KR20050016991A - Mchir antagonists - Google Patents

Mchir antagonists

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Publication number
KR20050016991A
KR20050016991A KR10-2005-7000232A KR20057000232A KR20050016991A KR 20050016991 A KR20050016991 A KR 20050016991A KR 20057000232 A KR20057000232 A KR 20057000232A KR 20050016991 A KR20050016991 A KR 20050016991A
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South Korea
Prior art keywords
quinolinyl
propanediamine
methyl
compound
methoxy
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KR10-2005-7000232A
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Korean (ko)
Inventor
아심쿠마르 레이
엠마마르가레타 시그프리그슨
안나스티나마리아 리누슨
페르닐라마리에 산드베르그
토르드 인가르츠
아네트마리에 스벤슨
케이 브릭크만
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아스트라제네카 아베
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Priority to KR10-2005-7000232A priority Critical patent/KR20050016991A/en
Publication of KR20050016991A publication Critical patent/KR20050016991A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms

Abstract

본 발명은 하기 화학식 (I)의 화합물, 이의 광학 이성질체 및 라세미산염, 및 이의 약학적으로 허용가능한 염을 제공하며, 하기 화학식에서, R1은 1개 이상의 플루오로로 임의 치환된 C1-4알콕시기 또는 1개 이상의 플루오로로 임의 치환된 C1-4알킬기를 나타내고; n은 0 또는 1을 나타내며; R2는 1개 이상의 플루오로로 임의 치환된 C1-4알킬기 또는 1개 이상의 플루오로로 임의 치환된 C1-4알콕시기를 나타내고; m은 0 또는 1을 나타내며; R3은 H 또는 Cl-4알킬기를 나타내고; L1은 알킬렌 사슬 (CH2)r을 나타내거나(여기서, r은 2 또는 3을 나타냄), 또는 L1은 시클로헥실기를 나타내거나(여기서, R3과 R4를 각각 갖는 2개의 질소는 시클로헥실기의 1,3 또는 1,4 위치를 통해 시클로헥실기에 연결됨), 또는 L1은 시클로펜틸기를 나타내며(여기서, R3과 R4를 각각 갖는 2개의 질소는 시클로펜틸기의 1,3 위치를 통해 시클로펜틸기에 연결됨), 부가적으로 R5가 9,10-메타노안트라센-9(10H)-일을 나타낼 때, 기 -L1-N(R4)-는 함께 피페리디닐 질소를 통해 L2에, 피페리딜 고리의 4 위치를 통해 N-R3에 연결된 피페리딜 고리를 나타내고, 단, R5가 9,10-메타노안트라센-9(10H)-일을 나타낼 때, r은 단지 2이며; R4는 H 또는 1개 이상의 아릴기 또는 헤테로아릴기로 임의 치환된 C1-4알킬기를 나타내고: L2는 결합 또는 알킬렌 사슬 (CH2) s를 나타내며(여기서, s는 1, 2 또는 3을 나타내고, 알킬렌 사슬은 1개 이상의 C1-4알킬기, 페닐 또는 헤테로아릴로 임의 치환됨); R5는 페닐 또는 헤테로아릴기에 임의 융합된 아릴, 헤테로시클릭기 또는 C3-8시클로알킬기를 나타낸다. 또한, 본 발명은 이러한 화합물의 제조 방법; 비만, 정신 장애, 인식 장애, 기억 장애, 정신분열증, 간질, 및 관련 질병, 및 신경 장애, 예컨대, 치매, 다발성 경화증, 파키슨씨병, 헝틴턴 무도병 및 알츠하이머병 및 통증 관련 장애의 치료시 이의 용도; 및 이를 함유하는 약학 조성물을 제공한다.The present invention provides a compound of formula (I), its optical isomers and racemates, and pharmaceutically acceptable salts thereof, wherein R 1 is C 1- optionally substituted with one or more fluoro. A C 1-4 alkyl group optionally substituted with 4 alkoxy groups or one or more fluoro; n represents 0 or 1; R 2 represents a C 1-4 alkyl group optionally substituted with one or more fluoro or a C 1-4 alkoxy group optionally substituted with one or more fluoro; m represents 0 or 1; R 3 represents H or C 1-4 alkyl group; L 1 represents an alkylene chain (CH 2 ) r (where r represents 2 or 3), or L 1 represents a cyclohexyl group (wherein R 3 and R 4 each have two nitrogens) Is connected to the cyclohexyl group via the 1,3 or 1,4 position of the cyclohexyl group, or L 1 represents a cyclopentyl group (wherein two nitrogens each having R 3 and R 4 are 1 of the cyclopentyl group). Connected to the cyclopentyl group via position 3), additionally when R 5 represents 9,10-methanoanthracene-9 (10H) -yl, the groups -L 1 -N (R 4 )-together piperidi A piperidyl ring linked to L 2 through niyl nitrogen and to NR 3 via the 4 position of the piperidyl ring, provided that R 5 represents 9,10-methanoanthracene-9 (10H) -yl , r is only 2; R 4 represents H or a C 1-4 alkyl group optionally substituted with one or more aryl groups or heteroaryl groups: L 2 represents a bond or an alkylene chain (CH 2 ) s where s is 1, 2 or 3 Wherein the alkylene chain is optionally substituted with one or more C 1-4 alkyl groups, phenyl or heteroaryl; R 5 represents an aryl, heterocyclic group or C 3-8 cycloalkyl group optionally fused to a phenyl or heteroaryl group. In addition, the present invention provides a method for preparing such a compound; Its use in the treatment of obesity, mental disorders, cognitive disorders, memory disorders, schizophrenia, epilepsy, and related diseases, and neurological disorders such as dementia, multiple sclerosis, Parkinson's disease, Hentin's chorea and Alzheimer's disease and pain related disorder ; And pharmaceutical compositions containing the same.

Description

ＭＣＨＩＲ 길항제{MCHIR ANTAGONISTS}MHCHI AN antagonist {MCHIR ANTAGONISTS}

본 발명은 화학식 (I)의 어떠한 N-시클로알킬, 아릴 또는 헤테로아릴 N'-퀴놀린-2-일 알킬디아민; 이러한 화합물의 제조 방법; 비만, 정신 장애 및 신경 장애의 치료시 이의 용도; 및 이를 함유하는 약학 조성물에 관한 것이다. The present invention relates to any N-cycloalkyl, aryl or heteroaryl N'-quinolin-2-yl alkyldiamine of formula (I); Methods of making such compounds; Its use in the treatment of obesity, mental disorders and neurological disorders; And pharmaceutical compositions containing the same.

멜라닌 농축 호르몬(MCH)은 15년 전에 어류에서 최초로 분리된 고리형 펩티드이다. 포유동물에서, MCH 유전자 발현은 불확정 구역(zona inserta)과 외측 시상하부 영역(lateral hypothalamic area)의 복면에 위치한다(Breton 등, Molecular and Cellular Neurosciences, Vol.4, 271-284 (1993)). 뇌의 후반부는 먹고 마시는 것과 같은 행동, 각성 및 운동성과 연관된다(Baker, B., Trends Endocrinol. Metab. 5: 120-126 (1994), Vol.5, No.3, 120-126 (1994)). 포유동물에서의 생물학적 활성이 완전히 밝혀지지는 않았지만, 최근의 연구는 MCH가 식욕 및 체중 증가를 촉진함을 밝혔다(US 5,849,708). 따라서, MCH 및 이의 작동제는 AIDS, 신장 질환, 또는 화학요법으로 인한 신경성 무식욕증 및 체중 감소를 위한 치료제로 제안되어 왔다. 유사하게, MCH의 길항제는 비만 및 강박성 식욕 및 과다 체중으로 특징지워지는 기타 질병의 치료제로 사용될 수 있다. MCH 투사는 위해감지(nociception) 과정에 중요한 영역인 척수를 포함한 뇌를 통해 발견되며,이는 화학식 (I)의 화합물과 같이, MCH1r을 통해 작용하는 작용제가 통증의 치료에 유용할 것임을 나타낸다. Melanin enrichment hormone (MCH) is the first cyclic peptide isolated from fish 15 years ago. In mammals, MCH gene expression is located in the masking of the zona inserta and the lateral hypothalamic area (Breton et al., Molecular and Cellular Neurosciences, Vol. 4, 271-284 (1993)). The second half of the brain is associated with behaviors, arousal and motility such as eating and drinking (Baker, B., Trends Endocrinol. Metab. 5: 120-126 (1994), Vol. 5, No. 3, 120-126 (1994) ). Although the biological activity in mammals is not fully understood, recent studies have shown that MCH promotes appetite and weight gain (US 5,849,708). Thus, MCH and its agonists have been proposed as therapeutics for AIDS, kidney disease, or anorexia nervosa and weight loss due to chemotherapy. Similarly, antagonists of MCH can be used to treat obesity and other diseases characterized by obsessive compulsive appetite and overweight. MCH projection is found throughout the brain, including the spinal cord, which is an important area for the process of nociception, indicating that agents acting through MCH1r, such as compounds of formula (I), will be useful in the treatment of pain.

MCH의 2개의 수용체(MCH1r(Shimomura 등, Biochem Biophys Res Commun 1999 Aug 11; 261(3): 622-6) 및 MCH2r(Hilol 등, J Biol Chem 2001 Jun 8; 276(23): 20125-9))가 인간에서 확인되었으며, 설치류에서는 단지 하나의 수용체(MCH1r)만이 존재한다(Tan 등, Genomics. 2002 Jun; 79(6): 785-92). MCH1r가 결여된 마우스는 MCH에 대한 급식 반응이 증가되지 않고 결핍된(lean) 표현형을 나타내는데, 이는 이 수용체가 MCH의 급식 효과를 매개함을 나타내준다(Marsh 등, Proc Natl Acad Sci USA. 2002 Mar 5; 99(5): 3240-5). 덧붙여, MCH 수용체 길항제는 MCH의 급식 효과를 차단함이 밝혀졌으며(Takekawa 등, Eur J Pharmacol. 2002 Mar 8; 438(3): 129-35), 식이적으로 유도된 살찐 랫트에서 체중과 지방과다증을 감소시킴이 밝혀졌다(Borowsky 등, Nat Med. 2002 Aug; 8(8): 825-30). MCHlr의 분포와 서열이 보존된다는 사실은 이 수용체가 인간과 설치류에서 유사한 기능을 하리라는 것을 제안해 준다. 그러므로, MCH 수용체 길항제는 비만 및 과다 식욕과 과다 체중으로 특징지워지는 기타 장애의 치료제로서 제안되었다. Two receptors of MCH (MCH1r (Shimomura et al., Biochem Biophys Res Commun 1999 Aug 11; 261 (3): 622-6)) and MCH2r (Hilol et al., J Biol Chem 2001 Jun 8; 276 (23): 20125-9) ) Has been identified in humans and there is only one receptor (MCH1r) in rodents (Tan et al., Genomics. 2002 Jun; 79 (6): 785-92). Mice lacking MCH1r show a lean phenotype without increased feeding response to MCH, indicating that this receptor mediates the feeding effect of MCH (Marsh et al., Proc Natl Acad Sci USA. 2002 Mar 5; 99 (5): 3240-5). In addition, MCH receptor antagonists have been shown to block the feeding effects of MCH (Takekawa et al., Eur J Pharmacol. 2002 Mar 8; 438 (3): 129-35), and weight and hyperlipidemia in dietary induced fat rats. (Borowsky et al., Nat Med. 2002 Aug; 8 (8): 825-30). The fact that the distribution and sequence of MCHlr is preserved suggests that this receptor will function similarly in humans and rodents. Therefore, MCH receptor antagonists have been proposed as treatments for obesity and other disorders characterized by excessive appetite and overweight.

US 3,020,283은 어떠한 N,N'-비스 레피드-2-일 1,x-디아미노 C1-x 알칸(여기서, x는 2 내지 12의 정수임), 및 N,N'-비스 레피드-2-일디아미노시클로알칸이 구충제로 유용함을 공개한다.US 3,020,283 discloses any N, N'-bis rapid-2-yl 1, x-diamino C 1-x alkanes, where x is an integer from 2 to 12, and N, N'-bis rapid-2 -Ildiaminocycloalkanes are disclosed to be useful as repellents.

US 5,093,333은 콜린성계의 기능저하의 치료에 유용하여, 콜린성계를 포함하는 치매의 치료에 유용한 어떠한 N-치환된 (시클릭아미노알킬) 2-아미노퀴놀린을 공개한다.US 5,093,333 discloses any N-substituted (cyclicaminoalkyl) 2-aminoquinolines useful for the treatment of hypofunction of the cholinergic system, which is useful for the treatment of dementia including the cholinergic system.

US 4,203,988은 위분비 치료에 유용한 어떠한 피리디닐 및 퀴놀린일 우레아를 공개한다.US 4,203,988 discloses any pyridinyl and quinolinyl ureas useful for gastric secretion treatment.

W099/55677은 항세균제로 유용한 2-(아미노알킬아미노)퀴놀린-4-온을 공개한다.WO99 / 55677 discloses 2- (aminoalkylamino) quinolin-4-ones useful as antibacterial agents.

W002/58702는 과다 또는 비정상 혈관 수축 및 심근 장애로 특징지워지는 심장혈관 질환; 및 CNS의 질환, 예컨대, 중독, 정신분열증, 불안 및 우울증 및 대사 질환, 예컨대, 당뇨의 치료에 유용하다고 주장된 우로텐신 II의 길항제인 치환된 2-(아미노알킬 아미노)퀴놀린을 공개한다.W002 / 58702 is a cardiovascular disease characterized by excessive or abnormal vasoconstriction and myocardial disorders; And substituted 2- (aminoalkyl amino) quinolines, which are antagonists of urotensin II claimed to be useful in the treatment of diseases of the CNS such as addiction, schizophrenia, anxiety and depression and metabolic diseases such as diabetes.

본 발명은 비만 및 관련 장애, 정신 장애, 신경 장애 및 통증의 치료에 유용한 MCH1r 길항제인 화합물을 제공한다. The present invention provides compounds that are MCH1r antagonists useful for the treatment of obesity and related disorders, mental disorders, neurological disorders and pain.

본 발명은 하기 화학식 (I)의 화합물, 이의 광학 이성질체 및 라세미산염, 및 이의 약학적으로 허용가능한 염에 관한 것으로서:The present invention relates to compounds of formula (I), optical isomers and racemates thereof, and pharmaceutically acceptable salts thereof:

상기 화학식에서, In the above formula,

R1은 1개 이상의 플루오로로 임의 치환된 C1-4알콕시기 또는 1개 이상의 플루오로로 임의 치환된 C1-4알킬기를 나타내고;R 1 represents an optionally substituted C 1-4 alkyl group optionally substituted by a C 1-4 alkoxy group or one or more fluoro with one or more fluoro;

n은 0 또는 1을 나타내며; n represents 0 or 1;

R2는 1개 이상의 플루오로로 임의 치환된 C1-4알킬기 또는 1개 이상의 플루오로로 임의 치환된 C1-4알콕시기를 나타내고;R 2 represents a C 1-4 alkyl group optionally substituted with one or more fluoro or a C 1-4 alkoxy group optionally substituted with one or more fluoro;

m은 0 또는 1을 나타내며; m represents 0 or 1;

R3은 H 또는 C1-4알킬기를 나타내고;R 3 represents H or a C 1-4 alkyl group;

L1은 알킬렌 사슬 (CH2)r을 나타내거나(여기서, r은 2 또는 3을 나타냄), 또는 L1은 시클로헥실기를 나타내거나(여기서, R3과 R4를 각각 갖는 2개의 질소는 시클로헥실기의 1,3 또는 1,4 위치를 통해 시클로헥실기에 연결됨), 또는 L1은 시클로펜틸기를 나타내며(여기서, R3과 R4를 각각 갖는 2개의 질소는 시클로펜틸기의 1,3 위치를 통해 시클로펜틸기에 연결됨), 부가적으로 R5가 9,10-메타노안트라센-9(10H)-일을 나타낼 때, 기 -L1-N(R4)-는 함께 피페리디닐 질소를 통해 L2에, 피페리딜 고리의 4 위치를 통해 N-R3에 연결된 피페리딜 고리를 나타내고, 단, R5가 9,10-메타노안트라센-9(10H)-일을 나타낼 때, r은 단지 2이며;L 1 represents an alkylene chain (CH 2 ) r (where r represents 2 or 3), or L 1 represents a cyclohexyl group (wherein R 3 and R 4 each have two nitrogens) Is connected to the cyclohexyl group via the 1,3 or 1,4 position of the cyclohexyl group, or L 1 represents a cyclopentyl group (wherein two nitrogens each having R 3 and R 4 are 1 of the cyclopentyl group). Connected to the cyclopentyl group via position 3), additionally when R 5 represents 9,10-methanoanthracene-9 (10H) -yl, the groups -L 1 -N (R 4 )-together piperidi A piperidyl ring linked to L 2 through niyl nitrogen and to NR 3 via the 4 position of the piperidyl ring, provided that R 5 represents 9,10-methanoanthracene-9 (10H) -yl , r is only 2;

R4는 H 또는 1개 이상의 아릴기 또는 헤테로아릴기로 임의 치환된 C1-4알킬기를 나타내고:R 4 represents H or a C 1-4 alkyl group optionally substituted with one or more aryl groups or heteroaryl groups:

L2는 결합 또는 알킬렌 사슬 (CH2)s를 나타내며(여기서, s는 1, 2 또는 3을 나타내고, 알킬렌 사슬은 1개 이상의 C1-4알킬기, 페닐 또는 헤테로아릴로 임의 치환됨);L 2 represents a bond or an alkylene chain (CH 2 ) s where s represents 1, 2 or 3 and the alkylene chain is optionally substituted with one or more C 1-4 alkyl groups, phenyl or heteroaryl ;

R5는 페닐 또는 헤테로아릴기에 임의 융합된 아릴, 헤테로시클릭기 또는 C3-8시클로알킬기를 나타내고;R 5 represents an aryl, heterocyclic group or C 3-8 cycloalkyl group optionally fused to a phenyl or heteroaryl group;

단, 첫째로, n이 0이고, m이 1이며, R2가 퀴놀린 고리의 4-위치에 위치한 메틸이고, R3이 H이며, R4가 H이고, L1이 (CH2)2 또는 (CH2)3 또는 1,4-시클로헥실이며, L2가 결합일 때, R5는 4-메틸퀴놀린-2-일이 아니고;Provided that firstly n is 0, m is 1, R 2 is methyl at the 4-position of the quinoline ring, R 3 is H, R 4 is H, and L 1 is (CH 2 ) 2 or (CH 2 ) 3 or 1,4-cyclohexyl, when L 2 is a bond, R 5 is not 4-methylquinolin-2-yl;

둘째로, n이 0이고, m이 0 또는 1이며, R2가 퀴놀린 고리의 4-위치에 위치한 C1-3알콕시기이고, R3이 H 또는 C1-3알킬기이며, R4가 H 또는 C1-3알킬기이고, L1이 (CH2)3이고, L2가 1개 이상의 C1-3알킬기 또는 페닐로 임의 치환된 메틸렌일 때, R5는 1개, 2개 또는 3개의 C1-4알킬기 또는 할로로 임의 치환된 페닐, 티에닐 또는 인돌릴이 아니다.Second, n is 0, m is 0 or 1, R 2 is a C 1-3 alkoxy group located at 4-position of the quinoline ring, R 3 is H or C 1-3 alkyl group, and R 4 is H Or a C 1-3 alkyl group, L 1 is (CH 2 ) 3 , and when L 2 is methylene optionally substituted with one or more C 1-3 alkyl groups or phenyl, R 5 is one, two or three No phenyl, thienyl or indolyl optionally substituted with a C 1-4 alkyl group or halo.

본 명세서에 사용된 용어 "아릴"은 페닐, 나프틸, 또는 9,10-메타노안트라센-9(10H)-일을 의미하며, 각각은 1개 이상의 할로, C1-4알킬기, 페닐, 또는 화학식 NR6R7의 기(여기서, R6 및 R7은 독립적으로 H 또는 C1-4알킬기에서 선택됨)로 임의 치환된다.As used herein, the term "aryl" refers to phenyl, naphthyl, or 9,10-methanoanthracene-9 (10H) -yl, each of one or more halo, C 1-4 alkyl groups, phenyl, or Optionally substituted with a group of formula NR 6 R 7 , wherein R 6 and R 7 are independently selected from H or a C 1-4 alkyl group.

본 명세서에 사용된 용어 "헤테로아릴"은 티에닐, 푸릴 또는 피롤릴을 의미한다. As used herein, the term “heteroaryl” means thienyl, furyl or pyrrolyl.

본 명세서에 사용된 용어 "헤테로시클릭기"는 티에닐, 푸릴, 피리딜, 피롤릴, 퀴놀린일, 인돌릴, 벤조푸라닐 또는 벤조[b]티에닐을 의미하며, 각각은 1개 이상의 할로, C1-4알킬기, C1-4아실기 또는 니트로로 임의 치환된다. 한 군의 화합물에서, 용어 "헤테로시클릭기"는 티에닐, 푸릴, 피롤릴, 퀴놀린일, 인돌릴 또는 벤조[b]티에닐을 의미하며, 각각은 1개 이상의 할로, C1-4알킬기, C1-4아실기 또는 니트로로 임의 치환된다.As used herein, the term “heterocyclic group” means thienyl, furyl, pyridyl, pyrrolyl, quinolinyl, indolyl, benzofuranyl or benzo [b] thienyl, each of which is one or more halo Optionally substituted with a C 1-4 alkyl group, C 1-4 acyl group or nitro. In one group of compounds, the term “heterocyclic group” means thienyl, furyl, pyrrolyl, quinolinyl, indolyl or benzo [b] thienyl, each of one or more halo, C 1-4 alkyl groups Optionally substituted with a C 1-4 acyl group or nitro.

화학식 (I)의 한 군의 화합물, 이의 광학 이성질체 및 라세미산염, 및 이의 약학적으로 허용가능한 염에서: R1은 Cl-4알콕시기를 나타내고; n은 0 또는 1을 나타내며; R2는 C1-4알킬기를 나타내고; m은 0 또는 1을 나타내며; R3은 H 또는 C1-4알킬기를 나타내고; L1은 알킬렌 사슬 (CH2)r을 나타내거나(여기서, r은 2 또는 3을 나타냄, 단, R5가 9,10-메타노안트라센-9(10H)-일을 나타내는 경우, r은 단지 2임), 또는 L1은 시클로헥실기를 나타내며(여기서, R3 및 R4를 각각 갖는 2개의 질소가 시클로헥실기의 1,3 또는 1,4 위치를 통해 시클로헥실기에 연결됨), 부가적으로 R5가 9,10-메타노안트라센-9(10H)-일을 나타낼 때, 기 -L1-N(R4)-는 함께 피페리디닐 질소를 통해 L2에, 및 피페리딜 고리의 4 위치를 통해 N-R3에 연결된 피페리딜 고리를 나타내고; R4는 H 또는 1개 이상의 아릴기 또는 헤테로아릴기로 임의 치환된 C1-4알킬기를 나타내며; L2는 결합 또는 알킬렌 사슬 (CH2)s를 나타내고(여기서, s는 1, 2 또는 3을 나타내고, 알킬렌 사슬은 1개 이상의 C1-4알킬기, 페닐 또는 헤테로아릴로 임의 치환됨); R5는 페닐 또는 헤테로아릴기에 임의 융합된 아릴, 헤테로시클릭기 또는 C3-8시클로알킬기를 나타낸다.In one group of compounds of Formula (I), its optical isomers and racemates, and pharmaceutically acceptable salts thereof: R 1 represents a C 1-4 alkoxy group; n represents 0 or 1; R 2 represents a C 1-4 alkyl group; m represents 0 or 1; R 3 represents H or a C 1-4 alkyl group; L 1 represents an alkylene chain (CH 2 ) r (where r represents 2 or 3, provided that when R 5 represents 9,10-methanoanthracene-9 (10H) -yl, r is Only 2), or L 1 represents a cyclohexyl group, wherein two nitrogens having R 3 and R 4 , respectively, are linked to the cyclohexyl group through the 1,3 or 1,4 position of the cyclohexyl group; Additionally when R 5 represents 9,10-methanoanthracene-9 (10H) -yl, the groups -L 1 -N (R 4 )-together are in L 2 via piperidinyl nitrogen, and piperi A piperidyl ring linked to NR 3 via the 4 position of the dill ring; R 4 represents H or a C 1-4 alkyl group optionally substituted with one or more aryl groups or heteroaryl groups; L 2 represents a bond or an alkylene chain (CH 2 ) s where s represents 1, 2 or 3 and the alkylene chain is optionally substituted with one or more C 1-4 alkyl groups, phenyl or heteroaryl ; R 5 represents an aryl, heterocyclic group or C 3-8 cycloalkyl group optionally fused to a phenyl or heteroaryl group.

화학식 (I)의 화합물에서 R1, R2, R3, R4, R5, L 1, L2, n, m, r 및 s의 추가적 특정 값은 이하와 같다. 이러한 값들은 상기 또는 하기 서술된 어떠한 정의, 청구항 또는 구체예에 적절히 사용될 수 있음은 이해될 것이다.Further specific values of R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , n, m, r and s in the compound of formula (I) are as follows. It will be understood that such values may be appropriately used in any of the definitions, claims or embodiments described above or below.

특히 R1은 C1-4알콕시기를 나타낸다. 더욱 특히 R1은 메톡시를 나타낸다. 가장 특히 R1은 n이 1일 때, 6-메톡시를 나타낸다. 특히 n은 1을 나타낸다.In particular, R 1 represents a C 1-4 alkoxy group. More particularly R 1 represents methoxy. Most particularly R 1 represents 6-methoxy when n is 1. In particular, n represents 1.

특히 R2는 C1-4알킬기를 나타낸다. 더욱 특히 R2는 메틸을 나타낸다. 가장 특히 R2는 m이 1일 때, 4-메틸을 나타낸다. 특히 m은 1을 나타낸다.In particular, R 2 represents a C 1-4 alkyl group. More particularly R 2 represents methyl. Most particularly R 2 represents 4-methyl when m is 1. In particular, m represents 1.

특히 L1은 트리메틸렌, 1,3-시클로펜틸, 1,3-시클로헥실 또는 1,4-시클로헥실을 나타내거나, 또는 R5가 9,10-메타노안트라센-9(10H)-일을 나타낼 때, L1은 부가적으로 에틸렌을 나타낸다. 한 군의 화학식 (I)의 화합물에서, L1은 트리메틸렌을 나타낸다. 두번째 군의 화학식 (I)의 화합물에서, L1은 1,3-시클로헥실을 나타낸다. 세번째 군의 화학식 (I)의 화합물에서, L1은 1,4-시클로헥실을 나타낸다. 네번째 군의 화학식 (I)의 화합물에서, L1은 1,3-시클로펜틸을 나타낸다.In particular L 1 represents trimethylene, 1,3-cyclopentyl, 1,3-cyclohexyl or 1,4-cyclohexyl, or R 5 represents 9,10-methanoanthracene-9 (10H) -yl When indicated, L 1 additionally represents ethylene. In one group of compounds of Formula (I), L 1 represents trimethylene. In the second group of compounds of formula (I), L 1 represents 1,3-cyclohexyl. In the third group of compounds of formula (I), L 1 represents 1,4-cyclohexyl. In the fourth group of compounds of formula (I), L 1 represents 1,3-cyclopentyl.

특정 군의 화합물에서, 기 -L1-N(R4)-는 함께 피페리디닐 질소를 통해 L2에, 및 피페리딜 고리의 4 위치를 통해 N-R3에 연결된 피페리딜 고리를 나타내며, 단, R5가 9, 10-메타노안트라센-9(10H)-일을 나타낸다.In a particular group of compounds, the group -L 1 -N (R 4 )-together represents a piperidyl ring linked to L 2 via piperidinyl nitrogen and to NR 3 via the 4 position of the piperidyl ring, Provided that R 5 represents 9, 10-methanoanthracene-9 (10H) -yl.

특히 R3은 H 또는 C1-4알킬기, 특히 메틸을 나타낸다. 특정 군의 화학식 (I)의 화합물에서, R3은 H를 나타낸다.In particular R 3 represents H or a C 1-4 alkyl group, in particular methyl. In certain groups of compounds of Formula (I), R 3 represents H.

특히 L2는 결합, 메틸렌, 메틸메틸렌, 페닐로 임의 치환된 디메틸렌, 또는 메틸로 임의 치환된 트리메틸렌을 나타낸다. 특정 군의 화학식 (I)의 화합물에서, L2는 메틸렌을 나타낸다.In particular L 2 represents a bond, methylene, methylmethylene, dimethylene optionally substituted with phenyl, or trimethylene optionally substituted with methyl. In certain groups of compounds of formula (I), L 2 represents methylene.

특히 R4는 H 또는 헤테로아릴기로 임의 치환된 C1-4알킬기를 나타낸다. 더욱 특히 R4는 H, C1-4알킬기 또는 티에닐메틸을 나타낸다. 특정 군의 화학식 (I)의 화합물에서, R4는 H를 나타낸다.In particular R 4 represents a C 1-4 alkyl group optionally substituted with H or a heteroaryl group. More particularly R 4 represents H, a C 1-4 alkyl group or thienylmethyl. In certain groups of compounds of formula (I), R 4 represents H.

특히 R5는 페닐, 2-나프틸 또는 9,10-메타노안트라센-9(10H)-일을 나타내며, 각각은 1개 이상의 메틸, 클로로, 디메틸아미노 또는 페닐로 임의 치환된다.In particular R 5 represents phenyl, 2-naphthyl or 9,10-methanoanthracene-9 (10H) -yl, each optionally substituted with one or more methyl, chloro, dimethylamino or phenyl.

더욱 특히 R5는 4,5,6,7-테트라히드로티아나프트-4-일, 벤조[b]티엔-3-일, 2-티에닐, 3-티에닐, 2-푸릴, 3-푸릴, 벤조푸라닐, 피리딜, 1H-피롤-2-일, 1H-인돌-3-일, 또는 2-퀴놀린일을 나타내며, 각각은 1개 이상의 니트로, 메틸, 아세틸 또는 클로로로 임의 치환된다.More particularly R 5 is 4,5,6,7-tetrahydrothianaft-4-yl, benzo [b] thien-3-yl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, Benzofuranyl, pyridyl, 1H-pyrrole-2-yl, 1H-indol-3-yl, or 2-quinolinyl, each optionally substituted with one or more nitro, methyl, acetyl or chloro.

가장 특히 R5는 시클로프로필, 페닐, 2,4,6-트리메틸페닐, 3,4-디클로로페닐, 2-나프틸, 9,10-메타노안트라센-9(1OH)-일, 2-티에닐, 3-티에닐, 5-니트로-3-티에닐, 2,5-디메틸-3-티에닐, 3-푸라닐, 5-메틸-2-푸라닐, 1-아세틸-1H-인돌-3-일, 4,5,6,7-테트라히드로티아나프트-4-일, 벤조[b]티엔-3-일, 1H-인돌-3-일, 2- 퀴놀린일, 1,1'-비페닐-4-일, 4-(디메틸아미노)페닐, 1H-피롤-2-일 또는 2,5-디클로로-3-티에닐을 나타낸다.Most particularly R 5 is cyclopropyl, phenyl, 2,4,6-trimethylphenyl, 3,4-dichlorophenyl, 2-naphthyl, 9,10-methanoanthracene-9 (1OH) -yl, 2-thienyl , 3-thienyl, 5-nitro-3-thienyl, 2,5-dimethyl-3-thienyl, 3-furanyl, 5-methyl-2-furanyl, 1-acetyl-1H-indole-3- 1,4,5,6,7-tetrahydrothianaphth-4-yl, benzo [b] thien-3-yl, 1H-indol-3-yl, 2-quinolinyl, 1,1'-biphenyl- 4-yl, 4- (dimethylamino) phenyl, 1H-pyrrole-2-yl or 2,5-dichloro-3-thienyl.

이러한 염이 가능한 경우 용어 "약학적으로 허용가능한 염"은 약학적으로 허용가능한 산-부가 염 및 염기-부가 염 모두를 포함한다. 화학식 (I)의 화합물의 적절한 약학적으로 허용가능한 염은 예컨대, 충분히 염기성인 화학식 (I)의 화합물의 산-부가 염, 예컨대, 무기산 또는 유기산, 예컨대, 염산, 염화브롬산, 황산, 트리플루오로아세트산, 구연산 또는 말레산과의 산-부가 염; 또는 예컨대, 충분히 산성인 화학식 (I)의 화합물의 염, 예컨대, 알칼리 금속 염 또는 알칼리 토금속 염, 예컨대, 나트륨, 칼슘 또는 마그네슘 염, 또는 암모늄 염, 또는 유기 염기, 예컨대, 메틸아민, 디메틸아민, 트리메틸아민, 피페리딘, 모르폴린 또는 트리스-(2-히드록시에틸)아민과의 염이다. Where such salts are possible, the term “pharmaceutically acceptable salts” includes both pharmaceutically acceptable acid-addition salts and base-addition salts. Suitable pharmaceutically acceptable salts of compounds of formula (I) are, for example, acid-addition salts of compounds of formula (I) which are sufficiently basic, such as inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoro Acid-addition salts with roacetic acid, citric acid or maleic acid; Or, for example, salts of compounds of formula (I) which are sufficiently acidic, such as alkali metal or alkaline earth metal salts such as sodium, calcium or magnesium salts, or ammonium salts, or organic bases such as methylamine, dimethylamine, Salts with trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine.

명세서 및 첨부된 청구항을 통해, 주어진 화학식 또는 화학 명칭은 모든 이의 입체 및 광학 이성질체, 라세미산염, 및 상이한 비율의 분리된 거울상 이성질체의 혼합물(이러한 이성질체 및 거울상 이성질체가 존재하는 경우), 및 이의 약학적으로 허용가능한 염을 포함할 수 있다. 이성질체는 종래의 기술들, 예컨대, 크로마토그래피 또는 분별 결정을 사용하여 분리될 수 있다. 거울상 이성질체는 라세민산염을 예컨대, 분별 결정, 해상 또는 HPLC로 분리하여 분리될 수 있다. 부분 입체 이성질체는 이성질체 혼합물을 예컨대, 분별 결정, HPLC 또는 플래쉬 크로마토그래피로 분리하여 분리될 수 있다. 선택적으로, 입체이성질체는 라세미화나 에피머화를 유발하지 않는 조건 하에서 키랄 출발 물질로부터 키랄 합성하거나, 또는 키랄 시약으로 유도하여 제조될 수 있다. 모든 입체이성질체들은 본 발명의 범위 이내에 포함된다.Throughout the specification and the appended claims, the chemical formulas or chemical names given are given to all of their stereo and optical isomers, racemates, and mixtures of different proportions of the enantiomers (if such isomers and enantiomers are present), and pharmaceuticals thereof May be included as an acceptable salt. Isomers may be separated using conventional techniques such as chromatography or fractional crystals. Enantiomers can be separated by separating racemates, eg by fractional crystallization, resolution or HPLC. Diastereoisomers may be separated by separating the isomeric mixture, eg, by fractional crystallization, HPLC or flash chromatography. Optionally, stereoisomers can be prepared by chiral synthesis from chiral starting materials or by induction with chiral reagents under conditions that do not cause racemization or epimerization. All stereoisomers are included within the scope of the present invention.

