Hz), 7.14 (s, 2H), 7.17 (dd, 1H, J = 5.1 Hz, 1.2 Hz), 7.62 (s, 1H), 8.50 ( d, 1H, J = 5.1 Hz)

제조예 131Preparation Example 131

4-[N-(2,3-디메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (2,3-dimethoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4yl] methyl] amino] piperidine dihydrochloride :

1-(tert-부톡시카르보닐)-4-[N-(2,3-디메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(613mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (2,3-dimethoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] Methyl] amino] piperidine (613 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 512mg (88%)Quantity: 512mg (88%)

실시예 102Example 102

4-[N-(2,3-디메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]-1-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (2,3-dimethoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1-[[2- Synthesis of (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

4-[N-(2,3-디메톡시페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2염산염(113mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(59mg)을 실시예 2와 동일하게 반응시키고, 이어서, 염산염으로 하여 표기 화합물을 담황색 분말로서 얻었다.4- [N- (2,3-dimethoxyphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine dihydrochloride (113 mg) And 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (59 mg) were reacted in the same manner as in Example 2, and then the title compound was obtained as a pale yellow powder using hydrochloride.

수량: 21mg (12%)Quantity: 21mg (12%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.76-1.96(m, 4H), 2.00-2.13(m, 2H), 2.86-3.00(m, 2H), 3.42-3.60(m, 1H), 3.54(s, 2H), 3.82(s, 3H), 3.88(s, 3H), 3.90(s, 3H), 3.97(s, 6H), 4.41(s, 2H), 6.57(d, 1H, J=8.0Hz), 6.62(d, 1H, J=8.2Hz), 6.85(dd, 1H, J=8.4Hz, 8.4Hz), 7.11-7.29(m, 6H), 7.59(s, 1H), 7.63(s, 1H), 8.50(d, 1H, J=4.9Hz), 8.59(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.76-1.96 (m, 4H), 2.00-2.13 (m, 2H), 2.86-3.00 (m, 2H), 3.42-3.60 (m, 1H), 3.54 (s, 2H), 3.82 (s, 3H), 3.88 (s, 3H), 3.90 (s, 3H), 3.97 (s, 6H), 4.41 (s, 2H), 6.57 (d, 1H , J = 8.0 Hz), 6.62 (d, 1H, J = 8.2 Hz), 6.85 (dd, 1H, J = 8.4 Hz, 8.4 Hz), 7.11-7.29 (m, 6H), 7.59 (s, 1H), 7.63 (s, 1H), 8.50 (d, 1H, J = 4.9 Hz), 8.59 (d, 1H, J = 4.9 Hz)

제조예 132Preparation Example 132

1-(tert-부톡시카르보닐)-4-[[4-(트리플루오로메톡시)페닐]아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4-[[4- (trifluoromethoxy) phenyl] amino] piperidine

1-(tert-부톡시카르보닐)-4-피페리돈(5.00g)과 4-(트리플루오로메톡시)아닐린(4.23g)을 제조예 37과 동일하게 반응시켜 표기 화합물을 백색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4-piperidone (5.00 g) and 4- (trifluoromethoxy) aniline (4.23 g) were reacted in the same manner as in Production Example 37 to obtain the title compound as a white powder.

수율: 5.22g (60%)Yield: 5.22 g (60%)

¹H-NMR(400MHz, CDC1₃) δ: 1.25-1.40(m, 2H), 1.47(s, 9H), 1.98-2.08(m, 2H), 2.83-2.98(m, 2H), 3.34-3.43(m, 1H), 3.97-4.12(m, 2H), 6.58(d, 2H, J=8.8Hz), 7.03(d, 2H, J=8.8Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.25-1.40 (m, 2H), 1.47 (s, 9H), 1.98-2.08 (m, 2H), 2.83-2.98 (m, 2H), 3.34-3.43 ( m, 1H), 3.97-4.12 (m, 2H), 6.58 (d, 2H, J = 8.8 Hz), 7.03 (d, 2H, J = 8.8 Hz)

제조예 133Preparation Example 133

1-(tert-부톡시카르보닐)-4-[N-[4-(트리플루오로메톡시)페닐]-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- [4- (trifluoromethoxy) phenyl] -N-[[2- (3,4,5-trimethoxyphenyl) pyridine-4- Synthesis of I] methyl] amino] piperidine:

1-(tert-부톡시카르보닐)-4-[[4-(트리플루오로메톡시)페닐]아미노]피페리딘(721mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[[4- (trifluoromethoxy) phenyl] amino] piperidine (721 mg) and 4-chloromethyl-2- (3,4,5-trimeth The oxyphenyl) pyridine (588 mg) was reacted in the same manner as in Example 9 to obtain the title compound as light yellow amorphous crystals.

수량: 543mg (44%)Quantity: 543mg (44%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.52-1.66(m, 2H), 1.81-1.91(m, 2H), 2.73-2.88(m, 2H), 3.88-3.99(m, 1H), 3.89(s, 3H), 3.93(s, 6H), 4.15-4.34(m, 2H), 4.48(s, 2H), 6.68(d, 2H, J=9.2Hz), 7.07(d, 2H, J=8.6Hz), 7.12(dd, 1H, J=5.2Hz, 1.3Hz), 7.15(s, 2H), 7.52(s, 1H), 8.58(d, 1H, J=5.2Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.52-1.66 (m, 2H), 1.81-1.91 (m, 2H), 2.73-2.88 (m, 2H), 3.88-3.99 ( m, 1H), 3.89 (s, 3H), 3.93 (s, 6H), 4.15-4.34 (m, 2H), 4.48 (s, 2H), 6.68 (d, 2H, J = 9.2 Hz), 7.07 (d , 2H, J = 8.6Hz), 7.12 (dd, 1H, J = 5.2Hz, 1.3Hz), 7.15 (s, 2H), 7.52 (s, 1H), 8.58 (d, 1H, J = 5.2Hz)

제조예 134Preparation Example 134

4-[N-[4-(트리플루오로메톡시)페닐]-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘·2염산염의 합성:4- [N- [4- (trifluoromethoxy) phenyl] -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine · 2 Synthesis of Hydrochloride:

1-(tert-부톡시카르보닐)-4-[N-[4-(트리플루오로메톡시)페닐]-N-[[2-(3,4,5-트리플루오로메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(543mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- [4- (trifluoromethoxy) phenyl] -N-[[2- (3,4,5-trifluoromethoxyphenyl) pyridine-4 -Yl] methyl] amino] piperidine (543 mg) was treated in the same manner as in Production Example 94 to obtain the title compound as a pale yellow powder.

수량: 481mg (93%)Quantity: 481mg (93%)

제조예 135Preparation Example 135

1-(tert-부톡시카르보닐)-4-[N-[4-(트리플루오로메톡시)페닐]-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- [4- (trifluoromethoxy) phenyl] -N-[[3- (3,4,5-trimethoxyphenyl) pyridine-5- Synthesis of I] methyl] amino] piperidine:

1-(tert-부톡시카르보닐)-4-[[4-(트리플루오로메톡시)페닐]아미노]피페리딘(721mg)과 5-클로로메틸-3-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 처리하여 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[[4- (trifluoromethoxy) phenyl] amino] piperidine (721 mg) and 5-chloromethyl-3- (3,4,5-trimeth Toxyphenyl) pyridine (588 mg) was treated in the same manner as in Example 9 to obtain the title compound as light yellow amorphous crystals.

수량: 201mg (16%)Quantity: 201mg (16%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.54-1.67(m, 2H), 1.82-1.90(m, 2H), 2.74-2.86(m, 2H), 3.84-3.91(m, 1H), 3.88(s, 3H), 3.89(s, 6H), 4.16-4.30(m, 2H), 4.52(s, 2H), 6.67(s, 2H), 6.72(d, 2H, J=9.4Hz), 7.06(d, 2H, J=8.4Hz), 7.64(t, 1H, J=2.1Hz), 8.49(d, 1H, J=2.2Hz), 8.68(d, 1H, J=2.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.54-1.67 (m, 2H), 1.82-1.90 (m, 2H), 2.74-2.86 (m, 2H), 3.84-3.91 ( m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 4.16-4.30 (m, 2H), 4.52 (s, 2H), 6.67 (s, 2H), 6.72 (d, 2H, J = 9.4 Hz), 7.06 (d, 2H, J = 8.4 Hz), 7.64 (t, 1H, J = 2.1 Hz), 8.49 (d, 1H, J = 2.2 Hz), 8.68 (d, 1H, J = 2.1 Hz )

제조예 136Preparation Example 136

4-[N-[4-(트리플루오로메톡시)페닐]-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘·2염산염의 합성:4- [N- [4- (trifluoromethoxy) phenyl] -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine · 2 Synthesis of Hydrochloride:

1-(tert-부톡시카르보닐)-4-[N-[4-(트리플루오로메톡시)페닐]-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘(201mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- [4- (trifluoromethoxy) phenyl] -N-[[3- (3,4,5-trimethoxyphenyl) pyridine-5- Il] methyl] amino] piperidine (201 mg) was treated in the same manner as in Production Example 94 to obtain the title compound as a pale yellow powder.

수량: 185mg (96%)Quantity: 185mg (96%)

제조예 137Preparation Example 137

1-(tert-부톡시카르보닐)-4-[N-[41(트리플루오로메톡시)페닐]-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- [41 (trifluoromethoxy) phenyl] -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperi Dean's Synthesis:

1-(tert-부톡시카르보닐)-4-[[4-(트리플루오로메톡시)페닐]아미노]피페리딘(721mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(586mg)를 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[[4- (trifluoromethoxy) phenyl] amino] piperidine (721 mg) and 3- (3,4,5-trimethoxyphenyl) benzylchloride (586 mg) was reacted in the same manner as in Example 9 to obtain the title compound as light yellow amorphous crystals.

수량: 1.06g (86%)Quantity: 1.06g (86%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.56-1.68(m, 2H), 1.83-1.90(m, 2H), 2.71-2.86(m, 2H), 3.87-3.90(m, 1H), 3.88(s, 3H), 3.89(s, 6H), 4.16-4.29(m, 2H), 4.51(s, 2H), 6.70(d, 2H, J=9.3Hz), 6.70(s, 2H), 7.04(d, 2H, J=8.5Hz), 7.22(d, 1H, J=7.8Hz), 7.34-7.44(m, 3H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.56-1.68 (m, 2H), 1.83-1.90 (m, 2H), 2.71-2.86 (m, 2H), 3.87-3.90 ( m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 4.16-4.29 (m, 2H), 4.51 (s, 2H), 6.70 (d, 2H, J = 9.3 Hz), 6.70 (s , 2H), 7.04 (d, 2H, J = 8.5 Hz), 7.22 (d, 1H, J = 7.8 Hz), 7.34-7.44 (m, 3H)

제조예 138Preparation Example 138

4-[N-[4-(트리플루오로메톡시)페닐]-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘·염산염의 합성:Synthesis of 4- [N- [4- (trifluoromethoxy) phenyl] -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine hydrochloride:

1-(tert-부톡시카르보닐)-4-[N-[4-(트리플루오로메톡시)페닐]-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘(1.06g)을 제조예 94와 동일하게 처리하여 표기 화합물건을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- [4- (trifluoromethoxy) phenyl] -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] py Ferridine (1.06 g) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 795mg (84%)Quantity: 795mg (84%)

실시예 103 내지 110Examples 103-110

이들의 화합물은 제조예 134, 136, 138에서 얻어진 아민체와 제조예 3, 42, 48에서 얻어진 클로라이드체를 반응시킴으로서 얻어졌다. 얻어진 유리 염기는 염산염으로 하였다. 수율과 유리 염기의 NMR 데이터를 이하에 나타낸다.These compounds were obtained by making the amine body obtained by manufacture example 134, 136, 138, and the chloride body obtained by manufacture example 3, 42, 48 react. The obtained free base was made into hydrochloride. The yield and NMR data of the free base are shown below.

제조예 139Preparation Example 139

1-(tert-부톡시카르보닐)-4-[[ 4-(메틸티오)페닐]아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4-[[4- (methylthio) phenyl] amino] piperidine

1-(tert-부톡시카르보닐)-4-피페리돈(5.00g)과 4-(메틸티오)아닐린(3.33g)을 제조예 37과 동일하게 반응시켜 표기 화합물을 백색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4-piperidone (5.00 g) and 4- (methylthio) aniline (3.33 g) were reacted in the same manner as in Production Example 37 to obtain the title compound as a white powder.

수율: 3.80g (49%)Yield: 3.80 g (49%)

¹H-NMR(400MHz, CDC1₃) δ: 1.26-1.38(m, 2H), 1.46(s, 9H), 1.98-2.06(m,2H), 2.41(s, 3H), 2.88-2.97(m, 2H), 3.36-3.45(m, 2H), 3.48-3.56(br, 1H), 3.96-4.12(m, 2H), 6.55(d, 2H, J=8.8Hz), 7.21(d, 2H, J=8.8Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.26-1.38 (m, 2H), 1.46 (s, 9H), 1.98-2.06 (m, 2H), 2.41 (s, 3H), 2.88-2.97 (m, 2H), 3.36-3.45 (m, 2H), 3.48-3.56 (br, 1H), 3.96-4.12 (m, 2H), 6.55 (d, 2H, J = 8.8 Hz), 7.21 (d, 2H, J = 8.8 Hz)

제조예 140Preparation 140

1-(tert-부톡시카르보닐)-4-[N-[4-(메틸티오)페닐]-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- [4- (methylthio) phenyl] -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] Synthesis of Methyl] amino] piperidine:

1-(tert-부톡시카르보닐)-4-[[4-(메틸티오)페닐]아미노]피페리딘(644mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 처리하여 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[[4- (methylthio) phenyl] amino] piperidine (644 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl ) Pyridine (588 mg) was treated in the same manner as in Example 9 to obtain the title compound as pale yellow amorphous crystals.

수량: 671mg (58%)Quantity: 671mg (58%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.50-1.66(m, 2H), 1.81-1.89(m, 2H), 2.40(s, 3H), 2.74-2.87(m, 2H), 3.88-3.94(m, 1H), 3.90(s, 3H), 3.94(s, 6H), 4.15-4.29(m, 2H), 4.48(s, 2H), 6.67(d, 2H, J=9.0Hz), 7.11-7.18(m, 1H), 7.16(s, 2H), 7.22(d, 2H, J=6.6Hz), 7.54(s, 1H), 8.57(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.50-1.66 (m, 2H), 1.81-1.89 (m, 2H), 2.40 (s, 3H), 2.74-2.87 (m, 2H), 3.88-3.94 (m, 1H), 3.90 (s, 3H), 3.94 (s, 6H), 4.15-4.29 (m, 2H), 4.48 (s, 2H), 6.67 (d, 2H, J = 9.0 Hz), 7.11-7.18 (m, 1H), 7.16 (s, 2H), 7.22 (d, 2H, J = 6.6 Hz), 7.54 (s, 1H), 8.57 (d, 1H, J = 5.1 Hz)

제조예 141Preparation Example 141

4-[N-[4-(메틸티오)페닐]-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘·2염산염의 합성:4- [N- [4- (methylthio) phenyl] -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine dihydrochloride of synthesis:

1-(tert-부톡시카르보닐)-4-[N-[4-(메틸티오)페닐]-N-[[2-(3,4,5-트리플루오로메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(671mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- [4- (methylthio) phenyl] -N-[[2- (3,4,5-trifluoromethoxyphenyl) pyridin-4-yl ] Methyl] amino] piperidine (671mg) was treated in the same manner as in Production Example 94 to obtain the title compound as a pale yellow powder.