이하 정의는 명세서 및 첨부된 청구항을 통해 적용될 수 있다.The following definitions can be applied throughout the specification and the appended claims.

달리 언급하거나 지시한 바 없으면, 용어 "알킬"은 직쇄 또는 분지쇄 알킬기를 나타낸다. 상기 알킬의 예에는 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소-부틸, sec-부틸 및 t-부틸이 포함된다. 바람직한 알킬기는 메틸, 에틸, 프로필, 이소프로필 및 t-부틸이다. Unless otherwise stated or indicated, the term "alkyl" refers to a straight or branched chain alkyl group. Examples of such alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and t-butyl. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl and t-butyl.

달리 언급하거나 지시한 바 없으면, 용어 "알콕시"는 기 0-알킬을 나타내며, 여기서 알킬은 상기 정의된 바와 같다.Unless stated or indicated otherwise, the term “alkoxy” refers to the group 0-alkyl, wherein alkyl is as defined above.

달리 언급하거나 지시한 바 없으면, 용어 '할로"는 플루오로, 염소, 브롬 또는 요오드를 의미한다.Unless otherwise stated or indicated, the term "halo" means fluoro, chlorine, bromine or iodine.

본 발명은 The present invention

N-(9,10-메타노안트라센-9(10H)-일메틸)-N'-(2-퀴놀린일)-1,2-에탄디아민;N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N '-(2-quinolinyl) -1,2-ethanediamine;

N-(6-메톡시-4-메틸-2-퀴놀린일)-N'-(3-티에닐메틸)-1,3-프로판디아민; N- (6-methoxy-4-methyl-2-quinolinyl) -N '-(3-thienylmethyl) -1,3-propanediamine;

N-(9,10-메타노안트라센-9(10H)-일메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민;N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine;

N-(2-퀴놀린일)-N'-(3-티에닐메틸)-1,3-프로판디아민; N- (2-quinolinyl) -N '-(3-thienylmethyl) -1,3-propanediamine;

N-(9,10-메타노안트라센-9(10H)-일메틸)-N'-(2-퀴놀린일)-1,4-시클로헥산디아민; N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N '-(2-quinolinyl) -1,4-cyclohexanediamine;

N-[(1-아세틸-1H-인돌-3-일)메틸]-N'-(6-메톡시-4-메틸-2-퀴놀린일)-1,3-프로판디아민; N-[(1-acetyl-1H-indol-3-yl) methyl] -N '-(6-methoxy-4-methyl-2-quinolinyl) -1,3-propanediamine;

N-(9,10-메타노안트라센-9(10H)-일메틸)-N'-(2-퀴놀린일)-1,3-시클로헥산디아민; N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N '-(2-quinolinyl) -1,3-cyclohexanediamine;

N-(2-퀴놀린일)-N'-[1-(3-티에닐)에틸]-1,3-프로판디아민; N- (2-quinolinyl) -N '-[1- (3-thienyl) ethyl] -1,3-propanediamine;

N-(2-퀴놀린일)-N'-(3-티에닐메틸)-1,3-시클로헥산디아민; N- (2-quinolinyl) -N '-(3-thienylmethyl) -1,3-cyclohexanediamine;

N-(9,10-메타노안트라센-9(10H)-일메틸)-N'-(6-메톡시-4-메틸-2-퀴놀린일)-1,3-프로판디아민; N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N '-(6-methoxy-4-methyl-2-quinolinyl) -1,3-propanediamine;

N-(2-퀴놀린일)-N'-(4,5,6,7-테트라히드로티아나프트-4-일)-1,3-프로판디아민; N- (2-quinolinyl) -N '-(4,5,6,7-tetrahydrothianaphth-4-yl) -1,3-propanediamine;

N-메틸-N'-(2-퀴놀린일)-N-(3-티에닐메틸)-1,3-프로판디아민; N-methyl-N '-(2-quinolinyl) -N- (3-thienylmethyl) -1,3-propanediamine;

N-(2-퀴놀린일)-N',N'-비스(3-티에닐메틸)-1,3-프로판디아민; N- (2-quinolinyl) -N ', N'-bis (3-thienylmethyl) -1,3-propanediamine;

N-(9,10-메타노안트라센-9(10H)-일메틸)-N-메틸-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N-methyl-N '-(2-quinolinyl) -1,3-propanediamine;

N-(2-퀴놀린일)-N'-[(2,4,6-트리메틸페닐)메틸]-1,3-프로판디아민; N- (2-quinolinyl) -N '-[(2,4,6-trimethylphenyl) methyl] -1,3-propanediamine;

N-(2-페닐에틸)-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (2-phenylethyl) -N '-(2-quinolinyl) -1,3-propanediamine;

N-(1-벤조[b]티엔-3-일에틸)-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (1-benzo [b] thien-3-ylethyl) -N '-(2-quinolinyl) -1,3-propanediamine;

N-[(3,4-디클로로페닐)메틸]-N'-(2-퀴놀린일)-1,3-시클로헥산디아민;N-[(3,4-dichlorophenyl) methyl] -N '-(2-quinolinyl) -1,3-cyclohexanediamine;

N-(9,10-메타노안트라센-9(10H)-일메틸)-N'-메틸-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N'-methyl-N '-(2-quinolinyl) -1,3-propanediamine;

N-(2-퀴놀린일)-N'-(2-티에닐메틸)-1,3-프로판디아민; N- (2-quinolinyl) -N '-(2-thienylmethyl) -1,3-propanediamine;

N-(3-푸라닐메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (3-furanylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine;

N-[(3,4-디클로로페닐)메틸]-N-메틸-N'-(2-퀴놀린일)-1,3-프로판디아민; N-[(3,4-dichlorophenyl) methyl] -N-methyl-N '-(2-quinolinyl) -1,3-propanediamine;

N-[1-(9,10-메타노안트라센-9(10H)-일메틸)-4-피페리디닐]-2-퀴놀린아민; N- [1- (9,10-Methanoanthracene-9 (10H) -ylmethyl) -4-piperidinyl] -2-quinolinamine;

N-(1H-인돌-3-일메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (1H-indol-3-ylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine;

N-(2-나프탈레닐메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (2-naphthalenylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine;

N-(2,2-디페닐에틸)-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (2,2-diphenylethyl) -N '-(2-quinolinyl) -1,3-propanediamine;

N-(1H-인돌-3-일메틸)-N'-(6-메톡시-4-메틸-2-퀴놀린일)-1,3-프로판디아민; N- (1H-indol-3-ylmethyl) -N '-(6-methoxy-4-methyl-2-quinolinyl) -1,3-propanediamine;

N-[(3,4-디클로로페닐)메틸-N'-(2-퀴놀린일)-1,3-프로판디아민; N-[(3,4-dichlorophenyl) methyl-N '-(2-quinolinyl) -1,3-propanediamine;

N-[(3,4-디클로로페닐)메틸]-N'-(2-퀴놀린일)-1,4-시클로헥산디아민; N-[(3,4-dichlorophenyl) methyl] -N '-(2-quinolinyl) -1,4-cyclohexanediamine;

N,N'-디-(2-퀴놀린일)-1,3-프로판디아민; N, N'-di- (2-quinolinyl) -1,3-propanediamine;

N-(2-퀴놀린일)-N'-(2-퀴놀린일메틸)-1,3-프로판디아민; N- (2-quinolinyl) -N '-(2-quinolinylmethyl) -1,3-propanediamine;

N-[(1-아세틸-1H-인돌-3-일)메틸]-N'-(2-퀴놀린일)-1,3-프로판디아민; N-[(1-acetyl-1H-indol-3-yl) methyl] -N '-(2-quinolinyl) -1,3-propanediamine;

N-(시클로프로필메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (cyclopropylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine;

N-(2-퀴놀린일)-N'-(3-티에닐메틸)-1,4-시클로헥산디아민; N- (2-quinolinyl) -N '-(3-thienylmethyl) -1,4-cyclohexanediamine;

N-([1,1'-비페닐]-4-일메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민; N-([1,1'-biphenyl] -4-ylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine;

N-(6-메톡시-4-메틸-2-퀴놀린일)-N'-[3-(5-메틸-2-푸라닐)부틸]-1,3-프로판디아민; N- (6-methoxy-4-methyl-2-quinolinyl) -N '-[3- (5-methyl-2-furanyl) butyl] -1,3-propanediamine;

N-[[4-(디메틸아미노)페닐]메틸]-N'-(2-퀴놀린일)-1,3-프로판디아민; N-[[4- (dimethylamino) phenyl] methyl] -N '-(2-quinolinyl) -1,3-propanediamine;

N-(1H-피롤-2-일메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (1H-pyrrol-2-ylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine;

N-[3-(5-메틸-2-푸라닐)부틸]-N'-(2-퀴놀린일)-1,3-프로판디아민; N- [3- (5-methyl-2-furanyl) butyl] -N '-(2-quinolinyl) -1,3-propanediamine;

N-[(5-니트로-3-티에닐)메틸]-N'-(2-퀴놀린일)-1,3-프로판디아민; N-[(5-nitro-3-thienyl) methyl] -N '-(2-quinolinyl) -1,3-propanediamine;

N-(6-메톡시-4-메틸-2-퀴놀린일)-N'-[(5-니트로-3-티에닐)메틸]-1,3-프로판디아민; N- (6-methoxy-4-methyl-2-quinolinyl) -N '-[(5-nitro-3-thienyl) methyl] -1,3-propanediamine;

N-(6-메톡시-4-메틸-2-퀴놀린일)-N'-(1H-피롤-2-일메틸)-1,3-프로판디아민;N- (6-methoxy-4-methyl-2-quinolinyl) -N '-(1H-pyrrol-2-ylmethyl) -1,3-propanediamine;

N-[(3,4-디클로로페닐)메틸]-N'-메틸-N'-2-퀴놀린일)-1,3-프로판디아민; N-[(3,4-dichlorophenyl) methyl] -N'-methyl-N'-2-quinolinyl) -1,3-propanediamine;

N-[1-(2,5-디메틸-3-티에닐)에틸]-N'-(2-퀴놀린일)-1,3-프로판디아민; N- [1- (2,5-dimethyl-3-thienyl) ethyl] -N '-(2-quinolinyl) -1,3-propanediamine;

N-[1-(2,5-디클로로-티오펜-3-일)-에틸]-N'-(2-퀴놀린일)-1,3-프로판디아민;N- [1- (2,5-Dichloro-thiophen-3-yl) -ethyl] -N '-(2-quinolinyl) -1,3-propanediamine;

N-[(1-아세틸-1H-인돌-3-일)메틸]-N'-퀴놀린-2-일시클로헥산-1,3-디아민; N-[(1-acetyl-1H-indol-3-yl) methyl] -N'-quinolin-2-ylcyclohexane-1,3-diamine;

N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-(3-티에닐메틸)시클로펜탄-1,3-디아민;N- (6-methoxy-4-methylquinolin-2-yl) -N '-(3-thienylmethyl) cyclopentane-1,3-diamine;

N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-[(1-메틸-1H-인돌-3-일)메틸]시클로펜탄-1,3-디아민;N- (6-methoxy-4-methylquinolin-2-yl) -N '-[(1-methyl-1H-indol-3-yl) methyl] cyclopentane-1,3-diamine;

(1S,3S)-N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-[(1-메틸-1H-인돌-3-일)메틸]시클로펜탄-1,3-디아민;(1S, 3S) -N- (6-methoxy-4-methylquinolin-2-yl) -N '-[(1-methyl-1H-indol-3-yl) methyl] cyclopentane-1,3- Diamine;

(1S,3S)-N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-(3-티에닐메틸)시클로펜탄-1,3-디아민;(1S, 3S) -N- (6-methoxy-4-methylquinolin-2-yl) -N '-(3-thienylmethyl) cyclopentane-1,3-diamine;

N-[(1-아세틸-1H-인돌-3-일)메틸]-N'-(6-메톡시-4-메틸퀴놀린-2-일)시클로헥산-1,3-디아민; N-[(1-acetyl-1H-indol-3-yl) methyl] -N '-(6-methoxy-4-methylquinolin-2-yl) cyclohexane-1,3-diamine;

N-(1H-인돌-3-일메틸)-N'-(6-메톡시-4-메틸퀴놀린-2-일)시클로헥산-1,3-디아민; N- (1H-indol-3-ylmethyl) -N '-(6-methoxy-4-methylquinolin-2-yl) cyclohexane-1,3-diamine;

N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-(3-티에닐메틸)시클로헥산-1,3-디아민;N- (6-methoxy-4-methylquinolin-2-yl) -N '-(3-thienylmethyl) cyclohexane-1,3-diamine;

N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-[(1-메틸-1H-인돌-3-일)메틸]시클로헥산-1,3-디아민; N- (6-methoxy-4-methylquinolin-2-yl) -N '-[(1-methyl-1H-indol-3-yl) methyl] cyclohexane-1,3-diamine;

N-(1-벤조푸란-2-일메틸)-N'-(6-메톡시-4-메틸퀴놀린-2-일)시클로헥산-1,3-디아민; N- (1-benzofuran-2-ylmethyl) -N '-(6-methoxy-4-methylquinolin-2-yl) cyclohexane-1,3-diamine;

N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-(피리딘-2-일메틸)시클로헥산-1,3-디아민; 및 N- (6-methoxy-4-methylquinolin-2-yl) -N '-(pyridin-2-ylmethyl) cyclohexane-1,3-diamine; And

N-(4-메틸퀴놀린-2-일)-N'-(3-티에닐메틸)시클로헥산-1,3-디아민N- (4-methylquinolin-2-yl) -N '-(3-thienylmethyl) cyclohexane-1,3-diamine

에서 선택된 화합물 및 이의 약학적으로 허용가능한 염을 제공한다. It provides a compound selected from and pharmaceutically acceptable salts thereof.

제조 방법Manufacturing method

본 발명의 화합물은 하기 방법들 중 어떠한 방법에 따라 하기 나타낸 것처럼 제조될 수 있다. 그러나, 본 발명은 이들 방법들로 제한되는 것은 아니며, 화합물은 또한 선행 기술에서 구조적으로 관련된 화합물에 대해 서술된 바와 같이 제조될 수 있다. The compounds of the present invention can be prepared as shown below according to any of the following methods. However, the present invention is not limited to these methods, and compounds may also be prepared as described for structurally related compounds in the prior art.

화학식 (I)의 화합물은 하기 화학식 (II)의 화합물을 하기 화학식 (III)의 화합물과 반응시켜 제조될 수 있다:Compounds of formula (I) may be prepared by reacting a compound of formula (II) with a compound of formula (III)

상기 화학식에서, In the above formula,

R1, R2, R3, R4, R5, L1, n 및 m은 으로 앞서 정의된 바와 같고,R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , n and m are as defined above,

L2'는 화합물 (II)와 (III)의 반응 후, 환원성 알킬화 조건 하에서 환원시 L2를 내는 기를 나타낸다. 예컨대, 화학식 (II)의 화합물과 화학식 (III)의 화합물은 함께 0℃ 내지 250℃ 범위의 온도, 바람직하게는 50℃ 내지 150℃ 범위의 온도에서, 임의적으로는 비활성 용매(예컨대, 메탄올, 디클로로메탄 또는 아세트산)의 존재하에, 임의적으로 중합체를 지탱하는 환원제(예컨대, (폴리스티릴메틸)트리메틸-암모늄 시아노보로히드리드 또는 소디엄 시아노보로히드리드)의 존재하에 반응될 수 있다.L 2 ′ represents a group giving L 2 upon reduction under reductive alkylation conditions after the reaction of compounds (II) and (III). For example, the compound of formula (II) and the compound of formula (III) may be combined together at a temperature in the range from 0 ° C. to 250 ° C., preferably in the range from 50 ° C. to 150 ° C., optionally with an inert solvent (eg methanol, dichloro Methane or acetic acid), optionally in the presence of a reducing agent (such as (polystyrylmethyl) trimethyl-ammonium cyanoborohydride or sodium cyanoborohydride) that supports the polymer.

화학식 (II)의 화합물은 하기 화학식 (IV)의 화합물을 하기 화학식 (V)의 화합물과 0℃ 내지 250℃ 범위의 온도에서, 바람직하게는 50℃ 내지 150℃ 범위의 온도에서, 임의적으로는 비활성 용매(예컨대, 톨루엔)의 존재하에, 임의적으로는 촉매 크로스-커플링 시스템(예컨대, Pd(OAc)2 및 2-(디-t부틸포스피노)비페닐 또는 BINAP)의 존재하에, 임의적으로는 염기(예컨대, NaOtBu)의 존재하에 반응시킴으로써 제조될 수 있다:The compound of formula (II) is optionally inert to a compound of formula (IV) with a compound of formula (V) at a temperature in the range of 0 ° C to 250 ° C, preferably at a temperature in the range of 50 ° C to 150 ° C. In the presence of a solvent (eg toluene), optionally in the presence of a catalytic cross-coupling system (eg, Pd (OAc) 2 and 2- (di- t butylphosphino) biphenyl or BINAP) It can be prepared by reacting in the presence of a base (eg, NaO t Bu):

상기 화학식에서,In the above formula,

R1, R2, n 및 m은 앞서 정의된 바와 같고, X는 할로, 특히 클로로 또는 브로모이다. 화학식 (II)의 어떠한 화합물은 신규한 것이며, 본 발명의 추가 양태로서 유용한 중간체로 청구된다.R 1 , R 2 , n and m are as defined above and X is halo, in particular chloro or bromo. Any compound of formula (II) is novel and is claimed as an intermediate useful as a further aspect of the invention.

본 발명의 화합물들은 종래의 기술들을 사용하여 이들의 반응 혼합물에서 분리될 수 있다. The compounds of the present invention can be separated from their reaction mixtures using conventional techniques.

본 기술 분야의 당업자라면 본 발명의 화합물을 선택적 방식으로, 및 일부 경우에는 더욱 편리한 방식으로 얻기 위해 전술된 개별적인 방법 단계를 상이한 순서로 수행하거나, 및/또는 개별적인 반응을 전체 과정에 있어 상이한 단계에 수행할 수 있음을 이해할 것이다(즉, 화학적 변형이 상기 연관된 것과 상이한 중간체에서 특정 반응에 의해 수행될 수 있다). 임의적으로, 화학식 (V)의 질소는 화학식 (IV)의 화합물과의 반응 이전에 보호될 수 있으며, 그 후, 얻어진 화학식 (II)의 화합물은 화학식 (III)의 화합물과 반응시키기 이전에 탈보호될 수 있다. 아민 보호기, 예컨대, t-BOC 기는 본 기술 분야의 당업자에게 공지되어 있다. Those skilled in the art will perform the individual process steps described above in a different order to obtain the compounds of the invention in an optional manner, and in some cases in a more convenient manner, and / or the individual reactions may be carried out at different stages throughout the process. It will be understood that it may be performed (ie, chemical modifications may be carried out by specific reactions in intermediates different from those associated above). Optionally, the nitrogen of formula (V) may be protected prior to reaction with the compound of formula (IV), after which the compound of formula (II) obtained is deprotected prior to reacting with the compound of formula (III) Can be. Amine protecting groups such as t-BOC groups are known to those skilled in the art.

"비활성 용매"라는 표현은 소정의 산물의 수율에 악 영향을 주지 않는 방식으로 출발 물질, 시약, 중간체 또는 산물과 반응하지 않는 용매를 나타낸다.The expression "inert solvent" denotes a solvent that does not react with the starting materials, reagents, intermediates or products in a manner that does not adversely affect the yield of a given product.

약학 제제Pharmaceutical preparations

본 발명의 화합물은 일반적으로 경구, 비경구, 정맥내, 근육내, 피하 또는 기타 주입가능한 수단, 구강, 직장, 질, 경피 및/또는 비강 경로 및/또는 흡입을 통해; 유리 산으로 또는 약학적으로 허용가능한 유기 또는 무기 염기-부가 염으로; 활성 성분을 포함하는 약학 제제의 형태로; 약학적으로 허용가능한 제형으로 주입될 수 있다. 치료될 장애와 환자, 및 투여 경로에 따라, 조성물은 다양한 투여량으로 투여될 수 있다.Compounds of the invention are generally orally, parenterally, intravenously, intramuscularly, subcutaneously or other injectable means, oral, rectal, vaginal, transdermal and / or nasal routes and / or inhalation; As a free acid or as a pharmaceutically acceptable organic or inorganic base-addition salt; In the form of a pharmaceutical preparation comprising the active ingredient; It may be injected in a pharmaceutically acceptable formulation. Depending on the disorder to be treated and the patient, and the route of administration, the composition can be administered in various dosages.

인간의 치료적 치료시 본 발명의 화합물의 적절한 하루 투여량은 약 0.001-10 mg/kg 체중이며, 0.01-1 mg/kg 체중이 바람직하다. Appropriate daily dosages of the compounds of the present invention in therapeutic treatment of humans are about 0.001-10 mg / kg body weight, with 0.01-1 mg / kg body weight being preferred.

경구 제제는 O.5 mg 내지 500 mg의 범위, 예컨대, 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg 및 250 mg의 활성 화합물의 투여량을 제공하도록, 본 기술 분야의 당업자에게 공지된 방법으로 제제화될 수 있는 정제나 캡슐이 특히 바람직하다. Oral formulations are described herein to provide a dosage of an active compound in the range of 0.5 mg to 500 mg, such as 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg and 250 mg. Particular preference is given to tablets or capsules which can be formulated by methods known to those skilled in the art.

본 발명의 추가 양태에 따라, 본 발명의 어떠한 화합물 또는 이의 약학적으로 허용가능한 염을, 약학적으로 허용가능한 어주번트, 희석제 및/또는 담체와 함께 포함하는 약학 제제를 또한 제공한다.According to a further aspect of the invention, there is also provided a pharmaceutical formulation comprising any compound of the invention or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable adjuvant, diluent and / or carrier.

본 발명의 화합물은 또한 비만, 정신 장애, 신경 장애 및 통증과 연관된 장애의 치료에 유용한 기타 치료제와 함께 배합될 수 있다. The compounds of the present invention may also be combined with other therapeutic agents useful for the treatment of obesity, mental disorders, neurological disorders and disorders associated with pain.

약리학적 성질Pharmacological Properties

화학식 (I)의 화합물은 비만, 정신 장애, 예컨대, 정신병, 불안, 불안-우울성 장애, 우울증, 인식 장애, 기억 장애, 정신분열증, 간질, 및 관련 질병, 및 신경 장애, 예컨대, 치매, 다발성 경화증, 레이나우드 증후군, 파키슨씨병, 헝틴턴 무도병 및 알츠하이머병의 치료에 유용하다. 이 화합물은 또한 면역, 심장혈관, 생식 및 내분비 장애, 및 호흡계 및 위장계 관련 질환의 치료에 잠재적으로 유용하다. 이 화합물은 또한 담배 소비의 중지, 니코틴 의존성의 치료 및/또는 니코틴 금단 증상의 치료, 니코틴에 대한 갈망 감소를 위한 작용제로서, 및 항-흡연제로서 잠재적으로 유용하다. 이 화합물은 또한 금연시 일반적으로 수반되는 체중의 증가를 감소시킬 수 있다. 이 화합물은 또한 설사(Diarrhoea)의 치료 또는 예방을 위한 작용제로 잠재적으로 유용하다. Compounds of formula (I) are used for obesity, mental disorders such as psychosis, anxiety, anxiety-depressive disorders, depression, cognitive disorders, memory disorders, schizophrenia, epilepsy, and related diseases, and neurological disorders such as dementia, multiple It is useful for the treatment of sclerosis, Reynaud's syndrome, Parkinson's disease, Hentinton chorea and Alzheimer's disease. This compound is also potentially useful for the treatment of immune, cardiovascular, reproductive and endocrine disorders, and diseases associated with respiratory and gastrointestinal systems. This compound is also potentially useful as an agent for stopping tobacco consumption, treating nicotine dependence and / or treating nicotine withdrawal symptoms, reducing cravings for nicotine, and as an anti-smoker. This compound can also reduce the increase in body weight normally associated with smoking cessation. This compound is also potentially useful as an agent for the treatment or prevention of diarrhoea.

이 화합물은 또한 니코틴, 알콜, 코카인, 암페타민, 오피에이트, 벤조디아제핀 및 바르비투레이트와 같은 정신운동-활성제를 포함하는(이로 제한되지는 않음) 중독성 성분의 갈망/재발을 감소시키는 작용제로 잠재적으로 유용하다. 이 화합물은 또한 약물 중독 및/또는 약물 남용을 치료하는 작용제로서 잠재적으로 유용하다.This compound is also potentially useful as an agent to reduce craving / relapse of addictive components, including but not limited to psychomotor-active agents such as nicotine, alcohol, ***e, amphetamines, opiates, benzodiazepines and barbiturates Do. This compound is also potentially useful as an agent to treat drug addiction and / or drug abuse.

따라서, 남용 성분에 대한 갈망을 감소시키는 데 활성이 있고, 남용된 성분에 의해 유발되는 교감 반응 속도를 악화시키지 않으며, 바람직한 약학동력 효과를 가지는 화합물 및 치료 방법을 제공하는 것이 바람직하다.Thus, it is desirable to provide compounds and methods of treatment that are active in reducing cravings for abuse ingredients, do not deteriorate the rate of sympathetic reaction caused by abused ingredients, and have desirable pharmacokinetic effects.

이 화합물은 또한 급성 및 만성 지각적 통증, 염증성 통증 및 신경병증 통증 및 편두통을 포함하는(이로 제한되지는 않음) 통증 장애의 치료를 위한 작용제로서 잠재적으로 유용하다. This compound is also potentially useful as an agent for the treatment of pain disorders including but not limited to acute and chronic perceptual pain, inflammatory pain and neuropathic pain and migraine headaches.

다른 양태에서, 본 발명은 약제로 유용한 앞서 청구된 화학식 (I)의 화합물을 제공한다.In another aspect, the present invention provides a compound of formula (I) as claimed above which is useful as a medicament.

추가 양태에서, 본 발명은 약리학적으로 유효한 양의 화학식 (I)의 화합물을 이를 필요로 하는 환자에게 투여하는 것을 포함하는, 비만, 정신 장애, 예컨대, 정신병, 불안, 불안-우울성 장애, 우울증, 쌍극성 장애, ADHD, 인식 장애, 기억 장애, 정신분열증, 간질, 및 관련 질병, 신경 장애, 예컨대, 치매, 다발성 경화증, 파키슨씨병, 헝틴턴 무도병 및 알츠하이머병 및 통증 관련 장애, 예컨대, 급성 및 만성 지각적 통증, 염증성 통증 및 신경병증 통증 및 편두통의 치료 또는 예방을 위한 약제의 제조에 있어서의 화학식 (I)의 화합물의 용도를 제공한다. In a further aspect, the invention comprises administering a pharmacologically effective amount of a compound of formula (I) to a patient in need thereof, obesity, mental disorders such as psychosis, anxiety, anxiety-depressive disorder, depression , Bipolar disorders, ADHD, cognitive impairment, memory disorders, schizophrenia, epilepsy, and related diseases, neurological disorders such as dementia, multiple sclerosis, Parkinson's disease, Hentinton's chorea and Alzheimer's disease and pain related disorders such as acute And the use of a compound of formula (I) in the manufacture of a medicament for the treatment or prevention of chronic perceptual pain, inflammatory pain and neuropathic pain and migraine headaches.

또 다른 추가적 양태에서, 본 발명은 약리학적으로 유효한 양의 화학식 (I)의 화합물을 이를 필요로 하는 환자에게 투여하는 것을 포함하는, 비만, 정신 장애, 예컨대, 정신병, 불안, 불안-우울성 장애, 우울증, 쌍극성 장애, ADHD, 인식 장애, 기억 장애, 정신분열증, 간질, 및 관련 질병, 및 신경 장애, 예컨대, 치매, 다발성 경화증, 파키슨씨병, 헝틴턴 무도병 및 알츠하이머병 및 통증 관련 장애, 예컨대, 급성 및 만성 지각적 통증, 염증성 통증 및 신경병증 통증 및 편두통의 치료 방법을 제공한다. In yet a further aspect, the invention comprises administering a pharmacologically effective amount of a compound of formula (I) to a patient in need thereof, obesity, mental disorders such as psychosis, anxiety, anxiety-depressive disorder , Depression, bipolar disorder, ADHD, cognitive impairment, memory disorder, schizophrenia, epilepsy, and related diseases, and neurological disorders such as dementia, multiple sclerosis, Parkinson's disease, Hentinton's chorea and Alzheimer's disease and pain related disorders, For example, methods of treating acute and chronic perceptual pain, inflammatory pain and neuropathic pain and migraine headaches are provided.

본 발명의 화합물은 특히 비만 치료에 적합하다.The compounds of the present invention are particularly suitable for the treatment of obesity.

배합 요법Combination therapy

본 발명의 화합물은 고혈압, 고지혈증, 이상지혈증, 당뇨 및 비만과 같은 아테롬성 동맥경화증의 발달 및 진행과 연관된 장애의 치료에 유용한 다른 치료제와 배합할 수 있다. 예컨대, 본 발명의 화합물은 열발생, 지방분해, 지방 흡착, 물림(satiety), 또는 소화관 운동성에 영향을 주는 화합물과 배합하여 사용할 수 있다. 본 발명의 화합물은 LDL:HDL 비를 감소시키는 다른 치료제, 또는 LDL-콜레스테롤의 순환 값의 감소를 초래하는 다른 치료제와 배합할 수 있다. 당뇨를 갖는 환자에서, 본 발명의화합물은 또한 미세-혈관증과 연관된 합병증을 치료하는 데 사용되는 치료제와 배합될 수 있다. The compounds of the present invention can be combined with other therapeutic agents useful for the treatment of disorders associated with the development and progression of atherosclerosis such as hypertension, hyperlipidemia, dyslipidemia, diabetes and obesity. For example, the compounds of the present invention can be used in combination with compounds that affect heat generation, lipolysis, fat adsorption, satiety, or digestive tract motility. The compounds of the present invention may be combined with other therapeutic agents that reduce the LDL: HDL ratio, or with other therapeutic agents that result in a decrease in the circulation value of LDL-cholesterol. In patients with diabetes, the compounds of the present invention may also be combined with therapeutic agents used to treat complications associated with micro-angiopathy.

본 발명의 화합물은 대사 증후군 또는 유형 2 당뇨 및 이와 연관된 합병증을 치료하는 기타 요법들과 함께 사용될 수 있으며, 이에는 비구아니드 약물, 인슐린(합성 인슐린 유사체) 및 경구 항고혈당제(이는 식사 글루코즈 조절제 및 알파-글루코시다제 저해제로 나누어짐)를 포함한다. The compounds of the present invention can be used in combination with other therapies to treat metabolic syndrome or type 2 diabetes and associated complications, including biguanide drugs, insulin (synthetic insulin analogs) and oral antihyperglycemic agents (which are dietary glucose modulators). And alpha-glucosidase inhibitors.

본 발명의 다른 양태에서, 화학식 (I)의 화합물, 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그는 PPAR 조절제와 함께 투여될 수 있다. PPAR 조절제에는 PPAR 알파 및/또는 감마 작동제, 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그를 포함하나, 이로 제한되지는 않는다. 적절한 PPAR 알파 및/또는 감마 작동제, 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그는 본 기술 분야에 잘 알려져 있다.In another embodiment of the invention, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate, or prodrug thereof, may be administered with a PPAR modulator. PPAR modulators include, but are not limited to, PPAR alpha and / or gamma agonists, or pharmaceutically acceptable salts, solvates, solvates of these salts, or prodrugs thereof. Suitable PPAR alpha and / or gamma agonists, or pharmaceutically acceptable salts, solvates, solvates, or prodrugs thereof, are well known in the art.

덧붙여, 본 발명의 배합물은 설포닐우레아와 함께 사용될 수 있다. 본 발명은 또한 본 발명의 화합물을 콜레스테롤 저하제와 함께 포함한다. 본 출원에서 언급된 콜레스테롤 저하제에는 HMG-CoA 환원제(3-히드록시-3-메틸글루타릴 조효소 A 환원제)의 저해제를 포함하나, 이로 제한되지 않는다. 적절하게, HMG-CoA 환원제 저해제는 스타틴이다.In addition, the combinations of the present invention may be used with sulfonylureas. The present invention also includes a compound of the present invention together with a cholesterol lowering agent. Cholesterol lowering agents referred to in this application include, but are not limited to, inhibitors of HMG-CoA reducing agents (3-hydroxy-3-methylglutaryl coenzyme A reducing agents). Suitably, the HMG-CoA reducing agent inhibitor is a statin.

본 출원에 있어서, 용어 "콜레스테롤 저하제"는 또한 HMG-CoA 환원제 저해제의 화학적 변형체, 예컨대, 에스터, 프로드러그 및 대사산물(활성 또는 불활성 여부에 상관없이)을 포함한다. In the present application, the term "cholesterol lowering agent" also includes chemical variants of HMG-CoA reducing agent inhibitors, such as esters, prodrugs and metabolites (whether active or inactive).

본 발명은 또한 본 발명의 화합물을 회장 담즙산 전달계의 저해제(IBAT 저해제)와 함께 포함한다. 본 발명은 또한 본 발명의 화합물을 담즙산 결합 수지와 함께 포함한다.The invention also encompasses compounds of the invention in combination with inhibitors of the ileal bile acid delivery system (IBAT inhibitors). The present invention also includes compounds of the present invention in combination with bile acid binding resins.

본 발명의 부가적 추가 양태에 따라, 이러한 치료적 치료를 필요로 하는 인간과 같은 온혈 동물에게, 임의적으로 약학적으로 허용가능한 희석제 또는 담체와 함께, 유효한 양의 화학식 (I)의 화합물, 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물 또는 프로드러그의 투여를, 임의적으로 약학적으로 허용가능한 희석제 또는 담체와 함께, CETP(콜레스테롤 에스터 전이 단백질) 저해제; 콜레스테롤 흡착 길항제; MTP(마이크로솜 전이 단백질) 저해제; 니코틴산 유도체(느린 방출 및 배합 산물 포함); 피토스테롤 화합물; 프로부콜; 항-비만 화합물, 예컨대, 오를리스탯(EP 129,748) 및 시부트르아민(GB 2,184,122 및 US 4,929,629); 항고혈압 화합물, 예컨대, 안지오텐신 전환 효소(ACE) 저해제, 안지오텐신 II 수용체 길항제, 안드레날린성 차단제, 알파 안드레날린성 차단제, 베타 안드레날린성 차단제, 혼합된 알파/베타 안드레날린성 차단제, 아드레날린성 흥분제, 칼슘 채널 차단제, AT-1 차단제, 염분배설제, 이뇨제 또는 혈관확장제; CB1 길항제 또는 역 작동제; 기타 멜라닌 농축 호르몬(MCH) 길항제; PDK 저해제; 또는 핵 수용체, 예컨대, LXR, FXR, RXR, 및 ROR 알파의 조절제; SSRI; 세로토닌 길항제; 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물 또는 프로드러그에서 선택된 1개 이상의 작용제와 동시 투여, 순차적 투여, 또는 분리 투여하는 것을 포함하는 배합 치료를 제공한다.According to a further further aspect of the invention, to a warm-blooded animal such as a human in need of such therapeutic treatment, an effective amount of a compound of formula (I), optionally thereof, together with a pharmaceutically acceptable diluent or carrier, Administration of pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts, optionally together with pharmaceutically acceptable diluents or carriers, includes CETP (cholesterol ester transfer protein) inhibitors; Cholesterol adsorption antagonists; MTP (microsomal transfer protein) inhibitors; Nicotinic acid derivatives (including slow release and combination products); Phytosterol compounds; Probucol; Anti-obesity compounds such as orliststat (EP 129,748) and sibutramine (GB 2,184,122 and US 4,929,629); Antihypertensive compounds such as angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, andrenergic blockers, alpha andrenergic blockers, beta andrenergic blockers, mixed alpha / beta andrenergic blockers, adrenergic stimulants, Calcium channel blockers, AT-1 blockers, salt excretion agents, diuretics or vasodilators; CB1 antagonists or inverse agonists; Other melanin enrichment hormone (MCH) antagonists; PDK inhibitors; Or modulators of nuclear receptors such as LXR, FXR, RXR, and ROR alpha; SSRI; Serotonin antagonists; Or combination administration, sequential administration, or separate administration with one or more agents selected from pharmaceutically acceptable salts, solvates, solvates or prodrugs of such salts thereof.

따라서, 본 발명의 부가적 특징에서, 인간과 같은 온혈 동물에 유효한 양의 화학식 (I)의 화합물, 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그를, 이 배합 단락에서 서술된 화합물의 다른 분류 중 하나에서 선택된 화합물 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그의 유효한 양과 함께 동시 투여, 순차적 투여 또는 분리 투여하는 것을 포함하는 이러한 치료를 필요로 하는 인간과 같은 온혈 동물에서 유형 2 당뇨 및 이와 연관된 합병증의 치료 방법을 제공한다. Thus, in an additional feature of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate, or prodrug thereof, in an effective amount for a warm blooded animal such as a human, is combined Such as simultaneous administration, sequential administration or separate administration with an effective amount of a compound selected from one of the other classes of compounds described in the paragraph or a pharmaceutically acceptable salt, solvate, solvate, or prodrug thereof thereof Provided are methods of treating Type 2 diabetes and related complications in warm blooded animals such as humans in need thereof.

따라서, 본 발명의 부가적 특징에서, 인간과 같은 온혈 동물에 유효한 양의 화학식 (I)의 화합물, 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그를, 이 배합 단락에서 서술된 화합물의 다른 분류 중 하나에서 선택된 화합물 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그의 유효한 양과 함께 동시 투여, 순차적 투여 또는 분리 투여하는 것을 포함하는 이러한 치료를 필요로 하는 인간과 같은 온혈 동물에서 고지혈증 질병의 치료 방법을 제공한다. Thus, in an additional feature of the invention, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate, or prodrug thereof, in an effective amount for a warm blooded animal such as a human, is combined Such as simultaneous administration, sequential administration or separate administration with an effective amount of a compound selected from one of the other classes of compounds described in the paragraph or a pharmaceutically acceptable salt, solvate, solvate, or prodrug thereof thereof Provided are methods of treating hyperlipidemic diseases in warm-blooded animals such as humans in need thereof.

따라서, 본 발명의 추가적 양태에서, 화학식 (I)의 화합물, 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그, 및 이 배합 단락에서 서술된 화합물의 다른 분류 중 하나에서 선택된 화합물 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그를, 약학적으로 허용가능한 희석제 또는 담체와 함께 포함하는 약학 조성물을 제공한다. Thus, in a further aspect of the invention, one of the compounds of formula (I), or a pharmaceutically acceptable salt, solvate, solvate, or prodrug thereof, and other classes of compounds described in this combination paragraph Provided is a pharmaceutical composition comprising a compound selected from or a pharmaceutically acceptable salt, solvate, solvate, or prodrug thereof with a pharmaceutically acceptable diluent or carrier.

따라서, 본 발명의 추가적 양태에서, 화학식 (I)의 화합물, 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그, 및 이 배합 단락에서 서술된 화합물의 다른 분류 중 하나에서 선택된 화합물 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그를 포함하는 킷트를 제공한다. Thus, in a further aspect of the invention, one of the compounds of formula (I), or a pharmaceutically acceptable salt, solvate, solvate, or prodrug thereof, and other classes of compounds described in this combination paragraph Kits comprising a compound selected from pharmaceutically acceptable salts, solvates, solvates of such salts, or prodrugs thereof are provided.

따라서, 본 발명의 추가적 양태에서, a) 제1 단위 제형내 화학식 (I)의 화합물, 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그; b) 제2 단위 제형내 이 배합 단락에서 서술된 화합물의 다른 분류 중 하나에서 선택된 화합물 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그; 및 c) 상기 제1 및 제2 제형을 포함하는 용기를 포함하는 킷트를 제공한다. Thus, in a further aspect of the invention, a) a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate, or prodrug thereof, in a first unit dosage form; b) a compound selected from one of the other classes of compounds described in this formulation section in the second unit dosage form or a pharmaceutically acceptable salt, solvate, solvate, or prodrug thereof; And c) a container comprising said first and second formulations.

따라서, 본 발명의 추가적 양태에서, a) 제1 단위 제형내 약학적으로 허용가능한 희석제 또는 담체와 함께 화학식 (I)의 화합물, 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그; b) 제2 단위 제형내 이 배합 단락에서 서술된 화합물의 다른 분류 중 하나에서 선택된 화합물 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그; 및 c) 상기 제1 및 제2 제형을 포함하는 용기를 포함하는 킷트를 제공한다. Thus, in a further aspect of the invention, a) a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt, together with a pharmaceutically acceptable diluent or carrier in a first unit dosage form, Or prodrugs; b) a compound selected from one of the other classes of compounds described in this formulation section in the second unit dosage form or a pharmaceutically acceptable salt, solvate, solvate, or prodrug thereof; And c) a container comprising said first and second formulations.

따라서, 본 발명의 다른 특징에서, 인간과 같은 온혈 동물에서의 대사 증후군 또는 유형 2 당뇨 및 이와 연관된 합병증의 치료에 사용하는 약제의 제조에 있어서, 화학식 (I)의 화합물, 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그, 및 이 배합 단락에서 서술된 다른 화합물 중 하나 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그의 용도를 제공한다. Thus, in another aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable thereof, in the manufacture of a medicament for use in the treatment of metabolic syndrome or type 2 diabetes and associated complications in a warm blooded animal such as a human Provides the use of possible salts, solvates, solvates, or prodrugs of such salts, and one or other pharmaceutically acceptable salts, solvates, solvates of such salts, or prodrugs thereof, as described in this formulation section. do.

따라서, 본 발명의 다른 특징에서, 인간과 같은 온혈 동물에서의 고지혈증 질병의 치료에 사용하는 약제의 제조에 있어서, 화학식 (I)의 화합물, 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그, 및 이 배합 단락에서 서술된 다른 화합물 중 하나 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그의 용도를 제공한다. Thus, in another aspect of the invention, in the preparation of a medicament for use in the treatment of hyperlipidemic diseases in warm-blooded animals such as humans, the compounds of formula (I), or pharmaceutically acceptable salts, solvates thereof, of such salts Solvates, or prodrugs, and one or other pharmaceutically acceptable salts, solvates, solvates of such salts, or prodrugs thereof, as described in this formulation section.

따라서, 본 발명의 추가 양태에서, 이러한 치료적 치료를 필요로 하는 인간과 같은 온혈 동물에, 약학적으로 허용가능한 희석제 또는 담체와 함께, 유효한 양의 화학식 (I)의 화합물, 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그의 투여를, 약학적으로 허용가능한 희석제 또는 담체와 함께, 이 배합 단락에서 서술된 다른 화합물 중 하나 또는 이의 약학적으로 허용가능한 염, 용매화물, 이러한 염의 용매화물, 또는 프로드러그의 유효한 양을 동시 투여, 순차적 투여 또는 분리 투여하는 것을 포함하는 배합 치료를 제공한다.Thus, in a further aspect of the invention, in warm-blooded animals such as humans in need of such therapeutic treatment, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier Administration of an acceptable salt, solvate, solvate of such salt, or prodrug, together with a pharmaceutically acceptable diluent or carrier, one of the other compounds described in this formulation section or a pharmaceutically acceptable salt, solvent thereof Provided are combination therapies comprising simultaneous, sequential or separate administration of an effective amount of a cargo, solvate of such salt, or prodrug.

이제 본 발명은 이하 본 발명의 범위를 제한하지 않는 실시예들로 보다 상세히 설명될 것이다. The invention will now be described in more detail with examples which do not limit the scope of the invention.

약자Abbreviation

aq. 수성aq. Mercury

Ac 아세틸 Ac acetyl

BINAP rac-2,2'-비스(디페닐-포스피노)-1,1'-비나프틸BINAP rac- 2,2'-bis (diphenyl-phosphino) -1,1'-binaftil

Bu 부틸 Bu Butyl

DMF N,N'-디메틸포름아미드 DMF N, N'-dimethylformamide

EtOAc 에틸 아세테이트 EtOAc ethyl acetate

Et20 디에틸 에테르Et 2 0 diethyl ether

HEK 인간 배아 신장HEK human embryo kidney

HOAc 아세트산 HOAc acetic acid

HPLC 고성능 액체 크로마토그래피 HPLC high performance liquid chromatography

LC-MS 액체 크로마토그래피 질량 분광학 LC-MS Liquid Chromatography Mass Spectroscopy

MeOH 메탄올 MeOH Methanol

폴-BH3CN (폴리스티릴메틸)트리메틸암모늄 시아노보로히드리드Paul-BH 3 CN (polytyrylmethyl) trimethylammonium cyanoborohydride

폴-CHO 4-벤질옥시벤즈알데히드 폴리스티렌 Paul-CHO 4-benzyloxybenzaldehyde polystyrene

TFA 트리플루오로아세트산 TFA trifluoroacetic acid

THF 테트라히드로푸란 THF tetrahydrofuran

MeCN 아세토니트릴 MeCN acetonitrile

NEt3 트리에틸아민NEt 3 triethylamine

트리스 트리스히드록시메틸아미노메탄 Tris trishydroxymethylaminomethane

tt tert tert

rt. 실온 rt. Room temperature

sat. 포화된 sat. Saturated

br 브로드 br broad

bs 브로드 싱글렛 bs broad singlet

bt 브로드 트리플렛 bt broad triplet

d 더블렛d doublet

dd 더블렛의 더블렛 dd doublet doublet

m 멀티플렛m multiplet

q 쿼텟 q quarts

s 싱글렛s singlet

t 트리플렛 t triplet

tt 트리플렛의 트리플렛 tt triplet triplet

td 더블렛의 트리플렛 triplet of td doublet

bd 브로드 더블렛 bd broad doublet

일반 실험 과정General Experiment Process

플래쉬 컬럼 크로마토그래피는 매트랙스(Matrex) 노말 상 실리카 겔 60Å(30-70) μM을 사용하였다. 질량 스펙트럼은 공기-보조 전자분무 인터페이스가 장착된 마이크로매스 ZQ 단일 4중극자 상에 기록된다(LC-MS). 정제는 엑스테라(XTerra) 100 mm x 19 mm C18 5 ㎛ 컬럼이 장착된 질량 트리거 분획 수집기를 갖는 반 예비 준비 HPLC(Shimadzu QP 8000) 또는 Ace ㎛ 5 5 ㎛ C8 100 mm x 21.2 mm 컬럼이 장착된 질량 트리거 분획 수집기를 갖는 워터스 프랙션린스(Waters FractionLynx) HPLC 또는 크로마실(Kromasil) 10 ㎛ C8 250 mm x 20 mm 컬럼이 장착된 UV-검출기를 갖는 워터스 프렙(Waters Prep) LC 2000, 또는 워터스 시메트리(Waters Symmetry)?100 mm x 19 mm C18 5 ㎛ 컬럼이 장착된 반 예비 HPLC(Shimadzu LC-8A, Shimadzu SPD-10A UV-vis.-검출기) 상에서 수행하였다. 1H NMR 및 13C NMR 스펙트럼은 배리언 유니티 플러스(Varian Unity Plus) 400 mHz, 또는 배리언(Varian) INOVA 500 MHz 또는 브루커 아밴스(Bruker Avance) 300 MHz 상에서 298 K에서 얻었다. 화학적 쉬프트는 용매 잔여 피크를 내부 표준으로 하여 ppm으로 나타내었다: CDC13 δH 7.26, δC 77.2; MeOH-d4 δ H 3.31, δC 49.0; DMSO-d6 δH 2.50; δC 39.5 ppm, DMF-d7 δH 2.75/2.95/8.05, 아세톤-d6 δH 2.05, THF-d8 δH 1.74/3.60 ppm. 마이크로파 가열은 퍼스날 케미스트리(Personal Chemistry, 스웨덴 웁살라 소재)의 스미쓰 크리에이터(Smith Creator)에서 단일 노드 가열을 사용하여 수행하였다.Flash column chromatography used 60 μs (30-70) μM silica gel on Matrex normal. Mass spectra are recorded on a micromass ZQ single quadrupole equipped with an air-assisted electrospray interface (LC-MS). Purification was performed using a semi-preparative preparative HPLC (Shimadzu QP 8000) or Ace μm 5 5 μm C8 100 mm × 21.2 mm column with a mass trigger fraction collector equipped with an XTerra 100 mm × 19 mm C18 5 μm column. Waters Prep LC 2000 with Waters FractionLynx HPLC or Kromasil 10 μm C8 250 mm × 20 mm column with Mass Trigger Fraction Collector, or Waters Simmetry Waters Symmetry— performed on semi-preparative HPLC (Shimadzu LC-8A, Shimadzu SPD-10A UV-vis.-detector) equipped with a 100 mm × 19 mm C18 5 μm column. 1 H NMR and 13 C NMR spectra were obtained at 298 K on Varian Unity Plus 400 mHz, or on Varian INOVA 500 MHz or Bruker Avance 300 MHz. Chemical shifts are given in ppm with solvent residual peaks as internal standard: CDC1 3 δ H 7.26, δ C 77.2; MeOH-d 4 δ H 3.31, δ C 49.0; DMSO-d 6 δ H 2.50; δ C 39.5 ppm, DMF-d 7 δ H 2.75 / 2.95 / 8.05, acetone-d 6 δ H 2.05, THF-d 8 δ H 1.74 / 3.60 ppm. Microwave heating was performed using single node heating at Smith Creator, Personal Chemistry, Uppsala, Sweden.

출발 물질 및 중간체의 합성Synthesis of Starting Materials and Intermediates

A1 N-퀴놀린-2-일프로판-1,3-디아민 A1 N-quinolin-2-ylpropane-1,3-diamine

2-클로로퀴놀린(4.80 mmol, 1.0 g), 1,3-프로판디아민(7.20 mmol, 0.534 g), NaOtBu(6.72 mmol, 0.646 g), Pd(OAc)2(0.048 mmol, 0.011 g), 및 2-(디-t부틸포스피노)비페닐(0.048 mmol, 0.014 g)의 톨루엔(12 mL) 내 혼합물을 LC-MS가 출발 물질이 소비되었음을 나타낼 때까지 100℃, 질소하에서 교반하였다. 반응 혼합물을 실온으로 냉각하고, Et2O(100 mL)에 붓고, 여과 에이드의 플러그를 통해 여과하였다. 여과물을 농축하고, 잔류물을 미리 팩킹된 Si02 컬럼(70 g) 상에서 정제하고, CH2Cl2(0.5% HOAc 함유, 300 mL), CH2Cl2:MeOH(5:1, 300 mL), 및 마지막으로 CH2Cl2:MeOH:H20(10:6:1, 1% Et3N 함유)로 용출하여, 0.915 g(95%)의 표제 화합물을 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.85(d, J = 10.1 Hz, 1H), 7.62-7.58(m, 2H), 7.51(t, J = 8.5 Hz, 1H), 7.20(t, J = 8.0 Hz, 2H), 6.76(d, J = 8.8 Hz, 1H), 3.61(t, J = 6.5 Hz, 2H), 2.92(t, J = 6.6 Hz, 2H), 1.93(퀸텟, J = 6.8 Hz, 2H).2-chloro-quinoline (4.80 mmol, 1.0 g), 1,3- propanediamine (7.20 mmol, 0.534 g), NaO t Bu (6.72 mmol, 0.646 g), Pd (OAc) 2 (0.048 mmol, 0.011 g), And a mixture of toluene (12 mL) of 2- (di- t butylphosphino) biphenyl (0.048 mmol, 0.014 g) was stirred under nitrogen at 100 ° C. until LC-MS indicated the starting material was consumed. The reaction mixture was cooled to rt, poured into Et 2 O (100 mL) and filtered through a plug of filtration aid. The filtrate was concentrated and the residue was purified on prepacked Si0 2 column (70 g), CH 2 Cl 2 (containing 0.5% HOAc, 300 mL), CH 2 Cl 2 : MeOH (5: 1, 300 mL ), And finally eluted with CH 2 Cl 2 : MeOH: H 2 O (containing 10: 6: 1, 1% Et 3 N) to afford 0.915 g (95%) of the title compound. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.85 (d, J = 10.1 Hz, 1H), 7.62-7.58 (m, 2H), 7.51 (t, J = 8.5 Hz, 1H), 7.20 (t , J = 8.0 Hz, 2H), 6.76 (d, J = 8.8 Hz, 1H), 3.61 (t, J = 6.5 Hz, 2H), 2.92 (t, J = 6.6 Hz, 2H), 1.93 (Quintet, J = 6.8 Hz, 2H).

A2 N-(6-메톡시-4-메틸-2-퀴놀린일)-1,3-프로판디아민 A2 N- (6-methoxy-4-methyl-2-quinolinyl) -1,3-propanediamine

표제 화합물을 A1 제조에 대해 서술된 과정을 사용하여 2-클로로-6-메톡시-4-메틸퀴놀린과 1,3-프로판디아민으로부터 제조하였다. 수율은 정량화하였다. 1H NMR(400 MHz, DMSO-d6) δ7.42(d, J = 9.1 Hz, 1H), 7.12-7.078(m, 2H), 6.57(s, 1H), 3.80(s, 3H), 3.37(t, J = 6.6 Hz, 2H), 2.66(bt, J = 6.6 Hz, 2H), 2.43(s, 3H), 1.67(퀸텟, J = 6.8 Hz, 2H).The title compound was prepared from 2-chloro-6-methoxy-4-methylquinoline and 1,3-propanediamine using the procedure described for A1 preparation. Yield was quantified. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.42 (d, J = 9.1 Hz, 1H), 7.12-7.078 (m, 2H), 6.57 (s, 1H), 3.80 (s, 3H), 3.37 (t, J = 6.6 Hz, 2H), 2.66 (bt, J = 6.6 Hz, 2H), 2.43 (s, 3H), 1.67 (quintet, J = 6.8 Hz, 2H).

A3 N-퀴놀린-2-일시클로헥산-1,4-디아민A3 N-quinolin-2-ylcyclohexane-1,4-diamine

표제 화합물을 A1 제조에 대해 서술된 과정을 사용하여 2-클로로퀴놀린과 시클로헥산-1,4-디아민으로부터 이성질체의 혼합물로 제조하였다. 수율은 94%이었다. 1H NMR(400 MHz, MeOH-d4, 다수 이성질체) δ7.92(d, J = 9.1 Hz, 1H), 7.63(d, J = 8.3 Hz, 1H), 7.60(d, J = 8.1 Hz, 1H), 7.54-7.50(m, 1H), 7.22(t, J = 8.0 Hz, 1H), 6.92(d, J = 9.3 Hz, 1H), 4.17-4.09(m, 1H), 3.29-3.21(m, 1H), 2.22-2.08(m, 1H), 1.94-1.75(m, 6H), 1.69-1.37(m, 1H).The title compound was prepared as a mixture of isomers from 2-chloroquinoline and cyclohexane-1,4-diamine using the procedure described for A1 preparation. Yield 94%. 1 H NMR (400 MHz, MeOH-d 4 , Many Isomers) δ7.92 (d, J = 9.1 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.54-7.50 (m, 1H), 7.22 (t, J = 8.0 Hz, 1H), 6.92 (d, J = 9.3 Hz, 1H), 4.17-4.09 (m, 1H), 3.29-3.21 (m , 1H), 2.22-2.08 (m, 1H), 1.94-1.75 (m, 6H), 1.69-1.37 (m, 1H).

A4 N-퀴놀린-2-일시클로헥산-1,3-디아민 A4 N-quinolin-2-ylcyclohexane-1,3-diamine

표제 화합물을 A1 제조에 대해 서술된 과정을 사용하여 2-클로로퀴놀린과 시클로헥산-1,3-디아민으로부터 부분입체 이성질체의 혼합물로 제조하였다. 수율은 84%이었다. 1H NMR(400 MHz, MeOH-d4, 다수 이성질체) δ7.82(d, J = 8.9 Hz, 1H), 7.61-7.57(m, 2H), 7.48(t, J = 8.5 Hz, 1H), 7.19(d, J = 7.9 Hz, 1H), 6.73(d, J = 9.1 Hz, 1H), 4.12-4.04(m, 1H), 3.28-3.21(m, 2H), 2.56-2.50(m, 1H), 2.07(t, J = 12.0 Hz, 1H), 1.98-1.93(m, 1H), 1.82-1.75(m, 1H), 1.62-1.49(m, 1H), 1.41-1.23(m, 2H).The title compound was prepared as a mixture of diastereomers from 2-chloroquinoline and cyclohexane-1,3-diamine using the procedure described for A1 preparation. Yield 84%. 1 H NMR (400 MHz, MeOH-d 4 , Many Isomers) δ 7.82 (d, J = 8.9 Hz, 1H), 7.61-7.57 (m, 2H), 7.48 (t, J = 8.5 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 6.73 (d, J = 9.1 Hz, 1H), 4.12-4.04 (m, 1H), 3.28-3.21 (m, 2H), 2.56-2.50 (m, 1H) , 2.07 (t, J = 12.0 Hz, 1H), 1.98-1.93 (m, 1H), 1.82-1.75 (m, 1H), 1.62-1.49 (m, 1H), 1.41-1.23 (m, 2H).

A5 N-퀴놀린-2-일에탄-1,2-디아민 A5 N-quinolin-2-ylethane-1,2-diamine

표제 화합물을 A1 제조에 대해 서술된 과정을 사용하여 2-클로로퀴놀린과 1,2-에탄디아민으로부터 제조하였다. 수율은 65%이었다. 1H NMR(400 MHz, MeOH-d4) δ7.81(d, J = 9.1 Hz, 1H), 7.61-7.56(m, 2H), 7.47(t, J = 8.5 Hz, 1H), 7.16(t, J = 8.1 Hz, 1H), 6.74(d, J = 8.9 Hz, 1H), 3.55(t, J = 6.2 Hz, 2H), 2.91(t, J = 6.1 Hz, 2H).The title compound was prepared from 2-chloroquinoline and 1,2-ethanediamine using the procedure described for A1 preparation. Yield 65%. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.81 (d, J = 9.1 Hz, 1H), 7.61-7.56 (m, 2H), 7.47 (t, J = 8.5 Hz, 1H), 7.16 (t , J = 8.1 Hz, 1H), 6.74 (d, J = 8.9 Hz, 1H), 3.55 (t, J = 6.2 Hz, 2H), 2.91 (t, J = 6.1 Hz, 2H).

A6 N-메틸-N'-퀴놀린-2-일프로판-1,3-디아민 A6 N-methyl-N'-quinolin-2-ylpropane-1,3-diamine

표제 화합물을 A1 제조에 대해 서술된 과정을 사용하여 2-클로로퀴놀린과 N'-메틸-1,3-프로판디아민으로부터 제조하였다. 수율은 61%이었다. 1H NMR(400 MHz, MeOH-d4) δ7.87(d, J = 9.06 Hz, 1H), 7.64-7.59(m, 2H), 7.56-7.50(m, 1H), 7.22(t, J = 7.4 Hz, 1H), 6.78(d, J = 8.9 Hz, 1H), 3.63(t, J = 6.3 Hz, 2H), 3.03(t, J = 6.5 Hz, 2H), 2.65(s, 3H), 2.02(m, 2H).The title compound was prepared from 2-chloroquinoline and N'-methyl-1,3-propanediamine using the procedure described for A1 preparation. Yield 61%. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.87 (d, J = 9.06 Hz, 1H), 7.64-7.59 (m, 2H), 7.56-7.50 (m, 1H), 7.22 (t, J = 7.4 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 3.63 (t, J = 6.3 Hz, 2H), 3.03 (t, J = 6.5 Hz, 2H), 2.65 (s, 3H), 2.02 (m, 2 H).

A7 N-메틸-N-퀴놀린-2-일프로판-1,3-디아민A7 N-methyl-N-quinolin-2-ylpropane-1,3-diamine

표제 화합물을 A6의 제조로부터 분리하였다. 1H NMR(400 MHz, MeOH-d4) δ8.03(d, J = 9.1 Hz, 1H), 7.69-7.59(m, 2H), 7.58-7.52(m, 1H), 7.22(t, J = 7.4 Hz, 1H), 7.08(d, J = 9.1 Hz, 1H), 3.88(t, J = 6.2 Hz, 2H), 3.16(s, 3H), 2.94(t, J = 6.4 Hz, 2H), 2.02(m, 2H).The title compound was isolated from the preparation of A6. 1 H NMR (400 MHz, MeOH-d 4 ) δ 8.03 (d, J = 9.1 Hz, 1H), 7.69-7.59 (m, 2H), 7.58-7.52 (m, 1H), 7.22 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 9.1 Hz, 1H), 3.88 (t, J = 6.2 Hz, 2H), 3.16 (s, 3H), 2.94 (t, J = 6.4 Hz, 2H), 2.02 (m, 2 H).

A8 N-피페리딘-4-일퀴놀린-2-아민 A8 N-piperidin-4-ylquinolin-2-amine

표제 화합물을 A1 제조에 대해 서술된 과정을 사용하여 2-클로로퀴놀린과 피페리딘-4-일아민으로부터 제조하였다. 수율은 18%이었다. 1H NMR(400 MHz, MeOH-d4) δ7.77(d, J = 9.1 Hz, 1H), 7.59(d, J = 8.3 Hz, 1H), 7.54(d, J = 8.3 Hz, 1H), 7.46(t, J = 8.5 Hz, 1H), 7.21-7.07(m, 1H), 6.71(d, J = 9.8 Hz, 1H), 4.13-4.06(m, 1H), 3.13(d, J = 12.5 Hz, 2H), 2.80(dt, J = 3.1, 13.7 Hz, 2H), 2.10-2.06(m, 2H), 1.56-1.46(m, 2H).The title compound was prepared from 2-chloroquinoline and piperidin-4-ylamine using the procedure described for A1 preparation. Yield 18%. 1 H NMR (400 MHz, MeOH-d 4 ) δ7.77 (d, J = 9.1 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.46 (t, J = 8.5 Hz, 1H), 7.21-7.07 (m, 1H), 6.71 (d, J = 9.8 Hz, 1H), 4.13-4.06 (m, 1H), 3.13 (d, J = 12.5 Hz , 2H), 2.80 (dt, J = 3.1, 13.7 Hz, 2H), 2.10-2.06 (m, 2H), 1.56-1.46 (m, 2H).

A9 9-포밀-9,10-디히드로-9,10-메타노안트라센 A9 9-formyl-9,10-dihydro-9,10-methanoanthracene

이하 참조 문헌들에 따라 제조하였다: H. Sunagawa 등; Chem. Pharm. Bull. Vol. 27(1979) pp 1806-1812; 미국 특허 제4,224,344호, Sunagawa 등, Sumitomo, Ltd.; Sep. 23, 1980; 미국 특허 제4,358,620호, Sunagawa 등, Sumitomo, Ltd.; Nov. 9, 1982. Prepared according to the following references: H. Sunagawa et al .; Chem. Pharm. Bull. Vol. 27 (1979) pp 1806-1812; US Patent No. 4,224,344, Sunagawa et al., Sumitomo, Ltd .; Sep. 23, 1980; U.S. Patent No. 4,358,620, Sunagawa et al., Sumitomo, Ltd .; Nov. 9, 1982.

A10 (1R,3S)-3-[(A10 (1R, 3S) -3-[( terttert -부톡시카보닐)아미노]시클로펜틸 메탄설포네이트-Butoxycarbonyl) amino] cyclopentyl methanesulfonate

이하 참조 문헌들에 따라 (-)-2-아자비시클로[2.2.1]헵트-5-엔-3-온(>95% ee)로부터 제조하였다: H. Bergstrand 등; Astra AB; New Pharmaceutically Active Compounds; W09811103; Mars 19, 1998.Prepared from (−)-2-azabicyclo [2.2.1] hept-5-en-3-one (> 95% ee) according to the following references: H. Bergstrand et al .; Astra AB; New Pharmaceutically Active Compounds; W09811103; Mars 19, 1998.

A11 A11 terttert -부틸[(1S,3S)-3-아지도시클로펜틸]카바메이트 -Butyl [(1S, 3S) -3-azidocyclopentyl] carbamate

NaN3(16.6 g, 0.25 mmol)를 (1R,3S)-3-[(tert-부톡시카보닐)아미노]시클로펜틸 메탄설포네이트(20 g, 크루드, ~0.05 mol)의 DMF(250 mL) 내 교반된 용액에 질소 대기 하에서 첨가하였다. 이 혼합물을 50℃로 18시간 동안(밤새) 가열하였다. 이 혼합물을 실온에 도달하도록 방치하고, H20(200 mL)에 붓고, EtOAc(2 x 400 mL), 200 mL Et2O로 추출하여, 농축하였다. 잔류물을 플래쉬 크로마토그래피로 정제하여 (280 g 실리카 겔, 6 x 22 cm 컬럼, 용출액으로 EtOAc/헵탄(2:3 -> 1:1) 사용), 표제 화합물(16.5 g, DMF로 오염됨)을 밝은 누르스름한 오일로 얻었으며, 추가 정제없이 다음 단계에 사용하였다. 1H NMR(CDCl3) δ4.52(bs, 1H), 4.00-4.10(m, 2H), 1.98-2.22(m, 3H), 1.62-1.78(m, 2H), 1.42-1.52(m, 1H), 1.44(s, 9H).NaN 3 (16.6 g, 0.25 mmol) was converted to DMF (250 mL) of (1R, 3S) -3-[( tert -butoxycarbonyl) amino] cyclopentyl methanesulfonate (20 g, crude, ˜0.05 mol) To the stirred solution). The mixture was heated to 50 ° C. for 18 hours (overnight). The mixture was left to reach room temperature, poured into H 2 0 (200 mL), extracted with EtOAc (2 × 400 mL), 200 mL Et 2 O and concentrated. The residue was purified by flash chromatography (280 g silica gel, 6 x 22 cm column, using EtOAc / heptanes (2: 3-> 1: 1) as eluent), title compound (16.5 g, contaminated with DMF). Was obtained as a light yellowish oil and used in the next step without further purification. 1 H NMR (CDCl 3 ) δ4.52 (bs, 1H), 4.00-4.10 (m, 2H), 1.98-2.22 (m, 3H), 1.62-1.78 (m, 2H), 1.42-1.52 (m, 1H ), 1.44 (s, 9 H).

A12 A12 terttert -부틸[(1S,3S)-3-아미노시클로펜틸]카바메이트 -Butyl [(1S, 3S) -3-aminocyclopentyl] carbamate

MeOH(300 mL) 내 A11의 tert-부틸[(1S,3S)-3-아미노시클로펜틸]카바메이트(16.5 g, 크루드, ~0.05 mol)와 1.7 g Pd-C(10% 페이스트)를 함유하는 플라스크를 수 주일 동안 수소 기체(풍선)의 양압(positive pressure)에 노출하였다. 촉매를 여과하고, 혼합물을 농축하여, 표제 화합물(9.5 g)을 걸쭉한 무색 점성 오일로 얻었다. 1H NMR(DMSO-d6) δ6,74(bd, 1H), 3.86-3.92(m, 1H), 3.28(퀸텟, 1H), 1.73-1.98(m, 2H), 1.43-1.59(m, 2H), 1.22-1.41(m, 1H), 1.36(s, 9H), 1.07-1.20(m, 1H). 13C NMR(DMSO-d6) δ155.0, 77.2, 50.8, 50.0, 42.6, 34.2, 31.2, 28.3. LC-MS [M+H]+ 201.Contains tert -butyl [(1S, 3S) -3-aminocyclopentyl] carbamate (16.5 g, crude, ˜0.05 mol) and 1.7 g Pd-C (10% paste) of A11 in MeOH (300 mL) The flask was exposed to positive pressure of hydrogen gas (balloon) for several weeks. The catalyst was filtered off and the mixture was concentrated to give the title compound (9.5 g) as a thick colorless viscous oil. 1 H NMR (DMSO-d 6 ) δ 6,74 (bd, 1H), 3.86-3.92 (m, 1H), 3.28 (quintet, 1H), 1.73-1.98 (m, 2H), 1.43-1.59 (m, 2H ), 1.22-1.41 (m, 1H), 1.36 (s, 9H), 1.07-1.20 (m, 1H). 13 C NMR (DMSO-d 6 ) δ 155.0, 77.2, 50.8, 50.0, 42.6, 34.2, 31.2, 28.3. LC-MS [M + H] + 201.