수량: 602mg (94%)Quantity: 602mg (94%)

제조예 142Preparation Example 142

1-(tert-부톡시카르보닐)-4-[N-[4-(메틸티오)페닐]-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- [4- (methylthio) phenyl] -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] Synthesis of Methyl] amino] piperidine:

1-(tert-부톡시카르보닐)-4-[[4-(메틸티오)페닐]아미노]피페리딘(645mg)과 5-클로로메틸-3-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 처리하여 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[[4- (methylthio) phenyl] amino] piperidine (645 mg) and 5-chloromethyl-3- (3,4,5-trimethoxyphenyl ) Pyridine (588 mg) was treated in the same manner as in Example 9 to obtain the title compound as pale yellow amorphous crystals.

수량: 312mg (27%)Quantity: 312mg (27%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.53-1.63(m, 2H), 1.83-1.89(m, 2H), 2.40(s, 3H), 2.73-2.85(m, 2H), 3.87-3.91(m, 1H), 3.88(s, 3H), 3.90(s, 6H), 4.16-4.30(m, 2H), 4.50(s, 2H), 6.67(s, 2H), 6.71(d, 2H, J=9.0Hz), 7.21(d, 2H, J=9.0Hz), 7.64(s, 1H), 8.48(d, 1H, J=2.2Hz), 8.66(d, 1H, J=2.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.53-1.63 (m, 2H), 1.83-1.89 (m, 2H), 2.40 (s, 3H), 2.73-2.85 (m, 2H), 3.87-3.91 (m, 1H), 3.88 (s, 3H), 3.90 (s, 6H), 4.16-4.30 (m, 2H), 4.50 (s, 2H), 6.67 (s, 2H), 6.71 (d, 2H, J = 9.0Hz), 7.21 (d, 2H, J = 9.0Hz), 7.64 (s, 1H), 8.48 (d, 1H, J = 2.2Hz), 8.66 (d, 1H, J = 2.1 Hz)

제조예 143Preparation Example 143

4-[N-[4-(메틸티오)페닐]-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘·2염산염의 합성:4- [N- [4- (methylthio) phenyl] -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride synthesis:

1-(tert-부톡시카르보닐)-4-[N-[4-(메틸티오)페닐]-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘(312mg)을 제조예 94와 동일하게 처리하여 표기화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- [4- (methylthio) phenyl] -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] Methyl] amino] piperidine (312 mg) was treated in the same manner as in Production Example 94 to obtain the title compound as a pale yellow powder.

수량: 251mg (84%)Quantity: 251mg (84%)

제조예 144Preparation Example 144

1-(tert-부톡시카르보닐)-4-[N-[4-(메틸티오)페닐]-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- [4- (methylthio) phenyl] -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine Synthesis of:

1-(tert-부톡시카르보닐)-4-[N-[(메틸티오)페닐]아미노]피페리딘(645mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(586mg)를 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4- [N-[(methylthio) phenyl] amino] piperidine (645 mg) and 3- (3,4,5-trimethoxyphenyl) benzylchloride (586 mg ) Was reacted in the same manner as in Example 9 to obtain the title compound as pale yellow amorphous crystals.

수량: 1.10g(95%)Quantity: 1.10 g (95%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.55-1.68(m, 2H), 1.81-1.90(m, 2H), 2.39(s, 3H), 2.73-2.86(m, 2H), 3.87-3.91(m, 1H), 3.88(s, 3H), 3.89(s, 6H), 4.15-4.29(m, 2H), 4.50(s, 2H), 6.68-6.73(m, 4H), 7.19-7.24(m, 3H), 7.33-7.43(m, 3H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.55-1.68 (m, 2H), 1.81-1.90 (m, 2H), 2.39 (s, 3H), 2.73-2.86 (m, 2H), 3.87-3.91 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 4.15-4.29 (m, 2H), 4.50 (s, 2H), 6.68-6.73 (m, 4H) , 7.19-7.24 (m, 3H), 7.33-7.43 (m, 3H)

제조예 145Preparation Example 145

4-[N-[4-(메틸티오)페닐]-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘·염산염의 합성:Synthesis of 4- [N- [4- (methylthio) phenyl] -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine hydrochloride:

1-(tert-부톡시카르보닐)-4-[N-[4-(메틸티오)페닐]-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘(1.109)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- [4- (methylthio) phenyl] -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine (1.109) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 866mg (89%)Quantity: 866mg (89%)

실시예 111 내지 118Examples 111-118

이들의 화합물은 제조예 141, 143, 145에서 얻어진 아민체와 제조예 3, 42, 48에서 얻어진 클로라이드체를 반응시킴으로서 얻어졌다. 얻어진 유리염기는 염산염으로 하였다. 수율과 유리염기의 NMR 데이터는 아래에 나타낸다.These compounds were obtained by making the amine body obtained by manufacture example 141, 143, 145, and the chloride body obtained by manufacture example 3, 42, 48 react. The obtained free base was made into hydrochloride. Yield and free base NMR data are shown below.

제조예 146Preparation Example 146

1-(tert-부톡시카르보닐)-4-[(4-메틸페닐)아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4-[(4-methylphenyl) amino] piperidine:

1-(tert-부톡시카르보닐)-4-피페리돈(5.00g)과 p-톨루이딘(2.56g)을 제조예 37과 동일하게 반응시켜 표기 화합물을 백색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4-piperidone (5.00 g) and p-toluidine (2.56 g) were reacted in the same manner as in Production Example 37 to obtain the title compound as a white powder.

수율: 5.79g (83%)Yield: 5.79 g (83%)

¹H-NMR(400MHz, CDC1₃) δ: 1.25-1.36(m, 2I-I), 1.46(s, 9H), 1.99-2.06(m,2H), 2.23(s, 3H), 2.86-2.96(m, 2H), 3.30-3.43(m, 2H), 3.96-4.10(m, 2H), 6.53(d, 2H, J=8.4Hz), 6.98(d, 2H, J=8.0Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.25-1.36 (m, 2I-I), 1.46 (s, 9H), 1.99-2.06 (m, 2H), 2.23 (s, 3H), 2.86-2.96 ( m, 2H), 3.30-3.43 (m, 2H), 3.96-4.10 (m, 2H), 6.53 (d, 2H, J = 8.4 Hz), 6.98 (d, 2H, J = 8.0 Hz)

제조예 147Preparation Example 147

1-(tert-부톡시카르보닐)-4-[(4-메틸페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4-[(4-methylphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperi Dean's Synthesis:

1-(tert-부톡시카르보닐)-4-[N-(4-메틸페닐)아미노]피페리딘(581mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 처리하여 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-methylphenyl) amino] piperidine (581 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) was treated in the same manner as in Example 9 to obtain the title compound as pale yellow amorphous crystals.

수량: 1.00g (91%)Quantity: 1.00g (91%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.55-1.59(m, 2H), 1.81-1.90(m, 2H), 2.23(s, 3H), 2.72-2.86(m, 2H), 3.81-3.94(m, 1H), 3.89(s, 3H), 3.93(s, 6H), 4.14-4.30(m, 2H), 4.45(s, 2H), 6.66(d, 2H, J=8.6Hz), 7.02(d, 2H, J=8.2Hz), 7.13-7.16(m, 3H), 7.55(s, 1H), 8.55(d, 1H, J=8.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.55-1.59 (m, 2H), 1.81-1.90 (m, 2H), 2.23 (s, 3H), 2.72-2.86 (m, 2H), 3.81-3.94 (m, 1H), 3.89 (s, 3H), 3.93 (s, 6H), 4.14-4.30 (m, 2H), 4.45 (s, 2H), 6.66 (d, 2H, J = 8.6 Hz), 7.02 (d, 2H, J = 8.2 Hz), 7.13-7.16 (m, 3H), 7.55 (s, 1H), 8.55 (d, 1H, J = 8.1 Hz)

제조예 148Preparation Example 148

4-[N-(4-메틸페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (4-methylphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-메틸페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(1.00g)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-methylphenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] Piperidine (1.00 g) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 924mg (97%)Quantity: 924mg (97%)

제조예 149Preparation Example 149

1-(tert-부톡시카르보닐)-4-[N-(4-메틸페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (4-methylphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] Synthesis of Piperidine:

1-(tert-부톡시카르보닐)-4-[(4-메틸페닐)아미노]피페리딘(581mg)과 5-클로로메틸-3-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 처리하여 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[(4-methylphenyl) amino] piperidine (581 mg) and 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg ) Was treated in the same manner as in Example 9 to obtain the title compound as a pale yellow amorphous crystal.

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.52-1.70(m, 2H), 1.82-1.90(m, 2H), 2.23(s, 3H), 2.72-2.86(m, 2H), 3.77-3.86(m, 1H), 3.88(s, 3H), 3.90(s, 6H), 4.10-4.28(m, 2H), 4.47(s, 2H), 6.67(s, 2H), 6.70(d, 2H, J=8.6Hz), 7.01(d, 2H, J=8.2Hz), 7.67(dd, 1H, J=2.1Hz, 2.1Hz), 8.50(d, 1H, J=2.0Hz), 8.64(d, 1H, J=2.2Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.52-1.70 (m, 2H), 1.82-1.90 (m, 2H), 2.23 (s, 3H), 2.72-2.86 (m, 2H), 3.77-3.86 (m, 1H), 3.88 (s, 3H), 3.90 (s, 6H), 4.10-4.28 (m, 2H), 4.47 (s, 2H), 6.67 (s, 2H), 6.70 (d, 2H, J = 8.6 Hz), 7.01 (d, 2H, J = 8.2 Hz), 7.67 (dd, 1H, J = 2.1 Hz, 2.1 Hz), 8.50 (d, 1H, J = 2.0 Hz), 8.64 (d, 1H, J = 2.2 Hz)

제조예 150Preparation 150

4-[N-(4메틸페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (4methylphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-메틸페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘(426mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-methylphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] Piperidine (426 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 400mg (99%)Quantity: 400mg (99%)

제조예 151Preparation Example 151

1-(tert-부톡시카르보닐)-4-[N-(4-메틸페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘의 합성Synthesis of 1- (tert-butoxycarbonyl) -4- [N- (4-methylphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine

1-(tert-부톡시카르보닐)-4-[(4-메틸페닐)아미노]피페리딘(581mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(586mg)를 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색 부정형 결정으로서 얻었다.Example 1- (tert-butoxycarbonyl) -4-[(4-methylphenyl) amino] piperidine (581 mg) and 3- (3,4,5-trimethoxyphenyl) benzylchloride (586 mg) The reaction was carried out in the same manner as 9 to obtain the title compound as pale yellow amorphous crystals.

수량: 1.03g (94%)Quantity: 1.03g (94%)

¹H-NMR(400MHz, CDC1₃) δ: 1.44(s, 9H), 1.50-1.66(m, 2H), 2.72-2.85(m, 2H), 3.82-3.92(m, 1H), 3.88(s, 3H), 3.89(s, 6H), 4.11-4.30(m, 2H), 4.47(s, 2H), 6.68(d, 2H, J=8.6Hz), 6.71(s, 2H), 7.00(d, 2H, J=8.8Hz), 7.23-7.27(m, 1H), 7.32-7.44(m, 3H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.44 (s, 9H), 1.50-1.66 (m, 2H), 2.72-2.85 (m, 2H), 3.82-3.92 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 4.11-4.30 (m, 2H), 4.47 (s, 2H), 6.68 (d, 2H, J = 8.6 Hz), 6.71 (s, 2H), 7.00 (d, 2H) , J = 8.8 Hz), 7.23-7.27 (m, 1H), 7.32-7.44 (m, 3H)

제조예 152Preparation Example 152

4-[N-(4-메틸페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘·염산염의 합성:Synthesis of 4- [N- (4-methylphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine hydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-메틸페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘(1.03g)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-methylphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine (1.03 g) Was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 882mg (97%)Quantity: 882mg (97%)

실시예 119 내지 126Examples 119-126

이들의 화합물은 제조예 148, 150, 152로 얻어진 아민체와 제조예 3, 42, 48에서 얻어진 클로라이드체를 반응시킴으로서 얻어졌다. 얻어진 유리 염기는 염산염으로 하였다. 수율과 유리 염기의 NMR 데이터를 이하에 나타낸다.These compounds were obtained by making the amine body obtained by manufacture examples 148, 150, and 152 react with the chloride body obtained by manufacture examples 3, 42, and 48. The obtained free base was made into hydrochloride. The yield and NMR data of the free base are shown below.

제조예 153Preparation Example 153

1-(tert-부톡시카르보닐)-4-[[4-(트리플루오로메틸)페닐]아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4-[[4- (trifluoromethyl) phenyl] amino] piperidine

1-(tert-부톡시카르보닐)-4-피페리돈(5.00g)과 4-(트리플루오로)아닐린(3.85g)을 제조예 37과 동일하게 반응시켜 표기 화합물을 백색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4-piperidone (5.00 g) and 4- (trifluoro) aniline (3.85 g) were reacted in the same manner as in Production Example 37 to obtain the title compound as a white powder.

수율: 3.30g (40%)Yield: 3.30 g (40%)

¹H-NMR(400MHz, CDC1₃) δ: 1.30-1.41(m, 2H), 1.47(s, 9H), 2.00-2.07(m, 2H), 2.88-2.99(m, 2H), 3.32-3.52(m, 1H), 3.83-3.89(m, 1H), 4.00-4.14(m, 2H), 6.59(d, 2H, J=8.4Hz), 7.39(d, 2H, J=8.4Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.30-1.41 (m, 2H), 1.47 (s, 9H), 2.00-2.07 (m, 2H), 2.88-2.99 (m, 2H), 3.32-3.52 ( m, 1H), 3.83-3.89 (m, 1H), 4.00-4.14 (m, 2H), 6.59 (d, 2H, J = 8.4 Hz), 7.39 (d, 2H, J = 8.4 Hz)

제조예 154Preparation Example 154

1-(tert-부톡시카르보닐)-4-[N-[4-(트리플루오로메틸)페닐]-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- [4- (trifluoromethyl) phenyl] -N-[[2- (3,4,5-trimethoxyphenyl) pyridine-4- Synthesis of I] methyl] amino] piperidine:

1-(tert-부톡시카르보닐)-4-[[4-(트리플루오로메틸)페닐]아미노]피페리딘(688mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 처리하여 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[[4- (trifluoromethyl) phenyl] amino] piperidine (688 mg) and 4-chloromethyl-2- (3,4,5-trimeth Toxyphenyl) pyridine (588 mg) was treated in the same manner as in Example 9 to obtain the title compound as light yellow amorphous crystals.

수량: 412mg (34%)Quantity: 412mg (34%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.54-1.68(m, 2H), 1.81-1.90(m, 2H), 2.77-2.90(m, 2H), 3.89(s, 3H), 3.92(s, 6H), 3.98-4.07(m, 1H), 4.18-4.33(m, 2H), 4.55(s, 2H), 6.73(d, 2H, J=8.8Hz), 7.09(d, 1H, J=3.7Hz), 7.13(s,2H), 7.44(d, 2H, J=8.8Hz), 7.49(s, 1H), 8.58(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.54-1.68 (m, 2H), 1.81-1.90 (m, 2H), 2.77-2.90 (m, 2H), 3.89 (s, 3H), 3.92 (s, 6H), 3.98-4.07 (m, 1H), 4.18-4.33 (m, 2H), 4.55 (s, 2H), 6.73 (d, 2H, J = 8.8 Hz), 7.09 (d , 1H, J = 3.7 Hz, 7.13 (s, 2H), 7.44 (d, 2H, J = 8.8 Hz), 7.49 (s, 1H), 8.58 (d, 1H, J = 5.1 Hz)

제조예 155Preparation Example 155

4-[N-[4-(트리플루오로메틸)페닐]-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘·2염산염의 합성:4- [N- [4- (trifluoromethyl) phenyl] -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine · 2 Synthesis of Hydrochloride:

1-(tert-부톡시카르보닐)-4-[N-[4-(트리플루오로메틸)페닐]-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(412mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- [4- (trifluoromethyl) phenyl] -N-[[2- (3,4,5-trimethoxyphenyl) pyridine-4- Il] methyl] amino] piperidine (412 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 359mg (91%)Quantity: 359mg (91%)

제조예 156Preparation Example 156

1-(tert-부톡시카르보닐)-4-[N-[4-(트리플루오로메틸)페닐]-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- [4- (trifluoromethyl) phenyl] -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] py Synthesis of Ferridine:

1-(tert-부톡시카르보닐)-4-[[4-(트리플루오로메틸)페닐]아미노]피페리딘(689mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(586mg)를 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[[4- (trifluoromethyl) phenyl] amino] piperidine (689 mg) and 3- (3,4,5-trimethoxyphenyl) benzylchloride (586 mg) was reacted in the same manner as in Example 9 to obtain the title compound as light yellow amorphous crystals.

수량: 522mg (44%)Quantity: 522mg (44%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.58-1.70(m, 2H), 1.83-1.90(m, 2H), 2.76-2.87(m, 2H), 3.87(s, 6H), 3.88(s, 3H), 3.96-4.06(m, 1H), 4.15-4.30(m, 2H), 4.58(s, 2H), 6.68(s, 2H), 6.76(d, 2H, J=8.8Hz), 7.19(s, 1H, J=7.4Hz), 7.33-7.44(m, 5H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.58-1.70 (m, 2H), 1.83-1.90 (m, 2H), 2.76-2.87 (m, 2H), 3.87 (s, 6H), 3.88 (s, 3H), 3.96-4.06 (m, 1H), 4.15-4.30 (m, 2H), 4.58 (s, 2H), 6.68 (s, 2H), 6.76 (d, 2H, J = 8.8 Hz), 7.19 (s, 1 H, J = 7.4 Hz), 7.33-7.44 (m, 5H)

제조예 157Preparation Example 157

4-[N-[4-(트리플루오로메틸)페닐]-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘·염산염의 합성:Synthesis of 4- [N- [4- (trifluoromethyl) phenyl] -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine hydrochloride:

1-(tert-부톡시카르보닐)-4-[N-[4-(트리플루오로메틸)페닐]-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘(522mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- [4- (trifluoromethyl) phenyl] -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] py Ferridine (522 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 460mg (99%)Quantity: 460mg (99%)

실시예 127 내지 132Examples 127-132

이들의 화합물은 제조예 155, 157에서 얻어진 아민체와 제조예 3, 42, 48에서 얻어진 클로라이드체를 반응시킴으로서 얻어졌다. 얻어진 유리 염기는 염산염으로 하였다. 수율과 유리 염기의 NMR 데이터를 이하에 나타낸다.These compounds were obtained by making the amine bodies obtained in Production Examples 155 and 157 react with the chloride bodies obtained in Production Examples 3, 42 and 48. The obtained free base was made into hydrochloride. The yield and NMR data of the free base are shown below.

제조예 158Preparation Example 158

1-(tert-부톡시카르보닐)-4-(4-브로모페닐)아미노피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4- (4-bromophenyl) aminopiperidine:

1-(tert-부톡시카르보닐)-4-피페리돈(5.00g)과 4-브로모아닐린(4.11g)을 제조예 37과 동일하게 반응시켜 표기 화합물을 백색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4-piperidone (5.00 g) and 4-bromoaniline (4.11 g) were reacted in the same manner as in Production Example 37 to obtain the title compound as a white powder.

수율: 3.09g (36%)Yield: 3.09 g (36%)

¹H-NMR(400MHz, CDC1₃) δ: 1.25-1.37(m, 2H), 1.46(s, 9H), 1.97-2.05(m, 2H), 2.86-2.96(m, 2H), 3.33-3.42(m, 2H), 3.47-3.57(m, 1H), 3.96-4.12(m, 2H), 6.47(d, 2H, J=8.8Hz), 7.24(d, 2H, J=9.0Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.25-1.37 (m, 2H), 1.46 (s, 9H), 1.97-2.05 (m, 2H), 2.86-2.96 (m, 2H), 3.33-3.42 ( m, 2H), 3.47-3.57 (m, 1H), 3.96-4.12 (m, 2H), 6.47 (d, 2H, J = 8.8 Hz), 7.24 (d, 2H, J = 9.0 Hz)

제조예 159Preparation Example 159

1-(tert-부톡시카르보닐)-4-[N-(4-브로모페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (4-bromophenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] Synthesis of Amino] piperidine:

1-(tert-부톡시카르보닐)-4-(4-브로모페닐)아미노피페리딘(711mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 처리하여 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4- (4-bromophenyl) aminopiperidine (711 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg ) Was treated in the same manner as in Example 9 to obtain the title compound as a pale yellow amorphous crystal.

수량: 607mg (50%)Quantity: 607mg (50%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.50-1.64(m, 2H), 1.81-1.88(m, 2H), 2.74-2.88(m, 2H), 3.86-3.94(m, 1H), 3.89(s, 3H), 3.93(s, 6H), 4.14-4.32(m, 2H), 4.46(s, 2H), 6.59(d, 2H, J=9.1Hz), 7.10(d, 1H, J=5.2Hz), 7.14(s, 2H), 7.28(d, 2H, J=9.1Hz), 7.50(s, 1H), 8.57(d, 1H, J=5.0Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.50-1.64 (m, 2H), 1.81-1.88 (m, 2H), 2.74-2.88 (m, 2H), 3.86-3.94 ( m, 1H), 3.89 (s, 3H), 3.93 (s, 6H), 4.14-4.32 (m, 2H), 4.46 (s, 2H), 6.59 (d, 2H, J = 9.1 Hz), 7.10 (d , 1H, J = 5.2Hz), 7.14 (s, 2H), 7.28 (d, 2H, J = 9.1Hz), 7.50 (s, 1H), 8.57 (d, 1H, J = 5.0Hz)

제조예 160Preparation Example 160

4-[N-(4-브로모페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (4-bromophenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-브로모페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(607mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-bromophenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] Amino] piperidine (607 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 541mg (93%)Quantity: 541mg (93%)

제조예 161Preparation Example 161

1-(tert-부톡시카르보닐)-4-[N-(4-브로모페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (4-bromophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] Synthesis of Amino] piperidine:

1-(tert-부톡시카르보닐)-4-[N-(4-브로모페닐)아미노]피페리딘(711mg)과 5-클로로메틸-3-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 처리하여 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-bromophenyl) amino] piperidine (711 mg) and 5-chloromethyl-3- (3,4,5-trimethoxyphenyl ) Pyridine (588 mg) was treated in the same manner as in Example 9 to obtain the title compound as pale yellow amorphous crystals.

수량: 347mg (28%)Quantity: 347mg (28%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.52-1.67(m, 2H), 1.80-1.89(m, 2H), 2.72-2.87(m, 2H), 3.82-3.92(m, 1H), 3.89(s, 3H), 3.90(s, 6H), 4.14-4.33(m, 2H), 4.50(s, 2H), 6.63(d, 2H, J=9.2Hz), 6.65(s, 2H), 7.28(d, 2H, J=9.4Hz), 7.61(s, 1H), 8.47(d, 1H, J=2.0Hz), 8.67(d, 1H, J=2.2Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.52-1.67 (m, 2H), 1.80-1.89 (m, 2H), 2.72-2.87 (m, 2H), 3.82-3.92 ( m, 1H), 3.89 (s, 3H), 3.90 (s, 6H), 4.14-4.33 (m, 2H), 4.50 (s, 2H), 6.63 (d, 2H, J = 9.2 Hz), 6.65 (s , 2H), 7.28 (d, 2H, J = 9.4 Hz), 7.61 (s, 1H), 8.47 (d, 1H, J = 2.0 Hz), 8.67 (d, 1H, J = 2.2 Hz)

제조예 162Preparation Example 162

4-[N-(4-브로모페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (4-bromophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-브로모페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘(347mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-bromophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] Amino] piperidine (347 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 302mg (91%)Quantity: 302mg (91%)

제조예 163Preparation Example 163

1-(tert-부톡시카르보닐)-4-[N-(4-브로모페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4- [N- (4-bromophenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine :

1-(tert-부톡시카르보닐)-4-[N-(4-브로모페닐)아미노]피페리딘(711mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(586mg)를 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-bromophenyl) amino] piperidine (711 mg) and 3- (3,4,5-trimethoxyphenyl) benzylchloride (586 mg ) Was reacted in the same manner as in Example 9 to obtain the title compound as pale yellow amorphous crystals.

수량: 1.14g (93%)Quantity: 1.14g (93%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.52-1.67(m, 2H), 1.80-1.89(m, 2H), 2.72-2.86(m, 2H), 3.84-3.91(m, 1H), 3.88(s, 3H), 3.89(s, 6H), 4.11-4.32(m, 2H), 4.49(s, 2H), 6.62(d, 2H, J=9.2Hz), 6.69(s, 2H), 7.19(d, 1H, J=7.6Hz), 7.25(d, 2H, J=5.5Hz), 7.32-7.42(m, 3H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.52-1.67 (m, 2H), 1.80-1.89 (m, 2H), 2.72-2.86 (m, 2H), 3.84-3.91 ( m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 4.11-4.32 (m, 2H), 4.49 (s, 2H), 6.62 (d, 2H, J = 9.2 Hz), 6.69 (s , 2H), 7.19 (d, 1H, J = 7.6 Hz), 7.25 (d, 2H, J = 5.5 Hz), 7.32-7.42 (m, 3H)

제조예 164Preparation Example 164

4-[N-(4-브로모페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘·염산염의 합성:Synthesis of 4- [N- (4-bromophenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine hydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-브로모페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘(1.03g)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-bromophenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine (1.03 g) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 973mg (84%)Quantity: 973mg (84%)

실시예 133 내지 140Examples 133 to 140

이들의 화합물은 제조예 160, 162, 164로 얻어진 아민체와 제조예 3, 42, 48에서 얻어진 클로라이드체를 반응시킴으로서 얻어졌다. 얻어진 유리 염기는 염산염으로 하였다. 수율과 유리 염기의 NMR 데이터를 이하에 나타낸다.These compounds were obtained by making the amine body obtained by manufacture examples 160, 162, 164, and the chloride body obtained by manufacture examples 3, 42, 48 react. The obtained free base was made into hydrochloride. The yield and NMR data of the free base are shown below.

제조예 165Preparation Example 165

1-(tert-부톡시카르보닐)-4-[(4-클로로페닐)아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4-[(4-chlorophenyl) amino] piperidine:

1-(tert-부톡시카르보닐)-4-피페리돈(5.00g)과 4-클로로아닐린(3.05g)을 제조예 37과 동일하게 반응시켜 표기 화합물을 백색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4-piperidone (5.00 g) and 4-chloroaniline (3.05 g) were reacted in the same manner as in Production Example 37 to obtain the title compound as a white powder.

수율: 3.80g (49%)Yield: 3.80 g (49%)

¹H-NMR(400MHz, CDC1₃) δ: 1.24-1.38(m, 2H), 1.46(s, 9H), 1.97-2.05(m, 2H), 2.86-2.96(m, 2H), 3.32-3.42(m, 2H), 3.51(br, 1H), 6.52(d, 2H, J=9.0Hz), 7.11(d, 2H, J=9.0Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.24-1.38 (m, 2H), 1.46 (s, 9H), 1.97-2.05 (m, 2H), 2.86-2.96 (m, 2H), 3.32-3.42 ( m, 2H), 3.51 (br, 1H), 6.52 (d, 2H, J = 9.0 Hz), 7.11 (d, 2H, J = 9.0 Hz)

제조예 166Preparation Example 166

1-(tert-부톡시카르보닐)-4-[N-(4-클로로페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (4-chlorophenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino ] Synthesis of piperidine:

1-(tert-부톡시카르보닐)-4-[(4-클로로페닐)아미노]피페리딘(621mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 처리하여 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[(4-chlorophenyl) amino] piperidine (621 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine ( 588 mg) was treated in the same manner as in Example 9 to obtain the title compound as pale yellow amorphous crystals.

수량: 789mg (69%)Quantity: 789mg (69%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.51-1.68(m, 2H), 1.80-1.89(m, 2H), 2.72-2.86(m, 2H), 3.87-3.90(m, 1H), 3.89(s, 3H), 3.93(s, 6H), 4.64(s, 2H), 6.64(d, 2H, J=9.0Hz), 7.14(d, 1H, J=5.3Hz), 7.15(d, 2H, J=9.0Hz),7.51(s, 2H), 8.57(d, 2H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.51-1.68 (m, 2H), 1.80-1.89 (m, 2H), 2.72-2.86 (m, 2H), 3.87-3.90 ( m, 1H), 3.89 (s, 3H), 3.93 (s, 6H), 4.64 (s, 2H), 6.64 (d, 2H, J = 9.0 Hz), 7.14 (d, 1H, J = 5.3 Hz), 7.15 (d, 2H, J = 9.0 Hz), 7.51 (s, 2H), 8.57 (d, 2H, J = 5.1 Hz)

제조예 167Preparation Example 167

4-[N-(4-클로로페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (4-chlorophenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-클로로페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(789mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-chlorophenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino ] Piperidine (789 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 673mg (90%)Quantity: 673mg (90%)

제조예 168Preparation 168

1-(tert-부톡시카르보닐)-4-[N-(4-클로로페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (4-chlorophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino ] Synthesis of piperidine:

1-(tert-부톡시카르보닐)-4-[(4-클로로페닐)아미노]피페리딘(621mg)과 5-클로로메틸-3-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 처리하여 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[(4-chlorophenyl) amino] piperidine (621 mg) and 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine ( 588 mg) was treated in the same manner as in Example 9 to obtain the title compound as pale yellow amorphous crystals.

수량: 268mg (24%)Quantity: 268mg (24%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.56-1.76(m, 2H), 1.80-1.90(m, 2H), 2.76-2.83(m, 2H), 3.86-3.90(m, 1H), 3.89(s, 3H), 3.90(s, 6H), 4.15-4.30(m, 2H), 4.50(s, 2H), 6.66(s, 2H), 6.68(d, 2H, J=9.2Hz), 7.15(d, 2H, J=9.0Hz), 7.63(s, 1H), 8.47(d, 1H, J=2.0Hz), 8.66(d, 1H, J=2.0Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.56-1.76 (m, 2H), 1.80-1.90 (m, 2H), 2.76-2.83 (m, 2H), 3.86-3.90 ( m, 1H), 3.89 (s, 3H), 3.90 (s, 6H), 4.15-4.30 (m, 2H), 4.50 (s, 2H), 6.66 (s, 2H), 6.68 (d, 2H, J = 9.2 Hz), 7.15 (d, 2H, J = 9.0 Hz), 7.63 (s, 1H), 8.47 (d, 1H, J = 2.0 Hz), 8.66 (d, 1H, J = 2.0 Hz)

제조예 169Preparation Example 169

4-[N-(4클로로페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (4chlorophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-클로로페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘(268mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-chlorophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino ] Piperidine (268 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 233mg (91%)Quantity: 233mg (91%)

제조예 170Preparation 170

1-(tert-부톡시카르보닐)-4-[N-(4-클로로페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4- [N- (4-chlorophenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine

1-(tert-부톡시카르보닐)-4-[(4-클로로페닐)아미노]피페리딘(622mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(586mg)를 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[(4-chlorophenyl) amino] piperidine (622mg) and 3- (3,4,5-trimethoxyphenyl) benzylchloride (586mg) The reaction was carried out in the same manner as in Example 9 to obtain the title compound as pale yellow amorphous crystals.