A13 N-(6-메톡시-4-메틸퀴놀린-2-일)시클로헥산-1,3-디아민A13 N- (6-methoxy-4-methylquinolin-2-yl) cyclohexane-1,3-diamine

2-클로로-6-메톡시-4-메틸퀴놀린(1.20 mmol, 0.250 g), 1,3-시클로헥산디아민(3.61 mmol, 0.412 g), NaOtBu(1.70 mmol, 0.162 g), Pd(OAc)2(0.02 mmol, 0.004 g), 및 2-(디-t부틸포스피노)비페닐(0.034 mmol, 0.010 g)의 톨루엔(5 mL) 내 혼합물을 100℃에서 아르곤 하에 24시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고, 1% NEt3가 함유된 BtOAc/MeOH 5:1로 희석하고, 짧은(~2 cm) 실리카 컬럼에 집접 로딩하였다. 1% NEt3가 함유된 BtOAc/MeOH 5:1로 용출하여, 0.241 g(70%)의 표제 화합물을 부분입체 이성질체의 혼합물로 얻었다(~6:1). 1H NMR(400 MHz, MeOH-d4) δ7.52(d, J = 9.1 Hz, 1H, 다수 이성질체), 7.52(d, J = 9.1 Hz, 1H, 소수 이성질체), 7.12(dd, J = 9.1, 2.8 Hz, 1H), 7.05(d, J = 2.8 Hz, 1H), 6.62(bs, 1H, 소수 이성질체), 6.53(bs, 1H, 다수 이성질체), 4.27(m, 1H, 소수 이성질체), 3.88(tt, J = 11.6, 3.8 Hz, 1H, 다수 이성질체), 3.80(s, 3H), 3.02(m, 1H, 소수 이성질체), 2.76(tt, J = 11. 4,3. 8 Hz, 1H, 다수 이성질체), 2.44(bs, 3H, 소수 이성질체), 2.42(bs, 3H, 다수 이성질체), 2.21(m, 1H), 2.02-0.96(m, 7H); 13C NMR(101 MHz, MeOH-d4, 다수 이성질체) δ156.8, 155.9, 145.3, 144.1, 127.5, 125.1, 120.8, 114.2, 104.8, 55.9, 50.5, 49.6, 43.5, 35.8, 33.6, 24.3, 18.9; LC-MS [M+H]+ 286.1.2-chloro-6-methoxy-4-methylquinoline (1.20 mmol, 0.250 g), 1,3-cyclohexanediamine (3.61 mmol, 0.412 g), NaO t Bu (1.70 mmol, 0.162 g), Pd (OAc ) 2 (0.02 mmol, 0.004 g), and a mixture of toluene (5 mL) of 2- (di- t butylphosphino) biphenyl (0.034 mmol, 0.010 g) were stirred at 100 ° C. under argon for 24 h. The reaction mixture was cooled to room temperature, diluted with BtOAc / MeOH 5: 1 with 1% NEt 3 and directly loaded onto a short (˜2 cm) silica column. Elution with BtOAc / MeOH 5: 1 with 1% NEt 3 gave 0.241 g (70%) of the title compound as a mixture of diastereomers (˜6: 1). 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.52 (d, J = 9.1 Hz, 1H, multiple isomers), 7.52 (d, J = 9.1 Hz, 1H, minor isomers), 7.12 (dd, J = 9.1, 2.8 Hz, 1H), 7.05 (d, J = 2.8 Hz, 1H), 6.62 (bs, 1H, minor isomers), 6.53 (bs, 1H, multiple isomers), 4.27 (m, 1H, minor isomers), 3.88 (tt, J = 11.6, 3.8 Hz, 1H, multiple isomers), 3.80 (s, 3H), 3.02 (m, 1H, minor isomers), 2.76 (tt, J = 11.4,3.8 Hz, 1H , Majority isomer), 2.44 (bs, 3H, minor isomers), 2.42 (bs, 3H, majority isomers), 2.21 (m, 1H), 2.02-0.96 (m, 7H); 13 C NMR (101 MHz, MeOH-d 4 , Multi-isomer) δ 156.8, 155.9, 145.3, 144.1, 127.5, 125.1, 120.8, 114.2, 104.8, 55.9, 50.5, 49.6, 43.5, 35.8, 33.6, 24.3, 18.9 ; LC-MS [M + H] + 286.1.

A14 N-(4-메틸퀴놀린-2-일)시클로헥산-1,3-디아민 A14 N- (4-methylquinolin-2-yl) cyclohexane-1,3-diamine

2-클로로-4-메틸퀴놀린(0.200 g, 1.13 mmol) 및 1,3-디아미노시클로헥산(0.51 g, 4.5 mmol)의 3 mL의 피리딘 내 용액을 단일 노드 마이크로파 가열하였다(210℃, 1시간). 이 반응 혼합물을 실온으로 냉각하고, 증발하였다. 원산물을 실리카 겔 상에서 플래쉬 크로마토그래피하고, EtOAc/MeOH/Et3N 50:50:1로 용출하여, 0.24 g(84%)의 표제 화합물을 부분입체 이성질체의 혼합물로 얻었다(~2.7:1). 1H NMR(300 MHz, MeOH-d4) δ7.7-7.8(m, 1H), 7.58-7.63(m, 1H), 7.45-7.55(m, 1H), 7.18-7.25(m, 1H), 6.70(bs, 1H, 소수 이성질체), 6.61(bs, 1H, 다수 이성질체), 4.44(m, 1H, 소수 이성질체), 4.06(m, 1H, 다수 이성질체), 2.48-2.55(m, 3H 플러스 1H, 다수 이성질체), 2.32(m, 1H, 소수 이성질체), 1.2-2.1(m, 8H).A solution in 3 mL of pyridine of 2-chloro-4-methylquinoline (0.200 g, 1.13 mmol) and 1,3-diaminocyclohexane (0.51 g, 4.5 mmol) was heated to a single node microwave (210 ° C., 1 hour). ). The reaction mixture was cooled to room temperature and evaporated. The crude product was flash chromatographed on silica gel and eluted with EtOAc / MeOH / Et 3 N 50: 50: 1 to give 0.24 g (84%) of the title compound as a mixture of diastereomers (˜2.7: 1). . 1 H NMR (300 MHz, MeOH-d 4 ) δ 7.7-7.8 (m, 1H), 7.58-7.63 (m, 1H), 7.45-7.55 (m, 1H), 7.18-7.25 (m, 1H), 6.70 (bs, 1H, minor isomers), 6.61 (bs, 1H, multiple isomers), 4.44 (m, 1H, minor isomers), 4.06 (m, 1H, multiple isomers), 2.48-2.55 (m, 3H plus 1H, Majority isomers), 2.32 (m, 1H, minor isomers), 1.2-2.1 (m, 8H).

실시예 1Example 1

N-(9,10-메타노안트라센-9(10H)-일메틸)-N'-(퀴놀린-2-일)-1,2-에탄디아민 N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N '-(quinolin-2-yl) -1,2-ethanediamine

폴-BH3CN(150 mg, CH2Cl2 내에 미리 팽창됨)을 N-퀴놀린-2-일에탄-1,2-디아민(0.299 mmol, 0.056 g)과 9-포밀-9,10-디히드로-9,10-메타노안트라센(0.225 mmol, 0.050 g)의 MeOH:CH2Cl2(1:1, 1% HOAc 함유, 2.5 mL) 내 용액에 첨가하고, 결과 슬러리를 단일 노드 마이크로파 가열하였다(100℃, 5분). 수지를 여과하고, 일부분의(1-2 mL) CH2Cl2와 MeOH로 세척하고, 여과물을 농축하였다. 잔류물을 CH2Cl 2(5 mL)에 용해하고, 폴-CHO(140 mg)을 첨가한 후, 슬러리를 실온에서 60분 동안 교반하였다. 수지를 여과하고, 일분의(1-2 mL 각각) CH2Cl2로 세척하였다. 여과물을 농축하고, 잔류물을 SiO2(EtOAc:MeOH 9:1) 상에서 정제하여, 0.078 g(88%)의 표제 화합물을 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.85(d, J = 8.9 Hz, 1H), 7.56(dd, J = 1.2, 9.0 Hz, 1H), 7.39(dt, J = 1.4, 11.5 Hz, 1H), 7.22(d, J = 7.3 Hz, 2H), 7.14(dt, J = 1.2, 7.9 Hz, 1H), 7.12-7.06(m, 3H), 6.86(dt, J = 1.2, 7.5 Hz, 2H), 6.82-6.75(m, 3H), 4.30(s, 1H), 4.02(s, 2H), 3.80(t, J = 5.2 Hz, 2H), 3.39(t, J = 5.6 Hz, 2H), 2.55(s, 2H). 실시예 2 내지 45는 아민을 언급된 알데히드와 반응하여 실시예 1에 서술된 과정을 사용하여 수행하였다.Paul-BH 3 CN (150 mg, pre-expanded in CH 2 Cl 2 ) was added N-quinolin- 2- yleethane-1,2-diamine (0.299 mmol, 0.056 g) and 9-formyl-9,10-di Hydro-9,10-methanoanthracene (0.225 mmol, 0.050 g) was added to a solution in MeOH: CH 2 Cl 2 (containing 1: 1, 1% HOAc, 2.5 mL) and the resulting slurry was heated to single node microwaves. (100 ° C., 5 minutes). The resin was filtered off, washed with a portion (1-2 mL) CH 2 Cl 2 and MeOH, and the filtrate was concentrated. The residue was dissolved in CH 2 Cl 2 (5 mL) and Paul-CHO (140 mg) was added and the slurry was stirred at room temperature for 60 minutes. The resin was filtered off and washed with a quarter (1-2 mL each) CH 2 Cl 2 . The filtrate was concentrated and the residue was purified on SiO 2 (EtOAc: MeOH 9: 1) to afford 0.078 g (88%) of the title compound. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.85 (d, J = 8.9 Hz, 1H), 7.56 (dd, J = 1.2, 9.0 Hz, 1H), 7.39 (dt, J = 1.4, 11.5 Hz , 1H), 7.22 (d, J = 7.3 Hz, 2H), 7.14 (dt, J = 1.2, 7.9 Hz, 1H), 7.12-7.06 (m, 3H), 6.86 (dt, J = 1.2, 7.5 Hz, 2H), 6.82-6.75 (m, 3H), 4.30 (s, 1H), 4.02 (s, 2H), 3.80 (t, J = 5.2 Hz, 2H), 3.39 (t, J = 5.6 Hz, 2H), 2.55 (s, 2 H). Examples 2 to 45 were carried out using the procedure described in Example 1 by reacting an amine with the aldehydes mentioned.

실시예 2Example 2

N-(6-메톡시-4-메틸-2-퀴놀린일)-N'-(3-티에닐메틸)-1,3-프로판디아민 N- (6-methoxy-4-methyl-2-quinolinyl) -N '-(3-thienylmethyl) -1,3-propanediamine

이 화합물을 N-(6-메톡시-4-메틸-2-퀴놀린일)-1,3-프로판디아민과 3-티오펜카르복살데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액: 5% CH3CN -> 100% CH3CN, 10분, 25 ml/분)을 사용하여 정제하여, 표제 화합물을 34% 수율로 얻었다. 1H NMR(400 MHz, DMF-d7) δ7.48-7.46(m, 1H), 7.45(d, J = 9.1 Hz, 1H), 7.32-7.31(m, 1H), 7.17(dd, J = 2.6, 13.5 Hz, 2H), 7.13(t, J = 4.2 Hz, 1H), 6.67(s, 1H), 3.88(s, 3H), 3.77(s, 2H), 3.53(t, J = 6.6 Hz, 2H), 2.69(t, J = 6.7 Hz, 2H), 2.49(s, 3H), 1.82(퀸텟, J = 6.7 Hz, 2H).This compound was prepared from N- (6-methoxy-4-methyl-2-quinolinyl) -1,3-propanediamine and 3-thiophenecarboxaldehyde, and HPLC (95% 0.1 M ammonium acetate buffer: 5 Purification using% CH 3 CN-> 100% CH 3 CN, 10 min, 25 ml / min) afforded the title compound in 34% yield. 1 H NMR (400 MHz, DMF-d 7 ) δ 7.48-7.46 (m, 1H), 7.45 (d, J = 9.1 Hz, 1H), 7.32-7.31 (m, 1H), 7.17 (dd, J = 2.6, 13.5 Hz, 2H), 7.13 (t, J = 4.2 Hz, 1H), 6.67 (s, 1H), 3.88 (s, 3H), 3.77 (s, 2H), 3.53 (t, J = 6.6 Hz, 2H), 2.69 (t, J = 6.7 Hz, 2H), 2.49 (s, 3H), 1.82 (quintet, J = 6.7 Hz, 2H).

실시예 3Example 3

N-(9,10-메타노안트라센-9(10H)-일메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine

이 화합물은 N-퀴놀린-2-일-1,3-프로판디아민과 9-포밀-9,10-디히드로-9,10-메타노안트라센으로부터 제조하였으며, SiO2(CH2Cl2:MeOH 20:1 -> 10:1, 1% HOAc 함유) 상에서 정제하여, 표제 화합물을 50% 수율로 얻었다. 1H NMR(MeOH-d4, 400 MHz) δ7.85(d, J = 8.9 Hz, 1H), 7.57(dd, J = 1.4, 9.3 Hz, 1H), 7.36-7.32(m, 5H), 7.31-7.22(m, 5H), 7.14(t, J = 8.0 Hz, 1H), 7.01-6.93(m, 5H), 6.75(d, J = 9.1 Hz, 1H), 4.43(s, 1H), 4.21(s, 2H), 3.70(t, J = 6.4 Hz, 2H), 3.31(t, J = 1.4 Hz, 2H), 2.65(s, 2H), 2.23(퀸텟, J = 6.5 Hz, 2H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and 9-formyl-9,10-dihydro-9,10-methanoanthracene, and SiO 2 (CH 2 Cl 2 : MeOH 20 : 1-> 10: 1, containing 1% HOAc) to give the title compound in 50% yield. 1 H NMR (MeOH-d 4 , 400 MHz) δ 7.85 (d, J = 8.9 Hz, 1H), 7.57 (dd, J = 1.4, 9.3 Hz, 1H), 7.36-7.32 (m, 5H), 7.31 -7.22 (m, 5H), 7.14 (t, J = 8.0 Hz, 1H), 7.01-6.93 (m, 5H), 6.75 (d, J = 9.1 Hz, 1H), 4.43 (s, 1H), 4.21 ( s, 2H), 3.70 (t, J = 6.4 Hz, 2H), 3.31 (t, J = 1.4 Hz, 2H), 2.65 (s, 2H), 2.23 (quintet, J = 6.5 Hz, 2H).

실시예 4Example 4

N-(2-퀴놀린일)-N'-(3-티에닐메틸)-1,3-프로판디아민 N- (2-quinolinyl) -N '-(3-thienylmethyl) -1,3-propanediamine

이 화합물은 N-퀴놀린-2-일-1,3-프로판디아민과 3-티오펜-카르복살데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액: 5% CH3CN -> 100% CH3CN, 15분, 25 ml/분)을 사용하여 정제하여, 표제 화합물을 74% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.86(d, J = 8.4 Hz, 1H), 7.61(d, J = 8.0 Hz, 1H), 7.50-7.48(m, 2H), 7.43(t, J = 8.5 Hz, 1H), 7.27(d, J = 8.9 Hz, 1H), 7.20(t, J = 7.7 Hz, 1H), 7.15-7.13(m, 1H), 6.75(d, 7 = 9.5 Hz, 1H), 4.23(s, 2H), 3.65(t, J = 6.2 Hz, 2H), 3.06(t, J = 7.1 Hz, 2H), 2.05(퀸텟, J = 6.4 Hz, 2H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and 3-thiophene-carboxaldehyde, and HPLC (95% 0.1 M ammonium acetate buffer: 5% CH 3 CN-> 100% CH) 3 CN, 15 min, 25 ml / min) to afford the title compound in 74% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.86 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.50-7.48 (m, 2H), 7.43 (t , J = 8.5 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.15-7.13 (m, 1H), 6.75 (d, 7 = 9.5 Hz , 1H), 4.23 (s, 2H), 3.65 (t, J = 6.2 Hz, 2H), 3.06 (t, J = 7.1 Hz, 2H), 2.05 (quintet, J = 6.4 Hz, 2H).

실시예 5Example 5

N-(9,10-메타노안트라센-9(10H)-일메틸)-N'-(2-퀴놀린일)-1,4-시클로헥산디아민 N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N '-(2-quinolinyl) -1,4-cyclohexanediamine

이 화합물을 N-퀴놀린-2-일시클로헥산-1,4-디아민과 9-포밀-9,10-디히드로-9,10-메타노안트라센으로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액: 5% CH3CN -> 100% CH3CN, 15분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 부분입체 이성질체의 혼합물로 25% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4, 다수 이성질체) δ7.78(d, J = 9.1 Hz, 1H), 7.59(d, J = 8.5 Hz, 1H), 7.55(d, J = 9.1 Hz, 1H), 7.46(t, J = 8.5 Hz, 1H), 7.24(d, J = 7.7 Hz, 2H), 7.16-7.12(m, 3H), 6.97-6.89(m, 4H), 6.79(d, J = 8.9 Hz, 1H), 4.27(s, 1H), 4.23-4.19(m, 1H), 3.67(s, 2H), 2.90-2.85(m, 1H), 2.51(d, J = 1.4 Hz, 2H), 1.94-1.85(m, 4H), 1.82-1.67(m, 4H).This compound was prepared from N-quinolin-2-ylcyclohexane-1,4-diamine and 9-formyl-9,10-dihydro-9,10-methanoanthracene, and HPLC (95% 0.1 M ammonium acetate buffer) : 5% CH 3 CN-> 100% CH 3 CN, 15 min, 25 ml / min) to give the title compound as a mixture of diastereomers in 25% yield. 1 H NMR (400 MHz, MeOH-d 4 , Many Isomers) δ7.78 (d, J = 9.1 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 9.1 Hz, 1H), 7.46 (t, J = 8.5 Hz, 1H), 7.24 (d, J = 7.7 Hz, 2H), 7.16-7.12 (m, 3H), 6.97-6.89 (m, 4H), 6.79 (d, J = 8.9 Hz, 1H), 4.27 (s, 1H), 4.23-4.19 (m, 1H), 3.67 (s, 2H), 2.90-2.85 (m, 1H), 2.51 (d, J = 1.4 Hz, 2H) , 1.94-1.85 (m, 4H), 1.82-1.67 (m, 4H).

실시예 6Example 6

N-[(1-아세틸-1H-인돌-3-일)메틸]-N'-(6-메톡시-4-메틸-2-퀴놀린일)-1,3-프로판디아민 N-[(1-acetyl-1H-indol-3-yl) methyl] -N '-(6-methoxy-4-methyl-2-quinolinyl) -1,3-propanediamine

이 화합물을 N-(6-메톡시-4-메틸-2-퀴놀린일)-1,3-프로판디아민과 1-아세틸-3-인돌카르복살데히드로부터 제조하였으며, SiO2(CH2Cl2:MeOH 40:1 -> 2:1) 상에서 정제하여, 표제 화합물을 36% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4, 다수 로타머) δ8.33(d, J = 7.5 Hz, 1H), 7.59(d, J = 7.5 Hz, 1H), 7.55(s, 1H), 7.31(d, J = 7.3 Hz, 1H), 7.26-7.21(m, 2H), 7.10(d, J = 2.8 Hz, 1H), 6.98(dd, J = 2.8, 11.9 Hz, 1H), 6.54(s, 1H), 4.08(s, 2H), 3.84(s, 3H), 3.57(t, J = 6.3 Hz, 2H), 2.97(t, J = 6.6 Hz, 2H), 2.49(s, 3H), 2.47(d, J = 0.8 Hz, 3H), 2.01-1.94(m, 2H).This compound was prepared from N- (6-methoxy-4-methyl-2-quinolinyl) -1,3-propanediamine and 1-acetyl-3-indolecarboxaldehyde, and SiO 2 (CH 2 Cl 2 : Purification on MeOH 40: 1-> 2: 1) afforded the title compound in 36% yield. 1 H NMR (400 MHz, MeOH-d 4 , Many Rotamers) δ 8.33 (d, J = 7.5 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.55 (s, 1H), 7.31 (d, J = 7.3 Hz, 1H), 7.26-7.21 (m, 2H), 7.10 (d, J = 2.8 Hz, 1H), 6.98 (dd, J = 2.8, 11.9 Hz, 1H), 6.54 (s, 1H), 4.08 (s, 2H), 3.84 (s, 3H), 3.57 (t, J = 6.3 Hz, 2H), 2.97 (t, J = 6.6 Hz, 2H), 2.49 (s, 3H), 2.47 ( d, J = 0.8 Hz, 3H), 2.01-1.94 (m, 2H).

실시예 7Example 7

N-(9,10-메타노안트라센-9(10H)-일메틸)-N'-(2-퀴놀린일)-1,3-시클로헥산디아민 N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N '-(2-quinolinyl) -1,3-cyclohexanediamine

이 화합물을 N-퀴놀린-2-일시클로헥산-1,3-디아민과 9-포밀-9,10-디히드로-9,10-메타노안트라센으로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액: 5% CH3CN -> 100% CH3CN, 15분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 부분입체 이성질체의 혼합물로 60% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4, 다수 이성질체) δ7.75(d, J = 8.8 Hz, 1H), 7.62(d, J = 8.5 Hz, 1H), 7.53(d, J = 8.6, 1H), 7.46(dt, 1.2, 7.4 Hz, 1H), 7.23-7.08(m, 5H), 6.95-6.84(m, 4H), 6.68(d, J = 9.0 Hz, 1H), 4.23(s, 1H), 4.15-4.05(m, 1H), 3.65(d, J = 2.6 Hz, 2H), 2.92-2.81(m, 1H), 2.53-2.39(m, 3H), 2.13-2.01(m, 2H), 1.91-1.81(m, 2H), 1.60-1.46(m, 1H), 1.29-1.12(m, 2H).This compound was prepared from N-quinolin-2-ylcyclohexane-1,3-diamine and 9-formyl-9,10-dihydro-9,10-methanoanthracene, and HPLC (95% 0.1 M ammonium acetate buffer) : 5% CH 3 CN-> 100% CH 3 CN, 15 min, 25 ml / min) to give the title compound as a mixture of diastereomers in 60% yield. 1 H NMR (400 MHz, MeOH-d 4 , Many Isomers) δ7.75 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 8.6, 1H ), 7.46 (dt, 1.2, 7.4 Hz, 1H), 7.23-7.08 (m, 5H), 6.95-6.84 (m, 4H), 6.68 (d, J = 9.0 Hz, 1H), 4.23 (s, 1H) , 4.15-4.05 (m, 1H), 3.65 (d, J = 2.6 Hz, 2H), 2.92-2.81 (m, 1H), 2.53-2.39 (m, 3H), 2.13-2.01 (m, 2H), 1.91 -1.81 (m, 2H), 1.60-1.46 (m, 1H), 1.29-1.12 (m, 2H).

실시예 8Example 8

N-(2-퀴놀린일)-N'-[1-(3-티에닐)에틸]-1,3-프로판디아민 N- (2-quinolinyl) -N '-[1- (3-thienyl) ethyl] -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 3-아세틸티오펜으로부터 제조하였으나, 단일 노드 마이크로파 가열하였으며(140℃, 5분), Si02(CH2Cl2:MeOH 1: 0 -> 0:1) 상에서 정제하여, 표제 화합물을 30% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.80(d, J = 9.1 Hz, 1H), 7.58(d, J = 7.9 Hz, 1H), 7.48-7.37(m, 4H), 7.18(t, J = 7.4 Hz, 1H), 7.06(d, J = 5.0 Hz, 1H), 6.70(d, J = 8.9 Hz, 1H), 4.42-4.38(m, 1H), 3.59-3.55(m, 2H), 2.91-2.79(m, 2H), 2.02-1.93(m, 2H), 1.56(d, J = 6.7 Hz, 3H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and 3-acetylthiophene, but was subjected to single node microwave heating (140 ° C., 5 minutes), and Si0 2 (CH 2 Cl 2 : MeOH 1 : 0-> 0: 1) to give the title compound in 30% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.80 (d, J = 9.1 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.48-7.37 (m, 4H), 7.18 (t , J = 7.4 Hz, 1H), 7.06 (d, J = 5.0 Hz, 1H), 6.70 (d, J = 8.9 Hz, 1H), 4.42-4.38 (m, 1H), 3.59-3.55 (m, 2H) , 2.91-2.79 (m, 2H), 2.02-1.93 (m, 2H), 1.56 (d, J = 6.7 Hz, 3H).

실시예 9Example 9

N-(2-퀴놀린일)-N'-(3-티에닐메틸)-1,3-시클로헥산디아민 N- (2-quinolinyl) -N '-(3-thienylmethyl) -1,3-cyclohexanediamine

이 화합물을 N-퀴놀린-2-일시클로헥산-1,3-디아민과 3-티오펜카르복살데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액: 5% CH3CN -> 100% CH3CN, 15분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 부분입체 이성질체의 혼합물로 33% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4, 다수 이성질체) δ7.81(d, J = 8.9 Hz, 1H), 7.58(t, J = 9.1 Hz, 2H), 7.50-7.46(m, 3H), 7.20-7.15(m, 2H), 6.71(d, J = 8.9 Hz, 1H), 4.12(s, 2H), 4.09-4.00(m, 1H), 3.12-3.04(m, 1H), 2.59(d, J = 11.9 Hz, 1H), 2.15(d, J = 12.7 Hz, 1H), 2.08(d, J = 14.0 Hz, 1H), 1.98-1.93(m, 1H), 1.79(s, 1H), 1.57-1.45(m, 1H), 1.37-1.21(m, 2H).This compound was prepared from N-quinolin-2-ylcyclohexane-1,3-diamine and 3-thiophenecarboxaldehyde, and HPLC (95% 0.1 M ammonium acetate buffer: 5% CH 3 CN-> 100% CH) 3 CN, 15 min, 25 ml / min) gave the title compound in a mixture of diastereomers in 33% yield. 1 H NMR (400 MHz, MeOH-d 4 , Many Isomers) δ 7.81 (d, J = 8.9 Hz, 1H), 7.58 (t, J = 9.1 Hz, 2H), 7.50-7.46 (m, 3H), 7.20-7.15 (m, 2H), 6.71 (d, J = 8.9 Hz, 1H), 4.12 (s, 2H), 4.09-4.00 (m, 1H), 3.12-3.04 (m, 1H), 2.59 (d, J = 11.9 Hz, 1H), 2.15 (d, J = 12.7 Hz, 1H), 2.08 (d, J = 14.0 Hz, 1H), 1.98-1.93 (m, 1H), 1.79 (s, 1H), 1.57- 1.45 (m, 1 H), 1.37-1.21 (m, 2 H).

실시예 10Example 10

N-(9,10-메타노안트라센-9(10H)-일메틸)-N'-(6-메톡시-4-메틸-2-퀴놀린일)-1,3-프로판디아민 N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N '-(6-methoxy-4-methyl-2-quinolinyl) -1,3-propanediamine

이 화합물을 N-(6-메톡시-4-메틸-2-퀴놀린일)-1,3-프로판디아민과 9-포밀-9,10-디히드로-9,10-메타노안트라센으로부터 제조하였으며, HPLC(95% 0.1 M 암모늄아세테이트완충액: 5% CH3CN -> 100% CH3CN, 10분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 20% 수율로 얻었다. 1H NMR(400 MHz, DMF-d7) δ7.36-7.31(m, 5H), 7.20(d, J = 2.8 Hz, 1H), 7.11(dd, J = 11.9, 2.8 Hz, 1H), 6.97(d, J = 3.0 Hz, 2H), 6.95(d, J = 3.2 Hz, 2H), 6.65(s, 1H), 4.40(s, 1H), 4.01(s, 2H), 3.88(s, 3H), 3.62(t, J = 6.5 Hz, 2H), 3.25-3.21(m, 2H), 2.61(s, 2H), 2.49(s, 3H), 2.14-2.08(m, 2H).This compound was prepared from N- (6-methoxy-4-methyl-2-quinolinyl) -1,3-propanediamine and 9-formyl-9,10-dihydro-9,10-methanoanthracene, Purification using HPLC (95% 0.1 M ammonium acetate buffer: 5% CH 3 CN-> 100% CH 3 CN, 10 min, 25 ml / min) afforded the title compound in 20% yield. 1 H NMR (400 MHz, DMF-d 7 ) δ7.36-7.31 (m, 5H), 7.20 (d, J = 2.8 Hz, 1H), 7.11 (dd, J = 11.9, 2.8 Hz, 1H), 6.97 (d, J = 3.0 Hz, 2H), 6.95 (d, J = 3.2 Hz, 2H), 6.65 (s, 1H), 4.40 (s, 1H), 4.01 (s, 2H), 3.88 (s, 3H) , 3.62 (t, J = 6.5 Hz, 2H), 3.25-3.21 (m, 2H), 2.61 (s, 2H), 2.49 (s, 3H), 2.14-2.08 (m, 2H).

실시예 11Example 11

N-(2-퀴놀린일)-N'-(4,5,6,7-테트라히드로티아나프트-4-일)-1,3-프로판디아민(선택적 명칭 N-퀴놀린-2-일-N'-(4,5,6,7-테트라히드로-1-벤조티엔-4-일)프로판- 1,3-디아민) N- (2-quinolinyl) -N '-(4,5,6,7-tetrahydrothianaphth-4-yl) -1,3-propanediamine (optional name N-quinolin-2-yl-N' -(4,5,6,7-tetrahydro-1-benzothien-4-yl) propane-1,3-diamine)

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 4-케토-4,5,6,7-테트라히드로티아나프텐으로부터 제조하였으나, 단일 노드 마이크로파 가열하였으며(120℃, 15분), SiO2(CH2Cl2:MeOH 10:0 -> 4:1) 상에서 정제하여, 표제 화합물을 34% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.82(d, J = 9.3 Hz, 1H), 7.57(d, J = 8.5 Hz, 1H), 7.38(t, J = 8.3 Hz, 1H), 7.22(d, J = 5.7 Hz, 1H), 7.18-7.12(m, 3H), 6.73(d, J = 8.4 Hz, 1H), 4.19(t, J = 5.9 Hz, 1H), 3.76-3.69(m, 1H), 3.56-3.50(m, 1H), 3.00(t, J = 7.2 Hz, 2H), 2.71-2.64(m, 1H), 2.54-2.47(m, 1H), 2.09-1.94(m, 3H), 1.87-1.78(m, 1H), 1.75-1.65(m, 1H), 1.64-1.56(m, 1H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and 4-keto-4,5,6,7-tetrahydrothianaphthene but heated to single node microwave (120 ° C., 15 minutes). ), SiO 2 (CH 2 Cl 2 : MeOH 10: 0-> 4: 1) to give the title compound in 34% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.82 (d, J = 9.3 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.38 (t, J = 8.3 Hz, 1H), 7.22 (d, J = 5.7 Hz, 1H), 7.18-7.12 (m, 3H), 6.73 (d, J = 8.4 Hz, 1H), 4.19 (t, J = 5.9 Hz, 1H), 3.76-3.69 (m , 1H), 3.56-3.50 (m, 1H), 3.00 (t, J = 7.2 Hz, 2H), 2.71-2.64 (m, 1H), 2.54-2.47 (m, 1H), 2.09-1.94 (m, 3H ), 1.87-1.78 (m, 1H), 1.75-1.65 (m, 1H), 1.64-1.56 (m, 1H).

실시예 12Example 12

N-메틸-N'-(2-퀴놀린일)-N-(3-티에닐메틸)-1,3-프로판디아민 N-methyl-N '-(2-quinolinyl) -N- (3-thienylmethyl) -1,3-propanediamine

이 화합물을 N-메틸-N'-퀴놀린-2--일프로판-1,3-디아민과 3-티오펜카르복살데히드로부터 제조하였으며, Si02(CH2Cl2:MeOH 10:0 -> 4:1) 상에서 정제하여, 표제 화합물을 24% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.80(d,J = 8.8 Hz, 1H), 7.59-7.55(m, 2H), 7.46(dt, J = 1.4, 8.0 Hz, 1H), 7.31(dd, J = 2.8, 7.8 Hz, 1H), 7.22(bs, 1H), 7.16(dt, J = 1.2, 7.4 Hz, 1H), 7.06(dd, J = 1.2. 8,4. 7 Hz, 1H), 6.70(d, J = 8.8Hz, 1H), 3.62(s, 2H), 3.48(t, J = 6.8 Hz, 2H), 2.54(t, J = 7.3 Hz, 2H), 2.25(s, 3H), 1.90(퀸텟, J = 7.0 Hz, 2H).This compound was prepared from N-methyl-N'-quinolin-2--ylpropane-1,3-diamine and 3-thiophenecarboxaldehyde, and Si0 2 (CH 2 Cl 2 : MeOH 10: 0-> 4 Purification on 1 :) gave the title compound in 24% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.80 (d, J = 8.8 Hz, 1H), 7.59-7.55 (m, 2H), 7.46 (dt, J = 1.4, 8.0 Hz, 1H), 7.31 (dd, J = 2.8, 7.8 Hz, 1H), 7.22 (bs, 1H), 7.16 (dt, J = 1.2, 7.4 Hz, 1H), 7.06 (dd, J = 1.2, 8,4.7 Hz, 1H ), 6.70 (d, J = 8.8 Hz, 1H), 3.62 (s, 2H), 3.48 (t, J = 6.8 Hz, 2H), 2.54 (t, J = 7.3 Hz, 2H), 2.25 (s, 3H ), 1.90 (quintet, J = 7.0 Hz, 2H).

실시예 13Example 13

N-(2-퀴놀린일)-N',N'-비스(3-티에닐메틸)-1,3-프로판디아민 N- (2-quinolinyl) -N ', N'-bis (3-thienylmethyl) -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 3-티오펜-카르복살데히드로부터 제조하였으나, 단일 노드 마이크로파 가열하였으며(110℃, 5분), SiO2(CH3Cl:MeOH 10:1 -> 2:1) 상에서 정제하여, 표제 화합물을 30% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.82(d, J = 8.8 Hz, 1H), 7.60(t, J = 7.5 Hz, 2H), 7.49(t, J = 8.9 Hz, 1H), 7.32(m, 1H), 7.23(bs, 2H), 7.19(m, 2H), 7.10(d, J = 4.2 Hz, 2H), 6.65(d, J = 9.1 Hz, 1H), 3.65(s, 4H), 3.49(t, J = 6.6 Hz, 2H), 2.59(t, J = 6.6 Hz, 2H), 1.91(퀸텟, J = 7. 0 Hz, 2H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and 3-thiophene-carboxaldehyde, but heated to single node microwave (110 ° C., 5 min), and SiO 2 (CH 3 Cl: Purification on MeOH 10: 1-> 2: 1) afforded the title compound in 30% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.82 (d, J = 8.8 Hz, 1H), 7.60 (t, J = 7.5 Hz, 2H), 7.49 (t, J = 8.9 Hz, 1H), 7.32 (m, 1H), 7.23 (bs, 2H), 7.19 (m, 2H), 7.10 (d, J = 4.2 Hz, 2H), 6.65 (d, J = 9.1 Hz, 1H), 3.65 (s, 4H ), 3.49 (t, J = 6.6 Hz, 2H), 2.59 (t, J = 6.6 Hz, 2H), 1.91 (quintet, J = 7. 0 Hz, 2H).

실시예 14Example 14

N-(9,10-메타노안트라센-9(10H)-일메틸)-N-메틸-N'-(2-퀴놀린일)-1,3-프로판디아민 N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N-methyl-N '-(2-quinolinyl) -1,3-propanediamine

이 화합물을 N-메틸-N'-퀴놀린-2-일프로판-1,3-디아민과 9-포밀-9,10-디히드로-9,10-메타노안트라센으로부터 제조하였으며, SiO2(CH2Cl2:MeOH 10:0 -> 4:1) 상에서 정제하여, 표제 화합물을 11% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.71(d, J = 8.2 Hz, 1H), 7.56(t, J = 8.2 Hz, 2H), 7.45(t, J =7.4 Hz, 1H), 7.19-7.14(m, 5H), 6.89-6.83(m, 4H), 6.40(d, J = 8.8 Hz, 1H), 4.20(s, 1H), 3.51-3.48(m, 4H), 2.76(t, J = 6.9 Hz, 2H), 2.56(s, 2H), 2.43(s, 3H), 1.96-1.89(m, 2H).This compound was prepared from N-methyl-N'-quinolin-2-ylpropane-1,3-diamine and 9-formyl-9,10-dihydro-9,10-methanoanthracene, and SiO 2 (CH 2 Purification over Cl 2 : MeOH 10: 0-> 4: 1) afforded the title compound in 11% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ7.71 (d, J = 8.2 Hz, 1H), 7.56 (t, J = 8.2 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 7.19-7.14 (m, 5H), 6.89-6.83 (m, 4H), 6.40 (d, J = 8.8 Hz, 1H), 4.20 (s, 1H), 3.51-3.48 (m, 4H), 2.76 (t, J = 6.9 Hz, 2H), 2.56 (s, 2H), 2.43 (s, 3H), 1.96-1.89 (m, 2H).