수량: 1.04g (92%)Quantity: 1.04g (92%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.58-1.67(m, 2H), 1.82-1.91(m, 2H), 2.74-2.86(m, 2H), 3.85-3.92(m, 1H), 3.88(s, 3H), 3.89(s, 6H), 4.35-4.41(m, 2H), 4.49(s, 2H), 6.66(d, 2H, J=9.2Hz), 6.70(s, 2H), 7.12(d, 2H, J=9.0Hz), 7.20(d, 2H, J=7.3Hz), 7.33-7.43(m, 3H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.58-1.67 (m, 2H), 1.82-1.91 (m, 2H), 2.74-2.86 (m, 2H), 3.85-3.92 ( m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 4.35-4.41 (m, 2H), 4.49 (s, 2H), 6.66 (d, 2H, J = 9.2 Hz), 6.70 (s , 2H), 7.12 (d, 2H, J = 9.0 Hz), 7.20 (d, 2H, J = 7.3 Hz), 7.33-7.43 (m, 3H)

제조예 171Preparation Example 171

4-[N-(4-클로로페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘·염산염의 합성:Synthesis of 4- [N- (4-chlorophenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine hydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-클로로페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘(1.04g)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-chlorophenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine (1.04 g ) Was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 899mg (97%)Quantity: 899mg (97%)

실시예 141 내지 148Examples 141 to 148

이들의 화합물은 제조예 167, 169, 171에서 얻어진 아민체와 제조예 3, 42, 48에서 얻어진 클로라이드체를 반응시킴으로서 얻어졌다. 얻어진 유리 염기는 염산염으로 하였다. 수율과 유리 염기의 NMR 데이터를 이하에 나타낸다.These compounds were obtained by reacting the amine bodies obtained in Production Examples 167, 169 and 171 with the chloride bodies obtained in Production Examples 3, 42 and 48. The obtained free base was made into hydrochloride. The yield and NMR data of the free base are shown below.

제조예 172Preparation Example 172

1-(tert-부톡시카르보닐)-4-[(3,4-디플루오로페닐)아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4-[(3,4-difluorophenyl) amino] piperidine

1-(tert-부톡시카르보닐)-4-피페리돈(5.00g)과 3,4-디플루오로아닐린(3.09g)을 제조예 37과 동일하게 반응시켜 표기 화합물을 백색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4-piperidone (5.00 g) and 3,4-difluoroaniline (3.09 g) were reacted in the same manner as in Production Example 37 to obtain the title compound as a white powder.

수율: 4.66g (62%)Yield: 4.66 g (62%)

1H-NMR(400MHz, CDC1₃) δ: 1.24-1.37(m, 2H), 1.46(s, 9H), 1.97-2.05(m,2H), 2.85-2.96(m, 2H), 3.26-3.36(m, 1H), 3.38-3.52(m, 1H), 3.96-4.14(m, 2H), 6.22-6.28(m, 1H), 6.38(ddd, 1H, J=12.7Hz, 6.6Hz, 2.9Hz), 6.94(dd, 1H, J=19.1Hz, 9.0Hz)1 H-NMR (400 MHz, CDC1 ₃ ) δ: 1.24-1.37 (m, 2H), 1.46 (s, 9H), 1.97-2.05 (m, 2H), 2.85-2.96 (m, 2H), 3.26-3.36 (m , 1H), 3.38-3.52 (m, 1H), 3.96-4.14 (m, 2H), 6.22-6.28 (m, 1H), 6.38 (ddd, 1H, J = 12.7 Hz, 6.6 Hz, 2.9 Hz), 6.94 (dd, 1H, J = 19.1Hz, 9.0Hz)

제조예 173Preparation Example 173

1-(tert-부톡시카르보닐)-4-[N-(3,4-디플루오로페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (3,4-difluorophenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl Synthesis of] methyl] amino] piperidine:

1-(tert-부톡시카르보닐)-4-[(3,4-디플루오로페닐)아미노]피페리돈(625mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 처리하여 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[(3,4-difluorophenyl) amino] piperidone (625 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl ) Pyridine (588 mg) was treated in the same manner as in Example 9 to obtain the title compound as pale yellow amorphous crystals.

수량: 534mg (47%)Quantity: 534mg (47%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.50-1.70(m, 2H), 1.82-1.90(m, 2H), 2.73-2.88(m, 2H), 3.90(s, 3H), 3.94(s, 6H), 4.15-4.30(m, 2H), 4.43(s, 2H), 6.33-6.39(m, 1H), 6.52(ddd, 1H, J=13.6Hz, 6.4Hz, 3.1Hz), 6.98(dd, 1H, J=19.1Hz, 9.2Hz), 7.11(dd, 1H, J=5.0Hz, 1.3Hz), 7.16(s, 2H), 7.51(s, 1H), 8.58(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.50-1.70 (m, 2H), 1.82-1.90 (m, 2H), 2.73-2.88 (m, 2H), 3.90 (s, 3H), 3.94 (s, 6H), 4.15-4.30 (m, 2H), 4.43 (s, 2H), 6.33-6.39 (m, 1H), 6.52 (ddd, 1H, J = 13.6 Hz, 6.4 Hz, 3.1 Hz), 6.98 (dd, 1H, J = 19.1 Hz, 9.2 Hz), 7.11 (dd, 1H, J = 5.0 Hz, 1.3 Hz), 7.16 (s, 2H), 7.51 (s, 1H), 8.58 (d , 1H, J = 5.1Hz)

제조예 174Preparation Example 174

4-[N-(3,4-디플루오로페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘·2염산염의 합성:4- [N- (3,4-difluorophenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine dihydrochloride Synthesis of:

1-(tert-부톡시카르보닐)-4-[N-(3,4-디플루오로페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(534mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (3,4-difluorophenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl ] Methyl] amino] piperidine (534 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 442mg (87%)Quantity: 442mg (87%)

제조예 175Preparation Example 175

1-(tert-부톡시카르보닐)-4-[N-(3,4-디플루오로페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (3,4-difluorophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl Synthesis of] methyl] amino] piperidine:

1-(tert-부톡시카르보닐)-4-[(3,4-디플루오로페닐)아미노]피페리딘(625mg)과 5-클로로메틸-3-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 처리하여 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[(3,4-difluorophenyl) amino] piperidine (625 mg) and 5-chloromethyl-3- (3,4,5-trimethoxy Phenyl) pyridine (588 mg) was treated in the same manner as in Example 9 to obtain the title compound as light yellow amorphous crystals.

수량: 350mg (31%)Quantity: 350mg (31%)

제조예 176Preparation Example 176

4-[N-(3,4-디플루오로페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘·2염산염의 합성:4- [N- (3,4-difluorophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride Synthesis of:

1-(tert-부톡시카르보닐)-4-[N-(3,4-디플루오로페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘(350mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (3,4-difluorophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl ] Methyl] amino] piperidine (350 mg) was treated in the same manner as in Production Example 94 to obtain the title compound as a pale yellow powder.

수량: 305mg (92%)Quantity: 305mg (92%)

제조예 177Preparation Example 177

1-(tert-부톡시카르보닐)-4-[N-(3,4-디플루오로페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (3,4-difluorophenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperi Dean's Synthesis:

1-(tert-부톡시카르보닐)-4-[(3,4-디플루오로페닐)아미노]피페리딘(625mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(586mg)를 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[(3,4-difluorophenyl) amino] piperidine (625 mg) and 3- (3,4,5-trimethoxyphenyl) benzylchloride ( 586 mg) was reacted in the same manner as in Example 9 to obtain the title compound as pale yellow amorphous crystals.

수량: 1.04g (92%)Quantity: 1.04g (92%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.52-1.66(m, 2H), 1.81-1.89(m, 2H), 2.72-2.85(m, 2H), 3.78(tt, 1H, J=11.8Hz, 3.8Hz), 3.88(s, 3H), 3.90(s, 6H), 4.12-4.30(m, 2H), 4.45(s, 2H), 6.36-6.42(m, 1H), 6.54(ddd, 1H, J=13.9Hz, 6.8Hz, 2.9Hz), 6.71(s, 2H), 6.95(dd, 1H, J=19.2Hz, 9.2Hz), 7.20(d, 1H, J=7.4Hz), 7.36-7.43(m, 3H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.52-1.66 (m, 2H), 1.81-1.89 (m, 2H), 2.72-2.85 (m, 2H), 3.78 (tt, 1H, J = 11.8 Hz, 3.8 Hz), 3.88 (s, 3H), 3.90 (s, 6H), 4.12-4.30 (m, 2H), 4.45 (s, 2H), 6.36-6.42 (m, 1H), 6.54 (ddd, 1H, J = 13.9 Hz, 6.8 Hz, 2.9 Hz), 6.71 (s, 2H), 6.95 (dd, 1H, J = 19.2 Hz, 9.2 Hz), 7.20 (d, 1H, J = 7.4 Hz ), 7.36-7.43 (m, 3H)

제조예 178Preparation Example 178

4-[N-(3,4-디플루오로페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘·염산염의 합성:Synthesis of 4- [N- (3,4-difluorophenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine hydrochloride:

1-(tert-부톡시카르보닐)-4-[(3,4-디플루오로페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘(980mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4-[(3,4-difluorophenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine ( 980 mg) was treated in the same manner as in Production Example 94 to obtain the title compound as a pale yellow powder.

수량: 819mg (94%)Quantity: 819mg (94%)

실시예 149 내지 156Examples 149-156

이들의 화합물은 제조예 174, 176, 178에서 얻어진 아민체와 제조예 3, 42, 48에서 얻어진 클로라이드체를 반응시킴으로서 얻어졌다. 얻어진 유리 염기는 염산염으로 하였다. 수율과 유리 염기의 NMR 데이터를 이하에 나타낸다.These compounds were obtained by reacting the amine bodies obtained in Production Examples 174, 176, and 178 with the chloride bodies obtained in Production Examples 3, 42, and 48. The obtained free base was made into hydrochloride. The yield and NMR data of the free base are shown below.

제조예 179Preparation Example 179

1-(tert-부톡시카르보닐)-4-[(4-플루오로페닐)아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4-[(4-fluorophenyl) amino] piperidine

1-(tert-부톡시카르보닐)-4-피페리돈(5.00g)과 4-플루오로아닐린(2.66g)을제조예 37과 동일하게 반응시켜 표기 화합물을 백색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4-piperidone (5.00 g) and 4-fluoroaniline (2.66 g) were reacted in the same manner as in Production Example 37 to obtain the title compound as a white powder.

수율: 4.99g (71%)Yield: 4.99 g (71%)

¹H-NMR(400MHz, CDC1₃) δ: 1.23-1.36(m, 2H), 1.46(s, 9H), 1.97-2.05(m, 2H), 2.84-2.96(m, 2H), 3.30-3.39(m, 2H), 3.96-4.14(m, 2H), 6.51-6.57(m, 2H), 6.84-6.91(m, 2H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.23-1.36 (m, 2H), 1.46 (s, 9H), 1.97-2.05 (m, 2H), 2.84-2.96 (m, 2H), 3.30-3.39 ( m, 2H), 3.96-4.14 (m, 2H), 6.51-6.57 (m, 2H), 6.84-6.91 (m, 2H)

제조예 180Preparation Example 180

1-(tert-부톡시카르보닐)-4-[N-(4-플루오로페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (4-fluorophenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] Synthesis of Amino] piperidine:

1-(tert-부톡시카르보닐)-4-[(4-플루오로페닐)아미노]피페리딘(589mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 처리하여 표기화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[(4-fluorophenyl) amino] piperidine (589 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) was treated in the same manner as in Example 9 to obtain the title compound as pale yellow amorphous crystals.

수량: 702mg (64%)Quantity: 702mg (64%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.48-1.64(m, 2H), 1.81-1.90(m, 2H), 2.72-2.85(m, 2H), 3.69-3.98(m, 1H), 3.89(br, 3H), 3.94(m, 6H), 4.16-4.28(m, 2H), 4.43(s, 2H), 6.66-6.73(m, 2H), 6.91(dd, 2H, J=9.2Hz, 9.2Hz),7.12-7.16(m, 3H), 7.53(s, 1H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.48-1.64 (m, 2H), 1.81-1.90 (m, 2H), 2.72-2.85 (m, 2H), 3.69-3.98 ( m, 1H), 3.89 (br, 3H), 3.94 (m, 6H), 4.16-4.28 (m, 2H), 4.43 (s, 2H), 6.66-6.73 (m, 2H), 6.91 (dd, 2H, J = 9.2 Hz, 9.2 Hz), 7.12-7.16 (m, 3H), 7.53 (s, 1H)

제조예 181Preparation Example 181

4-[N-(4-플루오로페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (4-fluorophenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-플루오로페닐)-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(702mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-fluorophenyl) -N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] Amino] piperidine (702 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 561mg (84%)Quantity: 561mg (84%)

제조예 182Preparation Example 182

1-(tert-부톡시카르보닐)-4-[N-(4-플루오로페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (4-fluorophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] Synthesis of Amino] piperidine:

1-(tert-부톡시카르보닐)-4-[(4-플루오로페닐)아미노]피페리딘(589mg)과 5-클로로메틸-3-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 처리하여 표기화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[(4-fluorophenyl) amino] piperidine (589 mg) and 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) was treated in the same manner as in Example 9 to obtain the title compound as pale yellow amorphous crystals.

수량: 190mg (17%)Quantity: 190mg (17%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.50-1.73(m, 2H), 1.82-1.90(m, 2H), 2.71-2.85(m, 2H), 3.71(tt, 1H, J=11.7Hz, 3.1Hz), 3.89(s, 3H), 3.90(s, 6H), 4.12-4.30(m, 2H), 4.45(s, 2H), 6.66(s, 2H), 6.73-6.78(m, 2H), 6.91(dd, 2H, J=9.2Hz, 8.2Hz), 7.65(s, 1H), 8.49(d, 1H, J=2.0Hz), 8.65(d, 1H, J=2.0Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.50-1.73 (m, 2H), 1.82-1.90 (m, 2H), 2.71-2.85 (m, 2H), 3.71 (tt, 1H, J = 11.7 Hz, 3.1 Hz), 3.89 (s, 3H), 3.90 (s, 6H), 4.12-4.30 (m, 2H), 4.45 (s, 2H), 6.66 (s, 2H), 6.73- 6.78 (m, 2H), 6.91 (dd, 2H, J = 9.2 Hz, 8.2 Hz), 7.65 (s, 1H), 8.49 (d, 1H, J = 2.0 Hz), 8.65 (d, 1H, J = 2.0 Hz)

제조예 183Preparation Example 183

4-[N-(4-플루오로페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (4-fluorophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-플루오로페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘(190mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-fluorophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] Amino] piperidine (190 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 165mg (91%)Quantity: 165mg (91%)

제조예 184Preparation Example 184

1-(tert-부톡시카르보닐)-4-[N-(4-플루오로페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4- [N- (4-fluorophenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine :

1-(tert-부톡시카르보닐)-4-[(4-플루오로페닐)아미노]피페리딘(589mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(586mg)를 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-[(4-fluorophenyl) amino] piperidine (589 mg) and 3- (3,4,5-trimethoxyphenyl) benzylchloride (586 mg) In the same manner as in Example 9, the title compound was obtained as light yellow amorphous crystals.

수량: 1.01g (92%)Quantity: 1.01g (92%)

¹H-NMR(400MHz, CDC1₃) δ: 1.44(s, 9H), 1.51-1.65(m, 2H), 1.82-1.90(m, 2H), 2.82-2.84(m, 2H), 3.78(tt, 1H, J=11.7Hz, 3.5Hz), 3.88(s, 3H), 3.90(s, 6H), 4.10-4.30(m, 2H), 4.45(s, 2H), 6.68-6.73(m, 4H), 6.89(dd, 2H, J=9.2Hz, 8.2Hz), 7.21-7.25(m, 1H), 7.32-7.41(m, 3H) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.44 (s, 9H), 1.51-1.65 (m, 2H), 1.82-1.90 (m, 2H), 2.82-2.84 (m, 2H), 3.78 (tt, 1H, J = 11.7 Hz, 3.5 Hz, 3.88 (s, 3H), 3.90 (s, 6H), 4.10-4.30 (m, 2H), 4.45 (s, 2H), 6.68-6.73 (m, 4H), 6.89 (dd, 2H, J = 9.2 Hz, 8.2 Hz), 7.21-7.25 (m, 1H), 7.32-7.41 (m, 3H)

제조예 185Preparation 185

4-[N-(4-플루오로페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘·염산염의 합성:Synthesis of 4- [N- (4-fluorophenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine hydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-플루오로페닐)-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘(1.0AG)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-fluorophenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine (1.0 AG) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 790mg (88%)Quantity: 790mg (88%)

실시예 157 내지 164Examples 157-164

이들의 화합물은 제조예 181,183, 185에서 얻어진 아민체와 제조예 3, 42, 48에서 얻어진 클로라이드체를 반응시킴으로서 얻어졌다. 얻어진 유리 염기는 염산염으로 하였다. 수율과 유리 염기의 NMR 데이터를 이하에 나타낸다.These compounds were obtained by making the amine body obtained in manufacture example 181,183, 185, and the chloride body obtained in manufacture example 3, 42, 48 react. The obtained free base was made into hydrochloride. The yield and NMR data of the free base are shown below.

제조예 186Preparation 186

1-(tert-부톡시카르보닐)-4-페닐아미노피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4-phenylaminopiperidine:

1-(tert-부톡시카르보닐)-4-피페리돈(5.00g)과 아닐린(2.23g)을 제조예 37과 동일하게 반응시켜 표기 화합물을 백색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4-piperidone (5.00 g) and aniline (2.23 g) were reacted in the same manner as in Production Example 37 to obtain the title compound as a white powder.

수율: 3.77g (57%)Yield: 3.77 g (57%)

¹H-NMR(400MHz, CDC1₃) δ: 1.25-1.38(m, 2H), 1.47(s, 9H), 2.00-2.07(m, 2H), 2.87-2.97(m, 2H), 3.38-3.53(m, 2H), 3.96-4.14(m, 2H), 6.57-6.62(m, 2H), 6.70(tt, 1H, J=6.2Hz, 1.0Hz), 7.17(dd, 2H, J=8.6Hz, 7.2Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.25-1.38 (m, 2H), 1.47 (s, 9H), 2.00-2.07 (m, 2H), 2.87-2.97 (m, 2H), 3.38-3.53 ( m, 2H), 3.96-4.14 (m, 2H), 6.57-6.62 (m, 2H), 6.70 (tt, 1H, J = 6.2 Hz, 1.0 Hz), 7.17 (dd, 2H, J = 8.6 Hz, 7.2 Hz)

제조예 187Preparation Example 187

1-(tert-부톡시카르보닐)-4-[N-페닐-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:Of 1- (tert-butoxycarbonyl) -4- [N-phenyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine synthesis:

1-(tert-부톡시카르보닐)-4-페닐아미노피페리딘(553mg)과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 처리하여 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-phenylaminopiperidine (553 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) The same treatment was carried out to obtain the title compound as pale yellow amorphous crystals.

수량: 760mg (71%)Quantity: 760mg (71%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.53-1.63(m, 2H), 1.83-1.91(m, 2H), 2.76-2.90(m, 2H), 3.86-3.97(m, 1H), 3.89(s, 3H), 3.93(s, 6H), 4.14-4.32(m, 2H), 4.49(s, 2H), 6.71-6.78(m, 3H), 7.14(s, 1H), 7.15(s, 2H), 7.21(dd, 2H, J=8.8Hz, 7.4Hz), 7.55(s, 1H), 8.56(d, 1H, J=5.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.53-1.63 (m, 2H), 1.83-1.91 (m, 2H), 2.76-2.90 (m, 2H), 3.86-3.97 ( m, 1H), 3.89 (s, 3H), 3.93 (s, 6H), 4.14-4.32 (m, 2H), 4.49 (s, 2H), 6.71-6.78 (m, 3H), 7.14 (s, 1H) , 7.15 (s, 2H), 7.21 (dd, 2H, J = 8.8 Hz, 7.4 Hz), 7.55 (s, 1H), 8.56 (d, 1H, J = 5.1 Hz)

제조예 188Preparation Example 188

4-[N-페닐-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N-phenyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-페닐-N-[[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(760mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N-phenyl-N-[[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine ( 760 mg) was treated in the same manner as in Production Example 94 to obtain the title compound as a pale yellow powder.

수량: 652mg (90%)Quantity: 652mg (90%)

제조예 189Preparation Example 189

1-(tert-부톡시카르보닐)-4-[N-페닐-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘의 합성:Of 1- (tert-butoxycarbonyl) -4- [N-phenyl-N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine synthesis:

1-(tert-부톡시카르보닐)-4-N-페닐아미노피페리딘(553mg)(와)과 5-클로로메틸-3-(3,4,5-트리메톡시페닐)피리딘(588mg)을 실시예 9와 동일하게 처리하여 표기 화합물을 담황색 부정형 결정으로서 얻었다.1- (tert-butoxycarbonyl) -4-N-phenylaminopiperidine (553 mg) and 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) Was treated in the same manner as in Example 9 to obtain the title compound as pale yellow amorphous crystals.

수량: 222mg (21%)Quantity: 222mg (21%)

¹H-NMR(400MHz, CDC1₃) δ: 1.45(s, 9H), 1.52-1.67(m, 2H), 1.82-1.91(m, 2H), 2.74-2.87(m, 2H), 3.88-3.90(m, 1H), 3.88(s, 3H), 3.89(s, 6H), 4.14-4.31(m, 2H), 4.53(s, 2H), 6.67(s, 2H), 6.74-6.80(m, 3H), 7.21(dd, 2H, J=8.8Hz, 7.2Hz), 7.67(s, 1H), 8.50(d, 1H, J=5.3Hz, 2.2Hz), 8.66(d, 1H, J=2.1Hz) ¹ H-NMR (400 MHz, CDC1 ₃ ) δ: 1.45 (s, 9H), 1.52-1.67 (m, 2H), 1.82-1.91 (m, 2H), 2.74-2.87 (m, 2H), 3.88-3.90 ( m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 4.14-4.31 (m, 2H), 4.53 (s, 2H), 6.67 (s, 2H), 6.74-6.80 (m, 3H) , 7.21 (dd, 2H, J = 8.8 Hz, 7.2 Hz), 7.67 (s, 1H), 8.50 (d, 1H, J = 5.3 Hz, 2.2 Hz), 8.66 (d, 1H, J = 2.1 Hz)

제조예 190Preparation Example 190

4-[N-페닐-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N-phenyl-N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-페닐-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘(222mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N-phenyl-N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine ( 222 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound as a pale yellow powder.

수량: 197mg (94%)Quantity: 197mg (94%)

제조예 191Preparation Example 191

1-(tert-부톡시카르보닐)-4-[N-페닐-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4- [N-phenyl-N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine

1-(tert-부톡시카르보닐)-4-페닐아미노피페리딘(553mg)과 3-(3,4,5-트리메톡시페닐)벤질클로라이드(586mg)를 실시예 9와 동일하게 반응시켜 표기 화합물을 담황색 부정형 결정으로 얻었다.1- (tert-butoxycarbonyl) -4-phenylaminopiperidine (553 mg) and 3- (3,4,5-trimethoxyphenyl) benzylchloride (586 mg) were reacted in the same manner as in Example 9. The title compound was obtained as light yellow amorphous crystals.

수량: 1.06g (100%)Quantity: 1.06g (100%)

¹H-NMR(400MHz, CDCl₃) δ: 1.45(s, 9H), 1.52-1.68(m, 2H), 1.83-1.92(m, 2H), 2.73-2.86(m, 2H), 3.88(s, 3H), 3.89(s, 6H), 3.94(tt, 1H, J=11.7Hz, 3.3Hz), 4.14-4.30(m, 2H), 4.52(s, 2H), 6.69-6.78(m, 6H), 7.17-7.27(m, 2H), 7.32-7.42(m, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45 (s, 9H), 1.52-1.68 (m, 2H), 1.83-1.92 (m, 2H), 2.73-2.86 (m, 2H), 3.88 (s, 3H), 3.89 (s, 6H), 3.94 (tt, 1H, J = 11.7 Hz, 3.3 Hz), 4.14-4.30 (m, 2H), 4.52 (s, 2H), 6.69-6.78 (m, 6H), 7.17-7.27 (m, 2H), 7.32-7.42 (m, 3H)

제조예 192Preparation Example 192

4-[N-페닐-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘·염산염의 합성:Synthesis of 4- [N-phenyl-N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine hydrochloride:

1-(tert-부톡시카르보닐)-4-[N-페닐-N-[3-(3,4,5-트리메톡시페닐)벤질]아미노]피페리딘(1.06g)을 제조예 94와 동일하게 처리하여 표기 화합물을 담황색 분말로서 얻었다.1- (tert-butoxycarbonyl) -4- [N-phenyl-N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine (1.06 g) was prepared. The same procedure was followed to obtain the title compound as a pale yellow powder.

수량: 909mg (97%)Quantity: 909mg (97%)

실시예 165 내지 169Examples 165-169

이들의 화합물은 제조예 188, 190, 192에서 얻어진 아민체와 제조예 3, 48에서 얻어진 클로라이드체를 반응시킴으로서 얻어졌다. 얻어진 유리 염기는 염산염으로 하였다. 수율과 유리 염기의 NMR 데이터를 이하에 나타낸다.These compounds were obtained by making the amine body obtained by manufacture examples 188, 190, and 192 react with the chloride body obtained by manufacture examples 3 and 48. The obtained free base was made into hydrochloride. The yield and NMR data of the free base are shown below.

제조예 193 내지 203Preparation Examples 193-203

이들의 화합물은 제조예 1에서 3까지 방법을 이용해 제조했다. 구조와 NMR데이터를 아래에 나타냈다.These compounds were manufactured using the method of manufacture example 1 thru | or 3. The structure and NMR data are shown below.

제조예 204Preparation Example 204

1-(tert-부톡시카르보닐)-4-[N-(4-메톡시페닐)-N-[(2-페닐피리딘-4-일)메틸]아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4- [N- (4-methoxyphenyl) -N-[(2-phenylpyridin-4-yl) methyl] amino] piperidine

4-(p-아니시디노)-(tert-부톡시카르보닐)피페리딘(612mg)과 4-클로로메틸-2-페닐피리딘(204mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 얻었다.4- (p-anisidino)-(tert-butoxycarbonyl) piperidine (612 mg) and 4-chloromethyl-2-phenylpyridine (204 mg) were reacted in the same manner as in Example 9 to obtain the title compound.

수량:407mg (43%)Quantity: 407mg (43%)

제조예 205Preparation Example 205

4-[N-(4-메톡시페닐)-N-[(2-페닐피리딘-4-일)메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (4-methoxyphenyl) -N-[(2-phenylpyridin-4-yl) methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4메톡시페닐)-N-[(2-페닐피리딘-4일)메틸]아미노]피페리딘(407mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4methoxyphenyl) -N-[(2-phenylpyridin-4yl) methyl] amino] piperidine (407 mg) was prepared in Preparation Example 94. The same treatment was carried out to obtain the title compound.

수량: 365mg (95%)Quantity: 365mg (95%)

제조예 206Preparation Example 206

1-(tert-부톡시카르보닐)-4-[N-(4-메톡시페닐)-N-[[2-(2-메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (4-methoxyphenyl) -N-[[2- (2-methoxyphenyl) pyridin-4-yl] methyl] amino] piperidine Synthesis of:

4-(p-아니시디노)-(tert-부톡시카르보닐)피페리딘(306mg)과 4-클로로메틸-2-(2-메톡시페닐)피리딘(234mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 얻었다.4- (p-anisidino)-(tert-butoxycarbonyl) piperidine (306 mg) and 4-chloromethyl-2- (2-methoxyphenyl) pyridine (234 mg) were reacted in the same manner as in Example 9. To obtain the title compound.

수량: 237mg (72%)Quantity: 237mg (72%)

제조예 207Preparation Example 207

4-[N-(4-메톡시페닐)-N-[[2-(2-메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (4-methoxyphenyl) -N-[[2- (2-methoxyphenyl) pyridin-4-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-메톡시페닐)-N-[[2-(2-메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(360mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 이득1- (tert-butoxycarbonyl) -4- [N- (4-methoxyphenyl) -N-[[2- (2-methoxyphenyl) pyridin-4-yl] methyl] amino] piperidine (360 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound.

수량: 365mg (65%)Quantity: 365mg (65%)

제조예 208Preparation Example 208

1-(tert-부톡시카르보닐)-4-[N-(4-메톡시페닐)-N-[[2-(3-메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N- (4-methoxyphenyl) -N-[[2- (3-methoxyphenyl) pyridin-4-yl] methyl] amino] piperidine Synthesis of:

4-(p-아니시디노)-(tert-부톡시카르보닐)피페리딘(306mg)과 4-클로로메틸-2-(3-메톡시페닐)피리딘(234mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 얻었다.4- (p-anisidino)-(tert-butoxycarbonyl) piperidine (306 mg) and 4-chloromethyl-2- (3-methoxyphenyl) pyridine (234 mg) were reacted in the same manner as in Example 9. To obtain the title compound.

수량: 550mg (이론량)Quantity: 550mg (Theoretical quantity)

제조예 209Preparation Example 209

4-[N-(4-메톡시페닐)-N-[[2-(3-메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- (4-methoxyphenyl) -N-[[2- (3-methoxyphenyl) pyridin-4-yl] methyl] amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4메톡시페닐)-N-[[2-(3-메톡시페닐)피리딘-4-일]메틸]아미노]피페리딘(550mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4methoxyphenyl) -N-[[2- (3-methoxyphenyl) pyridin-4-yl] methyl] amino] piperidine ( 550 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound.

수량: 436mg (85%)Quantity: 436mg (85%)

제조예 210Preparation Example 210

1-(tert-부톡시카르보닐)-4-[N-[2-(4-에톡시페닐)피리딘-4-일]메틸-N-(4-메톡시페닐)아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4- [N- [2- (4-ethoxyphenyl) pyridin-4-yl] methyl-N- (4-methoxyphenyl) amino] piperidine :

4-(p-아니시디노)-(tert-부톡시카르보닐)피페리딘(306mg)과 4-클로로메틸-2-(4-에톡시페닐)피리딘(248mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 얻었다.4- (p-anisidino)-(tert-butoxycarbonyl) piperidine (306 mg) and 4-chloromethyl-2- (4-ethoxyphenyl) pyridine (248 mg) were reacted in the same manner as in Example 9. To obtain the title compound.