실시예 15Example 15

N-(2-퀴놀린일)-N'-[(2,4,6-트리메틸페닐)메틸]-1,3-프로판디아민 N- (2-quinolinyl) -N '-[(2,4,6-trimethylphenyl) methyl] -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 2,4,6-트리메틸-벤즈알데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액: 5% CH3CN -> 100% CH3CN, 15분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 27% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.87(d, J = 9.0 Hz, 1H), 7.59(dd, J = 9.3, 1.6 Hz, 1H), 7.27-7.23(m, 1H), 7.18-7.14(m, 1H), 6.96(s, 2H), 6.90(d, J = 8.4 Hz, 1H), 6.78(d, J = 8.9 Hz, 1H), 4.30(s, 2H), 3.71(t, J = 6.2 Hz, 2H), 3.21(t, J = 6.7 Hz, 2H), 2.39(s, 6H), 2.31(s, 3H), 2.16(퀸텟, J = 6.5 Hz, 2H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and 2,4,6-trimethyl-benzaldehyde, and HPLC (95% 0.1 M ammonium acetate buffer: 5% CH 3 CN-> 100% CH 3 CN, 15 min, 25 ml / min) to afford the title compound in 27% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.87 (d, J = 9.0 Hz, 1H), 7.59 (dd, J = 9.3, 1.6 Hz, 1H), 7.27-7.23 (m, 1H), 7.18 -7.14 (m, 1H), 6.96 (s, 2H), 6.90 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 4.30 (s, 2H), 3.71 (t, J = 6.2 Hz, 2H), 3.21 (t, J = 6.7 Hz, 2H), 2.39 (s, 6H), 2.31 (s, 3H), 2.16 (quintet, J = 6.5 Hz, 2H).

실시예 16Example 16

N-(2-페닐에틸)-N'-(2-퀴놀린일)-1,3-프로판디아민 N- (2-phenylethyl) -N '-(2-quinolinyl) -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 페닐 아세트알데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액:5% CH3CN -> 100% CH3CN, 15분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 4% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.88(d, J = 9.0 Hz, 1H), 7.65-7.52(m, 3H), 7.30-7.19(m, 4H), 7.15(d, J = 1.7 Hz, 1H), 7.13(s, 1H), 6.77(d, J = 9.1 Hz, 1H), 3.65(t, J = 6.3 Hz, 2H), 3.22-3.18(m, 2H), 3.11(t, J = 6.8 Hz, 2H), 2.95-2.91(m, 2H), 2.04(퀸텟, J = 6.5 Hz, 2H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and phenyl acetaldehyde, HPLC (95% 0.1 M ammonium acetate buffer: 5% CH 3 CN-> 100% CH 3 CN, 15 min. , 25 ml / min) to give the title compound in 4% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.88 (d, J = 9.0 Hz, 1H), 7.65-7.52 (m, 3H), 7.30-7.19 (m, 4H), 7.15 (d, J = 1.7 Hz, 1H), 7.13 (s, 1H), 6.77 (d, J = 9.1 Hz, 1H), 3.65 (t, J = 6.3 Hz, 2H), 3.22-3.18 (m, 2H), 3.11 (t, J = 6.8 Hz, 2H), 2.95-2.91 (m, 2H), 2.04 (quintet, J = 6.5 Hz, 2H).

실시예 17Example 17

N-(l-벤조[b]티엔-3-일에틸)-N'-(2-퀴놀린일)-1,3-프로판디아민 N- (l-benzo [b] thien-3-ylethyl) -N '-(2-quinolinyl) -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 3-아세틸티아나프텐으로부터 제조하였으나, 단일 노드 마이크로파 가열하였으며(120℃, 2 x 5분), SiO2(CH2Cl2:MeOH 10:0 -> 4:1) 상에서 정제하여, 표제 화합물을 30% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.88-7.80(m, 2H), 7.77(d, J = 8.9 Hz, 1H), 7.58(s, 1H), 7.55(dd, J = 1.4, 9.1 Hz, 1H), 7.37-7.27(m, 4H), 7.14(t, J = 8.0 Hz, 1H), 6.66(d, J = 9.2 Hz, 1H), 4.70(q, J = 6.9 Hz, 1H), 3.64-3.52(m, 2H), 3.03-2.97(m, 1H), 2.91-2.85(m, 1H), 1.98(옥텟, J = 6.7 Hz, 2H), 1.65(d, J = 6.6 Hz, 3H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and 3-acetylthianaphthene, but was subjected to single node microwave heating (120 ° C., 2 × 5 minutes), and SiO 2 (CH 2 Cl 2 : MeOH 10: 0-> 4: 1) afforded the title compound in 30% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.88-7.80 (m, 2H), 7.77 (d, J = 8.9 Hz, 1H), 7.58 (s, 1H), 7.55 (dd, J = 1.4, 9.1 Hz, 1H), 7.37-7.27 (m, 4H), 7.14 (t, J = 8.0 Hz, 1H), 6.66 (d, J = 9.2 Hz, 1H), 4.70 (q, J = 6.9 Hz, 1H) , 3.64-3.52 (m, 2H), 3.03-2.97 (m, 1H), 2.91-2.85 (m, 1H), 1.98 (octet, J = 6.7 Hz, 2H), 1.65 (d, J = 6.6 Hz, 3H ).

실시예 18Example 18

N-[(3,4-디클로로페닐)메틸]-N'-(2-퀴놀린일)-1,3-시클로헥산디아민 N-[(3,4-dichlorophenyl) methyl] -N '-(2-quinolinyl) -1,3-cyclohexanediamine

이 화합물을 N-퀴놀린-2-일시클로헥산-1,4-디아민과 3,4-디클로로벤즈알데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액:5% CH3CN -> 100% CH3CN, 15분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 부분입체 이성질체의 혼합물로 66% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4, 다수 이성질체) δ7.79(d, J = 8.9 Hz, 1H), 7.60-7.53(m, 3H), 7.50-7.45(m, 2H), 7.31(dd, J = 2.0, 10.1 Hz, 1H), 7.18-7.14(m, 1H), 6.70(d, J = 9.2 Hz, 1H), 4.04-3.96(m, 1H), 3.89(s, 2H), 2.88-2.81(m, 1H), 2.47(d, J = 12.1 Hz, 1H), 2.06(d, J = 12.1 Hz, 2H), 1.92-1.86(m, 1H), 1.80-1.67(m, 1H), 1.54-1.42(m, 1H), 1.29-1.12(m, 2H).This compound was prepared from N-quinolin-2-ylcyclohexane-1,4-diamine and 3,4-dichlorobenzaldehyde, and HPLC (95% 0.1 M ammonium acetate buffer: 5% CH 3 CN-> 100% CH 3 Purification using CN, 15 min, 25 ml / min) afforded the title compound as a mixture of diastereomers in 66% yield. 1 H NMR (400 MHz, MeOH-d 4 , Many Isomers) δ 7.79 (d, J = 8.9 Hz, 1H), 7.60-7.53 (m, 3H), 7.50-7.45 (m, 2H), 7.31 (dd) , J = 2.0, 10.1 Hz, 1H), 7.18-7.14 (m, 1H), 6.70 (d, J = 9.2 Hz, 1H), 4.04-3.96 (m, 1H), 3.89 (s, 2H), 2.88- 2.81 (m, 1H), 2.47 (d, J = 12.1 Hz, 1H), 2.06 (d, J = 12.1 Hz, 2H), 1.92-1.86 (m, 1H), 1.80-1.67 (m, 1H), 1.54 -1.42 (m, 1 H), 1.29-1.12 (m, 2H).

실시예 19Example 19

N-(9,10-메타노안트라센-9(10H)-일메틸)-N'-메틸-N'-(2-퀴놀린일)-1,3-프로판디아민 N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N'-methyl-N '-(2-quinolinyl) -1,3-propanediamine

이 표제 화합물을 실시예 14의 합성으로부터 분리하였다. 1H NMR(400 MHz, MeOH-d4) δ7.90(d, J = 9.0 Hz, 1H), 7.56(d, J = 8.3 Hz, 1H), 7.35(t, J = 8.2 Hz, 1H), 7.27-7.23(m, 3H), 7.15-7.10(m, 3H), 7.02(d, J = 8.8 Hz, 1H), 6.94-6.86(m, 4H), 4.26(s, 1H), 3.87(t, J = 6.9 Hz, 2H), 3.63(s, 2H), 3.18(s, 3H), 2.85(t, J = 6.6 Hz, 2H), 2.49(s, 2H), 2.01(퀸텟, J = 7.0 Hz, 2H).This title compound was isolated from the synthesis of Example 14. 1 H NMR (400 MHz, MeOH-d 4 ) δ7.90 (d, J = 9.0 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.27-7.23 (m, 3H), 7.15-7.10 (m, 3H), 7.02 (d, J = 8.8 Hz, 1H), 6.94-6.86 (m, 4H), 4.26 (s, 1H), 3.87 (t, J = 6.9 Hz, 2H), 3.63 (s, 2H), 3.18 (s, 3H), 2.85 (t, J = 6.6 Hz, 2H), 2.49 (s, 2H), 2.01 (Quintet, J = 7.0 Hz, 2H).

실시예 20Example 20

N-(2-퀴놀린일)-N'-(2-티에닐메틸)-1,3-프로판디아민 N- (2-quinolinyl) -N '-(2-thienylmethyl) -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 2-티오펜카르복살데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액: 5% CH3CN -> 100% CH3CN, 15분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 18% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.84(d, J = 8.9 Hz, 1H), 7.60(dd, J = 1.7, 9.3 Hz, 1H), 7.47-7.42(m, 3H), 7.37(d, J = 8.4 Hz, 2H), 7.20-7.17(m, 1H), 7.10(d, J = 3.2 Hz, 1H), 7.00(dd, J = 3.7, 8.4 Hz, 1H), 6.74(d, J = 9.4 Hz, 1H), 4.28(s, 2H), 3.61(t, J = 6.5 Hz, 2H), 2.96(t, J = 7.1 Hz, 2H), 2.00(퀸텟, J = 6.8 Hz, 2H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and 2-thiophenecarboxaldehyde, and HPLC (95% 0.1 M ammonium acetate buffer: 5% CH 3 CN-> 100% CH 3 CN, 15 min, 25 ml / min) afforded the title compound in 18% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.84 (d, J = 8.9 Hz, 1H), 7.60 (dd, J = 1.7, 9.3 Hz, 1H), 7.47-7.42 (m, 3H), 7.37 (d, J = 8.4 Hz, 2H), 7.20-7.17 (m, 1H), 7.10 (d, J = 3.2 Hz, 1H), 7.00 (dd, J = 3.7, 8.4 Hz, 1H), 6.74 (d, J = 9.4 Hz, 1H), 4.28 (s, 2H), 3.61 (t, J = 6.5 Hz, 2H), 2.96 (t, J = 7.1 Hz, 2H), 2.00 (Quintet, J = 6.8 Hz, 2H) .

실시예 21Example 21

N-(2-푸라닐메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민 N- (2-furanylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 3-푸랄데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액:5% CH3CN -> 100% CH3CN, 15분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 21% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.86(d, J = 8.4 Hz, 1H), 7.61(d, J = 9.5 Hz, 1H), 7.54(d, J = 6.8 Hz, 2H), 7.50-7.41(m, 2H), 7.21(t, J = 8.1 Hz, 1H), 6.75(d, 7 = 9.1 Hz, 1H), 6.46(t, J = 0.9 Hz, 1H), 4.04(s, 2H), 3.64(t, J = 6.4 Hz, 2H), 3.02(t, J = 6.7 Hz, 2H), 2.03(퀸텟, J = 6.6 Hz, 2H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and 3-furalhydro, HPLC (95% 0.1 M ammonium acetate buffer: 5% CH 3 CN-> 100% CH 3 CN, 15 Min, 25 ml / min) to give the title compound in 21% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.86 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 9.5 Hz, 1H), 7.54 (d, J = 6.8 Hz, 2H), 7.50-7.41 (m, 2H), 7.21 (t, J = 8.1 Hz, 1H), 6.75 (d, 7 = 9.1 Hz, 1H), 6.46 (t, J = 0.9 Hz, 1H), 4.04 (s, 2H ), 3.64 (t, J = 6.4 Hz, 2H), 3.02 (t, J = 6.7 Hz, 2H), 2.03 (quintet, J = 6.6 Hz, 2H).

실시예 22Example 22

N-[(3,4-디클로로페닐)메틸]-N-메틸-N'-(2-퀴놀린일)-1,3-프로판디아민 N-[(3,4-dichlorophenyl) methyl] -N-methyl-N '-(2-quinolinyl) -1,3-propanediamine

이 화합물을 N-메틸-N'-퀴놀린-2-일프로판-1,3-디아민과 3,4-디클로로벤즈알데히드로부터 제조하였으며, SiO2(CH2Cl2:MeOH 10:0 -> 4:1) 상에서 정제하여, 표제 화합물을 20% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.79(d, J = 9.3 Hz, 1H), 7.60-7. 55(m, 2H), 7.49-7. 44(m, 2H), 7.33(d, J = 9.3 Hz, 1H), 7.22-7. 13(m, 2H), 6.68(d, J = 8.8 Hz, 1H), 3.49(t, J = 7.4 Hz, 2H), 3.49(s, 2H), 2.52(t, J = 7.4 Hz, 2H), 2.22(s, 3H), 1.87(퀸텟, J = 7.2 Hz, 2H).This compound was prepared from N-methyl-N'-quinolin-2-ylpropane-1,3-diamine and 3,4-dichlorobenzaldehyde, and SiO 2 (CH 2 Cl 2 : MeOH 10: 0-> 4: 1 Purification)) gave the title compound in 20% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.79 (d, J = 9.3 Hz, 1H), 7.60-7. 55 (m, 2 H), 7.49-7. 44 (m, 2H), 7.33 (d, J = 9.3 Hz, 1H), 7.22-7. 13 (m, 2H), 6.68 (d, J = 8.8 Hz, 1H), 3.49 (t, J = 7.4 Hz, 2H), 3.49 (s, 2H), 2.52 (t, J = 7.4 Hz, 2H), 2.22 (s, 3 H), 1.87 (quintet, J = 7.2 Hz, 2H).

실시예 23Example 23

N-[1-(9,10-메타노안트라센-9(10H)-일메틸)-4-피페리딘일]-2-퀴놀린아민 N- [1- (9,10-Metanoanthracene-9 (10H) -ylmethyl) -4-piperidinyl] -2-quinolinamine

이 화합물을 N-피페리딘-4-일퀴놀린-2-아민과 9-포밀-9,10-디히드로-9,10-메타노안트라센으로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액: 5% CH3CN -> 100% CH3CN, 15분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 53% 수율로 얻었다. 1H NMR(400 MHz, THF-d8) δ7.77(d, J = 9.0 Hz, 1H), 7.64(d, J = 9.1 Hz, 1H), 7.57(d, J = 8.2 Hz, 1H), 7.47(t, J = 8.4 Hz, 1H), 7.27(d, J = 6.6 Hz, 4H), 7.15(t, J = 8.0 Hz, 1H), 6.99-6.90(m, 4H), 6.68(d, J = 9.0 Hz, 1H), 4.30(s, 1H), 4.22-4.15(m, 1H), 3.51(s, 2H), 3.12(d, J = 11.9 Hz, 2H), 2.63(s, 2H), 2.52(dt, J = 2.6, 12.6 Hz, 2H), 2.14(d, J = 13.2 Hz, 2H), 1.59(dq, J = 4.4, 12.7 Hz, 2H).This compound was prepared from N-piperidin-4-ylquinolin-2-amine and 9-formyl-9,10-dihydro-9,10-methanoanthracene, and HPLC (95% 0.1 M ammonium acetate buffer: 5% CH 3 CN-> 100% CH 3 CN, 15 min, 25 ml / min) to give the title compound in 53% yield. 1 H NMR (400 MHz, THF-d 8 ) δ7.77 (d, J = 9.0 Hz, 1H), 7.64 (d, J = 9.1 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.47 (t, J = 8.4 Hz, 1H), 7.27 (d, J = 6.6 Hz, 4H), 7.15 (t, J = 8.0 Hz, 1H), 6.99-6.90 (m, 4H), 6.68 (d, J = 9.0 Hz, 1H), 4.30 (s, 1H), 4.22-4.15 (m, 1H), 3.51 (s, 2H), 3.12 (d, J = 11.9 Hz, 2H), 2.63 (s, 2H), 2.52 (dt, J = 2.6, 12.6 Hz, 2H), 2.14 (d, J = 13.2 Hz, 2H), 1.59 (dq, J = 4.4, 12.7 Hz, 2H).

실시예 24Example 24

N-(1H-인돌-3-일메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민 N- (1H-indol-3-ylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 인돌-3-카르복살데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액:5% CH3CN -> 100% CH3CN, 15분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 19% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.83(d, J = 8.9 Hz, 1H), 7.63(d, J = 8.6 Hz, 1H), 7.58(d, J = 8.2 Hz, 1H), 7.41(d, J = 8.5 Hz, 1H), 7.33-7.29(m, 2H), 7.19-7.13(m, 3H), 7.06(t, J = 7.7 Hz, 1H), 6.72(d, J = 9.4 Hz, 1H), 4.41(s, 2H), 3.66(t, J = 6.1 Hz, 2H), 3.10(t, J = 6.7 Hz, 2H), 2.06(퀸텟, J = 6.6 Hz, 2H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and indole-3-carboxaldehyde, and HPLC (95% 0.1 M ammonium acetate buffer: 5% CH 3 CN-> 100% CH 3) CN, 15 min, 25 ml / min) to give the title compound in 19% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.83 (d, J = 8.9 Hz, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.33-7.29 (m, 2H), 7.19-7.13 (m, 3H), 7.06 (t, J = 7.7 Hz, 1H), 6.72 (d, J = 9.4 Hz , 1H), 4.41 (s, 2H), 3.66 (t, J = 6.1 Hz, 2H), 3.10 (t, J = 6.7 Hz, 2H), 2.06 (quintet, J = 6.6 Hz, 2H).

실시예 25Example 25

N-(2-나프틸메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민 N- (2-naphthylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 2-나프탈데히드로부터 제조하였으나, 반응을 NaBH3CN을 사용하여 실온에서 수행하였으며(단일 노드 마이크로파 가열 않함), SiO2(CH2Cl2:MeOH 40:1 -> 10:1, 1% HOAc 함유) 상에서 정제하여, 표제 화합물을 73% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.91-7.87(m, 4H), 7.80-7.77(m, 1H), 7.61(d, J = 8.3 Hz, 1H), 7.56-7.50(m, 3H), 7.27-7.16(m, 3H), 6.79(d, J = 9.1 Hz, 1H), 4.38(s, 2H), 3.68(t, J = 6.3 Hz, 2H), 3.18(t, J = 7.2 Hz, 2H), 2.12(퀸텟, J = 6.6 Hz, 2H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and 2-naphthaldehydro, but the reaction was carried out at room temperature using NaBH 3 CN (without single node microwave heating), SiO 2 ( CH 2 Cl 2 : MeOH 40: 1-> 10: 1, containing 1% HOAc) afforded the title compound in 73% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ7.91-7.87 (m, 4H), 7.80-7.77 (m, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.56-7.50 (m, 3H), 7.27-7.16 (m, 3H), 6.79 (d, J = 9.1 Hz, 1H), 4.38 (s, 2H), 3.68 (t, J = 6.3 Hz, 2H), 3.18 (t, J = 7.2 Hz, 2H), 2.12 (Quintet, J = 6.6 Hz, 2H).

실시예 26Example 26

N-(2,2-디페닐에틸)-N'-(2-퀴놀린일)-1,3-프로판디아민 N- (2,2-diphenylethyl) -N '-(2-quinolinyl) -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 디페닐아세트알데히드로부터 제조하였으나, 반응을 NaBH3CN을 사용하여 실온에서 수행하였으며(단일 노드 마이크로파 가열 않함), SiO2(CH2Cl2:MeOH 30:1 -> 10:1, 1% HOAc 함유) 상에서 정제하여, 표제 화합물을 53% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.86(d, J = 9.1 Hz, 1H), 7.61(d, J = 7.0 Hz, 1H), 7.45(t, J = 8.3 Hz, 1H), 7.34-7.19(m, 12H), 6.73(d, J = 8.9 Hz, 1H), 4.32(t, J = 8.0 Hz, 1H), 3.75(d, J = 8.0 Hz, 2H), 3.58(t, J = 6. 2 Hz, 2H), 3.08(t, J = 7.2 Hz, 2H), 2.05-1.98(m, 2H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and diphenylacetaldehyde, but the reaction was carried out at room temperature using NaBH 3 CN (without single node microwave heating), SiO 2 (CH 2 Cl 2 : MeOH 30: 1-> 10: 1, containing 1% HOAc) to afford the title compound in 53% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.86 (d, J = 9.1 Hz, 1H), 7.61 (d, J = 7.0 Hz, 1H), 7.45 (t, J = 8.3 Hz, 1H), 7.34-7.19 (m, 12H), 6.73 (d, J = 8.9 Hz, 1H), 4.32 (t, J = 8.0 Hz, 1H), 3.75 (d, J = 8.0 Hz, 2H), 3.58 (t, J = 6. 2 Hz, 2H), 3.08 (t, J = 7.2 Hz, 2H), 2.05-1.98 (m, 2H).

실시예 27Example 27

N-(1H-인돌-3-일메틸)-N'-(6-메톡시-4-메틸-2-퀴놀린일)-1,3-프로판디아민N- (1H-indol-3-ylmethyl) -N '-(6-methoxy-4-methyl-2-quinolinyl) -1,3-propanediamine

이 화합물을 N-(6-메톡시-4-메틸-2-퀴놀린일)-1,3-프로판디아민과 인돌-3-카르복살데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄아세테이트완충액:5% CH3CN -> 100% CH3CN, 15분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 22% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.60(d, J = 8.5 Hz, 1H), 7.41(d, J = 8.2 Hz, 1H), 7.31(s, 1H), 7.18-7.02(m, 4H), 6.96(dd, J = 2.7, 12.0 Hz, 1H), 6.61(s, 1H), 4.38(s, 2H), 3.84(s, 3H), 3.61(t, J = 5.8 Hz, 2H), 3.09(t, J = 6.6 Hz, 2H), 2.50(d, J = 0.8 Hz, 3H), 2.04(퀸텟, J = 6.5 Hz, 2H).This compound was prepared from N- (6-methoxy-4-methyl-2-quinolinyl) -1,3-propanediamine and indole-3-carboxaldehyde. HPLC (95% 0.1 M ammonium acetate buffer: 5) Purification using% CH 3 CN-> 100% CH 3 CN, 15 min, 25 ml / min) afforded the title compound in 22% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ7.60 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.31 (s, 1H), 7.18-7.02 (m , 4H), 6.96 (dd, J = 2.7, 12.0 Hz, 1H), 6.61 (s, 1H), 4.38 (s, 2H), 3.84 (s, 3H), 3.61 (t, J = 5.8 Hz, 2H) , 3.09 (t, J = 6.6 Hz, 2H), 2.50 (d, J = 0.8 Hz, 3H), 2.04 (quintet, J = 6.5 Hz, 2H).

실시예 28Example 28

N-[(3,4-디클로로페닐)메틸]-N'-(2-퀴놀린일)-1,3-프로판디아민 N-[(3,4-dichlorophenyl) methyl] -N '-(2-quinolinyl) -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 3,4-디클로로-벤즈알데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액: 5% CH3CN -> 100% CH3CN, 15분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 44% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.82(d, J = 9.3 Hz, 1H), 7.58(d, J = 8.2 Hz, 1H), 7.50(d, J = 2.2 Hz, 1H), 7.44-7.41(m, 2H), 7.37(d, J =8. 3 Hz, 1H), 7.24(dd, J = 2.5, 10.5 Hz, 1H), 7.19-7.15(m, 1H), 6.72(d, J = 8.9 Hz, 1H), 3.92(s, 2H), 3.59(t, J = 7.5 Hz, 2H), 2.87(t, J = 7.6 Hz, 2H), 1.96(퀸텟, J = 6.7 Hz, 2H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and 3,4-dichloro-benzaldehyde, and HPLC (95% 0.1 M ammonium acetate buffer: 5% CH 3 CN-> 100% CH 3 CN, 15 min, 25 ml / min) to afford the title compound in 44% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.82 (d, J = 9.3 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 2.2 Hz, 1H), 7.44-7.41 (m, 2H), 7.37 (d, J = 8.3 Hz, 1H), 7.24 (dd, J = 2.5, 10.5 Hz, 1H), 7.19-7.15 (m, 1H), 6.72 (d, J = 8.9 Hz, 1H), 3.92 (s, 2H), 3.59 (t, J = 7.5 Hz, 2H), 2.87 (t, J = 7.6 Hz, 2H), 1.96 (Quintet, J = 6.7 Hz, 2H) .

실시예 29Example 29

N-[(3,4-디클로로페닐)메틸]-N'-(2-퀴놀린일)-1,4-시클로헥산디아민 N-[(3,4-dichlorophenyl) methyl] -N '-(2-quinolinyl) -1,4-cyclohexanediamine

이 화합물을 N-퀴놀린-2-일시클로헥산-1,4-디아민과 3,4-디클로로벤즈알데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액:5% CH3CN -> 100% CH3CN, 15분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 이성질체의 혼합물로 45% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.84(d, J = 9.1 Hz, 1H), 7.65-7.46(m, 5H), 7.35(dd, J = 2.0, 10.3 Hz, 1H), 7.20-7.15(m, 1H), 6.82(d, J = 9.1 Hz, 1H), 4.20-4.16(m, 1H), 3.95(s, 2H), 2.92-2.85(m, 1H), 2.22-2.16(m, 1H), 2.02-1.98(m, 2H), 1.89-1.84(m, 2H), 1.79-1.67(m, 3H).This compound was prepared from N-quinolin-2-ylcyclohexane-1,4-diamine and 3,4-dichlorobenzaldehyde, and HPLC (95% 0.1 M ammonium acetate buffer: 5% CH 3 CN-> 100% CH 3 CN, 15 min, 25 ml / min) to give the title compound in 45% yield as a mixture of isomers. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.84 (d, J = 9.1 Hz, 1H), 7.65-7.46 (m, 5H), 7.35 (dd, J = 2.0, 10.3 Hz, 1H), 7.20 -7.15 (m, 1H), 6.82 (d, J = 9.1 Hz, 1H), 4.20-4.16 (m, 1H), 3.95 (s, 2H), 2.92-2.85 (m, 1H), 2.22-2.16 (m , 1H), 2.02-1.98 (m, 2H), 1.89-1.84 (m, 2H), 1.79-1.67 (m, 3H).

실시예 30Example 30

N,N'-디-(2-퀴놀린일)-1,3-프로판디아민 N, N'-di- (2-quinolinyl) -1,3-propanediamine

이 표제 화합물을 2-퀴놀린일-1,3-프로판디아민의 합성으로부터 3% 수율로 분리하였다. 1H NMR(400 MHz, MeOH-d4) δ7.77(d, J = 8.5 Hz, 2H), 7.71(d, J = 8.9 Hz, 2H), 7.55(m, 4H), 7.20(t, J = 7.8 Hz, 2H), 6.61(d, J = 8.9 Hz, 2H), 3.59(bs, 4H), 1.92(bt, J = 5.7 Hz, 2H).This title compound was isolated in 3% yield from the synthesis of 2-quinolinyl-1,3-propanediamine. 1 H NMR (400 MHz, MeOH-d 4 ) δ7.77 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.9 Hz, 2H), 7.55 (m, 4H), 7.20 (t, J = 7.8 Hz, 2H), 6.61 (d, J = 8.9 Hz, 2H), 3.59 (bs, 4H), 1.92 (bt, J = 5.7 Hz, 2H).

실시예 31Example 31

N-(2-퀴놀린일)-N'-(2-퀴놀린일메틸)-1,3-프로판디아민 N- (2-quinolinyl) -N '-(2-quinolinylmethyl) -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 2-퀴놀린-카르복살데히드로부터 제조하였으며, SiO2(EtOAc:MeOH 1:0 -> 0:1) 상에서 정제하여, 표제 화합물을 27% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ8.23(d, J = 8.5 Hz, 1H), 7.98(d, J = 8.5 Hz, 1H), 7.88(d, J = 8.1 Hz, 1H), 7.77(d, J = 8.9 Hz, 1H), 7.74-7.70(m, 1H), 7.58-7.47(m, 4H), 7.33(t, J = 8.5 Hz, 1H), 7.12(t, J = 8.0 Hz, 1H), 6.69(d, J = 8.7 Hz, 1H), 4.13(s, 2H), 3.60(t, J = 6.6 Hz, 2H), 2.87(t, J = 6.9 Hz, 2H), 1.96(퀸텟, J = 6.7 Hz, 2H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and 2-quinoline-carboxaldehyde, and purified on SiO 2 (EtOAc: MeOH 1: 0-> 0: 1) to give the title compound. Was obtained in 27% yield. 1 H NMR (400 MHz, MeOH-d4) δ 8.23 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 8.9 Hz, 1H), 7.74-7.70 (m, 1H), 7.58-7.47 (m, 4H), 7.33 (t, J = 8.5 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.69 (d, J = 8.7 Hz, 1H), 4.13 (s, 2H), 3.60 (t, J = 6.6 Hz, 2H), 2.87 (t, J = 6.9 Hz, 2H), 1.96 (Quintet, J = 6.7 Hz, 2H).

실시예 32Example 32

N-[(1-아세틸-1H-인돌-3-일)메틸]-N'-(2-퀴놀린일)-1,3-프로판디아민 N-[(1-acetyl-1H-indol-3-yl) methyl] -N '-(2-quinolinyl) -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 1-아세틸-3-인돌카르복살데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액: 5% CH3CN -> 100% CH3CN, 10분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 25% 수율로 얻었다. 1H NMR(400 MHz, 아세톤-d6, 다수 로타머) δ7.77(d, J = 8.9 Hz, 1H), 7.69(d, J = 8.7 Hz, 1H), 7.61(s, 1H), 7.57(dd, J = 9.3, 1.4 Hz, 1H), 7.52(d, J = 8.5 Hz, 1H), 7.38(d, J = 7.5 Hz, 1H), 7.28(s, 1H), 7.10(d, J = 8.9 Hz, 2H), 7.02-6.98(m, 1H), 6.69(d, J = 8.9 Hz, 1H), 4.01(s, 2H), 3.64-3.61(m, 2H), 2.86-2.81(m, 2H), 2.53(s, 3H), 1.90-1.86(m, 2H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and 1-acetyl-3-indolecarboxaldehyde, and HPLC (95% 0.1 M ammonium acetate buffer: 5% CH 3 CN-> 100 Purification using% CH 3 CN, 10 min, 25 ml / min) afforded the title compound in 25% yield. 1 H NMR (400 MHz, Acetone-d 6 , Many Rotamers) δ7.77 (d, J = 8.9 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.61 (s, 1H), 7.57 (dd, J = 9.3, 1.4 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.28 (s, 1H), 7.10 (d, J = 8.9 Hz, 2H), 7.02-6.98 (m, 1H), 6.69 (d, J = 8.9 Hz, 1H), 4.01 (s, 2H), 3.64-3.61 (m, 2H), 2.86-2.81 (m, 2H ), 2.53 (s, 3 H), 1.90-1.86 (m, 2 H).

실시예 33Example 33

N-(시클로프로필메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민 N- (cyclopropylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 시클로프로판카르복살데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액:5% CH3CN -> 100% CH3CN, 15분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 17% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ8.07(d, J = 8.1 Hz, 1H), 7.74(t, J = 6.4 Hz, 2H), 7.65(t, J = 7.8 Hz, 1H), 7.36(t, J = 7.5 Hz, 1H), 6.93(d, J = 8.7 Hz, 1H), 3.67(t, J = 6.6 Hz, 2H), 3.16(t, J = 7.3 Hz, 2H), 2.93(d, J = 7.5 Hz, 2H), 2.10(퀸텟, J = 7.3 Hz, 2H), 1.12-1.02(m, 1H), 0.71-0.67(m, 2H), 0.40-0.37(m, 2H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and cyclopropanecarboxaldehyde, and HPLC (95% 0.1 M ammonium acetate buffer: 5% CH 3 CN-> 100% CH 3 CN, 15 min, 25 ml / min) to afford the title compound in 17% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 8.07 (d, J = 8.1 Hz, 1H), 7.74 (t, J = 6.4 Hz, 2H), 7.65 (t, J = 7.8 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 3.67 (t, J = 6.6 Hz, 2H), 3.16 (t, J = 7.3 Hz, 2H), 2.93 ( d, J = 7.5 Hz, 2H), 2.10 (Quintet, J = 7.3 Hz, 2H), 1.12-1.02 (m, 1H), 0.71-0.67 (m, 2H), 0.40-0.37 (m, 2H).

실시예 34Example 34

N-(2-퀴놀린일)-N'-(3-티에닐메틸)-1,4-시클로헥산디아민 N- (2-quinolinyl) -N '-(3-thienylmethyl) -1,4-cyclohexanediamine

이 화합물을 N-퀴놀린-2-일시클로헥산-1,4-디아민과 3-티오펜카르복살데히드로부부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액:5% CH3CN -> 100% CH3CN, 15분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 부분입체 이성질체의 혼합물로 27% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4, 다수 이성질체) δ7.78(d, J = 8.9 Hz, 1H), 7.58(d, J = 8.5 Hz, 1H), 7.55(dd, J = 9.3, 1.2 Hz, 1H), 7.45(t, J = 8.5 Hz, 1H), 7.35(dd, J = 7.9, 3.0 Hz, 1H), 7.26-7.24(m, 1H), 7.16-7.10(m, 2H), 6.78(d, J = 9.1 Hz, 1H), 4.18-4.16(m, 1H), 3.81(s, 2H), 2.65(셉텟, J = 4.1 Hz, 1H), 1.92-1.83(m, 2H), 1.80-1.64(m, 5H), 1.64-1.54(m, 1H).This compound was prepared from N-quinolin-2-ylcyclohexane-1,4-diamine and 3-thiophenecarboxaldehyde. HPLC (95% 0.1 M ammonium acetate buffer: 5% CH 3 CN-> 100) Purification using% CH 3 CN, 15 min, 25 ml / min) afforded the title compound as a mixture of diastereomers in 27% yield. 1 H NMR (400 MHz, MeOH-d 4 , Multi-isomer) δ7.78 (d, J = 8.9 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.55 (dd, J = 9.3, 1.2 Hz, 1H), 7.45 (t, J = 8.5 Hz, 1H), 7.35 (dd, J = 7.9, 3.0 Hz, 1H), 7.26-7.24 (m, 1H), 7.16-7.10 (m, 2H), 6.78 (d, J = 9.1 Hz, 1H), 4.18-4.16 (m, 1H), 3.81 (s, 2H), 2.65 (septet, J = 4.1 Hz, 1H), 1.92-1.83 (m, 2H), 1.80- 1.64 (m, 5 H), 1.64-1.54 (m, 1 H).