수량: 515mg (99%)Quantity: 515mg (99%)

제조예 211Preparation Example 211

4-[N-[2-(4-에톡시페닐)피리딘-4-일]메틸-N-(4-메톡시페닐)아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- [2- (4-ethoxyphenyl) pyridin-4-yl] methyl-N- (4-methoxyphenyl) amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-[2-(4-에톡시페닐)피리딘-4-일]메틸-N-(4-메톡시페닐)아미노]피페리딘(515mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 얻었다.1- (tert-butoxycarbonyl) -4- [N- [2- (4-ethoxyphenyl) pyridin-4-yl] methyl-N- (4-methoxyphenyl) amino] piperidine (515 mg ) Was treated in the same manner as in Preparation Example 94 to obtain the title compound.

수량: 418mg (80%)Quantity: 418mg (80%)

제조예 212Preparation Example 212

1-(tert-부톡시카르보닐)-4-[N-[[2-(3,4-디메톡시페닐)피리딘-4-일]메틸]-N-(4-메톡시페닐)아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N-[[2- (3,4-dimethoxyphenyl) pyridin-4-yl] methyl] -N- (4-methoxyphenyl) amino] py Synthesis of Ferridine:

4-(p-아니시디노)-(tert-부톡시카르보닐)피페리딘(306mg)과 4-클로로메틸-2-(3,4-디메톡시페닐)피리딘(264mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 얻었다.4- (p-anisidino)-(tert-butoxycarbonyl) piperidine (306 mg) and 4-chloromethyl-2- (3,4-dimethoxyphenyl) pyridine (264 mg) were the same as in Example 9. Reaction was carried out to obtain the title compound.

수량: 600mg (이론량)Quantity: 600 mg (theoretical amount)

제조예 213Preparation Example 213

4-[N-[[2-(3,4-디메톡시페닐)피리딘-4-일]메틸]-N-(4-메톡시페닐)아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N-[[2- (3,4-dimethoxyphenyl) pyridin-4-yl] methyl] -N- (4-methoxyphenyl) amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-[[2-(3,4-디메톡시페닐)피리딘-4-일]메틸]-N-(4-메톡시페닐)아미노]피페리딘(600mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 얻었다.1- (tert-butoxycarbonyl) -4- [N-[[2- (3,4-dimethoxyphenyl) pyridin-4-yl] methyl] -N- (4-methoxyphenyl) amino] py Ferridine (600 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound.

수량: 416mg (80%)Quantity: 416mg (80%)

제조예 214Preparation Example 214

1-(tert-부톡시카르보닐)-4-[N-[[2-(2-플루오로페닐)피리딘-4-일]메틸]-N-(4-메톡시페닐)아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N-[[2- (2-fluorophenyl) pyridin-4-yl] methyl] -N- (4-methoxyphenyl) amino] piperidine Synthesis of:

4-(p-아니시디노)-(tert-부톡시카르보닐)피페리딘(306mg)과 4-클로로메틸-2-(2-플루오로페닐)피리딘(222mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 얻었다.4- (p-anisidino)-(tert-butoxycarbonyl) piperidine (306 mg) and 4-chloromethyl-2- (2-fluorophenyl) pyridine (222 mg) were reacted in the same manner as in Example 9. To obtain the title compound.

수량: 530mg (이론량)Quantity: 530mg (Theoretical quantity)

제조예 215Preparation Example 215

4-[N-[2-(2-플루오로페닐)피리딘-4-일]메틸-N-(4-메톡시페닐)아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- [2- (2-fluorophenyl) pyridin-4-yl] methyl-N- (4-methoxyphenyl) amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-[2-(2-플루오로페닐)피리딘-4-일]메틸-N-(4-메톡시페닐)아미노]피페리딘(530mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 얻었다.1- (tert-butoxycarbonyl) -4- [N- [2- (2-fluorophenyl) pyridin-4-yl] methyl-N- (4-methoxyphenyl) amino] piperidine (530 mg ) Was treated in the same manner as in Preparation Example 94 to obtain the title compound.

수량: 432mg (85%)Quantity: 432mg (85%)

제조예 216Preparation Example 216

1-(tert-부톡시카르보닐)-4-[N-[2-(3-플루오로페닐)피리딘-4-일]메틸-N-(4-메톡시페닐)아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4- [N- [2- (3-fluorophenyl) pyridin-4-yl] methyl-N- (4-methoxyphenyl) amino] piperidine :

4-(p-아니시디노)-(tert-부톡시카르보닐)피페리딘(153mg)과 4-클로로메틸-2-(3-플루오로페닐)피리딘(111mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 얻었다.4- (p-anisidino)-(tert-butoxycarbonyl) piperidine (153 mg) and 4-chloromethyl-2- (3-fluorophenyl) pyridine (111 mg) were reacted in the same manner as in Example 9. To obtain the title compound.

수량: 270mg (이론량)Quantity: 270mg (Theoretical quantity)

제조예 217Preparation Example 217

4-[N-[2-(3-플루오로페닐)피리딘-4-일]메틸-N-(4-메톡시페닐)아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- [2- (3-fluorophenyl) pyridin-4-yl] methyl-N- (4-methoxyphenyl) amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-[2-(3-플루오로페닐)피리딘-4-일]메틸-N-(4-메톡시페닐)아미노]피페리딘(270mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 얻었다.1- (tert-butoxycarbonyl) -4- [N- [2- (3-fluorophenyl) pyridin-4-yl] methyl-N- (4-methoxyphenyl) amino] piperidine (270 mg ) Was treated in the same manner as in Preparation Example 94 to obtain the title compound.

수량: 193mg (70%)Quantity: 193mg (70%)

제조예 218Preparation Example 218

1-(tert-부톡시카르보닐)-4-[N-[2-(4-플루오로페닐)피리딘-4-일]메틸-N-(4-메톡시페닐)아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4- [N- [2- (4-fluorophenyl) pyridin-4-yl] methyl-N- (4-methoxyphenyl) amino] piperidine :

4-(p-아니시디노)-(tert-부톡시카르보닐)피페리딘(306mg)과 4-클로로메틸-2-(4-플루오로페닐)피리딘(222mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 얻었다.4- (p-anisidino)-(tert-butoxycarbonyl) piperidine (306 mg) and 4-chloromethyl-2- (4-fluorophenyl) pyridine (222 mg) were reacted in the same manner as in Example 9. To obtain the title compound.

수량: 550mg (이론량)Quantity: 550mg (Theoretical quantity)

제조예 219Preparation Example 219

4-[N-[2-(4-플루오로페닐)피리딘-4-일]메틸-N-(4-메톡시페닐)아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- [2- (4-fluorophenyl) pyridin-4-yl] methyl-N- (4-methoxyphenyl) amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-[2-(4-플루오로페닐)피리딘-4-일]메틸-N-(4-메톡시페닐)아미노]피페리딘(550mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 얻었다.1- (tert-butoxycarbonyl) -4- [N- [2- (4-fluorophenyl) pyridin-4-yl] methyl-N- (4-methoxyphenyl) amino] piperidine (550 mg ) Was treated in the same manner as in Preparation Example 94 to obtain the title compound.

수량:439mg (88%)Quantity: 439mg (88%)

제조예 220Preparation Example 220

1-(tert-부톡시카르보닐)-4-[N-[[2-(3,4-디플루오로페닐)피리딘-4-일]메틸]-N-(4-메톡시페닐)아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N-[[2- (3,4-difluorophenyl) pyridin-4-yl] methyl] -N- (4-methoxyphenyl) amino] Synthesis of Piperidine:

4-(p-아니시디노)-(tert-부톡시카르보닐)피페리딘(306mg)과 4-클로로메틸-2-(3,4-디플루오로페닐)피리딘(240mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 얻었다.4- (p-anisidino)-(tert-butoxycarbonyl) piperidine (306 mg) and 4-chloromethyl-2- (3,4-difluorophenyl) pyridine (240 mg) The reaction was carried out in the same manner to obtain the title compound.

수량: 590mg (이론량)Quantity: 590mg (Theoretical quantity)

제조예 221Preparation Example 221

4-[N-[[2-(3,4-디플루오로페닐)피리딘-4-일]메틸]-N-(4-메톡시페닐)아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N-[[2- (3,4-difluorophenyl) pyridin-4-yl] methyl] -N- (4-methoxyphenyl) amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-(4-메톡시페닐)-N-[[2-(3,4-디플루오로페닐)피리딘-4-일]메틸]아미노]피페리딘(590mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 얻었다.1- (tert-butoxycarbonyl) -4- [N- (4-methoxyphenyl) -N-[[2- (3,4-difluorophenyl) pyridin-4-yl] methyl] amino] Piperidine (590 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound.

수량: 483mg (93%)Quantity: 483mg (93%)

제조예 222Preparation Example 222

1-(tert-부톡시카르보닐)-4-[N-[[2-(3,5-디플루오로페닐)피리딘-4-일]메틸]-N-(4-메톡시페닐)아미노]피페리딘의 합성:1- (tert-butoxycarbonyl) -4- [N-[[2- (3,5-difluorophenyl) pyridin-4-yl] methyl] -N- (4-methoxyphenyl) amino] Synthesis of Piperidine:

4-(p-아니시디노)-(tert-부톡시카르보닐)피페리딘(306mg)과 4-클로로메틸-2-(3,5-디플루오로페닐)피리딘(240mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 얻었다.4- (p-anisidino)-(tert-butoxycarbonyl) piperidine (306 mg) and 4-chloromethyl-2- (3,5-difluorophenyl) pyridine (240 mg) The reaction was carried out in the same manner to obtain the title compound.

수량: 530mg (이론량)Quantity: 530mg (Theoretical quantity)

제조예 223Preparation Example 223

4-[N-[[2-(3,5-디플루오로페닐)피리딘-4-일]메틸]-N-(4-메톡시페닐)아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N-[[2- (3,5-difluorophenyl) pyridin-4-yl] methyl] -N- (4-methoxyphenyl) amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-[[2-(3,5-디플루오로페닐)피리딘-4-일]메틸]-N-(4-메톡시페닐)아미노]피페리딘(530mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 얻었다.1- (tert-butoxycarbonyl) -4- [N-[[2- (3,5-difluorophenyl) pyridin-4-yl] methyl] -N- (4-methoxyphenyl) amino] Piperidine (530 mg) was treated in the same manner as in Preparation Example 94 to obtain the title compound.

수량: 418mg (81%)Quantity: 418mg (81%)

제조예 224Preparation Example 224

1-(tert-부톡시카르보닐)-4-[N-[2-(4-클로로페닐)피리딘-4-일]메틸-N-(4-메톡시페닐)아미노]피페리딘의 합성:Synthesis of 1- (tert-butoxycarbonyl) -4- [N- [2- (4-chlorophenyl) pyridin-4-yl] methyl-N- (4-methoxyphenyl) amino] piperidine

4-(p-아니시디노)-(tert-부톡시카르보닐)피페리딘(306mg)과 4-클로로메틸-2-(4-클로로페닐)피리딘(238mg)을 실시예 9와 동일하게 반응시켜 표기 화합물을 얻었다.4- (p-anisidino)-(tert-butoxycarbonyl) piperidine (306 mg) and 4-chloromethyl-2- (4-chlorophenyl) pyridine (238 mg) were reacted in the same manner as in Example 9. The title compound was obtained.

수량: 600mg (이론량)Quantity: 600 mg (theoretical amount)

제조예 225Preparation Example 225

4-[N-[2-(4-클로로페닐)피리딘-4-일]메틸-N-(4-메톡시페닐)아미노]피페리딘·2염산염의 합성:Synthesis of 4- [N- [2- (4-chlorophenyl) pyridin-4-yl] methyl-N- (4-methoxyphenyl) amino] piperidine dihydrochloride:

1-(tert-부톡시카르보닐)-4-[N-[2-(4-클로로페닐)피리딘-4-일]메틸-N-(4-메톡시페닐)아미노]피페리딘(600mg)을 제조예 94와 동일하게 처리하여 표기 화합물을 얻었다.1- (tert-butoxycarbonyl) -4- [N- [2- (4-chlorophenyl) pyridin-4-yl] methyl-N- (4-methoxyphenyl) amino] piperidine (600 mg) Was treated in the same manner as in Preparation Example 94 to obtain the title compound.

수량: 447mg (86%)Quantity: 447mg (86%)

실시예 170 내지 202Examples 170-202

이들의 화합물은 제조예 96, 205, 207, 209, 211,213, 215, 217, 219, 221, 223, 225에서 얻어진 아민 성분과 제조예 3, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203으로 얻어진 클로라이드체를 반응시켜 얻었다. 얻어진 유리 염기는 염산염으로 하였다. 수율과 유리 염기의 NMR 데이터를 이하에 나타낸다.These compounds include the amine component obtained in Production Examples 96, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, and Production Examples 3, 193, 194, 195, 196, 197, 198, 199, It obtained by making the chloride bodies obtained by 200, 201, 202, and 203 react. The obtained free base was made into hydrochloride. The yield and NMR data of the free base are shown below.

제조예 226Preparation Example 226

4-[N-[3-(3,4,5-트리메톡시페닐)벤질]-N-[4-(메틸술포닐)페닐]아미노]피페리딘의 합성:Synthesis of 4- [N- [3- (3,4,5-trimethoxyphenyl) benzyl] -N- [4- (methylsulfonyl) phenyl] amino] piperidine:

4-[N-[3-(3,4,5-트리메톡시페닐)벤질]-N-[4-(메틸티오)페닐]아미노]피페리딘·염산염(52mg, 제조예 145에서 제조)을 디클로로메탄(1㎖)에 용해하고, 0℃에서 3-클로로과벤조산(69mg)을 가했다. 혼합물을 실온으로 되돌리고, 3시간 교반한 후, 포 화 탄산수소나트륨을 가했다. 유기층을 분리한 후, 수층을 다시 클로로포름으로 추출하고, 유기층을 합하고, 포화 식염수로 세정한 후, 무수 황산나트륨으로 건조하고, 감압하 농축했다. 얻어진 담황색 유상물은 정제하지 않고, 다음 스텝에 이용했다.4- [N- [3- (3,4,5-trimethoxyphenyl) benzyl] -N- [4- (methylthio) phenyl] amino] piperidine hydrochloride (52 mg, prepared in Preparation Example 145) Was dissolved in dichloromethane (1 mL), and 3-chloroperbenzoic acid (69 mg) was added at 0 占 폚. The mixture was returned to room temperature, stirred for 3 hours, and then saturated sodium hydrogencarbonate was added. After separating an organic layer, the aqueous layer was extracted with chloroform again, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained pale yellow oily substance was used for the next step without refine | purifying.

실시예 203Example 203

4-[N-[3-(3,4,5-트리메톡시페닐)벤질]-N-[4-(메틸술포닐)페닐]아미노]-1-[2-(3,4,5-트리메톡시페닐)피리딘-4-일]메틸]피페리딘·2염산염의 합성:4- [N- [3- (3,4,5-trimethoxyphenyl) benzyl] -N- [4- (methylsulfonyl) phenyl] amino] -1- [2- (3,4,5- Synthesis of trimethoxyphenyl) pyridin-4-yl] methyl] piperidine dihydrochloride:

제조예 226에서 얻어진 조 4-[N-[3-(3,4,5-트리메톡시페닐)벤질]-N-[4-(메틸술포닐)페닐]아미노]피페리딘과 4-클로로메틸-2-(3,4,5-트리메톡시페닐)피리딘(29mg)을 실시예 2와 동일한 방법으로 반응시켰다. 유리 염기를 2염산염에 변 환시켜 표기 화합물을 담황색 분말로서 얻었다.Crude 4- [N- [3- (3,4,5-trimethoxyphenyl) benzyl] -N- [4- (methylsulfonyl) phenyl] amino] piperidine and 4-chloro obtained in Preparation Example 226. Methyl-2- (3,4,5-trimethoxyphenyl) pyridine (29 mg) was reacted in the same manner as in Example 2. The free base was converted to dihydrochloride to give the title compound as a pale yellow powder.

수량: 23mg (2단계에서 26%)Quantity: 23mg (26% in 2nd stages)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.70-1.97(m, 4H), 2.16-2.28(m, 2H), 2.95-3.04(m, 2H), 2.99(s, 3H), 3.59(s, 2H), 3.82(s, 3H), 3.87-3.97(m, 1H), 3.90(s, 3H), 3.91(s, 3H), 3.92(s, 3H), 3.96(s, 9H), 4.65(s, 2H), 6.59(s, 1H), 6.75(d, 2H, J=9.3Hz), 7.19-7.30(m, 7H), 7.39(dd, 1H, J=7.6Hz, 7.6Hz), 7.60(s, 1H), 7.68(d, 2H, J=9.0Hz), 8.60(d, 1H, J=4.9Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.70-1.97 (m, 4H), 2.16-2.28 (m, 2H), 2.95-3.04 (m, 2H), 2.99 (s, 3H) , 3.59 (s, 2H), 3.82 (s, 3H), 3.87-3.97 (m, 1H), 3.90 (s, 3H), 3.91 (s, 3H), 3.92 (s, 3H), 3.96 (s, 9H ), 4.65 (s, 2H), 6.59 (s, 1H), 6.75 (d, 2H, J = 9.3 Hz), 7.19-7.30 (m, 7H), 7.39 (dd, 1H, J = 7.6 Hz, 7.6 Hz ), 7.60 (s, 1H), 7.68 (d, 2H, J = 9.0 Hz), 8.60 (d, 1H, J = 4.9 Hz)

실시예 204Example 204

4-[N-(4-메톡시페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]-1-[[2-(3-메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (4-methoxyphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] -1-[[2- (3 Synthesis of -methoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

4-[N-(4-메톡시페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘·2염산염(139mg, 제조예 98참조)과 4-클로로메틸-2-(3-메톡시페닐)피리딘(70mg, 제조예 195참조)을 실시예 2와 동일하게 반응시켜 표기 화합물을 3염산염으로서 얻었다.4- [N- (4-methoxyphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride (139 mg, Example 98) and 4-chloromethyl-2- (3-methoxyphenyl) pyridine (70 mg, see Preparation Example 195) were reacted in the same manner as in Example 2 to obtain the title compound as a trihydrochloride salt.

수량: 131mg (66%)Quantity: 131mg (66%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.70-1.95(m, 4H), 2.05-2.25(m, 2H), 2.90-3.08(m, 2H), 3.45-3.68(m, 3H), 3.72(s, 3H), 3.88(s, 3), 3.90(s, 9H), 4.46(s, 2H), 6.70-6.85(m, 4H), 6.96(d, 1H, J=8.3Hz), 7.21(br, 1H), 7.38(t, 1H, J=7.8Hz), 7.55(t, 1H, J=7.8Hz), 7.59(s, 1H), 7.63-7.75(m, 2H), 8.50(s, 1H), 8.62(br, 1H) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.70-1.95 (m, 4H), 2.05-2.25 (m, 2H), 2.90-3.08 (m, 2H), 3.45-3.68 (m, 3H), 3.72 (s, 3H), 3.88 (s, 3), 3.90 (s, 9H), 4.46 (s, 2H), 6.70-6.85 (m, 4H), 6.96 (d, 1H, J = 8.3 Hz ), 7.21 (br, 1H), 7.38 (t, 1H, J = 7.8 Hz), 7.55 (t, 1H, J = 7.8 Hz), 7.59 (s, 1H), 7.63-7.75 (m, 2H), 8.50 (s, 1H), 8.62 (br, 1H)

실시예 205Example 205

4-[N-(4-메톡시페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]아미노]-1-[[2-(3,4-디메톡시페닐)피리딘-4-일]메틸]피페리딘의 합성:4- [N- (4-methoxyphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] amino] -1-[[2- (3,4 Synthesis of -dimethoxyphenyl) pyridin-4-yl] methyl] piperidine:

4-[N-(4-메톡시페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘·2염산염(139mg, 제조예 98참조) 와 4-클로로메틸-2-(3,4-디메톡시페닐)피리딘(80mg, 제조예 197참조)을 실시예 2와 동일하게 반응시켜 표기 화합물을 3염산염으로서 얻었다.4- [N- (4-methoxyphenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride (139 mg, Production Example 98) and 4-chloromethyl-2- (3,4-dimethoxyphenyl) pyridine (80 mg, see Production Example 197) were reacted in the same manner as in Example 2 to obtain the title compound as a trichloride salt.

수량: 139mg (67%)Quantity: 139mg (67%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.70-1.95(m, 4H), 2.05-2.20(m, 2H), 2.90-3.05(m, 2H), 3.45-3.60(m, 3H), 3.73(s, 3H), 3.88(s, 3H), 3.89(s, 6H), 3.94(s, 3H), 4.00(s, 3H), 4.46(s, 2H), 6.65(s, 2H) 6.74-6.82(m, 4H), 6.94(d, 1H, J=8.3Hz), 7.15(br, 1H), 7.52(br, 1H), 7.58-7.71(m, 3H), 8.50(s, 1H), 8.57(d, 1H, J=5.2Hz), 8.62(br, 1H) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.70-1.95 (m, 4H), 2.05-2.20 (m, 2H), 2.90-3.05 (m, 2H), 3.45-3.60 (m, 3H), 3.73 (s, 3H), 3.88 (s, 3H), 3.89 (s, 6H), 3.94 (s, 3H), 4.00 (s, 3H), 4.46 (s, 2H), 6.65 (s, 2H ) 6.74-6.82 (m, 4H), 6.94 (d, 1H, J = 8.3 Hz), 7.15 (br, 1H), 7.52 (br, 1H), 7.58-7.71 (m, 3H), 8.50 (s, 1H ), 8.57 (d, 1H, J = 5.2 Hz), 8.62 (br, 1H)

실시예 206Example 206

4-[N-(4-플루오로페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]-1-[[2-(3-메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (4-fluorophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] -1-[[2- (3 Synthesis of -methoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

4-[N-(4-플루오로페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘·2염산염(135mg, 제조예 183참조)과 4-클로로메틸-2-(3-메톡시페닐)피리딘(70mg, 제조예 195참조)을 실시예 2와 동일하게 반응시켜 표기 화합물을 3염산염으로서 얻었다.4- [N- (4-fluorophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride (135 mg, Production Example 183) and 4-chloromethyl-2- (3-methoxyphenyl) pyridine (70 mg, see Preparation Example 195) were reacted in the same manner as in Example 2 to obtain the title compound as a trichloride salt.

수량: 178mg (92%)Quantity: 178mg (92%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.73-1.95(m, 4H), 2.10-2.25(m, 2H), 2.93-3.05(m, 2H), 3.57(s, 2H), 3.64(br, 1H), 3.88(s, 3H), 3.89(s, 9H), 4.51(s, 2H), 6.66(s, 2H), 6.70-6.76(m, 2H), 6.90(t, 2H,J=8.3Hz), 6.96(d, 1H, J=8.3Hz), 7.21(br, 1H), 7.38(t, 1H, J=8.0Hz), 7.54(d, 1H, J=7.8Hz), 7.58(s, 1H), 7.65(s, 1H), 7.74(br, 1H), 8.50(s, 1H), 8.61(d, 1H, J=5.1Hz), 8.65(br, 1H) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.73-1.95 (m, 4H), 2.10-2.25 (m, 2H), 2.93-3.05 (m, 2H), 3.57 (s, 2H) , 3.64 (br, 1H), 3.88 (s, 3H), 3.89 (s, 9H), 4.51 (s, 2H), 6.66 (s, 2H), 6.70-6.76 (m, 2H), 6.90 (t, 2H , J = 8.3 Hz), 6.96 (d, 1H, J = 8.3 Hz), 7.21 (br, 1H), 7.38 (t, 1H, J = 8.0 Hz), 7.54 (d, 1H, J = 7.8 Hz), 7.58 (s, 1H), 7.65 (s, 1H), 7.74 (br, 1H), 8.50 (s, 1H), 8.61 (d, 1H, J = 5.1 Hz), 8.65 (br, 1H)

실시예 207Example 207

4-[N-(4-플루오로페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]-1-[[2-(3,4-디메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산의 합성:4- [N- (4-fluorophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] -1-[[2- (3 Synthesis of, 4-dimethoxyphenyl) pyridin-4-yl] methyl] piperidinetrihydrochloride:

4-[N-(4-플루오로페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘·2염산염(135mg, 제조예 183참조)과 4-클로로메틸-2-(3,4-디메톡시페닐)피리딘(80mg, 제조예 197참조)을 실시예 2와 동일하게 반응시켜 표기 화합물을 3염산염으로서 얻었다.4- [N- (4-fluorophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride (135 mg, Production Example 183) and 4-chloromethyl-2- (3,4-dimethoxyphenyl) pyridine (80 mg, see Preparation Example 197) were reacted in the same manner as in Example 2 to obtain the title compound as a trichloride salt.

수량: 195mg (96%)Quantity: 195mg (96%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.70-1.95(m, 4H), 2.10-2.24(m, 2H), 2.94-3.09(m, 2H), 3.57(s, 2H), 3.64(br, 1H), 3.88(s, 3H), 3.89(s, 6H), 3.94(s, 3H), 4.00(s, 3H), 4.51(s, 2H), 6.65(s, 2H), 6.69-6.78(m, 2H), 6.86-6.97(m, 3H), 7.16(d, 1H, J=4.9Hz), 7.51(d, 1H, J=8.5Hz), 7.60-7.70(m, 3H), 8.50(s, 1H), 8.58(d, 1H, J=4.9Hz), 8.65(s, 1H) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.70-1.95 (m, 4H), 2.10-2.24 (m, 2H), 2.94-3.09 (m, 2H), 3.57 (s, 2H) , 3.64 (br, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 3.94 (s, 3H), 4.00 (s, 3H), 4.51 (s, 2H), 6.65 (s, 2H), 6.69-6.78 (m, 2H), 6.86-6.97 (m, 3H), 7.16 (d, 1H, J = 4.9 Hz), 7.51 (d, 1H, J = 8.5 Hz), 7.60-7.70 (m, 3H) , 8.50 (s, 1H), 8.58 (d, 1H, J = 4.9 Hz), 8.65 (s, 1H)

실시예 208Example 208

4-[N-(3,4-디플루오로페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]-1-[[2-(3-메톡시페닐)피리딘-4-일]메틸]피페리딘·3염산염의 합성:4- [N- (3,4-difluorophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] -1-[[2 Synthesis of-(3-methoxyphenyl) pyridin-4-yl] methyl] piperidinetrichloride:

4-[N-(3,4-디플루오로페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘·2염산염(160mg, 제조예 176참조)과 4-클로로메틸-2-(3-메톡시페닐)피리딘(80mg, 제조예 195참조)을 실시예 2와 동일하게 반응시켜 표기 화합물을 3염산염으로서 얻었다.4- [N- (3,4-difluorophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride (160 mg, see Preparation Example 176) and 4-chloromethyl-2- (3-methoxyphenyl) pyridine (80 mg, see Preparation Example 195) were reacted in the same manner as in Example 2 to obtain the title compound as a trichloride salt.

수량: 130mg (57%)Quantity: 130mg (57%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃) δ: 1.73-1.90(m, 4H), 2.01-2.24(m, 2H), 2.92-3.05(m, 2H), 3.57(s, 2H), 3.67(br, 1H), 3.88(s, 3H), 3.89(s, 3H), 3.90(s, 6H), 4.52(s, 2H), 6.36-6.42(m, 1H), 6.50-6.58(m, 1H), 6.67(s, 2H), 6.93- 7.01(m, 2H), 7.20(br, 1H), 7.38(t, 1H, J=7.8Hz), 7.52-7.62(m, 2H), 7.62-7.72(m, 2H), 8.48(br, 1H), 8.61(br, 1H), 8.66(d, 1H, J=2.0Hz) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ) δ: 1.73-1.90 (m, 4H), 2.01-2.24 (m, 2H), 2.92-3.05 (m, 2H), 3.57 (s, 2H) , 3.67 (br, 1H), 3.88 (s, 3H), 3.89 (s, 3H), 3.90 (s, 6H), 4.52 (s, 2H), 6.36-6.42 (m, 1H), 6.50-6.58 (m , 1H), 6.67 (s, 2H), 6.93- 7.01 (m, 2H), 7.20 (br, 1H), 7.38 (t, 1H, J = 7.8Hz), 7.52-7.62 (m, 2H), 7.62- 7.72 (m, 2H), 8.48 (br, 1H), 8.61 (br, 1H), 8.66 (d, 1H, J = 2.0 Hz)

실시예 209Example 209

4-[N-(4-메틸티오페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]-1-[[2-(3-메톡시페닐)피리딘-4-일]메틸]피페리딘의 합성:4- [N- (4-methylthiophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] -1-[[2- (3 Synthesis of -methoxyphenyl) pyridin-4-yl] methyl] piperidine:

4-[N-(4-메틸티오페닐)-N-[[3-(3,4,5-트리메톡시페닐)피리딘-5-일]메틸]아미노]피페리딘·2염산염(121mg, 제조예 143참조)과 4-클로로메틸-2-(3-메톡시페닐)피리딘(55mg, 제조예 195참조)을 실시예 2와 동일하게 반응시켜 표기 화합물을 얻었다.4- [N- (4-methylthiophenyl) -N-[[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride (121 mg, Preparation Example 143) and 4-chloromethyl-2- (3-methoxyphenyl) pyridine (55 mg, see Preparation Example 195) were reacted in the same manner as in Example 2 to obtain the title compound.