실시예 35Example 35

N-([1,1'-비페닐]-4-일메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민 N-([1,1'-biphenyl] -4-ylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 4-비페닐카르복살데히드로부터 제조하였으나, 반응을 NaBH3CN을 사용하여 실온에서 수행하였으며(단일 노드 마이크로파 가열 않함), SiO2(CH2Cl2:MeOH 30:1 -> 10:1, 1% HOAc 함유) 상에서 정제하여, 표제 화합물을 46% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.84(d, J = 9.2 Hz, 1H), 7.62-7.56(m, 5H), 7.48-7.40(m, 5H), 7.36(t, J = 7.1 Hz, 1H), 7.23(d, J = 8. 5Hz, 1H), 7.16(t, J = 8.5 Hz, 1H), 6.74(d, J = 8.5 Hz, 1H), 4.21(s, 2H), 3.66(t, J = 5.8 Hz, 2H), 3.08(t, J = 7.0 Hz, 2H), 2.07(m, 2H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and 4-biphenylcarboxaldehyde, but the reaction was carried out at room temperature using NaBH 3 CN (without single node microwave heating), SiO Purification on 2 (CH 2 Cl 2 : MeOH 30: 1-> 10: 1, containing 1% HOAc) afforded the title compound in 46% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.84 (d, J = 9.2 Hz, 1H), 7.62-7.56 (m, 5H), 7.48-7.40 (m, 5H), 7.36 (t, J = 7.1 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.16 (t, J = 8.5 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H), 4.21 (s, 2H), 3.66 (t, J = 5.8 Hz, 2H), 3.08 (t, J = 7.0 Hz, 2H), 2.07 (m, 2H).

실시예 36Example 36

N-(6-메톡시-4-메틸-2-퀴놀린일)-N'-[3-(5-메틸-2-푸라닐)부틸]-1,3-프로판디아민 N- (6-methoxy-4-methyl-2-quinolinyl) -N '-[3- (5-methyl-2-furanyl) butyl] -1,3-propanediamine

이 화합물을 N-(6-메톡시-4-메틸-2-퀴놀린일)-1,3-프로판디아민과 3-(5-메틸-2-푸릴)부티르알데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액:5% CH3CN -> 100% CH3CN, 10분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 46% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.54(d, J = 8.9 Hz, 1H), 7.22(dd, J = 2.6, 8.7 Hz, 1H), 7.19(d, J = 2.8 Hz, 1H), 6.72(d, J = 1.0 Hz, 1H), 5.96-5.94(m, 2H), 3.92(s, 3H), 3.56(t, J =6.6 Hz, 2H), 2.93-2.88(m, 2H), 2.77-2.75(m, 2H), 2.66(t, J = 7.4 Hz, 2H), 2.53(d, J = 0.8 Hz, 3H), 2.25(d, J = 0.8 Hz, 3H), 1.90-1.82(m, 2H), 1.72-1.67(m, 1H), 1.21(d, J = 7.0 Hz, 3H).This compound was prepared from N- (6-methoxy-4-methyl-2-quinolinyl) -1,3-propanediamine and 3- (5-methyl-2-furyl) butyraldehyde, and HPLC (95%) Purification using 0.1 M ammonium acetate buffer: 5% CH 3 CN-> 100% CH 3 CN, 10 min, 25 ml / min) gave the title compound in 46% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.54 (d, J = 8.9 Hz, 1H), 7.22 (dd, J = 2.6, 8.7 Hz, 1H), 7.19 (d, J = 2.8 Hz, 1H ), 6.72 (d, J = 1.0 Hz, 1H), 5.96-5.94 (m, 2H), 3.92 (s, 3H), 3.56 (t, J = 6.6 Hz, 2H), 2.93-2.88 (m, 2H) , 2.77-2.75 (m, 2H), 2.66 (t, J = 7.4 Hz, 2H), 2.53 (d, J = 0.8 Hz, 3H), 2.25 (d, J = 0.8 Hz, 3H), 1.90-1.82 ( m, 2H), 1.72-1.67 (m, 1H), 1.21 (d, J = 7.0 Hz, 3H).

실시예 37Example 37

N-[[4-(디메틸아미노)페닐]메틸]-N'-(2-퀴놀린일)-1,3-프로판디아민 N-[[4- (dimethylamino) phenyl] methyl] -N '-(2-quinolinyl) -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 4-디메틸-아미노벤즈알데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액: 5% CH3CN -> 100% CH3CN, 15분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 22% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.85(d, J = 9.0 Hz, 1H), 7.60(dd, J = 1.5, 9.4 Hz, 1H), 7.39(t, J = 8.5 Hz, 1H), 7.24-7.17(m, 4H), 6.74(d, J = 9.1 Hz, 1H), 6.70(d, J = 9.0 Hz, 2H), 4.07(s, 2H), 3.65(t, J = 6.2 Hz, 2H), 3.04(t, J = 6.6 Hz, 2H), 2.94(s, 6H), 2.05(퀸텟, J = 6.6 Hz, 2H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and 4-dimethyl-aminobenzaldehyde, and HPLC (95% 0.1 M ammonium acetate buffer: 5% CH 3 CN-> 100% CH 3 CN) , 15 min, 25 ml / min) to give the title compound in 22% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.85 (d, J = 9.0 Hz, 1H), 7.60 (dd, J = 1.5, 9.4 Hz, 1H), 7.39 (t, J = 8.5 Hz, 1H ), 7.24-7.17 (m, 4H), 6.74 (d, J = 9.1 Hz, 1H), 6.70 (d, J = 9.0 Hz, 2H), 4.07 (s, 2H), 3.65 (t, J = 6.2 Hz , 2H), 3.04 (t, J = 6.6 Hz, 2H), 2.94 (s, 6H), 2.05 (quintet, J = 6.6 Hz, 2H).

실시예 38Example 38

N-(1H-피롤-2-일메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민 N- (1H-pyrrole-2-ylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 피롤-2-카르복살데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액:5% CH3CN -> 100% CH3CN, 10분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 61% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.86(d, J = 9.3 Hz, 1H), 7.61(dd, J = 1.7, 9.8 Hz, 1H), 7.46-7.42(m, 1H), 7.22-7.18(m, 2H), 6.81(dd, J = 1.5, 4.3 Hz, 1H), 6.75(d, J = 8.9 Hz, 1H), 6.22(dd, J = 1.8, 5.0 Hz, 1H), 6.13(t, J = 3.2 Hz, 1H), 4.18(s, 2H), 3.66(t, J = 6.3 Hz, 2H), 3.03(t, J = 6.8 Hz, 2H), 2.04(퀸텟, J = 6.5 Hz, 2H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and pyrrole-2-carboxaldehyde, and HPLC (95% 0.1 M ammonium acetate buffer: 5% CH 3 CN-> 100% CH 3) CN, 10 min, 25 ml / min) afforded the title compound in 61% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.86 (d, J = 9.3 Hz, 1H), 7.61 (dd, J = 1.7, 9.8 Hz, 1H), 7.46-7.42 (m, 1H), 7.22 -7.18 (m, 2H), 6.81 (dd, J = 1.5, 4.3 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 6.22 (dd, J = 1.8, 5.0 Hz, 1H), 6.13 ( t, J = 3.2 Hz, 1H), 4.18 (s, 2H), 3.66 (t, J = 6.3 Hz, 2H), 3.03 (t, J = 6.8 Hz, 2H), 2.04 (Quintet, J = 6.5 Hz, 2H).

실시예 39Example 39

N-[3-(5-메틸-2-푸라닐)부틸]-N'-(2-퀴놀린일)-1,3-프로판디아민 N- [3- (5-methyl-2-furanyl) butyl] -N '-(2-quinolinyl) -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 3-(5-메틸-2-푸릴)-부티르알데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액:5% CH3CN -> 100% CH3CN, 10분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 19% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.86(d, J = 8.9 Hz, 1H), 7.62(dd, J = 1.2, 9.3 Hz, 2H), 7.58(d, J = 8.5 Hz, 2H), 7.53-7.49(m, 2H), 7.24-7.20(m, 1H), 6.76(d, J = 9.1 Hz, 1H), 5.86(d, J = 3.0 Hz, 2H), 5.84-5.83(m, 2H), 3.62(t, J = 6.4 Hz, 2H), 2.98(t, J = 6.7 Hz, 2H), 2.92-2.75(m, 4H), 2.18(d, J = 0.8 Hz, 3H), 1.98(퀸텟, J = 6.6 Hz, 3H), 1.90(s, 3H), 1.87-1.78(m, 4H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and 3- (5-methyl-2-furyl) -butyraldehyde, and HPLC (95% 0.1 M ammonium acetate buffer: 5% CH 3 CN-> 100% CH 3 CN, 10 min, 25 ml / min) to give the title compound in 19% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.86 (d, J = 8.9 Hz, 1H), 7.62 (dd, J = 1.2, 9.3 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H ), 7.53-7.49 (m, 2H), 7.24-7.20 (m, 1H), 6.76 (d, J = 9.1 Hz, 1H), 5.86 (d, J = 3.0 Hz, 2H), 5.84-5.83 (m, 2H), 3.62 (t, J = 6.4 Hz, 2H), 2.98 (t, J = 6.7 Hz, 2H), 2.92-2.75 (m, 4H), 2.18 (d, J = 0.8 Hz, 3H), 1.98 ( Quintet, J = 6.6 Hz, 3H), 1.90 (s, 3H), 1.87-1.78 (m, 4H).

실시예 40Example 40

N-[(5-니트로-3-티에닐)메틸]-N'-(2-퀴놀린일)-1,3-프로판디아민 N-[(5-nitro-3-thienyl) methyl] -N '-(2-quinolinyl) -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 5-니트로티오펜-3-카르복살데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액:5% CH3CN -> 100% CH3CN, 15분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 64% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.94(d, J = 1.7 Hz, 1H), 7.87(d, J = 9.1 Hz, 1H), 7.78(d, J = 1.0 Hz, 1H), 7.61(d, J = 8.5 Hz, 1H), 7.48-7.40(m, 2H), 7.20(t, J = 7.4 Hz, 1H), 6.76(d, J = 8.8 Hz, 1H), 4.11(s, 2H), 3.64(t, J = 6.6 Hz, 2H), 3.03(t, J = 6.8 Hz, 2H), 2.04(퀸텟, J = 6.6 Hz, 2H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and 5-nitrothiophene-3-carboxaldehyde, and HPLC (95% 0.1 M ammonium acetate buffer: 5% CH 3 CN-> Purification using 100% CH 3 CN, 15 min, 25 ml / min) afforded the title compound in 64% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ7.94 (d, J = 1.7 Hz, 1H), 7.87 (d, J = 9.1 Hz, 1H), 7.78 (d, J = 1.0 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.48-7.40 (m, 2H), 7.20 (t, J = 7.4 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 4.11 (s, 2H ), 3.64 (t, J = 6.6 Hz, 2H), 3.03 (t, J = 6.8 Hz, 2H), 2.04 (quintet, J = 6.6 Hz, 2H).

실시예 41Example 41

N-(6-메톡시-4-메틸-2-퀴놀린일)-N'-[(5-니트로-3-티에닐)메틸]-1,3-프로판디아민 N- (6-methoxy-4-methyl-2-quinolinyl) -N '-[(5-nitro-3-thienyl) methyl] -1,3-propanediamine

이 화합물을 N-(6-메톡시-4-메틸-2-퀴놀린일)-1,3-프로판디아민과 5-니트로티오펜-3-카르복살데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액:5% CH3CN -> 100% CH3CN, 10분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 63% 수율로 얻었다. 1H NMR(400 MHz, DMF-d7) δ8.09(d, J = 1.8 Hz, 1H), 7.87-7.87(m, 1H), 7.46(d, J = 8.9 Hz, 1H), 7.19(d, J = 2.8 Hz, 1H), 7.15(dd, J = 2.8, 11.7 Hz, 1H), 6.67(d, J = 1.0 Hz, 1H), 3.88(s, 3H), 3.78(s, 2H), 3.54(t, J = 6.6 Hz, 2H), 2.70(t, J = 6.7 Hz, 2H), 2.49(d, J = 1.0 Hz, 3H), 1.82(퀸텟, J = 6.7 Hz, 2H).This compound was prepared from N- (6-methoxy-4-methyl-2-quinolinyl) -1,3-propanediamine and 5-nitrothiophene-3-carboxaldehyde, and HPLC (95% 0.1 M ammonium) Acetate buffer: 5% CH 3 CN-> 100% CH 3 CN, 10 min, 25 ml / min) to afford the title compound in 63% yield. 1 H NMR (400 MHz, DMF-d 7 ) δ 8.09 (d, J = 1.8 Hz, 1H), 7.87-7.87 (m, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.19 (d , J = 2.8 Hz, 1H), 7.15 (dd, J = 2.8, 11.7 Hz, 1H), 6.67 (d, J = 1.0 Hz, 1H), 3.88 (s, 3H), 3.78 (s, 2H), 3.54 (t, J = 6.6 Hz, 2H), 2.70 (t, J = 6.7 Hz, 2H), 2.49 (d, J = 1.0 Hz, 3H), 1.82 (quintet, J = 6.7 Hz, 2H).

실시예 42Example 42

N-(6-메톡시-4-메틸-2-퀴놀린일)-N'-(1H-피롤-2-일메틸)-1,3-프로판디아민N- (6-methoxy-4-methyl-2-quinolinyl) -N '-(1H-pyrrole-2-ylmethyl) -1,3-propanediamine

이 화합물을 N-(6-메톡시-4-메틸-2-퀴놀린일)-1,3-프로판디아민과 피롤-2-카르복살데히드로부터 제조하였으며, HPLC(95% 0.1 M 암모늄 아세테이트 완충액: 5% CH3CN -> 100% CH3CN, 10분, 25 ml/분)를 사용하여 정제하여, 표제 화합물을 83% 수율로 얻었다. 1H NMR(400 MHz, DMF-d7) δ7.56(d, J = 8.9 Hz, 1H), 7.36(d, J = 2.8 Hz, 1H), 7.31(dd, J = 3.0, 11.9 Hz, 1H), 6.95-6.93(m, 1H), 6.86(d, J = 0.8 Hz, 1H), 6.19-6.17(m, 1H), 6.15-6.13(m, 1H), 4.13(s, 2H), 4.05(s, 3H), 3.71(t, J = 6.5 Hz, 2H), 2.99(t, J = 6.9 Hz, 2H), 2.66(d, J = 0.8 Hz, 3H), 2.11-2.10(m, 2H).This compound was prepared from N- (6-methoxy-4-methyl-2-quinolinyl) -1,3-propanediamine and pyrrole-2-carboxaldehyde, and HPLC (95% 0.1 M ammonium acetate buffer: 5 Purification using% CH 3 CN-> 100% CH 3 CN, 10 min, 25 ml / min) afforded the title compound in 83% yield. 1 H NMR (400 MHz, DMF-d 7 ) δ 7.56 (d, J = 8.9 Hz, 1H), 7.36 (d, J = 2.8 Hz, 1H), 7.31 (dd, J = 3.0, 11.9 Hz, 1H ), 6.95-6.93 (m, 1H), 6.86 (d, J = 0.8 Hz, 1H), 6.19-6.17 (m, 1H), 6.15-6.13 (m, 1H), 4.13 (s, 2H), 4.05 ( s, 3H), 3.71 (t, J = 6.5 Hz, 2H), 2.99 (t, J = 6.9 Hz, 2H), 2.66 (d, J = 0.8 Hz, 3H), 2.11-2.10 (m, 2H).

실시예 43Example 43

N-[(3,4-디클로로페닐)메틸]-N'-메틸-N'-2-퀴놀린일)-1,3-프로판디아민 N-[(3,4-dichlorophenyl) methyl] -N'-methyl-N'-2-quinolinyl) -1,3-propanediamine

이 표제 화합물을 실시예 22의 합성으로부터 분리하였다. 1H NMR(400 MHz, MeOH-d4) δ7.93(d, J = 9.3 Hz, 1H), 7.60(d, J = 7.7 Hz, 1H), 7.45-7.37(m, 3H), 7.32(d, J = 8.3 Hz, 1H), 7.18-7.14(m, 1H), 7.09(dd, J = 2.0, 10.3 Hz, 1H), 6.99(d, J = 9.3 Hz, 1H), 3.83(t, J = 6.7 Hz, 2H), 3.65(s, 2H), 3.12(s, 3H), 2. 58(t, J = 6.7 Hz, 2H), 1.91(퀸텟, J = 7.0 Hz, 2H).This title compound was isolated from the synthesis of Example 22. 1 H NMR (400 MHz, MeOH-d 4 ) δ7.93 (d, J = 9.3 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.45-7.37 (m, 3H), 7.32 (d , J = 8.3 Hz, 1H), 7.18-7.14 (m, 1H), 7.09 (dd, J = 2.0, 10.3 Hz, 1H), 6.99 (d, J = 9.3 Hz, 1H), 3.83 (t, J = 6.7 Hz, 2H), 3.65 (s, 2H), 3.12 (s, 3H), 2. 58 (t, J = 6.7 Hz, 2H), 1.91 (quintet, J = 7.0 Hz, 2H).

실시예 44Example 44

N-[1-(2,5-디메틸-3-티에닐)에틸]-N'-(2-퀴놀린일)-1,3-프로판디아민 N- [1- (2,5-dimethyl-3-thienyl) ethyl] -N '-(2-quinolinyl) -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 3-아세틸-2,5-디메틸티오펜으로부터 제조하였으나, 단일 노드 마이크로파 가열하였으며(120℃, 10분), SiO2(CH2Cl2:MeOH 10:0 -> 4:1) 상에서 정제하여, 표제 화합물을 26% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.84(d, J = 9.1 Hz, 1H), 7.61(dd, J = 1.7, 9.7 Hz, 1H), 7.49-7.45(m, 1H), 7.33(d, J = 9.1 Hz, 1H), 7.21(t, J = 7.8 Hz, 1H), 6.72(d, J = 9.4 Hz, 1H), 6.43(s, 1H), 4.40(q, J = 6.9 Hz, 1H), 3.71-3.55(m, 2H), 2.99-2.83(m, 2H), 2.27(s, 3H), 2.25(s, 3H), 2.06-1.95(m, 2H), 1.91(s, 3H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and 3-acetyl-2,5-dimethylthiophene, but was heated in a single node microwave (120 ° C., 10 minutes), and SiO 2 (CH Purification on 2 Cl 2 : MeOH 10: 0-> 4: 1) afforded the title compound in 26% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.84 (d, J = 9.1 Hz, 1H), 7.61 (dd, J = 1.7, 9.7 Hz, 1H), 7.49-7.45 (m, 1H), 7.33 (d, J = 9.1 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 6.72 (d, J = 9.4 Hz, 1H), 6.43 (s, 1H), 4.40 (q, J = 6.9 Hz , 1H), 3.71-3.55 (m, 2H), 2.99-2.83 (m, 2H), 2.27 (s, 3H), 2.25 (s, 3H), 2.06-1.95 (m, 2H), 1.91 (s, 3H ).

실시예 45Example 45

N-[1-(2,5-디클로로-티오펜-3-일)-에틸]-N'-(2-퀴놀린일)-1,3-프로판디아민N- [1- (2,5-Dichloro-thiophen-3-yl) -ethyl] -N '-(2-quinolinyl) -1,3-propanediamine

이 화합물을 N-퀴놀린-2-일-1,3-프로판디아민과 1-(2,5-디클로로-티오펜-3-일)-에타논으로부터 제조하였으나, 단일 노드 마이크로파 가열하였으며(120℃, 5분), SiO2(CH2Cl2:MeOH 10:0 -> 4:1) 상에서 정제하여, 표제 화합물을 11% 수율로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.79(d, J = 8.8 Hz, 1H), 7.56(bt, J = 8.0 Hz, 2H), 7.49-7.44(m, 1H), 7.16(dt, J = 1.2, 7.4 Hz, 1H), 6.70(s, 1H), 6.69(bd, J = 9.0 Hz, 1H), 3.93(q, J = 6.7 Hz, 1H), 3.59(m, 1H), 3.47(m, 1H), 2.50(m, 2H), 1.81(m, 2H), 1.28(d, J = 6. 9 Hz, 3H).This compound was prepared from N-quinolin-2-yl-1,3-propanediamine and 1- (2,5-dichloro-thiophen-3-yl) -ethanone, but single node microwave heated (120 ° C., 5 min), purified on SiO 2 (CH 2 Cl 2 : MeOH 10: 0-> 4: 1) to afford the title compound in 11% yield. 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.79 (d, J = 8.8 Hz, 1H), 7.56 (bt, J = 8.0 Hz, 2H), 7.49-7.44 (m, 1H), 7.16 (dt , J = 1.2, 7.4 Hz, 1H), 6.70 (s, 1H), 6.69 (bd, J = 9.0 Hz, 1H), 3.93 (q, J = 6.7 Hz, 1H), 3.59 (m, 1H), 3.47 (m, 1H), 2.50 (m, 2H), 1.81 (m, 2H), 1.28 (d, J = 6. 9 Hz, 3H).

실시예 46Example 46

N-[(1-아세틸-1H-인돌-3-일)메틸]-N'-퀴놀린-2-일시클로헥산-1,3-디아민N-[(1-acetyl-1H-indol-3-yl) methyl] -N'-quinolin-2-ylcyclohexane-1,3-diamine

N-퀴놀린-2-일시클로헥산-1,3-디아민(1.01 mmol, 0.243 g)과 1-아세틸-1H-인돌-4-카르복살데히드(0.63 mmol, 0.118 g)의 MeOH:CH2Cl2(1:2, 1% HOAc 함유, 9 mL) 내 용액을 상온에서 1시간 동안 교반한 후, NaBH3CN(2.50 mmol, 0.16 g)의 MeOH(1.5 mL) 내 용액을 첨가하였다. 이 반응 혼합물을 LC/MS가 출발 물질이 소비되었음을 나타낼 때까지 실온에서 교반하였다. 메탄올(10 mL)을 첨가하고, 반응 혼합물을 농축하였다. 잔류물을 SiO2 상에서 정제하고, CH2Cl2:MeOH(95:5) 및 마지막으로 CH2Cl2:MeOH(9:1)로 용출하여, 0.095 g(37%)의 표제 화합물을 부분입체 이성질체의 혼합물(약 3:1)로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ8.36(d, J = 8.1 Hz, 1H, 다수 이성질체), 8.32(d, J = 8.3 Hz, 1H, 소수 이성질체), 7.77(d, J = 8.9 Hz, 1H), 7.63-7.12(m, 8H), 6.73(d, J = 8.9 Hz, 1H, 소수 이성질체), 6.69(d, J = 8.9 Hz, 1H, 다수 이성질체), 4.42(m, 1H, 소수 이성질체), 4.06-3.96(m, 1H, 다수 이성질체), 3.97(s, 2H, 다수 이성질체), 3.96(s, 2H, 소수 이성질체), 3.00(m, 1H, 소수 이성질체), 2.82(tt, J = 11.2, 3.6 Hz, 1H, 다수 이성질체), 2.60(s, 3H, 다수 이성질체), 2.50-2.42(m, 1H), 2.46(s, 3H, 소수 이성질체), 2.14-1.09(m, 7H). 13C NMR(75 MHz, DMSO-d6) δ(이성질체의 혼합물) 168.4, 156.0, 148.0, 137.4, 137.2, 136.0, 129.8, 129.4, 127.3, 125.9, 125.3, 123.5, 123.2, 122.7, 121.8, 121.5, 119.0, 118. 8, 116.7, 111.6, 111.0, 55.4, 52.3, 48.5, 46.0, 42.0, 41.8, 39.5, 32.7, 32.6, 31.7, 23.9, 22.1, 19.9. LC-MS [M+H]+ 413.MeOH: CH 2 Cl 2 of N-quinolin-2-ylcyclohexane-1,3-diamine (1.01 mmol, 0.243 g) and 1-acetyl-1H-indole-4-carboxaldehyde (0.63 mmol, 0.118 g) The solution in (1: 2, containing 1% HOAc, 9 mL) was stirred for 1 h at room temperature, followed by addition of a solution in MeOH (1.5 mL) of NaBH 3 CN (2.50 mmol, 0.16 g). The reaction mixture was stirred at room temperature until LC / MS indicated the starting material was consumed. Methanol (10 mL) was added and the reaction mixture was concentrated. The residue was purified on SiO 2 and eluted with CH 2 Cl 2 : MeOH (95: 5) and finally CH 2 Cl 2 : MeOH (9: 1) to afford 0.095 g (37%) of the title compound as a diastereomer. Obtained as a mixture of isomers (about 3: 1). 1 H NMR (400 MHz, MeOH-d 4 ) δ8.36 (d, J = 8.1 Hz, 1H, multiple isomers), 8.32 (d, J = 8.3 Hz, 1H, minor isomers), 7.77 (d, J = 8.9 Hz, 1H), 7.63-7.12 (m, 8H), 6.73 (d, J = 8.9 Hz, 1H, minor isomers), 6.69 (d, J = 8.9 Hz, 1H, multiple isomers), 4.42 (m, 1H , Minor isomers), 4.06-3.96 (m, 1H, multiple isomers), 3.97 (s, 2H, multiple isomers), 3.96 (s, 2H, minor isomers), 3.00 (m, 1H, minor isomers), 2.82 (tt , J = 11.2, 3.6 Hz, 1H, multiple isomers), 2.60 (s, 3H, multiple isomers), 2.50-2.42 (m, 1H), 2.46 (s, 3H, minor isomers), 2.14-1.09 (m, 7H ). 13 C NMR (75 MHz, DMSO-d 6 ) δ (mixture of isomers) 168.4, 156.0, 148.0, 137.4, 137.2, 136.0, 129.8, 129.4, 127.3, 125.9, 125.3, 123.5, 123.2, 122.7, 121.8, 121.5, 119.0, 118. 8, 116.7, 111.6, 111.0, 55.4, 52.3, 48.5, 46.0, 42.0, 41.8, 39.5, 32.7, 32.6, 31.7, 23.9, 22.1, 19.9. LC-MS [M + H] + 413.

실시예 47Example 47

(1S,3S)-N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-(3-티에닐메틸)시클로펜탄-1,3- 디아민(1S, 3S) -N- (6-methoxy-4-methylquinolin-2-yl) -N '-(3-thienylmethyl) cyclopentane-1,3-diamine

a) tert-부틸{(1S,3S)-3-[(6-메톡시-4-메틸퀴놀린-2-일)아미노]시클로펜틸} 카바메이트a) tert -butyl {(1S, 3S) -3-[(6-methoxy-4-methylquinolin-2-yl) amino] cyclopentyl} carbamate

2-클로로-6-메톡시-4-메틸퀴놀린(3.33 mmol, 0.690 g), tert-부틸[(1S,3S)-3-아미노시클로펜틸]카바메이트(5.0 mmol, 1.00 g), NaOtBu(4.66 mmol, 0.45 g), Pd(OAc)2(0.33 mmol, 0.075 g), 및 BINAP(0.33 mmol, 0.207 g)의 톨루엔(30 mL) 내 혼합물을 100℃에서 질소하에 LC/MS가 출발 물질이 소비되었음을 나타낼 때까지 교반하였다. 이 반응 혼합물을 실온으로 냉각하고, Et2O(300 mL)에 부어, 염수로 세척하였다. 그 후, 유기층을 분리하고, Na2S04로 건조하고, 건조 증발하였다. 잔류물을 SiO2 컬럼 상에서 정제하고, CH2Cl2:MeOH(95:5)로 용출하여, 0.618 g(50%)의 표제 화합물을 얻었다. LC-MS [M+2H]+ 373.2-chloro-6-methoxy-4-methylquinoline (3.33 mmol, 0.690 g) , tert -butyl [(1S, 3S) -3-aminocyclopentyl] carbamate (5.0 mmol, 1.00 g), NaO t Bu (4.66 mmol, 0.45 g), a mixture of Pd (OAc) 2 (0.33 mmol, 0.075 g), and BINAP (0.33 mmol, 0.207 g) in toluene (30 mL) under nitrogen at 100 ° C. Stir until it was consumed. The reaction mixture was cooled to rt, poured into Et 2 O (300 mL) and washed with brine. After that, the organic layer was separated, dried over Na 2 SO 4 , and evaporated to dryness. The residue was purified on a SiO 2 column and eluted with CH 2 Cl 2 : MeOH (95: 5) to give 0.618 g (50%) of the title compound. LC-MS [M + 2H] + 373.

b) (1S,3S)-N-(6-메톡시-4-메틸퀴놀린-2-일)시클로펜탄-1,3-디아민 b) (1S, 3S) -N- (6-methoxy-4-methylquinolin-2-yl) cyclopentane-1,3-diamine

CHCl3(7 mL) 내 tert-부틸{(1S,3S)-3-[(6-메톡시-4-메틸퀴놀린-2-일)아미노]시클로펜틸}카바메이트(1.48 mmol, 0.550 g)와 TFA(3 mL)를 LC/MS가 출발 물질이 소비되었음을 나타낼 때까지 실온에서 교반하였다. 그 후, 이 혼합물을 건조 증발하였다. pH를 2 N NaOH 용액으로 10으로 조정한 후, EtOAc로 추출하였다. 유기층을 분리하고, MgSO4로 건조 및 농축하여, 0.400 g(99%)의 표제 화합물을 얻었다. 1H NMR(300 MHz, CDCl3) δ8 7.57(d, 1H), 7.16-7.20(dd 1H), 7.04(d, 1H), 6.51(s, 1H), 5.24(br, 1H), 4.44(m, 1H), 3.86(s, 3H), 3.50(m, 1H), 2.73(br, 2H), 2.51(s, 3H), 2.26(m, 2H), 2.06(m, 1H), 1.85(m, 1H), 1.41(m, 2H). Tert -butyl {(1S, 3S) -3-[(6-methoxy-4-methylquinolin-2-yl) amino] cyclopentyl} carbamate (1.48 mmol, 0.550 g) in CHCl 3 (7 mL) TFA (3 mL) was stirred at rt until LC / MS indicated starting material was consumed. This mixture was then evaporated to dryness. The pH was adjusted to 10 with 2 N NaOH solution and then extracted with EtOAc. The organic layer was separated, dried over MgSO 4 and concentrated to give 0.400 g (99%) of the title compound. 1 H NMR (300 MHz, CDCl 3 ) δ8 7.57 (d, 1H), 7.16-7.20 (dd 1H), 7.04 (d, 1H), 6.51 (s, 1H), 5.24 (br, 1H), 4.44 (m , 1H), 3.86 (s, 3H), 3.50 (m, 1H), 2.73 (br, 2H), 2.51 (s, 3H), 2.26 (m, 2H), 2.06 (m, 1H), 1.85 (m, 1H), 1.41 (m, 2H).

c) (1S,3S)-N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-(3-티에닐메틸)시클로펜탄- 1,3-디아민c) (1S, 3S) -N- (6-methoxy-4-methylquinolin-2-yl) -N '-(3-thienylmethyl) cyclopentane-1,3-diamine

MeOH:CH2Cl2(1:1, 1 % HOAc 함유, 5 mL) 내 (1S,3S)-N-(6-메톡시-4-메틸퀴놀린-2-일)시클로펜탄-1,3-디아민(0.74 mmol, 0.200 g)과 티오펜-3-카복실알데히드(0.74 mmol, 0.083 g)를 상온에서 1시간 동안 교반한 후, NaBH3CN(1.48 mmol, 0.093 g)의 MeOH(1 mL) 내 용액을 첨가하였다. 이 반응 혼합물을 실온에서 LC-MS가 출발 물질이 소비되었음을 나타낼 때까지 교반하였다. 메탄올(5 mL)을 첨가하고, 반응 혼합물을 농축하였다. 잔류물을 MeCN에 용해하고, 여과하였다. 그 후, 여과물을 건조 증발하고, MeCN(10 mL)에 용해하고, 예비 HPLC(H2O:MeCN)로 정제하여, 0.180 g(95%)의 표제 화합물을 얻었다. 1H NMR(300 MHz, CDCl3) δ7.58(d, 1H), 7.27-7.29(m, 1H), 7.19-7.23(dd, 1H), 7.13(d, 1H), 7.04-7.08(m, 2H), 6.53(s, 1H), 4.75(br, 1H), 4.38(m, 1H), 3.89(s, 3H), 3.80(s, 2H), 3.33-3.38(m, 1H), 2.54(s, 3H), 2.31(m, 1H), 1.95-2.08(m, 2H), 1.85(m, 1H), 1.49-1.53(m, 2H). 13C NMR(CDCl3) δ155.6, 155.1, 144.9, 141.7, 128.0, 127.8, 126.2, 124.2, 122.0, 120.7, 111.4, 104.0, 57.7, 56.0, 52.3, 47.9, 41.2, 32.9, 32.2, 19.6. MS (ESI) 368 (M+H+).(1S, 3S) -N- (6-methoxy-4-methylquinolin-2-yl) cyclopentane-1,3- in MeOH: CH 2 Cl 2 (containing 1: 1, 1% HOAc, 5 mL) Diamine (0.74 mmol, 0.200 g) and thiophene-3-carboxyaldehyde (0.74 mmol, 0.083 g) were stirred at room temperature for 1 hour, followed by NaBH 3 CN (1.48 mmol, 0.093 g) in MeOH (1 mL). The solution was added. The reaction mixture was stirred at room temperature until LC-MS indicated starting material was consumed. Methanol (5 mL) was added and the reaction mixture was concentrated. The residue was dissolved in MeCN and filtered. The filtrate was then evaporated to dryness, dissolved in MeCN (10 mL) and purified by preparative HPLC (H 2 O: MeCN) to afford 0.180 g (95%) of the title compound. 1 H NMR (300 MHz, CDCl 3 ) δ 7.58 (d, 1H), 7.27-7.29 (m, 1H), 7.19-7.23 (dd, 1H), 7.13 (d, 1H), 7.04-7.08 (m, 2H), 6.53 (s, 1H), 4.75 (br, 1H), 4.38 (m, 1H), 3.89 (s, 3H), 3.80 (s, 2H), 3.33-3.38 (m, 1H), 2.54 (s , 3H), 2.31 (m, 1H), 1.95-2.08 (m, 2H), 1.85 (m, 1H), 1.49-1.53 (m, 2H). 13 C NMR (CDCl 3 ) δ 155.6, 155.1, 144.9, 141.7, 128.0, 127.8, 126.2, 124.2, 122.0, 120.7, 111.4, 104.0, 57.7, 56.0, 52.3, 47.9, 41.2, 32.9, 32.2, 19.6. MS (ESI) 368 (M + H + ).

실시예 48Example 48

(1S,3S)-N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-[(1-메틸-1H-인돌-3-일)메틸]시클로펜탄-1,3-디아민(1S, 3S) -N- (6-methoxy-4-methylquinolin-2-yl) -N '-[(1-methyl-1H-indol-3-yl) methyl] cyclopentane-1,3- Diamine

MeOH:CH2Cl2(1:1, 1 % HOAc 함유, 5 mL) 내 (1S,35)-N-(6-메톡시-4-메틸퀴놀린-2-일)시클로펜탄-1,3-디아민(0.74 mmol, 0.200 g)과 1-메틸 인돌-3-카복시알데히드(0.74 mmol, 0.118 g)를 상온에서 1시간 동안 교반하고, NaBH3CN(1.48 mmol, 0.093 g)의 MeOH(1 mL) 내 용액을 첨가하였다. 이 반응 혼합물을 LC/MS가 출발 물질이 소비되었음을 나타낼 때까지 실온에서 교반하였다. 메탄올(5 mL)을 첨가하고, 반응 혼합물을 농축하였다. 잔류물을 MeCN에 용해하고, 여과하였다. 그 후, 여과물을 건조 증발하고, MeCN(10 mL)에 용해하여, 예비 HPLC(H20:MeCN)로 정제하여, 0.050 g(16%)의 표제 화합물을 얻었다. 1H NMR(300 MHz, CDCl3) δ7.61-7.68(m, 2H), 7.25-7.30(m, 3H), 7.10-7.15(m, 2H), 7.03(s, 1H), 6.56(s, 1H), 4.90(br, 1H), 4.40-4.44(q, 1 H), 3.98(s, 2H), 3.81(s, 3H), 3.48(s, 3H), 3.44-3.48(m, 1H), 2.56(s, 3H), 2.31-2.35(m, 1H), 2.02-2.10(m, 2H), 1.84-1.91(m, 1H), 1.54-1.60(m, 2H). 13C NMR(CDCl3) δ155.4, 154.8, 144.6, 143.0, 137.2, 127.6, 127.5, 123.9, 121.8, 120.4, 119.1, 118.9, 113.2, 111.0, 109.4, 103.7, 57.4, 55.7, 52.1, 43.2, 40.8, 32.7, 32.6, 31.8, 19.3. LC-MS [M+H]+ 415.(1S, 35) -N- (6-methoxy-4-methylquinolin-2-yl) cyclopentane-1,3- in MeOH: CH 2 Cl 2 (1: 1, containing 1% HOAc, 5 mL) Diamine (0.74 mmol, 0.200 g) and 1-methyl indole-3-carboxyaldehyde (0.74 mmol, 0.118 g) were stirred at room temperature for 1 hour, followed by MeOH (1 mL) of NaBH 3 CN (1.48 mmol, 0.093 g). My solution was added. The reaction mixture was stirred at room temperature until LC / MS indicated the starting material was consumed. Methanol (5 mL) was added and the reaction mixture was concentrated. The residue was dissolved in MeCN and filtered. The filtrate was then evaporated to dryness, dissolved in MeCN (10 mL) and purified by preparative HPLC (H 2 O: MeCN) to afford 0.050 g (16%) of the title compound. 1 H NMR (300 MHz, CDCl 3 ) δ7.61-7.68 (m, 2H), 7.25-7.30 (m, 3H), 7.10-7.15 (m, 2H), 7.03 (s, 1H), 6.56 (s, 1H), 4.90 (br, 1H), 4.40-4.44 (q, 1H), 3.98 (s, 2H), 3.81 (s, 3H), 3.48 (s, 3H), 3.44-3.48 (m, 1H), 2.56 (s, 3H), 2.31-2.35 (m, 1H), 2.02-2.10 (m, 2H), 1.84-1.91 (m, 1H), 1.54-1.60 (m, 2H). 13 C NMR (CDCl 3 ) δ 155.4, 154.8, 144.6, 143.0, 137.2, 127.6, 127.5, 123.9, 121.8, 120.4, 119.1, 118.9, 113.2, 111.0, 109.4, 103.7, 57.4, 55.7, 52.1, 43.2, 40.8 , 32.7, 32.6, 31.8, 19.3. LC-MS [M + H] + 415.

실시예 49Example 49

N-[(1-아세틸-1H-인돌-3-일)메틸]-N'-(6-메톡시-4-메틸퀴놀린-2-일)시클로헥산-1,3-디아민 N-[(1-acetyl-1H-indol-3-yl) methyl] -N '-(6-methoxy-4-methylquinolin-2-yl) cyclohexane-1,3-diamine

N-(6-메톡시-4-메틸퀴놀린-2-일)시클로헥산-1,3-디아민(0.526 mmol, 0.150 g)과 1-아세틸-1H-인돌-3-카발데히드(0.53 mmol, 0.098 g)의 1% HOAc(5 mL)를 함유하는 CH2Cl2/MeOH 2:1 내 교반된 용액에, 소디엄 시아노보로히드리드(0.89 mmol, 0.056 g)를 첨가하였다. 24시간 후에, 이 혼합물을 농축하고, 플래쉬 크로마토그래피로 정제하여, 0.119 g(50%)의 표제 화합물의 다수 부분입체 이성질체를 얻었다. 1H NMR(400 MHz, CDCl3) δ8.43(d, J = 8.1 Hz, 1H), 7.61-7.57(m, 2H), 7.37-7.26(m, 3H), 7.19(dd, J = 9.1, 2.8 Hz, 1H), 7.06(d, J = 12.8 Hz, 1H), 6.42(s, 1H), 4.88(br, 1H), 4.04-3.95(m, 3H), 3.86(s, 3H), 2.82(m, 1H), 2.58(s, 3H), 2.48(s, 3H), 2.44-2.38(m, 1H), 2.11-1.82(m, 4H), 1.52-1.11(m, 4H); 13C NMR(101 MHz, CDCl3) δ168.6, 155.0, 154.7, 144.0, 143.5, 136.2, 130.0, 127.9, 125.4, 124.1, 123.7, 122.7, 121.9, 120.0, 119.0, 116.8, 112.1, 103.8, 55.7(2C), 48.7, 42.1, 40.1, 33.1, 32.8, 24.1, 22.4, 19.1; LC-MS [M+H]+ 457.3. 소수 부분입체 이성질체를 분리하여, HPLC(95% 0.1M 암모늄 아세테이트 완충액: 5% CH3CN -> 100% CH3CN, 10 mL/분)로 추가 정제하여, 0.027 g(11%)의 표제 화합물의 소수 부분입체 이성질체를 얻었다. 1H NMR(500 MHz, CDCl3) δ8.43(bs, 1H), 7.62(d, J = 7.5 Hz, 1H), 7.57(d, J = 9.1 Hz, 1H), 7.37-7.25(m, 3H), 7.18(d, J = 8.3 Hz, 1H), 7.07(s, 1H), 6.50(s, 1H), 4.69(bs, 1H), 4.29(bs, 1H), 4.01(d, J = 13.6 Hz, 1H), 3.96(d, J = 13.6 Hz, 1H), 3.88(s, 3H), 3.03(bs, 1H), 2.53(s, 3H), 2.52(s, 3H), 1.92-1.4(m, 9H); LC-MS [M+H]+ 457.3.N- (6-methoxy-4-methylquinolin-2-yl) cyclohexane-1,3-diamine (0.526 mmol, 0.150 g) and 1-acetyl-1H-indole-3-carbaldehyde (0.53 mmol, 0.098 To a stirred solution in CH 2 Cl 2 / MeOH 2: 1 containing g) 1% HOAc (5 mL) was added sodium cyanoborohydride (0.89 mmol, 0.056 g). After 24 hours, this mixture was concentrated and purified by flash chromatography to give 0.119 g (50%) of the multiple diastereomers of the title compound. 1 H NMR (400 MHz, CDCl 3 ) δ 8.43 (d, J = 8.1 Hz, 1H), 7.61-7.57 (m, 2H), 7.37-7.26 (m, 3H), 7.19 (dd, J = 9.1, 2.8 Hz, 1H), 7.06 (d, J = 12.8 Hz, 1H), 6.42 (s, 1H), 4.88 (br, 1H), 4.04-3.95 (m, 3H), 3.86 (s, 3H), 2.82 ( m, 1H), 2.58 (s, 3H), 2.48 (s, 3H), 2.44-2.38 (m, 1H), 2.11-1.82 (m, 4H), 1.52-1.11 (m, 4H); 13 C NMR (101 MHz, CDCl 3 ) δ 168.6, 155.0, 154.7, 144.0, 143.5, 136.2, 130.0, 127.9, 125.4, 124.1, 123.7, 122.7, 121.9, 120.0, 119.0, 116.8, 112.1, 103.8, 55.7 ( 2C), 48.7, 42.1, 40.1, 33.1, 32.8, 24.1, 22.4, 19.1; LC-MS [M + H] + 457.3. Fractional diastereomers were separated and further purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH 3 CN-> 100% CH 3 CN, 10 mL / min) to give 0.027 g (11%) of the title compound. Hydrophobic diastereomers of were obtained. 1 H NMR (500 MHz, CDCl 3 ) δ 8.43 (bs, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.57 (d, J = 9.1 Hz, 1H), 7.37-7.25 (m, 3H ), 7.18 (d, J = 8.3 Hz, 1H), 7.07 (s, 1H), 6.50 (s, 1H), 4.69 (bs, 1H), 4.29 (bs, 1H), 4.01 (d, J = 13.6 Hz , 1H), 3.96 (d, J = 13.6 Hz, 1H), 3.88 (s, 3H), 3.03 (bs, 1H), 2.53 (s, 3H), 2.52 (s, 3H), 1.92-1.4 (m, 9H); LC-MS [M + H] + 457.3.

실시예 50Example 50

N-(1H-인돌-3-일메틸)-N'-(6-메톡시-4-메틸퀴놀린-2-일)시클로헥산-1,3-디아민 N- (1H-indol-3-ylmethyl) -N '-(6-methoxy-4-methylquinolin-2-yl) cyclohexane-1,3-diamine

이 표제 화합물을 실시예 49의 합성으로부터 분리하였으며, HPLC(95% 0.1M 암모늄 아세테이트 완충액: 5% CH3CN -> 100% CH3CN, 10 mL/분)로 추가 정제하여, 0.013 g(6%)의 표제 화합물을 단일 부분입체 이성질체로 얻었다. 1H NMR(400 MHz, MeOH-d4) δ7.62(d, J = 7.9 Hz, 1H), 7.53(d, J = 9.1 Hz, 1H), 7.36(d, J = 8.3 Hz, 1H), 7.26(s, 1H), 7.17-7.09(m, 3H), 7.06(m, 1H), 6.57(s, 1H), 4.05(s, 2H), 3.92(tt, J = 11.4, 3.8 Hz, 1H), 3.86(s, 3H), 2.86(tt, J = 11.3, 3.7 Hz, 1H), 2.49(s, 3H), 2.47-2.41(m, 1H), 2.08-2.02(m, 1H), 1.90-1.82(m, 1H), 1.52-1.40(m, 1H), 1.24-1.11(m, 3H); LC-MS [M+H]+ 415.3.This title compound was isolated from the synthesis of Example 49 and further purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH 3 CN-> 100% CH 3 CN, 10 mL / min) to give 0.013 g (6 %) Of the title compound as a single diastereomer. 1 H NMR (400 MHz, MeOH-d 4 ) δ7.62 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 9.1 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.26 (s, 1H), 7.17-7.09 (m, 3H), 7.06 (m, 1H), 6.57 (s, 1H), 4.05 (s, 2H), 3.92 (tt, J = 11.4, 3.8 Hz, 1H) , 3.86 (s, 3H), 2.86 (tt, J = 11.3, 3.7 Hz, 1H), 2.49 (s, 3H), 2.47-2.41 (m, 1H), 2.08-2.02 (m, 1H), 1.90-1.82 (m, 1 H), 1.52-1.40 (m, 1 H), 1.24-1.11 (m, 3H); LC-MS [M + H] + 415.3.

실시예 51Example 51

N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-(3-티에닐메틸)시클로헥산-1,3-디아민 N- (6-methoxy-4-methylquinolin-2-yl) -N '-(3-thienylmethyl) cyclohexane-1,3-diamine

CH2Cl2/MeOH 1:1(1.2 mL) 내 N-(6-메톡시-4-메틸퀴놀린-2-일)시클로헥산-1,3-디아민(0.16 mmol, 0.046 g), CH2Cl2(0.6 mL) 내 티오펜-3-카르복살데히드(0.12 mmol, 0.014 g), 및 HOAc(0.060 mL)를 폴-BH3CN(150 mg, CH2Cl2 내 미리 팽창됨, 0.6 mL)에 첨가하였다. 결과 슬러리를 단일 노드 마이크로파 가열하였다(100℃, 5분). 수지를 여과하고, 일부분(1-2 mL)의 CH2Cl2과 MeOH로 세척하여, 여과물을 농축하였다. 잔류물을 HPLC(95% 0.1M 암모늄 아세테이트 완충액: 5% CH3CN -> 100% CH3CN, 10 mL/분)으로 정제하여, 0.021 g(39%)의 표제 화합물을 부분입체 이성질체의 혼합물로 얻었다(~5:1). 1H NMR(400 MHz, MeOH-d4) δ7.56(m, 1H, 소수 이성질체), 7.55(d, J = 9.1 Hz, 1H, 다수 이성질체), 7.44-7.40(m, 2H), 7.33(dd, J = 5.0, 3.0 Hz, 1H, 소수 이성질체), 7.25(m, 1H, 소수 이성질체), 7.19-7.13(m, 3H) 7.07(dd, J = 5.0, 1.2 Hz, 1H, 소수 이성질체), 6.66(bs, 1H, 소수 이성질체), 6.59(bs, 1H, 다수 이성질체), 4.36(m, 1H, 소수 이성질체), 4.02(s, 2H, 다수 이성질체), 4.01(s, 2H, 소수 이성질체), 3.94(tt, J = 11.5, 3.7 Hz, 1H, 다수 이성질체), 3.87(s, 3H, 소수 이성질체), 3.86(s, 3H, 다수 이성질체), 3.10(m, 1H, 소수 이성질체), 2.94(tt, J = 11.6, 3.7 Hz, 1H, 다수 이성질체), 2.52-2.46(m, 1H, 다수 이성질체), 2.52(s, 3H, 소수 이성질체), 2.50(s, 3H, 다수 이성질체), 2.34-2. 28(m, 1H, 소수 이성질체), 2.12-1.15(m, 7H); 13C NMR(101 MHz, MeOH-d4, 다수 이성질체) δ156.6, 156.2, 145.7, 143.7, 137.9, 129.0, 127.5, 127.3, 125.4, 125.2, 120.9, 114.3, 104.9, 56.3, 56.0, 49.3, 45.1,38.9, 33.6, 31.4, 23.9, 18.9; LC-MS [M+H]+ 382.2.N- (6-methoxy-4-methylquinolin-2-yl) cyclohexane-1,3-diamine (0.16 mmol, 0.046 g) in CH 2 Cl 2 / MeOH 1: 1 (1.2 mL), CH 2 Cl Thiophen-3-carboxaldehyde (0.12 mmol, 0.014 g), and HOAc (0.060 mL) in 2 (0.6 mL) were diluted with Paul-BH 3 CN (150 mg, preexpanded in CH 2 Cl 2 , 0.6 mL). Was added. The resulting slurry was heated to single node microwave (100 ° C., 5 min). The resin was filtered off and washed with a portion (1-2 mL) of CH 2 Cl 2 and MeOH to concentrate the filtrate. The residue was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH 3 CN-> 100% CH 3 CN, 10 mL / min) to afford 0.021 g (39%) of the title compound as a mixture of diastereomers (~ 5: 1). 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.56 (m, 1H, minor isomers), 7.55 (d, J = 9.1 Hz, 1H, multiple isomers), 7.44-7.40 (m, 2H), 7.33 ( dd, J = 5.0, 3.0 Hz, 1H, minor isomers), 7.25 (m, 1H, minor isomers), 7.19-7.13 (m, 3H) 7.07 (dd, J = 5.0, 1.2 Hz, 1H, minor isomers), 6.66 (bs, 1H, minor isomers), 6.59 (bs, 1H, multiple isomers), 4.36 (m, 1H, minor isomers), 4.02 (s, 2H, multiple isomers), 4.01 (s, 2H, minor isomers), 3.94 (tt, J = 11.5, 3.7 Hz, 1H, multiple isomers), 3.87 (s, 3H, minor isomers), 3.86 (s, 3H, multiple isomers), 3.10 (m, 1H, minor isomers), 2.94 (tt , J = 11.6, 3.7 Hz, 1H, multiple isomers), 2.52-2.46 (m, 1H, multiple isomers), 2.52 (s, 3H, minor isomers), 2.50 (s, 3H, multiple isomers), 2.34-2. 28 (m, 1H, minor isomers), 2.12-1.15 (m, 7H); 13 C NMR (101 MHz, MeOH-d 4 , many isomers) δ 156.6, 156.2, 145.7, 143.7, 137.9, 129.0, 127.5, 127.3, 125.4, 125.2, 120.9, 114.3, 104.9, 56.3, 56.0, 49.3, 45.1 , 38.9, 33.6, 31.4, 23.9, 18.9; LC-MS [M + H] + 382.2.

실시예 52Example 52

N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-[(1-메틸-1H-인돌-3-일)메틸]시클로헥산-1,3-디아민 N- (6-methoxy-4-methylquinolin-2-yl) -N '-[(1-methyl-1H-indol-3-yl) methyl] cyclohexane-1,3-diamine

CH2Cl2/MeOH 1:1(1.2 mL) 내 N-(6-메톡시-4-메틸퀴놀린-2-일)시클로헥산-1,3-디아민(0.16 mmol, 0.046 g), CHCl2(0.6 mL) 내 1-메틸인돌-3-카르복살데히드(0.13 mmol, 0.021 g), 및 HOAc(0.060 mL)를 폴-BH3CN(150 mg, CH2Cl2 내 미리 팽창됨, 0.6 mL)에 첨가하였다. 결과 슬러리를 단일 노드 마이크로파 가열하였다(100℃, 10분). 수지를 여과하고, 일부분(1-2 mL)의 CH2Cl2과 MeOH로 세척하여, 여과물을 농축하였다. 잔류물을 HPLC(95% 0.1M 암모늄 아세테이트 완충액: 5% CH3CN -> 100% CH3CN, 10 mL/분)로 정제하여, 0.021 g(34%)의 표제 화합물을 부분입체 이성질체의 혼합물로 얻었다(~6:1). 1H NMR(400 MHz, MeOH-d4) δ7.65(d, J = 8.1 Hz, 1H, 다수 이성질체), 7.59-7.55(m, 1H, 소수 이성질체), 7.54(d, J = 9.1 Hz, 1H, 다수 이성질체), 7.37(d, J = 8.3 Hz, 1H, 다수 이성질체), 7.30(d, J = 8.3 Hz, 1H, 소수 이성질체), 7.27(s, 1H, 다수 이성질체), 7.23-7.07(m, 5H), 7.01-6.97(m, 1H, 소수 이성질체), 6.62(s, 1H, 소수 이성질체), 6.58(s, 1H, 다수 이성질체), 4.36(m, 1H, 소수 이성질체), 4.20(s, 2H), 3.95(tt, J = 11.4, 3.7 Hz, 1H, 다수 이성질체), 3.87(s, 3H, 소수 이성질체), 3.85(s, 3H, 다수 이성질체), 3.78(s, 3H, 다수 이성질체), 3.59(s, 3H, 소수 이성질체), 3.21(m, 1H, 소수 이성질체), 3.07(tt, J = 11.5, 3. 4 Hz, 1H, 다수 이성질체), 2.58-2.40(m, 1H), 2.51(s, 3H, 소수 이성질체), 2.49(s, 3H, 다수 이성질체), 2.18-1.19(m, 7H); LC-MS [M+H]+ 429.3.N- (6-methoxy-4-methylquinolin-2-yl) cyclohexane-1,3-diamine (0.16 mmol, 0.046 g) in CH 2 Cl 2 / MeOH 1: 1 (1.2 mL), CHCl 2 ( 1-methylindole-3-carboxaldehyde (0.13 mmol, 0.021 g), and HOAc (0.060 mL) in Paul-BH 3 CN (150 mg, pre-expanded in CH 2 Cl 2 , 0.6 mL) in 0.6 mL) Was added. The resulting slurry was heated to single node microwave (100 ° C., 10 minutes). The resin was filtered off and washed with a portion (1-2 mL) of CH 2 Cl 2 and MeOH to concentrate the filtrate. The residue was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH 3 CN-> 100% CH 3 CN, 10 mL / min) to afford 0.021 g (34%) of the title compound as a mixture of diastereomers. (~ 6: 1). 1 H NMR (400 MHz, MeOH-d 4 ) δ7.65 (d, J = 8.1 Hz, 1H, multiple isomers), 7.59-7.55 (m, 1H, minor isomers), 7.54 (d, J = 9.1 Hz, 1H, multiple isomers), 7.37 (d, J = 8.3 Hz, 1H, multiple isomers), 7.30 (d, J = 8.3 Hz, 1H, minor isomers), 7.27 (s, 1H, multiple isomers), 7.23-7.07 ( m, 5H), 7.01-6.97 (m, 1H, minor isomers), 6.62 (s, 1H, minor isomers), 6.58 (s, 1H, multiple isomers), 4.36 (m, 1H, minor isomers), 4.20 (s , 2H), 3.95 (tt, J = 11.4, 3.7 Hz, 1H, multiple isomers), 3.87 (s, 3H, minor isomers), 3.85 (s, 3H, multiple isomers), 3.78 (s, 3H, multiple isomers) , 3.59 (s, 3H, minor isomers), 3.21 (m, 1H, minor isomers), 3.07 (tt, J = 11.5, 3. 4 Hz, 1H, multiple isomers), 2.58-2.40 (m, 1H), 2.51 (s, 3H, minor isomers), 2.49 (s, 3H, multiple isomers), 2.18-1.19 (m, 7H); LC-MS [M + H] + 429.3.

실시예 53Example 53

N-(1-벤조푸란-2-일메틸)-N'-(6-메톡시-4-메틸퀴놀린-2-일)시클로헥산-1,3- 디아민 N- (1-benzofuran-2-ylmethyl) -N '-(6-methoxy-4-methylquinolin-2-yl) cyclohexane-1,3-diamine

CH2Cl2/MeOH 1:1(1.2 mL) 내 N-(6-메톡시-4-메틸퀴놀린-2-일)시클로헥산-1,3-디아민(0.14 mmol, 0.040 g), CHCl2(0.6 mL) 내 벤조푸란-2-카르복살데히드(0.13 mmol, 0.018 g), 및 HOAc(0.060 mL)를 폴-BH3CN(150 mg, CH2Cl2 내 미리 팽창됨, 0.6 mL)에 첨가하였다. 결과 슬러리를 단일 노드 마이크로파 가열하였다(100℃, 10분). 수지를 여과하고, 일부분(1-2 mL)의 CH2Cl2과 MeOH로 세척하여, 여과물을 농축하였다. 잔류물을 바이오테이지 호리즌(Biotage Horizon) 25 mm 실리카 컬럼(직선 구배 EtOAc/MeOH 19:1, 1% NEt3 함유 -> EtOAc/MeOH 1:1, 1% NEt3 함유, 10 mL/분)으로 정제하여, 0.015 g(26%)의 표제 화합물을 부분입체 이성질체의 혼합물로 얻었다(~10:1). 1H NMR(400 MHz, MeOH-d4) δ7.54-7.10(m, 7H), 6.68(s, 1H, 다수 이성질체), 6.61(s, 1H, 소수 이성질체), 6.57(s, 1H, 다수 이성질체), 6.47(s, 1H, 소수 이성질체), 4.31(m, 1H, 소수 이성질체), 3.95(s, 2H), 3.95-3.85(m, 1H, 다수 이성질체), 3.85(s, 3H), 2.89(m, 1H, 소수 이성질체), 2.72(tt, J = 11.2, 3.6 Hz, 1H, 다수 이성질체), 2.48(s, 3H), 2.40-2.34(m, 1H), 2.06-1.05(m, 7H); LC-MS [M+H]+ 416.2.N- (6-methoxy-4-methylquinolin-2-yl) cyclohexane-1,3-diamine (0.14 mmol, 0.040 g) in CH 2 Cl 2 / MeOH 1: 1 (1.2 mL), CHCl 2 ( Benzofuran-2-carboxaldehyde (0.13 mmol, 0.018 g), and HOAc (0.060 mL) in Paul-BH 3 CN (150 mg, preexpanded in CH 2 Cl 2 , 0.6 mL) in 0.6 mL) It was. The resulting slurry was heated to single node microwave (100 ° C., 10 minutes). The resin was filtered off and washed with a portion (1-2 mL) of CH 2 Cl 2 and MeOH to concentrate the filtrate. The residue was subjected to Biotage Horizon 25 mm silica column (straight gradient EtOAc / MeOH 19: 1, containing 1% NEt 3- > EtOAc / MeOH 1: 1, containing 1% NEt 3 , 10 mL / min) Purification of the compound to give 0.015 g (26%) of the title compound as a mixture of diastereomers (˜10: 1). 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.54-7.10 (m, 7H), 6.68 (s, 1H, multiple isomers), 6.61 (s, 1H, minor isomers), 6.57 (s, 1H, multiple Isomers), 6.47 (s, 1H, minority isomers), 4.31 (m, 1H, minority isomers), 3.95 (s, 2H), 3.95-3.85 (m, 1H, multiple isomers), 3.85 (s, 3H), 2.89 (m, 1H, minor isomers), 2.72 (tt, J = 11.2, 3.6 Hz, 1H, multiple isomers), 2.48 (s, 3H), 2.40-2.34 (m, 1H), 2.06-1.05 (m, 7H) ; LC-MS [M + H] + 416.2.

실시예 54Example 54

N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-(피리딘-2-일메틸)시클로헥산-1,3-디아민 N- (6-methoxy-4-methylquinolin-2-yl) -N '-(pyridin-2-ylmethyl) cyclohexane-1,3-diamine

CH2Cl2/MeOH 1:1(1.2 mL) 내 N-(6-메톡시-4-메틸퀴놀린-2-일)시클로헥산-1,3-디아민(0.14 mmol, 0.040 g), CH2Cl2(0.6 mL) 내 피리딘-2-카르복살데히드(0.13 mmol, 0.014 g), 및 HOAc(0.060 mL)를 폴-BH3CN(150 mg, CH2Cl2 내 미리 팽창됨, 0.6 mL)에 첨가하였다. 결과 슬러리를 단일 노드 마이크로파 가열하였다(100℃, 10분). 수지를 여과하고, 일부분(1-2 mL)의 CH2Cl2과 MeOH로 세척하여, 여과물을 농축하였다. 잔류물을 바이오테이지 호리즌 25 mm 실리카 컬럼(직선 구배 EtOAc/MeOH 19:1, 1% NEt3 함유 -> EtOAc/MeOH 1:1, 1% NEt3 함유, 10 mL/분)으로 정제하여, 0.015 g(45%)의 표제 화합물을 부분입체 이성질체의 혼합물로 얻었다(~10:1). 1H NMR(400 MHz, MeOH-d4) δ8.49(m, 1H, 다수 이성질체), 8.42(m, 1H, 소수 이성질체), 7.78(td, J = 7.7, 1.8 Hz, 1H, 다수 이성질체), 7.65(td, J = 7.7, 1.8 Hz, 1H, 소수 이성질체), 7.52(d, J = 9.1 Hz, 1H, 다수 이성질체), 7.44(d, J = 7.9 Hz, 1H, 다수 이성질체), 7.37(d, J = 7.9 Hz, 1H, 소수 이성질체), 7.30-7.27(m, 1H), 7.23-7.08(m, 2H), 6.64(bs, 1H, 소수 이성질체), 6.57(bs, 1H, 다수 이성질체), 4.36(m, 1H, 소수 이성질체), 3.95-3.87(m, 1H, 다수 이성질체), 3.92(s, 2H), 3.86(s, 3H, 소수 이성질체), 3.85(s, 3H, 다수 이성질체), 3.29(m, 1H, 소수 이성질체), 2.69(tt, J = 11.2, 3.7 Hz, 1H, 다수 이성질체), 2.50(s, 3H, 소수 이성질체), 2.49(s, 3H, 다수 이성질체), 2.40-2.32(m, 1H), 2.08-1.98(m, 2H), 1.88-1.07(m, 5H); LC-MS [M+H]+ 377.2.N- (6-methoxy-4-methylquinolin-2-yl) cyclohexane-1,3-diamine (0.14 mmol, 0.040 g) in CH 2 Cl 2 / MeOH 1: 1 (1.2 mL), CH 2 Cl Pyridine-2-carboxaldehyde (0.13 mmol, 0.014 g), and HOAc (0.060 mL) in 2 (0.6 mL) were added to Pol-BH 3 CN (150 mg, preexpanded in CH 2 Cl 2 , 0.6 mL). Added. The resulting slurry was heated to single node microwave (100 ° C., 10 minutes). The resin was filtered off and washed with a portion (1-2 mL) of CH 2 Cl 2 and MeOH to concentrate the filtrate. The residue was purified by Biotage Horizon 25 mm silica column (straight gradient EtOAc / MeOH 19: 1, containing 1% NEt 3- > EtOAc / MeOH 1: 1, containing 1% NEt 3 , 10 mL / min), 0.015 g (45%) of the title compound was obtained as a mixture of diastereomers (˜10: 1). 1 H NMR (400 MHz, MeOH-d 4 ) δ8.49 (m, 1H, multiple isomers), 8.42 (m, 1H, minor isomers), 7.78 (td, J = 7.7, 1.8 Hz, 1H, multiple isomers) , 7.65 (td, J = 7.7, 1.8 Hz, 1H, minor isomers), 7.52 (d, J = 9.1 Hz, 1H, multiple isomers), 7.44 (d, J = 7.9 Hz, 1H, multiple isomers), 7.37 ( d, J = 7.9 Hz, 1H, minor isomers), 7.30-7.27 (m, 1H), 7.23-7.08 (m, 2H), 6.64 (bs, 1H, minor isomers), 6.57 (bs, 1H, multiple isomers) , 4.36 (m, 1H, minor isomers), 3.95-3.87 (m, 1H, multiple isomers), 3.92 (s, 2H), 3.86 (s, 3H, minor isomers), 3.85 (s, 3H, multiple isomers), 3.29 (m, 1H, minor isomers), 2.69 (tt, J = 11.2, 3.7 Hz, 1H, multiple isomers), 2.50 (s, 3H, minor isomers), 2.49 (s, 3H, multiple isomers), 2.40-2.32 (m, 1 H), 2.08-1.98 (m, 2H), 1.88-1.07 (m, 5H); LC-MS [M + H] + 377.2.

실시예 55Example 55

N-(4-메틸퀴놀린-2-일)-N'-(3-티에닐메틸)시클로헥산-1,3-디아민 N- (4-methylquinolin-2-yl) -N '-(3-thienylmethyl) cyclohexane-1,3-diamine

2 mL의 CH2Cl2/MeOH 1:1 내 N-(4-메틸퀴놀린-2-일)시클로헥산-1,3-디아민(75 mg, 0.29 mmol), 및 1 mL의 CH2Cl2 내 3-티오펜알데히드(26 mg, 0.23 mmol), 및 0.10 mL의 아세트산을 폴-BH3CN(0.25 g, 1 mL의 CH2Cl2 내 미리 팽창됨)에 첨가하였다. 결과 슬러리를 단일 노드 마이크로파 가열하였다(100℃, 10분). 수지를 여과하고, 일부분(1-2 mL)의 CH2Cl2과 MeOH로 세척하였다. 여과물을 화합하고, 1 g SCX-2로 미리 팩킹된 이온-교환 컬럼에 붓고, 10 mL의 MeOH로 세척하고, 산물을 10% Et3N를 함유하는 MeOH로 용출하였다. 순도가 만족스럽지 않아, 산물을 바이오테이지 호리즌 12 mm 실리카 컬럼(직선 구배 EtOAc/MeOH 9:1 -> EtOAc/MeOH 1:1, 10 mL/분)으로 추가 정제하여, 20 mg(19%)의 표제 화합물을 부분입체 이성질체의 혼합물로 얻었다(~3:1). 1H NMR(300 MHz, MeOH-d4) δ7.68-7.75(m, 1H), 7.5-7.6(m, 1H), 7.0-7.5(m, 5H), 6.61(bs, 1H, 소수 이성질체), 6.54(bs, 1H, 다수 이성질체), 4.36(m, 1H, 소수 이성질체), 4.11(s, 2H, 다수 이성질체), 4.09(s, 2H, 소수 이성질체), 3.95(m, 1H, 다수 이성질체), 3.09(m, 1H, 다수 이성질체; MeOH-d4 시그날 하에 불명료한 소수 이성질체), 2.35-2.6(m, 4H; 이에 의해 2.48, 3H, 소수 이성질체, 및 2.46, 3H, 다수 이성질체), 1.1-2.2(m, 7H). 13C NMR(75 MHz, MeOH-d4, 다수 이성질체) δ179.4, 157.3, 148.0, 146.7, 134.7, 130.4, 128.9, 128.0, 127.0, 125.6, 124.8, 123.0, 113.9, 68.1, 56.4, 44.2, 37.5, 33.1,30.2, 23.8, 18.8. LC-MS [M+H]+ 352.3.In 2 mL of CH 2 Cl 2 / MeOH 1: 1 in N- (4-methylquinolin-2-yl) cyclohexane-1,3-diamine (75 mg, 0.29 mmol), and in 1 mL of CH 2 Cl 2 3-thiophenaldehyde (26 mg, 0.23 mmol), and 0.10 mL of acetic acid were added to Paul-BH 3 CN (0.25 g, preexpanded in 1 mL of CH 2 Cl 2 ). The resulting slurry was heated to single node microwave (100 ° C., 10 minutes). The resin was filtered off and washed with a portion (1-2 mL) of CH 2 Cl 2 and MeOH. The filtrates were combined and poured into an ion-exchange column prepacked with 1 g SCX-2, washed with 10 mL of MeOH, and the product eluted with MeOH containing 10% Et 3 N. Purity was not satisfactory, and the product was further purified by Biotage Horizon 12 mm silica column (straight gradient EtOAc / MeOH 9: 1-> EtOAc / MeOH 1: 1, 10 mL / min) to 20 mg (19%) The title compound was obtained as a mixture of diastereomers (˜3: 1). 1 H NMR (300 MHz, MeOH-d 4 ) δ7.68-7.75 (m, 1H), 7.5-7.6 (m, 1H), 7.0-7.5 (m, 5H), 6.61 (bs, 1H, minor isomers) , 6.54 (bs, 1H, multiple isomers), 4.36 (m, 1H, minor isomers), 4.11 (s, 2H, multiple isomers), 4.09 (s, 2H, minor isomers), 3.95 (m, 1H, multiple isomers) , 3.09 (m, 1H, multiple isomers; unambiguous minor isomers under MeOH-d 4 signal), 2.35-2.6 (m, 4H; thereby 2.48, 3H, minor isomers, and 2.46, 3H, multiple isomers), 1.1- 2.2 (m, 7 H). 13 C NMR (75 MHz, MeOH-d 4 , Multi-isomer) δ 179.4, 157.3, 148.0, 146.7, 134.7, 130.4, 128.9, 128.0, 127.0, 125.6, 124.8, 123.0, 113.9, 68.1, 56.4, 44.2, 37.5 , 33.1, 30.2, 23.8, 18.8. LC-MS [M + H] + 352.3.