수량: 71mg (44%)Quantity: 71mg (44%)

¹H-NMR(400MHz, 유리 염기로서 측정, CDC1₃): 1.72-1.83(m, 4H), 2.12-2.20(m, 2H), 2.37(s, 3H), 2.97(d, 2H, J=10.8Hz), 3.56(s, 2H), 3.75-3.81(m, 1H), 3.86(s, 3H), 3.87(s, 6H), 4.54(s, 2H), 6.64-6.69(m, 3H), 6.94(dd, 1H, J=7.8Hz, 1.9Hz), 7.17-7.26(m, 4H), 7.35(t, 1H, J=7.8Hz), 7.51-7.66(m, 4H), 8.47(s, 1H), 8.59(d, 1H, J=4.6Hz), 8.63(s, 1H) ¹ H-NMR (400 MHz, measured as free base, CDC1 ₃ ): 1.72-1.83 (m, 4H), 2.12-2.20 (m, 2H), 2.37 (s, 3H), 2.97 (d, 2H, J = 10.8 Hz), 3.56 (s, 2H), 3.75-3.81 (m, 1H), 3.86 (s, 3H), 3.87 (s, 6H), 4.54 (s, 2H), 6.64-6.69 (m, 3H), 6.94 (dd, 1H, J = 7.8Hz, 1.9Hz), 7.17-7.26 (m, 4H), 7.35 (t, 1H, J = 7.8Hz), 7.51-7.66 (m, 4H), 8.47 (s, 1H) , 8.59 (d, 1H, J = 4.6 Hz), 8.63 (s, 1H)

시험예 1Test Example 1

(세포 접착 저해작용)(Cell adhesion inhibitory effect)

로스(Ross) 등의 방법(J. Biol. Chem., 267, 8537-8543 (1992))을 참고로 하여 행했다. 즉, 사람 제대정맥 유래 혈관내피 세포(HUVEC)를 48웰 플레이트로 콘플루언트가 될 때까지 배양 후, TNFα를 첨가했다. 첨가 5시간 후에 PKH2(Sigma-Aldrich제)로 형광 표지한 사람 단구/조직구 유래 세포인 U937을 각 웰에 1×10⁶세포 첨가했다. 실온에서 1시간 정치하고, 접착되어 있지 않은 U937을 세정하여 흘린 후, 1% Triton X-100에 세포를 용해하고, 잔존하는 형광 강도를 측정하였다(여기 파장 485nm, 측정 파장 530nm). HUVEC은 EGM-2(Sanko Junyaku K. K.)에서, 또한, U937은 10% FCS 함유 RPMI 1640에서 배양했다. 시험 화합물의 첨가는 HUVEC으로는 TNFα첨가시에, U937로는 세포접착 시험의 24시간 전에 행했다. 저해활성은 A=(시험화합물 무첨가에서 TNFα 자극한 HUVEC으로의 U937의 접착 세포수), B=(시험화합물 무첨가에서 TNFα 무자극의 HUVEC으로의 U937의 접착 세포수), C=(시험화합물 첨가에서 TNFα 자극한 HUVEC으로의 U937의 접착 세포수)일 때, [(A-C) /(A-B) × 100(%)]으로서 산정했다. 이 결과를 표 1에 나타낸다. 대조 화합물로서 일본국 특개평 9-143075호 공보의 시험 화합물 1 및 일본국 특개평 11-92382호 공보의 딜라젭(dilazep)을 동시에 평가했다.Ross et al. (J. Biol. Chem., 267, 8537-8543 (1992)). That is, TNFα was added after culturing until human umbilical vein-derived vascular endothelial cells (HUVEC) became confluent in 48-well plates. Five hours after the addition, U937, a human monocyte / tissue sphere-derived cell fluorescently labeled with PKH2 (manufactured by Sigma-Aldrich), was added to each well 1 × 10 ⁶ cells. After standing at room temperature for 1 hour and washing and flowing U937 which was not adhered, the cells were dissolved in 1% Triton X-100, and the remaining fluorescence intensity was measured (excitation wavelength 485 nm, measurement wavelength 530 nm). HUVECs were incubated in EGM-2 (Sanko Junyaku KK) and U937 in RPMI 1640 with 10% FCS. The test compound was added at the time of TNFα addition by HUVEC and 24 hours before the cell adhesion test by U937. Inhibitory activity was A = (the number of U937 adherent cells to TNFα-stimulated HUVEC without test compound), B = (the number of U937 adherent cells to HUVEC without TNFα stimulated without test compound), C = (added test compound The number of U937 adherent cells in TNFα-stimulated HUVEC) was calculated as [(AC) / (AB) × 100 (%)]. The results are shown in Table 1. As a control compound, test compound 1 of Japanese Patent Laid-Open No. 9-143075 and dilazep of Japanese Patent Laid-Open No. 11-92382 were simultaneously evaluated.

표 1Table 1

실시예Example IC₅₀(μM)IC ₅₀ (μM) 33 0.30.3 55 0.20.2 77 0.30.3 1010 0.040.04 1313 0.030.03 1616 0.30.3 1919 0.30.3 2323 0.030.03 2929 0.030.03 3636 0.20.2 4040 0.20.2 4242 0.070.07 6767 0.090.09 8888 0.070.07 8989 0.090.09 111111 0.080.08 157157 0.090.09 시험 화합물 1Test compound 1 1010 딜라젭Dilatus >10> 10

상기에 나타난 바와 같이, 본 발명의 화합물은 분자의 양단에, 각각, 페닐-피리딜기, 또는 비페닐기를 가지는 환상 아민 화합물인 것을 특징으로 하고 있다.As indicated above, the compound of the present invention is characterized by being a cyclic amine compound having a phenyl-pyridyl group or a biphenyl group at both ends of the molecule.

제조예 91에서 얻어진 분자의 양단에 피리딜기를 가지는 환상 아민 화합물의 세포 접착 저해작용을 상기와 동일하게 측정했다. 그 결과, 이 화합물은 10μM의 고농도에서도 세포 접착 저해작용을 나타내지 않았다.The cell adhesion inhibitory effect of the cyclic amine compound having a pyridyl group at both ends of the molecule obtained in Production Example 91 was measured in the same manner as above. As a result, the compound did not show cell adhesion inhibition even at a high concentration of 10 μM.

이하에 구체적인 제제예를 나타낸다.Specific formulation examples are shown below.

제제예 1(캅셀제)Formulation example 1 (product made in capsule)

실시예 13의 화합물30mgCompound 30 of Example 13

미결정 셀루로오즈 30mgMicrocrystalline Cellulose 30mg

락토오즈 57mgLactose 57mg

스테아린산마그네슘 3mgMagnesium Stearate 3mg

전량 120mg120 mg

상기 성분을 통상의 방법에 의해 혼합한 후, 젤라틴 캅셀에 충전하여 캅셀제를 얻었다.After mixing the said component by a conventional method, it filled into gelatin capsule and obtained the capsule agent.

제제예 2 (정제)Formulation Example 2 (Tablet)

실시예 13의 화합물30mgCompound 30 of Example 13

전분 44mgStarch 44mg

전분(김용) 5.6mgStarch (for seaweed) 5.6mg

스테아린산마그네슘 0.4mgMagnesium Stearate 0.4mg

카르복시메틸셀루로오즈 칼슘 20mgCarboxymethyl Cellulose Calcium 20mg

전량 100mg100 mg total

상기 성분을 통상의 방법에 의해 혼합하여 정제를 얻었다.The above components were mixed by a conventional method to obtain a tablet.

제제예 3(주사제)Formulation Example 3 (Injectable)

실시예 13의 화합물(100mg) 및 염화나트륨(900mg)을 약 80㎖의 주사용 증류수에 용해하고, 이어서, 얻어진 용액에 주사용 증류수를 가하여 총량 100㎖로 하였다. 이것을 무균 여과한 후, 앰플 10개에 분주하고, 씰링하여 무균의 주사제를 얻었다.The compound of Example 13 (100 mg) and sodium chloride (900 mg) were dissolved in about 80 mL of distilled water for injection, and then distilled water for injection was added to the obtained solution to obtain a total amount of 100 mL. After sterile filtration of this, 10 ampoules were dispensed and sealed to obtain a sterile injection.

본 발명 화합물(1)은 우수한 세포 접착 저해작용 및 세포 침윤 저해작용을 가지며, 알레르기, 서식, 류머티즘, 동맥경화증, 염증, 쉐그렌 증후군 등의 예방 또는 치료용 의약으로서 유용하다.The compound (1) of the present invention has excellent cell adhesion inhibitory effect and cell invasion inhibitory effect, and is useful as a medicament for preventing or treating allergy, habitat, rheumatism, arteriosclerosis, inflammation, and Sjogren's syndrome.

Claims (17)

일반식(1)General formula (1) 〔식중, R¹, R²및 R³는 각각 독립하여 수소원자, 할로겐원자, 히드록시기, 알킬기, 할로겐 치환 알킬기, 알콕시기, 알킬티오기, 카르복실기, 알콕시카르보닐기 또는 알카노일기를 나타내고;[Wherein, R ¹ , R ² and R ³ each independently represent a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group, a halogen substituted alkyl group, an alkoxy group, an alkylthio group, a carboxyl group, an alkoxycarbonyl group or an alkanoyl group; W¹및 W²는 각각 독립하여 N, 또는 CH를 나타내고;W ¹ and W ² each independently represent N or CH; X는 O, NR⁴, CONR⁴또는 NR⁴CO를 나타내고;X represents O, NR ⁴ , CONR ⁴ or NR ⁴ CO; R⁴는 수소원자, 알킬기, 알케닐기, 알키닐기, 치환 또는 무치환 아릴기, 치환 또는 무치환 헤테로아릴기, 치환 또는 무치환 아랄킬기, 또는 치환 또는 무치환 헤테로아랄킬기를 나타내고;R ⁴ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted heteroaralkyl group; l, m 및 n은 각각 0 또는 1의 수를 나타낸다]l, m and n each represent a number of 0 or 1] 로 표시되는 환상 아민 화합물, 그의 염 또는 이들의 용매화물.Cyclic amine compounds, salts thereof, or solvates thereof. 제 1항에 있어서, R¹, R²및 R³가 각각 독립하여, 수소원자, 할로겐원자, 히드록시기, C₁-C₈-알킬기, 할로겐 치환 C₁-C₈-알킬기, C₁-C₈-알콕시기, C₁-C₈-알킬티오기, 카르복실기, C₁-C₆-알콕시카르보닐기 또는 C₁-C₆-알카노일기인 화합물.The method of claim 1, wherein, R ^1, R ² and R ³ are each independently a hydrogen atom, a halogen atom, a hydroxy group, C ₁ -C ₈ - alkyl group, halogen-substituted C ₁ -C ₈ - alkyl, C ₁ -C ₈ A compound which is a -alkoxy group, a C ₁ -C ₈ -alkylthio group, a carboxyl group, a C ₁ -C ₆ -alkoxycarbonyl group or a C ₁ -C ₆ -alkanoyl group. 제 1항 또는 제 2항에 있어서, R⁴가, 수소원자, C₁-C₈-알킬기, C₃-C₈-알케닐기, C₃-C₈-알키닐기, 치환 또는 무치환 C₆-C₁₄-아릴기, 치환 또는 무치환이어 질소 원자를 1∼4개 함유하는 5 또는 6원환으로 이루어진 헤테로아릴기, 치환 또는 무치환 C₆-C₁₄-아릴-C₁-C₆-알킬기, 또는 치환 또는 무치환이며 질소 원자를 1∼4개 함유하는 5 또는 6원환으로 이루어진 헤테로아릴-C₁-C₆-알킬기인 화합물.The compound according to claim 1 or 2, wherein R ⁴ is a hydrogen atom, a C ₁ -C ₈ -alkyl group, a C ₃ -C ₈ -alkenyl group, a C ₃ -C ₈ -alkynyl group, a substituted or unsubstituted C _6- A C ₁₄ -aryl group, a substituted or unsubstituted heteroaryl group consisting of a 5 or 6 membered ring containing 1 to 4 nitrogen atoms, a substituted or unsubstituted C ₆ -C ₁₄ -aryl-C ₁ -C ₆ -alkyl group, Or a substituted or unsubstituted heteroaryl-C ₁ -C ₆ -alkyl group consisting of a 5 or 6 membered ring containing 1 to 4 nitrogen atoms. 제 1항 내지 제 3항의 어느 1항에 있어서, R⁴에 있어서의 아릴기, 아랄킬기, 헤테로아릴기 또는 헤테로아랄킬기의 치환기가 알킬기, 알콕시기, 할로겐 치환 알콕시기, 알킬티오기, 알킬술피닐기, 알킬술포닐기, 할로겐원자, 니트로기, 아미노기, 아세틸아미노기, 트리플루오로메틸기 및 알킬렌디옥시기로부터 선택되는 1∼3개의 기 또는 원자인 화합물.The substituent of an aryl group, aralkyl group, heteroaryl group or heteroaralkyl group in R ⁴ is an alkyl group, an alkoxy group, a halogen-substituted alkoxy group, an alkylthio group or an alkylsulfide according to any one of claims 1 to 3. A compound which is 1 to 3 groups or atoms selected from a silyl group, an alkylsulfonyl group, a halogen atom, a nitro group, an amino group, an acetylamino group, a trifluoromethyl group and an alkylenedioxy group. 제 1항 내지 제 4항의 어느 1항에 있어서, X 가 NR⁴이고, R⁴가 치환 또는 무치환C₆-C₁₄-아릴기 또는 치환 또는 무치환이며 질소 원자를 1∼4개 함유하는 5 또는 6원환으로 이루어진 헤테로아릴기인 화합물.5. A compound according to any one of claims 1 to 4, wherein X is NR ⁴ , R ⁴ is a substituted or unsubstituted C ₆ -C ₁₄ -aryl group or a substituted or unsubstituted 5 containing 1 to 4 nitrogen atoms. Or a heteroaryl group consisting of a 6-membered ring. 제 1항 내지 제 5항의 어느 1항에 있어서, W²가 N인 화합물.The compound of any one of claims 1-5, wherein W ² is N. 7. 제 1항 내지 제 6항의 어느 1항 기재의 화합물을 유효 성분으로 함유하는 의약.A pharmaceutical comprising the compound according to any one of claims 1 to 6 as an active ingredient. 제 7항에 있어서, 세포 접착 및/또는 세포 침윤에 기인하는 질환의 치료약인 의약.The medicament according to claim 7, which is a drug for treating a disease caused by cell adhesion and / or cell infiltration. 제 8항에 있어서, 질환이 알레르기, 천식, 염증, 류머티즘, 동맥경화 및 쉐그렌 증후군으로부터 선택되는 질환인 의약.The medicament according to claim 8, wherein the disease is a disease selected from allergy, asthma, inflammation, rheumatism, arteriosclerosis and Sjogren's syndrome. 제 1항 내지 제 6항의 어느 1항 기재의 화합물 및 약학적으로 허용되는 담체를 함유하는 의약 조성물.A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier. 제 10항에 있어서, 세포 접착 및/또는 세포 침윤에 기인하는 질환의 치료용 의약 조성물인 의약.The pharmaceutical according to claim 10, which is a pharmaceutical composition for treating a disease caused by cell adhesion and / or cell infiltration. 제 11항에 있어서, 질환이 알레르기, 천식, 염증, 류머티즘, 동맥경화 및 쉐그렌 증후군으로부터 선택되는 질환인 의약 조성물.The pharmaceutical composition according to claim 11, wherein the disease is a disease selected from allergy, asthma, inflammation, rheumatism, arteriosclerosis and Sjogren's syndrome. 제 1항 내지 제 6항의 어느 1항 기재의 화합물의 의약 제조를 위한 사용.Use for the pharmaceutical preparation of a compound according to any one of claims 1 to 6. 제 13항에 있어서, 의약이 세포 접착제 및/또는 세포 침윤에 기인하는 질환의 치료약으로의 사용.The use according to claim 13, wherein the medicament is for treating a disease resulting from cell adhesive and / or cell infiltration. 제 14항에 있어서, 질환이 알레르기, 천식, 염증, 류머티즘, 동맥경화 및, 쉐그렌 증후군으로부터 선택되는 질환으로의 사용.The use according to claim 14, wherein the disease is selected from allergy, asthma, inflammation, rheumatism, arteriosclerosis, and Sjogren's syndrome. 제 1항 내지 제 6항의 어느 1항 기재의 화합물의 유효량을 투여하는 것을 특징으로 하는 세포 접착 및/또는 세포 침윤에 기인하는 질환의 처치방법.A method for treating a disease caused by cell adhesion and / or cell infiltration, comprising administering an effective amount of the compound of any one of claims 1 to 6. 제 16항에 있어서, 질환이 알레르기, 천식, 염증, 류머티즘, 동맥경화 및 쉐그렌 증후군으로부터 선택되는 질환의 처치 방법.17. The method of claim 16, wherein the disease is selected from allergy, asthma, inflammation, rheumatism, arteriosclerosis, and Sjogren's syndrome.