부록Appendix

출발 물질의 명칭/참조 번호Name / reference number of starting material

상업적 출발 물질(CAS 번호): 2-클로로퀴놀린, 612-62-4; 2-클로로-6-메톡시-4-메틸퀴놀린, 6340-55-2; 1,3-디아미노프로판, 109-76-2; 에틸렌디아민, 107-15-3; 1,3-시클로헥산디아민, 3385-21-5; 1,4-시클로헥산디아민, 3114-70-3; 4-아미노피페리딘, 13035-19-3; N-메틸-1,3-프로판디아민, 6291-84-5; 3-티오펜카르복살데히드, 498-62-4; 3-아세틸티오펜, 1468-83-3; 4-케토-4,5,6,7-테트라히드로티아나프텐, 13414-95-4; 3-아세틸티아나프텐, 1128-05-8; 2-티오펜카르복살데히드, 98-03-3; 5-니트로티오펜-3-카르복살데히드, 75428-45-4; 3-아세틸-2,5-디메틸티오펜, 2530-10-01; 1-아세틸-3-인돌카르복살데히드, 22948-94-3; 인돌-3-카르복살데히드, 487-89-8; 피롤-2-카르복살데히드, 1003-29-8; 2,4,6-트리메틸-벤즈알데히드, 487-68-3; 페닐아세트알데히드, 122-78-1; 3,4-디클로로벤즈알데히드, 6287-38-3; 2-나프탈데히드, 66-99-9; 2-퀴놀린카르복살데히드, 5470-96-2; 디페닐아세트알데히드, 947-91-1; 4-비페닐카르복살데히드, 3218-36-8; 4-디메틸아미노벤즈알데히드, 100-10-7; 3-푸랄데히드, 498-60-2; 3-(5-메틸-2-푸릴)부티르알데히드, 31704-80-0; 시클로프로판카르복살데히드, 1489-69-6; 1-메틸인돌-3-카르복살데히드, 19012-03-4; 벤조푸란-2-카르복살데히드, 4265-16-1; 피리딘-2-카르복살데히드, 1121-60-4 3-아세틸-2,5-디클로로티오펜, 36157-40-1; (-)-2-아자비시클로[2.2.1]헵트-5-엔-3-온, 79200-56-9 및 2-클로로-4-메틸퀴놀린 634-47-9.Commercial starting material (CAS No.): 2-chloroquinoline, 612-62-4; 2-chloro-6-methoxy-4-methylquinoline, 6340-55-2; 1,3-diaminopropane, 109-76-2; Ethylenediamine, 107-15-3; 1,3-cyclohexanediamine, 3385-21-5; 1,4-cyclohexanediamine, 3114-70-3; 4-aminopiperidine, 13035-19-3; N-methyl-1,3-propanediamine, 6291-84-5; 3-thiophenecarboxaldehyde, 498-62-4; 3-acetylthiophene, 1468-83-3; 4-keto-4,5,6,7-tetrahydrothianaphthene, 13414-95-4; 3-acetylthianaphthene, 1128-05-8; 2-thiophenecarboxaldehyde, 98-03-3; 5-nitrothiophene-3-carboxaldehyde, 75428-45-4; 3-acetyl-2,5-dimethylthiophene, 2530-10-01; 1-acetyl-3-indolecarboxaldehyde, 22948-94-3; Indole-3-carboxaldehyde, 487-89-8; Pyrrole-2-carboxaldehyde, 1003-29-8; 2,4,6-trimethyl-benzaldehyde, 487-68-3; Phenylacetaldehyde, 122-78-1; 3,4-dichlorobenzaldehyde, 6287-38-3; 2-naphthalaldehyde, 66-99-9; 2-quinolinecarboxaldehyde, 5470-96-2; Diphenylacetaldehyde, 947-91-1; 4-biphenylcarboxaldehyde, 3218-36-8; 4-dimethylaminobenzaldehyde, 100-10-7; 3-furaldede, 498-60-2; 3- (5-methyl-2-furyl) butyraldehyde, 31704-80-0; Cyclopropanecarboxaldehyde, 1489-69-6; 1-methylindole-3-carboxaldehyde, 19012-03-4; Benzofuran-2-carboxaldehyde, 4265-16-1; Pyridine-2-carboxaldehyde, 1121-60-4 3-acetyl-2,5-dichlorothiophene, 36157-40-1; (-)-2-azabicyclo [2.2.1] hept-5-en-3-one, 79200-56-9 and 2-chloro-4-methylquinoline 634-47-9.

약학적 성질Pharmaceutical Properties

MCH1 수용체 라디오리간드 결합MCH1 Receptor Radioligand Binding

분석은 인간 멜라닌 농축 호르몬 수용체 1(MCH1r)를 안정적으로 발현하는 HEK293 세포의 막 상에서 수행하였다(Lembo 등, Nature Cell Biol 1 267-271). 분석은 웰당 최종 반응 부피 200 ㎕로 96-웰 플레이트 포멧에서 수행하였다. 결합 완충액(50 mM 트리스, 3 mM MgCl2, 0.05 % 소 혈청 알부민(BSA) 및 라디오리간드 125I-MCH(IM344 Amersham))에 희석된 6.1 ㎍의 막 단백질을 함유하는 각 웰은 웰당 10000 cpm(분당 계수)가 되도록 첨가하였다. DMSO 내 적절한 농도의 경쟁적 길항제 2 ㎕를 함유하는 각 웰을 준비하고, 실온에서 60분 동안 두었다. 비특이적 결합은 이 후 1 μM MCH(멜라민 농축 호르몬, H-1482 Bachem)과 항온 처리하여 결정하였다. 마이크로 96 하베스터(Skatron Instruments, 노르웨이)를 사용하여 반응물을 GF/A 여과기로 옮겨 반응을 종결시켰다. 여과기를 분석 완충액으로 세척하였다. 필터에 남아있는 라디오리간드는 a1450 마이크로베타 TRILUX(Wallac, 필란드)를 사용하여 정량하였다.Assays were performed on membranes of HEK293 cells stably expressing human melanin enriched hormone receptor 1 (MCH1r) (Lembo et al., Nature Cell Biol 1 267-271). Assays were performed in 96-well plate format with 200 μl final reaction volume per well. Each well containing 6.1 μg of membrane protein diluted in binding buffer (50 mM Tris, 3 mM MgCl 2 , 0.05% bovine serum albumin (BSA) and radioligand 125 I-MCH (IM344 Amersham)) was weighed at 10000 cpm per well ( Counts per minute). Each well containing 2 μl of the appropriate concentration of competitive antagonist in DMSO was prepared and left at room temperature for 60 minutes. Nonspecific binding was then determined by incubation with 1 μM MCH (melamine enriched hormone, H-1482 Bachem). The reaction was terminated by transferring the reaction to a GF / A filter using a Micro 96 Harvester (Skatron Instruments, Norway). The filter was washed with assay buffer. Radioligand remaining in the filter was quantified using a1450 microbeta TRILUX (Wallac, Finland).

비특이적 결합은 측정된 모든 값에서 빼주었다. 최대 결합은 어떠한 경쟁자의 부재하에 비특이적 결합에 대해 측정된 값을 뺀 이후에 결정되었다. 화합물의 결합을 다양한 농도에서 방정식 y =A+((B-A)/l+((C/x)^D)))에 따라 플랏하였으며, IC50은 A가 곡선의 아래 평탄역, 즉 극소 y값이고, B가 곡선의 위 평탄역, 즉 극대 y값이며, C가 곡선 중심에서의 x값인 경우 추정된다. 이는 A + B = 100일 때, log EC50 값을 나타낸다. D는 기울기 인자이다. x는 초기 알려진 x값이다. y는 초기 알려진 y값이다.Nonspecific binding was subtracted from all measured values. Maximum binding was determined after subtracting the value measured for nonspecific binding in the absence of any competitor. The binding of the compounds was plotted according to the equation y = A + ((BA) / l + ((C / x) ^ D))) at various concentrations, IC 50 is where A is the flat region of the curve, i.e. the minimum y value, It is estimated when B is the flat top of the curve, i.e. the maximum y value, and C is the x value at the center of the curve. This represents the log EC50 value when A + B = 100. D is the slope factor. x is the initial known x value. y is the initial known y value.

본 명세서에 예시된 화합물들은 상기 분석에서 2 μmol 이하의 IC50을 가졌다. 바람직한 화합물은 1 μmol 이하의 활성을 가진다. 예컨대, 실시예 1, 29 및 53의 IC50은 각각 0.01, 0.40 및 0.56 μmol이다.The compounds exemplified herein had an IC 50 of 2 μmol or less in the assay. Preferred compounds have an activity of 1 μmol or less. For example, the IC 50 of Examples 1, 29 and 53 are 0.01, 0.40 and 0.56 μmol, respectively.

분석은 또한 랫트 멜라닌 농축 호르몬 수용체 1(MCH1r)를 안정적으로 발현하는 HEK293 세포의 막 상에서 수행하였다(Lembo 등, Nature Cell Biol 1 267-271). 분석은 웰당 최종 반응 부피 200 ㎕로 96-웰 플레이트 포멧에서 수행하였다. 결합 완충액(50 mM 트리스, 3 mM MgCl2, 0.05 % 소 혈청 알부민(BSA) 및 라디오리간드 125I-MCH(IM344 Amersham))에 희석된 6.1 ㎍의 막 단백질을 함유하는 각 웰은 웰당 10000 cpm(분당 계수)가 되도록 첨가하였다. DMSO 내 적절한 농도의 경쟁적 길항제 2 ㎕를 함유하는 각 웰을 준비하고, 실온에서 60분 동안 두었다. 비특이적 결합은 이 후 1 μM MCH(멜라민 농축 호르몬, H-1482 Bachem)과 항온 처리하여 결정하였다. 마이크로 96 하베스터(Skatron Instruments, 노르웨이)를 사용하여 반응물을 GF/A 여과기로 옮겨 반응을 종결시켰다. 여과기를 분석 완충액으로 세척하였다. 필터에 남아있는 라디오리간드는 a1450 마이크로베타 TRILUX(Wallac, 필란드)를 사용하여 정량하였다.The assay was also performed on membranes of HEK293 cells stably expressing rat melanin enriched hormone receptor 1 (MCH1r) (Lembo et al., Nature Cell Biol 1 267-271). Assays were performed in 96-well plate format with 200 μl final reaction volume per well. Each well containing 6.1 μg of membrane protein diluted in binding buffer (50 mM Tris, 3 mM MgCl 2 , 0.05% bovine serum albumin (BSA) and radioligand 125 I-MCH (IM344 Amersham)) was weighed at 10000 cpm per well ( Counts per minute). Each well containing 2 μl of the appropriate concentration of competitive antagonist in DMSO was prepared and left at room temperature for 60 minutes. Nonspecific binding was then determined by incubation with 1 μM MCH (melamine enriched hormone, H-1482 Bachem). The reaction was terminated by transferring the reaction to a GF / A filter using a Micro 96 Harvester (Skatron Instruments, Norway). The filter was washed with assay buffer. Radioligand remaining in the filter was quantified using a1450 microbeta TRILUX (Wallac, Finland).

Claims (21)

하기 화학식 (I)의 화합물, 이의 광학 이성질체 및 라세미산염, 및 이의 약학적으로 허용가능한 염:A compound of formula (I), its optical isomers and racemates, and pharmaceutically acceptable salts thereof: 상기 화학식에서, In the above formula, R1은 1개 이상의 플루오로로 임의 치환된 C1-4알콕시기 또는 1개 이상의 플루오로로 임의 치환된 C1-4알킬기를 나타내고;R 1 represents an optionally substituted C 1-4 alkyl group optionally substituted by a C 1-4 alkoxy group or one or more fluoro with one or more fluoro; n은 0 또는 1을 나타내며; n represents 0 or 1; R2는 1개 이상의 플루오로로 임의 치환된 C1-4알킬기 또는 1개 이상의 플루오로로 임의 치환된 C1-4알콕시기를 나타내고;R 2 represents a C 1-4 alkyl group optionally substituted with one or more fluoro or a C 1-4 alkoxy group optionally substituted with one or more fluoro; m은 0 또는 1을 나타내며; m represents 0 or 1; R3은 H 또는 C1-4알킬기를 나타내고;R 3 represents H or a C 1-4 alkyl group; L1은 알킬렌 사슬 (CH2)r을 나타내거나(여기서, r은 2 또는 3을 나타냄), 또는 L1은 시클로헥실기를 나타내거나(여기서, R3과 R4를 각각 갖는 2개의 질소는 시클로헥실기의 1,3 또는 1,4 위치를 통해 시클로헥실기에 연결됨), 또는 L1은 시클로펜틸기를 나타내며(여기서, R3과 R4를 각각 갖는 2개의 질소는 시클로펜틸기의 1,3 위치를 통해 시클로펜틸기에 연결됨), 부가적으로 R5가 9,10-메타노안트라센-9(10H)-일을 나타낼 때, 기 -L1-N(R4)-는 함께 피페리디닐 질소를 통해 L2에, 피페리딜 고리의 4 위치를 통해 N-R3에 연결된 피페리딜 고리를 나타내고, 단, R5가 9,10-메타노안트라센-9(10H)-일을 나타낼 때, r은 단지 2이며;L 1 represents an alkylene chain (CH 2 ) r (where r represents 2 or 3), or L 1 represents a cyclohexyl group (wherein R 3 and R 4 each have two nitrogens) Is connected to the cyclohexyl group via the 1,3 or 1,4 position of the cyclohexyl group, or L 1 represents a cyclopentyl group (wherein two nitrogens each having R 3 and R 4 are 1 of the cyclopentyl group). Connected to the cyclopentyl group via position 3), additionally when R 5 represents 9,10-methanoanthracene-9 (10H) -yl, the groups -L 1 -N (R 4 )-together piperidi A piperidyl ring linked to L 2 through niyl nitrogen and to NR 3 via the 4 position of the piperidyl ring, provided that R 5 represents 9,10-methanoanthracene-9 (10H) -yl , r is only 2; R4는 H 또는 1개 이상의 아릴기 또는 헤테로아릴기로 임의 치환된 C1-4알킬기를 나타내고:R 4 represents H or a C 1-4 alkyl group optionally substituted with one or more aryl groups or heteroaryl groups: L2는 결합 또는 알킬렌 사슬 (CH2)s를 나타내며(여기서, s는 1, 2 또는 3을 나타내고, 알킬렌 사슬은 1개 이상의 C1-4알킬기, 페닐 또는 헤테로아릴로 임의 치환됨);L 2 represents a bond or an alkylene chain (CH 2 ) s where s represents 1, 2 or 3 and the alkylene chain is optionally substituted with one or more C 1-4 alkyl groups, phenyl or heteroaryl ; R5는 페닐 또는 헤테로아릴기에 임의 융합된 아릴, 헤테로시클릭기 또는 C3-8시클로알킬기를 나타내고;R 5 represents an aryl, heterocyclic group or C 3-8 cycloalkyl group optionally fused to a phenyl or heteroaryl group; 단, 첫째로, n이 0이고, m이 1이며, R2가 퀴놀린 고리의 4-위치에 위치한 메틸이고, R3이 H이며, R4가 H이고, L1이 (CH2)2 또는 (CH2)3 또는 1,4-시클로헥실이며, L2가 결합일 때, R5는 4-메틸퀴놀린-2-일이 아니고;Provided that firstly n is 0, m is 1, R 2 is methyl at the 4-position of the quinoline ring, R 3 is H, R 4 is H, and L 1 is (CH 2 ) 2 or (CH 2 ) 3 or 1,4-cyclohexyl, when L 2 is a bond, R 5 is not 4-methylquinolin-2-yl; 둘째로, n이 0이고, m이 0 또는 1이며, R2가 퀴놀린 고리의 4-위치에 위치한 C1-3알콕시기이고, R3이 H 또는 C1-3알킬기이며, R4가 H 또는 C1-3알킬기이고, L1이 (CH2)3이고, L2가 1개 이상의 C1-3알킬기 또는 페닐로 임의 치환된 메틸렌일 때, R5는 1개, 2개 또는 3개의 C1-4알킬기 또는 할로로 임의 치환된 페닐, 티에닐 또는 인돌릴이 아니다.Second, n is 0, m is 0 or 1, R 2 is a C 1-3 alkoxy group located at 4-position of the quinoline ring, R 3 is H or C 1-3 alkyl group, and R 4 is H Or a C 1-3 alkyl group, L 1 is (CH 2 ) 3 , and when L 2 is methylene optionally substituted with one or more C 1-3 alkyl groups or phenyl, R 5 is one, two or three No phenyl, thienyl or indolyl optionally substituted with a C 1-4 alkyl group or halo. 제1항에 있어서, R1이 C1-4알콕시기를 나타내는 것인 화합물.The compound of claim 1, wherein R 1 represents a C 1-4 alkoxy group. 제1항 또는 제2항에 있어서, R2가 C1-4알킬기를 나타내는 것인 화합물.The compound of claim 1 or 2, wherein R 2 represents a C 1-4 alkyl group. 제1항 내지 제3항 중 어느 하나의 항에 있어서, L1이 트리메틸렌, 1,3-시클로헥실 또는 1,4-시클로헥실을 나타내거나, 또는 R5가 9,10-메타노안트라센-9(10H)-일을 나타낼 때, L1이 부가적으로 에틸렌을 나타내는 것인 화합물.4. The compound of claim 1, wherein L 1 represents trimethylene, 1,3-cyclohexyl or 1,4-cyclohexyl, or R 5 is 9,10-methanoanthracene- 4. L 1 additionally represents ethylene when representing 9 (10H) -yl. 제1항 내지 제4항 중 어느 하나의 항에 있어서, L1이 트리메틸렌을 나타내는 것인 화합물.The compound of any one of claims 1-4, wherein L 1 represents trimethylene. 제1항 내지 제5항 중 어느 하나의 항에 있어서, L1이 1,3-시클로헥실을 나타내는 것인 화합물.The compound of any one of claims 1-5, wherein L 1 represents 1,3-cyclohexyl. 제1항 내지 제6항 중 어느 하나의 항에 있어서, L1이 1,4-시클로헥실을 나타내는 것인 화합물.The compound of any one of claims 1 to 6, wherein L 1 represents 1,4-cyclohexyl. 제1항 내지 제7항 중 어느 하나의 항에 있어서, L1이 1,3-시클로펜틸을 나타내는 것인 화합물.The compound of any one of claims 1-7, wherein L 1 represents 1,3-cyclopentyl. 제1항 내지 제8항 중 어느 하나의 항에 있어서, R3이 H를 나타내는 것인 화합물.The compound of any one of claims 1-8, wherein R 3 represents H. 10. 제1항 내지 제9항 중 어느 하나의 항에 있어서, L2가 메틸렌을 나타내는 것인 화합물.The compound of any one of claims 1-9, wherein L 2 represents methylene. 제1항 내지 제10항 중 어느 하나의 항에 있어서, R4가 H를 나타내는 것인 화합물.The compound of any one of claims 1-10, wherein R 4 represents H. 12. 제1항 내지 제11항 중 어느 하나의 항에 있어서, R5가 각각이 1개 이상의 메틸, 클로로, 디메틸아미노 또는 페닐로 임의 치환된 페닐, 2-나프틸 또는 9,10-메타노안트라센-9(10H)-일을 나타내는 것인 화합물.12. The phenyl, 2-naphthyl or 9,10-methanoanthracene-according to claim 1, wherein R 5 is each optionally substituted with one or more methyl, chloro, dimethylamino or phenyl. 9 (10H) -yl. 제1항 내지 제12항 중 어느 하나의 항에 있어서, R5가 각각이 1개 이상의 니트로, 메틸, 아세틸 또는 클로로로 임의 치환된 4,5,6,7-테트라히드로티아나프트-4-일, 벤조[b]티엔-3-일, 2-티에닐, 3-티에닐, 2-푸릴, 3-푸릴, 벤조푸라닐, 피리딜, 1H-피롤-2-일, 1H-인돌-3-일, 또는 2-퀴놀린일을 나타내는 것인 화합물.The compound of claim 1, wherein R 5 is each 4,5,6,7-tetrahydrothianaphth-4-yl, each optionally substituted with one or more nitro, methyl, acetyl or chloro. , Benzo [b] thien-3-yl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, benzofuranyl, pyridyl, 1H-pyrrole-2-yl, 1H-indole-3- One, or 2-quinolinyl. N-(9,10-메타노안트라센-9(10H)-일메틸)-N'-(2-퀴놀린일)-1,2-에탄디아민;N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N '-(2-quinolinyl) -1,2-ethanediamine; N-(6-메톡시-4-메틸-2-퀴놀린일)-N'-(3-티에닐메틸)-1,3-프로판디아민; N- (6-methoxy-4-methyl-2-quinolinyl) -N '-(3-thienylmethyl) -1,3-propanediamine; N-(9,10-메타노안트라센-9(10H)-일메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민;N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine; N-(2-퀴놀린일)-N'-(3-티에닐메틸)-1,3-프로판디아민; N- (2-quinolinyl) -N '-(3-thienylmethyl) -1,3-propanediamine; N-(9,10-메타노안트라센-9(10H)-일메틸)-N'-(2-퀴놀린일)-1,4-시클로헥산디아민; N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N '-(2-quinolinyl) -1,4-cyclohexanediamine; N-[(1-아세틸-1H-인돌-3-일)메틸]-N'-(6-메톡시-4-메틸-2-퀴놀린일)-1,3-프로판디아민; N-[(1-acetyl-1H-indol-3-yl) methyl] -N '-(6-methoxy-4-methyl-2-quinolinyl) -1,3-propanediamine; N-(9,10-메타노안트라센-9(10H)-일메틸)-N'-(2-퀴놀린일)-1,3-시클로헥산디아민; N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N '-(2-quinolinyl) -1,3-cyclohexanediamine; N-(2-퀴놀린일)-N'-[1-(3-티에닐)에틸]-1,3-프로판디아민; N- (2-quinolinyl) -N '-[1- (3-thienyl) ethyl] -1,3-propanediamine; N-(2-퀴놀린일)-N'-(3-티에닐메틸)-1,3-시클로헥산디아민; N- (2-quinolinyl) -N '-(3-thienylmethyl) -1,3-cyclohexanediamine; N-(9,10-메타노안트라센-9(10H)-일메틸)-N'-(6-메톡시-4-메틸-2-퀴놀린일)-1,3-프로판디아민; N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N '-(6-methoxy-4-methyl-2-quinolinyl) -1,3-propanediamine; N-(2-퀴놀린일)-N'-(4,5,6,7-테트라히드로티아나프트-4-일)-1,3-프로판디아민; N- (2-quinolinyl) -N '-(4,5,6,7-tetrahydrothianaphth-4-yl) -1,3-propanediamine; N-메틸-N'-(2-퀴놀린일)-N-(3-티에닐메틸)-1,3-프로판디아민; N-methyl-N '-(2-quinolinyl) -N- (3-thienylmethyl) -1,3-propanediamine; N-(2-퀴놀린일)-N',N'-비스(3-티에닐메틸)-1,3-프로판디아민; N- (2-quinolinyl) -N ', N'-bis (3-thienylmethyl) -1,3-propanediamine; N-(9,10-메타노안트라센-9(10H)-일메틸)-N-메틸-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N-methyl-N '-(2-quinolinyl) -1,3-propanediamine; N-(2-퀴놀린일)-N'-[(2,4,6-트리메틸페닐)메틸]-1,3-프로판디아민; N- (2-quinolinyl) -N '-[(2,4,6-trimethylphenyl) methyl] -1,3-propanediamine; N-(2-페닐에틸)-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (2-phenylethyl) -N '-(2-quinolinyl) -1,3-propanediamine; N-(1-벤조[b]티엔-3-일에틸)-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (1-benzo [b] thien-3-ylethyl) -N '-(2-quinolinyl) -1,3-propanediamine; N-[(3,4-디클로로페닐)메틸]-N'-(2-퀴놀린일)-1,3-시클로헥산디아민;N-[(3,4-dichlorophenyl) methyl] -N '-(2-quinolinyl) -1,3-cyclohexanediamine; N-(9,10-메타노안트라센-9(10H)-일메틸)-N'-메틸-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (9,10-methanoanthracene-9 (10H) -ylmethyl) -N'-methyl-N '-(2-quinolinyl) -1,3-propanediamine; N-(2-퀴놀린일)-N'-(2-티에닐메틸)-1,3-프로판디아민; N- (2-quinolinyl) -N '-(2-thienylmethyl) -1,3-propanediamine; N-(3-푸라닐메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (3-furanylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine; N-[(3,4-디클로로페닐)메틸]-N-메틸-N'-(2-퀴놀린일)-1,3-프로판디아민; N-[(3,4-dichlorophenyl) methyl] -N-methyl-N '-(2-quinolinyl) -1,3-propanediamine; N-[1-(9,10-메타노안트라센-9(10H)-일메틸)-4-피페리디닐]-2-퀴놀린아민; N- [1- (9,10-Methanoanthracene-9 (10H) -ylmethyl) -4-piperidinyl] -2-quinolinamine; N-(1H-인돌-3-일메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (1H-indol-3-ylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine; N-(2-나프탈레닐메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (2-naphthalenylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine; N-(2,2-디페닐에틸)-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (2,2-diphenylethyl) -N '-(2-quinolinyl) -1,3-propanediamine; N-(1H-인돌-3-일메틸)-N'-(6-메톡시-4-메틸-2-퀴놀린일)-1,3-프로판디아민; N- (1H-indol-3-ylmethyl) -N '-(6-methoxy-4-methyl-2-quinolinyl) -1,3-propanediamine; N-[(3,4-디클로로페닐)메틸-N'-(2-퀴놀린일)-1,3-프로판디아민; N-[(3,4-dichlorophenyl) methyl-N '-(2-quinolinyl) -1,3-propanediamine; N-[(3,4-디클로로페닐)메틸]-N'-(2-퀴놀린일)-1,4-시클로헥산디아민; N-[(3,4-dichlorophenyl) methyl] -N '-(2-quinolinyl) -1,4-cyclohexanediamine; N,N'-디-(2-퀴놀린일)-1,3-프로판디아민; N, N'-di- (2-quinolinyl) -1,3-propanediamine; N-(2-퀴놀린일)-N'-(2-퀴놀린일메틸)-1,3-프로판디아민; N- (2-quinolinyl) -N '-(2-quinolinylmethyl) -1,3-propanediamine; N-[(1-아세틸-1H-인돌-3-일)메틸]-N'-(2-퀴놀린일)-1,3-프로판디아민; N-[(1-acetyl-1H-indol-3-yl) methyl] -N '-(2-quinolinyl) -1,3-propanediamine; N-(시클로프로필메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (cyclopropylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine; N-(2-퀴놀린일)-N'-(3-티에닐메틸)-1,4-시클로헥산디아민; N- (2-quinolinyl) -N '-(3-thienylmethyl) -1,4-cyclohexanediamine; N-([1,1'-비페닐]-4-일메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민; N-([1,1'-biphenyl] -4-ylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine; N-(6-메톡시-4-메틸-2-퀴놀린일)-N'-[3-(5-메틸-2-푸라닐)부틸]-1,3-프로판디아민; N- (6-methoxy-4-methyl-2-quinolinyl) -N '-[3- (5-methyl-2-furanyl) butyl] -1,3-propanediamine; N-[[4-(디메틸아미노)페닐]메틸]-N'-(2-퀴놀린일)-1,3-프로판디아민; N-[[4- (dimethylamino) phenyl] methyl] -N '-(2-quinolinyl) -1,3-propanediamine; N-(1H-피롤-2-일메틸)-N'-(2-퀴놀린일)-1,3-프로판디아민; N- (1H-pyrrol-2-ylmethyl) -N '-(2-quinolinyl) -1,3-propanediamine; N-[3-(5-메틸-2-푸라닐)부틸]-N'-(2-퀴놀린일)-1,3-프로판디아민; N- [3- (5-methyl-2-furanyl) butyl] -N '-(2-quinolinyl) -1,3-propanediamine; N-[(5-니트로-3-티에닐)메틸]-N'-(2-퀴놀린일)-1,3-프로판디아민; N-[(5-nitro-3-thienyl) methyl] -N '-(2-quinolinyl) -1,3-propanediamine; N-(6-메톡시-4-메틸-2-퀴놀린일)-N'-[(5-니트로-3-티에닐)메틸]-1,3-프로판디아민; N- (6-methoxy-4-methyl-2-quinolinyl) -N '-[(5-nitro-3-thienyl) methyl] -1,3-propanediamine; N-(6-메톡시-4-메틸-2-퀴놀린일)-N'-(1H-피롤-2-일메틸)-1,3-프로판디아민;N- (6-methoxy-4-methyl-2-quinolinyl) -N '-(1H-pyrrol-2-ylmethyl) -1,3-propanediamine; N-[(3,4-디클로로페닐)메틸]-N'-메틸-N'-2-퀴놀린일)-1,3-프로판디아민; N-[(3,4-dichlorophenyl) methyl] -N'-methyl-N'-2-quinolinyl) -1,3-propanediamine; N-[1-(2,5-디메틸-3-티에닐)에틸]-N'-(2-퀴놀린일)-1,3-프로판디아민; N- [1- (2,5-dimethyl-3-thienyl) ethyl] -N '-(2-quinolinyl) -1,3-propanediamine; N-[1-(2,5-디클로로-티오펜-3-일)-에틸]-N'-(2-퀴놀린일)-1,3-프로판디아민;N- [1- (2,5-Dichloro-thiophen-3-yl) -ethyl] -N '-(2-quinolinyl) -1,3-propanediamine; N-[(1-아세틸-1H-인돌-3-일)메틸]-N'-퀴놀린-2-일시클로헥산-1,3-디아민; N-[(1-acetyl-1H-indol-3-yl) methyl] -N'-quinolin-2-ylcyclohexane-1,3-diamine; N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-(3-티에닐메틸)시클로펜탄-1,3-디아민;N- (6-methoxy-4-methylquinolin-2-yl) -N '-(3-thienylmethyl) cyclopentane-1,3-diamine; N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-[(1-메틸-1H-인돌-3-일)메틸]시클로펜탄-1,3-디아민;N- (6-methoxy-4-methylquinolin-2-yl) -N '-[(1-methyl-1H-indol-3-yl) methyl] cyclopentane-1,3-diamine; (1S,3S)-N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-[(1-메틸-1H-인돌-3-일)메틸]시클로펜탄-1,3-디아민;(1S, 3S) -N- (6-methoxy-4-methylquinolin-2-yl) -N '-[(1-methyl-1H-indol-3-yl) methyl] cyclopentane-1,3- Diamine; (1S,3S)-N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-(3-티에닐메틸)시클로펜탄-1,3-디아민;(1S, 3S) -N- (6-methoxy-4-methylquinolin-2-yl) -N '-(3-thienylmethyl) cyclopentane-1,3-diamine; N-[(1-아세틸-1H-인돌-3-일)메틸]-N'-(6-메톡시-4-메틸퀴놀린-2-일)시클로헥산-1,3-디아민; N-[(1-acetyl-1H-indol-3-yl) methyl] -N '-(6-methoxy-4-methylquinolin-2-yl) cyclohexane-1,3-diamine; N-(1H-인돌-3-일메틸)-N'-(6-메톡시-4-메틸퀴놀린-2-일)시클로헥산-1,3-디아민; N- (1H-indol-3-ylmethyl) -N '-(6-methoxy-4-methylquinolin-2-yl) cyclohexane-1,3-diamine; N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-(3-티에닐메틸)시클로헥산-1,3-디아민;N- (6-methoxy-4-methylquinolin-2-yl) -N '-(3-thienylmethyl) cyclohexane-1,3-diamine; N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-[(1-메틸-1H-인돌-3-일)메틸]시클로헥산-1,3-디아민; N- (6-methoxy-4-methylquinolin-2-yl) -N '-[(1-methyl-1H-indol-3-yl) methyl] cyclohexane-1,3-diamine; N-(1-벤조푸란-2-일메틸)-N'-(6-메톡시-4-메틸퀴놀린-2-일)시클로헥산-1,3-디아민; N- (1-benzofuran-2-ylmethyl) -N '-(6-methoxy-4-methylquinolin-2-yl) cyclohexane-1,3-diamine; N-(6-메톡시-4-메틸퀴놀린-2-일)-N'-(피리딘-2-일메틸)시클로헥산-1,3-디아민; 및 N- (6-methoxy-4-methylquinolin-2-yl) -N '-(pyridin-2-ylmethyl) cyclohexane-1,3-diamine; And N-(4-메틸퀴놀린-2-일)-N'-(3-티에닐메틸)시클로헥산-1,3-디아민N- (4-methylquinolin-2-yl) -N '-(3-thienylmethyl) cyclohexane-1,3-diamine 에서 선택된 화합물 및 이의 약학적으로 허용가능한 염. And a pharmaceutically acceptable salt thereof. 약제로 사용하기 위한 제1항 내지 제14항 중 어느 하나의 항에 따른 화학식 (I)의 화합물. A compound of formula (I) according to any one of claims 1 to 14 for use as a medicament. 제1항 내지 제14항 중 어느 하나의 항에 따른 화학식 (I)의 화합물, 및 약학적으로 허용가능한 어주번트, 희석제 또는 담체를 포함하는 약학 제제.A pharmaceutical preparation comprising a compound of formula (I) according to any one of claims 1 to 14 and a pharmaceutically acceptable adjuvant, diluent or carrier. 비만과 연관된 질병의 치료 또는 예방을 위한 약제의 제조에 있어, 제1항 내지 제14항 중 어느 하나의 항에 따른 화학식 (I)의 화합물의 용도. Use of a compound of formula (I) according to any one of claims 1 to 14 in the manufacture of a medicament for the treatment or prevention of diseases associated with obesity. 약리학적으로 유효한 양의 제1항 내지 제14항 중 어느 하나의 항에 따른 화합물을 이를 필요로 하는 환자에게 투여하는 단계를 포함하는, 비만, 정신 장애, 불안, 불안-우울성 장애, 우울증, 쌍극성 장애, ADHD, 인식 장애, 기억 장애, 정신분열증, 간질, 및 관련 질병, 및 신경 장애 및 통증 관련 장애의 치료 방법. Obesity, mental disorders, anxiety, anxiety-depressive disorders, depression, comprising administering a pharmacologically effective amount of a compound according to any one of claims 1 to 14 to a patient in need thereof Methods of treating bipolar disorder, ADHD, cognitive impairment, memory disorder, schizophrenia, epilepsy, and related diseases, and neurological and pain related disorders. 비만 치료에 사용하기 위한 제1항 내지 제14항 중 어느 하나의 항에 따른 화합물.The compound according to any one of claims 1 to 14 for use in the treatment of obesity. 하기 화학식 (II)의 화합물을 하기 화학식 (III)과 반응시키는 단계를 포함하는 화학식 (I)의 화합물의 제조 방법:A process for preparing a compound of formula (I) comprising the step of reacting a compound of formula (II) with formula (III): 상기 화학식에서, In the above formula, R1, R2, R3, R4, R5, L1, n 및 m은 앞서 정의된 바와 같고,R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , n and m are as defined above, L2'는 화합물 (II)와 (III)의 반응 후, 환원성 알킬화 조건 하에서 환원시 L2를 내는 기를 나타낸다.L 2 ′ represents a group giving L 2 upon reduction under reductive alkylation conditions after the reaction of compounds (II) and (III). 하기 화학식 (II)의 중간체:Intermediates of Formula (II) 상기 화학식에서, In the above formula, R1, R2, R3, R4, L1, n 및 m은 제1항에서 정의된 바와 같다.R 1 , R 2 , R 3 , R 4 , L 1 , n and m are as defined in claim 1.
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